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BACKGROUND: Precise prognostication is the key to optimum and effective treatment planning for early-stage hormone receptor (HR) positive, HER2/neu negative breast cancer patients. Differences in the breast cancer incidence and tumor anatomical features at diagnosis, pharmacogenomics data between Western and Indian women along with the vast diversity in the economic status and differences in insurance policies of these regions; suggest recommendations put forward for Western women might not be applicable to Indian/Asian women. Opinions from oncologists through a voting survey on various prognostic factors/tools to be considered for planning adjuvant therapy are consolidated in this report for the benefit of oncologists of the sub-continent, SAARC and Asia's LMIC (low and middle-income countries). METHODS: A three-phase DELPHI survey was conducted to collect opinions on prognostic factors considered for planning adjuvant therapy in early-stage HR+/HER2/neu negative breast cancer patients. A panel of 25 oncologists with expertise in breast cancer participated in the survey conducted in 2021. The experts provided opinions as 'agree' or disagree' or 'not sure' in phases-1 and 2 which were conducted virtually; in the final phase-3, all the panel experts met in person and concluded the survey. RESULTS: Opinions on 41 statements related to prognostic factors/tools and their implications in planning adjuvant endocrine/chemotherapy were collected. All the statements were supported by the latest data from the clinical trials (prospective/retrospective). The statements with opinions of consensus less than 66% were disseminated in phase-2, and later in phase-3 with supporting literature. In phase-3, all the opinions from panelists were consolidated and guidelines were framed. CONCLUSIONS: This consensus guideline will assist oncologists of India, SAARC and LMIC countries in informed clinical decision-making on adjuvant treatment in early HR+/HER2/neu negative breast cancer patients.
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Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Estudos Prospectivos , Países em Desenvolvimento , Estudos Retrospectivos , Inquéritos e Questionários , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapêuticoRESUMO
BACKGROUND: This study evaluated outcomes among patients with advanced/metastatic non-small-cell lung cancer (NSCLC) treated at Asian centers participating in the global named-patient-use (NPU) program for afatinib. METHODS: Patients had progressed after initial benefit with erlotinib or gefitinib, and/or had an EGFR or HER2 mutation, had no other treatment options, and were ineligible for afatinib trials. The recommended starting dose of afatinib was 50 mg/day. Dose modifications were allowed, and afatinib was continued as long as deemed beneficial. Response and survival information was provided voluntarily. Safety reporting was mandatory. RESULTS: 2242 patients (26% aged ≥ 70 years, 96% with adenocarcinoma) received afatinib at centers in 10 Asian countries. Most were heavily pre-treated, including prior treatment with erlotinib or gefitinib. Of 1281 patients tested, 1240 had EGFR mutations (common: 1034/1101; uncommon: 117/1101). There were no new safety signals, the most common adverse events being rash and diarrhea. Objective response rate (ORR) was 24% overall (n = 431 with data available), 27% for patients with common EGFR mutations (n = 230) and 28% for those with uncommon mutations (n = 32); median time to treatment failure (TTF) in these groups was 7.6 months (n = 1550), 6.4 months (n = 692) and 8.4 months (n = 83), respectively. In patients with EGFR exon 20 insertions (n = 23) and HER2 mutations (n = 12), median TTF exceeded 12 months. CONCLUSIONS: Patient outcomes in this study were similar to those reported in the analysis of the global NPU. Afatinib achieved clinical benefits in patients with refractory NSCLC. ORR and TTF were similar between patients with tumors harboring uncommon and common EGFR mutations.
