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.

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.

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.

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.

Suppression of lysosomal acid alpha-glucosidase impacts the modulation of transcription factor EB translocation in pancreatic cancer.

Lysosomal degradation plays a crucial role in the metabolism of biological macromolecules supplied by autophagy. The regulation of the autophagy-lysosome system, which contributes to intracellular homeostasis, chemoresistance, and tumor progression, has recently been revealed as a promising therapeutic approach for pancreatic cancer (PC). However, the details of lysosomal catabolic function in PC cells have not been fully elucidated. In this study, we show evidence that suppression of acid alpha-glucosidase (GAA), one of the lysosomal enzymes, improves chemosensitivity and exerts apoptotic effects on PC cells through the disturbance of expression of the transcription factor EB. The levels of lysosomal enzyme were elevated by gemcitabine in PC cells. In particular, the levels of GAA were responsive to gemcitabine in a dose-dependent and time-dependent manner. Small interfering RNA against the GAA gene (siGAA) suppressed cell proliferation and promoted apoptosis in gemcitabine-treated PC cells. In untreated PC cells, we observed accumulation of depolarized mitochondria. Gene therapy using adenoviral vectors carrying shRNA against the GAA gene increased the number of apoptotic cells and decreased the tumor growth in xenograft model mice. These results indicate that GAA is one of the key targets to improve the efficacy of gemcitabine and develop novel therapies for PC.

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.

Arantius' Ligament Approach to Middle Hepatic Vein in Laparoscopic Extended Medial Segmentectomy (with Video).

BACKGROUND: Under laparoscopy-specific caudal and lateral view, Aranitius' ligament could be the landmark for the root of the venous trunks in the left hepatic lobe.1-3 We performed laparoscopic hepatic extended medial segmentectomy including the middle hepatic vein (MHV) using the Arantius' approach. METHODS: An 86-year-old man was referred to our hospital for hepatocellular carcinoma, 4.5 cm in size, located in the medial hepatic segment (Video 1). After pneumoperitoneum and placement of four working ports, the Arantius' ligament was exposed, isolated, and divided. The liver parenchyma underneath the Arantius' ligament was opened to widely expose the root of the MHV, umbilical fissure vein (UFV), and left hepatic vein (LHV). After dividing the Glissonean branches for segment 4 (G4), the parenchymal tissue between MHV and LHV was divided. The trunk of the MHV was fully exposed and was divided using the endo-stapling device. Parenchymal resection was further proceeded along the dorsal side of the MHV, and the planned hepatectomy was completed. RESULTS: The operation time was 337 min, and the estimated blood loss was 400 g. His postoperative course was uneventful, and he was discharged on postoperative day 10. CONCLUSIONS: The significance of Arantius' ligament approach is short-cut exposure of the MHV as the anatomical landmark during the initial process of the surgery under laparoscopy-specific caudal and lateral view, and is a reasonable technique in extended medial segmentectomy including the MHV.

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 Prognostic Significance of C-reactive Protein-To-Lymphocyte Ratio in Colorectal Liver Metastases.

BACKGROUND: The preoperative systemic inflammation has been reported to predict tumor recurrence and survival in various cancers, including colorectal liver metastases (CRLM). However, more sensitive biomarker is required to improve perioperative management of CRLM. Therefore, we developed a novel indicator; C-reactive protein-to-lymphocyte ratio (CLR). The aim of this study is to evaluate the prognostic significance of CLR in patients with CRLM after hepatic resection. MATERIALS AND METHODS: The study comprised 197 patients who had undergone hepatic resection for CRLM between January 2000 and December 2018. We retrospectively investigated the relation between CLR and disease-free survival and overall survival after hepatic resection and compared their prognostic significance with that of the C-reactive protein-to-albumin ratio and neutrophil-to-lymphocyte ratio. RESULTS: Optimal cutoff level of the CLR by receiver operating characteristics analysis was 62.8 × 10-6. By multivariate analysis, CLR was an independent predictor of disease-free survival [hazard ratio (HR): 1.463, 95% confidence interval (CI): 1.003-2.135, P = 0.048), whereas lymph node metastases>4 (HR: 1.804, 95% CI: 1.100-2.958, P = 0.019) and CLR (HR: 1.656, 95% CI: 1.007-2.724, P = 0.047) were independent predictors of overall survival, while the C-reactive protein-to-albumin ratio and neutrophil-to-lymphocyte ratio were not. CONCLUSIONS: CLR may be an independent and significant indicator of poor long-term outcomes in patients with CRLM after hepatic resection.

Transferrin predicts outcome in patients who underwent liver resection for colorectal liver metastases.

INTRODUCTION: The aim of this study is to investigate the relationship between preoperative serum transferrin level and long-term outcomes in patients with colorectal liver metastases after hepatic resection. METHODS: We retrospectively investigated 72 patients who underwent hepatic resection for colorectal liver metastases and explored the relationship between serum transferrin level and long-term outcomes. RESULTS: In multivariate analysis, H3 (odds ratio 3.43, 95% confidence interval 1.11-10.89 and P = 0.03) was an independent and significant predictor of the disease-free survival, and a transferrin level ≥ 190 mg/dl (odds ratio 0.20, 95% confidence interval 0.05-0.79 and P = 0.02) and the time to recurrence after hepatectomy <1 year (odds ratio 11.30, 95% confidence interval 2.63-48.59 and P < 0.01) were independent and significant predictors of the overall survival. CONCLUSIONS: The serum transferrin level is a useful predictor of poor overall survival in patients with colorectal liver metastases after hepatic reaction.

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.