Appendectomy and Long-term Colorectal Cancer Incidence, Overall and by Tumor Fusobacterium nucleatum Status.

OBJECTIVE: To test hypotheses that appendectomy history might lower long-term colorectal cancer risk and that the risk reduction might be strong for tumors enriched with Fusobacterium nucleatum, bacterial species implicated in colorectal carcinogenesis. BACKGROUND: The absence of the appendix, an immune system organ and a possible reservoir of certain pathogenic microbes, may affect the intestinal microbiome, thereby altering long-term colorectal cancer risk. METHODS: Utilizing databases of prospective cohort studies, namely the Nurses' Health Study and the Health Professionals Follow-up Study, we examined the association of appendectomy history with colorectal cancer incidence overall and subclassified by the amount of tumor tissue Fusobacterium nucleatum​​ (Fusobacterium animalis). We used an inverse probability weighted multivariable-adjusted duplication-method Cox proportional hazards regression model. RESULTS: During the follow-up of 139,406 participants (2,894,060 person-years), we documented 2811 incident colorectal cancer cases, of which 1065 cases provided tissue F. nucleatum analysis data. The multivariable-adjusted hazard ratio of appendectomy for overall colorectal cancer incidence was 0.92 (95% CI, 0.84-1.01). Appendectomy was associated with lower F. nucleatum-positive cancer incidence (multivariable-adjusted hazard ratio, 0.53; 95% CI, 0.33-0.85; P=0.0079), but not F. nucleatum-negative cancer incidence (multivariable-adjusted hazard ratio, 0.98; 95% CI, 0.83-1.14), suggesting a differential association by F. nucleatum status (Pheterogeneity=0.015). This differential association appeared to persist in various participant/patient strata including tumor location and microsatellite instability status. CONCLUSIONS: Appendectomy likely lowers the future long-term incidence of F. nucleatum-positive (but not F. nucleatum-negative) colorectal cancer. Our findings do not support the existing hypothesis that appendectomy may increase colorectal cancer risk.

Prognostic significance of occult vertebral fracture in patients undergoing pancreatic resection for pancreatic cancer.

OBJECTIVE: The prognostic impact of occult vertebral fracture (OVF) in patients with malignancies is a new cutting edge in cancer research. This study was performed to analyze the prognostic impact of OVF after surgery for pancreatic cancer. METHODS: This study involved 200 patients who underwent surgical treatment of pancreatic ductal adenocarcinoma. OVF was diagnosed by quantitative measurement using preoperative sagittal computed tomography image reconstruction from the 11th thoracic vertebra to the 5th lumbar vertebra. RESULTS: OVF was diagnosed in 65 (32.5 %) patients. The multivariate analyses showed that male sex (p = 0.01), osteopenia (p < 0.01), OVF (p < 0.01), a carbohydrate antigen 19-9 level of ≥400 U/mL (p < 0.01), advanced stage of cancer (p < 0.01), and non-adjuvant chemotherapy (p = 0.02) were independent risk factors for overall survival. An age of ≥74 years (p < 0.01) and obstructive jaundice (p = 0.03) were independent risk factors for OVF. Furthermore, the combination of OVF and osteopenia further worsened disease-free survival and overall survival compared with osteopenia or OVF alone (p < 0.01; respectively). CONCLUSION: Evaluation of preoperative OVF might be a useful prognostic indicator for patients with pancreatic ductal adenocarcinoma.

Protein kinase C delta enhances the diagnostic performance of hepatocellular carcinoma.

BACKGROUND: The conventional markers for hepatocellular carcinoma (HCC), α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), have several limitations; both have low sensitivity in patients with early-stage HCC; low sensitivity for AFP with HCC after eliminating hepatitis C virus (HCV); low specificity for DCP in patients with non-viral HCC, which is increasing worldwide; low specificity for AFP in patients with liver injury; and low specificity for DCP in patients treated with warfarin. To overcome these issues, the identification of novel biomarkers is an unmet need. OBJECTIVE: This study aimed to assess the usefulness of serum protein kinase C delta (PKCδ) for detecting these HCCs. METHODS: PKCδ levels were measured using a sandwich enzyme-linked immunosorbent assay in 363 chronic liver disease (CLD) patients with and without HCC. RESULTS: In both viral and non-viral CLD, PKCδ can detect HCCs with high sensitivity and specificity, particularly in the very early stages. Notably, the value and sensitivity of PKCδ were not modified by HCV elimination status. Liver injury and warfarin administration, which are known to cause false-positive results for conventional markers, did not modify PKCδ levels. CONCLUSIONS: PKCδ is an enhanced biomarker for the diagnosis of HCC that compensates for the drawbacks of conventional markers.