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Background & objectives: Diagnosis of myelodysplastic syndromes (MDS) is subjective in low-grade cases with <5 per cent blasts or <15 per cent ring sideroblasts. Flow cytometry (FCM) has been used to diagnose MDS; but, it still has only an adjunctive role. This study was conducted to evaluate the role of FCM to diagnose MDS and correlate the number of aberrancies with revised international prognostic scoring system (R-IPSS). Methods: This study included 44 consecutive clinically suspected cases of MDS with refractory cytopenia(s) and 10 controls. Patients were divided into two groups: (i) proven MDS cases (n=26), and (ii) suspected MDS (n=18). Ogata quantitative approach, pattern analysis and aberrant antigen expression were studied. Results: Ogata score ≥2 correctly diagnosed 80.7 per cent (21/26) while aberrant antigen and pattern analysis with flow score of ≥3 could diagnose 92.3 per cent (24/26) patients with proven MDS. Combination of both with flow score ≥3 could diagnose 100 per cent patients. Eight patients in suspected MDS group with persistent cytopenia on follow up were labelled as probable MDS. Ogata score ≥2 was present in 5 of 8 and pattern analysis score ≥3 was present in six probable MDS patients. Combination of both with flow score ≥3 was present in seven of eight patients. Spearman's correlation between Ogata score and R-IPSS, pattern analysis and R-IPSS and combination of both scores and R-IPSS showed significant positive correlation in proven MDS as well as when proven and probable MDS patients were combined. Interpretation & conclusions: Our results showed that combined Ogata approach and pattern analysis, demonstration of ≥3 aberrancies in >1 cell compartment could diagnose most MDS patients. Patients with high flow scores had high R-IPSS scores. Patient with flow score ≥3 and borderline cytomorphology should be observed closely for the development of MDS.
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Síndromes Mielodisplásicas , Citometria de Fluxo , Humanos , Imunofenotipagem , Índia/epidemiologia , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/epidemiologia , PrognósticoRESUMO
PURPOSE: Breast and/or ovarian cancers are among the most common cancers in women across the world. In the Indian population, the healthcare burden of breast and/or ovarian cancers has been steadily rising, thus stressing the need for early detection, surveillance, and disease management measures. However, the burden attributable to inherited mutations is not well characterized. METHODS: We sequenced 1010 unrelated patients and families from across India with an indication of breast and/or ovarian cancers, using the TruSight Cancer panel which includes 14 genes, strongly associated with risk of hereditary breast and/or ovarian cancers. Genetic variations were identified using the StrandNGS software and interpreted using the StrandOmics platform. RESULTS: We were able to detect mutations in 304 (30.1%) cases, of which, 56 mutations were novel. A majority (84.9%) of the mutations were detected in the BRCA1/2 genes as compared to non-BRCA genes (15.1%). When the cases were stratified on the basis of age at diagnosis and family history of cancer, the high rate of 75% of detection of hereditary variants was observed in patients whose age at diagnosis was below 40 years and had first-degree family member(s) affected by breast and/or ovarian cancers. Our findings indicate that in the Indian population, there is a high prevalence of mutations in the high-risk breast cancer genes: BRCA1, BRCA2, TP53, and PALB2. CONCLUSION: In India, socioeconomic inequality limiting access to treatment is a major factor towards increased cancer burden; therefore, incorporation of a cost-effective and comprehensive multi-gene test will be helpful in ensuring widespread implementation of genetic screening in the clinical practice for hereditary breast and/or ovarian cancers.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Mama/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Detecção Precoce de Câncer , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Índia/epidemiologia , Programas de Rastreamento , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologiaRESUMO
Colorectal cancer incidences are on a rise in India. In this study, we have analyzed the mutation frequencies of six potential biomarkers, their coexistence, association with clinicopathological characteristics, and tumor location in Indian colorectal cancer patients. Next-generation sequencing was performed to identify mutations in the six potential biomarker genes using formalin-fixed paraffin-embedded tissue blocks of 112 colorectal cancer patients. The mutation frequency observed in KRAS, BRAF, PIK3CA, NRAS, TP53, and APC was 35.7%, 7.1%, 16.1%, 6.3%, 39.3%, and 29.5%, respectively. The significant associations of mutations were KRAS with age less than 60 years (p = 0.041), PIK3CA with males (p = 0.032), tumor stage I-II (p = 0.013), lack of metastasis in lymph nodes (p = 0.040), NRAS with rectum (p = 0.002), and APC with T2 stage of tumor growth (p = 0.013). No single patient harbored mutations in these six genes or any five genes simultaneously. Significance was noted in coexistence of KRAS with APC (p = 0.024) and mutual exclusion of KRAS with BRAF (p = 0.029). PIK3CA exon 9 was observed to be more frequently associated with KRAS mutations than PIK3CA exon 20 (p = 0.072). NRAS mutations were mutually exclusive with BRAF and PIK3CA mutations. As per our knowledge, this is the first next-generation sequencing-based biomarker study in Indian colorectal cancer patients. Frequent coexistence of gene mutations in pairs and triplets suggests that synergistic effect of overlapping mutations might further trigger the disease. In addition, infrequent coexistence of multiple gene mutations hints toward different signaling pathways for colorectal cancer tumorigenesis.
