Ubiquitin-specific protease 7 inhibitors reveal a differentiated mechanism of p53-driven anti-cancer activity.

The USP7 deubiquitinase regulates proteins involved in the cell cycle, DNA repair, and epigenetics and has been implicated in cancer progression. USP7 inhibition has been pursued for the development of anti-cancer therapies. Here, we describe the discovery of potent and specific USP7 inhibitors exemplified by FX1-5303. FX1-5303 was used as a chemical probe to study the USP7-mediated regulation of p53 signaling in cells. It demonstrates mechanistic differences compared to MDM2 antagonists, a related class of anti-tumor agents that act along the same pathway. FX1-5303 synergizes with the clinically approved BCL2 inhibitor venetoclax in acute myeloid leukemia (AML) cell lines and ex vivo patient samples and leads to strong tumor growth inhibition in in vivo mouse xenograft models of multiple myeloma and AML. This work introduces new USP7 inhibitors, differentiates their mechanism of action from MDM2 inhibition, and identifies specific opportunities for their use in the treatment of AML.

Short-term Outcomes After Laparoscopic IPOM Versus Robot-assisted Retromuscular Repair of Small to Medium Ventral Hernias: A Nationwide Database Study.

OBJECTIVE: To examine the short-term outcomes after laparoscopic intraperitoneal onlay mesh (IPOM) compared with robot-assisted retromuscular repair of small to medium-sized ventral hernia. BACKGROUND: With the introduction of a robot-assisted approach, retromuscular mesh placement is technically more feasible compared with laparoscopic IPOM, with potential gains for the patient, including avoidance of painful mesh fixation and intraperitoneal mesh placement. METHODS: This was a nationwide cohort study of patients undergoing either laparoscopic IPOM or robot-assisted retromuscular repair of a ventral hernia with a horizontal fascial defect <7 cm in the period 2017 to 2022, matched in a 1:2 ratio using propensity scores. Outcomes included postoperative hospital length of stay, 90-day readmission, and 90-day operative reintervention, and multivariable logistic regression analysis was performed to adjust for the relevant confounder. RESULTS: A total of 1136 patients were included for analysis. The rate of IPOM-repaired patients hospitalized > 2 days was more than 3 times higher than after robotic retromuscular repair (17.3% vs. 4.5%, P < 0.001). The incidence of readmission within 90 days postoperatively was significantly higher after laparoscopic IPOM repair (11.6% vs. 6.7%, P =0.011). There was no difference in the incidence of patients undergoing operative intervention within the first 90 days postoperatively (laparoscopic IPOM 1.9% vs. robot-assisted retromuscular 1.3%, P =0.624). CONCLUSIONS: For patients undergoing first-time repair of a ventral hernia, robot-assisted retromuscular repair was associated with a significantly reduced incidence of prolonged length of postoperative hospital stay and risk of 90-day readmission compared to laparoscopic IPOM.

Trends in Use of Laparoscopic Intraperitoneal Onlay Mesh for Ventral Hernia Repair.

This cohort study examines changes in the proportion of laparoscopic intraperitoneal onlay mesh procedures performed for hernia repair in Denmark since initial description of the procedure.

Outcomes After Spigelian Hernia Repair: A Nationwide Database Study.

BACKGROUND: Spigelian hernia is a rare hernia of the abdominal wall. Due to lack of evidence, there is no standard recommendation for surgical technique of Spigelian hernia repair. The aim of this study was to evaluate the outcomes after open and laparoscopic, elective and emergency repair of Spigelian hernias on a nationwide basis. METHODS: Nationwide data from the Danish Ventral Hernia Database and the National Patient Registry was assessed to analyze outcomes after Spigelian hernia repair. A total of 365 patients were operated for Spigelian hernia in Denmark from 2007 to 2018. Ninety-day readmission, 90-day reoperation and long-term operation for recurrence were evaluated, as well as possible differences between open and laparoscopic, and elective and emergency repairs. RESULTS: Most of the patients (80.5%, 294/365) were operated by laparoscopic approach and 19.5% (71/365) were operated by open approach. Elective surgery was performed in 83.6% (305/365) of the patients and 16.4% (60/365) underwent emergency repair. There were no significant differences in 90-day readmission or reoperation rates between open or laparoscopic Spigelian hernia repairs, P = 0.778 and P = 0.531. Ninety-day readmission and 90-day reoperation rates were also comparable for elective versus emergency repair, P = 0.399 and P = 0.766. No difference was found in operation for recurrence rates between elective and emergency, nor open and laparoscopic Spigelian hernia repairs. CONCLUSIONS: This study demonstrates that 16% of Spigelian hernia repairs are done in the emergency setting. Open and laparoscopic approach are comparable in terms of early readmission, reoperation, and recurrence rates.

