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The aim of this review was to evaluate the clinical significance of serum tumor markers, particularly CEA, CA19-9, and CA72-4, in patients with gastric cancer. A systematic literature search was performed using PubMed/MEDLINE with the keywords “gastric cancer” and “tumor marker,” to select 4,925 relevant reports published before the end of November 2012. A total of 187 publications contained data for CEA and CA19-9, and 19 publications contained data related to all three tumor markers. The positive rates were 21.1 % for CEA, 27.8 % for CA19-9, and 30.0 % for CA72-4. These three markers were significantly associated with tumor stage and patient survival. Serum markers are not useful for early cancer, but they are useful for detecting recurrence and distant metastasis, predicting patient survival, and monitoring after surgery. Tumor marker monitoring may be useful for patients after surgery because the positive conversion of tumor markers usually occurs 2–3 months before imaging abnormalities. Among other tumor markers, alpha-fetoprotein (AFP) is useful for detecting and predicting liver metastases. Moreover, CA125 and sialyl Tn antigens (STN) are useful for detecting peritoneal metastases. Although no prospective trial has yet been completed to evaluate the clinical significance of these serum markers, this literature survey suggests that combinations of CEA, CA19-9, and CA72-4 are the most effective ways for staging before surgery or chemotherapy. In particular, monitoring tumor markers that were elevated before surgery or chemotherapy could be useful for detection of recurrence or evaluation of the response.

BackgroundAdvanced low rectal cancer has a non-negligible risk of lateral pelvic lymph node (LPLN) metastasis (LPLNM) and lateral local recurrence (LR) after neoadjuvant (chemo)radiotherapy and total mesorectal excision. LPLN dissection (LPLND) reduces LR but increases postoperative complications and sexual/urinary dysfunction.ObjectiveThe aim of this study was to develop a new radiomics-based prediction model for LPLNM in patients with rectal cancer.MethodsA total of 247 patients with rectal cancer and enlarged LPLNs treated by (chemo)radiotherapy and LPLND were enrolled in this retrospective, multicenter study. LPLN radiomic features were extracted from pretreatment portal venous-phase computed tomography images. A radiomics score of LPLN was constructed based on the least absolute shrinkage and selection operator regression in a primary cohort of 175 patients. Model performance was assessed in terms of discrimination, calibration, and decision curve analysis, and was externally validated in 72 patients.ResultsThe radiomics score showed significantly better discrimination compared with pretreatment short-axis diameter measurements in both the primary (area under the curve [AUC] 0.91 vs. 0.83, p = 0.0015) and validation (AUC 0.90 vs. 0.80, p = 0.0298) cohorts. Decision curve analysis also indicated the superiority of the radiomics score. In a subanalysis of patients with a short-axis diameter ≥ 7 mm, the radiomics nomogram, incorporating the radiomics score and LPLN shrinkage to ≤ 4 mm, had better discrimination compared with a model incorporating only LPLN shrinkage in both cohorts.ConclusionsRadiomics-based prediction modeling provides individualized risk estimation of LPLNM in rectal cancer patients treated with (chemo)radiotherapy, and outperforms measurements of pretreatment LPLN diameter.

BackgroundThis study aimed to investigate the effect of sarcopenia on the prognosis of advanced lower rectal cancer patients receiving neoadjuvant chemoradiotherapy (CRT). Sarcopenia has been recognized as an adverse factor for surgical outcomes in several malignancies. However, the impact of preoperative sarcopenia on rectal cancer patients receiving CRT is still unknown.MethodsThis retrospective study included cT3-T4 anyN M0 lower rectal cancer patients who underwent CRT followed by R0 resection at our institution between October 2003 and December 2016. CRT consisted of 5-fluorouracil-based oral chemotherapy and long course radiation (50.4 Gy/28 fr). The psoas muscle area at the third lumbar vertebra level was evaluated by computed tomography before and after CRT, and was adjusted by the square of the height to obtain the psoas muscle mass index (PMI). Sarcopenia was defined as the sex-specific lowest quartile of the PMI. We assessed the association between pre- and post-CRT sarcopenia and postoperative prognosis.ResultsAmong 234 patients, 55 and 179 patients were categorized as sarcopenia and non-sarcopenia patients, respectively. Although post-CRT sarcopenia correlated with residual tumor size, it had no association with other pathological features. The median follow-up period was 72.9 months, and the 5-year DFS and OS were 67.0% and 85.8%, respectively. Multivariate analysis showed that post-CRT sarcopenia was independently associated with poor DFS (HR: 1.76; P = 0.036), OS (HR: 2.01; P = 0.049), and recurrence in the liver (HR: 3.01; P = 0.025).ConclusionsSarcopenia is a poor prognostic indicator in lower advanced rectal cancer patients treated with CRT.

