The grading standards and surgical strategies tumor thrombus.
\r\n\tHowever, despite the positive outlook and trends in routing protocol design, there are still several open or unresolved challenges that researchers are still grappling with. Providing adequate responses to those challenges is essential for next-generation networks in order to maintain its reputation and sustain its preponderance in cyber and physical security. Some of the challenges include, but are not limited to, the following:
\r\n\t• Robustness and reliability of routing protocol
\r\n\t• Reduced dependencies on heterogeneous networks
\r\n\t• Security of routing protocols
\r\n\t• Dynamic Adhoc routing Protocols
\r\n\t• Routing in 5G Networks
\r\n\t• Routing IoT enabled networks
\r\n\t• Scalable and dependable routing system architectures
\r\n\t• QoS and QoE Models and Routing Architectures
\r\n\t• Context-Aware Services and Models
\r\n\t• Routing Mobile Edge Computing
\r\n\tThe goal of the book is to present the state of the art in routing protocol and report on new approaches, methods, findings, and technologies developed or being developed by the research community and the industry to address the aforementioned challenges.
\r\n\tThe book will focus on introducing fundamental principles and concepts of key enabling technologies for routing protocol applied for next-generation networks, disseminate recent research and development efforts in this fascinating area, investigate related trends and challenges, and present case studies and examples.
\r\n\tThe book also investigates the advances and future in research and development in Routing Protocols in the context of new generation communication networks.
The Chinese Cancer Registry Annual Report of 2015 indicates that renal cell carcinoma (RCC) represents approximately 2–3% of new cases of malignant tumor in China annually and the trend in the morbidity of RCC has been increasing [1]. The hallmark of RCC is its biological characteristic of invading the renal vein and/or inferior vena cava (IVC), which occurs in 4–10% of patients [2]. Past clinical decision making mostly adopts conservative treatment, in terms of high morbidity and mortality rates during this kind of procedures. Radical nephrectomy (RN) with tumor thrombectomy is the standard approach for treating such challenging cases [3]. These patients were able to obtain, as literature reported, better long-term survival, and the tumor-specific survival rate is in up to 50% [4, 5, 6, 7].
\nWith the development of laparoscopy and robotic technology and the accumulation of practical experience in surgery, we noted that the height of IVC thrombus could not sufficiently guide the choice of surgical strategy, considering that only the thrombus height was assessed. Several factors, such as the effect of neoadjuvant targeted molecular therapy (TMT), invasion of the IVC wall, venous occlusion, establishment of collateral circulation, IVC thromboembolism, and primary tumor location, can determine the surgical strategy. The present comprehensive review describes how those factors influence surgical strategy and patient outcomes.
\nRCC tends to invade the renal venous system, forming a thrombus that invades the IVC and even involving the right atrium [2]. RN with tumor thrombectomy is the standard approach for treating such challenging cases. The grading system based on tumor thrombus height was created to determine surgical strategies. As early as 1987, the Mayo Clinic had adopted the “NEVES grading.” Level I is defined as a tumor thrombus that is <2 cm apart from the orificium of the renal vein. Level II is defined as a tumor thrombus extending to the IVC >2 cm above the renal vein but below the hepatic veins. Level III is defined as a tumor thrombus that extends above the hepatic veins but below the diaphragm. Level IV is defined as a tumor thrombus located above the diaphragm. Surgical strategies are varied in corresponding levels. Traction of the liver is required in levels I to II. Turning-up the liver, blocking-up vessels located below the diaphragm, and clamping the portal vein are required in levels II to III. The establishment of an extracorporeal circulation is necessary in levels III and IV [8]. In 2002, the University of Miami divided level III tumor thrombus into four categories ulteriorly, which corresponded to diverse surgical strategies [9]. However, the most classic guideline is the “5-level classification” of a tumor thrombus, which was proposed by the Mayo Clinic in 2004 [10]. Idiographic grading standards and surgical strategies are shown in Table 1.
