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Transforming growth factor beta (TGFβ) is a multipotent immunosuppressive cytokine. TGFβ excludes immune cells from tumors, and TGFβ inhibition improves the efficacy of cytotoxic and immune therapies. Using preclinical colorectal cancer models in cell type-conditional TGFβ receptor I (ALK5) knockout mice, we interrogate this mechanism. Tumor growth delay and radiation response are unchanged in animals with Treg or macrophage-specific ALK5 deletion. However, CD8αCre-ALK5 flox/flox (ALK5 ΔCD8 ) mice reject tumors in high proportions, dependent on CD8 + T cells. ALK5 ΔCD8 mice have more tumor-infiltrating effector CD8 + T cells, with more cytotoxic capacity. ALK5-deficient CD8 + T cells exhibit increased CXCR3 expression and enhanced migration towards CXCL10. TGFβ reduces CXCR3 expression, and increases binding of Smad2 to the CXCR3 promoter. In vivo CXCR3 blockade partially abrogates the survival advantage of an ALK5 ΔCD8 host. These data demonstrate a mechanism of TGFβ immunosuppression through inhibition of CXCR3 in CD8 + T cells, thereby limiting their trafficking into tumors. TGFβ has a role in cancer immunosuppression but the exact mechanisms haven’t been fully elucidated. Here, using mouse models deficient in TGFβ-signaling, the authors show that loss of ALK5 in CD8 + T cells enhances their tumour trafficking and cytotoxicity suggesting that ALK5 inhibitors may have clinical utility.

BackgroundTotal mesorectal excision (TME) is the gold standard for oncologic resection in low and mid rectal cancers. However, abdominal approaches to TME can be hampered by poor visibility, inadequate retraction, and distal margin delineation. Transanal TME (taTME) is a promising hybrid technique that was developed to mitigate the difficulties of operating in the low pelvis and to optimize the circumferential resection and distal margins.MethodsThe objective of this study was to characterize our experience implementing taTME at our institution in a technically challenging patient population. We performed a retrospective review of consecutive patients who underwent taTMEs between November 2013 and May 2019 for rectal cancer at a tertiary community cancer center. Outcome measures included pathologic grading of TME specimen, post-operative complications, and oncologic outcomes.ResultsForty-four patients with mid and low rectal cancer underwent low anterior resection via taTME. The most common staging modality was rectal MRI which demonstrated T3 or T4 tumors in 89% of our patients prior to neoadjuvant. Eighty-six percent of patients underwent neoadjuvant chemoradiation. The initial cases were performed sequentially as a single team, but we later transitioned to a synchronous, two-team approach. Ninety-one percent of TME grades were complete or near complete. Only one patient (2.3%) had a positive circumferential margin. Six patients developed anastomotic leaks with an overall anastomotic complication rate of 18.2%. Two patients (4.5%) with primary rectal cancer developed local recurrence, one of which developed multifocal local recurrence.ConclusionsUsing the taTME approach on selected locally advanced low rectal cancers, especially in technically complex irradiated and obese male patients, has yielded comparably safe and effective outcomes to laparoscopic proctectomy.

Transanal endoscopic microsurgery (TEM) is a minimally invasive technique for full-thickness excision of benign and malignant rectal neoplasms located 4 to 24 cm above the anal verge. Entrance into the peritoneal cavity during TEM has been regarded as a complication that mandates conversion to open laparotomy for adequate repair of the defect. This study compares the rate of complications arising from TEM with and without intraperitoneal entry. Patients undergoing peritoneal entry were compared to those who did not. No perioperative deaths occurred. There was no significant difference in the incidence of postoperative complications. No major complications occurred with peritoneal entry, and all peritoneal entries were closed transanally via endoscope. Entry into the peritoneum during TEM is not associated with an increased incidence of complication. Entry into the peritoneum during TEM excision does not mandate conversion to open laparotomy but may be safely repaired endoscopically. Lesions likely to be above the peritoneal reflection and within reach of the endoscope (4 to 24 cm) should be considered for TEM excision.

