Peripheral blood mononuclear cells (PBMCs) respond to altered physiological conditions to alleviate the threat. Production of the 70 kDa heat shock protein (HSP70) is up-regulated to protect proteins ...from degradation. Sequestosome-1 (p62) binds to altered proteins and the p62-protein complex is degraded by autophagy. P62 is also a regulator of intracellular kinase activity and cell differentiation. We hypothesized that the PBMC response to a malignant breast mass involves elevated production of HSP70 and a decrease in intracellular p62. In this study 46 women had their breast mass excised. PBMCs were isolated and intracellular levels of HSP70 and p62 were quantitated by ELISA. Differences between women with a benign or malignant breast mass were determined. A breast malignancy was diagnosed in 38 women (82.6%) while 8 had a benign lesion. Mean intracellular HSP70 levels were 79.3 ng/ml in PBMCs from women with a malignant lesion as opposed to 44.2 ng/ml in controls (p = 0.04). The mean PBMC p62 level was 2.3 ng/ml in women with a benign breast lesion as opposed to 0.6 ng/ml in those with breast cancer (p < 0.001). Mean p62 levels were lowest in women with invasive carcinoma and a positive lymph node biopsy when compared to those with in-situ carcinoma or absence of lymphadenopathy, respectively. Intracellular HSP70 and p62 levels in PBMCs differ between women with a malignant or benign breast lesion. These measurements may be of value in the preoperative triage of women with a breast mass.
•Black patients had lower overall survival on univariate analysis; race was no longer associated with survival on adjusted multivariate analyses.•Black patients had significantly longer time from EMB ...to surgery than any other group.•Across the health system, Black patients had higher rates of persistence disease following primary treatment than any other group.•Hospital site was significantly associated with overall survival, highlighting the fact that survival outcomes are impacted by social determinants of health.•Palliative care referral rates were higher for Black patients compared to White after adjusting for stage and histology.
National data have shown worse endometrial cancer (EC) outcomes among racial and ethnic minorities. We aimed to analyze EC patient outcomes within a large urban academic health system, with a focus on patterns of care and recurrence rates.
This was a retrospective chart review of EC patients at three system hospitals from 1/1/07–12/31/17. Demographic and clinical factors, including time from EMB to surgery, rate of chemotherapy completion, persistent or recurrent disease, and palliative care referrals were extracted. Descriptive statistics and survival curves were generated. Analysis was done using SAS version 9.4.
Black patients had lower overall survival compared to all others on univariate analysis only (p < 0.0001). Hospital site was associated with OS, with the academic anchor and satellite 1 having higher rates of all-cause mortality compared to satellite 2 (HR 4.68 academic anchor, 95 % CI 1.72–12.76, HR 5.36 satellite 1, 95 % CI 1.85–15.52). Time from EMB to surgery and rates of persistent disease following primary treatment were higher in Black patients. After adjusting for stage and grade, chemotherapy completion rate was significantly associated with race. Palliative care was utilized more for Black than White patients after adjusting for stage and grade (p = 0.005).
Racial disparities in EC are caused by a complex web of interconnected factors that ultimately lead to worse outcomes in Black women. While precision medicine has helped to close the gap, social determinants of health should be addressed, and models focusing on the complex interactions between biologic, genetic, and social factors should be utilized.
Objective To investigate whether interleukin-1β (IL-1β) and interleukin-1 receptor antagonist (IL-1RA) serum levels in the early luteal phase differ in IVF cycles that result in an ectopic pregnancy ...(EP) when compared with other outcomes. Design Retrospective cohort. Setting Not applicable. Patient(s) A total of 307 women whose serum samples were available, with the following IVF outcomes: 103 live births, 80 negative pregnancy tests, 52 biochemical pregnancies, 47 EPs, and 25 miscarriages. Intervention(s) Serum samples were obtained on cycle days 24 and 28 (cycle day 14 = day of egg retrieval). Levels of IL-1β and IL-1RA were determined by quantitative ELISA performed by blinded personnel. Main Outcome Measure(s) IL-1β and IL-1RA levels, IL-1β-to-IL-1RA ratio versus cycle outcome. Result(s) The IL-1β levels were predictive of an EP. At cycle days 24 and 28 the mean IL-1β levels were higher in patients with an EP (127.1 pg/mL and 166.9 pg/mL, respectively) than in women with any other IVF outcome (15.8–55.3 pg/mL and 14.8–75.5 pg/mL, respectively). At cycle day 24 the IL-1β-to-IL-1RA ratio was 0.18 in the ectopic group versus 0.01–0.09 in the other groups. Conclusion(s) Elevated IL-1β levels and IL-1β-to-IL-1RA ratio as early as 4 days before the first pregnancy test are associated with an EP. If confirmed by prospective studies, clinical application of these findings could potentially improve EP detection.
As clinical efforts towards breast-conserving therapy and prolonging survival of those with metastatic breast cancer increase, innovative approaches with the use of biologics are on the rise. Two ...areas of current focus are cancer immunotherapy and autophagy, both of which have been well-studied independently but have recently been shown to have intertwining roles in cancer. An increased understanding of their interactions could provide new insights that result in novel diagnostic, prognostic, and therapeutic strategies. In this breast cancer-focused review, we explore the interactions between autophagy and two clinically relevant immune checkpoint pathways; the programmed cell death-1 receptor with its ligand (PD-L1)/PD-1 and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)/CD80 and CD86 (B7-1 and B7-2). Furthermore, we discuss emerging preclinical and clinical data supporting targeting both immunotherapy and autophagy pathway manipulation as a promising approach in the treatment of breast cancer.
