The Impact of Li Fraumeni and Germline Retinoblastoma Mutations on Leiomyosarcoma Initiation, Outcomes and Genetic Testing Recommendations.

PURPOSE: Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous, occurring mostly in sporadic but also syndromic settings. The role of pathogenic germline variants (PGV) as LMS drivers and impact on outcome remain uncertain. EXPERIMENTAL DESIGN: We perform a comprehensive clinicopathologic and molecular analysis using a tumor-normal DNA next-generation sequencing assay (MSK-IMPACT) of germline-associated LMS compared to sporadic LMS. RESULTS: Among 285 LMS [120 soft tissue LMS (STLMS), 165 uterine (ULMS)] with germline testing, 78 (27%, 43 STLMS, 35 ULMS) cases harbored PGV: 35/78 (45%) of PGV carriers showing biallelic inactivation of the corresponding gene in the tumor (26 STLMS, 9 ULMS). The most frequent germline predispositions were TP53 (Li-Fraumeni syndrome) (17 patients, 16 in STLMS) and RB1 (retinoblastoma) (13 patients, 11 in STLMS). Germline TP53 and somatic RB1 alterations often co-occurred in the tumor, and vice versa. Other biallelically inactivated PGV were enriched in DNA damage repair-related genes: CHEK2, MSH2, MSH6, RAD51D, BRCA2 and FANCA. Monoallelic PGV were mostly in ULMS and associated with co-occurring TP53 and RB1 somatic alterations. STLMS patients with biallelic but not monoallelic PGV were significantly younger than sporadic STLMS patients (median ages 38 vs 52 vs 58 years). No differences in disease-specific or progression-free survival were observed in germline-associated vs sporadic LMS, regardless of biallelic status. CONCLUSIONS: While ULMS patients had a relatively low proportion of PGV, a high percentage of STLMS patients with PGV had tumor biallelic status, indicating that PGV drive tumorigenesis in these individuals. These findings have significant implications for genetic testing recommendations.

Basket study of oral progesterone antagonist onapristone extended release in progesterone receptor-positive recurrent granulosa cell, low-grade serous ovarian cancer, or endometrioid endometrial cancer.

OBJECTIVE: To determine the safety and efficacy of the oral progesterone antagonist onapristone extended release (onapristone-XR) in patients with recurrent progesterone receptor (PR)-positive adult-type granulosa cell tumor (aGCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC). METHODS: This single-institution phase II study included patients with PR-positive aGCT, LGSOC, or EEC who received ≥1 prior line of chemotherapy. Patients were enrolled from 5/2019-5/2020. PR status was evaluated via immunohistochemistry. Eligible patients had PR expression ≥1% on tissue collected within 3 years of enrollment. Patients received 50 mg of onapristone-XR twice daily until disease progression or treatment discontinuation. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints were response duration, clinical benefit rate (CBR), and safety. RESULTS: Five patients with LGSOC and 1 with EEC enrolled, but both cohorts closed early due to slow accrual. Fourteen patients with aGCT enrolled and completed stage 1 accrual. No responses were observed. Four patients with LGSOC were evaluable, with median PFS of 4.4 months (range, 1.8-NE) and CBR of 50% (range, 6.8%-93.2%). All 14 patients with aGCT were evaluable, with median PFS of 2.8 months (range, 1.6-4.9), 6-month PFS rate of 21.4% (range, 5.2%-44.8%), 12-month PFS rate of 14.3% (range, 2.3%-36.6%), and a CBR of 35.7% (range, 12.8%-64.9%). CONCLUSIONS: The study did not meet its primary endpoint. While onapristone-XR was well tolerated in all 3 arms, no objective responses were observed.

Novel Androgen Receptor Splice Variant 7 in Gynecologic Tumors.

