This statement was developed to promote international consensus on the definition of borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) which was adopted by the National Comprehensive ...Cancer Network (NCCN) in 2006, but which has changed yearly and become more complicated. Based on a symposium held during the 20th meeting of the International Association of Pancreatology (IAP) in Sendai, Japan, in 2016, the presenters sought consensus on issues related to BR-PDAC. We defined patients with BR-PDAC according to the three distinct dimensions: anatomical (A), biological (B), and conditional (C). Anatomic factors include tumor contact with the superior mesenteric artery and/or celiac artery of less than 180° without showing stenosis or deformity, tumor contact with the common hepatic artery without showing tumor contact with the proper hepatic artery and/or celiac artery, and tumor contact with the superior mesenteric vein and/or portal vein including bilateral narrowing or occlusion without extending beyond the inferior border of the duodenum. Biological factors include potentially resectable disease based on anatomic criteria but with clinical findings suspicious for (but unproven) distant metastases or regional lymph nodes metastases diagnosed by biopsy or positron emission tomography-computed tomography. This also includes a serum carbohydrate antigen (CA) 19–9 level more than 500 units/ml. Conditional factors include the patients with potentially resectable disease based on anatomic and biologic criteria and with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. The definition of BR-PDAC requires one or more positive dimensions (e.g. A, B, C, AB, AC, BC or ABC). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumor and vessels, but that biological and conditional dimensions are also important. The aim in presenting this consensus definition is also to highlight issues which remain controversial and require further research.
Background
Although distant metastasis from pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, some single center studies reported that lung metastasis has a favorable prognosis. The aim ...of this study is to evaluate the prognostic value of site‐specific metastasis after pancreatectomy for PDAC, with a focus on lung metastasis.
Methods
Data from 117 cases of lung metastasis after pancreatectomy were collected retrospectively from 23 institutions in Japan. To compare the sites of metastasis we also collected the data of 134 patients with liver only metastasis, 67 patients with peritoneal only metastasis and 121 patients with locoregional recurrence alone.
Results
In patients with lung only metastasis, the median time from recurrence to death (RTD) was 23.1 months, which was better in comparison to other sites of recurrence. In lung metastasis group, the patients who underwent pulmonary resection had better long‐term outcomes in comparison to those who did not. (RTD: 29.2 vs 15.2, P < .001). In the multivariate analysis, solitary metastasis (HR 5.03; 95% CI 1.195‐21.144, P = .022) and postoperative chemotherapy (HR 14.089; 95% CI 1.729‐114.77, P = .023) were identified as significant prognostic factors after lung resection.
Conclusions
Surgical resection is a favorable option for selected patients with a solitary lung metastasis and for whom adjuvant chemotherapy can be administrated.
Highlight
Homma and colleagues revealed that patients with lung metastases from pancreatic cancer had a better prognosis than those with liver, peritoneal or local recurrence in this retrospective multicenter analysis. Pulmonary resection was a favorable option for selected patients with a solitary lung metastasis to whom adjuvant chemotherapy could be administered.
Hepatocellular carcinoma (HCC) is estimated to be the fourth leading cause of cancer-related deaths globally, and its overall prognosis is dismal because most cases are diagnosed at a late stage and ...are unamenable to curative treatment. The emergence of immune checkpoint inhibitors (ICIs) has dramatically improved the therapeutic efficacy for advanced hepatocellular carcinoma; however, their response rates remain unsatisfactory, partly because >50% of HCC exhibit an ICI-nonresponsive tumor microenvironment characterized by a paucity of cytotoxic T cells (immune-cold), as well as difficulty in their infiltration into tumor sites (immune excluded). To overcome this limitation, combination therapies with locoregional therapies, including ablation, transarterial embolization, and radiotherapy, which are usually used for early stage HCCs, have been actively explored to enhance ICI efficacy by promoting the release of tumor-associated antigens and cytokines, and eventually accelerating the so-called cancer–immunity cycle. Various combination therapies have been investigated in early- to late-phase clinical trials, and some have shown promising results. This comprehensive article provides an overview of the immune landscape for HCC to understand ICI efficacy and its limitations and, subsequently, reviews the status of combinatorial therapies of ICIs with locoregional therapy for HCC.
