Development and Validation of a Post-Radiotherapy Prediction Model for Bowel Dysfunction After Rectal Cancer Resection.

BACKGROUND & AIMS: The benefit of radiotherapy for rectal cancer is based largely on a balance between a decrease in local recurrence and an increase in bowel dysfunction. Predicting postoperative disability is helpful for recovery plans and early intervention. We aimed to develop and validate a risk model to improve the prediction of major bowel dysfunction after restorative rectal cancer resection with neoadjuvant radiotherapy using perioperative features. METHODS: Eligible patients more than 1 year after restorative resection following radiotherapy were invited to complete the low anterior resection syndrome (LARS) score at 3 national hospitals in China. Clinical characteristics and imaging parameters were assessed with machine learning algorithms. The post-radiotherapy LARS prediction model (PORTLARS) was constructed by means of logistic regression on the basis of key factors with proportional weighs. The accuracy of the model for major LARS prediction was internally and externally validated. RESULTS: A total of 868 patients reported a mean LARS score of 28.4 after an average time of 4.7 years since surgery. Key predictors for major LARS included the length of distal rectum, anastomotic leakage, proximal colon of neorectum, and pathologic nodal stage. PORTLARS had a favorable area under the curve for predicting major LARS in the internal dataset (0.835; 95% CI, 0.800-0.870, n = 521) and external dataset (0.884; 95% CI, 0.848-0.921, n = 347). The model achieved both sensitivity and specificity >0.83 in the external validation. In addition, PORTLARS outperformed the preoperative LARS score for prediction of major events. CONCLUSIONS: PORTLARS could predict major bowel dysfunction after rectal cancer resection following radiotherapy with high accuracy and robustness. It may serve as a useful tool to identify patients who need additional support for long-term dysfunction in the early stage. CLINICALTRIALS: gov, number NCT05129215.

CXCL16 inhibits epithelial regeneration and promotes fibrosis during the progression of radiation enteritis.

Radiation enteritis (RE) is a prevalent complication of radiotherapy for pelvic malignant tumors, characterized by severe intestinal epithelial destruction and progressive submucosal fibrosis. However, little is known about the pathogenesis of this disease, and so far, there is no specific targeted therapy. Here, we report that CXCL16 is upregulated in the injured intestinal tissues of RE patients and in a mouse model. Genetic deletion of Cxcl16 mitigates fibrosis and promotes intestinal stem cell-mediated epithelial regeneration after radiation injury in mice. Mechanistically, CXCL16 functions on myofibroblasts through its receptor CXCR6 and activates JAK3/STAT3 signaling to promote fibrosis and, at the same time, to transcriptionally modulate the levels of BMP4 and hepatocyte growth factor (HGF) in myofibroblasts. Moreover, we find that CXCL16 and CXCR6 auto- and cross-regulate themselves in positive feedback loops. Treatment with CXCL16 neutralizing monoclonal antibody attenuates fibrosis and improves the epithelial repair in RE mouse model. Our findings emphasize the important role of CXCL16 in the progression of RE and suggest that CXCL16 signaling could be a potential therapeutic target for RE. © 2022 The Pathological Society of Great Britain and Ireland.

Diverting colostomy is an effective procedure for ulcerative chronic radiation proctitis patients after pelvic malignancy radiation.

