Prophylactic hyperthermic intraperitoneal chemotherapy in T4 colorectal cancer: Can it improve the oncologic prognosis? - A propensity score matching study.

BACKGROUND: Some studies show that cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) may improve overall survival and is a possible curative treatment for selected colorectal cancer (CRC) patients with restricted peritoneal metastasis (PM). The value of HIPEC in preventing PM of CRC is still controversial. MATERIALS AND METHODS: In this retrospective propensity score matching (PSM) cohort study, all patients with cT4N0-2M0 undergoing treatment at a single institution in China (2014-2018) were reviewed. The 3-year disease-free survival (DFS) was set as the primary outcome, and the 3-year PM rate was also analyzed. RESULTS: 220 patients were included in this study for analysis. After 1:3 PSM: HIPEC (n = 45) and No HIPEC (n = 135). Through analysis, it was found that prophylactic HIPEC correlated to better DFS [hazard ratio (HR) 0.43, 95 % confidence interval (CI) 0.19-0.95; p = 0.037], and N2 stage correlated to worse DFS [HR 1.97, 95 % CI 1.09-3.56; p = 0.025]. For laparoscopic surgery subgroup analyses, 3-year PM rate of patients with laparoscopic surgery was 13.8 % in No HIPEC group, and 2.6 % in HIPEC group (p = 0.070). Besides, no post-operative death occurred, the anastomotic leakage rate was 2.2 % in HIPEC group and 0.7 % in the control group (p = 0.439). CONCLUSIONS: Prophylactic HIPEC may improve the prognosis in patients with cT4N0-1M0 CRC, but not in cT4N2M0 CRC, and it does not significantly increase surgery-related complications. Laparoscopic surgery followed by HIPEC for T4 stage CRC may not increase risk of PM.

Primary Surgery Followed by Selective Chemoradiotherapy Versus Preoperative Chemoradiotherapy Followed by Surgery for Locally Advanced Rectal Cancer: A Randomized Clinical Trial.

PURPOSE: The aim of this work was to determine whether locally advanced rectal cancer (LARC) with negative mesorectal fascia (MRF) predicted by magnetic resonance imaging (MRI) can be excluded from preoperative radiation therapy treatment. METHODS AND MATERIALS: This multicenter, open-label, non-inferiority, randomized clinical trial enrolled patients with LARC within 6 to 12 cm from the anal verge and with negative MRI-predicted MRF. Participants were randomized to the intervention group (primary surgery, in which the patients with positive pathologic [CRM] circumferential margins were subjected to chemoradiotherapy [CRT] and those with negative CRM underwent adjuvant chemotherapy according to pathologic staging) or the control group (preoperative CRT, in which all patients underwent subsequent surgery and adjuvant chemotherapy). The primary endpoint was 3-year disease-free survival (DFS). RESULTS: A total of 275 patients were randomly assigned to the intervention (n = 140) and control (n = 135) groups, in which 33.57% and 28.15% patients were at clinical T4 stage and 85.92% and 80.45% patients were at "bad" or "ugly" risk in the intervention and control groups, respectively. There were 2 patients (1.52%) and 1 patient (0.77%) with positive CRM in the intervention and control groups, respectively (P > .05). The non-adherence rates for the intervention and control groups were 3.6% and 23.7%, respectively. After a median follow-up of 34.6 months (IQR, 18.2-45.7), 43 patients had positive events (28 patients and 15 patients in the intervention and control groups, respectively). There were 6 patients (4.4%) with local recurrence in the intervention group and none in the control group, which led to the termination of the trial. The 3-year DFS rate was 81.82% in the intervention group (95% CI, 78.18%-85.46%) and 85.37% in the control group (95% CI, 81.75%-88.99%), with a difference of -3.55% (95% CI, -3.71% to -3.39%; hazard ratio, 1.76; 95% CI, 0.94-3.30). In the per-protocol data set, the difference between 3-year DFS rates was -5.44% (95% CI, -5.63% to -5.25%; hazard ratio, 2.02; 95% CI, 1.01-4.06). CONCLUSIONS: Based on the outcomes of this trial, in patients with LARC and MRI-negative MRF, primary surgery could negatively influence their DFS rates. Therefore, primary surgery was an inferior strategy compared with preoperative CRT followed by surgery and cannot be recommended for patients with LARC.

Sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line therapy in RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer: an open-label, single-arm, phase II trial.

Background: Microsatellite stable (MSS) and RAS-mutant metastatic colorectal cancer (mCRC) patients are characterized by an immunosuppressive microenvironment and a low response rate to immunotherapy. Chemotherapy and anti-angiogenesis therapy have been reported to potentially promote immunotherapy response. This study aims to assess the preliminary anti-tumor activity and safety of sintilimab plus bevacizumab, oxaliplatin and capecitabine as a treatment option for patients with RAS-mutant MSS mCRC. Methods: This study was an open-label, single-arm, phase II trial in China. Patients with unresectable, RAS-mutant and MSS metastatic colorectal adenocarcinoma received treatment by intravenous sintilimab (200 mg, day 1) plus bevacizumab (7.5 mg/kg, day 1), oxaliplatin (135 mg/m2, day 1) and oral capecitabine (1 g/m2, day 1-14) in each 21-day cycle. The primary endpoints included objective response rate (ORR) and adverse events. Biomarker analysis was performed to identify potential predictors of good response to treatment. This study is registered with ClinicalTrials.gov, number NCT04194359. Findings: Between April 2021 and December 2021, 25 patients were enrolled. Two (8%) patients showed complete response (CR), 19 (76%) had partial response (PR) and 4 (16%) presented with stable disease. ORR reached 84% (95% CI, 63.9-95.5) and the disease control rate was 100% (95% CI, 86.3-100). The median progression-free survival (PFS) was 18.2 months for the full analysis set. The most common treatment-related adverse events (TRAEs) in all grades were anemia (21/25, 84%), neutropenia (20/25, 80%), and hand-foot syndrome (14/25, 56%). The most frequent grade 3 or 4 TRAEs were neutropenia (3/25, 12%) and increased alanine transaminase (2/25, 8%). No grade 5 adverse events occurred. In the exploration of biomarkers, 5 patients could be characterized as TTN/OBSCN "double-hit" after treatment, and the copy number variants burden was significantly decreased in tumor tissues after treatment compared with the baseline. Nanostring panel RNA sequencing analysis indicated a better tumor immune microenvironment cell infiltration in CR/PR patients compared with non-CR/PR patients as well as the PFS-long (≥12.5 months) group compared with the PFS-short group. Interpretation: Combination treatment with sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line treatment demonstrated a promising antitumor activity and a manageable safety profile in RAS-mutant, MSS and unresectable mCRC. Exploratory biomarker assessment analysis showed that some RAS-mutant and MSS patients changed into "immune-hot" subtype after the treatment. Funding: This study was supported by the Key R&D Program of Zhejiang Province (2021C03125 to Ying Yuan), the National Natural Science Foundation of China (81872481 to Ying Yuan, 82072624 to Kefeng Ding), the Fundamental Research Funds for the Central Universities (No. 226-2022-00009 to Kefeng Ding), and the Zhejiang Provincial Natural Science Foundation of China (No. LY22H160024 to Hanguang Hu).

The Disulfiram/Copper Complex Induces Autophagic Cell Death in Colorectal Cancer by Targeting ULK1.

Colorectal cancer (CRC) is highly prevalent worldwide, but there has been limited development of efficient and affordable treatment. Induced autophagy has recently been recognized as a novel therapeutic strategy in cancer treatment, and disulfiram (DSF), a well-known antialcohol drug, is also found to inhibit tumor growth in various malignancies. Recently, DSF has been reported to induce excessive autophagy in oral squamous cells; however, little is known about whether it can induce autophagy and suppress proliferation in CRC. In this study, we investigate the effect of DSF with copper (DSF/Cu) on CRC both in vitro and in vivo and find that the combination significantly inhibits CRC cell viability and mainly induces autophagy instead of apoptosis. Furthermore, we use whole genome CRISPR library screening and identify a new mechanism by which DSF triggers autophagy by ULK1. Overall, these findings provide a potential CRC treatment.

Prediction of efficacy of neoadjuvant chemoradiotherapy for rectal cancer: the value of texture analysis of magnetic resonance images.

