A new concurrent chemotherapy with vinorelbine and mitomycin C in combination with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck

Objective: The purpose of this pilot study was to evaluate the feasibility and toxicity of concurrent chemotherapy with vinorelbine and mitomycin C in combination with accelerated radiotherapy (RT) in patients with locally advanced cancer of the head and neck. Patients and Methods: Between January 2003 and March 2004, 15 patients with T4/N2-3 squamous cell carcinoma (12/15) and with N3 cervical lymph node metastases of carcinoma of unknown primary (3/15) were treated with chemotherapy and simultaneous accelerated RT. Results: 11 patients completed therapy without interruption or dose reduction. Grade 3 - 4 acute mucosal toxicity was observed in 9/15 patients, grade 4 hematologic toxicity in 6/15 patients. At a median follow-up of 7.5 months, 2 patients have died of intercurrent disease, 2 patients have experienced local relapse; 5 patients are alive with no evidence of disease at the primary tumor site. Discussion: The described regimen is highly effective, but led to remarkable side effects

EMA-amplicon-based sequencing informs risk assessment analysis of water treatment systems

Illumina amplicon-based sequencing was coupled with ethidium monoazide bromide (EMA) pre-treatment to monitor the total viable bacterial community and subsequently identify and prioritise the target organisms for the health risk assessment of the untreated rainwater and rainwater treated using large-volume batch solar reactor prototypes installed in an informal settlement and rural farming community. Taxonomic assignments indicated that Legionella and Pseudomonas were the most frequently detected genera containing opportunistic bacterial pathogens in the untreated and treated rainwater at both sites. Additionally, Mycobacterium, Clostridium sensu stricto and Escherichia/Shigella displayed high (≥80%) detection frequencies in the untreated and/or treated rainwater samples at one or both sites. Numerous exposure scenarios (e.g. drinking, cleaning) were subsequently investigated and the health risk of using untreated and solar reactor treated rainwater in developing countries was quantified based on the presence of L. pneumophila, P. aeruginosa and E. coli. The solar reactor prototypes were able to reduce the health risk associated with E. coli and P. aeruginosa to below the 1 × 10−4 annual benchmark limit for all the non-potable uses of rainwater within the target communities (exception of showering for E. coli). However, the risk associated with intentional drinking of untreated or treated rainwater exceeded the benchmark limit (E. coli and P. aeruginosa). Additionally, while the solar reactor treatment reduced the risk associated with garden hosing and showering based on the presence of L. pneumophila, the risk estimates for both activities still exceeded the annual benchmark limit. The large-volume batch solar reactor prototypes were thus able to reduce the risk posed by the target bacteria for non-potable activities rainwater is commonly used for in water scarce regions of sub-Saharan Africa. This study highlights the need to assess water treatment systems in field trials using QMRA

Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B

Voltage-gated potassium channels (Kv) are important regulators of membrane potential in vascular smooth muscle cells, which is integral to controlling intracellular Ca2+ concentration and regulating vascular tone. Previous work indicates that Kv channels can be modulated by receptor-driven alterations of cyclic AMP-dependent protein kinase (PKA) activity. Here, we demonstrate that Kv channel activity is maintained by tonic activity of PKA. Whole-cell recording was used to assess the effect of manipulating PKA signalling on Kv and ATP-dependent K+ channels of rat mesenteric artery smooth muscle cells. Application of PKA inhibitors, KT5720 or H89, caused a significant inhibition of Kv currents. Tonic PKA-mediated activation of Kv appears maximal as application of isoprenaline (a β-adrenoceptor agonist) or dibutyryl-cAMP failed to enhance Kv currents. We also show that this modulation of Kv by PKA can be reversed by protein phosphatase 2B/calcineurin (PP2B). PKA-dependent inhibition of Kv by KT5720 can be abrogated by pre-treatment with the PP2B inhibitor cyclosporin A, or inclusion of a PP2B auto-inhibitory peptide in the pipette solution. Finally, we demonstrate that tonic PKA-mediated modulation of Kv requires intact caveolae. Pre-treatment of the cells with methyl-β-cyclodextrin to deplete cellular cholesterol, or adding caveolin-scaffolding domain peptide to the pipette solution to disrupt caveolae-dependent signalling each attenuated PKA-mediated modulation of the Kv current. These findings highlight a novel, caveolae-dependent, tonic modulatory role of PKA on Kv channels providing new insight into mechanisms and the potential for pharmacological manipulation of vascular tone

