Risk Factors of Postoperative Complication and Hospital Mortality after Colorectal Perforation Surgery.

Objectives: Colorectal perforation is associated with high morbidity and mortality rates after surgery. We investigated various clinical features of patients who underwent emergency surgery for colorectal perforation and explored the risk factors for postoperative complications and hospital mortality. Methods: Data from 147 patients who underwent surgery for colorectal perforation were retrospectively reviewed. We investigated various clinical and operative factors, including inflammation-based prognostic scores (IBPSs), and evaluated the risk factors for postoperative complications and hospital mortality due to colorectal perforation. Results: Among 147 patients, the most frequent postoperative complication was wound infection (32 cases, 21.8%), followed by intra-abdominal abscesses (27 cases, 18.4%) after surgery for colorectal perforation. Time from onset to surgery ≥ 2 days (Hazard ratio [HR] = 2.810, p = 0.0383) and prognostic nutritional index (PNI) < 30 (HR = 3.190, p = 0.0488) were identified as risk factors for intra-abdominal abscess, while neutrophil-lymphocyte ratio (NLR) < 6.15 (HR = 5.020, p = 0.0009) was identified as a risk factor for wound infection. Time from onset to surgery ≥ 2 days (HR = 7.713, p = 0.0492), severe postoperative complications (Clavien-Dindo grade ≥ IIIa) (HR = 10.98, p = 0.0281), and platelet-lymphocyte ratio (PLR) < 144 (HR = 18.84, p = 0.0190) were independent predictive factors for hospital mortality. Conclusions: Time from onset to surgery and IBPSs such as PNI, NLR, and PLR, may be associated with postoperative complications and hospital mortality due to colorectal perforation.

Efficacy and safety of neoadjuvant nab-paclitaxel plus gemcitabine therapy in patients with borderline resectable pancreatic cancer: A multicenter single-arm phase II study (NAC-GA trial).

Background: Nab-paclitaxel plus gemcitabine is a standard treatment for metastatic/locally advanced pancreatic cancer. The effectiveness of neoadjuvant therapy with nab-paclitaxel plus gemcitabine (GnP-NAT) in patients with borderline resectable pancreatic cancer (BRPC) remains unclear. Patients and Methods: This single-arm phase II trial included 61 patients with BRPC that were treated with two cycles of GnP-NAT, (nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2), on days 1, 8, and 15 over a 4-week period, which comprised one cycle. The primary endpoint was overall survival time. In the absence of disease progression, patients underwent planned pancreatectomy. Results: Median overall survival, the primary endpoint, was 25.2 months, and the median recurrence-free survival was 12.3 months. The overall rate of grade 3/4 events was 73.8%. One patient, who had a history of radiation therapy for past esophageal cancer, died from exacerbation via pneumonia. The overall resection rate was 73.8% (n = 45), and the R0 resection rate was 63.9% (n = 39). Overall, postoperative complications were found in 19 patients (42%) with 24 events, and nine patients (20%) with nine events ≥ grade IIIa, based on Dindo's classification. Conclusions: This protocol treatment is thought to be a feasible, safe, and promising treatment regimen, but we caution against its use in patients with a history of interstitial lung disease and/or prior pulmonary irradiation. The survival data from this study suggest the need for further investigations of GnP-NAT efficacy in patients with BRPC, as well as prospective evaluation of adverse events. Clinical Trial Registration: UMIN Clinical Trials Registry, UMIN000024154 and ClinicalTrials.gov, NCT02926183.

Cancer-associated fibroblasts reuse cancer-derived lactate to maintain a fibrotic and immunosuppressive microenvironment in pancreatic cancer.

