Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer.

MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.

Lymphatic Mapping in Colon Cancer Depending on Injection Time and Tracing Agent: A Systematic Review and Meta-Analysis of Prospective Designed Studies.

An optimized lymph node yield leads to better survival in colon cancer, but extended lymphadenectomy is not associated with survival benefits. Lymphatic mapping shows several colon cancers feature aberrant drainage pathways inducing local recurrence when not resected. Currently, different protocols exist for lymphatic mapping procedures. This meta-analysis assessed which protocol has the best capacity to detect tumor-draining and possibly metastatic lymph nodes. A systematic review was conducted according to PRISMA guidelines, including prospective trials with in vivo tracer application. The risk of bias was evaluated using the QUADAS-2 tool. Traced lymph nodes, total resected lymph nodes, and aberrant drainage detection rate were analyzed. Fifty-eight studies met the inclusion criteria, of which 42 searched for aberrant drainage. While a preoperative tracer injection significantly increased the traced lymph node rates compared to intraoperative tracing (30.1% (15.4, 47.3) vs. 14.1% (11.9, 16.5), p = 0.03), no effect was shown for the tracer used (p = 0.740) or the application sites comparing submucosal and subserosal injection (22.9% (14.1, 33.1) vs. 14.3% (12.1, 16.8), p = 0.07). Preoperative tracer injection resulted in a significantly higher rate of detected aberrant lymph nodes compared to intraoperative injection (26.3% [95% CI 11.5, 44.0] vs. 2.5% [95% CI 0.8, 4.7], p < 0.001). Analyzing 112 individual patient datasets from eight studies revealed a significant impact on aberrant drainage detection for injection timing, favoring preoperative over intraoperative injection (OR 0.050 [95% CI 0.010-0.176], p < 0.001) while indocyanine green presented itself as the superior tracer (OR 0.127 [95% CI 0.018-0.528], p = 0.012). Optimized lymphatic mapping techniques result in significantly higher detection of aberrant lymphatic drainage patterns and thus enable a personalized approach to reducing local recurrence.

Risk stratification of cirrhotic patients undergoing esophagectomy for esophageal cancer: A single-centre experience.

BACKGROUND: Concomitant liver cirrhosis is a crucial risk factor for major surgeries. However, only few data are available concerning cirrhotic patients requiring esophagectomy for malignant disease. METHODS: From a prospectively maintained database of esophageal cancer patients, who underwent curative esophagectomy between 01/2012 and 01/2016, patients with concomitant liver cirrhosis (liver-cirrhotic patients, LCP) were compared to non-liver-cirrhotic patients (NLCP). RESULTS: Of 170 patients, 14 cirrhotic patients with predominately low MELD scores (≤ 9, 64.3%) were identified. Perioperative outcome was significantly worse for LCP, as proofed by 30-day (57.1% vs. 7.7, p<0.001) and 90-day mortality (64.3% vs. 9.6%, p<0.001), anastomotic leakage rate (64.3 vs. 22.3%, p = 0.002) and sepsis (57.1 vs. 21.5%, p = 0.006). Even after adjustment for age, gender, comorbidities, and surgical approach, LCP revealed higher odds for 30-day and 90-day mortality compared to NLCP. Moreover, 5-year survival analysis showed a significantly poorer long-term outcome of LCP (p = 0.023). For risk stratification, none of the common cirrhosis scores proved prognostic impact, whereas components as Bilirubin (auROC 94.4%), INR (auROC = 90.0%), and preoperative ascites (p = 0.038) correlated significantly with the perioperative outcome. CONCLUSION: Curative esophagectomy for cirrhotic patients is associated with a dismal prognosis and should be evaluated critically. While MELD and Child score failed to predict perioperative mortality, Bilirubin and INR proofed excellent prognostic capacity in this cohort.

Management of Esophageal Cancer-Associated Respiratory-Digestive Tract Fistulas.

Respiratory-digestive tract fistulas are fatal complications that occur in esophageal cancer treatment. Interdisciplinary treatment strategies are still evolving, especially in anatomical treatment stratification. Thus, this study aims to evaluate general therapeutic strategies for this rare condition. Medical records were reviewed for esophageal cancer-associated respiratory-digestive tract fistula patients treated between January 2008 and September 2021. Fistulas were classified according to being surgery- and tumor-associated. Treatment strategies, clinical success, and survival were analyzed. A total of 51 patients were identified: 28 had tumor-associated fistulas and 23 surgery-associated fistulas. Risk factors for fistula development such as radiation (OR = 0.290, p = 0.64) or stent implantation (OR = 1.917, p = 0.84) did not correlate with lack of symptom control for RDF patients. In contrast, advanced lymph node metastasis as another risk factor was associated with persistent symptoms after treatment for RDF patients (OR = 0.611, p = 0.01). Clinical success significantly correlated with bilateral fistula repair in surgery-associated fistulas (p = 0.01), while tumor-associated fistulas benefited the most from non-surgical (p = 0.04) or combined surgical and non-surgical intervention (p = 0.04) and a bilateral fistula repair (p = 0.02) in terms of overall survival. The therapeutic strategy should aim for bilateral fistula closure. A multidisciplinary, stepwise approach might have the best chance for restoration or symptom control with optimized overall survival in selected patients.

Robotic rectal resection preserves anorectal function: Systematic review and meta-analysis.

BACKGROUND: Improving survival rates in rectal cancer patients has generated a growing interest in functional outcomes after total mesorectal excision (TME). The well-established low anterior resection syndrome (LARS) score assesses postoperative anorectal impairment after TME. Our meta-analysis is the first to compare bowel function after open, laparoscopic, transanal, and robotic TME. METHODS: All studies reporting functional outcomes after rectal cancer surgery (LARS score) were included, and were compared with a consecutive series of robotic TME (n = 48). RESULTS: Thirty-two publications were identified, including 5 565 patients. Anorectal function recovered significantly better within one year after robotic TME (3.8 [95%CI -9.709-17.309]) versus laparoscopic TME (26.4 [95%CI 19.524-33.286]), p = 0.006), open TME (26.0 [95%CI 24.338-29.702], p = 0.002) and transanal TME (27.9 [95%CI 22.127-33.669], p = 0.003). CONCLUSIONS: Robotic TME enables better recovery of anorectal function compared to other techniques. Further prospective, high-quality studies are needed to confirm the benefits of robotic surgery.

Systematic review analysis of robotic and transanal approaches in TME surgery- A systematic review of the current literature in regard to challenges in rectal cancer surgery.

Several patients' and pathological characteristics in rectal surgery can significantly complicate surgical loco regional tumor clearance. The main factors are obesity, short tumor distance from anal verge, bulky tumors, and narrow pelvis, which have been shown to be associated to poor surgical results in open and laparoscopic approaches. Minimally invasive surgery has the potential to reduce perioperative morbidity with equivalent short- and long-term oncological outcomes compared to conventional open approach. Achilles' heel of laparoscopic approaches is conversion to open surgery. High risk for conversion is evident for patients with bulky and low tumors as well as male gender and narrow pelvis. Hence, patient's characteristics represent challenges in rectal cancer surgery especially in minimally invasive approaches. The available surgical techniques increased remarkably with recently developed and implemented improvements of minimally invasive rectal cancer surgery. The controversial discussions about sense and purpose of these novel approaches are still ongoing in the literature. Herein, we evaluate, if latest technical advances like transanal approach or robotic assisted surgery have the potential to overcome known challenges and pitfalls in rectal cancer surgery in demanding surgical cases and highlight the role of current minimally invasive approaches in rectal cancer surgery.