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Neoplasias Colorretais/genética , Proteínas de Neoplasias/genética , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Classe I de Fosfatidilinositol 3-Quinases , Estudos de Coortes , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Índia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Adulto JovemRESUMO
BACKGROUND AIMS: A phase II clinical trial of an autologous dendritic cell (DC) formulation for the management of refractory solid malignant tumors was conducted across six sites in India with an objective to study safety and efficacy. METHODS: A total of 51 patients with refractory cancer (either sex) with life expectancy ≥3 months, Eastern Cooperative Oncology Group score ≤2, available tumor tissue and adequate organ and bone marrow function were recruited. Monocytes obtained by leukapheresis, differentiated into DCs by cytokines and primed with autologous tumor lysate (fresh tissue biopsy or paraffin block). On the 8th day, mature DCs were analyzed for expression of CD40, CD80, CD83, CD86, DC205 and DC209. The treatment regime consisted of six doses (intravenous) over 14 weeks with 2 post-treatment follow-up visits, 6 weeks apart. Safety was assessed at all visits and responses were evaluated on days 58, 100 and 184 or at end of the study. RESULTS: A total of 38 patients were evaluated for safety and efficacy. One adverse event classified as possibly related was an episode of rigors or chills with mild pyrexia during one infusion. Objective response rate by Response Evaluation Criteria In Solid Tumors was 28.9% (11/38) and immune-related response criteria was 42.1% (16/38); 90% confidence interval for objective response rate was (17.2, 43.3) and (28.5, 56.7) by Response Evaluation Criteria In Solid Tumors and immune-related response criteria, respectively. The median time to treatment progression was >9 weeks. Median overall survival was 397 days. An increase in the expression of interferon-γ was not significant. CONCLUSIONS: Therapy was safe. The responses, time to treatment progression and survival are encouraging for patients with aggressive refractory disease.
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Vacinas Anticâncer , Carcinoma/terapia , Neoplasias do Colo/terapia , Células Dendríticas/transplante , Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia/métodos , Neoplasias Ovarianas/terapia , Adulto , Idoso , Antígenos CD/metabolismo , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Carcinoma/imunologia , Carcinoma/mortalidade , Diferenciação Celular , Extratos Celulares/imunologia , Células Cultivadas , Neoplasias do Colo/imunologia , Neoplasias do Colo/mortalidade , Citocinas/imunologia , Células Dendríticas/imunologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , Recidiva , Análise de Sobrevida , Resultado do TratamentoRESUMO
Malignant melanoma is an aggressive, notorious tumor showing great variability in morphological and immunohistochemical expression, thus commonly leading to an erroneous diagnosis. Within the melanoma group, amelanotic melanoma, with its wide clinical presentations, lack of pigmentation, and varied histological appearances, has taken on a new persona as a master masquerader. Use of immunohistochemistry in the diagnosis of malignant tumors, including melanoma, is primordial and indispensable. However, the problem gets compounded in scenario of aberrant antigenic expression. The present case posed multiple diagnostic challenges in form of atypical clinical presentation, variant morphology, as well as aberrant antigenic expression. Here, we present the case of a 72-year-old male who, upon his initial presentation, was thought to be sarcomatoid anaplastic plasmacytoma, but 5 months later another biopsy from a different site revealed the actual diagnosis of amelanotic melanoma.
