Rectal cancer - avoiding surgery?

Nonoperative treatment of rectal cancer is gaining popularity. Several trials recently demonstrated advantages in disease-free survival with total neoadjuvant treatment (TNT) with the addition of the watch and wait (WW) strategy for locally advanced rectal cancer. On longer follow-up, an unexpected increased risk in local recurrence in the TNT group at the RAPIDO trial suggested early surgery for nonresponding tumours. The WW option is globally accepted for a complete clinical response; however, a high rate of regrowth was found in a registry with an increased risk of distant metastases, questioning the deleterious effect of deferral of surgery in this group. The short- and long-term toxic effects of neoadjuvant treatment are costs to consider in the National Comprehensive Cancer Network guidelines compared with the European Society for Medical Oncology guidelines, which favour surgery alone if good mesorectal resection is assured with increasing surgical proficiency adjusted to the precise anatomical location.

Transanal minimally invasive surgery for benign and malignant rectal lesions: midterm outcomes from a tertiary center.

BACKGROUND: Although transanal minimally invasive surgery (TAMIS) for rectal neoplasia has gained wide acceptance, the mid-term and long-term outcomes are not widely reported in the literature. OBJECTIVE: Describe the mid-term outcomes of patients who underwent TAMIS for benign and malignant rectal lesions in a single center. DESIGN: Retrospective cohort study. SETTINGS: Tertiary referral center. PATIENTS AND METHODS: Demographic, clinical, and oncological outcomes of patients who underwent TAMIS between January 2015 and December 2022 were prospectively collected. The indication for TAMIS was based on the National Comprehensive Cancer Network guidelines. The follow up for the cancer patients included clinical examination, tumor markers every 6 months and MRI rectum at the end of one year. In addition, colonoscopy and CT scan at years one and three and a final CT scan and colonoscopy at year five. MAIN OUTCOME MEASURES: Mid-term oncological and clinical outcome. RESULTS: Thirty elective TAMIS procedures included adenocarcinoma for 33.3% (n=10) of the patients, 20% (n=6) neuroendocrine tumor and the 40% (n=12) were adenomatous lesions. Negative resection margins were achieved in all malignant lesions. Perioperative complications occurred in 2 patients (6.6%), one patient had breaching into the peritoneal cavity, and postoperative hypotension occurred in another patient. The median follow-up time was 23 months (range: 5-72 months). Two patients with adenoma and positive margins developed recurrent adenoma (6.6%) and one patient with initial polypectomy biopsy of adenocarcinoma, had TAMIS with histopathology of adenoma and distant metastasis had developed. CONCLUSIONS: TAMIS for local excision of rectal neoplasia is a valid option with favorable mid-term outcomes provided there is adherence to careful selection criteria. LIMITATIONS: Retrospective nature and small number of the patients.

Perioperative and Oncological Outcomes of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Metastasis of Rectal Origin.

BACKGROUND: The peritoneum is a common metastatic site of colorectal cancer (CRC) and associated with worse oncological outcomes. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has been shown to improve outcomes in selected patients. Studies have demonstrated significant difference in survival of patients with primary colon and rectal tumors both in local and in metastatic setting; but only few assessed outcomes of CRS/HIPEC for rectal and colon tumors. We studied the perioperative and oncological outcomes of patients undergoing CRS/HIPEC for rectal cancer. METHODS: A retrospective analysis of a prospectively maintained database between 2009 and 2021 was performed. RESULTS: 199 patients underwent CRS/HIPEC for CRC. 172 patients had primary colon tumors and 27 had primary rectal tumors. Primary rectal location was associated with longer surgery (mean 4.32, hours vs 5.26 h, p = 0.0013), increased blood loss (mean 441cc vs 602cc, p = 0.021), more blood transfusions (mean 0.77 vs 1.37units, p = 0.026) and longer hospitalizations (mean 10 days vs 13 days, p = 0.02). Median disease-free survival (DFS) was shorter in rectal primary group; 7.03 months vs 10.9 months for colon primaries (p = 0.036). Overall survival was not statistically significant; 53.2 months for rectal and 60.8 months for colon primary tumors. Multivariate analysis indicated origin (colon vs rectum) and Peritoneal Cancer Index to be independently associated with DFS. CONCLUSIONS: Patients with rectal carcinoma undergoing CRS/HIPEC for peritoneal metastasis had worse peri-operative and oncological outcomes. Overall survival was excellent in both groups. This data may be used for risk stratification when considering CRS/HIPEC for patients with rectal primary.