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.

Predictors for early recurrence beyond up-to-7 or distant metastasis after hepatocellular carcinoma resection: proposal for borderline resectable HCC.

BACKGROUND: The recurrence rate after curative resection for hepatocellular carcinoma (HCC) reaches over 70% after 5 years and early recurrence (within 1 year) is now recognized as having a poor prognosis and has limited treatment options. METHODS: We retrospectively reviewed 184 consecutive patients who underwent curative hepatic resection for HCC. Severe early recurrence was defined as multiple (beyond up-to-7) liver recurrence or distant metastasis after hepatic resection within 1 year. We divided the participants into two groups according to severe early recurrence and analyzed clinicopathological and long-term outcomes. RESULTS: Among the patients with multiple or distant metastasis (n = 59), 49 patients (83%) had recurrence within 1 year. Overall survival (OS) and recurrence-free survival (RFS) were significantly worse in the severe early recurrence group than in the others group. Logistic regression analysis revealed that severe early recurrence was significantly associated with macroscopic vascular invasion (MVI), tumor burden score (TBS) > 4.70, and ALBI grade 2. In patients with scores of 2 and 3 (the sum of the three factors), OS and RFS rates were significantly poorer than those of patients with scores of 0 or 1. Positive predictive value and negative predictive value for severe early recurrence was 68.4% and 84.2%, respectively. Furthermore, a validation study demonstrated that cases with these factors were at high risk of severe early recurrence and had poor prognosis. CONCLUSIONS: In this retrospective analysis, MVI, TBS, and ALBI could predict severe early recurrence after hepatic resection for HCC, and patients with these risk factors had a poor prognosis.

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.

Osteosarcopenia is a significant predictor of recurrence and the prognosis after resection for extrahepatic bile duct cancer.

PURPOSE: This study examined the impact of osteosarcopenia on recurrence and the prognosis after resection for extrahepatic biliary tract cancer (EBTC). METHODS: We retrospectively analyzed 138 patients after resection for perihilar cholangiocarcinoma (11), distal cholangiocarcinoma (54), gallbladder carcinoma (30), or ampullary carcinoma (43). Osteosarcopenia is defined as the concomitant occurrence of osteopenia and sarcopenia. We investigated the relationship between osteosarcopenia and the overall survival (OS) and disease-free survival (DFS) in univariate and multivariate analyses. RESULTS: Osteosarcopenia was identified in 38 patients (27.5%) before propensity score (PS) matching. In the multivariate analysis, the independent recurrence factors were the prognostic nutrition index (p = 0.015), osteosarcopenia (p < 0.001), poorly differentiated adenocarcinoma (p = 0.004), perineural invasion (p = 0.002), and non-curability (p = 0.008), whereas the independent prognostic factors were prognostic nutrition index (p = 0.030), osteosarcopenia (p < 0.001), poorly differentiated adenocarcinoma (p = 0.007), lymphatic invasion (p = 0.018), and non-curability (p = 0.004). After PS matching, there was no significant difference in the variables between the patients with and without osteosarcopenia (n = 34 each). The 5-year DFS and OS after PS matching in patients with osteosarcopenia were significantly worse than in patients without osteosarcopenia (17.6% vs. 38.8%, p = 0.013 and 20.6% vs. 57.4%, p = 0.0005, respectively). CONCLUSIONS: Preoperative osteosarcopenia could predict the DFS and OS of patients after resection for EBTC.

Histological and radiological analysis of simultaneous dual hepatic vein embolization for right-sided major hepatectomy.

