Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial.

BACKGROUND: Platinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3-4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy. MATERIALS AND METHODS: Patients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level). RESULTS: 414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56-0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF. CONCLUSIONS: IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy. CLINICAL TRIAL NUMBER: NCT01086826, www.clinicaltrials.gov.

Diffraction effects in length measurements by laser interferometry.

High-accuracy dimensional measurements by laser interferometers require corrections because of diffraction, which makes the effective fringe-period different from the wavelength of a plane (or spherical) wave λ0. By using a combined X-ray and optical interferometer as a tool to investigate diffraction across a laser beam, we observed wavelength variations as large as 10-8λ0. We show that they originate from the wavefront evolution under paraxial propagation in the presence of wavefront- and intensity-profile perturbations.

Fulminant Epstein-Barr virus-associated hemophagocytic syndrome in a renal transplant patient and review of the literature.

We describe a rare fulminant case of Epstein-Barr virus-associated hemophagocytic syndrome (HPS) in a 37-year-old female renal transplant patient, indistinguishable from severe sepsis clinically and in the laboratory. HPS involves rapidly escalating immune system activation, resulting in a cytokine cascade, which can, especially in immunocompromised patients, lead to multi-organ failure, and even death. Thirty-two Herpesviridae-associated HPS cases in renal transplant patients have been reported and are reviewed. Overall mortality is 47% (15/32 cases).

Polarization delivery in heterodyne interferometry.

Optically heterodyned laser interferometry, as applied to measuring linear displacements, requires different optical frequencies to be encoded onto unique polarization states. To eliminate non-linear contributions to the interferometer signal, the frequency difference must be introduced after beam splitting and the interfering beams must be recombined via spatially separated paths. The polarization jitter of the frequency-shifted beams still originates a noise in the beat-signal phase. A formula is given expressing the noise amplitude in terms of the illuminating beam's extinction ratio.

Effects of lasalocid and intermittent feeding of chlortetracycline on the growth of prepubertal dairy heifers.

Forty Holstein heifers entered the 12-wk study at approximately 12 wk of age. At enrollment, heifers were blocked by birth date and assigned to 1 of 4 treatments: (1) carrier (30 g; control); (2) lasalocid + carrier (1 mg/kg of body weight; L); (3) chlortetracycline + carrier (22 mg/kg of body weight; CTC); (4) L + CTC + carrier (CTCL). Heifers on CTC and CTCL were provided treatment Monday through Friday and carrier only on Saturday and Sunday. These heifers were provided their respective treatment during wk 1 to 4, 6, and 10; wk 5, 7 to 9, and 11 to 12 heifers were provided the nonmedicated carrier. Heifers were individually fed a total mixed ration with treatments top-dressed at 1200 h daily. Dry matter intake was monitored for each heifer and feed provided was adjusted according to individual intakes. Skeletal measurements were taken weekly and blood samples were obtained every Monday, Wednesday, and Friday. Blood samples were analyzed for thyroxine concentration via radial immunoassay. Heifers supplemented with L had lower average daily gain , overall body weight gain, and trends for lower daily body length gain and overall girth gain compared with CTC heifers, but similar to control and CTCL heifers. Heifers fed L had lower hip height gain and overall hip height gain compared with CTCL heifers, but similar to control and CTC heifers. Heifers fed L had lower overall withers height gain compared with control heifers, but similar to CTC and CTCL heifers. No treatment effect on thyroxine concentrations was observed. These data indicate that L did not increase growth. Results from this experiment indicate that supplementing heifers with L was not beneficial and no benefits to supplementing heifers with CTC or the combination of CTC and L were evident compared with control heifers. Heifers in this study experienced minimal health problems and were regarded to be under low stress levels. Supplementing CTC and L may be beneficial to growing heifers under conditions where disease exposure and stressors are greater.

Crystal bending in triple-Laue X-ray interferometry. Part II. Phase-contrast topography.

In a previous paper [Sasso et al. (2023). J. Appl. Cryst.56, 707-715], the operation of a triple-Laue X-ray interferometer having the splitting or recombining crystal cylindrically bent was studied. It was predicted that the phase-contrast topography of the interferometer detects the displacement field of the inner crystal surfaces. Therefore, opposite bendings result in the observation of opposite (compressive or tensile) strains. This paper reports on the experimental confirmation of this prediction, where opposite bendings were obtained by copper deposition on one or the other of the crystal sides.

Crystal bending in triple-Laue X-ray interferometry. Part I. Theory.

