The receptor protein tyrosine phosphatase PTPRK promotes intestinal repair and catalysis-independent tumour suppression.

PTPRK is a receptor tyrosine phosphatase linked to the regulation of growth factor signalling and tumour suppression. It is stabilized at the plasma membrane by trans homophilic interactions upon cell-cell contact. It regulates cell-cell adhesion, but is also reported to regulate numerous cancer-associated signalling pathways. However, its signalling mechanism remains to be determined. Here, we find that PTPRK regulates cell adhesion signalling, suppresses invasion and promotes collective, directed migration in colorectal cancer cells. In vivo, PTPRK supports recovery from inflammation-induced colitis. In addition, we confirm that PTPRK functions as a tumour suppressor in the mouse colon and in colorectal cancer xenografts. PTPRK regulates growth factor and adhesion signalling, and suppresses epithelial to mesenchymal transition (EMT). Contrary to the prevailing notion that PTPRK directly dephosphorylates EGFR, we find that PTPRK regulation of both EGFR and EMT is independent of its catalytic function. This suggests that additional adaptor and scaffold functions are important features of PTPRK signalling.

Percutaneous interstitial brachytherapy ablation for targeting oligometastatic gynecologic cancers.

INTRODUCTION: Treatment of recurrent oligometastatic gynecologic malignancy may involve targeted surgery, thermal ablation, or CT-guided high-dose-rate interstitial brachytherapy ablation (CT-HDR-IBTA). The purpose of this study was to describe the safety and efficacy of CT-HDR-IBTA for oligometastatic gynecologic malignancies. METHODS: With institutional review board approval (IRB) approval and compliance with the Health Insurance Portability and Accountability Act of 1996 (HIPAA) compliance, we searched our database to assemble a single-arm study cohort of all patients with oligometastatic gynecologic cancers who underwent CT-HDR-IBTA from 2012-2022 with follow-up. The electronic record was reviewed to determine relevant clinicopathological variables including patient demographics, prior treatments, clinical course, local control, and local and distant recurrence with follow-up imaging. RESULTS: The study cohort comprised 37 lesions in 34 patients treated with CT-HDR-IBTA for recurrent oligometastatic uterine (n = 17), cervix (n = 1), or ovarian cancer (n = 16) with an average lesion size of 2.5 cm with an average patient age of 61.4 years. Each lesion was treated with an average radiation dose of 23.8 Gy in 1.8 fractions and a median follow-up time of 24.0 months. The primary efficacy of CT HDR ITBA was 73% with a median progression-free survival of 8.0 months (95% CI 3.6-12.8 months) and with 58% of patients still alive at 43 months with median overall survival not reached. The rate of Grade 1 adverse events was 22% without any Grade 2, 3 or 4 events. CONCLUSIONS: CT HDR IBTA was safe and effective for treating oligometastatic gynecologic cancers in a heavily pretreated cohort.

Ovarian Hyperthecosis in a 12-year-old Chinese Girl Presenting With Virilization.

All girls presenting with virilization (which signifies severe hyperandrogenism) warrant thorough investigation. Ovarian hyperthecosis (OHT) is a rare cause of virilization in premenopausal women. Here, we report the case of a previously healthy 12-year-old Chinese girl with signs of virilization at puberty. Her serum total testosterone was elevated at 5.1 nmol/L (146.97 ng/dL) (normal: <1.4 nmol/L, <40.35 ng/dL). Workup for Cushing syndrome, sex development disorders, congenital adrenal hyperplasia, and adrenal and ovarian androgen-secreting tumors was unrevealing. Ovarian and adrenal venous sampling demonstrated ovarian hyperandrogenism without lateralization. Ovarian biopsy revealed nests of theca cells in the stroma of the right ovary, substantiating the diagnosis of OHT. A single dose of a GnRH analog resulted in the complete suppression of serum testosterone, supporting the diagnosis of OHT. Medical treatment with hormonal replacement therapy normalized serum testosterone levels. Our case report illustrates the diagnostic approach to virilization among girls at puberty and the diagnosis of OHT as the underlying pathology.

Comparison of Mirena and Liletta levonorgestrel intrauterine devices for the treatment of endometrial intraepithelial neoplasia and grade 1 endometrioid endometrial cancer.

