Soichiro Ishihara

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

AbstractBackgroundnRetrospective studies have shown that primary tumor resection improves the prognosis of patients with colorectal cancer with unresectable metastasis (mCRC). Prognostic significance of lymph node dissection (LND) in mCRC has not been examined previously. The aim of this study was to investigate the prognostic impact of primary tumor resection and LND in mCRC.MethodsnA total of 1,982 patients with mCRC from January 1997 to December 2007 were retrospectively studied. The impact of primary tumor resection and LND on overall survival (OS) was analyzed using Cox proportional hazards model and propensity score analysis to mitigate the selection bias. Covariates in the models for propensity scores included treatment period, institution, age, sex, carcinoembryonic antigen, tumor location, histology, depth, lymph node metastasis, lymphovascular invasion, and number of metastatic organs.ResultsIn a multivariate analysis, primary tumor resection and treatment in the latter period were associated with an improved OS, and age over 70xa0years, female sex, lymph node metastasis, and multiple organ metastasis were associated with a decreased OS. In the propensity-matched cohort, patients treated with primary tumor resection showed a significantly better OS than those without tumor resection (median OS 13.8 vs. 6.3xa0months; pxa0=xa00.0001). Furthermore, among patients treated with primary tumor resection, patients treated with D3 LND showed a significantly better OS than those with less extensive LND (median OS 17.2 vs. 13.7xa0months; pxa0<xa00.0001).ConclusionsIt was suggested that primary tumor resection with D3 LND improves the survival of patients with mCRC.

Nuclear Notch3 Expression is Associated with Tumor Recurrence in Patients with Stage II and III Colorectal Cancer

AbstractBackgroundnThe importance of Notch signaling in colorectal cancer (CRC) tumorigenesis has been recently recognized. However, the significance of Notch3 expression and its association with Notch1 expression in CRC is unclear. In the present study, we investigated Notch1 and Notch3 expression in Stage II and III CRC to assess their association with clinicopathological characteristics.nMethodsThe protein expression of Notch1 and Notch3 was examined using immunohistochemistry in 305 CRC specimens. Nuclear expression of Notch1 and Notch3 and their associations with clinicopathological characteristics and distant relapse-free survival (dRFS) were evaluated.ResultsNuclear Notch1 was overexpressed in 37xa0% of specimen, and nuclear Notch3 in 38xa0%. Nuclear Notch3 expression correlated with tumor differentiation status (Pxa0=xa00.0099). Nuclear expression of Notch1 and Notch3 was associated with tumor recurrence (Pxa0=xa00.0311 and Pxa0=xa00.0053, respectively). In multivariate analysis, nuclear Notch3 expression [hazard ratio (HR)xa0=xa01.71; 95xa0% confidence interval (CI), 1.06–2.78; Pxa0=xa00.0271), lymph node metastasis, and venous involvement were independently correlated with dRFS. In subgroup analysis, nuclear Notch3 expression was strongly associated with dRFS in Stage II CRC (HRxa0=xa03.47; 95xa0% CI 1.44–9.22; Pxa0=xa00.0055). Both nuclear Notch1 and Notch3 were positive in 67 specimens (22xa0%) and both were negative in 144 specimens (47xa0%). Coexpression of nuclear Notch1 and Notch3 had an additive effect toward poorer dRFS compared with a negative subtype (HRxa0=xa02.48; 95xa0% CI, 1.41–4.40; Pxa0=xa00.0019).ConclusionsNuclear Notch3 expression might be a novel predictive marker for recurrence in Stage II and III CRC.

Nomogram prediction of metachronous colorectal neoplasms in patients with colorectal cancer.

OBJECTIVEnTo construct a predictive model of postoperative colorectal neoplasm development using a nomogram.nnnBACKGROUNDnAlthough patients with colorectal cancer (CRC) are known to be at high risk of developing metachronous adenoma or CRC, no statistical model for predicting the incidence of postoperative colorectal lesions has been reported.nnnMETHODSnA total of 309 CRC patients who underwent surgical resection received regular endoscopic follow-up to detect the development of metachronous adenoma or adenocarcinoma. The patients were divided into the derivation set (n = 209) and the validation set (n = 100). The nomogram to predict the 3- and 5-year adenoma-free survival rates was constructed using the derivation set, and a calibration plot and concordance index (c-index) were calculated. The predictive utility of the nomogram was validated in the validation set.nnnRESULTSnSex, age, and number of synchronous lesions at the time of surgery for primary CRC were adopted as variables for the nomogram. The nomogram showed moderate calibration, with a c-index of 0.709 in the derivation set and 0.712 in the validation set.nnnCONCLUSIONSnA nomogram based on sex, age, and number of synchronous lesions at the time of surgery has the ability to predict postoperative adenoma-free survival.

