Crystal structure and mechanistic studies of the PPM1D serine/threonine phosphatase catalytic domain.

Protein phosphatase 1D (PPM1D, Wip1) is induced by the tumor suppressor p53 during DNA damage response signaling and acts as an oncoprotein in several human cancers. Although PPM1D is a potential therapeutic target, insights into its atomic structure were challenging due to flexible regions unique to this family member. Here, we report the first crystal structure of the PPM1D catalytic domain to 1.8 Å resolution. The structure reveals the active site with two Mg2+ ions bound, similar to other structures. The flap subdomain and B-loop, which are crucial for substrate recognition and catalysis, were also resolved, with the flap forming two short helices and three short ß-strands that are followed by an irregular loop. Unexpectedly, a nitrogen-oxygen-sulfur bridge was identified in the catalytic domain. Molecular dynamics simulations and kinetic studies provided further mechanistic insights into the regulation of PPM1D catalytic activity. In particular, the kinetic experiments demonstrated a magnesium concentration-dependent lag in PPM1D attaining steady-state velocity, a feature of hysteretic enzymes that show slow transitions compared with catalytic turnover. All combined, these results advance the understanding of PPM1D function and will support the development of PPM1D-targeted therapeutics.

GEN1 as a risk factor for human congenital anomalies of the kidney and urinary tract.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are prevalent birth defects. Although pathogenic CAKUT genes are known, they are insufficient to reveal the causes for all patients. Our previous studies indicated GEN1 as a pathogenic gene of CAKUT in mice, and this study further investigated the correlation between GEN1 and human CAKUT. METHODS: In this study, DNA from 910 individuals with CAKUT was collected; 26 GEN1 rare variants were identified, and two GEN1 (missense) variants in a non-CAKUT group were found. Mainly due to the stability results of the predicted mutant on the website, in vitro, 10 variants (eight CAKUT, two non-CAKUT) were selected to verify mutant protein stability. In addition, mainly based on the division of the mutation site located in the functional region of the GEN1 protein, 8 variants (six CAKUT, two non-CAKUT) were selected to verify enzymatic hydrolysis, and the splice variant GEN1 (c.1071 + 3(IVS10) A > G) was selected to verify shear ability. Based on the results of in vitro experiments and higher frequency, three sites with the most significant functional change were selected to build mouse models. RESULTS: Protein stability changed in six variants in the CAKUT group. Based on electrophoretic mobility shift assay of eight variants (six CAKUT, two non-CAKUT), the enzymatic hydrolysis and DNA-binding abilities of mutant proteins were impaired in the CAKUT group. The most serious functional damage was observed in the Gen1 variant that produced a truncated protein. A mini-gene splicing assay showed that the variant GEN1 (c.1071 + 3(IVS10) A > G) in the CAKUT group significantly affected splicing function. An abnormal exon10 was detected in the mini-gene splicing assay. Point-mutant mouse strains were constructed (Gen1: c.1068 + 3 A > G, p.R400X, and p.T105R) based on the variant frequency in the CAKUT group and functional impairment in vitro study and CAKUT phenotypes were replicated in each. CONCLUSION: Overall, our findings indicated GEN1 as a risk factor for human CAKUT.

Nafamostat mesylate decreases skin flap necrosis in a mouse model of type 2 diabetes by protecting the endothelial glycocalyx.

The success rate of flap tissue reconstruction has increased in recent years owing to advancements in microsurgical techniques. However, complications, such as necrosis, are still more prevalent in diabetic patients compared to non-diabetic individuals, presenting an ongoing challenge. To address this issue, many previous studies have examined vascular anastomoses dilation and stability, primarily concerning surgical techniques or drugs. In contrast, in the present study, we focused on microvascular damage of the peripheral microvessels in patients with diabetes mellitus and the preventative impact of nafamostat mesylate. Herein, we aimed to investigate the effects of hyperglycemia on glycocalyx (GCX) levels in mice with type 2 diabetes. We examined the endothelial GCX (eGCX) in skin flap tissue of 9-12-week-old type 2 diabetic mice (db/db mice) using a perforator skin flap and explored treatment with nafamostat mesylate. The growth rates were compared after 1 week. Heterotype (db/+) mice were used as the control group. Morphological examination of postoperative tissues was performed at 1, 3, 5, and 7 days post-surgery. In addition, db/db mice were treated with 30 mg/kg/day of nafamostat mesylate daily and were evaluated on postoperative day 7. Seven days after surgery, all db/db mice showed significant partial flap necrosis. Temporal observation of the skin flaps revealed a stasis-like discoloration and necrosis starting from the contralateral side of the remaining perforating branch. The control group did not exhibit flap necrosis, and the flap remained intact. In the quantitative assessment of endothelial glycans using lectins, intensity scoring showed that the eGCX in the db/db group was significantly thinner than that in the db/+ group. These results were consistent with the scanning electron microscopy findings. In contrast, treatment with nafamostat mesylate significantly improved the flap engraftment rate and suppressed eGCX injury. In conclusion, treatment with nafamostat mesylate improves the disrupted eGCX structure of skin flap tissue in db/db mice, potentially ameliorating the impaired capillary-to-venous return in the skin flap tissue.

