Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers.

RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. Notably, oral administration of RMC-6236 was tolerated in vivo and drove profound tumor regressions across multiple tumor types in a mouse clinical trial with KRASG12X xenograft models. Translational PK/efficacy and PK/PD modeling predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Consistent with this, we describe here objective responses in two patients (at 300 mg daily) with advanced KRASG12X lung and pancreatic adenocarcinoma, respectively, demonstrating the initial activity of RMC-6236 in an ongoing phase I/Ib clinical trial (NCT05379985). SIGNIFICANCE: The discovery of RMC-6236 enables the first-ever therapeutic evaluation of targeted and concurrent inhibition of canonical mutant and wild-type RAS-GTP in RAS-driven cancers. We demonstrate that broad-spectrum RAS-GTP inhibition is tolerable at exposures that induce profound tumor regressions in preclinical models of, and in patients with, such tumors.

Postoperative bleeding after complex abdominal wall reconstruction: A post hoc analysis of a randomized clinical trial.

BACKGROUND: Abdominal wall reconstruction requires extensive dissection of the abdominal wall, exposure of the retroperitoneum, and aggressive chemoprophylaxis to reduce the risk of thromboembolic complications. The need for early anticoagulation puts patients at risk for bleeding. We aimed to quantify postoperative blood loss, incidence of transfusion and reoperation, and associated risk factors in patients undergoing complex abdominal wall reconstruction. METHODS: All patients underwent a posterior component separation with transversus abdominis release and placement of retromuscular mesh for ventral hernias <20 cm wide and were enrolled in a clinical trial assessing the utility of trans-fascial mesh fixation. A post hoc analysis was performed to quantify postoperative hemoglobin drop, blood transfusions, and procedural interventions for ongoing bleeding during the first 30 postoperative days. Multivariate logistic regression was used to identify predictors of transfusion. RESULTS: In 325 patients, hemoglobin decreased by 3.61 (±1.58) g/dL postoperatively. Transfusion incidence was 9.5% (n = 31), and 3.1% (n = 10) required a surgical intervention for bleeding. Initiation of therapeutic anticoagulation postoperatively resulted in a higher likelihood of requiring surgical intervention for bleeding (odds ratio 10.4 [95% confidence interval 2.75-43.8], P < .01). Use of perioperative therapeutic anticoagulation was associated with higher rates of transfusion (odds ratio 3.51 [95% confidence interval 1.34-8.53], P < .01). Neither intraoperative blood loss nor operative times were associated with an increased transfusion requirement or need for operative intervention. CONCLUSION: Patients undergoing transversus abdominis release are at a high risk of postoperative bleeding that can require transfusion and reoperation. Patients requiring postoperative therapeutic anticoagulation are at particularly high risk.

Sequential surgeries following transversus abdominis release for abdominal wall reconstruction: Insights from a single-center analysis.

INTRODUCTION: Abdominal surgery following transversus abdominis release (TAR) procedure commonly involves incisions through the previously implanted mesh, potentially creating vulnerabilities for hernia recurrence. Despite the popularity of the TAR procedure, current literature regarding post-AWR surgeries is limited. This study aims to reveal the incidence and outcomes of post-TAR non-hernia-related abdominal surgeries of any kind. METHODS: Adult patients who underwent non-hernia-related abdominal surgery following ventral hernia repair with concurrent TAR procedure and permanent synthetic mesh in the Cleveland Clinic Center for Abdominal Core Health between January 2014 and January 2022 were queried from a prospectively collected database in the Abdominal Core Health Quality Collaborative. We evaluated 30-day wound morbidity, perioperative complications, and long-term hernia recurrence. RESULTS: A total of 1137 patients who underwent TAR procedure were identified, with 53 patients (4.7%) undergoing subsequent non-hernia-related abdominal surgery post-TAR. Small bowel obstruction was the primary indication for reoperation (22.6%), and bowel resection was the most frequent procedure (24.5%). 49.1% of the patients required urgent or emergent surgery, with the majority (70%) having open procedures. Fascia closure was achieved by absorbable sutures in 50.9%, and of the open cases, fascia closure was achieved by running sutures technique in 35.8%. 20.8% experienced SSO, the SSOPI rate was 11.3%, and 26.4% required more than a single reoperation. A total of 88.7% were available for extended follow-up, spanning 17-30 months, resulting in a 36.1% recurrent hernia diagnosis rate. CONCLUSIONS: Abdominal surgery following TAR surgery is associated with significant comorbidities and significantly impacts hernia recurrence rates. Our study findings underscore the significance of making all efforts to minimize reoperations after TAR procedure and offers suggestions on managing the abdominal wall of these complex cases.

