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.

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.

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.

Prognostic impact of abdominal aortic calcification in patients who underwent hepatectomy for intrahepatic cholangiocarcinoma.

PURPOSE: Abdominal aortic calcification (AAC), an indicator of systemic arteriosclerosis, is associated with short- and long-term outcomes in malignancies. We investigated the prognostic impact of AAC in patients who underwent hepatectomy for intrahepatic cholangiocarcinoma (IHCC). METHODS: The study cohort comprised 46 patients who underwent hepatectomy for IHCC between January 2008 and September 2020. The AAC volume measured by preoperative computed tomography was used to construct a model of the calcified segment from the renal artery to the common iliac artery bifurcation. We investigated the relationship between AAC and the long-term outcomes. The AAC volume cutoff value was calculated from a receiver-operating characteristic curve based on the three-year survival. RESULTS: According to our cutoff AAC volume of 3,700 mm3, 11 patients (24%) had high AAC volumes. The high-AAC group was significantly older than the low-AAC group (73 vs. 62 years old, p < 0.01). A multivariate analysis of the cancer-specific survival showed that a high serum carbohydrate antigen 19-9 concentration (hazard ratio [HR] 5.57, p = 0.01), high AAC volume (HR 3.03, p = 0.04), and [high?] T3 or T4 levels (HR 9.05, p < 0.01) were independently associated with a poor prognosis. CONCLUSION: AAC is a useful predictor of the oncological prognosis in patients undergoing hepatectomy for IHCC.

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.

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.

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.

Triple Intercostal Transthoracic Ports in Laparoscopic Hepatectomy for a Tumor in a Cranially Protruded Liver (with Video).

BACKGROUND: It is difficult to laparoscopically approach tumors of the anatomically anomalous right lobe of the liver, such as cranially protruded liver. The intercostal port has been useful for laparoscopic hepatectomy, especially for tumors located in the dome of the liver. PLoS One. 15:e0234919; Surg Endosc. 31:1280-1286; J Gastrointest Surg. 21:2135-2143; J Hepatobiliary Pancreat Sci. 21:E65-68; Surg Oncol. 38:101576; Thus, we introduce our technique using triple intercostal transthoracic ports for laparoscopic hepatectomy for hepatocellular carcinoma located in segment 8. The right lobe of the liver was cranially protruded and located at the same level of the heart. PATIENT AND METHODS: The patient was placed in left lateral decubitus position. After the pneumoperitoneum and adhesiolysis, the hepatoduodenal ligament was controlled. Three additional intercostal ports with balloons were introduced transdiaphragmatically for liver parenchymal resection after confirmation of the lung edge by mandatory ventilation. A 12-mm and a 5-mm port were inserted into the sixth and seventh intercostal space for the operator's hands, while a 5-mm port was inserted into the fourth intercostal space for the assist's right hand. The liver parenchymal resection was performed using a cavitron ultrasonic surgical aspirator (CUSA) through the 12-mm intercostal port, followed by its completion without exposing the tumor. The 12-mm port hole on the diaphragm was sutured and a 12-Fr chest tube was introduced in the right thoracic cavity. RESULTS: The operation time was 131 min, and the blood loss was 20 g. The patient was discharged on postoperative day 7 without any complication. CONCLUSION: Triple intercostal ports could be a feasible procedure for a tumor with limited laparoscopic access from the abdominal port due to the anatomically anomalous liver.

Novel combined fibrosis-based index predicts the long-term outcomes of hepatocellular carcinoma after hepatic resection.

AIM: Liver fibrosis influences liver regeneration and surgical outcomes. The fibrosis-4 (FIB-4) index is strongly associated with liver fibrosis and cirrhosis. This study aimed to examine the prognostic significance of the combination of FIB-4 index and Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) (PIVKA-II-FIB-4 index score) in patients who underwent curative resection for hepatocellular carcinoma (HCC). METHODS: We included 284 patients who underwent elective hepatic resection for HCC between January 2000 and December 2018. We retrospectively investigated how FIB-4 index is related to disease-free survival and overall survival. RESULTS: According to a receiver operating characteristic (ROC) analysis, the optimal cutoff value of the FIB-4 index was 3.44. In a multivariate analysis, high PIVKA-II and FIB-4 index values were independent predictors of both disease-free survival (P = 0.013 and P = 0.005, respectively) and overall survival (P = 0.048 and P < 0.001, respectively). We classified the PIVKA-II and FIB-4 index levels into two groups (high vs. low) and calculated a new score (PIVKA-II-FIB-4 index score; 0-2) by the sum of each measurement (high, 1; low, 0). The 5 year overall survival rates of patients with PIVKA-II-FIB-4 index scores of 0, 1, and 2 were 84.9, 74.4, and 47.1%, respectively (P < 0.001). CONCLUSION: The combination of the preoperative PIVKA-II and FIB-4 index may be a prognostic factor of HCC after hepatic resection, suggesting that the combined score is useful in assessing the liver fibrosis status in cancer cases.

