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Background: Particle therapy (PT) as an initial hepatocellular carcinoma (HCC) treatment has been reported to be effective; however, its efficacy for the treatment of recurrent HCC remains unclear., Objective: This study aimed to evaluate the efficacy of PT compared with repeat liver resection for treating recurrent HCC after initial LR, with a focus on prognostic outcomes., Methods: Between 2005 and 2019, 89 and 49 patients underwent repeat LR and PT for recurrent HCC after initial LR, respectively. The 5-year overall survival (OS) and recurrence-free survival (RFS) were evaluated using propensity score matching. Treatment-related complications were scored using the National Institute Common Terminology Criteria for Adverse Events (CTCAE) and were compared between the repeat LR and PT groups., Results: In the entire cohort, the 5-year OS was significantly better in the repeat LR group than in the PT group (75% vs. 48%; p = 0.0003), and the 5-year RFS was comparable in both groups (22% vs. 13%; p = 0.088). Propensity score matching created 34 pairs of patients; no significant differences in the 5-year OS (65% vs. 48%; p = 0.310) and RFS (21% vs. 8%; p = 0.271) were observed between the repeat LR and PT groups. The proportion of CTCAE grade ≥3 complications was 8.8% and 5.9% in the repeat LR and PT groups, respectively (p = 0.641)., Conclusions: After initial LR, the prognosis and treatment-related complications in patients with recurrent HCC were comparable between the repeat LR and PT groups in the matched cohort; therefore, PT may remain one of the multidisciplinary treatment options for recurrent HCC., (© 2024. Society of Surgical Oncology.)

Background: Few reports have discussed the association between total tumor volume (TTV) and prognosis in patients with colorectal liver metastases (CRLM). The present study aimed to evaluate the usefulness of TTV for predicting recurrence-free survival and overall survival (OS) in patients receiving initial hepatic resection or chemotherapy, and to investigate the value of TTV as an indicator for optimal treatment selection for patients with CRLM., Patients and Methods: This retrospective cohort study included patients with CRLM who underwent hepatic resection (n = 93) or chemotherapy (n = 78) at the Kobe University Hospital. TTV was measured using 3D construction software and computed tomography images., Results: A TTV of 100 cm 3 has been previously reported as a significant cut-off value for predicting OS of CRLM patients receiving initial hepatic resection. For patients receiving hepatic resection, the OS for those with a TTV ≥ 100 cm 3 was significantly reduced compared with those with a TTV < 100 cm 3 . For patients receiving initial chemotherapy, there were no significant differences between the groups divided according to TTV cut-offs. Regarding OS of patients with TTV ≥ 100 cm 3 , there was no significant difference between hepatic resection and chemotherapy (p = 0.160)., Conclusions: TTV can be a predictive factor of OS for hepatic resection, unlike for initial chemotherapy treatment. The lack of significant difference in OS for CRLM patients with TTV ≥ 100 cm 3 , regardless of initial treatment, suggests that chemotherapeutic intervention preceding hepatic resection may be indicated for such patients., (© 2023. Society of Surgical Oncology.)

Background: Sarcopenia, defined as a loss of skeletal muscle mass and quality, is found in 30-65% of patients with pancreatic ductal adenocarcinoma (PDAC) at diagnosis, and is a poor prognostic factor. However, it is yet to be evaluated why sarcopenia is associated with poor prognosis. Therefore, this study elucidated the tumor characteristics of PDAC with sarcopenia, including driver gene alterations and tumor microenvironment., Patients and Methods: We retrospectively analyzed 162 patients with PDAC who underwent pancreatic surgery between 2008 and 2017. We defined sarcopenia by measuring the skeletal muscle mass at the L3 level using preoperative computed tomography images and evaluated driver gene alteration (KRAS, TP53, CDKN2A/p16, and SMAD4) and tumor immune (CD4 + , CD8 + , and FOXP3 + ) and fibrosis status (stromal collagen)., Results: In localized-stage PDAC (stage ≤ IIa), overall survival (OS) and recurrence-free survival were significantly shorter in the sarcopenia group than in the non-sarcopenia group (2-year OS 89.7% versus 59.1%, P = 0.03; 2-year RFS 74.9% versus 50.0%, P = 0.02). Multivariate analysis revealed that sarcopenia was an independent poor prognostic factor in localized-stage PDAC. Additionally, tumor-infiltrating CD8 + T cells in the sarcopenia group were significantly less than in the non-sarcopenia group (P = 0.02). However, no difference was observed in driver gene alteration and fib.rotic status. These findings were not observed in advanced-stage PDAC (stage ≥ IIb)., Conclusions: Sarcopenia was associated with a worse prognosis and decreased tumor-infiltrating CD8 + T cells in localized-stage PDAC. Sarcopenia may worsen a patient's prognosis by suppressing local tumor immunity., (© 2023. The Author(s).)