Real-world effectiveness of ustekinumab and vedolizumab in TNF-exposed pediatric patients with ulcerative colitis.

OBJECTIVES: Vedolizumab (VDZ) and ustekinumab (UST) are second-line treatments in pediatric patients with ulcerative colitis (UC) refractory to antitumor necrosis factor (anti-TNF) therapy. Pediatric studies comparing the effectiveness of these medications are lacking. Using a registry from ImproveCareNow (ICN), a global research network in pediatric inflammatory bowel disease, we compared the effectiveness of UST and VDZ in anti-TNF refractory UC. METHODS: We performed a propensity-score weighted regression analysis to compare corticosteroid-free clinical remission (CFCR) at 6 months from starting second-line therapy. Sensitivity analyses tested the robustness of our findings to different ways of handling missing outcome data. Secondary analyses evaluated alternative proxies of response and infection risk. RESULTS: Our cohort included 262 patients on VDZ and 74 patients on UST. At baseline, the two groups differed on their mean pediatric UC activity index (PUCAI) (p = 0.03) but were otherwise similar. At Month 6, 28.3% of patients on VDZ and 25.8% of those on UST achieved CFCR (p = 0.76). Our primary model showed no difference in CFCR (odds ratio: 0.81; 95% confidence interval [CI]: 0.41-1.59) (p = 0.54). The time to biologic discontinuation was similar in both groups (hazard ratio: 1.26; 95% CI: 0.76-2.08) (p = 0.36), with the reference group being VDZ, and we found no differences in clinical response, growth parameters, hospitalizations, surgeries, infections, or malignancy risk. Sensitivity analyses supported these findings of similar effectiveness. CONCLUSIONS: UST and VDZ are similarly effective for inducing clinical remission in anti-TNF refractory UC in pediatric patients. Providers should consider safety, tolerability, cost, and comorbidities when deciding between these therapies.

Long-term mesh-related complications from minimally invasive intraperitoneal onlay mesh for small to medium-sized ventral hernias.

INTRODUCTION: Intraperitoneal onlay mesh (IPOM) placement for small to medium-sized hernias has garnered negative attention due to perceived long-term risk of mesh-related complications. However, sparse data exists supporting such claims after minimally invasive (MIS) IPOM repairs and most is hindered by the lack of long-term follow-up. We sought to report long-term outcomes and mesh-related complications of MIS IPOM ventral hernia repairs. METHODS AND PROCEDURES: Adult patients who underwent MIS IPOM ventral hernia repair at our institution were identified in the Abdominal Core Health Quality Collaborative database from October 2013 to October 2020. Outcomes included hernia recurrence and mesh-related complications or reoperations up to 6 years postoperatively. RESULTS: A total of 325 patients were identified. The majority (97.2%) of cases were elective, non-recurrent (74.5%), and CDC class I (99.4%). Mean hernia width was 4.16 ± 3.86 cm. Median follow-up was 3.6 (IQR 2.8-5) years. Surgeon-entered or patient-reported follow-up was available for 253 (77.8%) patients at 3 years or greater postoperatively. One patient experienced an early small bowel obstruction and was reoperated on within 30 days. Two-hundred forty-five radiographic examinations were available up to 6 years postoperatively. Twenty-seven patients had hernia recurrence on radiographic examination up to 6 years postoperatively. During long-term follow-up, two mesh-related complications required reoperations: mesh removed for chronic pain and mesh removal at the time of colon surgery for perforated cancer. Sixteen additional patients required reoperation within 6 years for the following reasons: hernia recurrence (n = 5), unrelated intraabdominal pathology (n = 9), obstructed port site hernia (n = 1), and adhesive bowel obstruction unrelated to the prosthesis (n = 1). The rate of reoperation due to intraperitoneal mesh complications was 0.62% (2/325) with up to 6 year follow-up. CONCLUSION: Intraperitoneal mesh for repair of small to medium-sized hernias has an extremely low rate of long-term mesh-related complications. It remains a safe and durable option for hernia surgeons.

