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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 clinical significance of many RAS-family mutations in colorectal cancer (CRC) remains unclear. The purpose of this study was to investigate the relationship of 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. 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 in 2014–2018. The RAS mutation rate was significantly associated with age and histology. Patients with KRAS exon 2 mutations exhibited shorter RFS 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 RFS in patients with stage I–III CRC. In stage I–III CRC patients, KRAS exon 2 mutations have the worst prognosis, while RAS wild type, RAS exon 3 mutations, RAS exon 4 mutations and NRAS mutations have better prognoses.

Objective The accuracy of identifying a CRT-response by a pre-operative radiological examination is limited, and another approach is necessary. We constructed endoscopic image-based radiomics classifiers to predict the response of locally advanced rectal cancers (LARCs) to neoadjuvant chemotherapy (NA-CRT). Design: We enrolled 90 patients who had undergone NA-CRT followed by surgery. We selected 5,255 pre- and post-CRT endoscopic images of the tumors and extracted 860 texture features from each image. Using the extracted texture features, we applied 12 machine learning models to construct radiomics classifiers. The performances of the radiomics classifiers to predict a pathological complete response (pCR) and a CRT-response (good or not) were evaluated with a double cross-validation technique by calculating the area under the receiver operating characteristics curve (AUROC). Results In the prediction of pCR using pre-CRT images, the cubic support vector machine (SVM) model showed the highest AUROC of 0.816 in the image-basis analysis, and the AUROC of 0.904 in the patient-basis analysis. In the prediction of pCR using post-CRT images, the quadratic SVM model showed the highest AUROC (0.839) in the image-basis analysis, and the AUROC of 0.958 in the patient-basis analysis. The Gaussian SVM model demonstrated the best performances to predict a CRT-response in both pre- and post-CRT images with AUROCs of 0.792 and 0.841 in the image-basis analysis and 0.857 and 0.950 in the patient-basis analysis, respectively. Conclusion Our endoscopic image-based radiomics classifiers demonstrated robust performances to predict the CRT-response of LARCs and may contribute to the patients' management.

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.

Colorectal cancer (CRC) is a major cancer, and its precise diagnosis is especially important for the development of effective therapeutics. In a series of metabolome analyses, the levels of very long chain fatty acids (VLCFA) were shown to be elevated in CRC tissues, although the endogenous form of VLCFA has not been fully elucidated. In this study we analyzed the amount of nonesterified fatty acids, acyl-CoA species, phospholipids and neutral lipids such as cholesterylesters using liquid-chromatography–mass spectrometry. Here we showed that VLCFA were accumulated in triacylglycerol (TAG) and nonesterified forms in CRC tissues. The levels of TAG species harboring a VLCFA moiety (VLCFA-TAG) were significantly correlated with that of nonesterified VLCFA. We also showed that the expression level of elongation of very long-chain fatty acids protein 1 (ELOVL1) is increased in CRC tissues, and the inhibition of ELOVL1 decreased the levels of VLCFA-TAG and nonesterified VLCFA in CRC cell lines. Our results suggest that the upregulation of ELOVL1 contributes to the accumulation of VLCFA-TAG and nonesterified VLCFA in CRC tissues.

Epithelioid hemangioma is a rare benign vascular tumor that consists of capillary-sized vessels lined by epithelioid endothelial cells. Diffuse cavernous hemangioma is a congenital benign vascular neoplasm consisting of increased dilated vessels. We report a case of epithelioid hemangioma and diffuse cavernous hemangioma that co-occurred in the rectum. To our knowledge, this is the first report in which two rare vascular lesions coexisted. Because both epithelioid hemangioma and diffuse cavernous hemangioma are often clinically confounded by malignant tumors, differentiating these benign lesions from other possible malignant tumors is significant.