Glycolysis is highly enhanced in pancreatic ductal adenocarcinoma (PDAC) cells; thus, glucose restrictions are imposed on nontumor cells in the PDAC tumor microenvironment (TME). However, little is known about how such glucose competition alters metabolism and confers phenotypic changes in stromal cells in the TME. Here, we report that cancer-associated fibroblasts (CAFs) with restricted glucose availability utilize lactate from glycolysis-enhanced cancer cells as a fuel and exert immunosuppressive activity in the PDAC TME. The expression of lactate dehydrogenase A (LDHA), which regulates lactate production, was a poor prognostic factor for patients with PDAC, and LDHA depletion suppressed tumor growth in a CAF-rich murine PDAC model. Coculture of CAFs with PDAC cells revealed that most of the glucose was taken up by the tumor cells and that CAFs consumed lactate via monocarboxylate transporter 1 to enhance proliferation through the TCA cycle. Moreover, lactate-stimulated CAFs upregulated IL-6 expression and suppressed cytotoxic immune cell activity synergistically with lactate. Finally, the LDHA inhibitor FX11 reduced tumor growth and improved antitumor immunity in CAF-rich PDAC tumors. Our study provides insight regarding the crosstalk among tumor cells, CAFs, and immune cells mediated by lactate and offers therapeutic strategies for targeting LDHA enzymatic activity in PDAC cells.

Effect of duration of adjuvant chemotherapy with S-1 (6 versus 12 months) for resected pancreatic cancer: the multicenter clinical randomized phase II postoperative adjuvant chemotherapy S-1 (PACS-1) trial.

BACKGROUND: Six-month adjuvant chemotherapy with S-1 is standard care for resected pancreatic cancer in Japan; however, the optimal duration has not been established. We aimed to evaluate the impact of duration of adjuvant chemotherapy with S-1. METHODS: We performed a multicenter, randomized, open-label, phase II study. Patients with histologically proven invasive pancreatic ductal carcinoma, pathological stage I-III, and no local residual or microscopic residual tumor were eligible. Patients were randomized 1:1 to receive 6- or 12-month adjuvant chemotherapy with S-1. The primary endpoint was 2-year overall survival (OS). Secondary endpoints were disease-free survival (DFS) and feasibility. RESULTS: A total of 170 patients were randomized (85 per group); the full analysis set was 82 in both groups. Completion rates were 64.7% (6-month group) and 44.0% (12-month group). Two-year OS was 71.5% (6-month group) and 65.4% (12-month group) (hazard ratio (HR): 1.143; 80% confidence interval CI 0.841-1.553; P = 0.5758). Two-year DFS was 46.4% (6-month group) and 44.9% (12-month group) (HR: 1.069; 95% CI 0.727-1.572; P = 0.6448). In patients who completed the regimen, 2-year DFS was 56.5% (6-month group) and 75.0% (12-month group) (HR: 0.586; 95% CI 0.310-1.105; P = 0.0944). Frequent (≥ 5%) grade ≥ 3 adverse events comprised anorexia (10.5% in the 6-month group) and diarrhea (5.3% vs. 5.1%; 6- vs. 12-month group, respectively). CONCLUSIONS: In patients with resected pancreatic cancer, 12-month adjuvant chemotherapy with S-1 was not superior to 6-month therapy regarding OS and DFS.

The Prognostic Role of Serine Racemase in Patients With Pancreatic Cancer: A New Marker in Cancer Metabolism.

OBJECTIVES: Serine racemase (SRR) participates in serine metabolism in central nervous systems. Serine racemase is only studied in colorectal cancer, and its role in pancreatic cancer (PC) is unknown. This study aims to investigate the role of SRR in PC. METHODS: Totally 182 patients with PC were enrolled in this study. Slices from patients were stained for SRR and CD8+ T cells. Kaplan-Meier methods were used to do survival analysis according to SRR expression from immunohistochemical staining. Univariate and multivariate Cox regression analysis was performed to clarify the independent prognostic value of SRR. Bioinformatic tools were used to explore and validate the expression, prognostic value, possible mechanism, and immune interaction of SRR in PC. RESULTS: The expression of SRR was lower in tumor tissue than normal tissue, also potentially decreased with the increasing tumor grade. Low SRR expression was an independent risk factor for overall survival (hazards ratio, 1.875; 95% confidence interval, 1.175-2.990; P = 0.008) in patients with PC. Serine racemase was positively correlated with CD8+ T cells infiltration and possibly associated with CCL14 and CXCL12 expression. CONCLUSIONS: Serine racemase plays a prognostic role in PC and may be a potentially therapeutic target.

