Frequency and risk factors of bleomycin-induced pulmonary toxicity in South Indian patients with germ-cell tumors.

AIM: Bleomycin, etoposide, and cisplatin (BEP) regimen is the standard treatment for germ-cell tumors (GCTs). Bleomycin-induced pulmonary toxicity (BPT) is fatal and dose-limiting toxicity associated with this regimen. In this study, we aimed to identify the frequency and risk factors of BPT in South Indian GCT patients receiving BEP regimen. PATIENTS AND METHODS: The study was carried out in the Department of Medical Oncology, Regional Cancer Centre at a tertiary care hospital in South India. All the patients with GCT (testicular and ovarian) who were receiving BEP regimen from December 2014 to May 2018 were included in the study. BPT was defined as the presence of radiological features and/or clinical symptoms during or post-treatment. RESULTS: BPT was observed in 11 (27%) patients of 41 analyzed patients. Five (12%) patients developed BPT during treatment whereas six (15%) patients developed BPT post-treatment. Cumulative bleomycin dose ≥240 mg (relative risk 3.8, confidence interval: 1.2-12.2,P =0.02) was found to increase the risk of BPT. Three-year overall survival in patients with and without toxicity was 82% and 93%, respectively. CONCLUSIONS: The frequency of BPT in the study population is 27%, and cumulative bleomycin dose ≥240 mg has been found to be associated with increased risk of developing BPT. BPT does not negatively impact survival outcome in GCT patients receiving BEP regimen.

Association of NUDT15*3 and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia.

Genetic variants influencing the pharmacokinetics and/or pharmacodynamics of the chemotherapeutic drugs used in Acute Lymphoblastic Leukemia (ALL) therapy often contribute to the occurrence of treatment related toxicity (TRT). In this study, we explored the association of candidate genetic variants with early hematological TRT (grade 3-4) occurring within the first 100 days of low-dose methotrexate and 6-mercaptopurine based maintenance therapy (n = 73). Fourteen variants in the following candidate genes were genotyped using allele discrimination assay by real-time PCR: ABCB1, DHFR, GGH, FPGS, MTHFR, RFC1, SLCO1B1, TPMT, and NUDT15. Methotrexate polyglutamate (MTXPG3-5) levels in red blood cells were measured by LC-MS/MS. Early hematological TRT (grade 3-4) was seen in 54.9% of patients. The NUDT15*3 allele was associated with early TRT occurrence [HR: 3.04 (95% CI: 1.5-6.1); p = 0.007]. Sensitivity of early TRT prediction improved (from 30.7% to 89.7%) by considering FPGS variant (rs1544105) carrier status along with NUDT15*3 allele [HR = 2.7 (1.5-4.7, p = 0.008)]. None of the considered genetic variants were associated with MTXPG3-5 levels, which in turn were not associated with early TRT. NUDT15*3 allele carrier status could be used as a stratifying marker for Indian ALL patients to distinguish patients at high or low risk of developing early hematological TRT.

Variants in XPC, Noxa and TLR4 genes are not associated with bleomycin-induced lung injury in Hodgkin lymphoma patients.

Aim: Pulmonary toxicity is a well-known adverse reaction of bleomycin. In this study, we investigated the influence of XPC, PMAIP1/Noxa and TLR4 genetic variants on the development of bleomycin-induced lung injury (BILI) in south Indian patients with Hodgkin lymphoma. Materials & methods: Hodgkin lymphoma patients receiving adriamycin, bleomycin, vinblastine and dacarbazine regimen were recruited for the study and BILI was diagnosed based on symptoms and/or radiological signs. DNA samples were genotyped using real-time PCR. Results: A total of 78 patients were recruited in the study and BILI was observed in 17 (21.8%) patients. Polymorphisms in XPC, PMAIP1/Noxa and TLR4 genes were not associated with the development of BILI. Conclusion: The selected genetic polymorphisms do not predict the risk of BILI in south Indian population.

Frequency distribution of BLMH, XPO5 and HFE gene polymorphisms in the South Indian population and their association with Hodgkin Lymphoma.