Background/aim The prognosis of colorectal cancer is reported to differ depending on the tumor site, and clinical differences depending on the site of occurrence have gained attention. The aim was to compare nutrition index and inflammatory markers according to the site of colon cancer. Patients and methods We retrospectively analyzed 272 cases of stage I-III colon cancer (55% males, 45% females). The clinical characteristics, nutrition index and inflammatory markers were compared between patients with right colon cancer (RCC, n=119) and those with left colon cancer (LCC, n=153), and the relapse-free survival was then compared. Results RCC was associated with older age (p=0.03), female gender (p=0.003), higher T stage (p=0.01), elevated platelet/lymphocyte ratio (PLR) (p=0.009), and elevated CONUT score (p=0.028). The prognostic values differed between RCC and LCC (RCC: CONUT score, p=0.04, LCC: PLR, p=0.02). Conclusion RCC was associated with an elevated CONUT score and PLR. In RCC, the CONUT score was an independent recurrence factor, and in LCC, the PLR was an independent recurrence factor.

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. We aimed to stratify stage I CRC based on the recurrence risk and evaluate optimal post-operative surveillance durations based on this stratification. 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. 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. Our new classification properly stratified the recurrence risks of stage I CRC patients, and may help reduce unnecessary post-operative surveillance.

The Controlling Nutritional Status (CONUT) score is a marker of nutrition and is associated with poor survival in various kinds of cancers. However, no reports have yet compared risk factors for colorectal cancer recurrence using a nutritional index. We assessed the predictive value of the CONUT score compared with the modified Glasgow Prognostic Score (mGPS) and Prognostic Nutritional Index (PNI) in colorectal cancer (CRC) patients. We performed a retrospective cohort study of the medical records of 336 consecutive patients with stage I-I I I CRC who underwent curative resection at a single institution in 2012–2017. Univariate and multivariate analyses were conducted to identify prognostic factors associated with relapse-free survival (RFS) and overall survival (OS). The low CONUT score group exhibited higher RFS and longer OS compared to the high CONUT score group (82.2% vs. 63.3%, p = 0.002 and 95.5% and 86.2%, p = 0.005, respectively). The Akaike’s information criterion values of each index for RFS and OS were superior in CONUT score (723.71 and 315.46, respectively) compared to those of PNI (726.95 and 316.52) and mGPS (728.15 and 318.07, respectively). The CONUT score was found to be a good predictor of RFS and OS in patients with resectable CRC.

Purpose: T The world is becoming longer-lived, and the number of elderly colorectal cancer patients is increasing. It is very important to identify simple and inexpensive postoperative predictors in elderly colorectal cancer patients. The geriatric nutritional risk index (GNRI) is a marker of systemic nutrition and is associated with poor survival in various kinds of cancers. A few reports have investigated recurrence factors using preoperative GNRI with CRC patients. This study aimed to investigate whether preoperative GNRI is associated with recurrence-free survival (RFS) and overall survival (OS) in elderly patients with CRC.Methods: This study retrospectively enrolled 259 patients with StageⅠ-Ⅲ CRC who were more than 65 years old and underwent curative surgery at a single institution in 2012–2017. We classified them into low GNRI (RFS: ≤90.5, OS ≤101.1) group and high GNRI (RFS:>90.5, OS >101.1) group.Results: Multivariable analyses showed low GNRI group was an independent risk factor for 3-year RFS (P = 0.006) and OS (P = 0.001) in the patients with CRC. Kaplan-Meier analysis showed 3-year RFS and 3-year OS were significantly worse in the low GNRI group than in high GNRI group (p = 0.001, 0.0037).Conclusion: A low-preoperative GNRI was significantly associated with a poor prognosis in elderly CRC patients.

