BACKGROUND: Microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR) is a biomarker for responses to immune checkpoint inhibitors (ICIs). Whether mechanisms underlying microsatellite instability alter responses to ICIs is unclear. This article reports data from a prospective phase 2 pilot study of pembrolizumab in patients with recurrent MSI-H endometrial cancer (EC) analyzed by whole exome sequencing (WES) and potential mechanisms of primary/secondary ICI resistance (NCT02899793). METHODS: Patients with measurable MSI-H/dMMR EC confirmed by polymerase chain reaction/immunohistochemistry were evaluated by WES and received 200 mg of pembrolizumab every 3 weeks for ≤2 years. The primary end point was the objective response rate (ORR). Secondary end points included progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-five patients (24 evaluable) were treated. Six patients (25%) harbored Lynch/Lynch-like tumors, whereas 18 (75%) had sporadic EC. The tumor mutation burden was higher in Lynch-like tumors (median, 2939 mutations/megabase [Mut/Mb]; interquartile range [IQR], 867-5108 Mut/Mb) than sporadic tumors (median, 604 Mut/Mb; IQR, 411-798 Mut/Mb; P = .0076). The ORR was 100% in Lynch/Lynch-like patients but only 44% in sporadic patients (P = .024). The 3-year PFS and OS proportions were 100% versus 30% (P = .017) and 100% versus 43% (P = .043), respectively. CONCLUSIONS: This study suggests prognostic significance of Lynch-like cancers versus sporadic MSI-H/dMMR ECs for ORR, PFS, and OS when patients are treated with pembrolizumab. Larger confirmatory studies in ECs and other MSI-H/dMMR tumors are necessary. Defective antigen processing/presentation and deranged induction in interferon responses serve as mechanisms of resistance in sporadic MSI-H ECs. Oligoprogression in MSI-H/dMMR patients appears salvageable with surgical resection and/or local treatment and the continuation of pembrolizumab off study. Clinical studies evaluating separate MSI-H/dMMR EC subtypes treated with ICIs are warranted.

BackgroundThe effect of moderately elevated blood glucose levels among non-diabetic subjects on cancer prognosis is not well described. The goal of this study was to examine the association of elevated random blood glucose (RBG) levels in non-diabetic breast cancer patients with overall survival (OS) and time to tumor recurrence (TTR).ResultsForty-nine deaths and 32 recurrences occurred among 148 eligible study subjects during 855.44 person-years of follow-up, with median follow-up of 5.97 years. We observed that patients with elevated RBG levels experienced significantly shorter OS (hazard ratio [HR], 3.01; 95 % confidence interval [CI] (1.70–5.33); P < 0.001) and shorter TTR (HR, 2.08; CI (1.04–4.16); P = 0.04) as compared to patients with non-elevated RBG levels. After controlling for tumor grade, tumor stage, race, and BMI, elevated RBG continued to display high and statistically significant association with shorter OS (HR, 3.50; CI (1.87–6.54); P < 0.001). Adjustment for age, race, and BMI strengthened HR of RBG for TTR. The association of RGB with TTR lost its borderline statistical significance upon controlling for both tumor grade and stage.ConclusionsThe data suggest that elevated blood glucose is associated with poor prognosis of breast cancer patients. Given the potential clinical implication, these findings warrant further investigation.

To determine if pregnant women decreasing/quitting tobacco use will have improved fetal outcomes. Retrospective analysis of pregnant smokers from 6/1/2006-12/31/2007 who received prenatal care and delivered at a tertiary medical care center in West Virginia. Variables analyzed included birth certificate data linked to intervention program survey data. Patients were divided into four study groups: <8 cigarettes/day-no reduction, <8 cigarettes/day-reduction, ≥8 cigarettes/day-no reduction, and ≥8 cigarettes/day-reduction. Analysis performed using ANOVA one-way test for continuous variables and Chi-square for categorical variables. Inclusion criteria met by 250 patients. Twelve women (4.8%) quit smoking; 150 (60%) reduced; 27 (10.8%) increased; and 61 (24.4%) had no change. Comparing the four study groups for pre-term births (<37 weeks), 25% percent occurred in ≥8 no reduction group while 10% occurred in ≥8 with reduction group (P = 0.026). The high rate of preterm birth (25%) in the non-reducing group depended on 2 factors: (1) ≥8 cigarettes/day at beginning and (2) no reduction by the end of prenatal care. Finally, there was a statistically significant difference in birth weights between the two groups: ≥8 cigarettes/day with no reduction (2,872.6 g) versus <8 cigarettes/day with reduction (3,212.4 g) (P = 0.028). Smoking reduction/cessation lowered risk of pre-term delivery (<37 weeks) twofold. Encouraging patients who smoke ≥8 cigarettes/day during pregnancy to decrease/quit prior to delivery provides significant clinical benefit by decreasing the likelihood of preterm birth. These findings support tobacco cessation efforts as a means to improve birth outcome.

Mini-allograft induced excellent disease control in MM patients with high-risk disease, but is still associated with a significant GVHD.

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