Perivascular epithelioid cell tumor (PEComa) belongs to a family of tumors characterized by coexpression of melanocytic and muscle markers. Recent studies have shown that sporadic and tuberous ...sclerosis complex-associated PEComa may respond to mTOR inhibitors underscoring the importance of recognizing this tumor. However, its occurrence in the gynecologic tract continues to be disputed owing to its common misclassification as other types of uterine sarcoma and its controversial relationship with epithelioid smooth muscle tumors. To more fully characterize PEComa of the female genital tract, 16 cases of gynecologic PEComa were identified (1990 to 2012) and formed the basis of this study. Each case was analyzed for conventional morphologic and immunohistochemical characteristics established for PEComa of extrauterine sites; clinical outcome data were obtained for all cases. The 16 patients were aged 28 to 60 (mean 49; median 50) years, and 1 had a history of tuberous sclerosis complex. Thirteen cases were primary of the uterus, 2 of the adnexa, and 1 of the vagina. Tumor size ranged from 0.3 to 25.0 (mean 8.7) cm. Three patients died of disease, 6 were alive with disease, and 7 were alive without evidence of disease at last follow-up (1 mo to 13 y follow-up; mean 26 mo). All patients with an adverse outcome met established criteria for malignancy as proposed for extrauterine sites (ie, 2 or more features present: size ≥5 cm, high-grade nuclear features, infiltration, necrosis, lymphovascular invasion, or a mitotic rate ≥1/50 high-power fields). Of the melanocytic markers, HMB45 was most commonly expressed (16/16 positive, 100%), followed by microphthalmia transcription factor (11/12 positive, 92%), MelanA (14/16 positive, 88%), and S100 protein (2/10 positive, 20%). Of the smooth muscle markers, desmin was most commonly expressed (15/15 cases, 100%), followed by SMA (14/15 cases, 93%) and h-caldesmon (11/12 cases, 92%). TFE3 immunopositivity was identified in 5 of 13 cases; however, 3 tested cases were negative for a TFE3 rearrangement by fluorescence in situ hybridization. Current criteria for malignancy appear to be valid in the female genital tract, although modified criteria, as described herein, may be more specific. Awareness of the characteristic features of PEComa is important to help distinguish it from epithelioid smooth muscle tumors and other mimics as PEComa may respond to unique chemotherapeutic regimens.
The female reproductive tract (FRT), similar to other mucosal sites, harbours a site-specific microbiome, which has an essential role in maintaining health and homeostasis. In the majority of women ...of reproductive age, the microbiota of the lower FRT (vagina and cervix) microenvironment is dominated by Lactobacillus species, which benefit the host through symbiotic relationships. By contrast, the upper FRT (uterus, Fallopian tubes and ovaries) might be sterile in healthy individuals or contain a low-biomass microbiome with a diverse mixture of microorganisms. When dysbiosis occurs, altered immune and metabolic signalling can affect hallmarks of cancer, including chronic inflammation, epithelial barrier breach, changes in cellular proliferation and apoptosis, genome instability, angiogenesis and metabolic dysregulation. These pathophysiological changes might lead to gynaecological cancer. Emerging evidence shows that genital dysbiosis and/or specific bacteria might have an active role in the development and/or progression and metastasis of gynaecological malignancies, such as cervical, endometrial and ovarian cancers, through direct and indirect mechanisms, including modulation of oestrogen metabolism. Cancer therapies might also alter microbiota at sites throughout the body. Reciprocally, microbiota composition can influence the efficacy and toxic effects of cancer therapies, as well as quality of life following cancer treatment. Modulation of the microbiome via probiotics or microbiota transplant might prove useful in improving responsiveness to cancer treatment and quality of life. Elucidating these complex host-microbiome interactions, including the crosstalk between distal and local sites, will translate into interventions for prevention, therapeutic efficacy and toxic effects to enhance health outcomes for women with gynaecological cancers.