Robot-assisted TAMIS: a systematic review of feasibility and outcomes.

BACKGROUND: In the advancement of transanal local excision, robot-assisted transanal minimal invasive surgery is the newest development. In the confined area of the rectum, robot-assisted surgery should, theoretically, be superior due to articulated utensils, video enhancement, and tremor reduction, however, this has not yet been investigated. The aim of this study was to review the evidence reported to-date on experience of using robot-assisted transanal minimal invasive surgery for treatment of rectal neoplasms. METHODS: A comprehensive literature search of Embase and PubMed from May to August 2021were performed. Studies including patients diagnosed with rectal neoplasia or benign polyps who underwent robot-assisted transanal minimal invasive surgery were included. All studies were assessed for risk of bias through assessment tools. Main outcome measures were feasibility, excision quality, and complications. RESULTS: Twenty-five studies with a total of 322 local excisions were included. The studies included were all retrospective, primarily case-reports, -series, and cohort studies. The median distance from the anal verge ranged from 3.5 to 10 cm and the median size was between 2.5 and 5.3 cm. Overall, 4.6% of the resections had a positive resection margin. The overall complication rate was at 9.5% with severe complications (Clavien-Dindo score III) at 0.9%. CONCLUSION: Based on limited, retrospective data, with a high risk of bias, robot-assisted transanal minimal invasive surgery seems feasible and safe for local excisions in the rectum.

Endoscopic Anterior Component Separation and Transversus Abdominus Release are not Associated with Increased Wound Morbidity Following Retromuscular Incisional Hernia Repair.

INTRODUCTION: Traditional anterior component separation during incisional hernia repair (IHR) is associated with a high rate of postoperative wound morbidity. Because extensive subcutaneous dissection is avoided by endoscopic anterior component separation (eACS) or open transversus abdominis release (TAR), we hypothesized that these techniques did not increase the incidence of surgical site occurrence (SSO) compared to IHR without component separation (CS). MATERIAL AND METHOD: This was a retrospective single-center cohort study of patients undergoing open retromuscular IHR comparing patients with or without the use of CS. Retromuscular mesh repair was performed in all patients, and CS was obtained by eACS or TAR. The primary outcome was 90-day incidence of postoperative SSO. Secondary outcomes included length of stay (LOS), 90-day readmission, 90-day reoperation rate and 3-year recurrence rate. RESULTS: A total of 321 patients underwent retromuscular repair, 168 (52.3%) of whom received either eACS or TAR. The addition of eACS or TAR was associated neither with development of SSO (odds ratio: 1.80, 95% confidence interval: 0.94-3.46, P = 0.077) nor with hernia recurrence (hazard ratio 0.77, 0.26-2.34, P = 0.648). There was no significant difference between the groups regarding the frequencies of 90-day readmission or 90-day reoperation. CONCLUSION: eACS or TAR as adjuncts to open retromuscular IHR were not associated with increased wound morbidity or hernia recurrence.

Less postoperative pain and shorter length of stay after robot-assisted retrorectus hernia repair (rRetrorectus) compared with laparoscopic intraperitoneal onlay mesh repair (IPOM) for small or medium-sized ventral hernias.