Hepatic ischemia-reperfusion injury causes liver damage during surgery. In hepatic ischemia-reperfusion injury, the blood coagulation cascade is activated, causing microcirculatory incompetence and ...cellular injury. Coagulation factor Xa (FXa)- protease-activated receptor (PAR)-2 signaling activates inflammatory reactions and the cytoprotective effect of FXa inhibitor in several organs. However, no studies have elucidated the significance of FXa inhibition on hepatic ischemia-reperfusion injury. The present study elucidated the treatment effect of an FXa inhibitor, edoxaban, on hepatic ischemia-reperfusion injury, focusing on FXa-PAR-2 signaling. A 60 min hepatic partial-warm ischemia-reperfusion injury mouse model and a hypoxia-reoxygenation model of hepatic sinusoidal endothelial cells were used. Ischemia-reperfusion injury mice and hepatic sinusoidal endothelial cells were treated and pretreated, respectively with or without edoxaban. They were incubated during hypoxia/reoxygenation in vitro. Cell signaling was evaluated using the PAR-2 knockdown model. In ischemia-reperfusion injury mice, edoxaban treatment significantly attenuated fibrin deposition in the sinusoids and liver histological damage and resulted in both anti-inflammatory and antiapoptotic effects. Hepatic ischemia-reperfusion injury upregulated PAR-2 generation and enhanced extracellular signal-regulated kinase 1/2 (ERK 1/2) activation; however, edoxaban treatment reduced PAR-2 generation and suppressed ERK 1/2 activation in vivo. In the hypoxia/reoxygenation model of sinusoidal endothelial cells, hypoxia/reoxygenation stress increased FXa generation and induced cytotoxic effects. Edoxaban protected sinusoidal endothelial cells from hypoxia/reoxygenation stress and reduced ERK 1/2 activation. PAR-2 knockdown in the sinusoidal endothelial cells ameliorated hypoxia/reoxygenation stress-induced cytotoxicity and suppressed ERK 1/2 phosphorylation. Thus, edoxaban ameliorated hepatic ischemia-reperfusion injury in mice by protecting against micro-thrombosis in sinusoids and suppressing FXa-PAR-2-induced inflammation in the sinusoidal endothelial cells.
Bleeding after major hepatobiliary pancreatic (HBP) surgery may be serious. Although postoperative abnormality of the hemostatic system are important elements that affect bleeding, routine activated ...partial thromboplastin time (APTT) assessment is considered inadequate to predict massive bleeding (MB). Recently, APTT-clot waveform analysis (CWA) was reported to be useful for detecting coagulation disorders.
APTT-CWA was performed using the ACL-TOP analyzer in 188 patients who underwent four major HBP surgeries (distal pancreatectomy, hepatectomy, subtotal stomach-preserving pancreatoduodenectomy (SSPPD), and SSPPD with combined resection and reconstruction of the portal vein) to analyze its usefulness in predicting the risk of bleeding.
Seventy (37.2%) patients developed MB and the incidence of MB was highest among patients who underwent hepatectomy. There were no significant differences in routine APTT, the first derivative peak (DP) time and 1/2 fibrin formation peak time between patients with MB and those without MB, throughout the postoperative course. On the other hand, the first and second DP heights were significantly lower in patients with MB than in those without MB and lowest in patients who underwent hepatectomy.
APTT-CWA was able to detect the detailed changes in the hemostatic system after major HBP surgery. The patterns of APTT-CWA after major HBP surgery differed among various surgical procedures according to invasiveness. The lower first and the second DP height, which were frequently observed in hepatectomy patients, may be useful for predicting the risk of MB.
