Prognostic and predictive significance of nuclear HIF1α expression in locally advanced HNSCC patients treated with chemoradiation with or without nimotuzumab

Background Anti-EGFR-based therapies have limited success in HNSCC patients. Predictive biomarkers are greatly needed to identify the patients likely to be benefited from these targeted therapies. Here, we present the prognostic and predictive association of biomarkers in HPV-negative locally advanced (LA) HNSCC patients.Methods Treatment-naive tumour tissue samples of 404 patients, a subset of randomised Phase 3 trial comparing cisplatin radiation (CRT) versus nimotuzumab plus cisplatin radiation (NCRT) were analysed to evaluate the expression of HIF1α, EGFR and pEGFR by immunohistochemistry and EGFR gene copy change by FISH. Progression-free survival (PFS), locoregional control (LRC) and overall survival (OS) were estimated by Kaplan–Meier method. Hazard ratios were estimated by Cox proportional hazard models.Results Baseline characteristics of the patients were balanced between two treatment groups (CRT vs NCRT) and were representative of the trial cohort. The median follow-up was of 39.13 months. Low HIF1α was associated with better PFS [HR (95% CI) = 0.62 (0.42–0.93)], LRC [HR (95% CI) = 0.56 (0.37–0.86)] and OS [HR (95% CI) = 0.63 (0.43–0.93)] in the CRT group. Multivariable analysis revealed HIF1α as an independent negative prognostic biomarker. For patients with high HIF1α, NCRT significantly improved the outcomes [PFS:HR (95% CI) = 0.55 (0.37–0.82), LRC:HR (95% CI) = 0.55 (0.36–0.85) and OS:HR (95% CI) = 0.54 (0.36–0.81)] compared to CRT. While in patients with low HIF1α, no difference in the clinical outcomes was observed between treatments. Interaction test suggested a predictive value of HIF1α for OS (P = 0.008).Conclusions High HIF1α expression is a predictor of poor clinical response to CRT in HPV-negative LA-HNSCC patients. These patients with high HIF1α significantly benefited with the addition of nimotuzumab to CRT.Clinical trial registration Registered with the Clinical Trial Registry of India (Trial registration identifier—CTRI/2014/09/004980).Subject terms: Tumour biomarkers, Head and neck cancer, Tumour biomarkers, Head and neck cancer, Predictive markers     

Alterations in hepatic microsomal mixed-function oxidase system during different levels of food restriction in adult male and female rats

Wistar strain adult male and female rats were given 25, 50 and 75% less food than an ad libitum-fed group of rats for 45 d and the effects of food restriction on hepatic drug metabolizing enzymes, microsomal electron transport components, NADPH-dependent lipid peroxidation and glutathione-S-transferase activities were studied. Compared to ad libitum-fed controls, the cytochrome P-450 levels were higher in food restricted male rats, while they were lower in food restricted females. The activities of NADPH cytochrome c reductase were lower in food restricted females than in ad libitum-fed controls. The activities of drug metabolizing enzymes, aminopyrine N-demethylase and acetanilide hydroxylase were higher in food restricted males, whereas in food restricted females these activities were lower than in respective groups fed ad libitum. Microsomal, NADPH-dependent lipid peroxidation was higher in 25 and 50% food restricted females while in 50 and 75% food restricted males it was lower than in ad libitum controls of the same sex. The cytosolic glutathione-S-transferase activities were lower in food restricted rats of both the sexes than in the same sexed controls. Another group of male and female rats were given 75% less food than the ad libitum-fed rats and refed for 3 d prior to killing. Here also, the effects of restriction were different between sexes. It is concluded that hepatic microsomal mixed-function oxidase system (MFOS) is altered due to feed restriction and food restriction followed by refeeding, in a sex-related manner.     

Influence of sugars on the activity of cellulase system from two basidiomycetes cultures

Influence of some sugars was studied on activity of purified cellulase enzymes produced by two white-rot basidiomycetes cultures in submerged fermentation. Exo- and endo-glucanases were found to be stimulated by glucose, sucrose and xylose, but β-glucosidase was inhibited by all sugars tested except sucrose being neutral. Cellobiose severely inhibited all three cellulase activities at all three concentrations taken in reaction mixture.     