Androgen receptor splicing variant 7 (AR-V7) is a truncated variant of the AR mRNA that may be a predictive biomarker for AR-targeted therapy. AR-V7 has been described in prostate, breast, salivary duct, and hepatocellular carcinomas as well as mammary and extra-mammary Paget disease. We report 2 gynecologic cancers occurring in the lower uterine segment and ovary and both harboring AR-V7 by targeted RNA sequencing. The uterine tumor was an undifferentiated carcinoma consisting of epithelioid cells and focally spindled cells arranged in sheets, nests, and cords associated with brisk mitotic activity and tumor necrosis. The ovarian tumor consisted of glands with cribriform and solid architecture and uniform cytologic atypia. ER and PR were positive in the ovarian tumor and negative in the uterine tumor. Both were positive for AR and negative for HER2, GATA3, and NKX3.1. DNA methylation profiling showed epigenetic similarity of the AR-V7-positive gynecologic cancers to AR-V7-positive breast cancers rather than to prostate cancers. AR-V7 may underpin rare gynecologic carcinomas with undifferentiated histology or cribriform growth reminiscent of prostatic adenocarcinoma and breast invasive ductal carcinoma.

Prognosis of isolated tumor cells and use of molecular classification in early stage endometrioid endometrial cancer.

OBJECTIVE: We assessed the prognosis and molecular subtypes of early stage endometrioid endometrial cancer with isolated tumor cells within sentinel lymph nodes (SLNs) compared with node negative disease. METHODS: Patients diagnosed with stage IA, IB, or II endometrioid endometrial cancer and primary surgical management were identified from January 1, 2007 to December 31, 2019. All SLNs underwent ultrastaging according to the institutional protocol. Patients with cytokeratin positive cells, micrometastases, and macrometastases were excluded. Clinical, pathology, and molecular subtype data were reviewed. RESULTS: Overall, 1214 patients with early stage endometrioid endometrial cancer met the inclusion criteria, of whom 1089 (90%) had node negative disease and 125 (10%) had isolated tumor cells. Compared with node negative disease, the presence of isolated tumor cells had a greater association with deep myometrial invasion, lymphovascular space invasion, receipt of adjuvant therapy, and adjuvant chemotherapy with or without radiation (p<0.01). There was no significant difference in survival rates between patients with isolated tumor cells and node negative disease (3 year progression free survival rate 94% vs 91%, respectively, p=0.21; 3 year overall survival rate 98% vs 96%, respectively, p=0.45). Progression free survival did not significantly differ among patients with isolated tumor cells who received no adjuvant therapy or chemotherapy with or without radiation (p=0.31). There was no difference in the distribution of molecular subtypes between patients with isolated tumor cells (n=28) and node negative disease (n=194; p=0.26). Three year overall survival rates differed significantly when stratifying the entire cohort by molecular subtype (p=0.04). CONCLUSIONS: Patients with isolated tumor cells demonstrated less favorable uterine pathologic features and received more adjuvant treatment with similar survival compared with patients with nodenegative disease. Among the available data, molecular classification did not have a significant association with the presence of isolated tumor cells, although copy number-high status was a poor prognostic indicator in early stage endometrioid endometrial cancer.

When it's not ovarian cancer: A case of a massive leiomyoma with hydropic change.

Background: Uterine leiomyomas are benign tumors characterized by pelvic pain and abnormal bleeding. Their evolution can lead to degenerative changes, occasionally mimicking malignancies on imaging, presenting diagnostic challenges. Case presentation: A 31-year-old nulliparous woman presented with symptoms of bloating, cramping, and abdominal distension. Imaging suggested an advanced ovarian malignancy, showing a complex adnexal mass and elevated CA-125 levels. During exploratory laparotomy, what was suspected to be ovarian cancer was instead identified as a large uterine mass on pathologic evaluation revealing a benign leiomyoma with extensive hydropic change. Conclusion: This case highlights the diagnostic intricacies associated with large complex adnexal masses and illustrates how benign conditions like leiomyomas with hydropic degeneration can mimic ovarian cancer. This emphasizes the importance of comprehensive preoperative and intraoperative assessments to tailor management and avoid unindicated radical procedures.

What to do with an incidental finding of a fused sagittal suture: a modified Delphi study.

