Optimizing Lower Extremity Local Flap Reconstruction in Peripheral Vascular Disease.

BACKGROUND: Local flaps remain a valuable reconstructive tool as a means for limb salvage for patients with advanced arterial disease. Our single-center, retrospective cohort study aims to compare the outcomes of different patterns of blood flow affected by vascular disease to pedicles in local flap reconstruction of the foot and ankle. METHODS: A retrospective review of 92 patients and 103 flaps was performed. On angiograms, pattern of blood flow to the flap pedicle was determined to be direct inline flow (DF) or indirect flow (IF). Patterns of IF were either by arterial-arterial connections (AC) or unnamed randomized collaterals (RC). Primary outcomes were immediate flap success and limb salvage. Comparative analyses were performed using the χ2 and Fisher tests for categorical variables. RESULTS: Among all flaps, 73.8% (n = 76/103) had DF and 26.2% (n = 27/103) had IF. Both groups experienced similar rates of immediate flap success (DF = 97.3% vs IF = 92.6%, P = 0.281) and limb salvage (DF = 75.% vs IF = 66.7%, P = 0.403). However, the rate of contralateral amputation was significantly higher in the IF group (26.9% vs 5.3%, P = 0.006). When comparing the 3 distinct patterns of blood flow (DF vs AC vs RC), pedicled flaps were more commonly supplied by DF and AC, while random pattern flaps were more commonly supplied by RC (P = 0.042). CONCLUSIONS: Alternative routes of revascularization can maintain local flap viability and achieve similar rates of limb salvage but risks contralateral amputation. We found that pedicled and local muscle flaps require inline blood flow or blood supply by ACs. Meanwhile, random pattern flap can be supported by random collaterals.

A Comparative Analysis of Patient-Reported Outcomes Following Free Tissue Transfer, Partial Foot Amputation, and Below-Knee Amputation in High-Risk Limb Salvage Patients.

BACKGROUND: The surgical decision for limb-salvage with free tissue transfer (FTT), partial foot amputation (PFA), or below-knee amputation (BKA) for complex lower extremity (LE) wounds hinges on several factors, including patient choice and baseline function. However, patient-reported outcome measures (PROMs) on LE function, pain, and QoL for chronic LE wound interventions are limited. Thus, the study aim was to compare PROMs in patients who underwent FTT, PFA, or BKA for chronic LE wounds. METHODS: PROMs were collected via QR code for all adult chronic LE wound patients who presented to a tertiary wound center between June 2022 and June 2023. A cross-sectional analysis of patients who underwent FTT, PFA, or BKA was conducted. The 12-Item Short Survey (SF-12), PROM Information System Pain Intensity (PROMIS-3a), and Lower Extremity Functional Scale (LEFS) were completed at 1, 3, and 6 months and 1, 3, and 5 years postoperatively. Patient demographics, comorbidities, preoperative characteristics, and amputation details were collected. RESULTS: Of 200 survey sets, 71 (35.5%) underwent FTT, 51 (25.5%) underwent PFA, and 78 (39.0%) underwent BKA. Median postoperative time points of survey completion between FTT (6.2 months, IQR: 23.1), PFA (6.8 months, IQR: 15.5), and BKA (11.1 months, IQR: 21.3) patients were comparable (P = 0.8672). Most patients were male (n = 92, 76.0%) with an average age and body mass index (BMI) of 61.8 ± 12.6 years and 30.3 ± 7.0 kg/m2, respectively. Comorbidities for FTT, PFA, and BKA patients included diabetes mellitus (DM; 60.6% vs 84.2% vs 69.2%; P = 0.165), peripheral vascular disease (PVD; 48.5% vs 47.4% vs 42.3%; P = 0.790), and chronic kidney disease (CKD; 12.1% vs 42.1% vs 30.8%; P = 0.084). No significant differences were observed between FTT, PFA, and BKA patients in mean overall PROMIS-3a T-scores (49.6 ± 14.8 vs 54.2 ± 11.8 vs 49.6 ± 13.7; P = 0.098), LEFS scores (37.5 ± 18.0 vs 34.6 ± 18.3 vs 38.5 ± 19.4; P = 0.457), or SF-12 scores (29.6 ± 4.1 vs 29.5 ± 2.9 vs 29.0 ± 4.0; P = 0.298). CONCLUSION: Patients receiving FTT, PFA, or BKA for chronic LE wounds achieve comparable levels of LE function, pain, and QoL postoperatively. Patient-centered functionally based surgical management for chronic LE wounds using interdisciplinary care, preoperative medical optimization, and proper patient selection optimizes postoperative PROMs.

A comparative analysis of peritoneal flap and intestinal vaginoplasty for management of vaginal stenosis.