A 47-year-old male patient without a documented past medical history was referred to Sanno Hospital because of constipation and abdominal pain, which he had had for more than 5 years. Abdominal X-ray and CT scan showed an enlarged ascending colon from the cecum to the transverse colon, without apparent mechanical obstruction. The patient was diagnosed with chronic idiopathic colonic pseudo-obstruction, and because his symptoms were resistant to medication, surgical treatment was required. Laparoscopic subtotal colectomy was performed without any complications. Constipation was relieved, and the patient began defecating 2-3 times a day without medication. Pathological specimens showed that Meissner's plexus and Auerbach's plexus had decreased and that there were fewer ganglion cells-findings consistent with chronic idiopathic intestinal pseudo-obstruction.

It has been shown that nutritional status correlates with survival in patients with various kinds of cancers. Besides, cancer causes inflammation which has been suggested to stimulate cancer progression. Therefore, inflammation status also has shown to reflect prognosis of cancers. In this study, we evaluated several kinds of nutritional and inflammation parameters in preoperative blood samples and constructed new risk model predicting a survival in patients with CRC (colorectal cancers). We retrospectively examined 286 patients with stage I-III CRC who had undergone curative resection in Teikyo University Hospital between 2013 to 2017. The association between overall survival (OS) and preoperative body mass index, albumin (Alb), cholesterol (Chol), and lymphocyte count, white blood cell count (WBC), neutrophil count (Neu), platelet count (Plt), C-reactive protein (CRP) were examined using Kaplan-Meier curve and log rank test. and eventually Alb, Chol, Neu, Plt, and CRP were shown to correlate with OS. Alb, Chol, Neu, Plt, and CRP were shown to correlate with OS. We constructed a new risk model (NIS: nutrition inflammation status) using these factors, and compared its usefulness with known models such as CRP-albumin ratio (CAR), Glasgow prognostic score (GPS), prognostic nutritional index (PNI), and neutrophil lymphocyte ratio (NLR). NIS prepared using nutritional indicators and inflammatory findings was useful as a new model for predicting overall survival in patients undergoing curative resection for CRC, compared with known models.

Background/Aim: To evaluate the benefits of the addition of oxaliplatin (OX) to fluoropyrimidine (FP)-based neoadjuvant chemoradiotherapy (CRT) for patients with locally advanced rectal cancers (LARCs). Patients and Methods: We performed retrospective analyses comparing the pathological complete response (pCR) rate, overall survival (OS), recurrence-free survival (RFS), and local recurrence-free survival (LRFS) between FP-based and FP+OX-based CRT groups and for patients who had completed the CRT. Results: One hundred patients were included in the analyses: the pCR rate, OS, RFS, and LRFS were similar between these groups. The FP+OX group showed significantly more frequent incompleteness of the CRT compared to the FP group (p=0.049). Among the patients who had completed the CRT, the FP+OX group demonstrated significantly improved LRFS compared to the FP group (p=0.048). Conclusion: The addition of OX to an FP regimen in neoadjuvant CRT for LARC may reduce local recurrence in patients who have achieved good compliance to CRT.

Background Although there are reports linking ulcerative colitis (UC) to prostate cancer (PC), those reports are of PC patients who were previously diagnosed with UC. There are no reports of the development of UC during radiotherapy. Here we describe the first case of a patient who developed UC during radiotherapy for PC. The UC progressed rapidly and required emergency surgery. Case presentation A 61-year-old Japanese man underwent a prostate biopsy at another hospital due to a high prostate-specific antigen level and was diagnosed with PC. Goserelin and bicalutamide treatment was initiated in 2019, and intensity-modulated radiotherapy (total of 60 Gy/20 Fr) was administered in 2020. Diarrhea began during the radiotherapy and bleeding began post-radiotherapy. He was admitted to another hospital 14 days after the end of the radiotherapy, and colonoscopy revealed a deep ulcer in the colon, which led to the suspicion of UC. He was transferred to our hospital, and colonoscopy showed a widespread map-like ulcer, pseudopolyposis, and very easy bleeding in the colon. We diagnosed severe UC, and it worsened rapidly with uncontrollable bleeding, which we considered an indication for surgery. Emergency surgery (a total colectomy and ileostomy creation) was performed. The specimens confirmed an extensively spreading ulcer throughout the colon. The pathological report was UC in the active phase. The postoperative course was good. Conclusions When a patient exhibits diarrhea while undergoing radiotherapy for PC, clinicians should be aware of the possibility of UC in addition to radiation colitis, and colonoscopy should be considered.

