Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study.

BACKGROUND: Pembrolizumab demonstrated durable antitumor activity in 233 patients with previously treated advanced microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors in the phase II multicohort KEYNOTE-158 (NCT02628067) study. Herein, we report safety and efficacy outcomes with longer follow-up for more patients with previously treated advanced MSI-H/dMMR noncolorectal cancers who were included in cohort K of the KEYNOTE-158 (NCT02628067) study. PATIENTS AND METHODS: Eligible patients with previously treated advanced noncolorectal MSI-H/dMMR solid tumors, measurable disease as per RECIST v1.1, and Eastern Cooperative Oncology Group performance status of 0 or 1 received pembrolizumab 200 mg Q3W for 35 cycles or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as per RECIST v1.1 by independent central radiologic review. RESULTS: Three hundred and fifty-one patients with various tumor types were enrolled in KEYNOTE-158 cohort K. The most common tumor types were endometrial (22.5%), gastric (14.5%), and small intestine (7.4%). Median time from first dose to database cut-off (5 October 2020) was 37.5 months (range, 0.2-55.6 months). ORR among 321 patients in the efficacy population (patients who received ≥1 dose of pembrolizumab enrolled ≥6 months before the data cut-off date) was 30.8% [95% confidence interval (CI) 25.8% to 36.2%]. Median duration of response was 47.5 months (range, 2.1+ to 51.1+ months; '+' indicates no progressive disease by the time of last disease assessment). Median progression-free survival was 3.5 months (95% CI 2.3-4.2 months) and median overall survival was 20.1 months (95% CI 14.1-27.1 months). Treatment-related adverse events (AEs) occurred in 227 patients (64.7%). Grade 3-4 treatment-related AEs occurred in 39 patients (11.1%); 3 (0.9%) had grade 5 treatment-related AEs (myocarditis, pneumonia, and Guillain-Barre syndrome, n = 1 each). CONCLUSIONS: Pembrolizumab demonstrated clinically meaningful and durable benefit, with a high ORR of 30.8%, long median duration of response of 47.5 months, and manageable safety across a range of heavily pretreated, advanced MSI-H/dMMR noncolorectal cancers, providing support for use of pembrolizumab in this setting.

Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study.

OBJECTIVE: Pembrolizumab demonstrated a clinically meaningful objective response rate in patients with previously treated, advanced MSI-H/dMMR endometrial cancer in the multicohort phase 2 KEYNOTE-158 study (ClinicalTrials.gov, NCT02628067). We present health-related quality of life (HRQoL) results for these patients. METHODS: This analysis included patients from cohorts D (endometrial cancer with any MSI status) and K (any MSI-H/dMMR solid tumor except colorectal) who had previously treated, advanced MSI-H/dMMR endometrial cancer. Patients received pembrolizumab 200 mg Q3W for 35 cycles. EORTC QLQ-C30 and EQ-5D-3L questionnaires were administered at baseline, at regular intervals during treatment, and 30 days after treatment discontinuation. Pre-specified exploratory analyses included changes from baseline to week 9 in QLQ-C30 global health status (GHS)/QoL and EQ-5D-3L visual analog scale (VAS) score for all patients and by best overall response. RESULTS: 84 of 90 enrolled patients completed ≥1 HRQoL questionnaire and were included in the analysis. QLQ-C30 and EQ-5D-3L compliance rates were 90% and 94%, respectively, at baseline, and 92% and 93% at week 9. Mean (95% CI) QLQ-C30 GHS/QoL scores improved from baseline to week 9 by 6.08 (0.71-11.46) points in the overall population, with greater improvement in patients who achieved complete or partial response (11.67 [5.33-18.00]-point increase). Mean (95% CI) EQ-5D-3L VAS scores improved by 6.00 (2.25-9.75) points in the overall population and 9.11 (5.24-12.98) points in patients with CR/PR. CONCLUSIONS: Pembrolizumab maintained or improved HRQoL in patients with previously treated, advanced MSI-H/dMMR endometrial cancer, further supporting efficacy and safety results from KEYNOTE-158 and pembrolizumab use in this setting.