Background: Optimal management of non-functioning pancreatic neuroendocrine tumors (PanNETs) ≤20 mm is controversial. The biological heterogeneity of these tumors poses challenges when deciding between resection and observation., Methods: In this multicenter, retrospective cohort study, we analyzed all patients (n = 78) who underwent resection of non-functioning PanNETs ≤20 mm at three tertiary medical centers from 2004 to 2020 to assess the utility of preoperatively available radiological features and serological biomarkers of non-functioning PanNETs in choosing an optimal surgical indication. The radiological features included non-hyper-attenuation pattern on enhancement computed tomography (CT; hetero/hypo-attenuation) and main pancreatic duct (MPD) involvement, and serological biomarkers included elevation of serum elastase 1 and plasma chromogranin A (CgA) levels., Results: Of all small non-functioning PanNETs, 5/78 (6%) had lymph node metastasis, 11/76 (14%) were WHO grade II, and 9/66 (14%) had microvascular invasion; 20/78 (26%) had at least one of these high-risk pathological factors. In the preoperative assessment, hetero/hypo-attenuation and MPD involvement were observed in 25/69 (36%) and 8/76 (11%), respectively. Elevated serum elastase 1 and plasma CgA levels were observed in 1/33 (3%) and 0/11 (0%) patients, respectively. On multivariate logistic regression analysis, hetero/hypo-attenuation (odds ratio [OR] 6.1, 95% confidence interval [CI] 1.7-22.2) and MPD involvement (OR 16.8, 95% CI 1.6-174.3) were significantly associated with the high-risk pathological factors. The combination of the two radiological worrisome features correctly predicted non-functioning PanNETs with high-risk pathological factors, with about 75% sensitivity, 79% specificity, and 78% accuracy., Conclusions: This combination of radiological worrisome features can accurately predict non-functioning PanNETs that may require resection., (© 2023. Society of Surgical Oncology.)

Background: Laparoscopic caudate lobe resection is a challenging procedure. Several researchers have reported the safety of laparoscopic liver resections;1.Transl Gastroenterol Hepatol. 1:56;2.Asian J Endosc Surg. 12:232-236;3.Ann Surg Oncol. 26:2980; however, a standardized procedure has not yet been established. Herein, we present a video showing laparoscopic Spiegel lobectomy in a patient with 6-cm hepatocellular carcinoma (HCC) using a novel approach., Patient and Methods: A 63-year-old man with a caudate lobe HCC was referred to our hospital. Computed tomography showed a 5 × 6 cm 2 HCC located in the Spiegel lobe, which profoundly displaced the inferior vena cava (IVC) to the lower right side, and mobilization of the Spiegel lobe was considered difficult. To perform the dissection between the Siegel lobe and IVC safely, we performed parenchymal transection along the ventral side of the IVC initially. The Spiegel lobe was then dislocated to the left side of the IVC. We dissected the left lateral side of the IVC, including the proper hepatic vein draining the caudate lobe and the left IVC ligament with a safe operative field, and successfully removed the Spiegel lobe with large HCC., Results: The operation time was 383 min. The blood loss was 10 mL. The patient was discharged on the seventh postoperative day without any complications. Histopathological examination revealed well-differentiated HCC with a negative surgical margin., Conclusions: Laparoscopic medial-to-lateral approach with initial parenchymal transection at the medial side of the Spiegel lobe followed by dissection of the left lateral side of the IVC is considered as a safe and effective procedure for large tumors in the Spiegel lobe., (© 2022. Society of Surgical Oncology.)