Background The term “mesenteric inflammatory veno-occlusive disease (MIVOD)” is used to describe an ischemic injury resulting from phlebitis or venulitis that affects the bowel or mesentery in the absence of arteritis. MIVOD is difficult to diagnose because of its rarity and frequent confusion with other diseases. The incidence and etiology of MIVOD remain unclear; only a few cases have been reported. We describe a case of the successful surgical management of a patient with MIVOD with characteristic images. Case presentation A 65-year-old Japanese man visited a hospital with the chief complaint of abdominal pain in January 2018. CT showed edema and thickening of the intestinal wall from the descending colon to the rectum. The patient was admitted to the hospital. Suspected diagnoses were enteritis, ulcerative colitis, amyloidosis, vasculitis, malignant lymphoma, and venous thrombus, but no definitive diagnosis was obtained. The patient was transferred to our hospital for the treatment of stenosis (located from the descending colon to the rectum) and bowel obstruction. An emergency transverse colostomy was performed. The sigmoid colon and mesentery were too rigid and edematous to resect. Colonic hemorrhage occurred 2 weeks after the surgery. With radiology intervention, coiling for the arteriovenous fistula in the descending colon was performed, and hemostasis was obtained. A colonoscopy at 6 months post-surgery showed neither ulceration nor stenosis in the rectum, indicating that the rectum could be preserved in the next surgery. However, severe stenosis in the descending and sigmoid colon remained unchanged. Ten months after the transverse colostomy, we performed a subtotal colectomy and ileorectal anastomosis, and an ileostomy was created. The sigmoid colon and mesentery were not so rigid compared to the first surgery’s findings, and we were able to resect intestine and mesentery. Histopathology revealed phlebitis and venulitis, fibrinoid necrosis, and normal arteries, meeting the diagnostic criteria for MIVOD. Postoperatively, the patient showed no recurrence for 8 months. Conclusion Clinicians should consider MIVOD when examining a patient with intestinal ischemia. When MIVOD is suspected, the patient is indicated for surgery based on an accurate diagnosis and good prognosis.

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.

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. 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). Univariate analysis revealed that elevated NLR, NLR7, and lymphatic invasion were significantly associated with decreased RFS (p

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. 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. 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

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. 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. 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. KRAS codon 12G-to-V or G-to-C mutations are independent prognostic factors in patients with stage I–III CRC.

Background: The number of ulcerative colitis (UC) patients is increasing in Japan and other countries. Selective depletion of myeloid lineage leucocytes by adsorptive granulocyte and monocyte apheresis (GMA) with an Adacolumn (JIMRO, Takasaki, Japan) was introduced as a nonpharmacologic treatment strategy in UC patients in 2000. GMA has been reported to be effective in clinical trials; however, the effect of concomitant prednisolone (PSL) on GMA needs to be clarified. Methods: Thirty-nine patients with active UC were treated with GMA at our institute between June 2009 and September 2018. All patients received GMA therapy once or twice a week with the Adacolumn. Conventional medication was to be continued during the whole GMA treatment course. The clinical response was retrospectively evaluated. Results: According to the partial Mayo score, remission was 33.3%, significant efficacy 25.6%, effective 25.6%, and no response 15.4%. The average partial Mayo score was 6.2 ± 1.4 at entry and significantly declined to 1.8 ± 1.8 after GMA sessions (p < 0.0001). The average number of bowel movements was 9.5 ± 5.6 at entry and significantly declined to 3.0 ± 2.8 after GMA sessions (p < 0.0001). In a comparison between the group treated with concomitant PSL and the group without PSL, the change in partial Mayo score or the number of bowel movements from entry to after GMA sessions was not significantly different. Among 24 patients treated by GMA with concomitant PSL, 75% (18/24) became steroid free. Conclusions: The effect of GMA with concomitant PSL and that of GMA without PSL were not different, and GMA was effective irrespective of PSL administration. The present study showed that GMA had efficacy and led many UC patients treated by PSL to be steroid free with no safety concern in the real world, although there is the possibility of recruitment bias due to the retrospective nature of the study.