BACKGROUND: In transgender or non-binary patients (TGNB) with failed penile inversion vaginoplasty (PIV), peritoneal flap vaginoplasty (PFV) and intestinal segment vaginoplasty (ISV) facilitate restoration of neovaginal depth and sexual function. This study compared the outcomes of revision PFV and ISV in TGNB patients with failed PIV. METHODS: TGNB patients who underwent secondary PFV or ISV from December 2018 to April 2023 were reviewed. RESULTS: Twenty-one (5.8%) patients underwent secondary PFV and 24 (6.6%) underwent secondary ISV, due to vaginal stenosis (n = 45, 100.0%). Mean duration to first successful dilation and average vaginal depth were comparable between the groups. Seven (33.3%) PFV patients experienced short-term complications, including introital dehiscence (n = 2, 9.5%), vaginal stenosis (n = 2, 9.5%), vaginal bleeding (n = 2, 9.5%), and reoperation (n = 2, 9.5%). Nine (42.9%) experienced long-term complications, including urethrovaginal fistula formation (n = 2, 9.5%), hypergranulation (n = 2, 9.5%), vaginal stenosis (n = 7, 33.3%), and reoperation (n = 6, 28.6%). Ten (41.7%) ISV patients experienced short-term complications, including dehiscence (n = 4, 19.0%), ileus (n = 2, 8.3%), introital stenosis (n = 2, 9.5%), and reoperation due to vaginal bleeding (n = 2, 8.3%). Six (25.0%) experienced long-term complications, including introital stenosis (n = 3, 12.5%), mucosal prolapse (n = 2, 8.3%), and reoperation due to mucosal prolapse (n = 4, 16.7%). Secondary PFV had a higher rate of vaginal stenosis (p = 0.003). There were no cases of partial or full-thickness flap necrosis. CONCLUSION: Revision PFV and ISV represent viable techniques for addressing vaginal stenosis secondary to PIV. Although PFV and ISV had comparable rates of short-term complications, ISV demonstrated a lower incidence of recurrent vaginal stenosis, which may inform operative decision-making.

Deep and Superficial Debridement Techniques in Lower Extremity Split-thickness Skin Grafting.

Background: Patients with nonhealing lower extremity (LE) wounds often require a split-thickness skin graft (STSG) for closure. Nonviable tissue must be debrided before STSG inset. Our study aimed to compare differences in debridement depth on STSG outcomes. Methods: Chronic, atraumatic LE wounds receiving STSG from December 2014 to December 2022 at a single institution were reviewed. Demographics, wound characteristics, operative details, and outcomes were collected. Superficially debrided wounds were compared with wounds receiving deep debridement (DD), defined by debriding to the level of white tissue underlying the granulation tissue. Subanalysis was performed on wounds that had a negative and positive postdebridement culture. Primary outcome was graft failure. Results: Overall, 244 wounds in 168 patients were identified. In total, 158 (64.8%) wounds were superficially debrided and 86 (35.3%) received DD. The cohort had a median Charlson Comorbidity Index of 4 [interquartile range (IQR): 3]. Diabetes (56.6%) and peripheral artery disease (36.9%) were prevalent. The only statically significant demographic difference between groups was congestive heart failure (SD: 14.9% versus DD: 3.0%, P = 0.017). Wound size, depth, and all microbiology results were similar between groups. Postoperatively, the DD group demonstrated significantly less graft failure (10.5% versus 22.2%, P = 0.023). In a multivariate regression, DD was independently associated with lower odds of graft failure (OR: 0.0; CI, 0.0-0.8; P = 0.034). Sub-analysis of graft failure supported this finding in culture-positive wounds (DD: 7.6% versus DD: 22.1%, P = 0.018) but not in culture-negative wounds (13.6% versus 22.2%, P = 0.507). Conclusions: The DD technique demonstrates improved outcomes in chronic, culture-positive LE wounds receiving STSG.

Understanding delays to parathyroidectomy: A mixed-methods approach.