Neoadjuvant chemotherapy with modified FOLFOXIRI for locally advanced rectal cancer to transform effectively EMVI and MRF from positive to negative: results of a long-term single center phase 2 clinical trial.

PURPOSE: Chemoradiotherapy (CRT) remains the standard treatment for locally advanced rectal cancer (LARC). This phase 2 clinical trial was designed to evaluate the efficacy and safety of neoadjuvant triplet chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in LARC. PATIENTS AND METHODS: The patients with LARC (the lower edge more than 5 cm from the anal verge) received up to 5 cycles of mFOLFOXIRI. MRI was performed to assess the baseline and postchemotherapy TN stage. Radical resection was performed within 4-6 weeks from the last dose of chemotherapy if the tumor shrank or remained stable. Adjuvant chemotherapy with mFOLFOX6 or XELOX was recommended. Postoperative radiation was planned for R1 resection, ypT4b, ypN2 and a positive CRM. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: From February 2016 to March 2019, 50 patients were enrolled. Forty-eight (96%) were clinically node-positive, 28 (56.5%) with MRF invasion and 39 (78.4%) were EMVI positive. The median cycle of neoadjuvant mFOLFOXIRI chemotherapy was 5 (range,1-5). A total of 46/50 (92%) patients underwent total mesorectal excision (TME) surgery, all with R0 resection. The pCR rate was 4.3% (2/46). Twenty-three of 46 (50%) patients with cN + achieved a pathological node-negative status. The proportions of pathologically positive CRM and EMVI were 2.2% and 34.7%, respectively. Adjuvant radiotherapy was given to 14/46 (30.4%) patients. The most common Grade 3 or > toxicities included neutrocytopenia (50%), leukopenia (14%) and diarrhea (12%) during the neoadjuvant chemotherapy period. Clinically meaningful postoperative complications included pneumonia (n = 1), pelvic infection (n = 1) and anastomotic fistula (n = 1). With a median follow-up time of 51.2 months, local recurrences and distant metastases were confirmed in 3 (6.5%) and 9 (19.6%) of cases, respectively. The 3-year disease free survival (DFS) and overall survival (OS)rates were 75.8% and 86.8%. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOXIRI yielded a significant down-staging effect and seemed to be effective in eliminating EMVI and transforming the positive MRF to negative in LARC. The survival results are promising. The long-term follow-up showed promising DFS and OS rates accompanied by a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03443661, 23/02/2018.

Rare presentation and retrograde diagnosis of total colonic aganglionosis in a female infant: a case report.

BACKGROUND: Total colonic aganglionosis is an extremely rare variant of Hirschsprung's disease, which is predominant in males and can be seen in 1:50,000 live births. The presented case not only depicts a rare case, but also unusual clinical, laboratory, and instrumental data. CASE PRESENTATION: A 2-day-old Caucasian female newborn was transferred to our hospital from maternity. The initial presentation was reverse peristalsis, abdominal distention, and inability to pass stool. Fever had started before the patient was transferred. Hirschsprung's disease was suspected, and tests such as contrast enema and rectal suction biopsy were done. Before enterostomy, the management of the disease included fluid resuscitation, colonic irrigation, antibiotic administration, enteral feeding, and supportive therapy. During ileostomy operation, no transition zone was visualized and full-thickness biopsy samples were retrieved from the rectum and descending colon. After surgical intervention, status significantly improved-defervescence and weight gain most importantly improved. CONCLUSION: It is well known that diagnosis of total colonic aganglionosis may be delayed for months or even years since the transition zone may not be visible and rectal suction biopsy, unlike full-thickness biopsy, is not always reliable. It might be more prudent not to be derailed because of negative radiography and rectal suction biopsy. Also, doctors should be more suspicious of the disease if signs and symptoms are starting to be consistent with Hirschsprung-associated enterocolitis, despite biopsy and radiology results.

Incidence of Disease Recurrence in Patients With Colon and Upper Rectum Adenocarcinoma Stage II and III Receiving Adjuvant Capecitabine Monotherapy: Do Number of Chemotherapy Cycles and Relative Dose Intensity of the Drug Play a Role?