Efficacy of laparoscopic liver resection for small hepatocellular carcinoma located in the posterosuperior segments: A multi-institutional study using propensity score matching by the Kyushu Study Group of Liver Surgery.

AIM: Laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) located in the posterosuperior segments (PS) have generally been considered more difficult than those for HCC in anterolateral segments (AL), but may be safe and feasible for selected patients with accumulated experience. In the present study, we investigated the effectiveness of LLR for single nodular HCCs ≤3 cm located in PS. METHODS: In total, 473 patients who underwent partial liver resection for single nodular HCCs ≤3 cm at the 18 institutions belonging to the Kyusyu Study Group of Liver Surgery from January 2010 to December 2018 were enrolled. The short-term outcomes of laparoscopic partial liver resection and open liver resection (OLR) for HCCs ≤3 cm, with subgroup analysis of PS and AL, were compared using propensity score-matching analysis. Furthermore, results were also compared between LLR-PS and LLR-AL. RESULTS: The original cohort of patients with HCC ≤3 cm included 328 patients with LLR and 145 with OLR. After matching, 140 patients with LLR and 140 with OLR were analyzed. Significant differences were found between groups in terms of volume of blood loss (median, 55 vs. 287 ml, p < 0.001), postoperative complications (0.71 vs. 8.57%, p = 0.003), and postoperative hospital stay (median, 9 vs. 14 days, p < 0.001). The results of subgroup analysis of PS were similar. Short-term outcomes did not differ significantly between LLR-PS and LLR-AL after matching. CONCLUSIONS: Laparoscopic partial resection could be the preferred option for single nodular HCCs ≤3 cm located in PS.

Prognostic significance of a novel index score based on the inflammation-based prognostic scores of patients with colorectal cancer.

BACKGROUND AND AIM: This study aimed to clarify the prognostic value of various inflammation-based prognostic scores (IBPSs) in patients who underwent radical surgery for colorectal cancer (CRC) and to develop a novel prognostic index using IBPSs and other predictive factors. METHODS: Data of 1157 patients who underwent radical surgery for CRC were reviewed. The predictive value of various IBPSs in determining the CRC prognosis was compared. A novel index score based on the IBPSs and other parameters that were associated with survival in patients with CRC was established, and its usefulness was evaluated. RESULTS: The patients were randomly divided into the training (n = 694) and validation (n = 463) sets. Male sex (P = 0.0001), age ≥ 75 years (P < 0.0001), a carcinoembryonic antigen (CEA) level of > 5 (P = 0.0009), a C-reactive protein/albumin ratio (CAR) of ≥ 0.04 (P = 0.0033), and a prognostic nutritional index (PNI) of < 43.1 (P = 0.0004) were poor independent prognostic factors of overall survival. The novel index score was calculated based on the scores of these five prognostic factors. The Kaplan-Meier survival curves showed that the CRC patients with higher novel index scores in the training and validation datasets had poorer overall survival. CONCLUSIONS: CAR and PNI were superior to other IBPSs for predicting the prognosis of CRC patients. The novel index score established based on sex, age, CEA level, CAR, and PNI can predict the prognosis of CRC with more precise and clearer stratification than the individual parameters alone.

Survival impact of pancreatic resection for metastases in the pancreas: A retrospective multi-center study.