Background: Pancreatic ductal adenocarcinoma (PDAC) concomitant with intraductal papillary mucinous neoplasm (IPMN) is defined as PDAC occurring apart from IPMN. This study comprehensively investigated the molecular biologic characteristics of PDAC concomitant with IPMN in major genetic alterations, tumor microenvironment, and prognosis by contrast with those of conventional PDAC., Methods: The study retrospectively reviewed the data of 158 surgically resected PDAC patients. The driver gene alteration status (KRAS, TP53, CDKN2A, SMAD4, and GNAS) together with the immune and fibrotic status in tumor was evaluated. The prognosis of PDAC concomitant with IPMN and that of conventional PDAC also were compared., Results: No statistically significant difference was found between PDAC concomitant with IPMN and conventional PDAC in the alteration frequency analysis of the major driver genes and the immune and fibrotic status in the tumor microenvironment. Overall survival and disease-free survival between patients who had PDAC concomitant with IPMN and those who had conventional PDAC did not show statistically significant differences in propensity-matched subjects. Furthermore, the co-existence of IPMN was not a poor prognostic factor in the multivariable-adjusted Cox proportional hazards model (hazard ratio, 0.95; 95 % confidence interval, 0.51-1.78)., Conclusions: In this study, PDAC concomitant with IPMN had tumor characteristics similar to those of conventional PDAC in terms of the major driver gene alterations, tumor microenvironment, and prognosis., (© 2022. Society of Surgical Oncology.)

Background: The optimal treatment for isolated local recurrence (ILR) of pancreatic adenocarcinoma (PDAC) after surgical resection remains unclear. This study aimed to evaluate the safety and efficacy of proton radiotherapy (PRT) for ILR of PDAC after surgery., Methods: The medical records of patients with ILR of PDAC after surgery who underwent proton beam therapy between 2011 and 2015 at Hyogo Ion Beam Medical Center were retrospectively studied., Results: The study analyzed 30 patients (14 women and 16 men) with a median age of 65 years (range 38-81 years) who had initially undergone pancreatoduodenectomy (n = 23) or distal pancreatectomy (n = 7) for their primary tumors. Upon ILR, PRT was administered with a median total cumulative dose of 67.5 gray equivalent (GyE) (range 50-67.5 GyE) using 19 to 25 fractions. For 25 patients, concurrent chemotherapy was administered using gemcitabine (n = 18) or S-1 (n = 7). Four patients (13.3%) experienced acute grade ≥ 3 gastrointestinal toxicities. After a median follow-up period of 17.6 months (range 2.1-50.4 months), 23 patients had experienced tumor progression and 10 had died. Nine patients (30%) experienced local tumor progression. The median overall, progression-free, and local progression-free survival rates were 26.1, 12.3, and 41.2 months, respectively. Pre-PRT serum levels of cancer antigen 19-9 higher than 100 U/mL and duke pancreatic monoclonal antigen type 2 higher than 150 U/mL were significantly associated with shorter progression-free survival rates., Conclusions: Proton radiotherapy for ILR of PDAC after surgery is well tolerated and produces good locoregional control and should be considered for eligible patients.

Purpose: This study was designed to assess the potential role of the preoperative serum level of elastase 1 as a risk factor for recurrence in patients with resectable well-differentiated pancreatic neuroendocrine neoplasms (PanNETs)., Methods: Preoperative serum elastase 1 levels were measured in 53 patients with PanNETs who underwent complete tumor resection in two tertiary referral centers between January 2004 and June 2017. The preoperative elastase 1 levels were correlated with clinicopathological characteristics, including tumor recurrence and recurrence-free survival., Results: The median elastase 1 level was 96 ng/dL (range: 21-990 ng/dL). Preoperative serum elastase 1 levels were significantly higher in those with tumors ≥ 20 mm in diameter (vs. < 20 mm, P = 0.018), WHO grade 2 (vs. grade 1, P = 0.035), and microscopic venous invasion (vs. without venous invasion, P = 0.039). The median preoperative serum level of elastase 1 was higher in patients with recurrence than in those without recurrence (251 vs. 80 ng/dL, P = 0.004). Receiver operating characteristic analysis of elastase 1 levels showed that a cutoff level of 250 ng/dL was associated with postoperative recurrence, with 63% sensitivity, 100% specificity, and 94% overall accuracy. Patients with higher elastase 1 levels showed significantly worse recurrence-free survival than that of those with lower levels (2-year recurrence-free survival rate: 25% and 92%, respectively, P < 0.001)., Conclusions: Our data provide the first evidence that high preoperative elastase 1 levels may be a risk factor for postoperative recurrence in patients with resectable PanNETs.