BACKGROUND: Patients from ethnic and racial minority groups with primary hyperparathyroidism may have greater time delays to curative parathyroidectomy. Contributing factors are unclear. METHODS: This was a sequential mixed-methods study. The quantitative phase was a retrospective chart review of adults with primary hyperparathyroidism who underwent parathyroidectomy between 2015 and 2020, collecting demographic and clinical data. Social vulnerability of the patients' residential area, measured with the Social Vulnerability Index, and relevant clinical time intervals were calculated. A multivariable analysis of factors associated with greater time intervals was performed. The qualitative phase involved semistructured interviews with endocrinologists, analyzed inductively for themes. RESULTS: On chart review of 1,083 patients, the median age was determined to be 61 years and 856 (79%) were female. Six hundred twenty-eight (57.9%) were non-Hispanic White and 456 (42.1%) were Hispanic ethnicity or Asian, Pacific Islander, Black, Native American, Other or Unknown race. Patients of Hispanic ethnicity, or Asian or Pacific Islander, Black, Native American, Other or Unknown race were more likely than non-Hispanic White patients to live in the most socially vulnerable areas (19.3% vs 5.9%, P < .01) and had greater time intervals than non-Hispanic White patients between index hypercalcemia and first parathyroid hormone level, surgical referral, or parathyroidectomy (all P < .05). On multivariable analysis, age (coefficient 7.9, 95% CI 2.8-13.0) and living in the most socially vulnerable areas (coefficient 297.9, 95% CI 87-508.7) were associated with greater days between index hypercalcemia and parathyroidectomy. In the study's qualitative phase, identified themes for reasons for care delays included socioeconomic, nonsocioeconomic patient, and nonsocioeconomic nonpatient factors. CONCLUSION: Care delays are driven by a combination of socioeconomic and nonsocioeconomic factors.

Optimizing the Use of Pedicled versus Random Pattern Local Flaps in the Foot and Ankle.

Background: The aim of this study was to compare the use of pedicled local (PFs) versus random pattern flaps (RpFs) in foot and ankle reconstruction in patients with chronic, nonhealing wounds. Methods: A single-center, retrospective review of 204 patients with 118 PFs and 86 RpFs was performed. The primary outcome included rates of limb salvage. Results: PFs were used more often in the hindfoot (44.1% versus 30.2%, P = 0.045), lateral and medial surface (39.8% versus 18.6%, P = 0.001), and wounds containing exposed bone and hardware (78.8% versus 62.8%, P = 0.018). RpFs were used more for forefoot (19.8% versus 10.2%, P = 0.053) and plantar defects (58.1% versus 30.3%, P = 0.000). RpFs had a higher rate of immediate success (100% versus 95.8%, P = 0.053), with no significant differences in rate of long-term limb salvage (77.1% versus 69.8%, P = 0.237). PFs had higher rates of ischemia requiring intervention (11.0% versus 3.5%, P = 0.048). RpFs had a higher rate of minor amputations (15.12% versus 6.8%, P = 0.053) but similar rates of major amputation (15.1% versus 16.1%, P = 0.848). There were no significant differences in rates of mortality or ambulatory status. Conclusions: Both RpFs and PFs remain reliable options to reconstruct defects of the foot and ankle. Optimizing the use of each flap type should consider wound characteristics. RpFs are preferred for dorsal and plantar defects, whereas PFs are protective for minor infections and preferred for deeper wounds despite a higher rate of partial necrosis.

The robotic-assisted free jejunal flap for neovaginal canal creation in gender-affirming vaginoplasties.

INTRODUCTION: One of the biggest challenges with gender-affirming vaginoplasty was the creation of a long-lasting, durable, patent, and self-lubricating neovaginal canal that allowed for spontaneous, pain-free sexual intercourse. The jejunum was a durable, physiologic, and intestinal option to create the neovaginal canal that minimizes the adverse effects of skin graft, peritoneal, and colonic vaginoplasties. Free jejunal vaginoplasties had been performed in cis females for congenital genitourinary anomalies like Mullerian agenesis or after gynecologic-oncologic surgery but had yet to be reported for gender-affirming vaginoplasties. The purpose of this report was to present a technique for a physiologic, intestinal, gender-affirming vaginoplasty without the disadvantages of colonic vaginoplasties. PATIENTS AND METHODS: This report presented six patients, all natal males who identified as female, undergoing robotic-assisted free jejunal flap gender-affirming vaginoplasty. Mean age was 35.8 years (range: 21-66). Mean body mass index was 33.2 kg/m2 (range: 28.0-41.0). The proximal aspect of the neovaginal canal was created intra-abdominally by elevating peritoneal flaps from the posterior bladder wall to be reflected downward into the external neovaginal canal. The jejunal flap was harvested. The greater saphenous vein was harvested to create an arteriovenous loop between the flap vessels and the recipient femoral artery in an end-to-side fashion and a branch of the femoral vein. The jejunal flap was passed intra-abdominally through the groin incision and then trans-peritoneally into the neovaginal canal. The jejunal segment was inset to the proximal peritoneal flaps and the distal inverted penoscrotal skin of the neovaginal introitus. RESULTS: Mean length of the harvest jejunal segment was 19.2 cm (range: 15-20). Mean time to ambulation, foley removal, and first vaginal dilation were 3.3 (range: 3-4), 4.0 (range: 3-5), and 4.5 days (range: 4-6), respectively. By a mean follow-up duration of 8.0 months (range: 1-14), mean vaginal depth and diameter were 7.0 and 1.3 cm (range: 1.0-1.5), respectively. Two (33.3%) patients experienced postoperative complications, including groin hematoma (n = 1, 16.7%) and reoperation for correction of dehiscence of the jejunal flap to the vaginal introitus (n = 1, 16.7%). CONCLUSION: Gender-affirming surgeons should consider a free vascularized segment of jejunum as an option to line the neovaginal canal in the correct patients.

