Tailored Management with Highly-Selective Diversion for Low Colorectal Anastomosis: Biochemical Postoperative Follow-Up and Long-Term Results from a Single-Institution Cohort.

BACKGROUND: Defunctioning stoma (DS) can decrease the rate of symptomatic anastomotic leakage (AL). Since 2010, we have used tailored, highly selective DS management for low colorectal anastomosis (LCRA). METHODS: In total, 433 rectal cancer patients underwent the same standardized procedure. Non-stoma (NS) management was used in patients with no surgical difficulties as well as good colonic preparation and quality of anastomoses. In all other cases, DS was used. C-reactive protein was measured during postoperative follow-up. Imbalance in the initial population was adjusted using propensity-score matching according to sex, age, body mass index, tumor location, and American Society of Anesthesiologists score. Rate of AL within 30 days, 5-year overall survival, local relapse-free survival, and disease-free survival were recorded. RESULTS: Anastomosis was mostly ultra-low and was performed equally by laparoscopy or robotic surgery. The overall rate of AL was 13.4%, with no significant differences between groups (DS, 12.2%; NS, 14.6%; p = 0.575). Operative time, blood loss, and hospital stay were significantly lower for NS patients. The rate of secondary stoma was 11.4% overall. Pathological results were similar, with a 98% R0 resection rate. With a median follow-up of 5.5 years for the NS and DS groups, the overall survival was 84.9% and 73.4%, respectively (p = 0.064), disease-free survival was 67.0% and 55.8%, respectively (p = 0.095), and local relapse-free survival was 95.2% and 88.7%, respectively (p = 0.084). The long-term, stoma-free rate was 89.1% overall. CONCLUSIONS: Tailoring DS for LCRA seems safe and could provide potential benefits in postoperative morbidity with the same long-term oncological results in NS patients. Prospective, multicentric studies should validate this approach.

Distal Pancreatectomy with Celiac Axis Resection (Modified Appleby Procedure) and Arterial Reconstruction for Locally Advanced Pancreatic Adenocarcinoma After FOLFIRINOX Chemotherapy and Chemoradiation Therapy.

BACKGROUND: Resectability of pancreatic carcinoma (PC) is directly linked to vascular extension (Tempero MA et al. in J Natl Compr Canc Netw 15(8):1028-1061, 2017. https://doi.org/10.6004/jnccn.2017.0131 ; Isaji S et al. in Pancreatology 18(1):2-11, 2018. https://doi.org/10.1016/j.pan.2017.11.011 ). Involvement of the celiac axis (CA) is typically a contraindication to surgery. High postoperative morbidity and subsequent poor prognosis have been observed in this case, especially for contact > 180° requiring arterial resection (Tempero MA et al. 2017). Recent medical advances in PC treatment, such as FOLFIRINOX-based chemotherapy eventually followed by chemoradiation therapy, offer the potential to select tumour for surgery and to obtain a negative-margin resection even in case of unresectable PC at diagnosis (Suker M et al. in Lancet Oncol 17(6):801-10, 2016. https://doi.org/10.1016/s1470-2045(16)00172-8 ; Pietrasz D et al. in Ann Surg Oncol 26(1):109-117, 2019. https://doi.org/10.1245/s10434-018-6931-6 ). A major pathologic response has been observed in more than 20% of patients after this treatment and is associated with an improved survival (Suker M et al. 2016; Pietrasz D et al. 2019). This evolution allows aggressive surgical strategies with the possibility of long-term disease control for patients showing a good response to induction treatment. PATIENT: This video presents the case of a 66-year-old man diagnosed with a locally advanced ductal adenocarcinoma of the pancreatic body with a 360° involvement of the CA and the hepatic artery. After eight courses of FOLFIRINOX chemotherapy and a capecitabin-based chemoradiation, a surgical exploration was planned for potential resection. TECHNIQUE: The key steps of the procedure are presented, i.e. surgical exposition, assessment of resectability with frozen sections of peri-arterial tissues, en bloc resection (Strasberg SM et al. in Surgery 133(5):521-527, 2003. https://doi.org/10.1067/msy.2003.146 ), and primary end-to-end arterial reconstruction. CONCLUSION: A modified Appleby operation for locally advanced PC is a technically challenging but feasible procedure in experienced teams. It offers the possibility of en bloc R0 resection of a locally advanced PC with the potential of long-term disease local control. This video may help surgeons to perform this complex intervention.

Robotic Radical Hysterectomy for Cervical Adenocarcinoma after Preoperative Brachytherapy in 10 Steps.

