Phase II multicohort study of atezolizumab monotherapy in multiple advanced solid cancers.

BACKGROUND: The programmed death-ligand 1 inhibitor atezolizumab had shown clinical activity against several advanced malignancies. PATIENTS AND METHODS: This phase II, open-label basket study (NCT02458638) was conducted in 16 main cohorts of patients aged ≥18 years with stage III or IV solid tumors. In stage I, 12 patients were enrolled into each cohort. Treatment was atezolizumab 1200 mg intravenously every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was the non-progression rate (NPR) at 18 weeks in treated, assessable patients. NPR ≤20% was not of interest for development as monotherapy, and NPR ≥40% was defined as the threshold of benefit/success. If ≥3 patients had non-progressive disease in stage I (interim analysis), 13 additional patients could be enrolled into stage II (final analysis). Secondary efficacy and safety endpoints were also evaluated. RESULTS: Overall, 474 patients were enrolled and treated; 433 were included in the efficacy set. Due partly to slow recruitment because of competing trials and limited efficacy at interim analyses, enrollment was stopped early, including in cohorts that passed stage I boundaries of success. NPR was >20% in five cohorts: cervical cancer {n = 27; NPR 44.4% [95% confidence interval (CI) 25.5% to 64.7%]}; follicular/papillary thyroid cancer [n = 11; 54.5% (95% CI 23.4% to 83.3%)]; thymoma [n = 13; 76.9% (95% CI: 46.2% to 95.0%)]; gastroenteropancreatic (GEP) and lung neuroendocrine tumors [NETs; n = 24; 41.7% (95% CI 22.1% to 63.4%)], and low/intermediate grade carcinoid GEP and lung NETs [n = 12; 58.3% (95% CI 27.7% to 84.8%)]. Treatment-related adverse events occurred in 55.3% of patients overall, and at grade 3, 4, and 5 in 10.3%, 1.7%, and 0.4%, respectively. CONCLUSIONS: Atezolizumab monotherapy was effective in the cervical cancer cohort. The interim benefit threshold was crossed in patients with follicular/papillary thyroid cancer, thymoma, and GEP and lung NETs, but recruitment was stopped before these signals could be confirmed in stage II. Safety was consistent with previous findings.

Perception of Dentists about Caries-risk Assessment tools in Jaipur, India: A Cross-sectional Study.

BACKGROUND: Caries risk assessment (CRA) is an essential element of contemporary clinical care for infants, children, and adolescents. CRA tools aid in the detection as well as documentation of caries risk predictors and let the health care professionals to be more active in identifying and referring high-risk patients for proper treatment and required prevention. The aim of the study was to assess the information-seeking behavior of dental practitioners of Jaipur regarding CRA tools. MATERIALS AND METHODS: A cross-sectional questionnaire-based survey was conducted among the dental practitioners of Jaipur city. A 17-itemed questionnaire was personally administered to 373 dental practitioners of Jaipur and their knowledge was assessed based on the questions about CRA tools and Cariogram. The data were analyzed using Chi-square test. RESULTS: Around 80.5% of the practitioners were aware of CRA tools among which only one-fourth were practicing CRA. Significant correlation of qualification, specialty, and years of practice was found with knowledge of CRA tools, practice of CRA and preventive treatment and attitude toward risk assessment. CONCLUSIONS: A substantial percentage of dentists did not practice CRA, but were interested in receiving more education about CRA and its tools.

The role of single serum progesterone measurement in conjunction with beta hCG in the management of suspected ectopic pregnancy.