Abdominal Wall Tension and Early Outcomes after Posterior Component Separation with Transversus Abdominis Release: Does a "Tension-Free" Closure Really Matter?

BACKGROUND: Ventral hernias result in fibrosis of the lateral abdominal wall muscles, increasing tension on fascial closure. Little is known about the effect of abdominal wall tension on outcomes after abdominal wall reconstruction. We aimed to identify an association between abdominal wall tension and early postoperative outcomes in patients who underwent posterior components separation (PCS) with transversus abdominis release (TAR). STUDY DESIGN: Using a proprietary, sterilizable tensiometer, the tension needed to bring the anterior fascial elements to the midline of the abdominal wall during PCS with TAR were recorded. Tensiometer measurements, in pounds (lb), were calibrated by accounting for the acceleration of Earth's gravity. Baseline fascial tension, change in fascial tension, and fascial tension at closure were evaluated with respect to 30-day outcomes, including wound morbidity, hospital readmission, reoperation, ileus, bleeding, and pulmonary complications. RESULTS: A total of 100 patients underwent bilateral abdominal wall tensiometry, for a total of 200 measurements (left and right side for each patient). Mean baseline anterior fascial tension was 6.78 lb (SD 4.55) on each side. At abdominal closure, the mean anterior fascial tension was 3.12 (SD 3.21) lb on each side. Baseline fascial tension and fascial tension after PCS with TAR at abdominal closure were not associated with surgical site infection, surgical site occurrence, readmission, ileus, and bleeding requiring transfusion. The event rates for all other complications were too infrequent for statistical analysis. CONCLUSION: Baseline and residual fascial tension of the anterior abdominal wall do not correlate with early postoperative morbidity in patients undergoing PCS with TAR. Further work is needed to determine if abdominal wall tension in this context is associated with long-term outcomes, such as hernia recurrence.

Reducing the incidence of surgical site infection after ventral hernia repair: Outcomes from the RINSE randomized control trial.

BACKGROUND: The clinical and financial impact of surgical site infection after ventral hernia repair is significant. Here we investigate the impact of dual antibiotic irrigation on SSI after VHR. METHODS: This was a multicenter, prospective randomized control trial of open retromuscular VHR with mesh. Patients were randomized to gentamicin â€‹+ â€‹clindamycin (G â€‹+ â€‹C) (n â€‹= â€‹125) vs saline (n â€‹= â€‹125) irrigation at time of mesh placement. Primary outcome was 30-day SSI. RESULTS: No significant difference was seen in SSI between control and antibiotic irrigation (9.91 vs 9.09 â€‹%; p â€‹= â€‹0.836). No differences were seen in secondary outcomes: SSO (11.71 vs 13.64 â€‹%; p â€‹= â€‹0.667); 90-day SSO (11.1 vs 13.9 â€‹%; p â€‹= â€‹0.603); 90-day SSI (6.9 vs 3.8 â€‹%; p â€‹= â€‹0.389); SSIPI (7.21 vs 7.27 â€‹%, p â€‹= â€‹0.985); SSOPI (3.6 vs 3.64 â€‹%; p â€‹= â€‹0.990); 30-day readmission (9.91 vs 6.36 â€‹%; p â€‹= â€‹0.335); reoperation (5.41 vs 0.91 â€‹%; p â€‹= â€‹0.056). CONCLUSION: Dual antibiotic irrigation with G â€‹+ â€‹C did not reduce the risk of surgical site infection during open retromuscular ventral hernia repair.

