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The median age at diagnosis is 72 years, and more men than women (2:1) are affected [1]. CLL is one of the B-cell chronic lymphoproliferative disorders. It is characterized by a progressive accumulation of functionally incompetent lymphocytes, which are usually monoclonal in origin.
\nCLL diagnosis depends on the presentation. For patients presenting with absolute lymphocytosis; CBC, flow cytometry of the peripheral blood, and examination of the peripheral smear are adequate to diagnose CLL [2]. Diagnosis of CLL using these tests requires identification of absolute B lymphocyte count (B-ALC) >5000/micrL sustained for at least 3 months, morphologically mature-appearing small lymphocytes, and flow cytometry showing the typical immunophenotype of CLL cells: extremely low levels of surface membrane immunoglobulin (SmIg) and either Kappa or Lambda (but not both), CD19, CD20, CD23 and CD5 positive cells. Evaluation of the bone marrow is not usually necessary, but is included in the evaluation of patients with unexplained cytopenias. Patients presenting with lymphadenopathy without lymphocytosis will need ideally an excisional lymph node biopsy or alternatively a needle biopsy showing mature lymphocytes with the previously mentioned phenotype to diagnose small lymphocytic lymphoma (SLL) which is considered by WHO the same disease as CLL with different manifestations [3].
\nMonoclonal B cell lymphocytosis is diagnosed when B-ALC is <5000/micrL persistently with no other manifestations of disease activity such as lymphadenopathy, hepatosplenomegaly, disease related cytopenias, or disease related symptoms. Patients with disease related cytopenias are diagnosed with CLL regardless of B-ALC and patients with any of the other manifestations are considered to have SLL [2]. Before 2008, the diagnosis of CLL was based on ALC equal or more than 5000/microL in the setting of appropriate immunophenotype. Patients with an absolute B lymphocyte count (B-ALC) less than 5000/microL and an ALC more than 5000/microL represented an overlap between CLL and monoclonal B cell lymphocytosis. The switch to using B-ALC for the diagnosis of CLL in 2008 eliminated this overlap [4, 5].
\nCLL is commonly thought of as an indolent disease associated with a prolonged clinical course and that patients with CLL will die from unrelated cause rather than the disease itself. It is important to know that this only happens in one third of the patients. More commonly, patients will have two phases of the disease: an initial asymptomatic phase (5–10 years) where the course will be benign, followed by the terminal phase (1–2 years) where performance status will decline due to recurring need for hospitalization. Some patients die quickly within 1–2 years of the diagnosis. Because of this variable natural clinical course of CLL, there have been always efforts to come up with reliable and clinically applicable criteria that would allow recognizing those patients with poor prognosis to start treatment as soon as possible and improve their survival and differentiate them from the other group where the prognosis is good and treatment can be delayed to avoid treatment toxicity [6, 7, 8].
\nRai and Binet staging systems are the most commonly used systems in practice and the international workshop Group on CLL (iwCLL) recommends using an integrated system using both methods [9]. Both systems depend on findings of CBC and physical exam findings only, addition of CT scan of the chest, abdomen, and pelvis is not routinely recommended to stratify patients.
\nRai staging system divides patients into 5 groups (Table 1). It was published initially in 1975, with initial reports showing one quarter of patients fall in stage 0 on presentation, half of patients fall in stages 1 and 2, and a quarter of them fall in stages 3 and 4. Later reports showed that more patients fall in earlier stages because of earlier diagnosis due to the more routine testing being done in recent years including CBC [10]. Median survival decreases from almost 12 years in stage 0 to a year and a half in stages 3 and 4 [11]. In 1980s, this staging system was modified to include three stages based on actuarial survival pattern: Low risk (Rai stage 0), intermediate risk (Rai stages 1 and 2), and high risk (Rai stage 3 and 4). Of note, if complete or partial remission is achieved with successful therapy, and a patient’s stage shifts from a higher risk to a lower risk category, the outlook for survival improves accordingly [12].
\nStage | \nClinical features | \nMedian survival (in years) | \n
---|---|---|
0 (low risk) | \nLymphocytosis only | \n>10 | \n
I and II (intermediate risk) | \nLymphadenopathy (I) and hepatosplenomegaly (II) | \n5–8 | \n
III and IV (high risk) | \nAnemia (III), thrombocytopenia (IV) | \n1.5 | \n
Rai staging system.
