Once daily cediranib and weekly paclitaxel to prevent malignant bowel obstruction in at-risk patients with platinum-resistant ovarian cancer (CEBOC): a single-arm, phase II safety trial.

OBJECTIVE: Cytotoxic chemotherapy for ovarian cancer can be augmented by co-administration of vascular endothelial growth factor inhibitors but these are contraindicated in patients with bowel obstruction due to the risk of gastrointestinal perforation. We evaluated the safety and feasibility of paclitaxel plus cediranib to treat patients with platinum-resistant ovarian cancer at risk of malignant bowel obstruction. METHODS: A phase II trial included eligible patients between March 2018 and February 2021, identified by clinical symptoms and radiographic risk factors for malignant bowel obstruction. Cediranib (20 mg/day) was added to paclitaxel (70 mg/m2/week) within 9 weeks of starting paclitaxel if pretreatment bowel symptoms had improved. The primary endpoint was the number of patients treated for ≥5 days with cediranib that were free of grade 3-5 gastrointestinal perforation or fistula. Secondary endpoints were hospitalization for bowel obstruction, grade ≥3 adverse events, treatment compliance assessed by relative dose intensity, objective response, progression-free survival, and overall survival. RESULTS: Thirty patients were recruited. Of these, 12 received paclitaxel alone and 17 received paclitaxel and cediranib in combination. One patient died before starting treatment. No patient developed a grade 3-5 gastrointestinal perforation or fistula (one sided 95% confidence interval (CI) upper limit 0.16). One patient required hospitalization for bowel obstruction but recovered with conservative management. The most common cediranib-related grade ≥3 adverse events were fatigue (3/17), diarrhorea (2/17), and hypomagnesemia (2/17). Relative dose intensity for paclitaxel was 90% (interquartile range (IQR) 85-100%; n=29) and for cediranib 88% (IQR 76-93%; n=17). The objective response in patients who received paclitaxel and cediranib was 65.0% (one complete and 10 partial responses). Median progression-free survival was 6.9 months (95% CI 4.4-11.5 months; n=17) and overall survival was 19.4 months (95% CI 10.1-20.4 months; n=17). Median follow-up was 12.4 months (8.9-not reached; n=17). CONCLUSIONS: The unexpectedly high withdrawal rate during paclitaxel alone, before introducing cediranib, meant we were unable to definitely conclude that paclitaxel plus cediranib did not cause gastrointestinal perforation or fistula. The regimen was however tolerated. TRIAL REGISTRATION NUMBER: EudraCT 2016-004618-93.

Practical Considerations for Delandistrogene Moxeparvovec Gene Therapy in Patients With Duchenne Muscular Dystrophy.

BACKGROUND: Delandistrogene moxeparvovec is a gene transfer therapy approved in the United States, United Arab Emirates, and Qatar for the treatment of ambulatory patients aged four through five years with a confirmed Duchenne muscular dystrophy (DMD)-causing mutation in the DMD gene. This therapy was developed to address the underlying cause of DMD through targeted skeletal, respiratory, and cardiac muscle expression of delandistrogene moxeparvovec micro-dystrophin, an engineered, functional dystrophin protein. METHODS: Drawing on clinical trial experience from Study 101 (NCT03375164), Study 102 (NCT03769116), and ENDEAVOR (Study 103; NCT04626674), we outline practical considerations for delandistrogene moxeparvovec treatment. RESULTS: Before infusion, the following are recommended: (1) screen for anti-adeno-associated virus rhesus isolate serotype 74 total binding antibody titers <1:400; (2) assess liver function, platelet count, and troponin-I; (3) ensure patients are up to date with vaccinations and avoid vaccine coadministration with infusion; (4) administer additional corticosteroids starting one day preinfusion (for patients already on corticosteroids); and (5) postpone dosing patients with any infection or acute liver disease until event resolution. Postinfusion, the following are recommended: (1) monitor liver function weekly (three months postinfusion) and, if indicated, continue until results are unremarkable; (2) monitor troponin-I levels weekly (first month postinfusion, continuing if indicated); (3) obtain platelet counts weekly (two weeks postinfusion), continuing if indicated; and (4) maintain the corticosteroid regimen for at least 60 days postinfusion, unless earlier tapering is indicated. CONCLUSIONS: Although the clinical safety profile of delandistrogene moxeparvovec has been consistent, monitorable, and manageable, these practical considerations may mitigate potential risks in a real-world clinical practice setting.

