Evolving multidisciplinary treatment of squamous cell carcinoma of the head and neck in India✰.

In this article, we highlight the evolution of a multimodal approach in the overall management of squamous cell carcinoma of the head and neck (SCCHN) in India; present advances in technology (newer surgical techniques), novel medical and radiotherapy (RT) approaches; review their roles for an integrated approach for treating SCCHN and discuss the current role of immunotherapy in SCCHN. For locally advanced (LA) SCCHN, the multidisciplinary approach includes surgery followed by RT, with or without chemotherapy (CT) or concurrent chemoradiotherapy. Improved surgical techniques of reconstruction and voice-preservation are being implemented. Advanced forms of high-precision conformal techniques like intensity-modulated radiotherapy are used to deliver highly conformal doses to tumors, sparing the surrounding normal tissue. Compared with RT alone, novel CT regimens and targeted therapeutic agents have the potential to improve locoregional control and survival and reduce treatment-induced toxicities. Several clinical trials have demonstrated efficacy, safety, and quality of life benefits of adding cetuximab to RT regimens in LASCCHN. Studies have also suggested a cetuximab-related laryngeal preservation benefit. At progression, platinum-based CT combined with cetuximab (a monoclonal anti-epidermal growth factor receptor antibody) is the only validated option available as the first-line therapy. Thus, an integrated multidisciplinary approach plays a key role in maximizing patient outcomes, reduction in treatment related morbidities that consequently impact quality of life of survivors.

Practical consensus recommendations regarding the use of hormonal therapy in metastatic breast cancer.

Metastatic breast cancer (MBC) is cancer that has spread from the breast to another part of the body or has come back in another distant location. Treatment options for MBC depend on several factors. One of these factors is the levels of hormone receptors (HRs) in the tumor. Cancers with high levels of HRs, called HR-positive, use the hormones estrogen and progesterone to grow and spread. Hormonal therapy is a type of treatment specifically for HR-positive breast cancer. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations in regards with the use of hormonal therapy and the management of HR-positive MBC for the benefit of community oncologists.

Practical consensus recommendations regarding the management of HER2 neu positive metastatic breast cancer.

Metastatic breast cancer (MBC) is cancer that has spread from the breast to another part of the body or has come back in another distant location. Treatment options for MBC depend on several factors, including where the cancer has spread, the patient's overall health, and the levels of hormone receptors and HER2 in the tumour. Over-expression of HER2 is generally considered to be a negative prognostic feature because it accompanies an increase in breast cancer mortality. However, the development of agents that specifically target HER2 has improved the management of patients with these tumours.[7],[8],[9],[10] This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations in regards with the use of these agents and the management of HER2 positive MBC for the benefit of community oncologists.

Transient receptor potential vanilloid 5 (TRPV5), a highly Ca2+ -selective TRP channel in the rat brain: relevance to neuroendocrine regulation.

Recent studies suggest an important role for transient receptor potential vanilloid (TRPV) ion channels in neural and neuroendocrine regulation. The TRPV subfamily consists of six members: TRPV1-6. While the neuroanatomical and functional correlates of TRPV1-4 have been studied extensively, relevant information about TRPV5 and TRPV6, which are highly selective for Ca2+ , is limited. We detected TRPV5 mRNA expression in the olfactory bulb, cortex, hypothalamus, hippocampus, midbrain, brainstem and cerebellum of the rat. TRPV5-immunoreactive neurones were conspicuously seen in the hypothalamic paraventricular (PVN), supraoptic (SON), accessory neurosecretory (ANS), supraoptic nucleus, retrochiasmatic part (SOR), arcuate (ARC) and medial tuberal nuclei, hippocampus, midbrain, brainstem and cerebellum. Glial cells also showed TRPV5-immunoreactivity. To test the neuroendocrine relevance of TRPV5, we focused on vasopressin, oxytocin and cocaine- and amphetamine-regulated transcript (CART) as representative candidate markers with which TRPV5 may co-exist. In the hypothalamic neurones, co-expression of TRPV5 was observed with vasopressin (PVN: 50.73±3.82%; SON: 75.91±2.34%; ANS: 49.12±4.28%; SOR: 100%) and oxytocin (PVN: 6.88±1.21; SON: 63.34±5.69%; ANS: 20.4±4.14; SOR: 86.5±1.74%). While ARC neurones express oestrogen receptors, 17ß-oestradiol regulates TRPV5, as well as CART neurones and astrocytes, in the ARC. Furthermore, ARC CART neurones are known to project to the preoptic area, and innervate and regulate GnRH neurones. Using double-immunofluorescence, glial fibrillary acidic protein-labelled astrocytes and the majority of CART neurones in the ARC showed TRPV5-immunoreactivity. Following iontophoresis of retrograde neuronal tracer, cholera toxin ß (CtB) into the anteroventral periventricular nucleus and median preoptic nucleus, retrograde accumulation of CtB was observed in most TRPV5-equipped ARC CART neurones. Next, we determined the response of TRPV5-elements in the ARC during the oestrous cycle. Compared to pro-oestrus, a significant increase (P<.001) in the percentage of TRPV5-expressing CART neurones was observed during oestrus, metoestrus, and dioestrus. TRPV5-immunoreactivity in the astrocytes, however, showed a significant increase during metoestrus and dioestrus. We suggest that the TRPV5 ion channel may serve as an important regulator of neural and neuroendocrine pathways in the brain.