BACKGROUND: Hodgkin lymphoma, a highly curable malignancy is currently treated with an adriamycin, bleomycin (BLM), vinblastine, and dacarbazine (ABVD) regimen. BLM-induced pulmonary toxicity (BPT) is one of the dose-limiting toxicities. Previous reports have revealed that genetic variants rs1050565, rs11077, and rs1800562 are involved in the development of BPT. These results cannot be extrapolated to the South Indian population because of their ethnic difference. This study aimed to determine the frequency of rs1050565, rs11077, and rs1800562 variants in South Indian healthy individuals and Hodgkin lymphoma cases. These frequencies were compared with 1000 genome populations' data. We also assessed if these variants modified the risk to Hodgkin lymphoma. MATERIAL AND METHODS: A total of 200 healthy individuals and 101 cases with Hodgkin lymphoma were recruited for this case-control study after ethical approval. Blood samples were collected from the study participants and DNA was extracted. Genotyping of rs1050565, rs11077, and rs1800562 variants was done using real-time polymerase chain reaction. A chi-square test was used to assess the differences in genotype frequency data between cases and controls. RESULTS: The minor allele frequencies of rs1050565 and rs11077 were 4.3% and 39%, respectively, whereas all the individuals were wild-type for rs1800562 mutation. The frequencies significantly differed from 1000 genome data. The variants did not alter the risk for Hodgkin lymphoma. CONCLUSIONS: We determined the frequencies of rs1050565, rs11077, and rs1800562 variants in South Indian healthy individuals, and the frequencies differed significantly from 1000 genome populations. We also found that the studied polymorphisms are not associated with Hodgkin lymphoma risk in the South Indian population.

Association of Voltage-Gated Sodium Channel Genetic Polymorphisms with Oxaliplatin-Induced Chronic Peripheral Neuropathy in South Indian Cancer Patients

Oxaliplatin is a platinum drug active against digestive tract cancers. Among its side effects, peripheral neuropathy is one of the dose-limiting toxicities. This affects around 50 to 70% of patients but the pathophysiology of development of oxaliplatin-induced peripheral neuropathy (OXAIPN) remains unclear. Sodium channels (SCNAs) play major role in neuronal electrical signaling processes and mutations in SCNAs lead to various neuronal diseases involving the central and peripheral nervous systems. In this study, we evaluated whether SCNA genetic variants might be associated with risk of chronic OXAIPN in patients with digestive tract cancers treated with oxaliplatin. Methodology: Blood samples from 228 digestive tract cancer patients who had received oxaliplatin in adjuvant and neoadjuvant or metastatic settings were obtained and genomic DNA was extracted by phenol-chloroform extraction. Genotyping was performed with the real-time polymerase chain reaction (RT-PCR) using validated real-time TaqMan single nucleotide polymorphism (SNP) genotyping assays. Neuropathy was evaluated and graded according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.03. Results: We found that the rs6746030 polymorphic variant of SCN9A was significantly associated with a higher incidence of chronic OXAIPN (GA+AA vs GG: OR=1.8, 95% CI=1.04-3.4, P=0.04; dominant model) while the rs6754031 variant was linked with a lower incidence (OR=0.45, 95% CI=0.22-0.77, P=0.005; dominant model). The SCN 10A polymorphic variant was associated with severity of chronic OXAIPN (P=0.006, OR=2.0, 95% CI=1.2 - 3.3). Conclusion: The results of the present prospective study provide evidence in support of a causal relationship between chronic OXAIPN and voltage gated sodium channel polymorphisms. However, further studies from independent groups are required to validate these results.

A Polymorphism Located Near PMAIP1/Noxa Gene Influences Susceptibility to Hodgkin Lymphoma Development in South India

Background: Single nucleotide polymorphisms (SNPs) in DNA repair and Toll-like receptor (TLR) genes have been reported to be associated with Hodgkin Lymphoma (HL) risk. Since such associations may be ethnicity dependent, polymorphisms in TLR4 rs1554973, Xeroderma pigmentosum C (XPC) rs2228000, rs2228001 and a variant near PMAIP1/Noxa gene rs8093763 were here investigated with regard to HL susceptibility in a south Indian population. Normative frequencies of SNPs were established and compared with data for 1000 genome populations. Methods: We conducted a case control study consisting of 200 healthy volunteers and 101 cases with HL. DNA samples were genotyped using real-time PCR. Linkage disequilibrium (LD) analysis between rs2228000 and rs2228001 was performed using HaploView (version 4.2). Results: Among the studied variants, we observed that a variant rs8093763 located near PMAIP1/Noxa gene was associated with HL risk (OR=1.72 and 95% CI=1.004-2.93). The major allele frequencies of XPC (rs2228000 and rs2228001), TLR4 (rs1554973) and PMAIP1/NOXA (rs8093763) variants were 79%, 66%, 67% and 59% respectively. The studied frequencies were significantly different from 1000 genome populations. Conclusion: The results suggest that a variant rs8093763 located near the PMAIP1/Noxa gene may modify risk of HL. We found variation in distribution of polymorphic frequencies between the study population and 1000 genome populations. The results may help identify individual risk of development of HL in our south Indian population.