OBJECTIVE: As many as 5% of normocephalic children may have a prematurely fused sagittal suture, yet the clinical significance and best course of management of this finding remain unclear. Providers in the Synostosis Research Group were surveyed to create a multicenter consensus on an optimal treatment and monitoring algorithm for this condition. METHODS: A four-round modified Delphi method was utilized. The first two rounds consisted of anonymous surveys distributed to 10 neurosurgeons and 9 plastic surgeons with expertise in craniosynostosis across 9 institutions, and presented 3 patients (aged 3 years, 2 years, and 2 months) with incidentally discovered fused sagittal sutures, normal cephalic indices, and no parietal dysmorphology. Surgeons were queried about their preferred term for this entity and how best to manage these patients. Results were synthesized to create a treatment algorithm. The third and fourth feedback rounds consisted of open discussion of the algorithm until no further concerns arose. RESULTS: Most surgeons preferred the term "premature fusion of the sagittal suture" (93%). At the conclusion of the final round, all surgeons agreed to not operate on the 3- and 2-year-old patients unless symptoms of intracranial hypertension or papilledema were present. In contrast, 50% preferred to operate on the 2-month-old. However, all agreed to utilize shared decision-making, taking into account any concerns about future head shape and neurodevelopment. Panelists agreed that patients over 18 months of age without signs or symptoms suggesting elevated intracranial pressure (ICP) should not undergo surgical treatment. CONCLUSIONS: Through the Delphi method, a consensus regarding management of premature fusion of the sagittal suture was obtained from a panel of North American craniofacial surgeons. Without signs or symptoms of ICP elevation, surgery is not recommended in patients over 18 months of age. However, for children younger than 18 months, surgery should be discussed with caregivers using a shared decision-making process.

Expanding the Spectrum of NR4A3 Fusion-Positive Gynecologic Leiomyosarcomas.

Recurrent gene fusions have been observed in epithelioid and myxoid variants of uterine leiomyosarcoma. PGR::NR4A3 fusions were recently described in a subset of epithelioid leiomyosarcomas exhibiting rhabdoid morphology. In this study, we sought to expand the clinical, morphologic, immunohistochemical, and genetic features of gynecologic leiomyosarcomas harboring NR4A3 rearrangements with PGR and novel fusion partners. We identified 9 gynecologic leiomyosarcomas harboring PGR::NR4A3, CARMN::NR4A3, ACTB::NR4A3, and possible SLCO5A1::NR4A3 fusions by targeted RNA sequencing. Tumors frequently affected premenopausal women, involving the uterine corpus, uterine cervix, or pelvis. All were similarly characterized by lobules of monomorphic epithelioid and/or spindled cells arranged in sheets, cords, trabeculae, and micro- and macrocysts associated with abundant myxoid matrix and hemorrhage, creating labyrinth-like or pulmonary edema-like architecture. Myogenic differentiation with frequent estrogen receptor and progesterone receptor staining and no CD10 expression characterized all tumors. All cases showed high NR4A3 RNA expression levels and NOR1 (NR4A3) nuclear staining similar to salivary gland acinic cell carcinomas and a subset of extraskeletal myxoid chondrosarcomas harboring NR4A3 rearrangements. NOR1 (NR4A3) immunohistochemistry may serve as a useful diagnostic marker of NR4A3 fusion-positive gynecologic leiomyosarcomas.

Direct-to-Implant vs Tissue Expander Placement in Immediate Breast Reconstruction: A Prospective Cohort Study.

BACKGROUND: Direct-to-implant (DTI) breast reconstruction after mastectomy has gained increasing popularity. While concerns over ischemic complications related to tension on the mastectomy flap persist, newer techniques and technologies have enhanced safety of this technique. OBJECTIVES: To compare clinical and patient-reported outcomes of DTI and 2-stage tissue expander (TE) reconstruction. METHODS: A prospective cohort design was utilized to compare the incidence of reconstructive failure among patients undergoing DTI and TE reconstruction by unadjusted bivariate and adjusted multivariable logistic regression analyses. Secondary clinical outcomes of interest included specific complications requiring intervention (infection, seroma, hematoma, mastectomy flap necrosis, incisional dehiscence, device exposure) and time to final drain removal. Patient-reported outcomes on BREAST-Q were also compared. RESULTS: A total of 134 patients (257 breasts) underwent DTI reconstruction and 222 patients (405 breasts) received TEs. DTI patients were significantly younger with lower BMIs; less diabetes, hypertension, and smoking; and smaller breast sizes; they also underwent more nipple-sparing mastectomies with prepectoral reconstructions. Rates of any complication (18% DTI vs 24% TE, P = .047), reconstructive failure (5.1% vs 12%, P = .004), and seroma (3.9% vs 11%, P < .001) were significantly lower in the DTI cohort on unadjusted analyses; however, there were no significant differences on adjusted regressions. Patient-reported satisfaction with breasts, psychosocial well-being, and sexual well-being were more substantively improved with DTI reconstruction. CONCLUSIONS: Prepectoral DTI reconstruction is a viable option for postmastectomy reconstruction in carefully selected patients, with no significant increase in reconstructive failure or other complications.