Objective: Current standard nonsurgical management of endometrial intraepithelial neoplasia (EIN) and grade 1 endometrioid endometrial cancer (g1EEC) is the Mirena levonorgestrel intrauterine device (M-IUD). This retrospective study was designed primarily to determine noninferiority of the Liletta IUD (L-IUD) for pathologic regression of EIN and g1EEC compared to the M-IUD at 6 months of continuous use. Secondary objectives include to determine noninferiority as above at 3, 9, and 12 months of continuous use and to identify factors including DNA mismatch repair (MMR) status associated with pathologic regression after LNG-IUD use. Methods: A retrospective observational study was performed with patients treated for EIN or g1EEC and managed continuously with M- or L-IUD. Patients with recent (within 6 months) or concurrent progesterone use were excluded. For the EIN group, the noninferiority margin of odds ratio was predetermined to be 0.58, and for the g1EEC group it was 0.64. Results: 62 patients from an academic center and a safety-net hospital were identified with continuous M-IUD (n = 44) or L-IUD (n = 18) use for EIN or g1EEC. 85% of patients treated with L-IUD were from a safety-net hospital, which had 63% with public insurance. At 3/6/9 months, 54/71/73% of patients with M-IUD and 80/83/100% with L-IUD had pathologic regression of EIN (95% confidence interval of estimated odds ratio 1.00-2.07/0.84-2.03/0.69-2.10). Lifetime smoking status, not MMR status, was significantly associated with pathologic regression. Conclusions: L-IUD is an effective fertility-sparing treatment for EIN. L-IUD is noninferior to M-IUD for pathologic regression of EIN after 3,6, and 9 months. Further larger studies are warranted to validate findings in EIN and g1EEC.

Use of platinum-based chemotherapy and pembrolizumab to treat squamous cell carcinoma arising in a mature teratoma of the ovary in a pre-menopausal woman with negative response: A case report.

Squamous cell carcinoma of the ovary (SCC) is a rare and aggressive disease and optimal treatment is unknown. Here we report the case of a 29- year-old woman who presented with abdominal pain and was ultimately found to have a multi-septate, gas containing pelvic mass with mixed fat, soft tissue, and calcified components concerning for a ruptured teratoma with fistulization to the distal ileum and cecum on imaging. Operative findings included a 20 cm pelvic mass arising from the right ovary with frank invasion into the ileum and cecum and dense adhesion to the anterior abdominal wall on surgical exploration. Pathologic specimens were remarkable for stage IIIC SCC of the ovary arising in a mature teratoma, with a tumor proportion score of 40%. She progressed on first line treatment with cisplatin, paclitaxel and pembrolizumab as well as second line treatment with gemcitabine and vinorelbine. She died nine months after her initial diagnosis.

Alarming trends and disparities in high-risk endometrial cancer.

PURPOSE OF REVIEW: To summarize the most recent publications highlighting the trends and disparities among patients diagnosed with high-risk endometrial cancer. RECENT FINDINGS: Endometrial cancer mortality continues to rise, driven by the increasing incidence of high-risk histologic subtypes that accounts for a disproportionate number of endometrial cancer deaths. The lack of progress made in endometrial cancer treatment, particularly of high-risk histologic subtypes, disproportionately affects black women who are more likely to be diagnosed with these aggressive tumor types. Even when accounting for high-risk histology, various factors across the spectrum of care may influence the survival disparities between black and white women, including timely access to guideline-concordant care, clinical trial enrollment, and systemic racism that impacts cancer outcomes. SUMMARY: In this review, we highlight the disproportionate impact of worsening endometrial cancer mortality and healthcare inequalities contributing to the endometrial cancer survival disparity between black and white women.

Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes.

PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04-7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04-1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01-1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

Trends in extent of surgical cytoreduction for patients with ovarian cancer.