The measured value of the (220) lattice-plane spacing of silicon 28 using scanning X-ray interferometry is essential to realize the kilogram by counting 28Si atoms. An assumption made is that the measured lattice spacing is the bulk value of an unstrained crystal forming the analyser of the interferometer. However, analytical and numerical studies of the X-ray propagation in bent crystals suggest that the measured lattice spacing might refer to the analyser surface. To confirm the result of these studies and to support experimental investigations of the matter by phase-contrast topography, a comprehensive analytical model is given of the operation of a triple-Laue interferometer having the splitting or recombining crystal bent.

Neutron interference from a split-crystal interferometer.

The first successful operation of a neutron interferometer with a separate beam-recombining crystal is reported. This result was achieved at the neutron interferometry setup S18 at the ILL in Grenoble by a collaboration between TU Wien, ILL, Grenoble, and INRIM, Torino. While previous interferometers have been machined out of a single-crystal block, in this work two crystals were successfully aligned on nanoradian and picometre scales, as required to obtain neutron interference. As a decisive proof-of-principle demonstration, this opens the door to a new generation of neutron interferometers and exciting applications.

Determination of the Avogadro constant by counting the atoms in a 28Si crystal.

The Avogadro constant links the atomic and the macroscopic properties of matter. Since the molar Planck constant is well known via the measurement of the Rydberg constant, it is also closely related to the Planck constant. In addition, its accurate determination is of paramount importance for a definition of the kilogram in terms of a fundamental constant. We describe a new approach for its determination by counting the atoms in 1 kg single-crystal spheres, which are highly enriched with the 28Si isotope. It enabled isotope dilution mass spectroscopy to determine the molar mass of the silicon crystal with unprecedented accuracy. The value obtained, NA = 6.022,140,78(18) × 10(23) mol(-1), is the most accurate input datum for a new definition of the kilogram.

Defocused travelling fringes in a scanning triple-Laue X-ray interferometry setup.

The measurement of the silicon lattice parameter by a separate-crystal triple-Laue X-ray interferometer is a key step for the realization of the kilogram by counting atoms. Since the measurement accuracy is approaching nine significant digits, a reliable model of the interferometer operation is required to quantify or exclude systematic errors. This paper investigates both analytically and experimentally the effect of the defocus (the difference between the splitter-to-mirror and analyser-to-mirror distances) on the phase of the interference fringes and the measurement of the lattice parameter.

Long-term persistency of hepatitis B immunity: an observational cross-sectional study on medical students and resident doctors.

Hepatitis B virus (HBV) is a main cause of chronic and acute hepatitis. Healthcare workers (HCWs), including medical students and resident doctors, have an occupational risk of HBV infection. The study aimed to evaluate the long-term persistence of protective anti-HBs antibody levels in healthcare students and resident doctors at risk for occupational exposure to HBV at 15 years after primary vaccination course. Further objective was to evaluate the anamnestic response observed in non-seroprotected subjects receiving a booster dose. Data were collected from the clinical documentation filled in during the occupational medical check of medical students and resident doctors undergoing Occupational Health Surveillance by the University of Ferrara. Of the 621 included individuals, 27.7% had an anti-HBs concentration < 10 mIU/mL. Subjects vaccinated during infancy had more frequently a concentration < 10 mIU/mL than those vaccinated during adolescence (42.7% vs 6.9%; p-value < 0.001). Multivariate analysis confirmed the statistical significance of the vaccination age. 94 subjects who had an anti-HBs concentration < 10 mIU/mL received a booster dose. The proportion of subjects who had an anamnestic response was higher in those vaccinated in infancy rather than during adolescence (94.1% vs 77.8% respectively). These findings suggest that the anti-HBs concentration decreases below 10 mIU/mL more frequently in subjects vaccinated during infancy. Immunological memory seems to persist after the decline of the anti-HB titer, as observed in response to a booster dose. In conclusion, vaccinated subjects at increased risk of HBV infection should be monitored and a booster dose administered if anti-HBs titer is below 10 mIU/mL.

Perioperative Chemoprophylaxis οr Treatment for Extensively Drug Resistant Gram-Negative Bacteria in Patients Undergoing Liver Transplantation Based on Preoperative Donor/Recipient Surveillance Cultures: A Prospective Study.

