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.

Molecular mechanism of Afadin substrate recruitment to the receptor phosphatase PTPRK via its pseudophosphatase domain.

Protein tyrosine phosphatase receptor-type kappa (PTPRK) is a transmembrane receptor that links extracellular homophilic interactions to intracellular catalytic activity. Previously we showed that PTPRK promotes cell-cell adhesion by selectively dephosphorylating several cell junction regulators including the protein Afadin (Fearnley et al, 2019). Here, we demonstrate that Afadin is recruited for dephosphorylation by directly binding to the PTPRK D2 pseudophosphatase domain. We mapped this interaction to a putative coiled coil (CC) domain in Afadin that is separated by more than 100 amino acids from the substrate pTyr residue. We identify the residues that define PTP specificity, explaining how Afadin is selectively dephosphorylated by PTPRK yet not by the closely related receptor tyrosine phosphatase PTPRM. Our work demonstrates that PTP substrate specificity can be determined by protein-protein interactions distal to the active site. This explains how PTPRK and other PTPs achieve substrate specificity despite a lack of specific sequence context at the substrate pTyr. Furthermore, by demonstrating that these interactions are phosphorylation-independent and mediated via binding to a non-catalytic domain, we highlight how receptor PTPs could function as intracellular scaffolds in addition to catalyzing protein dephosphorylation.

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.

Genome sequencing in congenital cataracts improves diagnostic yield.

Congenital cataracts are one of the major causes of childhood-onset blindness around the world. Genetic diagnosis provides benefits through avoidance of unnecessary tests, surveillance of extraocular features, and genetic family information. In this study, we demonstrate the value of genome sequencing in improving diagnostic yield in congenital cataract patients and families. We applied genome sequencing to investigate 20 probands with congenital cataracts. We examined the added value of genome sequencing across a total cohort of 52 probands, including 14 unable to be diagnosed using previous microarray and exome or panel-based approaches. Although exome or genome sequencing would have detected the variants in 35/52 (67%) of the cases, specific advantages of genome sequencing led to additional diagnoses in 10% (5/52) of the overall cohort, and we achieved an overall diagnostic rate of 77% (40/52). Specific benefits of genome sequencing were due to detection of small copy number variants (2), indels in repetitive regions (2) or single-nucleotide variants (SNVs) in GC-rich regions (1), not detectable on the previous microarray, exome sequencing, or panel-based approaches. In other cases, SNVs were identified in cataract disease genes, including those newly identified since our previous study. This study highlights the additional yield of genome sequencing in congenital cataracts.

Australia and New Zealand renal gene panel testing in routine clinical practice of 542 families.

Genetic testing in nephrology clinical practice has moved rapidly from a rare specialized test to routine practice both in pediatric and adult nephrology. However, clear information pertaining to the likely outcome of testing is still missing. Here we describe the experience of the accredited Australia and New Zealand Renal Gene Panels clinical service, reporting on sequencing for 552 individuals from 542 families with suspected kidney disease in Australia and New Zealand. An increasing number of referrals have been processed since service inception with an overall diagnostic rate of 35%. The likelihood of identifying a causative variant varies according to both age at referral and gene panel. Although results from high throughput genetic testing have been primarily for diagnostic purposes, they will increasingly play an important role in directing treatment, genetic counseling, and family planning.

Dermal Adipose Tissue Secretes HGF to Promote Human Hair Growth and Pigmentation.

Hair follicles (HFs) are immersed within dermal white adipose tissue (dWAT), yet human adipocyte‒HF communication remains unexplored. Therefore, we investigated how perifollicular adipocytes affect the physiology of human anagen scalp HFs. Quantitative immunohistomorphometry, X-ray microcomputed tomography, and transmission electron microscopy showed that the number and size of perifollicular adipocytes declined during anagen‒catagen transition, whereas fluorescence-lifetime imaging revealed increased lipid oxidation in adipocytes surrounding the bulge and/or sub-bulge region. Ex vivo, dWAT tendentially promoted hair shaft production, and significantly stimulated hair matrix keratinocyte proliferation and HF pigmentation. Both dWAT pericytes and PREF1/DLK1+ adipocyte progenitors secreted HGF during human HF‒dWAT co-culture, for which the c-Met receptor was expressed in the hair matrix and dermal papilla. These effects were reproduced using recombinant HGF and abrogated by an HGF-neutralizing antibody. Laser-capture microdissection‒based microarray analysis of the hair matrix showed that dWAT-derived HGF upregulated keratin (K) genes (K27, K73, K75, K84, K86) and TCHH. Mechanistically, HGF stimulated Wnt/ß-catenin activity in the human hair matrix (increased AXIN2, LEF1) by upregulating WNT6 and WNT10B, and inhibiting SFRP1 in the dermal papilla. Our study demonstrates that dWAT regulates human hair growth and pigmentation through HGF secretion, and thus identifies dWAT and HGF as important novel molecular and cellular targets for therapeutic intervention in human hair growth and pigmentation disorders.

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.

A Secondary Analysis of Integrated Pediatric Chronic Pain Services Related to Cost Savings.

Youth with chronic pain have high healthcare utilization and associated costs. Research supports integrated treatment; though, it's unclear which treatments are used and cost-effective. This study expands on work that found reduced service use and cost savings following participation in an outpatient integrated pediatric pain clinic. We explored which services were commonly used and which individual (psychotherapy, medication management, acupuncture, massage, biofeedback) and/or combinations of services were associated with service use reduction and cost savings. Medication management and psychotherapy were more common than complementary integrative medicine (CIM) services. Massage services were associated with reduced inpatient costs. There were trends of fewer emergency department visits for participants who received CIM services in addition to medication management and psychotherapy, and more visits for those with biofeedback. Findings suggest that a more detailed examination of service utilization is needed to better understand cost outcomes related to the integrated treatment of pediatric chronic pain.

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.

De-Risking Early-Stage Drug Development With a Bespoke Lattice Energy Predictive Model: A Materials Science Informatics Approach to Address Challenges Associated With a Diverse Chemical Space.

The solid-state properties of new chemical entities are critical to the stability and bioavailability of pharmaceutical drug products. The stability of the solid-state packing is described by the packing energy and an accurate prediction of this property for drug molecules would therefore be desirable. However, this has been difficult to achieve because of the lack of fundamental thermodynamic data on drug molecules. A potential solution would be to use calculated lattice energies to build a model and design molecules with desired physicochemical properties from an early stage, aligning with a "design by first intent" strategy for physicochemical properties. We first demonstrate the high correlation and interchangeability between QSPR models built using calculated lattice energies and experimental sublimation enthalpies for small organic molecules. We then present a QSPR model trained on in-house molecules using lattice energies calculated from crystal structures. The result is a model that enables fast prediction of the lattice energies of in-house molecules from 2-D molecular structure with reasonable accuracy (R2 = 0.92, root mean square error = 3.58 kcal/mol). We explore the model elements to improve our understanding of the molecular properties that contribute to lattice energy and then suggest potential cross-industry aspects that may enhance the application of the concept.