Emodin activates autophagy to suppress oxidative stress and pyroptosis via mTOR-ULK1 signaling pathway and promotes multi-territory perforator flap survival.

BACKGROUND: Multi-territory perforator flap reconstruction has been proven effective in treating large skin and soft tissue defects in clinical settings. However, in view of that the multi-territory perforator flap is prone to partial postoperative necrosis, increasing its survival is the key to the success of reconstruction. In this study, we aimed to clarify the effect of emodin on multi-territory perforator flap survival. METHODS: Flap survival was assessed by viability area analysis, infrared laser imaging detector, HE staining, immunohistochemistry, and angiography. Western blotting, immunofluorescence assays, and real-time fluorescent quantitative PCR were performed to detect the indicators of oxidative stress, pyroptosis and autophagy. RESULTS: After emodin treatment, the multi-territory perforator flap showed a significantly increased survival rate, which was shown to be closely related to the inhibition of oxidative stress and pyroptosis and enhanced autophagy. Meanwhile, the use of autophagy inhibitor 3 MA was found to reverse the inhibitory effects of emodin on oxidative stress and pyroptosis and weaken the improving effect of emodin on flap survival, suggesting that autophagy plays a critical role in emodin-treated flaps. Interestingly, our mechanistic investigations revealed that the positive effect of emodin on multi-territory perforator flap was attributed to the mTOR-ULK1 signaling pathway activation. CONCLUSIONS: Emodin can inhibit oxidative stress and pyroptosis by activating autophagy via the mTOR-ULK1 pathway, thereby improving the multi-territory perforator flap survival.

Indocyanine green angiography guidance for vascular preservation in skin and nipple sparing mastectomy.

PURPOSE: The skin and/or nipple-sparing approach has become an oncologically sound and desirable choice for women choosing mastectomy. Indocyanine green (ICG) perfusion imaging has been shown to reduce ischemic complications in mastectomy skin flaps. Immediate reconstruction requires a well-vascularized skin flap capable of tolerating full expansion. Identification of the perforating subcutaneous vessels to the skin envelope may allow for better and more consistent blood vessel preservation and flap perfusion. METHODS: The authors conducted an institutional review board-approved prospective study with 41 patients to assess the feasibility of using ICG perfusion imaging to visualize, cutaneously map, and preserve the vessels that supply the skin flap and nipple-areolar complex. For each patient, the number of vessels initially mapped, the number of vessels preserved, the extent to which each vessel was preserved, and the proportion of the flap with adequate perfusion (as defined by the SPY-Q > 20% threshold) was recorded and analyzed. RESULTS: Vessels were able to be identified and marked in a high majority of patients (90%). There was a moderate linear relationship between the number of vessels marked and the number preserved. Successful mapping of vessels was associated with lower rates of wound breakdown (p = 0.036). Mapping and preserving at least one vessel led to excellent flap perfusion (> 90%). No increase in complications was observed from utilizing ICG angiography preoperatively. CONCLUSION: This prospective study using preoperative ICG perfusion mapping demonstrated safety, feasibility, and good prognostic outcomes. LEVEL OF EVIDENCE: III.

Minimally invasive surgeries for spontaneous hypertensive intracerebral hemorrhage (MISICH): a multicenter randomized controlled trial.

