Dostarlimab for primary advanced or recurrent endometrial cancer

BACKGROUND: Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer. METHODS: We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed. RESULTS: Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P\u3c0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P\u3c0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group. CONCLUSIONS: Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.)

Combining TGF-β inhibition and angiotensin II blockade results in enhanced antifibrotic effect

Combining TGF-β inhibition and angiotensin II blockade results in enhanced antifibrotic effects.BackgroundAlthough angiotensin II (Ang II) blockade is rapidly becoming standard antifibrotic therapy in renal diseases, current data suggest that Ang II blockade alone cannot stop fibrotic disease. New therapies, such as antibodies to transforming growth factor-β (TGF-β), or drug combinations will be required to further slow or halt disease progression. Here, using the anti-Thy1 model of glomerulonephritis, the maximally therapeutic dose of the TGF-β neutralizing mouse monoclonal antibody (1D11) was determined and compared with the maximally effective dose of enalapril. Then, the effect of combining both treatments at maximal doses was determined.MethodsAfter disease induction with the anti-Thy1 antibody, OX-7, increasing doses of 1D11 were given intraperitoneally (IP) on days 1, 3, and 5. Enalapril was administered in drinking water from day 1. The fibrotic response was assessed at day 6.Results1D11 dose-dependently reduced fibrosis, with the 0.5 and 5 mg/kg doses showing maximal therapeutic effects, reducing period-acid Schiff (PAS) staining by 56% and 45%, respectively. Fibronectin and collagen I staining was reduced by 32% to 36%, respectively. Glomerular mRNA and production of fibronectin, plasminogen activator inhibitor-1 (PAI-1), TGF-β1, and p-Smad2 protein were also reduced. The maximal therapeutic effects of 1D11 and enalapril alone were very similar. However, combination therapy led to further reduction in disease. Notably, matrix deposition was reduced by 80%.ConclusionWhile 1D11 or enalapril at maximal doses reduce fibrosis equally, simultaneous blockade of Ang II and TGF-β reduces fibrotic disease considerably more, offering hope that such drug combinations may confer a therapeutic advantage over angiotensin blockade alone

Ground-Water Quality in Kentucky: Fluoride

Fluoride (F-) is an ion of the element fluorine, and is a natural component in most water resources. According to Hem (1989), fluoride concentrations in fresh water are generally less than 1 mg/L (milligrams per liter), and the concentration of fluoride in the world\u27s oceans is about 1.3 mg/L. The source of most fluoride in natural fresh-water resources is various rocks and minerals in bedrock and sediments

The HBI in a quasi-global model of the intracluster medium

In this paper we investigate how convective instabilities influence heat conduction in the intracluster medium (ICM) of cool-core galaxy clusters. The ICM is a high-beta, weakly collisional plasma in which the transport of momentum and heat is aligned with the magnetic field. The anisotropy of heat conduction, in particular, gives rise to instabilities that can access energy stored in a temperature gradient of either sign. We focus on the heat-flux buoyancy-driven instability (HBI), which feeds on the outwardly increasing temperature profile of cluster cool cores. Our aim is to elucidate how the global structure of a cluster impacts on the growth and morphology of the linear HBI modes when in the presence of Braginskii viscosity, and ultimately on the ability of the HBI to thermally insulate cores. We employ an idealised quasi-global model, the plane-parallel atmosphere, which captures the essential physics -- e.g. the global radial profile of the cluster -- while letting the problem remain analytically tractable. Our main result is that the dominant HBI modes are localised to the the innermost (~<20%) regions of cool cores. It is then probable that, in the nonlinear regime, appreciable field-line insulation will be similarly localised. Thus, while radio-mode feedback appears necessary in the central few tens of kpc, heat conduction may be capable of offsetting radiative losses throughout most of a cool core over a significant fraction of the Hubble time. Finally, our linear solutions provide a convenient numerical test for the nonlinear codes that tackle the saturation of such convective instabilities in the presence of anisotropic transport.Comment: MNRAS, in press; minor modifications from v

Adult Comorbidity Evaluation 27 score as a predictor of survival in endometrial cancer patients