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Purvish M. ParikhCancer-associated anemia (CAA) remains a major unmet need that compromises overall survival (OS) and quality of life (QoL). Currently, available guidelines do not take into consideration the unique challenges in low- and middle-income countries (LMIC). Our CAA patients have to battle preexisting impaired nutritional status, depleted body iron stores, financial limitations, and difficulty in having easily accessible affordable healthcare. Hence, we fulfilled the need of guidelines for LMIC. A group of subject experts were put together, given background literature, met in a face-to-face discussion, voted using Delphi process, and finally agreed on the contents of this guideline document. As many as 50% of cancer patients will have significant anemia (hemoglobin < 10 g/dL) at initial diagnosis. It is most commonly seen with gastrointestinal malignancies, head and neck cancers, and acute leukemias. The hemoglobin falls further after initiation of cancer directed therapy, due to chemotherapy itself or heightened nutritional deficiency. Its evaluation should include tests for complete blood count, red blood cell morphology, reticulocyte count, Coombs test, and levels of vitamin B12 and folic acid. Iron status should be monitored using test to measure serum iron, total iron binding capacity, transferring saturation, and serum ferritin levels. A minimum of 50% of cancer patients with anemia require iron supplements. The preferred mode of therapy is with intravenous (IV) iron using ferric carboxymaltose (FCM). Most patients respond satisfactorily to single dose of 1000 mg. It is also safe and does not require use of a test dose. Significant anemia is found in at least half of all cancer patients in India, South Asian Association for Regional Cooperation region, and other LMIC countries. Its awareness among healthcare professionals will prevent it from remaining undiagnosed (in up to 70% of all cancer patients) and adversely affecting OS and QoL. The benefits of treating them with IV iron therapy are quick replenishment of iron stores, hemoglobin returning to normal, better QoL, and avoiding risk of infections/reactions with blood transfusions. Many publications have proven the value of single-dose FCM in such clinical situations. CAA has been proven to be an independent prognostic factor that adversely affects both QoL and OS in cancer patients. Use of FCM as single IV dose of 1000 mg is safe and effective in the majority of patients with CAA.
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Epithelial ovarian cancer (EOC) is the most lethal gynaecological cancer among women worldwide, with the 5-year survival rate ranging between 30 and 40%. Due to the asymptomatic nature of the condition, it is more likely to be diagnosed at an advanced stage, requiring an aggressive therapeutic approach. Cytoreductive surgery (CRS) along with systemic chemotherapy with paclitaxel and carboplatin has been the mainstay of the treatment in the frontline management of EOC. In recent years, neo-adjuvant chemotherapy, followed by interval CRS has become an important strategy for the management of advanced EOC. Due to the high rate of recurrence, the oncology community has begun to shift its focus to molecular-targeted agents and maintenance therapy in the frontline settings. The rationale for maintenance therapy is to delay the progression or relapse of the disease, as long as possible after first-line treatment, irrespective of the amount of residual disease. Tumours with homologous recombination deficiency (HRD) including BReast CAncer gene (BRCA) mutations are found to be sensitive to polyadenosine diphosphate-ribose polymerase (PARP) inhibitors and understanding of HRD status has become important in the frontline setting. PARP inhibitors are reported to provide a significant improvement in progression-free survival and have an acceptable safety profile. PARP inhibitors have also been found to act regardless of BRCA status. Recently, PARP inhibitors as maintenance therapy in the frontline settings showed encouraging results in EOC; however, the results from further trials and survival data from ongoing trials are awaited for understanding the role of this pathway in treatment of EOC. This review discusses an overview of maintenance strategies in newly diagnosed EOC along with considerations for maintenance therapy in EOC with a focus on PARP inhibitors.
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Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Carboplatina/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Feminino , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêuticoRESUMO
PURPOSE: There are deficient data on prevalence of germline mutations in breast cancer susceptibility genes 1 and 2 (BRCA1/BRCA2) in Indian patients with ovarian cancer who are not selected by clinical features. METHODS: This prospective, cross-sectional, noninterventional study in nine Indian centers included patients with newly diagnosed or relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer. The primary objective was to assess the prevalence of BRCA1/BRCA2 mutations, and the secondary objective was to correlate BRCA1/BRCA2 status with clinicopathologic characteristics. Mutation testing was performed by a standard next-generation sequencing assay. RESULTS: Between March 2018 and December 2018, 239 patients with a median age of 53.0 (range, 23.0-86.0 years) years were included, of whom 203 (84.9%) had newly diagnosed disease, 36 (15.1%) had family history of ovarian or breast cancer, and 159 (66.5%) had serous subtype of epithelial ovarian cancer. Germline pathogenic or likely pathogenic mutations in BRCA1 and BRCA2 were detected in 37 (15.5%; 95% CI, 11.1 to 20.7) and 14 (5.9%; 95% CI, 3.2 to 9.6) patients, respectively, whereas variants of uncertain significance in these genes were seen in four (1.7%; 95% CI, 0.5 to 4.2) and six (2.5%; 95% CI, 0.9 to 5.4) patients, respectively. The prevalence of pathogenic or likely pathogenic BRCA mutations in patients with serous versus nonserous tumors, with versus without relevant family history, and ≤ 50 years versus > 50 years, were 40 of 159 (25.2%; 95% CI, 18.6 to 32.6) versus 11 of 80 (13.8%; 95% CI, 7.1 to 23.3; P = .0636), 20 of 36 (55.6%; 95% CI, 38.1 to 72.1) versus 41 of 203 (20.2%; 95% CI, 14.9 to 26.4; P < .0001), and 20 of 90 (22.2%; 95% CI, 14.1 to 32.2) versus 31 of 149 (20.8%; 95% CI, 14.6 to 28.2; P = .7956), respectively. CONCLUSION: There is a high prevalence of pathogenic or likely pathogenic germline BRCA mutations in Indian patients with ovarian cancer.
