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The early mechanisms of spontaneous tumor initiation that precede malignancy are largely unknown. We show that reduced aPKC levels correlate with stem cell loss and the induction of revival and metaplastic programs in serrated- and conventional-initiated premalignant lesions, which is perpetuated in colorectal cancers (CRCs). Acute inactivation of PKCλ/ι in vivo and in mouse organoids is sufficient to stimulate JNK in non-transformed intestinal epithelial cells (IECs), which promotes cell death and the rapid loss of the intestinal stem cells (ISCs), including those that are LGR5 + . This is followed by the accumulation of revival stem cells (RSCs) at the bottom of the crypt and fetal-metaplastic cells (FMCs) at the top, creating two spatiotemporally distinct cell populations that depend on JNK-induced AP-1 and YAP. These cell lineage changes are maintained during cancer initiation and progression and determine the aggressive phenotype of human CRC, irrespective of their serrated or conventional origin., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background/aim: In colorectal cancer surgery, the risk of surgical site infection (SSI) is relatively high. The development of SSI is related to longer and costlier hospitalization and reduced quality of life; therefore, perioperative prevention of SSI is important. Chemical bowel preparation (CBP) combined with mechanical bowel preparation (MBP) may be more effective in preventing surgical site infection (SSI) compared to MBP alone. Since May 2021, we have been administering oral kanamycin and metronidazole as CBP, in addition to MBP, as a preoperative treatment for colorectal cancer surgery on the day before surgery. In this study, we investigated the clinical value of CBP in addition to MBP in colorectal cancer surgery using propensity score matching (PSM)., Patients and Methods: From January 2017 to December 2021, 136 consecutive patients underwent radical surgery for sigmoid colon and rectal cancer at the Osaka Metropolitan University Hospital. Patients were divided into two groups: CBP and N-CBP. In the N-CBP group, we performed only preoperative MBP, whereas in the CBP group, we performed preoperative CBP in addition to MBP. We retrospectively analyzed this relationship with PSM., Results: Overall, 46 patients underwent preoperative CBP and MBP, 90 patients underwent preoperative MBP only. PSM was performed between the CBP and N-CBP groups based on the following ten factors: age, sex, diabetes mellitus, preoperative therapy, Glasgow Prognostic Score (GPS), operative time, blood loss, stoma, and pathological stage. After PSM, univariate and multivariate analyses of the relationship between SSI and clinicopathological factors were performed. Univariate analysis showed that age and CBP were correlated with the rate of SSI (p=0.039 and p=0.017, respectively), whereas sex was relatively correlated with the rate of SSI (p=0.066). The multivariate analysis of significant factors identified age of 75 or more and non-CBP as an independent risk factor for incisional SSI (HR=9.5; p=0.049 and HR=5.4×e -8 ; p=0.020)., Conclusion: Preoperative CBP in addition to MBP was effective in preventing incisional SSI during colorectal cancer surgery., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis., (© 2023. Springer Nature Limited.)

Cancer-associated fibroblasts(CAFs)remodel the extracellular matrix(ECM)and shape the tumor microenvironment (TME), resulting in immune escape and the promotion of tumor metastasis. Using an orthotopic tumor model of colorectal cancers(CRCs)in mice, we demonstrated that the single-cell RNA sequencing of orthotopic rectal tumors identified a subpopulation of CAFs that modulate the immune response. In this review, we report that understanding the role of CAFs in the TME concerning tumor immunity may lead to future avenues for CAF-targeted therapy.

Background: The powered circular stapler, which was developed with the aim of providing reliable and reproducible anastomosis, provides complete anastomosis, resulting in a reduced risk of anastomotic leakage. The aim of this study was to compare the incidence of anastomotic leakage between a conventional manual circular stapler (MCS) and the ECHELON CIRCULAR™ Powered Stapler (ECPS) in patients with left-sided colorectal cancer who underwent anastomosis with the double stapling technique., Methods: A total of 187 patients with left-sided colorectal cancer who underwent anastomosis with the double stapling technique with a conventional MCS or the ECPS during surgery at Osaka City University Hospital between January 2016 and July 2022 were enrolled in this study., Results: The incidence of anastomotic leakage in the ECPS group was significantly lower than that in the MCS group (4.4% versus 14.3%, p = 0.048). Furthermore, even after propensity score matching, an association was found between the use of the ECPS and a reduced incidence of anastomotic leakage., Conclusion: The ECPS has the potential to help reduce the rate of anastomotic leakage in left-sided colorectal surgery., (© 2023. The Author(s).)

Background/aim: In addition to oncological and treatment factors, the outcomes of cancer treatment are greatly influenced by host factors, such as the nutritional status. The aim of this study was to evaluate the association between the preoperative nutritional status and the prognosis of colorectal cancer patients using three nutritional indices., Patients and Methods: The target cohort consisted of 529 patients with stage I-III colorectal cancer, who underwent curative surgery between January 2015 and December 2019. The nutritional indices were calculated according to the equations that follow. Prognostic nutritional index (PNI)=10×serum albumin concentration (g/dl) +0.005×peripheral lymphocyte count (/μl). Nutritional risk index (NRI)=15.19×serum albumin concentration (g/dl)+41.7×present weight/usual weight. Geriatric nutritional risk index (GNRI)=14.89×serum albumin concentration (g/dl)+41.7×present weight/ideal weight. Ideal weight was calculated as follows: height(cm)-100-[(height(cm)-150)/4] for men and height(cm)-100-[(height(cm)-150)/2.5] for women., Results: In common with all nutritional indices (PNI, NRI and GNRI), the low-nutritional index group had significantly lower relapse-free and overall survival rates than the high-nutritional index group. Furthermore, a subgroup analysis according to the NRI showed the association of the NRI with the patient prognosis for each stage., Conclusion: The preoperative nutritional status may have a close relationship with the prognosis in patients who receive curative surgery for colorectal cancer., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Systemic inflammation is recognized as a hallmark of cancer that contributes to tumor development and progression in various malignancies. The Naples prognostic score (NPS) was established as a prognostic indicator for colorectal cancer (CRC). This study aims to examine the predictive value of the NPS for survival in CRC patients undergoing curative resection by a propensity score matching (PSM) analysis., Methods: A total of 533 CRC patients were enrolled in this study. Overall survival (OS) and disease-free survival (DFS) were compared between high-NPS and low-NPS groups. A time-dependent receiver operator characteristic (ROC) curve analysis was conducted to calculate the area under curve (AUC) of the NPS for OS. A multivariable Cox-proportional hazards regression analysis and PSM analysis were used to identify independent prognostic factors for OS and DFS. We compared the predictive value of the NPS to that of the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), Onodera prognostic nutritional index (PNI), and controlling nutritional status score (CONUT) for OS., Results: High-NPS was significantly associated with worse OS and DFS. After PSM, 123 patients were included in each group. A multivariate analysis revealed that Age ≥ 68, ASA-PS ≥ 3, high NPS and undifferentiated tumor type were independently associated with OS, while high NPS, advanced T and N stage were independently associated with DFS after PSM. The NPS had the greatest AUC for OS in comparison to the NLR, LMR, PNI and CONUT., Conclusions: We successfully validated the prognostic utility of the NPS for CRC patients after curative resection., (© 2023. The Author(s).)