Background A transrectal (TR) approach for natural orifice translumenal endoscopic surgery (NOTES) makes sense for colorectal surgery because the colotomy can be incorporated into subsequent anastomosis. Because cancer is a primary indication for left-sided colon resection, oncologic standards will have to be met by a NOTES procedure. This study aimed to assess whether pure TR rectosigmoidectomy can be performed with strict adherence to oncologic principles compared with a conventional laparoscopically assisted approach (LAP). Methods Human male cadavers were allocated to either TR ( n  = 4) or LAP ( n  = 2). A simulated sigmoid lesion was created at 25 cm. Transrectal retrograde mobilization of the rectosigmoid was performed using conventional transanal endoscopic microsurgery (TEM) instrumentation. After ligation of the superior hemorrhoidal artery and further mobilization, the specimen was delivered transanally and divided extracorporeally. Using a circular stapler, NOTES colorectal anastomosis was performed. Lymph node yield, adequate resection margins, and operative time were compared with LAP. Results Transrectal retrograde rectosigmoid dissection was achieved in all attempts (4/4) and showed numbers of lymph nodes (median, 5; range, 3–6) similar to the LAP group (median, 4.5; range, 2–7). One pure TR approach failed to resect the lesion. Three TR procedures required additional mobilization via an abdominal approach to provide adequate margins. The mean length of TR specimens was 16 ± 4 cm compared with 31 ± 9 cm achieved by LAP ( p  < 0.01). The TR operative time was significantly longer (247 ± 15 vs 110 ± 14 min). Conclusion Lymph node yield during TR rectosigmoidectomy was similar to that achieved by the LAP approach. However, conventional TEM instrumentation alone did not permit adequate colon mobilization. This indicates a need for flexible instrumentation or other technical solutions to perform true NOTES colectomies.

Local excision of rectal cancer is an attractive alternative to avoid the morbidity associated with radical rectal surgery. Oncologic concerns, specifically the inability to fully assess the status of the perirectal lymph nodes and the risk of local recurrence after local excision remain significant barriers to widespread adoption of this technique. Transanal endoscopic microsurgery is an alternative minimally invasive technique used for transanal excision of rectal polyps and tumors. It offers the advantage of better exposure, magnified stereoscopic view, and greater reach into the middle and upper rectum. This technique, combined with careful patient selection, has demonstrated optimistic results compared to standard transanal techniques and even total mesorectal excision when utilized for certain early rectal cancers.