Mesh versus suture repair of incisional hernias 2 cm or less: Is mesh necessary? A propensity score-matched analysis of the abdominal core health quality collaborative.

BACKGROUND: Mesh has been the acceptable standard for incisional hernia repair regardless of hernia size. It is not clear whether there is a size of incisional hernias in whom repair would be best performed without mesh. This study aims to compare outcomes of mesh versus suture repairs for incisional hernias <2 cm in size. METHODS: Incisional hernia repairs from 2012 to 2021 for hernias ≤2 cm in width were queried from the Abdominal Core Health Quality Collaborative. Those with 1-year follow up were considered. Hernia recurrence was defined using composite hernia recurrence, which combines both clinical and patient reported outcomes. Propensity score matching was performed between mesh and non-mesh using body mass index, smoking, diabetes, and drains as covariates. RESULTS: A total of 352 patients met inclusion criteria. After propensity score matching, there were 132 repairs with mesh and 71 without. There was no difference in recurrence rates at 1 year between mesh and non-mesh repairs (15% vs 24%, P = .12). Mesh was associated with a higher rate of 30-day postoperative complications (11% vs 1%, P = .017). There were no differences in 1-year quality of life scores. CONCLUSION: The repair of incisional hernias ≤2 cm without mesh results in similar recurrence rates, similar quality of life scores, and lower postoperative early complications compared with repairs with mesh. Our findings suggest that there may be select patients with small incisional hernias that could reasonably undergo incisional hernia repair without mesh. Longer-term follow-up is needed to confirm ideal candidates and durability of these repairs.

Recommendations for Standardizing MRI-based Evaluation of Perianal Fistulizing Disease Activity in Pediatric Crohn's Disease Clinical Trials.

BACKGROUND: Perianal fistulas and abscesses occur commonly as complications of pediatric Crohn's disease (CD). A validated imaging assessment tool for quantification of perianal disease severity and activity is needed to evaluate treatment response. We aimed to identify magnetic resonance imaging (MRI)-based measures of perianal fistulizing disease activity and study design features appropriate for pediatric patients. METHODS: Seventy-nine statements relevant to MRI-based assessment of pediatric perianal fistulizing CD activity and clinical trial design were generated from literature review and expert opinion. Statement appropriateness was rated by a panel (N = 15) of gastroenterologists, radiologists, and surgeons using modified RAND/University of California Los Angeles appropriateness methodology. RESULTS: The modified Van Assche Index (mVAI) and the Magnetic Resonance Novel Index for Fistula Imaging in CD (MAGNIFI-CD) were considered appropriate instruments for use in pediatric perianal fistulizing disease clinical trials. Although there was concern regarding the use of intravascular contrast material in pediatric patients, its use in clinical trials was considered appropriate. A clinically evident fistula tract and radiologic disease defined as at least 1 fistula or abscess on pelvic MRI were considered appropriate trial inclusion criteria. A coprimary clinical and radiologic end point and inclusion of a patient-reported outcome were also considered appropriate. CONCLUSION: Outcomes of treatment of perianal fistulizing disease in children must include MRI. Existing multi-item measures, specifically the mVAI and MAGNIFI-CD, can be adapted and used for children. Further research to assess the operating properties of the indices when used in a pediatric patient population is ongoing.

Open retromuscular keyhole compared with Sugarbaker mesh for parastomal hernia repair: Early results of a randomized clinical trial.