INTRODUCTION: The importance of preoperative donor/recipient colonization or donor infection by extensively drug-resistant Gram-negative bacteria (XDR-GNB) and its relation to serious post-transplantation infection pathogenicity in liver transplantation (LT) patients has not been clarified. AIM: Prevention of postoperative infection due to XDR-GNB with the appropriate perioperative chemoprophylaxis or treatment based on preoperative donor/recipient surveillance cultures in LT patients, as well as their outcome. MATERIALS AND METHOD: Twenty-six patients (20 male, 6 female) were studied (average preoperative Model for End-Stage Liver Disease score ≈15, range: 8-29) from January 2017 to January 2018. In all patients, blood, urine, and bronchial secretions culture samples as well as a rectal colonization culture were taken pre- and postoperatively, once weekly after LT, and after intensive care unit discharge. Recipients with positive XDR-GNB colonization and patients receiving a transplant from a donor with an XDR-GNB positive culture or colonization received the appropriate chemoprophylaxis one half hour preoperatively according to culture results. De-escalation of the antibiotic regimen was done in 2 to 5 days based on the colonization/culture results of the donor and recipient and their clinical condition. Evaluation for serious infection was done at 1 week and at 28 days for outcome results. RESULTS: Fourteen out of 26 recipients (53.8%) were positive for XDR-GNB colonization preoperative, with 2/14 (14.28%) presenting serious infection due to the same pathogen. Intensive care unit length of stay was significantly longer in colonized with XDR-GNB patients (P < .0001). The outcome of colonized patients was 6/14 (42.8%) expired, but only in 2/14 (14.2%) was mortality attributable to infection. CONCLUSION: Administering appropriate perioperative chemoprophylaxis and treatment may limit the frequency of XDR-GNB infections and intensive care unit length of stay and may improve the outcome in LT recipients.

Colonization and Infection With Extensively Drug Resistant Gram-Negative Bacteria in Liver Transplant Recipients.

BACKGROUND: Infections due to extensively drug resistant Gram-negative bacteria (GNB) after solid organ transplantation are increasing in prevalence and are associated with high morbidity and mortality. Surveillance culture (SC) seems to be an important tool for extensively drug resistant GNB control. The aim of this study was to evaluate colonization rates and subsequent infections by XDR-GNB in liver transplant recipients. MATERIAL AND METHODS: This was a prospective cohort study in patients who underwent liver transplantation (LT) between January 2016 and January 2018. Data on demographics, extensively drug resistant colonization, and 3-month clinical outcomes were obtained. Colonization was defined as a positive surveillance culture (SC-perirectal) immediately before transplantation, once weekly after LT, and after intensive care unit discharge, with emphasis to carbapenem-resistant Gram-negative bacteria (CR-GNB). RESULTS: Forty-four patients who underwent LT were included in the study. Ten patients (22.72%) were colonized with CR-GNB prior to transplantation, and 7/10 (70%) developed infection due to the same pathogen (5 patients bloodstream infections, 2 patients pneumonia) during the study period. Intensive care unit length of stay was significantly longer in colonized with CR-GNB patients (P < .05). Mortality rate was higher in colonized patients (30%) than in noncolonized (11.76%) (P = .2). CONCLUSION: Our study results suggest an overall 70% risk of CR-GNB infection among colonized patients. Given the high mortality rate and the difficulty in treating these infections, further research to investigate and develop strategies to eliminate the colonization is needed.

Determinants of adherence to seasonal influenza vaccination among healthcare workers from an Italian region: results from a cross-sectional study.

OBJECTIVES: Notwithstanding decades of efforts to increase the uptake of seasonal influenza (flu) vaccination among European healthcare workers (HCWs), the immunisation rates are still unsatisfactory. In order to understand the reasons for the low adherence to flu vaccination, a study was carried out among HCWs of two healthcare organisations in Liguria, a region in northwest Italy. METHODS: A cross-sectional study based on anonymous self-administered web questionnaires was carried out between October 2013 and February 2014. Through univariate and multivariate regression analysis, the study investigated the association between demographic and professional characteristics, knowledge, beliefs and attitudes of the study participants and (i) the seasonal flu vaccination uptake in the 2013/2014 season and (ii) the self-reported number of flu vaccination uptakes in the six consecutive seasons from 2008/2009 to 2013/2014. RESULTS: A total of 830 HCWs completed the survey. Factors statistically associated with flu vaccination uptake in the 2013/2014 season were: being a medical doctor and agreeing with the statements 'flu vaccine is safe', 'HCWs have a higher risk of getting flu' and 'HCWs should receive flu vaccination every year'. A barrier to vaccination was the belief that pharmaceutical companies influence decisions about vaccination strategies. DISCUSSION: All the above-mentioned factors, except the last one, were (significantly) associated with the number of flu vaccination uptakes self-reported by the respondents between season 2008/2009 and season 2013/2014. Other significantly associated factors appeared to be level of education, being affected by at least one chronic disease, and agreeing with mandatory flu vaccination in healthcare settings. CONCLUSIONS: This survey allows us to better understand the determinants of adherence to vaccination as a fundamental preventive strategy against flu among Italian HCWs. These findings should be used to improve and customise any future promotion campaigns to overcome identified barriers to immunisation.