Purpose Data suggest that DNA damage by poly (ADP-ribose) polymerase inhibition and/or reduced vascular endothelial growth factor signaling by vascular endothelial growth factor receptor inhibition ...may complement antitumor activity of immune checkpoint blockade. We hypothesize the programmed death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or cediranib combinations are tolerable and active in recurrent women's cancers. Patients and Methods This phase I study tested durvalumab doublets in parallel 3 + 3 dose escalations. Durvalumab was administered at 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks with either olaparib tablets twice daily or cediranib on two schedules. The primary end point was the recommended phase II dose (RP2D). Response rate and pharmacokinetic analysis were secondary end points. Results Between June 2015 and May 2016, 26 women were enrolled. The RP2D was durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice a day, or cediranib 20 mg, 5 days on/2 days off. No dose-limiting toxicity was recorded with durvalumab plus olaparib. The cediranib intermittent schedule (n = 6) was examined because of recurrent grade 2 and non-dose-limiting toxicity grade 3 and 4 adverse events (AEs) on the daily schedule (n = 8). Treatment-emergent AEs included hypertension (two of eight), diarrhea (two of eight), pulmonary embolism (two of eight), pulmonary hypertension (one of eight), and lymphopenia (one of eight). Durvalumab plus intermittent cediranib grade 3 and 4 AEs were hypertension (one of six) and fatigue (one of six). Exposure to durvalumab increased cediranib area under the curve and maximum plasma concentration on the daily, but not intermittent, schedules. Two partial responses (≥15 months and ≥ 11 months) and eight stable diseases ≥ 4 months (median, 8 months 4 to 14.5 months) were seen in patients who received durvalumab plus olaparib, yielding an 83% disease control rate. Six partial responses (≥ 5 to ≥ 8 months) and three stable diseases ≥ 4 months (4 to ≥ 8 months) were seen in 12 evaluable patients who received durvalumab plus cediranib, for a 50% response rate and a 75% disease control rate. Response to therapy was independent of PD-L1 expression. Conclusion To our knowledge, this is the first reported anti-PD-L1 plus olaparib or cediranib combination therapy. The RP2Ds of durvalumab plus olaparib and durvalumab plus intermittent cediranib are tolerable and active. Phase II studies with biomarker evaluation are ongoing.
Other than for breast cancer, endocrine therapy has not been highly effective for gynecologic cancers. Endocrine therapy resistance in estrogen receptor positive gynecologic cancers is still poorly ...understood. In this retrospective study, we examined the estrogen receptor (ER) signaling pathway activities of breast, ovarian, endometrial, and cervical cancers to identify those that may predict endocrine therapy responsiveness.
Clinical and genomic data of women with breast and gynecological cancers were downloaded from cBioPortal for Cancer Genomics. Estrogen receptor alpha (ESR1) expression level and sample-level pathway enrichment scores (EERES) were calculated to classify patients into four groups (low/high ESR1 and low/high EERES). Correlation between ESR1/EERES score and survival was further validated with RNAseq data from low-grade serous ovarian cancer. Pathway analyses were performed among different ESR1/EERES groups to identify genes that correlate with endocrine resistance, which are validated using Cancer Cell Line Encyclopedia gene expression and Genomics of Drug Sensitivity in Cancer data.
We identified a novel combined prognostic value of ESR1 expression and the corresponding estrogen response signaling (EERES score) for breast cancer. The combined prognostic value (ESR1/EERES) may be applicable to other gynecologic cancers. More importantly, we discovered that ER signaling can cross-regulate MEK pathway activation. We identified downstream genes in the MEK pathway (EPHA2, INAVA, MALL, MPZL2, PCDH1, and TNFRSF21) that are potential endocrine therapy response biomarkers.
This study demonstrated that targeting both the ER and the ER signaling activity related MEK pathway may aid the development of endocrine therapy strategies for personalized medicine.
An estimated 2–5% of endometrial cancers and 15–20% of high-grade, non-mucinous epithelial ovarian cancers have an underlying hereditary cause. Appropriate risk assessment, genetic counseling, and ...germline genetic testing for cancer predisposition genes in both gynecologic cancer patients and their at-risk relatives is essential for effective delivery of tailored cancer treatment and cancer prevention. However, significant disparities exist within medically underserved and minority populations in the United States regarding awareness of, access to, and use of genetic services. The objectives of this review are to summarize the literature on genetic counseling and genetic testing of gynecologic cancer patients, the cascade genetic testing of their families following the identification of a germline mutation associated with susceptibility to cancer, to highlight disparities between populations, and to present some potential remedies.