Recently, the complexity and costs of clinical trials have increased dramatically, especially in the area of new drug development. Risk-based monitoring (RBM) has been attracting attention as an efficient and effective trial monitoring approach, which can be applied irrespectively of the trial sponsor, i.e., academic institution or pharmaceutical company. In the RBM paradigm, it is expected that a statistical approach to central monitoring can help improve the effectiveness of on-site monitoring by prioritizing and guiding site visits according to central statistical data checks, as evidenced by examples of actual trial datasets. In this review, several statistical methods for central monitoring are presented. It is important to share knowledge about the role and performance capabilities of statistical methodology among clinical trial team members (i.e., sponsors, investigators, data managers, monitors, and biostatisticians) in order to adopt central statistical monitoring for assessing data quality in the actual clinical trial.

We aimed to investigate the effect of recent short-term weight gain on the incidence of nonalcoholic fatty liver disease (NAFLD) in nonobese (body mass index < 25 kg/m) participants. This retrospective cohort study included nonobese individuals who participated in an annual health checkup between 2008 and 2018 in Tokyo, Japan. We estimated the multivariable adjusted hazard ratio for the development of NAFLD diagnosed via ultrasound after a 3-kg unit gain in weight measured at a 2-year landmark time point postbaseline. Multivariable adjustments included weight change from the age of 20 and other relevant confounding factors. Sensitivity analyses using additional landmark time points at 1, 3, 4, and 5 years postbaseline and time-dependent Cox proportional hazards regressions were performed. Among the 27,064 nonobese participants (142,699 person years of follow-up), 2,895 were diagnosed with NAFLD. Approximately 90% of the patients with NAFLD maintained their nonobese status before disease diagnosis. The adjusted hazard ratio for the development of NAFLD (for a 3-kg unit of weight gain) at the 2-year landmark time point postbaseline was 1.60 (95% confidence interval, 1.46-1.76) in nonobese men and 1.66 (95% confidence interval, 1.51-1.83) in nonobese women. This association was maintained in the sensitivity analyses. Recent short-term weight gain is an independent risk factor for NAFLD development in nonobese men and women. Clinicians should be mindful of the association between weight gain and NAFLD onset, even in the nonobese population.

Remnant gastric cancer, most frequently defined as cancer detected in the remnant stomach after distal gastrectomy for benign disease and those cases after surgery of gastric cancer at least 5 years after the primary surgery, is often reported as a tumor with poor prognosis. The Task Force of Japanese Gastric Cancer Association for Research Promotion evaluated the clinical impact of remnant gastric cancer by systematically reviewing publications focusing on molecular carcinogenesis, lymph node status, patient survival, and surgical complications. A systematic literature search was performed using PubMed/MEDLINE with the keywords “remnant,” “stomach,” and “cancer,” revealing 1154 relevant reports published up to the end of December 2014. The mean interval between the initial surgery and the diagnosis of remnant gastric cancer ranged from 10 to 30 years. The incidence of lymph node metastases at the splenic hilum for remnant gastric cancer is not significantly higher than that for primary proximal gastric cancer. Lymph node involvement in the jejunal mesentery is a phenomenon peculiar to remnant gastric cancer after Billroth II reconstruction. Prognosis and postoperative morbidity and mortality rates seem to be comparable to those for primary proximal gastric cancer. The crude 5-year mortality for remnant gastric cancer was 1.08 times higher than that for primary proximal gastric cancer, but this difference was not statistically significant. In conclusion, although no prospective cohort study has yet evaluated the clinical significance of remnant gastric cancer, our literature review suggests that remnant gastric cancer does not adversely affect patient prognosis and postoperative course.

Purpose The impact of postoperative complications on survival after radical surgery for esophageal, gastric, and colorectal cancers remains controversial. We conducted a systematic review of recent publications to examine the effect of postoperative complications on oncological outcome. Methods A literature search of PubMed/MEDLINE was performed using the keywords “esophageal cancer,” “gastric cancer,” and “colorectal cancer,” obtaining 27 reports published online up until the end of April 2016. Articles focusing on (i) postoperative morbidity and oncological outcome; and (ii) body mass index (BMI), postoperative morbidity, and oncological outcome, were selected. Univariate and multivariate analyses (Cox proportional hazards model) were performed. Results Patients with postoperative complications had significantly poorer long‐term survival than those without complications. Complications were associated with impaired oncological outcomes. The hazard ratios for overall survival were 1.67 (95% confidence interval [CI], 1.31‐2.12), 1.59 (95% CI, 1.13‐2.24), and 1.55 (95% CI, 1.28‐1.87) in esophageal, gastric, and colorectal cancers, respectively. High BMI was associated with postoperative morbidity rate but not with poor oncological outcome. Low BMI was significantly associated with inferior oncological outcome. Conclusions Complications after radical surgery for esophageal, gastric, and colorectal cancers are associated with patient prognosis. Avoiding such complications might improve the outcomes. A systematic review of the impact of postoperative complications on long‐term survival of patients with gastrointestinal cancers showed that infectious complications, particularly pneumonia, were significant risk factors with negative impacts on patient survival.

