Short-term Outcomes of Laparoscopic Versus Open Liver Resection in the Elderly: A Propensity Score-matched Analysis.

BACKGROUND/AIM: With the aging of the population, there is a rising proportion of elderly patients undergoing liver resection. However, the safety and efficacy of laparoscopic liver resection (LLR) in the elderly have not yet been established. In this study, we compared the short-term results of LLR and open liver resection (OLR) in elderly patients using propensity score matched (PSM) analysis. PATIENTS AND METHODS: The study comprised 237 elderly patients aged 65 years and older who had undergone liver resection between 2015 to 2021, excluding biliary and vascular reconstruction and simultaneous surgeries other than liver resection. We conducted PSM analysis for baseline characteristics (age, sex, BMI, ASA-PS, disease, procedure, tumor size, and number of tumors) to eliminate potential selection bias. We then compared short-term postoperative outcomes between LLR and OLR groups in patients selected by PSM analysis. RESULTS: Applying PSM analysis, 90 cases each were selected for the LLR and OLR groups. The LLR group had a significantly lower complication rate (Clavien-Dindo: CD ≥II) (19% vs. 33%, p=0.03), especially bile leakage (CD ≥II) (0% vs. 6.7%, p=0.03) compared with those in the OLR group. In addition, a shorter operation time (244 min vs. 351 min, p<0.01), less blood loss (150 ml vs. 335 ml, p<0.01), and shorter hospital stay (8 days vs. 12 days, p<0.01) were observed in the LLR group. No operative or in-hospital deaths were observed in both groups. CONCLUSION: LLR can be safely performed in elderly patients and offers better short-term outcomes.

Prognostic impact of osteosarcopenia in patients undergoing pancreatic resection for pancreatic ductal adenocarcinoma.

BACKGROUND: We investigated the prognostic impact of osteosarcopenia, defined as the combination of osteopenia and sarcopenia, in patients undergoing pancreatic resection for pancreatic ductal adenocarcinoma (PDAC). METHODS: The relationship of osteosarcopenia with disease-free survival and overall survival was analyzed in 183 patients who underwent elective pancreatic resection for PDAC. Computed tomography was used to measure the pixel density in the midvertebral core of the 11th thoracic vertebra for evaluation of osteopenia and in the psoas muscle area of the 3rd lumbar vertebra for evaluation of sarcopenia. Osteosarcopenia was defined as the simultaneous presence of both osteopenia and sarcopenia. The study employed a retrospective design to examine the relationship between osteosarcopenia and survival outcomes. RESULTS: Osteosarcopenia was identified in 61 (33%) patients. In the univariate analysis, disease-free survival was significantly worse in patients with male sex (p = 0.031), pathological stage ≥ III PDAC (p = 0.001), NLR, ≥ 2.71 (p = 0.041), sarcopenia (p = 0.027), osteopenia (p = 0.001), and osteosarcopenia (p < 0.001), and overall survival was significantly worse in patients with male sex (p = 0.001), pathological stage ≥ III PDAC (p = 0.001), distal pancreatectomy (p = 0.025), sarcopenia (p = 0.003), osteopenia (p < 0.001), and osteosarcopenia (p < 0.001). In the multivariate analysis, the independent predictors of disease-free survival were osteosarcopenia (p < 0.001) and pathological stage ≥ III PDAC (p = 0.002), and the independent predictors of overall survival were osteosarcopenia (p < 0.001), male sex (p = 0.006) and pathological stage ≥ III PDAC (p = 0.001). CONCLUSION: Osteosarcopenia has an adverse prognostic impact on long-term outcomes in patients undergoing pancreatic resection for PDAC.

Proposal for Prognosis-Oriented Definition of Borderline Resectable Hepatocellular Carcinoma.

