Cardiovascular responses during free-diving in the sea.

Cardiac output has never been assessed during free-diving diving in the sea. Knowledge of human diving response in this setting is therefore scarce. 3 immersions were performed by 7 divers: at depths of 10 m, 20 m and 30 m. Each test consisted of 3 apnea phases: descent, static and ascent. An impedance cardiograph provided data on stroke volume, heart rate and cardiac output. Mean blood pressure, arterial O2 saturation and blood lactate values were also collected. Starting from a resting value of 4.5±1.6 L∙min(-1), cardiac output at 10 m showed an increase up to 7.1±2.2 L∙min(-1) (p<0.01) during the descent, while conditions during the static and ascent phases remained unchanged. At 20 m cardiac output values were 7.3±2.4 L∙min(-1) and 6.7(±1).2 L∙min(-1) during ascent and descent, respectively (p<0.01), and 4.3±0.9 L∙min(-1) during static phase. At 30 m cardiac output values were 6.5±1.8 L∙min(-1) and 7.5±2 L∙min(-1) during descent and ascent, respectively (p<0.01), and 4.7±2.1 L∙min(-1) during static phase. Arterial O2 saturation decreased with increasing dive depth, reaching 91.1±3.4% (p<0.001 vs. rest) upon emergence from a depth of 30 m. Blood lactate values increased to 4.1±1.2 mmol∙L(-1) at the end of the 30 m dive (p<0.001 vs. rest). Results seem to suggest that simultaneous activation of exercise and diving response could lead to an absence of cardiac output reduction aimed at an oxygen-conserving effect.

Muscle ischemic preconditioning does not improve performance during self-paced exercise.

Muscle ischemic preconditioning (IP) has been found to improve exercise performance in laboratory tests. This investigation aims at verifying whether performance is improved by IP during self-paced exercise (SPE) in the field. 11 well-trained male runners performed 3 randomly assigned 5 000 m self-paced running tests on an outdoor track. One was the reference (RT) test, while the others were performed following muscle IP (IPT) and a control sham test (ST). Average speeds were measured during each test. Mean values in oxygen uptake (VO2), aerobic energy cost (AEC) during race and post-race blood lactate (BLa) were gathered. Data showed that none of the studied variables were affected by IPT or ST with respect to the RT test. Average speeds were 4.63±0.31, 4.62±0.31 and 4.60±0.25 m·s(-1) for the RT, the ST and the IPT tests, respectively. Moreover, there was no difference among tests in speed reached during each lap. VO2 was 3.5±0.69, 3.74±0.85 and 3.62±1.19 l·min(-1). AEC was 1.04±0.15, 1.08±0.1 and 1.09±0.15 kcal·kg(-1)·km(-1). Finally, post-race BLa levels reached 12.85±3.54, 11.88±4.74 and 12.82±3.6 mmol·l(-1). These findings indicate that performance during SPE is not ameliorated by ischemic preconditioning, thereby indicating that IP is not suitable as an ergogenic aid.

Combining in the melt physical and biological properties of poly(caprolactone) and chlorhexidine to obtain antimicrobial surgical monofilaments.

Bacterial infections on a sutured wound represent a critical problem, and the preparation of suture threads possessing antimicrobial properties is valuable. In this work, poly(caprolactone) (PCL) monofilaments were compounded at the concentration of 1, 2 and 4 % (w/w), respectively, to the antiseptic chlorhexidine diacetate (CHX). The incorporation was carried out in the melt by a single-step methodology, i.e. "online" approach. Mechanical tests revealed that the incorporation of CHX does not significantly change tensile properties of PCL fibres as the thermal profile adopted to prepare the compounded fibres does not compromise the antibacterial activity of CHX. In fact, CHX confers to compounded PCL fibres' antimicrobial property even at the lowest CHX concentration as revealed by microbiological assays performed on Escherichia coli, Micrococcus luteus and Bacillus subtilis strains. The scanning electron microscope micrographs and energy-dispersive X-ray analysis of compounded threads revealed that CHX is uniformly distributed on fibre surface and that the overall amount of superficial CHX increases by increasing compounded CHX concentration. This distribution determines a biphasic CHX release kinetics characterized by an initial rapid solubilisation of superficial CHX micro-crystals, followed by a slow and gradual release of CHX incorporated in the bulk. Interestingly, the compounded threads did not show any toxic effect compromising cell viability of human fibroblasts in vitro, differently from that observed using an equal amount of pure CHX. Thus, this study originally demonstrated the effectiveness of an "online" approach to confer antimicrobial properties to an organic thermoplastic polymeric material commonly used for medical devices.

