Trends in ovarian, fallopian tube, and primary peritoneal cancer incidence, mortality, and survival: A 15-year population-based analysis.

OBJECTIVE: To characterize trends in ovarian, fallopian tube, and primary peritoneal cancer incidence and incidence-based mortality based on histology and site of origin. METHODS: We obtained age-adjusted incidence and incidence-based mortality for patients with ovarian, fallopian tube, and primary peritoneal cancer from 2000 to 2019 from the US SEER 17 database. Joinpoint 4.9.1.0 was used to characterize log-linear time trends. RESULTS: The incidence and incidence-based mortality of all cancers trended down during the study period. The incidence of epithelial cancers decreased from 2004 to 2019 (AAPC -1.2%, p < 0.001), including that of high-grade (2006-2019: APC -1.2%, p < 0.05) and low-grade (2003-2019: APC -2.4%, p < 0.05) epithelial cancers. There was no change in incidence or incidence-based mortality for ovarian stromal and germ cell cancers. CONCLUSION: There has been a decrease in the incidence and incidence-based mortality of ovarian, fallopian tube, and primary peritoneal cancer, primarily due to reductions in advanced stage epithelial cancers originating in the ovary, fallopian tube, or peritoneum.

Trends in Uterine Cancer Mortality in the United States: A 50-Year Population-Based Analysis.

OBJECTIVE: To analyze mortality trends in uterine cancer in the United States over 50 years with an emphasis on age and race and ethnicity. METHODS: Data on uterine cancer deaths from 1969 to 2018 were obtained from the National Center for Health Statistics. Trends were examined by age and race and ethnicity after adjustment for the hysterectomy rate and pregnancy. RESULTS: Uterine cancer mortality decreased between 1969 and 1997 (from 6.03 to 4.00/100,000) but increased between 1997 and 2018 (from 4.00 to 5.02/100,000). From 2001 to 2018, mortality rates increased by 1.25-fold across all age groups. In 2018, the mortality rate from uterine cancer for patients aged 70 years or older and 60-69 years was sixfold and threefold higher, respectively, than in younger patients (aged 50-59 years) (54.87/100,000 vs 27.80/100,000 vs 8.70/100,000). The mortality rate for non-Hispanic Black women was 2.2-fold higher than for non-Hispanic White, Hispanic, and non-Hispanic Asian or Pacific Islander women (17.6/100,000 vs 7.82/100,000, 6.54/100,000, and 4.24/100,000, respectively). On an intersection analysis of age and race, non-Hispanic Black women aged older than 60 years had a threefold higher mortality rate than non-Hispanic White women (72/100,000 vs 24/100,000). A notable finding was that young non-Hispanic Black and Hispanic women (30-39 years) had the highest annual increases in mortality at 3.3% and 3.8% per year compared with 2.2% in non-Hispanic White women. CONCLUSION: Since 2001, the uterine cancer mortality rate has increased across all four racial and ethnic groups examined, with the highest increase seen among non-Hispanic Black women. The largest increase in mortality was observed among younger non-Hispanic Black and Hispanic women.

Clinicopathologic Evaluation and Molecular Profiling of Recurrent Stage IA Endometrial Endometrioid Carcinoma: A Case-control Study.

Most low-grade, early-stage endometrial endometrioid carcinomas (EEC) have an excellent prognosis; however, recurrences occur in a small subset with several studies reporting an increase in CTNNB1 exon 3 mutations in this population. Herein we evaluated 10 recurrent low-grade (FIGO 1 or 2), early-stage (FIGO IA) EECs matched to 10 nonrecurrent EECs to further characterize their clinicopathologic features and molecular phenotype. Cases were matched to controls based on size, grade, and depth of invasion. All tumors were evaluated for specific clinicopathologic parameters followed by next-generation sequencing using a 1213 gene panel. Recurrent EECs demonstrated no significant clinicopathologic differences when compared with nonrecurrent EECs, in terms of age, body mass index, pattern of invasion, presence of endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia, associated metaplastic changes, peritumoral lymphocytes, mitoses, and tumor-infiltrating lymphocytes. Both cohorts also showed a similar number of pathogenic mutations, including CTNNB1 exon 3 mutations, as well as tumor mutational burden and microsatellite profiles. Although in this particular study, the lack of correlation between CTNNB1 exon 3 mutation and recurrence might be secondary to a small sample size, it also suggests the presence of other contributing factors. Thus, it helps set the foundation for larger series incorporating whole genome, transcriptome, proteome, and epigenome analyses to answer this clinically important question.

Resilience in the Face of Pandemic: The Impact of COVID-19 on the Psychologic Morbidity and Health-Related Quality of Life Among Women With Ovarian Cancer.

