The Gastrohepatic Ligament Approach Using Multiple Traction Tapes in Laparoscopic Spleen-Preserving Distal Pancreatectomy with Preservation of Splenic Vessels (with Video).

BACKGROUND: The gastrohepatic ligament approach is a form of robot-assisted spleen-preserving distal pancreatectomy (SPDP).1,2 This approach does not require omentum transection, peri-splenic dissection, or stomach traction. METHODS: Considering the advantages of preserving collateral pathways around the spleen, the authors performed the gastrohepatic ligament approach in laparoscopic SPDP while preserving splenic vessels (LSPDP), with specific modifications for laparoscopic surgery. The following surgical technique was performed. First, the gastrohepatic ligament was divided extensively, and all subsequent procedures were performed through the gastrohepatic ligament route. The superior and inferior borders of the pancreas then were dissected to encircle the common hepatic and splenic arteries with vessel loops and to expose the superior mesenteric vein (SMV) and portal vein. After taping of the pancreas on the SMV, the pancreas was divided using a linear stapler. Next, the pancreas was dissected from proximal to distal with preservation of the splenic vessels. Re-taping and traction of the splenic vessels and pancreas could facilitate the dissection of the pancreas body, especially at the splenic hilum. The appropriate counter traction using traction tapes allowed efficient laparoscopic procedures. The LSPDP was performed for three patients, including one obese patient (body mass index, 36 kg/m2) and two patients with an anomalous left hepatic artery branching from the left gastric artery. RESULTS: The mean operation time was 186 min, and the intraoperative blood loss was 37 mL. CONCLUSION: The gastrohepatic ligament approach could be an option for performing LSPDP with the counter traction technique for low-grade malignant tumors.

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.

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.

Laparoscopic cholecystectomy with the Pringle maneuver for acute cholecystitis (with video).

Horiuchi and colleagues assessed the benefits of adding the Pringle maneuver to laparoscopic cholecystectomy for acute cholecystitis. Compared with laparoscopic cholecystectomy without the Pringle maneuver, including it reduced intraoperative bleeding. Laparoscopic cholecystectomy with the Pringle maneuver is a safe and feasible option that avoids conversion to open laparotomy and prevents serious complications.

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.

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.

Thrombomodulin expression impacts the recurrence and long-term survival in pancreatic cancer.

BACKGROUND: Pancreatic cancer is one of the most aggressive digestive cancers. The tumor expression of thrombomodulin (TM) is correlated with favorable prognosis in several types of cancer. However, this correlation has not been confirmed in hepato-pancreato-biliary cancer. The aim of this study was to evaluate the prognostic value of TM expression in resected pancreatic ductal adenocarcinoma. METHODS: The data of patients who underwent pancreatic resection for pancreatic invasive ductal adenocarcinoma were obtained from a prospectively maintained database. A total of 131 patients were included. Paraffin sections of tumor tissues were stained immunohistochemically using TM antibody. The patients were divided into two groups: the TM-positive or TM-negative group. RESULTS: The specimens were TM-positive in 72 cases. TM expression was a significant factor of favorable prognosis in univariate analysis for disease-free (DFS) and overall survival (OS). The median OS in the TM-positive patients was 32.9 mo, which was better than the 20.0 mo in TM-negative patients (P =.006). TM positivity retained its significance on multivariate analysis for DFS (hazard ratio [HR] 0.651, 95% confidence interval [CI] 0.433-0.979, P =.039) and OS (HR 0.569, 95% CI 0.376-0.862, P =.008). CONCLUSIONS: The tumor expression of TM is a favorable factor for OS in resected pancreatic invasive ductal adenocarcinoma.

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.

Mechanical tibial loading remotely suppresses brain tumors by dopamine-mediated downregulation of CCN4.

