Modulating Gut Microbiota Prevents Anastomotic Leak to Reduce Local Implantation and Dissemination of Colorectal Cancer Cells after Surgery.

PURPOSE: Anastomotic leak (AL) is a major complication in colorectal cancer surgery and consists of the leakage of intestinal content through a poorly healed colonic wound. Colorectal cancer recurrence after surgery is a major determinant of survival. We hypothesize that AL may allow cancer cells to escape the gut and lead to cancer recurrence and that improving anastomotic healing may prevent local implantation and metastatic dissemination of cancer cells. EXPERIMENTAL DESIGN: We investigated the association between AL and postoperative outcomes in patients with colorectal cancer. Using mouse models of poor anastomotic healing, we assessed the processes of local implantation and dissemination of cancer cells. The effect of dietary supplementation with inulin and 5-aminosalicylate (5-ASA), which activate PPAR-γ in the gut, on local anastomotic tumors was assessed in mice undergoing colonic surgery. Inulin and 5-ASA were also assessed in a mouse model of liver metastasis. RESULTS: Patients experiencing AL displayed lower overall and oncologic survival than non-AL patients. Poor anastomotic healing in mice led to larger anastomotic and peritoneal tumors. The microbiota of patients with AL displays a lower capacity to activate the antineoplastic PPAR-γ in the gut. Modulation of gut microbiota using dietary inulin and 5-ASA reinforced the gut barrier and prevented anastomotic tumors and metastatic spread in mice. CONCLUSIONS: Our findings reinforce the hypothesis that preventing AL is paramount to improving oncologic outcomes after colorectal cancer surgery. Furthermore, they pave the way toward dietary targeting of PPAR-γ as a novel way to enhance healing and diminish cancer recurrence.

Safety and clinical efficacy of EUS-guided pelvic abscess drainage.

Background and Objectives: EUS is a potential alternative for the drainage of abscesses. The aim of this study was to determine if EUS-guided pelvic abscess drainage is technically feasible, safe, and a valid option for abscess resolution. Methods: We conducted a retrospective review from 2002 to 2020 at a single quaternary institution. EUS-guided pelvic abscess drainage via the transrectal route was performed in all patients with or without drain/stent placement. Technical and clinical success of EUS-guided pelvic abscess drainage was analyzed. Descriptive analyses and Fisher exact test were performed. Results: Sixty consecutive patients were included in the study (53.5% male; mean age, 53.8 ± 17.9 years). Pelvic abscesses occurred mainly postoperatively (33 cases; 60.0%) and from complicated diverticulitis (14 cases; 23.3%). Mean diameter was 6.5 ± 2.4 cm (80% unilocular). Drainage was performed with EUS-guided stent placement (double-pigtail plastic or lumen-apposing metal) in 74.5% of cases and with aspiration alone for the remainder. Technical success occurred in 58 cases (97%). Of those with long-term follow-up after EUS-guided pelvic abscess drainage (n = 55; 91.7%), complete abscess resolution occurred in 72.7% of all cases. Recurrence occurred in 8 cases (14.5%) and persisted in 7 patients (12.5%), 7 of which were successfully retreated with EUS-guided pelvic abscess drainage. Accounting for these successful reinterventions, the overall rate of abscess resolution was 85.5%. Abscess resolution rate improved with drain placement (83%). Accounting for 7 repeat EUS-guided pelvic abscess drainages, overall abscess resolution improved. Two deaths occurred (3.4%) because of sepsis from failed source control in patients who had previously failed medical, radiological, and surgical treatment. Conclusions: EUS-guided pelvic abscess drainage is technically feasible, safe, and an effective alternative to radiological or open surgical drainage. It also offers favorable clinical outcomes in different clinical situations.

Gut microbiota influence anastomotic healing in colorectal cancer surgery through modulation of mucosal proinflammatory cytokines.