BACKGROUND: Pancreatic metastases from other primary malignancies are rare. There is no clear evidence for a treatment strategy for this condition. The purpose of this study was to assess the clinical outcomes, including prognostic factors for pancreatic resection of metastatic tumors in the pancreas, through a retrospective review. METHODS: Data of 35 patients who underwent pancreatic resection for pancreatic metastasis between 2005 and 2020 in eight Japanese institutions were included in this study. Survival analyses were performed using the Kaplan-Meier method, and comparisons were made using the Cox proportional hazards model. RESULTS: The median follow-up period was 35 months (range, 5-102 months). Median duration from resection for primary tumor to resection for metastatic pancreatic tumor was 10.6 years (range, 0.6-29.2 years). The 3- and 5-year survival rates after resection for metastatic tumors in the pancreas were 89% and 69%, respectively. In contrast, the 3- and 5-year disease-free survival rates after resection for metastatic tumors in the pancreas were 48% and 21%, respectively. Performance status ≥1 at the time of resection for metastatic tumors in the pancreas (HR: 7.56, p = 0.036) and pancreatic metastasis tumor diameter >42 mm (HR: 6.39, p = 0.02) were significant poor prognostic factors only in the overall survival. CONCLUSIONS: The prognosis of pancreatic resection for metastatic tumors in the pancreas is relatively good for selected patients. However, because it is prone to recurrence after radical surgery, it should only be considered in patients with good PS.

Prevention and Repair of Ultraviolet B-Induced Skin Damage in Hairless Mice via Transdermal Delivery of Growth Factors Immobilized in a Gel-in-Oil Nanoemulsion.

Ultraviolet (UV) radiation from the sun or artificial sources is one of the primary causes of skin damage, including sunburns, tanning, erythema, and skin cancer. Among the three different types of UV rays, UVB rays have a medium wavelength that can penetrate the epidermal layer of the skin, resulting in sunburn, suntan, blistering, and melanoma in case of chronic exposure. This study aimed to evaluate the preventive and therapeutic effects of a gel-in-oil nanogel dispersion (G/O-NGD) as a transdermal delivery biomolecular carrier for skin damage caused by UVB light. The efficacy of this carrier against UVB-induced skin damage was investigated in vivo by delivering different growth factors (GFs) encapsulated in a G/O-NGD. Artificial UVB light was used to induce skin damage in nude mice, followed by the transdermal application of five GF [vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), transforming growth factor (TGF)-1, and insulin-like growth factor (IGF)-α]-immobilized G/O-NGD. Among these GFs, VEGF and bFGF promoted angiogenesis, while EGF, TGF-1, and IGF-α promoted the repair and regeneration of damaged cells. The results showed that G/O-NGD was superior to heparin-immobilized G/O-NGD in reducing UVB-induced skin damage, such as erythema, epidermal water reduction, inflammation, and dermis thickening. In addition, G/O-NGD could prevent and treat abnormal follicle proliferation caused by UVB rays and exhibited potential to repair lipid glands. Overall, our results demonstrate the potential of G/O-NGDs for the treatment of UVB-induced skin damage.

Risk Factors of Complications from Central Bisectionectomy (H458) for Hepatocellular Carcinoma: A Multi-Institutional Single-Arm Analysis.

BACKGROUND: This study aims to clarify the perioperative risk factors and short-term prognosis of central bisectionectomy (CB) for hepatocellular carcinoma (HCC). METHODS: Surgical data from 142 selected patients out of 171 HCC patients who underwent anatomical CB (H458) between 2005 and 2020 were collected from 17 expert institutions in a single-arm retrospective study. RESULTS: Morbidities recorded by the International Study Group of Liver Surgery (ISGLS) from grade BC post-hepatectomy liver failure (PHLF) and bile leakage (PHBL), or complications requiring intervention were observed in 37% of patients. A multivariate analysis showed that increased blood loss (iBL) > 1500 mL from PHLF (risk ratio [RR]: 2.79), albumin level < 4 g/dL for PHBL (RR, 2.99), involvement of segment 1, a large size > 6 cm, or compression of the hepatic venous confluence or cava by HCC for all severe complications (RR: 5.67, 3.75, 6.51, and 8.95, respectively) (p < 0.05) were significant parameters. Four patients (3%) died from PHLF. HCC recurred in 50% of 138 surviving patients. The three-year recurrence-free and overall survival rates were 48% and 81%, respectively. CONCLUSIONS: Large tumor size and surrounding tumor involvement, or compression of major vasculatures and the related iBL > 1500 mL were independent risk factors for severe morbidities in patients with HCC undergoing CB.