BACKGROUND: The optimal repair of ventral hernia remains unknown. We aimed to evaluate the results after robotic-assisted laparoscopic transabdominal repair with retrorectus mesh placement (rRetrorectus) compared with laparoscopic intraperitoneal onlay mesh repair (IPOM) for patients with small- or medium-sized ventral hernia. METHODS: This was a retrospective cohort study of consecutive patients undergoing elective rRetrorectus or IPOM repair for small or medium-sized primary ventral or incisional hernias. The primary outcome was the postoperative need for transverse abdominis plane (TAP) block or epidural analgesia, secondary outcomes were length of stay and postoperative complications. All patients were followed for 30 days postoperatively. RESULTS: A total of 59 patients were included undergoing rRetrorectus (n = 27) and IPOM (n = 32). Patients in the two groups were comparable in terms of age, sex, comorbidities, smoking status, body mass index (BMI), and type of hernia. The median fascial defect area was slightly larger in the rRetrorectus group (9 cm2 vs. 6.2 cm2, P = 0.031). The duration of surgery was longer for rRetrorectus (median 117.2 min. vs. 84.4, P = 0.003), whereas the postoperative need for TAP block or epidural analgesia was less after rRetrorectus compared with IPOM (3.7% versus 43.7%, P = 0.002). There were no severe complications or reoperations after either procedure. The length of stay was shorter after rRetrorectus (median 0 vs. 1 day, P < 0.001). CONCLUSIONS: rRetrorectus was associated with reduced postoperative analgesic requirement and shorter length of stay compared with laparoscopic IPOM. Registration Clinicaltrial.gov: NCT05320055.

The European Hernia Society Prehabilitation Project: A Systematic Review of Intra-Operative Prevention Strategies for Surgical Site Occurrences in Ventral Hernia Surgery.

Background: Ventral hernia repair is one of the most commonly performed surgical procedures worldwide. To reduce the risk of complications, pre- and intra-operative strategies have received increasing focus in recent years. To assess possible preventive surgical strategies, this European Hernia Society endorsed project was launched. The aim of this review was to evaluate the current literature focusing on pre- and intra-operative strategies for surgical site occurrences (SSO) and specifically surgical site infection (SSI) in ventral hernia repair. Methods: A systematic review was conducted and reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Databases used were Pubmed and Web of Science. Original retrospective or prospective human adult studies describing at least one intra-operative intervention to reduce SSO after ventral hernia repair were considered eligible. Results: From a total of 4775 results, a total of 18 papers were considered suitable after full text reading. Prehospital chlorhexidine gluconate (CHG) scrub appears to increase the risk of SSO in patients undergoing ventral hernia repair, while there is no association between any type of surgical hat worn and the incidence of postoperative wound events. Intraoperative measures as prophylactic negative pressure therapy, surgical drain placement and the use of quilt sutures seem beneficial for decreasing the incidence of SSO and/or SSI. No positive effect has been shown for antibiotic soaking of a synthetic mesh, nor for the use of fibrin sealants. Conclusion: This review identified a limited amount of literature describing specific preventive measures and techniques during ventral hernia repair. An advantage of prophylactic negative pressure therapy in prevention of SSI was observed, but different tools to decrease SSIs and SSOs continuously further need our full attention to improve patient outcomes and to lower overall costs.

Long-term results after resection of primary duodenal adenocarcinoma: A retrospective cohort study.

BACKGROUND: Radical resection of duodenal adenocarcinoma (DA) offers the possibility of cure. The outcome after operation and adjuvant therapy is mainly based on small numbers due to the low incidence of the disease. We examined the long-term outcome after surgical treatment of DA. MATERIAL AND METHODS: This was a retrospective cohort study including all patients undergoing curatively intended resection for histologically confirmed DA at a single University hospital. Long-term survival was examined by the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox proportional hazards regression analysis was applied to adjust for confounding. RESULTS: A total of 96 patients were included. The median follow-up was 3.7 years (IQR 2.9-4.3), during which 18 patients (18.5%) had recurrence and 35 (36.5%) patients had died. The 3- and 5-year overall survival was 66.3% (55.6-76.9%) and 58.2% (46.2-70.2%), respectively. In the multivariable analysis, adjuvant therapy was associated with decreased mortality (HR 0.29, CI 0.11-0.76, P = 0.011) whereas positive lymph node ratio >0.20 was associated with increased mortality. CONCLUSION: Radical operation for DA has a median overall 5-year-survival of more than 50%. The indication for adjuvant chemotherapy remains to be addressed.

