Hereditary colorectal cancer (HCRC) accounts for < 5% of all colorectal cancer cases. Some of the unique characteristics commonly encountered in HCRC cases include early age of onset, ...synchronous/metachronous cancer occurrence, and multiple cancers in other organs. These characteristics necessitate different management approaches, including diagnosis, treatment or surveillance, from sporadic colorectal cancer management. There are two representative HCRC, named familial adenomatous polyposis and Lynch syndrome. Other than these two HCRC syndromes, related disorders have also been reported. Several guidelines for hereditary disorders have already been published worldwide. In Japan, the first guideline for HCRC was prepared by the Japanese Society for Cancer of the Colon and Rectum (JSCCR), published in 2012 and revised in 2016. This revised version of the guideline was immediately translated into English and published in 2017. Since then, several new findings and novel disease concepts related to HCRC have been discovered. The currently diagnosed HCRC rate in daily clinical practice is relatively low; however, this is predicted to increase in the era of cancer genomic medicine, with the advancement of cancer multi-gene panel testing or whole genome testing, among others. Under these circumstances, the JSCCR guidelines 2020 for HCRC were prepared by consensus among members of the JSCCR HCRC Guideline Committee, based on a careful review of the evidence retrieved from literature searches, and considering the medical health insurance system and actual clinical practice settings in Japan. Herein, we present the English version of the JSCCR guidelines 2020 for HCRC.
Inappropriate stoma site, improper management of stoma, and stoma complications lead to diminished quality of life of ostomates. Healthcare professionals involved in stoma creation and/or care should ...have the fundamental and updated knowledge of the management of stomas and their complications. This review article consists of the following major sections: principles of perioperative patient management, early complications, and late complications. In the "principles of perioperative patient management" section, the current concepts and trends in preoperative education, stoma site marking, postoperative education, and patient educational resources are discussed. In the "early complications" section, we have focused on the etiology and current management of ischemia/necrosis, fluid and electrolyte imbalances, mucocutaneous separation, and retraction. In the "late complications" section, we have focused on the etiology and current management of parastomal hernia, stoma prolapse, parastomal varices, and pyoderma gangrenosum. Pre- and postoperative patient education facilitates the patient's independence in stoma care and resumption of normal activities. Healthcare providers should have basic skills and updated knowledge on the management of stomas and complications of stomas, to act as the first crisis manager for ostomates.
Background
Anal metastasis of colorectal cancer is very rare and may present synchronously or metachronously, regardless of pre-existing anal diseases. We report a case of anal fistula metastasis ...after completion of neoadjuvant therapy for rectal cancer, followed by surgical resection of the primary tumor and metastatic lesion.
Case presentation
A 50-year-old man was diagnosed with rectal cancer located 5 cm from the anal verge, with a clinical stage of cT3N0M0. He denied any medical or surgical history, and physical examination revealed no perianal disease. He underwent preoperative chemoradiation therapy (CRT) consisting of a tegafur/gimeracil/oteracil potassium (S-1)-based regimen with 45 Gy of radiation. After completion of CRT, computed tomography (CT) revealed the primary tumor’s partial response, but a liver mass highly suggestive of metastasis was detected. This mass was later diagnosed as cavernous hemangioma 3 months after CRT initiation. He then underwent and completed six cycles of consolidation chemotherapy with a capecitabine-based regimen. Subsequent colonoscopy revealed the complete response of the primary tumor, but CT showed thickening of the edematous rectal wall. Therefore, we planned to perform low anterior resection as a radical surgery. However, he presented with persistent anal pain after the last chemotherapy, and magnetic resonance imaging revealed a high-intensity mass behind the anus, suggestive of an anal fistula. We considered the differential diagnosis of a benign anal fistula or implantation metastasis into the anal fistula. Fistulectomy was performed, and a pathological diagnosis of tubular adenocarcinoma, suggestive of implantation metastasis, was made. Thereafter, we performed laparoscopic abdominoperineal resection. Histopathological examination revealed well-differentiated adenocarcinoma, ypT2N0, with a grade 2 therapeutic effect. Subsequent immunohistochemistry of the resected anal fistula showed a CDX-2-positive, CK20-positive, CK7-negative, and GCDFP-15 negative tumor, with implantation metastasis. There was no cancer recurrence 21 months after the radical surgery.
Conclusions
This is the first report of anal fistula metastasis after neoadjuvant therapy for rectal cancer in a patient without a previous history of anal disease. If an anal fistula is suspected during or after neoadjuvant therapy, physical and radiological assessment, differential diagnosis, and surgical intervention timing for fistula must be carefully discussed.