PURPOSE: Simultaneous dual hepatic vein embolization (DHVE) has been proposed for safe right-sided hepatectomy, with good results for liver hypertrophy and function. However, the histological and radiological findings of DHVE have not been thoroughly investigated. METHODS: This study included 14 patients who underwent DHVE before right-sided major hepatectomy. DHVE was performed if the future liver remnant was < 35% or borderline, but with concomitant vascular resection. The liver function was assessed using the signal intensity on Gd-EOB-DTPA-MRI. A histological evaluation of the area of DHVE and portal vein embolization (PVE) were performed. RESULTS: The median pre- and post-functional liver remnants were 363 ml and 498 ml, respectively (p < 0.001). The median growth rate was 48.6%, and there was no post-hepatectomy liver failure in the patients who underwent DHVE. The signal intensity ratio in the area of DHVE was lower than that in the areas of PVE and the remnant liver (p < 0.01). The degree of congestion and necrosis was greater in the area of DHVE than in the area of PVE alone (p < 0.01 and p = 0.04, respectively). CONCLUSIONS: We observed good liver hypertrophy after DHVE and histological and radiological changes in the area of DHVE. Our findings provide a compelling rationale for further investigation of the mechanism of liver hypertrophy in DHVE.

Abdominal aortic calcification volume as a preoperative prognostic predictor for pancreatic cancer.

PURPOSE: Atherosclerosis and cancer may progress through common pathological factors. This study was performed to investigate the association between the abdominal aortic calcification (AAC) volume and outcomes following surgical treatment for pancreatic cancer. METHODS: The subjects of this retrospective study were 194 patients who underwent pancreatic cancer surgery between 2007 and 2020. The AAC volume was assessed through routine preoperative computed tomography. Univariate and multivariate analyses were performed to evaluate the impact of the AAC volume on oncological outcomes. RESULTS: A higher AAC volume (≥ 312 mm3) was identified in 66 (34%) patients, who were significantly older and had a higher prevalence of diabetes and sarcopenia. Univariate analysis revealed several risk factors for overall survival (OS), including male sex, an AAC volume ≥ 312 mm3, elevated carbohydrate antigen 19-9, prolonged operation time, increased intraoperative bleeding, lymph node metastasis, poor differentiation, and absence of adjuvant chemotherapy. Multivariate analysis identified an AAC volume ≥ 312 mm3, prolonged operation time, lymph node metastasis, poor differentiation, and absence of adjuvant chemotherapy as independent OS risk factors. The OS rate was significantly lower in the high AAC group than in the low AAC group. CONCLUSION: The AAC volume may serve as a preoperative prognostic indicator for patients with pancreatic cancer.

Western-Style Diet, pks Island-Carrying Escherichia coli, and Colorectal Cancer: Analyses From Two Large Prospective Cohort Studies.

BACKGROUND & AIMS: Evidence supports a carcinogenic role of Escherichia coli carrying the pks island that encodes enzymes for colibactin biosynthesis. We hypothesized that the association of the Western-style diet (rich in red and processed meat) with colorectal cancer incidence might be stronger for tumors containing higher amounts of pks+E coli. METHODS: Western diet score was calculated using food frequency questionnaire data obtained every 4 years during follow-up of 134,775 participants in 2 United States-wide prospective cohort studies. Using quantitative polymerase chain reaction, we measured pks+E coli DNA in 1175 tumors among 3200 incident colorectal cancer cases that had occurred during the follow-up. We used the 3200 cases and inverse probability weighting (to adjust for selection bias due to tissue availability), integrated in multivariable-adjusted duplication-method Cox proportional hazards regression analyses. RESULTS: The association of the Western diet score with colorectal cancer incidence was stronger for tumors containing higher levels of pks+E coli (Pheterogeneity = .014). Multivariable-adjusted hazard ratios (with 95% confidence interval) for the highest (vs lowest) tertile of the Western diet score were 3.45 (1.53-7.78) (Ptrend = 0.001) for pks+E coli-high tumors, 1.22 (0.57-2.63) for pks+E coli-low tumors, and 1.10 (0.85-1.42) for pks+E coli-negative tumors. The pks+E coli level was associated with lower disease stage but not with tumor location, microsatellite instability, or BRAF, KRAS, or PIK3CA mutations. CONCLUSIONS: The Western-style diet is associated with a higher incidence of colorectal cancer containing abundant pks+E coli, supporting a potential link between diet, the intestinal microbiota, and colorectal carcinogenesis.

Molecular Characteristics of Early-Onset Colorectal Cancer According to Detailed Anatomical Locations: Comparison With Later-Onset Cases.

INTRODUCTION: Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management. METHODS: Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases. RESULTS: The proportions of MSI-high, CIMP-high, and BRAF -mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF -mutated) (all Ptrend <0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors ( P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend <0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend. DISCUSSION: Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups.

