Analysis of Circulating DNA to Assess Prognoses for Metastatic Colorectal Cancer Patients Treated with Regorafenib Dose-Escalation Therapy: A Retrospective, Exploratory Analysis of the RECC Trial.

INTRODUCTION: Regorafenib is a multi-kinase inhibitor approved for patients with metastatic colorectal cancer (mCRC) who were previously treated with standard therapies. A few reports showed the impact of KRAS mutation on therapeutic efficacy of regorafenib. Only one study reported poor prognoses for patients treated with regorafenib who had large amounts of circulating cell-free DNA (cfDNA). In the present study, we evaluated the impact of KRAS mutations in tissue or plasma and amounts of cfDNA on prognoses of mCRC patients treated with regorafenib. METHOD: This is a biomarker investigation of the RECC study, which evaluated efficacy of regorafenib dose-escalation therapy. Plasma samples were obtained just before initiation of treatment with regorafenib. KRAS mutations were evaluated using tissue and plasma samples. cfDNA was extracted from plasma samples and quantified. RESULTS: Forty-five patients were enrolled in this biomarker study. Median progression-free survival (PFS) and overall survival (OS) of patients without KRAS mutations in tissues were 1.9 months (95% confidence interval [CI] 1.7-2.0) and 8.9 months (95% CI: 6.5-11.2), and those of patients with KRAS mutations were 1.4 months (95% CI: 1.3-1.5) and 6.8 months (95% CI: 5.0-8.5). Median PFS and OS of patients with plasma KRAS mutations were 1.9 months (95% CI: 1.8-1.9) and 7.0 months (95% CI: 5.3-8.7), respectively. Median PFS and OS of patients without plasma KRAS mutations were 1.7 months (95% CI: 1.1-2.3) and 8.9 months (95% CI: 6.7-11.2), respectively. Prior to administration of regorafenib, KRAS mutations were detected in 6 of 16 (37.5%) patients who had no tissue KRAS mutations. Median OS of patients with high cfDNA concentration (>median) was significantly poorer than that of patients with low cfDNA. CONCLUSION: KRAS mutations in the tissue or plasma have no impact on efficacy of regorafenib. KRAS emerging mutations were observed in quite a few patients. Large amounts of cfDNA may indicate poorer prognoses for patients receiving late-line regorafenib chemotherapy.

The robust performance of carcinoembryonic antigen levels after adjuvant chemotherapy for the recurrence risk stratification in patients with colorectal cancer.

BACKGROUND AND OBJECTIVES: Most guidelines of colorectal cancers (CRCs) recommend evaluating the serum carcinoembryonic antigen (CEA) level during postoperative surveillance to detect tumor recurrence, which originates from postsurgery residual tumor cells. We hypothesized that the postadjuvant chemotherapy CEA level may be the most accurate biomarker to predict tumor recurrence, and we evaluated the prognostic significance of the postadjuvant chemotherapy CEA level in patients with stage II and III CRCs. PATIENTS AND METHODS: We retrospectively analyzed the cases of 150 Stage II-III CRC patients who had undergone curative surgery and adjuvant chemotherapy. Preoperative, postoperative, and postadjuvant chemotherapy CEA levels were evaluated, and their associations with recurrence-free survival (RFS) were assessed. RESULTS: The Kaplan-Meier curves showed that a high preoperative CEA level, high postoperative CEA, and high postadjuvant chemotherapy CEA were associated with poor RFS (p = .001, .0001, and .001, respectively). The multivariate analysis demonstrated that high postadjuvant chemotherapy CEA was an independent factor for poor RFS (HR 2.55, 95% confidence interval: 1.08-6.05, p = .033), whereas high preoperative and postoperative CEA levels were not. CONCLUSIONS: The serum levels of postadjuvant chemotherapy CEA were a strong prognostic biomarker in patients with Stage II-III CRCs who had undergone surgery followed by adjuvant chemotherapy.

Proposal for a post-operative surveillance strategy for stage I colorectal cancer patients based on a novel recurrence risk stratification: a multicenter retrospective study.

