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Shruti Kate,1 Anuradha Chougule,2 Amit Joshi,1 Vanita Noronha,1 Vijay Patil,1 Rohit Dusane,3 Leena Solanki,1 Priyanka Tiwrekar,2 Vaishakhi Trivedi,1 Kumar Prabhash1 1Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India; 2Department of Molecular Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India; 3Department of Biostatistics, Clinical Research Secretariat, Tata Memorial Hospital, Mumbai, Maharashtra, India Background: The significance of uncommon EGFR mutations in newly diagnosed advanced non-small-cell lung cancer (NSCLC) patients is incompletely known. We aimed to analyze the demographic profile, outcome, and treatment attributes of these patients.Patients and methods: We retrospectively surveyed 5,738 advanced NSCLC patients who underwent EGFR testing in our center from 2013 to 2017 by in-house primer probes on real time PCR platform. Descriptive data were accumulated from electronic medical records. Survival plot was calculated using Kaplan–Meier method and compared between groups using log-rank test.Results: Out of 1,260 EGFR mutation-positive patients, 83 (6.58%) had uncommon mutations in isolation or in various combinations. Uncommon mutations were more frequent in men, never-smokers, and adenocarcinomas. Overall, exon 18 G719X, exon 20 insertion, exon 20 T790M, exon 20 S768I, and exon 21 (L858R/L861Q) were present in 9.6%, 19.3%, 12%, 3.6%, and 3.6% patients, respectively. Dual mutation positivity was found in 50.6% patients. On classifying patients as per tyrosine kinase inhibitor (TKI) sensitivity, it was found that majority of the patients had a combination TKI sensitive and insensitive mutations. The median duration of follow-up was 13 months. Five patients were lost to follow-up. Median progression-free survival on first line therapy was 6.7 months (95% CI: 4.8–8.5). Median overall survival (OS) of patients who received TKI during the course of their disease was 20.2 months (95% CI: 11.4–28.9). Median overall survival (mOS) of the entire cohort was 15.8 months (95% CI: 10.1–21.5). Among all uncommon mutations, patients with dual mutations did better, with an mOS time of 22.6 months (95% CI: 8.2–37.0, P=0.005). It was observed that TKI sensitive/TKI insensitive dual mutations had a superior OS of 28.2 months (95% CI: 15.2–41.2, P=0.039) as compared to TKI sensitive and TKI insensitive EGFR mutations.Conclusion: Uncommon EGFR mutations constitute a heterogeneous group, hence, it is imperative to understand each subgroup more to define optimal treatment. Keywords: uncommon EGFR mutations, advanced NSCLC, tyrosine kinase inhibitors, complex EGFR mutations, dual EGFR mutations

Vidya H Veldore,1,* Anuradha Choughule,2,* Tejaswi Routhu,1 Nitin Mandloi,1 Vanita Noronha,2 Amit Joshi,2 Amit Dutt,3 Ravi Gupta,1 Ramprasad Vedam,1 Kumar Prabhash2 1MedGenome Labs Private Ltd,, Bangalore, India; 2Tata Memorial Centre, Parel, Mumbai, India; 3The Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Center, Kharghar, Navi Mumbai, Maharashtra, India *These authors contributed equally to this work Abstract: Plasma cell-free tumor DNA, or circulating tumor DNA (ctDNA), from liquid biopsy is a potential source of tumor genetic material, in the absence of tissue biopsy, forEGFRtesting. Our validation study reiterates the clinical utility of ctDNA next generation sequencing (NGS) for EGFR mutation testing in non-small cell lung cancer (NSCLC). A total of 163 NSCLC cases were included in the validation, of which 132 patients had paired tissue biopsy and ctDNA. We chose to validate ctDNA using deep sequencing with custom designed bioinformatics methods that could detect somatic mutations at allele frequencies as low as 0.01%. Benchmarking allele specific real time PCR as one of the standard methods for tissue-based EGFR mutation testing, the ctDNA NGS test was validated on all the plasma derived cell-free DNA samples. We observed a high concordance (96.96%) between tissue biopsy and ctDNA for oncogenic driver mutations in Exon 19 and Exon 21 of the EGFR gene. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of the assay were 91.1%, 100% 100%, 95.6%, and 97%, respectively. A false negative rate of 3% was observed. A subset of mutations was also verified on droplet digital PCR. Sixteen percent EGFR mutation positivity was observed in patients where only liquid biopsy was available, thus creating options for targeted therapy. This is the first and largest study from India, demonstrating successful validation of circulating cell-free DNA as a clinically useful material for molecular testing in NSCLC. Keywords: liquid biopsy, NSCLC, EGFR, ctDNA, NGS

