Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression.

BACKGROUND: In non-small-cell lung cancers with programmed death-ligand 1 (PD-L1) expression on ≥50% of tumor cells, first-line treatment with the PD-1 inhibitor pembrolizumab improves survival compared with platinum-doublet chemotherapy. Whether higher PD-L1 levels within the expression range of 50%-100% predict for even greater benefit to pembrolizumab is currently unknown. PATIENTS AND METHODS: In this multicenter retrospective analysis, we analyzed the impact of PD-L1 expression levels on the overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients who received commercial pembrolizumab as first-line treatment of non-small-cell lung cancer (NSCLC) with a PD-L1 expression of ≥50% and negative for genomic alterations in the EGFR and ALK genes . RESULTS: Among 187 patients included in this analysis, the ORR was 44.4% [95% confidence interval (CI) 37.1% to 51.8%], the mPFS was 6.5 months (95% CI 4.5-8.5), and the mOS was not reached. The median PD-L1 expression level among patients who experienced a response to pembrolizumab was significantly higher than among patients with stable or progressive disease (90% versus 75%, P < 0.001). Compared with patients with PD-L1 expression of 50%-89% (N = 107), patients with an expression level of 90%-100% (N = 80) had a significantly higher ORR (60.0% versus 32.7%, P < 0.001), a significantly longer mPFS [14.5 versus 4.1 months, hazard ratio (HR) 0.50 (95% CI 0.33-0.74), P < 0.01], and a significantly longer mOS [not reached versus 15.9 months, HR 0.39 (95% CI 0.21-0.70), P = 0.002]. CONCLUSION: Among patients with NSCLC and PD-L1 expression of ≥50% treated with first-line pembrolizumab, clinical outcomes are significantly improved in NSCLCs with a PD-L1 expression of ≥90%. These findings have implications for treatment selection as well as for clinical trial interpretation and design.

Perturbation of hyaluronan interactions by soluble CD44 inhibits growth of murine mammary carcinoma cells in ascites.

Hyaluronan accumulates in ascites during intraperitoneal proliferation of TA3/St murine mammary carcinoma cells and at sites of their invasion of the peritoneal wall. To determine whether hyaluronan is functionally involved in these events, ascites tumor formation was compared in mice injected intraperitoneally with stable transfectants of TA3/St cells that overexpress soluble CD44, a hyaluronan-binding protein, versus in mice injected with transfectants expressing mutated soluble CD44 that does not bind hyaluronan. The soluble CD44 transfectants temporarily grew at a reduced rate within the peritoneal cavity, then went into G(1) arrest and were subsequently cleared from the peritoneum. However, transfectants overexpressing mutant soluble CD44 that does not bind hyaluronan exhibited similar ascites accumulation, growth rates, and cell-cycle profiles in vivo to wild-type and vector-transfected TA3/St cells, all of which continued to grow until the tumors became fatal. The soluble CD44-transfected TA3/St cells also failed to attach to and form tumors in the peritoneal wall. When grown in vitro in soft agar, the soluble CD44 transfectants exhibited a dramatic reduction in colony formation compared to wild-type, vector-transfected, and mutant soluble CD44-transfected TA3/St cells. Thus, perturbation of hyaluronan interactions by soluble CD44 has a direct effect on the growth characteristics of these tumor cells, leading to inhibition of anchorage-independent growth in vitro and ascites growth in vivo.

Expanding the CNS role to the community.

As health care reform results in fewer acute care days and cost-containment is emphasized, the role of the CNS becomes more important, although not necessarily in acute care, which has been the tradition. If the CNS role is to survive health care reform, it must expand into the community. The literature supports the effectiveness of the CNS in the community. Interviews with nurse managers also strongly support the practice of the CNS in the community to include case management, consultation to community agencies, and community-based practice.

An educational program to overcome language and cultural barriers to genetic services.

Providing genetic services to families who do not speak English and whose cultures are quite diverse presents a unique challenge to genetic specialists. One approach that is being employed successfully is the use of specially trained genetic assistants to provide outreach, case finding, referral, support, interpretation, advocacy, and follow-up counseling. A basic genetic assistant training program for five bicultural/bilingual Southeast Asian case managers is described. The course syllabus can be used to train health workers who represent a variety of cultures and languages.

Nutrient intake comparisons between Framingham and rural and Urban Puriscal, Costa Rica. Associations with lipoproteins, apolipoproteins, and low density lipoprotein particle size.