Binet staging system takes into consideration five potential sites of involvement: cervical, axillary, and inguinal lymphadenopathy (each area counts as one either unilateral or bilateral), spleen, and liver, in addition to the presence of anemia and/or thrombocytopenia. Based on these factors, Binet staging system divide patients into three groups (Table 2) [13].
\nStage | \nClinical features | \nMedian survival (in years) | \n
---|---|---|
A | \n<3 areas of lymphadenopathy; no anemia or thrombocytopenia | \nComparable to age-matched controls | \n
B | \nThree or more areas of lymphadenopathy; no anemia or thrombocytopenia | \n7 | \n
C | \nHemoglobin <100 g/L or platelets <100 x 109 g/L | \n2 | \n
Binet staging system.
One important practical concept is to reliably differentiate between autoimmune cytopenias and cytopenias related to CLL because patients with autoimmune cytopenias have better outcome than Binet stage C patients although still worse than stage A and they can normalize their counts with treatments directed at the autoimmune cytopenia thus delay CLL treatment [14, 15].
\nBoth systems are not very effective for predicting early disease progression. Although routine imaging is not recommended for staging of patients with CLL, visceral adenopathy may occur in early-stage disease and might predict an early disease progression. It is not known if the presence of visceral adenopathy warrants any specific change in therapy [16].
\nHistorically, the presence of CD38 by flow cytometry appeared to be independently associated with an adverse prognosis as well as Increased levels of ZAP-70 detected by flow cytometry [17]. It is a tyrosine kinase normally expressed by NK and T cells, and required for normal T cell receptor signaling. ZAP-70 is not normally expressed in B lymphocytes, but has been found in a subset of patients with CLL. The clinical significance of CD38 and ZAP-70 have declined overtime with better understanding of CLL cytogenetics.
\nCurrently, we use cytogenetics, molecular studies, lymphocyte doubling time, and beta-2 microglobulin [18]. Patients with del(13q) have favorable outcome, patients with trisomy 12 have intermediate outcome while patients with del(11q) and del(17p)/P53 have poor outcome. The prognosis of patients with del(11q) has improved with the use of certain treatment regimens (e.g., fludarabine, cyclophosphamide, rituximab) while that of del(17p) or TP53 mutations remains poor despite such treatments. Analysis of CLL8 trial showed worse outcome in patients with SF3B1 and RPS15 gene mutations. Also, patients with complex karyotype and NOTCH1 mutations have more aggressive course.
\nThe lymphocyte doubling time is the number of months it takes the absolute lymphocyte count to double. Doubling time <12 months is associated with a progressive course and a longer doubling time is associated with an indolent course. This factor is somewhat limited in usefulness because it takes time to measure. In patients with early stage disease, the presence of a short doubling time may favor more aggressive therapy. Higher levels of Beta-2 microglobulin (B2M) are associated with poorer outcome. B2M should be interpreted with caution in the context of renal disease, or alternatively GFR-adjusted B2M can be used although lacks validation in prospective studies [19]. Moreover, approximately half of CLL clones will demonstrate unmutated immunoglobulin heavy chain variable regions (IGHV), a finding associated with shorter survival overall and a higher risk of relapse following conventional treatment, including chemoimmunotherapy and hematopoietic cell transplantation [20].
\nAn international group of investigators did a comprehensive analysis [21] to develop a prognostic index for CLL. Using data from 3472 treatment naive patients participating in prospective, randomized clinical trials, five independent prognostic factors were identified: TP53 deletion or mutation, or both, IGHV mutational status, serum B2M concentration, clinical stage, and age. Using weighted grading of the independent factors, a prognostic index was derived that separated patients into four risk groups with significantly different overall survival at 5 years: low (93%), intermediate (79%), high (63%), and very high risk (23%). This chronic lymphocytic leukemia international prognostic index (CLL-IPI) has now been validated by several other groups and is expected to improve patient counseling and the planning of clinical trials. Other risk scores have been proposed, but none of them has been generally accepted. Of note, none of the scores (including the CLL-IPI) affects the decision of when to initiate therapy.