Effect of auto-oxidized phospholipids on oxidative enzyme assays based on tetrazolium salt reduction.

The influence of auto-oxidized phospholipids on the reduction of the tetrazolium salt MTT coupled to the NAD+-dependent lactate dehydrogenase reaction was studied. The following results were obtained: (1) peroxidized phosphatidylcholine interfered in the time-course of the lactate dehydrogenase-mediated MTT reduction; (2) there was a time-dependent decrease in the hydroperoxide content of phosphatidylcholine vesicles during the incubation; (3) the diminution of phosphatidylcholine hydroperoxides required the presence of all the components of the system except MTT; (4) hydroperoxide diminution and MTT reduction were mediated by the superoxide radical O2-, since both processes were inhibited by superoxide dismutase; (5) EDTA inhibited the hydroperoxide decrease and abolished the interference of peroxidized phosphatidylcholine with MTT reduction. It was concluded that hydroperoxides compete with MTT for the electrons coming from substrate oxidation. The superoxide radical O2- and traces of some contaminating metal ion are involved in the process. This is a potential complication in the study of the effect of lipids on enzymatic activities assayed by the tetrazolium salt method.

Damage of Escherichia coli cells by t-butylhydroperoxide involves the respiratory chain but is independent of the presence of oxygen.

The action of t-butylhydroperoxide (tBOOH) on Escherichia coli cells has been studied as a model system for organic peroxide toxicity. Exposure of E. coli cells to tBOOH led to progressive and irreversible impairment of the respiratory function, an effect which was dependent on the availability of substrate. The effect of tBOOH on growth of E. coli with different carbon sources and alternative terminal electron acceptors was investigated. It was found that the sensitivity of E. coli to tBOOH under diverse growth conditions implicating a functional respiratory chain was greater than when the bacterium grew by fermentation. Also the mutant E. coli SASX76, which requires exogenous 5-aminolevulinic acid to synthesize the cytochromes, was more resistant to tBOOH when lacking a functional respiratory chain. These data point to the respiratory chain as a major target in the in vivo action of tBOOH. Experiments with isolated membranes also showed a tBOOH-induced damage of the respiratory chain monitored by impairment of the NADH oxidase. The effect of tBOOH was produced even under anaerobiosis, indicating that development of cell damage was independent of oxygen and, therefore, that neither oxygen-derived radicals nor lipid peroxidation were involved.

Study of a time lag in the assay of Escherichia coli membrane-bound dehydrogenases based on tetrazolium salt reduction.

The Escherichia coli membrane-bound D-lactate dehydrogenase and succinate dehydrogenase were assayed on the basis of the phenazine methosulfate- (PMS-) mediated reduction of the tetrazolium salt, MTT. An initial slower phase (lag) in the time-course of the reaction was observed and analyzed. The results were as follows. (1) The time lag in the assay of the D-lactate dehydrogenase was eliminated by preincubating the membranes with PMS plus D-lactate, with PMS plus succinate, or with PMS plus NADH (conditions which implicated PMS reduction). (2) When the D-lactate dehydrogenase was assayed by another method based on the measurement of the pyruvate formed, neither was a time lag observed nor was the enzyme activity affected by membrane preincubation with PMS plus D-lactate. (3) Although the superoxide radical was involved in MTT reduction, this radical seemed not to participate in the generation of the time lag. (4) Membranes whose D-lactate dehydrogenase activity had previously been destroyed by heating at 80 degrees C for 1 min, were able to prolong the time lag in MTT reduction when added to the assay medium for the D-lactate dehydrogenase from untreated membranes, whereas membranes previously heated at 100 degrees C instead of 80 degrees C did not have this effect. It was concluded that the E. coli membranes interfered in the dehydrogenase assay based on the PMS-mediated reduction of MTT. The time lag was interpreted as a period during which the interfering substance reacted with reduced PMS inhibiting the reduction of MTT.