Mesenchymal colorectal cancer (mCRC) is microsatellite stable (MSS), highly desmoplastic, with CD8 + T cells excluded to the stromal periphery, resistant to immunotherapy, and driven by low levels of the atypical protein kinase Cs (aPKCs) in the intestinal epithelium. We show here that a salient feature of these tumors is the accumulation of hyaluronan (HA) which, along with reduced aPKC levels, predicts poor survival. HA promotes epithelial heterogeneity and the emergence of a tumor fetal metaplastic cell (TFMC) population endowed with invasive cancer features through a network of interactions with activated fibroblasts. TFMCs are sensitive to HA deposition, and their metaplastic markers have prognostic value. We demonstrate that in vivo HA degradation with a clinical dose of hyaluronidase impairs mCRC tumorigenesis and liver metastasis and enables immune checkpoint blockade therapy by promoting the recruitment of B and CD8 + T cells, including a proportion with resident memory features, and by blocking immunosuppression., Competing Interests: Declaration of interests A.M.-O., A.D., Y.N., J.M., and M.T.D.-M. are co-inventors of Weill Cornell Medicine patent applications covering methods for treating mesenchymal colorectal cancer. J.M., M.T.D.-M., and D.S. are co-founders of Zelambio., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background/aim: Predictive markers for survival and therapeutic efficacy in stage IV colorectal cancer have not been established. As described in our previous report, D-dimer levels may have potential utility as an indicator of cancer activity. The present study evaluated the significance of the D-dimer level as a marker for the survival and treatment outcomes in patients with stage IV colorectal cancer., Patients and Methods: A total of 34 patients who underwent surgery for stage IV colorectal cancer between February 2017 and October 2019 were enrolled. The D-dimer level was measured using a blood sample obtained at the first visit to our hospital., Results: The median preoperative D-dimer level was 1.2 μg/ml (range=0.5-41.0 μg/ml). We divided patients into two groups using a D-dimer level of 2.0 μg/ml as the cut-off value based on receiver operating characteristic curve analysis. The group with a high-D-dimer-level had a significantly shorter overall survival than that with a low D-dimer level. Progression-free survival after first-line chemotherapy tended to be better in those with a low D-dimer level group than in the high-D-dimer-level group., Conclusion: The preoperative D-dimer level may be a useful indicator for survival and chemotherapeutic outcome in patients with stage IV colorectal cancer., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Postoperative complications of colorectal cancer mainly include infections (surgical site infection, remote infection, etc.), post-operative ileus (POI), and anastomosis leakage. POI reportedly prolongs the hospital stay and increases medical costs. Therefore, predicting POI is very important. There have been some reports on the relationships between sarcopenia and postoperative complications in colorectal cancer patients, but none have been limited to POI. We therefore conducted a retrospective clinical study with a logistic regression analysis to confirm the risk factors for ileus after colorectal cancer surgery., Methods: We retrospectively analyzed 213 patients who underwent elective oncological colorectal surgery for colorectal cancer from November 2017 to July 2021. The skeletal muscle mass (SMM, kg) was estimated using a whole-body bioelectrical impedance analysis (BIA), and the skeletal muscle index (SMI) was calculated as the SMM/height 2 . We divided all patients into 2 groups based on a low SMI (male < 8.958 kg/m 2 , female < 8.443 kg/m 2 ) or normal SMI. Preoperative and intraoperative factors as well as, postoperative outcomes were then compared between the two groups., Results: The median (range) age of the 213 included patients was 72.0 (33-91) years old. Complications were noted in 96 patients (45.1%), including 21 (9.9%) with POI. There were 68 (31.9%) low SMI patients. POI occurred significantly more frequently in low SMI patients (19.1%) than in normal SMI patients (5.5%) (p = 0.005). In the multivariate analysis, bleeding (p = 0.039) and a low SMI (p = 0.031) were significantly associated with POI. In addition, a propensity score matching analysis was performed to further reduce the selection bias. As a result, a low SMI was the only independent POI predictor among the 78 matched cases., Conclusion: A preoperative low SMI in colorectal cancer patients was considered a risk factor for POI., (© 2022. The Author(s).)

Background: The surgical Apgar score (SAS) predicts postoperative complications (POCs) following gastrointestinal surgery. Recently, the SAS was reported to be a predictor of not only POCs but also prognosis. However, the impact of the SAS on oncological outcomes in patients with colorectal cancer (CRC) has not been fully examined. The present study therefore explored the oncological significance of the SAS in patients with CRC, using a propensity score matching (PSM) method., Methods: We retrospectively analyzed 639 patients who underwent radical surgery for CRC. The SAS was calculated based on three intraoperative parameters: estimated blood loss, lowest mean arterial pressure, and lowest heart rate. All patients were classified into 2 groups based on the SAS (≤6 and >6). The association of the SAS with the recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS) was analyzed., Results: After PSM, each group included 156 patients. Univariate analyses revealed that a lower SAS (≤6) was significantly associated with a worse OS and CSS. A multivariate analysis revealed that the age ≥75 years old, ASA-Physical Status ≥3, SAS ≤6, histologically undifferentiated tumor type, and an advanced pStage were independent factors for the OS, and open surgery, a SAS ≤6, histologically undifferentiated tumor type and advanced pStage were independent factors for the CSS., Conclusions: A lower SAS (≤6) was an independent prognostic factor for not only the OS but also the CSS in patients with CRC, suggesting that the SAS might be a useful biomarker predicting oncological outcomes in patients with CRC., (© 2022. The Author(s).)

We examined the controlling nutritional status(CONUT)score and the long-term prognosis of colorectal cancer surgery cases. We retrospectively examined the prognosis of colorectal cancer patients who underwent surgery between January 2013 and December 2015. We targeted 449 patients who were able to calculate the CONUT score. A total of 266 patients (59.2%)had normal nutritional status(1 or less)and 183 patients(40.8%)had mildly poor or worse nutritional status (2 or more). The CONUT score was calculated through preoperative blood tests. The relationship between the CONUT score and overall survival was examined in the low and high groups. Overall survival was significantly shorter in the high group but relapse-free survival did not differ significantly between the 2 groups. There was no difference in cancer-specific survival between the 2 groups, but the survival time due to death from other diseases was significantly shorter in the high group. The CONUT score obtained from preoperative blood sampling suggested that the overall survival time was short in the malnourished group, and that it could be used as an index of prognosis due to death from other diseases.

This study aimed to assess short-term and long-term outcomes and to identify the factors that affect outcomes for patients with colorectal cancer aged 80 years or older. Two hundred patients with colorectal cancer who were underwent resection of the primary tumor between January 2013 and December 2018 were enrolled. Short-term outcomes of elderly patients with poor PS and of those who take antithrombotic agents and of those who were underwent open surgery were poor. Long-term outcomes of elderly patients with high GNRI and of those who were underwent D3 lymph nodes dissection were better. Laparoscopic surgery with D3 lymph nodes dissection for elderly patients who were more than 80 years old should be useful to improve short- and long-term outcomes. GNRI might be a prognostic predictive factor for patients with colorectal cancer aged 80 years or older.