Right-Lateral Pringle Maneuver Using Endovascular Clip for Open and Laparoscopic Hepatectomy After Esophagectomy (with Video).

BACKGROUND: Laparoscopic hepatectomy after esophageal cancer surgery is a technically challenging procedure as it is difficult to control hepatic inflow due to adhesion 1. Ann Hepatobiliary Pancreat Surg. 22:344-349; 2. Dis Esophagus. 28:483-487; 3. Surg Endosc. 35:5375-5380; 4. Surg Laparosc Endosc Percutan Tech. 23:e103-105. Thus, we introduce our technique for hepatic inflow control using an endovascular clip. METHODS: After the confirmation of space between the right and dorsal side of the hepatoduodenal ligament and the inferior vena cava, an endovascular clip was introduced laterally from the right side of the hepatoduodenal ligament to control hepatic inflow. The control of hepatic inflow was confirmed using intraoperative Doppler ultrasound and then a hepatic parenchymal transection was performed. The video demonstrates our technique using an endovascular clip for hepatic inflow control to perform safe open or laparoscopic hepatectomy after esophageal cancer surgery. Patient 1 was an 82-year-old woman with a history of laparoscopic assisted esophagectomy for esophageal neuroendocrine cancer. She underwent open anatomical resection of segment 3 for a 38-mm liver tumor. Patient 2 was a 71-year-old man with a history of laparoscopic esophagectomy for esophageal cancer. He underwent laparoscopic partial resection of segment 6 for a 24-mm liver tumor. RESULTS: The operation times were 105 and 123 min, and the estimated blood loss was 30 g and 10 g, respectively. The patients' postoperative courses were uneventful and the patients were discharged on postoperative days 9 and 8, respectively. CONCLUSION: Right-lateral Pringle maneuver using an endovascular clip may be a safe and feasible technique in both open and laparoscopic hepatectomy after esophagectomy.

Sustained Systemic Inflammatory Response Predicts Survival in Patients with Hepatocellular Carcinoma After Hepatic Resection.

BACKGROUND: Preoperative systematic inflammatory response, represented by neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and C-reactive protein-albumin ratio (CAR), has been associated with long-term outcomes in patients with hepatocellular carcinoma (HCC). However, the impact of sustained systematic inflammatory response after resection remains unclear. METHODS: This study comprised 210 patients who had undergone primary hepatic resection for HCC between 2008 and 2018. Preoperative and postoperative NLR, LMR, and CAR were evaluated, and patients were then classified into three groups according to the status of each marker: persistently high inflammatory state (elevated group), preoperatively low inflammatory state (normal group), and preoperatively high but postoperatively low inflammatory state (normalized group). Multivariate Cox proportional hazard models were conducted to assess disease-free and overall survival, adjusting for potential confounders. RESULTS: In multivariate analysis, sex (p = 0.002), hepatitis B surface antigen (HBsAg) positivity (p = 0.002), serum α-fetoprotein (AFP) level ≥ 20 ng/mL (p < 0.001), multiple tumors (p < 0.001), microvascular invasion (p = 0.003), type of resection (p = 0.007), and elevated CAR (hazard ratio [HR] 2.40, 95% confidence interval [CI] 1.55-3.73; p < 0.001) were independent and significant predictors of cancer recurrence, while sex (p = 0.05), HBsAg positivity (p = 0.03), serum AFP level ≥20 ng/mL (p = 0.009), multiple tumors (p = 0.03), microvascular invasion (p = 0.006), and elevated CAR (HR 2.10, 95% CI 1.13-3.91; p = 0.02) were independent predictors of overall survival. CONCLUSIONS: Sustained elevated CAR may be an independent and significant indicator of poor long-term outcomes in patients with HCC after hepatic resection, suggesting the interplay of the host's inflammatory state and tumor recurrence and progression in HCC.

Systemic inflammation adversely affects response to anamorelin in patients with pancreatic cancer.