\nIn the 1940’s, steroids were the first systemic therapy for CLL. The risk of infection, other adverse effects from long term steroid use as well as transient nature of responses, steroids do not have a central role in the treatment of CLL. They can be used along with anti-CD 20 Ab to achieve remission in some patients.
\nSteroids were followed by the use of alkylating agent chlorambucil in the treatment of CLL, either in combination or as a single agent. These treatments produced objective response rates but mostly resulted on partial responses [22, 23]. This was followed by a long time period before newer drugs were introduced in the treatment of CLL. Fludarabine has been used in various combinations to improve outcomes in CLL. When compared to CAP (cyclophosphamide, doxorubicin and prednisone), fludarabine showed favorable results [24]. Even when it was compared to chlorambucil, fludarabine induced higher response rates but did not offer any survival advantage at the expense of higher toxicities especially from infection and neutropenia [25]. Cladribine in combination with prednisone achieved response rates similar to fludarabine when compared to chlorambucil but failed to demonstrate any survival benefit [26, 27]. Cyclophosphamide combined with fludarabine in previously untreated patients showed lower prevalence of residual disease and increased progression free survival (PFS) but again no benefit in overall survival (OS) [28]. When rituximab was combined with fludarabine and cyclophosphamide there was an improvement in PFS as well as OS [29]. This was observed across multiple phase 3 randomized trials [30, 31]. Subset analysis of these trials led to the discovery that patients with mutated IGHV status, FCR led to long term remissions [30, 32].
\nIndication for treatment of CLL include severe fatigue, weight loss, night sweats, fever without infection, threatened organ function, progressive lymphadenopathy, anemia or thrombocytopenia that is progressive in nature, autoimmune anemia or thrombocytopenia not responsive to steroids [2]. In addition to these factors, patient age, performance status, presence or absence of del(17p) or TP53 mutation, IGHV mutation status should be assessed prior to initiating treatment in patients with indications to treat. Imaging should be considered as well to evaluate disease burden.
\nThe CLL 8 trial was a pivotal one that established chemoimmunotherapy as the standard of care for patients that can tolerate it. The FCR regimen (fludarabine, cyclophosphamide and rituxan) was compared against FC (fludarabine, cyclophosphamide). Previously untreated CLL patients were randomized to either receive 6 cycles of FCR or FC. The FCR regimen resulted in higher ORR (90% v/s 80%) and CR rates 94% v/s 22%). The median OS was not reached for FCR and was about 86 months for the FC regimen. Subset analysis showed that the maximal benefit was derived by fit patients with CLL, especially those with mutated IGHV [32]. The FCR regimen however has its share of side effects and cannot be given to older patients.
\nThe CCL2M trial looked at the feasibility of Bendamustine-Rituxan (BR) in untreated CLL patients and the results were found to be encouraging [33]. This prompted its comparison to other treatment regimens. The MABLE study looked at BR versus Chlorambucil-Rituxan in patients ineligible to receive fludarabine. Complete response rates were higher in the BR arm (24%) as compared to the chlorambucil-rituxan arm. Overall response rate and overall survival were not different among the two arms. However the PFS (40 months v/s 30 months) and Minimal Residual Disease (MRD) negativity (66% v/s 36%) were higher in the BR arm as compared to the Chlorambucil- rituxan arm [34].
\nCLL10 trial compared BR with FCR. The primary end point was PFS with the objective to assess non inferiority of BR as compared to FCR. The trial confirmed the superiority of FCR therapy (Median PFS 55 vs. 42 months) in fit patients and in patients with IGHV mutated status. However, in patients over 65 years of age the toxicity profile was better with BR.
\nThe CLL11 trial found that chlorambucil-obinutuzumab had better PFS (26.7 months) as compared to rituximab-chlorambucil (16.3 months). The PFS for chlorambucil monotherapy was the shortest (11.1 months). The obinutuzumab-chlorambucil arm also had trend towards OS benefit as compared to the other 2 arms. The study population included CLL patients with comorbidities [35]. Based on these 2 trials both BR and chlorambucil- rituxan or obinutuzumab-chlorambucil are acceptable alternatives in elderly patients or those with comorbidities.
\nOn a similar note, the COMPLEMENT 1 trial showed the combining ofatumumab to chlorambucil in fludarabine ineligible patients showed better PFS (22.4 months) as compared to the monotherapy arm (13.1 months) [36].