STUDY OBJECTIVE: Minimally invasive surgery decreases postoperative morbidity after radical hysterectomy (RH) for early-stage cervical cancer. However, a randomized trial and large retrospective data question its safety after observing lower rates of survival than open surgery [1,2]. The causes of this higher recurrence rate are not definitely established but may result from cancer exposure to the peritoneum during vaginal section and cancerous cells' spillage enhanced by pneumoperitoneum or a uterine manipulator. The aim of this surgical video was to present a standardized step-by-step approach for robotic RH according to the recent recommendations from the ARCAGY -Group of National Investigators for the Study of Ovarian and Breast Cancers surgeon's group [3]. DESIGN: Step-by-step video demonstration of the technique. SETTING: Tertiary center specialized in gynecologic oncology and minimally invasive surgery. INTERVENTIONS: A 48-year-old woman was diagnosed with a stage IB2 endocervical adenocarcinoma (International Federation of Gynecology and Obstetrics 2018) with a tumor size of 27 mm. Surgery was planned after preoperative pulsed dose rate uterovaginal brachytherapy. Surgery was performed following 10 reproducible steps: • Pelvic sentinel node identification according to the SENTICOL-III trial • Right infundibulopelvic and round ligaments transection • Right uterine vessels transection • Parametrectomy • Right uterosacral ligament transection • Bladder mobilization • Identical left dissection • Rectovaginal space development • Colpectomy by vaginal route after complete pneumoperitoneum exsufflation • Robotic vaginal cuff closure and pelvic inspection Thorough robotically assisted vaginal cuff closure was carried out as a comparative study suggesting that abdominal closure may decrease vaginal complications and dehiscence [3]. CONCLUSION: No international recommendations for the RH approach have yet been endorsed. Patients must be clearly informed about the benefit-risk ratio of the surgical route. If a minimally invasive RH is still decided, the patient should be referred to experienced centers, and precautionary measures must be implemented [4]. Colpotomy by vaginal route without pneumoperitoneum is recommended. Uterine manipulators have to be strictly avoided. Preoperative brachytherapy has been reported in experienced centers in France with favorable histologic response with high rates of pathologic complete response (near 70%) and seems particularly worthwhile for tumor sizes ranging from 2 to 4 cm or presenting with lymphovascular invasion [5].

Colibactin-positive Escherichia coli induce a procarcinogenic immune environment leading to immunotherapy resistance in colorectal cancer.

Colibactin-producing E. coli (CoPEC) are frequently detected in colorectal cancer (CRC) and exhibit procarcinogenic properties. Because increasing evidence show the role of immune environment and especially of antitumor T-cells in CRC development, we investigated the impact of CoPEC on these cells in human CRC and in the APCMin/+ mice colon. T-cell density was evaluated by immunohistochemistry in human tumors known for their CoPEC status. APCmin/+ mice were chronically infected with a CoPEC strain (11G5). Immune cells (neutrophils and T-cell populations) were then quantified by immunofluorescent staining of the colon. The quantification of lymphoid populations was also performed in the mesenteric lymph nodes (MLNs). Here, we show that the colonization of CRC patients by CoPEC is associated with a decrease of tumor-infiltrating T lymphocytes (CD3+ T-cells). Similarly, we demonstrated, in mice, that CoPEC chronic infection decreases CD3+ and CD8+ T-cells and increases colonic inflammation. In addition, we noticed a significant decrease in antitumor T-cells in the MLNs of CoPEC-infected mice compared to that of controls. Moreover, we show that CoPEC infection decreases the antimouse PD-1 immunotherapy efficacy in MC38 tumor model. Our findings suggest that CoPEC could promote a procarcinogenic immune environment through impairment of antitumor T-cell response, leading to tumoral resistance to immunotherapy. CoPEC could thus be a new biomarker predicting the anti-PD-1 response in CRC.

Intestinal Microbiota: A Novel Target to Improve Anti-Tumor Treatment?

Recently, preclinical and clinical studies targeting several types of cancer strongly supported the key role of the gut microbiota in the modulation of host response to anti-tumoral therapies such as chemotherapy, immunotherapy, radiotherapy and even surgery. Intestinal microbiome has been shown to participate in the resistance to a wide range of anticancer treatments by direct interaction with the treatment or by indirectly stimulating host response through immunomodulation. Interestingly, these effects were described on colorectal cancer but also in other types of malignancies. In addition to their role in therapy efficacy, gut microbiota could also impact side effects induced by anticancer treatments. In the first part of this review, we summarized the role of the gut microbiome on the efficacy and side effects of various anticancer treatments and underlying mechanisms. In the second part, we described the new microbiota-targeting strategies, such as probiotics and prebiotics, antibiotics, fecal microbiota transplantation and physical activity, which could be effective adjuvant therapies developed in order to improve anticancer therapeutic efficiency.

Determination of biomarkers associated with neoadjuvant treatment response focusing on colibactin-producing Escherichia coli in patients with mid or low rectal cancer: a prospective clinical study protocol (MICARE).