Indocyanine Green Angiography for Detecting Quantitative Perfusion Changes in Deep Inferior Epigastric Perforator Flap Breast Reconstruction With Second Venous Drainage.

BACKGROUND: This study aims to compare perfusion dynamics using indocyanine green videoangiography before and after the creation of a second venous anastomosis between the superficial inferior epigastric vein and the retrograde internal mammary vein (IMV) in deep inferior epigastric perforator (DIEP) flap breast reconstructions. METHODS: Indocyanine green videoangiography performed during DIEP flap reconstructions was analyzed prospectively. The areas of interest were above the perforators with the highest intensity (complete perfusion), the most distal lateral edge of the flap (partial perfusion), and the next lowest intensity (ischemic). We compared the zone intensities before and after the second venous anastomosis, assessing venous drainage patency and functionality. Patient characteristics, operative details, and complications were collected. RESULTS: Seven patients (10 breasts) underwent DIEP reconstruction. Mean age was 54.5 ± 12.4 years. Mean operative duration was 575.5 ± 172.6 minutes. Donors included DIEV (n = 10, 100.0%), superficial inferior epigastric vein (n = 9, 90.0%), and superficial circumflex epigastric vein (n = 1, 10.0%). All DIEVs were anastomosed to the antegrade IMV (n = 10, 100.0%). Superficial inferior epigastric veins were anastomosed to the retrograde IMV (n = 10, 100.0%). Mean peak intensities of the complete perfusion zone before and after the second venous anastomosis were 160.7 ± 42.1 and 188 ± 42.1, respectively ( P = 0.163). Mean peak intensities of the partial perfusion zone were 100.8 ± 21.5 and 152 ± 31.5, respectively ( P < 0.001). Mean peak intensities of the ischemic zone were 90.4 ± 37.4 and 143.4 ± 45.3, respectively ( P = 0.012). CONCLUSION: These findings highlight the potential benefits of the super drainage technique in enhancing perfusion and reducing complications, emphasizing the need for further investigation and consideration of this technique in clinical practice.

Perioperative Patient-Initiated Communication in Gender-Affirming Mastectomy.

Background: Gender-affirming mastectomy (GAM) improves the psychosocial functioning and quality of life of transgender and non-binary (TGNB) individuals. However, the perioperative period is often marked by emotional stress, concerns about surgical outcomes, and physical discomfort. While inpatient procedures provide multiple opportunities to engage with and educate patients, outpatient surgeries, such as GAM, pose a unique challenge as patients are followed for <24 h postoperatively. Given the heightened emotional and psychological distress related to gender dysphoria TGNB individuals often experience, addressing these gaps can significantly improve outcomes. This study aims to characterize patient and surgical characteristics associated with patient-initiated communication (PIC) frequency in this population. Methods: A single-center retrospective review of TGNB patients undergoing GAM from February 2018 to November 2022 was conducted. Demographics, surgical characteristics, and frequency of and reasons for perioperative PIC (30 days before and after surgery) were recorded. The primary outcome was the incidence of perioperative PIC. The secondary outcomes included (1) the rationale for PIC and (2) patient and surgical characteristics associated with PIC. Results: A total of 352 patients were included. Of these, 285 (74.6%) initiated communication in the perioperative period, totaling 659 PICs. The median age was 25.0 (interquartile range [IQR]: 9.0) years. The median body mass index (BMI) was 28.5 (IQR: 8.5) kg/m2. The mean number of PICs was 0.7 ± 1.3 preoperatively and 1.3 ± 1.7 postoperatively (p < 0.001). The most frequent preoperative PIC subjects were administrative issues (AI; n = 66, 30.7%), preoperative requirements (n = 43, 20.0%), and cost and insurance (n = 33, 15.0%). The most frequent postoperative PIC subjects were wound care (n = 77, 17.3%), AI (n = 70, 15.0%), activity restrictions (n = 60, 13.5%), drainage (n = 56, 12.6%), and swelling (n = 37, 8.3%). Collectively, older patients (ß = 0.234, p = 0.001), those with a history of major depressive disorder or generalized anxiety disorder (2.4 ± 3.0 vs. 1.7 ± 1.9; p = 0.019), and those without postoperative drains (n = 16/17, 94.1% vs. n = 236/334, 70.7%; p = 0.025) engaged in higher levels of PIC. There were no significant associations between other patient characteristics, perioperative details, or complications and PIC frequency. Conclusions: Perioperative PIC is prevalent among the majority of GAM patients at our institution, with age, psychiatric diagnosis, and postoperative drain use identified as significant predictors. To mitigate PIC frequency, it is crucial to ensure adequate support staffing and provide comprehensive postoperative instructions, particularly concerning activity restrictions and drainage management. These interventions may reduce PICs in high-volume centers. Further research should investigate targeted interventions to further support TGNB patients during the perioperative period.