BACKGROUND: The recurrent risk of stage I colorectal cancer (CRC) is not clear, and the data regarding appropriate post-operative surveillance schedules in stage I CRC are scarce. OBJECTIVES: We aimed to stratify stage I CRC based on the recurrence risk and evaluate optimal post-operative surveillance durations based on this stratification. METHODS: We retrospectively analyzed the cases of 6607 stage I CRC patients from 24 institutions. To assess the patients' clinicopathological factors that impact recurrence-free survival (RFS), we performed univariate and multivariate analyses using Cox proportional hazards models. We divided the patients into classes based on their numbers of factors that were associated with poor RFI in the multivariate analysis. RESULTS: Recurrence occurred in 3.9% patients. The multivariate analysis revealed the independent factors for poor RFS: rectal cancer, T2 depth, presence of lymphatic invasion, high level of pre-operative carcinoembryonic antigen, and absence of D2-3 lymphadenectomy. We also divided the patients into three classes based on their numbers of these risk factors; the 3-year and 5-year RFS rates were 99.3% and 99.1% in the no-risk patients, 97.4% and 96.5% in the patients with 1-2 risks, and 92.1% and 90.0% in the patients with 3-5 risks, respectively. In the patients with no risk and in the patients with 1-2 risks after 3 years post-surgery, ≤ 1% recurrence occurred. Thus, post-operative surveillance may be omitted in these populations. CONCLUSIONS: Our new classification properly stratified the recurrence risks of stage I CRC patients, and may help reduce unnecessary post-operative surveillance.

Effectiveness of negative pressure wound therapy for the wound of ileostomy closure: a multicenter, phase II randomized controlled trial.

BACKGROUND: The American Society of Surgery and American Society for Surgical Infections issued guidelines for surgical site infections (SSIs) in December 2016. These guidelines recommend a purse-string suture (PSS) for stoma closure as it facilitates granulation and enables open wound drainage. This study investigated the effect of using negative pressure wound therapy (NPWT) along with standard PSS and aimed to determine the optimal period of NPWT use. METHODS: The patients were divided into three groups as follows: Group A, postoperative wound management alone with gauze exchange as the representative of conventional PSS; Group B, the performed management was similar to that of Group A plus NPWT for 1 week; and Group C, the performed management was similar to that of Group A plus NPWT for 2 weeks. Regarding objective measures, the wound reduction rate was the primary outcome, and the incidence of SSIs, length of hospital stay, and wound healing duration were the secondary outcomes. RESULTS: In total, 30 patients (male: 18, female: 12) were enrolled. The average age was 63 (range: 43-84) years. The wound reduction rate was significantly higher in Group B than in Group A on postoperative days (PODs) 7 (66.1 vs. 48.4%, p = 0.049) and 10 (78.6 vs. 58.2%, p = 0.011), whereas no significant difference was observed on POD 14. Compared with Group A, Group C (POD 7: 65.9%, POD 10: 69.2%) showed an increase in the wound reduction rate on POD 7, although the difference was not significant (p = 0.075). SSIs were observed in Groups B (n = 2) and C (n = 2) (20%) but not in Group A (0%). CONCLUSIONS: The most effective duration of NPWT use for ileostomy closure with PSS in terms of the maximum wound reduction rate was from PODs 3 to 10. However, NPWT did not shorten the wound healing duration. NPWT may reduce the wound size but should be used with precautions for SSIs. The small sample size (30 cases), the use of only one type of NPWT system, and the fact that wound assessment was subjective and not blinded were the limitations of this study. Further studies are needed to confirm our findings. TRIAL REGISTRATION: UMIN Clinical Trials Registry; UMIN000032174 (10/04/2018).

Significance of the 7th postoperative day neutrophil-to-lymphocyte ratio in colorectal cancer.