The Devil's in the Depot Details: Case of Iatrogenic Opioid Intoxication After Buprenorphine Injection Requiring Surgical Excision.

ABSTRACT: Monthly long-acting injectable buprenorphine (LAI-BUP) is a treatment option for moderate to severe opioid use disorder. Safe administration of LAI-BUP requires preexisting opioid tolerance to prevent sedation and respiratory depression. In the event of adverse medication effects including oversedation, LAI-BUP can be surgically excised up to 14 days after administration ( https://www.sublocadehcp.com/dosing-administration ). However, the manufacturer does not provide guidance on the proper procedure for excision, and no case reports have been published documenting this procedure. We report a case of a man with methamphetamine use disorder and multiple unintentional fentanyl overdoses who inadvertently received LAI-BUP for overdose protection. This resulted in significant sedation for days, ultimately necessitating excision 5 days after administration. His sedation improved moderately at 24 hours after excision and significantly by 36 hours after excision. Providers seeking to use LAI-BUP to prevent overdose among those with unintentional opioid exposure must ensure sublingual buprenorphine tolerance before injection to avoid iatrogenic harm. Although manufacturer instructions mention that LAI-BUP can be excised under local anesthesia within 14 days of insertion, ideal excision is best performed in a setting with surgical instruments and cautery-such as the operating room-as the depot can adhere strongly to the surrounding subcutaneous tissue.

Functional donor-site morbidity following reconstruction with pectoralis major flaps: A systematic review.

Background: Pectoralis major muscle/myocutaneous flaps (PMMFs) are commonly used in reconstructive surgery, but may result in shoulder disability on the donor side. A systematic review evaluating this morbidity could be beneficial for guiding patients and providers considering this procedure. Methods: In October 2022, a systematic review of studies evaluating quantitative/qualitative measures of functional morbidity after PMMF was conducted. The results were categorized into PMMF's effect on range of motion (ROM), strength, and ability to complete shoulder-related activities/quality of life. Results: Eleven studies were included for analysis, which analyzed standard PMMF and two PMMF variants that spared portions of the muscle. Three of five studies demonstrated reduced shoulder ROM for standard PMMF versus controls lasting at least 4 months after head and neck reconstruction. Two of five studies, including two prospective studies demonstrated reduced shoulder strength for standard PMMF versus controls lasting at least 3 months after surgery. Five of nine studies found significant impairment in the ability to conduct shoulder-related activities, including work, up to one year postoperatively for standard PMMF versus controls. Muscle-sparing PMMF variants exhibited more promising outcomes in some categories. Conclusion: Standard PMMF results in prolonged reductions in shoulder ROM and strength, which may impair patients in shoulder-related activities. Other reconstructive options should be considered in patients who frequently participate in such activities. For patients requiring PMMF, muscle-sparing PMMF variants should be considered as alternatives to the standard PMMF.

Contralateral prophylactic mastectomy: Weighing the risks of delayed chemotherapy, radiotherapy, and hormonal therapy.

BACKGROUND: Many patients with unilateral breast cancer opt for contralateral prophylactic mastectomy (CPM) at the time of therapeutic mastectomy (immediate CPM) or following completion of adjuvant therapy. Studies show that immediate CPM increases the risk of surgical complications related to unilateral mastectomy (UM) alone, which may lead to delays in adjuvant therapy initiation. However, it is unclear if these complications cause clinically significant delays in initiating adjuvant chemotherapy, radiotherapy, or hormonal therapy. METHODS: A retrospective chart review was conducted on patients with breast cancer who underwent immediate CPM versus UM alone at Columbia University Medical Center from January 2000 to December 2020. Patient demographic and oncologic characteristics; complications; and timing of adjuvant chemotherapy, radiotherapy, and/or hormonal therapy relative to therapeutic mastectomy were collected. RESULTS: In this study, 239 UM alone patients were propensity score matched to 239 immediate CPM patients. No significant difference in complication rates was found between the index and contralateral breasts in CPM patients. A similar percentage of CPM and UM patients experienced postoperative complications (19% vs. 17%, p = 0.64). No significant difference in time to adjuvant chemotherapy, radiotherapy, or hormonal therapy was found between CPM patients with complications and all CPM patients or all UM patients. CONCLUSIONS: There is a lack of clear guidance for clinical decision-making regarding timing of CPM relative to adjuvant therapy. Our study suggests that immediate CPM does not significantly increase the risks of postoperative complications or complication-related delays in the initiation of adjuvant chemotherapy, radiotherapy, or hormonal therapy. This information may help patients and providers to plan, select, and schedule breast cancer treatment options.

