Factors Affecting Nonfunctioning Small Pancreatic Neuroendocrine Neoplasms and Proposed New Treatment Strategies.

BACKGROUND & AIMS: Despite previously reported treatment strategies for nonfunctioning small (≤20 mm) pancreatic neuroendocrine neoplasms (pNENs), uncertainties persist. We aimed to evaluate the surgically resected cases of nonfunctioning small pNENs (NF-spNENs) in a large Japanese cohort to elucidate an optimal treatment strategy for NF-spNENs. METHODS: In this Japanese multicenter study, data were retrospectively collected from patients who underwent pancreatectomy between January 1996 and December 2019, were pathologically diagnosed with pNEN, and were treated according to the World Health Organization 2019 classification. Overall, 1490 patients met the eligibility criteria, and 1014 were included in the analysis cohort. RESULTS: In the analysis cohort, 606 patients (59.8%) had NF-spNENs, with 82% classified as grade 1 (NET-G1) and 18% as grade 2 (NET-G2) or higher. The incidence of lymph node metastasis (N1) by grade was significantly higher in NET-G2 (G1: 3.1% vs G2: 15.0%). Independent factors contributing to N1 were NET-G2 or higher and tumor diameter ≥15 mm. The predictive ability of tumor size for N1 was high. Independent factors contributing to recurrence included multiple lesions, NET-G2 or higher, tumor diameter ≥15 mm, and N1. However, the independent factor contributing to survival was tumor grade (NET-G2 or higher). The appropriate timing for surgical resection of NET-G1 and NET-G2 or higher was when tumors were >20 and >10 mm, respectively. For neoplasms with unknown preoperative grades, tumor size >15 mm was considered appropriate. CONCLUSIONS: NF-spNENs are heterogeneous with varying levels of malignancy. Therefore, treatment strategies based on tumor size alone can be unreliable; personalized treatment strategies that consider tumor grading are preferable.

Intraoperative artificial intelligence system identifying liver vessels in laparoscopic liver resection: a retrospective experimental study.

BACKGROUND: The precise recognition of liver vessels during liver parenchymal dissection is the crucial technique for laparoscopic liver resection (LLR). This retrospective feasibility study aimed to develop artificial intelligence (AI) models to recognize liver vessels in LLR, and to evaluate their accuracy and real-time performance. METHODS: Images from LLR videos were extracted, and the hepatic veins and Glissonean pedicles were labeled separately. Two AI models were developed to recognize liver vessels: the "2-class model" which recognized both hepatic veins and Glissonean pedicles as equivalent vessels and distinguished them from the background class, and the "3-class model" which recognized them all separately. The Feature Pyramid Network was used as a neural network architecture for both models in their semantic segmentation tasks. The models were evaluated using fivefold cross-validation tests, and the Dice coefficient (DC) was used as an evaluation metric. Ten gastroenterological surgeons also evaluated the models qualitatively through rubric. RESULTS: In total, 2421 frames from 48 video clips were extracted. The mean DC value of the 2-class model was 0.789, with a processing speed of 0.094 s. The mean DC values for the hepatic vein and the Glissonean pedicle in the 3-class model were 0.631 and 0.482, respectively. The average processing time for the 3-class model was 0.097 s. Qualitative evaluation by surgeons revealed that false-negative and false-positive ratings in the 2-class model averaged 4.40 and 3.46, respectively, on a five-point scale, while the false-negative, false-positive, and vessel differentiation ratings in the 3-class model averaged 4.36, 3.44, and 3.28, respectively, on a five-point scale. CONCLUSION: We successfully developed deep-learning models that recognize liver vessels in LLR with high accuracy and sufficient processing speed. These findings suggest the potential of a new real-time automated navigation system for LLR.

Survival outcome of patient with pT1N0 biliary tract cancer treated with surgery alone.

