Pembrolizumab monotherapy versus chemotherapy in platinum-pretreated, recurrent or metastatic nasopharyngeal cancer (KEYNOTE-122): an open-label, randomized, phase III trial.

BACKGROUND: Pembrolizumab previously demonstrated robust antitumor activity and manageable safety in a phase Ib study of patients with heavily pretreated, programmed death ligand 1 (PD-L1)-positive, recurrent or metastatic nasopharyngeal carcinoma (NPC). The phase III KEYNOTE-122 study was conducted to further evaluate pembrolizumab versus chemotherapy in patients with platinum-pretreated, recurrent and/or metastatic NPC. Final analysis results are presented. PATIENTS AND METHODS: KEYNOTE-122 was an open-label, randomized study conducted at 29 sites, globally. Participants with platinum-pretreated recurrent and/or metastatic NPC were randomly assigned (1 : 1) to pembrolizumab or chemotherapy with capecitabine, gemcitabine, or docetaxel. Randomization was stratified by liver metastasis (present versus absent). The primary endpoint was overall survival (OS), analyzed in the intention-to-treat population using the stratified log-rank test (superiority threshold, one-sided P = 0.0187). Safety was assessed in the as-treated population. RESULTS: Between 5 May 2016 and 28 May 2018, 233 participants were randomly assigned to treatment (pembrolizumab, n = 117; chemotherapy, n = 116); Most participants (86.7%) received study treatment in the second-line or later setting. Median time from randomization to data cut-off (30 November 2020) was 45.1 months (interquartile range, 39.0-48.8 months). Median OS was 17.2 months [95% confidence interval (CI) 11.7-22.9 months] with pembrolizumab and 15.3 months (95% CI 10.9-18.1 months) with chemotherapy [hazard ratio, 0.90 (95% CI 0.67-1.19; P = 0.2262)]. Grade 3-5 treatment-related adverse events occurred in 12 of 116 participants (10.3%) with pembrolizumab and 49 of 112 participants (43.8%) with chemotherapy. Three treatment-related deaths occurred: 1 participant (0.9%) with pembrolizumab (pneumonitis) and 2 (1.8%) with chemotherapy (pneumonia, intracranial hemorrhage). CONCLUSION: Pembrolizumab did not significantly improve OS compared with chemotherapy in participants with platinum-pretreated recurrent and/or metastatic NPC but did have manageable safety and a lower incidence of treatment-related adverse events.

Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal.

Background: Safety and efficacy of pembrolizumab, a humanized programmed death 1 monoclonal antibody, was assessed in KEYNOTE-028, a multicohort, phase Ib trial for patients with programmed death ligand 1 (PD-L1)-positive advanced solid tumors. We report results for the cohort of patients with advanced anal carcinoma. Patients and methods: Patients with PD-L1-positive tumors (≥1%) received intravenous pembrolizumab 10 mg/kg once every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter per Response Evaluation Criteria In Solid Tumors, version 1.1. Primary endpoints were safety and overall response rate per investigator review. Secondary endpoints included progression-free survival, overall survival, and response duration. Data cutoff date was 1 July 2015. Results: Of the 43 patients with advanced anal carcinoma evaluable for PD-L1 expression, 32 (74%) had PD-L1-positive tumors as assessed with the 22C3 prototype assay, of whom 25 were enrolled between April and September 2014. Sixteen patients (64%) experienced treatment-related adverse events; the most common ones were diarrhea and fatigue in four patients (16%) each and nausea in three patients (12%). There were no treatment-related deaths or discontinuations as of the data cutoff date. Among the 24 patients with squamous cell carcinoma histology, four had confirmed partial response, for an overall response rate of 17% [95% confidence interval (CI), 5%-37%) and 10 (42%) had confirmed stable disease, for a disease control rate of 58%. One additional patient with non-squamous histology had confirmed stable disease. Conclusion: In this population of patients with PD-L1-positive advanced squamous cell anal carcinoma, pembrolizumab demonstrated a manageable safety profile and encouraging antitumor activity. These data support further study of pembrolizumab for this patient population. ClinicalTrials.gov: NCT02054806.

Use of anti-inflammatory analgesics in sickle-cell disease.