Delandistrogene Moxeparvovec Gene Therapy in Ambulatory Patients (Aged ≥4 to <8 Years) with Duchenne Muscular Dystrophy: 1-Year Interim Results from Study SRP-9001-103 (ENDEAVOR).

OBJECTIVE: Delandistrogene moxeparvovec is approved in the USA for the treatment of ambulatory patients (4-5 years) with Duchenne muscular dystrophy. ENDEAVOR (SRP-9001-103; NCT04626674) is a single-arm, open-label study to evaluate delandistrogene moxeparvovec micro-dystrophin expression, safety, and functional outcomes following administration of commercial process delandistrogene moxeparvovec. METHODS: In cohort 1 of ENDEAVOR (N = 20), eligible ambulatory males, aged ≥4 to <8 years, received a single intravenous infusion of delandistrogene moxeparvovec (1.33 × 1014 vg/kg). The primary endpoint was change from baseline (CFBL) to week 12 in delandistrogene moxeparvovec micro-dystrophin by western blot. Additional endpoints evaluated included: safety; vector genome copies; CFBL to week 12 in muscle fiber-localized micro-dystrophin by immunofluorescence; and functional assessments, including North Star Ambulatory Assessment, with comparison with a propensity score-weighted external natural history control. RESULTS: The 1-year safety profile of commercial process delandistrogene moxeparvovec in ENDEAVOR was consistent with safety data reported in other delandistrogene moxeparvovec trials (NCT03375164 and NCT03769116). Delandistrogene moxeparvovec micro-dystrophin expression was robust, with sarcolemmal localization at week 12; mean (SD) CFBL in western blot, 54.2% (42.6); p < 0.0001. At 1 year, patients demonstrated stabilized or improved North Star Ambulatory Assessment total scores; mean (SD) CFBL, +4.0 (3.5). Treatment versus a propensity score-weighted external natural history control demonstrated a statistically significant difference in least squares mean (standard error) CFBL in North Star Ambulatory Assessment, +3.2 (0.6) points; p < 0.0001. INTERPRETATION: Results confirm efficient transduction of muscle by delandistrogene moxeparvovec. One-year post-treatment, delandistrogene moxeparvovec was well tolerated, and demonstrated stabilized or improved motor function, suggesting a clinical benefit for patients with Duchenne muscular dystrophy. ANN NEUROL 2023;94:955-968.

Multi-Maintenance Olaparib Therapy in Relapsed, Germline BRCA1/2-Mutant High-Grade Serous Ovarian Cancer (MOLTO): A Phase II Trial.

PURPOSE: A single maintenance course of a PARP inhibitor (PARPi) improves progression-free survival (PFS) in germline BRCA1/2-mutant high-grade serous ovarian cancer (gBRCAm-HGSOC). The feasibility of a second maintenance course of PARPi was unknown. PATIENTS AND METHODS: Phase II trial with two entry points (EP1, EP2). Patients were recruited prior to rechallenge platinum. Patients with relapsed, gBRCAm-HGSOC were enrolled at EP1 if they were PARPi-naïve. Patients enrolled at EP2 had received their first course of olaparib prior to trial entry. EP1 patients were retreated with olaparib after RECIST complete/partial response (CR/PR) to platinum. EP2 patients were retreated with olaparib ± cediranib after RECIST CR/PR/stable disease to platinum and according to the platinum-free interval. Co-primary outcomes were the proportion of patients who received a second course of olaparib and the proportion who received olaparib retreatment for ≥6 months. Functional homologous recombination deficiency (HRD), somatic copy-number alteration (SCNA), and BRCAm reversions were investigated in tumor and liquid biopsies. RESULTS: Twenty-seven patients were treated (EP1 = 17, EP2 = 10), and 19 were evaluable. Twelve patients (63%) received a second course of olaparib and 4 received olaparib retreatment for ≥6 months. Common grade ≥2 adverse events during olaparib retreatment were anemia, nausea, and fatigue. No cases of MDS/AML occurred. Mean duration of olaparib treatment and retreatment differed (12.1 months vs. 4.4 months; P < 0.001). Functional HRD and SCNA did not predict PFS. A BRCA2 reversion mutation was detected in a post-olaparib liquid biopsy. CONCLUSIONS: A second course of olaparib can be safely administered to women with gBRCAm-HGSOC but is only modestly efficacious. See related commentary by Gonzalez-Ochoa and Oza, p. 2563.