TGF-β is an immunosuppressive cytokine that is upregulated in colorectal cancer. TGF-β blockade improved response to chemoradiotherapy in preclinical models of colorectal adenocarcinoma. We aimed to test the hypothesis that adding the TGF-β type I receptor kinase inhibitor galunisertib to neoadjuvant chemoradiotherapy would improve pathological complete response rates in patients with locally advanced rectal cancer. This was an investigator-initiated, single-arm, phase 2 study done in two medical centres in Portland (OR, USA). Eligible patients had previously untreated, locally advanced, rectal adenocarcinoma, stage IIA–IIIC or IV as per the American Joint Committee on Cancer; Eastern Cooperative Oncology Group status 0–2; and were aged 18 years or older. Participants completed two 14-day courses of oral galunisertib 150 mg twice daily, before and during fluorouracil-based chemoradiotherapy (intravenous fluorouracil 225 mg/m2 over 24 h daily 7 days per week during radiotherapy or oral capecitabine 825 mg/m2 twice per day 5 days per week during radiotherapy; radiotherapy consisted of 50·4–54·0 Gy in 28–30 fractions). 5–9 weeks later, patients underwent response assessment. Patients with a complete response could opt for non-operative management and proceed to modified FOLFOX6 (intravenous leucovorin 400 mg/m2 on day 1, intravenous fluorouracil 400 mg/m2 on day 1 then 2400 mg/m2 over 46 h, and intravenous oxaliplatin 85 mg/m2 on day 1 delivered every 2 weeks for eight cycles) or CAPEOX (intravenous oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks for four cycles). Patients with less than complete response underwent surgical resection. The primary endpoint was complete response rate, which was a composite of pathological complete response in patients who proceeded to surgery, or clinical complete response maintained at 1 year after last therapy in patients with non-operative management. Safety was a coprimary endpoint. Both endpoints were assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02688712, and is active but not recruiting. Between Oct 19, 2016, and Aug 31, 2020, 38 participants were enrolled. 25 (71%) of the 35 patients who completed chemoradiotherapy proceeded to total mesorectal excision surgery, five (20%) of whom had pathological complete responses. Ten (29%) patients had non-operative management, three (30%) of whom ultimately chose to have total mesorectal excision. Two (67%) of those three patients had pathological complete responses. Of the remaining seven patients in the non-operative management group, five (71%) had clinical complete responses at 1 year after their last modified FOLFOX6 infusion. In total, 12 (32% [one-sided 95% CI ≥19%]) of 38 patients had a complete response. Common grade 3 adverse events during treatment included diarrhoea in six (16%) of 38 patients, and haematological toxicity in seven (18%) patients. Two (5%) patients had grade 4 adverse events, one related to chemoradiotherapy-induced diarrhoea and dehydration, and the other an intraoperative ischaemic event. No treatment-related deaths occurred. The addition of galunisertib to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer improved the complete response rate to 32%, was well tolerated, and warrants further assessment in randomised trials. Eli Lilly via ExIST program, The Providence Foundation.

BackgroundThe management of rectal cancer has evolved over the years, including the recent rise of Transanal Total Mesorectal Excision (TaTME). TaTME addresses the limitations created by the bony confines of the pelvis, bulky tumours, and fatty mesorectum, particularly for low rectal cancers. However, guidance is required to ensure safe implementation and to avoid the pitfalls and potential major morbidity encountered by the early adopters of TaTME. We report a broad international consensus statement, which provides a basis for optimal clinical practice.MethodsForty international experts were invited to participate based on clinical and academic achievements. The consensus statements were developed using Delphi methodology incorporating three successive rounds. Consensus was defined as agreement by 80% or more of the experts.ResultsA total of 37 colorectal surgeons from 20 countries and 5 continents (Europe, Asia, North and South America, Australasia) contributed to the consensus. Participation to the iterative Delphi rounds was 100%. An expert radiologist, pathologist, and medical oncologist provided recommendations to maximize relevance to current practice. Consensus was obtained on all seven different chapters: patient selection and surgical indication, perioperative management, patient positioning and operating room set up, surgical technique, devices and instruments, pelvic anatomy, TaTME training, and outcomes analysis.ConclusionsThis multidisciplinary consensus statement achieved more than 80% approval and can thus be graded as strong recommendation, yet acknowledging the current lack of high level evidence. It provides the best possible guidance for safe implementation and practice of Transanal Total Mesorectal Excision.