BACKGROUND: Intracerebral hemorrhage (ICH) is a common stroke type with high morbidity and mortality. There are mainly three surgical methods for treating ICH. Unfortunately, thus far, no specific surgical method has been proven to be the most effective. We carried out this study to investigate whether minimally invasive surgeries with endoscopic surgery or stereotactic aspiration (frameless navigated aspiration) will improve functional outcomes in patients with supratentorial ICH compared with small-bone flap craniotomy. METHODS: In this parallel-group multicenter randomized controlled trial conducted at 16 centers, patients with supratentorial hypertensive ICH were randomized to receive endoscopic surgery, stereotactic aspiration, or craniotomy at a 1:1:1 ratio from July 2016 to June 2022. The follow-up duration was 6 months. Patients were randomized to receive endoscopic evacuation, stereotactic aspiration, or small-bone flap craniotomy. The primary outcome was favorable functional outcome, defined as the proportion of patients who achieved a modified Rankin scale (mRS) score of 0-2 at the 6-month follow-up. RESULTS: A total of 733 patients were randomly allocated to three groups: 243 to the endoscopy group, 247 to the aspiration group, and 243 to the craniotomy group. Finally, 721 patients (239 in the endoscopy group, 246 in the aspiration group, and 236 in the craniotomy group) received treatment and were included in the intention-to-treat analysis. Primary efficacy analysis revealed that 73 of 219 (33.3%) in the endoscopy group, 72 of 220 (32.7%) in the aspiration group, and 47 of 212 (22.2%) in the craniotomy group achieved favorable functional outcome at the 6-month follow-up (P = .017). We got similar results in subgroup analysis of deep hemorrhages, while in lobar hemorrhages the prognostic outcome was similar among three groups. Old age, deep hematoma location, large hematoma volume, low preoperative GCS score, craniotomy, and intracranial infection were associated with greater odds of unfavorable outcomes. The mean hospitalization expenses were ¥92,420 in the endoscopy group, ¥77,351 in the aspiration group, and ¥100,947 in the craniotomy group (P = .000). CONCLUSIONS: Compared with small bone flap craniotomy, endoscopic surgery and stereotactic aspiration improved the long-term outcome of hypertensive ICH, especially deep hemorrhages. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02811614.

Standardized Pre-clinical Surgical Animal Model Protocol to Investigate the Cellular and Molecular Mechanisms of Ischemic Flap Healing.

BACKGROUND: Some of the most complex surgical interventions to treat trauma and cancer include the use of locoregional pedicled and free autologous tissue transfer flaps. While the techniques used for these reconstructive surgery procedures have improved over time, flap complications and even failure remain a significant clinical challenge. Animal models are useful in studying the pathophysiology of ischemic flaps, but when repeatability is a primary focus of a study, conventional in-vivo designs, where one randomized subset of animals serves as a treatment group while a second subset serves as a control, are at a disadvantage instigated by greater subject-to-subject variability. Our goal was to provide a step-by-step methodological protocol for creating an alternative standardized, more economical, and transferable pre-clinical animal research model of excisional full-thickness wound healing following a simulated autologous tissue transfer which includes the primary ischemia, reperfusion, and secondary ischemia events with the latter mimicking flap salvage procedure. RESULTS: Unlike in the most frequently used classical unilateral McFarlane's caudally based dorsal random pattern skin flap model, in the herein described bilateral epigastric fasciocutaneous advancement flap (BEFAF) model, one flap heals under normal and a contralateral flap-under perturbed conditions or both flaps heal under conditions that vary by one within-subjects factor. We discuss the advantages and limitations of the proposed experimental approach and, as a part of model validation, provide the examples of its use in laboratory rat (Rattus norvegicus) axial pattern flap healing studies. CONCLUSIONS: This technically challenging but feasible reconstructive surgery model eliminates inter-subject variability, while concomitantly minimizing the number of animals needed to achieve adequate statistical power. BEFAFs may be used to investigate the spatiotemporal cellular and molecular responses to complex tissue injury, interventions simulating clinically relevant flap complications (e.g., vascular thrombosis) as well as prophylactic, therapeutic or surgical treatment (e.g., flap delay) strategies in the presence or absence of confounding risk factors (e.g., substance abuse, irradiation, diabetes) or favorable wound-healing promoting activities (e.g., exercise). Detailed visual instructions in BEFAF protocol may serve as an aid for teaching medical or academic researchers basic vascular microsurgery techniques that focus on precision, tremor management and magnification.

Pharmacological and cell-based treatments to increase local skin flap viability in animal models.

Local skin flaps are frequently employed for wound closure to address surgical, traumatic, congenital, or oncologic defects. (1) Despite their clinical utility, skin flaps may fail due to inadequate perfusion, ischemia/reperfusion injury (IRI), excessive cell death, and associated inflammatory response. (2) All of these factors contribute to skin flap necrosis in 10-15% of cases and represent a significant surgical challenge. (3, 4) Once flap necrosis occurs, it may require additional surgeries to remove the entire flap or repair the damage and secondary treatments for infection and disfiguration, which can be costly and painful. (5) In addition to employing appropriate surgical techniques and identifying healthy, well-vascularized tissue to mitigate the occurrence of these complications, there is growing interest in exploring cell-based and pharmacologic augmentation options. (6) These agents typically focus on preventing thrombosis and increasing vasodilation and angiogenesis while reducing inflammation and oxidative stress. Agents that modulate cell death pathways such as apoptosis and autophagy have also been investigated. (7) Implementation of drugs and cell lines with potentially beneficial properties have been proposed through various delivery techniques including systemic treatment, direct wound bed or flap injection, and topical application. This review summarizes pharmacologic- and cell-based interventions to augment skin flap viability in animal models, and discusses both translatability challenges facing these therapies and future directions in the field of skin flap augmentation.

