Summary of T staging and current National Comprehensive Cancer Network (NCCN) recommended wide local excision margins for melanoma.
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"3377",leadTitle:null,fullTitle:"Mental Disorders - Theoretical and Empirical Perspectives",title:"Mental Disorders",subtitle:"Theoretical and Empirical Perspectives",reviewType:"peer-reviewed",abstract:"This book brings together an international array of stars of the mental health professions to create a cutting edge volume that sheds light on many important and heretofore poorly understood issues in psychopathology. 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Surgical management of melanoma encompasses primary biopsy and complete wide local excision (WLE) of the tumor, as well as the surgical treatment of metastatic melanoma, including both cutaneous and internal metastases. The management of a melanoma suspect lesion starts with the initial biopsy of the lesion. A great variety of techniques can be used for the biopsy of melanomas, and the choice of the technique is dependent on multiple factors (patient’s age, strength of clinical suspicion of melanoma, thickness of the tumor, localization, etc.). Once the clinical diagnosis of melanoma is confirmed histologically, local tumor control is established by wide local excision. The margins for WLE are determined by the T stage of the tumor, and are between 0.5-2.0 cm. Certain clinical melanoma types (e.g. lentigo maligna) require special attention, as the recommended margins can differ from those generally advised for other melanoma types.
Important surgical procedures include wide local excision with safety margins, sentinel lymph node biopsy, regional lymph node dissection and reconstruction of defects after melanoma excision. A plastic surgeon of the appropriate specialty should perform the excision and reconstruction.
Performing surgery of locoregional and distant metastases depends on various factors. However, in highly selected patients, complete surgical resection of the metastases may result in prolonged survival. In addition, combination of surgery with novel immuno-, and targeted therapies, may result in an even better outcome in the future for patientswith stage IV disease.
Early diagnosis and complete removal of the malignant cells are of paramount importance in the treatment of malignant melanoma. This usually requires a two-step approach. First, pigmented or amelanotic lesions suspicious for melanoma should be promptly biopsied and submitted to pathological evaluation, and second, the tumor should be subsequently excised with adequate surgical margins. The margins of the final excision are determined with the tumor characteristics in mind, as determined by the histopathological analysis of the biopsy specimen. Thus, removal of appropriate biopsy sample containing the fragment with the worst prognostic characteristics, is of substantial importance. As extensive loss of tissues may potentially influence the feasibility of further surgical interventions, such as the sentinel lymph node biopsy, the use of proper biopsy techniques is essential during the primary treatment of melanoma.
Recommendations regarding the width of the surgical margin of excision are nowadays clearly defined for primary melanoma, and are based on the histopathological features of the melanoma. These recommendations, however, are sometimes difficult or impossible to follow, like in the case of specially localized melanomas, or certain melanoma subtypes. This chapter summarizes the available evidence regarding different biopsy techniques and the surgical management of primary melanoma.
The primary aim of performing biopsy in the case of a melanoma suspect lesion is to establish or exclude the diagnosis of melanoma. An additional goal is to ensure accurate pathological staging of the tumor in order to enable adequate surgical management by performing wide local excision (WLE). Excisional, incisional and shave biopsy techniques are used in the surgical treatment of melanoma.
The preferred biopsy technique for most melanomas is excisional biopsy.[1,2] This means that the entire lesion is removed with an additional 1-3 mm margin of normal-appearing skin. Wider excisions, however, should be avoided, to permit subsequent lymphatic mapping for sentinel lymph node biopsy. Generally, the excised tissue sample should contain part of the subcutaneous fat as well, and should be oriented to aid subsequent histopathological evaluation. The positioning of the excision also should possibly allow for subsequent wider excisions. The excisional biopsy technique can be used in most melanomas, when primary closure of the wound is feasible. Although the lowest frequency of positive margins is reported when excisional biopsy is used, positive margins and even residual melanoma on WLE do occur.[3]
The reported frequency of excisional biopsy technique used for diagnosing melanoma varies significantly with centers, countries, and individuals, and ranges between 10 and 86 percent.[1,3-6] Thus, in a significant portion of melanoma suspect lesions, a biopsy technique other than excisional biopsy are used. Even guidelines that emphasize the importance of excisional biopsy in melanoma management state that incisional biopsy may be appropriate in certain clinical circumstances. Such clinical scenarios may include cases when excisional biopsy is not feasible due to the large size or the location (nose, ear, face, palm, and sole) of the lesion, concerns about cosmesis or low clinical suspicion of melanoma.
In the case of incisional biopsy only a portion of the lesion is removed, either by a punch biopsy or using a scalpel (Figure 1.a-c). As incisional biopsy specimens contain only part of the lesion, concerns regarding misdiagnosis, staging inaccuracy or diagnostic uncertainty may arise. Careful selection of the biopsy site is therefore crucial to ensure that the biopsy best represents the entire lesion, both in terms of the type and the T stage of the tumor. This is usually achieved by sampling the thickest, most raised area of the tumor, or the darkest part of flat lesions. Complex lesions containing multiple suspicious foci may require more than one simultaneous biopsy sampling. Both in case of punch biopsy and incisional biopsy adequate depth (reaching to the subcutaneous fat) of the sampling should be guaranteed.
The theory that incisional biopsy, by cutting through the neoplastic tissue, represents an increased risk for lymphatic or hematologous metastatisation, and thus it should be regarded as a harmful procedure, has been refuted by several earlier studies.[3,7] Moreover, Molenkamp et al. reported slightly better survival in patients with residual tumor cells in their re-excision samples, compared to patients without residual cells in their re-excision specimen.[3] The authors speculated that immunity against residual tumor cells, triggered by biopsy induced wound healing, might be responsible for this finding.
In the case of shave biopsy a superficial, a few mm deep flat section of the skin is removed (Figure 1.d). Shave biopsy is ideally performed at the level of the deep dermis, however, the depth of excision is often compromised with the desire to provide a cosmetically good result. Shave biopsy of primary melanoma, as it often results in incomplete removal of the tumor and thus compromises pathological staging of the tumor, is not recommended in most of the cases for melanoma biopsy. However, if the index of melanoma suspicion is low, shave biopsy may be performed. When performing shave biopsy in pigmented lesions, deep scoop shave biopsy is the preferred technique.
The biopsy of the pigmented lesion should not only establish or exclude the diagnosis of melanoma, but also provide information on the T stage of the tumor. Ideally, this initial T stage will be the same as the one achieved after the wide local excision of the tumor. This will ensure that the original treatment plan regarding the width of the surgical margin and the requirement for sentinel lymph node biopsy, does not need subsequent adjustment. As these treatment parameters are primarily determined by Breslow’s depth of the tumor, achieving appropriate deep margin sampling is of paramount importance during melanoma biopsy.
Theoretically, sampling errors may stem from several scenarios (Figure 1.a-d). Tumor depth determination may be compromised by not representative tissue sampling (Figure 1a), positive deep biopsy margin (Figure 1b) or not representative tumor depth (Figure 1c). Diagnostic inaccuracy, as a consequence of inappropriate tumor depth measurement, may (Figure 1b) or may not (Figure 1c) lead to upstaging after wide local excision. In a recent study, positive deep margins were found in 12%, 32%, 17% and 24% of cases undergoing excisional, shave, punch and incisional biopsies, respectively.[4] After wide local excision, tumor depth was more than the biopsy depth in 44% of the cases with residual tumors in WLE, and resulted in T-stage reclassification in 22% of cases. Reclassification was necessary in 2%, 7%, 24% and 24% of cases when the initial diagnosis was established by excisional, shave, punch or incisional biopsy, respectively. Diagnostic inaccuracy led to subsequent treatment change in 2%, 5%, 18% and 18% of cases when excisional, shave, punch or incisional biopsy, respectively, was used for initial sampling. Although there is no data regarding the tumor thickness in the individual biopsy groups, it is likely that shave biopsy was more frequently used for thinner and incisional techniques for thicker melanomas. This may explain why initial punch and incisional biopsy so frequently required later reclassification in this study.
Diagnostic inaccuracy arising from different forms of sampling error using incisional (punch) biopsy or shave biopsy techniques. Inadequate punch biopsy sampling of pigmented lesion (a) may result in non-representative tissue sampling. Tissue sample is removed from the benign part of the pigmented lesion, while missing the malignant part leading to false negative diagnosis. Inadequate depth of punch biopsy sampling (b) results in positive deep margin on histology. Accurate T stage cannot be established, and histological reevaluation after WLE will result in the upstaging of the tumor from T1 to T2. Inadequate assessment of melanoma depth due to failure in sampling the deepest part of the tumor (c). Accurate T stage cannot be established, however, reevaluation will not result in upstaging. Positive deep margin after shave biopsy sampling of melanoma (d). Proper T stage cannot be established, and diagnostic inaccuracy may result in upstaging after WLE.
It must also be emphasized that a rather substantial part of excised melanomas are clinically not suspected to be melanoma, and vice versa, in a smaller, but significant portion of pigmented lesions, the clinical diagnosis of melanoma is not confirmed by the histopathological examination. The mean number of pigmented lesions to be excised to detect one melanoma was 29 (range 11-83) in a study among general practitioners in Perth, Australia.[8] Thus, in cases of clinical uncertainty, shave or incisional biopsies may help to establish early melanoma diagnosis, and biopsies may also help to avoid unnecessary wide excisions in case of benign lesions.
Several studies have compared the effect of biopsy techniques on the prognosis of melanoma.[9-13] While in some studies a decreased survival rate was associated with incisional, shave or needle aspiration biopsy compared to those who had excisional biopsy, these studies included either low number of patients or significant age differences among patient groups.[12,13] Other, more recent studies, involving significantly higher numbers of patients, found no negative effect of non-radical diagnostic techniques on the survival of melanoma patients.[10,11] Moreover, Molenkamp et al. reported slightly better survival in patients with residual tumor cells in their re-excision samples,[3] and speculated that biopsy induced wound healing may theoretically trigger immunity against residual tumor cells. In summary, incisional (punch or scalpel) and shave biopsies may be used for the initial diagnosis of melanoma, although, excisional biopsy, when feasible, is recommended as the first choice.
Although, when feasible, excisional biopsy is the recommended technique for initial diagnosis of melanoma, there are certainly significant differences among melanoma subtypes, which, consequently, require different surgical approaches. The most critical factors when choosing the appropriate biopsy technique are clinical estimate of depth and size and localization of the lesion. Although there are no general rules regarding biopsy techniques for different clinical types of melanoma, some practical recommendations can be formulated. It must be emphasized as well that in case of lesions requiring amputation of the anatomical unit (e.g. digit or ear), histological confirmation of the diagnosis of melanoma is necessary before performing the final procedure.
Once the histopathological examination of the biopsy sample established the diagnosis of melanoma, the entire tumor should be surgically removed with adequate safety margins from the surrounding healthy-appearing skin. The wide local excision is intended to provide adequate surgical control of the tumor spread by removing all tumor cells from the primary tumor bed and the potential satellite lesions from the immediate vicinity of the tumor. Additionally, WLE provides tissue samples for the final T staging of melanoma.