Our aim was to test the use of single serum progesterone measurement together with beta hCG in the management of women with pregnancy of unknown location. This was a retrospective study of 126 patients presenting with a clinical picture suggestive of ectopic pregnancy, when ultrasound examination was inconclusive. All the patients had serum progesterone level measured by radioimmunoassay in conjunction with beta hCG. The study showed that a protocol combining single serum progesterone measurement and beta hCG is helpful in managing women with suspected ectopic pregnancies, when the ultrasound examination is inconclusive. High levels of progesterone are reassuring as regards ongoing viable pregnancies and low levels allow a definitive differentiation between viable and non-viable pregnancies. However, low progesterone could not efficiently differentiate between miscarriage and ectopic pregnancy. The use of beta hCG levels in conjunction with serum progesterone is helpful, particularly with serum progesterone levels between 16-80 nmol/l.

Drug-induced alterations to gene and protein expression in intestinal epithelial cell 6 cells suggest a role for calpains in the gastrointestinal toxicity of nonsteroidal anti-inflammatory agents.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used extensively as therapeutic agents, despite their well documented gastrointestinal (GI) toxicity. At this time, the mechanisms responsible for NSAID-associated GI damage are incompletely understood. In this study, we used microarray analysis to generate a novel hypothesis about cellular mechanisms that underlie the GI toxicity of NSAIDs. Monolayers of intestinal epithelial cells (IEC-6) were treated with NSAIDs that either exhibit (indomethacin, NS-398 [N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide]) or lack (SC-560 [5-(4-chlorphenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole]) inhibitory effects on IEC-6 migration. Bioinformatic analysis of array data identified the calpain cysteine proteases and their endogenous inhibitor calpastatin as potential targets of NSAIDs shown previously to retard IEC-6 migration. Accordingly, quantitative real-time reverse transcription polymerase chain reaction and immunoblotting were performed to assess the effects of NSAIDs on the expression of mRNA and protein for calpain 8, calpain 2, calpain 1, and calpastatin. In treated IEC-6 monolayers, NS-398 decreased the expression of mRNA for calpain 2 and calpain 8. Both NS-398 and indomethacin decreased the protein expression of calpains 8, 2, and 1. None of the NSAIDs affected expression of calpastatin mRNA or protein. The calpain inhibitors, N-acetyl-Leu-Leu-methioninal and N-acetyl-Leu-Leu-Nle-CHO, retarded IEC-6 cell migration in a concentration-dependant fashion, and these inhibitory effects were additive with those of indomethacin and NS-398. Our experimental results suggest that the altered expression of calpain proteins may contribute to the adverse effects of NSAIDs on intestinal epithelial restitution.

Depolarization and decreased surface expression of K+ channels contribute to NSAID-inhibition of intestinal restitution.

Non-steroidal anti-inflammatory drugs (NSAIDs) contribute to gastrointestinal ulcer formation by inhibiting epithelial cell migration and mucosal restitution; however, the drug-affected signaling pathways are poorly defined. We investigated whether NSAID inhibition of intestinal epithelial migration is associated with depletion of intracellular polyamines, depolarization of membrane potential (E(m)) and altered surface expression of K(+) channels. Epithelial cell migration in response to the wounding of confluent IEC-6 and IEC-Cdx2 monolayers was reduced by indomethacin (100 microM), phenylbutazone (100 microM) and NS-398 (100 microM) but not by SC-560 (1 microM). NSAID-inhibition of intestinal cell migration was not associated with depletion of intracellular polyamines. Treatment of IEC-6 and IEC-Cdx2 cells with indomethacin, phenylbutazone and NS-398 induced significant depolarization of E(m), whereas treatment with SC-560 had no effect on E(m). The E(m) of IEC-Cdx2 cells was: -38.5+/-1.8 mV under control conditions; -35.9+/-1.6 mV after treatment with SC-560; -18.8+/-1.2 mV after treatment with indomethacin; and -23.7+/-1.4 mV after treatment with NS-398. Whereas SC-560 had no significant effects on the total cellular expression of K(v)1.4 channel protein, indomethacin and NS-398 decreased not only the total cellular expression of K(v)1.4, but also the cell surface expression of both K(v)1.4 and K(v)1.6 channel subunits in IEC-Cdx2. Both K(v)1.4 and K(v)1.6 channel proteins were immunoprecipitated by K(v)1.4 antibody from IEC-Cdx2 lysates, indicating that these subunits co-assemble to form heteromeric K(v) channels. These results suggest that NSAID inhibition of epithelial cell migration is independent of polyamine-depletion, and is associated with depolarization of E(m) and decreased surface expression of heteromeric K(v)1 channels.