Lymphatic Microsurgical Preventive Healing Approach for the Primary Prevention of Lymphedema: A 4-Year Follow-Up.

BACKGROUND: Axillary lymph node dissection (ALND) remains the leading cause of lymphedema nationally, and there is still no cure for the disease. The lymphatic microsurgical preventive healing approach (LYMPHA) is a promising option for lymphedema prophylaxis in patients undergoing ALND, but long-term outcomes of the LYMPHA are not well established. METHODS: The authors conducted a retrospective review of patients undergoing ALND at their center from November of 2012 to November of 2016 and assembled two cohorts, those who received the LYMPHA and those who did not (non-LYMPHA). Patient data were collected to evaluate lymphedema risk and long-term lymphedema incidence of each group. RESULTS: Forty-five women were included in both our LYMPHA and non-LYMPHA cohorts. Mean body mass index (27.7 kg/m2 versus 29.9 kg/m2; P = 0.15) and radiation therapy rates (60.0% versus 68.9%; P = 0.51) did not differ between groups. Non-LYMPHA patients underwent complete mastectomy more frequently than LYMPHA patients (97.8% versus 77.8%; P = 0.007), but had a similar number of nodes removed during ALND (14.4 versus 15.8; P = 0.32). Median follow-up time was greater than 4 years for both LYMPHA and non-LYMPHA groups (57.0 months versus 63.0 months; P = 0.07). Overall, lymphedema incidence was 31.1% in the LYMPHA group and 33.3% in the non-LYMPHA group (P > 0.99). No significant differences in lymphedema incidences were observed between the LYMPHA and non-LYMPHA groups for patients with obesity, patients who received radiation therapy, or patients with obesity who also received radiation therapy (P > 0.05 for all subgroups). CONCLUSIONS: The LYMPHA may not prevent lymphedema long-term in patients who undergo ALND. More long-term studies are needed to determine the true potential of the procedure. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Complications Associated with Contralateral Prophylactic Mastectomy: A Systematic Review and Meta-Analysis.

BACKGROUND: No meta-analysis has examined whether contralateral prophylactic mastectomy increases complication risk for unilateral breast cancer patients undergoing unilateral mastectomy. METHODS: Fifteen studies on complications of unilateral mastectomy plus contralateral prophylactic mastectomy met inclusion criteria. Meta-analyses compared complications of (1) diseased versus contralateral breasts in unilateral plus contralateral prophylactic mastectomy patients and (2) patients undergoing unilateral plus contralateral prophylactic mastectomy versus unilateral alone when grouped by reconstructive method. RESULTS: For all unilateral plus contralateral prophylactic mastectomy patients, the diseased breast was significantly more prone to complications versus the contralateral breast (relative risk, 1.24; p = 0.03). In studies that stratified by reconstructive method, the complication risk was significantly higher for unilateral plus contralateral prophylactic mastectomy versus unilateral mastectomy alone for patients with no reconstruction (relative risk, 2.03; p = 0.0003), prosthetic-based reconstruction (relative risk,1.42; p = 0.003), and autologous reconstruction (relative risk, 1.32; p = 0.005). The only prospective trial showed similar results, including for more severe complications. Smaller retrospective studies without stratification by reconstructive method showed similar complications for unilateral plus contralateral prophylactic mastectomy versus unilateral mastectomy alone (relative risk, 1.06; p = 0.70). These groups had similar incidences of complication-related delay in adjuvant therapy, as demonstrated by one study. CONCLUSIONS: After unilateral plus contralateral prophylactic mastectomy, diseased breasts are at higher risk for complications. Stronger evidence supports higher complication risk for unilateral plus contralateral prophylactic mastectomy than unilateral alone. More work is needed to determine the effect of complications on timing of adjuvant therapy.

Leadership Roles, Academic Appointments, and Scholarly Activity-Does a Fellowship after Plastic Surgery Training Make a Difference?