Factors influencing intraoperative conversion from double- to single-incision mastectomy with free nipple grafts in 352 transgender and non-binary patients.

BACKGROUND: Double-incision mastectomy (DIM) with free nipple grafts (FNG) is a common technique employed in gender-affirming mastectomy (GAM), but is associated with a high scar burden. Intraoperatively, the surgeon may opt for a single-incision mastectomy (SIM) along the inframammary folds (IMF) to optimize aesthetic outcomes. This study sought to identify factors predictive of intraoperative conversion. METHODS: From February 2018 to November 2022, TGNB patients who underwent GAM at a single institution were retrospectively reviewed. Data regarding patient characteristics, perioperative details, postoperative complications, and aesthetic satisfaction were collected. RESULTS: A total of 352 patients were identified. Median age and body mass index (BMI) were 25.0 years (IQR: 9.0) and 28.5 kg/m2 (IQR: 8.5), respectively. Most patients received IMF incisions (n = 331, 94.0%); of whom, 66 (19.9%) underwent intraoperative conversion from DIM to SIM with FNG. Larger breast cup-size (p < 0.001) and a greater degree of ptosis (p = 0.002) preoperatively were significantly associated with intraoperative conversion to SIM. There was no significant association between intraoperative conversion and the ratio of intermammary distance to the width of the chest wall (p = 0.086). Overall complication rates were significantly higher among patients with diabetes mellitus (p = 0.015) and a greater degree of ptosis (p = 0.018). 77.8% (n = 274) of patients were satisfied with their aesthetic outcome. NPWT usage was associated with higher rates of aesthetic satisfaction (83.6% vs. 77.8%; p = 0.005). CONCLUSION: Patients with larger breast cup size and greater degree of ptosis should be counseled preoperatively that they may be at a higher risk of conversion to a singular incision.

Positive Bacterial Cultures on Spinal Wound Closure Do Not Predict Postoperative Outcomes.

BACKGROUND: Complex surgical back wounds represent significant morbidity in patients who have undergone spinal procedures requiring closure or revision by plastic surgeons. This study aimed to assess the utility of bacterial wound culture data for predicting surgical outcomes of wound management. METHODS: This study is a single-institution retrospective review of consecutive patients who required plastic surgery intervention for wound infection following spinal procedures between the years 2010 and 2021 (n = 70). Statistical analysis was performed for demographics, comorbidities, perioperative laboratory studies, and treatment methods. The primary outcomes of interest were rate of postoperative complications after soft tissue reconstruction and reconstructive failure. The secondary outcome of interest was time to healing in number of days. RESULTS: The overall complication rate after wound closure was 31.4%, with wound infection in 12.9%, seroma in 10%, dehiscence in 12.9%, and hematoma in 1.4%. Increasing number of debridements before wound closure increased the likelihood of a surgical complication of any kind (odds ratio [OR], 1.772; 95% confidence interval [CI], 1.045-3.002). Positive wound cultures before reconstruction were associated with development of seroma only (OR, 0.265; 95% CI, 0.078-0.893). Use of incisional vacuum-assisted closure devices significantly decreased the odds of postoperative wound dehiscence (OR, 0.179; 95% CI, 0.034-0.904) and increased odds of healing (hazard ratio, 3.638; 95% CI, 1.547-8.613). CONCLUSIONS: Positive wound cultures were not significantly associated with negative outcomes after complex closure or reconstruction of infected spinal surgical wounds. This finding emphasizes the importance of clinical judgment with a multidisciplinary approach to complex surgical back wounds over culture data for wound closure timing.

Surgical techniques and outcomes of thyroid chondroplasty in transfeminine individuals: A systematic review.

Thyroid chondroplasty (TC) in facial gender-affirming surgery (FGAS) is aimed at modifying the thyroid cartilage to achieve a more feminine laryngeal appearance. This study evaluated open versus endoscopic techniques to TC and associated outcomes and complications. A systematic review (SR) of articles pertaining to TC was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Twelve articles representing 368 patients were included for analysis. Nine articles described open approaches, and three articles described endoscopic techniques. The rate of total complications was 4.3% (n = 12) in the open approach compared to 15% (n = 13) in the endoscopic approach. Positive esthetic results were reported in 92% of cases performed with the open approach and 90% with the endoscopic approach. In the open approach, seven (2.5%) patients requested additional removal of cartilage, and three (1.1%) requested scar revision. In the endoscopic approach, three (3.7%) patients requested additional cartilage removal. In addition, data of individuals who underwent "cervical tracheoplasty" for gender dysphoria from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was reviewed, and there was no incidence of wound or major complications among patients who underwent tracheoplasty alone. Although the advantage of the endoscopic approach is a scarless neck incision, the rate of complications is higher with the open approach. Endoscopic approaches are still not widely used, and continued investigations are warranted to improve familiarity with this approach and reduce postoperative complications.