Current recommendations for surgical management of melanoma are based on randomized clinical trials completed several years ago.[14-20] The margin of wide local excision depends on the T stage of the melanoma, which is primarily determined by the depth of tumor invasion (see Table 1. for staging). While there has been considerable debate regarding the radicality of surgery, current guidelines recommend 0.5 – 2.0 cm surgical margins (see Table 1. for recommended surgical margins).[1]
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Tis | \n\t\t\tin situ | \n\t\t\tNA | \n\t\t\t0.5-1.0 | \n\t\t\t0.5 cm on face, neck, hands, feet 1.0 cm if significant residual pigment near the biopsy site | \n\t\t
T1 | \n\t\t\t≤1.0 | \n\t\t\ta: w/o ulceration and mitosis <1/mm2\n\t\t\t\t b: with ulceration or mitoses ≥1/mm2\n\t\t\t | \n\t\t\t1.0 | \n\t\t\t\n\t\t |
T2 | \n\t\t\t1.01-2.00 | \n\t\t\ta: w/o ulceration b: with ulceration | \n\t\t\t1.0-2.0 | \n\t\t\t\n\t\t |
T3 | \n\t\t\t2.01-4.00 | \n\t\t\ta: w/o ulceration b: with ulceration | \n\t\t\t2.0 | \n\t\t\t\n\t\t |
T4 | \n\t\t\t≥4.00 | \n\t\t\ta: w/o ulceration b: with ulceration | \n\t\t\t2.0 | \n\t\t\t\n\t\t |
Summary of T staging and current National Comprehensive Cancer Network (NCCN) recommended wide local excision margins for melanoma.
Most melanomas on the trunk and the proximal part of the extremities may be surgically managed according to the generally recommended margins for re-excision. Certain melanoma types, however, owing to their unique localization (face, acral region of the extremities) or type (lentigo maligna), require special approach, and allow only compromised excisional margins.
In general, the NCCN guideline recommends 0.5-1.0 mm margins for in situ melanomas.[1] These recommendations, however, are based on expert consensus, as there are no randomized prospective studies that have examined the surgical margins for melanoma in situ. Recently it has been shown that almost all (99%) melanoma in situ lesions are completely removed with a 0.9 mm margin, and a margin of 0.6 mm provides negative resection margins in 86% of cases.[21] Another recent study found that in situ melanoma lesions that were not lentigo maligna type, were unlikely to recur if completely removed, even with narrow margins (Figure 2.a).[22] On the other hand, a significantly higher incomplete excision rate was found in the lentigo maligna group (Figure 2.b), compared with the non-lentigo maligna type in situ melanomas (29.3% vs. 5.9%, respectively). Thus, the authors propose more aggressive treatment, if possible, for in situ melanomas of lentigo maligna type.
There is no generally accepted consensus regarding the appropriate surgical margins for eyelid melanomas. In this melanoma group, guidelines for WLE are impractical, and cannot be used in the majority of cases. In a recent retrospective study, local, nodal and distant metastases occurred in 21%, 11% and 4% of 56 cases with eyelid melanomas, respectively.[23] Pathological margins of >2 mm were associated with increased disease-free survival, compared with margins ≤2 mm. Lower eyelid melanomas were found to have significantly higher recurrence rate than upper eyelid tumors.
Although external ear melanoma had been considered to be a more aggressive type of melanoma, this hypothesis is not supported by more recent evidence. Histologically, melanomas arising on the external ear are most frequently superficial spreading melanomas (33-46%), followed almost equally by lentigo maligna (19.6%-26%) and nodular (16-22%) types. While narrower excisional margins and Mohs surgery are gaining acceptance in the treatment of ear melanoma as well, the use of these techniques are associated with significant (30%) recurrence rates.[24] Therefore, management should follow standard melanoma treatment recommendations in external ear melanoma cases, if feasible (Figure 2.c).
Achieving melanoma-free resection margins is often difficult in this melanoma type (Figure 2.d). This may be attributed to the close proximity of critical anatomic structures, the presence of satellite formation, multifocality, angiolymphatic invasion, and submucosal spread, which are common features in oral cavity and sinonasal melanoma. The 2-year and 5-year survival rates for mucosal melanoma of the head and neck are 54% and 32%, respectively. Taking into account the high recurrence rate in this melanoma subtype, even apparently localized lesions may require radical surgery with planned reconstruction.[25,26]
Melanomas in special anatomical regions require individual surgical approach. In case of in situ melanoma not lentigo maligna type (a), a 5-6 mm surgical margin is sufficient to ensure clear resection margins. In case of lentigo maligna type in situ melanomas (b), a wider, 10 mm margin is recommended, if feasible. Management of external ear melanomas (c) should follow standard melanoma treatment recommendations, if feasible. Mucosal melanomas of the head and neck region (d) require radical surgery with planned reconstruction in most cases. For mucosal melanoma of the female genitalia (e) wide excision with a 1-2 cm margin is recommended. Melanoma of the glans, preputium or urethra (f) wide local excision or penectomy provides effective local control.
Although 70% of patients present with clinically localized disease, the overall prognosis of this melanoma type is poor. Surgical management of vulvar melanoma (Figure 2.e) consist of wide excision with a 1-cm margin for melanomas with a thickness of <1 mm, and a 2-cm margin for thicker lesions.[27,28]
Melanoma of the glans, preputium or urethra is certainly an uncommon entity. Therefore, standard recommendations are not available for the management of this subtype of melanoma. Partial penectomy or WLE provided effective local control for low stage penile (Figure 2.f) or urethral melanomas and all scrotal lesions.[29]
Because of the rarity and the advanced stage at which most patients present, a standard surgical intervention has not been established to date for anorectal melanoma. Usually, wide local excision (with negative margin) is the preferred surgical management in most patients. Extensive disease that is not amenable to local excision, may require abdominoperineal resection.[30]
The face is an important area because it encompasses the eyes, nose, mouth and it is in proximity to the ears. The surgical radicality of extension must often be compromised to avoid injury to these structures. These structures limit the excision margins for surgical treatment of melanomas occurring on the face. In the management of cutaneous melanoma the first step is the wide local excision.
The first goal is to treat the cancer with maximal protection of function and aesthetics. We need take notice of the size and the localization of the defect, what kind of tissues are missing (bone, muscle, fat, skin, cartilage, etc.), the base of the wound, the acceptable functional impairment, the morbidity of the donor area, the moveable area around the defect, the history of the patient (previous operation or irradiation) and the expectations of the patient too. Ideally incisions should be within the relaxed skin tension lines (RSTL) or parallel to them, so the scars will be functionally and aesthetically superior. The RSTL is a complex interaction of the external and internal factors, which contains the skin as well.
If there is a melanoma on the neck, middle or lower area of the face, we can perform an elliptical excision parallel to the RSTL with a 3 to 5 mm safety border, undermining the surrounding area and closing the wound primarily.[17] If the tumor size is bigger we need to prepare local flaps to cover the defect. Local flaps\' blood supply are very reliable, random pattern from the surrounding tissues or axial pattern from a named source artery. The laxity, quality and texture of the surrounding skin is the best to prepare local flaps and it is the nearest approach to the defect’s skin.
If the size of the defect is too big and there is no possibility for local flaps,skin grafting can be performed. There are split-thickness and full-thickness skin grafting. The split-thickness skin is0.25-0.75 mm thick, the procedure is simple, fast, and not demanding. The donor area heals spontaneously and is fit to be used again as a donor area, although the graft may contract and become hypo-or hyperpigmented. The full-thickness skin is 0.8-1.1 mm thick, it rarely contracts and/or gets pigmented, it is more resistant against external cues compared to split-thickness grafts, and the subcutaneous layer may regenerate. On the other hand, this surgical technique ismore demanding for the patient, and it requires a good blood supply of therecipient area, which limits the size of the graft. Lastly, the donor area need to be sutured /closed primarily.
Recommended flaps are: rotational facial flaps, bilobed flaps, transpositonal flaps, V-Y advancement flaps (Figure 3.). It is uncommon to use distant flaps on the face except for some cases, when there is not enough skin in the surrounding areas, due to irradiation or previous operations.
Removal of extensive melanoma from the face and reconstruction with combined local flaps. Melanoma (lentigo maligna type) on the face. Note markings of planned flaps (a). Extensive tissue defect after excision of melanoma with surgical margins. Reconstruction with combined local flaps (b). Good cosmetical result on 10th postoperative day (c).
After primary melanoma excision the choice of repair depends on the size and location of the defect, surrounding tissue mobility, degree of vascular compromise, extent of lamella loss, skin texture and color match. It is not common to excise and primarily close the wounds around the eyes.[31] In general it is done, if the size of the melanoma is very small, the melanoma is in situ, there is a sufficient skin laxity, or the patient\'s general health status does not permit more intensive surgical intervention. In the periocular region a 5 mm margin of excision for thin eyelid melanomas is recommended.[32,33] Care must be taken to avoid placing too much tension on the eyelid. If the defect involves one third of the eyelid margins, we can perform pentagonal wedge closure after the excision.
We have to pay attention to the canthal regions and the lower eyelid to avoid their injuries, leading to dryness and ectropium. We should also pay attention to the eyebrows and try to reconstruct them.
In this region primarily we perform local flaps and skin grafting or cartilage grafting to cover the defects after melanoma excision. The local flaps can be skin, skin-subcutaneous and skin-muscles flaps from the surrounding area, where the laxity, quality and texture are the best suited to cover these defects. Their blood supply can show random pattern from the subcutaneous layer or axial pattern from a named source artery. In these cases it is advisable to do cantopexy to prevent ectropium evolution.
Recommended flaps are: V-Y advancement flap, Tenzel and Mustarde rotation flaps, Romboid-Limberg transpositional flaps, Median and Paramedian forehead flaps and Glabellar flap.[31,33]
Full-thickness skin graft is used in this region to minimize scaring and pigmentation. It protects against extrinsic factors and the subcutaneous layer may regenerate. Disadvantages of full-thickness skin grafting include demanding surgery, the need for good blood supply in the recipient area and the need for suturing in the donor area. The size of this graft is also limited (Figure 4.).
If the tumor involves the tarsal plates and after the excision of the melanoma a tarsal defect develops, auricular or nasal free cartilage graft can be used to cover the defect. Generally, the cartilage graft can be covered with a local flap to reconstruct the total eyelid layers. In these cases composite grafts may be used as well, which contain skin, cartilage and, if necessary, conjunctiva.
Occasionally, if the patient’s general health status is poor, it is acceptable in the medial canthal area to leave the defect open, and let it heal by second-intention. Adequate wound management and dressing should be applied to help the granulation and epithelisation. Another use of second-intention healing is to delay skin grafting. After granulation the skin graft procedure can be performed.[31,33]
Full-thickness skin grafting for the reconstruction of lower eyelid defect after excision of melanoma. Lower eyelid defect (a) and full-thickness skin graft covering of the defect (b).