Background Fellowship training is becoming more popular in plastic surgery, with over half of residents pursuing advanced training. Here, we investigate how clinical and research fellowship training impacts career trajectory and scholastic achievement in academic plastic surgery. Methods Plastic surgery faculty members, from programs recognized by the American Council of Academic Plastic Surgeons, were identified using institutional Web sites. Data extracted included faculty demographics, training history, academic positions, and research productivity. Continuous and categorical variables were compared using t -tests and chi-square, respectively. Results In total, 949 faculty members were included, with 657 (69%) having completed fellowship training. Integrated program residents were more likely to complete a fellowship when compared with independent residents ( p < 0.0001). Fellowship trained faculty were more likely to have graduated from a higher ranked residency program, in terms of both overall and research reputation ( p = 0.005 and p = 0.016, respectively). When controlling for years in practice, there was no difference found in number of publications, Hirsch index (h-index), or National Institutes of Health funding between faculty between the two cohorts ( p > 0.05). In a subanalysis comparing hand, craniofacial, microsurgery, and research fellowships, those who completed a research fellowship had higher h-indices and were more likely to reach full professor status ( p < 0.001 and p = 0.001, respectively). Fellowship training had no effect on being promoted to Chief/Chair of departments ( p = 0.16). Conclusion Fellowship training is common among academic plastic surgeons. In this study, both clinical and research fellowships were associated with various aspects of academic success. However, fellowship training alone did not affect attainment of leadership positions.

Activin-A, Growth Differentiation Factor-11 and Transforming Growth Factor-ß as predictive biomarkers for platinum chemotherapy in advanced non-small cell lung cancer.

BACKGROUND: Despite advances in immunotherapy and targeted therapy, platinum-based chemotherapy remains crucial for many patients with advanced non-small cell lung cancer (NSCLC). Resistance to platinum chemotherapy is common, and predictive biomarkers are needed to tailor treatment to patients likely to respond. In vitro evidence implicates the transforming growth factor-ß (TGF-ß) superfamily ligands activin-A and growth differentiation factor 11 (GDF-11) in innate platinum resistance. We performed a validation study to assess their utility as predictive biomarkers of platinum chemotherapy response in advanced NSCLC. PATIENTS AND METHODS: Our study included 123 adult patients with advanced NSCLC without a driver mutation treated with platinum chemotherapy. 98 patients were from a retrospective cohort and 25 from a prospective cohort. We performed immunohistochemistry staining for Activin-A, GDF-11 and TGF-ß on tumour samples for each patient and analysed IHC expression with objective radiological response and overall survival. RESULTS: The overall median survival was 14.8 months. We performed statistical analysis around a cytoplasmic score of 8/18 for Activin-A and GDF-11 based on previously published work, and 110/30 for TGF-ß based on a calculated cutpoint for significance. No survival difference was detected between these groups for Activin-A (p=0.35), GDF-11 (p=0.57) or TGF-ß (p=0.34). There was no association between rates of progressive disease and high Activin-A expression (p=0.43), high GDF-11 expression (p=1.0) or high TGF-ß expression p=0.89). CONCLUSION: Within the confines of our study, Activin-A, GDF-11 and TGF-ß expression was not a predictor of objective radiological response to chemotherapy or overall survival.

Disparities in Research during Plastic Surgery Training: How Can We Level the Playing Field?

Background: Lack of female and ethnically underrepresented in medicine (UIM) surgeons remains concerning in academic plastic surgery. One barrier to inclusion may be unequal opportunity to publish research. This study evaluates the extent of this challenge for plastic surgery trainees and identifies potential solutions. Methods: Data were collected on academic plastic surgeons' research productivity during training. Bivariate analysis compared publication measures between genders and race/ethnicities at different training stages (pre-residency/residency/clinical fellowship). Multivariate analysis determined training experiences independently associated with increased research productivity. Results: Overall, women had fewer total publications than men during training (8.89 versus 12.46, P = 0.0394). Total publications were similar between genders before and during residency (P > 0.05 for both) but lower for women during fellowship (1.32 versus 2.48, P = 0.0042). Women had a similar number of first-author publications during training (3.97 versus 5.24, P = 0.1030) but fewer middle-author publications (4.70 versus 6.81, P = 0.0405). UIM and non-UIM individuals had similar productivity at all training stages and authorship positions (P > 0.05 for all). Research fellowship completion was associated with increased total, first-, and middle-author training publications (P < 0.001 for all). Conclusions: Less research productivity for female plastic surgery trainees may reflect a disparity in opportunity to publish. Fewer middle-author publications could indicate challenges with network-building in a predominately male field. Despite comparable research productivity during training relative to non- UIM individuals, UIM individuals remain underrepresented in academic plastic surgery. Creating research fellowships for targeting underrepresented groups could help overcome these challenges.