Response to docetaxel and cisplatin induction chemotherapy of locally advanced head and neck squamous cell carcinoma: a multicenter, non-comparative, open-label interventional pilot study.

BACKGROUND: Docetaxel, cisplatin plus 5-fluorouracil is an efficacious induction regimen but is more toxic than cisplatin plus 5-fluorouracil. This study aimed to determine whether docetaxel and cisplatin without 5-fluorouracil maintains efficacy while decreasing toxicity. METHODS: A multicenter non-comparative pilot study of locally advanced squamous cell carcinoma of the head and neck was performed. Patients received primary therapy comprising three cycles of 75 mg/m2 docetaxel and 75 mg/m2 cisplatin followed by concurrent chemoradiotherapy. The primary endpoint was the response rate to the docetaxel and cisplatin induction regimen. RESULTS: A total of 26 patients were enrolled: of these, 23 (88.5 per cent) received all three docetaxel and cisplatin cycles. Common grade 3-4 adverse events were febrile neutropenia (19.2 per cent of patients), diarrhoea (19.2 per cent) and non-neutropenic infection (15.4 per cent). The overall response rate to docetaxel and cisplatin induction chemotherapy was 65.4 per cent. A total of 23 patients (88.5 per cent) subsequently received chemoradiotherapy with a median radiotherapy dose of 70 Gy. The response rate to chemoradiotherapy was 73 per cent. At a median follow up of 44 months, the 3-year progression-free survival and overall survival rates were 62 per cent and 69 per cent, respectively. CONCLUSION: Docetaxel and cisplatin induction chemotherapy is a feasible induction regimen with comparable efficacy to docetaxel, cisplatin and 5-fluorouracil induction chemotherapy.

Practical recommendation for rash and diarrhea management in Indian patients treated with tyrosine kinase inhibitors for the treatment of non-small cell lung cancer.

Tyrosine kinase inhibitors (TKIs) are a pharmaceutical class of small molecules, orally available with manageable safety profile, approved worldwide for the treatment of several neoplasms, including lung, breast, kidney and pancreatic cancer as well as gastro-intestinal stromal tumours and chronic myeloid leukaemia. In recent years, management of lung cancer has been moving towards molecular-guided treatment, and the best example of this new approach is the use of the tyrosine kinase inhibitors (TKIs) in patients with mutations in the epidermal growth factor receptor (EGFR). The identification of molecular predictors of response can allow the selection of patients who will be the most likely to respond to these tyrosine kinase inhibitors (TKIs). Gastrointestinal (GI) adverse events (AEs) are frequently observed in patients receiving EGFR tyrosine kinase inhibitor therapy and are most impactful on the patient's quality of life. Dermatologic side effects are also relatively common among patients treated with EGFR inhibitors. Evidence has emerged in recent years to suggest that the incidence and severity of rash, positively correlated with response to treatment.These skin disorders are generally mild or moderate in severity and can be managed by appropriate interventions or by reducing or interrupting the dose. Appropriate and timely management make it possible to continue a patient's quality of life and maintain compliance; however if these adverse events (AEs) are not managed appropriately, and become more severe, treatment cessation may be warranted compromising clinical outcome. Strategies to improve the assessment and management of TKI related skin AEs are therefore essential to ensure compliance with TKI therapy, thereby enabling patients to achieve optimal benefits. This article provides a consensus on practical recommendation for the prevention and management of diarrhoea and rash in Non-Small Cell Lung Cancer (NSCLC) patients receiving TKIs.

A New Drug Combinatory Effect Prediction Algorithm on the Cancer Cell Based on Gene Expression and Dose-Response Curve.