The nose is a three-layered structure of a skin and fibrofatty covering, a bony and cartilaginous framework and an inner lining of vestibular skin and nasal mucosa. Nasal defect may involve these layers alone or in combination.[34,35] The nose is divided into topographic subunits, as tip, dorsum, sidewalls, alar lobules, soft triangles and columella.[34,35] A wide range of techniques including defect and subunit reconstruction – using simple as well as more complex flap and multistaged procedures – must be in the surgeon\'s armamentarium. When a defect involves greater than 50% of a subunit, replacement of the entire subunit should be considered. We can perform primary wound closure after elliptical excision with undermining the surrounding area only on the dorsal region if the size of the tumor is not too large and the skin is loose. Second-intention healing is good only for superficial wounds on concave surfaces.[34] If the tumor size is bigger we can use local flaps from the middle face and the frontal region. (Figure 5. and 6.) The nasal tip, columella and alar regions are more difficult, and primary closure is usually not possible. Instead we use local flaps, skin grafting and composite grafting in these regions. The advantages of local flaps over skin grafts include better contour, color and texture match and less scar contracture. The most common local flap is the nasolabial flap, while the forehead flap remains the workhorse for major nasal reconstruction with numerous modifications.[34] Some others are the dorsonasal flap, glabellar flap, advancement flap from the middle face, and flaps from the upper perioral region. These local flaps are useful for defects of about 2 cm or less. If the tumor is large enough to require a tip and alar nose amputation, we can use reconstructive surgical methods or prosthetic devices. Full-thickness skin grafting is easy to perform and it is useful in the reconstruction of superficial defects in the areas of the tip and alar lobules (Figure 7.). On the other hand, it may heal with a contrasting flattened and shiny appearance.[34,35] The term composite graft means that skin and cartilage are grafted together from the conchal region, helical rim or helical root.
Glabellar flap for the reconstruction of a defect on the dorsum of the nose after wide excision of melanoma. Extensive melanoma on the dorsum of the nose (a). The defect and preparing glabellar flap (b). Suturing the flap (c) and postoperative results 3 weeks after operation (d).
Forehead flap for the resonstruction of nasal and glabellar defect after melanoma excision. Melanoma on the nose and glabellar region (a). After ecxision and performing forehead flap (b) Suturing the flap. Good cosmetical result (c).
Split-thickness skin grafting for the reconstruction of extensive defect on the tip of the nose after excision of melanoma. Melanoma involving the tip and alar lobules of the nose (a-b) Split-thickness skin graft covering of the defect (c).
On the ear after wide excision, which includes skin and subcutaneous tissue removing, primary closure is usually not performed. There are many options for the reconstruction of aurical defects including direct closure, second-intention healing, full thickness skin grafts and local flaps.[36,37] The defects of the posterior wall of the ear, where the skin is more abundant and loose, can often be closed primarily. If the defect is in the central and anterior region with intact cartilage, most defects will do well by second intention healing or full thickness skin grafting.[37] If the defect involves the cartilage the most common surgical procedure is wedge excision, which means excising the skin and cartilage together in a V or W form. After these excisions we should reconstruct the cartilage and then the skin. If larger excisions are necessary, we need to use local flaps, which are from the earlobe, pre-and retroauricular regions. These flaps iclude direct advancement flap, rotational flaps, transposition and subcutaneous island flaps. If more than one third of the ear is involved by the tumor, we need to perform partial amputation. If the tumor is in an advanced stage, it may be necessary to amputate the whole ear. Amputation requires more complex reconstructive surgical methods to restore the ear or prosthetic devices can be used.
Melanomas in the perioral regions are not common. The tumor can involve the skin, the oral orbicular muscle and the mucosal layer alone or together.[37] In this region we should pay attention to protect the muscular-, sensorial-, and the closing function of the mouth, the adequate oral access for eating and to the use of dentures, to the symmetry, the upper/lower lip ratio and the quality of scars.[37] After tumor excision, if the defect is less than one half of the lip width, we can use primary wound closure after undermining the surrounding layers. Primary closure offers the best aesthetic result and should be prioritized. In the upper lip we can perform wedge excision while in the lower lip W-shape excision is used. In cases of large tumor size the defect can be covered by local skin-, and skin-mucosal flaps originating from the perioral region or from the lips and the inner surface of the mouth. The ideal donor areas for labial reconstruction are the remaining labial tissue and the opposing lip.[37] The lip is elastic and can be elongated, which is a very useful for reconstruction.
Recommended local flaps are: V-Y advancement flap, Rotational flap, Nasolabial flap, Forehead flap, Abby flap, Estlander flap, Karapandzic flap (Figure 8.).
Reconstruction of facial defect with local flap after removal of melanoma. Large defect in the nasolabial region after melanoma excision (a). Preparing the local flap (b). Closing the wound with sutures (c). Good postoperative result 2 weeks after the operation (d).
The skin of the hand and toe is specialized and structurally unique, balancing the need for sensing, mobility for complex motor skills on the hand, durability to withstand wear and tear on the toe.[38] Earlier melanomas arising on the skin and/or nail bed of the digits were mostfrequently managed with amputation at the proximal joint from the tumor. Recently tissue- sparing excision is performed increasingly.[38] When excising melanomas on the toes, amputations should be limited to preserve as much length and function of the digit as possible without compromising the necessary safety border. It requires a more conservative surgery, wide excision and only partial resection of the affected phalanx.[38] The excision is done in the subcutaneous layer and on the fingertip, the entire nail complex needs to be removed. In these cases the defect can be covered with a local flap, like V-Y advancement flap, or we can use local flaps from the neighboring digits. If the bone is not directly involved it is not necessary to remove the total phalanx or metacarpus or metatarsus, since the removal of bone in these localisations does not have oncological benefit (Figure 9.).
Surgical management of amelanotic melanoma on the toe. Melanoma present on the distal phalanx of the toe (a). Amputation at the distal phalanx (b). Suturing of the wound (c).
Melanomas arising between the digits is difficult to treat. Covering to these defects can be done with full thickness skin grafts and local flaps. It may be necessary to remove the phalanx and metacarpuses and/or metatarsuses depending on the progression of the tumor.
Acral lentiginous melanoma tends to be diagnosed at later stages due to medical diagnostic mistakes and patients’ poor attention to lesions arising on extremities.[38] The reconstruction of the defects after melanoma excision on the dorsal or plantar region of the hand is challenging. Generally we can use full thickness skin grafts or local flaps and we should pay attention to retaining function. First, it is important to cover the joints, tendons and bones. If the defect is large we can perform distal flaps with microsurgical techniques. It is important to mind the weight-bearing regions of the foot, because reconstructing these defects requires a flap from the adjacent area or a free flap with microvascular anastomoses that contain adequate soft tissue to cover the defect and to supply the function too.
Locoregional recurrence can occur as regional nodal disease or as satellite or in-transit metastases.
In-transit metastases are locoregional relapses found between the primary melanoma and the draining lymphatic basin. By definition lesions that occur more than 2 cm from the primary melanoma are termed in-transit metastases. The ones that are located closer (≤ 2 cm) are regarded as satellite lesions (Figure 10). The risk factors for the development of in-transit metastases include lymph node involvement and was confirmed as the most important prognostic factor by Weide et al.[39] Furthermore the risk of local recurrence increases significantly as the thickness of the primary melanoma increases and with the presence of ulceration.[15,39] Both satellite and in-transit metastases are regarded as stage IIIB (without regional nodal metastases) or stage IIIC (with regional nodal metastases) disease by the 2009 American Joint Committee on Cancer staging system and are associated with worse prognosis than local recurrence.[40] Patient with locoregional recurrences should undergo staging procedures (e.g. PET, CT scans) to rule out presence of distant metastatic disease. If there is no evidence of extraregional disease, the treatment strategies for in-transit metastatic disease depend on the size, number and location of the lesions.
Satelitte metastases (red arrows) around primary melanoma (a) and multiple cutaneous and subcutaneous in transit metastases on the lower leg (b).
In case of solitar lesion or limited disease surgical excision of the metastases with histologically negative margins is the adequate treatment. The precise width of surgical margin is not determined. The resection should be with generous margin depending on the anatomic site involved. Multifocal metastases within a circumscribed area may be resected en-bloc. Primary closure is prefered if possible, however skin grafting or flaps may be done for skin coverege. In patients, who have surgical resectable in-tranist metastases and have not had a lymphanedectomy previously a sentinel lymph node biopsy (SLNB) may be considered.[41,42] Some authors recommend performing SLNB even for patients who had undergone SLN biopsy earlier or lymph node dissection suggesting a potential benefit for proper staging and for administering the adequate therapy.[43,44]
In the presence of multiple, inoperable, locoregional cutaneous metastases on the extremity isolated limb perfusion (ILP) should be considered.[45,46] A systematic review of twenty two studies, including 2 018 patients[47] who had isolated limb perfusion concluded that the median complete response rate to ILP was of 58.20%, with a median overall response rate of 90.35%. Amputation for extensive regional recurrence is rarely indicated, as patients in such cases have a high risk of development of metastases in distant organs and no survival benefit can be achived.
For refractory-, recurrent and for anatomically unresectable lesions intralesional (interferon, interleukin-2) or topical (imiquimod, diphencyprone) therapy, cryosurgery, electrochemotherapy, laser-, radio-, and systemic therapy may also be an effective treatment opition.[48-51] Electrochemotherapy combines inravenous or intralesional cytotoxic drug, most commonly cisplatin or belomycin and intralesional electric pulses (Figure 11.). The electric pulse creates cell membrane poration resulting in a better penetration of the chemotherapeutic agent.[52,53] A study has reported a 72% objective response rate of the total of 54 lesions treated with electrochemotherapy.[53] However, superiority of one over the other has not been proven and the choice of the method depends on individual factors.
Electrochemoterapy (bleomycin) of multiple cutaneous and subcutaneous melanoma metastases. Before (a) and 10 days after (b) therapy. Photos courtesy of Erika Kis MD, PhD, Department of Dermatology and Allergology, University of Szeged, Hungary.
Patients suspicious for regional lymphnode recurrence should have a fine needle biopsy to confirm the diagnosis and a workup (PET CT or CT scans) to rule out distant metastases. Then lymphadenectomy should be performed in patients who did not have one or the lymphnode disscetion was uncompleted. For patients who have undergone previous lymphadenectomy, excision of the recurrent tumor is still indicated, if feasible. In this case the marking of the lymphnodes by ultrasound prior the surgery makes the surgeon’s job easier. In patients with recurrent disease limited to the regional lymph node basin, completion lymphadenectomy offers the best potentially curative treatment option and can provide excellent long-term survival for selected patients.[54]
Metastatic melanoma has a poor prognosis and a median survival of 6-10 months depending on the site of metastasis.[40] These patients are classified as stage IV according to the American Joint Committee on Cancer (AJCC 2009) staging manual and seperated into three groups (Table 2.). Stage IV patients with M1a disease have higher survival rates than patients with lung metastases (M1b), who have a better prognosis than those with M1c disease with or without elevated lactate dehydrogenase serum levels (LDH).[55]
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
M1a | \n\t\t\tMetastases of the skin, subcutis or lymph nodes beyond regional lymph nodes | \n\t\t\tnormal | \n\t\t
M1b | \n\t\t\tLung metastases | \n\t\t\tnormal | \n\t\t
M1c | \n\t\t\tDistant metastases at other location or Distant metastases at any location with elevated serum levels of LDH | \n\t\t\tnormal elevated | \n\t\t
M classification of distant metastases in melanoma according to AJCC 2009.