Preoperative short-term radiation therapy (25 Gy, 2.5 Gy twice daily) for primary resectable rectal cancer (phase II)

To evaluate the feasibility, effectiveness, and long-term bowel function of preoperative hyperfractionated accelerated radiotherapy in primary resectable rectal cancer. A total of 184 consecutive patients (median age 65 years, male : female=2 : 1) with clinical T3Nx rectal adenocarcinoma received preoperative pelvic radiation therapy with single fractions of 2.5 Gy twice daily (interval 6 h between fractions) to a total dose of 25 Gy within 1 week. Surgery was conducted the following week. Postoperative histology revealed UICC stage I in 33%, stage II in 26%, stage III in 34%, and stage IV in 7% of the patients. Median follow-up was 43 months (53 months for surviving patients). The actuarial 4-year-local-recurrence rate was 2.1%, overall recurrence 23%. Disease-specific and disease-free survivals at 4 years (excluding stage IV) were 82 and 69%, respectively. Overall survival for 4 years was 68%. Postoperative mortality was 0.5% (one patient), early anastomotic leakage occurred in 11.4%, and anastomotic stenosis requiring treatment in 6%, of 132 patients with primary anastomosis. Seven of 184 patients (3.8%) died of abdominal complications, all within the first year. Bowel function was satisfactory after more than 5 years. Local control in primarily resectable rectal cancer after 10 × 2.5 Gy is excellent, warranting further evaluation of this treatment

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group

BACKGROUND AND PURPOSE: The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results. MATERIALS AND METHODS: Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint. RESULTS: For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005). CONCLUSION: The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer

A meta-analysis of hyperfractionated and accelerated radiotherapy and combined chemotherapy and radiotherapy regimens in unresected locally advanced squamous cell carcinoma of the head and neck

BACKGROUND: Former meta-analyses have shown a survival benefit for the addition of chemotherapy (CHX) to radiotherapy (RT) and to some extent also for the use of hyperfractionated radiation therapy (HFRT) and accelerated radiation therapy (AFRT) in locally advanced squamous cell carcinoma (SCC) of the head and neck. However, the publication of new studies and the fact that many older studies that were included in these former meta-analyses used obsolete radiation doses, CHX schedules or study designs prompted us to carry out a new analysis using strict inclusion criteria. METHODS: Randomised trials testing curatively intended RT (≥60 Gy in >4 weeks/>50 Gy in <4 weeks) on SCC of the oral cavity, oropharynx, hypopharynx, and larynx published as full paper or in abstract form between 1975 and 2003 were eligible. Trials comparing RT alone with concurrent or alternating chemoradiation (5-fluorouracil (5-FU), cisplatin, carboplatin, mitomycin C) were analyzed according to the employed radiation schedule and the used CHX regimen. Studies comparing conventionally fractionated radiotherapy (CFRT) with either HFRT or AFRT without CHX were separately examined. End point of the meta-analysis was overall survival. RESULTS: Thirty-two trials with a total of 10 225 patients were included into the meta-analysis. An overall survival benefit of 12.0 months was observed for the addition of simultaneous CHX to either CFRT or HFRT/AFRT (p < 0.001). Separate analyses by cytostatic drug indicate a prolongation of survival of 24.0 months, 16.8 months, 6.7 months, and 4.0 months, respectively, for the simultaneous administration of 5-FU, cisplatin-based, carboplatin-based, and mitomycin C-based CHX to RT (each p < 0.01). Whereas no significant gain in overall survival was observed for AFRT in comparison to CFRT, a substantial prolongation of median survival (14.2 months, p < 0.001) was seen for HFRT compared to CFRT (both without CHX). CONCLUSION: RT combined with simultaneous 5-FU, cisplatin, carboplatin, and mitomycin C as single drug or combinations of 5-FU with one of the other drugs results in a large survival advantage irrespective the employed radiation schedule. If radiation therapy is used as single modality, hyperfractionation leads to a significant improvement of overall survival. Accelerated radiation therapy alone, especially when given as split course radiation schedule or extremely accelerated treatments with decreased total dose, does not increase overall survival