Background/aim: The identification of risk factors for recurrence after resection of colorectal liver metastasis is necessary in order to establish a more effective treatment strategy. In addition to well-known prognostic factors, such as the tumor diameter and number of metastatic tumors, a large amount of intraoperative blood loss (IBL) and blood transfusion have recently been reported to be associated with shorter long-term survival. The aim of this study was to assess the impact of IBL and blood transfusion on the prognosis of colorectal liver metastasis after curative resection., Patients and Methods: A total of 104 patients who underwent R0 resection for colorectal liver metastasis were enrolled in this study., Results: The high-IBL (>300 ml) group had significantly shorter relapse-free survival after hepatic resection in comparison to the low-IBL (≤300 ml) group (p=0.0025). Patients with blood transfusion had significantly shorter relapse-free survival after hepatic resection in comparison to patients without blood transfusion (p=0.0026)., Conclusion: A large amount of IBL and blood transfusion may have a negative impact on long-term survival in patients who undergo hepatic resection for colorectal liver metastasis., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Blood transfusion and a large amount of intraoperative blood loss (IBL) have been reported to have a negative impact on long-term survival via immunosuppression. In recent years, thanks to the spread of laparoscopic surgery and the development of surgical devices, the average amount of IBL has decreased, as has the need for perioperative blood transfusion. Under such conditions, the prognostic significance of the amount of IBL is unclear. The aim of this study was to assess the impact of the amount of IBL on long-term survival., Patients and Methods: A total of 277 patients who underwent laparoscopic surgery for stage II/III colorectal cancer were enrolled., Results: The median amount of IBL was 30 ml, and 16 patients received blood transfusion. The overall survival rates were significantly better in the low-IBL (≤100 ml) group than in the high-IBL (>100 ml) group regardless of the blood transfusion. As the amount of IBL increased, the decline rate of the peripheral lymphocyte count increased., Conclusion: A large amount of IBL was associated with poor long-term survival, regardless of blood transfusion, in patients with colorectal cancer., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The tumor microenvironment plays an important role in tumor progression. Tumor-associated macrophages (TAMs) have been reported to promote proliferation, invasion, metastasis, angiogenesis, and immunosuppression. Furthermore, angiogenesis has been reported to induce chemoresistance due to the inefficient distribution of drugs to cancer cells. However, the impact of TAMs on chemoresistance via angiogenesis in colorectal cancer (CRC) remains unclear. The aim of the study was to evaluate the impact of TAMs on the chemotherapeutic outcome in CRC., Patients and Methods: We enrolled 54 patients who underwent chemotherapy for unresectable metastatic CRC after resection of the primary tumor. We evaluated the density of TAMs and the degree of angiogenesis by immunohistochemistry and then explored the correlation between the density of TAMs and chemotherapeutic outcome. Furthermore, we assessed any correlation between the density of TAMs and that of neovascularity., Results: The high-TAMs group had a significantly worse progression-free survival (p=0.0006) and a poorer response rate (p=0.0274) than the low-TAMs group. In addition, a positive correlation was observed between the density of TAMs and the degree of neovascularity (r=0.665, p=0.0004)., Conclusion: TAMs were shown to promote chemoresistance via angiogenesis in CRC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab is the preferred first-line treatment for right-sided metastatic colorectal cancer with RAS mutation. However, severe adverse events are common in Japanese patients. We report the successful management of multiple stage IV colorectal cancers in a patient who received multidisciplinary treatment, including chemotherapy and Japanese Kampo medicine. A 68-year-old man presented with epigastralgia and appetite loss and was diagnosed with multiple stage IV colorectal cancers. Colonoscopy identified type II tumors in the ascending colon, sigmoid colon, and upper rectum. Histopathological examination of a biopsy specimen revealed well- to moderately differentiated tubular adenocarcinoma. Enhanced computed tomography of the thorax and abdomen showed multiple pulmonary nodules and para-aortic lymph node swelling. Laparoscopic loop-ileostomy was performed to avoid bowel obstruction due to severe stenosis of ascending colon cancer. Intraoperative observation revealed two white nodules suggestive of metastasis in the lateral area of the liver. Therefore, we diagnosed multiple stage IV colorectal cancers with multiple metastases (lung, liver, and distant lymph nodes). His postoperative course was uneventful, and chemotherapy was started. Since the cancer cells harbored a RAS mutation, he received FOLFOXIRI plus bevacizumab. Japanese Kampo medicine consisting of Hangeshashinto and Juzen-taiho-to, to prevent diarrhea and fatigue, was administered daily. After 12 courses of chemotherapy, though circumferential stenosis still existed in the ascending colon, the tumors in the sigmoid colon and upper rectum were unclear. Enhanced computed tomography showed shrinkage of the pulmonary nodules and para-aortic lymph node; therefore, laparoscopic-assisted ileocecal resection was performed. The postoperative histopathological examination revealed moderately differentiated adenocarcinoma. The patient recovered uneventfully, and Kampo medicine consisting of Ninjin'yoeito was administered for postoperative weakness. Administration of adjuvant chemotherapy in this patient led to a near complete response that has been maintained without recurrence for 2 years and 8 months without reduced quality of life., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Tumor-infiltrating lymphocytes (TILs) have been reported to reflect the anti-tumor immune status. However, recent investigations have demonstrated that intratumoral fibrosis is important as a factor affecting the infiltration of TILs. This study investigated the organ specificities of TIL infiltration and intratumoral fibrosis in primary colorectal cancer and distant metastases, as well as the relationship between the distribution of TILs and intratumoral fibrosis., Methods: Patients who underwent resection of primary tumors or distant metastases for colorectal cancer with distant metastases were enrolled. We evaluated the TIL infiltration by immunohistochemical staining with CD3&CD8 and intratumoral fibrosis by immunohistochemical staining with α-SMA positive cancer-associated fibroblasts and Masson's trichrome staining against collagen fibers. The "ImageJ" was used to evaluate fibrosis, and the density of TILs in the dense and sparse areas of fibrosis was calculated. The Immunoscore (IS) was obtained based on the density of CD3+/CD8+TILs in the tumor center and invasive margin of the primary tumor., Results: The degree of CD3+/CD8+TIL infiltration in peritoneal metastases was significantly lower than that in liver and lung metastases. The area ratio of α-SMA positive cancer-associated fibroblasts and collagen fibers in peritoneal metastases was significantly higher than that of liver and lung metastases. Furthermore, the density of TILs in the high-fibrosis area was significantly lower than that in the low-fibrosis area. In the high-IS group of primary tumors, the degree of TIL infiltration in distant metastases was significantly higher than that in the low-IS group., Conclusion: The infiltration of T lymphocytes into tumors is prevented in peritoneal metastases of colorectal cancer due to the high intratumoral fibrosis, which may lead to treatment resistance and a poor prognosis., Competing Interests: The authors have declared that no competing interests exist.

Background/aim: No biomarkers that predict the benefit from anti-vascular endothelial growth factor (VEGF) antibodies have been identified. It is necessary to discover biomarkers that can identify patients who are more likely to benefit from bevacizumab-containing treatment, especially those who are more likely to benefit from treatment with bevacizumab beyond progression (BBP). Levels of serum lactate dehydrogenase (LDH), reported to be an indirect marker of hypoxia and angiogenesis, may be a useful marker for monitoring the efficacy of suppression of angiogenesis., Patients and Methods: The clinical data of 91 patients with unresectable metastatic colorectal cancer who were treated with bevacizumab-containing chemotherapy as first-line treatment were collected and studied., Results: In the second-line treatment, the bevacizumab plus chemotherapy group showed significantly better progression-free survival (PFS) in comparison to the chemotherapy-alone group in patients with low post-first-line-treatment serum LDH levels. On the other hand, no significant differences in the PFS rate were observed between the two groups in patients with high post-first-line-treatment serum LDH levels., Conclusion: The post-first-line-treatment serum LDH levels may, therefore, be useful marker for predicting the efficacy of treatment with BBP., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The aim of this study was to investigate the efficacy and safety of adjuvant chemotherapy in elderly patients with stage III colorectal cancer in a real-world setting., Patients and Methods: A total of 165 patients of ≥70 years of age with stage III colorectal cancer who underwent a curative operation between 2008 and 2020 were enrolled in this study., Results: Among septuagenarians, the relapse-free and overall survival rates in the single-agent therapy group and the combination therapy group were significantly better than those in the group treated by surgery alone. However, no significant differences were observed in the relapse-free and overall survival rates of the single-agent therapy group and the combination therapy group. Among octogenarians in whom all regimens were single-agent therapy, adjuvant chemotherapy tended to improve the relapse-free and overall survival rates but not the time to recurrence or cancer-specific survival., Conclusion: Single-agent adjuvant chemotherapy may be a useful treatment option for septuagenarians with stage III colorectal cancer. However, the efficacy of adjuvant chemotherapy in octogenarians was not shown in this study., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Recently, elevated levels of postoperative inflammatory markers have been reported to be associated with poorer long-term survival outcomes, regardless of the occurrence of infectious complications, in gastroenterological malignancies. The aim of this study was to evaluate the association between postoperative inflammation and shorter long-term survival after resection of colorectal liver metastases., Patients and Methods: A total of 104 patients who underwent R0 resection for colorectal liver metastases were enrolled. The CRP max levels were defined as the highest postoperative serum C-reactive protein levels during hospital stay., Results: The high-CRP max group had a significantly lower relapse-free survival rate than the low-CRP max group, regardless of the occurrence of infectious complications., Conclusion: In colorectal liver metastasis as well as other malignancies, elevated postoperative levels of serum C-reactive protein are associated with shorter long-term survival, regardless of the occurrence of infectious complications., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A 66‒year‒old man was admitted to our hospital because of anemia and a positive fecal occult blood test in the medical examination. Colonoscopy revealed a type 2 advanced sigmoid colon cancer with circular stenosis. Computed tomography (CT)colonography was performed to examine the oral colon. The apple core signs were found both in the sigmoid and transverse colon. We diagnosed a double colon cancer and performed a laparoscopic left hemicolectomy and sigmoidectomy. The tumor was histopathologically diagnosed as a multiple cancer including a transverse and a sigmoid colon cancer. Although evaluations of the intestine for colon cancer with stenosis are performed by enema examination or endoscopic examination after colon stent placement, both examinations are invasive. CT colonography is considered to be a minimally invasive and an effective preoperative examination for colorectal cancer with stenosis.