Currently there is no gold standard care for treatment of stage IV disease. The therapeutic landscape for melanoma is rapidly changing. The first novel agent showing overall survival benefit in unresectable stage III or metastatic melanoma was an anti-CTLA4 blocking monoclonal antibody (ipilimumab) approved by the FDA in 2011.[56] Since then target therapies have been approved for the treatment of metastatic melanoma (BRAF inhibitors: dabrafenib, vemurafenib, MEK inhibitor: trametinib).[57-59] Moreover new immun (e.g. PD-1 inhibitors) and target therapies are on their way. The impact of these drugs on survival rates are clear and promising, but surgery of distant metastases could increase this rate.
Numerous studies, mainly retrospective, showed that patients in whom complete surgical excision of metastases was carried out have a 5-year survival rate of 15–28 % vs. 5-10% in patients who received systemic therapy alone.[60-64] The prospective trial of the Southwest Oncology Group showed a median overall survival of 21 months (overall survival at 3 and 4 years were 36% and 31% respectively) in 64 patients whose metastases had been completely resected. The majority of the patients had one disease site (n=50) and skin and soft tissue sites were present in more than 50% of the cases. The authors concluded that aggressive surgical therapy with follow up adjuvant therapy can be an appropriate cure for these selected patients.[65] International MMAIT-IV trial further supported the role of surgery for stage IV melanoma. In this prospective trial patients who had undergone complete resection of their metatstatic disease were treated with two types of immunotherapy. The 5-year survival was 40–45%.[66] The Multicenter Selective Lymphadenectomy Trial (MSLT-I) also suggested that patients with complete resection exhibit an improved survival compared to patients receiving systemic therapy alone, regardless of site and number of metastases.[67]
Despite that these data are persuasive for surgery in patients with distant metastases, surgery is rarley used in stage IV melanoma except for palliation. Many oncologists believe that once melanoma has spread to a distant site, surgery is not helpful because patients already have occult micrometastases and circulating tumor cells. In the report of Koyanagi et al[68,69] 52% of stage IV patients had detectable circulating tumor cells. However the presence of tumor cells in the blood do not obviously generate metastatic lesions. Most of stage IV melanoma patients at first have disease progression in one organ and the number of metastases in the site can vary.
The advantage of surgical resection of metastatic melanoma is that it may delay disease progression by interrupting the metastatic cascade associated with hematogenous seeding of cells to other sites.[70,71] Surgical resection also decreases tumor burden thus reducing tumor-induced immunosuppression. Metastases greater than 2 cm are eradicated easier with surgery than with systemic treatments.[72] In addition, surgical resection has less side-effects than systemic therapeutic agents.
The recent development of imaging techniques has led to more accurate detection of metastases (size of 5-10mm), aiding surgeons in improved delineation of the extent of the disease and planing for the operation. In line with this development in surgical techniques, anesthesia and intensive supportive care have reduced operative mortality and morbidity rate even for multiple metastectomy.[71] It is evident that appropriate patient selection is essential for a good outcome.
Surgery in metastatic diseases is most effective in patients with small number of metastases and/or few metastatic organ sites.[73] Based on the MSLT-I study and Wevers et al, the percent of stage IV patients eligible for surgery can range widely from more than half to only 22%.[67,74] In deciding about surgery, one should consider underlying co-morbidities, performance status and life expectany. If no survival benefit and/or advantage in quality of life can be achieved with surgical metastectomy, it may be disregarded. It has been shown by numerous studies that complete (R0) resection is associated with a better survial and in all cases completness should be strained by the surgeon.[75-78] Further prognostic factors are prolonged disease-free survival and a tumour-volume doubling time of >60 days.[73,79,80] (Table 3.).
• Feasibility of complete surgical resection (R0) | \n\t\t
• Number of metastases | \n\t\t
• Site of metastases | \n\t\t
• Tumor doubling time | \n\t\t
• Disease free interval | \n\t\t
• Other therapy modalities | \n\t\t
• Acceptable functional deficit | \n\t\t
• Co-morbidities | \n\t\t
Factors to consider prior to surgical resection in stage IV melanoma
Multiple disease sites are not a contraindication to surgical resection but all of the factors mentioned above should be considered before procedure. Reccurent disease can be treated with repeated metastectomy.[81-83] Ollila et al points out that prolonged disease-free interval prior to recurrence and complete surgical metastasectomy of the recurrence were the two most important prognostic factors for survival after recurrence.
In the case of large tumor masses, when surgery can not be carried out, effective systemic treatment prior to surgery is advisable in order to treat the initially unresectable disease. Neoadjuvant setting has been successfully applied in several solid tumors (e.g. breats, head and neck cancer) but it has not been used in advanced cutaneous melanoma, because no effective systemic treatments were available for this disease. The presence of new systemic therapies (biological and target) may change this. Several case reports have shown the beneficial effects of BRAF inhibitors. Patients with unresectable bulky disease regained surgical suitabilty after taking the drug for a couple of months[84-86] (Figure 12).
Neoadjuvant BRAFi in the treatment of melanoma. The 52 year-old patient with unknown primary melanoma and inoperable metastases in the left axillary region (a). BRAF inhibitor (vemurafenib) was initiated. After 3 months of BRAF inhibitor treatment the tumor almost completly regressed (b). Subsequently, the patient underwent surgery for the remnant disease (c).
In contrast to BRAF inhibitors, ipilimumab seems to be a less effective agent in neoadjuvant setting because of its mechanism of action and relatively slow pattern of time response. However the surgical excision of lesions that are resistant to treatment with ipilimumab may improve outcomes for some patients. Other immuntherapies are in development (PD-1 inhibitors) which show an earlier tumor response compared to ipilimumab.[87] Overall, surgical resection of metastatic lesion in highly selected patients appears to offer a survival advantage over systemic treatment modalities alone. The decision for surgery of stage IV melanoma patients should be discussed at an interdisciplinary tumor board. After complete metastectomy, adjuvant therapy may be indicated as melanoma is likely to recur. Surgical resection should be considered more often than it is currently practiced, since the combined advances in imaging techniques and promising novel systemic agents can improve patients’ quality of life and clinical outcomes.
Almost 40% of patients with stage IV melanoma have M1a disease.[88] Median survival of patients in this group is 18-40 months. Skin and soft tissue metastases are usually associated with a better prognosis than distant lymph node disease (Figure 13.). Positive prognostic factors for M1a disease are fewer lesions, longer disease-free interval, and smaller size of tumors.[61] Skin and soft tissue metastases should be resected as soon as possible before the metastases becomes large and, if applicable, with wide margins (2 cm). In case of lymphnode metastases regional lymphnode dissection is performed (for details see section on lymph node dissection). Factors to consider prior to surgical resection in stage IV melanoma are summarized in Table 3. Complete surgical resection of M1a disease can promote survival up to 60 months, even after recurrence.[81] Metastases can ulcerate causing pain, bleeding, infection, and decreased quality of life. Surgical resection for palliation may be indicated in these situations.
Multiple distant soft tissue metastases (a) and multiple distant skin metastases (b).
The lung is the most typical site of visceral metastases (40%) for melanoma. Pulmonary metastases are associated with a longer survival than metastases to other visceral sites.[40] A growing number of studies have shown that pulmonary metastectomy improves survival [89-96] (Table 4). Tafra et al reported that of 984 melanoma patients with lung metastases, the 106 patients that underwent metastectomy had better 5 year survival than patients treated with non-surgical methods (27% vs. 3%, respectively).[79] Chua et al conducted a large single center study with 1737 patients.[89] 292 patients had surgery for lung metastases and the 5-year survival for this patient group was 38%.
According to the various reports, factors predictive of improved survival are: ability to achieve a complete resection, prolonged disease-free interval (>36 months), 2 or fewer pulmonary nodules,[89-91] size of the largest metastasis <2 cm, prior response to chemotherapy/immunotherapy, and male sex.[92] While the disease may recurr, most of the data demonstrate that long term survival can be achieved with repeated metastectomy (in cases of extra-thoracic lesions also) in suitable patients.[91]
The presence of multiple and even bilateral pulmonary nodules is not a contraindication to surgery.[89,97] Interestingly, hilar or mediastinal lymph node involvement did not have an effect on survival.[93] In most cases pulmonary metastectomy involves wedge resection and segmentectomy with occasional indication for lobectomy.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Andrews et al[91] | \n\t\t\t86 | \n\t\t\t35 | \n\t\t\t33 | \n\t\t
Chua et al[89] | \n\t\t\t292 | \n\t\t\t23 | \n\t\t\t34 | \n\t\t
Leo et al[93] | \n\t\t\t282 | \n\t\t\t19 | \n\t\t\t22 | \n\t\t
Neuman et al[94] | \n\t\t\t26 | \n\t\t\t40 | \n\t\t\t29 | \n\t\t
Ollila et al[61] | \n\t\t\t45 | \n\t\t\t23.1 | \n\t\t\t15.6 | \n\t\t
Petersen et al[90] | \n\t\t\t318 | \n\t\t\t19 | \n\t\t\t21 | \n\t\t
Schunan et al[92] | \n\t\t\t30 | \n\t\t\t18.3 | \n\t\t\t35.1 | \n\t\t
Tafra et al[79] | \n\t\t\t106 | \n\t\t\t23 | \n\t\t\t27 | \n\t\t
Younes et al[96] | \n\t\t\t48 | \n\t\t\t32 | \n\t\t\t36 | \n\t\t
Studies of pulmonary metastectomy in patients with lung metastases from melanoma
OS: overall survival
As mentioned earlier, patient selection in Stage IV disease is very important. Tumor doubling time (TDT), an index calculated on the basis of tumour growth rate as detected on the chest radiographs, is one of the major factors predictive of survival and should be used as a consideration in the decision of whether or not to operate.[80] Patients undergoing surgical managment of lung metastases should have pulmonary function and clinical condition suitable for the operation, controlled primary lesion, metastases that appeared technically resectable on diagnostic imaging, and preoperative biopsy consistent with melanoma.
The spread of advanced imaging techniques (CT, PET) contribute to the earlier detection of melanoma metastases and give a more precise preoperative image of the location, thus aiding the accurate selection of surgery candidates (Figure 14.).
Solitary pulmonary metastases in a 40 year-old patient (red arrow). b. Post surgical scarring at the site of the metastases (blue arrow).
Upper aerodigestive tract metastases of melanoma are extremily rare. The patients are usually symptomatic with hemoptysis or cough. Treatments with approriate aggressive multimodal therapies are needed in such cases (metastectomy, segmental resection, laser excision, external beam radiation).[98-100]
In conclusions, findings are suggestive that pulmonary metastectomy for carefully selected patients warrant a favourable outcome.