PURPOSE: To identify patient and hospital characteristics associated with extended surgical cytoreduction in the treatment of ovarian cancer. METHODS: A retrospective analysis using the National Inpatient Sample (NIS) database identified women hospitalized for surgery to remove an ovarian malignancy between 2013 and 2017. Extended cytoreduction (ECR) was defined as surgery involving the bowel, liver, diaphragm, bladder, stomach, or spleen. Chi-square and logistic regression were used to analyze patient and hospital demographics related to ECR, and trends were assessed using the Cochran-Armitage test. RESULTS: Of the estimated 79,400 patients undergoing ovarian cancer surgery, 22% received ECR. Decreased adjusted odds of ECR were found in patients with lower Elixhauser Comorbidity Index (ECI) scores (OR 0.61, p<0.001 for ECI 2, versus ECI≥3) or residence outside the top income quartile (OR 0.71, p<0.001 for Q1, versus Q4), and increased odds were seen at hospitals with high ovarian cancer surgical volume (OR 1.25, p<0.001, versus low volume). From 2013 to 2017, there was a decrease in the proportion of cases with extended procedures (19% to 15%, p<0.001). There were significant decreases in the proportion of cases with small bowel, colon, and rectosigmoid resections (p<0.001). Patients who underwent ECR were more likely treated at a high surgical volume hospital (37% vs 31%, p<0.001) over the study period. For their hospital admission, patients who underwent ECR had increased mortality (1.6% vs. 0.5%, p<0.001), length of stay (9.6 days vs. 5.2 days, p<0.001), and mean cost ($32,132 vs. $17,363, p<0.001). CONCLUSIONS: Likelihood of ECR was associated with increased medical comorbidity complexity, higher income, and undergoing the procedure at high surgical volume hospitals. The proportion of ovarian cancer cases with ECR has decreased from 2013-17, with more cases performed at high surgical volume hospitals.

Combining ReACp53 with Carboplatin to Target High-Grade Serous Ovarian Cancers.

Ovarian malignancies are a leading cause of cancer-related death for US women. High-grade serous ovarian carcinomas (HGSOCs), the most common ovarian cancer subtype, are aggressive tumors with poor outcomes. Mutations in TP53 are common in HGSOCs, with a subset resulting in p53 aggregation and misregulation. ReACp53 is a peptide designed to inhibit mutant p53 aggregation and has been shown efficacious in targeting cancer cells in vitro and in vivo. As p53 regulates apoptosis, combining ReACp53 with carboplatin represents a logical therapeutic strategy. The efficacy of this combinatorial approach was tested in eight ovarian cancer cell lines and 10 patient HGSOC samples using an in vitro organoid drug assay, with the SynergyFinder tool utilized for calculating drug interactions. Results demonstrate that the addition of ReACp53 to carboplatin enhanced tumor cell targeting in the majority of samples tested, with synergistic effects measured in 2 samples, additivity measured in 14 samples, and antagonism measured in 1 sample. This combination was found to be synergistic in OVCAR3 ovarian cancer cells in vitro through enhanced apoptosis, and survival of mice bearing OVCAR3 intraperitoneal xenografts was extended when treated with the addition of ReACp53 to carboplatin versus carboplatin alone. Results suggest that carboplatin and ReACp53 may be a potential strategy in targeting a subset of HGSOCs.

Matched sequential tumor molecular profiling in solid malignancies may impact clinical practice.

OBJECTIVES: To determine if performing repeat tumor molecular profiling in solid malignancies over time can identify new findings that impact clinical care. METHODS: All patients with a solid malignancy and more than 1 tumor molecular analysis were identified at a single institution. Each test report was examined to identify the genomic alterations. Chart review was performed to determine subsequent therapies following each test result and the impact of tumor profiling on clinical practice. RESULTS: At a single institution, 110 patients were identified with having more than 1 tumor molecular analysis, with 98 subjects having test results available for review. Eighty-seven patients had differences in reported results at the time of subsequent analysis. These differences may reflect changes in tumor biology, be attributed to intra-patient or intra-tumor heterogeneity or be due to technical updates of the next generation sequencing platforms. Among the 98 subjects with solid tumors, the median time between tests was 10 months (range 0.5-66 months), with the majority of tests performed at the time of disease progression or recurrence. In this population, a total of 30 patients received targeted therapies that were associated with actionable findings on any tumor molecular analysis. Of these, 6 patients had new genomic findings identified on sequential testing that affected treatment. CONCLUSIONS: The future of cancer care must include precision medicine approaches. Evolution of next generation sequencing has contributed to this effort. Results of this single institution study summarize the reported findings on tumor molecular testing and suggest that subsequent testing may impact clinical care in a subset of patients. While only 6% of patients in this study saw a change in treatment based on new findings on sequential testing reports, this approach may be more clinically relevant in the future with the development of novel targeted therapies. This may be especially significant in a patient population that has progressed on standard therapies and where treatment options are limited.

