Background
Although the prognosis of patients experiencing recurrences after surgery for pancreatic cancer is extremely poor, patients who develop recurrence in the lung have a better prognosis ...compared to other types of recurrence. We performed a histo-immunological analysis of the metastatic specimens to identify specific features of this patient subgroup.
Methods
We performed immunohistochemistry for CD4+, CD8+, CD45RO+, Foxp3, and PD-L1 in the lung (
n
= 22), peritoneal (
n
= 18), and liver (
n
= 6) metastases of pancreatic cancer. As microenvironmental and immunonutritional investigations, the tumor-stroma ratio and prognostic nutritional index (PNI) were utilized in the integrative analysis of immunological features.
Results
We identified significantly increased tumor-infiltrating CD4+, CD8+, and CD45RO+ cells in lung metastasis, compared with peritoneal and liver metastases (lung vs. peritoneum/liver, CD4:
P
< 0.001/
P
= 0.015, CD8:
P
< 0.001/
P
= 0.038, CD45RO:
P
= 0.022/
P
= 0.012). The CD8/Foxp3 ratio was higher in the lung than in the liver (
P
= 0.024). PD-L1 expression was significantly higher in lung metastasis than in peritoneal metastasis (
P
= 0.010). Furthermore, we found that lung metastasis had fewer cancer stroma than peritoneal metastasis (
P
< 0.001). A higher PNI was observed in patients with lung metastasis, and PNI was positively correlated with tumor-infiltrating lymphocytes in metastatic sites.
Conclusion
We identified that lung metastasis revealed an immunologically “hot” tumor with increased TILs and PD-L1 expression. This specific feature suggests that patients with lung metastasis can be candidates for immunotherapy, such as immune checkpoint inhibitors; therefore, our study provides a framework for developing individualized treatment strategies for this patient subgroup.
Background
Late-onset biliary complications (LBC) after pancreatoduodenectomy (PD) can be serious. This study aimed to clarify the frequency and risk factors of severe LBC after PD.
Methods
We ...defined LBC as biliary complications occurring 3 months after PD and severe LBC as cases that required intensive care. A total of 318 patients who underwent PD between 2010 and 2018 with at least 1 year of postoperative follow-up were evaluated.
Results
Hospitalization for severe LBC was required in 59 patients (19%), of whom 20 had liver abscesses (6.3%); 18, acute cholangitis (5.7%); 12, biliary stones (3.8%); and 21, biliary strictures (6.6%). Interventional radiological or endoscopic treatment was required in 32 patients (10%), of whom 9 had a benign primary disease with biliary stones and/or strictures. Thirteen of the remaining 23 patients with a malignant primary disease had liver abscesses and cholangitis. Significant independent risk factors for severe LBC in patients with malignant primary disease were recurrence around the hepaticojejunostomy (odds ratio 6.5,
P
= 0.013) and chemotherapy (odds ratio 13.5,
P
< 0.001).
Conclusions
Severe LBC after PD may occur regardless of whether the primary disease is benign or malignant. The course of severe LBC differs according to the primary disease, and therefore, appropriate follow-up and optimal treatment should be recommended according to the condition of the patient and the disease state.
Nectin-4 belongs to the nectin family that has diverse physiological and pathological functions in humans. Recent studies have also suggested some roles for Nectin-4 in several human cancers. ...However, the precise roles and clinical relevance of Nectin-4 in tumors are largely unknown.
Nectin-4 expression was investigated in 123 patients with pancreatic cancer by immunohistochemistry. Furthermore, we investigated the association of Nectin-4 in pancreatic cancer with tumor proliferation, angiogenesis and immunity by using immunohistochemistry and siRNA interference method.
Patients with high Nectin-4 expression had poorer postoperative prognosis than those with low expression. Importantly, multivariate analysis indicated that Nectin-4 expression had a significant independent prognostic value in pancreatic cancer (HR = 1.721, 1.085-2.730; P = 0.021). Tumor Nectin-4 expression was significantly correlated with Ki67 expression. In addition, siRNA-mediated gene silencing of Nectin-4 significantly inhibited the cell proliferation in human pancreatic cancer cells, Capan-2 and BxPC-3. Furthermore, Nectin-4 expression was also positively correlated with VEGF expression and intratumoral microvessel density. However, there were no significant correlations of tumor Nectin-4 expression with tumor-infiltrating T cells.
Nectin-4 is a significant prognostic predictor, and may play a critical role in pancreatic cancer. Nectin-4 may be novel therapeutic target for pancreatic cancer.
This retrospective multicenter study aimed to evaluate the risk of postpancreatectomy hemorrhage (PPH) in patients receiving antithrombotic agents (ATAs). PPH is the most severe complication after ...pancreatectomy. However, there is little known about the strength of the association between ATA use, PPH, and other clinical outcomes.
Between 2007 and 2016, 1,297 patients underwent pancreatectomy at 2 surgical centers. ATA use included aspirin, clopidogrel, ticlopidine, warfarin, direct oral anticoagulants, and intravenous unfractionated heparin. The ATA group was composed of 144 patients who were taking ATAs before surgery.
