Oligo-like liver metastasis: A novel prognostic indicator to improve survival in pancreatic cancer.

Purpose: Whether surgical intervention for patients with oligometastatic recurrence can improve their post-recurrent prognosis is unclear. In this study, we introduce a novel concept of oligometastasis in post-surgical pancreatic ductal adenocarcinoma (PDAC) patients with hepatic recurrence, which we call "oligo-like liver metastasis (OLLM)." Patients with OLLM have better post-recurrence prognosis and could therefore be eligible for surgical intervention. Methods: A total of 121 PDAC patients who underwent radical resection, and who had an initial and single-organ metastasis to the liver, were analyzed. Independent prognostic factors for overall survival after recurrence (OSAR) were examined, and patients with all of these factors were defined as OLLM. The clinicopathological features and post-recurrent prognosis of OLLM patients were evaluated. In addition, a detailed analysis using the oligo-score, which was based on the prognostic factors, was performed. Results: The prognostic analysis revealed that short recurrence-free interval (RFI) (<6 months), short stable disease interval (SDI) (≤3 months), and four or more recurrent tumors were independent poor prognostic factors. OLLM patients were defined as those with all three conditions: long RFI (≥6 months), long SDI (>3 months), and three or less recurrent tumors. OLLM patients had a significantly better prognosis for OSAR than non-OLLM patients (HR = 0.272, p < 0.001). Further analysis demonstrated that the OSAR of patients could be stratified using the oligo-score, which was calculated based on the prognostic factors. Conclusion: We recommend that OLLM should be used to predict which patients are most likely to experience better post-recurrent prognosis after surgery with curative intent.

Comparative analysis of liver resection in Non-B Non-C and hepatitis virus-associated hepatocellular carcinoma.

BACKGROUND: The incidence of non-hepatitis B and non-hepatitis C hepatocellular carcinoma (NBNC-HCC) is increasing in our country. This study assesses the feasibility of employing an identical surgical treatment strategy for resectable NBNC-HCC as that for hepatitis virus-associated HCC (HV-HCC). METHODS: A retrospective analysis (1993-2023) of 1321 curative liver resections for HCC at a single institution was performed. Propensity score matching ensured a balanced comparison of preoperative clinical factors, including tumor status and background liver condition. RESULTS: The proportion of NBNC-HCC cases has gradually increased, reaching up to 70 %. After matching, 294 of 473 NBNC-HCC patients and 294 of 848 HV-HCC patients were compared. Operative outcomes, including operation time, blood loss, type of surgical procedure, and morbidity, were comparable. Long-term outcome analysis showed similar recurrence-free survival (HR: 0.86, 95 % CI: 0.70-1.06, P = 0.167) and overall survival (HR: 0.98, 95 % CI: 0.79-1.23, P = 0.865) for NBNC-HCC. Multivariable analysis identified ICGR15 ≥ 15 %, ALBI grade 2 or 3, aspartate aminotransferase ≥40, tumor size > 5 cm, multiple tumors, macrovascular invasion, and microvascular invasion as independent prognostic factors for overall survival, while hepatitis B or C virus status lost significance. CONCLUSIONS: Despite the increasing incidence of NBNC-HCC, comparable outcomes were achieved between the two groups of matched cohort.

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 Recombinant Peptide Device Combined with Adipose Tissue-Derived Stem Cells Enhances Subcutaneous Islet Engraftment.

Subcutaneous space has been considered an attractive site for islet graft transplantation; however, the oxygen tension and vascularization are insufficient for islet graft survival. We investigated whether subcutaneous pre-implantation of a recombinant peptide (RCP) device with adipose tissue-derived stem cells (ADSCs) enhanced subcutaneous islet engraftment. RCP devices with/without syngeneic ADSCs were pre-implanted into the subcutaneous space of C57BL/6 mice. Syngeneic islets (300 or 120 islet equivalents (IEQs)) were transplanted into the pre-treated space after diabetes induction using streptozotocin. The cure rates of groups in which RCP devices were implanted four weeks before transplantation were significantly better than the intraportal transplantation group when 300 IEQs of islets were transplanted (p < 0.01). The blood glucose changes in the RCP+ADSCs-4w group was significantly ameliorated in comparison to the RCP-4w group when 120 IEQs of islets were transplanted (p < 0.01). Immunohistochemical analyses showed the collagen III expression in the islet capsule of the RCP+ADSCs-4w group was significantly enhanced in comparison to the RCP-4w and RCP+ADSCs-d10 groups (p < 0.01, p < 0.01). In addition, the number of von Willebrand factor-positive vessels within islets in the RCP+ADSCs-4w group was significantly higher than the RCP-4w group. These results suggest that using ADSCs in combination with an RCP device could enhance the restoration of the extracellular matrices, induce more efficient prevascularization within islets, and improve the graft function.