PURPOSE: The COVID-19 pandemic has created new challenges for ovarian cancer survivors. This study aims to evaluate the psychologic morbidity and alterations in medical care caused by the pandemic. METHODS: Advanced-stage ovarian cancer survivors at our institution were contacted for participation in a cross-sectional telephone-based quantitative survey study assessing pandemic-related psychologic morbidity. Psychologic domains using validated measures were explored: health-related quality of life (HRQOL; functional assessment of cancer therapy [FACT-G7]), anxiety (generalized anxiety disorder-7 [GAD7]), depression (Patient Health Questionnarie-2 [PHQ2]), global health Patient-Reported Outcomes Measurement Information System - Global Physical Health/Global Mental Health (PROMIS-GMH/GPH), resilience (brief resilience scale), and loneliness (English Longitudinal Study on Aging). Novel COVID-19 pandemic questions were drawn from a larger survey developed in our department. RESULTS: Fifty-nine percent (61 of 104) of contacted patients completed the survey. One quarter of respondents had high resilience, with only 10% reporting low resilience. Only one patient screened positive for depression, and two for anxiety. Increased loneliness was reported by 43% of respondents. Patients' overall HRQOL was good (median = 21; range = 6-28). Few patients experienced treatment delays, with only four experiencing chemotherapy interruption and two reporting surgical delays. Multiple regression analyses revealed that high FACT-G7 HRQOL was predicted by age > 65 years, high self-reported mental health, high resilience, and being off chemotherapy. Lower COVID-19 concern was predicted by recurrent cancer and high resilience. CONCLUSION: Despite the far-reaching impact of the COVID-19 pandemic, ovarian cancer survivors' HRQOL has been maintained. Older age, high resilience, high mental health, and being off chemotherapy predicted better HRQOL. Ovarian cancer survivors remain resilient in the face of the pandemic, and the support of clinicians to preserve this invaluable personal resource is critical for well-being.

Outcomes after targeted treatment based on somatic tumor genetic testing for women with gynecologic cancers.

OBJECTIVE: Molecular tumor profiling and next-generation sequencing are being increasingly utilized, but there are limited data on the therapeutic implications and potential benefits of targeted treatments. We aim to characterize gynecologic oncology patients referred for somatic tumor genetic mutation testing and assess survival outcomes, efficacy, and toxicities of those receiving targeted therapy. METHODS: We conducted a retrospective chart review of gynecologic oncology patients referred for somatic tumor testing by next generation sequencing between 1/1/2012-8/23/2019. The primary objective was to compare overall and progression free survival between those treated with targeted therapy (group 1) versus traditional treatment (group 2). RESULTS: Most patients (70%) had additional treatment options available based on actionable mutations. The median number of somatic mutations identified was 5 (range 0-53). Patients in group 1 had more actionable somatic mutations (median 2 versus 0, p < 0.001). There was no difference in OS (median 64 versus 76 months, p = 0.97) or PFS (median 2 versus 8 months, p = 0.05) between the groups. While fewer patients in group 1 experienced neuropathy (0 versus 5, p = 0.02), grade I/II thrombocytopenia (7 versus 13, p = 0.03), grade III/IV thrombocytopenia (0 versus 4, p = 0.02), and grade III/IV neutropenia (1 versus 9, p = 0.002), all other non-hematologic toxicities were similar in the two groups. CONCLUSIONS: Most gynecologic cancer patients have actionable mutations and may benefit from a personalized targeted therapy treatment plan. Next generation sequencing can be used to identify clinically actionable mutations in gynecologic cancers and guide the selection of treatments, thereby expanding treatment options without worsening survival or toxicity.

Germline mutations in Black patients with ovarian, fallopian tube and primary peritoneal carcinomas.

OBJECTIVE: Routine genetic testing for ovarian cancer and identification of germline mutations can help improve early detection of cancer as well as guide treatment. Knowledge of genetic counseling and referral rates for genetic testing has been lower for Black patients, compared to White patients. We aimed to describe the demographics and presence of germline mutations in Black individuals with ovarian, fallopian tube or peritoneal carcinoma at two large academic institutions. METHODS: Fifty-one Black patients with invasive epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were identified via institutional tissue banks over a 20-year time-period. Germline DNA was sequenced using BROCA, a targeted capture and parallel sequencing assay that identified pathogenic germline mutations in ovarian carcinoma susceptibility genes. RESULTS: Germline mutations in ovarian cancer susceptibility genes were found in 25.5% of women, most commonly BRCA1 and BRCA2. This mutation frequency mirrors those previously described among predominantly White populations. Our data suggests there may be an advantage in survival among those with germline mutations, although this was not statistically significant. CONCLUSIONS: Given similar frequencies of germline mutations between Black and White patients with ovarian cancer, we conclude that there are not major differences in the genetic predisposition to ovarian carcinoma. Equitable access to genomic advancements including germline and tumor sequencing would facilitate equal access to PARP inhibitors, the standard of care for patients with BRCA mutated advanced ovarian cancer.

