OTSC Proctology clip as appropriate treatment for complicated anorectal fistula.

PURPOSE: Evaluation of the effectiveness and tolerability of the application of an OTSC (Ovesco Endoscopy AG Tuebingen, Germany) Proctology clip as an innovative strategy of anorectal fistulae closure when established treatment strategies had already failed or were not feasible. METHODS: Retrospective single-center study including consecutive patients treated between March 2014 and March 2016 with the OTSC Proctology system for anorectal fistula closure, including one rectovaginal and one rectourethral fistula. The primary outcome was the healing rate with a minimum follow up of 6 months. Healing was defined as closure of the internal fistula ostium and absence of secretion or local inflammation during follow up. RESULTS: A total of 66 fistula closures by the OTSC Proctology clip were investigated, including cryptoglandular fistulas (45/66 patients, 68%), fistulas associated with CED (19/66 patients, 29%), and other non-cryptoglandular fistulas (2/66 patients, 4%). 47% (31/66 patients) had a failed previous therapy. In that selected collective, a successful fistula closure was achieved in 29/66 cases (44%) after a median follow up time of 40 months (6-61 months). Suprasphincteric and high transsphincteric fistulas showed healing in 63% and 42% in CD associated fistulas. CONCLUSION: Fistula closure by the OTSC Proctology clip is an innovative, sphincter protecting treatment strategy in anorectal fistulas that can achieve long-term cure in complex anorecta.

The Smac mimetic BV6 cooperates with STING to induce necroptosis in apoptosis-resistant pancreatic carcinoma cells.

Pancreatic cancer (PC) still remains a major cause of cancer-related death worldwide and alternative treatments are urgently required. A common problem of PC is the development of resistance against apoptosis that limits therapeutic success. Here we demonstrate that the prototypical Smac mimetic BV6 cooperates with the stimulator of interferon (IFN) genes (STING) ligand 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) to trigger necroptosis in apoptosis-deficient PC cells. Pharmacological inhibition of key components of necroptosis signaling, such as receptor-interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL), significantly rescues PC cells from 2'3'-cGAMP/BV6/zVAD.fmk-mediated cell death, suggesting the induction of necroptosis. Consistently, 2'3'-cGAMP/BV6 co-treatment promotes phosphorylation of MLKL. Furthermore, we show that 2'3'-cGAMP stimulates the production of type I IFNs, which cooperate with BV6 to trigger necroptosis in apoptosis-deficient settings. STING silencing via siRNA or CRISPR/Cas9-mediated gene knockout protects PC cells from 2'3'-cGAMP/BV6/zVAD.fmk-mediated cell death. Interestingly, we demonstrate that nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNFα), and IFN-regulatory factor 1 (IRF1) signaling are involved in triggering 2'3'-cGAMP/BV6/zVAD.fmk-induced necroptosis. In conclusion, we show that activated STING and BV6 act together to exert antitumor effects on PC cells with important implications for the design of new PC treatment concepts.

The MEGNA Score and Preoperative Anemia are Major Prognostic Factors After Resection in the German Intrahepatic Cholangiocarcinoma Cohort.

BACKGROUND: Surgical resection is associated with the best long-term results for intrahepatic cholangiocarcinoma (ICC); however, long-term outcomes are still poor. OBJECTIVE: The primary aim of this study was to validate the recently proposed MEGNA score and to identify additional prognostic factors influencing short- and long-term survival. PATIENTS AND METHODS: This was a retrospective analysis of a German multicenter cohort operated at 10 tertiary centers from 2004 to 2013. Patients were clustered using the MEGNA score and overall survival was analyzed. Cox regression analysis was used to identify prognostic factors for both overall and 90-day survival. RESULTS: A total of 488 patients undergoing liver resection for ICC fulfilled the inclusion criteria and underwent analysis. Median age was 67 years, 72.5% of patients underwent major hepatic resection, and the lymphadenectomy rate was 86.9%. Median overall survival was 32.2 months. The MEGNA score significantly discriminated the long-term overall survival: 0 (68%), I (48%), II (32%), and III (19%) [p <0.001]. In addition, anemia was an independent prognostic factor for overall survival (hazard ratio 1.78, 95% confidence interval 1.29-2.45; p <0.01). CONCLUSION: Hepatic resection provides the best long-term survival in all risk groups (19-65% overall survival). The MEGNA score is a good discriminator using histopathologic items and age for stratification. Correction of anemia should be attempted in every patient who responds to treatment. Perioperative liver failure remains a clinical challenge and contributes to a relevant number of perioperative deaths.