PURPOSE: High neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation and is associated with poor survival in localized or metastatic cancer. Preoperative NLR in colorectal cancer reportedly correlates with recurrence-free survival and is useful as a recurrence prediction factor. No reports have yet investigated recurrence factors using postoperative NLR. This study assessed the predictive value of NLR preoperatively and on the first (NLR1) and seventh day (NLR7) postoperatively in patients with stage II colorectal cancer. METHODS: We performed a retrospective cohort study involving patients undergoing colorectal resection at a single institution between January 2012 and December 2016; we used medical records of 176 consecutive patients with stage II colorectal cancer undergoing curative tumor resection. NLRs as well as clinical, histopathologic, and laboratory data were analyzed. Univariate and multivariate analyses were conducted to identify prognostic factors associated with recurrence-free survival (RFS). RESULTS: Univariate analysis revealed that elevated NLR, NLR7, and lymphatic invasion were significantly associated with decreased RFS (p < 0.05). NLR7 was revealed as significant via multivariate analysis (p = 0.013). The 3-year RFS rate was 87.1% for patients with normal NLR7 and 70.3% for those with elevated NLR7. CONCLUSION: Elevated seventh-day postoperative NLR is a significant independent predictor of reduced RFS for patients with stage II colorectal cancer and may be a potential biomarker for identifying candidates for adjuvant chemotherapy.

G12V and G12C mutations in the gene KRAS are associated with a poorer prognosis in primary colorectal cancer.

PURPOSE: The increased incidence of colorectal cancer (CRC) has necessitated the development of novel prognostic and predictive factors from which new diagnostic tests could evolve. Evidence suggests the KRAS gene represents such a factor; its mutations are considered to be early indicators of CRC progression. This study assessed the prognostic impact of specific known KRAS codon 12/13 mutations on survival in patients with CRC. METHODS: Formalin-fixed paraffin-embedded tissue blocks or sections from primary were obtained from patients registered between 2014 and 2016 for genomic DNA extraction. KRAS gene was analyzed by direct sequencing or Luminex assay. The primary endpoint was the frequency of KRAS gene mutations and the secondary endpoints were differences in KRAS mutation rates by various stratification factors. Univariate and multivariate analyses were performed to investigate relationships between KRAS mutation rates and patient background factors. RESULTS: Sequencing of 200 CRC primary tumor samples demonstrated 74 (37.5%) with KRAS mutations in codons 12 (77%; 57/74) and 13 (23%; 17/74), all of which were TNM stages I-III. Tumors with KRAS mutations were more frequently located in the right side of the colon. Multivariate analysis indicated that G12V or G12C mutations were associated with poor prognosis [hazard ratio (HR) = 3.77, 95% confidence interval (CI), 1.54-8.39 and HR = 6.57; 95% CI, 1.90-17.7, respectively] in terms of recurrence-free survival. CONCLUSION: KRAS codon 12G-to-V or G-to-C mutations are independent prognostic factors in patients with stage I-III CRC.

Angiotensin I-converting enzyme inhibitors/angiotensin II receptor blockers may reduce tumor recurrence in left-sided and early colorectal cancers.

BACKGROUND: Angiotensin signaling is suggested to be involved in tumorigenesis, tumor proliferation, and metastases. In colorectal cancer (CRC), it was demonstrated that angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may reduce the risk of CRC; however, their impact on tumor recurrence remains unknown. Therefore, in this study, we evaluated the impact of ACEIs/ARBs on tumor recurrence in CRC patients. PATIENTS AND METHODS: We retrospectively investigated the clinicopathological data of 461 stage I-III CRC patients. We divided the patients into those who took an ACEI and/or ARB (the ACEI/ARB+ group) and those who did not (the ACEI/ARB- group), and we compared the two groups' recurrence-free survival (RFS) using a Kaplan-Meier curve analysis and log rank test. We also examined the impact of AGTR1 expression on tumor recurrence, using two public CRC datasets. RESULTS: The Kaplan-Meier curves showed a trend toward improved RFS in the ACEI/ARB+ group versus the ACEI/ARB- group (p = 0.063). Subgroup analyses demonstrated that the RFS was significantly better in the ACEI/ARB+ group versus the ACEI/ARB- group in the patients with left-sided CRC (p = 0.030) and those with stage I CRC (p = 0.009). Consistent with these findings, the AGTR1 expression was higher in the left-sided versus right-sided colon (p = 0.048). High AGTR1 expression levels were associated with poor RFS in the GSE39582 dataset's stage I-III CRC patients (p < 0.001), and this finding was also validated in the GSE17536 dataset (p = 0.023). CONCLUSION: ACEI/ARB treatment may reduce tumor recurrence in left-sided CRC and early-stage CRC.

