Fecal and Tissue Microbiota Are Associated with Tumor T-Cell Infiltration and Mesenteric Lymph Node Involvement in Colorectal Cancer.

Colorectal cancer (CRC) is associated with alterations of the fecal and tissue-associated microbiome. Preclinical models support a pathogenic role of the microbiome in CRC, including in promoting metastasis and modulating antitumor immune responses. To investigate whether the microbiome is associated with lymph node metastasis and T cell infiltration in human CRC, we performed 16S rRNA gene sequencing of feces, tumor core, tumor surface, and healthy adjacent tissue collected from 34 CRC patients undergoing surgery (28 fecal samples and 39 tissue samples). Tissue microbiome profiles-including increased Fusobacterium-were significantly associated with mesenteric lymph node (MLN) involvement. Fecal microbes were also associated with MLN involvement and accurately classified CRC patients into those with or without MLN involvement. Tumor T cell infiltration was assessed by immunohistochemical staining of CD3 and CD8 in tumor tissue sections. Tumor core microbiota, including members of the Blautia and Faecalibacterium genera, were significantly associated with tumor T cell infiltration. Abundance of specific fecal microbes including a member of the Roseburia genus predicted high vs. low total and cytotoxic T cell infiltration in random forests classifiers. These findings support a link between the microbiome and antitumor immune responses that may influence prognosis of locally advanced CRC.

Phase I trial of Bermekimab with nanoliposomal irinotecan and 5-fluorouracil/folinic acid in advanced pancreatic ductal adenocarcinoma.

In this phase I dose-escalation trial, we assess the maximum tolerated dose (MTD) of Bermekimab in combination with Nanoliposomal Irinotecan (Nal-Iri) and 5-Fluorouracil/Folinic Acid (5-FU/FA). Secondarily, we investigate effects on weight, lean body mass, quality-of-life, the gut microbiome composition, inflammatory biomarkers, progression-free survival, and overall survival. This was a single-arm, open-label adaptive Bayesian dose-escalation study of Bermekimab combined with Nal-Iri and 5FU/FA in patients with advanced or locally advanced PDAC who failed gemcitabine-based chemotherapy. 22 patients enrolled between 2017 and 2019. 3 of 21 patients experienced dose-limiting toxicities attributable to the chemotherapy backbone. 58% (10/17) of patients exhibited weight stability. Physical performance status was preserved among all subjects. Patients reported improvements in quality-of-life metrics via QLQ-PAN26 questioner (-3.6, p = 0.18) and functional well-being (1.78, p = 0.02). Subjects exhibited a decrease in inflammatory cytokines, notably, vascular endothelial growth factor (-0.86, p = 0.017) with Bermekimab. Bermekimab treatment was associated with an increased abundance of gut health-promoting bacterial genera Akkermansia, with 3.82 Log2-fold change from baseline. In sum, Bermekimab is safe to be used in conjunction with Nal-Iri and 5-FU/FA chemotherapy. This benign toxicological profile warrants further Phase I/II investigation of Bermekimab in combinatorial strategies, and the impact of anti-IL-1α antibodies on the gut microbiome.Clinical trials registration: NCT03207724 05/07/2017.

Spinal cord complications after thoracic aortic surgery: long-term survival and functional status varies with deficit severity.

OBJECTIVE: Paraplegia after thoracoabdominal aneurysm (TAA) repair has been associated with poor survival. Little information exists concerning the spectrum of severity that characterizes spinal cord ischemic (SCI) complications. This study stratified SCI by deficit severity to determine its impact on late survival and functional outcomes. METHODS: A review of our prospectively maintained thoracic aortic database was performed from May 1987 through December 2005 to identify patients who experienced SCI of any extent after TAA repair. During this period, 576 patients underwent descending thoracic aortic repair (93 open, 105 endovascular [TEVAR]) or open TAA repair (279 extent I to III; 99 extent IV). To stratify severity of SCI, we created a spinal cord ischemia deficit (SCID) scale, which is defined as: I, flaccid paralysis; II, average neurologic muscle grade indicating <50% function; and III, average neurologic muscle grade indicating >50% function. Long-term outcomes were evaluated in relation to these groups by actuarial methods. RESULTS: During the study period, 64 (11.1%) patients developed SCI of any severity (7 of 105 [6.6%] TEVAR, 57 of 471 [12%] open). These were stratified by SCID level: I, 24 (37.5%); II, 31 (48.4%); and III, 9 (14.1%). SCI was immediate in 33 (54.1%) and delayed in 28 (45.9%). Most SCI (6 of 7) associated with TEVAR was delayed. The 30-day mortality was significantly higher in the SCI group than the overall patient cohort (15 of 64 [23.4%] vs 41 of 512 [8%], P < .001) and varied by SCID level: I, 11 of 24 (45.8%); II, 4 of 31 (12.9%); and III, 0 of 9 (0%; P = .001). The 5-year actuarial survival for all SCI was lower than for non-SCI patients (25% +/- 6% vs 51% +/- 3%, P < .001) and varied linearly with SCID level but was similar between SCID II/III and the non-SCI patients (41% +/- 10% vs 51% +/- 3%, P = .281). No SCID I patients were alive at 5 years. No patients with SCID I recovered the ability to walk, but eight of 11 (73%) with SCID II and the nine (100%) with SCID III could ambulate with or without assistance at last follow-up. CONCLUSION: Survival and functional outcomes correlate with SCI severity. Patients with SCID I have a poor long-term outlook. Survival of SCID II/III patients is similar to non-SCI patients; most recover the ability to ambulate.