\nHowever, with the advent of novel agents the landscape of treatment in CLL has significantly changed. The RESONATE-2 study compared single agent chlorambucil to ibrutinib which is a Bruton’s Tyrosine Kinase inhibitor. The ORR (92% v/s 36%) as well as PFS at 2 years (89% v/s 34%) in favor of ibrutinib (Figure 1). Based on the results of this study ibrutinib was approved for use in the first line setting of CLL. Results from the ECOG ACRIN Cancer research group trial E1912 were recently published. The study compared FCR versus Ibrutinib + Rituxan (IR) in treatment naive patients without deletion 17p. IR was found to be superior to FCR in all subgroups except for the IGHV mutated group. IR group saw significant less neutropenia and infectious complications as well as compared to FCR [38].
\nProgression-free survival of Ibrutinib vs. Chlorambucil [
The alliance intergroup study showed that in older patients above 65, ibrutinib should be the standard of care as PFS was better in the ibrutinib arms then the BR arms [39]. However this study did not suggest a benefit of adding anti-CD 20 MAB therapy to ibrutinib monotherapy. In the older patient group, where chlorambucil is a treatment option, the iLLUMINATE trial showed that ibrutinib plus obinutuzumab combination resulted in better PFS as compared to chlorambucil plus obinutuzumab, albeit with greater serious adverse events [40]. Between the RESONATE-2 study and ECOG ACRIN study, ibrutinib has been established a first line recommendation in both younger as well as older patients with CLL.
\nRecently, CLL14 trial studied the combination of fixed-duration venetoclax and obinutuzumab versus obinutuzumab and chlorambucil in 432 treatment-naïve patients with CLL and coexisting medical conditions. Patients were evenly randomized to receive 12 months of venetoclax alongside 6 months of obinutuzumab or 6 months of obinutuzumab followed by 6 months of chlorambucil. Results from the trial showed the venetoclax combination reduced the risk of disease progression or death by 67% versus obinutuzumab plus chlorambucil in patients with treatment-naïve CLL and co-existing medical conditions (HR, 0.33; 95% CI, 0.22-0.51; P < .0001). The overall response rate (ORR) was 85% with venetoclax/obinutuzumab versus 71% in the control arm (P = .0007). The complete response (CR) or CR with incomplete hematologic recovery (CRi) rates were 50% versus 23%, respectively. The rate of minimal residual disease (MRD)-negativity in the bone marrow was 57% in the venetoclax arm compared with 17% in the obinutuzumab/chlorambucil arm. The MRD-negativity rates in the peripheral blood were 76% versus 35%, respectively. Venetoclax and obinutuzumab combination is the only chemotherapy-free option with fixed duration that proven to provide such a durable response.
\nIbrutinib provides durable responses and is well tolerated in patients with del(17p). Historically this group of patients generally have poorer outcomes as compared to patients with CLL but without del(17p) [41]. Other treatments in the front-line setting are listed in NCCN for these patients however none of them are very effective. The CAPTIVATE trial is currently on going looking at venetoclax along with ibrutinib in the upfront setting.
\nIs summary, as far as front line therapy is concerned, for fit patients with IGVH mutated status it is reasonable to use chemo-immunotherapy such as FCR or BR. All other patients including young or older patients with high risk disease such as those with unmutated IGHD, 17p del or p53 mutation or 11q deletion it’s recommended to treat with a novel agent such as ibrutinib as there has been accumulating evidence of better efficacy when compared to chemoimmunotherapy alone.
\nThe International Workshop on CLL (iwCLL) defines relapsed disease when it occurs in patients who have previously achieved either a complete or partial remission but then develop progressive disease after a period of 6 months or more. Patients who fail to achieve either a partial or complete remission with therapy or those who develop disease progression within 6 months of last therapy are defined to have refractory disease. This distinction is principally made because many patients with progressive disease occurring later after the discontinuation of treatment can be successfully retreated using the same medication, or by switching to other available treatments. In contrast, patients who have refractory disease are unlikely to respond to a trial of the previously used therapy and have a much poorer prognosis [2]. Of note, The iwCLL response criteria were originally developed using data from patients treated with single agents (i.e., fludarabine, chlorambucil). As first-line therapy has evolved, the overall response rate and median progression-free survival have increased. The definitions of relapsed and refractory disease will likely change as therapy improves especially that we depend on expected progression free survival (PFS) in practice more than the 6 months rule to choose the next regimen as illustrated below.