Cervical follicular dendritic cell sarcoma: a case report and review of the literature.

Follicular dendritic cell (FDC) sarcoma is a rare tumour with a low-to-intermediate grade of malignancy. It frequently occurs in cervical, mediastinal and axillary lymph nodes. In approximately 30% of cases an extranodal localization has been reported (tonsils, oral cavity, mediastinum, liver, and spleen). Very little is known about possible treatment options and overall prognosis. This case reports a 66 year-old patient, who underwent surgical removal of a persistently enlarged right cervical lymph node. The histopathological examination revealed a spindle cell tumour with lymphocyte and plasma cell infiltrates. Neoplastic cells stained positive for CD21, CD23 and CD35, thus confirming the diagnosis of FDC sarcoma. The neoplasm recurred two years later and partial regression was achieved by IGEV rescue therapy. We briefly discuss clinical history, histopathological differential diagnosis and treatment options of FDC sarcoma.

Vascular endothelial growth factor receptor tyrosine kinase inhibitors for the treatment of advanced non-small cell lung cancer.

Introduction: Angiogenesis is the process by which the tumor develops its potential for growth and distant metastasis. The main proangiogenic switch is vascular endothelial growth factor (VEGF), which, along with its receptor VEGFR, is a target for biological drugs such as multi-targeted tyrosine kinase inhibitors used for many neoplasms, including non-small cell lung cancer (NSCLC).Areas covered: The fact that angiokinase inhibitors act on several signaling molecules simultaneously means that the use of alternative transmission pathways, which nullifies the effect of drugs directed against a single target, is avoided. Nevertheless, most of these drugs have failed to improve any outcome in NSCLC patients. The authors discuss these points and provide their expert perspectives.Expert opinion: Multikinase inhibitors are the fruit of research which regards cancer as a complex system of interacting processes. However, the lack of predictive biomarkers of response has limited the development of this class of drugs in NSCLC. Combination trials with chemotherapy, immunotherapy or other targeted drugs are ongoing, and while some have already confirmed the role of antiangiogenic small molecules in integrated regimes, others are still evaluating the efficacy of these drugs and raising questions about their cost and tolerability.

Fast wide-volume functional imaging of engineered in vitro brain tissues.

The need for in vitro models that mimic the human brain to replace animal testing and allow high-throughput screening has driven scientists to develop new tools that reproduce tissue-like features on a chip. Three-dimensional (3D) in vitro cultures are emerging as an unmatched platform that preserves the complexity of cell-to-cell connections within a tissue, improves cell survival, and boosts neuronal differentiation. In this context, new and flexible imaging approaches are required to monitor the functional states of 3D networks. Herein, we propose an experimental model based on 3D neuronal networks in an alginate hydrogel, a tunable wide-volume imaging approach, and an efficient denoising algorithm to resolve, down to single cell resolution, the 3D activity of hundreds of neurons expressing the calcium sensor GCaMP6s. Furthermore, we implemented a 3D co-culture system mimicking the contiguous interfaces of distinct brain tissues such as the cortical-hippocampal interface. The analysis of the network activity of single and layered neuronal co-cultures revealed cell-type-specific activities and an organization of neuronal subpopulations that changed in the two culture configurations. Overall, our experimental platform represents a simple, powerful and cost-effective platform for developing and monitoring living 3D layered brain tissue on chip structures with high resolution and high throughput.

Novel immunotherapy in the treatment of advanced non-small cell lung cancer.