Phyllodes tumor of the vulva: A case report and literature review highlighting a novel manifestation of Cowden syndrome.

Cowden syndrome is a rare hereditary cancer syndrome characterized by a germline PTEN mutation which results in an increased risk of developing breast, thyroid, and endometrial carcinoma, as well as widespread benign hamartomas. Phyllodes tumor (PT) is a rare fibroepithelial tumor that accounts for less than 1% of all breast tumors. As mammary-type glands can be found in the anogenital region, PTs can rarely arise in this location. We describe the presentation, workup and management of a PT of the vulva that developed in a patient with Cowden syndrome. This report represents the first time a vulvar PT has been described in association with Cowden syndrome and should be considered in the differential diagnosis of a slow-growing vulvar mass.

Improving Value-Based Care Education in a Fellowship by Incorporating ACGME Competencies.

BACKGROUND: Most value-based care educational interventions teach knowledge of cost but fail to recognize the interrelatedness of the Accreditation Council for Graduate Medical Education (ACGME) competencies of medical knowledge, patient care, practice-based learning and improvement, and systems-based practice. OBJECTIVE: We analyzed the impact on clinical decision-making of an educational curriculum that incorporated the spectrum of ACGME competencies. METHODS: Five didactic sessions for a gynecologic oncology fellowship were modified to incorporate cost- and value-based care considerations for each clinical topic addressed. After discussion, the group of fellows identified 1 high-value and 5 low-value practices to target for improvement. The fellows then undertook a chart audit of clinical decisions occurring for patients seen in the outpatient clinics. The frequency of low- and high-value practices was compared before and after the educational intervention. RESULTS: A total of 126 patients with a cervical cancer diagnosis were seen by participants in the outpatient setting during the entire observation period. After the intervention, the occurrence of 3 identified low-value practices was reduced by 13% to 33%, demonstrating modest effect sizes (effect size ϕ = 0.2-0.3). One high-value practice (smoking cessation counseling) increased 100% after a fellow-initiated quality improvement project was undertaken. Two low-value practices, including routine surveillance imaging, remained unchanged. CONCLUSIONS: Overlaying value-based concepts in didactic conference teaching resulted in measurable changes in decision-making behavior. Engaging learners in a subsequent, focused quality practice review served as a vital part of their educational experience and allowed us to assess learner competency in its practical application.

Utilization of a Wide Array of Nonvalidated Outcome Scales in Pediatric Orthopaedic Publications: Can't We All Measure the Same Thing?

PURPOSE: Clinical changes are best evaluated with standardized, validated outcomes, including both patient-reported outcome measures and surgeon-reported outcome measures (PROMs and SROMs). The purpose of this study was to describe the spectrum of outcome measures used in pediatric orthopaedic publications over the past 10 years and to determine the proportion that are in fact age-appropriate, validated, and appropriately applied in terms of condition and population. METHODS: The Journal of Bone and Joint Surgery, The Bone and Joint Journal, Journal of Pediatric Orthopaedics A and B, and Journal of Children's Orthopaedics were systematically searched for studies including children aged 18 and below, over a 10-year period from January 2005 to December 2014. Economic evaluations, letters, editorials, review articles, and clinical guidelines were excluded. SROMs and PROMs used were extracted, as were details on subject age and condition for which they were used. Each outcome scale was assessed for validity, and the proportion of scales used appropriately was calculated. Cochrane-Armitage test of trend was used to determine changes in PROM and SROM utilization over the study period. RESULTS: A total of 4614 articles were identified, of which 2251 met inclusion and exclusion criteria. In total, 259 (11.5%) of studies used a PROM, whereas 326 (14.5%) used a SROM. A total of 230 different outcome scales were identified; 115 were patient reported and 115 were surgeon reported. However, only 18.7% of SROMs and 38.3% of PROMs were applied to an age and disease-appropriate demographic. Overall, there was a significant increase in the overall utilization of PROMs during the study period (P=0.004), but no corresponding increase in pediatric-validated PROMs (P=0.164). SROM utilization did not significantly change over the study period (P=0.337). CONCLUSIONS: Within the field of pediatric orthopaedics, an expansive variety of outcome scales are used, many of which have not been validated in children. Improved uniformity in reporting of outcomes and use of disease and age-validated outcomes scales is essential to improve multicenter research collaboration and data quality to generate appropriate evidence-based conclusions and treatment strategies in pediatric orthopaedics. LEVEL OF EVIDENCE: Level IV-systematic review.

No association of reproductive risk factors with breast cancer tumor grade.