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Neoplasias das Tubas Uterinas , Neoplasias Ovarianas , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/genética , Proteína BRCA2/genética , Estudos Transversais , Neoplasias das Tubas Uterinas/epidemiologia , Neoplasias das Tubas Uterinas/genética , Feminino , Humanos , Índia/epidemiologia , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Prevalência , Estudos Prospectivos , Adulto JovemRESUMO
Immuno-oncology (IO) approaches such as cytokine therapy, immune-checkpoint blockers (ICBs), cancer vaccines, and cell-based therapies have revolutionized cancer treatment. ICBs provide better response-to-toxicity profile among various IO approaches; however, they can cause dysregulation of host immune system resulting in immune-mediated adverse events (imAEs). The skin and gastrointestinal system are most commonly affected. Although reversible, imAEs may cause life-threatening conditions if untreated. Risk assessment and appropriate patient selection before treatment initiation may prevent most imAEs. Key factors in effectively managing imAEs include baseline clinical evaluation, appropriate diagnostic tests, severity grading, timely decision on discontinuation or reintroduction of ICB treatment, and intervention with immunosuppressive and/or immunomodulatory agents. Patient and healthcare provider awareness is critical for identifying and managing lower grade imAEs. Immediate reporting is important for successfully managing and preventing or worsening of imAEs. Pretreatment sensitization of patients should address barriers to reporting such as fear of ICB discontinuation, ignorance of symptoms, financial constraints, and self-medication. Physicians should rely on clinical presentation and diagnostic work-up (including imaging) to accurately identify, characterize, and differentiate imAEs from metastasis. Treatment-related new symptoms should be dealt with a high level of suspicion. Corticosteroids are initiated if symptoms do not resolve within a week from onset and tapered over a month to avoid rebound of symptoms. ICB therapy should be permanently discontinued in most cases of grade 3-4 imAEs. A multidisciplinary approach involving oncologists, oncosurgeons, primary care physicians, and nurses is necessary in effectively managing imAEs and facilitating better clinical outcomes.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Imunoterapia/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Humanos , Imunoterapia/métodosRESUMO
BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most common type of mesenchymal neoplasm of gastrointestinal tract. The incidence of GIST in India is not known and its treatment strategy in our country is largely derived from studies in other global populations. Some of the most important features of this type of cancer include its size, site of origin, mitotic index, histology and Immunohistochemistry. In this report we have studied these parameters in the Indian GIST patients presenting at our center. Additionally, we have also studied the mutational spectrum of these GISTs by next generation sequencing. METHODS: Thirty one Indian patients of GIST were enrolled in this study and information regarding age, gender, tumor location and size was collected from their records. Immunohistochemistry studies were performed by the pathologist. Mutational analysis of these samples was performed by next generation sequencing. RESULTS AND DISCUSSION: The most common site of GIST occurrence in our study was stomach. The tumor size for all 31 patients ranged between 0.6 cms to 20 cms. A spindle-cell pattern was present in 24 out of 31 of the cases. 29 out of 31 subjects were positive for CD117 expression. C-KIT was the most highly mutated gene indentified in our patients. Apart from these findings we observed many similarities as well as dissimilarities between the results of our study and literature published previously. CONCLUSIONS: The dissimilarities in the results of our study and published literature could be attributed to the genetic or ethnic differences that exist between the Indian population and other global populations. The results of our study warrant a need to conduct studies of GIST in a much larger population of India. Such large scale studies may also help in better treatment and/or prevention of GIST in developing countries like India.