FSH stimulates ovarian cancer cell growth by action on growth factor variant receptor.

A number of FSH receptor (FSH-R) isoforms with distinct structural motifs and signaling paradigms have been described, including a single transmembrane domain variant that functions as a growth factor type receptor (FSH-R3). This study tested the hypothesis that FSH can stimulate ovarian cancer cell proliferation by acting on FSH-R3, using the tumorigenic mouse ovarian surface epithelial cell (MOSEC) line ID8. FSH enhanced ID8 proliferation in a concentration-dependent fashion. Moreover, FSH-treatment of ID8 elicited intracellular events consistent with activation of FSH-R3 and distinct from those associated with activation of the canonical G-protein coupled FSH-R isoform (FSH-R1). Specifically, the FSH-R3 signaling pathway included cAMP-independent activation of ERK downstream of an SNX-482 sensitive component likely to be the Cav2.3 calcium channel. Northern analysis using probes specific for exons 7 and 11 of FSH-R identified consistently only one 1.9kb transcript. Immunoblot analysis confirmed expression of FSH-R3 but not FSHR-1 in ID8. Together, these data suggest that FSH-R3 signaling promotes proliferation of ovarian cancer cells.

Removal of catheter at midnight versus early morning: the patients' perspective.

BACKGROUND: With an increasing role of the patient as a partner in making a combined decision in care plan goals, it is important to identify the patient's perspective of the experience of removal of catheter (ROC). METHODS: A non-consecutive prospective randomized study was performed in 84 patients who underwent a transurethral resection of the prostate to determine the impact of midnight versus early-morning ROC on sleep deprivation, over all discomfort to the patient. RESULTS: There was no difference in the patient experience in both groups. We found a reduced frequency during the first 6 h of ROC at midnight. However, there was an increased incidence of sleep disturbances in this group. This may in part be due to an anxiety of urge incontinence and may be allayed by appropriate counselling. There was no delay in discharge of the patients in both groups. CONCLUSION: The patients must, therefore, be given the choice of ROC either at midnight or early morning, as the advantages of a reduced frequency must be correlated with an increased incidence of sleep disturbances.

An unusual presentation of metastatic testicular tumour.

We report a unique case of metastatic malignant teratoma from an undescended testis which presented with acute pulmonary embolism. After chemotherapy, the undescended right testicle was resected along with a cord of non- obstructing inferior venal caval tumour which extended into the right atrium with tumour floating free within the atrium at the end of the cord of tumour. The presentation, diagnosis and treatment of testicular tumours is described and the literature pertaining to testicular tumours in military personnel reviewed.

The trends of vasectomy reversal in the forces.

A reversal of a vasectomy is required in about 3% of men who undergo vasectomy. We set out to examine the relationships between the age at which vasectomy was performed and the interval before subsequent reversal within the context of the armed forces. Thirty seven patients were identified from hospital records, as having undergone a reversal of vasectomy in the preceding two years, and thirty one sets of notes were available for inspection. Ages at vasectomy and at reversal were recorded and, where stated in the notes, if there had been a change in partner prior to the reversal request. Twelve (39%) men were under the age of thirty years at the time of their vasectomy, with a mean time to reversal of 4.4 years. Nineteen (61%) were over the age of thirty years at time of the vasectomy and their mean time to reversal was 7.2 years. Where recorded, the reason for requesting a reversal was a change in partner in 90% of men. Men who had their vasectomies before reaching the age of thirty were more likely to undergo reversal in a significantly shorter period of time when compared to those over thirty years. The disseminated criteria for vasectomy should be adhered to and appropriate preoperative counselling by surgeons may be useful.