A case of intussusception developed at the site of ileocolic anastomosis after laparoscopic right hemicolectomy.

BACKGROUND: Intussusception is a relatively common condition seen in children. In comparison, adult intussusception is rare and usually occurs as a complication in patients with organic diseases. It is responsible for 1% of all bowel obstructions, in most of intussusceptions a malignant tumor is involved. Herein, we present an extremely unusual case of intussusception that occurred as a complication at the site of a functional end-to-end anastomosis. CASE PRESENTATION: A 57-year-old female patient was diagnosed with tumors in the ascending and descending colon and was referred to our department. Laparoscopic hemicolectomy and laparoscopic descending colectomy were performed. The mechanical intestinal obstruction occurred on the 9th day postoperatively, and computed tomography scan revealed intussusception at the site of the ileocolic anastomosis. Endoscopic reduction was attempted, but the procedure was challenging. Surgery was then performed and revealed that the site of ileocolic anastomosis firmly adhered to the side wall and right retroperitoneum. However, the intestine in the oral side of the anastomosis was not fixed. Examination of the anastomotic site revealed that the ileum had passed through the anastomosis and prolapsed into the transverse colon. The ileocolic anastomosis was resected. End-to-end anastomosis was performed, and surgery was then completed. No neoplastic lesions were observed in the resected tissue of the lead point of intussusception. The postoperative clinical course was favorable, and the patient was discharged on the 11th day after the second round of surgery. CONCLUSIONS: There are no reports the anastomosis is involved as part of the intussception, as observed in the present case. Intussusception should thus be considered as one of the causes of postoperative mechanical intestinal obstruction.

A rare case of perivascular epithelioid cell tumor (PEComa) of the greater omentum.

BACKGROUND: A tumor composed exclusively or predominantly of human melanin black 45 (HMB45)-positive epithelioid cells is called a perivascular epithelioid cell tumor (PEComa). We report a very rare case of a PEComa of the greater omentum. CASE PRESENTATION: MRI conducted to examine the orthopedic disease of the patients, a 49-year-old Japanese woman, also identified a tumor in her pelvis. A CT scan revealed a tumor mass on the right side of the pelvic floor and clear nutrient vessels originating from the splenic and celiac arteries. An omental primary tumor or accessory spleen was thus suspected, and tumor resection was performed. The tumor was a light brown solid tumor with a smooth margin, measuring 5.2 × 3.8 × 3.5 cm. Histopathologically, the tumor was composed mainly of spindle and epithelioid cells, and large and small blood vessel formation was observed. In the immunohistochemical staining, tumor cells were positive for human melanin black 45 (HMB-45) and Melan-A and partially positive for alpha-smooth muscle actin. The final diagnosis was PEComa of the greater omentum. CONCLUSIONS: Although omental PEComa is very rare, it should be considered as a differential disease of an omental primary tumor.

Prognostic impact of primary tumor resection and lymph node dissection in stage IV colorectal cancer with unresectable metastasis: a propensity score analysis in a multicenter retrospective study.