Liver metastases can occur both in cases of cutaneous and/or ocular melanoma. It is important to distinguish them, as in metastastic ocular melanoma the liver is the predominant metastatic site (89% of cases) and often the first and only site of metastases.[100,101] In contrast, cutaneous melanoma metastases can occur in the lungs, lymph nodes, brain and soft tissue. Only few patients develop liver (15%-20%) and bowel metastases.[102,103] The difference in metastatic presentation is most likely driven by the absence of lymphatics in the uveal tract, therefore melanoma spreads hematogenously.[104]
Studies evaluating the role of surgery in the treatment of hepatic metastases from melanoma are mainly retrospective case series from single institutions. Some of these studies included non-surgical (chemotherapy, best supportive care etc) comparator arm, while others did not have a control group.[76-78,105-108] (Table 5.)
The comparative studies showed a longer median overall survival in patients who underwent hepatic resection compared to non-surgical treatment in both ocular and cutaneous melanomas. Overall survival was 2-4 months for patients with unresected hepatic metastases versus 28 months for those with completly resected liver metastases.[78] A recent metaanalysis of five studies also revealed a significant improvment in overall survival after surgery compared to non-surgical procedures.[109] The majority of noncomparative studies also reported benefit from resection of metastases.[66,75,110-114]
All studies observed that R0 resection was associated with longer overall survival than R1 or R2 surgery.[75-78]
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t \n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Adam et al[110] | \n\t\t\tCutaneous and ocular | \n\t\t\t1452 | \n\t\t\t19 | \n\t\t\t21 | \n\t\t
Caralt et al[117] | \n\t\t\tCutaneous and ocular | \n\t\t\tNR | \n\t\t\t26.3 | \n\t\t\tNR | \n\t\t
Chua et al[115] | \n\t\t\tCutaneous and ocular | \n\t\t\t23 | \n\t\t\t21 | \n\t\t\tNR | \n\t\t
de Ridder et al[75] | \n\t\t\tOcular, cutanous and unknown | \n\t\t\t32 | \n\t\t\t29 | \n\t\t\t3 | \n\t\t
Faries et al[107] | \n\t\t\tCutaneous and ocular | \n\t\t\t1078 | \n\t\t\t24.8 | \n\t\t\t30 | \n\t\t
Frenkel et al[76] | \n\t\t\tOcular | \n\t\t\t74 | \n\t\t\t23 | \n\t\t\tNR | \n\t\t
Groeschl et al[111] | \n\t\t\tNR | \n\t\t\tNR | \n\t\t\t39 | \n\t\t\t36 | \n\t\t
Herman et al[118] | \n\t\t\tCutaneous and ocular | \n\t\t\t367 | \n\t\t\t22 | \n\t\t\tNR | \n\t\t
Kim et al[119] | \n\t\t\tCutaneous and GI tract | \n\t\t\tNR | \n\t\t\t9.5 | \n\t\t\t4 | \n\t\t
Kodjikian et al[116] | \n\t\t\tOcular | \n\t\t\t63 | \n\t\t\t20.5 | \n\t\t\t24 | \n\t\t
Mariani et al[77] | \n\t\t\tOcular | \n\t\t\t798 | \n\t\t\t23.0 | \n\t\t\tNR \n\t\t\t | \n\t\t
Marshall et al[105] | \n\t\t\tOcular | \n\t\t\t188 | \n\t\t\t24.0 | \n\t\t\tNR | \n\t\t
Pawlik et al[114] | \n\t\t\tCutaneous and ocular | \n\t\t\t40 | \n\t\t\t29.4 | \n\t\t\t21 for ocular | \n\t\t
Pilati et al[66] | \n\t\t\tCutaneous and ocular | \n\t\t\t36 | \n\t\t\t15 | \n\t\t\tNR | \n\t\t
Piperno-Neumann et al[108] | \n\t\t\tOcular | \n\t\t\t470 | \n\t\t\t21 | \n\t\t\tNR | \n\t\t
Ripley et al[112] | \n\t\t\tCutaneous and ocular | \n\t\t\t539 | \n\t\t\t36 | \n\t\t\t53 | \n\t\t
Rivoire et al[106] | \n\t\t\tOcular | \n\t\t\t63 | \n\t\t\t25 | \n\t\t\tNR | \n\t\t
Rose et al[78] | \n\t\t\tCutaneous | \n\t\t\t1750 | \n\t\t\t28 | \n\t\t\t29 | \n\t\t
Ryu et al[113] | \n\t\t\tCutaneous and ocular | \n\t\t\t33 | \n\t\t\t29 | \n\t\t\t42 | \n\t\t
Studies of hepatic resection in patients with liver metastases from melanoma
OS: overall survival; NR: not reported
The outcome of surgery is also influenced by the number of metastases, length of disease-free interval and limited disease distribution.[78,115,116] However, eligibility for surgery upon the extent of disease and the number of metastases varied in the studies. In the Kodjikian study[116], the cut-off number for resection liver metastases was 10 or less lesions.
Recurrence rates following hepatic resection in the studies ranged between 72% to 75%.[78,111] All in all the hepatic resection for malignant melanoma is a safe operation.
60-day mortality rates were recorded in some reviews at 1.9% and 2.3% and postoperative complications after metastectomy occured in 15% to 20% of cases.[78,111]
In the treatment of hepatic metastases, systemic and /or non-surgical therapies can be applied in the form of adjuvant or neoadjuvant settings that supplement surgical resection. There are no clear data yet to determine the most efficacious time for the administration of systemic therapy secondary to surgery. Pawlik et al found that patients who had received adjuvant systemic therapy prior the hepatic resection had increased survival compared to patients having resection alone.[114] Adam et al reported increased survival in patients responsive to neoadjuvant chemotherapy.[110]
The data mentioned above indicate that both ocular and cutaneous metastatic melanoma patients with liver metastases benefit from surgery. To achieve this outcome, accurate patient selection is crucial. Only patients with limited disease/metastases who can be rendered surgically free of disease should be considered as candidates for hepatic resection. For patients with unresectable metastatic melanoma, systemic and /or regional (hepatic intra-arterial chemotherapy, hepatic arterial embolization, isolated/percutaneous hepatic perfusion) therapies should be taken into consideration.
Gastrointestinal (GI) tract is an uncommon metastatic site for melanoma malignum occuring in only 2-5% of patients. However, more than a quarter of patients with melanoma at autopsy revealed GI metastases.[120,121] Patients with metastases to the GI are often symptomatic with pain (29–64%), obstruction (27%), bleeding (27%), palpable mass (12%) or weight loss (9%).[122] In addition, the high incidence of metastases of melanoma in the small intestine has been recently assigned to the presence of functionally active chemokine CCR9 on melanoma cells that facilitate metastases to the small bowel.[123] In a large number of cases palliative surgery is needed to alleviate bleeding and /or obstruction. Looking at the survival benefit of surgery, some studies found significantly improved survival in patients who underwent surgery and had a complete resection.[121,124,125] Ollila et al. reported a 5-year survival rate of 41% after complete resection.[121]
In conclusion, metastatic melanoma of the gastrointestinal tract is very rare, but should be suspected in any patient with a history of cutaneous melanoma and new gastrointestinal symptoms. Surgical interventions for symptomatic patients with melanoma of the gastrointestinal tract significantly relieve pain and improve quality of life and may confer a survival advantage.
Duodenal melanoma metastasis.
Isolated metastases to the spleen, pancreas or the adrenal glands are extremely rare. Few reports have demonstrated that surgical resection improves the 5-year survival.[62,126] Analysis of patients with solitary metastases to the adrenal glands yielded median survival times of 60 months.[127] In the study of Wood et al, sixty patients underwent adrenalectomy, hepatectomy, splenectomy, or pancreatectomy for melanoma metastases. The reported 5-year survival in the group after complete resection was 24%, whereas in the incomplete resection group, there were no 5-year survivors.[62,126]
Metastatic disease to the brain is a frequent manifestation of melanoma with cerebral metastases accounting for 20-54% of deaths from melanoma.[128] It is associated with significant morbidity and mortality and poor prognosis. The median survival upon diagnosis of the cranial metastases is approximately 4 months.[129] Non-systemic treatment options are surgery, and stereotactic or palliative whole-brain radiotherapy.[130,131]
Usually patients present with symptoms such as seizures, vertigo, nausea, and vision alteration. In patients with good performance status and controlled primary disease, the surgical resection of solitary cerebral metastases is preferred. Positive prognostic factors in cases of brain metastases are younger age, good performance status, lack of neurologic symptoms, lack of extracranial disease and single focus of disease. Surgery might also be indicated for palliative reasons. If the solitary lesion is unresectable due to localization or extracranial disease, the determination of BRAF status is essential, since the efficacy of BRAF inhibitor dabrafenib in cerebral metastatic disease has been shown.[132] If no mutation is detected in BRAF, ipilimumab might be a treatment option[133] (for details see chapter ‘Treatment of Brain metastases’).
Pre-operative CT scan with multiple melanoma metastases. Brain metastases are indicated with red arrows (a). Post surgical CT scan (b).
Skelatal metastases are present in 5-17% of stage IV patients and have a poor prognosis. [134] Colman et al conducted the largest retrospective analysis of melanoma patients with bone metastases.[135] The study compared the survival rate of the group of patients who underwent surgery with wide resection of metastases with the group who received other surgery or were treated without operation. The observed 1-year overall survival rate in the resection group was twice as high as that of matched historical controls (50.0 vs. 24.8%). They found that overall survival may be improved in carefully selected patients where all known macroscopic tumor can be resected.[134-137]
At the end of the twentieth century, humanity had great scientific advances, one of the main ones being the development of telecommunications. Today they have become particularly important since these technologies have allowed globalization and thereby improve both life in general and business life. Year after year, telecommunications technology evolves and with it, different applications have been created, which spread rapidly in all regions of the planet. Together with this communication phenomenon, electromagnetic signals, which have a certain influence on the environment, have increased due to the power of electromagnetic irradiation. This is how the electromagnetic spectrum for its irradiation depends on its wavelength and its frequency, concentrating a certain amount of propagated energy in the form of packages called quanta, postulated by Max Planck (1858–1947).
where h is the Planck’s constant (6.626 × 10–34 J × s−1) and ν is the wave frequency (Hz).
In consideration of this Planck’s postulate, the propagation of the energy of the irradiation of the electromagnetic field has an influence of interaction with matter; in addition, the living organisms of the planet are considered to be biochemical and bioelectric, which adapt to different conditions of the environment where it is evident that today pollution has increased compared to previous times. For this reason, the propagation analysis of electromagnetic waves must be based on the optical properties of interaction with matter that, depending on the distance to the source and the time of exposure, more electromagnetic energy can be concentrated.
Consequently, it is important to consider that the electromagnetic force is composed of electric and magnetic fields, which are intrinsic properties of matter and can be presented statically and/or dynamically, where the emission of these variables is known as “electromagnetic radiation.” The moving electric charges produce electric currents of different intensity, giving rise to the propagation of electromagnetic waves in the medium. Figure 1 shows the schematic distribution of the electromagnetic spectrum.