Gene expression data before and after treatment with an individual drug and the IC20 of dose-response data were utilized to predict two drugs' interaction effects on a diffuse large B-cell lymphoma (DLBCL) cancer cell. A novel drug interaction scoring algorithm was developed to account for either synergistic or antagonistic effects between drug combinations. Different core gene selection schemes were investigated, which included the whole gene set, the drug-sensitive gene set, the drug-sensitive minus drug-resistant gene set, and the known drug target gene set. The prediction scores were compared with the observed drug interaction data at 6, 12, and 24 hours with a probability concordance (PC) index. The test result shows the concordance between observed and predicted drug interaction ranking reaches a PC index of 0.605. The scoring reliability and efficiency was further confirmed in five drug interaction studies published in the GEO database.

Clinical and epidemiological study of EGFR mutations and EML4-ALK fusion genes among Indian patients with adenocarcinoma of the lung.

BACKGROUND: Mutation in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) is a common feature observed in lung adenocarcinoma. A fusion gene between echinoderm microtubule-associated protein-like 4 (EML4) and the intracellular domain of anaplastic lymphoma kinase (ALK), named EML4-ALK, has been identified in a subset of non-small-cell lung cancer (NSCLC) tumors. The objective of this study was to determine the prevalence of EGFR mutations and EML4-ALK fusions in Indian patients with NSCLC (adenocarcinoma) as well as evaluate their clinical characteristics. PATIENTS AND METHODS: Patients with NSCLC, adenocarcinoma histology, whose tumors had been tested for EGFR mutational status, were considered for this study. ALK gene rearrangement was detected by fluorescence in situ hybridization using the Vysis ALK Break Apart Rearrangement Probe Kit. ALK mutation was tested in samples that were negative for EGFR mutation. RESULTS: A total of 500 NSCLC adenocarcinoma patients were enrolled across six centers. There were 337 (67.4%) men and 163 (32.6%) women with a median age of 58 years. One hundred and sixty-four (32.8%) blocks were positive for EGFR mutations, whereas 336 (67.2%) were EGFR wild-type. Of the 336 EGFR-negative blocks, EML4-ALK fusion gene was present in 15 (4.5%) patients, whereas 321 (95.5%) tumors were EML4-ALK negative. The overall incidence of EML4-ALK fusion gene was 3% (15/500). CONCLUSION: The incidence of EGFR mutations (33%) in this Indian population is close to the reported incidence in Asian patients. EML4-ALK gene fusions are present in lung adenocarcinomas from Indian patients, and the 3% incidence of EML4-ALK gene fusion in EGFR mutation-negative cases is similar to what has been observed in other Western and Asian populations. The mutual exclusivity of EML4-ALK and EGFR mutations suggests implementation of biomarker testing for tumors harboring ALK rearrangements in order to identify patients that can benefit from newer targeted therapies.

ICON 2013: practical consensus recommendations for hormone receptor-positive Her2-negative advanced or metastatic breastcancer.

The management of hormone receptor-positive Her2-negative breast cancer patients with advanced or metastatic disease is a common problem in India and other countries in this region. This expert group used data from published literature, practical experience, and opinion of a large group of academic oncologists, to arrive at practical consensus recommendations for use by the community oncologists.

Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects.

BACKGROUND: Change in breast density may predict outcome of women receiving adjuvant hormone therapy for breast cancer. We performed a prospective clinical trial to evaluate the impact of inherited variants in genes involved in oestrogen metabolism and signalling on change in mammographic percent density (MPD) with aromatase inhibitor (AI) therapy. METHODS: Postmenopausal women with breast cancer who were initiating adjuvant AI therapy were enrolled onto a multicentre, randomised clinical trial of exemestane vs letrozole, designed to identify associations between AI-induced change in MPD and single-nucleotide polymorphisms in candidate genes. Subjects underwent unilateral craniocaudal mammography before and following 24 months of treatment. RESULTS: Of the 503 enrolled subjects, 259 had both paired mammograms at baseline and following 24 months of treatment and evaluable DNA. We observed a statistically significant decrease in mean MPD from 17.1 to 15.1% (P<0.001), more pronounced in women with baseline MPD ≥20%. No AI-specific difference in change in MPD was identified. No significant associations between change in MPD and inherited genetic variants were observed. CONCLUSION: Subjects with higher baseline MPD had a greater average decrease in MPD with AI therapy. There does not appear to be a substantial effect of inherited variants in biologically selected candidate genes.

Management of primary and metastatic triple negative breast cancer: perceptions of oncologists from India.