Proximal Shift of Colorectal Cancer Along With Aging

INTRODUCTIONnAlthough several reports have documented the increased incidence of right-sided colorectal cancer (CRC) in the elderly, especially in women, the gender-specific, age-related changes in the characteristics of CRCs, especially related to the cancer localization, have not been fully investigated. This study evaluated the age-related changes in the clinicopathologic features of CRCs, according to the gender.nnnMATERIALS AND METHODSnA total of 1059 consecutive patients with CRCs who were admitted to the authors surgical department between February 2005 and June 2012 were retrospectively reviewed. The patients were divided into male (nxa0= 632) and female (nxa0= 427) groups and then according to the age group, and the correlation between the age group and the other clinicopathologic features was analyzed by univariate and multivariate analysis.nnnRESULTSnThe number of concomitant adenomas found was significantly increased along with increasing age in men, and the presence of concomitant adenoma was the only independent age-related factor of male CRC in the multivariate analysis (Pxa0= .0044). In contrast, in women, the location of the CRC progressively shifted to the right side (proximal colon) with increasing age, and the presence of right-sided CRC was the only independent factor of female CRC in the multivariate analysis (Pxa0< .0001).nnnCONCLUSIONnThere was a significant gender-specific difference in the age-related changes in the characteristics of CRC. Increasing the number of concomitant adenomas and the shift of CRC localization to the proximal colon were the gender-specific characteristics of male and female CRC, respectively.

Prediction of the preoperative chemoradiotherapy response for rectal cancer by peripheral blood lymphocyte subsets

BackgroundAlthough neoadjuvant chemoradiotherapy (CRT) has become a standard procedure to downstage locally advanced rectal cancer prior to surgery, markers to predict the response to CRT have not been fully identified. The aim of this study was to identify predictive factors of response to CRT, especially focusing on peripheral blood leukocyte subsets.MethodsA total of 45 consecutive patients diagnosed with primary rectal cancer were prospectively enrolled and received CRT followed by curative resection. The numbers of each lymphocyte subset in peripheral blood pre- and post-CRT were analyzed using flow cytometry. According to the pathological response to CRT, patients were classified into high (Hi-R) and low (Lo-R) response groups.ResultsHi-R cases had significantly higher numbers of pre-CRT lymphocytes (pu2009=u20090.018), T lymphocytes (pu2009=u20090.009) and helper T lymphocytes (Th lymphocytes, pu2009=u20090.015) compared to the Lo-R cases. With the receiver-operating characteristic curve for numbers of pre-CRT T lymphocytes, the area under the curve (AUC) was 0.733, and the optimal cutoff value was 1196/μl, with 76.5% sensitivity, 67.8% specificity, 59.1% positive and 82.6% negative predictive values. The numbers of pre-CRT Th lymphocytes and cytotoxic lymphocytes were both independent predictors of the high CRT response in the multivariate analysis.ConclusionsIn addition to the direct cytotoxicity of CRT, recent studies have demonstrated the induction of an immunological host response, which also contributed to the tumor regression induced by CRT. Our result suggested the potential role of circulating T lymphocytes in predicting the response to CRT in colorectal cancer patients.

Incidence and prognostic significance of positive peritoneal lavage in colorectal cancer

PurposeThe significance of peritoneal lavage cytology as a prognostic marker has been examined in various types of cancer. However, the meaning of positive peritoneal lavage cytology in colorectal cancer is still controversial. The aim of this review is to evaluate the prognostic significance of positive peritoneal lavage cytology in colorectal cancer.MethodsAn English literature search was performed on all studies published between 1998 and 2014 that compared the detection of peritoneal free cancer cells with survival or recurrence.ResultsEighteen articles met the inclusion criteria. All studies employed one (or more) of the three techniques used to detect free cancer cells in the peritoneal cavity: (1) conventional cytology, (2) immunocytochemistry or (3) polymerase chain reaction. The incidence of positive peritoneal lavage cytology ranged from 2.2 to 47.2xa0% across the studies. The factors correlated with positive peritoneal lavage cytology were tumor penetration and metastases (lymph node, liver and peritoneum). In nine studies, positive lavage findings were associated with a worse survival, and it was associated with increased recurrence in 13 studies.ConclusionPositive peritoneal lavage cytology seems to be an indicator of a poor prognosis in colorectal cancer patients. Further studies are needed to clarify the prognostic impact of peritoneal lavage cytology, by comparing the different methods used for the collection of the peritoneal lavage.