Potent application of topoisomerase I inhibitor plus PARP inhibitor has been suggested to be an effective strategy for cancer therapy. Reportedly, mismatch repair (MMR)-deficient colon cancer cells ...are sensitive to topoisomerase I inhibitor, presumably due to microsatellite instability (MSI) of the MRE11 locus. We examined the synergy of SN-38, an active metabolite of irinotecan, in combination with the PARP inhibitor olaparib in colon cancer cells showing different MMR status, such as MSI or microsatellite stable (MSS) phenotype. Treatment with SN-38 and olaparib in combination almost halved the IC50 of SN-38 for a broad spectrum of colon cancer cells independent of the MMR status. Furthermore, olaparib potentiated S-phase-specific double-strand DNA breaks (DSB) induced by SN-38, which is followed by Rad51 recruitment. siRNA-mediated knockdown of Rad51, but not Mre11 or Rad50, increased the sensitivity to olaparib and/or SN-38 treatment in colon cancer cells. In vivo study using mouse xenograft demonstrated that olaparib was effective to potentiate the antitumor effect of irinotecan. In conclusion, olaparib shows a synergistic effect in colon cancer cells in combination with SN-38 or irinotecan, potentiated by the Rad51-mediated HR pathway, irrespective of the Mre11-mediated failure of the MRN complex. These results may contribute to future clinical trials using PARP inhibitor plus topoisomerase I inhibitor in combination. Furthermore, the synergistic effect comprising topoisomerase I-mediated DNA breakage-reunion reaction, PARP and Rad51-mediated HR pathway suggests the triple synthetic lethal pathways contribute to this event and are applicable as a potential target for future chemotherapy.
Differentiation of colorectal cancers (CRCs) with deep submucosal invasion (T1b) from CRCs with superficial invasion (T1a) or no invasion (Tis) is not straightforward. This study aimed to develop a ...computer-aided diagnosis (CADx) system to establish the diagnosis of early-stage cancers using nonmagnified endoscopic white-light images alone.
From 5108 images, 1513 lesions (Tis, 1074; T1a, 145; T1b, 294) were collected from 1470 patients at 10 academic hospitals and assigned to training and testing datasets (3:1). The ResNet-50 network was used as the backbone to extract features from images. Oversampling and focal loss were used to compensate class imbalance of the invasive stage. Diagnostic performance was assessed using the testing dataset including 403 CRCs with 1392 images. Two experts and 2 trainees read the identical testing dataset.
At a 90% cutoff for the per-lesion score, CADx showed the highest specificity of 94.4% (95% confidence interval CI, 91.3-96.6), with 59.8% (95% CI, 48.3-70.4) sensitivity and 87.3% (95% CI, 83.7-90.4) accuracy. The area under the characteristic curve was 85.1% (95% CI, 79.9-90.4) for CADx, 88.2% (95% CI, 83.7-92.8) for expert 1, 85.9% (95% CI, 80.9-90.9) for expert 2, 77.0% (95% CI, 71.5-82.4) for trainee 1 (vs CADx; P = .0076), and 66.2% (95% CI, 60.6-71.9) for trainee 2 (P < .0001). The function was also confirmed on 9 short videos.
A CADx system developed with endoscopic white-light images showed excellent per-lesion specificity and accuracy for T1b lesion diagnosis, equivalent to experts and superior to trainees. (Clinical trial registration number: UMIN000037053.)
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Abstract
Overexpression of satellite RNAs in heterochromatin induces chromosomal instability (CIN) through the DNA damage response and cell cycle checkpoint activation. Although satellite RNAs may be ...therapeutic targets, the associated mechanisms underlying drug sensitivity are unknown. Here, we determined whether satellite RNAs reflect drug sensitivity to the topoisomerase I inhibitor camptothecin (CPT) via CIN induction. We constructed retroviral vectors expressing major satellite and control viruses, infected microsatellite stable mouse colon cancer cells (CT26) and MC38 cells harboring microsatellite instability, and assessed drug sensitivity after 48 h. Cells overexpressing satellite RNAs showed clear features of abnormal segregation, including micronuclei and anaphase bridging, and elevated levels of the DNA damage marker γH2AX relative to controls. Additionally, overexpression of satellite RNAs enhanced MC38 cell susceptibility to CPT half-maximal inhibitory concentration: 0.814 μM (control) vs. 0.332 μM (MC38 cells with a major satellite),
p
= 0.003 but not that of CT26. These findings imply that MC38 cells, which are unlikely to harbor CIN, are more susceptible to CIN-induced CPT sensitivity than CT26 cells, which are characterized by CIN. Furthermore, CPT administration upregulated p53 levels but not those of p21, indicating that overexpression of major satellite transcripts likely induces CPT-responsive cell death rather than cellular senescence.