Physical characterization of the hair of Mexican women.

Hairs collected from 257 Mexican women, residing in Mexico City, were characterized by instrumental measurements for comparison to more-commonly reported Caucasian, Asian and African hairs. Subjects were subdivided into five age groups and their hairs were characterized by fibre dimension, shape and tensile strength. Results show that Mexican hair appears to be intermediate of Asian and Caucasian hair in diameter and cross-sectional ellipticity. Such findings seem in line with the early and late ethnic origins of Mexican people. Results also illustrate and confirm the large intra- and inter-individual variability within any single hair property. Unexpectedly high levels of hair tensile damage were sometimes encountered.

Des cheveux prélevés sur 257 mexicaines, résidant dans la ville de Mexico, ont été mesurés et comparés avec des cheveux caucasiens, asiatiques et africains, généralement mieux connus. Les sujets ont été répartis en 5 catégories d'âge et leurs cheveux caractérisés selon la dimension de la fibre, leur forme et leur résistance mécanique. Les résultats montrent que les cheveux mexicains se situent, en termes de diamètre et d'ellipticité, entre les asiatiques et les caucasiens. Cela semble en cohérence avec les origines ethniques récentes et anciennes du peuple mexicain. Les résultats illustrent aussi et confirment la grande diversité intra et inter individu pour toutes les propriétés du cheveu. Des cheveux anormalement fragiles lorsque soumis à un test de tension ont parfois été rencontrés.

Differential effects of very high doses of doxercalciferol and paricalcitol on serum phosphorus in hemodialysis patients.

BACKGROUND: Treatment of secondary hyperparathyroidism (SHPT) includes use of calcitriol (1,25D(3)) to suppress parathyroid hormone (PTH), but dosing of 1,25D(3) is limited by the development of hypercalcemia and a high calcium x phosphorus (Ca x P) product due to gut absorption of calcium and phosphorus as well as enhanced bone resorption. The vitamin D analog 19-Nor-1,25(OH)2-vitamin D2 (paricalcitol) and the prohormone 1alpha-OH-vitamin D2 (doxercalciferol) have been proposed as alternatives which may cause less hypercalcemia and elevated Ca x P, while still suppressing PTH. METHODS: We performed a prospective study to assess the acute bone mobilization effects of very high doses of paricalcitol and doxercalciferol. 13 hemodialysis patients received 160 mcg of paricalcitol and 120 mcg of doxercalciferol on 2 separate occasions in a research center while on a low calcium, low phosphorus diet, and sevelamer alone as a phosphorus binder. Changes in Ca, PO4, and PTH were measured over 36 h. RESULTS: Serum phosphorus rose faster, and peaked significantly higher at 36 h following doxercalciferol (2.12 +/- 0.11 mmol/l) than paricalcitol (1.85 +/- 0.07 mmol/l; p = 0.025). Ca x P product also rose more following doxercalciferol than paricalcitol, and peaked higher at 36 h (5.02 +/- 0.26 vs. 4.54 +/- 0.21 mmol/l; p = 0.061). In contrast, suppression of PTH at 36 h was comparable (63% after paricalcitol and 65% with doxercalciferol). CONCLUSION: Consistent with animal studies, paricalcitol provides profound PTH suppression, while stimulating bone resorption and/or intestinal absorption less than doxercalciferol, resulting in less elevation of serum phosphorus and Ca x P.

A controlled trial of the early treatment of secondary hyperparathyroidism with calcitriol in hemodialysis patients.

