Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189.

BACKGROUND: In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab. PATIENTS AND METHODS: Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators' choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed-platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS. RESULTS: After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed-platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed-platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed-platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed-platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed-platinum and 66.8% of patients receiving placebo plus pemetrexed-platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off. CONCLUSIONS: Pembrolizumab plus pemetrexed-platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed-platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC.

Psychoactive drug interactions.

Interactions can arise from serial or simultaneous administration of 2 or more drugs. Interactions with other medications can enhance or diminish either the clinical usefulness of a drug, or its toxic effects. Interactions can arise from changes in absorption, protein binding, metabolism, excretion or activity at a common site of action. Drug interactions of clinical interest to psychiatrists are described. The drugs include: stimulants, neuroleptics, tricyclic antidepressants, monoamine oxidase inhibitors, lithium, anticonvulsants, and sedatives and hypnotics.

Is there a need for postoperative surveillance after day case groin surgery in children?

There is increasing awareness of the value of day case paediatric surgery in fulfilling the needs of the community. Is this cost effective, are there hidden complications and is there a need for routine follow-up? Seven hundred and thirty-one children attending the Red Cross War Memorial Children's Hospital day surgery unit over a 32-month period, and undergoing 912 procedures confined to the inguinoscrotal region, were enrolled in the study. Surgical procedures performed included inguinal herniotomy, orchidopexy and circumcision. Of the 731 children, 159 consecutive children had their inguinal and perineal skin flora analysed preoperatively and in 59 of these children three skin swabs were taken from the groin area: before routine skin preparation for surgery, after the skin preparation and on completion of the operation. Staphylococcus epidermidis predominated as the normal skin flora (70%), followed by Escherichia coli (19%) and Proteus mirabilis (10%), while S. aureus was only found in 2.5% of cases. The efficacy of cleaning with 4% chlorhexidine and 2% povidone-iodine in 70% alcohol is shown by virtual complete eradication of the organisms isolated from the preoperative skin cultures. In only 2 cases (3.4%) were organisms (S. aureus and S. epidermidis respectively) isolated following skin preparation. Cultures taken at the end of operative procedures grew predominantly S. epidermidis (5 cases, 8.5%). Children were discharged from the day unit once they had taken fluids and had passed urine. The wounds were also checked for any evidence of bleeding. Follow-up was done 2 weeks later by means of a visit to the day unit where the same surgeon assessed wound healing according to the Southampton Wound Assessment Scale. Ninety-four per cent of the wounds had healed by primary intention; 4.5% had minor complications and 1.5% had septic complications. Our trial confirms that wound sepsis is an infrequent but significant complication of day case groin surgery. Routine follow-up by surgical day units of minor surgical cases is not warranted and will incur unnecessary cost. Only 1.5% of postoperative cases will require further medical attention and septic lesions in the lymphatic drainage area should be regarded as risk factors.

Tin-polyimide and indium-polyimide thin-film composites as soft x-ray bandpass filters.

A tin-polyimide and an indium-polyimide soft x-ray bandpass filter were fabricated with thicknesses of 1400 and 1750 A for the metal and polyimide components, respectively. The transmission of each filter was measured at the Stanford Synchrotron Radiation Laboratory. The transmission of the tin-polyimide filter was found to be ~40% for radiation with wavelengths between 60 and 80 A. The transmission of the indium-polyimide filter was greater than 40% between 70 and 90 A. The indium was ~5% more transmissive than the tin and attained a maximum transmission of ~48% at 76 A. Such filters have potential applications to soft x-ray telescopes that operate in this region. They might also be of interest to investigators who work with x-ray microscopes that image live biological specimens in the 23-44-A water window.

Induction of diploid androgenetic and mitotic gynogenetic Nile tilapia (Oreochromis niloticus L.).

Androgenesis is a potentially valuable technique for recovering fish from gene banks composed of cryopreserved sperm, developing inbred lines, and analyzing patterns of inheritance. The procedure for producing diploid organisms whose nuclear DNA is wholly of paternal origin is dependent on: (1) the denucleation of "host" eggs, and (2) the inhibition of the first mitotic division in order to double the haploid sperm chromosome complement following fertilization of host eggs. Denucleation of tilapia (Oreochromis niloticus L.) eggs was carried out using UV irradiation. Treatment durations of 5-8 min (total dose of 450-720 J/m(2)) produced acceptable yields of viable denucleated eggs [22.9±1.6% (±SE) of controls] as estimated by the survival of haploid androgenetic tilapia to 48 h post-fertilization. Successful mitotic inhibition was accomplished using a heat-shock of 42.5 °C for 3-4 min, applied at 2.5-min intervals from 22.5 to 30 min post-fertilization (mpf). The mean survival of androgenetic diploid fish to yolk-sac absorption for treatment groups varied from 0.4% to 5.3%, relative to the controls. Differences in the suceptibility of eggs from different females to UV irradiation were a significant factor in the overall yield of androgenetic diploids. Paternal effects did not significantly influence the androgenetic yield, suggesting that individual males would not be selected against. For comparative purposes mitotic gynogenetic "mitogyne" diploids were produced from UV-irradiated sperm. Mean survival to yolk-sac absorption varied from 0.5% to 10.64%, relative to controls. Similar optima for androgenetic and gynogenetic induction were found in the period 25-27.5 mpf (minutes post-fertilization). Induction treatments would appear to be operating on the same developmental events in both these techniques, and the results suggest that the UV irradiations used do relatively little damage to the eggs beyond nuclear inactivation. The results indicate that the production of androgenetic O. niloticus is possible on a consistent basis and that the application of this technique may be useful in quantitative and conservation genetics.