INTRODUCTION: Lung cancers remain the principal cause of death cancer-related worldwide with a poor survival rate at five years from diagnosis. In patients with NSCLC harboring specific genetic alterations the anti EGFR TKIs and the ALK TKIs have improved the response rate and the quality of life compared to standard platinum-based chemotherapy. New approaches possibly applicable at the major of patients are needed. Areas covered: The discovery that the immune system plays a fundamental role in the fight against cancer. The cancer cells use mechanisms able to avoid the immune control has led to the development of drugs able to overcome this escape route. The best known checkpoint pathways are the CTLA-4 and PD-1/PD-L1; they suppress T-cell activity in different ways: CTLA-4 regulates T-cell activity at an early stage whereas PD-1 regulates later effector T-cell activity within tissue and tumors. The best characterized checkpoint inhibitors in advanced NSCLC setting are ipilimumab and tremelimumab, (anti-CTLA-4 antibodies), nivolumab and pembrolizumab (anti-PD-1 antibodies), atezolizumab and durvalumab (anti-PD-L1 antibodies). Nivolumab and pembrolizumab have received the FDA and EMA approval for the treatment of NSCLC in second-line setting. Expert commentary: The role played by tumor microenvironment may be the next area of research to overcome the resistance at the checkpoint inhibitors as well as the identification of biomarkers to better select patients. In addition checkpoint inhibitors are investigate in combination with other agent involved in immune control with promising results in solid tumors.

Carboplatin plus vinorelbine, a new well-tolerated and active regimen for the treatment of extensive-stage small-cell lung cancer: a phase II study. Gruppo Oncologico Centro-Sud-Isole.

PURPOSE: To evaluate the activity and toxicity of the combination carboplatin plus vinorelbine in extensive small-cell lung cancer (SCLC). PATIENTS AND METHODS: A two-stage optimal Simon design was applied. To proceed after the first stage, responses from 8 of 11 treated patients were needed. Overall, 31 responses of 43 treated patients were required to comply with the design parameters. Inclusion criteria were cytohistologically proven SCLC; extensive disease; age of 70 years or less; Eastern Cooperative Oncology group performance status (ps ECOG) of 2 or less; normal cardiac, hepatic, renal, and bone marrow functions; and no previous chemotherapy. Patients were staged by physical examination; biochemistry; chest radiograph; brain, thoracic; and abdominal computed tomographic (CT) scans, and bone scan. All patients received carboplatin 300 mg/m2 intravenously (i.v.) day 1 and vinorelbine 25 mg/m2 i.v. on days 1 and 8 every 4 weeks up to six cycles. Of 43 enrolled patients, 36 were men and 7 women, with a median age of 63 years (range, 46 to 70 years). RESULTS: All patients were assessable for response and toxicity. We observed 32 (74%) objective responses, with 23% complete responses. Median time to progression was 25 weeks, and median survival was 37 weeks. The treatment was well tolerated. The reported main toxicities were leukopenia grade 3 in 21% of patients and grade 4 in 5% of patients, anemia grade 2 in 11% of patients and grade 3 in 2% of patients, and thrombocytopenia grade 3 in 7% of patients. CONCLUSION: These data show that carboplatin plus vinorelbine is an active and well-tolerated regimen in extensive SCLC. In view of the activity, low toxicity, and ease of administration, it may be a reasonable alternative to more toxic cisplatin-containing regimens.

Phase I study of epirubicin plus vinorelbine with or without G-CSF in advanced non-small cell lung cancer.

The present phase I study was designed to determine the maximum tolerated dose (MTD) of epirubicin, administered every 3 weeks to patients with advanced non-small cell lung cancer (NSCLC), and combined with a conventional dose of vinorelbine [25 mg/m2 intravenously (i.v.) days 1 and 8] with or without the support of granulocyte-colony stimulating factor (G-CSF). 18 patients entered the study. The patients received the following four dose levels of epirubicin (i.v., day 1): 50 mg/m2 (3 patients) and 60 mg/m2 (6 patients) without G-CSF, 75 mg/m2 (3 patients) and 90 mg/m2 (6 patients) with G-CSF (5 micrograms/kg days 4-6 and 9-15). In the patients treated without G-CSF the MTD of epirubicin was 60 mg/m2 and leukopenia was the dose-limiting toxicity. In the patients treated with G-CSF the MTD was 90 mg/m2, myelotoxicity being the dose-limiting toxicity. We observed 1/3 partial response (PR) with epirubicin at the dose of 75 mg/m2 and 2/6 PR at 90 mg/m2. These results would indicate the usefulness of a phase II study with epirubicin at the dose of 90 mg/m2 in association with conventional dose of vinorelbine with the support of G-CSF in advanced NSCLC.