•APTT-clot waveform analysis was more sensitive than conventional APTT assay in detecting hemostatic disorders.•Patterns of APTT-clot waveform analysis differed among four major hepatobiliary pancreatic surgeries.•The first and second derivative peak heights were useful in predicting the risk of massive bleeding.
In many malignancies including intrahepatic cholangiocarcinoma (iCCA), prognostic significance of host-related inflammatory / immunonutritional markers have attracted a lot of attention. However, it ...is unclear which is the strongest prognostic indicator for iCCA among these markers. The aim of this study was to firstly evaluate the prognostic utility of inflammatory / immunonutritional markers in resected iCCA patients using a multiple comparison in addition to a new marker, lymphocyte-to-C-reactive protein (CRP) score.
A total of sixty iCCA patients, who underwent surgical resection between October 2004 and April 2019, were enrolled in this study. Their clinical and pathological data were retrospectively assessed using univariate and multivariate analysis to determine prognostic predictors for disease specific survival (DSS). Moreover, these patients, who were divided into high and low groups based on lymphocyte-to-CRP score, were compared these survival outcomes using Kaplan-Meier analysis with a log-rank test.
In multivariate analysis, the significant prognostic factors were preoperative lymphocyte-to-CRP score (p = 0.008), preoperative CRP-to-albumin ratio (CAR; p = 0.017), pathological T category (p = 0.003), and pathological vascular invasion (p < 0.001). Resected iCCA patients with a low lymphocyte-to-CRP score (score 0) had significant better prognosis than patients with a high score (score 1 or 2) (p = 0.016). Notably, the mortality of the high lymphocyte-to-CRP score group did not show statistically difference from the poor mortality of unresected iCCA patients (p = 0.204).
Preoperative lymphocyte-to-CRP score was the strongest prognostic indicator in iCCA patients with surgical resection. In these patients, early intervention with nutritional support should be considered prior to operation.
Background
The main etiology of NAFLD and NASH after pancreatic resection is still unclear, and the therapeutic strategy has yet to be established. The focus of this review is how predict and prevent ...NAFLD/NASH after pancreaticoduodenectomy.
Methods
From April 2005 to October 2008, 54 patients who underwent pancreaticoduodenectomy in our institution were enrolled in this study. From the pre-, intra- and postoperative risk factors, we identified the most influential risk factors of postoperative NAFLD by uni- and multivariate analyses. Moreover, a postoperative NAFLD scoring system was proposed based on these risk factors.
Results
The incidence of postoperative NAFLD was 37.0% (20/54). Of these, 10% (2/20) of patients were diagnosed as having NASH by percutaneous liver biopsy. By multivariate analysis, pancreatic adenocarcinoma (
p
< 0.05), pancreatic resection line (
p
< 0.01) and postoperative diarrhea (
p
< 0.01) were identified as the most influential factors concerning postoperative NAFLD. Based on these results, we proposed a postoperative NAFLD scoring system (0–10) and evaluated the correlation between the score and decreasing rates of CT values, revealing a significant correlation (
r
= 0.829
p
< 0.001). The prevalence of postoperative NAFLD in the patients with our scores of 0–3, 4–6 and 7–10 points was 0 (0/22), 35 (6/17) and 93% (14/15), respectively.
Conclusions
In conclusion, NAFLD develops frequently in patients who undergo PD, and some patients even progress to NASH. A postoperative NAFLD scoring system makes it possible to predict the occurrence of NAFLD after PD, and aggressive nutrition support is needed for patients with high scores.
Endoscopic biliary stenting (EBS) is commonly used for preoperative drainage of localized perihilar cholangiocarcinoma (LPHC). This study retrospectively compared the utility of inside stent (IS) and ...conventional stent (CS) for preoperative EBS in patients with LPHC.
EBS was performed in 56 patients with LPHC. EBS involved the placement of a CS (n = 32) or IS (n = 24). Treatment outcomes were compared between these two groups.