Background/aim: The neutrophil-to-lymphocyte ratio (NLR) and the density of tumor-infiltrating lymphocytes (TILs) have been reported as immunological prognostic factors for various cancers. We evaluated the association between the prognosis and the immunological status in patients who underwent complete resection of pulmonary metastases of colorectal cancer (CRC)., Patients and Methods: We evaluated the associations between the NLR before the resection of pulmonary metastases and the relapse-free survival (RFS) or overall survival (OS), or between the density of TILs in the pulmonary metastasis and the RFS or OS., Results: The RFS and OS were significantly worse in the NLR-High group than in the NLR-Low group. The RFS was significantly longer in the CD3 + TILs-High group than in the CD3 + TILs-Low group., Conclusion: The NLR and the density of TILs may have prognostic significance in patients who undergo complete resection of pulmonary metastases of CRC., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: We previously showed that an elevated postoperative serum C-reactive protein (CRP) level has a negative impact on long-term survival outcomes, regardless of the occurrence of infectious complications in colorectal cancer. However, the cause of postoperative inflammation could not be properly evaluated, because patient background factors, such as the surgical approach (open/laparoscopic), were not unified., Patients and Methods: A total of 277 patients who underwent laparoscopic surgery for stage II/III colorectal cancer were enrolled., Results: The high-CRP group had lower relapse-free and overall survival rates in comparison to the low-CRP group. A high postoperative serum CRP level was significantly associated with a larger tumor diameter and longer operation time, and tended to be associated with a higher T stage and larger amount of bleeding., Conclusion: Larger tumor volume, longer operation time and larger amount of bleeding were associated with the promotion of postoperative inflammation, which worsened long-term survival outcomes in colorectal cancer., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

We examined 22 cases who underwent preoperative chemotherapy in our hospital from 2013 April to 2018 December. Seven patients were treated as neoadjuvant chemotherapy(NAC). Out of 15 patients with unresectable diseases before chemotherapy, 6 patients were able to R0 resection after chemotherapy(conversion). Although only one patients was underwent RM1 resection, the other patients were underwent RM0 resection. The median overall survival was 42 months in NAC group, 28 months in conversion group, and 17 months in palliative resection group, respectively. Recurrence was observed in 1 patient in NAC group, however, all patients had recurrent disease in conversion group. In this study, although further examination should be done according to the clinical significance of preoperative chemotherapy, preoperative chemotherapy may be carried out without severe adverse event and severe postoperative complication.

Background/aim: The efficacy of trifluridine/thymidine phosphorylase inhibitor (FTD/TPI) plus bevacizumab as later-line treatment for metastatic colorectal cancer (mCRC) has been demonstrated. However, little is known about the impact of a usage history of bevacizumab in front-line treatment on the clinical benefit of combining bevacizumab with FTD/TPI., Patients and Methods: A total of 62 patients with mCRC treated with FTD/TPI±bevacizumab was enrolled and assessed for chemotherapeutic efficacy and adverse events., Results: Regardless of the usage history of bevacizumab in front-line treatment, the FTD/TPI plus bevacizumab group had a significantly better progression-free survival rate than the FTD/TPI monotherapy group, and no significant differences in the safety profile were observed between the two groups., Conclusion: Combining bevacizumab with FTD/TPI improves the survival outcomes with manageable toxicity, regardless of the usage history of bevacizumab in front-line treatment, in patients with mCRC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Inflammation is known to promote the progression of cancer, and there is increasing evidence that inflammation caused by the antitumor response of the host and post-operative infectious complications worsens the prognosis for colorectal cancer. However, the impact of post-operative inflammation caused by surgical stress on long-term survival is unclear., Patients and Methods: A total of 274 patients who underwent curative operation for stage II/III colorectal cancer were enrolled and assessed for the serum C-reactive protein (CRP) levels on postoperative day (POD) 1 and 7 and postoperative infectious complications., Results: The high POD-1 CRP group had a significantly lower relapse-free and overall survival rate than the low POD-1 CRP group. Similarly, the high POD-7 CRP group had a significantly lower relapse-free and overall survival rate than the low POD-7 CRP group. Sub-group analysis limited to patients without postoperative infectious complications indicated that the high POD-7 CRP group tended to have a lower relapse-free survival rate and a significantly lower overall survival rate than the low POD-7 CRP group., Conclusion: Inflammation caused by postoperative infectious complications and by surgical stress worsens long-term survival outcomes after a curative operation for colorectal cancer., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Growing evidence indicates that inflammation contributes to cancer progression, and several inflammatory markers have been reported to be associated with the clinical outcomes in patients with various types of cancer. Recently, the advanced lung cancer inflammation index (ALI) has been developed as a prognostic marker in patients with lung cancer. The difference between the ALI and the inflammatory markers reported in the previous studies is that the ALI contains not only indices related to inflammation but also the body mass index (BMI), which was reported to correlate with the sarcopenic status. The aim of this study was to evaluate the prognostic significance of the ALI in patients with unresectable metastatic colorectal cancer., Methods: We retrospectively reviewed a database of 159 patients who underwent combination chemotherapy for unresectable metastatic colorectal cancer between 2008 and 2016. The BMI was calculated by dividing the weight by height squared. The neutrophil-to-lymphocyte ratio (NLR) was calculated from a blood sample by dividing the absolute neutrophil count by the absolute lymphocyte count. The ALI was defined as follows: ALI=BMI × serum albumin concentration/NLR., Results: The overall survival rate was significantly worse in the low-ALI group than in the high-ALI group (p < 0.0001). Furthermore, the ALI was an independent prognostic factor for the overall survival (hazard ratio: 2.773, 95% confidence interval: 1.773-4.335, p < 0.001)., Conclusions: A newly developed prognostic marker, the ALI, was found to be a novel prognostic marker in patients with unresectable metastatic colorectal cancer as well as in patients with lung cancer.