PURPOSE: To explore the clinical feasibility of predicting the efficacy of neoadjuvant chemoradiotherapy (nCRT) for rectal cancer on the basis of texture analysis (TA) of T2-weighted imaging (T2WI). METHODS: The cohort for this prospective study comprised 136 patients with rectal cancer to be treated with nCRT, all of whom underwent three MR scans (pre-, early, and post-nCRT). Treatment efficacy was assessed on the basis of the outcomes of pathologic complete response (pCR) and non-pCR as determined by postoperative pathological examination. Extraction and analysis of texture features in T2WI of defined tumor regions were performed by AK software. Pre- and early-nCRT texture features were selected as potential predictors of outcomes by logistic regression analysis, and a prediction model for pCR was developed. A receiver operating characteristic (ROC) curve was used to assess the predictive power of texture features in pre- and early-nCRT images. RESULTS: Univariate logistic regression analysis demonstrated that the pre-nCRT features of energy, entropy, and skewness, and early-nCRT features of variance, kurtosis, energy, and entropy were independent predictors of pCR. A prediction model incorporating these predictors was constructed by multivariate logistic regression, The AUCs of pre-nCRT, early, and combined models were 0.751, 0.831, and 0.873, respectively; the sensitivities 66, 71, and 75%, respectively; and the specificities 87.22, 86.11, and 91.67%, respectively. CONCLUSIONS: TA of T2WI images can predict the efficacy of nCRT for rectal cancer, possibly providing a new marker of tumor biological response in clinical practice.

Functional Genetic Variations at the microRNA Binding-Site in the CD44 Gene Are Associated with Risk of Colorectal Cancer in Chinese Populations.

CD44 as one of the most putative stem cell markers plays a key role in many cellular processes, including cancer cell growth and migration. Functional single nucleotide polymorphisms (SNPs) of CD44 may modulate its gene functions and thus cancer risk. In the current study, we investigated if polymorphisms in the 3'-untranslated region (UTR) of CD44 are associated with increased susceptibility to colorectal cancer (CRC) by conducting a case-control study of 946 CRC patients and 989 cancer-free controls. Three polymorphisms (rs13347C/T, rs10836347C/T, rs11821102G/A) in the 3'-UTR of CD44 were genotyped. We found that the variant genotypes (CT and TT) of rs13347 (adjusted odds ratio (OR)=1.79, 95% confidence interval (CI)=1.50-2.17) increased an individual's susceptibility to CRC, compared with rs13347CC homozygous genotypes. We also found that CRC patients with the CT/TT genotype had a 1.6-fold increased risk for developing advanced (stage III + IV) CRC. Furthermore, functional assays showed that the C to T base change at rs13347C/T disrupts the binding site for the microRNA hsa-mir-509-3p, thereby increasing CD44 transcriptional activity and expression level. These findings suggest that the rs13347C/T in microRNA binding site may be potential biomarkers for genetic susceptibility to CRC.

Design, synthesis and biological evaluation of nitro oxide donating N-hydroxycinnamamide derivatives as histone deacetylase inhibitors.

Novel nitro oxide (NO)-donating N-hydroxycinnamamide derivatives 12a-j were designed and synthesized by coupling the carboxyl group of N-hydroxycinnamamides with phenylsulfonylfuroxan through various diols or alkylol amines, and their in vitro biological activities were evaluated. It was discovered that most of target compounds showed good histone deacetylases (HDACs) inhibition and anti-tumor activities, particularly for 12j, which had great HDACs inhibitory activities (IC50s=0.15-0.26 µM) and antiproliferative effects (IC50s=3.21-7.12 µM) comparable to suberoylanilide hydroxamic acid (SAHA) (IC50s=0.16-1.41 µM for HDACs, IC50s=3.15-7.45 µM for cancer cell inhibition). Furthermore, compound 12j with strong antitumor activities produced high levels of NO (up to 8.0 µM of nitrites/nitrates) in colon cancer cells, and its antiproliferative activity was nearly half-diminished by hemoglobin (10 µM), an NO scavenger. These results suggest that the strong antiproliferative activity of 12j could be attributed to the additive effects of high levels of NO production and inhibition of HDAC in the cancer cells.

[Clinical study of a new intracolonic drainage to protect low rectal anastomotic leakage].

