The gene expressions of netrin-1 dependence receptors, DCC and UNC5C, are frequently downregulated in many cancers. We hypothesized that downregulation of DCC and UNC5C has an important growth regulatory function in gastric tumorigenesis. In the present study, a series of genetic and epigenetic analyses for DCC and UNC5C were performed in a Japanese cohort of 98 sporadic gastric cancers and corresponding normal gastric mucosa specimens. Loss of heterozygosity (LOH) analyses and microsatellite instability (MSI) analysis was applied to determine chromosomal instability (CIN) and MSI phenotypes, respectively. More than 5 % methylation in the DCC and UNC5C promoters were found in 45 % (44/98) and 32 % (31/98) gastric cancers, respectively, and in 9 % (9/105) and 5 % (5/105) normal gastric mucosa, respectively. Overall, 70 % (58 of 83 informative cases) and 51 % (40 of 79 informative cases) of gastric cancers harbored either LOH or aberrant methylation in the DCC and UNC5C genes, respectively. In total, 77 % (51 of 66 informative cases) of gastric cancers showed cumulative defects in these two dependence receptors and were significantly associated with chromosomal instability. Both DCC and UNC5C were inactivated in 97 % of CIN-positive gastric cancers and in 55 % of CIN-negative gastric cancers. Defect in netrin receptors is a common feature in gastric cancers. DCC alterations are apparent in the early stages, and UNC5C alterations escalate with the progression of the disease, suggesting that the cumulative alterations of netrin-1 receptors was a late event in gastric cancer progression and emphasizing the importance of this growth regulatory pathway in gastric carcinogenesis.

Open pancreaticoduodenectomy (OPD) is an essential surgical procedure for expert hepato-biliary-pancreatic (HBP) surgeons. However, there is no standard for how many surgeries must be performed by a surgeon in training before they are considered to have enough experience to ensure surgical safety. Cumulative Sum (CUSUM) analysis was performed using the surgical data of OPDs performed during the training period of board-certified expert surgeons of the Japanese Society of Hepato-Biliary-Pancreatic Surgery. Fourteen HBP surgeons participated in this study and performed 334 OPDs during their training period. The median (interquartile range) values for operative time, blood loss, and length of hospital stay were 455 (397–519) minutes, 450 (234–-716) ml, and 28 (21–38) days, respectively. CUSUM analysis showed inflection points at 20 surgeries performed for operative time. After 20 procedures, operative time was significantly shorter (461 min vs. 425 min, p = 0.021) and blood loss was significantly lower (470 ml vs. 340 ml, p = 0.038). No significant differences between within 20 and after 21 procedures were found in the complication rate (53% vs. 48%, p = 0.424) and rate of in-hospital deaths (1.5% vs.1.4%. p = 0.945). Up to 20 surgeries, PDAC and another malignant tumor had longer operative time than benign/low malignant diseases (486 min vs. 472 min vs. 429 min, p < 0.001), and higher blood loss (500 ml vs. 502 ml vs. 355 ml, p < 0.001). Mortality rate was higher at PDAC cases (5% vs. 0% vs. 0%, p = 0.01). After the 21 procedures, these outcomes were improved and no differences in by primary disease were observed. Multivariable analysis showed that within 20 surgeries were independent risk factors of longer operative time (HR2.6, p = 0.013) and higher blood loss (HR2.0, p = 0.049). To stabilize the surgical outcome of OPD for malignant disease, at least 20 surgeries should be performed at a certified institution during surgeon training. Clinical trial number: Not applicable.

Complete (R0) resection remains the primary surgical objective for colorectal liver metastases (CRLM), but margin width cannot be interpreted independently of tumor anatomy, biology, and the amount of functional liver sacrificed to obtain it. This focused narrative review re-examines surgical margins from the perspective of parenchymal preservation and longitudinal multimodal treatment. We distinguish parenchymal R1 exposure (R1par), an undesirable transection-surface event associated with local recurrence, from planned vascular R1 detachment (R1vasc), which has shown more favorable outcomes than R1par in selected retrospective series but remains dependent on careful anatomical selection. Vessel-skeletonized parenchymal-sparing hepatectomy (VESPAH) is presented as one operative model for achieving complete macroscopic clearance while preserving intrahepatic vascular architecture. We further propose “treatment continuity”—preservation of the physiological and anatomical capacity to receive indicated systemic therapy and repeat local treatment—as a reportable surgical outcome. A four-axis framework integrating technical resectability, functional reserve, tumor biology, and future treatment options is outlined. R0 resection should remain the goal, but the quality of hepatectomy for CRLM may be more comprehensively assessed by considering both the margin achieved at the index operation and the treatments that remain feasible thereafter.

Complete (R0) resection remains the primary surgical objective for colorectal liver metastases (CRLM), but margin width cannot be interpreted independently of tumor anatomy, biology, and the amount of functional liver sacrificed to obtain it. This focused narrative review re-examines surgical margins from the perspective of parenchymal preservation and longitudinal multimodal treatment. We distinguish parenchymal R1 exposure (R1par), an undesirable transection-surface event consistently associated with local recurrence in retrospective series, from planned vascular R1 detachment (R1vasc), which has shown more favorable outcomes than R1par in selected retrospective series but remains dependent on careful anatomical selection. Vessel-skeletonized parenchymal-sparing hepatectomy (VESPAH) is presented as one operative model for achieving complete macroscopic clearance while preserving intrahepatic vascular architecture; the evidence for this model is confined to retrospective series and is therefore illustrative and hypothesis-generating rather than confirmatory. We further propose “treatment continuity”—preservation of the physiological and anatomical capacity to receive indicated systemic therapy and repeat local treatment—as a reportable surgical outcome. A four-axis framework integrating technical resectability, functional reserve, tumor biology, and future treatment options is outlined, together with a minimum set of reporting elements for margin phenotype and operational definitions for four candidate measures of treatment continuity. R0 resection should remain the goal, but the quality of hepatectomy for CRLM may be more comprehensively assessed by considering both the margin achieved at the index operation and the treatments that remain feasible thereafter.