Laparoscopic intraperitoneal versus enhanced-view totally extraperitoneal retromuscular mesh repair for ventral hernia: a retrospective cohort study.

BACKGROUND: Laparoscopic enhanced-view totally extraperitoneal retromuscular repair (eTEP-RM) was recently introduced as a new technique for ventral hernia repair. The aim of the current study was to examine the outcomes of laparoscopic eTEP-RM compared with laparoscopic IPOM for patients with primary ventral and incisional hernia. METHODS: This was a retrospective cohort study of patients undergoing laparoscopic ventral hernia repair at a single University Hospital from June 2017 to November 2020. Medical charts of all patients subjected to IPOM and eTEP-RM were evaluated to identify patient- and procedure related variables, as well as postoperative 30-day outcomes. RESULTS: A total of 72 patients were included in the study, 43 and 29 of whom underwent IPOM and eTEP-RM repair, respectively. Patient demographics showed no differences in terms of gender, age, smoking and comorbidity. The median age was 57 years and body mass index 30.5 kg/m2. The rate of patients with incisional hernia was higher in the IPOM group (39.5% vs. 20.7%, p = 0.154). There was no difference in horizontal and vertical hernia size defect. The duration of surgery was significantly shorter for IPOM (mean 82.4 vs. 103.4 min, p = 0.010), whereas the length of stay was significantly longer after IPOM (median 1 days vs. 0 days (p < 0.001). The rate of patients requiring postoperative transversus abdominis plane (TAP) block or epidural analgesia was significantly higher after IPOM (33% vs. 0%, p = 0.002). A subgroup analysis on patients undergoing primary ventral hernia showed similar results. CONCLUSION: The study found laparoscopic eTEP-RM safe and effective compared to traditional laparoscopic IPOM. The patients undergoing eTEP-RM had significantly reduced need for additional analgesic treatment and length of stay.

Leveraging Twitter and its Unique #HashTag Capability: A Novel Social Media Resource From the European Hernia Society.

Background: Digital and Social Media (#SoMe) platforms have revolutionized the way information is shared, classified and accessed among medical professionals worldwide. The aim of this study was to review the hashtags used on Twitter by @EuroHerniaS to provide a practical roadmap for easier social media utilization for hernia surgery stakeholders. Methods: The hashtags used in tweets and retweets of the @EuroHerniaS Twitter feed were collated since its foundation in November 2016. Results: The first hashtag used was #HerniaSurgery. Since foundation to July 2021, the @EuroHerniaS Twitter feed has used 90 separate hashtags. The number of new hashtags per year was increasing leading to the development of an online library. The increasing diversity of hernia related hashtags allows for the more detailed posting and searching of hernia related information on the #SoMe platform Twitter. Conclusion: The more detailed use of hashtags on Twitter is to be encouraged. Hernia surgeons can make use of them both when posting and reviewing posts to aid the categorization of posts.

Impact of the COVID-19 pandemic on the management of colorectal cancer in Denmark.

INTRODUCTION: The COVID-19 pandemic has had a global impact on cancer care but the extent to which this has affected the management of colorectal cancer (CRC) in different countries is unknown. CRC management in Denmark was thought to have been relatively less impacted than in other nations during the first wave of the pandemic. The aim of this study was to determine the pandemic's impact on CRC in Denmark. METHODS: The Danish national cancer registry identified patients with newly diagnosed with CRC from 1 March 2020 to 1 August 2020 (pandemic interval) and corresponding dates in 2019 (prepandemic interval). Data regarding clinicopathological demographics and perioperative outcomes were retrieved and compared between the two cohorts. RESULTS: Total CRC diagnoses (201 versus 359 per month, P = 0.008) and screening diagnoses (38 versus 80 per month, P = 0.016) were both lower in the pandemic interval. The proportions of patients presenting acutely and the stage at presentation were, however, unaffected. For those patients having surgery, both colonic and rectal cancer operations fell to about half the prepandemic levels: colon (187 (i.q.r. 183-188) to 96 (i.q.r. 94-112) per month, P = 0.032) and rectal cancers (63 (i.q.r. 59-75) to 32 (i.q.r. 28-42) per month, P = 0.008). No difference was seen in surgical practice or postoperative 30-day mortality rate (colon 2.2 versus 2.2 per cent, P = 0.983; rectal 1.0 versus 2.9 per cent, P = 0.118) between the cohorts. Treatment during the pandemic interval was not independently associated with death at 30 or 90 days. CONCLUSION: The initial wave of the COVID-19 pandemic reduced the number of new diagnoses made and number of operations but had limited impact on technique or outcomes of CRC care in Denmark.