OBJECTIVE: To investigate the value of using protective new intracolonic drainage in decreasing low colorectal anastomotic leakage. METHODS: One hundred and nineteen cases of rectal cancer accepted low anterior resection were randomly assigned to study group (n=55) and control group (n=64). The study group was added with a new intracolonic drainage composed of biofragmentable anastomosis ring and condom during operation. The control group was added with protective ileostomy during operation. The results of surgery were compared between the two groups. RESULTS: All the cases were followed up over three months and there were no perioperative death. There were no significant differences in physiopathological factors such as age, sex, body type, site of tumor, size of tumor, differentiation of tumor, site of anastomosis, condition of nutrition, concomitant disease between the two groups. In the study group, anastomotic leakage occurred in 4 cases (7.3%), the drainage devices were ablated 18.3 days after operations and there were no drainage-related complications; light anastomotic stenosis occurred in 3 cases (5.5%) three months after operations. Among the cases with leakage, no severe abdominal infection was found, the time of abdominal drainage was 4.8 days, and the amount of abdominal drainage was 12.8 ml/d in primary three days after leakage. In the control group, anastomotic leakage occurred in 7 cases (10.9%), ostomy-related complications occurred in 29 cases (45.3%), anastomotic stenosis occurred in 18 cases (28.1%) and severe anastomotic stenosis occurred in 4 cases (6.3%) after three months. Among the cases with leakage, severe infection occurred in two cases, anastomotic spoiled occurred in one case, the amount of abdominal drainage was 35.4 ml/d in primary three days after leakage, and the time of abdominal drainage was 17.1 days. There was no significant difference in the rate of anastomotic leakage between the two groups (P>0.05). But there were significant differences in the amount of abdominal drainage, the time of abdominal drainage and abdominal infection in the cases of anastomotic leakage (P<0.01). There was significant difference in anastomotic stenosis after three months between the two groups (P<0.01). CONCLUSIONS: The intracolonic drainage is a simple, safe and effective method in protecting low colorectal anastomotic leakage, and avoiding harmful results caused by anastomotic leakage. Compared with protective ileostomy, intracolonic drainage can avoid stomy-related physical mental suffering and complications, the rate of later anastomotic stenosis is less, and the time of abdominal drainage is shorter in the cases with leakage.

[Rule of lymph node metastasis in colorectal cancer and its affecting factors].

OBJECTIVE: To investigate the rule of lymph node metastasis in colorectal cancer and its affecting factors, and to provide clues for clinical diagnosis and treatment of colorectal cancer patients. METHODS: The clinical data of 1166 cases of colorectal cancer receiving surgical resection were analyzed retrospectively.The relationships between clinicopathologic variables and lymph node metastases were evaluated by crosstabs and logistic regression in SPSS 10.0 for windows. RESULTS: The rate of lymph node metastasis in colorectal cancer was 49.7%. After entering crosstabs estimation, gender and tumor site were not significantly correlated with lymph node metastasis in colorectal cancer(chi2=1.46, r=0.035, P>0.05 and chi2=3.86, r=0.012, P>0.05). Age, tumor size, the massive type of the tumor, the differentiating degree of the tumor, histology type and the depth of tumor invasion were proved to be independent factors influencing the lymph node metastasis in colorectal cancer (chi2 =13.1, r=0.064, P<0.05 and chi2=77.161, r=0.245, P<0.01 and chi2=144.831, r=0.341, P<0.01 and chi2=128.310, r=0.318, P<0.01 and chi2=120.418, r=0.319, P<0.01 and chi2=227.287, r=0.434, P<0.01). After entering logistic regression estimation, the correlativity of risk factor of lymph node metastasis in colorectal cancer: the depth of tumor invasion > the massive type of the tumor>the differentiating degree of the tumor > tumor size. Preoperative blood serum CEA level was significantly correlated with lymph node metastasis (chi2=509.599, r=0.661, P<0.01). CONCLUSION: The depth of tumor invasion is the most risk factor of lymph node metastasis in colorectal cancer. Preoperative high level of blood serum CEA indicates the occurrence of lymph node metastasis.

[The morphological alterations of jejunal mucosa accepting early enteral nutrition for post-operative patients with severe acute pancreatitis].