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Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Adulto , Idoso , Análise Mutacional de DNA , Feminino , Seguimentos , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/epidemiologia , Tumores do Estroma Gastrointestinal/genética , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Epithelial ovarian cancer (EOC) is usually diagnosed late at an advanced stage. Though EOC initially responds to treatment, the recurrence rate is pretty high. The efficacy of different targeted therapies reduces with each recurrence. Hence there is need of effective maintenance therapy in recurrent EOC. Recently, polyADP-ribose polymerase (PARP) inhibitors (PARPi) have been approved both for initial treatment of EOC and as its maintenance treatment. PARPi have also been found to act regardless of BRCA status or homologous recombination (HR) deficiency. Several trials testing PARPi early in maintenance therapy are in progress and their results will shed light on the optimal timing of maintenance therapy that gives the most benefit with least toxicity. Right patient selection for maintenance treatment is also a challenge. Hence, though PARPi are emerging as a promising maintenance treatment in recurrent EOC with prolongation of progression free survival (PFS), results from further trials and overall survival (OS) data from current trials are awaited to fulfill the gaps in understanding the role of this pathway in treatment of EOC. This review discusses the current therapies for EOC, challenges in the treatment of recurrent EOC, recent developments and trials in recurrent EOC maintenance with special focus on PARPi and future perspectives.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Carcinoma Epitelial do Ovário/etiologia , Carcinoma Epitelial do Ovário/mortalidade , Feminino , Humanos , Quimioterapia de Manutenção , Terapia de Alvo Molecular , Mutação , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/mortalidade , Recidiva , Retratamento , Resultado do TratamentoRESUMO
BACKGROUND: Outcome in multiple myeloma (MM) has improved substantially over recent years as a result of the availability of multiple novel agents with acceptable safety profile. STUDY DESIGN: Prospective observational study at a tertiary care institute. METHODS: Twenty-five newly diagnosed patients of MM were treated with bortezomib and dexamethasone induction with monitoring for response and safety, followed by peripheral blood autologous stem cell transplant (PBASCT) in eligible patients or maintenance. RESULTS: Out of 25 patients, 32% attained complete response (CR), 56% very good partial response (VGPR), 4% PR, and 8% showed no response. The overall response rate was 92%. In our study, 56% of patients showed hematological side effects, out of which thrombocytopenia was seen in 32%, anemia in 16%, and leukopenia in 8%. Six patients developed bortezomib-induced peripheral neuropathy, out of which four had grade 1 (66.66%), one had grade 2 (16.66%), and 1 (16.66%) had grade 3 toxicity. Sixteen patients were eligible for PBASCT, out of which eight patients received this therapy while as remaining eight patients opted for two more cycles of induction therapy followed by maintenance. After completing 18 months of maintenance, all the eight patients who underwent PBASCT were in CR. Out of the 15 patients who did not receive PBASCT five attained CR, eight VGPR while as two patients relapsed. CONCLUSION: Bortezomib plus dexamethasone is highly effective and well-tolerated regimen for frontline treatment of MM with a higher quality of response in an advanced stage and renal failure patients.
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BACKGROUND: Incidence of Chronic Myeloid Leukemia (CML) is continuously increasing and expected to reach 100,000 patients every year by 2030. Though the discovery of Imatinib Mesylate (IM) has brought a paradigm shift in CML treatment, 20% patients show resistance to this tyrosine kinase inhibiter (TKI). Therefore, it is important to identify markers, which can predict the occurrence and prognosis of CML. Clinical Exome Sequencing, panel of more than 4800 genes, was performed in CML patients to identify prognostic and susceptibility markers in CML. METHODS: Enrolled CML patients (n=18) were segregated as IM responders (n=10) and IM failures (n=8) as per European Leukemia Net (ELN), 2013 guidelines. Healthy controls (n=5) were also enrolled. DNA from blood of subjects was subjected to Next Generation Sequencing. Rare mutations present in one patient group and absent in another group were considered as prognostic markers, whereas mutations present in more than 50% patients were considered as susceptibility markers. RESULT: Mutations in genes associated with cancer related functions were found in different patient groups. Four variants: rs116201358, rs4014596, rs52897880 and rs2274329 in C8A, UNC93B1, APOH and CA6 genes, respectively, were present in IM responders; whereas rs4945 in MFGE8 was present in IM failures. Mutations in HLA-DRB1 (rs17878951), HLA-DRB5 (rs137863146), RPHN2 (rs193179333), CYP2F1 (rs116958555), KCNJ12 (rs76684759) and FUT3 (rs151218854) were present as susceptibility markers. CONCLUSION: The potential genetic markers discovered in this study can help in predicting response to IM as frontline therapy. Susceptibility markers may also be used as panel for individuals prone to have CML.
