Kirti Srivastava

Impact of Toll-like receptors [TLR] 2 (−196 to −174 del) and TLR 4 (Asp299Gly, Thr399Ile) in cervical cancer susceptibility in North Indian women

OBJECTIVE(S) Targeting the Toll-like receptor (TLR) signaling pathway in elucidating the cellular and molecular mechanisms of human diseases, including cervical cancer, is gaining tremendous importance. The aim of our study was to identify the role of TLR 2(-196 to -174 del) and TLR 4(Asp299Gly and Thr399Ile) gene polymorphisms in cervical cancer susceptibility in North Indian women. METHODS For the study, blood samples were collected from histopathologically confirmed patients of cervical cancer (n=150) and unrelated, healthy female controls of similar ethnicity (n=150). Genomic DNA was extracted from peripheral blood leukocytes using salting-out method. TLR 2 and TLR 4 genotyping was done using Polymerase Chain Reaction and Restriction Fragment Length Polymorphism followed by 10% polyacrylamide gel electrophoresis. RESULTS TLR 2 del allele showed significant association (p=0.048, OR=1.6 [95%CI=1.00-2.51]) with cervical cancer susceptibility, while no significant association was found with TLR 4 (Asp299Gly and Thr399Ile). However, TLR 4 Thr/Ile genotype was found to be significantly associated with early stage (Stage II) of cervical cancer (p=0.044, OR=2.51 [95%CI=1.03-6.12]). Furthermore, TLR 2 ins/del genotype showed strong association (p=0.015, OR=1.95 [95%CI=1.14-3.33]) with tobacco usage in women with cervical cancer. CONCLUSION(S) Our study highlighted the involvement of TLR 2 (-196 to -174 del) and TLR 4 (Thr399Ile) gene polymorphisms in cervical cancer susceptibility. The TLR gene polymorphisms, upon further evaluation, may be helpful in elucidation of immunobiological mechanisms associated with cervical cancer susceptibility.

Circadian variation in radiation-induced intestinal mucositis in patients with cervical carcinoma†

Mucositis, a radiotherapy‐associated toxicity, is an important factor determining morbidity and treatment compliance. Gastrointestinal mucositis in patients undergoing radiotherapy may also depend on time of administration of radiation in addition to several other factors. The presence of any correlation between the severity of acute gastrointestinal mucositis in cervical carcinoma patients and the time of irradiation was prospectively evaluated.

Diagnostic Role of Survivin in Urinary Bladder Cancer

BACKGROUND Early diagnosis of carcinoma of bladder remains a challenge. Survivin, a member of the inhibitor of apoptosis (IAP) protein family, is frequently activated in bladder carcinoma. The objective of this study was to investigate urinary survivin as a marker for diagnosis of urinary bladder. MATERIALS AND METHODS We examined urinary survivin concentration in 28 healthy individuals, 46 positive controls and 117 cases of histologically proven TCC prior to transurethral resection, using ELISA, and compared values with findings for urinary cytology. RESULTS Survivin was found to be significantly higher in the cancer group (P<0.05). A cut off value of 17.7 pg/ml was proposed, with an approximate sensitivity of 82.9% and specificity of 81.1% (P<0.0001), whereas urine cytology had a sensitivity of 66.7% and a specificity of 96.0%. CONCLUSIONS Urinary survivin can be used as a non-invasive diagnostic biomarker for TCC bladder, both for primary and recurrent disease.

Cyclooxygenase-2 gene polymorphisms and risk of cervical cancer in a North Indian population.