BACKGROUND: In order to document the understanding of current evidence for the management of triple negative breast cancer and application of this knowledge in daily practice, we conducted an interactive survey of practicing Indian oncologists. MATERIALS AND METHODS: A core group of academic oncologists devised two hypothetical triple negative cases (metastatic and early breast cancer, respectively) and multiple choice options under different clinical circumstances. The respondents were practicing oncologists in different Indian cities who participated in either an online survey or a meeting. The participants electronically chose their preferred option based on their everyday practice. RESULTS: A total of 152 oncologists participated. Just over half (53.8%) preferred taxane based chemotherapy as first-line chemotherapy in the metastatic setting. In the adjuvant setting, a taxane regimen was chosen by 61%. Over half of respondents (52.6%) underestimated the baseline survival of a patient with node positive triple-negative tumor and 18.9% overestimated this survival compared to the estimate of the Adjuvant! program. DISCUSSION: This data offers insight into the perceptions and practice of a diverse cross-section of practicing oncologists in India with respect to their therapeutic choices in metastatic and adjuvant settings in triple negative breast cancer.

Cetuximab plus radiotherapy in patients with unresectable locally advanced squamous cell carcinoma of head and neck region--a open labelled single arm phase II study.

PURPOSE: To evaluate feasibility, safety and outcome of cetuximab concurrent with radiotherapy in locally advanced head-neck cancer. MATERIALS AND METHODS: Between March 2007 and January 2008 eligible cases of locally advanced unresectable (Stage IV) squamous cell carcinoma of head and neck were enrolled in this single arm, open labeled phase II Study. They were treated with cetuximab for a duration of 8 weeks and concomitant RT for 7 weeks (starting one week after initiating Cetuximab). RESULTS: A total of 19 eligible patients were enrolled. The median age of patients was 53 years, all patients happening to be male. The performance status of the patients was 0/1. The location of the primary tumor was oropharynx in 12 cases, oral cavity in 4, larynx in 2, and hypopharynx in one case. The overall response rate (ORR) was 68.42% and the overall survival at 2 year was 84 %. All 13 patients who completed two years follow-up after completion of study treatment continued to be alive with no evidence of disease progression. One patient also remained alive with progressive disease. CONCLUSIONS: Cetuximab concurrent with radiotherapy is a safe and effective option in advanced head-neck cancer patients.

TRPV1 expression-dependent initiation and regulation of filopodia.

Transient receptor potential vanilloid subtype 1 (TRPV1), a non-selective cation channel, is present endogenously in dorsal root ganglia (DRG) neurons. It is involved in the recognition of various pain producing physical and chemical stimuli. In this work, we demonstrate that expression of TRPV1 induces neurite-like structures and filopodia and that the expressed protein is localized at the filopodial tips. Exogenous expression of TRPV1 induces filopodia both in DRG neuron-derived F11 cells and in non-neuronal cells, such as HeLa and human embryonic kidney (HEK) cells. We find that some of the TRPV1 expression-induced filopodia contain microtubules and microtubule-associated components, and establish cell-to-cell extensions. Using live cell microscopy, we demonstrate that the filopodia are responsive to TRPV1-specific ligands. But both, initiation and subsequent cell-to-cell extension formation, is independent of TRPV1 channel activity. The N-terminal intracellular domain of TRPV1 is sufficient for filopodial structure initiation while the C-terminal cytoplasmic domain is involved in the stabilization of microtubules within these structures. In addition, exogenous expression of TRPV1 results in altered cellular distribution and in enhanced endogenous expression of non-conventional myosin motors, namely myosin IIA and myosin IIIA. These data indicate a novel role of TRPV1 in the regulation of cellular morphology and cellular contact formation.

TRPV1 at nerve endings regulates growth cone morphology and movement through cytoskeleton reorganization.

While the importance of Ca(2+) channel activity in axonal path finding is established, the underlying mechanisms are not clear. Here, we show that transient receptor potential vanilloid receptor 1 (TRPV1), a member of the TRP superfamily of nonspecific ion channels, is physically and functionally present at dynamic neuronal extensions, including growth cones. These nonselective cation channels sense exogenous ligands, such as resenifera toxin, and endogenous ligands, such as N-arachidonoyl-dopamine (NADA), and affect the integrity of microtubule cytoskeleton. Using TRPV1-transiently transfected F11 cells and embryonic dorsal root ganglia explants, we show that activation of TRPV1 results in growth cone retraction, and collapse and formation of varicosities along neurites. These changes were due to TRPV1-activation-mediated disassembly of microtubules and are partly Ca(2+)-independent. Prolonged activation with very low doses (1 nM) of NADA results in shortening of neurites in the majority of isolectin B4-positive dorsal root ganglia neurones. We postulate that TRPV1 activation plays an inhibitory role in sensory neuronal extension and motility by regulating the disassembly of microtubules. This might have a role in the chronification of pain.