Frailty and surgical outcomes in gastrointestinal cancer: Integration of geriatric assessment and prehabilitation into surgical practice for vulnerable patients.

As life expectancy increases, the older population continues to grow rapidly, resulting in increased requirement for surgery for older patients with gastrointestinal cancer. Older individuals represent a heterogeneous group in terms of physiological reserves, co-morbidity, cognitive impairment, and disability. Owing to the lack of treatment guidelines for vulnerable patients with gastrointestinal cancer, these patients are more likely to be at risk of undertreatment or overtreatment. Hence, the identification of frail patients with gastrointestinal cancer would improve cancer treatment outcomes. Although there is no standardized geriatric assessment tool, a growing body of research has shown associations of frailty with adverse postoperative outcomes and poor prognosis after resection of gastrointestinal tract and hepatobiliary-pancreatic cancers. Emerging evidence suggests that prehabilitation, which includes exercise and nutritional support, can improve preoperative functional capacity, postoperative recovery, and surgical outcomes, particularly in frail patients with gastrointestinal cancer. We reviewed major geriatric assessment tools for identification of frail patients and summarized clinical studies on frailty and surgical outcomes, as well as prehabilitation or rehabilitation in gastrointestinal tract and hepatobiliary-pancreatic cancers. The integration of preoperative geriatric assessment and prehabilitation of frail patients in clinical practice may improve surgical outcomes. In addition, improving preoperative vulnerability and preventing functional decline after surgery is important in providing favorable long-term survival in patients with gastrointestinal cancer. Further clinical trials are needed to examine the effects of minimally invasive surgery, and chemotherapy in frail patients with gastrointestinal cancer.

The malignant potential of pancreatic intraductal papillary mucinous neoplasm is reflected in expression levels of fucosylated glycans in α1 -acid glycoprotein.

BACKGROUND: Pancreatic intraductal papillary mucinous neoplasm (IPMN) involves multiple histopathological stages from benign to malignant lesions. Further, a biomarker to diagnose the malignant IPMN (IPMC) is clinically relevant. Recently, we found that serum fucosylated α1 -acid glycoprotein (fAGP) level markedly elevated along with disease progression in large cohorts of patients with various cancers. METHODS: The fAGP level was retrospectively analyzed in preoperative sera from 109 patients with IPMN, and the clinical relevance of fAGP was compared with currently available predictors as standard. RESULTS: The fAGP level in IPMC was found to be significantly higher than in benign IPMN (P = .0012). At a cutoff value of 27.04 U/µg, its sensitivity, specificity, and accuracy for IPMC were determined to be 83.61%, 65.96%, and 75.93%, respectively. Multivariate analyses revealed that the fAGP level was the only independent risk factor for predicting IPMC. Additionally, a combination of the fAGP level and 18 F-fluorodeoxyglucose uptake on the PET/CT imaging in the lesions seemed to offer the best diagnosis of IPMN. Accordingly, 27 of the 28 patients who were positive in both tests had IPMC, while patients who are negative had benign IPMN. CONCLUSIONS: The fAGP level appeared to be a relevant biomarker for malignant potential of IPMN.

Proposal of nomograms to predict clinical outcomes in patients with ampulla of Vater cancer based on the Korea-Japan collaborative study.