INTRODUCTION/BACKGROUND: Adjuvant capecitabine monotherapy is an option for colon and upper rectum adenocarcinoma patients, providing they have stage II disease with an intermediate risk of recurrence, or stage III but they are above 70's or they have comorbidities. We wanted to examine whether the number of chemotherapy cycles and the relative dose intensity (RDI) of capecitabine monotherapy in the adjuvant setting are affecting disease recurrence. PATIENTS AND METHODS: We included patients with completely resected stage II and III colon and upper rectum cancer who received adjuvant capecitabine monotherapy, from 2003 until May 2020. Patients with early relapse, i.e. during chemotherapy or within 6 months after the completion of adjuvant chemotherapy, and those with rectal cancer who received radiotherapy were excluded. Patients were divided into 3 groups based on the number of chemotherapy cycles received and the RDI. Group A included patients with ≤4 cycles of chemotherapy, group B patients with >4 cycles of chemotherapy and RDI ≤80%, and group C patients with >4 cycles of chemotherapy and RDI >80%. Study's endpoint, was recurrence free survival (RFS). RESULTS: Two hundred twenty six patients with stage II and III disease (164 and 62 respectively) were included. Sixteen, 166 and 44 were included in groups A, B and C respectively. After a median follow-up of 41 months, 21 patients (9,3%) had relapsed. Patients belonging to group C were found to have a trend for lower relapse rate compared to patients belonging to group A or group B. CONCLUSION: Number of adjuvant capecitabine cycles and RDI might play a role in RFS in patients with stage II and III colon and upper rectum adenocarcinoma.

Patterns of Care for Patients With Locally Advanced Rectal Cancer Treated with Total Neoadjuvant Therapy at Predominately Academic Centers between 2016-2020: An NCDB Analysis.

Total neoadjuvant therapy (TNT) has emerged as the preferred approach for locally advanced rectal cancer (LARC), defined as T3/4 or any T with N+ disease. Our objective was to (1) determine the proportion of patients with LARC receiving TNT over time, (2) determine the most common method in which TNT is being delivered, and (3) determine what factors are associated with a greater likelihood of receiving TNT in the United States. Retrospective data was obtained from the National Cancer Database (NCDB) for patients diagnosed with rectal cancer between 2016 and 2020. Patients were excluded if they had M1 disease, T1-2 N0 disease, incomplete staging information, nonadenocarcinoma histology, received RT to a nonrectum site, or received a nondefinitive RT dose. Data were analyzed using linear regression, χ2 test, and binary logistic regression. Of the 26,375 patients included, most patients were treated at an academic facility (94.6%). Five thousand three (19.0%) patients received TNT, and 21,372 (81.0%) patients did not receive TNT. The proportion of patients receiving TNT increased significantly over time, from 6.1% in 2016 to 34.6% in 2020 (slope = 7.36, 95% CI 4.58-10.15, R2 = 0.96, P = .040). The most common TNT regimen was multiagent chemotherapy followed by long-course chemoradiation (73.2% of cases from 2016-2020). There was a significant increase in utilization of short-course RT as part of TNT from 2.8% in 2016 to 13.7% in 2020 (slope = 2.74, 95% CI 0.37-5.11, R2 = 0.82, P = .035). Factors associated with a lower likelihood of TNT usage included age >65, female gender, Black race, and T3 N0 disease. TNT use in the United States has increased significantly from 2016-2020, with approximately 34.6% of patients with LARC receiving TNT in 2020. The observed trend appears to be in line with the recent National Comprehensive Cancer Network guidelines recommending TNT as the preferred approach.

The role and mechanism of flavonoid herbal natural products in ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory disease of the intestine that presents clinically with abdominal pain, mucopurulent stools, and posterior urgency. The lesions of UC are mainly concentrated in the rectal and colonic mucosa and submucosa. For patients with mild to moderate UC, the best pharmacological treatment includes glucocorticoids, immunosuppressants, antibiotics, and biologics, but the long-term application can have serious toxic side effects. Currently, nearly 40% of UC patients are treated with herbal natural products in combination with traditional medications to reduce the incidence of toxic side effects. Flavonoid herbal natural products are the most widely distributed polyphenols in plants and fruits, which have certain antioxidant and anti-inflammatory activities. Flavonoid herbal natural products have achieved remarkable efficacy in the treatment of UC. The pharmacological mechanisms are related to anti-inflammation, promotion of mucosal healing, maintenance of intestinal immune homeostasis, and regulation of intestinal flora. In this paper, we summarize the flavonoid components of anti-ulcerative colitis and their mechanisms reported in the past 10 years, to provide a basis for rational clinical use and the development of new anti-ulcerative colitis drugs.