Readmissions after ovarian cancer cytoreduction surgery: The first 30 days and beyond.

BACKGROUND AND OBJECTIVES: Postoperative readmissions are often used to assess quality of surgical care. This study compared 30-day vs 31- to 90-day readmission following surgery for ovarian, fallopian tube, or primary peritoneal cancer. METHODS: This retrospective study of the 2010-2015 Nationwide Readmissions Database characterized 90-day readmissions following cytoreductive surgery for these cancers. Each patient's first postoperative hospitalization was included. Univariate analysis compared patient demographics and reasons for readmission. Multivariable regression identified independent predictors of readmission. RESULTS: Of an estimated 76 652 patients, 10 264 (13.4%) were readmitted within 30 days, and 6942 (9.1%) between 31 and 90 days. The 30-day readmissions were more frequently associated with postoperative infection, while 31- to 90-day readmissions were more frequently associated with renal or hematologic diagnoses. Predictors of any 90-day readmission included index hospitalization longer than 7 days (adjusted odds ratio (AOR) 1.61 [1.48-1.75], P < .001), extended surgical procedure (AOR 1.41 [1.30-1.53], P < .001), pulmonary circulation disorder (AOR = 1.34 [1.13-1.60], P = .001), and diabetes mellitus (AOR = 1.12 [1.02-1.24], P = .020). CONCLUSIONS: Readmission rates remain high during the 31- to 90-day postoperative period in ovarian cancer patients, although these readmissions are less frequently related to postoperative complications. Prospective study is merited to optimize surveillance beyond the initial 30 days after ovarian cancer surgery.

Paraneoplastic Raynaud phenomenon associated with metastatic ovarian cancer: A case report and review of the literature.

•Paraneoplastic syndromes are rarely associated with ovarian malignancies.•Paraneoplastic syndromes may be the presenting symptom of an underlying malignancy.•Rheumatologic disorders with unusual presentations may be malignancy related.•These rheumatologic disorders are often refractory to standard treatments.

Revealing hidden genetic diagnoses in the ocular anterior segment disorders.

PURPOSE: Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion. METHODS: We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases. RESULTS: We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6. CONCLUSIONS: We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.

Expression of Stromal Progesterone Receptor and Differential Methylation Patterns in the Endometrium May Correlate with Response to Progesterone Therapy in Endometrial Complex Atypical Hyperplasia.

Progesterone therapy is a viable treatment for complex atypical hyperplasia (CAH) and endometrial adenocarcinoma, though reliable molecular determinants of response are not available. To explore if analysis of pre-therapy endometrial biopsies could yield biomarkers of response to progesterone, patients with CAH or adenocarcinoma undergoing treatment with progestins were included in this cross-sectional study. Immunohistochemistry for progesterone receptor (PR) was performed. Manual PR expression scores (PRES) were first calculated for biopsies by counting PR-positive nuclei in 12 sensitive vs 9 resistant samples. Significant differences in manual PRES were detected in the stroma (p < 0.01) and total endometrium (p < 0.01) for sensitive vs resistant patients. Manual PRES in the stroma had the highest accuracy in segregating sensitive vs resistant patients (96%). Differences in epithelial PRES were not significant. To validate these findings, a correlation between manual PRES and visual PRES was performed in the 21 patients. An additional 11 patients were analyzed to test if visual PRES would be predictive of response to progesterone. Visual PRES in epithelia and stroma in the 32 specimens was calculated. Significant differences in visual PRES were detected in the stroma for sensitive vs resistant samples (p < 0.01), while differences in epithelial and total endometrium were not significant. Whole genome bisulfite sequencing was performed on DNA isolated using pre-therapy biopsies from 6 sensitive and 6 resistant patients in this cohort. Differentially methylated regions were identified in the stroma and epithelium when evaluating sensitive vs resistant samples. Pathways involved in cell adhesion demonstrated the greatest difference in methylation in these samples.

Comprehensive genomic profiling of recurrent endometrial cancer: Implications for selection of systemic therapy.