Muscle versus Fascia Free Tissue Transfer for Treatment of Chronic Osteomyelitis in the Comorbid Population.

BACKGROUND: In patients with chronic lower extremity (LE) wounds, chronic osteomyelitis confers additional complexity to achieving adequate treatment. Previous reviews demonstrate increased rates of osteomyelitis recurrence in patients who receive muscle flaps compared with fasciocutaneous flaps for LE limb salvage; however, these studies were not limited to atraumatic populations who receive exclusively free flaps. Thus, this study compared rates of recurrence in chronic osteomyelitis patients undergoing LE reconstruction with fasciocutaneous versus muscle free flaps. METHODS: Patients undergoing free tissue transfer (FTT) between July 2011 and July 2021 were retrospectively reviewed. Patients were stratified into fasciocutaneous and muscle free flap groups. Primary outcomes included osteomyelitis recurrence, flap complications, limb salvage, and ambulatory status. RESULTS: Forty-eight patients with pathologic diagnosis of chronic osteomyelitis of the wound bed were identified, of which 58.3% received fasciocutaneous (n = 28) and 41.7% received muscle flaps (n = 20). The most common comorbidities included diabetes mellitus (n = 29, 60.4%), peripheral neuropathy (n = 27, 56.3%) and peripheral vascular disease (n = 24, 50.0%). Methicillin-resistant or methicillin -sensitive Staphylococcus aureus were the most common pathogen in 18.7% (n = 9) of procedures. The majority of patients underwent a median of three debridements followed by negative pressure wound therapy prior to receiving FTT. At a median follow-up of 16.6 months, the limb salvage and ambulatory rates were 79.2 (n = 38) and 83.3% (n = 40), respectively. The overall rate of microsurgical flap success was 93.8% (n = 45). Osteomyelitis recurred in 25% of patients (n = 12) at a median duration of 4.0 months. There were no significant differences in rates of osteomyelitis recurrence, flap complications, limb salvage, ambulation, and mortality. On multivariate analysis, flap composition remained a nonsignificant predictor of osteomyelitis recurrence (odds ratio: 0.975, p = 0.973). CONCLUSION: This study demonstrates that flap composition may not influence recurrence of osteomyelitis following free flap reconstruction of chronic LE wounds, suggesting that optimal flap selection should be based on wound characteristics and patient goals.

Neurological Complications and Clinical Outcomes of Infective Endocarditis.

OBJECTIVES: The aim of this study is to explore the clinical features associated with neurological complications of infective endocarditis (IE) and to assess the impact of neurological complications on clinical outcomes. MATERIALS AND METHODS: The frequency of relevant clinical features was compared in a case series of IE patients with and without neurological complications admitted to a single health care system from 2015 to 2019. Variables with significant differences (p ≤ 0.05) in baseline characteristics in univariate logistic regression models were entered into multivariable models along with age to determine associations with neurological complications, unfavorable discharge outcomes (modified Rankin score ≥ 3), and in-hospital mortality. RESULTS: 260 patients with a mean age of 51 (±18) years and 103 (40%) females were included. Neurological complications occurred in 165 (63%) patients, with the most common being septic emboli (66 patients, 25%). In the regression analyses, antiplatelet usage (aOR 1.87, 95% CI [1.05-3.32]) and mitral valve vegetations (aOR 2.66, 95% CI [1.22-5.79]) were independently associated with neurological complications. Territorial infarction (aOR 4.13, 95% CI [1.89-9.06]) and encephalopathy (aOR 3.95, 95% CI [1.19-13.05]) were associated with an increased risk of unfavorable outcome, while cardiac surgery was associated with a lower risk of both unfavorable outcome (aOR 0.40, 95% CI [0.22-0.71]) and in-hospital mortality (aOR 0.18, 95% CI [0.09-0.35]). CONCLUSIONS: Neurological complications are common in IE patients and are associated with mitral valve endocarditis and antiplatelet usage. Of the neurological complications, territorial infarcts and encephalopathy are associated with unfavorable discharge outcomes.

Phase II study of enzalutamide in androgen receptor positive, recurrent, high- and low-grade serous ovarian cancer.