Schematic presentation of electromagnetic spectrum (source:
Box 1 | Box 2 | ||||
---|---|---|---|---|---|
Mouse ID | Initial mass (g) | Final mass at the end of adaptation time (g) | Mouse ID | Initial mass (g) | Final mass at the end of adaptation time (g) |
1 | 11.54 | 19.45 | 1 | 10.45 | 20.71 |
2 | 13.45 | 20.45 | 2 | 9.25 | — |
3 | 11.23 | 23.81 | 3 | 10.33 | 24.56 |
4 | 10.45 | — | 4 | 12.31 | 24.67 |
5 | 12.25 | 29.83 | 5 | 11.37 | 20.12 |
6 | 12.64 | 29.68 | 6 | 12.15 | 31.84 |
7 | 11.34 | — | 7 | 11.57 | 22.64 |
8 | 10.57 | — | 8 | 10.28 | — |
9 | 12.52 | 24.67 | 9 | 9.92 | 27.37 |
10 | 9.89 | 23.58 | 10 | 9.72 | — |
11 | 10.29 | — | 11 | 10.84 | 25.36 |
12 | 11.64 | 23.37 | 12 | 11.71 | 23.37 |
Body mass control at adaptation time.
Source: U.A. “T.F.”—FAUTAPO—Physic Department, Investigation Roberto Vera.
It is important to note that electromagnetic waves are transverse, between the intensities of the magnetic field E and the magnetic field H, generating an irradiation called the Poynting S vector, in honor of John Henry Poynting [1].
Electromagnetic radiation does not need a medium to propagate; however, air is known as a propagation medium which has certain conduction impedance, defined by the following equation:
where Z is the air impedance, μ0 is the magnetic permeability, ε0 is the electric permittivity, and K is the dielectric constant. According to Milford et al., K is 1.00059 [2].
The air impedance must be quasi-constant. Additionally, the interaction of electromagnetic fields with matter must be considered, where different behaviors are expected, which is due to the different electromagnetic optical properties. According to Kraus and Fleisch, other properties of electromagnetic radiation emission are attenuation, which consists of the interaction of the electromagnetic field with some material, which has the property of exponentially decreasing its initial value and is given by the following equation:
where ∝ is the attenuation constant (Np × m−1), μ is the permeability of the medium (H × m−1), σ is the conductivity of the medium (Ω−1 × m−1), and ω is the frequency (rad × s−1).
The wave penetration consists of a damping of the incident waves, since it is inversely proportional to the thickness of the material, which dissipates its energy as it travels. This energy is transformed into heat, which occurs by incidence of the wave that when crossing causes the molecules to vibrate causing molecular movements [3]. It is given by the following equation:
where δ is the penetration constant (m), μ is the permeability of the medium (H × m−1), σ is the conductivity of the medium (Ω−1 × m−1), and π is number pi.
It is noted that these forms of communication have reached the general public, thanks to the constant innovations in systems and infrastructures introduced by mobile phone companies. Despite the fact that a large part of the current terminals belong to the second generation of mobile telephony, the current and future new developments are focused on the evolution of the third and even the fourth generation (3.5G, 3.75G, and 4G) [4]. However, we must consider in the last 2 years, there has been a great technological advance in 5G technology. Although it is still under development and testing, it will be implemented very soon (Figure 2).
Cell phone evolution timeline (source:
Given this description, it clarifies that information and communication technology (ICT) is applied today, which facilitate new roles to work efficiently. For this reason, the work carried out by Ruiz-Palmeros and his collaborators in this technology concludes with the following context: “The first factor, excessive or inappropriate use of the mobile phone, included the difficulty in controlling behavior and impulses. The second factor was abstinence and the grouped elements in which concern was expressed about the possibility of not having a telephone. The third factor, by elements, referred to the difficulty of stopping the use of the telephone and family problems. The fourth factor explains the increase in data consumption” [5]. This situation leads to raise a critical and reflective aspect of the gravity or influence that communication technology has on biological bodies; so, the interest of this work focuses on observing the behavior of the direct and indirect influence of the emission of electromagnetic fields with a thorough analysis of experimentation in laboratory organisms, such as mice.
Mice are one of the most fertile and numerous groups of mammals on Earth due to the extraordinary ability of their populations to reproduce. They have large numbers of offspring, which is one of the primary reasons they make up the largest group of mammals; the second is that they have a short gestation (pregnancy) period. They are grouped in the Rodentia order and are characterized by very sharp and curved teeth like a chisel that is used to gnaw hard objects.
Rodents are the order with the most species within the group of mammals; there are more than 400 genera and some 2000 species. Among the best known species are mice, rats, chinchillas, and squirrels. Rodents that are closely related to humans (commensal rodents) such as the brown, Norwegian, or water rat (
Given these described aspects, the interest of this document focuses on verifying in a qualitative and quantitative way the real behavior of the exposure of mice to non-ionizing electromagnetic fields. Additionally, it is important to take the main biological aspects of mice according to the laboratory animal management guide. These groups mark their vital areas with urine, forming a network of odors that then allows them to overcome narrow bridges in total darkness. Dominant males and reproductive females create 3-cm-high olfactory stalagmites that announce the presence of their territories to animals nearby. In addition, it is important to take note of the sensory characteristics that they have, which are as follows:
Smell: used to guide their movements around vital areas where feces, urine, and genital secretions contribute to leaving traces of odor. Traces are detected and can be followed or avoided by other individuals.
Touch: their main action is the whiskers; this is because the mice and rats have the ability to control their position; they are in constant movement during the exploration, contacting the ground, walls, and any nearby object; in addition, they are the ones that announce the changes of the climate in the environment.
Hearing: they have a keen sense of hearing, in addition to listening in the range audible to humans, they can capture ultrasonic sounds including those emitted by themselves in that range (between 22 kHz and 90 kHz), and these are used for social communications between them.
Sight: they are specialized for night vision; they have high sensitivity to light, but poor visual acuity. Rodents have good depth perception and are able to correctly assess the effort required to perform any type of jump; apparently they do not detect colors, capturing them as gray variants; yellow and green are probably the most attractive colors being perceived as light gray.
Taste: the sense of taste is highly developed; they have a great ability to detect minimum amounts of bitter, acidic, toxic, or unpleasant substances, which complicates control with toxic baits.
It is also important to consider the predominant physical abilities: digging, climbing, jumping, and mainly gnawing, where their upper and lower incisors constantly grow, being worn away by this action [6]. This is how these conditions set the characteristics for experimentation and development of executed work.
Based on the statements described above, it is important to consider the main behavioral characteristics that developed when mice exposed to electromagnetic fields. For this situation, it is important to reflect on the geographical place where it was made, the city of Potosí, with an average altitude of 3950 m above sea level, with temperatures ranging from 18°C in spring and summer to less than 5°C in the autumn and winter seasons.
The procedure carried out in this quasi-experimental evaluation starts from an exhaustive analysis in the control and observation of mice before and after irradiation to electromagnetic fields generated by mobile phones and signals that exist in the environment. For this reason, the evaluation is carried out in stages or phases, the selection of samples in an organized and equitable manner in each glass box. The first phase consisting of the time of adaptation and acclimatization to the environmental conditions of the region; in this, the metabolic data that the mouse undergoes and its behavior within its habit are registered before being affected by electromagnetic fields, learn about the different abilities particular of mice. Also, at this stage, it is important to record the levels of non-ionizing radiations, for its analysis and to subsequently observe the increase that is made with mobile sources such as cellular sources. In the second phase, it analyzes the characteristics of the cell phones, where the irradiation power must not exceed the permissible limits established in the ICNIRP. Subsequently, the phones are introduced gradually, observing and recording the behavior of the mice within their habit, applying the Likert scale method to demonstrate the level of behavior that each mouse has and thus, demonstrate the influence caused by the fields electromagnetic on mice.
Thus, the mice are housed in glass boxes with appropriate dimensions which are designed to facilitate their behavior since they:
have adequate, safe space and protect them from external threats;
provide adequate ventilation;
provide ease of cleaning and are resistant to frequent disinfection and sterilization;
allow the observation of the animal;
facilitate the access or extraction of animals to verify their increase or decrease in body mass;
there are no sharp edges or projections that can cause injury to the animal; and
a running wheel is incorporated for their development.
In consideration of these aspects, it is also important to consider the instruments for analyzing the irradiation of electromagnetic fields. For this, three radiofrequency spectrum analyzers were used to observe the level of concentration of concentrated electromagnetic energy in the environment where the rats are located. These instruments are Spectran NF5030, HF2025E, and HF6040, from the German industry, with calibration certification; they analyze electromagnetic pollution with a margin of error of 0.7%, at 2.5% based on the standards established by the ICNIRP [8]. These regulations allow us to establish the real situation in a quasi-experimental environment, where the interest is focused on observing the behavior of animals exposed to these electromagnetic fields that are not noticeable.
With all these aspects, a rodent laboratory (bioterium) was implemented, considering the main aspects of hygiene, safety, and size control in the intrinsic metabolism of each mouse. It is also important to mention that the biosecurity elements are particularly important, where they can ensure control against any pest and/or disease that may be emitted while cleaning or controlling the dwellings where the experimental mice are located (Figure 3).
Implementation of the Mice Lab at the Physics Department, “Tomás Frías Autonomous University.”
Once the environment is adequate, we proceed with the applied research methodological principles [9], seeking to generate knowledge on the topic developed. Therefore, this is fundamentally based on the findings that the use of wireless communication technology used in our environment implies addressing the issue of the current situation of settlement and/or proliferation of telecommunication antennas. For this reason, the study of this work concentrates on an explanatory methodology; it is used in order to try to determine the causes and consequences of the aforementioned phenomenon, giving the survey of why in some regions of the planet, there is so much problem of settlement or exposure to electromagnetic fields that are generated by the antennas of telecommunication and/or by the latest generation cell phones based on a coherent state of the question and without manipulation of information. We use of the logical tools of research centered on the inductive method this is focused on the observation and analysis of the situation, allowing conclusions to be drawn from the events that occurred in mice exposed to electromagnetic fields, considering that this is quasi-experimental, in the fact that it is intended to manipulate some specific variables, such as the density of mobile phones, which emit a certain amount of electromagnetic radiation, taking into account that there is no full control over all variables. Finally, longitudinal monitoring is assumed, which characterized the monitoring of the behavior of mice exposed to electromagnetic fields considering a specific observation period (Figure 4).
Laboratory instrumentation (bioterium), Physic Department, “Tomás Frías Autonomous University.”
Based on the established methodologies, we start with the climatic variables of the laboratory such as temperature and relative humidity (RH) in the environment. For this cold weather situation, the mice gradually adapt according to their habit of developing in glass cages, where they present concerns for their immunological and psychological development. Initially, the mouse has a social characteristic and is kept in groups without any problem; these groups form quickly once they are introduced to the glass cage. However, the males of both strains (boxes) begin to show their aggressiveness on the 15th day, even though these groups have not fully established themselves in their habitat. Low temperatures in the laboratory cause a death of 15% of the samples, which causes a controlled heat system to be introduced at certain hours of the night, in order to avoid the loss of the samples. Once these environmental conditions of temperature and humidity were established, the mice showed greater social activity among themselves. At the time of providing the corresponding food, there should have been a procedure for an adequate food balance, such as composition, meeting growth needs, and coat maintenance, the latter being a main aspect of observation, which thanks to this I show some allergies and/or poor digestion in gnawing some cereals.
