The role of microRNA in head and neck cancer: Current knowledge and perspectives

Head and neck cancer is one of the most commonly diagnosed malignancies worldwide. Patients with advanced disease stages frequently develop recurrences or distant metastasis, which results a five-year survival rates of less than 60% despite considerable advances in multimodality therapy. A better understanding of molecular basis of tumorigenesis is required to improve clinical outcomes and to develop new anti-cancer drugs. microRNAs (miRNAs) are a class of small, non-coding, RNA molecules that modulate gene expression post-Transcriptionally. They are important regulator in normal biological process; however miRNAs deregulation has been observed in many different tumors and is involved in tumorigenesis. miRNAs may act as tumor suppressors or as oncogenes. Several studies on head and neck cancer demonstrated how aberrant expression of miRNAs is involved in proliferation, metastasis, chemoresistence, and radioresistance. In addition, miRNAs are excellent biomarker targets because they circulate stable in human body fluids and can be obtained with non-invasive methods. Moreover, miRNAs up and down regulation has been correlated with specific cancer phenotype (poor prognosis, aggressiveness and resistance to treatment), playing a role as prognostic biomarkers. This review summarizes current finding on miRNAs in head and neck cancer and their potential role as target for next drug therapy. © 2014 by the authors

Induction chemotherapy followed by alternating chemo-radiotherapy in stage IV undifferentiated nasopharyngeal carcinoma

In locally advanced undifferentiated nasopharyngeal carcinoma (UNPC), concomitant chemo-radiotherapy is the only strategy that gave better results over radiation alone in a phase III trial. Adding effective chemotherapy to a concomitant chemo-radiotherapy programme may be a way to improve the results further. 30 patients with previously untreated T4 and/or N2–3 undifferentiated nasopharyngeal carcinoma were consecutively enrolled and initially treated with 3 courses of epidoxorubicin, 90 mg/m2, day 1 and cisplatin, 40 mg/m2, days 1 and 2, every 3 weeks. After a radiological and clinical response assessment patients underwent 3 courses of cisplatin, 20 mg/m2/day, days 1–4 and fluorouracil, 200 mg/m2/day, days 1–4, i.v. bolus, (weeks 1, 4, 7) alternated to 3 courses of radiation (week 2–3, 5–6, 8–9–10), with a single daily fractionation, up to 70 Gy. WHO histology was type 2 in 30% and type 3 in 70% of the patients. 57% had T4 and 77% N2–3 disease. All the patients are evaluable for toxicity and response. All but one received 3 courses of induction chemotherapy. Toxicity was mild to moderate in any case. At the end of the induction phase 10% of CRs, 83.3% of PRs and 6.7% of SD were recorded. All the patients but one had the planned number of chemotherapy courses in the alternating phase and all received the planned radiation dose. One patient out of 3 developed grade III–IV mucositis. Haematological toxicity was generally mild to moderate. At the final response evaluation 86.7% of CRs and 13.3% of PRs were observed. At a median follow-up of 31 months, 13.3% of patients had a loco-regional progression and 20% developed distant metastases. The 3-year actuarial progression-free survival and overall survival rates were 64% and 83%. Induction chemotherapy followed by alternating chemo-radiotherapy is feasible and patients' compliance optimal. This approach showed a very promising activity on locally advanced UNPC and merits to be investigated in phase III studies. © 2000 Cancer Research Campaign http://www.bjcancer.co

Proteasome stress sensitizes malignant pleural mesothelioma cells to bortezomib-induced apoptosis

Abstract Based on promising results in preclinical models, clinical trials have been performed to evaluate the efficacy of the first-in-class proteasome inhibitor bortezomib towards malignant pleural mesothelioma (MPM), an aggressive cancer arising from the mesothelium of the serous cavities following exposure to asbestos. Unexpectedly, only minimal therapeutic benefits were observed, thus implicating that MPM harbors inherent resistance mechanisms. Identifying the molecular bases of this primary resistance is crucial to develop novel pharmacologic strategies aimed at increasing the vulnerability of MPM to bortezomib. Therefore, we assessed a panel of four human MPM lines with different sensitivity to bortezomib, for functional proteasome activity and levels of free and polymerized ubiquitin. We found that highly sensitive MPM lines display lower proteasome activity than more bortezomib-resistant clones, suggesting that reduced proteasomal capacity might contribute to the intrinsic susceptibility of mesothelioma cells to proteasome inhibitors-induced apoptosis. Moreover, MPM equipped with fewer active proteasomes accumulated polyubiquitinated proteins, at the expense of free ubiquitin, a condition known as proteasome stress, which lowers the cellular apoptotic threshold and sensitizes mesothelioma cells to bortezomib-induced toxicity as shown herein. Taken together, our data suggest that an unfavorable load-versus-capacity balance represents a critical determinant of primary apoptotic sensitivity to bortezomib in MPM

Pharmacokinetic and metabolism determinants of fluoropyrimidines and oxaliplatin activity in treatment of colorectal patients