Background/aim: New drugs for metastatic colorectal cancer (mCRC) have been recently developed for use in later-line chemotherapy and have contributed to further prolongation of the survival of patients. However, in later-line chemotherapy, treatment failure may lead to discontinuation of chemotherapy and the transition to best supportive care. Therefore, a biomarker able to predict the effects of later-line chemotherapy is required. The C-reactive protein-to-albumin ratio (CAR), which is an inflammatory marker, has been reported to correlate with therapeutic outcome in patients with mCRC who underwent first-line chemotherapy. However, the significance of the CAR as a marker for predicting the chemotherapeutic outcome in patients with mCRC treated with later-line chemotherapy is unknown., Patients and Methods: We retrospectively reviewed the medical records of 40 patients with mCRC who were treated with trifluridine/thymidine phosphorylase inhibitor (FTD/TPI) as a later-line chemotherapy. The CAR was calculated from the blood samples obtained within 1 week before the initiation of FTD/TPI by dividing the serum C-reactive protein level by the serum albumin level., Results: According to the receiver operating characteristic curve analysis, we set 0.122 as the CAR cut-off, and patients were classified into groups with high or low CAR. The low-CAR group had a significantly higher disease control rate than the high-CAR group. The progression-free and overall survival rates were significantly better in the low-CAR group than in the high-CAR group. A high-CAR was associated with a greater number of prior regimens, higher serum lactate dehydrogenase level and more organs with metastases, considered to be correlated with the rate of disease progression. However, no significant differences were observed in the incidence of grade 3 or more adverse events, the relative dose intensity, or the rate of discontinuing chemotherapy between the two groups., Conclusion: The CAR may be a useful indicator for predicting the chemotherapeutic outcome in patients with mCRC treated with FTD/TPI as a late-line chemotherapy. The correlation between a high-CAR and poor prognosis was presumed to be due to the rate of cancer growth and increased resistance to chemotherapy rather than an insufficient dose of the drug., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The density of tumor-infiltrating lymphocytes has been reported to reflect the antitumor immune status, and many reports have shown that tumor-infiltrating CD8 + and total T-lymphocytes may be strong prognostic biomarkers in colorectal cancer. We previously reported that the density of tumor-infiltrating immune cells in hematoxylin and eosin (H&E)-stained sections may be an easily available prognostic biomarker. However, it remains unclear whether the density of tumor-infiltrating immune cells in H&E-stained sections accurately reflects the antitumor immune status., Patients and Methods: A total of 308 patients who underwent curative resection for stage II/III colorectal cancer were enrolled. The density of both tumor-infiltrating immune cells in H&E-stained sections and tumor-infiltrating lymphocyte subsets was assessed by immunohistochemistry., Results: The density of tumor-infiltrating immune cells in H&E-stained sections was significantly and positively correlated with that of tumor-infiltrating CD4 + /CD8 + /total T-lymphocytes., Conclusion: The density of tumor-infiltrating immune cells in H&E-stained sections may be a reasonable immunological biomarker., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Numerous reports indicate that tumor-infiltrating lymphocytes (TILs) are a prognostic factor in various cancers and that they must be good biomarkers. However, the methods of evaluating TILs differ in each study; thus, there is not yet a standardized methodology for evaluating TILs. The purpose of this study is to evaluate the prognostic significance of tumor-infiltrating lymphocytes (TILs) in patients with colorectal cancer (CRC) using the new method proposed by the International TILs Working Group in breast cancer and to standardize the method of evaluating TILs in CRC., Methods: We retrospectively reviewed a database of 160 patients with Stage II or III CRC. The density of TILs was assessed by measuring the area occupied by mononuclear cells over the stromal area on hematoxylin and eosin (H-E)-stained sections. We set 42% as the cut-off percentage of the area occupied by TILs according to the receiver operating characteristic curve, and we classified patients into the high-TILs and the low-TILs groups., Results: The rates of relapse-free survival (RFS) and overall survival (OS) in the high-TILs group were significantly higher than those in the low-TILs group. A multivariate analysis showed that the density of TILs was independently associated with RFS and OS. Moreover, the density of TILs assessed by an observer was significantly associated with the density of TILs assessed by the automated imaging software program., Conclusions: The new method for evaluating TILs, which was recommended by the International TILs Working Group in breast cancer, might be a useful predictive factor in colorectal cancer patients.

Background: The anticancer immune response has been reported to correlate with cancer progression. Tumor-infiltrating lymphocytes (TILs), which are one of the indicators of host immunity, affect the tumor growth, metastasis and chemoresistance. Both TILs in the primary tumor and those in the metastatic tumor have been reported to be a useful predictor of the survival and therapeutic outcome. However, the correlation between the density of TILs in the primary and metastatic tumor is unclear. The aim of this study was to elucidate the correlation between the density of TILs in the primary and metastatic tumor., Methods: A total of 24 patients with stage IV colorectal cancer who underwent concurrent resection of the primary tumor and liver metastasis were enrolled in order to assess the correlation between the density of TILs in the primary tumor and that in the metastatic tumor. Hematoxylin and eosin (HE)-stained tumor sections were used for the evaluation of TILs. The density of TILs was assessed by the measurement of the area occupied by mononuclear inflammatory cells over the total stromal area at the invasive margin. In addition, to evaluate TIL subsets and the activation/suppression status of the lymphocytes, immunohistochemistry for CD4, CD8, Forkhead boxprotein P3 (FOXP3), programmed cell death 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), inducible T-cell co-stimulator (ICOS), Glucocorticoid induced tumor necrosis factor receptor related protein (GITR), Human Leukocyte Antigen - antigen D Related (HLA-DR) and Granzyme B was performed, and the number of immunoreactive lymphocytes was counted., Results: According to the evaluation using the HE-stained sections, the density of tumor-infiltrating mononuclear inflammatory cells in the primary tumor was significantly associated with that in the metastatic tumor. In addition, according to the immunohistochemistry evaluation, the density of CD4 + , CD8 + and FOXP3 + TILs in the primary tumor and that in the metastatic tumor were significantly correlated with that in the metastatic tumor. Furthermore, the activation/suppression marker values of the lymphocytes (i.e., such as PD-1, ICOS, Granzyme B and the PD-1/CD8 ratio) in the primary tumor were correlated with values in the metastatic tumor., Conclusions: The local immune status of the primary tumor was revealed to be similar to that of the metastatic tumor. This suggests that the evaluation of the local immunity of the primary tumor may be a substitute for the evaluation of the local immunity of the metastatic lesion. Therefore, information on the primary tumor may be useful when considering treatment strategies for metastatic lesions.