OBJECTIVES: To assess whether comprehensive genomic profiling (CGP) in the setting of routine clinical care allows molecular classification of recurrent endometrial cancer (EC) into the four Cancer Genome Atlas (TCGA) categories: POLE ultramutated, microsatellite instable, copy-number low, and copy-number high and whether this approach can identify genomic alterations (GAs) which inform treatment decisions. METHODS: Archival tissues from 74 patients diagnosed with recurrent EC were prospectively analyzed using hybrid-capture-based genomic profiling. Tumor mutational burden and microsatellite instability were measured. Clinically relevant GAs (CRGAs) were defined as GAs associated with targeted therapies available on-label or in mechanism-driven clinical trials. RESULTS: Using POLE mutational analysis, mismatch repair status, and p53 mutational analysis as surrogate for 'copy-number' status CGP segregated all cases into four TCGA molecular subgroups. While recurrent serous ECs were predominantly copy-number high, we found no clear prevalence of a specific molecular subtype in endometrioid, clear cell or undifferentiated tumors. Every tumor sample had at least one GA and 91% (67/74) had at least one CRGA. In this series 32% (24/74) of patients received a matched therapy based on the results of CGP. Objective responses to the matched therapy were seen in 25% (6/24) of patients with an additional 37.5% (9/24) achieving stable disease leading to a clinical benefit rate of 62.5% with a median treatment duration of 14.6 months (range 4.3-69 months). CONCLUSIONS: CGP allows molecular classification of EC into four TCGA categories and allows identification of potential biomarkers for matched therapy in the setting of routine clinical care.

Ovarian cancer screening in menopausal females with a family history of breast or ovarian cancer.

OBJECTIVE: To determine whether annual screening reduces ovarian cancer mortality in women with a family history of breast or ovarian cancer. METHODS: Data was obtained from the Prostate, Lung, Colorectal, and Ovarian cancer trial, a randomized multi-center trial conducted to determine if screening could reduce mortality in these cancers. The trial enrolled 78,216 women, randomized into either a screening arm with annual serum cancer antigen 125 and pelvic ultrasounds, or usual care arm. This study identified a subgroup that reported a first degree relative with breast or ovarian cancer. Analysis was performed to compare overall mortality and disease specific mortality in the screening versus usual care arm. In patients diagnosed with ovarian cancer, stage distribution, and survival were analyzed as a secondary endpoint. RESULTS: There was no significant difference in overall mortality or disease specific mortality between the two arms. Ovarian cancer was diagnosed in 48 patients in the screening arm and 44 patients in the usual care arm. Screened patients were more likely to be diagnosed at an earlier stage than usual care patients. Patients in the screening arm diagnosed with ovarian cancer experienced a significantly improved survival compared to patients in the usual care arm; relative risk 0.66 (95% CI, 0.47 to 0.93). CONCLUSION: Screening did not appear to decrease ovarian cancer mortality in participants with a family history of breast or ovarian cancer. Secondary endpoints, however, showed notable differences. Significantly fewer patients were diagnosed with advanced stage disease in the screening arm; and survival was significantly improved. Further investigation is warranted to assess screening efficacy in women at increased risk.

Impact of host ageing on the metastatic phenotype.

Ageing impacts multiple host mechanisms involved in cancer progression. Here we show that poorly metastatic Lewis lung carcinoma (LLC) cells form less bulky metastatic deposits in aged mice (>52 weeks) relative to their young (4-6 weeks) counterparts. Serial selection of LLC cells for increased metastatic capability in either young or old mice led in both cases to exaggerated growth of pulmonary nodules after only 5 cycles of in vivo passage. The respective metastatic cellular variants established in young (Y-series) or old (O-series) mice differed in cell morphology and constitutive activity of growth factor receptors, especially phospho-PDGFRa and phospho-EPHA7. These cell lines also exhibited marked differences in their time dependent profiles of cellular impedance (CI), which reflects their physical properties, such as cell shape, adhesion and interactions with substrata. In confluent monolayer culture Y-series cell lines generated high and increasing CI values, while these values remained low and constant in the O-series of cell lines. These observations suggest that the selective pressure of the metastatic microenvironment in young versus old hosts is sufficiently different to results in the enrichment of distinct, age-related metastatic phenotypes of cancer cells. Thus, age could inform therapeutic approaches to metastatic cancers.