INTRODUCTION: Adjuvant chemotherapy (AC) with S-1 or capecitabine monotherapy is now the standard of care for resected biliary tract cancer (BTC) according to the Adjuvant S-1 for Cholangiocarcinoma Trial (ASCOT) and the BILCAP study. Patients selection criteria, especially regarding pT1N0 BTC, differed in both trials. We aimed to clarify the survival outcomes regarding resected pT1N0 BTC without AC. METHODS: Among patients with macroscopically complete resection for BTC treated without AC between September 1992 and December 2020, the survival outcomes of those with pT1N0 BTC, except for intrahepatic cholangiocarcinoma, according to the Union for International Cancer Control 7th and 8th edition (TNM7 and 8), were investigated. RESULTS: Of 749 patients who underwent curative resection for BTC, 69 were identified as having pT1N0 BTC according to TNM8. Six patients (9 %) developed recurrence during the median follow-up period of 53 months (range: 14-263 months) with only one patient (2 %) being pT1N0 according to TNM7. Based on TNM8, the 5-year recurrence-free survival, disease-specific survival, and overall survival reached 90.7 % (95 % confidence interval [CI]: 80.3-95.7 %), 96.4 % (95 % CI: 86.1-99.1 %), and 85.3 % (95 % CI: 71.2-92.8 %), respectively. Perineural invasion (PNI) was significantly associated with recurrence, and the recurrence rate in patients with PNI reached as high as 40 %. CONCLUSIONS: The survival outcomes regarding resected pT1N0 BTC according to TNM7 were excellent without AC; however, those of TNM8 were not, with PNI being associated with recurrence risk.

Liver functional assessment using time-associated change in the liver-to-spleen signal intensity ratio on enhanced magnetic resonance imaging: a retrospective study.

BACKGROUND: Liver-to-spleen signal intensity ratio (LSR) is evaluated by magnetic resonance imaging (MRI) in the hepatobiliary phase and has been reported as a useful radiological assessment of regional liver function. However, LSR is a passive (non-time-associated) assessment of liver function, not a dynamic (time-associated) assessment. Moreover, LSR shows limitations such as a dose bias of contrast medium and a timing bias of imaging. Previous studies have reported the advantages of time-associated liver functional assessment as a precise assessment of liver function. For instance, the indocyanine green (ICG) disappearance rate, which is calculated from serum ICG concentrations at multiple time points, reflects a precise preoperative liver function for predicting post-hepatectomy liver failure without the dose bias of ICG or the timing bias of blood sampling. The aim of this study was to develop a novel time-associated radiological liver functional assessment and verify its correlation with traditional liver functional parameters. METHODS: A total of 279 pancreatic cancer patients were evaluated to clarify fundamental time-associated changes to LSR in normal liver. We defined the time-associated radiological assessment of liver function, calculated using information on LSR from four time points, as the "LSR increasing rate" (LSRi). We then investigated correlations between LSRi and previous liver functional parameters. Furthermore, we evaluated how timing bias and protocol bias affect LSRi. RESULTS: Significant correlations were observed between LSRi and previous liver functional parameters such as total bilirubin, Child-Pugh grade, and albumin-bilirubin grade (P < 0.001 each). Moreover, considerably high correlations were observed between LSRi calculated using four time points and that calculated using three time points (r > 0.973 each), indicating that the timing bias of imaging was minimal. CONCLUSIONS: This study propose a novel time-associated radiological assessment, and revealed that the LSRi correlated significantly with traditional liver functional parameters. Changes in LSR over time may provide a superior preoperative assessment of regional liver function that is better for predicting post-hepatectomy liver failure than LSR using the hepatobiliary phase alone.

Relationships between physical and immunological tumor microenvironment in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is physically palpated as a hard tumor with an unfavorable prognosis. Assessing physical features and their association with pathological features could help to elucidate the mechanism of physical abnormalities in cancer tissues. A total of 93 patients who underwent radical surgery for pancreatic and bile duct cancers at a single center hospital during a 28-month period were recruited for this study that aimed to estimate the stiffness of PDAC tissues compared to the other neoplasms and assess relationships between tumor stiffness and pathological features. Physical alterations and pathological features of PDAC, with or without preoperative therapy, were analyzed. The immunological tumor microenvironment was evaluated using multiplexed fluorescent immunohistochemistry. The stiffness of PDAC correlated with the ratio of Azan-Mallory staining, α-smooth muscle actin, and collagen I-positive areas of the tumors. Densities of CD8+ T cells and CD204+ macrophages were associated with tumor stiffness in cases without preoperative therapy. Pancreatic ductal adenocarcinoma treated with preoperative therapy was softer than that without, and the association between tumor stiffness and immune cell infiltration was not shown after preoperative therapy. We observed the relationship between tumor stiffness and immunological features in human PDAC for the first time. Immune cell densities in the tumor center were smaller in hard tumors than in soft tumors without preoperative therapies. Preoperative therapy could alter physical and immunological aspects, warranting further study. Understanding of the correlations between physical and immunological aspects could lead to the development of new therapies.