Pathological complete response of initially unresectable multiple liver metastases achieved using combined peptide receptor radionuclide therapy and somatostatin analogs following pancreatic neuroendocrine tumor resection: a case report.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) serves as a novel and effective treatment option for somatostatin receptor-positive unresectable liver metastases of pancreatic neuroendocrine tumors (PNETs). However, there are few reported cases of surgical resection for initially unresectable liver metastases of PNET that were converted to resectable after PRRT. Here we report a case where PRRT and somatostatin analogs (SSAs) led to a pathological complete response of initially unresectable multiple liver metastases following PNET resection. CASE PRESENTATION: A 52-year-old man underwent pylorus-preserving pancreaticoduodenectomy for PNET at age 40 and subsequent hepatectomies for resectable liver metastases at 44 and 47 years of age. At age 48, a follow-up examination revealed unresectable multiple liver metastases, and PRRT with 177Lu-DOTATATE therapy was initiated. After four cycles of PRRT, most liver metastases diminished according to imaging studies, and the remaining two hepatic lesions continued to shrink with additional lanreotide. Conversion surgery for liver metastases was successfully performed, revealing no viable tumor cells in tissue specimens. Seventeen months after surgery, imaging showed no detectable residual tumor or recurrence. We present a review of the relevant literature that highlights the significance of our findings. CONCLUSIONS: This rare case highlights the pathological complete response of initially unresectable multiple liver metastases achieved by PRRT and SSAs following PNET resection, suggesting their potential as a multimodality treatment option for unresectable PNET.

Clinicopathological Findings and Treatment Outcomes of Patients with Primary Hepatobiliary Neuroendocrine Neoplasms: A Retrospective Single-institution Analysis.

Objective Primary hepatobiliary neuroendocrine neoplasms (NENs) are rare tumors exhibiting several morphological and behavioral characteristics. Considering the lack of relevant data on this topic, we evaluated the clinicopathological features and treatment outcomes of patients with primary hepatobiliary NENs. Methods/Patients We examined 43 consecutive patients treated at the National Cancer Center Hospital with pathological diagnoses of primary hepatobiliary NEN between 1980 and 2016. Results Nine patients were diagnosed with neuroendocrine tumor (NET) G1, 9 with NET G2, and 25 with neuroendocrine carcinoma (NEC) based on the World Health Organization 2019 classification. Patients with NEC had primary sites across the hepatobiliary organs, although sites in patients with NET G1 and NET G2 only included the liver and ampulla of Vater. Patients with primary extrahepatic bile duct or ampulla of Vater NENs tended to be diagnosed earlier than patients with primary gallbladder NENs. The median survival times in the NET G1, NET G2, and NEC groups were 167.9, 97.4, and 11.1 months, respectively. A good performance status, absence of distant metastases, and low tumor grade were identified as independent predictors of a favorable prognosis. Conclusion The NET-to-NEC ratio and tumor stage distribution at the diagnosis differed depending on the primary site. Patients with G1 and G2 NETs who underwent surgical resection had good prognoses, whereas those with NEC exhibited more advanced disease and poorer prognoses. The performance status, staging classification, and tumor grade are important factors to consider when devising an appropriate treatment strategy and predicting the prognoses of patients with primary hepatobiliary NEN.

Novel insights into the intraepithelial spread of extrahepatic cholangiocarcinoma: clinicopathological study of 382 cases on extrahepatic cholangiocarcinoma.

Background: Extrahepatic cholangiocarcinoma (eCCA) is a rare and aggressive disease and consisted of conventional eCCA and intraductal papillary neoplasm of the bile duct (IPNB). Intraepithelial spread (IES) of cancer cells beyond the invasive area is often observed in IPNBs; however, the prevalence of IES remains to be examined in conventional eCCAs. Here, we evaluated the clinicopathological features of eCCAs according to tumor location, with a focus on the presence of IES. The IES extension was also compared among biliary tract cancers (BTCs). Methods: We examined the prevalence and clinicopathological significance of IES in eCCAs (n=382) and the IES extension of BTCs, including gallbladder (n=172), cystic duct (n=20), and ampullary cancers (n=102). Results: Among the invasive eCCAs, IPNB had a higher rate of IES (89.2%) than conventional eCCAs (57.0%). Among conventional eCCAs, distal eCCAs (75.4%) had a significantly higher prevalence of IES than perihilar eCCAs (41.3%). The presence of IES was associated with a significantly higher survival rate in patients with distal eCCAs (P=0.030). Extension of the IES into the cystic duct (CyD) in distal eCCAs that cancer cells reached the junction of the CyD was a favorable prognostic factor (P<0.001). The association of survival with IES, either on the extrahepatic bile duct or on the CyD, differed depending on the tumor location and type of eCCA. The extension properties of IES were also dependent on different types of tumors among BTCs; usually, the IES incidence became higher than 50% in the tissues that the tumor developed, whereas IES extension to other tissues decreased the incidence. Conclusion: Thus, eCCAs have different clinicopathological characteristics depending on the tumor location and type.