The recent guidelines from the European and American Hernia Societies recommend a continuous small-bite suturing technique with slowly absorbable sutures for fascial closure of midline abdominal wall ...incisions to reduce the incidence of wound complications, especially for incisional hernia. However, this is based on low-certainty evidence. We could not find any recommendations for skin closure. The wound closure technique is an important determinant of the risk of wound complications, and a comprehensive approach to prevent wound complications should be developed.
We propose a single-institute, prospective, randomized, blinded-endpoint trial to assess the superiority of the combination of continuous suturing of the fascia without peritoneal closure and continuous suturing of the subcuticular tissue (study group) over that of interrupted suturing of the fascia together with the peritoneum and interrupted suturing of the subcuticular tissue (control group) for reducing the incidence of midline abdominal wall incision wound complications after elective gastroenterological surgery with a clean-contaminated wound. Permuted-block randomization with an allocation ratio of 1:1 and blocking will be used. We hypothesize that the study group will show a 50% reduction in the incidence of wound complications. The target number of cases is set at 284. The primary outcome is the incidence of wound complications, including incisional surgical site infection, hemorrhage, seroma, wound dehiscence within 30 days after surgery, and incisional hernia at approximately 1 year after surgery.
This trial will provide initial evidence on the ideal combination of fascial and skin closure for midline abdominal wall incision to reduce the incidence of overall postoperative wound complications after gastroenterological surgery with a clean-contaminated wound. This trial is expected to generate high-quality evidence that supports the current guidelines for the closure of abdominal wall incisions from the European and American Hernia Societies and to contribute to their next updates.
UMIN-CTR UMIN000048442. Registered on 1 August 2022. https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000055205.
Colorectal carcinoma (CRC) remains the major cause of cancer death in humans. Although chromosomal structural anomaly is presumed to play an important role in the carcinogenesis of CRC, chromosomal ...copy number alterations (CNA) and loss of heterozygosity (LOH) have not yet been analyzed extensively at high resolution in CRC. Here we aim to identify recurrent CNA and LOH in human CRC with the use of single nucleotide polymorphism‐typing microarrays, and to reveal their relevance to clinical outcome. Surgically resected CRC specimens and paired normal mucosa were obtained from a consecutive series of 94 patients with CRC, and both of them were subjected to genotyping with Affymetrix Mapping 50K arrays. CNA and LOH were inferred computationally on every single nucleotide polymorphism site by integrating the array data for paired specimens. Our large dataset reveals recurrent CNA in CRC at chromosomes 7, 8, 13, 18, and 20, and recurrent LOH at chromosomes 1p, 4q, 5q, 8p, 11q, 14q, 15q, 17p, 18, and 22. Frequent uniparental disomy was also identified in chromosomes 8p, 17p, and 18q. Very common CNA and LOH were present at narrow loci of <1 Mbp containing only a few genes. In addition, we revealed a number of novel CNA and LOH that were linked statistically to the prognosis of the patients. The precise and large‐scale measurement of CNA and LOH in the CRC genome is efficient for pinpointing prognosis‐related genome regions as well as providing a list of unknown genes that are likely to be involved in CRC development. (Cancer Sci 2008; 99: 1835–1840)
Background
Complex interactions among endogenous and exogenous factors influence the incidence of colorectal cancer (CRC). Germline mutations in mismatch repair (MMR) genes causing Lynch syndrome ...(LS) are major endogenous factors. The exogenous factor, alcohol consumption, is potentially associated with CRC incidence among patients with LS. However, insufficient data are available to determine whether alcohol consumption influences the time of the first onset of CRC associated with sex, MMR gene mutations, and anatomical tumor site.
Methods
Among 316 patients with LS identified in a Japanese LS cohort, we included 288 with data on age, sex, proband status, alcohol status, smoking status, tumor location, and MMR gene mutations. Multivariable analysis assessed the association of alcohol consumption with earlier onset of the first CRC.
Results
Ever drinkers were associated with higher risk of the first onset of CRC than never drinkers (HR 1.54, 95%CI 1.14–2.07,
P
= 0.004). The association of the first onset of CRC with alcohol consumption was stronger in men, carriers of pathogenic
MLH1
and
MSH2
mutations (vs those with pathogenic
MSH6, PMS2
and
EPCAM
mutations), and tumors in the proximal colon cancer (vs distal colon and rectal cancer).
Conclusions
Alcohol consumption was associated with earlier onset of the first CRC in Japanese LS cohort. The association was stronger in men, carriers of pathogenic
MLH1
and
MSH2
mutations, and tumors located in the proximal colon. Our findings illuminate the mechanism of LS-associated carcinogenesis and serve as a recommendation for discontinuing or ceasing alcohol consumption.
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