Developing Novel Genomic Risk Stratification Models in Soft Tissue and Uterine Leiomyosarcoma.

PURPOSE: Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous tumors. Despite recent large-scale genomic studies, current LMS risk stratification is not informed by molecular alterations. We propose a clinically applicable genomic risk stratification model. EXPERIMENTAL DESIGN: We performed comprehensive genomic profiling in a cohort of 195 soft tissue LMS (STLMS), 151 primary at presentation, and a control group of 238 uterine LMS (ULMS), 177 primary at presentation, with at least 1-year follow-up. RESULTS: In STLMS, French Federation of Cancer Centers (FNCLCC) grade but not tumor size predicted progression-free survival (PFS) or disease-specific survival (DSS). In contrast, in ULMS, tumor size, mitotic rate, and necrosis were associated with inferior PFS and DSS. In STLMS, a 3-tier genomic risk stratification performed well for DSS: high risk: co-occurrence of RB1 mutation and chr12q deletion (del12q)/ATRX mutation; intermediate risk: presence of RB1 mutation, ATRX mutation, or del12q; low risk: lack of any of these three alterations. The ability of RB1 and ATRX alterations to stratify STLMS was validated in an external AACR GENIE cohort. In ULMS, a 3-tier genomic risk stratification was significant for both PFS and DSS: high risk: concurrent TP53 mutation and chr20q amplification/ATRX mutations; intermediate risk: presence of TP53 mutation, ATRX mutation, or amp20q; low risk: lack of any of these three alterations. Longitudinal sequencing showed that most molecular alterations were early clonal events that persisted during disease progression. CONCLUSIONS: Compared with traditional clinicopathologic models, genomic risk stratification demonstrates superior prediction of clinical outcome in STLMS and is comparable in ULMS.

Establishing guidelines for sentinel lymph node ultrastaging in endometrial cancer.

BACKGROUND: Many sentinel lymph node (SLN) ultrastaging protocols for endometrial cancer exist, but there is no consensus method. OBJECTIVE: This study aims to develop guidelines for size criteria in SLN evaluation for endometrial cancer, to determine whether a single cytokeratin AE1:AE3 immunohistochemical slide provides sufficient data for diagnosis, and to compare cost efficiency between current and limited ultrastaging protocols at a large tertiary care institution. METHODS: Our current SLN ultrastaging protocol consists of cutting two adjacent paraffin block sections at two levels (L1 and L2), 50 µm apart, with two slides at each level stained with hematoxylin and eosin and cytokeratin AE1:AE3 immunohistochemistry. We retrospectively reviewed digitized L1 and L2 slides of all positive ultrastaged SLNs from patients treated for endometrial cancer between January 2013 and January 2020. SLN diagnosis was defined by measuring the largest cluster of contiguous tumor cells in a single cross section: macrometastasis (>2.0 mm), micrometastasis (>0.2 to ≤2.0 mm or >200 cells), or isolated tumor cells (≤0.2 mm or ≤200 cells). Concordance between L1 and L2 results was evaluated. Cost efficiency between current (two immunohistochemical slides per block) and proposed limited (one immunohistochemical slide per block) protocols was compared. RESULTS: Digitized slides of 147 positive SLNs from 109 patients were reviewed; 4.1% of SLNs were reclassified based on refined size criteria. Complete concordance between L1 and L2 interpretations was seen in 91.8% of SLNs. A false-negative rate of 0%-0.9% in detecting micrometastasis and macrometastasis using a limited protocol was observed. Estimated charge-level savings of a limited protocol were 50% per patient. CONCLUSION: High diagnostic accuracy in SLN interpretation may be achieved using a limited ultrastaging protocol of one immunohistochemical slide per block and linear measurement of the largest cluster of contiguous tumor cells. Implementation of the proposed limited ultrastaging protocol may result in laboratory cost savings with minimal impact on health outcomes.