BackgroundTransanal TME (taTME) combines abdominal and transanal dissection to facilitate sphincter preservation in patients with low rectal tumors. Few phase II/III trials report long-term oncologic and functional results. We report early results from a North American prospective multicenter phase II trial of taTME (NCT03144765).Methods100 patients with stage I–III rectal adenocarcinoma located ≤ 10 cm from the anal verge (AV) were enrolled across 11 centers. Primary and secondary endpoints were TME quality, pathologic outcomes, 30-day and 90-day outcomes, and stoma closure rate. Univariable regression analysis was performed to assess risk factors for incomplete TME and anastomotic complications.ResultsBetween September 2017 and April 2022, 70 males and 30 females with median age of 58 (IQR 49–62) years and BMI 27.8 (IQR 23.9–31.8) kg/m2 underwent 2-team taTME for tumors located a median 5.8 (IQR 4.5–7.0) cm from the AV. Neoadjuvant radiotherapy was completed in 69%. Intersphincteric resection was performed in 36% and all patients were diverted. Intraoperative complications occurred in 8% including 3 organ injuries, 2 abdominal and 1 transanal conversion. The 30-day and 90-day morbidity rates were 49% (Clavien–Dindo (CD) ≥ 3 in 28.6%) and 56% (CD ≥ 3 in 30.4% including 1 mortality), respectively. Anastomotic complications were reported in 18% including 10% diagnosed within 30 days. Higher anastomotic risk was noted among males (p = 0.05). At a median follow-up of 5 (IQR 3.1–7.4) months, 98% of stomas were closed. TME grade was complete or near complete in 90%, with positive margins in 2 cases (3%). Risk factors for incomplete TME were ASA ≥ 3 (p = 0.01), increased time between NRT and surgery (p = 0.03), and higher operative blood loss (p = 0.003).ConclusionWhen performed at expert centers, 2-team taTME in patients with low rectal tumors is safe with low conversion rates and high stoma closure rate. Mid-term results will further evaluate oncologic and functional outcomes.

AimThe benefits and short-term outcomes of transanal total mesorectal excision (taTME) for rectal cancer have been demonstrated previously, but questions remain regarding the oncologic outcomes following this challenging procedure. The purpose of this study was to analyze the oncologic outcomes following taTME at high-volume centers in the USA.MethodsThis was a multicenter, retrospective observational study of 8 tertiary care centers. All consecutive taTME cases for primary rectal cancer performed between 2011 and 2020 were included. Clinical, histopathologic, and oncologic data were analyzed. Primary endpoints were rate of local recurrence, distal recurrence, 3-year disease recurrence, and 3-year overall survival. Secondary endpoints included perioperative complications and TME specimen quality.ResultsA total of 391 patients were included in the study. The median age was 57 years (IQR: 49, 66), 68% of patients were male, and the median BMI was 27.4 (IQR: 24.1, 31.0). TME specimen was complete or near complete in 94.5% of cases and the rates of positive circumferential radial margin and distal resection margin were 2.0% and 0.3%, respectively. Median follow-up time was 30.7 months as calculated using reverse-KM estimator (CI 28.1–33.8) and there were 9 cases (2.5%) of local recurrence not accounting for competing risk. The 3-year estimated rate of disease recurrence was 19% (CI 15–25%) and the 3-year estimated overall survival was 90% (CI 87–94%).ConclusionThis large multicenter study confirms the oncologic safety and perioperative benefits of taTME for rectal cancer when performed by experienced surgeons at experienced referral centers.

Background: Recently, limited abdominal computed tomography (CT) scans have been reported (Rao, New England Journal of Medicine, 1998) to have accuracy as high as 98%. We compare our hospital’s CT accuracy ordered by emergency room (ER) physicians with that of experienced surgeons provided only with the ER history and physical examination in the evaluation of appendicitis. Methods: All charts of patients 16 years or older with limited CT scans ordered by ER from January 1, 1996, through February 28, 1998, were reviewed. CT scans ordered when appendicitis was not in the differential were excluded from analysis. Pathology and clinical follow-up were criterion standards. Four surgeons reviewed ER history and physical and placed them into one of three categories: appendectomy, observe to rule out appendicitis, or discharge with follow-up (included admitting to another service or treating for another disorder). Results: A total of 526 charts were reviewed; 129 met the criteria for the study. The accuracy of CT scans as used by our ER was not as high as reported in the literature. In addition, surgeon accuracy approached that of the CT scan even without the ability to evaluate the patients in person. Noncontrast CTs were ordered before surgical evaluation in contrast to the Rao protocol, likely reducing their accuracy. Conclusions: Ordering CT scans to evaluate for appendicitis prior to surgical evaluation is of limited value.