OBJECTIVES: We sought to determine the safety and efficacy of the oral androgen receptor antagonist enzalutamide in patients with previously treated, recurrent, AR-positive (AR+) ovarian cancer. METHODS: This was a single-institution phase II study of patients with AR+ ovarian cancer with measurable disease with 1-3 prior lines of chemotherapy; patients were screened for enrollment from 11/2013-7/2018. Following consent, archival tissue was evaluated for AR+. Enrolled patients received daily enzalutamide 160 mg until progression of disease or treatment discontinuation. Adverse events were graded by CTCAE v4.0. Co-primary endpoints were 6-month progression-free survival (PFS6) and overall response rate (ORR) by RECIST 1.1 criteria. RESULTS: During the study period, 160 patients were screened and 59 (45 high-grade serous [HGS] and 14 low-grade serous [LGS]) consented to treatment on study. There was 1 confirmed and 1 unconfirmed partial response. The ORR was 1.7% (90% CI: 0.2-100%). The overall PFS6 rate (as binary) was 22% (90% CI: 15.1-100%). The 6-month PFS rate (as time to event) was 19.8% for HGS patients (90% CI: 12.7-100%) and 38.5% (90% CI: 21.7%-100%) for LGS patients. Grade 3 toxicities occurred in 6 patients (one toxicity (Grade 3 rash) was considered a dose-limiting toxicity). One patient died of cardiac arrest after 42 days on treatment of a cardiac arrest not attributed to study drug. CONCLUSIONS: The study met its primary endpoint, with a PFS6 rate of 22% (n = 13); however, the overall response rate was low. Enzalutamide was well tolerated and may be a potential treatment option in select patients.

R4 RGS proteins suppress engraftment of human hematopoietic stem/progenitor cells by modulating SDF-1/CXCR4 signaling.

Homing and engraftment of hematopoietic stem/progenitor cells (HSPCs) into the bone marrow (BM) microenvironment are tightly regulated by the chemokine stromal cell-derived factor-1 (SDF-1) and its G-protein-coupled receptor C-X-C motif chemokine receptor 4 (CXCR4), which on engagement with G-protein subunits, trigger downstream migratory signals. Regulators of G-protein signaling (RGS) are GTPase-accelerating protein of the Gα subunit and R4 subfamily members have been implicated in SDF-1-directed trafficking of mature hematopoietic cells, yet their expression and influence on HSPCs remain mostly unknown. Here, we demonstrated that human CD34+ cells expressed multiple R4 RGS genes, of which RGS1, RGS2, RGS13, and RGS16 were significantly upregulated by SDF-1 in a CXCR4-dependent fashion. Forced overexpression of RGS1, RGS13, or RGS16 in CD34+ cells not only inhibited SDF-1-directed migration, calcium mobilization, and phosphorylation of AKT, ERK, and STAT3 in vitro, but also markedly reduced BM engraftment in transplanted NOD/SCID mice. Genome-wide microarray analysis of RGS-overexpressing CD34+ cells detected downregulation of multiple effectors with established roles in stem cell trafficking/maintenance. Convincingly, gain-of-function of selected effectors or ex vivo priming with their ligands significantly enhanced HSPC engraftment. We also constructed an evidence-based network illustrating the overlapping mechanisms of RGS1, RGS13, and RGS16 downstream of SDF-1/CXCR4 and Gαi. This model shows that these RGS members mediate compromised kinase signaling and negative regulation of stem cell functions, complement activation, proteolysis, and cell migration. Collectively, this study uncovers an essential inhibitory role of specific R4 RGS proteins in stem cell engraftment, which could potentially be exploited to develop improved clinical HSPC transplantation protocols.

Clinical Predictors of Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy.

Importance: Chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory hematologic malignant neoplasm causes severe neurologic adverse events ranging from encephalopathy and aphasia to cerebral edema and death. The cause of neurotoxicity is incompletely understood, and its unpredictability is a reason for prolonged hospitalization after CAR T-cell infusion. Objective: To identify clinical and laboratory parameters predictive of neurotoxicity and to develop a prognostic score associated with its risk. Design, Setting, and Participants: This single-center diagnostic/prognostic accuracy study was conducted at Brigham and Women's Hospital/Dana Farber Cancer Institute from April 2015 to February 2020. A consecutive sample of all patients undergoing CAR T-cell therapy with axicabtagene ciloleucel for relapsed or refractory lymphoma were assessed for inclusion (n = 213). Patients who had previously received CAR T cells or who were treated for mantle cell lymphoma were excluded (n = 9). Patients were followed up for a minimum of 30 days from the date of CAR T-cell infusion. Main Outcomes and Measures: The primary outcomes were measures of performance (accuracy, sensitivity, specificity, area under the curve) of a diagnostic tool to predict the occurrence of CAR-associated neurotoxicity, as graded by the Common Terminology Criteria for Adverse Events criteria. Results: Two hundred four patients (127 men [62.2%]; mean [SD] age, 60.0 [12.1] years) were included in the analysis, of which 126 (61.8%) comprised a derivation cohort and 78 (38.2%), an internal validation cohort. Seventy-three patients (57.9%) in the derivation cohort and 45 patients (57.7%) in the validation cohort experienced neurotoxicity. Clinical and laboratory values obtained early in admission were used to develop a multivariable score that can predict the subsequent development of neurotoxicity; when tested on an internal validation cohort, this score had an area under the curve of 74%, an accuracy of 77%, a sensitivity of 82%, and a specificity of 70% (positive:negative likelihood ratio, 2.71:0.26). Conclusions and Relevance: The score developed in this study may help predict which patients are likely to experience CAR T-cell-associated neurotoxicity. The score can be used for triaging and resource allocation and may allow a large proportion of patients to be discharged from the hospital early.