The impact of S-1 for the patient with lymph nodal metastasis biliary tract cancer as adjuvant chemotherapy: a multicenter database analysis.

INTRODUCTION: Although adjuvant chemotherapy is expected to improve the prognosis for patients with biliary tract cancer after curative resection, there is limited evidence regarding the efficacy and prognostic factors of adjuvant chemotherapy. We investigated the effective subgroups for whom adjuvant chemotherapy with S-1 in biliary tract cancer patients. METHODS: 413 patients who underwent curative resection for biliary tract cancer at our four affiliated hospitals between 2009 and 2019 were included in this study. The association of adjuvant chemotherapy with long-term outcomes in overall and patient subgroups were investigated by univariate and multivariate analyses. RESULTS: Among overall patients, adjuvant chemotherapy with S-1 did not improve disease free survival (p = 0.29) and overall survival (p = 0.83). In the subgroup analysis, adjuvant chemotherapy with S-1 improved both disease-free and overall survival in patients with lymph node metastasis, advanced Stage (III and IV), and microscopic residual tumor. In 135 patients with lymph node metastasis, adjuvant chemotherapy with S-1 was given in 67 patients (50%). In the patients with lymph node metastasis, preoperative bile duct drainage (p = 0.01) and adjuvant chemotherapy (p = 0.04) were independent and significant predictors of disease-free survival, while preoperative bile duct drainage (p = 0.03), tumor differentiation (p = 0.03), and adjuvant chemotherapy (p = 0.03) were independent and significant predictors of overall survival. CONCLUSION: After resection of biliary tract cancer, adjuvant chemotherapy with S-1 appears to benefit those who had lymph node metastasis.

Triple liver hanging maneuver for hepatic central bisectionectomy with caudate lobectomy for resection of huge hepatocellular carcinoma (with video).

Resection of huge hepatocellular carcinomas occupying the central portion of the liver is challenging. Exposure of an adequate liver transection plane using an anterior approach is likely to be difficult because of compression by the tumor. We herein propose a "triple liver hanging maneuver" technique for central bisectionectomy with caudate lobectomy for huge hepatocellular carcinomas stretching the hilar plate and the right and left hepatic veins. In this technique, the first tape is introduced for the transection plane along the right side of the umbilical portion to the anterior surface of the inferior vena cava. The second tape is introduced to lift the paracaval caudate Glissonean pedicles from the hilar plate. The third tape is introduced for the transection plane along the right hepatic vein to the anterior surface of the inferior vena cava. The triple liver hanging maneuver could be effective for huge tumors compressing major hepatic vessels.

The clinical management of peripancreatic fluid collection after distal pancreatectomy.

PURPOSE: Peripancreatic fluid collection (PFC) is a frequent radiological finding on postoperative computed tomography (CT) after distal pancreatectomy (DP). We evaluated the risk factors for drainage of PFC after DP to clarify the optimal management of PFC. METHODS: This study included 85 patients who underwent elective DP between January 2010 and December 2020. PFC was defined as an area of fluid located at the pancreatic resection margin on postoperative routine CT on approximately postoperative day 7 (first CT). We retrospectively investigated the relationship between clinical variables, including CT findings and PFC drainage. RESULTS: Drainage was performed in 19 patients (22.4%). Drainage for PFC was significantly associated with a longer postoperative hospital stay, higher PFC volume, presence of air bubbles, and higher white blood cell (WBC) count at the time of the first CT. According to the multivariate analyses, a PFC volume ≥ 60 mL and WBC count ≥ 12,400/µL on the day of the first CT were independent risk factors for PFC drainage after DP. The combination of these 2 factors showed 73.7% sensitivity and 90.9% specificity. CONCLUSION: The PFC volume and WBC count at the first CT were significantly associated with PFC drainage and may help determine the appropriate treatment.