Background: miR-96 is reported to inhibit reversion cysteine-rich Kazal motif (RECK), which is associated with tumor invasion, in solid cancer types (e.g. breast cancer, non-small cell lung cancer, esophageal cancer). The purpose of this study is to clarify whether miR-96 is similarly associated with tumor invasion in colorectal cancer., Materials and Methods: We performed western blotting to investigate the expression of RECK when miR-96 mimics or inhibitors were transferred into HCT-116 colorectal cancer cells. The RECK mRNA level was assessed by a reverse transcription polymerase chain reaction. An invasion assay was used to evaluate tumor invasion., Results: The expression of RECK was inhibited by the transfection of miR-96 mimics. RECK mRNA level was reduced by miR-96 mimics and increased by miR-96 inhibitor. In the invasion assay, miR-96 mimics were shown to promote tumor invasion., Conclusion: miR-96 may be associated with tumor invasion through inhibition of RECK expression in colorectal cancer., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The anticancer immune response has been reported to contribute to the success of chemotherapy. The aim of this study was to evaluate the significance of the measurement of tumor-infiltrating lymphocytes (TILs) in the primary tumor using the method proposed by the International TILs Working Group as a prognostic marker of chemotherapeutic outcomes in patients with stage IV colorectal cancer (CRC)., Patients and Methods: A total of 57 patients with stage IV CRC who underwent palliative chemotherapy after resection of the primary tumor were enrolled. Hematoxylin and eosin (H-E)-stained tumor sections were used for the evaluation of TILs. The density of TILs was assessed by measuring the area occupied by mononuclear inflammatory cells over the total stromal area at the invasive margin. Immunohistochemistry for CD8 was also performed, and the number of immunoreactive cytotoxic T-lymphocytes (CTLs) at the invasive margin was counted., Results: Thirty patients were classified into the high-TILs group, and 27 patients were classified into the low-TILs group. The high-TILs group had a significantly higher chemotherapeutic response rate (79.3% vs. 48.1%, p=0.025) and better progression-free survival (median survival time: 10.1 m vs. 7.3 m, p=0.0133) than the low-TILs group. Furthermore, the high-TILs group had a significantly better overall survival than the low-TILs group (median survival time: 35.5 m vs. 22.4 m, p=0.0221). The density of TILs evaluated using the H-E-stained sections showed a strong association with the number of CTLs (p<0.001)., Conclusion: The measurement of TILs in the primary tumor using the method proposed by the International TILs Working Group can be used as a prognostic marker of the clinical effectiveness of palliative chemotherapy in patients with stage IV CRC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Tumor-infiltrating lymphocytes (TILs) have been reported to reflect the antitumor immunity of the host and correlate with the therapeutic outcomes and survival. Nowadays TILs are attracting attention as new biomarkers of diseases such as colorectal cancer. TILs are classified into several subsets, among which CD8 + T cells directly attack cancer cells and play a central role in antitumor immunity. A high density of CD8 + TILs has been reported to correlate with a better clinical outcome. Programmed cell death-1 (PD-1) is recognized to be a surface marker for dysfunction of T lymphocytes. However, the prognostic significance of PD-1 + TILs remains unclear. The aim of this study was to evaluate the prognostic significance of the number of PD-1 + TILs and the tumor-infiltrating PD-1 + to CD8 + lymphocyte ratio (PD-1/CD8 ratio) in patients with colorectal cancer (CRC)., Patients and Methods: A total of 90 patients with stage II/III CRC who underwent curative surgery were enrolled in this study. Immunohistochemistry was used to assess the densities of PD-1 + TILs and CD8 + TILs. The PD-1/CD8 ratio was defined as the number of PD-1 + TILs divided by the number of CD8 + TILs. The optimum cut-off value for the number of PD-1 + TILs and the PD-1/CD8 ratio was determined via a receiver operating characteristic analysis. We then assessed the prognostic significance of the number of PD-1 + TILs and the PD-1/CD8 ratio., Results: The relapse-free and overall survival rates were significantly worse in the high-PD-1/CD8 ratio group than in the low-PD-1/CD8 ratio group (relapse-free survival: p=0.0257, overall survival: p=0.0363), although the number of PD-1 + TILs showed no prognostic significance., Conclusion: The PD-1/CD8 ratio may, therefore, be a useful prognostic marker for stage II/III CRC. What is important for predicting the prognosis may be the PD-1/CD8 ratio rather than the absolute number of PD-1 + TILs., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Inflammation is widely recognized to play an important role in cancer progression, and the peripheral monocyte count has been reported to correlate with the prognosis in patients with colorectal cancer. This is based on the hypothesis that the peripheral monocyte level and the density of tumor-associated macrophages (TAMs) in the cancer microenvironment correlate with each other. However, the influence of TAMs on the prognosis and the correlation between the peripheral monocyte count and the density of TAMs have not yet been elucidated., Methods: A total of 168 patients with stage II/III colorectal cancer were enrolled in this study. Preoperative blood samples were obtained at the time of the diagnosis before surgery. The expression of TAMs in the cancer microenvironment was assessed by immunohistochemistry., Results: The progression-free and overall survival rate were significantly worse in the high-TAMs group than in the low-TAMs group (p = 0.0012 and p = 0.0207, respectively). The peripheral monocyte count was significantly associated with the number of TAMs (correlation coefficients: 0.202, p = 0.047)., Conclusions: The peripheral monocyte count was associated with the density of the TAMs, which created a microenvironment favorable for cancer development and were correlated with a poor prognosis. Therefore, the peripheral monocyte count is a useful prognostic marker reflecting the status of the tumor microenvironment.

Purpose: We evaluated the prognostic significance of the peripheral lymphocyte count and lymphocyte percentage, which reflect the preoperative immune status, in patients with colorectal cancer (CRC) and then compared their accuracy as predictors of the survival., Methods: We retrospectively reviewed a database of 362 patients. We classified the patients into high lymphocyte count and low lymphocyte count groups. We also classified the patients into high lymphocyte percentage and low lymphocyte percentage groups., Results: The 5-year relapse-free survival (RFS) rate in the high lymphocyte count group tended to be higher than that in the low lymphocyte count group. The 5-year overall survival (OS) rate in the high lymphocyte count group was significantly higher than that in the low lymphocyte count group. In contrast, the 5-year RFS and OS rates in the high lymphocyte percentage group were both significantly higher than those in the low lymphocyte percentage group. A multivariate analysis showed that the lymphocyte percentage was independently associated with the OS., Conclusions: These findings suggest that the lymphocyte percentage is a good predictor of the OS and may be a stronger predictor of survival than the lymphocyte count in CRC patients.

Background: Binding to Sema4D and PlexinB1 induce angiogenesis and invasive growth in colorectal cancer (CRC). The expression of Semaphorin4D (Sema4D) and PlexinB1 has been shown to be related to the prognosis of patients with various malignancies. However, the correlation between the expression of Sema4D and PlexinB1 and the relapse-free survival in patients with colorectal cancer remains controversial., Methods: The study population included patients who underwent surgery for colorectal cancer (n = 226). The expression of Sema4D and PlexinB1 were analyzed by immunohistochemistry in tissue of stage I, II, and III colon cancers., Results: The immunohistochemical staining of colorectal cancer tissue specimens revealed that 95 (42 %) and 105 (46.4 %) of the specimens were positive for Sema4D and PlexinB1. The expression of Sema4D and PlexinB1 respectively were both found to be significantly related to stage, depth of tumor invasion, lymph node metastasis, lymphatic invasion, and venous invasion, respectively. Sixty-three patients (27.9 %) expressed both Sema4D and PlexinB1. The positive expression of both Sema4D and PlexinB1 was found to be an independent risk factor for a worse survival (HR 1.079, CI 1.013-2.868; P = 0.044)., Conclusion: The combination of Sema4D and PlexinB1 protein detected by immunohistochemistry was therefore useful for predicting disease recurrence in CRC patients.

