Modulation of rectal cancer stemness, patient outcome and therapy response by adipokines

Response to chemoradiotherapy (CRT) in patients with locally advanced rectal cancer is highly variable. Identification of CRT non-responders and definite accurate biomarkers of response are unmet needs. In turn, adipokines might impact on colorectal cancer development. We hypothesized that imbalance in leptin and adiponectin modulates stemness potential CRT response in rectal cancer. Pre-CRT serum and tissue samples were collected from a cohort of locally advanced rectal cancer patients (n = 33), submitted to long-course CRT and proctectomy. Adiponectin and leptin were measured by ELISA in serum. In tumour biopsies, mRNA expression of stemness-related genes was evaluated by qRT-PCR and transcription factor STAT3 by immunoblotting. Correlations with clinical data and accuracy of potential CRT response biomarkers were evaluated. Carcinoembryonic antigen (CEA) but not leptin or adiponectin distinguished CRT responders from non-responders (p < 0.05). However, higher leptin and lower adiponectin serum levels were associated with positive extramesorectal nodes and extramural vascular invasion. mRNA expression of stemness factors was inversely correlated with adiponectin but positively correlated with leptin. STAT3 phosphorylation presented similar results. CEA levels together with STAT3 activation and OCT4/KLF4 expression accurately identified rectal cancer patients, CRT non-responders (AUROC 0.80; p < 0.05). Adipokines might impact rectal cancer stemness and patient prognosis. The leptin/STAT3 signalling axis provides the rational for a potential biomarker panel that identifies rectal cancer patients who will not benefit from CRT treatment. (AU)

Modulation of rectal cancer stemness, patient outcome and therapy response by adipokines.

Response to chemoradiotherapy (CRT) in patients with locally advanced rectal cancer is highly variable. Identification of CRT non-responders and definite accurate biomarkers of response are unmet needs. In turn, adipokines might impact on colorectal cancer development. We hypothesized that imbalance in leptin and adiponectin modulates stemness potential CRT response in rectal cancer. Pre-CRT serum and tissue samples were collected from a cohort of locally advanced rectal cancer patients (n = 33), submitted to long-course CRT and proctectomy. Adiponectin and leptin were measured by ELISA in serum. In tumour biopsies, mRNA expression of stemness-related genes was evaluated by qRT-PCR and transcription factor STAT3 by immunoblotting. Correlations with clinical data and accuracy of potential CRT response biomarkers were evaluated. Carcinoembryonic antigen (CEA) but not leptin or adiponectin distinguished CRT responders from non-responders (p < 0.05). However, higher leptin and lower adiponectin serum levels were associated with positive extramesorectal nodes and extramural vascular invasion. mRNA expression of stemness factors was inversely correlated with adiponectin but positively correlated with leptin. STAT3 phosphorylation presented similar results. CEA levels together with STAT3 activation and OCT4/KLF4 expression accurately identified rectal cancer patients, CRT non-responders (AUROC 0.80; p < 0.05). Adipokines might impact rectal cancer stemness and patient prognosis. The leptin/STAT3 signalling axis provides the rational for a potential biomarker panel that identifies rectal cancer patients who will not benefit from CRT treatment.

Loop ileostomy in rectal cancer surgery: factors predicting reversal and stoma related morbidity.

PURPOSE: Loop ileostomy is performed in rectal cancer surgery to decrease the impact of anastomotic leak but it is associated with a significant complication rate. This study aimed to analyze the morbidity related to diverting ileostomy and to identify factors predictive of complications related to stoma management and reversal, as well as conversion into a permanent ileostomy. METHODS: A retrospective study was conducted on 112 patients submitted to oncological rectal resection and defunctioning ileostomy in a Portuguese colorectal unit between March 2012 and March 2019. RESULTS: Loop ileostomy was responsible for 13% of index surgery morbidity and 15% of patients' readmissions due to high output, stoma stenosis and parastomal hernia. Ileostomy was reversed in 89% cases with 7% Clavien-Dindo ≥ IIIb complications. An association was established between diabetes and higher stoma management morbidity (OR: 3.28 [95% CI: 1.039-10.426]. p = 0.041). Likewise, diabetes (OR: 0.17 [95% CI: 0.038; 6.90], p=0.015), oncological disease stage ≥ III (OR: 0.10 [95% CI: 0.005; 0.656], p=0.047) and index rectal surgery morbidity (OR: 0.23 [95% CI: 0.052; 0.955], p=0.041) were associated with less ileostomy closure. Complications of the index surgery also related to higher stoma reversal morbidity (OR: 5.11 [95% CI: 1.665; 16.346], p=0.005). CONCLUSIONS: Diabetes and complications of index rectal surgery were identified as predictive of ileostomy morbidity, closure rate and associated complications. It is essential to adjust treatment decisions to patient's morbidity risk and adopt a more selective approach concerning the use of an ileostomy.

