Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial.

BACKGROUND: TGF-ß is an immunosuppressive cytokine that is upregulated in colorectal cancer. TGF-ß blockade improved response to chemoradiotherapy in preclinical models of colorectal adenocarcinoma. We aimed to test the hypothesis that adding the TGF-ß type I receptor kinase inhibitor galunisertib to neoadjuvant chemoradiotherapy would improve pathological complete response rates in patients with locally advanced rectal cancer. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Eli Lilly via ExIST program, The Providence Foundation.

Laparoscopic Lavage in the Management of Hinchey III/IV Diverticulitis.

Diverticulitis manifestations may cover a spectrum of mild local inflammation to diffuse feculent peritonitis. Up to 35% of patients presenting with diverticulitis will have purulent (Hinchey grade III) or feculent (Hinchey grade IV) contamination of the abdomen, with a high-associated morbidity and mortality. Surgical management may involve segmental resection with or without restoration of bowel continuity. However, emergency resection for diverticulitis can be associated with high mortality rates, as well as low stoma reversal rates at 1 year. Therefore, laparoscopic peritoneal lavage has been proposed for use in selected patients with purulent peritonitis. The topic of laparoscopic peritoneal lavage for the treatment of perforated diverticulitis in the literature has been controversial. Our review of the recent data show that laparoscopic lavage may be safe and feasible in select patients with similar rates of mortality and major morbidity. There is, however, a concern regarding an associated higher rate of postoperative abscess and early reintervention risk.

TGFß suppresses CD8+ T cell expression of CXCR3 and tumor trafficking.

Transforming growth factor beta (TGFß) is a multipotent immunosuppressive cytokine. TGFß excludes immune cells from tumors, and TGFß inhibition improves the efficacy of cytotoxic and immune therapies. Using preclinical colorectal cancer models in cell type-conditional TGFß 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-ALK5flox/flox (ALK5ΔCD8) mice reject tumors in high proportions, dependent on CD8+ T cells. ALK5ΔCD8 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. TGFß reduces CXCR3 expression, and increases binding of Smad2 to the CXCR3 promoter. In vivo CXCR3 blockade partially abrogates the survival advantage of an ALK5ΔCD8 host. These data demonstrate a mechanism of TGFß immunosuppression through inhibition of CXCR3 in CD8+ T cells, thereby limiting their trafficking into tumors.

Outcomes of Abdominal Surgery in Patients With Mechanical Ventricular Assist Devices: A Multi-institutional Study.

OBJECTIVE: The aim of this study was to examine the outcomes of elective and emergent abdominal operations performed in end-stage heart failure patients supported with ventricular assist devices (VADs). SUMMARY OF BACKGROUND DATA: With the growing volume of end-stage heart failure patients receiving VADs, an increasing number of these patients require surgery for noncardiac pathology. There is a paucity of studies on the safety of abdominal operations in this population. METHODS: We performed a retrospective chart review across 3 hospitals of patients with VADs who underwent abdominal surgeries between 2003 and 2015. We used Chi-square, Fisher exact, and Mann-Whitney U tests for comparison of elective and emergent cases. RESULTS: Fifty-seven patients underwent 63 operations, of which 23 operations were elective, 24 were emergent, and 16 were emergently performed in the same admission as VAD placement and analyzed separately. Patients undergoing elective versus emergent procedures had similar comorbidities (Charlson score 2.9 vs 3.0). 43% versus 32% of patients had VADs as a destination therapy. Although perioperative anticoagulation approach was variable, holding warfarin and starting heparin/enoxaparin/bivalirudin bridge was most common (65% vs 54%). Although 2-fold higher in the emergent group (50 vs 100 mL, P = 0.06), median estimated blood loss was low. Postoperative bleeding requiring transfusion was not very common (13% vs 8%), whereas rate of ischemic cerebrovascular accident (4% each) and venous thromboembolism was low (0% vs 13%, P = 0.23). Thirty-day mortality rate was 4% versus 17%, P = 0.19. CONCLUSION: VAD patients have an acceptable risk profile for abdominal surgery.

Unique surgical approach to a twisted ileal-anal pouch.

Total proctocolectomy with ileal pouch-anal anastomosis can restore gastrointestinal continuity in patients requiring colectomy for ulcerative colitis, however, it can be associated with high morbidity. Reoperation for pouch-related complications is technically challenging and often leads to deterioration of pouch function or need for permanent stoma. We report a case of acute on chronic small bowel obstruction secondary to a 360-degree twist in the small bowel introduced during creation of the ileal-anal pouch. Our novel approach at repair has not been reported in past literature which included resection and re-anastomosis of the small bowel proximal to the pouch allowing for pouch salvage with return to function.