Background: Inflammation has been reported to play an important role in cancer progression, and several inflammatory markers, such as the neutrophil to lymphocyte ratio (NLR) and modified Glasgow prognostic score (mGPS), have been reported to be prognostic markers. The aim of this retrospective study was to evaluate the prognostic significance of the ratio of C-reactive protein to albumin (CRP/ALB ratio) in patients with colorectal cancer who undergo potentially curative surgery., Patients and Methods: A total of 705 patients who underwent potentially curative surgery for colorectal cancer were enrolled. The CRP/ALB ratio was calculated form the preoperative samples by dividing the serum C-reactive protein level by the serum albumin level. We evaluated the correlation between the CRP/ALB ratio and survival. Furthermore, we compared the accuracy of the CRP/ALB ratio as a predictor for survival with the mGPS., Results: We set 0.0271 as the cut-off value for the CRP/ALB ratio according to a receiver operating characteristic curve analysis. Based on the cut-off value of 0.0271, 347 patients were classified into the low CRP/ALB ratio group and 358 patients were classified into the high CRP/ALB ratio group. The group with high CRP/ALB ratio had significantly worse relapse-free survival (p=0.0003) and cancer-specific survival (p=0.0026) rates than those of the low CRP/ALB ratio group. According to a multivariate analysis, the CRP/ALB ratio was identified as an independent prognostic factor for relapse-free survival (p=0.025) and cancer-specific survival (p=0.045). Moreover, even in a sub-analysis limited to patients with an mGPS of 0, the high CRP/ALB ratio group had significantly worse relapse-free survival (p=0.0015) and cancer-specific survival (p=0.0131) rates than the low CRP/ALB ratio group., Conclusion: The preoperative CRP/ALB ratio is a useful prognostic marker in patients with colorectal cancer who undergo potentially curative surgery. Moreover, the CRP/ALB ratio may be superior to the mGPS for predicting survival., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: The usefulness of adjuvant chemotherapy for stage II colon cancer has not been established. Meanwhile, the presence of stage II colon cancer with high-risk factors for recurrence has been reported. To our knowledge, no prospective study of adjuvant chemotherapy for stage II colon cancer with high-risk factors has been implemented to date., Patients and Methods: This study is a prospective nonrandomized controlled study based on patients' selection of treatment option, including randomized therapeutic decision-making, to evaluate the usefulness of adjuvant chemotherapy with tegafur-uracil (UFT) with leucovorin (LV) for stage II colon cancer with high-risk factors for recurrence, compared with surgery alone. Five courses of UFT/LV therapy will be given as follows: UFT (300 mg/m(2)/d) with LV (75 mg/d) will be orally administered in 3 doses per day. Treatment will be received daily for 28 days, followed by a 7-day rest or will be received daily for 5 days, followed by a 2-day rest. For both regimens, 1 course will last 5 weeks, and 5 courses will be given. The primary end point is disease-free survival. A propensity score matching will be conducted based on 7 variables that represent risk factors to minimize selection bias in a comparison between the nonrandomized arms. For this nonrandomized comparison, a target sample size is set at 1200 (400 and 800 patients for the surgery alone and UFT/LV groups, respectively) and 1720 patients will be enrolled. In this study we aim to evaluate the therapeutic usefulness of adjuvant chemotherapy with UFT/LV for stage II colorectal cancer with risk factors for recurrence., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To evaluate the prognostic significance of the lymphocyte to monocyte ratio (LMR) in patients with unresectable metastatic colorectal cancer who received palliative chemotherapy., Methods: A total of 104 patients with unresectable metastatic colorectal cancer who underwent palliative chemotherapy were enrolled. The LMR was calculated from blood samples by dividing the absolute lymphocyte count by the absolute monocyte count. Pre-treatment LMR values were measured within one week before the initiation of chemotherapy, while post-treatment LMR values were measured eight weeks after the initiation of chemotherapy., Results: The median pre-treatment LMR was 4.16 (range: 0.58-14.06). We set 3.38 as the cut-off level based on the receiver operating characteristic curve. Based on the cut-off level of 3.38, 66 patients were classified into the high pre-treatment LMR group and 38 patients were classified into the low pre-treatment LMR group. The low pre-treatment LMR group had a significantly worse overall survival rate (P = 0.0011). Moreover, patients who demonstrated low pre-treatment LMR and normalization after treatment exhibited a better overall survival rate than the patients with low pre-treatment and post-treatment LMR values., Conclusion: The lymphocyte to monocyte ratio is a useful prognostic marker in patients with unresectable metastatic colorectal cancer who receive palliative chemotherapy.

Background: Markers of systemic inflammation, such as the neutrophil to lymphocyte ratio (NLR), C-reactive protein (CRP) level and Glasgow prognostic score (GPS), have been reported to be useful prognostic indicators for various types of cancers. However, most of the existing reports investigated the preoperative status, and the significance of markers of systemic inflammation remains unclear in patients with unresectable metastatic colorectal cancer. The aim of the present retrospective study was to evaluate the significance of markers of systemic inflammation for predicting the prognosis and chemotherapeutic outcomes and monitoring the progression of the tumor in patients with unresectable metastatic colorectal cancer receiving palliative chemotherapy., Patients and Methods: A total of 110 patients with unresectable metastatic colorectal cancer who underwent palliative chemotherapy for metastatic tumors were enrolled in the study. We evaluated the relationships between the survival/chemotherapeutic response and pre-/post-treatment markers of systemic inflammation. The pre-treatment markers of systemic inflammation were measured within one week before the initiation of chemotherapy and the post-treatment markers of systemic inflammation were measured eight weeks after initiation of chemotherapy., Results: The overall survival rates were significantly worse in the group with high pre-treatment NLR/CRP/GPS, and that with high post-treatment CRP/GPS; the progression-free survival rate was significantly worse in the high post-treatment CRP group. As for chemotherapeutic response, patients with a low post-treatment CRP level had a significantly higher disease control rate than those with a high post-treatment CRP level. Moreover, the patients with a high pre-treatment CRP level and normalization after treatment exhibited better overall and progression-free survival rates and had a significantly higher disease control rate than those with high pre- and post-treatment CRP levels., Conclusion: Pre-treatment markers of systemic inflammation are useful for predicting prognosis in patients with unresectable metastatic colorectal cancer who receive palliative chemotherapy. Moreover, the CRP level can be used as a marker for predicting chemotherapeutic outcome and monitoring the progression of the tumor., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: The preoperative prognostic nutritional index (PNI) has been reported to correlate with the prognosis in patents with various carcinomas. However, the prognostic significance of the postoperative PNI is unknown. The aim of this study was to evaluate the prognostic significance of the postoperative PNI in patients with colorectal cancer (CRC)., Methods: Two hundred and eighteen patients who underwent potentially curative surgery for stage II/III CRC were enrolled in this study. The PNI was calculated as 10 × serum albumin concentration (g/dl) + 0.005 × lymphocyte count (/mm(3)). The preoperative PNI was measured within two weeks before the operation and the postoperative PNI were measured at the first visit after leaving the hospital. We then examined the correlations between the preoperative/postoperative PNI and the prognosis for survival., Results: In the validation study, the median preoperative PNI was 47.90 (range: 32.45-61.36) and the median postoperative PNI was 48.69 (range: 32.62-66.96). According to the receiver operating characteristic (ROC) curve, we set 43.0 as the cut-off value in the validation study. For both the preoperative and postoperative PNI, the overall survival rates were significantly worse in the low PNI group in the validation study (preoperative PNI, p = 0.0374; postoperative PNI, p = 0.0005). In the multivariate analysis of the validation study, the combination of pre- and postoperative PNI was an independent predictor of poor overall survival (p = 0.006)., Conclusions: The postoperative PNI is, in addition to the preoperative PNI, a useful prognostic marker. The combination of pre- and postoperative PNI was an independent prognostic factor in patients with CRC who underwent potentially curative surgery and is important for considering the long-term outcome in patients with CRC.

Background: Recently, the preoperative immune-nutritional status has been reported to correlate with the survival rate in patients with colorectal cancer (CRC). However, there have been no reports on the relationship between the controlling nutritional status (CONUT) score and the clinical outcome after curative surgery for CRC. We herein evaluated the prognostic significance of the CONUT score in patients with CRC, and then compared the accuracy of the CONUT score and the prognostic nutritional index (PNI) as a predictor of survival., Methods: We retrospectively reviewed a database of 204 patients who underwent curative surgery for Stage II/III CRC. Patients were divided into two groups according to the CONUT score and the PNI., Results: The five-year cancer-specific survival (CSS) rate was significantly higher at 92.7% in the low CONUT group, compared to a rate of 81.0% in the high CONUT group (p=0.0016). The five-year CSS was 71.2% in the low PNI group and 92.3% in the high PNI group, which showed a significant difference (p=0.0155). A multivariate analysis showed that lymph node metastasis and the CONUT score were independent risk factors for CSS., Conclusion: This study suggested that the CONUT score is a strong independent predictor of the survival among CRC patients.