Amit Joshi,1 Saurabh Zanwar,1 Vanita Noronha,1 Vijay M Patil,1 Anuradha Chougule,2 Rajiv Kumar,3 Amit Janu,4 Abhishek Mahajan,4 Akhil Kapoor,1 Kumar Prabhash1 1Department of Medical Oncology, Tata Memorial Hospital, 2Molecular Laboratory, Department of Medical Oncology, 3Department of Pathology,4Department of Radiology, Tata Memorial Hospital, Mumbai, Maharashtra, India Background: EGFR tyrosine kinase inhibitors (TKIs) have greatly improved the outcomes of EGFR mutation-positive adenocarcinomas of the lung. In contrast, the significance of EGFR mutation in metastatic squamous cell carcinoma (SCC) of the lung has been debated.Methods: All patients with metastatic SCC who underwent EGFR mutation testing at our center from 2010 to 2015 were included for analysis. EGFRkinase domain mutations were tested using Taqman-based real-time polymerase chain reaction (PCR). Response assessment was done using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Kaplan–Meier method was used for calculating progression-free survival (PFS) and overall survival (OS).Results: EGFR mutation was detected in 29 out of 639 patients with SCC. Furthermore,19 out of the 29 patients received TKIs at some point during their treatment. TKI therapy led to a partial response in 5 out of 19 patients and stable disease in 4 out of 19 patients. The median PFS of patients treated with TKIs was 5.0months. The median OS of the whole EGFR-positive SCC cohort was 6.6months. On univariate analysis, patients having received TKI therapy was the only factor associated with a significantly better OS of 13.48months versus 2.58months (P=0.000). On multivariate analysis, patients receiving TKI therapy, Eastern Cooperative Oncology Group–Performance Scale (ECOG-PS) score

In locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN), concurrent chemoradiotherapy is an integral part of multimodality management both in the adjuvant and in the definitive settings. Although de-intensification strategies have been propelled to the forefront of clinical research in human papillomavirus (HPV) positive oropharyngeal cancer, three cycles of 100 mg/m 2 cisplatin given every 3 weeks concurrently with conventionally fractionated external beam radiotherapy represent a cost-effective and globally accessible treatment option for the majority of LA-SCCHN cases. Based on four large randomized trials, this regimen has become the non-surgical standard of care for cisplatin-eligible patients. Nevertheless, the outcomes in terms of efficacy, toxicity, and compliance have been rather disappointing. Therefore, there is an unmet need to find a better alternative. With limited support from randomized trials, weekly low-dose cisplatin regimens have replaced the standard high-dose schedule at some institutions. Four prospective trials exploring radiotherapy with and without weekly low-dose cisplatin have been published. Two of them were conducted in the 1980s, one of which had a negative outcome, the third study provided insufficient information on toxicity, and the fourth trial had to be prematurely terminated due to poor accrual. Moreover, the findings of two phase III trials comparing the two concurrent cisplatin regimens favored the high-dose protocol. We performed a composite meta-analysis of 59 prospective trials enrolling a total of 5,582 patients. The primary endpoint was overall survival. Reflecting different radiotherapy fractionation schemes and treatment intents, three meta-analyses were carried out, one for postoperative conventional chemoradiotherapy, one for definitive conventional chemoradiotherapy, and one for definitive altered fractionation chemoradiotherapy. In the former two settings, both high- and low-dose regimens yielded similar survival outcomes, thus, the primary objective was not met. When given concurrently with altered fractionation radiotherapy, patients treated with high-dose cisplatin had significantly longer overall survival than those who received low-dose cisplatin. In this article we provide a synthetic view of the results, discuss the issue of cumulative dose, compare two vs. three cycles of high-dose cisplatin, and present our three-step recommendations for use of the current standard of care, high-dose cisplatin, in clinical practice.