BACKGROUND: Retrospective studies have shown that primary tumor resection improves the prognosis of patients with colorectal cancer with unresectable metastasis (mCRC). Prognostic significance of lymph node dissection (LND) in mCRC has not been examined previously. The aim of this study was to investigate the prognostic impact of primary tumor resection and LND in mCRC. METHODS: A total of 1,982 patients with mCRC from January 1997 to December 2007 were retrospectively studied. The impact of primary tumor resection and LND on overall survival (OS) was analyzed using Cox proportional hazards model and propensity score analysis to mitigate the selection bias. Covariates in the models for propensity scores included treatment period, institution, age, sex, carcinoembryonic antigen, tumor location, histology, depth, lymph node metastasis, lymphovascular invasion, and number of metastatic organs. RESULTS: In a multivariate analysis, primary tumor resection and treatment in the latter period were associated with an improved OS, and age over 70 years, female sex, lymph node metastasis, and multiple organ metastasis were associated with a decreased OS. In the propensity-matched cohort, patients treated with primary tumor resection showed a significantly better OS than those without tumor resection (median OS 13.8 vs. 6.3 months; p = 0.0001). Furthermore, among patients treated with primary tumor resection, patients treated with D3 LND showed a significantly better OS than those with less extensive LND (median OS 17.2 vs. 13.7 months; p < 0.0001). CONCLUSIONS: It was suggested that primary tumor resection with D3 LND improves the survival of patients with mCRC.

Prediction of response to preoperative chemoradiotherapy in rectal cancer by using reverse transcriptase polymerase chain reaction analysis of four genes.

BACKGROUND: Patients with rectal cancer exhibit a wide spectrum of responses to chemoradiotherapy. Several gene expression signatures have been reported to predict the response to chemoradiotherapy in rectal cancer, but the lack of practical assays has restricted the clinical use of this technique. OBJECTIVE: We aimed to identify a set of discriminating genes that can be used for the clinical prediction of response to chemoradiotherapy in rectal cancer. DESIGN AND SETTINGS: This study is a retrospective analysis of tumor samples in a single institute. PATIENTS: Sixty-two patients who underwent preoperative chemoradiotherapy were studied. MAIN OUTCOME MEASURES: Gene expression was initially studied in 46 training samples by microarray analysis, and the association between gene expression and response to chemoradiotherapy was evaluated. Quantitative reverse transcriptase polymerase chain reaction was performed to validate the microarray expression levels of the discriminating genes. We developed a gene expression model for the prediction of response to chemoradiotherapy based on the reverse transcriptase polymerase chain reaction findings and validated it by using 16 independent test samples. RESULTS: We identified 24 discriminating probes with expression levels that differed significantly between responders and nonresponders. Among 18 genes identified by Gene Symbol, real-time reverse transcriptase polymerase chain reaction showed significant differences in the expression of 16 genes between responders and nonresponders. We constructed a predictive model by using different sets of these 16 genes, and the highest accuracy rate (89.1%) was obtained by using LRRIQ3, FRMD3, SAMD5, and TMC7. The predictive accuracy rate of this 4-gene signature in the independent set of 16 patients was 81.3%. LIMITATIONS: Validation in a different and large cohort of patients is necessary. CONCLUSIONS: The 4-gene signature identified in this study is closely associated with response to chemoradiotherapy in rectal cancer.

Number of Lymph Nodes in Rectal Cancer is Correlated with Response to Preoperative Chemoradiotherapy but is not Associated with Patient Survival.

BACKGROUND/AIMS: We aimed to clarify the oncological significance of the number of lymph nodes in rectal cancers treated with preoperative chemoradiotherapy. METHODOLOGY: We studied 126 curatively operated patients with clinical T3-T4 and M0 rectal cancers. The number of lymph nodes and clinicopathological features were compared between the patients treated with surgery alone (OP group, n = 45) and those treated with preoperative chemoradiotherapy (50-50.4 Gy in 25-28 fractions with tegafur-uracil and leucovorin, CRT group, n = 81). Factors influencing lymph node count and its prognostic significance were analyzed. RESULTS: The CRT group had significantly fewer lymph nodes than the OP group (12.4 vs. 21.1, P < 0.0001). High histological regression of rectal lesions was significantly correlated with decreased lymph node count in the CRT group. In the OP group, the 5-year cancer-specific survival rate of the patients with 12 or more lymph nodes was significantly better than those with fewer than 12 lymph nodes (75.1% vs. 33.3%, P = 0.02); in the CRT group, on the other hand, these survival rates did not differ (84.5% vs. 77.5%, P = 0.6). CONCLUSIONS: The number of lymph nodes in rectal cancer was correlated with the response of primary rectal lesions to chemoradiotherapy, and was not associated with patient survival.