•Despite increases in the rate of testing for BRCA and Lynch syndrome, many high-risk women remain unidentified.•Underserved populations who do not access genetics services are at risk of missing opportunities for cancer prevention.•Socioeconomic factors, poor communication, concerns about misuse of genetic data contribute to poor use of genetic services.•Research is needed to specifically identify barriers to receipt and use of cancer genetics services.
An updated World Health Organization (WHO) classification of female genital tumours was published in autumn 2020. We discuss the major new additions to and changes from the prior 2014 classification ...with a discussion of the reasons underlying these. A feature of the new classification is the greater emphasis on key molecular events with integration of morphological and molecular features. Most of the major changes from the prior classification pertain to uterine (corpus and cervix) and vulval tumours, but changes in all organs are covered.
We review the major new additions and changes in the new 2020 WHO Classification of Female Genital Tract Tumours. The updated 2020 Classification places a greater emphasis on key molecular events and on the integration of morphological and molecular features and represents a major step‐forward from the prior Classification.
Purpose
The purpose of the study is to evaluate existing literature for possible associations between female infertility, infertility-associated diagnoses, and the following areas of disease: ...psychiatric disorders, breast cancer, ovarian cancer, endometrial cancer, cardiovascular disease, and metabolic dysfunction.
Methods
The design of the study is a literature review. The patients were women included in 26 selected studies due to a diagnosis of infertility or a reproductive disorder associated with infertility. This study has no interventions, and the main outcome measure is the association between female infertility or a related diagnosis and psychiatric disorders, breast cancer, ovarian cancer, endometrial cancer, cardiovascular disease, and metabolic dysfunction.
Results
Female infertility and related reproductive disorders may have ramifications for women beyond reproductive health. An analysis of publications shows that women with infertility had higher rates of psychiatric disorders and endometrial cancer than the general population
1
–
10
. Data is conflicting about whether infertile women are at increased risk for breast cancer and ovarian cancer
7
,
8
,
10
–
20
. A generalized diagnosis of infertility was not clearly associated with an increased risk of cardiovascular disease or metabolic dysfunction, but women with infertility related to polycystic ovarian syndrome (PCOS) do appear more likely to develop cardiovascular disease and metabolic disorders such as diabetes than the general population
16
,
21
–
26
.
Conclusions
Female infertility and associated diagnoses have overall health implications. Beyond treatment of patients’ immediate reproductive needs, healthcare professionals must be aware of the broader health impact of specific causes of infertility in order to provide accurate counseling regarding long-term risk.
This phase I, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The ...objectives were to investigate the safety, tolerability, and pharmacokinetics of AZD5363, define a recommended dosing schedule, and evaluate preliminary clinical activity.
Patients were aged ≥18 years with World Health Organization (WHO) performance status of 0 to 1. Dose escalation was conducted within separate continuous and intermittent 4 days/week (4/7) or 2 days/week (2/7) schedules with safety, pharmacokinetic, and pharmacodynamic analyses. Expansion cohorts of approximately 20 patients each explored AZD5363 activity in
-mutant breast and gynecologic cancers.
MTDs were 320, 480, and 640 mg for continuous (
= 47), 4/7 (
= 21), and 2/7 (
= 22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for Common Terminology Criteria for Adverse Events grade ≥3 events, hyperglycemia (20%). The recommended phase II dose (480 mg bid, 4/7 intermittent) was assessed in
-mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the prespecified 20% response rate; therefore, the criteria to stop further recruitment to the
-mutant cohort were met.
At the recommended phase II dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. Proof-of-concept responses were observed in patients with
-mutant cancers treated with AZD5363.
.