Determining the Correct Resection Level in Patients with Hirschsprung Disease Using Contrast Enema and Full Thickness Biopsies: Can the Diagnostic Accuracy be Improved by Examining Submucosal Nerve Fiber Thickness?

BACKGROUND: Intraoperative resection level in patients with Hirschsprung disease (HD) is determined by contrast enema, surgeon's intraoperative judgement and full thickness biopsy (FTB) identifying ganglia. This study aims to evaluate diagnostic accuracy of contrast enema and FTB in determination of resection level and whether this can be improved by measuring submucosal nerve fiber diameter. METHODS: We retrospectively analyzed contrast enema and intraoperative FTBs obtained in our center, determining diagnostic accuracy for level of resection. Gold standard was pathological examination of resection specimen. Secondly, we matched transition zone pull-through (TZPT) patients with non-TZPT patients, based on age and length of resected bowel, to blindly compare nerve fibers diameters between two groups using group comparison. RESULTS: From 2000-2021, 209 patients underwent HD surgery of whom 180 patients (138 males; median age at surgery: 13 weeks) with 18 TZPTs (10%) were included. Positive predictive value of contrast enema was 65.1%. No caliber change was found in patients with total colon aganglionosis (TCA). Negative predictive value of surgeon's intraoperative judgement and FTB in determining resection level was 79.0% and 90.0% (91.2% single-stage, 84.4% two-stage surgery) respectively. Mean nerve fiber diameter in TZPT was 25.01 µm (SD= 5.63) and in non-TZPT 24.35 µm (SD= 6.75) (p = 0.813). CONCLUSION: Determination of resection level with combination of contrast enema, surgeon's intraoperative judgement and FTB results in sufficient diagnostic accuracy in patients with HD. If no caliber change is seen with contrast enema, TCA should be considered. Resection level or transition zone cannot be determined by assessment of submucosal nerve fiber diameter in FTB. TYPE OF STUDY: clinical research paper.

Creating a Safety Net Process to Improve Colon Cancer Diagnosis in Patients With Rectal Bleeding.

Background Failure to follow up on patients with rectal bleeding is common and may result in a delay in diagnosis of colorectal cancer or in missing high-risk adenomas. The authors' purpose was to create an electronic patient safety net for those diagnosed with rectal bleeding but who did not have colonoscopy to ensure proper detection of colonic abnormalities, including colon cancer. Methods In an integrated health delivery system serving < 4.6 million patients in Southern California, from 2014 to 2019, the authors electronically identified patients with rectal bleeding aged 45 to 80 years but with no recently documented colonoscopy. These cases were reviewed by a gastroenterologist to determine if colonoscopy was appropriate. The physician looked for known documentation as to the cause of rectal bleeding and verified no contraindications to the procedure; if indicated, testing was offered. Results Using the authors' safety net program, 1430 patients with rectal bleeding who needed and completed a colonoscopy were identified. Of those patients, 7.5% had an advanced adenoma or cancer, with a total of 20 cancers, and 34% had findings that warranted more frequent colonoscopy. Conclusions The authors designed a safety net system that was able to capture information on patients with rectal bleeding who had not had a colonoscopy and detected in 34% colonic pathology that would have otherwise gone undetected. The program did not require many resources to implement and had the ability to potentially prevent harm from reaching patients whose rectal bleeding did not get prompt workup. Other health systems and practices should consider implementing a similar system.

Current trends in nonoperative management for rectal adenocarcinoma: An unequal playing field?

BACKGROUND AND OBJECTIVES: Increasing evidence suggests patient-oriented benefits of nonoperative management (NOM) for rectal cancer. However, vigilant surveillance requires excellent access to care. We sought to examine patient, socioeconomic, and facility-level factors associated with NOM over time. METHODS: Using the National Cancer Database (2006-2017), we examined patients with Stage II-III rectal adenocarcinoma, who received neoadjuvant chemoradiation and received NOM versus surgery. Factors associated with NOM were assessed using multivariable logistic regression with backward stepwise selection. RESULTS: There were 59,196 surgical and 8520 NOM patients identified. NOM use increased from 12.9% to 15.9% between 2006 and 2017. Patients who were Black (adjusted odds ratio [aOR]: 1.36, 95% confidence interval [CI]: 1.26-1.47), treated at community cancer centers (aOR: 1.22, 95% CI: 1.12-1.30), without insurance (aOR: 1.87, 95% CI: 1.68-2.09), and with less education (aOR: 1.53, 95% CI: 1.42-1.65) exhibited higher odds of NOM. Patients treated at high-volume centers (aOR: 0.79, 95% CI: 0.74-0.84) and those who traveled >25.6 miles for care (aOR: 0.59, 95% CI: 0.55-0.64) had lower odds of NOM. CONCLUSIONS: Vulnerable groups who traditionally have difficulty accessing comprehensive cancer care were more likely to receive NOM, suggesting that healthcare disparities may be driving utilization. More research is needed to understand NOM decision-making in rectal cancer treatment.

