Impact of Surgical Margin Status on Survival and Recurrence After Pancreaticoduodenectomy for Distal Cholangiocarcinoma: Is Microscopic Residual Tumor (R1) Associated with Higher Rates of Local Recurrence?

BACKGROUND: Patients undergoing macroscopically curative resection for distal cholangiocarcinoma (DCC) have high recurrence rates and poor prognoses. This study aimed to investigate the impact of surgical margin status on survival and recurrence after resection of DCC, specifically focusing on microscopic residual tumor (R1) and its relationship to local recurrence. PATIENTS AND METHODS: This was a retrospective analysis of patients who had undergone pancreaticoduodenectomy (PD) for DCC between 2005 and 2021. Surgical margin was classified as R0, R1cis (positive bile duct margin with carcinoma in situ), and R1inv (positive bile duct margin with an invasive subepithelial component and/or positive radial margin). RESULTS: In total, 29 of 133 patients (21.8%) had R1cis and 23 (17.3%) R1inv. The 5-year overall survival (OS) for R0 (55.7%) did not differ significantly from that for R1cis/R1inv (47.4%/33.6%, respectively). The 5-year recurrence-free survival (RFS) for R0 was significantly longer than that for R1inv (50.1% vs. 17.4%, p = 0.003), whereas RFS did not differ significantly between those with R0 and R1cis. R1cis/R1inv status was not an independent predictor of OS and RFS in multivariate analysis. Cumulative incidence of isolated distant recurrence was significantly higher for R1cis/R1inv than for R0 (p = 0.0343/p = 0.0226, respectively), whereas surgical margin status was not significantly associated with rates of local or local plus distant recurrence. CONCLUSIONS: Surgical margin status does not significantly impact OS and RFS in patients undergoing PD for DCC following precise preoperative imaging evaluation. Additionally, R1 status is significantly linked to higher isolated distant recurrence rather than local recurrence, highlighting the importance of multidisciplinary therapy.

[A case of R0 resection in conversion surgery after duodenal stent placement for locally advanced unresectable pancreatic cancer with duodenal stenosis].

A 67-year-old man presented to our hospital with vomiting. Esophagogastroduodenoscopy revealed duodenal stenosis and atypical epithelium. A tumor in the pancreatic head, about 30mm in size, involving the superior mesenteric artery and a superior mesenteric vein was identified using abdominal contrast computed tomography (CT). Locally advanced pancreatic cancer was diagnosed in the patient through an endoscopic biopsy. Due to the duodenal stenosis complication, duodenal stent placement was conducted. After stent placement, oral intake was resumed, and improvement of the systemic condition led to chemotherapy (modified FOLFIRINOX). After chemotherapy, CT revealed decreased carcinoma progression and vascular invasion. Conversion surgery was improved, and R0 resection was achieved. Our study showed that duodenal stent placement could enhance prognosis;as a result, it was regarded as a good choice for multidisciplinary therapy.

NEXUS trial: a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant colorectal oligometastases.

BACKGROUND: The optimal treatment strategy for resectable BRAF V600E mutant colorectal oligometastases (CRM) has not been established due to the rarity and rapid progression of the disease. Since the unresectable recurrence rate is high, development of novel perioperative therapies are warranted. On December 2020, the BEACON CRC triplet regimen of encorafenib, binimetinib, and cetuximab was approved for unresectable metastatic colorectal cancer in Japan. METHODS: The NEXUS trial is a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant CRM. The key inclusion criteria are as follows: histologically diagnosed with colorectal adeno/adenosquamous carcinoma; RAS wild-type and BRAF V600E mutation by tissue or blood; and previously untreated resectable distant metastases. The triplet regimen (encorafenib: 300 mg daily; binimetinib: 45 mg twice daily; cetuximab: 400 mg/m2, then 250 mg/m2 weekly, 28 days/cycle) is administered for 3 cycles each before and after curative resection. The primary endpoint of the study is the 1-year progression-free survival (PFS) rate and the secondary end points are the PFS, disease-free survival, overall survival, and objective response rate. The sample size is 32 patients. Endpoints in the NEXUS trial as well as integrated analysis with the nationwide registry data will be considered for seeking regulatory approval for the perioperative use of the triplet regimen. DISCUSSION: The use of the triplet regimen in the perioperative period is expected to be safe and effective in patients with resectable BRAF V600E mutant CRM. TRIAL REGISTRATION: jRCT2031220025, April. 16, 2022.