WHAT IS KNOWN AND OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAIDs) have been commonly used to treat pain in sickle-cell disease (SCD), but NSAID use is associated with renal, gastrointestinal and cardiovascular toxicities. Our objective was to evaluate the use of aspirin and non-aspirin NSAIDs in SCD. COMMENT: Despite analgesic and anti-inflammatory benefits in SCD, non-aspirin NSAIDs are associated with renal, cardiovascular and gastrointestinal toxicities in this patient population. Aspirin may have less renal and cardiovascular toxicities. The different side effect profile of NSAIDs is related to the COX-1/COX-2 selectivity at their therapeutic doses. Individual risk factors and genetic biomarkers should be considered when selecting appropriate NSAIDs and their dose. WHAT IS NEW AND CONCLUSION: NSAIDs have the potential to be an important component of pain regimens in SCD, but the use of NSAIDs should be individualized based on potential side effects and patient risk factors and the lowest effective dose should be prescribed with proper monitoring in patients with SCD.

Quantitative Assessment of Muscle Activity and Joint Load in Braced and Unbraced Osteoarthritis Knee by External Strain Gauge Sensor.

OBJECTIVES: Altered biomechanics leads to the development of degenerative joint disease. The joint pressure and dynamic loading varies during activities of daily living. The study was undertaken to assess the muscle activation pattern of the medial and lateral knee compartments (tibiofemoral joint) during gait in osteoarthritis subjects without and with knee brace undergoing either exercise therapy or balance therapy. The joint load was assessed by the strain gauge transducer and the weight shift pattern is taken as an indicator for the muscle activation pattern. METHODS: In a prospective design study on 57 male subjects diagnosed osteoarthritis knee with Kellagren-Lawrennce scale walked barefooted with and without designed offloader knee brace on a level surface for three minutes. The subjects were allocated in two different study groups i.e. Conventional (exercise therapy) (Control Group, n=31) and Structured Neuromuscular Postural Training (SNPT) group (Balance therapy) (Study Group, n=26). The subjects were sub grouped as pre-elderly (40-60 Years) and elderly (>61 years) group in both. The quantitative assessment of muscle activity and joint loading with and without knee brace was done using designed strain gauge sensor instrument. The pressure changes of strain gauges of muscles around the knee joint viz. vastus medialis (VM), vastus lateralis (VL), semi membranosus/tendinosus (Medial Hamstring) (MH), Biceps Femoris (Lateral Hamstring) (LH), gastro-soleus (GS) and tibialis anterior (TA) muscles during normal gait were observed at baseline and 6 weeks follow up after undergoing exercise therapy or balance therapy treatment as per allocation of study groups. The digital values from MATLAB were recorded and analyzed. RESULTS: At the end of 6 weeks conventional/SNPT (structured neuromuscular postural training) treatments, medial hamstring muscle activity showed significant difference (p<0.001) in pre-elderly subgroup, while significant difference was seen in vastus laterals (VL), medial hamstring (MH) (p<0.005) and lateral hamstring (LH) muscles (p<0.001) in elderly subgroup. Further, the muscle co-contraction has been higher for vastus medialis-medial hamstring (VM-MH) pair compared to vastus lateralis-lateral hamstring (VL-LH) pair without brace at baseline. The application of offloader valgus knee brace significantly increases VL-LH co-contractions in magnitude and decreases in VM-MH co-contractions at 6 weeks follow up. CONCLUSION: Muscle activity increased in medial hamstring both in pre-elderly and elderly subjects. While, Vastus Laterals and lateral hamstring showed increased activities in elderly subjects. Hence, balance training and the application of off loader knee brace will be helpful to redistribute the load on medial tibiofemoral compartment.

Introducing dental hygienists in general practice to research - an in-practice evaluation programme in the United Kingdom.

AIM: To introduce dental hygienists (DHs) in the UK to the principles of research through a practice-based product evaluation programme. METHODS: The programme consisted of an initial training and orientation day with presentations on evidence-based practice, research methods and the structure of research papers. The programme and its aims were explained in detail, and participants were briefed on the methods to be used. Participants then recruited seven to ten patients from their practices (offices), carried out a baseline assessment of: plaque, gingival health, calculus and staining at anterior teeth, and gave the patients a questionnaire asking about their teeth and then provided a 3-month supply of a test toothpaste. About 10 weeks later, a follow-up assessment of the same variables was performed and the questionnaire was repeated. A second training day followed during which the DHs provided feedback of their experiences and received training in literature searching and critical appraisal of literature including interpretation of results. RESULTS: Sixty-five DHs attended the first training day; 31 were able to recruit sufficient patients and attend the second training day. The DHs recruited 168 patients who received baseline and follow-up assessments. All the variables improved overall. Feedback from the DHs was very positive, and patients expressed delight with the care they had received. CONCLUSIONS: Qualitative feedback for participating DHs suggests the programme met its aim and could be used in the future as a mechanism for helping DHs who want to increase their understanding of research methodology.