BACKGROUND: Chronic radiation proctitis (CRP) with rectal ulcer is a common complication after pelvic malignancy radiation, and gradually deteriorating ulcers will result in severe complications such as fistula. The aim of this study was to evaluate effect of colostomy on ulcerative CRP and to identify associated influence factors with effectiveness of colostomy. METHODS: Between November 2011 to February 2019, 811 hospitalized patients were diagnosed with radiation-induced enteritis (RE) in Sun Yat-sen University Sixth Affiliated Hospital, among which 284 patients presented with rectal ulcer, and 61 ulcerative CRP patients were retrospectively collected and analyzed. RESULTS: The overall effective rate of colostomy on ulcerative CRP was 49.2%, with a highest effective rate of 88.2% within 12 to 24 months after colostomy. 9 (31.1%) CRP patients with ulcers were cured after colostomy and 12 (19.67%) patients restored intestinal continuity, among which including 2 (3.3%) patients ever with rectovaginal fistula. 100% (55/55) patients with rectal bleeding and 91.4% (32/35) patients with anal pain were remarkably alleviated. Additionally, multivariable analysis showed the duration of stoma [OR 1.211, 95% CI (1.060-1.382), P = 0.005] and albumin (ALB) level post-colostomy [OR 1.437, 95% CI (1.102-1.875), P = 0.007] were two independent influence factors for the effectiveness of colostomy on the rectal ulcer of CRP patients. CONCLUSIONS: Colostomy was an effective and safe procedure for treating rectal ulcer of CRP patients, and also a potential strategy for preventing and treating fistula. Duration of stoma for 12-24 months and higher ALB level could significantly improve the effectiveness of colostomy on ulcerative CRP patients.

Risk Prediction and Treatment of LE-DVT in Patients with Chronic Radiation Intestinal Injury: A Retrospective Case-Control Study.

BACKGROUND: Chronic radiation intestinal injury (CRII) is the most common complication after pelvic malignancy radiation. Once hemorrhagic CRII patients suffer from lower extremity deep venous thrombosis (LE-DVT), hemostasis and anticoagulation therapy will be adopted simultaneously, but the treatment strategy is a paradox, as the condition is extremely intractable and serious. The aim of this study was to investigate the prevalence of and risk factors for LE-DVT in CRII patients and explore the treatment of hemorrhagic CRII patients with LE-DVT. METHODS: This was a retrospective study, and a total of 608 hospitalized CRII patients after pelvic radiotherapy were included from November 2011 to October 2018. Univariate and multivariate analyses were conducted to investigate the potential risk factors for LE-DVT in CRII patients. Furthermore, the treatment of hemorrhagic CRII patients with LE-DVT was explored. RESULTS: Among the CRII patients, 94 (15.5%) were with suspicious symptoms of LE-DVT in the lower limbs, and 32 (5.3%) were diagnosed with LE-DVT. Among the patients with LE-DVT, 65.6% (21/32) had bleeding simultaneously, and 29 (90.6%) had anemia with 24 (75.0%) having moderate to severe anemia. Multivariate analysis showed that a recent surgical history (≤6 months) (OR = 5.761, 95% CI: 2.506~13.246, p < 0.001), tumor recurrence or metastasis (OR = 3.049, 95% CI: 1.398~6.648, p = 0.005) and the hemoglobin (Hb) level (OR = 0.960, 95% CI: 0.942~0.979, p < 0.001) were significantly associated with the development of LE-DVT. ROC curve analysis showed that the AUC of the merged risk score of the independent risk factors was 0.822 (95% CI: 0.789~0.852), and the optimal Hb cutoff was 82.5 g/L. After colostomy, obvious bleeding remission was rapidly found in 84.6% of hemorrhagic CRII patients with LE-DVT. CONCLUSION: The prevalence of LE-DVT in hospitalized CRII patients was 5.3%. A recent surgical history, tumor recurrence or metastasis and a lower Hb level were independently associated with LE-DVT development in CRII patients. Colostomy could be a good choice for intractable hemorrhagic CRII patients with LE-DVT.

Hand-Object Interaction: From Human Demonstrations to Robot Manipulation.

Human-object interaction is of great relevance for robots to operate in human environments. However, state-of-the-art robotic hands are far from replicating humans skills. It is, therefore, essential to study how humans use their hands to develop similar robotic capabilities. This article presents a deep dive into hand-object interaction and human demonstrations, highlighting the main challenges in this research area and suggesting desirable future developments. To this extent, the article presents a general definition of the hand-object interaction problem together with a concise review for each of the main subproblems involved, namely: sensing, perception, and learning. Furthermore, the article discusses the interplay between these subproblems and describes how their interaction in learning from demonstration contributes to the success of robot manipulation. In this way, the article provides a broad overview of the interdisciplinary approaches necessary for a robotic system to learn new manipulation skills by observing human behavior in the real world.