Mechanical loading to the bone is known to be beneficial for bone homeostasis and for suppressing tumor-induced osteolysis in the loaded bone. However, whether loading to a weight-bearing hind limb can inhibit distant tumor growth in the brain is unknown. We examined the possibility of bone-to-brain mechanotransduction using a mouse model of a brain tumor by focusing on the response to Lrp5-mediated Wnt signaling and dopamine in tumor cells. The results revealed that loading the tibia with elevated levels of tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis, markedly reduced the progression of the brain tumors. The simultaneous application of fluphenazine (FP), an antipsychotic dopamine modulator, enhanced tumor suppression. Dopamine and FP exerted antitumor effects through the dopamine receptors DRD1 and DRD2, respectively. Notably, dopamine downregulated Lrp5 via DRD1 in tumor cells. A cytokine array analysis revealed that the reduction in CCN4 was critical for loading-driven, dopamine-mediated tumor suppression. The silencing of Lrp5 reduced CCN4, and the administration of CCN4 elevated oncogenic genes such as MMP9, Runx2, and Snail. In summary, this study demonstrates that mechanical loading regulates dopaminergic signaling and remotely suppresses brain tumors by inhibiting the Lrp5-CCN4 axis via DRD1, indicating the possibility of developing an adjuvant bone-mediated loading therapy.

Practical significance of pancreatectomy with lymphadenectomy around the superior mesenteric artery for pancreatic cancer: comparison of prognosis after adjusting for major prognostic factors.

INTRODUCTION: Although pancreatectomy with lymph node (LN) and nerve plexus dissection has usually been performed for pancreatic cancer, recent randomized controlled trials have questioned its survival benefits. However, superior mesenteric artery (SMA) LN dissection has still been included in standard treatment guidelines. METHODS: A total of 94 patients who underwent pancreaticoduodenectomy for resectable pancreatic cancer without LN enlargement around the SMA on imaging were identified between 2008 and 2017. Disease-free survival (DFS), overall survival (OS), and complications were compared between those with LN and hemicircumferential nerve plexus dissection around the SMA (SMA ly+) and those without thorough LN and nerve plexus dissection around the SMA (SMA ly-) after adjusting for major prognostic factors. RESULTS: A total of 78 and 16 patients with SMA ly+ and SMA ly- were identified, respectively. Our data demonstrated no difference in DFS and OS rates between both groups (P = 0.18 and 0.83, respectively). Patients with SMA ly+ had significantly more complications, particularly severe diarrhea, compared to those with SMA ly- (P = 0.001). CONCLUSION: LN and nerve plexus dissection around the SMA did not prolong survival and significantly increased the frequency of severe diarrhea, suggesting that performing in all cases carries less practical significance.

Feasible laparoscopic distal pancreatectomy for pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumor (PNET) cases are increasing; however, the treatment indication and procedure remain unestablished. The present study evaluated the indication, feasibility and safety of laparoscopic distal pancreatectomy (LDP) with our technique for PNET. A total of 13 patients with insulinoma and nonfunctional PNET <2 cm in diameter who underwent LDP and 13 patients with any size of PNET who underwent open distal pancreatectomy (ODP) between October 2009 and June 2019 were retrospectively reviewed and compared. The median age of patients was 45 (33-61) years, and 14 (54%) patients were male. The median follow-up periods were 70 months for the LDP group and 46 months for the ODP group. The tumor diameter of the patients who underwent LDP for PNET was 18±9 mm compared with 37±25 mm for those who underwent ODP. The operation time, estimated blood loss, and complication were 290.2±115 vs. 337±131 min (P=0.338), 122±172 vs. 649±693 ml (P=0.019) and 31 vs. 54% (P=0.234), respectively. Pancreatic fistula developed in 8% of patients who underwent LDP compared with 31% who underwent ODP (P=0.131). Notably, the postoperative hospitalization period was significantly shorter in the LDP group (11±7 vs. 21±13 days; P=0.022). Tumor grade of 2017 World Health Organization classification (G1/G2/G3/NEC/unknown) was 9/2/0/0/2 for the LDP group compared with 5/5/0/3/0 for the ODP group. Furthermore, lymph node metastasis was detected in only 1 patient who underwent ODP, for whom the maximum tumor diameter was 70 mm and was classified as G2. In addition, 2 patients in the ODP group developed postoperative lung and liver metastases. LDP for PNETs of <2 cm in selected patients can be safely performed; however, the extent of lymph node dissection needs to be clarified.

Intraoperative amylase level of pancreatic juice as a simple predictor of pancreatic fistula after pancreaticoduodenectomy.