Objective Definition and Optimized Strategy for "Biologically Borderline Resectable" Colorectal Liver Metastases.

BACKGROUND: The prognostic benefit of preoperative chemotherapy leading to conversion surgery for unresectable colorectal liver metastases (CRLM) is well recognized, while that of neoadjuvant chemotherapy (NAC) compared with upfront surgery (UFS) for resectable CRLM is negligible. This study aims to assess the prognostic benefit and search for optimal indication of NAC for resectable advanced CRLM by establishing an objective definition of biologically borderline resectable (bBR) CRLM. METHODS: A bicentric retrospective analysis of patients with CRLM undergoing curative-intent initial liver resection between 2007 and 2021 was performed. An original classification matrix was established, which reassessed technical resectability using virtual hepatectomy and oncological favorability using Beppu's nomogram. Patients with technically resectable but biologically unfavorable CRLM were classified into the bBR group. The propensity score matching analysis using preoperatively available factors was performed to assess long-term outcomes of the bBR-UFS and bBR-NAC groups. RESULTS: Of 831 patients reviewed, 240 were categorized into the bBR group: bBR -UFS (n = 139) and bBR-NAC (n = 101). Ten (10%) in the bBR-NAC group (n = 101) experienced biological status change from unfavorable to favorable after NAC (Biological Conversion) and showed significantly longer overall survival (hazard ratio 5.63, 95% confidence interval 1.37-23.1; P = 0.016) than the bBR-UFS group. However, after propensity score matching, no significant difference between the UFS and NAC groups (n = 67 for each) was found in long-term outcomes. CONCLUSIONS: NAC for bBR-CRLM did not enhance the prognostic impact of the following liver resection, except for a limited number of optimal candidates experiencing the Biological Conversion.

Enhanced Recognition Confidence of Millimeter-Sized Intrahepatic Targets by Real-Time Virtual Sonography.

OBJECTIVES: Real-time virtual sonography (RVS) is an artificial-intelligence-assisted ultrasonographic navigation system that displays synchronized preoperative computed tomography (CT) images corresponding to real-time intraoperative ultrasonograms (IOUS). This study aimed to investigate whether RVS can enhance IOUS identification of small intrahepatic targets found in preoperative CT. METHODS: Patients with small intrahepatic targets detected by preoperative thin-slice dynamic CT before liver resection were included. The targets included millimeter-sized liver tumors or a third-order or more distal portal branch and were marked on CT images using 3D simulation software. After laparotomy, the targets were searched using fundamental IOUS, and participating liver surgeons subjectively scored the target identifying confidence on a scale of 1-5 (5 points for detection with the highest confidence and one point for undetectable). Then, the search procedure was repeated using the RVS, and the scores were compared. RESULTS: Totally, 55 patients with 117 small targets were investigated. The median target size was 6.0 mm, and the median registration time was 3.6 seconds. The target identification confidence score significantly increased from 2.78 to 4.52 points after using RVS. Seventeen targets (14.5%) were undetectable in fundamental IOUS, and 14 of them were identified by RVS. The detectability of small liver tumors (2-5 points of identification confidence) by IOUS was 81.1 and 96.7% by RVS. CONCLUSION: RVS enhanced surgeons' confidence in identifying millimeter-sized intrahepatic targets found in preoperative CT.

Prognostic Impact of Radiological Splenic Artery Involvement in Pancreatic Ductal Adenocarcinoma of the Body and Tail.