A novel predictive model for postoperative delirium using multiple geriatric screening factors.

OBJECTIVES: The purpose of this study was to develop a new composite score to accurately predict postoperative delirium (POD) after major urological cancer surgery. METHODS: Our retrospective analysis included, in total, 449 consecutive patients who experienced major urological cancer surgery and a preoperative geriatric functional assessment at our institution (development cohort). Geriatric functional assessments included Geriatric 8, Instrumental Activities of Daily Living, and mini-cognitive assessment instrument (Mini-Cog). Multivariate analysis was used to identify factors related to POD and combined to create a predictive score. The composite score was externally validated using a cohort of 92 consecutive pancreatic cancer patients who underwent pancreaticoduodenectomy and a preoperative geriatric functional assessment (validation cohort). The predictive accuracy and performance of the composite score were evaluated using the area under the receiver operating characteristic curves (AUC) and calibration plots. RESULTS: In multivariate analysis of a development cohort, the following factors were significantly associated with POD: a Mini-Cog score of <3 (odds ratio [OR] = 9.5; p < 0.001), disability in the responsibility for medication (OR = 4.1; p = 0.03), and the preoperative use of benzodiazepine (OR = 6.4; p < 0.001). The composite score of these three factors showed excellent discrimination in predicting POD, with AUC values of 0.819 and 0.804 in development and validation cohorts, respectively. Calibration plots showing predicted probability and actual observation in both cohorts showed good agreement. CONCLUSIONS: A combined model of Mini-Cog, a disability in the responsibility for medication, and preoperative benzodiazepine use showed excellent discriminative power in predicting POD.

Surgical Outcomes of Pancreatectomy with Resection of the Portal Vein and/or Superior Mesenteric Vein and Jejunal Vein for Pancreatic Head Cancer: A Multicenter Study.

OBJECTIVE: The aim of this study was to investigate the safety and survival benefits of portal vein and/or superior mesenteric vein (PV/SMV) resection with jejunal vein resection (JVR) for pancreatic ductal adenocarcinoma (PDAC). SUMMARY BACKGROUND DATA: Few studies have shown the surgical outcome and survival of pancreatic resection with JVR, and treatment strategies for patients with PDAC suspected of jejunal vein (JV) infiltration remain unclear. METHODS: In total, 1260 patients who underwent pancreatectomy with PV/ SMV resection between 2013 and 2016 at 50 facilities were included; treatment outcomes were compared between the PV/SMV group (PV/ SMV resection without JVR; n = 824), PV/SMV-J1 V group (PV/SMV resection with first jejunal vein resection; n = 394), and PV/SMV-J2,3 V group (PV/SMV resection with second jejunal vein or later branch resection; n = 42). RESULTS: Postoperative complications and mortality did not differ between the three groups. The postoperative complication rate associated with PV/ SMV reconstruction was 11.9% in PV/SMV group, 8.6% in PV/SMV-J1 V group, and 7.1% in PV/SMV-J2,3V group; there were no significant differences among the three groups. Overall survival did not differ between PV/SMV and PV/SMV-J1 V groups (median survival; 29.2 vs 30.9 months, P = 0.60). Although PV/SMV-J2,3 V group had significantly shorter survival than PV/SMV group who underwent upfront surgery ( P = 0.05), no significant differences in overall survival of patients who received preoperative therapy. Multivariate survival analysis revealed that adjuvant therapy and R0 resection were independent prognostic factors in all groups. CONCLUSION: PV/SMV resection with JVR can be safely performed and may provide satisfactory overall survival with the pre-and postoperative adjuvant therapy.

Early postoperative decrease of skeletal muscle mass predicts recurrence and poor survival after surgical resection for perihilar cholangiocarcinoma.