Enhancing cancer-associated fibroblast fatty acid catabolism within a metabolically challenging tumor microenvironment drives colon cancer peritoneal metastasis.

Most cancer-related deaths result from the progressive growth of metastases. Patients with peritoneal metastatic (PM) colorectal cancer have reduced overall survival. Currently, it is still unclear why colorectal cancer (CRC) cells home to and proliferate inside the peritoneal cavity, and there is no effective consolidation therapy for improved survival. Using a proteomic approach, we found that key enzymes of fatty acid oxidation (FAO) were decreased in patients with PM colorectal cancer. Furthermore, we confirmed that carnitine palmitoyltransferase IA (CPT1A), a rate-limiting enzyme of FAO, was expressed at significantly low levels in patients with PM colorectal cancer, as determined by RT-qPCR, IHC, and GEO dataset analysis. However, lipidomics revealed no difference in FFA levels between PM and non-PM primary tumors. Here, we showed that cancer-associated fibroblasts (CAFs) promote the proliferation, migration, and invasion of colon cancer cells via upregulating CPT1A to actively oxidize FAs and conduct minimal glycolysis. In addition, coculture-induced glycolysis increased in cancer cells while fatty acid catabolism decreased with lower adiponectin levels. Importantly, inhibition of glycolysis significantly reduced the survival of CRC cells after incubation with conditioned medium from CAFsCPT1A-OE in vitro and impaired the survival and growth of organoids derived from CRC-PM. Finally, we found that directly blocking FAO in CAFsCPT1A-OE with etomoxir inhibits migration and invasion in vitro and decreases tumor growth and intraperitoneal dissemination in vivo, revealing a role for CAF CPT1A in promoting tumor growth and invasion. In conclusion, our results suggest the possibility of testing FAO inhibition as a novel approach and clinical strategy against CAF-induced colorectal cancer with peritoneal dissemination/metastases.

To what extent should the intestinal be resected proximally after radiotherapy: hint from a pathological view.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) is associated with post-operative anastomotic complications in rectal-cancer patients. Anastomosis involving at least one non-irradiated margin reportedly significantly reduces the risk of post-operative anastomotic complications in radiation enteritis. However, the exact scope of radiotherapy on the remaining sigmoid colon remains unknown. METHODS: We evaluated the radiation damage of proximally resected colorectal segments in 44 patients with rectal cancer, who received nCRT followed by conventional resection (nCRT-C, n = 21) or proximally extended resection (nCRT-E, n = 23). The segments from another 13 patients undergoing neoadjuvant chemotherapy (nCT) were used as control. We dissected these samples at a distance of 2 cm between the two adjacent sections. Radiation damage in proximally resected colorectal segments was evaluated using the radiation injury score (RIS) and the concentration and distribution patterns of angiostatin. RESULTS: Compared to those in the nCT group, the nCRT group showed higher RIS, levels of angiostatin, and proportion of diffuse pattern of angiostatin. With increasing distance from the tumor site, these parameters all gradually decreased; and the differences came to be not significant at the site that is over 20 cm from the tumor. The nCRT-E group showed lower RIS (median: 2 vs 4, P = 0.002) and a greater proportion of non-diffuse angiostatin (87% vs 55%, P = 0.039) at the proximal margins compared with the nCRT-C group. CONCLUSIONS: The severity of the radiation damage of the proximal colon is inversely proportional to the proximal-resection margin length. Little damage was left on the proximal margin that was over 20 cm from the tumor. Removal of an initial length of ≥20 cm from the tumor may be beneficial for rectal-cancer patients after nCRT.

[Efficacy analysis of proximally extended resection for locally advanced rectal cancer after neoadjuvant chemoradiotherapy].