Mitomycin C plus vindesine or cisplatin plus epirubicin in previously treated patients with symptomatic advanced non-small-cell lung cancer.

A total of 40 previously treated patients with symptomatic advanced non-small-cell lung cancer (NSCLC) were subjected to second-line chemotherapy with mitomycin C plus vindesine (MV) or cisplatin plus epirubicin (PE). The 12 patients treated with the MV regimen showed no objective response (OR) or symptom palliation. In the 28 patients who received the PE regimen, we obtained a 25% partial response rate, with amelioration of tumor-related symptoms occurring in 35.7% of cases and improvement in the performance status being noted in 25% of subjects. Both regimens were well tolerated. These data show that the administration of cisplatin-based second-line chemotherapy to patients with symptomatic advanced NSCLC may be useful.

Mitomycin C and vindesine: an ineffective combination chemotherapy in the treatment of malignant pleural mesothelioma.

Twelve patients with malignant pleural mesothelioma were subjected to mitomycin C (MMC) and vindesine (VDS) chemotherapy (MMC 10 mg/m2, i.v., d 1; VDS, 3 mg/m2, i.v., d 1-8, every 4 weeks). No objective response was obtained; 3 (25%) patients had stable disease and 9 (75%) progression of disease. We conclude that MMC plus VDS is an ineffective combination chemotherapy in the treatment of malignant pleural mesothelioma.

Mitomycin C etoposide and vinorelbine (MEV II) in the treatment of metastatic stage IV non small cell lung cancer.

AIMS AND BACKGROUND: In a prior study with a new non-cisplatin-based regimen including mytomycin C, etoposide and vindesine (MEV I) we observed a 37% response rate and very low toxicity in stage IV non small cell lung cancer. In an attempt to improve the activity of MEV I we evaluated a new regimen, MEV II, a modification of MEV I in which vinorelbine replaced vindesine. METHODS: 21 patients with metastatic stage IV non small cell lung cancer entered the phase II trial and were treated with the MEV II regimen (mitomycin C 8 mg/m2, i.v., d 1, etoposide 100 mg/m2, i.v., d 1-3, vinorelbine 30 mg/m2, i.v., d 1, every 4 weeks. RESULTS: We observed a partial response rate of 30% (95% confidence limits 10-50) with a median survival of 6 months. The worst reported toxicity was leukopenia grade 4 in 10% of patients including one who died of sepsis and grade 3 in 20%. CONCLUSIONS: The MEV II regimen showed a similar activity but greater toxicity than MEV I.

The role of EGFR tyrosine kinase inhibitors in the first-line treatment of advanced non small cell lung cancer patients harboring EGFR mutation.

Lung cancer continues to be the leading cause of cancer death worldwide. Among lung cancers, 80% are classified as nonsmall- cell lung cancer (NSCLC) and are mostly diagnosed at an advanced stage (either locally advanced or metastatic disease). In the last years, the discovery of the pivotal role in tumorigenesis of the Epidermal Growth Factor Receptor (EGFR) has provided a new class of targeted therapeutic agents: the EGFR tyrosine kinase inhibitors (EGFR-TKIs). Since the first reports of an association between somatic mutations in EGFR exons 19 and 21 and response to EGFR-TKIs, treatment of advanced NSCLC has changed dramatically. Histologic profile, clinical characteristics, and mutational profile of lung carcinoma have all been reported as predictive factors of response to EGFR-TKIs and other targeted therapies. In advanced NSCLC patients harboring EGFR mutations, the use of EGFR TKIs in first-line treatment has provided an unusually large progression-free survival (PFS) benefit with a negligible toxicity when compared with cytotoxic chemotherapy in phase III randomized trials. Considering the findings regarding the excellent benefit and better safety profile of EGFR TKIs in EGFR mutation positive patients, these targeted therapeutic agents can be now considered as first-line treatment in this setting of patients. This review will discuss the new evidences in the role of EGFR-TKIs in the first-line treatment of advanced NSCLC and their implication in the current clinical decision-making.

Natural killer clones recognize specific soluble HLA class I molecules.