Certain population groups are known to have higher than average anal cancer risk, namely persons living with HIV (PLHIV), men who have sex with men (MSM), women diagnosed with human papillomavirus ...(HPV)‐related gynecological precancerous lesions or cancer, solid organ transplant recipients (SOTRs) and patients with autoimmune diseases. Our aim was to provide robust and comparable estimates of anal cancer burden across these groups. Summary incidence rates (IRs), as cases per 100 000 person‐years (py), were calculated by fixed‐effects meta‐analysis. IRs were 85 (95% confidence interval CI = 82‐89) for HIV‐positive MSM (n = 7 studies; 2 229 234 py), 32 (95% CI = 30‐35) for non‐MSM male PLHIV (n = 5; 1626 448 py) and 22 (95% CI = 19‐24) for female PLHIV (n = 6; 1 472 123 py), with strong variation by age (eg, from 16.8 < 30 years to 107.5 ≥ 60 years for HIV‐positive MSM). IR was 19 (95% CI = 10‐36) in HIV‐negative MSM (n = 2; 48 135 py). Anal cancer IRs were much higher after diagnosis of vulvar (IR = 48 95% CI = 38‐61; n = 4; 145 147 py) than cervical (9 95% CI = 8‐12; n = 4; 779 098 py) or vaginal (IR = 10 95% CI = 3‐30; n = 4; 32 671) cancer, with equivalent disparity after respective precancerous lesions. IR was 13 (95% CI = 12‐15) in SOTRs (n = 5; 1 946 206 py), reaching 24.5 and 49.6 for males and females >10 years after transplant. Anal cancer IRs were 10 (95% CI = 5‐19), 6 (95% CI = 3‐11) and 3 (95% CI = 2‐4) for systemic lupus erythematosus, ulcerative colitis and Crohn's disease, respectively. In conclusion, a unifying anal cancer risk scale, based upon comprehensive meta‐analysis, can improve prioritization and standardization in anal cancer prevention/research initiatives, which are in their public health infancy.
What's new?
Anal cancer (AC) is quite rare in the general population. However, some groups are known to be at higher risk. In this meta‐analysis, the authors identified these groups (e.g., HIV‐positive status, other HPV‐related cancers, etc.), and were then able to develop an AC‐risk scale based on incidence estimates. Because there is currently no consensus regarding standardized screening for AC, this risk scale can help clinicians to prioritize and compare risk profiles for AC research and prevention initiatives. These can then be guided by similar principles of management for populations with similar absolute risk.
Purpose
To assess sexual/vaginal health issues and educational intervention preferences in women with a history of breast or gynecologic cancer.
Methods
Patients/survivors completed a cross-sectional ...survey at their outpatient visits. Main outcome measures were sexual dysfunction prevalence, type of sexual/vaginal issues, awareness of treatments, and preferred intervention modalities. Descriptive frequencies were performed, and results were dichotomized by age, treatment status, and disease site.
Results
Of 218 eligible participants, 109 (50%) had a history of gynecologic and 109 (50%) a history of breast cancer. Median age was 49 years (range 21–75); 61% were married/cohabitating. Seventy percent (
n
= 153) were somewhat-to-very concerned about sexual function/vaginal health, 55% (
n
= 120) reported vaginal dryness, 39% (
n
= 84) vaginal pain, and 51% (
n
= 112) libido loss. Many had heard of vaginal lubricants, moisturizers, and pelvic floor exercises (97, 72, and 57%, respectively). Seventy-four percent (
n
= 161) had used lubricants, 28% moisturizers (
n
= 61), and 28% pelvic floor exercises (
n
= 60). Seventy percent (
n
= 152) preferred the topic to be raised by the medical team; 48% (
n
= 105) raised the topic themselves. Most preferred written educational material followed by expert discussion (66%,
n
= 144/218). Compared to women ≥50 years old (41%,
n
= 43/105), younger women (54%,
n
= 61/113) preferred to discuss their concerns face-to-face (
p
= 0.054). Older women were less interested in online interventions (52%,
p
< 0.001), despite 94% having computer access.
Conclusion
Female cancer patients/survivors have unmet sexual/vaginal health needs. Preferences for receiving sexual health information vary by age. Improved physician–patient communication, awareness, and educational resources using proven sexual health promotion strategies can help women cope with treatment side effects.
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