The current role of blood-based biomarkers in surgical decision-making in patients with localised pancreatic cancer: A systematic review.

INTRODUCTION: The role of blood-based biomarkers in surgical decision-making in patients with localised pancreatic cancer remains unclear. This review aimed to report the utility of blood-based biomarkers focusing on prediction of response to neoadjuvant therapy, prediction of surgical resectability and early relapse after surgery. MATERIALS AND METHODS: MEDLINE/PubMed, Embase and Web of Science were searched till October 2019. Studies published between January 2000 and September 2019 with a minimum of 20 patients with pancreatic adenocarcinoma, reporting the utility of at least one blood-based biomarker in predicting response to neoadjuvant therapy and predicting surgical resectability or early relapse after surgery were included. RESULTS: A total of 2604 studies were identified, of which 24 comprising of 3367 patients and 12 blood-based biomarkers were included. All included studies were observational. Levels of carbohydrate antigen (CA)19-9 were reported in the majority of the studies. Levels of CA19-9 predicted the response to neoadjuvant therapy and early relapse in 10 studies. CA125 levels above 35 U/ml were predictive of surgical irresectability in two studies. However, marked variation in both timing of sampling and cut-off values was noted between studies. CONCLUSION: Despite some evidence of potential benefit, the utility of currently available blood-based biomarkers in aiding surgical decision-making in patients undergoing potentially curative treatment for pancreatic cancer is limited by methodological heterogeneity. Standardisation of future studies may allow a more comprehensive analysis of the biomarkers described in this review.

Recovery after laparoscopic parastomal hernia repair.

BACKGROUND: The perioperative care and postoperative period after laparoscopic hernia repair have not been well described. The aim of this study was to describe the postoperative course after laparoscopic parastomal hernia repair. METHODS: This was a prospective cohort study including consecutive patients undergoing laparoscopic parastomal hernia repair. The outcomes of interest were patient-reported pain, nausea and fatigue, time to stoma function, length of stay (LOS), use of transversus abdominis plane (TAP) block and epidural analgesia, the cumulative dose of morphine equivalent analgesics during the first 5 postoperative days, and postoperative complications. RESULTS: Forty patients were included, 20% had ileostomy and 80% colostomy. The mesh was placed according to Sugarbaker (87.5%) and keyhole (12.5%) technique. Twenty-two patients (55%) required peripheral nervous blockades postoperatively. The median number of days to stoma function was 3 days (range 2-3.8). The mean cumulative dose of morphine equivalent analgesics was 21.9 mg on the day of surgery, 27.8 mg on the first postoperative day (POD1), 23.9 on POD2, 17.3 mg on POD3, 15.3 mg on POD4, 8.9 mg on POD5, and 115.2 mg in total. The median LOS was 4 days (range 3-6). The incidence of postoperative complications was 25%. CONCLUSION: Laparoscopic parastomal hernia repair carried a high risk of complications. Further, analgesic treatment after surgery was insufficient, with high opioid requirements postoperatively, and more than half of the patients required peripheral nervous blockades, indicating that postoperative pain is a major issue in this patient group. Improved postoperative care for these patients is required.

Enhanced recovery after abdominal wall reconstruction: a systematic review and meta-analysis.