OBJECTIVE: Colorectal cancer (CRC) is the third most diagnosed cancer, and requires surgical resection and reconnection, or anastomosis, of the remaining bowel to re-establish intestinal continuity. Anastomotic leak (AL) is a major complication that increases mortality and cancer recurrence. Our objective is to assess the causal role of gut microbiota in anastomotic healing. DESIGN: The causal role of gut microbiota was assessed in a murine AL model receiving faecal microbiota transplantation (FMT) from patients with CRC collected before surgery and who later developed or not, AL. Anastomotic healing and gut barrier integrity were assessed after surgery. Bacterial candidates implicated in anastomotic healing were identified using 16S rRNA gene sequencing and were isolated from faecal samples to be tested both in vitro and in vivo. RESULTS: Mice receiving FMT from patients that developed AL displayed poor anastomotic healing. Profiling of gut microbiota of patients and mice after FMT revealed correlations between healing parameters and the relative abundance of Alistipes onderdonkii and Parabacteroides goldsteinii. Oral supplementation with A. onderdonkii resulted in a higher rate of leaks in mice, while gavage with P. goldsteinii improved healing by exerting an anti-inflammatory effect. Patients with AL and mice receiving FMT from AL patients presented upregulation of mucosal MIP-1α, MIP-2, MCP-1 and IL-17A/F before surgery. Retrospective analysis revealed that patients with AL present higher circulating neutrophil and monocyte counts before surgery. CONCLUSION: Gut microbiota plays an important role in surgical colonic healing in patients with CRC. The impact of these findings may extend to a vast array of invasive gastrointestinal procedures.

Prevalence of pks + bacteria and enterotoxigenic Bacteroides fragilis in patients with colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most diagnosed cancer and the second most common cause of cancer deaths worldwide. CRC patients present with an increase in pathogens in their gut microbiota, such as polyketide synthase-positive bacteria (pks +) and enterotoxigenic Bacteroides fragilis (ETBF). The pks + Escherichia coli promotes carcinogenesis and facilitates CRC progression through the production of colibactin, a genotoxin that induces double-strand DNA breaks (DSBs). ETBF is a procarcinogenic bacterium producing the B. fragilis toxin (bft) that promotes colorectal carcinogenesis by modulating the mucosal immune response and inducing epithelial cell changes. METHODS: Fecal samples were collected from healthy controls (N = 62) and CRC patients (N = 94) from the province of Québec (Canada), and a bacterial DNA extraction was performed. Fecal DNA samples were then examined for the presence of the pks island gene and bft using conventional qualitative PCR. RESULTS: We found that a high proportion of healthy controls are colonized by pks + bacteria (42%) and that these levels were similar in CRC patients (46%). bft was detected in 21% of healthy controls and 32% of CRC patients, while double colonization by both pks + bacteria and ETBF occurred in 8% of the healthy controls and 13% of the CRC patients. Most importantly, we found that early-onset CRC (< 50 years) patients were significantly less colonized with pks + bacteria (20%) compared to late-onset CRC patients (52%). CONCLUSIONS: Healthy controls had similar levels of pks + bacteria and ETBF colonization as CRC patients, and their elevated levels may place both groups at greater risk of developing CRC. Colonization with pks + bacteria was less prevalent in early-compared to late-onset CRC.

Implementing DPYD*2A Genotyping in Clinical Practice: The Quebec, Canada, Experience.

BACKGROUND: Fluoropyrimidines are used in chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. DPYD*2A polymorphism is one of the most studied variants. The study objective was to document the impact of implementing this test in routine clinical practice. METHODS: We retrospectively performed chart reviews of all patients who tested positive for a heterozygous or homozygous DPYD*2A mutation in samples obtained from patients throughout the province of Quebec, Canada. RESULTS: During a period of 17 months, 2,617 patients were tested: 25 patients tested positive. All were White. Twenty-four of the 25 patients were heterozygous (0.92%), and one was homozygous (0.038%). Data were available for 20 patients: 15 were tested upfront, whereas five were identified after severe toxicities. Of the five patients confirmed after toxicities, all had grade 4 cytopenias, 80% grade ≥3 mucositis, 20% grade 3 rash, and 20% grade 3 diarrhea. Eight patients identified with DPYD*2A mutation prior to treatment received fluoropyrimidine-based chemotherapy at reduced initial doses. The average fluoropyrimidine dose intensity during chemotherapy was 50%. No grade ≥3 toxicities were observed. DPYD*2A test results were available in an average of 6 days, causing no significant delays in treatment initiation. CONCLUSION: Upfront genotyping before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. The administration of chemotherapy at reduced doses appears to be safe in patients heterozygous for DPYD*2A. IMPLICATIONS FOR PRACTICE: Fluoropyrimidines are part of chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. This retrospective analysis demonstrates that upfront genotyping of DPYD before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. This approach was reported previously, but insufficient data concerning its application in real practice are available. This is likely the first reported experience of systematic DPYD genotyping all over Canada and North America as well.

Pelvic Aggressive Angiomyxoma: Major Challenges in Diagnosis and Treatment.