Therefore, the feeding that is supplied to the mice must have the necessary amounts in fiber and nutrients; in addition, it must be considered that these animals always seek to gnaw some food; that is why much of the diet is concentrated in cereals such as wheat and corn. However, their diet is also concentrated on green foods and nuts in addition to proportions of potatoes, carrots, and other foods that help in growth. It is evident that balanced food that exists for domestic animals such as cats and dogs are attractive to the mouse, the same that causes the fur of the mouse to increase and be much finer. This leads us to have two affirmations: the first is that the food has enough vitamins and they consume in greater quantity in addition to having the corresponding hardness to gnaw. The second is that the taste sensation in some mice causes the bowel movements to be inconsistent but rather causes foul smelling diarrhea that is not favorable to the mouse. Therefore, the nutrition of the mice had processes through which the biological body transforms and uses the nutrients to obtain enough energy, as well as to maintain and repair the tissues since the organism needs to acquire an external contribution of matter, essential for getting the substances that regulate the metabolic processes of the mouse.
It is important to consider the feeding for cold places should be a maximum of 5.7 to 7.5 g of food per mouse; the above is subject to consideration depending on the climate of the region. It should also be considered that the water supply should never be missing in either of the two sample boxes, in a quantity of 250 ml per day. The adaptation time of the mice in the climatic conditions of the city of Potosí was 33 days; currently, there was the loss of samples due to the climate conditions, where the extreme coldest temperature was −4°C. Despite the fact that the environment is controlled, it is important to consider that carbohydrate feeding increases between 10 and 15% on these cold days, since the body of the mice needs to create a greater amount of fat for their protection from weather conditions. In the laboratory, there is a heat regulator so that the temperature does not drop abruptly in the implemented environment (Table 1).
Once the adaptation of the mice has been achieved, parallel to this and for a time of 70 days, the accumulated average values of the power density of electromagnetic radiation are shown; according to the density of users, these levels of power increase during daylight hours, especially in the periods from 12:00 to 13:00 and approximately 18:30 to 20:00. This action is because many people today use the mobile phone, for immediate communication, which causes the concentration of power in some parts of the city to increase; so it is right where there is a telecommunication antenna, especially mobile telephony, will have a quasi-similar behavior to that of the following graph.
Although the graph in Figure 5 shows high peaks, it must be considered that the irradiation activity was continuous; this means that the levels of electromagnetic radiation increased progressively, making use of commercial mobile phones. Where the power density generated by each of the cell phones does not exceed the value of 5 (mW/cm2), this is based on the ICNIRP international standards, giving certainty of compliance with this.
Temporal behavior of the power density of non-ionizing radiation.
In knowledge of these aspects, it is important to explain the behavior of mice exposed to these electromagnetic fields. It should be considered that the irradiation was progressive, considering that adaptation to the environmental conditions of the city of Potosí, also influence mice, which influences the behavior of hyperactivity, feeding, and growth. For the analysis of the irradiation of electromagnetic fields on the mice, a detailed control was carried out, starting with the division and marking of each mouse, with great care, where it identifies individually the behavior of feeding (appetite), thirst (water consumption), sleep, aggressiveness, hyperactivity, irritability of the eyes, and bedding (mouse nest). Each of these aspects is considered as a variable, the same that is registered in a Likert table; this evaluation allows describing the physiological conditions, that is, the stress level of each mouse in the adaptation period, as well as in the gradual exposure to concentrated electromagnetic field levels in the experimental environment. The Likert levels adopted for this situation were as follows: normal level: 1 to 21; medium or moderate level: 22 to 42; and high or acute level: 43 to 63. Based on these considerations, Figure 6 shows the behavior of the mice in general.
Chart of stress levels without exposure (left) and with exposure (right) to EMF.
These last two graphs show admirable considerations at the level of the behavior of mice, especially on stress, generated by electromagnetic fields. It is interesting to discuss why this exposure to electromagnetic fields influences the behavior of mice, taking the following explanatory points of observation that are evident in experimentation.
In their habitat: a disordering in the path of their health needs, compared to the situation adaptive clutter in your shelter is more evident, foods are scattered everywhere. The presence of mobile phones in operation (without sound, vibration, or light emission) triggers a restless response in mice, where they try to gnaw and tear the object with greater force; in addition, they work on more than two subjects, trying to hide the equipment; for this action, they use the parts and other extremities, carrying small debris to cover said object, even though the mice avoid approaching the point where the mobile terminal is located. This aspect not only occurs with the cell phone but also with other electrical and electronic instruments, such as coils, radios, and current extenders.
In their diet
In the liquid consumption: they present a higher consumption which causes some fights and aggressiveness between them, noticing that we provide more water to avoid fights. Despite dividing the proportions of water into three different containers, the aggressiveness persists. In addition, it is important to mention that one of the water sources is close to the cell phone where the mice avoid going to it, with some of the samples approaching this source.
Within their hyperactivity: a low performance is observed, since there is greater aggressiveness among the mice, which at the time of getting on the spinning wheel, some of them approach and push it, causing the fall of this.
In their physiology: within the last 3 weeks of irradiation with electromagnetic fields, the mice have great irritation in the eyes, which when approaching to the activated source of electromagnetic radiation (mobile phone) avoid being close to it. The mice feel discomfort in the whiskers more frequently when the active electromagnetic signal is increased (when the cell phone is switched on); the frictions that are made in the presence of this physical agent develop irritation in the mouse’s snout.
All these exposed aspects show an explanation of how the influence of electromagnetic fields in prolonged periods influence the behavior of mice both in their stress levels and in their physiology.
The presence of electromagnetic fields within the environmental environment has grown progressively according to the human population density. The direct or indirect influence of these fields generates an uncomfortable presence in the habitat of an animal, especially for those animals that are sensitive to the variation of the intensities of static or dynamic electromagnetic fields, proof of this is the behavior of the mice within this study which are sensitive to the increase in the levels of electromagnetic fields.
Mice, without the influence of electromagnetic fields, present an organization within their habitat, which demonstrate dynamic hyperactivity in their life cycle. On the other hand, if the conditions of their habitat are abiotic due to the influence of electromagnetic fields, the mice present different levels of behavior, raising their stress conditions, for example, in aggressiveness and irritation of the eyes.
In an epilog, it can be concluded that the action of the electromagnetic fields generated by mobile phones directly influences mice on their level of behavior and their habitat. Furthermore, when the presence of this signal exists, the mice avoid proximity by activating intrinsic prevention in each one of them.
The authors are grateful to the FAUTAPO foundation, for making possible the purchase of equipment for the investigation of electromagnetic fields in the non-ionizing spectrum.
IntechOpen aims to ensure that original material is published while at the same time giving significant freedom to our Authors. To that end we maintain a flexible Copyright Policy guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Chapters",metaDescription:"IN TECH aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.\n\nWhen submitting a manuscript the Corresponding Author is required to accept the terms and conditions set forth in our Publication Agreement as follows:",metaKeywords:null,canonicalURL:"/page/publication-agreement-chapters",contentRaw:'[{"type":"htmlEditorComponent","content":"The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\\n\\n1. DEFINITIONS
\\n\\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\\n\\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\\n\\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\\n\\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\\n\\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\\n\\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\\n\\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\\n\\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\\n\\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\\n\\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\\n\\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\\n\\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\\n\\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\\n\\n3. CORRESPONDING AUTHOR'S DUTIES
\\n\\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\\n\\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\\n\\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\\n\\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\\n\\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\\n\\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\\n\\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\\n\\n4. CORRESPONDING AUTHOR'S WARRANTY
\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\\n\\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\\n\\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
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\n\nLast updated: 2020-11-27
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Due to its advantages of abundant resources, less in cost, great workability and high physical properties, fly ash leads to achieving high mechanical properties. Fly ash is considered as one of the largest generated industrial solid wastes or so-called industrial by-products, around the world particularly in China, India, and USA. The characteristics of fly ash allow it to be a geotechnical material to produce geopolymer cement or concrete as an alternative of ordinary Portland cement. Many efforts are made in this direction to formulate a suitable mix design of fly ash-based geopolymer by focusing on fly ash as the main prime material. The physical properties, chemical compositions, and chemical activation of fly ash are analyzed and evaluated in this review paper. Reference has been made to different ASTM, ACI standards, and other researches work in geopolymer area.",book:{id:"9916",slug:"zero-energy-buildings-new-approaches-and-technologies",title:"Zero-Energy Buildings",fullTitle:"Zero-Energy Buildings - New Approaches and Technologies"},signatures:"Aissa Bouaissi, Long Yuan Li, Mohd Mustafa Al Bakri Abdullah, Romisuhani Ahmad, Rafiza Abdul Razak and Zarina Yahya",authors:null},{id:"73729",doi:"10.5772/intechopen.93500",title:"Solar Energy and Its Purpose in Net-Zero Energy Building",slug:"solar-energy-and-its-purpose-in-net-zero-energy-building",totalDownloads:610,totalCrossrefCites:3,totalDimensionsCites:5,abstract:"The Net Zero Energy Building is generally described as an extremely energy-efficient building in which the residual electricity demand is provided by renewable energy. Solar power is also regarded to be the most readily available and usable form of renewable electricity produced at the building site. In contrast, energy conservation is viewed as an influential national for achieving a building’s net zero energy status. This chapter aims to show the value of the synergy between energy conservation and solar energy transfer to NZEBs at the global and regional levels. To achieve these goals, both energy demand building and the potential supply of solar energy in buildings have been forecasted in various regions, climatic conditions, and types of buildings. Building energy consumption was evaluated based on a bottom-up energy model developed by 3CSEP and data inputs from the Bottom-Up Energy Analysis System (BUENAS) model under two scenarios of differing degrees of energy efficiency intention. The study results indicate that the acquisition of sustainable energy consumption is critical for solar-powered net zero energy buildings in various building styles and environments. 