\nThe choice of treatment at relapse should consider how soon the relapse happens after initial treatment. If it happens sooner than the expected median PFS for the specific regimen is considered “Early relapse”, while it is considered “Late relapse” when it happens after the expected median PFS [42]. Prospective trials have reported median PFS for different regimens, as a rule of thumb, progression within 2–3 years of initial treatment with fludarabine, cyclophosphamide, and rituximab (FCR) or within 1 year of other chemoimmunotherapy regimens may be considered to have early relapse.
\nFor early relapsing CLL, it’s recommended to start a targeted therapy with either ibrutinib, idelalisib plus rituximab, or venetoclax with or without rituximab rather than retreatment with the prior therapy or a trial of another chemoimmunotherapy regimen. One series reported the median survival of 42 patients unresponsive to fludarabine as 48 weeks and only 11% responded to other chemoimmunotherapies [43]. The optimal length of treatment has not been defined but common practice to continue until disease progression or unacceptable toxicity.
\nIbrutinib: it is a common treatment of choice for patients with refractory or early relapsing disease. Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor [44]. The RESONATE trial which is a multicenter open label phase III trial showed better overall response rate (ORR), PFS, and overall survival (OS) compared to ofatumumab (an anti-CD20 monoclonal antibody) in patients with refractory/relapsed CLL, these benefits were found across all subgroups of patients, including those with high-risk features such as del(17p). This late observation was confirmed in the RENONATE-17 trial in 2016 where ORR was 83% at a median follow up of 28 months in 144 patients with relapsed/refractory CLL/SLL with del(17p) [45, 46]. Expected side effects from ibrutinib include diarrhea, fever, and nausea. Higher rates of atrial fibrillation (6–16%) and pneumonitis were noted in the clinical trials [47], atrial fibrillation is usually manageable without discontinuation of the drug. Another important side effect is increased risk of bleeding, ibrutinib should be used with caution if patient is on one anti-platelet medicine and should be avoided if on two anti-platelets or anticoagulants as fatal cases of bleeding happened in those scenarios. Also, Ibrutinib should be discontinued 3–7 days before and after surgery to decrease risk of perioperative bleeding. Patients should be also reminded to avoid NSAIDs [48]. Ibrutinib is associated with a usually “transient” lymphocytosis that peaks after approximately 4–8 weeks and resolves in the majority despite continued drug exposure with a median duration of 14 weeks. The starting dose of ibrutinib is 420 mg orally once daily, except for patients with mild liver impairment (child-pugh class A), the starting dose is reduced to 140 mg daily since it’s metabolized in the liver and is contraindicated in moderate to severe liver impairment.
\nIdelalisib: It is an oral inhibitor of phosphoinositide 3′-kinase (PI3K) delta. It is given in combination with Rituximab. A phase 3 multicenter trial compared Idelalisib and rituximab vs. placebo and rituximab in 220 patients with relapsed CLL showed superior ORR, PFS, and OS (81%, 93%, and 92%, respectively), these benefits were seen in all prespecified subgroups, including those with 17p deletion, TP53 mutation, and IGHV mutations [49]. Possible side effects include: pneumonia and febrile neutropenia most commonly, but also fatigue, nausea, and diarrhea have been reported. Idelalisib can cause severe elevations in AST and ALT, it is reversible on holding the drug and never led to permanent discontinuation in clinical trials. The starting dose is 150 mg twice daily. Other possible combinations are Idelalisib plus Bendamustine plus Rituxan or idelalisib plus ofatumumab, those combinations led to more grade 3 toxicities and treatment related deaths, respectively, so extreme caution should be paid while choosing patients for these combinations [50, 51]. As with ibrutinib, idelalisib can cause transient lymphocytosis that peaks in the second week of treatment and resolves spontaneously by week 12, adding Rituximab decrease its severity and shortens its duration. CMV monitoring and prophylaxis against Pneumocystis pneumonia (PCP) are important with idelalisib use. It carries a boxed warning regarding hepatotoxicity, colitis, and pneumonitis.