Background: Recently, a preoperative systemic inflammatory response has been reported to be a prognostic factor in patients with colorectal cancer (CRC). However, the prognostic significance of a systemic inflammatory response in the early stage after surgery in patients with CRC is unknown. The aim of this retrospective study was to evaluate the prognostic significance of a postoperative systemic inflammatory response in patients with CRC., Methods: Two hundred and fifty-four patients who underwent potentially curative surgery for stage II/III CRC were enrolled in this study. Univariate and multivariate analyses were performed to evaluate the relationship between the prognosis and clinicopathological factors, including the neutrophil-to-lymphocyte ratio (NLR) and Glasgow Prognostic Score (GPS), which were measured within two weeks before operation and at the first visit after leaving the hospital., Results: The overall survival rates were significantly worse in the high preoperative NLR/preoperative GPS/postoperative NLR group. A multivariate analysis indicated that only preoperative GPS, postoperative NLR, and the number of lymph node metastases were independent prognostic factors for a poor survival., Conclusions: The postoperative NLR is an independent prognostic factor in patients with CRC who underwent potentially curative surgery.

Background: The pretreatment albumin to globulin ratio (AGR) has been reported to correlate with the long-term survival in patients with various cancers. However, there are no reports regarding the correlation between the pretreatment AGR and chemotherapeutic outcomes in patients with unresectable metastatic colorectal cancer. The aim of this study was to evaluate the prognostic significance of the pretreatment AGR in patients with unresectable metastatic colorectal cancer., Methods: A total of 66 patients with unresectable metastatic colorectal cancer who underwent palliative chemotherapy for metastatic tumors were enrolled. The AGR was calculated as follows: Albumin/(Total protein - Albumin)., Results: The median pretreatment AGR was 1.254 (range: 0.849-1.840). We set 1.25 as the cut-off value based on the receiver operating characteristic curve. Based on the cut-off value of 1.25, 34 patients were classified into the high-AGR group and 32 patients were classified into the low-AGR group. The high-AGR group had a significantly higher chemotherapeutic disease control rate (p = 0.040) and better progression-free survival (p = 0.0171) and overall survival (p = 0.0360) rates than the low-AGR group. According to a multivariate analysis of survival, the AGR was identified to be an independent prognostic factor for progression-free survival (Hazard Ratio: 2.662, 95% Confidence Interval: 1.085-6.631, p = 0.033) and overall survival (Hazard Ratio: 2.247, 95% Confidence Interval: 1.069-4.722, p = 0.033)., Conclusions: The pretreatment AGR is a useful prognostic marker in patients with unresectable metastatic colorectal cancer who receive palliative chemotherapy.

Purpose: Previous studies have revealed that an elevated preoperative serum C-reactive protein (CRP) level is associated with a poor prognosis in patients with various malignant tumors. The aim of this study was to determine the clinical significance of the preoperative serum CRP level in patients with stage IV colorectal cancer., Methods: We enrolled 144 patients who underwent surgery for stage IV colorectal cancer. A total of 53 patients with a serum CRP level of ≥ 1.0 mg/dl were classified as the high CRP individuals. The association between the preoperative serum CRP level and survival was retrospectively assessed., Results: The cancer-specific survival of the patients with a high CRP level was significantly worse than that of the patients with a low CRP level. A multivariate analysis indicated that the curability (non-curative surgery), the number of organs with metastasis (more than one organ), the tumor diameter (≥ 5 cm), lymphatic involvement, histological differentiation (non-differentiated) and a high CRP level (≥ 1.0 mg/dl) were independent risk factors for a poor survival., Conclusions: A high preoperative serum CRP level is a convenient biomarker for identifying patients with a poor prognosis for stage IV colorectal cancer.

Purpose: Nutrition and immunity significantly affect the progression of cancer in cancer patients. Therefore, the evaluation of the nutritional and immune status would be useful as a prognostic factor and to determine the optimal treatment strategy for patients with unresectable metastatic colorectal cancer who are receiving chemotherapy. The aim of this retrospective study was to evaluate the prognostic significance of the nutritional and immune status in patients with unresectable metastatic colorectal cancer treated with chemotherapy., Methods: We retrospectively reviewed 80 patients with colorectal cancer. A total of 22 patients had metachronous unresectable cancer, and 58 patients had synchronous unresectable cancer. All patients underwent combination chemotherapy with oxaliplatin or irinotecan plus 5-fluorouracil/leucovorin as first-line chemotherapy. We then examined the correlations between the Onodera's prognostic nutritional index (OPNI) and the patients' clinicopathological features. The OPNI was calculated as follows: 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count (per mm(3)). According to the receiver operating characteristic (ROC) curve analysis, the cutoff value for OPNI was 44.5., Results: Patients with a pretreatment OPNI of ≧44.5 demonstrated a longer OS than those with a pretreatment OPNI of <44.5. Moreover, we categorized these patients into four groups according to the combination of the pre- and post-treatment OPNI. The patients in the group with both OPNIs ≥44.5 exhibited a better prognosis compared to the other group (p = 0.001)., Conclusion: The OPNI is considered to be a useful marker for predicting the long-term outcome in patients who receive chemotherapy for unresectable metastatic colorectal cancer.

Background: The function of a cysteine-glutamate exchanger (xCT) transporter is to increase the intracellular concentration of glutathione in order to protect cells from oxidative stress. In several types of cancer, xCT is thought to play a role in the onset of resistance to chemotherapy and radiotherapy. xCT is stabilized on the tumor cell surface after combining with cluster of differentiation 44 variant (CD44v)., Materials and Methods: We examined the xCT and CD44v6 expression in 304 primary tumor samples obtained from patients with colorectal cancer using immunohistochemical analysis., Results: Immunoreactivity for xCT was observed in 208 (68.4%) tumors. Among 218 patients with stage I-III disease who underwent curative surgery, the postoperative recurrence rate was 32.9% in those with xCT-positive tumors, which was significantly (p=0.003) higher than in those with xCT-negative tumors (10.7%). Immunoreactivity for CD44v6 was observed in 101 cases (33.2%), although the rate of postoperative recurrence in patients with CD44v6-positive tumors did not exhibit any significant correlation. Multivariate analyses revealed increased xCT expression to be an independent significant predictor of disease recurrence, in addition to depth of tumor invasion, lymph node metastasis and venous invasion., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aims: Previous studies have reported that elevated preoperative serum C-reactive protein (CRP) levels are associated with a poor prognosis in patients with various types of cancer. The aim of this study was to evaluate the prognostic significance of the preoperative serum CRP levels in patients with colorectal cancer and determine an appropriate cutoff value of the serum CRP level., Methodology: We enrolled 855 patients who underwent surgery for stage I-IV colorectal cancer. The median serum CRP level was 0.13 (range: 0.01-22.8). We set 0.6 as the cutoff value of the serum CRP level based on the receiver operating characteristic curve. The patients were classified into two groups according to the serum CRP level. The prognostic significance of an elevated serum CRP level was evaluated using a multivariate analysis., Results: The cancer-specific survival was significantly worse in the patients with a high serum CRP level. In particular, more significant differences were observed in the patients with stage IV disease. The multivariate analysis indicated that a high serum CRP level was an independent risk factor for poor survival., Conclusions: The preoperative serum CRP level is a convenient biomarker and predictor of a poor prognosis after surgery for colorectal cancer.