Background: The prognostic impact of pancreatic ductal adenocarcinoma (PDAC) invasion to the splenic vessel is controversial., Objective: The aim of this study was to assess the clinical value of pathological and radiological splenic vessel invasion in PDACs of the body and tail., Methods: Medical records of patients with resectable PDAC of the body and tail who underwent distal pancreatectomy between 2003 and 2016 at the Kobe University Hospital were retrospectively analyzed., Results: Overall, 68 patients (29 female and 39 male patients) were enrolled. Pathologically determined splenic vein invasion (p-SV) and splenic artery invasion (p-SA) were identified in 21 (30.9%) and 5 (7.4%) patients, respectively. The p-SV (but not p-SA) was an independent prognostic factor in multivariate analysis (p = 0.009). On analysis of recurrence patterns, patients with PDAC positive for p-SV were at a higher risk for liver metastasis (p = 0.022); however, the associations were not significant for other recurrence patterns. Liver metastasis occurred earlier in patients who were positive for p-SV (p = 0.015). Preoperative computed tomography effectively diagnosed pathological vessel invasion (SV: sensitivity, 95.2%, specificity, 72.3%; SA: sensitivity, 100%, specificity, 84.1%). Radiological SV invasion remained significant in multivariate analysis regarding postoperative survival (p = 0.007), and was also associated with early liver metastases (p = 0.008)., Conclusions: Pathological/radiological SV invasion were independent adverse prognostic factors associated with early liver metastasis in patients with PDAC of the body/tail. Assessment of these findings may be useful in determining optimal therapeutic options in these patients.

Background: The biological behavior of well-differentiated neuroendocrine tumors of the pancreas (PNETs) is difficult to predict. This study was designed to determine whether involvement of the main pancreatic duct (MPD) serves as a poor prognostic factor for PNETs., Methods: The involvement of the MPD in PNETs was defined as ductal stenosis inside the tumor mass associated with distal MPDs more than twofold larger in diameter than the proximal ducts. We examined the correlation between MPD involvement and other clinicopathological parameters, including nodal metastasis and recurrence-free survival, in 101 patients treated consecutively at three referral centers in Japan. All patients underwent surgical resection., Results: MPD involvement was observed in 13 of the 101 cases (13%) and was associated with multiple unfavorable clinicopathological features (e.g., larger tumor size, higher histological grade, more frequent nodal metastasis, and higher recurrence rates). Patients with MPD involvement also showed significantly worse recurrence-free survival than did those without ductal involvement (P < 0.001), with a 5 years recurrence-free rate of 41%. On multivariate analysis, MPD involvement was significantly associated with nodal metastasis [odds ratio (OR) 16; 95% confidence interval (CI) 3.8-89; P < 0.001] and recurrence (OR 8.0; 95% CI 1.7-46; P = 0.009). The radiology-pathology correlation revealed that stenosis of the MPD was due to periductal and/or intraductal tumor invasion. Cases with MPD involvement had microscopic venous invasion (P = 0.010) and perineural infiltration (P = 0.002) more frequently than did those with no ductal infiltration., Conclusions: MPD involvement in PNETs may serve as an imaging sign indicating an aggressive clinical course.

Background: This study aimed to evaluate the impact of preoperative biliary drainage (PBD) on the long-term survival of patients with pancreatic ductal adenocarcinoma (PDAC) who underwent pancreaticoduodenectomy (PD)., Methods: A multicenter observational study was performed using a common database of patients with resected PDAC from seven high-volume surgical institutions in Japan., Results: Of 932 patients who underwent PD for PDAC, 573 (62 %) underwent PBD, including 407 (44 %) who underwent endoscopic biliary drainage (EBD) and 166 (18 %) who underwent percutaneous transhepatic biliary drainage (PTBD). The patients who did not undergo PBD and those who underwent EBD had a significantly better overall survival than those who underwent PTBD, with median survival times of 25.7 months (P < 0.001), 22.3 months (P = 0.001), and 16.7 months, respectively. Multivariate analysis showed that seven clinicopathologic factors, including the use of PTBD but not EBD, were independently associated with poorer overall survival. Furthermore, patients who underwent PTBD more frequently experienced peritoneal recurrence (23 %) than those who underwent EBD (10 %; P < 0.001) and those who did not undergo PBD (11 %; P = 0.001). Multivariate analysis demonstrated that the independent risk factors for peritoneal recurrence included surgical margin status (P < 0.001) and use of PTBD (P = 0.004)., Conclusions: Use of PTBD, but not EBD, was associated with a poorer prognosis, with an increased rate of peritoneal recurrence among patients who underwent PD for PDAC.