BACKGROUND: Open parastomal hernia repair can be performed using retromuscular synthetic mesh in a keyhole or Sugarbaker configuration. Relative morbidity and durability are unknown. Here, we present perioperative outcomes of a randomized controlled trial comparing these techniques, including 30-day patient-reported outcomes, reoperations, and wound complications in ≤90 days. METHODS: This single-center randomized clinical trial compared open parastomal hernia repair with retromuscular medium-weight polypropylene mesh in the keyhole and Sugarbaker configuration for permanent stomas between April 2019 and April 2022. Adult patients with parastomal hernias requiring open repair with sufficient bowel length for either technique were included. Patient-reported outcomes were collected at 30 days; 90-day outcomes included initial hospital length of stay, readmission, wound morbidity, reoperation, and mesh- or stoma-related complications. RESULTS: A total of 150 patients were randomized (75 keyhole and 75 Sugarbaker). There were no differences in length of stay, readmission, reoperation, recurrence, or wound complications. Twenty-four patients (16%) required procedural intervention for wound morbidity. Ten patients (6.7%) required abdominal reoperation in ≤90 days, 7 (4.7%) for wound morbidity, including 3 partial mesh excisions (1 keyhole compared with 2 Sugarbaker; P = 1). Four mesh-related stoma complications requiring reoperations occurred, including stoma necrosis (n = 1), bowel obstruction (n = 1), parastomal recurrence (n = 1), and mucocutaneous separation (n = 1), all in the Sugarbaker arm (P = .12). Patient-reported outcomes were similar between groups at 30 days. CONCLUSION: Open parastomal hernia repair with retromuscular mesh in the keyhole and Sugarbaker configurations had similar perioperative outcomes. Patients will be followed to determine long-term relative durability, which is critical to understanding each approach's risk-benefit ratio.

Tipping the scale in abdominal wall reconstruction: An analysis of short- and long-term outcomes by body mass index.

BACKGROUND: Morbid obesity, with a body mass index 35 kg/m2, is a commonly used cutoff for denying elective transversus abdominis release. Although obesity is linked to short-term wound morbidity, its effect on long-term outcomes remains unknown, calling into question if a cutoff is justified. We sought to compare 1-year recurrence rates after transversus abdominis release based on body mass index and to evaluate short- and long-term outcomes. METHODS: Patients undergoing open, clean transversus abdominis release from August 2014 to January 2022 at our institution with 1-year follow-up completed were identified. Univariate and multivariable analyses were performed to determine the association of body mass index with 90-day wound events, 1-year hernia recurrence, and hernia-specific quality of life. Covariates included body mass index, diabetes, recurrent hernia, hernia width, fascial closure, surgical site occurrence requiring procedural intervention, previous abdominal wall surgical site infection, inflammatory bowel disease, mesh weight, and mesh-to-hernia size ratio. RESULTS: A total of 1,089 patients were included. Increasing body mass index was associated with surgical site infection (adjusted odds ratio = 1.59; 95% confidence interval, 1.14-1.77; P < .01) and surgical site occurrence (adjusted odds ratio = 1.42; 95% confidence interval, 1.13-1.74; P < .01) but was not associated with surgical site occurrence requiring procedural intervention. Hernia width was associated with surgical site occurrence (adjusted odds ratio = 1.4; 95% confidence interval, 1.08-1.82; P < .01) and surgical site occurrence requiring procedural intervention (adjusted odds ratio = 1.4; 95% confidence interval, 1.08-1.82; P = .01). Hernia recurrence rate at 1 year was lower for the body mass index ≥35 kg/m2 group (7% vs 12%; P = .02). Hernia width (odds ratio = 1.33; 95% confidence interval, 1.02-1.74; P = .04) was associated with recurrence; body mass index was not (P = .11). Both groups experienced significant improvement in hernia-specific quality of life at 1 year. CONCLUSION: Morbid obesity is associated with 90-day wound morbidity; however, short-term complications did not translate to higher reoperation or long-term recurrence rates. The impact of body mass index on hernia recurrence is likely overstated. An arbitrary body mass index cutoff of 35 kg/m2 should not be used to deny symptomatic patients abdominal wall reconstruction.

Evaluating the impact of lifting mandatory smoking cessation prior to elective abdominal wall reconstruction. A single-center experience.