Alterations in free radical scavenger system profile of type I diabetic rat brain

The activities of the enzymes related to glutathione synthesis, degradation, and functions as well as reactive oxygen scavenging enzymes were analyzed in different brain regions, such as cerebral hemisphere, cerebellum, brainstem, thalamus, and hypothalamus after 1 and 3 mo of streptozotocin-induced diabetes in rats. Parallel studies were also made in age-matched control rats and insulin-treated diabetic rats. The content of glutathione (GSH) and its synthesizing enzyme γ-glutamylcystein synthetase and also superoxide dismutase (SOD) and catalase activities (reactive oxygen scavenging enzymes) were significantly decreased from almost all the brain regions studied. However, glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), γ-glutamyl transpeptidase (γ-GTP), and glutamine synthetase (GS) activities were increased in the diabetic rat brain. Insulin treatment to the diabetic rats resulted in partial to full recovery in these enzymes activities. The present results emphasize the potentially serious alterations of brain free radical scavenger system in uncontrolled Type I diabetes.     

Retrospective prediction of birth weight by growth velocity curves during neonatal period

In this prospective study, birth weight of 304 babies born at Kamla Nehru Hospital Pune during study period was recorded. From these 304 babies, babies with birth weight above 2000 grams were selected (260 babies) to prepare growth velocity curves. Daily weight of these 260 babies was recorded for 30 days. The mean birth weight of study population was 2742.5 grams. Among the daily weight recorded babies, all the babies lost weight ranging from 92 to 218 grams (mean 121 grams) after birth. The weight loss continued upto 5 days. Days required to gain weight equal to birth weight ranged from 5 to 13 days. Total weight gain observed in 30 days was 734.7 grams. Predictive value of these curves was tested in 49 infants. Deviation upto 50 grams of predicted birth weight from actual birth weight was observed in 90% of babies on day-2, 79% on day-4, 65% on day-8 and 39% on day-30.     

Pre-emptive analgesia with epidural morphine or morphine and bupivacaine

Studies of preemptive analgesia in humans have shown conflicting results. The study design, patient population and the duration of assessment of postoperative pain are important in the evaluation of preemptive analgesia. We carried out a prospective, randomized, double-blind controlled study in 80 patients of physical status ASA 1-3 undergoing upper abdominal and thoracic surgery. Patients received two epidural injections, one 20 minutes before induction and the other at the end of surgery. Study solution was either morphine (50 micrograms/kg), with or without 0.1% bupivacaine in 10 ml of normal saline, or normal saline alone. The study groups (Pre M, Pre MB) were given either morphine or morphine-bupivacaine before induction and saline at the end of surgery. The control groups (Post M, Post MB) were given saline before induction and morphine or morphine-bupivacaine at the end of surgery. Postoperative pain was assessed with a Visual Analogue Scale (VAS) during coughing and deep breathing at six-hourly intervals for five days. Epidural morphine was given if the VAS exceeded 4. Pre MB compared to Post MB had a significantly increased interval between the analgesic top-ups (P < 0.01) and decreased total postoperative morphine requirements (P < 0.0001) and number of top-ups (P < 0.001). Pre M and Post M were comparable. Pre MB compared to Pre M had significantly decreased total postoperative morphine requirements (P < 0.0001) and number of top-ups (P < 0.0001). Epidural morphine plus bupivacaine is effective as a preemptive analgesic. Morphine plus bupivacaine has better efficacy than morphine given alone before the induction of anaesthesia.     

Cost savings associated with changes in routine laboratory tests ordered for victims of trauma

Not all trauma victims evaluated by the trauma service require a full complement of laboratory tests upon admission. This study set out to determine the cost savings and safety of limited laboratory testing of trauma victims. Before 1998, our admission trauma protocol included 11 laboratory tests for all trauma victims. In 1998, we created two categories: Trauma Blue--severe injury likely (Glasgow Coma Score <13; systolic blood pressure <100 mm Hg at any time; significant head, chest, abdominal, or proximal long bone injury; or clinical suspicion of need for operative or intensive care unit management) and Trauma Yellow--severe injury unlikely. The triage decision was made by the team leader or attending physician. Trauma Blue laboratory tests included an arterial blood gas, blood alcohol, type and screen or crossmatch, and urine dipstick. All patients who did not meet Trauma Blue criteria were entered in the Trauma Yellow group. There were only two tests for the Trauma Yellow group, a venous blood gas and blood alcohol. All arterial and venous blood gases measured pH, pO2, pCO2, HCO3, base deficit, hemoglobin, sodium, potassium, and ionized calcium. Other laboratory tests were done if requested by the trauma team leader or attending physician. All trauma admissions for a 3-month period were entered into this prospective study. The admitting trauma surgeon was surveyed after each admission to evaluate any problems in patient care. The test group was compared with a historical control of 100 consecutive patients under the original laboratory trauma protocol. One hundred and forty-eight (148) patients were entered into the study. Average laboratory cost per patient was $29.82 less with the study protocol. No patient care problem was identified. A cost savings of $29.82 per patient or $20,000.00 a year was realized for our institution, with no change in the quality of patient care. Trauma protocols designed to reflect a patient's potential for serious injury can result in a significant cost savings while preserving patient safety.