116 Background: Regorafenib, a multi-kinase inhibitor, significantly improved overall survival in previously treated metastatic colorectal cancer (mCRC) patients in the phase 3 CORRECT trial. Despite its significant benefits, various toxicities such as hand-foot skin reaction (HFSR), fatigue, and liver dysfunction have limited regorafenib use. The toxicities occur soon after treatment initiation, typically within the first cycle, and later improve. Although the standard daily dose of regorafenib is 160 mg, physicians have adopted various dosing regimens in clinical practice, indicating the need to optimize the dosing strategy to maintain the antitumor benefits. The ReDOS study demonstrated the effectiveness of a weekly dose-escalating strategy (WDES) of regorafenib starting with a lower daily dose. We conducted the phase II RECC study to evaluate the safety and efficacy of WDES for regorafenib in an Asian population. Methods: Patients with sufficient organ function who had previously received more than two lines of chemotherapy were included. Regorafenib was started at 80 mg/day and escalated to 120 mg/day in Week 2 and 160 mg/day in Week 3 if no severe drug-related toxicities were observed. The primary endpoint was progression-free survival (PFS) and secondary endpoints were time to treatment failure (TTF), response rate (RR), overall survival (OS), and safety. Tumor response and progression were assessed radiologically every 8 weeks. Results: From March 2017 to November 2018, 57 eligible patients were enrolled and all started regorafenib at 80 mg/day. Thirty-five patients (61%) were subsequently escalated to 120 mg/day and 16 (28%) to 160 mg/day. Forty patients (70.2%) finished Cycle 2 at 8 weeks. Only 8 patients (14%) discontinued treatment because of adverse events. The median PFS was 1.9 months, RR was 0%, and disease control rate was 32%. The most frequent adverse event ≥grade 3 was hypertension (17.5%), followed by HFSR (14%). No treatment-related deaths occurred. Conclusions: Regorafenib dose escalation was well tolerated with PFS similar to that reported in the CORRECT study, indicating that WDES may represent an option for regorafenib administration. Clinical trial information: UMIN000028933.

To verify the safety and validity of laparoscopic surgery for the treatment of colorectal cancer in elderly patients.A meta-analysis was performed of a systematic search of studies on an electronic database. Studies that compared laparoscopic colectomy (LAC) in elderly colorectal cancer patients with open colectomy (OC) were retrieved, and their short and long-term outcomes compared. Elderly people were defined as 65 years old or more. Inclusion criteria were set at: Resection of colorectal cancer, comparison between laparoscopic and OC and no significant difference in backgrounds between groups.Fifteen studies were identified for analysis. LAC was performed on 1436 patients, and OC performed on 1810 patients. In analyses of short-term outcomes, operation time for LAC was longer than for OC (mean difference = 34.4162, 95%CI: 17.8473-50.9851, P0.0001). The following clinical parameters were lower in LAC than in OC: Amount of estimated blood loss (mean difference = -93.3738, 95%CI: -132.3437 to -54.4039, P0.0001), overall morbidity (OR = 0.5427, 95%CI: 0.4425-0.6655, P0.0001), incisional surgical site infection (OR = 0.6262, 95%CI: 0.4310-0.9097, P = 0.0140), bowel obstruction and ileus (OR = 0.6248, 95%CI: 0.4519-0.8638, P = 0.0044) and cardiovascular complications (OR = 0.4767, 95%CI: 0.2805-0.8101, P = 0.0062). In analyses of long-term outcomes (median follow-up period: 36.4 mo in LAC, 34.3 mo in OC), there was no significant difference in overall survival (mean difference = 0.8321, 95%CI: 0.5331-1.2990, P = 0.4187) and disease specific survival (mean difference = 1.0254, 95%CI: 0.6707-1.5675, P = 0.9209). There was also no significant difference in the number of dissected lymph nodes (mean difference = -0.1360, 95%CI: -4.0553-3.7833, P = 0.9458).LAC in elderly colorectal cancer patients had benefits in short-term outcomes compared with OC except operation time. The long-term outcomes and oncological clearance of LAC were similar to that of OC. These results support the assertion that LAC is an effective procedure for elderly patients with colorectal cancer.