Closing the Gap: Training Experiences and Career Outcomes for Underrepresented Minorities in Plastic Surgery.

Background: The present study assesses training characteristics, scholastic achievements, and traditional career accomplishments of ethnically underrepresented in medicine (UIM) plastic and reconstructive surgery (PRS) faculty relative to non-UIM PRS faculty. Method: A cross-sectional analysis of core PRS faculty appointed to accredited United States residency training programs (n = 99) was performed. Results: Of the 949 US PRS faculty, a total of 51 (5.4%) were identified as UIM. Compared with non-UIM faculty, there were few differences when evaluating medical education, residency training, pursuit of advanced degrees, and attainment of subspecialty fellowship training. UIM faculty were more likely than non-UIM faculty to have graduated from a medical school outside the United States (25% versus 13%, P = 0.014). In addition, UIM faculty did not differ from non-UIM counterparts in traditional career accomplishments, including promotion to full professor, obtaining NIH funding, serving as program director, receiving an endowed professorship, appointment to a peer-reviewed editorial board, scholarly contributions (H-index and number of publications), and appointment to chief/chair of their division/department. Conclusions: The historical lack of ethnic diversity that comprise US academic PRS faculty persists. This study reveals that those UIM faculty who are able to obtain faculty appointments are equally successful in achieving scholastic success and traditional career accomplishments as their non-UIM counterparts. As we strive toward increasing representation of UIM physicians in academic plastic surgery, the field will benefit from efforts that promote a pipeline for underrepresented groups who traditionally face barriers to entry.

Identifying US Plastic Surgery Training Programs that Effectively Establish Gender and Ethnically Diverse Faculty.

Background: Successful strategies to improve the representation of female and ethnically underrepresented in medicine (UIM) physicians among US plastic and reconstructive surgery (PRS) faculty have not been adequately explored. Accordingly, we aimed to identify programs that have had success, and in parallel gather PRS program directors' and chiefs/chairs' perspectives on diversity recruitment intentionality and strategies. Methods: We conducted a cross-sectional analysis of the demographic composition of female and UIM faculty of PRS residency training programs. Separate lists of programs in the top quartile for female and UIM faculty representation were collated. Additionally, a 14-question survey was administered to program directors and chiefs/chairs of all 99 Accreditation Council for Graduate Medical Education-accredited PRS residency programs. The questions comprised three domains: (1) demographic information; (2) perceptions about diversity; and (3) recruitment strategies utilized to diversify faculty. Results: Female and UIM faculty representation ranged from 0% to 63% and 0% to 50%, respectively. Survey responses were received from program directors and chiefs/chairs of 55 institutions (55% response rate). Twenty-five (43%) respondents felt their program was diverse. Fifty-one (80%) respondents felt diversity was important to the composition of PRS faculty. Active recruitment of diverse faculty and the implementation of a diversity, equity, and inclusion committee were among the most frequently cited strategies to establish a culturally sensitive and inclusive environment. Conclusions: These findings reveal that female and UIM representation among US PRS faculty remains insufficient; however, some programs have had success through deliberate and intentional implementation of diversity, equity, and inclusion strategies.

c-MET/VEGFR-2 co-localisation impacts on survival following bevacizumab therapy in epithelial ovarian cancer: an exploratory biomarker study of the phase 3 ICON7 trial.

INTRODUCTION: Bevacizumab improves survival outcomes in women diagnosed with epithelial ovarian cancer (EOC). Pre-clinical data showed that the c-MET/VEGFR-2 heterocomplex negates VEGF inhibition through activation of c-MET signalling, leading to a more invasive and metastatic phenotype. We evaluated the clinical significance of c-MET and VEGFR-2 co-localisation and its association with VEGF pathway-related single nucleotide polymorphisms (SNPs) in women participating in the phase 3 trial, ICON7 (ClinicalTrials.gov identifier: NCT00262847). MATERIALS AND METHODS: Patients had FIGO stage I-IIA grade 3/poorly differentiated or clear cell carcinoma or stage IIB-IV epithelial ovarian, primary peritoneal or fallopian tube cancer. Immunofluorescence staining for co-localised c-MET and VEGFR-2 on tissue microarrays and genotyping of germline DNA from peripheral blood leukocytes for VEGFA and VEGFR-2 SNPs was performed. The significance of these biomarkers was assessed against survival. RESULTS: Tissue microarrays from 178 women underwent immunofluorescence staining. Multivariable analysis showed that greater c-MET/VEGFR-2 co-localisation predicted worse OS in patients treated with bevacizumab after adjusting for FIGO stage and debulking surgery outcome (hazard ratio [HR] 1.034, 95% confidence interval [95%CI] 1.010-1.059). Women in the c-MET/VEGFR-2HIGH group treated with bevacizumab demonstrated significantly reduced OS (39.3 versus > 60 months; HR 2.00, 95%CI 1.08-3.72). Germline DNA from 449 women underwent genotyping. In the bevacizumab group, those women with the VEGFR-2 rs2305945 G/G variant had a trend towards shorter PFS compared with G/T or T/T variants (18.3 versus 23.0 months; HR 0.74, 95%CI 0.53-1.03). CONCLUSIONS: In bevacizumab-treated women diagnosed with EOC, high c-MET/VEGFR-2 co-localisation on tumour tissue and the VEGFR-2 rs2305945 G/G variant, which may be biologically related, were associated with worse survival outcomes.

