Shyam Aggarwal

Feasibility study of docetaxel, oxaliplatin and capecitabine combination regimen in advanced gastric or gastroesophageal adenocarcinoma

BACKGROUND AND OBJECTIVES At present, there is no standard regimen for the treatment of gastroesophageal cancer. Docetaxel, cisplatin and fluorouracil (DCF) has been shown to be an effective regimen; however, toxicity is an area of concern in the palliative case setting. Capecitabine and oxaliplatin have been shown to be as effective as fluorouracil and cisplatin, respectively. To reduce the toxicity of DCF while maintaining efficacy, we conducted this study to evaluate the efficacy of docetaxel, oxaliplatin and capecitabine (DOX) combination in advanced gastroesophageal cancer. METHODS Patients with histologically confirmed metastatic or locally advanced adenocarcinoma of the stomach or gastroesophageal junction received docetaxel 25 mg/m2 and oxaliplatin 50 mg/m2 on days 1 and 8 with capecitabine 625 mg/m2 twice daily from day 1-14, in 21-day cycles. The primary endpoint was overall response rate (ORR). RESULTS Of 21 patients, there were 16 males and 5 females with a median age of 57 years, range 37-80 years. The primary tumor was located at the gastroesophageal junction in 7 patients and in other parts of the stomach in the remaining 14 patients. One patient had locally advanced tumor without distant metastases and 20 patients presented with metastatic disease. Grade 3/4 toxicities included diarrhea (24%), hand-foot syndrome (5%) and febrile neutropenia (5%). The ORR was 29%. The median survival was 8.4 months. At the time of analysis, 5 of the 21 patients (24%) were alive. CONCLUSIONS The DOX combination is tolerable, active and a promising day-care regimen for advanced gastroesophageal cancer.

Successful treatment of multicentric Castleman's disease accompanying myeloma with bortezomib.

Castlemans disease represents an atypical lymphoproliferative disorder which is non-clonal but can turn malignant in the form of lymphoma, Kaposis sarcoma or plasma cell dyscrasia. It has been reported in association with diseases like polyneuropathy organomegaly endocrinopathy monoclonal gammopathy skin changes syndrome and myeloma and very rarely it can be associated with cutaneous vasculitis as in our case. It relatively runs an aggressive course and has a shorter survival. No standard of care therapy is yet established for multicentric Castlemans disease accompanying myeloma. We successfully treated one such patient with bortezomib-based therapy.

Lack of any association of the CTLA-4 +49 G/A polymorphism with breast cancer risk in a North Indian population.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an important protein involved in the regulation of the immune system. The +49 G/A polymorphism is the only genetic variation in the CTLA-4 gene that causes an amino acid change in the resulting protein. It is therefore the most extensively studied polymorphism among all CTLA-4 genetic variants and contributions to increasing the likelihood of developing cancer are well known in various populations, especially Asians. However, there have hiterto been no data with respect to the effect of this polymorphism on breast cancer susceptibility in our North Indian population. We therefore assayed genomic DNA of 250 breast cancer subjects and an equal number of age-, sex- and ethnicity-matched healthy controls for the CTLA-4 +49 G/A polymorphism but no significant differences in either the gene or allele frequency were found. Thus the CTLA-4 +49 G/A polymorphism may be associated with breast cancer in other Asians, but it appears to have no such effect in North Indians. The study also highlights the importance of conducting genetic association studies in different ethnic populations.

Prevalence and coexistence of KRAS, BRAF, PIK3CA, NRAS, TP53, and APC mutations in Indian colorectal cancer patients: Next-generation sequencing-based cohort study.

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.

Hepatic Mucormycosis in a Patient of Acute Lymphoblastic Leukemia: A Case Report with Literature Review

Mucormycosis is an invasive opportunistic fungal infection associated with a high mortality rate, and normally occurs in immunocompromised patients. It can be encountered during neutropenia following chemotherapy in acute leukemia patients. The common sites involved are rhinocerebral, pulmonary, gastrointestinal and spleen. Hepatic involvement has been reported rarely. We hereby report a case of acute lymphoblastic leukemia who while on chemotherapy developed hepatic mucormycosis and was managed successfully despite its treatment being quite challenging, especially in the context of surgery in a neutropenic sick patient.

Erythroleukemia Presenting as Non-immune Haemolytic Anemia: A Rare Presentation.

Abstract Non-immune haemolysis is a rare manifestation of acute leukaemia and more so in acute myeloid leukemia. Here, we report a case of non-immune and non-fragmentation haemolysis as the initial presenting manifestation in a 55-year-old female with acute myeloid leukaemia (AML-M6). All other potential aetiologies of haemolysis were excluded, including drugs, paroxysmal nocturnal haemoglobinuria, immune and other known congenital and acquired causes of haemolytic anaemia. This case shows that malignant haematopoietic disorders should be considered in patients with newly diagnosed haemolysis.

Rosai-Dorfman disease of the paranasal sinuses and orbit.

Rosai-Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy, is a benign indolent disorder, characterized by enlarged lymph nodes filled with histiocytes. Extranodal involvement is uncommon. The disease rarely affects the nose and paranasal sinuses. We report a case that presented with a right nasal mass, extending into all the paranasal sinuses and right orbit without any accompanying lymphadenopathy. Because of the absence of lymphadenopathy it posed a diagnostic challenge until the pathology was confirmed on histopathological examination.

KDR Mutation: A High-Frequency Rare Mutation and its Correlation with other Somatic Mutations in Indian Colorectal Cancer Patients

Aim: This study aims to find out the frequency of KDR mutation in colorectal cancer patients and if any correlation exists between KDR mutation and demographical features or with other common and uncommon gene mutations occurring in colon cancer. Methods: FFPE samples of 112 patients were analyzed using next generation sequencing. Results: KDR gene was found to be mutated most frequently (19.6%). As compared to other uncommon gene mutations occurring among patients. 21/22 patients had the p.Q472H type of KDR mutation. It was significantly associated with mutations in PTEN (p=0.003), KRAS (p=0.026), APC (p=0.033), EGFR (p=0.036), NOTCH1 (p=0.029) and ERBB4 (p=0.008) mutations. More number of males (22.06%) harbored KDR mutations than the number of females (15.9%). A higher number of KDR mutations in Stage III (31%) as compared to other stages – I-II (19.23%) and IV (7.31%) was reported. KDR mutations were found to be in greater number in patients with lymph node metastasis (27.3%) as compared to liver metastasis (8%). However, a statistically significant association of any clinical parameter was not found. Conclusion: Our results suggest that although KDR is a rare somatic mutation in CRC, it plays a pivotal role in the development of colon cancer via angiogenesis pathway.

Patterns of epidermal growth factor receptor testing across 111 tertiary care centers in India: Result of a questionnaire-based survey

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.

Identification of prognostic and susceptibility markers in chronic myeloid leukemia using next generation sequencing

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.