BACKGROUND: Enhanced recovery after surgery (ERAS) are evidence-based protocols associated with improved patient outcomes. The use of ERAS pathways is well documented in various surgical specialties. The aim of this systematic review and meta-analysis was to examine the efficacy of ERAS protocols in patients undergoing abdominal wall reconstruction (AWR). METHODS: This systematic review and meta-analysis were reported according to PRISMA and MOOSE guidelines. The databases PubMed, EMBASE, CINAHL, Web of Science and Cochrane Library were searched for original studies comparing ERAS with standard care in patients undergoing AWR. The primary outcome was length of stay (LOS) and secondary outcomes were readmission and surgical site infection (SSI) and/or surgical site occurrences (SSO). RESULTS: Five studies were included in the meta-analysis. All were retrospective cohort studies including 453 patients treated according to ERAS protocols, and 494 patients treated according to standard care. The meta-analysis demonstrated that patients undergoing AWR managed with ERAS had a mean 0.89 days reduction in LOS compared with patients treated with standard care (95% CI - 1.70 to - 0.07 days, p = 0.03). There was no statistically significant difference in readmission rate (OR 1.00, 95% CI 0.53 to 1.87, p = 1.00) or SSI/SSO (OR 1.19, 95% CI 0.67 to 2.11, p = 0.56) between groups. CONCLUSIONS: The use of ERAS in patients undergoing AWR was found to significantly reduce LOS without increasing the readmission rate or SSI/SSO. Based on the existing literature, ERAS protocols should be implemented for patients undergoing AWR.

Spontaneous intestinal bleeding due to pseudoaneurism of the gastroduodenal artery: case report of a rare complication to median arcuate ligament syndrome.

Median arcuate ligament syndrome (MALS) is the compression of the celiac artery (CA) by the median arcuate ligament. MALS can cause pseudoaneurysm of the gastroduodenal artery, which can lead to fatal bleeding. A 40-year-old male with no prior medical history presented with symptoms of upper gastrointestinal hemorrhage (UGIH). Severe duodenal bleeding was confirmed although endoscopic hemostasis was impossible and final hemostasis was achieved following a subsequent open duodenotomy. A postoperative computed tomographic angiography (CTA) visualized a significant CA stenosis, post-stenotic dilatation and an aneurysm on a jejunal branch artery. The patient underwent coiling of the gastroduodenal artery, gastroepiploic artery and two pancreaticoduodenal arterial branches. The patient was diagnosed with MALS and 6 months later underwent open resection of the median arcuate ligament. MALS should be considered as a rare cause of upper gastrointestinal bleeding. The literature and proposed treatments are discussed.

Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis.

Fibrosis, or the accumulation of extracellular matrix, is a common feature of many chronic diseases. To interrogate core molecular pathways underlying fibrosis, we cross-examine human primary cells from various tissues treated with TGF-ß, as well as kidney and liver fibrosis models. Transcriptome analyses reveal that genes involved in fatty acid oxidation are significantly perturbed. Furthermore, mitochondrial dysfunction and acylcarnitine accumulation are found in fibrotic tissues. Substantial downregulation of the PGC1α gene is evident in both in vitro and in vivo fibrosis models, suggesting a common node of metabolic signature for tissue fibrosis. In order to identify suppressors of fibrosis, we carry out a compound library phenotypic screen and identify AMPK and PPAR as highly enriched targets. We further show that pharmacological treatment of MK-8722 (AMPK activator) and MK-4074 (ACC inhibitor) reduce fibrosis in vivo. Altogether, our work demonstrate that metabolic defect is integral to TGF-ß signaling and fibrosis.

[Minimally invasive surgery for malignant diseases in pancreas].

Unlike most other abdominal procedures, pancreatic resection for malignant tumours is still predominantly performed as open surgery. However, recent published randomised trials suggest that a laparoscopic approach is safe and may offer advantages in the early postoperative period. Likewise, early reports of robot-assisted pancreatic resection suggest advantages. This reveiw describes the current status of minimally invasive pancreatic surgery for malignant tumours, including both laparoscopic and robot-assisted approaches for pancreaticoduodenectomy and distal pancreatectomy.