Nimotuzumab provides survival benefit to patients with inoperable advanced squamous cell carcinoma of the head and neck: a randomized, open-label, phase IIb, 5-year study in Indian patients.

OBJECTIVE: Overexpression of epidermal growth factor receptor (EGFR) in many cancers makes it an attractive therapeutic target. This study evaluated the clinical utility of nimotuzumab, a monoclonal anti-EGFR antibody, used concurrently with radiotherapy (RT) and chemoradiotherapy (CRT) in squamous cell carcinoma of the head and neck (SCCHN). METHODS: This open-label study randomized 92 treatment-naïve patients (1:1) with advanced SCCHN into chemoradiation (CRT ± nimotuzumab) or radiation (RT ± nimotuzumab) group by investigator's discretion; these were further randomized into CRT + nimotuzumab or CRT and RT + nimotuzumab or RT groups, respectively. Treatment included 6 cycles each of cisplatin (50 mg/week), nimotuzumab (200 mg/week), and RT (total dose, 60-66 Gy). Response (tumor size reduction) was assessed at Month 6 post-treatment and survival, at Month 60. RESULTS: Forty and 36 patients in the chemoradiation and radiation groups, respectively (intent-to-treat population) were evaluated. Overall response at Month 6 post-treatment was 100% with CRT + nimotuzumab, 70% with CRT, 76% with RT + nimotuzumab, and 37% with RT. At Month 60, overall survival was 57% with CRT + nimotuzumab, 26% with CRT (P = 0.03), 39% with RT + nimotuzumab, and 26% with RT (P > 0.05). Median overall survival was not reached for CRT + nimotuzumab; it was 21.94 months for CRT (P = 0.0078), 14.36 months for RT + nimotuzumab, and 12.78 months for RT (P = 0.45). Risk of death was 64% lower with CRT + nimotuzumab than with CRT (95%CI: 0.37, 1.56), and 24% lower with RT + nimotuzumab than with RT (95%CI: 0.16, 0.79). Thus nimotuzumab was safe and well tolerated with few mild to moderate self-limiting adverse events. CONCLUSION: Concurrent use of nimotuzumab with CRT/RT is safe and provides long-term survival benefit.

Molecular variants of HPV-16 associated with cervical cancer in Indian population.

Human papilloma virus is a causative factor in the etiology of cervical cancer with HPV16 being the most prevalent genotype associated with it. Intratype variations in oncogenic E6/E7 and capsid L1 proteins of HPV 16 besides being of phylogenetic importance, are associated with risk of viral persistence and progression. The objective of this multicentric study was to identify HPV-16 E6, E7 and L1 variants prevalent in India and their possible biological effects. Squamous cell cervical cancer biopsies were collected from 6 centres in India and examined for the presence of HPV 16. Variants of HPV-16 were characterized by full length sequence analysis of L1, E6 and E7 genes in 412 samples. Similar distribution of the variants was seen from the different centres/regions, with the European variant E350G being the most prevalent (58%), followed by American Asian variant (11.4%). Fifty six changes were seen in E6 region, 31 being nonsynonymous. The most frequent being L83V (72.3%), Q14H (13.1%) and H78Y (12.1%). Twenty-nine alterations were seen in E7 region, with 12 being nonsynonymous. The most frequent being F57V (9%). L1 region showed 204 changes, of which 67 were nonsynonymous. The most frequent being 448insS (100%), and 465delD (100%), H228D (94%), T292A (85%). The identified variants some new and some already reported can disrupt pentamer formation, transcriptional regulation of the virus, L1 protein interface interaction, B and T cell epitopes, p53 degradation, and thus their distribution is important for development of HPV diagnostics, vaccine, and for therapeutic purpose.

Coexpression of Notch1 and NF-kappaB signaling pathway components in human cervical cancer progression.

OBJECTIVES: Features of deregulated Notch1 signaling and NF-kappaB activation have independently been reported in cervical cancers. Here, we have extended these observations and examined both these pathways simultaneously in human cervical cancer tissue. Further, we have investigated the potential cross-talk between these pathways in a human cervical cancer derived cell line CaSki, which mirrors features of Notch activation as in the majority of human cervical cancers. METHODS: Cervical tissue samples were analyzed for the expression of Notch1, Jagged 1, Hes1, pAKT, NF-kappaB p50, NF-kappaB p65, IkappaB-alpha, Bcl-2, CyclinD1, Cdk9, c-Fos, and p53 by immunohistochemistry. A total of 352 samples were analyzed which included 69 normal cervical tissue, 132 preinvasive lesions and 151 squamous cell carcinomas of the uterine cervix. Dual immunofluorescent analysis was performed to evaluate the coexpression of Notch1 and NF-kappaB. Transcriptional reporter assays and xenografts were undertaken with CaSki cells. RESULTS: Features of Notch1 activation as measured by intracellular Notch1, high levels of Jagged1, Hes1 and Cdk9 were paralleled by nuclear translocation of both NF-kappaB p50 and p65 with target gene expression (IkappaB-alpha, Bcl-2, and CyclinD1) in human cervical cancer sections. Reporter assays in CaSki cells are consistent with Notch being an upstream regulator of NF-kappaB. Further, the xenografts recreate key aspects of human cancer tissue. CONCLUSIONS: Results from this study suggest that there is a co-activation of Notch1 and NF-kappaB signaling pathways at the cellular level in the majority of human cervical cancers, with Notch as an upstream regulator.

Sinus histiocytosis with nodal and extranodal involvement--a case report.

A two and half years old male child of sinus histiocytosis with massive lymphadenopathy, paraplegia and spinal cord involvement was treated with surgery and radiotherapy for the spinal cord compression and later with chemotherapy for his nodal disease in the neck. There was a significant improvement in his neurologic status as well as in his nodal status reiterating the role of combination therapy in this disease.

Near-total laryngectomy in advanced cancers of the larynx and pyriform sinus: a comparative study of morbidity and functional and oncological outcomes.

This prospective study, performed from 1991 to 1996, analyzes the differences in oncological safety, functional utility, and surgical morbidity in 14 advanced lesions of the larynx (10 T3 and 4 T4; 7 N+) and 40 pyriform sinus lesions (1 T2, 20T3, and 19 T4; 29 N+) subjected to Pearson near-total laryngectomy. The laryngeal cancer patients healed much faster, with a minimal wound complication rate of 28%, in comparison to the 68% rate encountered in the pyriform sinus cases (p < .05). The 3-year disease-free survival rate for the laryngeal cancers was 74%, while the 5-year survival rates for pyriform sinus cases were 66% for medial wall lesions and 54% for lateral wall lesions. Lung-powered shunt speech deemed qualitatively superior by acoustic analysis was obtained in 81% of the individuals (93% in laryngeal cases and 76% in pyriform sinus cases). Aspiration-free deglutition was achieved by 90% over periods ranging from 15 to 30 days. This study conclusively attests to the therapeutic efficacy of near-total laryngectomy for advanced lesions of the larynx and pyriform sinus that are unsuitable for radiotherapy, that are deemed too large or risky (because of aspiration) for partial laryngectomy, and that in the past would have merited total laryngectomy.