BACKGROUND: Preoperative sarcopenia is a predictor of poor survival in cancer patients. We hypothesized that sarcopenia could progress as occult metastasis arose, especially after highly invasive surgery for highly aggressive malignancy. This study aimed to evaluate the associations of postoperative changes in skeletal muscle mass volume with survival outcomes in patients who underwent surgery for perihilar cholangiocarcinoma. METHODS: Fifty-six patients who underwent major hepatectomy with extrahepatic bile duct resection for perihilar cholangiocarcinoma were studied. The skeletal muscle index (SMI) at the third lumbar vertebra was calculated from axial computed tomography images taken preoperatively and 3-6 months postoperatively (early postoperative period). The associations of clinicopathological variables, including changes of SMI after surgery, with overall survival and recurrence-free survival were evaluated. Moreover, the associations of decreased SMI and elevated serum carbohydrate antigen 19-9 level with early recurrence and poor survival was compared. RESULTS: Among 56 patients, 26 (46%) had sarcopenia preoperatively and SMI decreased in 29 (52%) in the early postoperative period. During the median follow-up of 57.9 months, 35 patients (63%) developed recurrence and 29 (50%) died. Decreased SMI in the early postoperative period was independently associated with a shorter overall survival (hazard ratio, 2.39; 95% confidence interval, 1.00-6.18; P = 0.049) and a shorter recurrence-free survival (hazard ratio, 2.14; 95% confidence interval, 1.04-4.57; P = 0.039), whereas elevated carbohydrate antigen 19-9 level was not. CONCLUSIONS: Decreased SMI in the early postoperative period may be used as a predictor for recurrence and poor survival in patients undergoing surgery for perihilar cholangiocarcinoma.

Automated surgical workflow identification by artificial intelligence in laparoscopic hepatectomy: Experimental research.

BACKGROUND: To perform accurate laparoscopic hepatectomy (LH) without injury, novel intraoperative systems of computer-assisted surgery (CAS) for LH are expected. Automated surgical workflow identification is a key component for developing CAS systems. This study aimed to develop a deep-learning model for automated surgical step identification in LH. MATERIALS AND METHODS: We constructed a dataset comprising 40 cases of pure LH videos; 30 and 10 cases were used for the training and testing datasets, respectively. Each video was divided into 30 frames per second as static images. LH was divided into nine surgical steps (Steps 0-8), and each frame was annotated as being within one of these steps in the training set. After extracorporeal actions (Step 0) were excluded from the video, two deep-learning models of automated surgical step identification for 8-step and 6-step models were developed using a convolutional neural network (Models 1 & 2). Each frame in the testing dataset was classified using the constructed model performed in real-time. RESULTS: Above 8 million frames were annotated for surgical step identification from the pure LH videos. The overall accuracy of Model 1 was 0.891, which was increased to 0.947 in Model 2. Median and average accuracy for each case in Model 2 was 0.927 (range, 0.884-0.997) and 0.937 ± 0.04 (standardized difference), respectively. Real-time automated surgical step identification was performed at 21 frames per second. CONCLUSIONS: We developed a highly accurate deep-learning model for surgical step identification in pure LH. Our model could be applied to intraoperative systems of CAS.

Laparoscopic liver resection can be performed safely without intraoperative drain placement.

BACKGROUND: Laparoscopic liver resection (LLR) has become a standardized procedure with advances in surgical techniques and perioperative management in the last decade; however, the necessity of routine drain placement in LLR has not been fully investigated. This study aimed to evaluate the need for intraoperative drain placement (IDP) in LLR. METHODS: A total of 607 patients who underwent LLR for liver tumor at our institution between January 2015 and August 2021 were studied. Clinicopathological data, including intraoperative factors and postoperative outcomes, were compared between patients with and without IDP before and after propensity score matching. Variables shown to be different between the two groups were used for matching. Then, risk analysis for additional drainage procedure after surgery was performed in the original and matched cohorts. RESULTS: Of the 607 patients, 4 (0.7%) and 14 (2.3%) developed incisional and organ/space surgical site infections, respectively, and 9 (1.5%) required additional drainage procedure after surgery. Ninety-three patients (15.3%) underwent IDP. The incidence and severity of postoperative complications were similar between patients with and without IDP in both the original and matched cohorts. In the matched cohort, simultaneous colectomy (odds ratio, 14.051, 95% confidence interval, 1.103-178.987; P = 0.042), rather than IDP (odds ratio, 1.836, 95% confidence interval, 0.157-21.509; P = 0.629), was independently associated with the risk of additional drainage procedure after surgery. CONCLUSIONS: This study demonstrated that LLR could be performed safely without IDP.