Potential of miR-21 to Predict Incomplete Response to Chemoradiotherapy in Rectal Adenocarcinoma.

Background: Patients with locally advanced rectal adenocarcinoma (LARC) are treated with neoadjuvant chemoradiotherapy (CRT). However, biomarkers for patient selection are lacking, and the association between miRNA expression and treatment response and oncological outcomes is unclear. Objectives: To investigate miRNAs as predictors of response to neoadjuvant CRT and its association with oncological outcomes. Methods: This retrospective study analyzed miRNA expression (miR-16, miR-21, miR-135b, miR-145, and miR-335) in pre- and post-chemoradiation rectal adenocarcinoma tissue and non-neoplastic mucosa in 91 patients treated with neoadjuvant CRT (50.4 Gy) and proctectomy. Two groups were defined: a pathological complete responders group (tumor regression grade-TRG 0) and a pathological incomplete responders group (TRG 1, 2, and 3). Results: miR-21 and miR-135b were upregulated in tumor tissue of incomplete responders comparing with non-neoplastic tissue (p = 0.008 and p < 0.0001, respectively). Multivariate analysis showed significant association between miR-21 in pre-CRT tumor tissue and response, with a 3.67 odds ratio (OR) of incomplete response in patients with higher miR-21 levels (p = 0.04). Although with no significance, patients treated with 5-fluorouracil (5-FU) presented reduced odds of incomplete response compared with those treated with capecitabine (OR = 0.19; 95% confidence interval (CI) 0.03-1.12, p = 0.05). Moreover, significant differences were seen in overall survival (OS) in relation to clinical TNM stage (p = 0.0004), cT (p = 0.0001), presence of distant disease (p = 0.002), mesorectal tumor deposits (p = 0.003), and tumor regression grade (p = 0.04). Conclusion: miR-21 may predict response to CRT in rectal cancer (RC).

Evaluation of Tissue and Circulating miR-21 as Potential Biomarker of Response to Chemoradiotherapy in Rectal Cancer.

Response to chemoradiotherapy (CRT) in patients with locally advanced rectal cancer (RC) is quite variable and it is urgent to find predictive biomarkers of response. We investigated miR-21 as tissue and plasma biomarker of response to CRT in a prospective cohort of RC patients; The expression of miR-21 was analyzed in pre- and post-CRT rectal tissue and plasma in 37 patients with RC. Two groups were defined: Pathological responders (TRG 0, 1 and 2) and non-responders (TRG 3). The association between miR-21, clinical and oncological outcomes was assessed; miR-21 was upregulated in tumor tissue and we found increased odds of overexpression in pre-CRT tumor tissue (OR: 1.63; 95% CI: 0.40-6.63, p = 0.498) and pre-CRT plasma (OR: 1.79; 95% CI: 0.45-7.19, p = 0.414) of non-responders. The overall recurrence risk increased with miR-21 overexpression in pre-CRT tumor tissue (HR: 2.175, p = 0.37); Significantly higher miR-21 expression is observed in tumor tissue comparing with non-neoplastic. Increased odds of non-response is reported in patients expressing higher miR-21, although without statistical significance. This is one of the first studies on circulating miR-21 as a potential biomarker of response to CRT in RC patients.

Morestin Syndrome Beyond Thoracic Trauma.