Distant metastases of a squamous cell carcinoma of the tongue in peripheral skeletal muscles and adjacent soft tissues

A 66-year-old female patient was admitted to our department with a large tumor of the tongue measuring 10 cm in diameter. The tumor occupied nearly the entire oral cavity and showed exophytic and ulcerative areas. Histological analysis revealed a low grade squamous cell carcinoma (SCC) of the tongue. Bilateral enlarged cervical lymphatic masses were also present. The extent of the tumor infiltration was assessed by fluoro-2-deoxy-glucose-positron emission tomography (PET) scans showing an elevated activity of the tracer corresponding to the assumed cervical metastases. Additionally, pulmonary metastases were identified. Contrast enhanced computed tomography (CT) scans showed metastases in the soft tissues of the abdomen, legs and arms. Foci of distant metastases were found in the left upper anterior thoracal wall, near the intraabdominal portion of the aorta, near the right iliac crest and in both the right vastus medialis- and adductor magnus muscles. The final diagnosis was a T4N3M1(G3)(C3) SCC of the tongue with multiple distant thoracal, abdominal and intramuscular metastases. The survival expectancy was five weeks, and the patient finally deceased by cardiopulmonary complications

Ceramides bind VDAC2 to trigger mitochondrial apoptosis

Ceramides draw wide attention as tumor suppressor lipids that act directly on mitochondria to trigger apoptotic cell death. However, molecular details of the underlying mechanism are largely unknown. Using a photoactivatable ceramide probe, we here identify the voltage-dependent anion channels VDAC1 and VDAC2 as mitochondrial ceramide binding proteins. Coarse-grain molecular dynamics simulations reveal that both channels harbor a ceramide binding site on one side of the barrel wall. This site includes a membrane-buried glutamate that mediates direct contact with the ceramide head group. Substitution or chemical modification of this residue abolishes photolabeling of both channels with the ceramide probe. Unlike VDAC1 removal, loss of VDAC2 or replacing its membrane-facing glutamate with glutamine renders human colon cancer cells largely resistant to ceramide-induced apoptosis. Collectively, our data support a role of VDAC2 as direct effector of ceramide-mediated cell death, providing a molecular framework for how ceramides exert their anti-neoplastic activity

The modular systems biology approach to investigate the control of apoptosis in Alzheimer's disease neurodegeneration

Apoptosis is a programmed cell death that plays a critical role during the development of the nervous system and in many chronic neurodegenerative diseases, including Alzheimer's disease (AD). This pathology, characterized by a progressive degeneration of cholinergic function resulting in a remarkable cognitive decline, is the most common form of dementia with high social and economic impact. Current therapies of AD are only symptomatic, therefore the need to elucidate the mechanisms underlying the onset and progression of the disease is surely needed in order to develop effective pharmacological therapies. Because of its pivotal role in neuronal cell death, apoptosis has been considered one of the most appealing therapeutic targets, however, due to the complexity of the molecular mechanisms involving the various triggering events and the many signaling cascades leading to cell death, a comprehensive understanding of this process is still lacking. Modular systems biology is a very effective strategy in organizing information about complex biological processes and deriving modular and mathematical models that greatly simplify the identification of key steps of a given process. This review aims at describing the main steps underlying the strategy of modular systems biology and briefly summarizes how this approach has been successfully applied for cell cycle studies. Moreover, after giving an overview of the many molecular mechanisms underlying apoptosis in AD, we present both a modular and a molecular model of neuronal apoptosis that suggest new insights on neuroprotection for this disease