BACKGROUND: In this study, we aimed to develop and validate a nomogram to predict overall survival (OS) and recurrence-free survival (RFS) in patients who underwent curative resection of ampulla of Vater (AOV) cancer. This is the first study for nomograms in AOV cancer patients using retrospective data based on an international multicenter study. METHODS: A total of 2007 patients with AOV adenocarcinoma who received operative therapy between 2002 January and 2015 December in Korea and Japan were retrospectively assessed to develop a prediction model. Nomograms for 5-year OS and 3-year RFS were constructed by dividing the patients who received and who did not receive adjuvant therapy after surgery, respectively. Significant risk factors were identified by univariate and multivariate Cox analyses. Performance assessment of the four prediction models was conducted by the Harrell's concordance index (C-index) and calibration curves using bootstrapping. RESULTS: A total of 2007 and 1873 patients were collected for nomogram construction to predict 5-year OS and 3-year RFS. We developed four types of nomograms, including models for 5-year OS and 3-year RFS in patients who did not receive postoperative adjuvant therapy, and 5-year OS and 3-year RFS in patients who received postoperative adjuvant therapy. The C-indices of these nomograms were 0.795 (95% confidence interval [CI]: 0.766-0.823), 0.712 (95% CI: 0.674-0.750), 0.804 (95% CI: 0.7778-0.829), and 0.703 (95% CI: 0.669-0.737), respectively. CONCLUSIONS: This predictive model could help clinicians to choose optimal treatment and precisely predict prognosis in AOV cancer patients.

Thrombospondin-1 overexpression stimulates loss of Smad4 and accelerates malignant behavior via TGF-ß signal activation in pancreatic ductal adenocarcinoma.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and cancer-associated fibroblasts (CAFs) provide a favorable tumor microenvironment. Smad4 is known as tumor suppressor in several types of cancers including PDAC, and loss of Smad4 triggers accelerated cell invasiveness and metastatic potential. The thrombospondin-1 (TSP-1) can act as a major activator of latent transforming growth factor-ß (TGF-ß) in vivo. However, the roles of TSP-1 and the mediator of Smad4 loss and TGF-ß signal activation during PDAC progression have not yet been addressed. The aim is to elucidate the biological role of TSP-1 in PDAC progression. METHODS AND RESULTS: High substrate stiffness stimulated TSP-1 expression in CAFs, and TSP-1 knockdown inhibited cell proliferation with suppressed profibrogenic and activated stroma-related gene expressions in CAFs. Paracrine TSP-1 treatment for PDAC cells promoted cell proliferation and epithelial mesenchymal transition (EMT) with activated TGF-ß signals such as phosphorylated Akt and Smad2/3 expressions. Surprisingly, knockdown of DPC4 (Smad4 gene) induced TSP-1 overexpression with TGF-ß signal activation in PDAC cells. Interestingly, TSP-1 overexpression also induced downregulation of Smad4 expression and enhanced cell proliferation in vitro and in vivo. Treatment with LSKL peptide, which antagonizes TSP-1-mediated latent TGF-ß activation, attenuated cell proliferation, migration and chemoresistance with enhanced apoptosis in PDAC cells. CONCLUSIONS: TSP-1 derived from CAFs stimulates loss of Smad4 expression in cancer cells and accelerates malignant behavior by TGF-ß signal activation in PDAC. TSP-1 could be a novel therapeutic target, not only for CAFs in stiff stroma, but also for cancer cells in the PDAC microenvironment.

Risk factors for lymph node metastasis in patients with pancreatic neuroendocrine neoplasms.