BACKGROUND: Calcitriol is widely used in conjunction with phosphorus-binders containing calcium to treat secondary hyperparathyroidism in dialysis patients. Its efficacy in patients with severe hyperparathyroidism is diminished, in part, due to glandular hyperplasia associated with decreased calcitriol and calcium receptors. SUBJECTS AND METHODS: We, therefore, developed a prospective, randomized trial comparing i.v. calcitriol plus calcium carbonate (CaCO3) compared to CaCO3 alone (control) in patients with mild to moderate hyperparathyroidism who were within the first year of initiating hemodialysis. Patients underwent calcium (Ca) suppression/stimulation testing at baseline and after six and twelve months of treatment to indirectly assess parathyroid gland hyperplasia. RESULTS: In the calcitriol group, the amino-terminal parathyroid hormone (N-PTH) decreased significantly from a baseline value of 70 +/- 12 pg/ml at month zero to 22 +/- 7 and 19 +/- 6 pg/ml at months 6 and 12, respectively (the conversion factor of amino-terminal PTH to intact PTH is 6, i.e., 10 pg/ml N-PTH equals 60 pg/ml intact PTH). In contrast, the N-PTH levels in the CaCO3 alone group did not change. The change in nadir N-PTH levels at month 12 compared to month zero decreased by 14 +/- 7% in the calcitriol group but increased by 96 +/- 59% in the control group (p < 0.05). In addition, the increment in N-PTH levels during hypocalcemic stimulation decreased by 68 +/- 6% at month 12 compared to month zero but increased by 61 +/- 42% in the control group. Although total calcium and phosphorus levels were not different between the two groups, ionized calcium values were higher in the calcitriol group. The incidence of hypercalcemia was the same in both groups and the episodes were asymptomatic. CONCLUSION: Pulse calcitriol therapy is effective in preventing progression of secondary hyperparathyroidism in hemodialysis patients with mild to moderate disease. Based on Ca suppression/stimulation tests, calcitriol was more successful in preventing gland growth than CaCO3 alone. Further studies are needed to determine if the strategy of early treatment of mild to moderate hyperparathyroidism by pulse calcitriol is safe and effective in hemodialysis in patients.

Chlordiazepoxide and lavender oil alter unconditioned anxiety-induced c-fos expression in the rat brain.

Lavender oil has a long history of use for treating anxiety, but only recent research has examined its effects using standard behavioural methods used to test novel drugs. The aim of this study was to investigate the effects of inhaled lavender oil on anxiety related behaviour of rats in the open field and to compare them with the effects of chlordiazepoxide (CDP), a typical anxiolytic drug. Additionally c-fos immunochemistry was used to investigate whether lavender oil produced the same pattern of c-fos expression as CDP in eight different brain areas associated with anxiety. As previously found, lavender oil showed anxiolytic properties in the open field similar to but not as extensive as those of CDP. Immunochemistry results indicated that exposure to the open field increased c-fos expression, while CDP reversed the effects of this behavioural stressor on c-fos expression in all brain regions examined except the central nucleus of the amygdala, where c-fos expression increased. Lavender oil had similar effects to CDP on the paraventricular nucleus of the hypothalamus, the dorsomedial hypothalamic nucleus and the central nucleus of the amygdala. These results strengthen the suggestion that inhaling lavender oil has anxiolytic behavioural effects, but they are weaker than the effects of benzodiazepines, and there is limited evidence that they are mediated by the same neural processes.

Increased blood-brain barrier permeability and altered tight junctions in experimental diabetes in the rat: contribution of hyperglycaemia and matrix metalloproteinases.

AIMS/HYPOTHESIS: Although diabetes mellitus is associated with peripheral microvascular complications and increased risk of neurological events, the mechanisms by which diabetes disrupts the blood-brain barrier (BBB) are not known. Matrix metalloproteinase (MMP) activity is increased in diabetic patients, is associated with degradation of tight junction proteins, and is a known mediator of BBB compromise. We hypothesise that diabetes leads to compromise of BBB tight junctions via stimulation of MMP activity. MATERIALS AND METHODS: Diabetes was induced in the rat with streptozotocin. At 14 days after injection, BBB function was assessed by in situ brain perfusion. Tight junction proteins were assessed by immunoblot and immunofluorescence. Plasma MMP activity was quantified by fluorometric gelatinase assay and gel zymography. RESULTS: In streptozotocin-treated animals, permeability to [(14)C]sucrose increased concurrently with decreased production of BBB tight junction proteins occludin (also known as OCLN) and zona occludens 1 (ZO-1, also known as tight junction protein 1 or TJP1). Insulin treatment, begun on day 7, normalised blood glucose levels and attenuated BBB hyperpermeability to [(14)C]sucrose. Neither acute hyperglycaemia in naive animals nor acute normalisation of blood glucose in streptozotocin-treated animals altered BBB permeability to [(14)C]sucrose. Plasma MMP activity was increased in streptozotocin-treated animals. CONCLUSIONS/INTERPRETATION: These data indicate that diabetes increases BBB permeability via a loss of tight junction proteins, and that increased BBB permeability in diabetes does not result from hyperglycaemia alone. Increased plasma MMP activity is implicated in degradation of BBB tight junction proteins and increased BBB permeability in diabetes. Peripheral MMP activity may present a novel target for protection of the BBB and prevention of neurological complications in diabetes.