Fluoropyrimidines and oxaliplatin continued to be the mainstay of therapeutic regimens in the treatment of colorectal cancer (CRC). For this reason, pharmacokinetic and metabolism of these drugs were analyzed and the identification of accurate and validated predictive, prognostic and toxicity markers became necessary to develop an effective therapy adapted to the patient's molecular profile, while minimizing life-threatening toxicities. In this review, we discuss literature data, defining predictive and prognostic markers actually identified in the treatment of CRC. We analyzed predictive markers of fluoropyrimidines effectiveness, principally for 5-Fluorouracil (5-FU) and also for oral fluoropyrimidines, as thymidylate Synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), methylenetetrahydrofolate reductase (MTHFR), deoxyuridine triphosphate nucleotidohydrolase (dUTPase), micro-satellite instability. DPD represent the more studied 5-FU toxicity marker, followed by TS and OPRT. Oxaliplatin effectiveness is principally regulated by nucleotide excision repair (NER) pathway, including excision repair cross-complementation group 1 (ERCC1), X-ray cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XDP). The major oxaliplatin toxicity marker is represented by glutathione S-transferase (GST). All these results are based principally on retrospective studies. The future challenge became to validate molecular markers and their association with clinical outcomes in prospective trials, refining technologic platforms and bioin-formatics to accommodate the complexity of the multifaceted molecular map that may determine outcome, and determining CRC patients most likely to benefit from therapeutic interventions tailored specifically for them

Head and neck region consolidation radiotherapy and prophylactic cranial irradiation with hippocampal avoidance delivered with helical tomotherapy after induction chemotherapy for non-sinonasal neuroendocrine carcinoma of the upper airways

Background: Non-sinonasal neuroendocrine carcinomas (NSNECs) of the head and neck are considered an unfrequent clinico-pathological entity. Combined modality treatment represents an established therapeutic option for undifferentiated forms where distant metastasis is a common pattern of failure.Methods: We report on a case of NSNEC treated with sequential chemo-radiation consisting of 6 cycles of cisplatin and etoposide followed by loco-regional radiation to the head and neck and simultaneous prophylactic cranial irradiation to prevent from intracranial spread, delivered with helical tomotherapy with the 'hippocampal avoidance' technique in order to reduce neuro-cognitive late effects.Results: One year after the end of the whole combined modality approach, the patient achieved complete remission, with no treatment-related sub-acute and late effects.Conclusions: The present report highlights the importance of multidisciplinary management for NSNECs of the head and neck, as the possibility to achieve substantial cure rates with mild side effects with modern radiotherapy techniques. © 2012 Franco et al; BioMed Central Ltd

Risk of venous thromboembolism in people with lung cancer: a cohort study using linked UK healthcare data

Background: Venous thromboembolism is a potentially preventable cause of death in people with lung cancer. Identification of those most at risk and high risk periods may provide the opportunity for better targeted intervention. Methods: We conducted a cohort study using the Clinical Practice Research Datalink linked to Hospital Episode Statistics and Cancer Registry data. Our cohort comprised 10,598 people with lung cancer diagnosed between 1997 and 2006 with follow-up continuing to the end of 2010. Cox regression analysis was performed to determine which demographic, tumour and treatment-related factors (time-varying effects of chemotherapy and surgery) independently affected VTE risk. We also determined the effect of a VTE diagnosis on the survival of people with lung cancer. Results: People with lung cancer had an overall VTE incidence of 39.2 per 1000 person years (95% confidence Interval (CI), 35.4-43.5), though rates varied depending on the patient group and treatment course. Independent factors associated with increased VTE risk were: metastatic disease (hazard ratio (HR)=1.9, CI 1.2, 3.0 vs. local disease); adenocarcinoma sub-type (HR =2.0, CI 1.5, 2.7, vs. squamous cell; chemotherapy administration, (HR=2.1, CI 1.4, 3.0 vs. outside chemotherapy courses); and diagnosis via emergency hospital admission (HR=1.7, CI 1.2-2.3 vs. other routes to diagnosis). Patients with VTE had an approximately 50% higher risk of mortality than those without VTE. Conclusions: People with lung cancer have especially high risk of VTE if they have advanced disease, adenocarcinoma, or are undergoing chemotherapy. Presence of VTE is an independent risk factor for death

Standard (8 weeks) vs long (12 weeks) timing to minimally-invasive surgery after NeoAdjuvant Chemoradiotherapy for rectal cancer: A multicenter randomized controlled parallel group trial (TiMiSNAR)

Background: The optimal timing of surgery in relation to chemoradiation is still controversial. Retrospective analysis has demonstrated in the recent decades that the regression of adenocarcinoma can be slow and not complete until after several months. More recently, increasing pathologic Complete Response rates have been demonstrated to be correlated with longer time interval. The purpose of the trial is to demonstrate if delayed timing of surgery after neoadjuvant chemoradiotherapy actually affects pathologic Complete Response and reflects on disease-free survival and overall survival rather than standard timing. Methods: The trial is a multicenter, prospective, randomized controlled, unblinded, parallel-group trial comparing standard and delayed surgery after neoadjuvant chemoradiotherapy for the curative treatment of rectal cancer. Three-hundred and forty patients will be randomized on an equal basis to either robotic-assisted/standard laparoscopic rectal cancer surgery after 8 weeks or robotic-assisted/standard laparoscopic rectal cancer surgery after 12 weeks. Discussion: To date, it is well-know that pathologic Complete Response is associated with excellent prognosis and an overall survival of 90%. In the Lyon trial the rate of pCR or near pathologic Complete Response increased from 10.3 to 26% and in retrospective studies the increase rate was about 23-30%. These results may be explained on the relationship between radiation therapy and tumor regression: DNA damage occurs during irradiation, but cellular lysis occurs within the next weeks. Study results, whether confirmed that performing surgery after 12 weeks from neoadjuvant treatment is advantageous from a technical and oncological point of view, may change the current pathway of the treatment in those patient suffering from rectal cancer. Trial registration: ClinicalTrials.gov NCT3465982