Purse-string closure technique reduces the incidence of incisional hernias following the reversal of temporary ileostomy.

PURPOSE: The incidence of incisional hernia (IH) at ileostomy closure site has not been sufficiently evaluated. Temporary loop ileostomy is routinely used in patients after low anterior resection for rectal cancer. The goal of this study was to compare the IH rates of standard suture skin closure and purse-string skin closure techniques. PATIENTS AND METHODS: Patients undergoing ileostomy reversal and follow-up CT scan at the University Hospital Frankfurt between January 2009 and December 2015 were retrospectively analyzed regarding IH and associated risk factors. Patients received either direct stitch skin closure (group DC) or purse-string skin closure (group PS). RESULTS: In total, 111 patients underwent ileostomy reversal in the aforementioned period. In 88 patients, a CT scan was performed 12-24 months after ileostomy reversal for cancer follow-up. Median follow-up was 12 months. Median time interval between ileostoma formation and closure was 12 (± 4 SD) weeks. In 19 of 88 patients (21.5%), an IH was detected. The incidence of IH detected by CT scan was significantly lower in the PS group (n = 7, 12.9%) compared to the DC group (n = 12, 35.2%, p = 0.017). CONCLUSIONS: This retrospective study shows an advantage of the purse-string skin closure technique in ileostomy reversals. The use of this technique for skin closure following ileostomy reversals is recommended to reduce the IH rates. Randomized controlled trials are needed to confirm these findings.

Smac mimetic triggers necroptosis in pancreatic carcinoma cells when caspase activation is blocked.

Evasion of apoptosis represents a key mechanism of treatment resistance of pancreatic cancer (PC) and contributes to the poor prognosis of this cancer type. Here, we report that induction of necroptosis is an alternative strategy to trigger programmed cell death in apoptosis-resistant PC cells. We show that the second mitochondrial activator of caspases (Smac) mimetic BV6 that antagonizes inhibitor of apoptosis (IAP) proteins induces necroptosis in PC cells in which apoptosis is blocked by the caspase inhibitor zVAD.fmk. Intriguingly, BV6 switches autocrine/paracrine production of tumor necrosis factor (TNF)α by PC cells into a death signal and also acts in concert with exogenously supplied TNFα to trigger necroptosis, when caspase activation is simultaneously blocked. BV6 stimulates TNFα production and formation of the receptor-interacting protein (RIP)1/RIP3-containing necrosome complex in PC cells. Knockdown of TNF receptor 1 (TNFR1) protects PC cells from BV6- or BV6/TNFα-mediated cell death, demonstrating that TNFα autocrine/paracrine signaling by PC cells contributes to BV6-induced necroptosis. Importantly, genetic silencing of receptor interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain-like protein (MLKL) significantly rescues PC cells from BV6- or BV6/TNFα-induced cell death. Similarly, pharmacological inhibition of RIP1, RIP3 or MLKL significantly reduces BV6- or BV6/TNFα-stimulated cell death. By demonstrating that Smac mimetics can bypass resistance to apoptosis by triggering necroptosis as an alternative form of programmed cell death, our findings have important implications for the design of new treatment concepts for PC.

Salvage abdominoperineal excisions in recurrent anal cancer--impact of different reconstruction techniques on outcome, morbidity, and complication rates.