Sarcomas With RAD51B Fusions Are Associated With a Heterogeneous Phenotype.

RAD51B-rearranged sarcomas are rare neoplasms that exhibit a heterogeneous morphology. To date, 6 cases have been reported, all involving the uterus, including 4 perivascular epithelioid cell tumors (PEComas) and 2 leiomyosarcomas (LMS). In this study, we describe the morphologic, immunohistochemical, and molecular features of 8 additional sarcomas with RAD51B rearrangement, including the first extrauterine example. All patients were women with a median age of 57 years at presentation. Seven tumors originated in the uterus, and one in the lower extremity soft tissue, with a median tumor size of 12 cm. Histologically, 4 tumors showed predominantly spindle cell morphology with eosinophilic fibrillary cytoplasm, with or without nuclear pleomorphism, whereas 2 tumors exhibited pleomorphic epithelioid cells, featuring clear to eosinophilic, granular cytoplasm. Two neoplasms exhibited undifferentiated cytomorphology, including one with uniform small blue round cells. All tumors showed high-grade cytologic atypia and high mitotic activity (median: 30/10 high-power fields), whereas coagulative necrosis was noted in 6 cases and lymphovascular invasion in 2. By immunohistochemistry, 2 showed myoid and melanocytic markers in keeping with PEComa, whereas 4 cases were only positive for smooth muscle markers consistent with LMS (including 3 myxoid). The remaining 2 cases had a nonspecific immunoprofile. Five cases tested by targeted RNA sequencing (Archer FusionPlex, Illumina TruSight) showed different fusion partners (HMGA2, PDDC1, and CEP170). RAD51B rearrangements were identified by FISH in the remaining 3 cases. Targeted DNA sequencing in 2 cases was negative for TSC gene alterations. Clinical outcome, available in 5 patients (median follow-up, 19 months), revealed 3 local recurrences, 2 lung metastases, and 4 deaths due to disease. Our results expand the spectrum of sarcomas with RAD51B fusions, demonstrating variable clinical presentations, morphologic spectrum, and fusion partners. These tumors have a predilection for a uterine location, with either LMS, PEComa, or undifferentiated phenotypes, and are associated with an aggressive clinical course.

Cortiva vs AlloDerm in Prepectoral and Partial Submuscular Implant-Based Breast Reconstruction: A Randomized Clinical Trial.

BACKGROUND: Several acellular dermal matrices (ADMs) are utilized for soft tissue support in prosthetic breast reconstruction. Little high-level evidence supports the use of one ADM over another. Therefore, we sought to compare Cortiva 1mm Allograft Dermis to AlloDerm RTU, the most studied ADM in the literature. METHODS: A single-blinded randomized controlled trial comparing Cortiva to AlloDerm in prepectoral and subpectoral immediate prosthetic breast reconstruction was performed at two academic hospitals from March 2017 to December 2021. Reconstructions were direct-to-implant (DTI) or tissue expander (TE). Primary outcome was reconstructive failure, defined as TE explantation prior to planned further reconstruction, or explantation of DTI reconstructions before 3 months postoperatively. Secondary outcomes were additional complications, patient-reported outcomes (PROs), and cost. RESULTS: There were 302 patients included - 151 AlloDerm (280 breasts), 151 Cortiva (277 breasts). Reconstructions in both cohorts were majority TE (62% vs 38% DTI), smooth device (68% vs 32% textured), and prepectoral (80% vs 20% subpectoral). Reconstructive failure was no different between ADMs (AlloDerm 9.3% vs Cortiva 8.3%, p=0.68). There were no additional differences in any complications or PROs between ADMs. Seromas occurred in 7.6% of Cortiva but 12 % of AlloDerm cases, whose odds of seroma formation were two-fold (OR 1.93, 95% CI 1.01-3.67, p=0.047) higher. AlloDerm variable cost was 10-15% more than Cortiva, and there were no additional cost differences. CONCLUSION: When assessing safety, clinical performance, PROs, and cost, Cortiva is non-inferior to AlloDerm in immediate prosthetic breast reconstruction and may be cheaper with lower risk of seroma formation.