\nTumor thrombus level | \nDefinition | \nSurgical strategy | \n
---|---|---|
0 | \nTumor thrombus is limited to the renal vein | \nRadical nephrectomy of renal cell carcinoma | \n
I | \nTumor thrombus extend into IVC with <2 cm above the renal vein | \nTumor thrombus could be extruded to renal vein and then radical nephrectomy | \n
II | \nTumor thrombus extends in to IVC >2 cm above the renal vein but below the hepatic veins | \nThe traction of liver is required; blocking-up the section of IVC underneath hepatic vein | \n
III | \nTumor thrombus which extends above the hepatic veins but below diaphragm | \nThe mobilization of the liver; vena-venous bypass is required | \n
IV | \nTumor thrombus is above diaphragm | \nIntraoperative extracorporeal circulation is requisite | \n
The grading standards and surgical strategies tumor thrombus.
IVC = inferior vena cava.
Nevertheless, these grading systems are completely based on the experience of open surgery. Since Skinner first reported the open surgery of IVC tumor thrombectomy in 1972 [11], the technique of IVC tumor thrombectomy has been improving continuously. Some scholars had attempted to accomplish these surgeries with laparoscope in 2002 [12, 13]. In 2011, Abaza first reported on robot-assisted IVC tumor thrombus extraction [14]. In recent years, several medical centers have investigated the safety and feasibility of robot-assisted laparoscopic IVC thrombectomy (RAL-IVCTE) [15, 16, 17, 18]. Based on the anatomic characteristics of RCC, we reported the particular steps of robot-assisted surgery and concluded that RAL-IVCTE is safe, and different sides require different techniques [18]. Gu and colleagues performed a retrospective comparison between open and robotic surgeries in IVC thrombus. The study indicated that level I–II IVC tumor thrombectomy performed with robot-assisted surgery resulted in better perioperative periodical outcomes and analogous oncological outcomes compared with open surgery, marking that such surgery has entered the era of mini-traumatic surgery [19].
\nAfter general anesthesia induction and Foley catheter placement, the patients were positioned in a left lateral decubitus position with a 60–70° bump (Figure 1A and B). For right RCC, R-IVCTE and RN can be both completed with this position. For left RCC, R-IVCTE can be completed with this position. After R-IVCTE, the placement of patients was converted to a right lateral decubitus position with a 60–70° bump, and left RN was performed.
\nSurgical procedure for robot-assisted laparoscopic inferior vena cava thrombectomy. Patient position and port placement is shown, with three assistant ports used. (A and B). The inferior vena cava and left renal vein was exposed (C). The hepatic short vein was clipped and divided (D). Sequential clamping caudal IVC, left renal vein, and cephalic IVC were performed by vessel loops (E). The thrombus was removed (F). The IVC was closed with 5-0 polypropylene suture (G). Ligation and division of the left renal vein for the left RCC (H). Intraoperative IVC interruption in selected cases (I). IVC = inferior vena cava; RCC = renal cell carcinoma.
The hepatocolic, hepatorenal, and chain ligaments were incised. The liver required to be up-retracted. The anterior layer of the perirenal fascia was opened, the duodenum was dissected and retracted inside, and the IVC was exposed. Full dissection of the IVC, left renal vein, and part of the lumbar vein were required at the location of the tumor thrombus (Figure 1C). For level II IVC thrombus, the hepatic short vein, and even right central vein of the adrenal gland, was also clipped and divided (Figure 1D). Sequential clamping of the caudal IVC, left renal vein, and cephalic IVC were performed using vessel loops (Figure 1E). After the vessels were clamped, the IVC wall was cut, and the thrombus was removed (Figure 1F). After the IVC lumen was irrigated with heparinized saline, 5-0 polypropylene suture was used to close the IVC (Figure 1G). The tourniquets of the caudal IVC, left renal vein, and cephalic IVC were sequentially loosened. In the same position, right RN was completed.
\nThe patient position and port placement were the same as those for the right RCC. However, we suggest that left renal artery embolization must be performed 1–2 h preoperatively. The steps were similar in dissecting the IVC. Subsequently, we ligated and divided the left renal vein, which included the thrombus, with Endo-GIA (Figure 1H). The clamping sequence was the caudal IVC first, followed by the right renal artery, right renal vein, and cephalic IVC. After thrombus removal, the placement of the patients was converted to a right lateral decubitus position, with a 60–70°bump, and left RN was performed.