BACKGROUND: Squamous cell cancer of the anus (SCCA) is a rare disease of the gastrointestinal tract. Even though chemoradiation therapy is the treatment of choice, a substantial number of patients develop recurrent cancers or present with persisting SCCA. Therefore, abdominoperineal excisions as a salvage therapy are the only chance of cure. PATIENTS AND METHODS: Hospital files of all patients with recurrent squamous cell carcinoma of the anus who underwent abdominoperineal excision performed at the Department of General and Visceral Surgery of the University Hospital Frankfurt between January 2003 and December 2013 were retrospectively reviewed. RESULTS: Fourteen (nine males, five females) patients underwent abdominoperineal resections for recurrent SCCA. In six patients, the pelvic floor was closed by direct suture, four patients underwent reconstruction using a vertical rectus abdominis myocutaneous (VRAM) flap, and four patients received a gluteal myocutaneous flap. Patients receiving flap-mediated closure revealed a median hospital stay of 26 days (range 13-60 days) compared to 11 days (range 9-30 days) in patients with direct closure (p = 0.01). Two patients (14%) suffered from wound infections (Dindo-Clavien II), whereas three patients (21%) underwent up to seven reoperations for breakdown of their wounds and/or laparotomies (Dindo-Clavien IIIb). The calculated 5-year survival rate was 86%. Patients with rpT0/T1 stage had a significantly longer survival compared to patients presenting with rpT2/T3/T4 tumors. CONCLUSION: Abdominoperineal excisions in patients with recurrent SCCA can provide long-term local control and survival. The complication rate is not associated with the closure technique employed, but patients undergoing flap-mediated closure revealed a significantly longer hospital stay.

Abdominoperineal Excisions in the Treatment Regimen for Advanced and Recurrent Vulvar Cancers-Analysis of a Single-Centre Experience.

Vulva cancer is the fourth leading gynaecological malignancy, accounting for approximately 4 % of all gynaecological cancers. Surgery represents the treatment of choice, and cases of advanced or recurrent vulvar cancers are to date a major challenge to multidisciplinary teams. Abdominoperineal excision (APE) in combination with vulvectomy and inguinal lymphadenectomy is the only curative treatment option. Patients' files of all women with squamous cell carcinoma of the vulva who underwent abdominoperineal resection were retrospectively reviewed with special regards to technical challenges the general surgeon will face. Seven women were enrolled in this retrospective study with a median age of 71 years (range 56-79 years). In six patients, the pelvic floor after abdominoperineal excision could be closed by direct suture of the levator muscles. One woman underwent abdominoperineal resection with closure of the defect using a vertical rectus abdominis myocutaneous (VRAM) flap. All women underwent radical vulvectomy, in five patients in combination with bilateral inguinal lymph node dissection. Operation time was 377 min (range 130-505 min). The median overall survival after surgery was 27 months (range 4-84 months), with a calculated 5-year survival rate of 42 %. Women with negative lymph nodes revealed a longer survival time after surgery compared to women with lymph node metastases (15.5 vs. 72 months; p = 0.09). Abdominoperineal excisions represent a powerful tool in the multidisciplinary treatment regimen of advanced or recurrent vulvar cancer. Reconstruction of the pelvic floor usually does not require myocutaneous flaps, even when facing large tumours. Despite high complication rates, radical surgery was a feasible treatment with long-term survival potential without mortality.

The use of purse-string skin closure in loop ileostomy reversals leads to lower wound infection rates--a single high-volume centre experience.

PURPOSE: Wound infections affect not only the individual patient but lead to an increase in medical costs. After ileostomy reversal, surgical site infections are a common problem. The objective of the study was to compare the infection rates of purse-string and conventional skin closure techniques in a high volume setting. METHODS: Patients undergoing ileostomy reversal at the Goethe University Hospital between January 2009 and August 2012 were retrospectively analysed regarding surgical site infections and associated risk factors. Patients received either conventional skin closure (running, interrupted or stapled suturing; group C) or subcuticular purse-string suture (group PS). RESULTS: In total, 114 patients have been analysed. Conventional wound closure was performed in 81 patients and 33 patients received purse-string skin closure. The groups did not differ regarding age, gender, indication for ileostomy, previous chemotherapy, and operation time. Median hospital stay was 7 days (3-34) in group PS and 8 (3-53) in group C (p = 0.15). Wound infections only occurred in groups C (n = 10, 12 %) compared to group PS (n = 0; 0 %; p = 0.034), and the wound closure technique was the only significant factor associated with surgical site infection. Surgery performed by a resident under supervision was not a risk factor for complications compared to the procedure done by a senior surgeon (p = 0.73). CONCLUSION: This study reveals an advantage of the purse-string skin closure technique in ileostomy reversals analysing a large cohort of patients. Therefore, we recommend the use of the purse-string skin closure in ileostomy reversals as one way to lower wound infection rates.