Investigating Weekend Effect in the Management of Upper and Lower Extremity Degloving Injuries.

Background: Weekend presentation has been associated with adverse outcomes in emergent conditions, including stroke, myocardial infarction, and critical limb ischemia. We examine whether a weekend effect exists in the management of and outcomes after extremity degloving injuries. Methods: The cohort included adults presenting with open extremity degloving injuries to a tertiary level one trauma center between June 2018 and May 2022. We collected demographics, comorbidities, injury information, interventions, and complications. Propensity score weighting was used to minimize confounding differences between those presenting on weekends (Sat-Sun) versus weekdays (Mon-Fri). Weighted regressions were used to examine differences in interventions by day of presentation. Multivariable weighted regressions accounting for differences in interventions received were used to examine whether weekend presentation was associated with amputation risk, complications, or functional deficits. Results: Ninety-five patients with 100 open extremity degloving injuries were included. In total, 39% of injuries were weekend-presenting. There was a higher rate of noninsulin-dependent diabetes among patients presenting on weekends (P = 0.03). Weekend-presenting injuries had higher median Injury Severity Scores (P = 0.04). Propensity-weighted regression analysis revealed differences in interventions received on weekends, including lower rates of pedicled and free flaps and bone graft, and increased rates of negative-pressure wound therapy (P ≤ 0.02). Multivariable regression analysis revealed weekend presentation was a significant independent risk factor for amputation of the affected extremity [odds ratio 2.27, 95% CI (1.01-5.33), P = 0.05]. Conclusion: Weekend presentation may impact interventions received and amputation risk in patients presenting with open extremity degloving injuries.

Buccal Myomucosal Flap Repair for Velopharyngeal Dysfunction.

BACKGROUND: Velopharyngeal dysfunction (VPD) is the incomplete separation of the nasal and oral cavities during speech sound production that can persist following primary palatoplasty. Surgical technique used in management of VPD (palatal re-repair versus pharyngeal flap or sphincter pharyngoplasty) is often dictated by the preoperative velar closing ratio and closure pattern. Recently, buccal flaps have increased in popularity in management of VPD. Here, the authors investigate the effectiveness of buccal myomucosal flaps in the treatment of VPD. METHODS: A retrospective review was performed of all patients undergoing secondary palatoplasty with buccal flaps at a single center between 2016 and 2021. Preoperative and postoperative speech outcomes were compared. Speech assessments included perceptual examinations, graded on a four-point scale of hypernasality, and speech videofluoroscopy, from which the velar closing ratio was obtained. RESULTS: A total of 25 patients underwent buccal myomucosal flap procedures for VPD at a median of 7.1 years after primary palatoplasty. Patients had significantly increased velar closing postoperatively (95% versus 50%; P < 0.001) and improved speech scores ( P < 0.001). Three patients (12%) had continued hypernasality postoperatively. There were no occurrences of obstructive sleep apnea. CONCLUSIONS: Treatment of VPD with buccal myomucosal flaps leads to improved speech outcomes without the risk of obstructive sleep apnea. Traditionally, palatal re-repair techniques have been used for smaller preoperative velopharyngeal gaps; however, the addition of buccal flaps allows for anatomical velar muscle correction for patients with a larger preoperative velopharyngeal gap. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

DNA Methylation Signature of Synchronous Endometrioid Endometrial and Ovarian Carcinomas.

Next-generation sequencing (NGS) studies have demonstrated that co-occurring sporadic endometrioid endometrial carcinoma (EEC) and endometrioid ovarian carcinoma (EOC) are clonally related, suggesting that they originate from a single primary tumor. Despite clonality, synchronous EEC and EOC when diagnosed at early stage behave indolently, similar to isolated primary EEC or isolated primary EOC. In the present study, we compared the DNA methylation signatures of co-occurring EEC and EOC with those of isolated primary EEC and isolated primary EOC. We also performed targeted NGS to assess the clonal relatedness of 7 co-occurring EEC and EOC (4 synchronous EEC and EOC and 3 metastatic EEC based on pathologic criteria). NGS confirmed a clonal relationship in all co-occurring EEC and EOC. DNA methylation profiling showed distinct epigenetic signatures of isolated primary EEC and isolated primary EOC. Endometrial tumors from co-occurring EEC and EOC clustered with isolated primary EEC while their ovarian counterparts clustered with isolated primary EOC. Three co-occurring EEC and EOC cases with peritoneal lesions showed a closer epigenetic signature and copy number variation profile between the peritoneal lesion and EOC than EEC. In conclusion, synchronous sporadic EEC and EOC are clonally related but demonstrate a shift in DNA methylation signatures between ovarian and endometrial tumors as well as epigenetic overlap between ovarian and peritoneal tumors. Our results suggest that tumor microenvironment in the ovary may play a role in epigenetic modulation of metastatic EEC.