INTRODUCTION: Many studies identify active smoking as a significant risk factor for postoperative wound and mesh complications in patients undergoing abdominal wall reconstruction surgery. However, our group conducted an analysis using data from the ACHQC database, which revealed similar rates of surgical site infection (SSI) and surgical site occurrence requiring procedural intervention (SSOPI) between active smokers and non-smokers As a result, the Cl eveland Clinic Center for Abdominal Core Health instituted a policy change where active smokers were no longer subject to surgical delay. Our study aims to evaluate the impact of active smoking on the outcomes of these patients. METHODS: We identified active smoking patients who had undergone open, elective, clean ventral hernia repair (VHR) with transversus abdominis release (TAR) and permanent synthetic mesh at Cleveland Clinic Foundation. Propensity matching was performed to create a 1:3 ratio of "current-smokers" and "never-smokers" and compared wound complications and all 30-day morbidity between the two groups. RESULTS: 106 current-smokers and 304 never-smokers were matched. Demographics were similar between the two groups after matching, with the exception of chronic obstructive pulmonary disease (COPD) (22.1% vs. 13.4%, p â€‹< â€‹.001) and body mass index (BMI) (31.1 vs. 32.6, p â€‹= â€‹.02). Rates of SSI (12.2% vs. 6.9%, p â€‹= â€‹.13), SSO (21.7% vs. 13.2%, p â€‹= â€‹.052), SSOPI (11.3% vs. 6.3%, p â€‹= â€‹.13), and reoperation (1.9% vs. 3.9%, p â€‹= â€‹.53) were not significantly different between active smokers and never-smokers correspondingly. One case (0.3%) of partial mesh excision was observed in the never-smokers group (p â€‹= â€‹1). The current-smokers group exhibited a significantly higher incidence of pneumonia compared to the never-smokers group (5.7% vs. 0.7%, p â€‹= â€‹.005). CONCLUSION: Our study revealed that operating on active smokers did result in a slight increase in wound morbidity, although it did not reach statistical significance. Additionally, pulmonary complications were higher in the smoking group. Notably, we did not see any mesh infections in the smoking group during early follow up. We believe that this data is important for shared decision making on patients that are actively smoking contemplating elective hernia repair.

Revisiting femoral hernia diagnosis rates by patient sex in inguinal hernia repairs.

INTRODUCTION: Guidelines recommend MIS repairs for females with inguinal hernias, despite limited evidence. We investigated rates of femoral hernias intraoperatively noted during MIS and Lichtenstein repairs in females. METHODS: ACHQC was queried for adult females undergoing inguinal hernia repair between January 2014-November 2022. Outcomes included identified femoral hernia and size, hernia recurrence, quality of life, and sex-based recurrence. RESULTS: 1357 and 316 females underwent MIS and Lichtenstein inguinal repair respectively. Femoral hernias were identified more frequently in MIS than open repairs (27%vs12%; (p â€‹< â€‹0.001). Most femoral hernias in MIS (61%) and Lichtenstein repairs (62%) were <1.5 â€‹cm(p â€‹< â€‹0.001). Identification rates of femoral hernias >3 â€‹cm were 1% overall(p â€‹= â€‹0.09). Surgeon and patient-reported recurrences were similar between approaches at 1-5-years for females(p â€‹> â€‹0.05 for all) and similar between sexes(p â€‹> â€‹0.05). CONCLUSION: Most incidental femoral hernias are small and both repair approaches demonstrated similar outcomes. The recommendation for MIS inguinal hernia repairs in females is potentially overstated.

Quantitative Tension on the Abdominal Wall in Posterior Components Separation With Transversus Abdominis Release.