Simultaneous Co-surgeon Deep Inferior Epigastric Perforator (DIEP) Flap Breast Reconstructions: Feasibility and Clinical Outcomes.

BACKGROUND: A co-surgeon model is known to be favorable in microvascular breast reconstruction, but simultaneous co-surgeon deep inferior epigastric perforator (DIEP) flap cases have not been well-studied. The authors hypothesize that performing two simultaneous co-surgeon bilateral DIEP flap reconstructions results in non-inferior clinical outcomes and may improve patient access to care. METHODS: A single-institution, retrospective cohort study was performed utilizing record review to identify all cases of co-surgeon free-flap breast reconstructions over a 38-month period. Patients who underwent simultaneous bilateral DIEP flap breast reconstructions with the same two co-surgeons were identified. The control group consisted of subjects who underwent non-simultaneous reconstruction by the same co-surgeons within the same, preceding, or following month of those in the study group. Primary outcome variables were 90-day postoperative complications, while secondary outcomes were operating time, ischemia time, and length of stay. Descriptive statistics, univariate and multivariable regression analyses were performed. RESULTS: Overall, 137 subjects were identified and 64 met the inclusion criteria (n = 28 study, n = 36 control). There were no statistically significant differences between groups in body mass index, radiation, trainee experience, flap perforator number, immediate/delayed reconstruction, or length of stay. There were also no statistically significant differences in complications, including flap loss, anastomosis revision, take-back to the operating room, or re-admission. Operative time was longer in the simultaneous DIEP group (540.5 vs. 443.5 min, p < 0.01), but ischemia time was shorter in the simultaneous group (64.0 vs. 80.5 min, p < 0.01). CONCLUSIONS: A simultaneous co-surgeon approach to bilateral DIEP flap reconstruction may improve access to care and does not result in a higher complication rate compared with non-simultaneous bilateral DIEP flaps.

Impact of Mastectomy Flap Necrosis on Patient-Reported Quality-of-Life Measures After Nipple-Sparing Mastectomy: A Preliminary Analysis.

BACKGROUND: Mastectomy skin flap necrosis (SFN) is common following nipple-sparing mastectomy (NSM), but studies on its quality-of-life (QOL) impact are limited. We examined patient-reported QOL and satisfaction after NSM with/without SFN utilizing the BREAST-Q patient-reported outcome measure (PROM) survey. PATIENTS AND METHODS: Patients undergoing NSM between April 2018 and July 2021 at our institution were examined; the BREAST-Q PROM was administered preoperatively, and at 6 months and 1 year postoperatively. SFN extent/severity was documented at 2-3 weeks postoperatively; QOL and satisfaction domains were compared between patients with/without SFN. RESULTS: A total of 573 NSMs in 333 patients were included, and 135 breasts in 82 patients developed SFN (24% superficial, 56% partial thickness, 16% full thickness). Patients with SFN reported significantly lower scores in the satisfaction with breasts (p = 0.032) and psychosocial QOL domains (p = 0.009) at 6 months versus those without SFN, with scores returning to baseline at 1 year in both domains. In the "physical well-being-of-the-chest" domain, there was an overall decline in scores among all patients; however, there were no significant differences at any time point between patients with or without SFN. Sexual well-being scores declined for patients with SFN compared with those without at 6 months and also at 1 year, but this did not reach significance (p = 0.13, p = 0.2, respectively). CONCLUSIONS: Patients undergoing NSM who developed SFN reported significantly lower satisfaction and psychosocial well-being scores at 6 months, which returned to baseline by 1 year. Physical well-being of the chest significantly declines after NSM regardless of SFN. Future studies with larger sample sizes and longer follow-up are needed to determine SFN's impact on long-term QOL.

Sarcoma Size and Limb Dimensions Predict Complications, Recurrence, and Death in Patients with Soft Tissue Sarcoma in the Thigh: A Multidimensional Analysis.