BACKGROUND: Owing to advances in the multidisciplinary treatment of hepatocellular carcinoma (HCC), a conceptualization and definition for borderline resectable (BR) HCC, which carries a high risk of recurrence, is warranted. In this study, we aimed to define BR-HCC using a prognosis-oriented approach. STUDY DESIGN: The study included an original cohort of 221 patients and an independent validation cohort of 181 patients who had undergone primary hepatic resection for HCC. To define biological BR-HCC, we evaluated the risk factors for early recurrence beyond the Milan criteria within 1 year after hepatic resection using multivariable logistic regression models. Subsequently, we developed high-risk scores using the identified risk factors and defined BR-HCC. The utility of high-risk score was validated in the validation cohort. RESULTS: In the original cohort (hepatitis B virus:hepatitis C virus = 20%:29%), recurrence beyond the Milan criteria within 1 year was observed in 28 patients (13%), with a 5-year survival rate of 25%. Multivariable analysis identified risk factors for recurrence beyond the Milan criteria within 1 year, including serum alpha-fetoprotein levels of 12 ng/mL or more (p = 0.02), tumor diameters less than 5 cm (p = 0.02), tumor number 3 or more (p = 0.001), and macrovascular invasion (p = 0.04). BR-HCC was defined as a tumor with 2 or more identified risk factors, and 42 patients (19%) were diagnosed with BR-HCC, with a 5-year survival rate of 51%. In the validation cohort, 45 (25%) patients had BR-HCC, with a 5-year survival rate of 42%. CONCLUSIONS: The prognosis-oriented definition of BR-HCC enabled us to identify patients who are susceptible to early unresectable recurrence and have poor survival after hepatic resection for HCC. For patients with BR-HCC, preoperative systemic therapy may be a viable option to improve postresection outcomes.

Analysis of Preoperative Risk Factors for Early Recurrence in Patients After Hepatic Resection for Intrahepatic Cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis even after curative-intent hepatic resection due to a high recurrence rate. The aim of this study was to investigate preoperative risk factors for early recurrence after surgery for ICC, which may help to identify patients who need preoperative chemotherapy. METHODS: We retrospectively analyzed 51 patients who had undergone primary surgery for ICC. We investigated the association of preoperative clinical variables with recurrence within 1 year after resection for ICC. We then created a high-risk ICC score using the identified preoperative factors and investigated the association of the score with disease-free and overall survival. RESULTS: Recurrence within 1 year after surgery for ICC was significantly associated with poor overall survival (P < .01). In the multivariate analysis, preoperative tumor size > 5 cm (P = .03) and elevated C-reactive protein-to-albumin ratio (CAR) (P = .04) were significantly associated with recurrence within 1 year after surgery. A high-risk ICC score of 2 was associated with poor disease-free survival (P < .01) and overall survival (P = .02) compared with a score of 0 or 1. CONCLUSIONS: Our high-risk ICC score, combining preoperative tumor size and CAR, can be an indicator of early recurrence and poor survival in patients after hepatic resection for ICC. Our findings may provide better preoperative risk stratification of patients with ICC, and the high-risk ICC patients may benefit from preoperative therapy.

The postoperative platelet-to-lymphocyte ratio predicts the outcome of patients undergoing pancreaticoduodenectomy for pancreatic head cancer.

PURPOSE: The preoperative platelet-to-lymphocyte ratio (PLR) has been reported as an important prognostic index for pancreatic ductal adenocarcinoma (PDAC); however, the significance of the postoperative (post-op) PLR for this disease has not been elucidated. METHODS: We analyzed data on 118 patients who underwent pancreaticoduodenectomy for pancreatic head PDAC, collected from a prospectively maintained database. The post-op PLR was obtained by dividing the platelet count after surgery by the lymphocyte count on post-op day (POD) 14. The patients were divided into two groups according to a post-op PLR of < 310 or ≥ 310. Survival data were analyzed. RESULTS: A high post-op PLR was identified as a significant prognostic index on univariate analysis for disease-free survival (DFS) and overall survival (OS). The post-op PLR remained significant, along with tumor differentiation and adjuvant chemotherapy, on multivariate analysis for OS (hazard ratio = 2.077, 95% confidence interval: 1.220-3.537; p = 0.007). The post-op PLR was a significant independent prognostic index for poor DFS, along with tumor differentiation and lymphatic invasion, on multivariate analysis (hazard ratio = 1.678, 95% confidence interval: 1.056-2.667; p = 0.028). CONCLUSIONS: The post-op PLR in patients with pancreatic head PDAC was an independent predictor of DFS and OS after elective resection.

Occult Vertebral Fracture (OVF) in Patients Who Underwent Hepatectomy for Colorectal Liver Metastasis: Strong Association with Oncological Outcomes.