Introduction: Single nucleotide polymorphisms in the cyclooxygenase-2 (COX-2) might contribute to differential COX-2 expression and subsequent interindividual variability in susceptibility to cancer. This study sought to evaluate the effects of COX-2 +8473T/C (rs5275) and −765G/C (rs20417) gene polymorphisms on the risk of cervical cancer in women of Northern India. Methods: Peripheral blood samples were collected from 200 histopathologically confirmed patients with cervical cancer and 200 unrelated, healthy female controls of similar ethnicity. Questionnaire survey was conducted to comprehend the demographic data, smoking status, and cancer stage of patients. Polymerase chain reaction-based restriction fragment length polymorphism was used to detect the genotypes of the COX-2 gene. Results: Cyclooxygenase-2 +8473CC genotype was associated with a significantly reduced risk of cervical cancer (P = 0.036; odds ratio, 0.4; 95% confidence interval, 0.1−0.9), whereas COX-2 −765G/C polymorphism demonstrated no association. In addition, no significant association with clinical stages of cervical cancer and modulation of risk due to tobacco usage was observed in our study. Conclusions: Cyclooxygenase-2 +8473T/C gene polymorphism demonstrated protective effect in North Indian women. Further studies evaluating the role of COX-2 gene polymorphisms in ethnically diverse populations and a larger cohort may help in understanding the etiopathogenesis of cervical cancer in women worldwide.

Concurrent chemoradiation versus radiotherapy alone in cervical carcinoma: A randomized phase III trial.

Chemo‐radiotherapy (CRT) is the standard of care for treating almost all cervical carcinoma patients on the basis of the National Cancer Institute (NCI) alert. The disease burden in developing countries is more advanced with poor general condition than in patients in the trials prompting the NCI alert. Therefore, practicing CRT as standard of care should be tested in these patients.

Metastatic squamous cell carcinoma neck with occult primary: A retrospective analysis

Introduction: Metastatic carcinoma in the lymph nodes of the neck from an unknown primary is relatively rare, accounting for about 3% of all head and neck cancers. Management of secondary neck of undetermined primary is controversial. Materials and Methods: The case records of all the patients treated in the Department of Radiotherapy, Chatrapati Shahuji Maharaj Medical University, from Oct 1999 to Sep 2004, were studied and the patients with secondary neck without a known primary tumor were analyzed in detail to elucidate the outcome of various treatment modalities in various stages of the disease. One hundred and forty patients were found to be eligible for this analysis. Initial treatment could be divided into two categories: concurrent chemoradiation (n=76) and radiotherapy alone (n=64). Results: The patients who had received radiotherapy alone (53.1%) had lesser complete response as compared to those who had received chemoradiotherapy (68.4%). The overall survival duration in patients of the radiotherapy treatment group ranged from 5 to 60 months, with an average (±SD) of 31.06 ± 21.01 months, while in the chemoradiotherapy treatment group it ranged from 6 to 60 months, with an average (±SD) of 39.42 ± 21.33 months. Both hematological and nonhematological toxicities, although higher in the chemoradiotherapy group, showed statistically insignificant differences. Conclusion: To the best of our knowledge, this is the only study evaluating the role of concurrent chemoradiation in cases of secondary neck with primary unknown. The improved response rates along with an increased survival (both disease free and overall) show the superiority of chemoradiotherapy in the management of such cases.

Deep vein and artery thrombosis associated with cetuximab-based chemoradiotherapy

Molecular targeted agents have lower hematological toxicity. However, specific side-effects such as allergic rashes, skin reactions and high cost limit their use. We report a case of 35-year-old male patient with carcinoma of left tonsil treated with concurrent cetuximab and radiotherapy. After four weeks of treatment, the patient developed sudden onset of pain in the left calf region radiating to the left foot. Doppler study of the left lower limb revealed complete thrombosis of superficial femoral, popliteal and proximal tibial arteries and veins and no flow in anterior tibial artery and lower posterior tibial artery. Emergency embolectomy was done. After 48 h of observation, no improvement was noted. A repeat Doppler examination showed similar finding. Ultimately a left lower limb amputation was done. We report simultaneous arterio-venous thrombosis associated with cetuximab-based chemoradiotherapy. Oncologists should be aware of this possible complication to undertake early intervention.

Glutathione S-Transferase Gene Polymorphisms and Treatment Outcome in Cervical Cancer Patients under Concomitant Chemoradiation.