What do patients want to know about gender-affirming surgery? Analysis of common patient concerns and online health materials.

PURPOSE: Patients considering gender-affirming surgery often utilize online health materials to obtain information about procedures. However, the distribution of patient concerns and content of online resources for gender-affirming surgery have not been examined. We aimed to quantify and comprehensively analyze the most searched questions of patients seeking gender-affirming surgery and to examine the quality and readability of associated websites providing the answers. METHODS: Questions were extracted from Google using the search phrases "gender-affirming surgery," "transgender surgery," "top surgery," and "bottom surgery." Questions were categorized by topic and average search volume per month was determined. Websites linked to questions were categorized by type, and quality of the health information was evaluated utilizing the DISCERN instrument (16-80). Readability was assessed with the Flesch Reading Ease Score and Flesch-Kincaid Grade Level. RESULTS: Ninety questions and associated websites were analyzed. Common questions were most frequently answered by academic websites (30%). Topics included cost (27%), technical details of surgery (23%), and preoperative considerations (11%). Median (interquartile range) DISCERN score across all website categories was 42 (18). The mean readability was of a 12th-grade level, well above the grade six reading level recommended by the American Medical Association. CONCLUSIONS: Online gender-affirming surgery materials are difficult to comprehend and of poor quality. To enhance patient knowledge, informed consent, and shared decision-making, there is a substantial need to create understandable and high-quality online health information for those seeking gender-affirming surgery.

"Calvarial Vault Remodeling Technique for Lambdoid Craniosynostosis."

SUMMARY: Premature fusion of the lambdoid suture is the most uncommon single suture synostosis. It presents with a classic "windswept" appearance, with a trapezoid-shaped head and significant skull asymmetry notable for an ipsilateral mastoid bulge and contralateral frontal bossing. Due to the rarity of lambdoid synostosis, little is known about optimal techniques for its treatment. In particular, the proximity of the lambdoid suture to critical intracranial structures such as the superior sagittal and transverse sinuses represents a potential for significant intraoperative bleeding. Prior work has shown that parietal asymmetry persists after repair in these cases. Here, we present a technique for the treatment of unilateral lambdoid craniosynostosis along with two representative cases.This calvarial vault remodeling technique requires the removal of both ipsilateral and contralateral parietal bones. These are moved across hemispheres and re-inset on opposite sides to help correct the parietal asymmetry. Obliquely orientated barrel stave osteotomies are performed to provide a safe mechanism for correction of occipital flattening. Our early results show improvement in correction of volume asymmetry one year post-operatively relative to patients treated with prior calvarial vault remodeling techniques. We believe the technique presented here corrects the windswept appearance in patients with lambdoid craniosynostosis while also reducing the potential for complications. Further work will be necessary to confirm this technique's long-term efficacy in a larger cohort.

Compound Effect of Hypoalbuminemia and Obesity on Complications after Autologous Breast Reconstruction.