AIM: The impact of occult vertebral fracture (OVF) on oncological outcomes after surgery has not been investigated, although its significance in orthopedics has been much debated recently. We evaluated the prognostic significance of OVF on the long-term outcomes of patients with colorectal liver metastases (CRLM) after hepatectomy. METHODS: We included 140 patients with CRLM who underwent hepatectomy. OVF was identified using quantitative measurement and preoperative sagittal computed tomography image reconstruction from the 11th thoracic vertebra to the 5th lumber vertebra. RESULTS: OVF was identified in 48 (34%) of the patients. In multivariate analysis, lymph node metastases (p < 0.01), multiple tumors (p = 0.02), extrahepatic lesions (p < 0.01), OVF (p < 0.01), intraoperative bleeding (p = 0.04), and curability 1 or 2 (p < 0.01) were independent and significant predictors of disease-free survival and extrahepatic lesions (p < 0.01), osteosarcopenia (p = 0.02), and OVF (p < 0.01) were independent and significant predictors of overall survival. A higher age, adjuvant chemotherapy for a primary lesion before metachronous liver metastases, osteopenia, and hypoalbuminemia were independent risk factors for OVF. CONCLUSIONS: The evaluation of preoperative OVF is a useful prognostic factor for risk stratification and clinical decision-making for patients with CRLM.

A case of urinary bladder metastasis of hepatocellular carcinoma following use of immunotherapy/tyrosine kinase inhibitor.

Introduction: Here we present a rare case of hepatocellular carcinoma metastasis to the urinary bladder in a patient with metastatic HCC. Case presentation: An 83-year-old man developed gross hematuria during combined treatment with an anti-programmed death-ligand 1 inhibitor and an anti-vascular endothelial growth factor for metastatic HCC. A contrast-enhanced CT revealed a 15 × 15 mm soft tissue mass protruding from the posterior bladder wall. Cystoscopy further revealed a solitary submucosal mass located on the posterior wall. The patient underwent transurethral resection of bladder tumor. The pathological findings were consistent with a diagnosis of bladder metastasis from HCC. Following a 3-week interval after the surgical intervention, salvage therapy was resumed. Conclusion: During follow-up after TUR-BT in HCC patients who present with a bladder tumor, the possibility of HCC metastases to the urinary bladder should be excluded.

The Impact of Fibrinogen to Prognostic Nutritional Index Rate on Prognosis of Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: The aim of the present study was to evaluate the prognostic value of the ratio of serum fibrinogen to prognostic nutritional index (PNI; Fbg/PNI) in patients undergoing resection for pancreatic ductal adenocarcinoma. METHODS: A total of 140 patients who had undergone resection for pancreatic cancer were included. Patients were divided into two groups according to a Fbg/PNI ≥8.8 or <8.8. Survival data were analyzed using the log-rank test for univariate analysis and Cox proportional hazards for multivariate analysis. RESULTS: Fbg/PNI was a significant prognostic indicator in univariate analysis for overall survival (OS) and disease-free survival (DFS). Fbg/PNI retained significance in multivariate analysis for OS (hazard ratio, 1.81; 95% confidence interval, 1.19-2.77; P < .01) in addition to tumor differentiation and nodal involvement. Fbg/PNI was a significant independent prognostic indicator of poor DFS on multivariate analysis (hazard ratio, 1.54; 95% confidence interval, 1.05-2.26; P = .03). CONCLUSION: Preoperative Fbg/PNI is a novel significant independent prognostic indicator for OS and DFS following resection of pancreatic cancer with curative intent.

Superior mesenteric vein/portal vein contact in preoperative imaging indicates biological malignancy in anatomically resectable pancreatic cancer.