Background: Adjuvant chemotherapy (AC) is recommended as a standard treatment after curative resection in patients with pancreatic adenocarcinoma (PA). Although patients who failed to complete AC had significantly worse survival compared with those who completed AC for cancers in various organs, the effects of complete AC on survival in patients with PA have not been investigated. The purpose of this study was to clarify the impact of complete AC on PA patient survival and to identify independent risk factors for incomplete AC., Methods: Medical records of 236 consecutive PA patients who planned to undergo surgical resection with curative intent between January 2000 and September 2012 at Kobe University Hospital were retrospectively reviewed. Of these, the complete AC (n = 75) and the incomplete AC (n = 30) groups due to adverse events were compared., Results: Patient survival was significantly better in the complete AC group than in the incomplete AC group (median survival time 48.9 vs. 17.9 months; 5-year survival rate 42.7 vs. 17.1 %; p < 0.0001). Preoperative white blood cell count and postoperative serum albumin level were identified as independent risk factors for incomplete AC. By receiver operating characteristic curve analysis, the cutoff value of postoperative serum albumin level was 3.1 mg/dL., Conclusions: PA patients who completed AC had significantly better survival than those who failed to complete AC. Postoperative serum albumin level is a marker for failure to complete AC. Further prospective studies are needed to determine whether perioperative nutritional intervention could increase AC completion rate and improve prognosis in PA patients.

Background: Sorafenib is currently recommended as first-line therapy for patients with intermediate or advanced hepatocellular carcinoma (HCC) per Barcelona Clinic Liver Cancer staging. However, the median overall survival (OS) with sorafenib in these patients is 10.7 months with an overall response rate of 2 %. We retrospectively investigated the long-term outcomes and prognostic factors with reductive hepatectomy and sequential percutaneous isolated hepatic perfusion (PIHP) for refractory intermediate or advanced HCC., Methods: A total of 68 patients who had intermediate or advanced stage HCC without extrahepatic metastases were scheduled for reductive hepatectomy plus PIHP. All patients underwent reductive hepatectomy and PIHP with mitomycin C 20-40 mg/m(2) and/or doxorubicin 60-120 mg/m(2) 1-3 months after surgery (mean, 1.51 times/patient)., Results: The objective response rate of PIHP was 70.6 % (complete plus partial response). The median OS of all 68 patients was 25 months, and the 5-year OS rate was 27.6 %. Univariate and multivariate analyses indicated that tumor response to PIHP and normalization of serum des-γ-carboxy prothrombin concentrations after PIHP were independent prognostic factors for OS., Conclusions: The median OS of the study population treated by reductive hepatectomy and sequential PIHP was 25 months. This treatment strategy can offer a possible curative treatment to patients with refractory intermediate and advanced HCC.

Background: Complete hepatic venous isolation and extracorporeal charcoal hemoperfusion (HVI.CHP) can limit systemic exposure to high-dose chemotherapeutic agents when given by hepatic arterial infusion (HAI). The purpose of this study was to determine if the concomitant use of sodium thiosulfate (STS) could further expand the advantages of pharmacologic delivery of HVI.CHP for cisplatin (CDDP) during HAI chemotherapy., Methods: CDDP (4mg/kg) was administered over 20 minutes via HAI under conditions of HVI.CHP in 14 mongrel dogs. HVI.CHP was performed for 30 minutes after initiation of HAI. During CDDP infusion, 7 dogs each received 400 mg/kg STS (a 100-fold molar ratio to CDDP) over 20 minutes via the prefilter (STS group) circuit line, while the remaining 7 dogs (controls) received no STS. Blood samples were taken serially from the prefilter circuit line (hepatic venous blood), postfilter line, and the left carotid artery (systemic blood). The free and total CDDP concentrations in these samples were determined by flameless atomic absorption spectrophotometry., Results: During 20 minutes HAI of CDDP, the mean CDDP extraction ratios (ER) by CHP filter were always higher in the STS group than in the control group, regardless of the form (free or total) of CDDP. The differences between the STS and control groups in the extraction ratios of free and total CDDP were significant at all time points measured (P < .05). Consequently, systemic exposure to CDDP, as assessed by area under the time-concentration curve of total CDDP, was significantly lower in the STS group than in the control group (P < .05)., Conclusions: These results indicated that concomitant STS infusion could further increase the effect of HVI.CHP on CDDP removal after HAI.