BACKGROUND: Splenic artery (SpA) involvement heralds poor prognosis in pancreatic ductal adenocarcinoma (PDAC) of the body and tail but is not included in the resectability criteria. This study evaluated the prognostic impact of radiological SpA involvement in PDAC of the body and tail. METHODS: Preoperative computed tomography images of patients who underwent distal pancreatectomy for resectable PDAC of the body and tail (n = 242) at our hospital between 2004 and 2018 were graded according to splenic vessel involvement status as clear, abutment, or encasement. Clinicopathological prognostic factors and overall survival (OS) and recurrence-free survival (RFS) rates were compared between the three groups. The prognostic value of radiological involvement status was assessed using Harrell's concordance statistic (C-index) and time-dependent receiver-operating characteristic curve analysis and compared with pathological findings. RESULTS: The diagnostic concordance rate was 0.87 (weighted κ statistic). Prognosis worsened with progression from clear, abutment, to encasement status. SpA encasement (hazard ratio [HR] 1.97, p = 0.04) predicted poor OS in multivariate Cox hazard regression analysis. SpA abutment (HR 1.77, p = 0.017) and encasement (HR 1.86, p = 0.034) independently predicted poor RFS. Splenic vein abutment and encasement were not significant predictors of poor OS or RFS. SpA encasement without adjuvant chemotherapy had the poorest prognosis because of early distant metastasis. The prognostic value was higher for radiological SpA involvement than for pathological SpA invasion. CONCLUSIONS: Radiological SpA involvement status is a meaningful and reproducible prognostic indicator that can be used preoperatively for determining the treatment strategy in PDAC of the body and tail.

Chronological improvement of pancreatectomy for resectable but advanced pancreatic neuroendocrine neoplasms.

BACKGROUND: Progress of non-surgical treatments in the last decade has improved the prognosis of pancreatic neuroendocrine neoplasms (PanNEN). However, the improvement of surgery for advanced PanNEN remains unknown. This study aimed to investigate the chronological changes of the clinical impact of pancreatectomy for PanNEN. METHODS: Patients undergoing curative-intent pancreatectomy for PanNEN between 1991 and 2010 were categorized into the earlier period group, and those between 2011 and 2021 were into the later period group. Advanced PanNEN was defined as showing resectable synchronous liver metastases or invasion to portal venous systems or adjacent organs. The recurrence-free survival (RFS) and overall survival (OS) were analyzed among patients with non-advanced and advanced PanNENs. The independent prognostic risk factors were identified using a Cox proportional hazard model. RESULTS: A total of 189 patients (n = 54 in the earlier period and n = 135 in the later period) were included. The proportion of advanced PanNEN increased from 15% to 30% (P = 0.027). The RFS and OS of non-advanced PanNEN were similar between the periods. Whereas, among patients with advanced PanNEN, the later period group showed improved prognosis; The 5-year RFS of the earlier period vs. the later period was 0% vs. 27%, and the 5-year OS was 38% vs. 82% (p = 0.013). CONCLUSIONS: A radical surgical treatment for advanced PanNEN has shown prognostic improvement in this decade. However, more careful perioperative examinations and possibly, additional treatments are required for PanNEN with portal vein invasion.

Application of albumin-bilirubin grade and platelet count to indocyanine green-based criteria for hepatectomy: Predicting impaired liver function and postoperative outcomes of hepatocellular carcinoma.

BACKGROUND: Applicability of the albumin-bilirubin (ALBI) grade in preoperative decision-making criteria based on the indocyanine green retention (ICG) test remains unclear. This study aimed to predict abnormal ICG values using standard blood tests and evaluate the impact on postoperative outcomes among patients undergoing hepatectomy for hepatocellular carcinoma (HCC). METHODS: Data on 949 consecutive HCC patients undergoing curative-intent hepatectomy between 1996 and 2014 were retrospectively assessed. A nomogram using preoperative standard blood tests was created to predict abnormal ICGR15 (>15%). RESULTS: Three-hundred nine patients had abnormal ICGR15. Predictors of abnormal ICGR15 included in the nomogram were: ALBI grade >1 (hazard ratio [HR]: 2.16, 95% confidence interval [CI]: 1.59-2.94), platelet count <130 000/mm3 (HR: 2.27, 95% CI: 1.68-3.08), aspartate aminotransferase >50 (IU/L) (HR: 1.90, 95% CI: 1.29-2.81), and viral hepatitis infection (HR: 1.46, 95% CI: 1.03-2.07). The nomogram named the PLT-ALBI score was discriminative [C-statistics: 0.719 (0.684-0.754)], and reliable (Hosmer-Lemeshow Chi-Square: 9.05, p = 0.338). The higher PLT-ALBI score was associated with a more frequent incidence of clinically relevant posthepatectomy liver failure and poor overall survival. CONCLUSIONS: The PLT-ALBI score is applicable in distinguishing HCC patients with abnormal ICGR15. Patients with higher PLT-ALBI score require more careful postoperative care, despite following the ICG criteria.