BACKGROUND: Pancreatic cancer in contact with the superior mesenteric vein/portal vein is classified as resectable pancreatic cancer; however, the biological malignancy and treatment strategy have not been clarified. METHODS: Data from 186 patients who underwent pancreatectomy for pancreatic cancer were evaluated using a prospectively maintained database. The patients were classified as having resectable tumors without superior mesenteric vein/portal vein contact and with superior mesenteric vein/portal vein contact of ≤180°. Disease-free survival, overall survival, and prognostic factors were analyzed. RESULTS: In the univariate analysis, superior mesenteric vein/portal vein contact in resectable pancreatic cancer was a significant prognostic index for disease-free survival and overall survival. In the multivariate analysis for poor disease-free survival, the superior mesenteric vein/portal vein contact remained significant (hazard ratio = 2.13, 95% confidence interval: 1.29-3.51; p < 0.01). In the multivariate analysis, superior mesenteric vein/portal vein contact was a significant independent prognostic index for overall survival (hazard ratio = 2.17, 95% confidence interval: 1.27-3.70; p < 0.01), along with sex, tumor differentiation, nodal involvement, and adjuvant chemotherapy. Portal vein resection for superior mesenteric vein/portal vein contact did not improve the overall survival (p = 0.86). CONCLUSIONS: Superior mesenteric vein/portal vein contact in resectable pancreatic cancer was found to be an independent predictor of disease-free survival and overall survival after elective resection. Thus, pancreatic cancer in contact with the superior mesenteric vein/portal vein may be considered as borderline resectable pancreatic cancer.

Clinical Activity and Exploratory Resistance Mechanism of Milademetan, an MDM2 Inhibitor, in Intimal Sarcoma with MDM2 Amplification: An Open-Label Phase Ib/II Study.

Intimal sarcoma is an extremely rare, life-threatening malignant neoplasm. Murine double minute 2 (MDM2) amplification is observed in >70% of intimal sarcomas. Milademetan, an MDM2 inhibitor, may provide clinical benefit in this patient population. We conducted a phase Ib/II study in patients with MDM2-amplified, wild-type TP53 intimal sarcoma as a substudy of a large nationwide registry for rare cancers in Japan. Milademetan (260 mg) was administered orally once daily for 3 days every 14 days, twice in a 28-day cycle. Of 11 patients enrolled, 10 were included in the efficacy analysis. Two patients (20%) showed durable responses for >15 months. Antitumor activity correlated with TWIST1 amplification (P = 0.028) and negatively with CDKN2A loss (P = 0.071). Acquired TP53 mutations were detected in sequential liquid biopsies as a novel exploratory resistance mechanism to milademetan. These results suggest that milademetan could be a potential therapeutic strategy for intimal sarcoma. SIGNIFICANCE: Strategies to optimize outcomes could include the use of new biomarkers (TWIST1 amplification and CDKN2A loss) to select patients with MDM2-amplified intimal sarcoma who might benefit from milademetan and combination with other targeted treatments. Sequential liquid biopsy of TP53 can be used to evaluate disease status during treatment with milademetan. See related commentary by Italiano, p. 1765. This article is highlighted in the In This Issue feature, p. 1749.

The impact of C-reactive protein-albumin-lymphocyte (CALLY) index on the prognosis of patients with distal cholangiocarcinoma following pancreaticoduodenectomy.

Aim: The C-reactive protein (CRP)-albumin-lymphocyte (CALLY) index is a novel inflammation-based biomarker, which has been associated with long-term outcomes in patients with hepatocellular carcinoma. We aimed to investigate whether the CALLY index can predict the prognosis for distal cholangiocarcinoma after pancreaticoduodenectomy. Methods: The study comprised 143 patients who had undergone primary pancreaticoduodenectomy for distal cholangiocarcinoma between 2002 to 2019. The CALLY index was defined as (albumin × lymphocyte)/ (CRP × 104). We investigated the association of CALLY index with disease-free survival and overall survival by univariate and multivariate analyses. Results: Eighty-seven (61%) patients had a preoperative CALLY index <3.5. In multivariate analysis, obstructive jaundice drainage (P < .01), poorly differentiated tumor (P < .01), and CALLY index<3.5 (P = .02) were independent predictors of disease-free survival, while obstructive jaundice drainage (P < .01), poorly differentiated tumor (P < .01), and CALLY index <3.5 (P = .02) were independent predictors of overall survival. Conclusion: The CALLY index may be an independent and significant indicator of poor long-term outcomes in patients with distal cholangiocarcinoma after pancreaticoduodenectomy, suggesting the importance of comprehensive assessment for inflammatory status.