\nDuvelisib: it is an oral inhibitor of PI3K delta and gamma isoforms. The phase 3 DUO trial was the largest trial to study the efficacy of duvelisib, it included 319 patients assigned to duvelisib vs. ofatumumab. Duvelisib had higher ORR and median PFS (74% and 13.3 months, respectively) [52]. Duvelisib is usually reserved for patients with multiply relapsed disease, usually after treatment with ibrutinib and venetoclax, with or without prior chemoimmunotherapy. The starting dose is 25 mg administered orally twice a day over a 28-day treatment cycle. Toxicities include opportunistic infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Hepatic function and blood counts must be monitored for hepatotoxicity and neutropenia. Like idelalisib, it is recommended to use PCP and CMV prophylaxis.
\nVenetoclax: it is an oral inhibitor of BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of CLL cells. Initial phase 2 trials showed ORR more than 65% for venetoclax [53, 54]. The MURANO trial, an international phase 3 trial, compared Venetoclax plus rituximab vs. bendamustine plus rituximab in 389 patients with relapsed/refractory CLL showed higher PFS of 85% and OS of 92% at 2 years for the venetoclax arm, this effect was maintained in high risk patients and older adults. Patients assigned to venetoclax arm were also more likely to achieve undetectable minimal residual disease (uMRD) which is a status predictive of superior PFS [55]. The most common toxicities are pancytopenia, diarrhea, and upper respiratory tract infection. Because venetoclax increases risk of TLS, high risk patients (i.e. any lymph node >10 cm or lymph node >5 cm and ALC >25 x 109/L) should receive the first few doses in the inpatient setting with IV hydration, use of allopurinol or rasburicase, and frequent monitoring of TLS labs. Venetoclax is started at 20 mg daily and increased gradually over 5 weeks to a final daily dose of 400 mg. Rituximab is started after the patient has completed the escalation schedule and received the 400 mg dose for 7 days. It is common practice to use venetoclax after ibrutinib failure.
\nAlthough both options are valid in late relapsed CLL patients, each option has its advantages and disadvantages. Targeted therapy is generally the preferred option because they have better PFS and may improve OS, the best example on that is the MURANO trial mentioned above, patients who relapsed after 24 months of initial treatment with bendamustine and rituximab were included in the study, and still they had better PFS and OS [55]. Targeted therapy also offers the convenience of an oral regimen. On the other hand, retreatment with initial chemoimmunotherapy regimen may be considered for patients who experienced minimal toxicity with the initial treatment, targeted therapy is associated with unique toxicities and is often administered without breaks until the time of progression. In a phase 2 study, patients who were initially treated with FCR and relapsed after 3 years showed median survival of 5 years and estimated five-year survival rate of 70% when they were retreated with FCR, although the toxicities, especially myelosuppression, were more frequent [56].
\nPatients with CLL experience serial relapses and many will be treated with each of these agents at some point during their disease course. A preferred order for their use has not been established. A choice is primarily made based on the patient’s prior treatment and the regimens’ expected toxicities.
\nIn the setting of approval of novel agents in the treatment of CLL the number of transplants that are being performed in Europe and the United States are decreasing. In the chemoimmunotherapy era, patients with TP53 deletion/mutation, fludarabine refractoriness, early relapse (<24 months) after FCR treatment were in the highest risk group. Allogeneic Stem Cell Transplant (SCT) would be considered in these patients as the only viable treatment option. Today however, these patients have ibrutinib, idelalisib and venetoclax and various combination of novel agents with immunotherapy as possible treatment options. There are no randomized clinical trials that compare the outcomes of allogeneic SCT with conventional chemotherapy, chemoimmunotherapy or novel therapy regimens. Most transplants offered for CLL use reduced intensity conditioning (RIC), however no trials have been conducted to compare it to myeloablative conditioning. RIC resulted in reduced toxicity without compromising engraftment and anti-tumor activity [60]. Follow up results for studies with RIC indicate that about 40% of patients achieve long term disease control and RIC also overcomes the negative prognostic effect of TP53, fludarabine refractoriness as well as that of SF3B1 and NOTCH gene mutations [61, 62, 63]. Generally, allogeneic transplants are no longer offered to patients with del(17p) in first remission. In the relapsed setting the role of SCT must be weighed against the comorbidities, prior therapies, and duration of response to prior therapies as well as current mutation status including TP53, NOTCH1 and SF3B1. Patient must be informed about the side effect profile and non-relapse mortality associated with allogeneic transplant compared to the toxicity and side effect profile of novel agents. (Figure 2).