INTRODUCTION: A soft remnant texture of the pancreas is commonly accepted as a risk factor for postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD). However, its assessment is subjective. The aim of this study was to evaluate the significance of intraoperative amylase level of the pancreatic juice as a risk factor of POPF after PD. METHOD: This study included 75 patients who underwent PD between November 2014 and April 2020 at Jikei University Hospital. We investigated the relationship between pancreatic texture, intraoperative amylase level of pancreatic juice, results of the pathological evaluations, and the incidence of POPF. RESULTS: Twenty-three patients (31%) developed POPF. The significant predictors of POPF were non-ductal adenocarcinoma (p < 0.01), soft pancreatic remnant (p < 0.01), high intraoperative blood loss (p < 0.01), high intraoperative amylase level of pancreatic juice (p < 0.01), and low pancreatic fibrosis (p < 0.01). Multivariate analysis revealed that the significant independent predictors of POPF were high intraoperative blood loss (p < 0.01) and high intraoperative amylase level of pancreatic juice (p = 0.02). Receiver operating characteristic (ROC) analysis showed that the cut-off value for the intraoperative amylase level of pancreatic juice was 2.17 × 105 IU/L (area under the curve = 0.726, sensitivity = 95.7%, and specificity = 50.0%) CONCLUSIONS: The intraoperative amylase level of pancreatic juice is a reliable objective predictor for POPF after PD.

New classification-oriented treatment strategy for portal vein thrombosis after hepatectomy.

AIM: This study sought to evaluate the incidence, risk factors, and clinical outcomes of portal vein thrombosis after hepatectomy. Furthermore, we proposed a novel classification and treatment strategy for portal vein thrombosis after hepatectomy. METHODS: We retrospectively analyzed 398 patients who underwent hepatectomy and enhanced computed tomography imaging within 14 days after surgery in our hospital from 2009 to 2019. Portal vein thrombosis was classified into three categories according to the location of the thrombus - main, hilar, and peripheral - with main portal vein thrombosis further subclassified into three grades. Each patient's treatment strategy was determined based on their portal vein thrombosis classification and grading. From 2015, enhanced computed tomography imaging was performed routinely on patients who underwent anatomical hepatectomy on postoperative day 7. RESULTS: Portal vein thrombosis was diagnosed in 57 patients (14.3%) during the study period. Multivariate analysis revealed that a Pringle maneuver time of 75 minutes or longer was a significant predictor of portal vein thrombosis (P = .012). In total, 52 patients (91%) with portal vein thrombosis recovered by surgery, anticoagulant therapy, or without specific treatment. There was no instance of mortality recorded. CONCLUSIONS: Patients who undergo hepatectomy are at high risk for portal vein thrombosis, especially when the Pringle maneuver time is long. The proposed classification and treatment strategy may be useful for clinical management of patients with portal vein thrombosis after hepatectomy.

A Novel Prognostic Score Combining Preoperative Biliary Drainage and Inflammatory Status for Patients with Periampullary Cancers.

AIMS: The benefit of preoperative biliary drainage for patients with operable periampullary cancers is controversial because biliary drainage would activate inflammatory response such as cholangitis. The aim of this study was to identify a novel prognostic score in patients with operable periampullary cancers including pancreatic cancer and extrahepatic distal bile duct cancer with a typical reference to preoperative biliary drainage and inflammatory status. METHODS: Between 2000 and 2015, 246 patients were enrolled in this retrospective study. The patients were divided into four groups of the following three factors; the presence of preoperative biliary drainage, decreased serum albumin value (< 3.5 g dl-1), and increased CR P value (> 1.0 mg dl-1). The relationship between clinicopathological variables and disease-free survival (DFS) as well as over-all survival (OS) was investigated by univariate and multivariate analyses. To compare the sensitivity and specificity among the types of cancer, the area under the receiver operating characteristics curve (AUC) was evaluated in patients with pancreatic cancer and extrahepatic distal bile duct cancer. RESULTS: In multivariate analysis of DFS and OS, the novel prognostic factor combining preoperative biliary drainage and inflammatory status was an independent risk factor of tumor recurrence and prognosis as well as differentiation of the tumor and resected margin. CONCLUSION: The novel prognostic score combining preoperative biliary drainage and inflammatory status may be an independent predictor of tumor recurrence and prognosis in patients with periampullary cancers.

Assessment of Outcome of Hepatic Resection for Extremely Elderly Patients With a Hepatic Malignancy.