Space flight alters bacterial gene expression and virulence and reveals a role for global regulator Hfq.

A comprehensive analysis of both the molecular genetic and phenotypic responses of any organism to the space flight environment has never been accomplished because of significant technological and logistical hurdles. Moreover, the effects of space flight on microbial pathogenicity and associated infectious disease risks have not been studied. The bacterial pathogen Salmonella typhimurium was grown aboard Space Shuttle mission STS-115 and compared with identical ground control cultures. Global microarray and proteomic analyses revealed that 167 transcripts and 73 proteins changed expression with the conserved RNA-binding protein Hfq identified as a likely global regulator involved in the response to this environment. Hfq involvement was confirmed with a ground-based microgravity culture model. Space flight samples exhibited enhanced virulence in a murine infection model and extracellular matrix accumulation consistent with a biofilm. Strategies to target Hfq and related regulators could potentially decrease infectious disease risks during space flight missions and provide novel therapeutic options on Earth.

Long-term effects of calcium carbonate and 2.5 mEq/liter calcium dialysate on mineral metabolism.

Many investigators have shown that calcium carbonate (CaCO3) is an effective phosphate binder which also prevents the potential disabling effects of aluminum (Al) accumulation. However, hypercalcemia may develop in a substantial numbers of patients. Thus, to control serum phosphate (PO4) and prevent hypercalcemia, we performed studies in 21 patients on maintenance hemodialysis in which, in addition to the oral administration of CaCO3, the concentration of calcium (Ca) in the dialysate was reduced from 3.25 to 2.5 mEq/liter. The studies were divided in three periods: I. control, on Al-binders (one month); II. no Al-binders (one month); III. CaCO3 (seven months). Blood was obtained three times/week before dialysis for the first five months of the study and once a week for the remaining four months. During the control period, the mean serum calcium was 8.86 +/- 0.08 mg/dl. The value decreased to 8.65 +/- 0.07 mg/dl when phosphate binders containing aluminum were discontinued, and increased to 9.19 +/- 0.07 mg/dl (P less than 0.001 compared to period II) during oral supplementation with calcium carbonate. The mean serum phosphorus was 5.03 +/- 0.07 mg/dl during the control period, and increased to 7.29 +/- 0.91 mg/dl (P less than 0.001) after phosphate binders were discontinued. It decreased to 4.95 +/- 0.06 mg/dl (P less than 0.001) with the administration of calcium carbonate. During CaCO3 administration, serum Al decreased from 64.2 +/- 8.5 to 37.1 +/- 3.6 and 25.1 +/- 3.0 micrograms/liter (P less than 0.001) at three and seven months, respectively. Serum parathyroid hormone (PTH) decreased by 20%.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium carbonate as a phosphate binder in patients with chronic renal failure undergoing dialysis.