\nHematopoietic SCT for CLL by year [
MRD in CLL is assessed most commonly using multiparametric flow cytometry with a sensitivity to detect <1 CLL cell in 10,000 leukocytes. MRD – undetectable (MRD-U) has been defined detection of <1 CLL cell per 10,000 leukocytes [2]. MRD-U in the blood or bone marrow strongly correlates with longer PFS in the patients treated with chemoimmunotherapy has been noted in numerous studies [30, 57, 64]. However, MRD- U is rarely achieved in patients who are on ibrutinib, a drug that offers significant clinical benefit in PFS and survival in CLL patients [66]. So, there is consensus that while MRD- U is generally a favorable outcome for patients but its exact use case scenario in clinical practice is yet to be determined. As of now the potential use of MRD status in CLL patients is in the context of clinical trials, as a surrogate for PFS depending on the type of treatment used and possibly as a replacement for clinical and radiographic response assessments in the future.
\nMaurice Richter initially described the transformation of CLL into an more aggressive form of lymphoma and since then this has been recognized as Richter’s Transformation (RT) [67]. In most cases RT consists of transformation of CLL into Diffuse Large B Cell Lymphoma (DLBCL), however other aggressive lymphomas have been reported. As of now the reported incidence of RT in the era of novel agents is not very different from the incidence of RT in the chemoimmunotherapy era [68, 69] with incidence rates varying from 3–20% among various studies. RT is suspected when there is rapid clinical deterioration, worsening discordant lymphadenopathy to new onset cytopenia. However, its presentation can be varied. When RT is suspected a comprehensive evaluation with a PET/CT, image guided biopsy as well as a bone marrow biopsy is required. SUV of greater than 10 can distinguish RT form CLL with high sensitivity (91%) and specificity (95%) [70]. However, this has been disputed in the setting of novel agents and thus a concern for RT necessitates a biopsy of the index lesion preferably. RT primarily arises in the background of TP53 disruption and complex karyotype. MYC activation and CDKN2A/B likely play an important role in RT. Clonally related RT patients (>80% of RT DLBCL) respond very poorly to traditional chemotherapy for DLBCL, whereas clonally unrelated DLBCL RT patients respond to traditional chemotherapy just as de novo DLBCL. Thus, determination of clonal evolution is important but difficult to determine [71].Trials performed prior to the use of novel agents used R-CHOP or similar regimens as the standard therapy to treat RT. Fit patients who achieve a complete response or good partial response achieve benefit from a post induction strategy involving stem cell transplant [72]. Novel combinations, PDL-1 blockade and CAR-T or bispecific antibodies are being currently investigated as potential treatment options [72]. Figure 3 below shows a suggested treatment approach algorithm for suspected patients with RT.
\nRichter transformation. Adapted by ASH education handbook [
Hypogammaglobulinemia is the most predominant inherent immune defect in CLL patients, with subtypes IgG3 and IgG4 particularly affected. Hypogammaglobulinemia becomes more pronounced with longer disease duration and advanced-stage disease. There is generally no reversal in this defect, even with response to therapy. However, in one report, ibrutinib therapy resulted in partial reconstitution of humoral immunity, with an increase in IgA levels [73]. The most common site of infection in CLL patients is the respiratory tract, which may be related to serum IgA and IgG4 deficiencies and possibly to mucosal immune defects. The majority of patients with CLL will develop hypogammaglobulinemia at some point in the course of their disease. The use of prophylactic intravenous immunoglobulin (IVIG) to restore IgG levels is controversial. For most patients with CLL, prophylactic IVIG is
CLL is frequently associated with autoimmune phenomena, the most common being autoimmune hemolytic anemia (AIHA) [75]. Up to 33% of CLL cases have a positive direct antiglobulin test (DAT) during the course of disease, but overt AIHA occurs much less frequently. In a report of 1203 patients with CLL consecutive cases reported from a single institution, 52 (4.3%) cases of AIHA were observed, 19 at the time of diagnosis [76]. The prevalence of AIHA in patients with CLL have been reported in the range of 4–10%. It increases with disease stage. The autoantibodies that cause AIHA can be produced by nonmalignant B cells or, less commonly, by the malignant CLL clone itself [77, 78]. In practice, AIHA may occur in patients with no other requirement for treatment, or in patients in whom chemotherapy treatment is imminent or already started. Factors associated with an increased risk of development of AIHA at diagnosis included a high white blood count, older age, and male sex. AIHA alone was not itself associated with poor prognosis. The