Histological tumor necrosis in pancreatic cancer after neoadjuvant therapy.

The pathological prognostic factors in pancreatic cancer patients who have received neoadjuvant therapy (NAT) are still elusive. The aim of the present study was to investigate the prognostic potential of histological tumor necrosis (HTN) in patients who received NAT and to evaluate tumor changes after NAT. HTN was studied in 44 pancreatic cancer patients who received NAT followed by surgery (NAT group) compared with 263 patients who received upfront surgery (UFS group). The prognostic factors in the NAT group were analyzed, and carbonic anhydrase 9 (CA­9) expression was compared between the NAT and USF group to evaluate the hypoxic microenvironment changes during NAT. HTN was found in 15 of 44 patients in the NAT group, and its frequency was lower than that in the UFS group (34 vs. 51%, P=0.04). Cox proportional hazards models identified HTN as an independent risk factor for relapse­free survival in the NAT group [risk ratio (RR), 5.60; 95% confidence interval (CI): 2.27­14.26, P<0.01]. Significant correlations were found between HTN and CA­9 expression both in the NAT and UFS groups (P<0.01 for both). CA­9 expression was significantly upregulated in the NAT group overall, although this upregulation was specifically induced in patients without HTN. In conclusion, HTN was a poor prognostic factor in pancreatic cancer patients receiving NAT followed by surgery, and the present study suggests a close association between HTN and tumor hypoxia. Increased hypoxia after NAT may support the thesis for re­engineering the hypoxia­alleviating tumor microenvironment in NAT regimens for pancreatic cancer.

Component with abundant immune-related cells in combined hepatocellular cholangiocarcinoma identified by cluster analysis.

Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a heterogeneous tumor sharing histological features with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). The tumor immune microenvironment (TIME) of cHCC-CCA is unclear. We compared the TIME of cHCC-CCA with that of HCC and iCCA. Twenty-three patients with cHCC-CCA after hepatectomy were evaluated in this study. Twenty-three patients with iCCA and HCC were also included. iCCA was matched for size, and HCC was matched for size and hepatitis virus infection with cHCC-CCA. Immune-related cells among the iCCA-component of cHCC-CCA (C-com), HCC-component of cHCC-CCA (H-com), iCCA, and HCC were assessed using multiplex fluorescence immunohistochemistry. Among C-com, H-com, iCCA, and HCC, multiple comparisons and cluster analysis with k-nearest neighbor algorithms were performed using immunological variables. Although HCC had more T lymphocytes and lower PD-L1 expression than iCCA (P < 0.05), there were no significant differences in immunological variables between C-com and H-com. C-com tended to have more T lymphocytes than iCCA (P = 0.09), and C-com and H-com had fewer macrophages than HCC (P < 0.05). In cluster analysis, all samples were classified into two clusters: one cluster had more immune-related cells than the other, and 12 of 23 H-com and eight of 23 C-com were identified in this cluster. The TIME of C-com and H-com may be similar, and some immunological features in these components were different from those in HCC and some iCCA. Cluster analysis identified components with abundant immune-related cells in cHCC-iCCA.

The Assessment of Regional Liver Function Before Major Hepatectomy Using Magnetic Resonance Imaging.

BACKGROUND: The liver-to-spleen signal intensity ratio (LSR) on magnetic resonance imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid has been used as a parameter to assess liver function. LSR of the future remnant liver region (FR-LSR) is included in preoperative assessment of regional liver function. The aim of this study was to investigate the predictability of post-hepatectomy liver failure (PHLF) by FR-LSR. METHODS: Between May 2013 and May 2019, 127 patients underwent standardized EOB-MRI for diagnosis of liver tumor before major hepatectomy. The FR-LSR on EOB-MRI was calculated by a semiautomated three-dimensional volumetric analysis system. The cutoff value of FR-LSR in association with clinically relevant PHLF was determined according to the areas under the receiver operating characteristic curves. Then, FR-LSR and clinical variables were analyzed to assess the risk of clinically relevant PHLF. RESULTS: In patients with preoperative biliary drainage, metastatic liver tumor, estimated future remnant liver volume <50%, biliary reconstruction, operation time ≥ 480 min, estimated blood loss ≥ 1000 g, blood transfusion and a FR-LSR < 2.00 were associated with clinically relevant PHLF (P < .05 for all) in univariable analysis. The liver-to-spleen signal intensity ratio of the future remnant liver region < 2.00 was the only independent risk factor for clinically relevant PHLF in multivariable risk analysis (OR, 27.90; 95% CI: 7.99-136.40; P < .05). DISCUSSION: The present study revealed that FR-LSR calculated using a 3-dimensional volumetric analysis system was an independent risk factor for clinically relevant PHLF. The liver-to-spleen signal intensity ratio of the future remnant liver region might be a reliable preoperative parameter in liver functional assessment, enabling safe performance of major hepatectomy.