Histological tumor grade is a well-established marker of breast tumor aggressiveness and prognosis. A number of reproductive factors, including parity and age at first birth, have been shown to be related to breast cancer risk, but few studies have examined the association of these variables with breast cancer aggressiveness. In this study, 813 newly diagnosed breast cancer patients were surveyed for demographic and lifestyle characteristics. Tumor grade and other clinical variables were abstracted from medical records. Multivariate logistic regressions were performed with each reproductive factor as the independent variable of interest. Regressions were also stratified on menopausal status, hormone therapy use, and tumor receptor status. None of the reproductive factors examined including age of first period, number of pregnancies, number of births, and hormone usage was statistically significantly associated with tumor grade. Although more studies are needed to determine whether other factors unexplored in this study are related to tumor aggressiveness, our study indicates that these factors do not predict the aggressiveness of breast cancers.

Matrix stiffening promotes a tumor vasculature phenotype.

Tumor microvasculature tends to be malformed, more permeable, and more tortuous than vessels in healthy tissue, effects that have been largely attributed to up-regulated VEGF expression. However, tumor tissue tends to stiffen during solid tumor progression, and tissue stiffness is known to alter cell behaviors including proliferation, migration, and cell-cell adhesion, which are all requisite for angiogenesis. Using in vitro, in vivo, and ex ovo models, we investigated the effects of matrix stiffness on vessel growth and integrity during angiogenesis. Our data indicate that angiogenic outgrowth, invasion, and neovessel branching increase with matrix cross-linking. These effects are caused by increased matrix stiffness independent of matrix density, because increased matrix density results in decreased angiogenesis. Notably, matrix stiffness up-regulates matrix metalloproteinase (MMP) activity, and inhibiting MMPs significantly reduces angiogenic outgrowth in stiffer cross-linked gels. To investigate the functional significance of altered endothelial cell behavior in response to matrix stiffness, we measured endothelial cell barrier function on substrates mimicking the stiffness of healthy and tumor tissue. Our data indicate that barrier function is impaired and the localization of vascular endothelial cadherin is altered as function of matrix stiffness. These results demonstrate that matrix stiffness, separately from matrix density, can alter vascular growth and integrity, mimicking the changes that exist in tumor vasculature. These data suggest that therapeutically targeting tumor stiffness or the endothelial cell response to tumor stiffening may help restore vessel structure, minimize metastasis, and aid in drug delivery.

Probing the biophysical properties of primary breast tumor-derived fibroblasts.

As cancer progresses, cells must adapt to a new and stiffer environment, which can ultimately alter how normal cells within the tumor behave. In turn, these cells are known to further aid tumor progression. Therefore, there is potentially a unique avenue to better understand metastatic potential through single-cell biophysical assays performed on patient-derived cells. Here, we perform biophysical characterization of primary human fibroblastic cells obtained from mammary carcinoma and normal contralateral tissue. Through a series of tissue dissociation, differential centrifugation and trypsinization steps, we isolate an adherent fibroblastic population viable for biomechanical testing. 2D TFM and 3D migration measurements in a collagen matrix show that fibroblasts obtained from patient tumors generate more traction forces and display improved migration potential than their counterparts from normal tissue. Moreover, through the use of an embedded spheroid model, we confirmed the extracellular matrix (ECM) remodeling behavior of primary cells isolated from carcinoma. Overall, correlating biophysical characterization of normal- and carcinoma-derived samples from individual patient along with patient outcome may become a powerful approach to further our comprehension of metastasis and ultimately design drug targets on a patient-specific basis.

Comparative mechanisms of cancer cell migration through 3D matrix and physiological microtracks.

Tumor cell invasion through the stromal extracellular matrix (ECM) is a key feature of cancer metastasis, and understanding the cellular mechanisms of invasive migration is critical to the development of effective diagnostic and therapeutic strategies. Since cancer cell migration is highly adaptable to physiochemical properties of the ECM, it is critical to define these migration mechanisms in a context-specific manner. Although extensive work has characterized cancer cell migration in two- and three-dimensional (3D) matrix environments, the migration program employed by cells to move through native and cell-derived microtracks within the stromal ECM remains unclear. We previously reported the development of an in vitro model of patterned type I collagen microtracks that enable matrix metalloproteinase-independent microtrack migration. Here we show that collagen microtracks closely resemble channel-like gaps in native mammary stroma ECM and examine the extracellular and intracellular mechanisms underlying microtrack migration. Cell-matrix mechanocoupling, while critical for migration through 3D matrix, is not necessary for microtrack migration. Instead, cytoskeletal dynamics, including actin polymerization, cortical tension, and microtubule turnover, enable persistent, polarized migration through physiological microtracks. These results indicate that tumor cells employ context-specific mechanisms to migrate and suggest that selective targeting of cytoskeletal dynamics, but not adhesion, proteolysis, or cell traction forces, may effectively inhibit cancer cell migration through preformed matrix microtracks within the tumor stroma.