Predicting prognosis in colorectal cancer patients with curative resection using albumin, lymphocyte count and RAS mutations.

Colorectal cancer (CRC) poses a significant global health challenge, demanding reliable prognostic tools to guide treatment decisions. This study introduces a novel prognostic scoring system, the albumin-total lymphocyte count-RAS index (ALRI), integrating serum albumin, lymphocyte count, and RAS gene mutations. A cohort of 445 stage I-III CRC patients undergoing curative resection was analyzed, revealing ALRI's association with clinicopathological factors, including age, tumor location, and invasion depth. The ALRI demonstrated superior prognostic value, with a cutoff value of 2 distinguishing high and low-risk groups. The high-ALRI group exhibited elevated rates of recurrence. Univariate and multivariate analyses identified ALRI as an independent predictor for both 5 year recurrence-free survival (RFS) and overall survival (OS). Kaplan-Meier curves illustrated significant differences in RFS and OS between high and low-ALRI groups, emphasizing ALRI's potential as a prognostic marker. Importantly, ALRI outperformed existing nutritional indices, such as controlling nutritional status and neutrophil-to-lymphocyte ratio, in predicting overall survival. The study underscores the comprehensive insight provided by ALRI, combining inflammatory, nutritional, and genetic information for robust prognostication in CRC patients. This user-friendly tool demonstrates promise for preoperative prognosis and personalized treatment strategies, emphasizing the crucial role of inflammation and nutrition in CRC outcomes.

A case of rectal cancer complicated with segmental arterial mediolysis (SAM) safely treated with curative resection - A case report.

INTRODUCTION: Recent advances in diagnostic imaging techniques have led to an increasing number of case reports of segmental arterial mediolysis (SAM). However, reports of abnormalities associated with SAM of abdominal organs, including the bowel, are limited. SAM, a rare vascular disease that causes spontaneous intra-abdominal bleeding, including shock and intestinal ischemia, has been reported to be associated with high mortality, but it has not been reported to coexist with rectal cancer. CASE PRESENTATION: A 74 year-old male was referred to our hospital with a rectal cancer and he was admitted for further examination. Computed tomography angiography (CTA) revealed dissection and aneurysm in the celiac artery, superior mesenteric artery (SMA), and the inferior mesenteric artery were dilated, leading to a diagnosis of SAM. CLINICAL DISCUSSION: Surgery for rectal cancer requires cutting the inferior mesenteric artery. The risk of bleeding during surgery increases when SAM is associated with the inferior mesenteric artery. The radical surgery for rectal cancer was executed without complications, including significant bleeding. This was achieved through careful management of SAM, meticulous control of blood pressure throughout the surgical procedure, and the delicate treatment of the SMA. A pathological diagnosis of the resected inferior mesenteric artery at the time of radical surgery was performed, and a definitive diagnosis of SAM was made. CONCLUSION: We present a first known case in which high anterior resection was successfully performed for rectal cancer complicated by SAM. The relationship between cancer and SAM is unclear and further case accumulation is needed.

Laparoscopy-Assisted Restorative Proctocolectomy with Ileal Pouch-Anal Anastomosis in Middle Colic Artery Ligation Immediately before Specimen Removal.