Noise and thermal performance of a sub-attofarad capacitance sensor for precision measurements, with applications in gravitational wave detectors.

We describe the design principles, fabrication, and characterization of a precision AC resonant capacitance bridge (RCB) sensor, based on a resonant differential planar printed circuit board transformer with a solid (ungapped) MnZn ferrite core, demonstrating a short-term sensitivity at 293 K of 0.225 ± 0.005 aF/√Hz at around 120 kHz resonance frequency and 1 Hz Fourier measurement frequency. At 120 K, the RCB short term noise sensitivity is 0.118 ± 0.005 aF/√Hz. We compare the ungapped configuration to five different RCBs: three with a core gap of 65 µm and two with a core gap of 130 µm. Their average room temperature short term noise sensitivities are 0.30 ± 0.01 and 0.45 ± 0.01 aF/√Hz, while the cryogenic operation of these transformers at 120 K resulted in averaged sensitivities of 0.23 ± 0.01 and 0.36 ± 0.01 aF/√Hz, respectively. Multi-hour room temperature runs, with one core of each of the three gap types, proved the stability of their long-term sensitivities of 0.234 ± 0.005, 0.338 ± 0.009, and 0.435 ± 0.010 aF/√Hz for the ungapped (40-h duration) and the 65 and 130 µm (28-h duration) cores, respectively. At 0.1 mHz, a critical frequency for space gravitational wave detectors, the respective sensitivities are 0.25 ± 0.02, 0.35 ± 0.02, and 0.53 ± 0.07 aF/√Hz. Measurements with the ungapped transformer configuration for temperatures from 325 to 349 K further validate the dependence of the noise model on temperature and permeability. The performance of our RCB with an ungapped core matches the calculated performance value and shows an improvement in signal-to-noise ratio of two or more compared with capacitance bridges developed for similar applications. A further factor of about two noise reductions is achieved by cooling to 120 K.

Formulation optimization of serratiopeptidase-loaded PLGA microspheres using selected variables.

Serratiopeptidase-loaded poly (D,L-lactic-co-glycolic acid) (PLGA) microspheres were prepared using the modified double emulsion method. The effect of polymer concentration and external aqueous phase volume on microsphere size and entrapment efficiency was studied by 3(2) full factorial experiments. The results of analysis of variance test for measured responses indicated the test's significance (P < 0.05). The contribution of PLGA concentration on microsphere size and percentage yield was found to be higher than that of external aqueous phase volume, which produced a significant effect on entrapment efficiency. Microspheres demonstrated spherical particles in the size range of 19.08-41.14 microm and entrapment efficiency between 15.37 and 79.86%. The formulation using a medium level of polymer and a low level of external aqueous phase (PLGA: 300 mg; EAP: 100 mL) showed maximum entrapment (75.86 +/- 2.31%). The in vitro release profile of all formulations demonstrated a similar sustained release showing an initial burst followed by diffusion. The bioactivity of the peptide remained intact after microencapsulation as assayed by in vitro proteolytic activity. Response surface graphs are presented to examine the effects of independent variables on the responses studied. In conclusion, controlled-release serratiopeptidase-loaded PLGA microspheres demonstrating maximum entrapment were successfully prepared by an experimental design methodology with a minimum number of runs, representing an economical approach.

Preparation and characterization of herbal creams for improvement of skin viscoelastic properties.