Aggressive pelvic angiomyxoma is a very rare mesenchymal tumor that is usually diagnosed in premenopausal female patients. The current mainly reported treatment is wide surgical excision. Other treatment options, such as radiotherapy and hormonal therapy, have been suggested as potential alternatives. A 61-year-old postmenopausal female patient presented with hematuria that led to the identification of a perirectal mass on abdominopelvic imaging. A 46-year-old female patient presented with a perineal mass of unknown etiology. Despite extensive investigations, the diagnosis could not be confirmed before surgical resection in both patients. Surgical excisions were performed and revealed the presence of an aggressive angiomyxoma with positive estrogen and progesterone tumoral receptors in both cases. Radiological and clinical recurrence was noted in one patient. Tumor regression was noted in this patient after treatment with a luteinizing hormone-releasing hormone (LHRH) agonist with long-term remission. The diagnosis of a perirectal aggressive angiomyxoma is an exceedingly rare event. Preoperative biopsy and pathological diagnosis are challenging and often yields poor results. Its slow growth and expression of hormonal receptors make noninvasive therapeutic strategies, such as radiotherapy, gonadotropin-releasing hormone agonists, or even watchful waiting, valid options in selected patients. Due to the lack of reported cases, the best treatment has yet to be elucidated.

Differential Pathogenic Th17 Profile in Mesenteric Lymph Nodes of Crohn's Disease and Ulcerative Colitis Patients.

The drug targets IL23 and IL12 regulate pathogenicity and plasticity of intestinal Th17 cells in Crohn's disease (CD) and ulcerative colitis (UC), the two most common inflammatory bowel diseases (IBD). However, studies examining Th17 dysregulation in mesenteric lymph nodes (mLNs) of these patients are rare. We showed that in mLNs, CD could be distinguished from UC by increased frequencies of CCR6+CXCR3-RORγ+Tbet-CD4+ (Th17) memory T cells enriched in CD62Llow effector memory T cells (TEM), and their differentially expressed molecular profile. Th17 TEM cells (expressing IL17A, IL17F, RORC, and STAT3) displayed a higher pathogenic/cytotoxic (IL23R, IL18RAP, and GZMB, CD160, PRF1) gene signature in CD relative to UC, while non-pathogenic/regulatory genes (IL9, FOXP3, CTLA4) were more elevated in UC. In both CD and UC, IL12 but not IL23, augmented IFNγ expression in Th17 TEM and switched their molecular profile toward an ex-Th17 (Th1*)-biased transcriptomic signature (increased IFNG, and decreased TCF7, IL17A), suggesting that Th17 plasticity occurs in mLNs before their recruitment to inflamed colon. We propose that differences observed between Th17 cell frequencies and their molecular profile in CD and UC might have implications in understanding disease pathogenesis, and thus, therapeutic management of patients with IBD.

Sclerosing encapsulating peritonitis presenting as acute-on-chronic small-bowel obstruction in a patient with history of peritoneal carcinomatosis.

Sclerosing encapsulating peritonitis (SEP) is a whitish fibrous envelope that encapsulates intra-abdominal peritonealized organs. Although it pathophysiology is not well understood, several possible causes have been reported in the literature, including peritoneal dialysis, past abdominal surgeries, peritonitis, beta-blockers and peritoneal carcinomatosis (PC). Some idiopathic cases, with no apparent causes, were described. We present a SEP case in a 43-year-old woman with a surgical history of pancreatic and liver resection for metastatic pseudopapillary pancreatic tumor, followed by several peritonectomies for PC. She was admitted for acute-on-chronic small-bowel obstruction that did not resolve with conservative management. Surgical exploration revealed a fibrous sheath covering the small-bowel. Extensive dissection, along with small-bowel segmental resection and anastomosis, was performed. The specimen was cancer-free. The mechanism through which SEP develops in certain surgical patients is still unknown. This report presents a case of successful surgical management and a review of the literature.

The value of Botox-A in acute radiation proctitis: results from a phase I/II study using a three-dimensional scoring system.