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.

Efficacy of endoscopic ultrasound-guided tissue acquisition for solid pancreatic lesions 20 mm or less in diameter suspected as neuroendocrine tumors or requiring differentiation.

BACKGROUND: For non-functioning pancreatic neuroendocrine tumors (pNETs) ≤ 20 mm, most guidelines consider follow-up observations as an option; however, the various treatment strategies are defined by size alone, even though the Ki-67 index is important for malignancy grading. Endoscopic ultrasound-guided tissue acquisition (EUS-TA) is the standard for the histopathological diagnosis of solid pancreatic lesions; however, recent results for small lesions remain unclear. Therefore, we examined the efficacy of EUS-TA for solid pancreatic lesions ≤ 20 mm suspected as pNETs or requiring differentiation and the non-increase rate in tumor size in follow-up cases. METHODS: We retrospectively analyzed data of 111 patients (median age = 58 years) with lesions ≤ 20 mm suspected as pNETs or requiring differentiation who underwent EUS-TA. All patients underwent specimen evaluation by rapid onsite evaluation (ROSE). RESULTS: EUS-TA led to a diagnosis of pNETs in 77 patients (69.4%) and tumors other than pNETs in 22 patients (19.8%). The histopathological diagnostic accuracy of EUS-TA was 89.2% (99/111) overall, 94.3% (50/53) for 10-20 mm lesions, and 84.5% (49/58) for ≤ 10 mm lesions, with no significant difference in diagnostic accuracy (p = 0.13). The Ki-67 index was measurable in all patients with a histopathological diagnosis of pNETs. Among 49 patients with a diagnosis of pNETs who were followed up, one patient (2.0%) showed tumor enlargement. CONCLUSIONS: EUS-TA for solid pancreatic lesions ≤ 20 mm suspected as pNETs or requiring differentiation is safe and has adequate histopathological diagnostic accuracy, suggesting that follow-up observations of pNETs with a histological pathologic diagnosis are acceptable in the short term.

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.

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.

Automated Three-Dimensional Liver Reconstruction with Artificial Intelligence for Virtual Hepatectomy.

OBJECTIVE: To validate the newly developed artificial intelligence (AI)-assisted simulation by evaluating the speed of three-dimensional (3D) reconstruction and accuracy of segmental volumetry among patients with liver tumors. BACKGROUND: AI with a deep learning algorithm based on healthy liver computer tomography images has been developed to assist three-dimensional liver reconstruction in virtual hepatectomy. METHODS: 3D reconstruction using hepatic computed tomography scans of 144 patients with liver tumors was performed using two different versions of Synapse 3D (Fujifilm, Tokyo, Japan): the manual method based on the tracking algorithm and the AI-assisted method. Processing time to 3D reconstruction and volumetry of whole liver, tumor-containing and tumor-free segments were compared. RESULTS: The median total liver volume and the volume ratio of a tumor-containing and a tumor-free segment were calculated as 1035 mL, 9.4%, and 9.8% by the AI-assisted reconstruction, whereas 1120 mL, 9.9%, and 9.3% by the manual reconstruction method. The mean absolute deviations were 16.7 mL and 1.0% in the tumor-containing segment and 15.5 mL and 1.0% in the tumor-free segment. The processing time was shorter in the AI-assisted (2.1 vs. 35.0 min; p < 0.001). CONCLUSIONS: The virtual hepatectomy, including functional liver volumetric analysis, using the 3D liver models reconstructed by the AI-assisted methods, was reliable for the practical planning of liver tumor resections.

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.

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.

Role of adjuvant and neoadjuvant therapy for resectable biliary tract cancer.

Introduction: Although the safety of biliary tract cancer resection has improved over the years, the recurrence rate is still high, and the postoperative prognosis remains low after biliary tract cancer resection. Therefore, the development of effective adjuvant therapy is essential to improve treatment outcomes. Because biliary tract cancer is rare compared with other gastrointestinal cancers, there have been only a small number of clinical trials of adjuvant therapy. However, in recent years, the results of several large-scale randomized controlled trials have been published, and clinical trials investigating the efficacy of new regimens are currently ongoing.Areas covered: This review presents the results of previously published important phase II and III clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer and discusses their interpretation. The future direction of new research on resectable biliary tract cancer treatment is also discussed.Expert opinion: The foundations of large-scale clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer are underway, and new trials will establish evidence of their effectiveness. Additionally, breakthroughs in treatment through genetic and molecular research are expected.