Introduction: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical procedure for ulcerative colitis (UC). Intestinal ischemia may occur if the main blood vessels are ligated at an early stage of this surgery. Considering that the blood flow in the large intestine can be maintained by preserving the middle colic artery, we have used a new IPAA method: ligating the middle colic artery immediately before removal of the specimens ("M-method"). Here, we evaluated the M-method's clinical outcomes. Methods: Between April 2009 and December 2021, 13 patients underwent a laparoscopy-assisted IPAA procedure at our institution. The conventional method was used for 6 patients, and the M-method was used for the other 7 patients. We retrospectively analyzed the cases' clinical notes. Results: The M-method's rate of postoperative complications (Clavien-Dindo classification grade II or more) was significantly lower than that of the conventional method (14.2% vs. 83.3%). The M-method group's postoperative stay period was also significantly shorter (average 16.4 days vs. 55.5). There were significant differences in the albumin value and the ratio of the modified GPS score 1 or 2 on the 7th postoperative day between the M- and conventional methods (average 3.15 vs. 2.5, average 4/7 vs. 6/6). However, it is necessary to consider the small number of cases and the uncontrolled historical comparison. Conclusion: Late ligation of the middle colic artery may be beneficial for patients' post-surgery recovery and can be recommended for IPAAs in UC patients.

Prognostic Value of KRAS Exon-specific Mutations in Patients With Colorectal Cancer.

BACKGROUND/AIM: The clinical significance of many RAS-family mutations in colorectal cancer (CRC) remains unclear. The purpose of this study was to investigate the relationship of RAS mutations on an exon basis (i.e., mutations in KRAS exons 2, 3, and 4 and in NRAS) with clinicopathological features and prognosis in CRC. PATIENTS AND METHODS: We performed a retrospective cohort study of the medical records and frozen tissue samples of 268 consecutive patients with stage I-III CRC who underwent curative resection at a single institution between 2014 and 2018. RESULTS: The RAS mutation rate was significantly associated with age and histology. Patients with KRAS exon 2 mutations exhibited shorter recurrence-free survival compared to those with KRAS wild-type, KRAS exon 3 mutations, KRAS exon 4 mutations, and NRAS mutations (73.0% vs. 85.5%, 86.7%, 85.7%; p=0.031). Age and histology were independent risk factors for RAS mutations. RAS mutations were independent prognostic factors with respect to recurrence-free survival in patients with stage I-III CRC. CONCLUSION: In stage I-III CRC patients, KRAS exon 2 mutations had the worst prognosis, whereas KRAS wild type, exon 3 mutations, exon 4 mutations, and NRAS mutations had better prognoses.

Ceramide synthase CERS4 gene downregulation is associated with KRAS mutation in colorectal cancer.

Ceramide, the central molecule in sphingolipid synthesis, is a bioactive lipid that serves as a regulatory molecule in the anti-inflammatory responses, apoptosis, programmed necrosis, autophagy, and cell motility of cancer cells. In particular, the authors have reported differences in sphingolipid content in colorectal cancer tissues. The associations among genetic mutations, clinicopathological factors, and sphingolipid metabolism in colorectal cancer (CRC) have not been investigated. The objective of this study is to investigate the association between genes associated with sphingolipid metabolism, genetic variations in colorectal cancer (CRC), and clinicopathological factors in CRC patients. We enrolled 82 consecutive patients with stage I-IV CRC who underwent tumor resection at a single institution in 2019-2021. We measured the expression levels of genes related to sphingolipid metabolism and examined the relationships between CRC gene mutations and the clinicopathological data of each individual patient. The relationship between CRC gene mutations and expression levels of ceramide synthase (CERS), N-acylsphingosine amidohydrolase (ASAH), and alkaline ceramidase (ACER) genes involved in sphingolipid metabolism was examined CRES4 expression was significantly lower in the CRC KRAS gene mutation group (p = 0.004); vascular invasion was more common in colorectal cancer patients with high CERS4 expression (p = 0.0057). By examining the correlation between sphingolipid gene expression and clinical factors, we were able to identify cancer types in which sphingolipid metabolism is particularly relevant. CERS4 expression was significantly reduced in KRAS mutant CRC. Moreover, CRC with decreased CERS4 showed significantly more frequent venous invasion.

The first case of laparoscopic surgery for cecal cancer occurring in a blind loop.