BACKGROUND: Although PNENs generally have a better prognosis than pancreatic cancers, some PNENs display malignant behavior including lymph node (LN) metastasis. Complete tumor resection can be the only potentially curative treatment for patients with resectable PNENs. However, the indications for LN dissection are still controversial. Over the last decade, minimally invasive surgery such as laparoscopic pancreatic surgery (LPS) has been increasingly performed for pancreatic tumors including PNENs. AIM: To investigate the risk factors for LN metastasis in PNENs and to select appropriate patients for limited surgery by LPS. METHODS: From April 2001 to December 2019, 92 patients underwent pancreatic resection for PNENs at Kumamoto University Hospital. Finally, 82 patients were enrolled in this study. Using perioperative factors, we examined the predictive factors for LN metastasis in PNENs. RESULTS: Among the 82 patients, the percentage of LN metastasis according to the pathological findings was 12% (10/82 cases). The median tumor size was 12 mm (range: 5-90 mm). The median tumor size in the LN-positive group (37 mm) was significantly larger than that in the LN-negative group (12 mm) (P = 0.0001). Multivariate analyses revealed that larger tumor size (≥ 20 mm) was an independent risk factor for LN metastasis (odds ratio 16.8, P = 0.0062). In patients with small tumors (≤ 10 mm), LN metastasis was not found. CONCLUSION: Larger tumor size (≥ 20 mm) is an independent risk factor for LN metastasis in PNENs. In smaller PNENs (≤ 10 mm), we may be able to choose limited surgery without LN dissection.

Multimodal therapy with aggressive hepatectomy, everolimus, and octreotide for metastatic pancreatic neuroendocrine neoplasm enables 10-year survival.

The presence of neuroendocrine liver metastases is one of the poorest prognostic factors in patients with pancreatic neuroendocrine neoplasms, and surgical resection of neuroendocrine liver metastases is the only curable treatment. A 38-year-old man had a pancreatic neuroendocrine neoplasm with synchronous multiple liver metastases, and two surgeries and continuous everolimus and octreotide achieved R0 resection. However, multiple neuroendocrine liver metastases developed twice after more than 5 years of recurrence-free survival. Aggressive repeat hepatectomy was performed and he has survived for more than 10 years after the initial surgery. This report highlights that patients with pancreatic neuroendocrine neoplasms have a potential risk of recurrence even after 5 years of recurrence-free survival. In addition, combined aggressive hepatectomy and continuous medication can contribute dramatically to long-term survival even for late-stage recurrence of liver metastases.

Clinical impact of atrophic changes in remnant pancreas on the development of nonalcoholic fatty liver disease after pancreaticoduodenectomy.

Aim: The aim of this study was to evaluate risk factors for nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD), with a special focus on remnant pancreatic volume (RPV) as assessed using computed tomography (CT). Methods: From February 2004 to June 2017, 101 patients who underwent PD in our institution were enrolled. We defined a CT attenuation value of less than 40 HU as hepatic steatosis and measured RPV at 7 days, 3 months, and 1 year after PD using the SYNAPSE VINCENT system. The incidence of NAFLD and RPV were compared between the two groups according to reconstruction with pancreaticogastrostomy (PG) or pancreaticojejunostomy (PJ). Results: The incidence of NAFLD at 3 months after PD was 39.6% (40/101). The RPV ratio (RPV at 3 months or 1 year divided by RPV at 7 days after PD) at both 3 months and 1 year was significantly smaller in the PG group than in the PJ group (59% vs 73%, P < .001 and 53% vs 67% P < .01, respectively). A positive correlation between the RPV ratio and liver CT value at 3 months was found. The multivariate analysis identified three independent risk factors for NAFLD: female sex (odds ratio [OR] 8.16, 95% confidence interval [95% CI] 2.27-35.9, P < .001), PG reconstruction (OR 3.87, 95% CI 1.04-15.6, P = .04), and RPV ratio ≤60% (OR 3.44, 95% CI 1.06-11.8, P = .001). Conclusion: Atrophic change in the remnant pancreas is significantly associated with the development of NAFLD, and PJ reconstruction may be superior to PG from the viewpoint of NAFLD development.

Impairment of perioperative activities of daily living is associated with poor prognosis following hepatectomy for hepatocellular carcinoma.