Importance: Posterior components separation (PCS) is a commonly used myofascial release technique in ventral hernia repairs. The contribution of each release with anterior and posterior fascial advancement has not yet been characterized in patients with ventral hernias. Objective: To quantitatively assess the changes in tension on the anterior and posterior fascial elements of the abdominal wall during PCS to inform surgeons regarding the technical contribution of each step with those changes, which may help to guide intraoperative decision-making. Design, Setting, and Participants: This case series enrolled patients from December 2, 2021, to August 2, 2022, and was conducted at the Cleveland Clinic Center for Abdominal Core Health. The participants included adult patients with European Hernia Society classification M1 to M5 ventral hernias undergoing abdominal wall reconstruction with PCS. Intervention: A proprietary, sterilizable tensiometer measured the force needed to bring the fascial edge of the abdominal wall to the midline after each step of a PCS (retrorectus dissection, division of the posterior lamella of the internal oblique aponeurosis, and transversus abdominis muscle release [TAR]). Main Outcome: The primary study outcome was the percentage change in tension on the anterior and posterior fascia associated with each step of PCS with TAR. Results: The study included 100 patients (median [IQR] age, 60 [54-68] years; 52 [52%] male). The median (IQR) hernia width was 13.0 (10.0-15.2) cm. After complete PCS, the mean (SD) percentage changes in tension on the anterior and posterior fascia were -53.27% (0.53%) and -98.47% (0.08%), respectively. Of the total change in anterior fascial tension, retrorectus dissection was associated with a mean (SD) percentage change of -82.56% (0.68%), incision of the posterior lamella of the internal oblique with a change of -17.67% (0.41%), and TAR with no change. Of the total change in posterior fascial tension, retrorectus dissection was associated with a mean (SD) percentage change of -3.04% (2.42%), incision of the posterior lamella of the internal oblique with a change of -58.78% (0.39%), and TAR with a change of -38.17% (0.39%). Conclusions and Relevance: In this case series, retrorectus dissection but not TAR was associated with reduced tension on the anterior fascia, suggesting that it should be performed if anterior fascial advancement is needed. Dividing the posterior lamella of the internal oblique aponeurosis and TAR was associated with reduced tension on the posterior fascia, suggesting that it should be performed for posterior fascial advancement.

Oncogenic context shapes the fitness landscape of tumor suppression.

Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged-the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context-and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.

Early wound morbidity and clinical outcomes associated with P4HB mesh compared to permanent synthetic mesh in umbilical and small to medium, routine ventral hernia repairs.

Background: Permanent synthetic meshes such as polypropylene (PP) have been utilized for hernia repair for decades, but concerns remain regarding potential long-term, mesh-related complications. A resorbable polymer such as poly-4-hydroxybutyrate (P4HB) represents an alternative with high initial strength, that gradually resorbs, leaving an abdominal wall that is at least as strong as it would be in its native state. We aimed to compare early wound morbidity and clinical outcomes associated with P4HB to traditional, permanent PP in umbilical and small to medium, routine ventral hernias using data from the Abdominal Core Health Quality Collaborative (ACHQC). Methods: Inclusion criteria for the umbilical cohort included: all Centers for Disease Control and Prevention (CDC) wound classes, all Ventral Hernia Working Group (VHWG) hernia grades, and hernia defects <3 cm. The small to medium, routine ventral hernia cohort was limited to CDC class I wounds, VHWG hernia grades I and II, and hernia defects <5 cm. The study group was comprised of P4HB meshes; the comparator group was an aggregate of PP meshes. Clinical outcomes were assessed at 30 days. Results: There was no significant difference in early wound morbidity, readmission, or reoperation between the P4HB and PP cohorts. A small number of patients experienced SSO, with ≤4% requiring procedural intervention. None of the patients (0% in all cases) experienced skin/soft tissue necrosis, infected seroma, infected hematoma, exposed/contaminated/infected mesh, enterocutaneous fistula, graft failure, or pain requiring intervention at 30-days. However, P4HB was associated with significantly greater operative time, length of stay, and use of myofascial release compared to PP (p < 0.05 in all cases). Conclusions: Short-term clinical outcomes associated with resorbable P4HB mesh are comparable to permanent synthetic PP mesh in umbilical and small to medium, routine ventral hernia repairs, despite significant differences in operative time and length of stay. Longer-term follow-up is needed to expand on the clinical relevance of these short-term findings.

Ventral Hernia Repair: Does Mesh Position Matter?

Mesh positioning is a commonly discussed detail in ventral hernia repair and is often cited as a major contributor to the outcome of the operation. However, there is a paucity of data that establishes one plane as superior to others. In this article, we will provide an overview of all potential planes to place prosthetic material and review the relevant literature supporting each option and the complications associated with accessing each anatomic plane.