PURPOSE: Acute radiation proctitis (ARP) is a common side effect of pelvic radiotherapy, and its management is challenging in daily practice. The present phase I/II study evaluates the safety and efficacy of the botulinum toxin A (BTX-A) in ARP treatment for rectal cancer patients undergoing neoadjuvant high-dose-rate endorectal brachytherapy (HDREBT). METHODS AND MATERIALS: Fifteen patients, treated with neoadjuvant HDREBT, 26-Gy in 4 fractions, received the study treatment that consisted of a single injection of BTX-A into the rectal wall. The injection was performed post-HDREBT and prior to the development of ARP. The control group, 20 such patients, did not receive the BTX-A injection. Both groups had access to standard treatment with hydrocortisone rectal aerosol foam (Cortifoam) and anti-inflammatory and narcotic medication. The ARP was clinically evaluated by self-administered daily questionnaires using visual analog scores to document frequency and urgency of bowel movements, rectal burning/tenesmus, and pain symptoms before and after HDREBT. RESULTS: At the time of this analysis, there was no observed systemic toxicity. Patient compliance with the self-administered questionnaire was 100% from week 1 to 4, 70% during week 5, and 40% during week 6. The maximum tolerated dose was established at the 100-U dose level, and noticeable mean differences were observed in bowel frequency (p = 0.016), urgency (p = 0.007), and pain (p = 0.078). CONCLUSIONS: This study confirms the feasibility and efficacy of BTX-A intervention at 100-U dose level for study patients compared to control patients. A phase III study with this dose level is planned to validate these results.

Laparoscopic colectomy using cancer principles is appropriate for colonoscopically unresectable adenomas of the colon.

PURPOSE: This study was undertaken to determine the risks of cancer in unresectable polyps and to compare the short-term outcome of laparoscopic colectomy with that of open colectomy for benign polyps. METHODS: A retrospective review of all patients (n = 165) undergoing colectomy for an adenoma unresectable at colonoscopy was performed on patients collected in a prospective database. One hundred four patients underwent laparoscopic colectomy and 61 underwent open colectomy between 1991 and 2003. Follow-up was 7 to 155 (median, 90) months. RESULTS: In the laparoscopic group, 85% of the patients underwent a right colectomy and 15% underwent a left colectomy or a sigmoidectomy. Conversion to open colectomy occurred in 4.8% of the cases. Complications occurred in 14% of the patients, including 1 death. The median length of stay was 4 days. At final pathology, cancer was diagnosed in 15 patients: stage I in 8 patients, stage II in 5, and stage III in 2. In the open colectomy group, 69% of the patients underwent right colectomy. The complication rate reached 23% (P = .13), including death in 2 patients. The median length of stay was 6 days (P < .01). Cancer was diagnosed in 6 patients: stage I in 5 patients, and stage II in 1. Proximal (10 cm) and distal (13 cm) margins, lymph nodes harvest (9), incidence of cancer (13%), and high-grade dysplasia (22%) were similar between groups. There were no local recurrences, trocar site implants, or deaths due to cancer. CONCLUSION: Laparoscopic colectomy for polyps unresectable at colonoscopy is safe. Oncologic resection of the colon should be performed for all colonoscopically unresectable polyps due to the risk of cancer.

Risk of hypogonadism from scatter radiation during pelvic radiation in male patients with rectal cancer.

PURPOSE: Recent studies have reported fluctuations in sex hormones during pelvic irradiation. The objective of this study was to observe the effects of radiation on hormonal profiles for two treatment modalities: conventional external beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDRBT) given neoadjuvantly for patients with rectal cancer. METHODS AND MATERIALS: Routine serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone levels were collected from 119 consecutive male patients receiving either EBRT, using 45.0-50.4 Gy in 25-28 fractions with concurrent 5-fluorouracil chemotherapy or HDRBT using 26 Gy in 4 fractions. RESULTS: Thirty patients with initially abnormal profiles were excluded. Profiles included in this study were collected from 51 patients treated with EBRT and 38 patients treated with HDRBT, all of whom had normal hormonal profiles before treatment. Mean follow-up times were 17 months for the entire patient cohort-14 and 20 months, respectively-for the EBRT and HDRBT arms. Dosimetry results revealed a mean cumulative testicular dose of 1.24 Gy received in EBRT patients compared with 0.27 Gy in the HDRBT group. After treatment, FSH and LH were elevated in all patients but were more pronounced in the EBRT group. The testosterone-to-LH ratio was significantly lower (p = 0.0036) in EBRT patients for tumors in the lower third of the rectum. The 2-year hypogonadism rate observed was 2.6% for HDRBT compared with 17.6% for EBRT (p = 0.09) for tumors in the lower two thirds of the rectum. CONCLUSION: HDRBT allows better hormonal sparing than EBRT during neoadjuvant treatment of patients with rectal cancer.

Cytoreductive surgery with intraperitoneal chemohyperthermia for the treatment of pseudomyxoma peritonei: a prospective study.