The aim of this study was to formulate and evaluate herbal cosmetic creams for their improvement of skin viscoelastic and hydration properties. The cosmetic cream formulations were designed by using ethanolic extracts of Glycyrriza glabra, Curcuma longa (roots), seeds of Psorolea corlifolia, Cassia tora, Areca catechu, Punica granatum, fruits of Embelica officinale, leaves of Centella asiatica, dried bark of Cinnamon zeylanicum and fresh gel of Aloe vera in varied concentrations (0.12-0.9%w/w) and characterized using physicochemical and physiological measurements. The ethanolic extracts of herbs were incorporated in a cream base that is prepared by a phase inversion emulsification technique. The cream base was prepared by utilizing oil of Prunus amagdalus, Sesamum indicum, honey, cetyl alcohol, stearic acid, polysorbate monoleate, sorbitan monostearate, propylene glycol and glycerin. Physicochemical assessments and microbiological testing were completed for all formulations according to the methods of the Indian Standard Bureau. The studies were carried out for 6 weeks on normal subjects (6 males and 12 females, between 22 and 50 years) on the back of their volar forearm for evaluation of viscoelastic properties in terms of extensibility via a suction measurement, firmness using laboratory fabricated instruments such as ball bouncing and skin hydration using electric (resistance) measurement methods. The physicochemical parameters of formulations CAA1-CAA6, i.e. pH, acid value, saponification value, viscosity, spreadability, layer thickness microbial count and skin sensitivity were found to be in the range of 5.01 +/- 0.4-6.07 +/- 0.6, 3.3-5.1 +/- 0.2, 20-32, 5900-6755 cps, 60-99%, 25-50 mum, 31-46 colony-forming units (CFU) and a 0-1 erythema score. The formulations, CAA4 and CAA5, showed an increase in percentage extensibility (32.27 +/- 1.7% and 29.89 +/- 1.64%, respectively), firmness (28.86 +/- 0.86% and 29.89 +/- 2.8%, respectively) and improved skin hydration (15.97 +/- 0.55 and 18.27 +/- 0.99%, respectively) and were found more effective compared with the control product (C7) after the 6- week study.

Lipid carriers: a versatile delivery vehicle for proteins and peptides.

Lipid based carriers have attracted increasing scientific and commercial attention during the last few years as an alternative material for the delivery of peptides and proteins concerned with stability issues. This article presents an overview of different types of biocompatible and versatile lipid-based carriers employed for the delivery of therapeutic proteins and peptides. Such delivery systems are discussed and exemplified regarding both more traditional lipid based delivery systems such as liposomes and lipid emulsions as well as more novel structures, e.g., lipid microtubules, microbubbles, and solid lipid nanoparticles.

Effect of simvastatin on fracture healing--an experimental study.

Left femur was osteotomized and fixed with K wire in 21 rabbits. One group was fed simvastatin (120 mg/kg body wt/day) orally, whereas another group without medication served as control. Both groups were assessed radiologically, morphologically, histologically and biomechanically at 4, 8 and 12 weeks. An analysis of various parameters of study showed that simvastatin treated group had improved bone healing at 4 and 8 weeks of follow up, however, the difference was not significant statistically at 12 weeks. So it is concluded that Simvastatin favourably hastened the process of fracture healing in the rabbits at earlier phases.

Prolonged responses after autologous stem cell transplantation in African-American patients with multiple myeloma.

Multiple myeloma (MM) has a double incidence in African-American (AA) than in non-AA patients and previous studies have shown a higher mortality in the former patient population. Here, we retrospectively analyzed the results of autologous stem cell transplantation (ASCT) in 38 AA and 32 non-AA consecutive patients. The two groups were comparable at diagnosis for age, stage of the disease, cytogenetic abnormalities, beta(2) microglobulin and albumin blood levels, and plasma cell marrow infiltration. The rates of complete and partial response observed in AA and non-AA patients after induction chemotherapy (9 and 42 vs 13 and 33%) and at 2 months (31 and 25 vs 30 and 20%) following ASCT were similar. At 6 months after ASCT, a greater relapse rate was observed in non-AA patients (P=0.009). At a median follow-up of 26 months, AA patients had a greater event-free survival (P=0.02) than non-AA patients, whereas overall survival was comparable in the two groups. The initial finding that AA patients with MM, compared to non-AA patients, had more prolonged responses and comparable survival after ASCT suggests that intensified chemotherapy is equally effective in patients of various ethnicities.

In-vitro studies of tizanidine controlled-release microcapsular matrices.