diagnosis of AIHA is usually based on the presence of an isolated fall in hemoglobin associated with a positive DAT, increased reticulocytes, and serum bilirubin. There have been no controlled trials of treatment for AIHA in CLL and the treatment approach is based on personal and institutional experience. In general, AIHA is responsive to CLL treatment, but if there is no indication to treat CLL, AIHA should be treated as a separate entity with steroids and other immune suppressants, the details of which is beyond the scope of this chapter. There has been controversy whether some chemotherapy agents, particularly purine analogs, induce or worsen AIHA. In a trial comparing outcomes of treatments using chlorambucil, fludarabine, or fludarabine in combination with cyclophosphamide, a positive DAT was found in 14%, and AIHA occurred in 10% of patients [75]. AIHA occurred more often in patients treated with chlorambucil than fludarabine, and occurred least frequently in patients receiving the combination of fludarabine and cyclophosphamide. For patients requiring therapy, a positive DAT test had poor prognostic significance, even in the absence of AIHA. The results suggest that the most successful treatment of AIHA in patients requiring chemotherapy treatment is the treatment associated with the best response rate.
\nIn summary, there has been a significant change in how we manage patients in CLL over the last 5 years. We have shifted away from chemoimmunotherapy towards novel agents such as BTK, PIK3, and BCL-2 inhibitors, which are not only more efficacious but are also safer and better tolerated. New prognostic models are being developed, and it appears that MRD directed therapy will become the norm in the future. Many clinical trials are looking at various combinations of novel therapies, with a defined period of treatment based on MRD analysis, to enable patients to have a period of treatment-free remission instead of continuous therapy.
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His teaching interests revolve around global economies and markets while his research focuses on topics related to development and growth, global business decisions, and the economics of technical innovation.",institutionString:null,institution:{name:"University of Houston",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},{id:"88",title:"Marketing",coverUrl:"https://cdn.intechopen.com/series_topics/covers/88.jpg",isOpenForSubmission:!1,editor:null,editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:0,paginationItems:[]},overviewPagePublishedBooks:{paginationCount:1,paginationItems:[{type:"book",id:"11392",title:"Leadership in a Changing World",subtitle:"A Multidimensional Perspective",coverURL:"https://cdn.intechopen.com/books/images_new/11392.jpg",slug:"leadership-in-a-changing-world-a-multidimensional-perspective",publishedDate:"May 11th 2022",editedByType:"Edited by",bookSignature:"Muhammad Mohiuddin, Bilal Khalid, Md. 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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}},{id:"147824",title:"Mr.",name:"Pablo",middleName:null,surname:"Revuelta Sanz",slug:"pablo-revuelta-sanz",fullName:"Pablo Revuelta Sanz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"19",type:"subseries",title:"Animal Science",keywords:"Animal Science, Animal Biology, Wildlife Species, Domesticated Animals",scope:"The Animal Science topic welcomes research on captive and wildlife species, including domesticated animals. 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Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",annualVolume:11410,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},{id:"15",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",annualVolume:11411,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null,editorialBoard:[{id:"241413",title:"Dr.",name:"Azhar",middleName:null,surname:"Rasul",fullName:"Azhar Rasul",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRT1oQAG/Profile_Picture_1635251978933",institutionString:null,institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}},{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",fullName:"Sergey Sedykh",profilePictureURL:"https://mts.intechopen.com/storage/users/178316/images/system/178316.jfif",institutionString:null,institution:{name:"Novosibirsk State University",institutionURL:null,country:{name:"Russia"}}}]},{id:"17",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",annualVolume:11413,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},{id:"18",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",annualVolume:11414,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",fullName:"Shymaa Enany",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRqB9QAK/Profile_Picture_1626163237970",institutionString:null,institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"chapter.detail",path:"/chapters/13467",hash:"",query:{},params:{id:"13467"},fullPath:"/chapters/13467",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()