Evaluation Of Anti-inflammatory Mediated Anti-hemorrhoidal Activity of Lawsonia inermis on Croton Oil Induced Hemorrhoidal Rats.

BACKGROUND: Hemorrhoids are a common recto-anal disorder commonly known as piles or tissue clumps in the rectum. In normal individuals, they were known as anal cushions. In the anus, they are composed of rectal blood vessels, muscles, and elastic fibres. When bulged, it can cause bleeding, constipation, itching, severe pain, and bleeding in the anus. Inflammation of the anal cushion remains major pathogenesis for the development of hemorrhoids. Inflammatory mediators like neutrophils, TNF-α, and IL-6 seem to play a major role in the development of disease. OBJECTIVE: This study aims to carry out the ethanolic leaf extract of Lawsonia inermis (L. inermis) and evaluate its anti-hemorrhoidal activity both in vitro and in vivo. Furthermore, Molecular Docking was performed on the crystal structure of COX-2 with the selective compound 23d-(R) (PDB ID: 3NTG) protein. METHODS: The current study is to estimate an anti-inflammatory mediated anti-hemorrhoidal activity of ethanolic leaf extract of L. inermis at different doses of 200 mg/kg/ir and 400 mg/kg/ir in croton oil-induced hemorrhoidal rats. Pilex ointment is taken as a reference standard in the present study. Evan's blue extravasation technique were applied in the study to quantify the proinflammatory protein. RESULTS: From the study results, a dose-dependent effect was found for ethanolic leaf extract of Lawsonia inermis at 200 mg/kg and 400 mg/kg causing a significant reduction of serum Proinflammatory mediators TNF-α, IL-6, and plasma neutrophils in croton oil-induced hemorrhoidal rats. CONCLUSION: Studies represented that the plant extract can significantly inhibit protein denaturation of egg albumin in in vitro and found to reduce croton oil induced inflammatory mediators in hemorhhoidal rats.

Survival After Induction Chemotherapy and Chemoradiation Versus Chemoradiation and Adjuvant Chemotherapy for Locally Advanced Rectal Cancer.

BACKGROUND: Total neoadjuvant therapy (TNT) improves tumor response in locally advanced rectal cancer (LARC) patients compared to neoadjuvant chemoradiotherapy alone. The effect of TNT on patient survival has not been fully investigated. MATERIALS AND METHODS: This was a retrospective case series of patients with LARC at a comprehensive cancer center. Three hundred and eleven patients received chemoradiotherapy (chemoRT) as the sole neoadjuvant treatment and planned adjuvant chemotherapy, and 313 received TNT (induction fluorouracil and oxaliplatin-based chemotherapy followed by chemoradiotherapy in the neoadjuvant setting). These patients then underwent total mesorectal excision or were entered in a watch-and-wait protocol. The proportion of patients with complete response (CR) after neoadjuvant therapy (defined as pathological CR or clinical CR sustained for 2 years) was compared by the χ2 test. Disease-free survival (DFS), local recurrence-free survival, distant metastasis-free survival, and overall survival were assessed by Kaplan-Meier analysis and log-rank test. Cox regression models were used to further evaluate DFS. RESULTS: The rate of CR was 20% for chemoRT and 27% for TNT (P=.05). DFS, local recurrence-free survival, metastasis-free survival, and overall survival were no different. Disease-free survival was not associated with the type of neoadjuvant treatment (hazard ratio [HR] 1.3; 95% confidence interval [CI] 0.93-1.80; P = .12). CONCLUSIONS: Although TNT does not prolong survival than neoadjuvant chemoradiotherapy plus intended postoperative chemotherapy, the higher response rate associated with TNT may create opportunities to preserve the rectum in more patients with LARC.