Hypothyroidism and hypopituitarism as immune-related adverse events due to lenvatinib plus pembrolizumab therapy in the immediate postoperative period after laparoscopic hepatectomy for liver metastases from gastric cancer: a case report.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are emerging agents used for the treatment of various malignant tumors. As ICIs are generally used for unresectable malignant tumors, there have been only a few reports of patients who underwent surgery after receiving these drugs. Therefore, it remains unclear how immune-related adverse events (irAEs) affect the postoperative course. Here, we report a patient with advanced gastric cancer who underwent laparoscopic hepatectomy for liver metastases after an objective response with lenvatinib plus pembrolizumab and developed hypothyroidism and hypopituitarism as irAEs in the immediate postoperative period. CASE PRESENTATION: A 73-year-old man had undergone total gastrectomy for pT4aN2M0 gastric cancer followed by adjuvant chemotherapy with S-1 and docetaxel, and developed liver metastases in segments 6 and 7. He was enrolled in phase 2 clinical trial of lenvatinib plus pembrolizumab. He continuously achieved a partial response with the study treatment, and the liver metastases were decreased in size on imaging. The tumors were judged to be resectable and the patient underwent laparoscopic partial hepatectomy for segments 6 and 7. From the 1st postoperative day, the patient continuously presented with fever and general fatigue, and his fasting blood glucose level remained slightly lower than that before the surgery. On the 4th postoperative day, laboratory examination revealed hypothyroidism and hypopituitarism, which were suspected to be irAE caused by lenvatinib plus pembrolizumab after surgery. He received hydrocortisone first, followed by levothyroxine after adrenal insufficiency was recovered. Subsequently, his fever, general fatigue, and any abnormality regarding fasting blood glucose level resolved, and he was discharged on the 12th postoperative day. After discharge, his laboratory data for thyroid and pituitary function remained stable while receiving hydrocortisone and levothyroxine without recurrence of gastric cancer. CONCLUSION: We present a case of laparoscopic hepatectomy after receiving lenvatinib plus pembrolizumab and developed hypothyroidism and hypopituitarism after surgery. Regarding surgery after ICI therapy, it is important to recognize that irAEs might occur in the postoperative period.

BRAF V600E potentially determines "Oncological Resectability" for "Technically Resectable" colorectal liver metastases.

Despite reports on poor survival outcomes after hepatectomy for colorectal liver metastases (CRLM) with BRAF V600E mutation (mBRAF) exist, the role of mBRAF testing for technically resectable cases remains unclear. A single-center retrospective study was performed to investigate the survival outcomes of patients who underwent upfront hepatectomy for solitary resectable CRLM with mBRAF between January 2005 and December 2017 and to compare them with those of unresectable cases with mBRAF. Of 172 patients who underwent initial hepatectomy for solitary resectable CRLM, mBRAF, RAS mutations (mRAS), and wild-type RAS/BRAF (wtRAS/BRAF) were observed in 5 (2.9%), 73 (42.4%), and 93 (54.7%) patients, respectively. With a median follow-up period of 72.8 months, mBRAF was associated with a significantly shorter OS (median, 14.4 months) than wtRAS/BRAF (median, not reached [NR]) (hazard ratio [HR], 27.6; p < 0.001) and mRAS (median, NR) (HR, 9.9; p < 0.001), and mBRAF had the highest HR among all the indicators in the multivariable analysis (HR, 17.0; p < 0.001). The median OS after upfront hepatectomy for CRLM with mBRAF was identical to that of 28 unresectable CRLM with mBRAF that were treated with systemic chemotherapy (median, 17.2 months) (HR, 0.78; p = 0.65). When technically resectable CRLM are complicated with mBRAF, its survival outcome becomes as poor as unresectable cases; therefore, those with mBRAF should be considered as oncologically unresectable. Patients with CRLM should undergo pre-treatment mBRAF testing regardless of technical resectability. Clinical trial registration number: UMIN000034557.