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Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Genes Neoplásicos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Antígenos de Superfície/genética , Anidrases Carbônicas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Proteínas do Leite/genética , PrognósticoRESUMO
Background: Chronic myeloid leukemia (CML) is a hematological disorder caused by fusion of BCR and ABL genes. BCR-ABL dependent and independent pathways play equally important role in CML. TGFß-Smad pathway, an important BCR -ABL independent pathway, has scarce data in CML. Present study investigate the association between TGFß-Smad pathway and CML. Materials and Methods: Sixty-four CML patients and age matched healthy controls (n=63) were enrolled in this study. Patients were segregated into responder and resistant groups depending on their response to Imatinib mesylate (IM). TGFß1 serum levels were evaluated by ELISA and transcript levels of TGFß1 receptors, SMAD4 and SMAD7 were evaluated by Real-Time PCR. Sequencing of exons and exon-intron boundaries of study genes was performed using Next Generation Sequencing (NGS) in 20 CML patients. Statistical analysis was performed using SPSS version 16.0. Results:TGFß1 serum levels were significantly elevated (p = 0.02) and TGFßR2 and SMAD4 were significantly down-regulated (p = 0.012 and p = 0.043 respectively) in the patients. c.69A>G in TGFß1, c.1024+24G>A in TGFßR1 and g.46474746C>T in SMAD7 were the most important genetic variants observed with their presence in 10/20, 8/20 and 7/20 patients respectively. In addition, TGFßR1 transcript levels were reduced in CML patients with c.69A>G mutation. None of the genes differed significantly in terms of expression or genetic variants between responder and resistant patient groups. Conclusion: Our findings demonstrate the role of differential expression and genetic variants of TGFß-Smad pathway in CML. Decreased TGFßR2 and SMAD4 levels observed in the present study may be responsible for reduced tumor suppressive effects of this pathway in CML.
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BACKGROUND: We conducted a survey of 111 medical oncologists across India to understand the current pattern of epidermal growth factor receptor (EGFR) mutation testing at their respective centers. METHODS: Medical oncologists from 111 institutes across India were interviewed face to face using a structured questionnaire. They were divided into two groups - Group 1 with in-house EGFR testing and Group 2 who send samples to central/commercial laboratories outside their institutions. Answers of the two groups were analyzed to see the prevailing patterns of EGFR testing and differences between the two groups if any. RESULTS: Ninety-five percent (105/111) of medical oncologists recommended testing for EGFR mutations in patients with adenocarcinoma histology and 40% (44/111) recommended EGFR testing in squamous cell histology. The average time duration to get EGFR test results was 10 days in Group 1 centers versus 18 days in Group 2 centers. Ninety-six percent (106/111) of the medical oncologists from Group 1 centers requested for factoring additional sample for biomarker testing compared to 69% (77/111) of the oncologists from Group 2 centers. Sixty-nine percent (77/111) of medical oncologists in Group 1 centers would prefer to wait for the test results before initiating treatment compared to 46% (51/111) in Group 2. EGFR tyrosine-kinase inhibitors were used in only approximately 60% of patients with diagnosed EGFR mutation in the first line. For patients in whom chemotherapy was initiated while waiting for test results, 50% (56/111) of medical oncologists would prefer to complete 4-6 cycles before switching to targeted therapy. At the time of progression, rebiopsy was possible in approximately 25% of the patients. CONCLUSIONS: Turnaround time for molecular testing should improve so that eligible patients can benefit from targeted therapies in the first line. There is a need to increase the awareness among pulmonologists, oncologists, and interventional radiologists regarding the importance of adequate samples required for molecular tests.