Type of recurrence is associated with disease-free survival after salvage surgery for locally recurrent rectal cancer.

PURPOSE: To compare the characteristics and outcomes of rectal cancer patients with local recurrence at a perianastomotic site (PA), a surgical field (SF) site, or in lateral lymph nodes (LLN). METHODS: A total of 114 consecutive patients who underwent surgery for recurrent, non-metastatic rectal cancer at a single comprehensive cancer center between 1997 and 2012 were grouped on the basis of radiographic assessment of type of recurrence: PA, 76 (67%) patients; SF, 25 (22%) patients; LLN, 13 (11%) patients. Demographic, clinical, and pathological features were compared between the three groups, as were disease-free survival (DFS) and overall survival (OS). RESULTS: Recurrence type was associated with positive circumferential margin in the primary resection (PA, 4 [6%]; SF, 4 [19%]; LLN, 3 [25%]; P = 0.027), prior neoadjuvant therapy for the primary tumor (PA, 57 [75%]; SF, 18 [72%]; LLN, 4 [31%]; P = 0.007), and location of the primary tumor in the upper rectum (PA, 33 [45%]; SF, 5 [23%]; LLN, 1 [8%]; P < 0.001). Patients with PA had longer median DFS (PA, 5.1 years; SF, 1.5 years; LLN, 1.2 years; P = 0.036). There was a non-significant trend toward longer OS and higher rates of R0 resection for PA. CONCLUSION: Type of recurrence after salvage surgery for locally recurrent rectal cancer is associated with longer DFS in patients with PA recurrence.

Inflammation Modulation by Vitamin D and Calcium in the Morphologically Normal Colorectal Mucosa of Patients with Colorectal Adenoma in a Clinical Trial.

Increased COX-2 and decreased 15-hydroxyprostaglandin dehydrogenase (15-HPGD) expression promote prostaglandin-mediated inflammation and colorectal carcinogenesis. Experimental studies suggest that vitamin D and calcium may inhibit these pathways, but their effects on colorectal tissue COX-2 and 15-HPGD expression in humans are unknown. We tested the effects of supplemental vitamin D (1,000 IU/day) and/or calcium (1,200 mg/day) on COX-2 and 15-HPGD expression in the morphologically normal rectal mucosa from 62 paients with colorectal adenoma in a placebo-controlled chemoprevention trial. We measured biomarker expression using automated IHC and quantitative image analysis at baseline and 1-year follow-up, and assessed treatment effects using mixed linear models. The primary outcome was the COX-2/15-HPGD expression ratio, because these enzymes function as physiologic antagonists. After 1 year of treatment, the mean COX-2/15-HPGD expression ratio in full-length crypts proportionately decreased 47% in the vitamin D group (P = 0.001), 46% in the calcium group (P = 0.002), and 34% in the calcium + vitamin D group (P = 0.03), relative to the placebo group. Among individuals with the functional vitamin D-binding protein isoform DBP2 (GC rs4588*A), the COX-2/15-HPDG ratio decreased 70% (P = 0.0006), 75% (P = 0.0002), and 60% (P = 0.006) in the vitamin D, calcium, and combined supplementation groups, respectively, relative to placebo. These results show that vitamin D and calcium favorably modulate the balance of expression of COX-2 and 15-HPGD-biomarkers of inflammation that are strongly linked to colorectal carcinogenesis-in the normal-appearing colorectal mucosa of patients with colorectal adenoma (perhaps especially those with the DBP2 isoform). PREVENTION RELEVANCE: Supplemental calcium and vitamin D reduce indicators of cancer-promoting inflammation in normal colorectal tissue in humans, thus furthering our understanding of how they may help prevent colorectal cancer.

Butyrate enhances the efficacy of radiotherapy via FOXO3A in colorectal cancer patient­derived organoids.