Recognition and pathological features of periampullary region adenocarcinoma with an indeterminable origin.

Determination of the primary tumor in periampullary region carcinomas can be difficult, and the pathological assessment and clinicopathological characteristics remain elusive. In this study, we investigated the current recognition and practices for periampullary region adenocarcinoma with an indeterminable origin among expert pathologists through a cognitive survey. Simultaneously, we analyzed a prospective collection of cases with an indeterminable primary tumor diagnosed from 2008 to 2018 to elucidate their clinicopathological features. All cases with pathological indeterminable primary tumors were reported and discussed in a clinicopathological conference to elucidate if it was possible to distinguish the primary tumor clinically and pathologically. From the cognitive survey, over 85% of the pathologists had experienced cases with indeterminable primary tumors; however, 70% of the cases was reported as pancreatic cancer without definitive grounds. Interpretation of the main tumor mass varied, and no standardized method was developed to determine the primary tumor. During a prospective study, 42 of the 392 periampullary carcinoma cases (10.7%) were considered as tumors with a pathological indeterminable origin. After the clinicopathological conferences, 21 (5.4%) remained indeterminable and were considered final indeterminable cases. Histological studies showed that the tumors spread along both the bile duct and main pancreatic duct; this was the most representative finding of the final indeterminable cases. This study is the first to elucidate and recognize the current clinicopathological features of periampullary region adenocarcinomas with an indeterminable origin. Adequate assessment of primary tumors in periampullary region carcinomas will help to optimize epidemiological data of pancreatic and bile duct cancer.

Impact of previous history of choledochojejunostomy on the incidence of organ/space surgical site infection after hepatectomy.

PURPOSE: Impact of previous history of choledochojejunostomy (PCJ) on the incidence of organ/space surgical site infection (SSI) after hepatectomy remains unclear. The aim of this study was to investigate the incidence and causes of SSI after hepatectomy. METHODS: Patients who underwent hepatectomy of ≤1 Couinaud's sector between January 2011 and September 2019 were retrospectively analyzed. Incidence of and risk factors for organ/space SSI (Clavien-Dindo grade ≥2) after hepatectomy were investigated. RESULTS: Among 750 hepatectomies, 18 patients (2.4%) had a medical history of PCJ. Incidence of organ/space SSI was higher in patients with PCJ (50%) than in those without PCJ (3%, P < 0.001), and the trend was consistent even after estimated propensity score matched cohort. Multivariate analysis showed PCJ was a strong risk factor for organ/space SSI (grade ≥2), with the highest odds ratios (OR) among all other clinicopathological risk factors (OR, 32.25; P < 0.001). Among hepatectomies with PCJ, pneumobilia (OR, 12.25; P = 0.015), operation time ≥171 min (OR, 12.25; P = 0.016), and liver steatosis (OR, 24.00; P ≤ 0.005) were associated with organ/space SSI after hepatectomy. CONCLUSION: Previous history of choledochojejunostomy was a strong risk factor for organ/space SSI after hepatectomy. The high rate of organ/space SSI after hepatectomy with PCJ might be attributed to intrahepatic bile duct contamination, increased operation time, and histological liver steatosis.

Sarcomatoid hepatocellular carcinoma is distinct from ordinary hepatocellular carcinoma: Clinicopathologic, transcriptomic and immunologic analyses.