\nRecently, the latest research completed by our team investigated the surgical method of robot-assisted retro- or superohepatic vena caval tumor thrombectomy and its influence factor. We found that the surgical strategy for patients with retrohepatic vena caval tumor thrombi depends on the upper extent of the tumor thrombus [20]. In addition, the first porta hepatis and hepatic veins are important anatomical boundaries. The surgical technique was described as follows. If the retrohepatic thrombus was located inferior to the first porta hepatis (Figure 2A), some short hepatic veins should be ligated, but the liver should not be mobilized. If the retrohepatic thrombus was located between the first porta hepatis and hepatic veins (Figure 2B), mobilization of the right lobe of the liver is an important step. For retrohepatic thrombus located closer or above the second porta hepatis (liver vein) but below the infra-diaphragm (Figure 2C), mobilization both the right and left lobes of the liver can facilitate high proximal control of the superohepatic IVC. In addition, the first porta hepatis should be clamped. For superohepatic (level IV) thrombus, thoracoscope-assisted open atriotomy was performed to cut the atrial part of the thrombus, and vena caval tumor thrombectomy was subsequently performed by clamping the superodiaphragm IVC after cardiopulmonary bypass was established (Table 2).
\nThe first porta hepatis and hepatic veins are important anatomical boundaries on representative images of radiography. The retrohepatic thrombus inferior to the first porta hepatis (A). The retrohepatic thrombus inferior to the first porta hepatis (B). The retrohepatic thrombus closer or above the second porta hepatis (liver vein) but blew infra-diaphragm (C). FPH = first porta hepatis; SPH = second porta hepatis; IVC = inferior vena cava tumor.
Location of IVC thrombus | \nSurgical strategy | \n
---|---|
Retrohepatic but inferior to the FPH | \n\n
| \n
Retrohepatic and between the FPH and hepatic veins | \n\n
| \n
Retrohepatic and closer (level II) or above (level III) the second porta hepatis (liver vein) yet infra-diaphragm | \n\n
| \n
Superohepatic (level IV) | \n\n
| \n
Changes of techniques for robot-assisted retro- or supero-hepatic vena caval tumor thrombectomy in our method.
IVC = inferior vena cava; SHV = short hepatic vein; FPH = first porta hepatis.
Although mini-traumatic surgery has been applied in patients with RCC and tumor thrombus, level III and IV tumor thrombus might have lethal complications, including hemorrhage, thrombotic shedding, etc. The operative mortality and overall morbidity rates of postoperative complication of patients with tumor thrombus patients have been reported up to 5–10% and 38%, respectively [21]. Moreover, as tumor thrombus level advanced, the morbidity of perioperative periodical complications is higher accordingly. With regard to patients with level III and IV tumor thrombus, surgical strategies usually involve thoracotomy, dealing with retro- or superohepatic IVC, and establishing extracorporeal circulation, which can be achieved with the assistance of hepatobiliary and cardiovascular surgeons.
\nWith the targeted molecular therapy (TMT) of rising, TMT has been widely acknowledged as the most effective treatment for advanced RCC, particularly for patients with metastatic RCC. In recent years, targeted drugs have been reported to be applied in preoperative adjunctive therapy for tumor thrombus because of its high success rate in the treatment of advanced RCC [22, 23]. The purpose of administering target drugs was to lessen the height of tumor thrombus or shrink the primary lesions or metastases, which may enhance the safety and feasibility of surgical intervention. The results of some retrospective observations with a small sample present diversities [24, 25, 26]. After preoperative TMT, 44–76% of the patients’ IVC tumor thrombus had shrinkage in different degrees, with tumor thrombus degradation averaging approximately 20%. Cost and colleagues reported a retrospective outcome from a sample of 25 patients, wherein three patients (12%) had a reduction in the thrombus degradation, and one patient (4%) had an increase [25]. As a result of first-class evidence deficiency, this therapeutic regimen has not been recommended by the guidelines. Thus, further prospective investigations with a larger number of patients are needed to overcome the limitations.
\nFor patients with non-metastatic RCC and tumor thrombus, the recurrence rate of the tumor is approximately 50% at 3 years preoperatively, despite performing RN [27]. Thus, for these patients, only operative treatment may not be sufficient. Adjuvant IL-2/IFN applied in prophase postoperatively, chemotherapy, and hormone therapy are all negative for high-recurrence risk RCC [28]. Small molecules targeting the vascular endothelial growth factor pathway prolong the progression-free survival of patients with advanced RCC [29, 30]. Based on these, the postoperative application of antiangiogenic medicine for patients with high-relapse risk RCC will play a positive role. Three randomized controlled trials, currently, have reported the outcomes of adopting targeted therapy for high-recurrence risk RCC. Although a study found that sunitinib treatment 1-year postoperatively prolonged relapse-free survival for 1–2 years. Two other studies did not find a survival benefit [31, 32, 33]. Therefore, the European Association of Urological Surgeons does not recommend targeted drugs for postoperative RCC with high risk of relapse [34].