Neuronal subtype-specific growth cone and soma purification from mammalian CNS via fractionation and fluorescent sorting for subcellular analyses and spatial mapping of local transcriptomes and proteomes.

During neuronal development, growth cones (GCs) of projection neurons navigate complex extracellular environments to reach distant targets, thereby generating extraordinarily complex circuitry. These dynamic structures located at the tips of axonal projections respond to substrate-bound as well as diffusible guidance cues in a neuronal subtype- and stage-specific manner to construct highly specific and functional circuitry. In vitro studies of the past decade indicate that subcellular localization of specific molecular machinery in GCs underlies the precise navigational control that occurs during circuit 'wiring'. Our laboratory has recently developed integrated experimental and analytical approaches enabling high-depth, quantitative proteomic and transcriptomic investigation of subtype- and stage-specific GC molecular machinery directly from the rodent central nervous system (CNS) in vivo. By using these approaches, a pure population of GCs and paired somata can be isolated from any neuronal subtype of the CNS that can be fluorescently labeled. GCs are dissociated from parent axons using fluid shear forces, and a bulk GC fraction is isolated by buoyancy ultracentrifugation. Subtype-specific GCs and somata are purified by recently developed fluorescent small particle sorting and established FACS of neurons and are suitable for downstream analyses of proteins and RNAs, including small RNAs. The isolation of subtype-specific GCs and parent somata takes ~3 h, plus sorting time, and ~1-2 h for subsequent extraction of molecular contents. RNA library preparation and sequencing can take several days to weeks, depending on the turnaround time of the core facility involved.

Patients and Procedures of Facial Gender Confirmation Surgery: A NSQIP Study.

ABSTRACT: Various recent developments, including legislation in 2014 banning healthcare discrimination against gender minorities, have contributed to expanding insurance coverage for gender-affirming care, which includes facial gender confirmation surgery (FGCS). Increasing evidence suggests FGCS improves quality-of-life outcomes, but literature evaluating FGCS patient demographics, surgical risk factors, procedures, and complications is limited. Therefore, the authors conducted a study of a national surgical database from 2005 to 2019 attempting to fill in these literature gaps. Statistics were used to assess temporal trends after 2014. A total of 203 FGCS cases were identified, with the earliest occurring in 2013. Case volume increased annually from 2015-2019. The average patient age was 34.0 years and racial demographics largely mirrored national estimates for the transgender/non-binary population. Obesity (20.7%) and hypertension (3.9%) were the only patient co-morbidities, although a relatively high proportion were underweight (5.4%). The majority of cases were outpatient procedures (66.5%) conducted by either plastic surgery (38.9%) or otolaryngology (61.1%). Comparing FGCSs by anatomic site, the proportion of tracheal procedures decreased between 2015-17 and 2018-19 (25.6% vs. 10.7%, P = 0.0002) whereas the proportion of brow/forehead reconstructions increased (32.6% versus 63.1%, P = 0.0005). These changes coincided with an increase in mean operative time (168.6 minutes versus 260.0, P = 0.0002). Complications were rare (3.9%), and the most common was surgical site infection (3.4%), a previously unreported outcome in the FGCS literature. Overall, FGCS patients are mostly young healthy individuals from diverse racial/ethnic backgrounds, and they have few surgical complications. The increasing volume and complexity of FGCSs may be a result of expanding insurance coverage for previously unaffordable procedures.