Drug development for intraperitoneal chemotherapy against peritoneal carcinomatosis from gastrointestinal cancer

Intraperitoneal (IP) chemotherapy for peritoneal carcinomatosis (PC) from gastrointestinal cancer has been investigated and applied clinically for several decades. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy have been considered to be the optimal treatment options for selected patients with colorectal and gastric cancers with PC. Accumulating evidence suggests that the administration of IP paclitaxel for patients with PC from gastric cancer may improve the patient survival. The pharmacokinetics of such treatment should be considered to optimize IP chemotherapy. In addition, newly emerging molecular-targeted therapies and research into new drug delivery systems, such as nanomedicine or controlled absorption/release methods, are essential to improve the effects of IP chemotherapy. This review summarizes the current status and future prospects of IP chemotherapy for the treatment of gastrointestinal cancer.

Prognostic Significance of the Lymph Node Ratio in Stage IV Colorectal Cancer Patients who have Undergone Curative Resection

BackgroundThe lymph node ratio (LNR) was proposed as a prognostic indicator in Stage III colorectal cancer (CRC) patients in recent studies. The purpose of this study was to evaluate the prognostic impact of the LNR in Stage IV CRC patients who have undergone curative resection.MethodsA retrospective review of 119 Stage IV CRC patients who underwent curative resection in our institute from 1997 to 2009 was performed. Patients were divided into two groups (low LNR and high LNR) by means of their median LNR. A disease-free survival (DFS) and an overall survival (OS) were analyzed using the Kaplan–Meier curve; multivariate analysis was performed using the Cox proportional hazard model.ResultsThe cutoff value for the LNR was 0.111. For the entire study group, the 5-year DFS was 22xa0% and the 5-year OS was 65xa0%. DFS was not significantly different between patients in the low LNR group and the high LNR group (25 and 19xa0%, respectively; Pxa0=xa00.317), but OS was significantly higher in the low LNR group patients compared with the high LNR group patients (77 and 54xa0%, respectively; Pxa0<xa00.001). Using multivariate analysis, we identified the LNR as an independent prognostic factor for OS, with a hazard ratio of 3.08 (95xa0% CI 1.38–8.19; Pxa0=xa00.005).ConclusionsLNR is a potent prognostic indicator for stratification in Stage IV CRC patients who have undergone curative resection.

Changes in the plasma levels of cytokines/chemokines for predicting the response to chemoradiation therapy in rectal cancer patients.

In the present study, we aimed to characterize the predictive value of cytokines/chemokines in rectal cancer (RC) patients receiving chemoradiation therapy (CRT). Blood samples were obtained pre- and post-CRT from 35 patients with advanced RC, who received neoadjuvant CRT followed by surgery, and the correlation between plasma levels of cytokines/chemokines and the response to CRT was analyzed. The pre-CRT levels of soluble CD40-ligand (sCD40L) and the post-CRT levels of chemokine ligand-5 (CCL-5) were significantly associated with the depth of tumor invasion and with venous invasion. In addition, a significant decrease in sCD40L and CCL-5, as well as in platelet counts, was associated with a favorable response to CRT. A significant correlation between pre-CRT platelet counts and sCD40L was observed in patients with a favorable response. By contrast, higher post-CRT interleukin (IL)-6 was associated with a poor response. Platelets, immune system and cancer cells, cross-linked through various cytokines/chemokines, appear to play an important role in the response to CRT, and by understanding their roles, new approaches for the improvement of the therapy might be proposed.

Detection of carcinoembryonic antigen mRNA in peritoneal lavage by the transcription-reverse transcription concerted method indicates poor prognosis in patients with stage II and III colon cancer.

BACKGROUNDnPeritoneal dissemination and positive peritoneal lavage cytology are associated with poor prognosis in colorectal cancer. Carcinoembryonic antigen (CEA) messenger RNA (mRNA) is often used as a marker to detect micrometastases. We aimed to evaluate the prognostic significance of CEA mRNA in the peritoneal lavage of colon cancer patients.nnnMETHODSnColon cancer patients (n = 201) who underwent curative operative resection between August 2009 and February 2013 were enrolled. CEA mRNA in peritoneal lavage was measured using the transcription-reverse transcription concerted method, a quantitative RNA amplification method. The correlation between CEA mRNA and overall and peritoneal recurrence-free survival was evaluated.nnnRESULTSnPositive CEA mRNA in peritoneal lavage was an independent risk factor for overall recurrence-free survival in colon cancer (P < .0001). Positive CEA mRNA was a risk factor for poorer overall recurrence in stage II and III patients (P = .04 and P = .02, respectively). Moreover, among stage III patients with positive CEA mRNA, the postoperative chemotherapy group had significantly lower overall and peritoneal recurrence rates than the no postoperative chemotherapy group (P = .001).nnnCONCLUSIONnPositive CEA mRNA in peritoneal lavage was associated with high overall recurrence rates in stage II and III colon cancer. Further study is necessary to determinate the efficacy of aggressive postoperative chemotherapy for stage II and III colon cancer patients with positive CEA mRNA.