Large-scale public data reuse to model immunotherapy response and resistance.

Despite growing numbers of immune checkpoint blockade (ICB) trials with available omics data, it remains challenging to evaluate the robustness of ICB response and immune evasion mechanisms comprehensively. To address these challenges, we integrated large-scale omics data and biomarkers on published ICB trials, non-immunotherapy tumor profiles, and CRISPR screens on a web platform TIDE (http://tide.dfci.harvard.edu). We processed the omics data for over 33K samples in 188 tumor cohorts from public databases, 998 tumors from 12 ICB clinical studies, and eight CRISPR screens that identified gene modulators of the anticancer immune response. Integrating these data on the TIDE web platform with three interactive analysis modules, we demonstrate the utility of public data reuse in hypothesis generation, biomarker optimization, and patient stratification.

CD9 blockade suppresses disease progression of high-risk pediatric B-cell precursor acute lymphoblastic leukemia and enhances chemosensitivity.

CD9 has been implicated in cancer progression but its prognostic relevance and therapeutic potential in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are largely unknown. In a cohort of pediatric BCP-ALL patients, we found that CD9+ cases had a significantly lower 5-year relapse-free survival rate than CD9- cases. Multivariate analysis demonstrated that CD9 positivity independently predicted inferior survival outcomes, and could be applied with established prognostic features, including prednisone response and cytogenetic status, to refine patient stratification. Administration of CD9 antibody substantially suppressed disease progression in NOD/SCID mice xenografted with CD9+ cell lines and primary leukemic blasts from patients with high-risk and refractory BCP-ALL, without compromising hematopoietic stem cell engraftment. Combination of anti-CD9 with conventional chemotherapy further reduced leukemic burden and prolonged animal survival. Mechanistically, CD9 blockade inhibited leukemic cell proliferation, induced G0/G1 cell cycle arrest, activated p38, and enhanced chemotherapeutic agent-induced apoptosis. Further, CD9 physically interacted with integrin very late antigen-4, regulated affinity to vascular cell adhesion molecule-1, and was involved in leukemia-stroma interaction. Collectively, our study established CD9 as a new prognostic marker, validated the preclinical efficacy of CD9 antibody, and laid the foundation for clinical development of CD9-targeted therapy for high-risk and refractory pediatric BCP-ALL.

Formulation and evaluation of a mucoadhesive buccal tablet of mefenamic acid

Buccal route of administration has many advantages such as improving patient compliance, bypassing the GIT and hepatic first pass effect. The objectives are to formulate mucoadhesive buccal tablet using Mefenamic acid and compatible excipients, and to evaluate the product using quality control tests and in vitro tests. The ingredients were subjected to Differential Scanning Calorimetry and Fourier Transform Infrared Spectroscopy studies for compatibility test and the results showed no interaction. Two batches of mefenamic buccal tablet were prepared. The tablet thickness and diameter are 3.75 mm and 12 mm respectively. All tablets are within the specification of +/- 5%. The in-house tablet hardness is 6.8-15kg and percent friabilation is not more than 0.8%. The disintegration test showed that all tablets disintegrated within 4 hours. The content uniformity showed that tablets are within the range of 85%-115%. The tablet weight is within the 5% range. The percent swelling is 53.83% to 58.86% and moisture absorption is 14.79% to 15.56%. The surface pH of the tablet is close to the salivary pH, which means that it would not irritate the buccal mucosa. The buccal tablet has a mucoadhesiveness of 0.196 to 0.200. There was no change in pH and size after subjecting it to stability studies in human saliva. Drug release studies showed 80.7% to 83.4% after 3 hours. Even after 3 months of subjecting the tablets to 40 ºC and 75% RH, results are within acceptable range. The results show the potential of the formulation as a mucoadhesive buccal tablet.