KRAS mutation is an important predictive marker in determining resistance to anti-Epidermal Growth Factor Receptor (EGFR) antibody therapies. In order to clarify whether not only KRAS related signalling pathways but also other signalling pathways are altered in patients with colorectal cancers (CRCs) with KRAS mutations, we examined the differences in the gene expression signatures between CRCs with and without KRAS mutation.One-hundred and thirteen patients who underwent a surgical resection of a primary CRC were examined. KRAS mutational status was determined using the Peptide Nucleic Acid (PNA)-clamp real-time polymerase chain reaction (PCR) TaqMan assay. Gene expression profiles were compared between CRCs with and without KRAS mutation using the Human Genome GeneChip array U133.Among 113 CRCs, KRAS mutations were present in 35 tumours (31%). We identified 30 genes (probes) that were differentially expressed between CRCs with and without KRAS mutation (False Discovery Rate (FDR), p0.01), by which we were able to predict the KRAS status with an accuracy of 90.3%. Thirty discriminating genes included TC21, paired-like homeodomain 1 (PITX1), Sprouty-2, dickkopf homologue 4 (DKK-4), SET and MYND domain containing 3 (SMYD3), mitogen-activated protein kinase kinase kinase 14 (MAP3K14) and c-mer Proto-oncogene tyrosine kinase (MerTK). These genes were related to not only KRAS related signalling pathway but also to other signalling pathways, such as the Wnt-signalling pathway, the NF-kappa B activation pathway and the TGF-beta signalling pathway.KRAS mutant CRCs exhibited a distinct gene expression signature different from wild-type KRAS CRCs. Using human CRC samples, we were able to show that there is crosstalk between the KRAS-mediated pathway and other signalling pathways. These results are necessary to be taken into account in establishing chemotherapeutic strategies for patients with anti-EGFR-refractory KRAS mutant CRCs.

KRAS status is a useful predictive marker for anti-epidermal growth factor receptor antibody therapy.This study aimed to examine the concordance rate of KRAS mutation status between corresponding primary and metastatic colorectal cancer lesions, and also among multiple metastatic tumors. Furthermore, we examined the heterogeneity of KRAS mutations with respect to discordant KRAS status between primary and metastatic tumors.This study was retrospective in design.Forty-three patients with primary tumors and 113 metastatic tumors were studied.The KRAS mutational status was determined by the peptide nucleic acid clamp real-time polymerase chain reaction TaqMan assay. We also performed sequencing analysis to validate the KRAS mutational status. When KRAS status differed between primary and metastatic tumors, we examined the heterogeneity of KRAS status within individual primary tumors by microdissecting multiple samples in each patient.The frequency of KRAS mutations in primary tumors was 34.9%. A high concordance rate of KRAS (88.4-91.7%) mutations was observed between primary and metastatic tumors. All 5 cases (11.6%) with discordant KRAS status had heterogeneous KRAS status in primary tumors. However, in 10 concordant cases all microdissected areas showed an identical KRAS mutational status within each patient. The KRAS mutational statuses in all multiple liver and/or lung metastatic tumors were the same as those of the primary tumor.We could not validate KRAS status in microdissected samples by the direct sequence method that was used in the present study, because the quantity of DNA was not sufficient to perform direct sequencing.KRAS status in a primary site may be used for selecting patients who would benefit from anti-epidermal growth factor receptor therapy. However, KRAS status can be heterogeneous within a primary tumor, and thus different parts of such tumors should be examined for KRAS status to correctly predict the KRAS status in metastatic lesions.