BACKGROUND: Limb-sparing resections of thigh soft tissue sarcomas (STSs) can result in adverse outcomes. Identifying preoperative predictors for wound healing complications, tumor recurrence, and mortality is crucial for informed reconstructive decision-making. We hypothesized that preoperative measurements of thigh and tumor dimensions could serve as reliable indicators for postoperative complications, recurrence, and death. PATIENTS AND METHODS: In this retrospective cohort study conducted from March 2016 to December 2021, we analyzed patients undergoing thigh STS excisions followed by reconstruction. Preoperative magnetic resonance imaging or computed tomography scans provided necessary thigh and tumor dimensions. Univariate and multivariate regression assessed relationships between these dimensions and postoperative outcomes, including complications, recurrence, and death. RESULTS: Upon the analysis of 123 thighs, we found thigh width to be highly predictive of postoperative complications, even surpassing body mass index (BMI) and retaining significance in multivariate regression [odds ratio (OR) 1.19; 95% CI 1.03-1.39; p = 0.03]. Sarcoma-to-thigh width and thickness ratios predicted STS recurrence, with the thickness ratio retaining significance in multivariate regression (OR 1.03; 95% CI 1.001-1.05; p = 0.041). Notably, greater thigh thickness was independently protective against mortality in multivariate analysis (OR 0.80; 95% CI 0.65-0.98; p = 0.030). CONCLUSIONS: Thigh width outperformed BMI in association with postoperative complications. This may create an opportunity for intervention, where weight loss can play a role during the neoadjuvant therapy period to potentially reduce complications. Sarcoma-to-thigh width and thickness ratios, particularly the latter, hold substantial predictive value in terms of STS recurrence. Moreover, thigh thickness is an independent predictor of survival.

Complications of chest wall around malignant tumors: differences based on reconstruction strategy.

BACKGROUND: Malignant chest wall tumors need to be excised with wide resection to ensure tumor free margins, and the reconstruction method should be selected according to the depth and dimensions of the tumor. Vascularized tissue is needed to cover the superficial soft tissue defect or bone tissue defect. This study evaluated differences in complications according to reconstruction strategy. METHODS: Forty-five patients with 52 operations for resection of malignant tumors in the chest wall were retrospectively reviewed. Patients were categorized as having superficial tumors, comprising Group A with simple closure for small soft tissue defects and Group B with flap coverage for wide soft tissue defects, or deep tumors, comprising Group C with full-thickness resection with or without mesh reconstruction and Group D with full-thickness resection covered by flap with or without polymethyl methacrylate. Complications were evaluated for the 52 operations based on reconstruction strategy then risk factors for surgical and respiratory complications were elucidated. RESULTS: Total local recurrence-free survival rates in 45 patients who received first operation were 83.9% at 5 years and 70.6% at 10 years. The surgical complication rate was 11.5% (6/52), occurring only in cases with deep tumors, predominantly from Group D. Operations needing chest wall reconstruction (p = 0.0016) and flap transfer (p = 0.0112) were significantly associated with the incidence of complications. Operations involving complications showed significantly larger tumors, wider areas of bony chest wall resection and greater volumes of bleeding (p < 0.005). Flap transfer was the only significant predictor identified from multivariate analysis (OR: 10.8, 95%CI: 1.05-111; p = 0.0456). The respiratory complication rate was 13.5% (7/52), occurring with superficial and deep tumors, particularly Groups B and D. Flap transfer was significantly associated with the incidence of respiratory complications (p < 0.0005). Cases in the group with respiratory complications were older, more frequently had a history of smoking, had lower FEV1.0% and had a wider area of skin resected compared to cases in the group without respiratory complications (p < 0.05). Preoperative FEV1.0% was the only significant predictor identified from multivariate analysis (OR: 0.814, 95%CI: 0.693-0.957; p = 0.0126). CONCLUSIONS: Surgical complications were more frequent in Group D and after operations involving flap transfer. Severe preoperative FEV1.0% was associated with respiratory complications even in cases of superficial tumors with flap transfer.

Prophylactic pectoralis major flap to compensate for increased risk of pharyngocutaneous fistula in laryngectomy patients with low skeletal muscle mass (PECTORALIS): study protocol for a randomized controlled trial.