BACKGROUND: Obesity is among the risk factors identified that impair postoperative wound healing. Recently, malnutrition and sarcopenia have also been found to correlate with poor surgical outcomes; however, the effect of malnutrition in the setting of obesity is understudied, particularly in reconstructive surgery. The authors examine the American College of Surgeons National Surgery Quality Improvement Program database to determine the impact of obesity plus hypoalbuminemia on complications after autologous breast reconstruction. METHODS: Autologous breast reconstruction procedures (pedicled and free flaps) were collected from the 2009 to 2019 National Surgery Quality Improvement Program databases by CPT codes ( n = 23,690). Patients without height, weight, or preoperative serum albumin data ( n = 12,825) were excluded. Demographics and postoperative outcomes were compared in patients with obesity (body mass index >30 kg/m 2 ) and malnutrition (albumin <3.5 g/dL). Propensity score-matched cohorts with and without malnutrition were also compared. RESULTS: A total of 10,865 procedures were included in analysis; 4565 involved patients with obesity (42%). Obesity was associated with increased length of stay, reoperations, wound complications, and medical complications (all P < 0.001). Among patients with obesity, 198 had malnutrition (4.3%). The combination of obesity and malnutrition was associated with a higher rate of wound complications (16%) over obesity alone (9.2%) or malnutrition alone (9.2%, both P < 0.05). This difference is recapitulated in propensity score-matched analysis. CONCLUSION: Hypoalbuminemia, a marker of malnutrition, is underappreciated in obese patients and is associated with worse surgical outcomes after autologous breast reconstruction compared with obesity alone. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Inhibition of CXCR4 Enhances the Efficacy of Radiotherapy in Metastatic Prostate Cancer Models.

Radiotherapy (RT) is a standard treatment for patients with advanced prostate cancer (PCa). Previous preclinical studies showed that SDF1α/CXCR4 axis could mediate PCa metastasis (most often to the bones) and cancer resistance to RT. We found high levels of expression for both SDF1α and its receptor CXCR4 in primary and metastatic PCa tissue samples. In vitro analyses using PCa cells revealed an important role of CXCR4 in cell invasion but not radiotolerance. Pharmacologic inhibition of CXCR4 using AMD3100 showed no efficacy in orthotopic primary and bone metastatic PCa models. However, when combined with RT, AMD3100 potentiated the effect of local single-dose RT (12 Gy) in both models. Moreover, CXCR4 inhibition also reduced lymph node metastasis from primary PCa. Notably, CXCR4 inhibition promoted the normalization of bone metastatic PCa vasculature and reduced tissue hypoxia. In conclusion, the SDF1α/CXCR4 axis is a potential therapeutic target in metastatic PCa patients treated with RT.

Molecular-Based Immunohistochemical Algorithm for Uterine Leiomyosarcoma Diagnosis.

The morphologic assessment of uterine leiomyosarcoma (LMS) may be challenging, and diagnostic immunohistochemical (IHC) analysis is currently lacking. We evaluated the genomic landscape of 167 uterine LMS by targeted next-generation sequencing (NGS) to identify common genomic alterations. IHC analyses corresponding to these genomic landmarks were applied to a test cohort of 16 uterine LMS, 6 smooth muscle tumors of uncertain malignant potential (STUMP), and 6 leiomyomas with NGS data and a validation cohort of 8 uterine LMS, 12 STUMP, 21 leiomyomas and leiomyoma variants, 7 low-grade endometrial stromal sarcomas, and 2 diagnostically challenging uterine smooth muscle tumors. IHC results were individually interpreted by 3 pathologists blinded to NGS data. Overall, 94% of LMS showed ≥1 genomic alteration involving TP53, RB1, ATRX, PTEN, CDKN2A, or MDM2, with 80% showing alterations in ≥2 of these genes. In the test cohort, an initial panel of p53, Rb, PTEN, and ATRX was applied, followed by a panel of DAXX, MTAP, and MDM2 in cases without abnormalities. Abnormal p53, Rb, PTEN, and ATRX IHC expression was seen in 75%, 88%, 44%, and 38% of LMS, respectively, in the test cohort. Two or more abnormal IHC results among these markers were seen in 81% of LMS. STUMPs demonstrated only 1 IHC abnormality involving these markers. No IHC abnormalities were seen in leiomyomas. In the validation cohort, abnormal p53, Rb, and PTEN IHC results were seen in LMS, whereas rare STUMP or leiomyomas with bizarre nuclei showed IHC abnormalities involving only 1 of the markers. Abnormalities in ≥2 markers were present in both diagnostically challenging smooth muscle tumors, confirming LMS. Concordance was excellent among pathologists in the interpretation of IHC (κ = 0.97) and between IHC and NGS results (κ = 0.941). Uterine LMS exhibit genomic landmark alterations for which IHC surrogates exist, and a diagnostic algorithm involving molecular-based IHC may aid in the evaluation of unusual uterine smooth muscle tumors.