Identification and characterisation of novel tubulin-binding motifs located within the C-terminus of TRPV1.

Previously, we reported that TRPV1, the vanilloid receptor, interacts with soluble alphabeta-tubulin dimers as well as microtubules via its C-terminal cytoplasmic domain. The interacting region of TRPV1, however, has not been defined. We found that the TRPV1 C-terminus preferably interacts with beta-tubulin and less with alpha-tubulin. Using a systematic deletion approach and biotinylated-peptides we identified two tubulin-binding sites present in TRPV1. These two sequence stretches are highly conserved in all known mammalian TRPV1 orthologues and partially conserved in some of the TRPV1 homologues. As these sequence stretches are not similar to any known tubulin-binding sequences, we conclude that TRPV1 interacts with tubulin and microtubule through two novel tubulin-binding motifs.

Rapid disassembly of dynamic microtubules upon activation of the capsaicin receptor TRPV1.

The transmission of pain signalling involves the cytoskeleton, but mechanistically this is poorly understood. We recently demonstrated that the capsaicin receptor TRPV1, a non-selective cation channel expressed by nociceptors that is capable of detecting multiple pain-producing stimuli, directly interacts with the tubulin cytoskeleton. We hypothesized that the tubulin cytoskeleton is a downstream effector of TRPV1 activation. Here we show that activation of TRPV1 results in the rapid disassembly of microtubules, but not of the actin or neurofilament cytoskeletons. TRPV1 activation mainly affects dynamic microtubules that contain tyrosinated tubulins, whereas stable microtubules are apparently unaffected. The C-terminal fragment of TRPV1 exerts a stabilizing effect on microtubules when over-expressed in F11 cells. These findings suggest that TRPV1 activation may contribute to cytoskeleton remodelling and so influence nociception.

Molecular and functional characteristics, growth promoting effect and persistence of selected parent isolates and streptomycin resistant derivatives of rice rhizobacteria.

Molecular and functional characteristics of seven azospirilla and five phosphorus solubilizing bacteria (PSB) isolates of rice rhizosphere, growth promotion ability of two efficient strains, Azospirillum amazonense A10 (MTCC4716) and Bacillus megaterium P5 (MTCC4714) and their persistence based on streptomycin resistant derivatives (SRD), were determined. SDS-PAGE and isozyme banding patterns of the isolates were used to arbitrarily group the azospirilla into 4 and PSB into 3 clusters and as markers to ascertain their identity. The azospirilla produced 2.0 to 10.5 ppm of IAA like substances and showed nitrogenase activity of 0.02 to 3.55 nmole C2H4/hr/ml of pure culture. PSB isolates produced 7.8 to 15.0 ppm IAA like substances and 20 to 128 ppm soluble P. Induction of resistance to streptomycin resulted in changes of these properties. Co-inoculation of rice with SRD A10 and SRD P5 and their parental strains in separate treatments enhanced grain yield over control by 31 and 12.4%, respectively. Nitrogenase activity of rice roots under SRD co-inoculated treatment was higher (4.16 nmole C2H4/hr/hill) than that-under parental strains co-inoculated treatment (3.76 nmole C2H4/hr/hill). SDS-PAGE profile and population count of the strains confirmed their establishment in rice rhizosphere and persistence over a year after inoculation.

Identification and characterization of a Ca2+ -sensitive interaction of the vanilloid receptor TRPV1 with tubulin.

The vanilloid receptor TRPV1 plays a well-established functional role in the detection of a range of chemical and thermal noxious stimuli, such as those associated with tissue inflammation and the resulting pain. TRPV1 activation results in membrane depolarization, but may also trigger intracellular Ca2+ -signalling events. In a proteomic screen for proteins associated with the C-terminal sequence of TRPV1, we identified beta-tubulin as a specific TRPV1-interacting protein. We demonstrate that the TRPV1 C-terminal tail is capable of binding tubulin dimers, as well as of binding polymerized microtubules. The interaction is Ca2+ -sensitive, and affects microtubule properties, such as microtubule sensitivity towards low temperatures and nocodazole. Our data thus provide compelling evidence for the interaction of TRPV1 with the cytoskeleton. The Ca2+ -sensitivity of this interaction suggests that the microtubule cytoskeleton at the cell membrane may be a downstream effector of TRPV1 activation.

Hodgkin's disease relapse presenting as Pancoast's syndrome.

Among the various infrequent causes of Pancoast's syndrome, Hodgkin's disease is one. A 26 year old man was diagnosed as Hodgkin's disease. Five years later the disease relapsed producing Pancoast's syndrome. The importance of precise aetiological diagnosis before treatment of such cases with similar presentation is emphasized.