Open Thoracic Drainage Followed by Proximal Splenic Artery Embolization for Massive Hydrothorax Before Living Donor Liver Transplantation.

BACKGROUND: Hepatic hydrothorax is associated with postoperative infectious complications and mortality in patients undergoing living-donor liver transplantation (LDLT). Thus, preoperative management of massive hepatic hydrothorax is essential for improving the outcomes of LDLT. This study aimed to demonstrate our successful cases and strategy for treating massive hepatic hydrothorax. METHODS: Our strategy for hepatic hydrothorax includes (a) mini-thoracotomy under general anesthesia for the drainage of hydrothorax, (b) preoperative hepatic inflow modulation by proximal splenic arterial embolization, and (c) nutritional and physical intervention to improve the general condition. RESULTS: Two patients with massive hepatic hydrothorax were treated with our strategy. Both patients had end-stage liver disease secondary to primary biliary cholangitis. Their performance status deteriorated due to massive hydrothorax. After the intervention, their performance status significantly improved. After that, LDLTs with right lobe grafts were performed. The duration of the operation was 440 and 343 minutes, with an intraoperative blood loss of 1,700 and 1,600 g, respectively. Their postoperative courses were uneventful, and they were discharged on postoperative days 16 and 14. CONCLUSION: Our pre-LDLT multimodal management strategy for massive hepatic hydrothorax, including preoperative open thoracic drainage, pre-LDLT portal inflow modulation, and nutritional intervention, improved the preoperative condition of patients undergoing LDLT, resulting in successful outcomes.

Double cone-unit laparoscopic hepatic resection for tumors adjacent to the hepatic vein.

BACKGROUND: In tumor adjacent to the hepatic vein, it is important to treat two tertiary Glissonean pedicles that straddle to the hepatic vein in order to remove the tumor with a negative margin. The anatomical resection of the smallest unit may be considered to be the resection of the double cone-unit (DCU) in small tumor adjacent to the vein. PATIENTS AND METHODS: 127 patients who had undergone laparoscopic hepatectomy at the Jikei Medical University Hospital from 2020 through 2021. In 5 cases, Laparoscopic DCU resection was performed. If the CT image shows a hepatic vein near the tumor and the tumor is relatively small, less than 50 mm in size, DCU resection should be considered. After approaching the target Glissonean pedicles, the Bulldog Clamps were used to testing clamp it. After clamping it, the ICG was injected from peripheral veins. A few minutes later, the tumor-bearing portal territory could be identified as negative regions of fluorescence in the near infrared imaging system. The target hepatic vein, which runs between the two territories, was dissected where it transitions from the first to the second territory. RESULTS: The median operative time in these 5 patients was 279 min, and the median volume of blood loss was 290 g. The average tumor size was 33 mm and the average surgical margin was 4.5 mm. CONCLUSION: In small tumor adjacent to the hepatic vein, the anatomical hepatectomy of the smallest unit may be the Double Cone-Unit resection.

Multimodal Management for Refractory Biliary Stricture After Living Donor Liver Transplantation.

BACKGROUND: Biliary stricture is a common complication of living donor liver transplantation (LDLT). Endoscopic retrograde biliary drainage (ERBD) is the primary treatment of biliary stricture, which is sometimes refractory. This study aimed to evaluate the risk factors for biliary stricture after LDLT and present successful management for refractory biliary stricture. METHODS: Data from 26 patients who underwent LDLT were retrospectively analyzed. The relationship between the incidence of biliary strictures and clinical variables, including pre/intra/postoperative factors, was assessed. RESULTS: Univariate analysis showed that ABO incompatibility (P = .037) was a significant risk factor for biliary strictures. Case 1 was a 57-year-old woman who underwent LDLT using a left-lobe graft for primary biliary cholangitis (PBC) and developed a biliary stricture 1 month after surgery. Percutaneous transhepatic cholangiodrainage (PTCD) and embolization of the portal vein and hepatic artery were performed. Thereafter, ethanol was injected into the biliary duct, and the intervention was successfully completed. Case 2 was a 54-year-old woman who underwent LDLT using a right-lobe graft and duct-to-duct biliary reconstruction for PBC. Internal plastic stent insertion by ERBD was unsuccessful due to the significantly bending bile duct. After PTCD, the gun-site technique for the posterior branch and dual hepatic vascular embolization of the anterior branch was performed. The patient was followed up without an external fistula tube. CONCLUSION: ABO incompatibility was a risk factor for refractory biliary stricture. Appropriate procedures should be chosen based on stricture types.