PURPOSE: Anamorelin, a selective ghrelin receptor agonist, has been approved for pancreatic cancer treatment in Japan. We aimed to investigate whether systemic inflammation, represented by the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and C-reactive protein (CRP)-albumin ratio (CAR), could predict the effect of anamorelin in patients with advanced pancreatic cancer. METHODS: This study included 31 patients who had received anamorelin for advanced pancreatic cancer between 2021 and 2023. Patients' NLR, PLR, LMR, and CAR were evaluated before anamorelin administration. The patients were classified as responders and non-responders based on whether they gained body weight after 3 months of anamorelin administration. We investigated the association between systemic inflammation and anamorelin efficacy using a univariate analysis. RESULTS: Twelve (39%) patients were non-responders. A high serum CRP level (p = 0.007) and high CAR (p = 0.013) was associated with non-response to anamorelin. According to the receiver operating characteristics analysis, the CAR cutoff value was 0.06, and CAR ≥ 0.06 was a risk factor (odds ratio, 5.6 [95% confidence interval 1.2-27.1], p = 0.032) for non-response to anamorelin. CONCLUSION: CAR can be a predictor of non-response to anamorelin in patients with advanced pancreatic cancer, suggesting the importance of a comprehensive assessment of the inflammatory status.

A feasible and safe approach for repeat laparoscopic liver resection and patient selection based on standardized preoperative prediction of surgical difficulty.

PURPOSE: This study was performed to propose a strategy for repeat laparoscopic liver resection (RLLR) and investigate the preoperative predictive factors for RLLR difficulty. METHODS: Data from 43 patients who underwent RLLR using various techniques at 2 participating hospitals from April 2020 to March 2022 were retrospectively reviewed. Surgical outcomes, short-term outcomes, and feasibility and safety of the proposed techniques were evaluated. The relationship between potential predictive factors for difficult RLLR and perioperative outcomes was evaluated. Difficulties associated with RLLR were analyzed separately in two surgical phases: the Pringle maneuver phase and the liver parenchymal transection phase. RESULTS: The open conversion rate was 7%. The median surgical time and intraoperative blood loss were 235 min and 200 mL, respectively. The Pringle maneuver was successfully performed in 81% of patients using the laparoscopic Satinsky vascular clamp (LSVC). Clavien-Dindo class ≥III postoperative complications were observed in 12% of patients without mortality. An analysis of the risk factors for predicting difficult RLLR showed that a history of open liver resection was an independent risk factor for difficulty in the Pringle maneuver phase. CONCLUSION: We present a feasible and safe approach to address RLLR difficulty, especially difficulty with the Pringle maneuver using an LSVC, which is extremely useful in RLLR. The Pringle maneuver is more challenging in patients with a history of open liver resection.

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.

Prognostic significance of the cachexia index in patients with stage I-III colorectal cancer who underwent laparoscopic surgery.

PURPOSE: The prognostic significance of the cachexia index, a novel biomarker of cancer cachexia, remains unclear in colorectal cancer; we, therefore, evaluated this relationship. METHODS: This retrospective cohort study included 306 patients with stage I-III colorectal cancer who underwent R0 resection between April 2010 and March 2020. The cachexia index was calculated as (skeletal muscle index [cm2/m2] × serum albumin level [g/dL])/neutrophil-to-lymphocyte ratio. The overall and disease-free survival rates were analyzed using a Cox proportional hazards model. RESULTS: A low cachexia index was found in 94 patients. This group had significantly lower disease-free survival and overall survival than the high-cachexia index group (5-year survival, 86.3% vs. 63.1%, p < 0.01; 87.9% vs. 67.2%, p < 0.01). Multivariate analyses showed that T3 or T4 (hazard ratio [HR]: 2.56; 95% confidence interval CI 1.04-6.25, p = 0.039), stage III (HR: 3.77; 95% CI 1.79-7.93, p < 0.01), and a low cachexia index (HR: 2.27; 95% CI 1.31-3.90, p = 0.003) were significant independent predictors of the disease-free survival. CA19-9 ≥ 37.0 ng/mL (HR: 2.68; 95% CI: 1.37-5.24, p = 0.004), stage III (HR: 2.57; 95% CI 1.34-4.92, p = 0.004), and a low cachexia index (HR: 2.35; 95% CI 1.31-4.21, p = 0.004) were significant independent predictors of the overall survival. CONCLUSION: A low cachexia index might be a long-term prognostic factor of colorectal cancer.

The influence of serum cholinesterase levels and sarcopenia on postoperative infectious complications in colorectal cancer surgery.