Background Micro-randomized trials (MRTs) enhance the effects of mHealth by determining the optimal components, timings, and frequency of interventions. Appropriate handling of missing values is crucial in clinical research; however, it remains insufficiently explored in the context of MRTs. Our study aimed to investigate appropriate methods for missing data in simple MRTs with uniform intervention randomization and no time-dependent covariates. We focused on outcome missing data depending on the participants’ background factors. Methods We evaluated the performance of the available data analysis (AD) and the multiple imputation in generalized estimating equations (GEE) and random effects model (RE) through simulations. The scenarios were examined based on the presence of unmeasured background factors and the presence of interaction effects. We conducted the regression and propensity score methods as multiple imputation. These missing data handling methods were also applied to actual MRT data. Results Without the interaction effect, AD was biased for GEE, but there was almost no bias for RE. With the interaction effect, estimates were biased for both. For multiple imputation, regression methods estimated without bias when the imputation models were correct, but bias occurred when the models were incorrect. However, this bias was reduced by including the random effects in the imputation model. In the propensity score method, bias occurred even when the missing probability model was correct. Conclusions Without the interaction effect, AD of RE was preferable. When employing GEE or anticipating interactions, we recommend the multiple imputation, especially with regression methods, including individual-level random effects.

BackgroundAmong numerous systemic inflammatory biomarkers, it remains unclear which is the most prognostic for patients with stage II/III colon cancer. We aimed to compare the prognostic significance of systemic inflammatory biomarkers among patients with stage II/III colon cancer.MethodsWe included 1303 patients with stage II/III colon cancer who underwent potentially curative resection from July 2004 to December 2013. Sixteen systemic inflammatory biomarkers—derived from combinations of neutrophils, lymphocytes, monocytes, platelets, C-reactive protein (CRP), and albumin—were compared to identify the biomarker most associated with overall survival (OS) and disease-free survival (DFS) using receiver operating characteristic (ROC) curve analysis.ResultsNine inflammatory biomarkers were predictive for OS, among which lymphocyte-to-CRP ratio (LCR), CRP-to-albumin ratio (CAR), neutrophil × CRP, monocyte × CRP, and platelet × CRP were also predictive for DFS. Among these five inflammatory biomarkers, the area under the curve (AUC) value was highest (0.630) for LCR, being significantly higher than that for neutrophil × CRP (P = 0.010), monocyte × CRP (P = 0.007), or platelet × CRP (P = 0.010) for OS. When the prognostic impact of LCR and CAR were analyzed by multivariate analysis, only LCR was an independent predictor of both OS [hazard ratio (HR), 1.77; 95% confidence interval (CI), 1.23–2.60; P = 0.002] and DFS (HR, 1.29; 95% CI, 1.00–1.66; P = 0.048).ConclusionsLCR may be the most useful predictive factor for OS and DFS in patients with stage II or III colon cancer.

Aim To evaluate the feasibility and safety of total neoadjuvant therapy with long‐course chemoradiotherapy followed by consolidation chemotherapy in Japanese patients with locally advanced rectal cancer. Methods This prospective, multicenter, single‐arm, phase II trial was conducted at 10 centers. The eligibility criteria included age ≥20 y, locally advanced rectal cancer within 12 cm of the anal verge, and cT3‐4N0M or TanyN+M0 at diagnosis, enabling curative resection. The protocol treatment was capecitabine (1650 mg/m2/day)‐based long‐course chemoradiotherapy (50.4 Gy/28 fractions) and consolidation chemotherapy (CAPOX, four courses) followed by total mesorectal excision. Nonoperative management was allowed if a clinical complete response was achieved. The primary endpoint was the pathologic complete response rate. Results Among 28 enrolled patients (19 men, 9 women; median age, 69.5 [41–79] y), the long‐course chemoradiotherapy and consolidation chemotherapy completion rates were 100% and 96.4%, respectively. The clinical responses included clinical complete response, (35.7%, 10/28), near‐complete response (28.6%, 8/28), and incomplete response (32.1%, 9/28). Total mesorectal excision and nonoperative management were performed in 21 and six patients, respectively. The final analysis included 21 patients. Five patients (23.8% [90% confidence interval 11.8%–41.8%]) achieved pathologic complete response, while 10 of 28 patients (35.7%) achieved a pathological complete response or a sustained clinical complete response. No treatment‐related deaths occurred. Grade ≥3 adverse events included diarrhea (7.1%) and leukopenia (7.1%). Conclusion ENSEMBLE‐2 demonstrated comparable pathologic complete response rates and well‐tolerated safety of total neoadjuvant therapy with long‐course chemoradiotherapy followed by consolidation chemotherapy in Japanese patients with locally advanced rectal cancer. ENSEMBLE‐2 was a multicenter, single‐arm phase II clinical trial investigating the safety and efficacy of total neoadjuvant therapy for patients with locally advanced rectal cancer in Japan. The key eligibility criteria were age 20 y or older, locally advanced rectal cancer within 12 cm from the anal verge, and cT3‐4N0M0 or TanyN+M0 that was curatively resectable at diagnosis. Long‐course chemoradiotherapy was administered at 1.8 Gy per day over 28 d for a total dose of 50.4 Gy. Consolidative chemotherapy was initiated 14 ± 7 d after LCCRT. Surgery was performed with curative intent 21–56 d after consolidative chemotherapy. Additional lateral lymph node dissection was performed at the surgeon's discretion. The primary endpoint was the pathological complete rate.