BACKGROUND: The number of cancer patients with impairment of activities of daily living (ADLs) has increased. This study aimed to examine associations of perioperative Barthel index score, a validated measure of ADLs, with survival outcomes following hepatectomy for hepatocellular carcinoma (HCC). METHODS: We analyzed data of 492 consecutive patients who underwent hepatectomy for HCC between 2010 and 2018. Pre- and postoperative ADLs were assessed using the Barthel index (range, 0-100; higher scores indicate greater independence). Preoperative Barthel index score ≤85 or postoperative Barthel index score ≤85 was defined as impairment of perioperative ADLs. Cox proportional hazards regression was used to calculate hazard ratios (HRs) after adjusting for potential confounders. RESULTS: Among the 492 patients, 26 (5.2%) had a preoperative Barthel index score ≤85 and 95 (19%) had a postoperative Barthel index score ≤85. Impairment of perioperative ADLs was independently associated with shorter overall survival (multivariable HR: 1.75, 95% confidence interval [CI]: 1.06-2.81, p = 0.028). The association of impairment of perioperative ADLs with recurrence-free survival was not statistically significant. CONCLUSION: Impairment of perioperative ADLs is associated with poor prognosis following hepatectomy for HCC. Maintenance and improvement of perioperative ADLs would be important to provide favorable long-term outcomes in patients with HCC.

Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease.

Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)-NAFLD, predicted incident HCC over up to 15 years of longitudinal observation. High-risk PLS-NAFLD was associated with IDO1+ dendritic cells and dysfunctional CD8+ T cells in fibrotic portal tracts along with impaired metabolic regulators. PLS-NAFLD was validated in independent cohorts of patients with NAFLD who were HCC naïve (HCC incidence rates at 15 years were 22.7 and 0% in high- and low-risk patients, respectively) or HCC experienced (de novo HCC recurrence rates at 5 years were 71.8 and 42.9% in high- and low-risk patients, respectively). PLS-NAFLD was bioinformatically translated into a four-protein secretome signature, PLSec-NAFLD, which was validated in an independent cohort of HCC-naïve patients with NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6 and 0% in high- and low-risk patients, respectively). Combination of PLSec-NAFLD with our previously defined etiology-agnostic PLSec-AFP yielded improved HCC risk stratification. PLS-NAFLD was modified by bariatric surgery, lipophilic statin, and IDO1 inhibitor, suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific HCC risk prediction and facilitate clinical translation of NAFLD-directed HCC chemoprevention.

Survival impact of immune cells infiltrating peritumoral area of hepatocellular carcinoma.

Inflammatory and immune cells in the tumor microenvironment are reported to be associated with tumor progression in several cancers. In total, 225 patients who underwent initial and curative hepatectomy for hepatocellular carcinoma (HCC) from 2004 to 2013 were enrolled in this study. Tumor-associated neutrophils (TANs), M2 macrophages (TAMs; tumor-associated macrophages), CD8+ T cells, and regulatory T cells (Tregs) were evaluated by immunohistochemistry (IHC), and their relationships with patient clinicopathological characteristics and prognosis were evaluated. IHC was performed focusing on TANs first. We could not find a relationship between intratumoral and peritumoral TANs and clinicopathological features except for the fibrous capsule and infiltration of tumors into capsule. Next, TAMs, CD8+ cells and Tregs were evaluated by IHC. At the peritumoral area, TANs and TAMs (r = 0.36, p = 0.001) or Tregs (r = 0.16, p = 0.008) showed a positive correlation, whereas TANs and CD8+ cells showed a negative correlation (r = -0.16, p = 0.02). As for survival outcomes, at the peritumoral area, high TANs (p = 0.0398), low CD8+ cells (p = 0.0275), and high TAMs (p = 0.001) were significantly associated with worse overall survival (OS). In addition, high TANs (p = 0.010), and high TAMs (p = 0.00125) were significantly associated with worse disease-free survival (DFS). Finally, we established a risk signature model by combining the expression patterns of these cells. The high-risk signature group had significantly worse OS (p = 0.0277) and DFS (p = 0.0219) compared with those in the low-risk signature group. Our risk signature based on immune cells at the peritumoral area of the HCC can predict patient prognosis of HCC after curative hepatectomy.