BACKGROUND: Total laryngectomy (TL) is a surgical procedure commonly performed on patients with advanced laryngeal or hypopharyngeal carcinoma. One of the most common postoperative complications following TL is the development of a pharyngocutaneous fistula (PCF), characterized by a communication between the neopharynx and the skin. PCF can lead to extended hospital stays, delayed oral feeding, and compromised quality of life. The use of a myofascial pectoralis major flap (PMMF) as an onlay technique during pharyngeal closure has shown potential in reducing PCF rates in high risk patients for development of PCF such as patients undergoing TL after chemoradiation and low skeletal muscle mass (SMM). Its impact on various functional outcomes, such as shoulder and neck function, swallowing function, and voice quality, remains less explored. This study aims to investigate the effectiveness of PMMF in reducing PCF rates in patients with low SMM and its potential consequences on patient well-being. METHODS: This multicenter study adopts a randomized clinical trial (RCT) design and is funded by the Dutch Cancer Society. Eligible patients for TL, aged ≥ 18 years, mentally competent, and proficient in Dutch, will be enrolled. One hundred and twenty eight patients with low SMM will be centrally randomized to receive TL with or without PMMF, while those without low SMM will undergo standard TL. Primary outcome measurement involves assessing PCF rates within 30 days post-TL. Secondary objectives include evaluating quality of life, shoulder and neck function, swallowing function, and voice quality using standardized questionnaires and functional tests. Data will be collected through electronic patient records. DISCUSSION: This study's significance lies in its exploration of the potential benefits of using PMMF as an onlay technique during pharyngeal closure to reduce PCF rates in TL patients with low SMM. By assessing various functional outcomes, the study aims to provide a comprehensive understanding of the impact of PMMF deployment. The anticipated results will contribute valuable insights into optimizing surgical techniques to enhance patient outcomes and inform future treatment strategies for TL patients. TRIAL REGISTRATION: NL8605, registered on 11-05-2020; International Clinical Trials Registry Platform (ICTRP).

Female non-obstetric urogenital fistula repair: long-term patient-reported outcomes and a scoping literature review.

OBJECTIVE: To investigate long-term and patient-reported outcomes, including sexual function, in women undergoing urogenital fistula (UGF) repair, addressing the lack of such data in Western countries, where fistulas often result from iatrogenic causes. PATIENTS AND METHODS: We conducted a retrospective analysis at a tertiary referral centre (2010-2023), classifying fistulas based on World Health Organisation criteria and evaluating surgical approaches, aetiology, and characteristics. Both objective (fistula closure, reintervention rates) and subjective outcomes (validated questionnaires) were assessed. A scoping review of patient-reported outcome measures in UGF repair was also performed. RESULTS: The study included 50 patients: 17 (34%) underwent transvaginal and 33 (66%) transabdominal surgery. History of hysterectomy was present in 36 patients (72%). The median (interquartile range [IQR]) operating time was 130 (88-148) min. Fistula closure was achieved in 94% of cases at a median (IQR) follow-up of 50 (16-91) months and reached 100% after three redo fistula repairs. Seven patients (14%) underwent reinterventions for stress urinary incontinence after transvaginal repair (autologous fascial slings). Patient-reported outcomes showed median (IQR) scores on the International Consultation on Incontinence Questionnaire Female Lower Urinary Tract Symptoms Modules (ICIQ-FLUTS) of 5 (3-7) for filling symptoms, 1 (0-2) for voiding symptoms and 4.5 (1-9) for incontinence symptoms. The median (IQR) score on the ICIQ Female Sexual Matters Associated with Lower Urinary Tract Symptoms Module (ICIQ-FLUTSsex) was 3 (1-5). The median (IQR) ICIQ Satisfaction (ICIQ-S) outcome score and overall satisfaction with surgery item score was 22 (18.5-23.5) and 10 (8.5-10), respectively. Higher scores indicate higher symptom burden and treatment satisfaction, respectively. Our scoping review included 1784 women, revealing mixed aetiology and methodological and aetiological heterogeneity, thus complicating cross-study comparisons. CONCLUSIONS: Urogenital fistula repair at a specialised centre leads to excellent outcomes and high satisfaction. Patients with urethrovaginal fistulas are at increased risk of stress urinary incontinence, possibly due to the original trauma site of the fistula.

Results from a first-in-human phase I safety trial to evaluate the use of a vascularized pericranial/temporoparietal fascial flap to line the resection cavity following resection of newly diagnosed glioblastoma.