\nFor patients with non-metastatic RCC and tumor thrombus, a cohort study designed by the Chinese PLA General Hospital analyzed the efficacy and safety of the postoperative administration of sorafenib or sunitinib. The results showed that no survival benefit was observed for patients with tumor thrombus or IVC tumor thrombus who were administered postoperative adjuvant sorafenib or sunitinib [19].
\nSufficient preoperative imaging data is requisite for successful thrombectomy. However, several problems in the imaging diagnosis of IVC tumor thrombus still exist: Type-B ultrasound has difficulty in accurately diagnosing abnormal changes owing to numerous interferences. Magnetic resonance imaging (MRI) and computed tomography cannot effectively reflect the collateral circulation, and cannot define the degree of occlusion [35]. Therefore, more effective means are required to supplement these three routine examinations. IVC venography can observe the thrombus occlusion through the lateral position, which enables to maximize a rich data of tumor thrombus preoperatively and to make a more accurate surgical plan.
\nIVC venography has been widely used in the diagnosis of Budd-Chiari syndrome and other diseases [36]. There are still more applications in renal cancer with IVC tumor thrombus yet. Some studies reported that <15% of cases of patients with cancer thrombus would use IVC venography, and some researchers previously thought that the inspection might have false-positive or false-negative results. Meanwhile, there is a risk of emboli-induced pulmonary embolism or tumor embolus exfoliate diffusion. Therefore, performing IVC venography routinely is not recommended [37, 38].
\nHowever, with the improvement of radiographic technique in recent years, the safety of IVC venography has been observably improved, and this method may define the formation of collateral circulation of the vena cava and help develop a thrombectomy strategy, which has unique diagnostic advantages. Hence, conducting a new study for IVC venography is necessary. Based on our experience, we speculate that the following patients may be a candidate for IVC venography: (1) RCC with IVC tumor thrombus; (2) clearance of the tumor thrombus plane; (3) definition of the degree of occlusion; (4) existence of collateral circulation, which may affect intraoperative vascular resection; (5) detection of the variation of the communicating branches of vena cava, such as the variation communicating between IVC and vena azygos, which might interfere with the surgery.
\nWith regard to dealing with the IVC intraoperatively is one of the difficulties of IVC thrombectomy. There necessity of reconstruction after IVC resection is still controversial.
\nIndications for vena caval interruption include invasion of the venous walls, severe adhesion of the tumor to the vascular endothelium, complete occlusion of the vena cava, and the presence of distal thrombus [21, 39, 40]. In addition, the texture of the cancer thrombus is one of the influencing factors. With regard to preoperative imaging, the IVC in line with the indications of interruption and accompanied by sufficient collateral circulation, meanwhile, without serious cardiac, hepatic, and renal insufficiencies can be completely cut off. IVC venography and intraoperative ultrasound can help determine the disjointed lumina, which enables protection of the established collateral circulation trunk. IVC interruptions include complete and partial vena caval resections with reconstruction. Based on our experience, for right tumors, the height of the tumor thrombus, which is below the secondary hepatic portal, linear cutters are used to successively cut off the proximal, distal, and left renal veins of the tumor thrombus (Figure 1I). With regard to right tumor thrombus above the secondary hepatic portal, or left tumor thrombus above the level of the right renal vein and combined with distal thrombus, the vena cava can be resected partially. Methods for right thrombectomy include cutting off the lumina of the IVC below the secondary hepatic portal and reconstructing the lumina of the IVC above the secondary hepatic portal. The left thrombectomy procedure is resecting the lumina of the IVC below the level of the right renal vein and reconstructing the lumina of the IVC above the level of the renal vein.
\nMeanwhile, IVC interruption is safe and feasible during vena caval thrombectomy [39, 40], and the establishment of collateral circulation can avoid severe hemodynamic disorders. Different strategies of interruption ought to be generated preoperatively based on the height of tumor thrombus, tumor side, degree of vena caval obstruction and invasion, and establishment of collateral circulation.