BACKGROUND The incidence of endometrial cancer increases with age and is associated with medical comorbidities such as obesity and diabetes. While a few cohort studies of less than 500 patients showed an association between comorbidity and survival in endometrial cancer patients, the degree of association needs to be better described. The Adult Comorbidity Evaluation 27 (ACE-27) is a validated comorbidity instrument that provides a score (0–3) based on the number and severity of medical comorbidities. OBJECTIVE This study was performed to explore the association between medical comorbidities and survival of endometrial cancer patients. STUDY DESIGN Patients diagnosed with endometrial cancer from 2000–2012 were identified from the prospectively maintained Siteman Cancer Center tumor registry. Patients undergoing primary surgical treatment for endometrioid, serous and clear cell endometrial carcinoma were included. Patients primarily treated with radiation, chemotherapy or hormone therapy were excluded. Patients with uterine sarcomas or neuroendocrine tumors were excluded. Patients with missing ACE-27 scores were also excluded from analysis. Information including patient demographics, ACE-27 score, tumor characteristics, adjuvant treatment and survival data were extracted from the database. The association of ACE-27 and overall as well as recurrence-free survival was explored in a multivariable Cox regression analysis after controlling for variables found to be significantly associated with survival in univariable analysis. RESULTS A total of 2073 patients with a median age of 61 years (range 20–94) at diagnosis were identified. ACE-27 score was 0, 1, 2 and 3 in 22%, 38%, 28% and 12% of patients, respectively. Stage distribution was I (73%), II (5%), III (15%) and IV (7%) and grade distribution was 1 (52%), 2 (23%) and 3 (25%). Most patients had endometrioid histology (87%) followed by serous (11%) and clear cell (3%). The median OS for the entire cohort was 54 months [95% confidence interval (CI) 3, 154 months] and median PFS was 50 months [95% CI 2, 154 months]., On univariable analysis, age, race, marital status, stage, grade, histology and treatment type were significantly associated with overall survival and recurrence-free survival. After adjusting for these covariates, patients with ACE-27 score of 2 had a 52% higher risk of death [95% CI 1.16, 2.00] and patients with ACE-27 score of 3 had a 2.35-fold increased risk of death [95% CI 1.73, 3.21] compared to patients with an ACE-27 score of 0. Similarly, patients with ACE-27 score of 2 had a 38% higher risk of recurrence [95% CI 1.07, 1.78] and patients with ACE-27 score of 3 had a 2.05-fold increased risk of recurrence [95% CI 1.53, 2.75] compared to patients with an ACE-27 score of 0. We found no interaction between ACE-27 score and age, stage or treatment type. CONCLUSIONS Our findings demonstrate the importance of comorbidities in estimating the prognosis of endometrial cancer patients, even after adjusting for age and known tumor-specific prognostic factors like stage, grade, histology and adjuvant treatment

Quantification of ovarian lesion and fallopian tube vasculature using optical-resolution photoacoustic microscopy

The heterogeneity in the pathological and clinical manifestations of ovarian cancer is a major hurdle impeding early and accurate diagnosis. A host of imaging modalities, including Doppler ultrasound, MRI, and CT, have been investigated to improve the assessment of ovarian lesions. We hypothesized that pathologic conditions might affect the ovarian vasculature and that these changes might be detectable by optical-resolution photoacoustic microscopy (OR-PAM). In our previous work, we developed a benchtop OR-PAM and demonstrated it on a limited set of ovarian and fallopian tube specimens. In this study, we collected data from over 50 patients, supporting a more robust statistical analysis. We then developed an efficient custom analysis pipeline for characterizing the vascular features of the samples, including the mean vessel diameter, vascular density, global vascular directionality, local vascular definition, and local vascular tortuosity/branchedness. Phantom studies using carbon fibers showed that our algorithm was accurate within an acceptable error range. Between normal ovaries and normal fallopian tubes, we observed significant differences in five of six extracted vascular features. Further, we showed that distinct subsets of vascular features could distinguish normal ovaries from cystic, fibrous, and malignant ovarian lesions. In addition, a statistically significant difference was found in the mean vascular tortuosity/branchedness values of normal and abnormal tubes. The findings support the proposition that OR-PAM can help distinguish the severity of tubal and ovarian pathologies