Membrane-associated redox cycling of copper mediates hydroperoxide toxicity in Escherichia coli.

We are studying the action of tert-butylhydroperoxide (t-BOOH) on Escherichia coli as a model system for peroxide toxicity. In our previous report (De la Cruz-Rodriguez, L.C., Farías, R.N. and Massa, E.M. (1990) Biochim. Biophys. Acta 1015, 510-516), the respiratory chain was identified as a major target of t-BOOH. In the present paper, we study further the effect of t-BOOH on the NADH oxidase of the E. coli respiratory chain to clarify the mechanism of damage, especially regarding the identity and role of the metal ion involved. The results are: (a) t-BOOH toxicity is mediated by membrane-bound copper ions; (b) a small pool of the membrane-bound copper is reduced from Cu(II) to Cu(I) in the presence of NADH and other respiratory substrates (succinate, D-lactate); (c) this reduction of copper occurs at 37 degrees C but not at 0 degrees C or when the membranes are inactivated by previous heating; (d) the Cu(I) generated by reduction of Cu(II) during membrane preincubation with NADH, is oxidized by t-BOOH with simultaneous inactivation of the NADH oxidase, whereas treatment with only t-BOOH (without NADH) has no effect on the oxidase. It is concluded that the effect of t-BOOH on the respiratory chain is mediated by redox cycling of copper. It is proposed that the damage results from activation of the hydroperoxide through its interaction with Cu(I) in a site-specific Fenton-type reaction.

Serum levels of leptin and proinflammatory cytokines in patients with advanced-stage cancer at different sites.

Leptin is a recently identified hormone produced by the adipocyte ob gene which acts as a negative feedback signal critical to the normal control of food intake and body weight. A number of proinflammatory cytokines, such as interleukin (IL) 1alpha, IL-6, tumor necrosis factor (TNF) alpha and interferon (IFN) gamma, have been proposed as mediators of cancer cachexia. These data suggest that abnormalities in leptin production/release or in its feedback mechanism play a role in cancer patients. To elucidate this we studied the relationship between total serum leptin and serum cytokines IL-1alpha, IL-6, TNFalpha as well as the production of leptin and cytokines by peripheral blood mononuclear cells (PBMC) isolated from cancer patients. Sixteen advanced cancer patients (mainly stage IV) with tumors at different sites were included in the study. The serum levels of leptin in cancer patients were significantly lower than those of healthy individuals at all times (7 a.m., noon, 3 p.m.). No significant differences were found in circadian rhythm between patients and controls. Serum levels of IL-1alpha, IL-6, and TNFalpha were significantly higher in cancer patients than in healthy individuals. An inverse correlation between serum levels of leptin and IL-6 was found in cancer patients. The production in culture of leptin by unstimulated PBMCs and those stimulated by phytohemagglutinin M or by phorbol myristate acetate isolated from cancer patients was very low; no differences were observed in comparison with leptin production by PBMCs from healthy individuals.

Serum values of proinflammatory cytokines are inversely correlated with serum leptin levels in patients with advanced stage cancer at different sites.

Leptin is a recently identified hormone produced by the adipocyte ob gene which acts as a negative feedback signal critical to the normal control of food intake and body weight. A number of proinflammatory cytokines, such as interleukin 6, tumor necrosis factor alpha, and interferon gamma, have been proposed as mediators of cancer cachexia; these data suggest that abnormalities in leptin production/release or in its feedback mechanism play a role in cancer patients. We therefore studied the relationship between serum leptin and serum cytokines interleukin 6 and tumor necrosis factor alpha levels in advanced-stage cancer patients. Twenty-nine advanced stage cancer patients (all but one stage IV) with tumors at various sites were included in the study. A direct correlation between body mass index and serum leptin levels was found both in cancer patients and in healthy individuals. The serum levels of interleukin 6 were significantly higher in cancer patients than in healthy individuals. In cancer patients an inverse correlation was found between serum levels of leptin and proinflammatory cytokines. There was an inverse correlation between the Eastern Cooperative Oncology Group performance status scale and serum levels of leptin. Regarding survival, patients with very high serum levels of proinflammatory cytokines and very low levels of leptin had very short survival. Although obtained in a cancer patient population not overtly cachectic, our results provide further evidence that a simple dysregulation of leptin production and/or release cannot be involved in cancer-associated pathophysiological changes leading to cachexia.