Durable partial response to pembrolizumab, lenvatinib, and letrozole in a case of recurrent uterine carcinosarcoma with ESR1 gene amplification.

•ESR1 gene amplification occurs in 7% of uterine carcinosarcoma.•The presence of ESR1 gene amplification in recurrent uterine carcinosarcoma may be targeted by aromatase inhibitors.•ESR1 gene amplification may be identified through immunohistochemical staining for estrogen receptor followed by fluorescence in situ hybridization or tumor targeted gene sequencing.

Combined Treatment of Uterine Leiomyosarcoma with Gamma Secretase Inhibitor MK-0752 and Chemotherapeutic Agents Decreases Cellular Invasion and Increases Apoptosis.

Due to limited effective therapeutics for uterine leiomyosarcoma (uLMS), the impact of the gamma secretase inhibitor (GSI) MK-0752 with common chemotherapeutics was explored in uLMS. MTT assays were performed on two human uLMS cell lines, SK-UT-1B and SK-LMS-1, using MK-0752, docetaxel, doxorubicin, and gemcitabine, individually and in combination, to determine cell viability after treatment. Synergistic combinations were used in transwell invasion assays, cell cycle flow cytometry, proliferation assays, and RNA sequencing. In SK-UT-1B, MK-0752 was synergistic with doxorubicin and gemcitabine plus docetaxel. In SK-LMS-1, MK-0752 was synergistic with all individual agents and with the combination of gemcitabine plus docetaxel. MK-0752, gemcitabine, and docetaxel decreased invasion in SK-UT-1B 2.1-fold* and in SK-LMS-1 1.7-fold*. In SK-LMS-1, invasion decreased 1.2-fold* after treatment with MK-0752 and docetaxel and 2.2-fold* after treatment with MK-0752 and doxorubicin. Cell cycle analysis demonstrated increases in the apoptotic sub-G1 population with MK-0752 alone in SK-UT-1B (1.4-fold*) and SK-LMS-1 (2.7-fold**), along with increases with all combinations in both cell lines. The combination treatments had limited effects on proliferation, while MK-0752 alone decreased proliferation in SK-LMS-1 (0.63-fold**). Both MK-0752 alone and in combination altered gene expression and KEGG pathways. In conclusion, the combinations of MK-0752 with either doxorubicin, docetaxel, or gemcitabine plus docetaxel are potential novel therapeutic approaches for uLMS. (* p < 0.05, ** p < 0.01).

Reduced healthcare access contributes to delay of care in endometrial cancer.

OBJECTIVE: We aimed to characterize delays to care in patients with endometrioid endometrial cancer and the role healthcare access plays in these delays. METHODS: A chart review was performed of patients with endometrioid endometrial cancer who presented with postmenopausal bleeding at a diverse, urban medical center between 2006 and 2018. The time from symptom onset to treatment was abstracted from the medical record. This interval was subdivided to assess for delay to presentation, delay to diagnosis, and delay to treatment. RESULTS: We identified 484 patients who met the inclusion criteria. The median time from symptom onset to treatment was 4 months with an interquartile range of 2 to 8 months. Most patients had stage I disease at diagnosis (88.6%). There was no significant difference in race/ethnicity or disease stage at time of diagnosis between different groups. Patients who had not seen a primary care physician or general obstetrician-gynecologist in the year before symptom onset were more likely to have significantly delayed care (27.7% vs 14.3%, p = 0.02) and extrauterine disease (20.2% vs 4.9%, p < 0.01) compared to those with established care. Black and Hispanic patients were more likely to experience significant delays from initial biopsy to diagnosis. CONCLUSIONS: Delays exist in the evaluation of endometrial cancer. This delay is most pronounced in patients without an established outpatient primary care provider or obstetrician-gynecologist.

Inflammatory reaction to BioGlue™ masquerading as recurrence in patients with endometrial cancer: A report of two cases.

•BioGlue™, a glutaraldehyde-based vessel sealant, can cause a foreign body reaction.•Vessel sealants may be used for IVC repair during endometrial cancer staging.•Foreign body reaction to BioGlue™ may look like a cancer recurrence on imaging.•It is important to note prior use of vessel sealants in assessing paraaortic recurrence.

Heterogeneity in FoxP3- and GARP/LAP-Expressing T Regulatory Cells in an HLA Class II Transgenic Murine Model of Necrotizing Soft Tissue Infections by Group A Streptococcus.

Invasive group A streptococcus (GAS) infections include necrotizing soft tissue infections (NSTI) and streptococcal toxic shock syndrome (STSS). We have previously shown that host HLA class II allelic variations determine the risk for necrotizing fasciitis (NF), a dominant subgroup of NSTI, and STSS by modulating responses to GAS superantigens (SAgs). SAgs are pivotal mediators of uncontrolled T-cell activation, triggering a proinflammatory cytokine storm in the host. FoxP3-expressing CD4+ CD25+ T regulatory cells (Tregs) comprise phenotypically and functionally heterogeneous subsets with a profound ability to suppress inflammatory responses. Specifically, activated Tregs, which express glycoprotein A repetitions predominant (GARP) and display latent transforming growth factor ß1 (TGF-ß1) complexes (latency-associated peptide [LAP]), exhibit strong immunosuppressive functions. The significance of Tregs that may participate in suppressing inflammatory responses during NSTI is unknown. Here, we phenotypically characterized FoxP3/GARP/LAP-expressing Tregs in GAS-infected or SAg (SmeZ)-stimulated splenocytes from transgenic (tg) mice expressing human HLA-II DRB1*15 (DR15 allele associated with nonsevere NF/STSS-protective responses) or DRB1*0402/DQB1*0302 (DR4/DQ8 alleles associated with neutral risk for combined NF/STSS). We demonstrated both in vivo and in vitro that the neutral-risk allele upregulates expression of CD4+ CD25+ activated effector T cells, with a significantly lower frequency of Foxp3+/GARP+ LAP- but higher frequency of Foxp3- LAP+ Tregs than seen with the protective allele. Additional in vitro studies revealed that the presentation of SmeZ by the neutral-risk allele significantly increases proliferation and expression of effector cytokines gamma interferon (IFN-γ) and interleukin-2 (IL-2) and upregulates CD4+ CD25+ T cell receptors (TCRs) carrying specific Vß 11 chain (TCRVß11+) T cells and Th1 transcription factor Tbx21 mRNA levels. Our data suggest that neutral-risk alleles may drive Th1 differentiation while attenuating the induction of Tregs associated with suppressive function.