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Hepatitis B Virus (HBV) reactivation in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids is emerging to be an important cause of morbidity and mortality in patients with current or prior exposure to HBV infection. These patients suffer a dual onslaught of illness: one from the primary disease for which they are receiving the culprit drug that led to HBV reactivation, and the other from HBV reactivation itself. The HBV reactivation not only leads to a compromised liver function, which may culminate into hepatic failure; it also adversely impacts the treatment outcome of the primary illness. Hence, identification of patients at risk of reactivation before starting these drugs, and starting treatment aimed at prevention of HBV reactivation is the best strategy of managing these patients. There are no Indian guidelines on management of HBV infection in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids for the treatment of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions, or solid-organ or bone marrow transplantation. The Indian National Association for Study of the Liver (INASL) had set up a taskforce on HBV in 2016, with a mandate to develop consensus guidelines for management of various aspects of HBV infection, relevant to India. In 2017 the taskforce had published the first INASL guidelines on management of HBV infection in India. In the present guidelines, which are in continuation with the previous guidelines, the issues on management of HBV infection in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids are addressed.
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Mutation frequencies of common genetic alterations in colorectal cancer have been in the spotlight for many years. This study highlights few rare somatic mutations, which possess the attributes of a potential CRC biomarker yet are often neglected. Next-generation sequencing was performed over 112 tumor samples to detect genetic alterations in 31 rare genes in colorectal cancer. Mutations were detected in 26/31 (83.9 %) uncommon genes, which together contributed toward 149 gene mutations in 67/112 (59.8 %) colorectal cancer patients. The most frequent mutations include KDR (19.6 %), PTEN (17 %), FBXW7 (10.7 %), SMAD4 (10.7 %), VHL (8 %), KIT (8 %), MET (7.1 %), ATM (6.3 %), CTNNB1 (4.5 %) and CDKN2A (4.5 %). RB1, ERBB4 and ERBB2 mutations were persistent in 3.6 % patients. GNAS, FGFR2 and FGFR3 mutations were persistent in 1.8 % patients. Ten genes (EGFR, NOTCH1, SMARCB1, ABL1, STK11, SMO, RET, GNAQ, CSF1R and FLT3) were found mutated in 0.9 % patients. Lastly, no mutations were observed in AKT, HRAS, MAP2K1, PDGFR and JAK2. Significant associations were observed between VHL with tumor site, ERBB4 and SMARCB1 with tumor invasion, CTNNB1 with lack of lymph node involvement and CTNNB1, FGFR2 and FGFR3 with TNM stage. Significantly coinciding mutation pairs include PTEN and SMAD4, PTEN and KDR, EGFR and RET, EGFR and RB1, FBXW7 and CTNNB1, KDR and FGFR2, FLT3 and CTNNB1, RET and RB1, ATM and SMAD4, ATM and CDKN2A, ERBB4 and SMARCB1. This study elucidates few potential colorectal cancer biomarkers, specifically KDR, PTEN, FBXW7 and SMAD4, which are found mutated in more than 10 % patients.
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Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Mutação , Neoplasias Colorretais/metabolismo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/genéticaRESUMO
The present report illustrates a case of a 37-year-old Indian male patient diagnosed with adenocarcinoma of the sigmoid colon who underwent an anterior resection with total mesorectal excision surgery. He was administered adjuvant chemotherapy with 10 cycles of a FOLFOX-4 (folinic acid, fluorouracil and oxaliplatin) regimen but developed relapse. He was then put on a FOLFIRI (folinic acid, fluorouracil and irinotecan)-aflibercept (Zaltrap) regimen and received 12 cycles during the next 6 months. During the treatment period, a reduction in ascites along with a decline in serum carcinoembryonic antigen (CEA) level was observed, though the tumor size was unchanged. After completion of 12 cycles, the patient was asymptomatic but showed signs of progression in the form of increased CEA level. The FOLFIRI-aflibercept therapy was discontinued, and the patient was given supportive treatment, but he eventually died after another 6 months. The FOLFIRI-aflibercept treatment provided a progression-free survival of 6 months and an overall survival of 1 year to this patient, which corroborates the findings of the VELOUR trial.