Enhancing the radioresponsiveness of colorectal cancer (CRC) is essential for local control and prognosis. However, consequent damage to surrounding healthy cells can lead to treatment failure. We hypothesized that short­chain fatty acids (SCFAs) could act as radiosensitizers for cancer cells, allowing the administration of a lower and safer dose of radiation. To test this hypothesis, the responses of three­dimensional­cultured organoids, derived from CRC patients, to radiotherapy, as well as the effects of combined radiotherapy with the SCFAs butyrate, propionate and acetate as candidate radiosensitizers, were evaluated via reverse transcription­quantitative polymerase chain reaction, immunohistochemistry and organoid viability assay. Of the three SCFAs tested, only butyrate suppressed the proliferation of the organoids. Moreover, butyrate significantly enhanced radiation­induced cell death and enhanced treatment effects compared with administration of radiation alone. The radiation­butyrate combination reduced the proportion of Ki­67 (proliferation marker)­positive cells and decreased the number of S phase cells via FOXO3A. Meanwhile, 3/8 CRC organoids were found to be non­responsive to butyrate with lower expression levels of FOXO3A compared with the responsive cases. Notably, butyrate did not increase radiation­induced cell death and improved regeneration capacity after irradiation in normal organoids. These results suggest that butyrate could enhance the efficacy of radiotherapy while protecting the normal mucosa, thus highlighting a potential strategy for minimizing the associated toxicity of radiotherapy.

CSRP2 suppresses colorectal cancer progression via p130Cas/Rac1 axis-meditated ERK, PAK, and HIPPO signaling pathways.

Metastasis is a major cause of death in patients with colorectal cancer (CRC). Cysteine-rich protein 2 (CSRP2) has been recently implicated in the progression and metastasis of a variety of cancers. However, the biological functions and underlying mechanisms of CSRP2 in the regulation of CRC progression are largely unknown. Methods: Immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR) and Western blotting (WB) were used to detect the expression of CSRP2 in CRC tissues and paracancerous tissues. CSRP2 function in CRC was determined by a series of functional tests in vivo and in vitro. WB and immunofluorescence were used to determine the relation between CSRP2 and epithelial-mesenchymal transition (EMT). Co-immunoprecipitation and scanning electron microscopy were used to study the molecular mechanism of CSRP2 in CRC. Results: The CSRP2 expression level in CRC tissues was lower than in adjacent normal tissues and indicated poor prognosis in CRC patients. Functionally, CSRP2 could suppress the proliferation, migration, and invasion of CRC cells in vitro and inhibit CRC tumorigenesis and metastasis in vivo. Mechanistic investigations revealed a physical interaction between CSRP2 and p130Cas. CSRP2 could inhibit the activation of Rac1 by preventing the phosphorylation of p130Cas, thus activating the Hippo signaling pathway, and simultaneously inhibiting the ERK and PAK/LIMK/cortactin signaling pathways, thereby inhibiting the EMT and metastasis of CRC. Rescue experiments showed that blocking the p130Cas and Rac1 activation could inhibit EMT induced by CSRP2 silencing. Conclusion: Our results suggest that the CSRP2/p130Cas/Rac1 axis can inhibit CRC aggressiveness and metastasis through the Hippo, ERK, and PAK signaling pathways. Therefore, CSRP2 may be a potential therapeutic target for CRC.

Magnetic Resonance Rectal Enema Versus Computed Tomographic Colonography in the Diagnosis of Rectosigmoid Endometriosis.

OBJECTIVES: Rectosigmoid involvement by endometriosis causes intestinal symptoms such as constipation, diarrhea, and dyschezia. A precise diagnosis about the presence, location, and extent of bowel implants is required to plan the most appropriate treatment. The aim of the study was to compare the accuracy of magnetic resonance with distension of the rectosigmoid (MR-e) with computed colonography (CTC) for diagnosing rectosigmoid endometriosis. METHODS: This study was based on the retrospective analysis of a prospectively collected database of patients with suspicion of rectosigmoid endometriosis who underwent both MR-e and CTC, and subsequently were treated by laparoscopy. The findings of imaging techniques were compared with surgical and histological results. RESULTS: Of 90 women included in the study, 44 (48.9%) had rectosigmoid nodules and underwent bowel surgery. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for the diagnosis of rectosigmoid endometriosis were 88.6%, 93.5%, 92.9%, 89.6%, and 91.1% for CTC, and 93.2%, 97.9%, 97.6%, 93.8%, and 95.6% for MR-e. There was no significant difference in the accuracy of both radiologic examinations for diagnosing rectosigmoid endometriosis (P = 0.344). However, MR-e was more accurate than CTC in estimating the largest diameter of the main rectosigmoid nodule (P < 0.001). The pain perceived by the patients was significantly lower during MR-e than during CTC (P < 0.001). CONCLUSIONS: MR-e and CTC have similar diagnostic performance for the diagnosis of rectosigmoid involvement of endometriosis. However, MR-e is more accurate in the estimation of the largest diameter of main rectosigmoid nodule and more tolerated than CTC.