Phase I/II study of streptozocin monotherapy in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: This phase I/II study was conducted to evaluate the efficacy, safety and pharmacokinetics of streptozocin (STZ) in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors. METHODS: Twenty-two patients received up to 4 cycles of intravenous STZ at either 500 mg/m2 once daily for 5 consecutive days every 6 weeks (daily regimen) or at 1000-1500 mg/m2 once weekly for 6 weeks (weekly regimen). Tumor response was evaluated using the modified RECIST criteria ver. 1.1, and adverse events were assessed by grade according to the National Cancer Institute CTCAE (ver. 4.0). RESULTS: Fourteen (63.6%) patients completed the study protocol. No patients had complete response; partial response in 2 (9.1%), stable disease in 17 (77.3%), non-complete response/non-progressive disease in 2 (9.1%) and only 1 (4.5%) had non-evaluable disease. Excluding the latter, the response rate in the daily and weekly regimens was 6.7% (1/15) and 16.7% (1/6), respectively, with an overall response rate of 9.5% (2/21). However, the best overall response in each patient showed that the disease control rate was 100%.Adverse events occurred in all 22 patients, including 17 grade 3 adverse events in 11 patients; however, no grade 4 or 5 adverse events were reported. Prophylactic hydration and antiemetic treatment reduced the severity and incidence of nephrotoxicity, nausea and vomiting. Plasma STZ concentrations decreased rapidly after termination of infusion, with a half-life of 32-40 min. Neither repeated administration nor dose increases affected pharmacokinetic parameters. CONCLUSIONS: STZ may be a useful option for Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

A novel endoscopic technique using fully covered self-expandable metallic stents for benign strictures after hepaticojejunostomy: the saddle-cross technique (with video).

BACKGROUND: In recent years, the number of patients with hepaticojejunostomy anastomotic strictures has increased. Balloon dilation and placement of multiple plastic stents have proven effective for hepaticojejunostomy anastomotic strictures. However, for refractory strictures, there is often a need for repeated endoscopic procedures within a short period. This study aimed to assess the efficacy and safety of the new saddle-cross technique, which uses two fully covered self-expandable metallic stents. METHODS: This was a retrospective analysis of 20 patients with benign hepaticojejunostomy anastomotic strictures who underwent placement of two fully covered self-expandable metallic stents at the National Cancer Center, Japan, from November 2017 to June 2021. RESULTS: The technical and clinical success rates were 100% (20/20). The median time of the procedure was 61 (range 25-122) min. The scheduled stent removal rate was 70% (14/20). Spontaneous dislodgement of the stent was observed on computed tomography in five patients (25.0%). The non-restenosis rate 12 months after the saddle-cross technique was 88.2% (15/17). Procedure-related early adverse events included mild ascending cholangitis in three patients (15.0%) and sepsis in one patient (5.0%). Procedure-related late adverse events included mild ascending cholangitis in three patients (15.0%) and bile duct hyperplasia in one patient (5.0%). CONCLUSIONS: The saddle-cross technique performed using two fully covered self-expandable metallic stents resulted in promising long-term stricture resolution with a high technical success rate. Based on these findings, the saddle-cross method can be considered an option for the standard procedure for benign hepaticojejunostomy anastomotic strictures.

Hepatoid carcinoma and related entities of the extrahepatic bile duct: A clinicopathological study of four cases.