Made available in DSpace on 2018-08-01T23:46:15Z (GMT). No. of bitstreams: 1 tese_11064_Dissertação Final para Banca20170627-170515.pdf: 1700741 bytes, checksum: be8f93658c0f612b10654e4fbe66b877 (MD5) Previous issue date: 2017-06-22 Seria possível sintetizar a crítica marxiana à religião na famosa assertiva em que nosso autor relaciona religião ao ópio? Grande parte dos defensores, assim como os acusadores, diria que sim. Para investigar os fundamentos teóricos e filosóficos desta leitura hegemônica, precisaremos retornar a Hegel, pois para Marx a religião é o que Hegel entendia como tal. Isso é, a religião verdadeira alicerceia ético-politicamente o Estado verdadeiro. Este Estado divinizado em Hegel é o que é combatido por Marx, primordialmente a partir de Feuerbach. Em seguida, apresentaremos a crítica à religião no original pensamento de Marx a partir de sua bibliografia primária, suas elaborações, continuidades e descontinuidades ao longo de sua trajetória intelectual. Pretendemos considerar os diálogos, aproximações, afastamentos e superações que se dão em relação a Hegel e Feuerbach, as duas maiores fontes do pensamento marxiano no que diz respeito ao fenômeno religioso. Por fim, adentraremos detidamente na teoria do fetichismo em Marx, apresentando a leitura enquanto Santíssima Trindade de Mammon (mercadoria, dinheiro e capital), proposta de inversão dialética a partir da categoria Santíssima Trindade em Hegel. A crítica à religião dá um passo fundamental e se torna momento negativo para a teoria do fetichismo, surge algo epistemologicamente e ontologicamente novo. O fetiche é a categoria central para se compreender o capitalismo como religião, é a mediação entre a vida real e o reflexo religioso que ocorre pelo valor (nas três formas funcionais, mercadoria, dinheiro e capital), sujeito das relações sociais. Ainda, faremos uma crítica à Marx por não ter aplicado a sua dialética universal-particular na religião, tal como fez por exemplo com a filosofia e a política, permanecendo ainda tributário do pensamento de identidade hegeliano, o que significa um grave problema lógico-metodológico interno ao pensamento de Marx. Mesmo que consiga captar o caráter dialético da religião protesto e legitimação, ao mesmo tempo , acaba abandonando sua coerência lógica de unidade dialética entre teoria e práxis, não dá o devido relevo ao potencial utópico da religião e a possibilidade concreta de existência de uma religião antifetichista.

Vikram Gota,1 Krunal Kavathiya,1 Kartik Doshi,1 Murari Gurjar,1 Solai E Damodaran,1 Vanita Noronha,2 Amit Joshi,2 Kumar Prabhash2 1Department of Clinical Pharmacology, Advanced Centre for Treatment Research and Education in Cancer, 2Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India Background: Pemetrexed-platinum doublet therapy is a standard treatment for stage IIIb/IV nonsquamous non small cell lung cancer (NSCLC). While the regimen is associated with several grade ≥3 toxicities, hyponatremia is not a commonly reported adverse effect. Here we report an unusually high incidence of grade ≥3 hyponatremia in Indian patients receiving pemetrexed-platinum doublet, and the pharmacological basis for this phenomenon. Methods: Forty-six patients with advanced NSCLC were enrolled for a bioequivalence study of two pemetrexed formulations. All patients received the pemetrexed-platinum doublet for six cycles followed by single-agent pemetrexed maintenance until progression. Pharmacokinetic blood samples were collected at predefined time points during the first cycle and the concentration-time profile of pemetrexed was investigated by noncompartmental analysis. Hyponatremic episodes were investigated with serum electrolytes, serum osmolality, urinary sodium, and urine osmolality. Results: Sixteen of 46 patients (35%) had at least one episode of grade ≥3 hyponatremia. Twenty-four episodes of grade ≥3 hyponatremia were observed in 200 cycles of doublet chemotherapy. Plasma exposure to pemetrexed was significantly higher in patients with high-grade hyponatremia than in those with low-grade or no hyponatremia (P=0.063 and P=0.001, respectively). Pemetrexed clearance in high-grade hyponatremia was quite low compared with normal and low-grade hyponatremia (P=0.001 and P=0.055, respectively). Median pemetrexed exposure in this cohort was much higher than that reported in the literature from Western studies. Conclusion: Higher exposure to pemetrexed is associated with grade ≥3 hyponatremia. The pharmacogenetic basis for higher exposure to pemetrexed in Indian patients needs further investigation. Keywords: non small cell lung carcinoma, platinum compounds, pharmacokinetics, pharmacogenetics

Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil / /Universidade do Estado do Par?. Bel?m, PA. Brasil. Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Hospital Ofir Loiola. Bel?m, PA, Brasil. Hospital Ofir Loiola. Bel?m, PA, Brasil. Hospital Ofir Loiola. Bel?m, PA, Brasil. Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Embora a associa??o entre Papilomav?rus humano (HPV) e les?es malignas em c?rvice uterina esteja bem estabelecida, acredita-se que v?rios outros fatores possam estar implicados na g?nese do processo. Objetivou-se, com este estudo, verificar a preval?ncia de alguns desses fatores epidemiol?gicos em mulheres atendidas no Instituto Ofir Loiola, em Bel?m, Par?, no per?odo de mar?o de 1992 a maio de 1996. As pacientes foram submetidas ? bi?psia de colo uterino e, conforme diagn?stico histopatol?gico, reunidas em 3 grupos para melhor an?lise epidemiol?gica. No grupo A (155/228) reuniram-se aquelas com adenocarcinoma ou com carcinoma epiderm?ide invasor; no grupo B (54/228) as com neoplasia intra-epitelial grau II ou grau 111 (NIC II ou NIC 111) e no grupo C (19/228) as com cervicite cr?nica. A grande maioria das mulheres dos grupos A (41,1 por cento) e B (35,4 por cento) admitiu inicia??o sexual precoce. Esse percentual foi de 15,8 por cento nas pertencentes ao grupamento C. Por outro lado, a grande maioria das mulheres, nos tr?s grupos estudados, referiu de 1 a 3 parceiros, n?o caracterizando comportamento sexual prom?scuo. 69, 3 por cento, 54,9 por cento e 68,4 por cento das pacientes dos grupos A, B e C respectivamente referiram 6 ou mais gesta??es. Os anticoncepcionais hormonais foram utilizados por 20,8 por cento das pacientes do grupo A, 41,0 por cento das do grupo B e 66,7 por cento daquelas do grupo C. A pr?tica do tabagismo foi referida por 56,7 por cento, 48,1 por cento e 63,2 por cento das mulheres inclu?das nos grupamentos A, B e C, respectivamente

Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Sem Afilia??o. Sem Afilia??o. Sem Afilia??o. Sem Afilia??o. Sem Afilia??o. Sem Afilia??o. Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Estudou-se a preval?ncia do papilomav?rus humano (HPV) em 228 mulheres portadoras de les?es em c?rvice uterina, atendidas no Instituto Ofir Loiola, em Bel?m, Par?, no per?odo de mar?o de 1992 a maio de 1996. As pacientes foram submetidas ? bi?psia de colo uterino, sendo o material encaminhado para histopatologia e pesquisa de HPV por PCR e hibridiza??o por dot-blot. Distribu?ram-se as participantes em tr?s grupos, conforme e diagn?stico histopatol?gico. O grupo A constituiu-se de 155 mulheres com carcinoma epiderm?ide invasor ou com adenocarcinoma, o grupo B de 54 portadoras de neoplasia intra-epitelial cervical grau II ou III, e o grupo C de 19 pacientes com cervicite cr?nica. Observaram-se preval?ncias de HPV em 70,3 por cento, 63,0 por cento e 36,8por cento das mulheres dos grupamentos A, B e C, respectivamente, sendo o HPV 16 registrado em 60,4 por cento das amostras positivas do grupo A e 54,5 por cento daquelas do grupo B. Os tipos 16, 18 e 33 representaram 71,4 por cento dos detectados no grupo C It was studied the prevalence of human papillomavirus (HPV) among 228 women with lesions of uterine cervix attending the Ofir Loiola Institute, in Belem, Para, from March 1992 to May 1996. Histopathological examination was performed with all cervical biopsy samples obtained from these patients. In addition, specimens were analysed by both polimerase chain reaction and dot-blot hybridization to detect HPV DNA. The patients were assigned to three groups, according to the diagnosis made by histopathology, as follows: A, including 155 women suffering from invasive epidermoid carcinoma or adenocarcinoma; B, 54 patients having either cervical intraepithelial neoplasia grade II or III; and C, involving 19 women with chronic cervicitis. The prevalence rates of HPV in groups A, B and C were 70.3 per cent, 63 per cent and 36.8 per cent respectively. HPV 16 accounted for 60.4 per cent and 54.5 per cent of types identified in groups A and B, respectively. Altogether HPV types 16, 18 and 33 were detected in 71.4 per cent of positive patients belonging to group C.

Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Minist?rio da Sa?de. Funda??o Nacional de Sa?de. Instituto Evandro Chagas. Bel?m, PA, Brasil. Com o objetivo de determinar a preval?ncia de anticorpos IgG para o v?rus de Epstein Barr (EBV) e da infec??o causada por esse agente, foram colhidas 1.116 amostras de soro, sendo 853 oriundas de pacientes atendidos no ambulat?rio do Servi?o de Virologia Geral do Instituto Evandro Chagas no per?odo de junho de 95 a junho de1996; e 263 amostras de soro de indiv?duos assintom?ticos, procedentes da comunidade, coletados no per?odo de setembro a novembro de 94. Todas as amostras foram analisadas pelo procedimento imunoenzim?tico -"Elisa" (Kit da Clark laboratories, Jamestown-NY-USA). Do total de pacientes examinados, 72,5 por cento (807/1.116) possu?am anticorpos IgG para o EBV com ?ndices de preval?ncia de 66,9 por cento (571/853) e 89,7 por cento (236/263) a n?veis ambulatorial e comunit?rio, respectivamente (p 0,001). Em 6,7 por cento (58/853) dos casos sintom?ticos com detec??o de anticorpos IgM para o EBV observaram-se febre (60,3 por cento), linfadenopatia (50 por cento), erup??o cut?nea e faringite em (17,2 por cento).

Vanita Noronha,1,* Anuradha Choughule,2,* Vijay M Patil,1,* Amit Joshi,1 Rajiv Kumar,3 Deepa Susan Joy Philip,1 Shripad Banavali,2 Amit Dutt,4 Kumar Prabhash2 1Department of Medical Oncology, 2Department of Medical Oncology-Molecular Laboratory, 3Department of Pathology, Tata Memorial Hospital, 4Dutt Lab, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Mumbai, India *These authors contributed equally tothis work Background: There are limited data available on the treatment and outcome of epidermal growth factor receptor (EGFR) exon 20-mutated lung cancer patients. Hence, we planned an analysis of the demographic details, clinical profile and survival of lung cancer patients with exon 20 mutations. We compared our results to patients with EGFR tyrosine kinase inhibitor (TKI)-sensitizing activating and EGFR/anaplastic lymphoma kinase (ALK)-negative mutations. Methods: This was a retrospective analysis of lung cancer patients who were treated at our center between January 2010 and August 2014. We reviewed the results of EGFR mutation testing by real-time polymerase chain reaction and Sanger sequencing. We also reviewed the data relating to baseline demographics, clinical profile, patient treatment and outcome measures in terms of response and overall survival (OS). Results: A total of 580 patients fulfilled the selection criteria. In all, 227 (39.1%) patients had EGFR TKI-sensitizing activating mutations, 20 (3.4%) patients had exon 20 insertion mutations and 333 patients were EGFR/ALK mutation negative (57.5%). The median OS was 5months (95% confidence interval [CI] 0.17–9.8months) in exon 20 insertion mutations, 16.1months (95%CI 12.8–19.5months) in EGFR TKI-sensitizing activating mutations and 10months (95% CI 7.9–12.1months) in EGFR/ALK mutation-negative patients. The median OS was significantly better for the EGFR TKI-sensitizing activating mutation group (P=0.000, log-rank test) and forthe EGFR/ALK-negative group (P=0.037, log-rank test) compared to the exon 20-mutated group. Conclusion: Exon 20 mutation results in a poorer OS prognosis compared to EGFR- and ALK-negative patients and patients harboring EGFR TKI-sensitizing activating mutations. The incidence of de novo exon 20 insertions was 3.4%. Different types of exon mutations seem to have different outcomes. Keywords: exon 20, lung cancer, EGFR mutation, TKI resistance, insertions&nbsp