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In a broader perspective, we also investigate how housing has become ‘difficult’ in Europe and the poorest segments of the population run the risk of having their right to housing dramatically denied. Analysing housing in terms of its procedural dimension, we focus on two Italian case studies that evoke a new way of inhabiting the city, cases in which high standards characterised social housing and yet remain accessible to all. The Sharing hotel residence in Turin and Zoia social housing in Milan combine housing with other socially innovative measures in a framework of sustainability and avant-garde construction. These are significant examples that speak to issues such as temporariness, flexibility and the coordination of measures. These two cases both pursued objectives having to do with social, planning, architectural and environmental quality, albeit each in their own way. There are by now numerous examples of social housing in Europe and these have recently attracted growing interest in Italy as well; in this country, however, such projects represent valid instances of experimentation but are not at all widespread.",book:{id:"7650",slug:"different-strategies-of-housing-design",title:"Different Strategies of Housing Design",fullTitle:"Different Strategies of Housing Design"},signatures:"Rossana Galdini and Silvia Lucciarini",authors:[{id:"281246",title:"Dr.",name:"Silvia",middleName:null,surname:"Lucciarini",slug:"silvia-lucciarini",fullName:"Silvia Lucciarini"},{id:"282958",title:"Prof.",name:"Rossana",middleName:null,surname:"Galdini",slug:"rossana-galdini",fullName:"Rossana Galdini"}]},{id:"57401",doi:"10.5772/intechopen.71325",title:"Basic Schemes: Preparations for Applying Control Science to Sustainable Design",slug:"basic-schemes-preparations-for-applying-control-science-to-sustainable-design",totalDownloads:1251,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"It is the ultimate goal for humankind to deal with various problems and achieve sustainability. Control science can be applied to all goal-oriented tasks and has already produced remarkable results. Accordingly, applying control science to the task of achieving sustainability is a rational and reliable approach. In order to apply control science to sustainability issues, our first study has shown the “basic control system for sustainability” as well as the “model of sustainability.” After that, in order to identify system components of practical control systems for promoting sustainable design, we have devised “two-step preparatory work for sustainable design.” The two steps of this preparatory work are “determining the relationships between the standard human activities and sustainability” and “sustainability checkup on human activities as an object.”",book:{id:"5692",slug:"sustainable-home-design-by-applying-control-science",title:"Sustainable Home Design by Applying Control Science",fullTitle:"Sustainable Home Design by Applying Control Science"},signatures:"Kazutoshi Fujihira",authors:[{id:"69662",title:"BSc.",name:"Kazutoshi",middleName:null,surname:"Fujihira",slug:"kazutoshi-fujihira",fullName:"Kazutoshi Fujihira"}]},{id:"72850",doi:"10.5772/intechopen.92725",title:"Computational Analysis of a Lecture Room Ventilation System",slug:"computational-analysis-of-a-lecture-room-ventilation-system",totalDownloads:864,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"The level of Indoor Air Quality (IAQ) has become a big topic of research, and improving it using passive ventilation methods is imperative due to the cost saving potentials. Designing lecture buildings to use less energy or Zero Energy (ZE) has become more important, and analysing buildings before construction can save money in design changes. This research analyses the performance (thermal comfort [TC]) of a lecture room, investigate the use of passive ventilation methods and determine the energy-saving potential of the proposed passive ventilation method using Computational Fluid Dynamics (CFD). Results obtained showed that air change per hour at a wind velocity of 0.05 m/s was 3.10, which was below standards. Therefore, the lecture hall needs external passive ventilation systems (Solar Chimney [SC]) for improved indoor air quality at minimum cost. Also, it was observed that the proposed passive ventilation (SC) system with the size between 1 and 100 m3, made an improvement upon the natural ventilation in the room. There was a 66.69% increase after 10 years in the saving of energy and cost using Solar Chimney as compared to Fans, which depicts that truly energy and cost were saved using passive ventilation systems rather than mechanical ventilation systems.",book:{id:"9916",slug:"zero-energy-buildings-new-approaches-and-technologies",title:"Zero-Energy Buildings",fullTitle:"Zero-Energy Buildings - New Approaches and Technologies"},signatures:"Abayomi Layeni, Collins Nwaokocha, Olalekan Olamide, Solomon Giwa, Samuel Tongo, Olawale Onabanjo, Taiwo Samuel, Olabode Olanipekun, Oluwasegun Alabi, Kasali Adedeji, Olusegun Samuel, Jagun Zaid Oluwadurotimi, Olaolu Folorunsho, Jacob Adebayo and Folashade Oniyide",authors:null}],mostDownloadedChaptersLast30Days:[{id:"71982",title:"Net-Zero Energy Buildings: Principles and Applications",slug:"net-zero-energy-buildings-principles-and-applications",totalDownloads:2281,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Global warming and climate change are rising issues during the last couple of decades. With residential and commercial buildings being the largest energy consumers, sources are being depleted at a much faster pace in the recent decades. Recent statistics shows that 14% of humans are active participant to protect the environment with an additional 48% sympathetic but not active. In this chapter, net-zero energy buildings design tools and applications are presented that can help designers in the commercial and residential sectors design their buildings to be net-zero energy buildings. Case studies with benefits and challenges will be presented to illustrate the different designs to achieve a net-zero energy building (NZEB).",book:{id:"9916",slug:"zero-energy-buildings-new-approaches-and-technologies",title:"Zero-Energy Buildings",fullTitle:"Zero-Energy Buildings - New Approaches and Technologies"},signatures:"Maher Shehadi",authors:null},{id:"57400",title:"Case Study: Detached House Designed by Following the Control System",slug:"case-study-detached-house-designed-by-following-the-control-system",totalDownloads:1572,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"The previous chapter has demonstrated the control system for promoting sustainable housing design in which the sustainable design guidelines and sustainability checklist are incorporated. Following this control system, we have actually designed and constructed a detached house. To be concrete, the homeowner and the architects of the housing manufacture have designed the home’s parts, or elements, so that as much as possible the elements’ variables meet their desired values. The sustainable design guidelines and sustainability checklist have been readily accepted because the material and spatial elements are equivalent to real parts of the home. After the home started to be used, we have obtained external evaluations of the home’s sustainability performance. For example, CASBEE for Detached Houses, a comprehensive assessment system, has readily ranked the house in the highest “S.” An energy-saving performance assessment has shown that this home has reduced energy consumption by over 70%, as compared with the average home. On the other hand, the reactions of the occupants and visitors have indicated the comfort, healthiness and safety of this house. Furthermore, this home has received a sustainable housing award, especially due to its extremely high sustainability and energy-saving performance.",book:{id:"5692",slug:"sustainable-home-design-by-applying-control-science",title:"Sustainable Home Design by Applying Control Science",fullTitle:"Sustainable Home Design by Applying Control Science"},signatures:"Kazutoshi Fujihira",authors:[{id:"69662",title:"BSc.",name:"Kazutoshi",middleName:null,surname:"Fujihira",slug:"kazutoshi-fujihira",fullName:"Kazutoshi Fujihira"}]},{id:"67084",title:"Comprehensive Strategy for Sustainable Housing Design",slug:"comprehensive-strategy-for-sustainable-housing-design",totalDownloads:1383,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Sustainable housing needs to be designed to maximize occupants’ well-being and minimize the environmental load. The pursuit of combining these two different aspects toward sustainability is a goal-oriented task. The science of control can be applied to all goal-oriented tasks. Therefore, applying control science, we have been progressing in research on sustainable housing design. Our previous study has produced the control system for promoting sustainable housing design in which sustainable design guidelines and sustainability checklist are incorporated. Based on these accomplished results, this study has comprehensively visualized the process of producing and revising the sustainable design guidelines and sustainability checklist. Following this visualized process, also this study has concretely shown the production and revision processes of the sustainable design guidelines. The study results suggest that the comprehensive visualization can make these processes more manageable and help system designers to produce and revise the guidelines more efficiently. Furthermore, these results have led to indicating how to adjust the guidelines to different countries or regions as well as changing situations over time.",book:{id:"7650",slug:"different-strategies-of-housing-design",title:"Different Strategies of Housing Design",fullTitle:"Different Strategies of Housing Design"},signatures:"Kazutoshi Fujihira",authors:[{id:"69662",title:"BSc.",name:"Kazutoshi",middleName:null,surname:"Fujihira",slug:"kazutoshi-fujihira",fullName:"Kazutoshi Fujihira"}]},{id:"65804",title:"Effects of Street Geometry on Airflow Regimes for Natural Ventilation in Three Different Street Configurations in Enugu City",slug:"effects-of-street-geometry-on-airflow-regimes-for-natural-ventilation-in-three-different-street-conf",totalDownloads:1417,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Efficient natural ventilation is dependent on the micro climate conditions of an urban environment. This is affected by ambient wind flow, radiation and air temperatures. The airflow within the urban street can be cultivated into two regions. The first is a recirculation region, which forms in the near wake of each building. The Second is a ventilated region downstream of the recirculation region, formed when the street is sufficiently wide. The development of the flow into these two regions depends on geometry. This chapter looks at the impacts of street geometry on these regions of airflow cultivation in three different street configurations in high density residential settlements in Enugu city. It utilized schematic analysis of airflow regimes to identify the behaviors of flow in these street configurations relative to the height and width ratios of the street canyon. This schematic analysis can be utilized in preliminary design studies by city and building designers for justifying street dimensions and configurations in tropical regions where natural ventilation is paramount.",book:{id:"7650",slug:"different-strategies-of-housing-design",title:"Different Strategies of Housing Design",fullTitle:"Different Strategies of Housing Design"},signatures:"Jideofor Anselm Akubue",authors:[{id:"139659",title:"Dr.",name:"Akubue",middleName:"Jideofor",surname:"Anselm",slug:"akubue-anselm",fullName:"Akubue Anselm"}]},{id:"66000",title:"Fundamentals of Natural Ventilation Design within Dwellings",slug:"fundamentals-of-natural-ventilation-design-within-dwellings",totalDownloads:978,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Along with acoustical and lighting comfort, indoor air quality (IAQ) and thermal comfort upon households are essential to maintain a proper indoor environment, therefore ensuring a welfare toward the occupants. Nevertheless, sometimes, these features are neglected by building designers and constructers, causing problems such as the so-called sick building syndrome (SBS) and thermal discomfort, among others. Although there are short-term solutions such as purifiers, extractors, fans, and air conditioning, eventually these methods become not sustainable activities that consume energy and emit polluting gases such as chlorofluorocarbons. One alternative to this is natural ventilation, understood as the airflow throughout a building caused by changes of pressures naturally produced. In this chapter, the role of the early-stage building design as well as the correct occupant behavior is presented as essential to develop a naturally ventilated dwelling, which is an excellent alternative to achieve proper levels of indoor environment in a sustainable manner.",book:{id:"7650",slug:"different-strategies-of-housing-design",title:"Different Strategies of Housing Design",fullTitle:"Different Strategies of Housing Design"},signatures:"Ivan Oropeza-Perez",authors:[{id:"282172",title:"Dr.",name:"Ivan",middleName:null,surname:"Oropeza-Perez",slug:"ivan-oropeza-perez",fullName:"Ivan Oropeza-Perez"}]}],onlineFirstChaptersFilter:{topicId:"128",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:18,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713",scope:"
\r\n\tScientists have long researched to understand the environment and man’s place in it. The search for this knowledge grows in importance as rapid increases in population and economic development intensify humans’ stresses on ecosystems. Fortunately, rapid increases in multiple scientific areas are advancing our understanding of environmental sciences. Breakthroughs in computing, molecular biology, ecology, and sustainability science are enhancing our ability to utilize environmental sciences to address real-world problems.
\r\n\tThe four topics of this book series - Pollution; Environmental Resilience and Management; Ecosystems and Biodiversity; and Water Science - will address important areas of advancement in the environmental sciences. They will represent an excellent initial grouping of published works on these critical topics.