\nVena cava tumor thrombus with thrombosis is common. The prevalence of thrombosis gathered by the Urological Department of Chinese PLA General Hospital is 19.2%. Thrombosis, at the same time, is not found within the renal venous tumor thrombus; all thrombosis occurred in the vena cava tumor thrombus. Among them, vena caval thrombi were all located on the right, the thrombus was located in the distal end of the tumor thrombus, and the distal thrombus could reach the bifurcation of the iliac vessel. Preoperative MRI can help determine the location and length of the thrombus.
\nPreoperative anticoagulation therapy is recommended for patients with thrombosis, and medication should be administered from the diagnosis of tumor thrombus and thrombus. Low-molecular heparin is recommended for anticoagulation therapy, withdrawing drugs 24 h preoperatively, maintaining the international normalized ratio of 2–3, and anticoagulation therapy is continued for 48 h postoperatively and maintained for 6 months, except for the following: patients with tumor or tumor thrombus who did not undergo complete resection; those with metastasis; needs for systemic treatment; and patients with pulmonary embolism. Pre- and postoperative placement of the vena cava stent is not recommended only if the patient has pulmonary embolism and contraindications of anticoagulation therapy [41, 42]. Preoperative imaging examinations are required for patients with extensive thrombosis at the distal end of the tumor thrombus [43]. IVC interruption is recommended, which prevents embolization caused by thrombus shedding, for patients who meet the indications and possess sufficient collateral circulation.
\nBesides the previously mentioned issues, some problems need to be solved in the field of RCC with tumor thrombus. First, whether the tumor thrombus is invading the venous walls is an important issue in diagnosis and treatment process to decide on the preoperative surgical strategies. Furthermore, it may also relate to postoperative survival. However, because the diagnostic criteria of imaging and pathology are currently insufficient, further studies should be conducted.
\nSecond, the survival of patients with RCC and venous thrombus postoperatively was significantly worse than those with localized RCC, particularly in patients with preoperative distant metastases. For IVC tumor thrombus, particularly patients with level III–IV tumor thrombus, the perioperative risk and mortality are higher. At the same time, although some patients completed the radical resection of tumor, survival after surgery is still less than 6 months. Therefore, for patients with high surgical risk or short life expectancy, the necessity for surgery deserves further discussions. The prognosis of patients with RCC and venous tumor thrombus, at present, lacks the preoperative predicting models particularly related to imaging features. The study of preoperative imaging characteristics of tumor thrombus and biological behavior of the tumor and the prognosis of patients may provide some guidance for preoperative choice of treatment.
\nAugmented reality (AR) is a real-time technology to calculate the location and angle of the camera images and add corresponding images. The goal of this technology is to set the virtual world in the real world and interact with it on screen [44]. Based on individual anatomy, the AR and computer system have been used in partial nephrectomy as a new technology in vivo and in vitro [45, 46, 47]. To overcome the problem of soft tissue and organ shift, Teber and colleagues reported a new navigation approach added to endoscope that was used in laparoscopic partial nephrectomy [47]. The study showed that the new AR tracking system proved to be effective, with a reasonable margin of error and a time to match each other. In addition, combining pre- or intraoperative imaging features with real-time endoscopy will simplify and increase the accuracy of laparoscopic surgery [47]. Thus, AR combined with three-dimensional vision has a great application value in robotic surgery in the future.
\nFinally, although RCC invades the venous system to form tumor thrombus, the tissue components between the primary tumor of the kidney and the tumor thrombus has a large difference. Meanwhile, heterogeneity exists in primary RCC and tumor thrombus, which may be the reason why primary tumor and tumor thrombus response to preoperative targeted therapy was asynchronous, and drugs among different patients respond differently. Therefore, the research of heterogeneity between primary RCC and venous tumor thrombus may find a more effective therapeutic target and drug for the reduction of tumor thrombus level, which can provide the basis for selecting appropriate patients for neoadjuvant targeted therapy preoperatively.
\nOpen IVCTE is still a standard surgery for RCC with IVC thrombus. With the development of laparoscopy and robotic technology in recent years, the safety and feasibility of robot-assisted laparoscopic IVC thrombectomy have been investigated at several centers. Those successful experiences mark that such surgery tends to enter the era of mini-traumatic surgery. Considering the complexity of the patient and the high complication rates, multidisciplinary cooperation and detailed preoperative assessment will play an important role in surgical decisions in future. Some new or mature techniques will also provide a basis for the surgical strategies, including artificial blood vessel, augmented reality, transesophageal echocardiography, IVC venography, and so on. From a safety perspective, IVCTE is still a challenging technology. Only a hospital with skilled laparoscopic and mature surgical team is recommended. Preoperative TMT is expected to shrink the IVC thrombus and reduce the complexity of the surgery. However, prospective investigations are required in the future.