Preoperative recurrent biliary obstruction (RBO) occurred in 23 patients (71.9%) in the CS group and 7 (29.2%) in the IS group, with a significant difference (p = 0.002). The time to RBO (TRBO) was significantly longer in IS than in CS (log-rank: p < 0.001). The number of stent replacements was significantly lower in IS than CS 0.38 (0-3) vs. 1.88 (0-8), respectively; p < 0.001. Gemcitabine-based neoadjuvant chemotherapy (NAC) was administered to 26 patients (46.4%). Among patients who received NAC, TRBO was longer in IS than in CS group (log-rank: p < 0.001). The IS group had a significantly shorter preoperative and postoperative hospital stay than the CS group (20.0 vs. 37.0 days; p = 0.024, and 33.5 vs. 41.5 days; p = 0.016). Both the preoperative and the postoperative costs were significantly lower in the IS group than in the CS group (p = 0.049 and p = 0.0034, respectively).
Compared with CS, IS for preoperative EBS in LPHC patients resulted in fewer complications and lower re-intervention rates. The fact that the IS group had shorter preoperative and postoperative hospital stays and lower costs both preoperatively and postoperatively compared to the CS group may suggest that the use of IS has the potential to benefit not only the patient but also the healthcare system.
The optimal surgical indication after preoperative chemoradiotherapy (CRT) remains a subject of debate for patients with pancreatic ductal adenocarcinoma (PDAC) because early recurrence often occurs ...even after curative-intent resection. The present study aimed to identify perioperative risk factors of early recurrence for patients with PDAC who underwent curative-intent resection after preoperative CRT.
Two hundred three patients with PDAC who underwent curative-intent resection after preoperative CRT from February 2005 to December 2018 were retrospectively analyzed. The optimal threshold for differentiating between early and late recurrence was determined by the minimum p-value approach. Multivariate regression analysis was performed to identify predictive factors for early recurrence.
In 130 patients who developed recurrence after resection, 52 who had an initial recurrence within 12 months were defined as the early recurrence group, and the remaining 78 were defined as the late recurrence group. The incidence of hepatic recurrence was significantly higher in the early recurrence group than in the late recurrence group (39.7 vs. 15.4%). The early recurrence group had significantly lower 3-year rates of post-recurrence and overall survival than the late recurrence group (4.0 and 10.7% vs. 9.8 and 59.0%, respectively). Serum level of CA19-9 before surgery ≥56.8 U/ml was identified as an independent risk factor for early recurrence (OR:3.07, 95%CI:1.65-5.73, p<0.001) and associated with a significantly higher cumulative incidence rate of hepatic recurrence and lower rates of recurrence-free and overall survival.
Serum level of CA19-9 before surgery after preoperative CRT was a strong predictive factor for early recurrence.
Peripancreatic fluid collections have been observed in most patients with postoperative pancreatic fistula after distal pancreatectomy; however, optimal management remains unclear. This study aimed ...to evaluate the management and outcomes of patients with postoperative pancreatic fistula and verify the significance of computed tomography values for predicting peripancreatic fluid infections after distal pancreatectomy. We retrospectively investigated 259 consecutive patients who underwent distal pancreatectomy. Grade B postoperative pancreatic fistula patients were divided into two subgroups (B-antibiotics group and B-intervention group) and outcomes were compared. Predictive factor analysis of peripancreatic fluid infection was performed. Clinically relevant postoperative pancreatic fistulas developed in 88 (34.0%) patients. The duration of hospitalization was significantly longer in the B-intervention (n = 54) group than in the B-antibiotics group (n = 31; 41 vs. 17 days, p < 0.001). Computed tomography values of the infected peripancreatic fluid collections were significantly higher than those of the non-infected peripancreatic fluid collections (26.3 vs. 16.1 Hounsfield units, respectively; p < 0.001). The outcomes of the patients with grade B postoperative pancreatic fistulas who received therapeutic antibiotics only were considerably better than those who underwent interventions. Computed tomography values may be useful in predicting peripancreatic fluid collection infection after distal pancreatectomy.
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