PURPOSE: The efficacy of systemic therapies for glioblastoma (GBM) remains limited due to the constraints of systemic toxicity and blood-brain barrier (BBB) permeability. Temporoparietal fascial flaps (TPFFs) and vascularized peri cranial flaps (PCF) are not restricted by the blood-brain barrier (BBB), as they derive their vascular supply from branches of the external carotid artery. Transposition of a vascularized TPFF or PCF along a GBM resection cavity may bring autologous tissue not restricted by the BBB in close vicinity to the tumor bed microenvironment, permit ingrowth of vascular channels fed by the external circulation, and offer a mechanism of bypassing the BBB. In addition, circulating immune cells in the vascularized flap may have better access to tumor-associated antigens (TAA) within the tumor microenvironment. We conducted a first-in-human Phase I trial assessing the safety of lining the resection cavity with autologous TPFF/PCF of newly diagnosed patients with GBM. METHODS: 12 patients underwent safe, maximal surgical resection of newly diagnosed GBMs, followed by lining of the resection cavity with a pedicled, autologous TPFF or PCF. Safety was assessed by monitoring adverse events. Secondary analysis of efficacy was examined as the proportion of patients experiencing progression-free disease (PFS) as indicated by response assessment in neuro-oncology (RANO) criteria and overall survival (OS). The study was powered to determine whether a Phase II study was warranted based on these early results. For this analysis, subjects who were alive and had not progressed as of the date of the last follow-up were considered censored and all living patients who were alive as of the date of last follow-up were considered censored for overall survival. For simplicity, we assumed that a 70% PFS rate at 6 months would be considered an encouraging response and would make an argument for further investigation of the procedure. RESULTS: Median age of included patients was 57 years (range 46-69 years). All patients were Isocitrate dehydrogenase (IDH) wildtype. Average tumor volume was 56.6 cm3 (range 14-145 cm3). Resection was qualified as gross total resection (GTR) of all of the enhancing diseases in all patients. Grade III or above adverse events were encountered in 3 patients. No Grade IV or V serious adverse events occurred in the immediate post-operative period including seizure, infection, stroke, or tumor growing along the flap. Disease progression at the site of the original tumor was identified in only 4 (33%) patients (median 23 months, range 8-25 months), 3 of whom underwent re-operation. Histopathological analyses of those implanted flaps and tumor bed biopsy at repeat surgery demonstrated robust immune infiltrates within the transplanted flap. Importantly, no patient demonstrated evidence of tumor infiltration into the implanted flap. At the time of this manuscript preparation, only 4/12 (33%) of patients have died. Based on the statistical considerations above and including all 12 patients 10/12 (83.3%) had 6-month PFS. The median PFS was 9.10 months, and the OS was 17.6 months. 4/12 (33%) of patients have been alive for more than two years and our longest surviving patient currently is alive at 60 months. CONCLUSIONS: This pilot study suggests that insertion of pedicled autologous TPFF/PCF along a GBM resection cavity is safe and feasible. Based on the encouraging response rate in 6-month PFS and OS, larger phase II studies are warranted to assess and reproduce safety, feasibility, and efficacy. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION FOR PROSPECTIVELY REGISTERED TRIALS: ClinicalTrials.gov ID NCT03630289, dated: 08/02/2018.

The Electrified Wire Technique in Complex Aortic Interventions: A Case Series.

OBJECTIVES: Electrosurgery has been long used in endovascular procedures, with only case reports in the aortic field. Our aim is to present a case series with the use of an electrified wire to perform catheter-based electrosurgery by applying external current through an electrocautery pen. METHODS: Single-center retrospective case series of all patients undergoing complex aortic surgery from October 2020 to August 2023, in whom the electrified wire technique was used: (1) Perforation of a dissection flap or left subclavian artery (LSA) in situ endograft fenestration-a 0.014" polytetrafluoroethylene (PTFE) insulated guidewire is detached from the insulation with a scalpel at the end and a cautery pen is here attached with a clamp. A curved tip catheter or sheath is positioned against the aortic flap or the endograft (through a left brachial access in this case) and the wire pushed, crossing the flap by activating the electrocautery pen and (2) slicing a dissection flap ("powered cheese-wire technique")-after same preparation as above, the middle section of the 0.014 guidewire is removed from the PTFE and bent into a V-shape. Once in the aorta, the guidewire crosses from the true lumen (TL) to the false lumen (FL) and a through-and-through access is obtained. Sheaths are positioned against the flap from both sides and moved up or down while the electricity is activated, slicing the flap and communicating both lumens. Technical success and technical-related complications were evaluated. RESULTS: Eleven cases concerning aortic dissections and 1 case of aortic atresia were treated. Four patients presented urgently, whereas the rest were planned procedures. Seven cases underwent perforation of a dissection flap, 2 cases underwent the powered cheese-wire technique, in 2 cases for an LSA in situ fenestration, and in 1 case to cross an aortic atresia at the aortic isthmus. The technique was in all cases successfully applied. No complications related to the technique occurred. CONCLUSIONS: The "electrified wire" technique is a feasible and ready-available tool that can be safely used in complex aortic interventions, especially to perforate aortic tissue like dissection flaps or to perform in situ fenestrated repairs by perforation of the endograft fabric. CLINICAL IMPACT: The electrified wire technique described herein is a straightforward technique that uses readily available tools to perform electrosurgery. We present its use in complex aortic procedures. However, it could be envisioned for any vascular procedure that requires crossing of the vessel or even prosthetic material. As we have described in this series, when used along with an adequate properative planning, it can be a safe tool of great utility, as has already been demonstarted in the field of the interventional cardiology.

Versatility of the myocutaneous pectoralis major flap in oncology reconstruction: A literature review and practical application.