Highlights • Nonbacterial thrombotic endocarditis (NBTE) is a rare complication of cancer. • NBTE may precede the diagnosis of an occult gynecologic malignancy. • Malignancy - induced NBTE must be ...considered in patients with unprovoked venous thromboembolism. • The most effective treatment is anticoagulation and treatment of the underlying cancer.
•Cervical cancer may present with underlying mixed histopathology.•Sequencing revealed a FGFR2-TACC2 fusion in neuroendocrine small cell carcinoma of the cervix.•The understanding genomic ...heterogeneity of cervical cancer continues to evolve with expansion of clinical trial options.
Neuroendocrine small cell carcinoma of the uterine cervix portends a dismal prognosis with limited treatment options. Rarely, tumors of mixed-lineage appear in gynecologic malignancies. Here, we report a 77-year-old woman who presented with complete uterine prolapse and 4-month history of vaginal bleeding. Histopathologic evaluation revealed a mixed adenoid cystic carcinoma and neuroendocrine small cell carcinoma of the uterine cervix. The tumor was PD-L1 and HPV 35 positive. The patient was treated with up-front surgery and adjuvant radiation. Independent, histology-specific alterations in FGFR2 and a FGFR2-TACC2 fusion were identified. Progression of disease occurred within 6 months for which she received chemotherapy and immunotherapy. However, the patient expired within a year. We comprehensively review how screening for and targeting of FGFR alterations in recurrent and metastatic cervical cancer might serve as a touchstone for future treatment regimens.
To investigate the role of adjuvant chemotherapy (CT) in the management of ovarian non-granulosa cell (GC) sex cord-stromal tumors (SCSTs).
The National Cancer Database was accessed and patients ...diagnosed between 2004 and 2013 with a malignant non-GC SCST were selected. Overall survival (OS) was evaluated with Kaplan-Meier curves and compared with the log-rank test. Multivariate survival analysis was performed with Cox regression. Factors associated with the administration of CT were evaluated with the chi-square test and binary logistic regression.
A total of 391 patients were identified. The majority had a Sertoli-Leydig cell tumor (SLCT) (73.2%) and early stage disease (84.8%). A total of 203 (51.9%) patients received CT. Advanced disease stage, younger age, high-grade histology, White race, large tumor size and SLCT histology were associated with administration of CT. For patients with early stage disease, there was no difference in OS between those who did (n=134) and did not receive CT (n=157), p=0.40; 5-year OS rates were 81.7% and 84.6%, respectively. No mortality benefit was observed (hazard ratio=0.73; 95% confidence interval=0.38-1.4) after controlling for tumor histology. Median OS of women with advanced stage disease who received CT (n=41) was 34.96 months compared to 15.51 months for those who did not (n=11), p=0.013.
Adjuvant CT was associated with improved survival for patients with advanced stage non-GC SCSTs. No clear benefit was found for those with early stage disease.
Objective Women with vestibulodynia exhibit increased pain sensitivity to contact with the vaginal vestibule as well as with vaginal penetration. The mechanism(s) responsible for this effect remains ...incompletely defined. Based on reports of a possible role for proteases in induction of pain, we compared levels of proteases and protease inhibitors in vaginal secretions from women with vestibulodynia and controls. Study Design Vaginal secretions from 76 women with vestibulodynia and from 41 control women were assayed by an enzyme-linked immunosorbent assay for the protease inhibitors, secretory leukocyte protease inhibitor (SLPI) and human epididymis protein-4 (HE-4), and the proteases, kallikrein-5 and cathepsins B and S. Concentrations between subjects and controls were compared and levels related to clinical and demographic variables. Results Concentrations of HE-4 and SLPI were markedly reduced in vaginal samples from women with vestibulodynia compared with controls ( P ≤ .006). All other compounds were similar in both groups. HE-4 ( P = .0195) and SLPI ( P = .0033) were lower in women with secondary, but not primary, vestibulodynia than in controls. Subjects who had constant vulvar pain had lower levels of HE-4 and SLPI than did healthy control women ( P ≤ .006) or women who experienced vulvar pain only during sexual intercourse ( P ≤ .0191). There were no associations between HE-4 or SLPI levels and event associated with symptom onset, duration of symptoms, age, number of lifetime sexual partners, or age at sex initiation. Conclusion Insufficient vaginal protease inhibitor production may contribute to increased pain sensitivity in an undefined subset of women with secondary vestibulodynia who experience constant vulvar pain.
Microsatellite instability-high (MSI-H) tumors are characterized by high tumor mutation burden and responsiveness to checkpoint blockade. We identified tumor-specific frameshifts encoding multiple ...epitopes that originated from indel mutations shared among patients with MSI-H endometrial, colorectal, and stomach cancers. Epitopes derived from these shared frameshifts have high population occurrence rates, wide presence in many tumor subclones, and are predicted to bind to the most frequent MHC alleles in MSI-H patient cohorts. Neoantigens arising from these mutations are distinctly unlike self and viral antigens, signifying novel groups of potentially highly immunogenic tumor antigens. We further confirmed the immunogenicity of frameshift peptides in T cell stimulation experiments using blood mononuclear cells isolated from both healthy donors and MSI-H cancer patients. Our study uncovers the widespread occurrence and strong immunogenicity of tumor-specific antigens derived from shared frameshift mutations in MSI-H cancer and Lynch syndrome patients, suitable for the design of common “off-the-shelf” cancer vaccines.
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•MSI-H tumors are enriched in recurrent shared immunogenic frameshifts•Shared frameshifts are expressed on RNA and protein levels•Shared frameshifts produce exceptional T cell responses
Tumors that have high levels of mutations within microsatellites (MSI-H) demonstrate specific frameshifts that are then expressed at the RNA and protein levels across endometrial, colorectal, and stomach cancers. Epitopes from these frameshifts yield neoantigens that are distinct from self and viral antigens and elicit T cell responses.
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