PURPOSE: Cholinesterase is a nutritional marker associated with sarcopenia. The present study evaluated the relationship between cholinesterase and postoperative infectious complications in patients undergoing colorectal resection for colorectal cancer. METHODS: The study involved 231 patients who had undergone colorectal resection for colorectal cancer. We retrospectively investigated the relationship between preoperative serum cholinesterase levels and postoperative infectious complications. Univariate and multivariate analyses were performed to identify independent risk factors for postoperative infectious complications. We then performed stratified analyses to assess the interaction between cholinesterase and clinical variables to predict postoperative infectious complications. RESULTS: In the multivariate analysis, the body mass index (P = 0.010), serum cholinesterase levels (P = 0.005), sarcopenia (P = 0.003) and blood loss (P < 0.001) were independent risk factors for postoperative infectious complications. In stratified analyses, the association between serum cholinesterase levels and postoperative infectious complications differed by the sarcopenia status (Pinteraction = 0.006). CONCLUSION: Preoperative serum cholinesterase levels may be useful for predicting postoperative infectious complications in colorectal cancer surgery. The association differs by the sarcopenia status, suggesting a potential interaction between nutritional markers and sarcopenia.

Inhibition of lysosomal acid ß-glucosidase induces cell apoptosis via impairing mitochondrial clearance in pancreatic cancer.

Sphingolipid metabolism plays an important role in the formation of cellular membranes and is associated with malignant potential and chemosensitivity of cancer cells. Sphingolipid degradation depends on multiple lysosomal glucosidases. We focused on acid ß-glucosidase (GBA), a lysosomal enzyme the deficiency of which is related to mitochondrial dysfunction. We analyzed the function of GBA in pancreatic ductal adenocarcinoma (PDAC). Human PDAC cell lines (PANC-1, BxPC-3 and AsPC-1) were examined under conditions of GBA knockdown via the short interfering RNA (siRNA) method. We assessed the morphological changes, GBA enzyme activity, GBA protein expression, cell viability, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) and mitophagy flux of PDAC cells. The GBA protein level and enzyme activity differed among cell lines. GBA knockdown suppressed cell proliferation and induced apoptosis, especially in PANC-1 and BxPC-3 cells, with low GBA enzyme activity. GBA knockdown also decreased the MMP and impaired mitochondrial clearance. This impaired mitochondrial clearance further induced dysfunctional mitochondria accumulation and ROS generation in PDAC cells, inducing apoptosis. The antiproliferative effects of the combination of GBA suppression and gemcitabine were higher than those of gemcitabine alone. These results showed that GBA suppression exerts a significant antitumor effect and may have therapeutic potential in the clinical treatment of PDAC.

Immune cell profiles in the tumor microenvironment of early-onset, intermediate-onset, and later-onset colorectal cancer.

BACKGROUND: Despite heightened interest in early-onset colorectal cancer (CRC) diagnosed before age 50, little is known on immune cell profiles of early-onset CRC. It also remains to be studied whether CRCs diagnosed at or shortly after age 50 are similar to early-onset CRC. We therefore hypothesized that immune cell infiltrates in CRC tissue might show differential heterogeneity patterns between three age groups (< 50 "early onset," 50-54 "intermediate onset," ≥ 55 "later onset"). METHODS: We examined 1,518 incident CRC cases with available tissue data, including 35 early-onset and 73 intermediate-onset cases. To identify immune cells in tumor intraepithelial and stromal areas, we developed three multiplexed immunofluorescence assays combined with digital image analyses and machine learning algorithms, with the following markers: (1) CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 for T cells; (2) CD68, CD86, IRF5, MAF, and MRC1 (CD206) for macrophages; and (3) ARG1, CD14, CD15, CD33, and HLA-DR for myeloid cells. RESULTS: Although no comparisons between age groups showed statistically significant differences at the stringent two-sided α level of 0.005, compared to later-onset CRC, early-onset CRC tended to show lower levels of tumor-infiltrating lymphocytes (P = 0.013), intratumoral periglandular reaction (P = 0.025), and peritumoral lymphocytic reaction (P = 0.044). Compared to later-onset CRC, intermediate-onset CRC tended to show lower densities of overall macrophages (P = 0.050), M1-like macrophages (P = 0.062), CD14+HLA-DR+ cells (P = 0.015), and CD3+CD4+FOXP3+ cells (P = 0.039). CONCLUSIONS: This hypothesis-generating study suggests possible differences in histopathologic lymphocytic reaction patterns, macrophages, and regulatory T cells in the tumor microenvironment by age at diagnosis.