Enhancement of major histocompatibility complex (MHC) class I expression leads to protection from natural killer (NK) cell recognition in several systems. MHC class I gene products are released from the cell surface and can be found in sera as soluble forms. To investigate the possible immunoregulatory role of soluble HLA (sHLA) in NK cell-target recognition, several sHLA antigens were studied for their ability to induce NK cell cytotoxicity modulation. NK cell-target recognition was inhibited by the addition of sHLA during the cytotoxicity assay. Our results indicate that sHLA molecules can down-regulate NK killing at the effector level. Moreover, different NK clones are able to specifically recognize different sHLA antigens. Kp43 molecules seem to be involved in the NK recognition of sHLA-B7.

A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer. The DISTAL 01 study.

Docetaxel (75 mg m(-2) 3-weekly) is standard second-line treatment in advanced non-small-cell lung cancer (NSCLC) with significant toxicity. To verify whether a weekly schedule (33.3 mg m(-2) for 6 weeks) improved quality of life (QoL), a phase III study was performed with 220 advanced NSCLC patients, < or =75 years, ECOG PS < or =2. QoL was assessed by EORTC questionnaires and the Daily Diary Card (DDC). No difference was found in global QoL scores at 3 weeks. Pain, cough and hair loss significantly favoured the weekly schedule, while diarrhoea was worse. DDC analysis showed that loss of appetite and overall condition were significantly worse in the 3-week arm in the first week, while nausea and loss of appetite were more severe in the weekly arm in the third week. Response rate and survival were similar, hazard ratio of death in the weekly arm being 1.04 (95% CI 0.77-1.39). A 3-weekly docetaxel was more toxic for leukopenia, neutropenia, febrile neutropenia and hair loss; any grade 3-4 haematologic toxicity was significantly more frequent in the standard arm (25 vs 6%). The weekly schedule could be preferred for patients candidate to receive docetaxel as second-line treatment for advanced NSCLC, because of some QoL advantages, lower toxicity and no evidence of strikingly different effect on survival.

Mitomycin C plus vindesine plus etoposide (MEV) versus mitomycin C plus vindesine plus cisplatin (MVP) in stage IV non-small-cell lung cancer: A phase III multicentre randomised trial. The "Gruppo Oncologico Centro-Sud-Isole' (G.O.C.S.I.).

PURPOSE: To compare mitomycin C plus vindesine plus etoposide (MEV) vs. mitomycin C plus vindesine plus cisplatin (MVP) in the treatment of stage IV non-small-cell lung cancer. PATIENTS AND METHODS: 204 patients were entered in a phase III multicentre randomised trial from June 1990 to December 1994 and stratified according to the ECOG performance status (0-1 vs. 2). MVP was given in the following dosages: mitomycin C 8 mg/m2+vindesine 3 mg/m2+cisplatin 100 mg/m2 i.v. day 1 and vindesine 3 mg/m2 i.v. day 8 with cycles repeated every 4 weeks. MEV was given in the following dosages: mitomycin C 8 mg/m2+vindesine 3 mg/ m2 i.v. day 1 and etoposide 100 mg/m2 i.v. days 1 to 3 with cycles repeated every 3 weeks. For both treatments a maximum of 6 cycles was planned. Response and toxicity were evaluated according to WHO. Subjective responses were assessed by numerical scales. Analyses were made on the basis of intent to treat. RESULTS: The objective response rate was 21.4% (1 CR + 21 PR among 103 patients) in the MEV and 28.7% (1 CR + 28 PR among 101 patients) in the MVP arm (P = 0.48). Symptoms were similar in the two arms. 196 patients progressed and 182 died. The median times to progression were 10 weeks (95% CI 9-12) and 12 weeks (95% CI 10-15) and median survivals were 29 weeks (95% CI 25-36) and 28 weeks (95% CI 25-35) in the MEV and MVP arms, respectively. The relative risks of progressing and of dying were 0.89 (95% CL 0.66-1.20) and 0.96 (95% CL 0.71-1.30), respectively, for patients receiving MVP as compared with those receiving MEV at multivariate analysis adjusted by sex, age, histologic type, number of metastatic sites, performance status at entry, and centre. CONCLUSIONS: In the present study, no significant differences were observed in response rate, survival or palliation of symptoms between the MEV and MVP regimens, while toxicity was significantly more frequent and severe with MVP. Thus, MEV should be considered a reasonable alternative to the MVP regimen in the treatment of stage IV NSCLC.