Inhibition of acid ceramidase elicits mitochondrial dysfunction and oxidative stress in pancreatic cancer cells.

Although the inhibition of acid ceramidase (AC) is known to induce antitumor effects in various cancers, there are few reports in pancreatic cancer, and the underlying mechanisms remain unclear. Moreover, there is currently no safe administration method of AC inhibitor. Here the effects of gene therapy using siRNA and shRNA for AC inhibition with its mechanisms for pancreatic cancer were investigated. The inhibition of AC by siRNA and shRNA using an adeno-associated virus 8 (AAV8) vector had antiproliferative effects by inducing apoptosis in pancreatic cancer cells and xenograft mouse model. Acid ceramidase inhibition elicits mitochondrial dysfunction, reactive oxygen species accumulation, and manganese superoxide dismutase suppression, resulting in apoptosis of pancreatic cancer cells accompanied by ceramide accumulation. These results elucidated the mechanisms underlying the antitumor effect of AC inhibition in pancreatic cancer cells and suggest the potential of the AAV8 vector to inhibit AC as a therapeutic strategy.

The Significance of the Rapid Turnover Protein Score as a Predictor of the Long-Term Outcomes in Hepatocellular Carcinoma After Hepatic Resection.

BACKGROUND: Nutritional status assessment is essential in cancer patients because a poor nutritional status has been associated with poor outcomes; however, the impact of rapid turnover proteins (RTPs), such as prealbumin, transferrin, and retinol-binding protein, on the outcomes of hepatocellular carcinoma (HCC) has not been well-investigated. We therefore examined the prognostic significance of RTPs in patients with HCC after curative resection. METHODS: This study included 150 patients who underwent elective hepatic resection for HCC between January 2011 and December 2018. The prealbumin, transferrin, and retinol-binding protein levels were classified into two groups (high vs. low); the RTP score (0-3) was calculated as the sum of each RTP measurement (high = 0; low = 1). We retrospectively investigated the relationship between the RTP score and disease-free and overall survival. RESULTS: Multivariate analysis showed that a high RTP score (P = 0.022), presence of sarcopenia (P = 0.001), and stage III or higher (P = 0.005) were independent predictors of disease-free survival, while a high RTP score (P < 0.001), presence of sarcopenia (P = 0.017), and stage III or higher (P = 0.012) were independent predictors of overall survival. In patients with high RTP scores, positive hepatitis B and C viral infection, high indocyanine green (ICG) at 15 min (ICGR15), Child-Pugh grade B, poorly differentiated carcinoma, and postoperative ascites were more common than in patients with low RTP scores. CONCLUSION: The preoperative RTP score may be a prognostic factor in patients with hepatocellular carcinoma after hepatic resection, suggesting an important role of RTP in the assessment of nutritional status in cancer patients.

The novel index using preoperative C-reactive protein and neutrophil-to-lymphocyte ratio predicts poor prognosis in patients with pancreatic cancer.

BACKGROUND: Several kinds of systemic inflammatory response, classified into two types: C-reactive protein (CRP)-based type and blood cell count-based type, were reported as a prognostic indicator in patients with pancreatic cancer (PC). However, there is no consensus which types is more sensitive predictor in patients with PC. Therefore, we here developed a novel biomarker, C-NLR, which consists of both CRP and neutrophil-to-lymphocyte ratio (NLR), and we evaluated the prognostic significance of C-NLR in patients with PC after pancreatic resection. METHODS: A total of 217 patients was comprised in this study. We retrospectively investigated the relation between C-NLR and disease-free survival (DFS) and overall survival (OS) after pancreatic resection. RESULTS: Optimal cutoff level of C-NLR was defined as 0.206 by a ROC analysis. By multivariate analysis, age (P = 0.024), TNM stage (P < 0.001), and C-NLR (HR: 1.373, 95% CI: 1.005-1.874, P = 0.046) were independent predictors of DFS, whereas TNM stage (P = 0.016) and C-NLR (HR: 1.468, 95% CI: 1.042-2.067, P = 0.028) were independent predictors of OS. CONCLUSION: Preoperative C-NLR can be a prognostic indicator in patients with PC after pancreatic resection, suggesting the importance of both CRP and blood cell count in predicting therapeutic outcomes.