Phosphate binders that contain aluminum are frequently prescribed to treat hyperphosphatemia in patients with chronic renal failure, but an accumulation of aluminum can lead to osteomalacia. To evaluate the efficacy of calcium carbonate as an alternative phosphate binder, we studied 20 patients maintained on dialysis during three consecutive periods. In period 1, the patients took aluminum hydroxide for a month (mean dose, 5.6 g per day; range, 1.5 to 14.0). In period 2, they took no phosphate binders for a month, and in period 3, they took calcium carbonate (Os-Cal) for two months (mean dose, 8.5 g per day; range, 2.5 to 17). The mean (+/- SE) serum calcium level during period 1 was 9.6 +/- 0.2 mg per deciliter; this decreased slightly (to 9.3 +/- 0.1) during period 2 and increased to 10.0 +/- 0.2 during period 3. The mean (+/- SE) serum phosphorus level during period 1 was 4.8 +/- 0.1 mg per deciliter; this increased to 7.3 +/- 0.3 during period 2, but returned to the control value (4.8 +/- 0.2) during period 3. Six of the 20 patients continued to need aluminum hydroxide during period 3 for satisfactory control of hyperphosphatemia. Calcium carbonate successfully lowered serum phosphorus levels and raised serum calcium levels in the majority of our patients, thereby confirming that this agent may be a satisfactory substitute for traditional phosphate binders that contain aluminum. The possibility that long-term treatment could cause such side effects as metastatic calcification will require further investigation.

Transgene expression patterns indicate that spaceflight affects stress signal perception and transduction in arabidopsis.

The use of plants as integral components of life support systems remains a cornerstone of strategies for long-term human habitation of space and extraterrestrial colonization. Spaceflight experiments over the past few decades have refined the hardware required to grow plants in low-earth orbit and have illuminated fundamental issues regarding spaceflight effects on plant growth and development. Potential incipient hypoxia, resulting from the lack of convection-driven gas movement, has emerged as a possible major impact of microgravity. We developed transgenic Arabidopsis containing the alcohol dehydrogenase (Adh) gene promoter linked to the beta-glucuronidase (GUS) reporter gene to address specifically the possibility that spaceflight induces the plant hypoxia response and to assess whether any spaceflight response was similar to control terrestrial hypoxia-induced gene expression patterns. The staining patterns resulting from a 5-d mission on the orbiter Columbia during mission STS-93 indicate that the Adh/GUS reporter gene was activated in roots during the flight. However, the patterns of expression were not identical to terrestrial control inductions. Moreover, although terrestrial hypoxia induces Adh/GUS expression in the shoot apex, no apex staining was observed in the spaceflight plants. This indicates that either the normal hypoxia response signaling is impaired in spaceflight or that spaceflight inappropriately induces Adh/GUS activity for reasons other than hypoxia.

Calcium acetate as a phosphorus binder in hemodialysis patients.

Much interest is currently centered on the use of calcium acetate as a phosphorus binder in patients with renal failure. Therefore, this compound in subjects previously stable on calcium carbonate and undergoing high-efficiency hemodialysis with a dialysate calcium of 2.5 mEq/L was evaluated. Twenty subjects were switched from generic calcium carbonate to a single calcium carbonate preparation for a period of 2 months. This was followed by a phase (1 month) in which calcium acetate was substituted for calcium carbonate at a dose containing half the amount of elemental calcium. Subjects then continued calcium acetate for 6 months. It was found that calcium acetate allowed comparable control of immunoreactive parathyroid hormone, calcium, and phosphorus levels compared with calcium carbonate. This occurred with half the amount of elemental calcium ingested in the form of calcium acetate (349 +/- 25 versus 699 +/- 75 mmol/day; P less than 0.001). With this lower dose, the overall incidence of hypercalcemia was the same with each formulation. In the eight subjects concurrently receiving i.v. calcitriol, the incidence of hypercalcemia was significantly higher during the first month of calcium acetate compared with that in those not receiving this compound (P less than 0.05). Of those four subjects receiving the high dose of calcitriol (2 micrograms thrice weekly), all required either reduction in the dose or discontinuation of the drug. Thus, mineral metabolism could be controlled adequately with calcium acetate despite using half as much elemental calcium compared with calcium carbonate. This, however, did not result in a lower incidence of hypercalcemia, particularly in those receiving i.v. calcitriol.