Cancer occurrence in a blind loop is extremely rare. An 86-year-old Japanese woman underwent colonoscopy for tarry stools and weight loss; it revealed a bypass of the transverse colon and small intestine, cecal cancer, and a polyp. She had suffered from acute appendicitis and had undergone two surgeries at age 25: an appendectomy and then a bypass surgery between the transverse colon and the small intestine. We performed a laparoscopy-assisted ileocecal resection for the cancer and polyp in the blind loop with an end-to-side instrumental anastomosis. The pathological examination demonstrated that the cancer was medullary carcinoma (T2, N0, M0, Stage I) and the polyp was tubular adenoma. Two months have passed since the patient's discharge, and she is free of abdominal complaints. Our literature search identified 10 cases of cancer in a blind loop. Laparoscopy-assisted surgery may be possible in patients who have undergone blind-loop surgery.

Radiation-induced apoptosis of peripheral blood lymphocytes is correlated with histological regression of rectal cancer in response to preoperative chemoradiotherapy.

PURPOSE: The response of rectal cancer to preoperative chemoradiotherapy (PRT) varies widely among patients, and predictors of the response remain to be elucidated. The purpose of this study is to investigate whether radiation-induced apoptosis (RIA) of peripheral blood lymphocytes (PBLs) reflects the underlying intrinsic radiosensitivity of rectal cancer. METHODS: Forty-one patients with clinical T3-4, M0 low rectal cancers, treated with PRT and curative surgery, were retrospectively studied. PBLs were obtained from blood samples of the patients, irradiated at 0, 2, 8, and 16 Gy in vitro, and analyzed for RIA by flow cytometry using Annexin V (AV) and propidium iodide (PI). The correlation of the RIA of PBLs and histological regression of rectal cancer in response to PRT was examined. RESULTS: Both the proportions of AV+/PI- PBLs (early apoptosis) and AV+/PI + PBLs (late apoptosis) were significantly higher in patients with high histological regression than in those with low histological regression. Age, sex, tumor size, and clinical T and N stages did not affect the RIA of PBLs. CONCLUSIONS: This study showed that the RIA of PBLs is correlated with the histological regression of rectal cancer in response to PRT and suggested that the radiosensitivity of rectal cancer might be estimated by the RIA of PBLs.

Tumor location is a prognostic factor in poorly differentiated adenocarcinoma, mucinous adenocarcinoma, and signet-ring cell carcinoma of the colon.

PURPOSE: Cancers which arise in the proximal and distal colon are suggested to be different clinically, pathologically, and genetically. The aim of this study is to clarify whether clinical behavior of colonic poorly differentiated adenocarcinoma, mucinous adenocarcinoma, and signet-cell carcinoma (Por/Muc/Sig cancers), minor and aggressive subpopulation in colonic cancers, differs in accordance with the tumor location. METHODS: A total of 3,175 patients with curatively resected colonic cancers were studied. Clinical and pathological features were compared between Por/Muc/Sig cancers and well or moderately differentiated adenocarcinomas (Wel/Mod cancers) and between proximal and distal cancers in each histologic type. RESULTS: Por/Muc/Sig cancers (n = 213) were more advanced in the TNM stage and showed worse disease-specific survival than Wel/Mod cancers (n = 2,692). In Por/Muc/Sig cancers, but not in Wel/Mod cancers, proximal cancers showed significantly better disease-specific survival than distal cancers (88.9% vs. 76.5%, p = 0.0234), and a multivariate analysis showed that proximal tumor location was an independent predictor of fair prognosis (hazard ratio (HR), 0.458; 95% confidence interval (CI), 0.218-0.961; p = 0.0390). In addition, female gender also was an independent predictor of fair prognosis in Por/Muc/Sig cancers (HR, 0.373; 95% CI, 0.151-0.922) and not in Wel/Mod cancers. CONCLUSIONS: Proximal Por/Muc/Sig cancers were suggested to be a distinct subpopulation with a favorable oncologic outcome. Tumor location and gender might be helpful in the risk stratification after curative surgery for Por/Muc/Sig cancers.