Morestin syndrome (MS) is a rare clinical manifestation consequent to an acute compression trauma to the thorax. In such an event, the sudden elevated pressure that happens to the airway and the rapid and retrograde blood flow results in capillary rupture in the head and neck vessel territory. This case reports a car accident victim that was dragged by a truck down a road with closed thoracic trauma resulting in MS. The patient presented with ecchymotic mask, neck and facial cyanosis and petechiae, ocular hemorrhage, otorrhagia, left clavicle fracture and spleen laceration that resolved with conservative measures. In this article, the authors present a specific acute syndrome due to trauma, with potential severe complications that should be recognized early and subject to a multidisciplinary and systemic approach in the emergency setting.

Preoperative enteral nutrition in adults with complicated Crohn's disease: Effect on disease outcomes and gut microbiota.

OBJECTIVES: The use of exclusive enteral nutrition (EEN) in patients with Crohn's disease (CD) before surgical resection can reduce disease activity and improve nutritional status. The mechanism of EEN action is unclear, but it might involve modulation of the intestinal microbiota. The aim of this study was to evaluate the effects (namely changes in gut microbiota) of preoperative EEN in adults with complicated CD referred to surgery. METHODS: This was a prospective study of adult patients with CD referred to surgery. Patients with body mass index <18.5 kg/m2, weight loss >10 %, serum albumin <3 g/dL, or a combination of some or all three, received EEN for ≥2 wk. The effects of EEN on clinical (Harvey-Bradshaw Index [HBI]) and laboratory markers (C-reactive protein [CRP], serum albumin, and fecal calprotectin) and fecal microbiota were analyzed after EEN (before surgery) and 6 mo later. We used 16 S rRNA gene sequencing to determine changes in the fecal microbiota. RESULTS: Fifteen patients were included, of whom 60% were men with a mean age of 45.4 ± 19.1 y. Of those, 10 received EEN. The median duration of preoperative EEN was 41.5 d (15-70 d). During EEN, there was a significant reduction in mean HBI (8.7 ± 1.9 versus 4.1 ± 2.4; P = 0.001) and CRP (11.7 ± 10.3 versus 0.8 ± 0.8 mg/dL; P = 0.008) and an increase in serum albumin (3.1 ± 0.6 versus 4 ± 0.6 g/dL; P = 0.022). Two patients did not require surgery after EEN. The overall microbial composition changed after EEN (Permutational analysis of variance test, P = 0.046) and there was a significant reduction in α diversity (8 ± 2.3 versus 5.2 ± 1.5; P = 0.023). EEN significantly changed the relative abundance of 11 taxonomic operational units (OTUs). At the family level, we found this was mainly due to the decrease in the Enterobacteriaceae family (7 OTUs). Six months after surgery, α diversity was not different from that before or after EEN; at this time point 6 OTUs were significantly different, mainly due to the decrease of Clostridiales order (3 OTUs). The incidence of postoperative complications and hospital length of stay were similar in EEN and immediate surgery groups, as well as clinical and endoscopic recurrence rates 6 mo after surgery. CONCLUSIONS: Preoperative EEN improved disease activity and nutritional status in patients with CD referred to surgery. Despite being malnourished, patients given EEN did not have increased postoperative complications compared with well-nourished patients. During EEN, overall microbiota composition changed and α diversity decreased. EEN did not influence postoperative recurrence and gut microbiota 6 mo after surgery.

[Pancreatic ectopia]. / Ectopia pancreática.

Pancreatic ectopia (PE) consists in the existence of pancreatic tissue outside its usual location in the normal pancreas. This rare condition, with an uncertain incidence, occurs most often in the stomach, duodenum and jejunum. The ectopic pancreas is usually asymptomatic but it may become clinically significant when it becomes affected with the same kind of complications which affect the normal pancreas - inflammation, bleeding, obstruction of the anatomic structure where it is located and malignant transformation. As the most common site of this kind of lesion is the submucosa, endoscopic ultrasonography is the most useful exam in its characterization; the final diagnosis is, however, histological. Surgical resection is indicated in symptomatic cases and when there is malignant transformation of the lesion. In this article the author presents a clinical case of gastric PE and makes a theoretical review about this entity, its etiopathogenesis, semiology, method of diagnosis and therapy, noting the indications and surgical options to treat this rare condition.