PURPOSE: Pseudomyxoma peritonei is a rare disease. Recently, cytoreductive surgery with intraperitoneal hyperthermic chemotherapy has emerged as a promising treatment for this debilitating condition. The aim of this prospective study was to evaluate this treatment strategy. METHOD: Twenty-seven patients with pseudomyxoma peritonei who were treated by cytoreductive surgery and intraperitoneal chemohyperthermia between 1997 and 2003 were identified from a prospective database. RESULTS: Clinical presentation included suspected appendicitis (33 percent), increased abdominal girth (30 percent), and a suspected ovarian mass (26 percent). Twenty-two patients underwent surgery elsewhere before referral. Seventeen complications occurred in 12 patients (44 percent). Six were considered major: three anastomotic leaks, two pleural effusions, and one intra-abdominal abscess. Histologic examination demonstrated Grade 1, 2, and 3 disease in 8 (30 percent), 10 (37 percent), and 9 patients (33 percent), respectively. Pathologic grade showed a significant influence on the complication rate (P = 0 0.008). The actuarial five-year survival was 100 percent for patients with Grade 1 disease, whereas actuarial one-, two-, three-, and five-year survival for Grades 2 and 3 were 100, 80, 64, and 32 percent, respectively (P = 0.008). CONCLUSIONS: Cytoreductive surgery with intraperitoneal hyperthermic chemotherapy is a feasible treatment for pseudomyxoma peritonei. It is associated with acceptable morbidity when performed by an experienced surgical team. Histologic grade is the major determinant of survival.

Fibrin glue treatment of complex anal fistulas has low success rate.

PURPOSE: Fibrin glue has been used to treat anal fistulas in an attempt to avoid more radical surgical intervention. Reported success rates vary widely. The purpose of this study was to review the use of fibrin glue in the management of complex anal fistulas at a tertiary referral center. METHODS: This study was designed as a retrospective review of all patients treated with fibrin glue injection for complex anal fistulas in the Section of Colon and Rectal Surgery, Washington University School of Medicine/Barnes-Jewish Hospital. Demographics, previous treatment, operative information, and early follow-up were obtained from the patients' medical records. Phone interviews were conducted to determine successful healing or recurrence of fistulas requiring further treatment. Statistical analysis was by Fisher's exact test. The institutional review board approved the study. RESULTS: A total of 42 patients (19 males; median age, 44 (range, 20-76) years) were treated between 1999 and 2002. Three patients were lost to follow-up and were excluded from the study. Etiology of fistulas were cryptoglandular (n = 22), Crohn's disease (n = 13), or coloanal and ileal pouch-anal anastomotic (n = 4). Fistulas were classified as deep transsphincteric (n = 33), superficial transsphincteric (n = 1), supralevator (n = 2), or rectovaginal (n = 3). Initially, most patients had "closure" of the fistula but recrudescence was common. Durable healing was only achieved in 31 percent (12/39). Healing rates by etiology were cryptoglandular 23 percent (5/22), Crohn's disease 31 percent (4/13), and ileal pouch-anal anastomotic 75 percent (3/4; P = 0.14). Success rates by classification were deep transsphincteric 33 percent (11/33), superficial transsphincteric 0 percent (0/1), supralevator 0 percent (0/2), and rectovaginal 33 percent (1/3; P = 1). The success rate for patients with no previous treatment was 38 percent (8/21) vs. 22 percent (4/18) in those whose fistulas had been previously treated ( P = 0.32). Eight patients underwent a second fibrin glue treatment and only one of them healed (12.5 percent). Median follow-up for successfully healed fistula was 26 months. CONCLUSIONS: Fibrin glue treatment for complex anal fistulas has a low success rate and most recrudescences occurred within three months. However, given the low morbidity and relative simplicity of the procedure, fibrin glue should still be considered as a first-line treatment for patients with complex anal fistulas.

Hand-assisted laparoscopic colectomy techniques.

Laparoscopic colon and rectal surgery has gained popularity over the last 10 years. The experience obtained from the more simple surgeries, such as cholecystectomy and appendectomy, and the development of better instruments have made colorectal standard laparoscopic surgery an easier procedure. However, the downside associated with this technique includes longer operative times, higher costs, loss of tactile sensation, and a two-dimensional view. In the last 5 years, a new type of instrument has appeared on the market: the hand-assist device. It gives back the tactile feeling and allows the surgeon to retrieve a three-dimensional evaluation of the abdomen. This instrument has changed the laparoscopic surgery field and permitted the expansion of laparoscopic colectomy to the most challenging and complex cases. Hand-assisted laparoscopic surgery seems to retain the same benefits as standard laparoscopic surgery and improve the operative time and the learning curve. This article reviews the benefits and the indications for the use of the hand-assist device, and the characteristics and types of hand-assist devices available and their instruction for use. It also focuses on the technical aspects of hand-assisted laparoscopic surgery.