BACKGROUND/AIM: We aimed to assess surgical outcome and long-term survival after elective hepatic resection for hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) in patients aged 80 years or older. PATIENTS AND METHODS: This study included 100 patients aged 70 years or older, who underwent hepatic resection for HCC or CRLM between January 2000 and December 2012. Outcomes and clinicopathological data were compared between the elderly (aged 70-79 years; n=84) and extremely elderly groups (aged 80 years or older; n=16). RESULTS: Incidence of postoperative complications, in-hospital mortality, and postoperative OS in the extremely elderly group were comparable with those of the elderly group. In patients with HCC, the extremely elderly group was associated with shorter DFS (p=0.030) in univariate analysis, while multivariate analysis showed significant and independent factors of cancer recurrence. CONCLUSION: Hepatic resection for HCC and CRLM in patients aged 80 years and older may be safe and acceptable with appropriate selection. For HCC in patients aged 80 years and older, hepatic resection may be effective when negative surgical margins can be achieved.

Assessment of Outcome of Hepatic Resection for Extremely Elderly Patients With a Hepatic Malignancy.

BACKGROUND/AIM: We aimed to assess surgical outcome and long-term survival after elective hepatic resection for hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM) in patients aged 80 years or older. PATIENTS AND METHODS: This study included 100 patients aged 70 years or older, who underwent hepatic resection for HCC or CRLM between January 2000 and December 2012. Outcomes and clinicopathological data were compared between the elderly (aged 70-79 years; n=84) and extremely elderly groups (aged 80 years or over; n=16). RESULTS: Incidence of postoperative complications, in-hospital mortality, and postoperative OS in the extremely elderly group were comparable with those of the elderly group. In patients with HCC, the extremely elderly group was associated with shorter DFS (p=0.030) in univariate analysis, while multivariate analysis showed significant and independent factors of cancer recurrence. CONCLUSION: Hepatic resection for HCC and CRLM in patients aged 80 years and over may be safe and acceptable with appropriate selection. For HCC in patients aged 80 years and over, hepatic resection may be effective when negative surgical margins can be achieved.

Correction: Hiroshi Sugano et al. Nafamostat Mesilate Enhances the Radiosensitivity and Reduces the Radiation-Induced Invasive Ability of Colorectal Cancer Cells. Cancers 2018, 10, 386.

The authors would like to make a correction to their published paper [...].

Forced expression of DYRK2 exerts anti-tumor effects via apoptotic induction in liver cancer.

Liver cancer is highly aggressive and globally exhibits a poor prognosis. Therefore, the identification of novel molecules that can become targets for future therapies is urgently required. We have reported that dual-specificity tyrosine-regulated kinase 2 (DYRK2) functions as a tumor suppressor by regulating cell survival, differentiation, proliferation and apoptosis. However, the research into its clinical application as a molecular target has remained to be explored. Here we showed that DYRK2 knockdown enhanced tumor growth of liver cancer cells. Conversely and more importantly, adenovirus-mediated overexpression of DYRK2 resulted in inhibition of cell proliferation and tumor growth, and induction of apoptosis both in vitro and in vivo. Furthermore, we found that liver cancer patients with low DYRK2 expression had a significantly shorter overall survival. Given the findings that DYRK2 regulates proliferation and apoptosis of cancer cells, DYRK2 expression could be a promising predictive marker of the prognosis in liver cancer. Stabilized or forced expression of DYRK2 may become thus a potential target for novel gene therapy against liver cancer.

Finite-element analysis of the mouse proximal ulna in response to elbow loading.

Bone is a mechano-sensitive tissue that alters its structure and properties in response to mechanical loading. We have previously shown that application of lateral dynamic loads to a synovial joint, such as the knee and elbow, suppresses degradation of cartilage and prevents bone loss in arthritis and postmenopausal mouse models, respectively. While loading effects on pathophysiology have been reported, mechanical effects on the loaded joint are not fully understood. Because the direction of joint loading is non-axial, not commonly observed in daily activities, strain distributions in the laterally loaded joint are of great interest. Using elbow loading, we herein characterized mechanical responses in the loaded ulna focusing on the distribution of compressive strain. In response to 1-N peak-to-peak loads, which elevate bone mineral density and bone volume in the proximal ulna in vivo, we conducted finite-element analysis and evaluated strain magnitude in three loading conditions. The results revealed that strain of ~ 1000 µstrain (equivalent to 0.1% compression) or above was observed in the limited region near the loading site, indicating that the minimum effective strain for bone formation is smaller with elbow loading than axial loading. Calcein staining indicated that elbow loading increased bone formation in the regions predicted to undergo higher strain.