Zero Mortality in Living-Donor Liver Transplantation for Primary Biliary Cholangitis in Patients With a Meld Score of <20.

BACKGROUND: Although primary biliary cholangitis (PBC) is considered a good indication for living-donor liver transplantation (LDLT), the postoperative results are not well known. METHODS: At Jikei University Hospital, 14 patients with PBC underwent LDLT from February 2007 to June 2022. We consider PBC with a Model for End-Stage Liver Disease (MELD) score of <20 to indicate LDLT. We performed a retrospective analysis of the patients' clinical records. RESULTS: The patients' median age was 53 years, and 12 of the 14 patients were female. A right graft was used in 5 patients, and 3 ABO-incompatible transplants were performed. The living donors were children in 6 cases, partners in 4 cases, and siblings in 4 cases. The preoperative MELD scores ranged from 11 to 19 (median, 15). The graft-to-recipient weight ratio ranged from 0.8 to 1.1 (median, 1.0). The median operative time for donors and recipients was 481 and 712 minutes, respectively. The median operative blood loss of donors and recipients was 173 and 1,800 mL, respectively. The median postoperative hospital stay of donors and recipients was 10 and 28 days, respectively. All recipients recovered satisfactorily and remained well during a median follow-up of 7.3 years. Three patients underwent a liver biopsy after LDLT because of acute cellular rejection without histologic findings of PBC recurrence. CONCLUSIONS: Living-donor liver transplantation provides satisfactory long-term survival for patients with PBC with a graft-to-recipient weight ratio of >0.7 and MELD score of <20 without hepatocellular damage and only portal vein hypertension.

Liver Only Living Donor Transplantation for Polycystic Disease in a Patient on Chronic Hemodialysis: Case Report.

BACKGROUND: Polycystic liver disease (PLD) is characterized by the progressive development of polycystic lesions in the kidney and the liver, possibly resulting in dual organ failure. We indicated living donor liver transplantation (LDLT) for a patient with end-stage liver and kidney disease (ELKD) due to PLD on uncomplicated chronic hemodialysis. CASE PRESENTATION: A 63-year-old man with ELKD and uncontrolled massive ascites due to PLD and hepatitis B on uncomplicated chronic hemodialysis was referred to us with a single possible 47-year-old female living donor. Because of the necessity of right lobe liver procurement from this small middle-aged donor and uncomplicated hemodialysis on this recipient, we considered LDLT, rather than dual organ transplantation, could be the most well-balanced option to save the life of this recipient with acceptable risk limits for this donor. A right lobe graft with 0.91 for graft recipient weight ratio was implanted with an uneventful operative procedure under intra- and postoperative continuous hemodiafiltration. The recipient was rescheduled on routine hemodialysis on day 6 after transplantation and recovered with a gradual decrease in ascites output. He was discharged on day 56. He continues to have a very good liver function and quality of life without ascites and uncomplicated routine hemodialysis 1 year after transplantation. The living donor was discharged 3 weeks after surgery and is also doing well. CONCLUSION: Although combined liver-kidney transplantation from a deceased donor could be the best option for ELKD due to PLD, LDLT can also be an acceptable option for ELKD with uncomplicated hemodialysis, considering the double equipoise theory for both lifesaving of the recipient and acceptable donor risk.

The Japanese 5-5-500 Rule Predicts Prognosis of Hepatocellular Carcinoma After Hepatic Resection.