Hepatoid carcinoma or related entities (HPC/RTs) are extremely rare, especially in the extrahepatic bile duct (EHBD). Only a few case reports have been published. We analyzed the clinicopathological features of HPCs/RTs in EHBD. HPC/RT of extrahepatic cholangiocarcinoma (eCCA) cases were selected based on the histological characteristics and immunohistochemical detection of spalt-like transcription factor 4 (SALL4) and/or alpha-fetoprotein (AFP). Four HPC/RT cases arose in the distal but not in the perihilar EHBD. The four patients with HPC/RT included one female and three males with a median age of 77 years. There are various macroscopic types of HPC/RT. The predominant histological features were two solid-type carcinomas that mimicked hepatocellular carcinoma and two well-differentiated tubular adenocarcinomas. Immunohistochemically, SALL4 and glypican-3 were expressed in all cases, and AFP was expressed in one case. Cancer cell phenotypes included intestinal, pancreatobiliary, and mixed pancreatobiliary and intestinal types. Focal neuroendocrine differentiation and severe perineural and lymphovascular invasions were also observed. HPC/RT recurred in two patients within 2 years, and one patient died 13 months postoperatively. It is suggested that the HPC/RT of EHBD shares common characteristics with HPC/RT arising in various organs, and has some unique characteristics. HPC/RT of EHBD might be more aggressive than conventional eCCA.

Is portal vein embolization safe and effective for patients with impaired liver function?

BACKGROUND AND OBJECTIVES: Portal vein embolization (PVE) is a safe and effective procedure used to increase the safety of extensive hepatectomy for selected patients. However, it is unknown whether PVE is safe for patients with impaired liver functional reserve. METHODS: Patients who underwent PVE from April 2007 to September 2016 in our hospital were retrospectively assessed. According to indocyanine green retention rate at 15 min (ICG-R15), we divided patients into Group A (≤10%), Group B (10%-20%), and Group C (>20%). We described and compared the treatment course and the outcome among the three groups. RESULTS: A total of 106 patients were assessed and divided into groups A (n = 46), B (n = 49), and C (n = 11). The morbidity and mortality after PVE showed no significant differences among the three groups (A:B:C = 37%:53%:64%, p = .16; A:B:C = 0%:0%:0%, p = 1.00, respectively). The morbidity and mortality after successive hepatectomy also showed no significant differences among the three groups (A:B:C = 55%:71%:78%, p = .19; A:B:C = 0%:2%:0%, p = 1.00, respectively). CONCLUSION: A patient with impaired liver functional reserve (ICG-R15 > 20%) can be a candidate for PVE and successive hepatectomy, as safely as a patient with normal and slightly impaired liver functional reserve (ICG-R15 ≤ 20%).

Adjuvant and neoadjuvant therapy for biliary tract cancer: a review of clinical trials.

Cancer originating in the biliary tract can be classified as bile duct cancer (cholangiocarcinoma), gallbladder cancer, or ampullary cancer. Bile duct cancer is further divided to intrahepatic, perihilar and distal bile duct subtypes according to the anatomical location of the tumor. The biological characteristics of each tumor are heterogeneous. However, because of the rarity of each disease, the efficacy of new drugs has been tested in groups of patients with different biliary tract cancers. In patients with metastatic or recurrent biliary tract cancer, recent randomized clinical trials revealed the non-inferiority of gemcitabine + S-1 and the superiority of gemcitabine + cisplatin + S-1 compared with gemcitabine + cisplatin in terms of overall survival, thereby establishing a new standard treatment. In the field of adjuvant therapy for biliary tract cancer, the British BILCAP (capecitabine compared with observation in resected biliary tract cancer) study revealed longer median overall survival in the capecitabine group than in the observation group in the per-protocol analysis (but not in the intention-to-treat analysis), bringing a shift toward postoperative management. Several other studies of adjuvant therapy are ongoing, and they may lead to reforms in treatment strategy for resectable biliary tract cancer in the future. The use of neoadjuvant therapy for biliary tract cancer is in its infancy, but it is expected to overcome the limitations of adjuvant therapy for this malignancy. In this review, we summarized the evidence available from clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer and described ongoing clinical trials.