Sarcomatoid hepatocellular carcinoma (SHCC), which was a rare histological subtype of hepatocellular carcinoma (HCC), is currently subclassified as poorly differentiated HCC because of insufficient evidence to define SHCC as a subtype of HCC. We aimed to assess the feasibility of classifying SHCC as a histological subtype of HCC by comprehensively identifying novel and distinct characteristics of SHCC compared to ordinary HCC (OHCC). Fifteen SHCCs (1.4%) defined as HCC with at least a 10% sarcomatous component, 15 randomly disease-stage-matched OHCCs and 163 consecutive OHCCs were extracted from 1106 HCCs in the Pathology Database (1997-2019) of our hospital. SHCC patients showed poor prognosis, and the tumors could be histologically subclassified into the pleomorphic, spindle and giant cell types according to the subtype of carcinomas with sarcomatoid or undifferentiated morphology in other organs. The transcriptomic analysis revealed distinct characteristics of SHCC featuring the upregulation of genes associated with epithelial-to-mesenchymal transition and inflammatory responses. The fluorescent multiplex immunohistochemistry results revealed prominent programmed death-ligand 1 (PD-L1) expression on sarcomatoid tumor cells and higher infiltration of CD4+ and CD8+ T cells in SHCCs compared to OHCCs. The density of CD8+ T cells in the nonsarcomatous component of SHCCs was also higher than that in OHCCs. In conclusion, the comprehensive analyses in our study demonstrated that SHCC is distinct from OHCC in terms of clinicopathologic, transcriptomic and immunologic characteristics. Therefore, it is reasonable to consider SHCC as a histological subtype of HCC.

Impact of Preoperative Circulating Tumor DNA Status on Survival Outcomes After Hepatectomy for Resectable Colorectal Liver Metastases.

BACKGROUND: The optimal perioperative management of patients who undergo hepatectomy for resectable colorectal liver metastases (CRLM) remains unclear due to the lack of reliable methods to stratify the risk of recurrence. METHODS: A single-center retrospective study was performed to investigate the impact of preoperative circulating tumor DNA (ctDNA) on survival outcomes of patients who underwent initial hepatectomy for solitary resectable CRLM between January 2005 and December 2017 using the comprehensive genotyping platform Guardant360®. RESULTS: Of 212 patients who underwent initial hepatectomy for solitary resectable CRLM, 40 patients for whom pre-hepatectomy plasma was available underwent ctDNA analysis. Among them, 32 (80%) had at least 1 somatic alteration in their ctDNA, while the other 8 (20%) had no detectable ctDNA. Among the patients with undetectable ctDNA, only one had recurrence and none died during a median follow-up period of 39.0 months. The recurrence-free survival was significantly shorter in patients who were positive for ctDNA than in those who were negative for ctDNA [median, 12.5 months vs not reached (NR); HR, 7.6; P = 0.02]. The overall survival also tended to be shorter in patients who were positive for ctDNA than those who were negative for ctDNA (median, 78.1 months vs NR; P = 0.14; HR not available). CONCLUSIONS: In patients undergoing hepatectomy for solitary resectable CRLM, the absence of detectable preoperative ctDNA identified patients with a high chance for a cure. Risk stratification according to preoperative ctDNA analysis may be an effective tool that can improve the perioperative management of these patients.

Clinical impact of radiofrequency ablation and stereotactic body radiation therapy for colorectal liver metastasis as local therapies for elderly, vulnerable patients.

BACKGROUND AND AIM: Surgical resection is the standard local therapy for patients with colorectal liver metastases (CRLM). However, elderly and vulnerable patients sometimes have various organ dysfunctions. We have to conduct nonsurgical local therapies for those patients who might not tolerate surgery or systemic chemotherapy. METHODS: We retrospectively reviewed medical records of 254 patients who underwent local therapies, including surgery, radiofrequency ablation (RFA), and stereotactic body radiation therapy (SBRT), for CRLM from January 2010 to December 2016, at seven tertiary-care institutions in Japan. This study was designed to include elderly, vulnerable patients who received local therapy for CRLM. For those undergoing liver resection, only those having one or more points of the Charlson comorbidity index (CCI) were enrolled. RESULTS: Of the total 169 enrolled patients, 122 patients underwent surgery, 42 RFA, and 5 SBRT as the first local therapy for CRLM. Median overall survival from the first local therapy was 5.9 years for the surgery group, 2.7 years for the RFA group, and 3.8 years for the SBRT group. The proportion of the patients with CCI ≧3 was significantly higher in the group of RFA/SBRT than surgery (P < 0.0001). In selected patients with CCI ≧3, there was no difference of the median survival time between the surgery group and the RFA group. CONCLUSIONS: We could have other treatment options to provide nonsurgical local therapies (RFA/SBRT) for elderly, vulnerable CRLM patients who have risks for surgery.