INTRODUCTION: The management of mid and low rectal cancer is based on neoadjuvant chemoradiotherapy (CRT) followed by standardised surgery. There is no biomarker in rectal cancer to aid clinicians in foreseeing treatment response. The determination of factors associated with treatment response might allow the identification of patients who require tailored strategies (eg, therapeutic de-escalation or intensification). Colibactin-producing Escherichia coli (CoPEC) has been associated with aggressive colorectal cancer and could be a poor prognostic factor. Currently, no study has evaluated the potential association between intestinal microbiota composition and tumour response to CRT in mid and low rectal cancer. The aim of this study is to assess the association between response to neoadjuvant CRT and faecal intestinal microbiota composition and/or CoPEC prevalence in patients with mid or low rectal cancer. METHODS AND ANALYSIS: This is a non-randomised bicentric prospective clinical study with a recruitment capacity of 200 patients. Three stool samples will be collected from participants with histological-proven adenocarcinome of mid or low rectum who meet eligibility criteria of the study protocol: one before neoadjuvant treatment start, one in the period between CRT end and surgery and one the day before surgery. In each sample, CoPEC will be detected by culture in special media and molecular (PCR) approaches. The global microbiota composition will be also assessed by the bacterial 16S rRNA gene sequencing. Neoadjuvant CRT response and tumour regression grade will be described using the Dworak system at pathological examination. Clinical data and survival outcomes will also be collected and investigated. ETHICS AND DISSEMINATION: MICARE was approved by the local ethics committee (Comité de Protection des Personnes Sud-Est II, 18 December 2019. Reference number 2019-A02493-54 and the institutional review board. Patients will be required to provide written informed consent. Results will be published in a peer reviewed journal. TRIAL REGISTRATION NUMBER: NCT04103567.

Colonization and immune modulation properties of Klebsiella pneumoniae biofilm-dispersed cells.

Biofilm-dispersal is a key determinant for further dissemination of biofilm-embedded bacteria. Recent evidence indicates that biofilm-dispersed bacteria have transcriptional features different from those of both biofilm and planktonic bacteria. In this study, the in vitro and in vivo phenotypic properties of Klebsiella pneumoniae cells spontaneously dispersed from biofilm were compared with those of planktonic and sessile cells. Biofilm-dispersed cells, whose growth rate was the same as that of exponential planktonic bacteria but significantly higher than those of sessile and stationary planktonic forms, colonized both abiotic and biotic surfaces more efficiently than their planktonic counterparts regardless of their initial adhesion capabilities. Microscopy studies suggested that dispersed bacteria initiate formation of microcolonies more rapidly than planktonic bacteria. In addition, dispersed cells have both a higher engulfment rate and better survival/multiplication inside macrophages than planktonic cells and sessile cells. In an in vivo murine pneumonia model, the bacterial load in mice lungs infected with biofilm-dispersed bacteria was similar at 6, 24 and 48 h after infection to that of mice lungs infected with planktonic or sessile bacteria. However, biofilm-dispersed and sessile bacteria trend to elicit innate immune response in lungs to a lesser extent than planktonic bacteria. Collectively, the findings from this study suggest that the greater ability of K. pneumoniae biofilm-dispersed cells to efficiently achieve surface colonization and to subvert the host immune response confers them substantial advantages in the first steps of the infection process over planktonic bacteria.

Therapeutic management of complex anal fistulas by installing a nitinol closure clip: study protocol of a multicentric randomised controlled trial--FISCLOSE.

INTRODUCTION: Complex anal fistulas are responsible for pain, faecal incontinence and impaired quality of life. The rectal mucosa advancement flap (RMAF) procedure to cover the internal opening of the fistula remains a strategy of choice. However, a new procedure for closing anal fistulas is now available with the use of a nitinol closure clip (OTSC Proctology, OVESCO), which should ensure a better healing rate. This procedure is currently becoming more widespread, though without robust scientific validation, and it is therefore essential to carry out a prospective evaluation in order to determine the efficacy and safety of this new medical device for complex anal fistulas. METHODS AND ANALYSIS: The FISCLOSE trial is aimed at evaluating the efficacy and safety of a nitinol closure clip compared to the RMAF procedure for the management of complex anal fistulas. This trial is a prospective, randomised, controlled, single-blind, bicentre and interventional study. Patients (n=46 per group) will be randomly assigned for management with either a closure clip or RMAF. The main objectives are to improve the healing rate of the anal fistula, lessen the postoperative pain and faecal incontinency, enhance the quality of life, and lower the number of reinterventions and therapeutic management costs. The primary outcome is the proportion of patients with a healed fistula at 3 months. The secondary outcomes are anal fistula healing (6 and 12 months), proctological pain (visual analogue scale), the faecal incontinence score (Jorge and Wexner questionnaire), digestive disorders and quality of life (Gastrointestinal Quality of Life Index and Euroqol EQ5D-3 L) up to 1 year. ETHICS AND DISSEMINATION: The study was approved by an independent medical ethics committee 1 (IRB00008526, CPP Sud-Est 6, Clermont-Ferrand, France) and registered by the competent French authority (ANSM, Saint Denis, France). The results will be disseminated in a peer-reviewed journal and presented at international congresses. TRIAL REGISTRATION NUMBER: NCT02336867; pre-result.