Stroke Systems of Care During the COVID-19 Epidemic in Kobe City.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) outbreak raised concerns over healthcare systems' ability to provide suitable care to stroke patients. In the present study, we examined the provision of stroke care in Kobe City during the COVID-19 epidemic, where some major stroke centers ceased to provide emergency care. METHODS: This was a cross-sectional study. The Kobe Stroke Network surveyed the number of stroke patients admitted to all primary stroke centers (PSCs) in the city between March 1 and May 23, 2020, and between March 3 and May 25, 2019. In addition, online meetings between all PSC directors were held regularly to share information. The survey items included emergency response system characteristics, number of patients with stroke hospitalized within 7 days of onset, administered treatment types (IV rt-PA, mechanical thrombectomy, surgery, and endovascular therapy), and stroke patients with confirmed COVID-19. RESULTS: During the period of interest in 2020, the number of stroke patients hospitalized across 13 PSCs was 813, which was 15.5% lower than that during the same period of 2019 (p = 0.285). The number of patients admitted with cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage decreased by 15.4% (p = 0.245), 16.1% (p = 0.659), and 14.0% (p = 0.715), respectively. However, the rates of mechanical thrombectomy and surgery for intracerebral hemorrhage were slightly increased by 12.1% (p = 0.754) and 5.0% (p = 0.538), respectively. PSCs that ceased to provide emergency care reported a decrease in the number of stroke cases of 65.7% compared with the same period in 2019, while other PSCs reported an increase of 0.8%. No case of a patient with stroke and confirmed COVID-19 was reported during the study period. CONCLUSION: Kobe City was able to maintain operation of its stroke care systems thanks to close cooperation among all city PSCs and a temporal decrease in the total number of stroke cases.

Issues associated with medical tourism for cancer care in Japan.

BACKGROUND: Medical tourism has grown globally, especially in oncology field, but it may cause serious problems. We aimed to elucidate concerns generated by medical tourism at a Japanese hospital and recommend solutions. METHODS: We evaluated 72 consecutive patients with cancer who had traveled from abroad to receive second opinions, clinical examinations or treatments at our hospital between January 2015 and December 2016. Data were retrospectively collected to include the purpose of patients' visits, presence and content of referral documents, details of treatments provided at our hospital, concordance between treatments received and patients' expectations, troublesome hospital incidents, risks of travel and problems with payment. RESULTS: The purpose of the visit was actual cancer treatment in the majority of the cases. Thirteen patients could speak neither Japanese nor English. Inadequate content in patient referral documents and discordance between information from the referring physician and findings at first examination were the main issues observed in the pre-treatment phase; 33 patients decided to receive treatment at our hospital. Language differences caused problems in patients' understanding of instructions and explanations during treatment. Additional problems included inaccurate self-evaluation of disease status, differences in cultural habits and requests for inappropriate and/or unavailable therapies. No major issues that could lead to injury in patients or medical staff were observed. Risks involved with returning home and transfer of treatment to local physicians were the main post-treatment issues. CONCLUSION: Medical tourism raises various issues. Institutional and medical staff should be adequately prepared by developing working systems.

Feasibility of Intraoperative Navigation for Liver Resection Using Real-time Virtual Sonography With Novel Automatic Registration System.

BACKGROUND: The clinical feasibility and usability of intraoperative ultrasonography (IOUS) tracked by computed tomography (CT) images have been proposed; however, it requires technically demanding manual registration procedure. STUDY DESIGN: A prospective study using real-time virtual sonography (RVS) with novel automatic registration system was conducted in four high-volume centers of liver resection from 2015 to 2016. The requiring time for registration of IOUS and CT images and positional error of confluence of middle hepatic venous tributaries (V8-MHV, V5-MHV) were measured in patients undergoing laparotomy. RESULTS: Automatic registration was successful in 43 of 52 enrolled patients (83%), with error ranges of 11.4 (3.1-69.4) mm for V8-MHV and 16.2 (4.3-66.8) mm for V5-MHV. Time required for total registration process was 36 (27-74) s. CONCLUSIONS: The RVS with novel automatic registration system can provide quick and easy registration and acceptable accuracy, which can promote the usage of IOUS.