OBJECTIVE: To evaluate the short-term outcomes and perioperative safety of proximally extended resection for locally advanced rectal cancer after neoadjuvant chemoradiotherapy. METHODS: From colorectal cancer database in The Sixth Affiliated Hospital of Sun Yat-sen University, a cohort of patients who underwent neoadjuvant chemoradiotherapy(1.8-2.0 Gy per day, 25-28 fractions, concurrent fluorouracil-based chemotherapy) followed by curative sphincter-preserving surgery for locally advanced rectal cancer between May 2016 and June 2017 were retrospectively identified. Exclusion criteria were synchronous colon cancer, intraoperatively confirmed distal metastasis, multiple visceral resection, and emergency operation. Thirty-one patients underwent proximal extended resection and two were excluded for incomplete extended resection, then 29 patients were enrolled as the extended group. Using propensity scores matching with 1/1 ration, 29 locally advanced rectal cancer patients who underwent conventional resection after neoadjuvant chemoradiotherapy at the same time were matched as the conventional group. Clinical data of two groups were analyzed, and the baseline characteristics and short-term outcomes were compared using the t test, χ2 test, or Mann-Whitney U test. RESULTS: Two groups were well balanced with respect to the baseline characteristics after propensity score matching. As compared with conventional group, patients in extended group had longer surgical specimen [(18.8±5.1) cm vs.(11.6±3.4) cm, t=6.314, P=0.000] and longer proximal resection margin [(14.8±5.5) cm vs.(8.2±3.0) cm, t=5.725, P=0.000], but also had longer total operating time [(322.4±100.7) min vs.(254.6±70.3) min, t=2.975, P=0.004] and more intraoperative blood loss [100(225) ml vs. 100(50) ml, Z=-2.403, P=0.016]. No significant differences were observed in the length of distal resection margin, ratio of positive resection margin, number of retrieved lymph node, time of analgesic use, time of draining tube use, time to first flatus, time to first oral diet, and postoperative hospital stay. During the perioperative period of 30 days, the morbidity of complication in extended group and conventional group was 17.2%(5/29) and 34.5% (10/29), respectively (P=0.134). CONCLUSION: Proximally extended resection is a radical and safe surgical alternative for locally advanced rectal cancer after neoadjuvant chemoradiotherapy, which can potentially reduce the risk of anastomosis complication.

Correlation between Disease Activity and Endorectal Ultrasound Findings of Chronic Radiation Proctitis.

The aim of this study was to summarize the imaging features of chronic radiation proctitis (CRP) on endorectal ultrasound (ERUS) and investigate the value of ERUS in the evaluation of disease activity. 40 CRP patients and 30 control patients were investigated by ERUS. Rectal wall thickness and layers, ulcers and rectovaginal fistulas were evaluated by B-mode ultrasound. Power Doppler imaging was used to evaluate the vascularity of the rectal wall using a semiquantitative score. Disease activity was calculated according to the National Cancer Institute Common Terminology Criteria for Adverse Events 4.0 (CTCAE 4.0). Imaging findings for patients with mild and severe CRP were compared. For 30 patients in the control group, the average maximum thickness of the rectal wall was 3.07 ± 0.73 mm, with all exhibiting typical wall stratification and level 0 vascularity. For the 40 CRP patients, there was marked thickening of the rectal wall (average thickness = 9.42 ± 1.94 mm), which was significantly thicker than in the control group (p < 0.05). The rectal walls of the mild group were significantly thinner than those of the severe group (8.71 ± 1.67 mm vs. 10.00 ± 2.00 mm, p < 0.05). Among the 22 severe cases, 19 cases (19/22, 86.4%) exhibited hyper-vascularity (level IV) or blurred wall stratification (including hypo-echoic submucosa, ulcer and fistula); 12 of the 18 mild cases (166.7%) exhibited a vascularity of level III and typical wall stratification. A significant association (p < 0.05) was observed between stratification and vascularity of the rectal wall and CRP activity. When ERUS findings of blurred rectal wall stratification or increasing vascularity (level IV) were used to evaluate CRP activity, the sensitivity was 86.4% (95% confidence interval: 64.0-96.4) and the specificity was 66.7% (95% confidence interval: 41.2-85.6). Thickening of the rectal wall, blurred wall stratification and increased vascularity are characteristic ERUS findings of CRP. ERUS is helpful in the comprehensive evaluation of disease activity and may provide objective evidence during treatment planning and follow-up.