Purpose Cisplatin based concomitant chemoradiation (CRT) is the standard treatment for locally advanced cervical cancer (CC). Glutathione S-transferase (GST), a phase II antioxidant enzyme is induced by oxidative stress generated by drugs and reactive oxidants. The present study was undertaken to evaluate the association of GSTM1, T1 and P1 polymorphisms with the outcome of CRT treatment in CC patients. Methods A total of 227 cervical cancer patients with stages IIB-IIIB treated with the same chemoradiotherapy regimen were enrolled and genotyped for GSTM1, T1 and P1 gene polymorphisms by multiplex polymerase chain reaction (mPCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). Overall survival was evaluated using Kaplan-Meier survival function and Cox proportional hazards model. All data were analyzed using SPSS (version 21.0). Results Stratified analysis showed that GSTM1 null (M1-) genotype was associated with a significantly better survival among patients with stage IIB cervical cancer (log-rank P = 0.004) than cases with stage IIIA/IIIB. Death and recurrence were significantly higher in patients with GSTM1 present genotype (M1+) (P = 0.037 and P = 0.003 respectively) and those with M1- showed reduced hazard of death with an adjusted hazard ratio ‘HR’ of 0.47 (95% CI, 0.269–0.802, P = 0.006). Women with M1- genotype as well as in combination with GSTT1 null (T1-), GSTP1 (AG+GG) and GSTT1 null/GSTP1 (AG+GG) showed better survival and also reduced risk of death (HR = 0.31, P = 0.016; HR = 0.45, P = 0.013; HR = 0.31, P = 0.02 respectively). Conclusions To the best of our knowledge, this is the first study to correlate the association of GSTM1, T1 and P1 gene polymorphisms with treatment outcome of CRT treated CC patients. Our results suggested that individuals with GSTM1 null genotype and in combination with GSTT1 null and GSTP1 (AG+GG) had a survival advantage. Such genetic studies may provide prognostic information in CRT treated CC patients.

Comparitive study of efficacy, tolerability of four field box technique vs. two field anterior posterior technique in locally advanced carcinoma cervix--a prospective analysis.

Purpose: The pelvic failure rate decreases with increase in the radiation dose but the complications increase. The four field pelvic technique has a theoretical advantage of providing a higher tumor dose with less dose to the surrounding normal tissue thus reducing the complications. Result: Eighty-three patients completed treatment, 42 in Arm A and 41 in Arm B. The complete response achieved in the two groups was 85.75% and 87.8% (p = 0.67). Skin reactions were more in Arm B (p < 0.05). Grade II GIT symptoms were more common in both the groups (p = 0.75). Grade I GUT toxicity was the most common toxicity in both the arms (p = 0.38). The most common hematological toxicity in the two arms was of grade II (p = 0.78). Material and method: After satisfying the eligibility criteria histo-pathologically proven locally advanced carcinoma cancer cervix patients were randomized to four (Arm A) or two (Arm B) field techniques. Conclusions: Both two and four field box techniques are equally effective and feasible as stastically insignificant difference in the response rate and acute toxicities was observed in the two arms.

A pilot study to evaluate the efficacy of cerrobend shielding stents in preventing adverse radiotherapeutic effects in buccal carcinoma patients.

BACKGROUND Radiation stents made of Lipowitz metal or cerrobend alloy are commonly used to shield uninvolved tissues from electron beams used in therapeutic radiation treatment of head and neck cancers. However, studies investigating the efficacy of cerrobend shielding stent in patients with unilateral buccal carcinoma remain rare. PURPOSE To evaluate the efficacy of cerrobend shielding stents in minimizing the potential adverse effects of radiation on oral tissues in buccal carcinoma patients. MATERIALS AND METHODS Twenty.eight participants were selected for the study based on predetermined inclusion criteria, out of which four participants were lost to follow-.up. Half of the remaining participants. (N = 12) were randomly given cerrobend shielding stent and the remaining 12 formed the control group. The effects of radiotherapy were evaluated by using Radiation Therapy Oncology Group. (RTOG) 0435 Head and Neck adverse effects grading tool. All participants were evaluated for xerostomia, mucositis, dysphagia, salivary changes, dysguesia, pain, trismus and radiation caries at baseline and 1 and 3. months post.radiotherapy. RESULTS All adverse effects were higher in control compared to study group, with post therapy difference for pain in swallowing, salivary changes, mucositis, dysphagia, dry mouth and caries being statistically significant. CONCLUSIONS Cerrobend alloy can be used effectively as shielding stent to reduce the adverse effects associated with external beam radiation therapy in unilateral buccal carcinoma patients.