Pectoralis major muscle flaps are considered versatile and allow large reconstructions of anatomical defects within a single surgical procedure. Considered a "workhorse" due to these characteristics, the pectoralis major muscle is an excellent option for surgical reconstruction. Several uses of this flap are described in the literature, such as protection of the jugulocarotid system after cervical lymph node dissection, oral, cervical, breast, diaphragmatic, hypopharyngeal, pharyngeal, laryngeal, and esophageal reconstructions.

Drain-free mastectomy and flap fixation: The interim analysis of a randomized controlled noninferiority trial.

INTRODUCTION: Flap fixation after mastectomy has proven to be one of the most promising solutions to reduce seroma formation. Drain placement remains standard practice in many clinics, even though this may be redundant after flap fixation. METHODS: This is a prospective randomized controlled trial comparing mastectomy and wound closure using flap fixation with or without drain placement. The primary outcome measure was clinically significant seroma (CSS) incidence. The aim of this interim analysis was to assess the assumptions for the sample size calculation and to provide preliminary results. RESULTS: Between July 2020 and January 2023, 112 patients were included. CSS incidence was 9.1% in the drain group and 21% in the no-drain group. In total, 10 patients were lost to follow-up. These numbers are similar to the ones used for the sample size calculation. In the drain group, three patients required interventions for wound complications compared to nine in the no-drain group (odds ratio: 3.612 [95% confidence interval: 0.898-14.537]). CONCLUSION: The sample size calculation seems to be correct and no protocol amendments are necessary. Current preliminary results show no significant differences in CSS incidence. Complete results should be awaited to draw a well-powered conclusion regarding drain policy after mastectomy.

Analyzing mastectomy and reconstruction weight in immediate autologous breast reconstruction: A preliminary study.

BACKGROUND: This study aims to explore the ideal breast size by assessing the relationship between mastectomy to free flap weight ratio and complications as well as patient-reported outcomes in autologous breast reconstruction (ABR). METHOD: A retrospective review of patients undergoing bilateral immediate ABR with mastectomy and flap weights available was completed. Patients were divided into three groups based on the ratio of mastectomy to flap weights. The patients were grouped as "maintained" if the flap weight was within 10% of the mastectomy weight. Patients with a weight difference greater than 10% were used to declare "downsized" or "upsized." Outcomes included complications and four domains of the BREAST-Q at 1-year postoperatively. RESULTS: Three hundred and fifty-nine patients were included in the analysis, of which 112 were downsized, 91 maintained, and 156 upsized, respectively. Presence of complications did not significantly differ among the groups. At 1-year postoperatively, Sexual Well-being significantly differed (p = 0.033). Between preoperative and 1 year, patients who upsized experienced an improvement in Satisfaction with Breasts by 16 points (p < 0.001), while patients who downsized experienced a decline in Physical Well-being of the Chest by 7 points (p = 0.016). Multivariable linear regression model showed that Sexual Well-being was 13 points lower in the downsized cohort than in the maintained cohort (ß = -13, 95% confidence interval: -21 to -5.4; p = 0.001). CONCLUSION: Although complication rates do not significantly differ between the three cohorts, patients who downsize may have lower Sexual Well-being postoperatively. Surgeons should consider our preliminary findings to counsel patients preoperatively about the predicted breast size and the impact of downsizing on sexual health.

Association of omental pedicled flap with anastomotic leak following low anterior resection for rectal cancer.

BACKGROUND AND OBJECTIVES: Anastomotic leak following colorectal anastomosis adversely impacts short-term, oncologic, and quality-of-life outcomes. This study aimed to assess the impact of omental pedicled flap (OPF) on anastomotic leak among patients undergoing low anastomotic resection (LAR) for rectal cancer using a multi-institutional database. METHODS: Adult rectal cancer patients in the US Rectal Cancer Consortium, who underwent a LAR for stage I-III rectal cancer with or without an OPF were included. Patients with missing data for surgery type and OPF use were excluded from the analysis. The primary outcome was the development of anastomotic leaks. Multivariable logistic regression was used to determine the association. RESULTS: A total of 853 patients met the inclusion criteria and OPF was used in 106 (12.4%) patients. There was no difference in age, sex, or tumor stage of patients who underwent OPF versus those who did not. OPF use was not associated with an anastomotic leak (p = 0.82), or operative blood loss (p = 0.54) but was associated with an increase in the operative duration [ß = 21.42 (95% confidence interval = 1.16, 41.67) p = 0.04]. CONCLUSIONS: Among patients undergoing LAR for rectal cancer, OPF use was associated with an increase in operative duration without any impact on the rate of anastomotic leak.