Regimens containing bevacizumab and 5-fluorouracil have achieved substantial progress in the treatment of colorectal cancer. However, individual responses to bevacizumab vary widely in regard to efficacy and toxicity.To be able to select patients who would benefit from bevacizumab, we aimed to establish a predictor model for response to bevacizumab therapy based on gene expression profiles.Retrospective analysis of tumor samples in the laboratory.The patient population comprised 25 patients with metastatic colorectal cancer treated with bevacizumab with either modified FOLFOX6 or FOLFIRI, from whom tumor samples were available for gene expression analysis.Response Evaluation Criteria in Solid Tumors were used to classify patients as responders or nonresponders to chemotherapy. Gene-expression profiles were determined with both microarray analysis and quantitative, real-time reverse-transcriptase polymerase chain reaction, and responders were compared with nonresponders, correcting for multiple comparisons. Genes that discriminated between groups on both analyses with the greatest accuracy were selected for the predictive model. Between-group differences in protein expression were confirmed with polymerase chain reaction and immunohistochemical staining.From 19 probes that differentiated between responders and nonresponders on microarray analyses, we identified 13 genes that were differentially expressed between responders and nonresponders on both microarray and real-time reverse-transcriptase polymerase chain reaction. A model using the genes for vascular endothelial growth factor-A, thymidylate synthase, and tissue inhibitor of metalloproteinase 3 predicted response to bevacizumab therapy with an accuracy of 96%, sensitivity of 90.9% (10/11), specificity of 100% (14/14), positive predictive value of 100% (10/10), and negative predictive value of 93.3% (14/15). The protein expression of vascular endothelial growth factor-A, thymidylate synthase, and tissue inhibitor of metalloproteinase 3 correlated with the findings of mRNA expression analyses.Validation of the model in a different cohort of patients is necessary.The present predictive model based on quantitative, real-time, reverse-transcriptase polymerase chain reaction assessment of vascular endothelial growth factor-A, thymidylate synthase, and tissue inhibitor of metalloproteinase 3 may enable selection of colorectal cancer patients who would benefit from bevacizumab therapy.

FOLFOX (a combination of leucovorin, fluorouracil and oxaliplatin) has achieved substantial success in the treatment of colorectal cancer (CRC) patients. However, about half of all patients show resistance to this regimen and some develop adverse symptoms such as neurotoxicity. In order to select patients who would benefit most from this therapy, we aimed to build a predictor for the response to FOLFOX using microarray gene expression profiles of primary CRC samples. Forty patients who underwent surgery for primary lesions were examined. All patients had metastatic or recurrent CRC and received modified FOLFOX6. Responders and nonresponders were determined according to the best observed response at the end of the first-line treatment. Gene-expression profiles of primary CRC were determined using Human Genome GeneChip arrays U133. We identified discriminating genes whose expression differed significantly between responders and nonresponders and then carried out supervised class prediction using the k-nearest-neighbour method. We identified 27 probes that were differentially expressed between responders and nonresponders at significant levels. Based on the expression of these genes, we constructed a FOLFOX response predictor with an overall accuracy of 92.5%. The sensitivity, specificity, positive and negative predictive values were 78.6%, 100%, 100% and 89.7%, respectively. The present model suggests the possibility of selecting patients who would benefit from FOLFOX therapy both in the metastatic and the adjuvant setting. To our knowledge, this is the first study to establish a prediction model for the response to FOLFOX chemotherapy based on gene expression by microarray analysis.