BACKGROUND: The 5-5-500 rule has been proposed to increase the candidates of liver transplantation for patients with hepatocellular carcinoma with reasonable recurrence rates. However, the clinical significance of the 5-5-500 rule in patients who underwent hepatic resection for hepatocellular carcinoma has not been fully investigated. PATIENTS AND METHODS: The study comprised 206 patients who had undergone primary hepatic resection for hepatocellular carcinoma between 2008 and 2018. We retrospectively investigated prognostic significance of the 5-5-500 rule and disease-free, as well as overall, survival and further prognostic stratification using inflammatory-based biomarkers. RESULTS: 132 patients (64%) were classified within the 5-5-500 rule, while 74 patients (36%) were classified outside the 5-5-500 rule. Among the patients outside the 5-5-500 rule, 62 patients had tumors greater than 5 cm, and 23 patients showed serum AFP levels greater than 500 ng/ml. In the multivariate analysis, being female (p<0.01), HBs-Ag positive (p<0.01), having an ICGR15 ≥15% (p=0.03), and being outside the 5-5-500 rule (p=0.01) were independent and significant predictors of disease-free survival, while being HBs-Ag positive (p=0.04), having poor tumor differentiation (p=0.03), and residing outside the 5-5-500 rule (p=0.01) were independent and negative predictors of overall survival. Elevated CRP-to-albumin ratio was associated with poor overall survival in the patients outside the 5-5-500 rule, but not in patients within the 5-5-500 rule (p=0.17). CONCLUSION: The 5-5-500 rule can be a prognostic factor in patients with hepatocellular carcinoma after hepatic resection. CRP-to-albumin ratio might be useful to stratify the outcomes in patients outside the 5-5-500 rule.

Osteosarcopenia predicts poor prognosis for patients with intrahepatic cholangiocarcinoma after hepatic resection.

PURPOSE: The concept of osteosarcopenia, which is concomitant osteopenia and sarcopenia, has been proposed as a prognostic indicator for cancer patients. The aim of this study was to evaluate the prognostic significance of osteosarcopenia in patients with intrahepatic cholangiocarcinoma (IHCC). METHODS: The subjects of this retrospective study were 41 patients who underwent hepatic resection for IHCC. Osteopenia was assessed with pixel density in the mid-vertebral core of the 11th thoracic vertebra and sarcopenia was assessed by the psoas muscle areas at the third lumbar vertebra. Osteosarcopenia was defined as the concomitant occurrence of osteopenia and sarcopenia. We analyzed the association of osteosarcopenia with disease-free and overall survival and evaluated clinicopathologic variables in relation to the osteosarcopenia. RESULTS: Eighteen (44%) of the 41 patients had osteosarcopenia. Multivariate analysis identified osteosarcopenia (hazard ratio 3.38, 95% confidence interval: 1.49-7.68, p < 0.01) as an independent predictor of disease-free survival, and age ≥ 65 years (p = 0.03) and osteosarcopenia (hazard ratio 6.46, 95% confidence interval: 1.76-23.71, p < 0.01) as independent predictors of overall survival. CONCLUSIONS: Preoperative osteosarcopenia may be a predictor of adverse prognosis for patients undergoing hepatic resection for IHCC, suggesting that preoperative management to maintain muscle and bone intensity could improve the prognosis.

High-Throughput Functional Evaluation of MAP2K1 Variants in Cancer.

Activating mutations in mitogen-activated protein kinase kinase 1 (MAP2K1) are involved in a variety of cancers and may be classified according to their RAF dependence. Sensitivity to combined BRAF and MEK treatments is associated with co-mutations of MAP2K1 and BRAF; however, the significance of less frequent MAP2K1 mutations is largely unknown. The transforming potential and drug sensitivity of 100 MAP2K1 variants were evaluated using individual assays and the mixed-all-nominated-in-one method. In addition, A375, a melanoma cell line harboring the BRAF V600E mutation, was used to evaluate the function of the MAP2K1 variants in combination with active RAF signaling. Among a total of 67 variants of unknown significance, 16 were evaluated as oncogenic or likely oncogenic. The drug sensitivity of the individual variants did not vary with respect to BRAF inhibitors, MEK inhibitors (MEKi), or their combination. Sensitivity to BRAF inhibitors was associated with the RAF dependency of the MAP2K1 variants, whereas resistance was higher in RAF-regulated or independent variants compared with RAF-dependent variants. Thus, the synergistic effect of BRAF and MEKis may be observed in RAF-regulated and RAF-dependent variants. MAP2K1 variants exhibit differential sensitivity to BRAF and MEKis, suggesting the importance of individual functional analysis for the selection of optimal treatments for each patient. This comprehensive evaluation reveals precise functional information and provides optimal combination treatment for individual MAP2K1 variants.