\nRCC tends to invade the venous system and form venous tumor thrombus in 4–10% of patients. Surgical treatment is the standard therapy for these patients; however, postoperative complications include hemorrhage, thrombotic shedding, and other risks. Because of the huge population and relatively backward treatment concepts, the proportion and number of patients with advanced RCC in China are significantly higher than those in developed countries, such as Europe and the United States. With regard to patients with RCC and tumor thrombus, the strategies for diagnosis and treatment are mostly based on open surgery. Several clinic-related strategies are no longer suitable for current laparoscopic and robot-assisted mini-traumatic surgeries owing to the development of surgical techniques and improvement of auxiliary equipment. With regard to the tumor thrombus, a series of retrospective and prospective studies are needed to be conducted, which would enable to solve some difficulties and issues in the course of diagnosis and treatment, to improve the clinical strategies of diagnosis and treatment of patients with RCC and tumor thrombus ulteriorly, and to provide our clinical work with more powerful reference and basis.
\nThis work was supported by the People’s Republic of China and the National High Technology Research and Development Program (“863” Program) of China: the screening and clinical validation of characteristic protein biomarkers in renal cancer based on a large-scale biobank (2014AA020607).
\nThe authors have declared that they have no conflict of interest.
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\\n\\nWaiver: 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.
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\\n\\nSeverance: 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 remainder of this Publication Agreement.
\\n\\nNo 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 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\\nGoverning 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.
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\n\nAUTHOR'S GRANT OF RIGHTS
\n\nSubject to the following Article, the 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 rights:
\n\nThe foregoing licenses shall survive the expiry or termination of this Publication Agreement for any reason.
\n\nThe Author, on his or her own behalf and on behalf of any Co-Authors, reserves the following rights in the Work 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 Work 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 Author, and any Co-Author, confirms that they 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 Work and all versions of it created during IntechOpen's editing process, including the published version is retained by the Author and any Co-Authors.
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\n\nAll rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
\n\nThe Author, on his or her own behalf and on behalf of any Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
\n\nAUTHOR'S DUTIES
\n\nWhen distributing or re-publishing the Work, the Author agrees to credit the Publication in which the Work has been published as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Publication in which the Work has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
\n\nThe Author agrees to:
\n\nThe Author is responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
\n\nThe 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 Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or photocopies of such consents.
\n\nThe Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example, from case reports or photographs.
\n\nThe Author shall respect confidentiality 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 Authors and Co-Authors are confidential and are intended only for the recipients. The contents of any communication 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\nAUTHOR'S WARRANTY
\n\nThe Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\n\nThe Author and Co-Authors confirm and warrant that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work 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) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement, or 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 Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses granted in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author and Co-Authors confirm and warrant that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) they have the authority to enter into this binding Publication Agreement on behalf of each Co-Author. The 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 Co-Author.
\n\nThe Author agrees to indemnify IntechOpen for all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\n\nNothing 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\nTERMINATION
\n\nIntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including, without limitation: (i) if the Author and/or any Co-Author materially breaches this Publication Agreement; (ii) if the Author and/or any individual Co-Author is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any corporate Co-Author 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 the event of termination, IntechOpen will notify the Author of the decision in writing.
\n\nINTECHOPEN’S DUTIES AND RIGHTS
\n\nUnless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\n\nIntechOpen has the right to include/use the Author and Co-Authors´ names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion, and marketing of the Work and has the right to contact the Author and Co-Authors until, and while, the Work is publicly available on any platform owned and/or operated by IntechOpen.
\n\nIntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors 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 Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the alleged infringer.
\n\nMISCELLANEOUS
\n\nFurther Assurance: The Author shall 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 providing IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\nThird 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\nEntire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces 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 (known as the "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 any fraudulent pre-contract misrepresentation or concealment.
\n\nWaiver: 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.
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\n\nAny modification to, or deletion of, a provision or part-provision under this clause shall not affect the validity and enforceability of the remainder of this Publication Agreement.
\n\nNo 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 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\nGoverning 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.
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