To assess cross-cultural relations between dietary intake and plasma lipoproteins, we randomly selected 222 men and 243 women from the urban and rural areas of Puriscal, Costa Rica; related their dietary composition (assessed by a food-frequency questionnaire), fitness level, and body fat to plasma lipids, apolipoproteins, and low density lipoprotein (LDL) particle size; and compared these data with those from a subsample of 280 adults from the Framingham Offspring Study. Total cholesterol and LDL cholesterol levels were significantly (p less than 0.0001) higher in Framingham (207 and 137 mg/dl, respectively) than in Puriscal (184 and 114 mg/dl, respectively) residents. Elevated triglyceride and apolipoprotein (apo) B levels (25% and 16% higher), low HDL cholesterol and apo A-I levels (12% and 29% lower), and smaller LDL particles (17%) were more frequent in Puriscal than in Framingham residents. Urban Puriscal residents had a significantly lower fitness level; increased body fat, total cholesterol, and triglyceride levels; decreased HDL cholesterol in men; and higher apo B levels in women compared with rural Puriscal residents. Body fat, animal fat, and saturated fat intakes were significantly correlated with total cholesterol, LDL cholesterol, and apo B levels in both men and women in Puriscal. Intakes of protein and animal fat were higher among urban (10.7% and 14.1%, respectively) compared with rural (8.9% and 9.9%, respectively) Puriscal residents and in Framingham (16.0% and 20.8%, respectively) compared with Puriscal residents. No significant differences were found in dietary cholesterol. Saturated fat (largely from palm oil in Puriscal) intakes were significantly different among the three groups: rural Puriscal, 10.7% of calories; urban Puriscal, 11.6%; and Framingham residents, 12.9%. These data indicate that the more atherogenic plasma lipid profile among urban compared with Puriscal residents was largely explained by increased adiposity, decreased fitness level, and higher saturated fatty acid intake. Puriscal residents consumed less animal fat and more carbohydrate than did Framingham residents, and these differences were associated with a 21% lower LDL cholesterol level, a 12% lower HDL cholesterol level, a 29% lower apo A-I level, a 25% higher triglyceride level, a 16% higher apo B level, and a 17% smaller LDL particle size. Some of these cross-cultural differences may be due to differences in ethnic background and physical activity as well.

Clinical and metabolic abnormalities in a boy with dietary deficiency of biotin.

Dietary deficiency of biotin was documented in an 11-year-old retarded boy as a consequence of a dietary prescription containing raw eggs. Clinical manifestations were alopecia totalis and an erythematous, exfoliative dermatosis. Metabolic characteristics included increased excretion of 3-methylcrotonylglycine, 3-hydroxyisovaleric acid, 3-hydroxypropionic acid, methylcitric acid, and lactic acid, as well as a propensity for the development of ketosis. The activities of propionyl coenzyme A carboxylase and 3-methylcrotonyl coenzyme A carboxylase in extracts of leukocytes were deficient. Treatment with biotin and the removal of raw eggs, which contain the biotin-binding protein, avidin, from the diet led to the reversal of all of the clinical and metabolic manifestations observed.

Congenital and neurological abnormalities in infants with phenylketonuria.

We reported the occurrence of congenital and neurological abnormalities in 150 children with phenylketonuria (PKU) age 1 year or older, who have been treated with a restricted phenylalanine diet, according to the protocol used in a nation-wide longitudinal collaborative study of children treated for PKU. The overall occurrence (9.3%) of congenital anomalies was not significantly different from that of a general population, except for an apparent increased incidence of pyloric stenosis. None of the subjects had a persistent major neurological defect.

Antenatal diagnosis of an XXX female. A dilemma for genetic counseling.

This report describes the first antenatal diagnosis of an XXX female. Over 150 postnatal cases of XXX females have been described. There is no specific phenotype associated with the sex chromosome abnormality and most such persons are fertile. The frequency of XXX females in mental institutions is 3.9 per 1,000 female subjects whereas the frequency in consecutive newborn infants is 1.1 per 1,000 newborns. Chi-square analysis shows this difference cannot be due to chance. On the other hand, data from consecutive newborn studies suggest that intellectual development in XXX newborns is within normal range. Available evidence favors normal development in XXX female infants although the risk for developmental disabilities may be higher for the XXX than for the XX infant.

Phenylketonuria. Experience at one center in the first year of screening in California.

One year's experience with phenylketonuria during the calendar year 1966, the first year for compulsory newborn screening in California, was reviewed. The over-all prevalence rate from reported cases in California during this period was one case per 19,500 persons tested. Fifty-seven persons suspected of having pku were evaluated, and 25 of them were determined to be phenylketonuric. Eleven of the 25 were infants in whom the abnormality was detected through the newborn screening program or because it was detected in a sibling through a screening program. All the newborn phenylketonuric patients were developing normally at the time of last report (although the follow-up periods were short). In nine of the other children, pku was detected because they were retarded. Five retarded children who were diagnosed as phenylketonuric at another clinic were given dietary assistance. Five additional infants had elevated serum phenylalanines but did not have the classic biochemical findings of pku and are being evaluated further. Nine infants with positive screening tests exhibited biochemical and clinical findings consistent with transient tyrosinemia. Eighteen other children were evaluated and found to have no metabolic abnormality. The newborn screening program for pku is of decided benefit in early identification of a group of infants who have a high rate of potentially serious metabolic disease. Early identification permits treatment soon enough to prevent mental retardation. Newly identified patients should be evaluated in a medical setting capable of careful pediatric, biochemical and nutritional surveillance.