OBJECTIVE: To investigate the morphological alterations and significances of jejunal mucosa responsible to post-operative patients with severe acute pancreatitis treated with enteral nutrition (EN) or total parenteral nutrition (TPN). METHODS: 40 patients were divided randomly into EN group and TPN group. The serum levels of prealbumin (PAB) and transferrin (TRF) were detected at a given time. Jejunal mucosa specimens were acquired through a new technique and observed in detail both under general microscope and electronic microscope. RESULTS: On seventh and fourteenth post-operative day, the serum level of PAB in EN group was remarkably higher than it in TPN group (P < 0.05). No difference was seen in TRF levels of 2 groups. On 14th post-operative day, it was found by general microscope that the height of jejunal mucosa villi was significantly higher in EN group than in TPN group (P < 0.05), and meantime it was also found by electronic microscope that the height of microvilli on jejunal mucosa epithelial cells in EN group was remarkably higher than it in TPN group (P < 0.05) and was higher than microvilli itself before EN start (P < 0.05). In TPN group, some pathological alterations could be seen in jejunal mucosa epithelial cells on 14th post-operative day, such as mitochondrial edema, crista swelling, dilation of rough endoplasmic reticulum and nucleolus, and the appearance of abnormal substances in intercellular attachments. However, none of above these pathological changes could be seen in EN group. CONCLUSION: Early enteral nutrition could protect the jejunal mucosa in post-operative patients with severe acute pancreatitis and have its results better than TPN alone.

[Study of prophylactic intra-iliac and hepatic arterial infusion chemotherapy against pelvic recurrence and liver metastasis after radical resection for rectal cancer].

OBJECTIVE: To study the effects of prophylactic intra-iliac and hepatic arterial infusion chemotherapy on pelvic recurrence and liver metastasis after radical resection for rectal cancer. METHODS: Eighty-four rectal cancer patients,undergone radical resection on Dukes stage B or C,were randomly assigned to postoperative intra-iliac and hepatic arterial infusion chemotherapy group(group I) and routine vein chemotherapy group(group II). Five-year survival and recurrence rates were compared between the two groups. RESULTS: Among the 84 rectal cancer patients with radical resection, the 5-year liver metastasis and pelvic recurrence rates were 30.2% (13/43) and 18.6% (8/43) respectively in group II, 17.1% (7/41) and 9.8% (4/41) in group I, the difference was significant between 2 groups (chi(2)=4.31, P<0.05). The mean tumor-free survival time was 26.2 months in group I and 15.8 months in group II (t=5.05, P<0.01), the difference was significant (t=5.05, P<0.01). The five-year survival rate in group I (65.9%) was significantly higher than that in group II (56.5%) (u=8.86, P<0.01). Cox multivariate analysis showed that, compared with those in group II, the relative risks of pelvic recurrence and liver metastasis in group I decreased 20% (coefficient of relative risk: 0.7959), and the five-year mortality also decreased 20% (coefficient of relative risk: 0.8034). CONCLUSION: Prophylactic intra-iliac and hepatic arterial infusion chemotherapy can reduce the rates of pelvic recurrence and liver metastasis after radical resection of rectal cancer.

[Establishment of whole pancreaticoduodenal allotransplantation model with jejunum drainage and portal venous drainage in pigs].

OBJECTIVE: To establish a pig model of pancreaticoduodenal transplantation with jejunum drainage and portal venous drainage. METHODS: Forty pigs were randomly divided into the donor group and recipient group. University of Wisconsin (UW) solution was used for both in situ flush and storage of all organs under cold storage conditions. Whole pancreaticoduodenal graft was harvested with segments of abdominal aorta and portal vein and shaped under cold UW solution. Then, the end-to-end anastomosis was performed with the donor iliac artery bifurcation Y graft to the recipient superior mesenteric arteries and celiac artery. Furthermore, type I diabetes model was made by removal of the recipient pancreas The venous anastomosis was reconstructed between the donor portal vein and the recipient superior mesenteric vein. Meanwhile, the end-to-side anastomosis was performed with the donor common iliac artery bifurcation Y graft to the recipient abdomial aorta, and the side-to-side intestinal anastomosis between the donor duodenum and the recipient jejunum was performed. RESULTS: Twenty piges were subjected to pancreaticoduodenal transplantation, in which 1 died from respiratory depression because of anesthesia, and 2 had thrombus and infarction in the pancreatic graft after transplantation. 17 cases showed normal blood sugar in peripheral circulation 24 hours after operation, the mean survival of the graft was 18.6 +/- 2.6 days. CONCLUSION: The technique of duodenal transplantation with jejunum drainage and portal venous drainage may pave the way for the further development of pancreas transplantation in clinical practice. It can be utilized in basic research of pancreas transplantation.