Epigallocatechin gallate inhibits dimethylhydrazine-induced colorectal cancer in rats.

BACKGROUND: Epigallocatechin gallate (EGCG) is a polyhydroxy phenolic compound extracted from tea and its antitumor effect has received widespread attention. We explored the inhibitory effect of EGCG on dimethylhydrazine (DMH)-induced colorectal cancer (CRC) using a rat model, predicted the interaction between EGCG and CRC target genes using a database, and explained the EGCG associated target pathways and mechanisms in CRC. AIM: To understand the inhibitory mechanisms of EGCG on CRC cell proliferation and identify its pharmacological targets by network pharmacology analysis. METHODS: DMH (40 mg/kg, s.c., twice weekly for eight weeks) was used to induce CRC in rats. After model establishment, the rats were administered with EGCG (50, 100, or 200 mg/kg, p.o., once daily for eight weeks) and killed 12 and 20 wk after the start of the experiment. Formation of aberrant crypt foci and tumor was studied by histological analysis. Using network pharmacology analysis, candidate and collective targets of EGCG and CRC were identified, and Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses were used to predict the pathways altered by EGCG. RESULTS: At week 12, high-dose EGCG treatment significantly reduced the tumor formation rate, total number of tumors, cancerous and non-cancerous tumors, tumor volume, ascites formation, and aberrant crypt foci count. At week 20, all three doses of EGCG were effective. Seventy-eight collective targets of EGCG and CRC were identified, of which 28 genes were dysregulated in CRC. Kyoto Encyclopedia of Genes and Genomes and GO analyses showed that the dysregulated genes were enriched in hsa05210 (CRC), hsa04115 (p53 signaling pathway), and hsa04151 (PI3K-Akt signaling pathway), GO:0043124 (negative regulation of I-kappaB kinase/NF-kappaB signaling pathway), GO:0043409 (negative regulation of mitogen-activated protein kinase cascade), and GO:2001244 (positive regulation of intrinsic apoptotic signaling pathway) respectively. CONCLUSION: EGCG inhibits the formation of DMH-induced CRC by regulating key pathways involved in tumorigenesis.

NORAD01-GRECCAR16 multicenter phase III non-inferiority randomized trial comparing preoperative modified FOLFIRINOX without irradiation to radiochemotherapy for resectable locally advanced rectal cancer (intergroup FRENCH-GRECCAR- PRODIGE trial).

BACKGROUND: Preoperative radiochemotherapy (RCT) is recommended in France prior to total mesorectal excision in patients with mid or low locally advanced rectal cancer (LARC) (cT3/T4 and/or N+) because it has been shown to improve local control. Preoperative RCT has also disadvantages including the absence of proven impact on metastatic recurrence and the risk of late side effects on bowel and genitourinary function. In patients with primarily resectable LARC, preoperative systemic chemotherapy without pelvic irradiation could be used as an alternative to RCT. METHODS: This study is a multicenter, open-label randomized, 2-arm phase III non-inferiority trial. Patients with mid or low resectable LARC (cT3N0 or cT1-T3N+ with circumferential resection margin [CRM] > 2 mm on pretreatment MRI) will be randomized to either modified FOLFIRINOX for 3 months or RCT (Cap50 intensified-modulated radiotherapy). All patients have restaging MRI after preoperative treatment. The primary endpoint is 3-year progression-free survival (PFS) from the time to randomization including progression during preoperative treatment. Secondary endpoints are treatment related toxicity, treatment compliance, R0 resection rate, sphincter saving surgery rate, postoperative morbidity and mortality rates, loco-regional recurrence free survival, overall survival, bowel and sexual functions at diagnosis, quality of life, radiologic and pathologic response after preoperative treatment. The number of patients required is 574. DISCUSSION: The choice of modified FOLFIRINOX for preoperative chemotherapy is supported by recent and consistent data on safety and efficacy of this regimen on rectal cancer. The use of preoperative chemotherapy instead of RCT could be associated with pronounced advantages in terms of functional results and quality of life in cancer survivors. However and first of all, the non-inferiority of preoperative chemotherapy compared to RCT on oncologic outcome has to be validated. If this study demonstrates the non-inferiority of chemotherapy compared to RCT, this can lead to a crucial change in clinical practice in a large subset of rectal cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03875781 (March 15, 2019). Version 1.1.