Oral microencapsulated controlled release preparations of tizanidine (TIZ) were tried. The designed system is able to maintain plasma concentration without the need of frequent dosing and reduce side effects unlike in case of conventional dosage form. Microcapsules were prepared by modified solvent evaporation technique using different proportions of cellulose acetate. The microcapsules (TIZ1, TIZ2 and TIZ3) were compressed in to tablets (T-TIZ1, T-TIZ2 and T-TIZ3) for oral delivery. The prepared microcapsules were white, free flowing and spherical in shape with the particle size varying from 175.92 +/- 9.82 to 194.94 +/- 14.28 mu. The t60% of TIZ release from microcapsules was found to be 2.39+/-0.6, 3.39+/-0.6 and 4.55+/-0.8 h respectively for formulation TIZ1, TIZ2 and TIZ3 while their tablets i.e., T-TIZ1, T-TIZ2, T-TIZ3 and marketed SR were in 5.28+/-1.5, 6.86+/-0.6, 8.25 +/-0.6 and 3.75+/-1.20 h respectively indicating more extension of time in tablet than microcapsules. The mechanism of drug release from tizanidine microcapsules and their tablets were studied by using Higuchi and Korsmeyer-Peppas models. The r-value for TIZ1, TIZ2 and TIZ3 indicates diffusion controlled with first order kinetic. The value of exponent coefficient (n) for T-TIZ1, T-TIZ2 and T-TIZ3 were found to be 0.844, 0.901 and 0.914 indicating anamolous, case-II and case-II transport release mechanism respectively.

Effect of processing variables on micro particulate system of aceclofenac.

Microparticulate systems of aceclofenac were prepared by modified solvent evaporation method using different variables such as polymer (cellulose acetate): drug ratios (1:9, 1:6, 1:3, and 1:1), agitation speeds (500-1,500 rpm) and stirring time (5-15 min). The effects of processing variables were evaluated by microparticle size and entrapment efficiency. The average microparticle size increases from 80.2+/-1.45 to 97.3+/-2.06 microm with increase in the polymer concentration while reduces with increase in agitation speed and stirring time; and at the higher speed gives irregular shape of particles. The highest entrapment efficiency, size uniformity, angle of repose (23.6+/-0.3 degree) and compressibility index (13.8+/-0.7%) of microparticles were found with 1:6 (polymer: drug ratio), at 1,000 rpm and 10 min stirring time among all microparticles. The in-vitro drug release study was carried out with prepared microcapsules (AC-1 to AC-4) of various polymer concentrations and optimized processing variables and compared with conventional and SR tablets. The conventional tablet and SR tablet releases maximum drug within 3 and 6h respectively while microparticulate system releases more than 12h. All formulations followed first order release kinetic and diffusion controlled drug release.

Effect of palonosetron (5HT-3 antagonist) and pantoprazole (proton pump inhibitor) against surgical esophagitis induced by forestomach and pylorus ligation in albino rats.

This study was embarked upon to evaluate the effects of pantoprazole and palonosetron on experimental esophagitis in albino wistar rats. Groups of rats, fasted for 36 h, were subjected to pylorus and forestomach ligation, supervened by treatment with normal saline (3 ml/kg, po, sham control), esophagitis control (3 ml/kg, po), pantoprazole (30 mg/kg, po), palonosetron (0.5 mg/kg, po), and their combination. Animals were sacrificed after 12 h and appraised for the volume of gastric juices, total acidity, free acidity, and esophagitis index. Esophageal tissues were further figured out biochemically for markers of oxidative stress and inflammatory mediators. The combination therapy comparably inhibited the esophagitis index (52.86%), gastric volume (66.04%), free acidity (43.76%), and total acidity (42.60%) in comparison with toxic control. The combination therapy also subsidized the biochemical and inflammatory markers to the purview less than toxic control. The morphological changes were scrutinized by scanning electron microscopy and were observed to demonstrate momentous protection by the amalgamation therapy. Combination therapy with pantoprazole and palonosetron flaunted sententious protection against experimental esophagitis.

Myeloma in young age.

Total 14 cases of myeloma in young age group (<40 years) have been reported out of 178 cases of myeloma in a time period of 7 years (1993-1999). Males predominated overfe males. Like adult myeloma, patients presented mostly with the backache, pain in pelvis, lower spine and weakness in about 60% of cases followed by swelling of bone in 40% of cases. One case presented with bleeding gum, malena and hepatosplenomegaly and was diagnosed as plasma cell leukemia. Radiological examination revealed lytic lesion in almost all the cases with fracture femur and rib in 28.57% of cases. Anaemia and raised ESR was noted in all the cases. Myeloma typing revealed IgG myeloma in 10 cases, light chain myeloma in 3 cases and IgA myeloma in one case. None of the patient was traceable after 2 years. Thus our study concludes that myeloma in the young age in India occurs in increased frequency and clinically presents just like adult and elderly myeloma, but serologically are predominantly of IgG type. There is also an increased frequency of solitary plasmacytoma as compared to adult myeloma.