A total of 35 patients developed PPH. The patients in the ATA group showed higher frequency (8.3% vs 2.0%, p < 0.001) of PPH compared with the control group (n = 1,153). In multivariate analysis, ATA use was an independent adverse risk factor for PPH (odds ratio OR 3.58, 95% CI 1.29–9.91, p = 0.014). Stratification by preoperative ATA therapy revealed a significant risk of PPH Grade C in patients receiving combined AT therapy. The median onset of late hemorrhage (>24 hours post-surgery) in the ATA group was later than in the control group (17.5 vs 8.5 days, p = 0.032), and the incidence tended to be higher in patients who restarted ATAs postoperatively.
History of ATA use is a significant risk factor for PPH, and postoperative resumption of ATAs appears to be associated with an increased risk of PPH. Patients receiving combined antithrombotic therapy may be at particularly high risk for PPH.
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The adhesion G-protein-coupled receptors (GPCRs) play crucial roles in tumour pathogenesis, however, their clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains unclear.
We ...analysed 796 PDAC patients, including 331 from public data sets (TCGA, ICGC and GSE57495) and 465 from independent cohorts (training: n = 321, validation: n = 144). Using in-vitro studies, we confirmed the biological function of the candidate GPCRs.
Analysis of all 33 adhesion GPCRs, led to identify GPR115, as the only significant prognostic factor in all public data sets. The patients with high GPR115 expression exhibited significantly poorer prognosis for OS and RFS, in training (P < 0.01, P < 0.01) and validation cohort (P < 0.01, P = 0.04). Multivariate analysis indicated that GPR115 high expression was an independent prognostic factor in both cohorts (HR = 1.43; P = 0.01, HR = 2.55; P < 0.01). A risk-prediction model using Cox regression by incorporating GPR115 and clinicopathological factors accurately predicted 5-year survival following surgery. In addition, GPR115 silencing inhibited cell proliferation and migration in PDAC cells.
We demonstrated that GPR115 has important prognostic significance and functional role in tumour progression; providing a rationale that this may be a potential therapeutic target in patients with PDAC.
Carbohydrate antigen (CA) 19-9 levels after resection are considered to predict prognosis; however, the significance of decreased CA19-9 levels after neoadjuvant therapy has not been clarified. This ...study aimed to define the prognostic significance of decreased CA19-9 levels after neoadjuvant therapy in patients with pancreatic adenocarcinoma.
Between 2001 and 2012, 240 consecutive patients received neoadjuvant therapy and subsequent resection at seven high-volume institutions in Japan. These patients were divided into three groups: Normal group (no elevation ≤37 U/ml before and after neoadjuvant therapy), Responder group (elevated levels > 37 U/ml before neoadjuvant therapy but decreased levels ≤37 U/ml afterwards), and Non-responder group (elevated levels > 37 U/ml after neoadjuvant therapy). Analyses of overall survival and recurrence patterns were performed. Uni- and multivariate analyses were performed to clarify the clinicopathological factors influencing overall survival. The initial metastasis sites were also evaluated in these groups.
The Responder group received a better prognosis than the Non-responder group (3-year overall survival: 50.6 and 41.6%, respectively, P = 0.026), but the prognosis was comparable to the Normal group (3-year overall survival: 54.2%, P = 0.934). According to the analysis of the receiver operating characteristic curve, the CA19-9 cut-off level defined as no elevation after neoadjuvant therapy was ≤103 U/ml. The multivariate analysis revealed that a CA19-9 level ≤ 103 U/ml, (P = 0.010, hazard ratio: 1.711; 95% confidence interval: 1.133-2.639), tumor size ≤27 mm (P = 0.040, 1.517; (1.018-2.278)), a lack of lymph node metastasis (P = 0.002, 1.905; (1.276-2.875)), and R0 status (P = 0.045, 1.659; 1.012-2.627) were significant predictors of overall survival. Moreover, the Responder group showed a lower risk of hepatic recurrence (18%) compared to the Non-responder group (31%), though no significant difference in loco-regional, peritoneal or other distant recurrence were observed between groups (P = 0.058, P = 0.700 and P = 0.350, respectively).
Decreased CA19-9 levels after neoadjuvant therapy predicts a better prognosis, with low incidence of hepatic recurrence after surgery.
Background
The novel 2019 coronavirus disease (COVID-19), which is caused by infection with the severe acute respiratory syndrome coronavirus 2, has spread rapidly around the world and has caused ...many deaths. COVID-19 involves a systemic hypercoagulable state and arterial/venous thrombosis which induces unfavorable prognosis. Herein, we present a first case in East Asia where an acute superior mesenteric artery (SMA) occlusion associated with COVID-19 pneumonia was successfully treated by surgical intervention.
Case presentation
A 70-year-old man presented to his local physician with a 3-day history of cough and diarrhea. A real-time reverse transcriptase-polymerase chain reaction test showed positive for COVID-19, and he was admitted to the source hospital with the diagnosis of moderate COVID-19 pneumonia. Eight days later, acute onset of severe abdominal pain appeared with worsening respiratory condition. Contrast CT showed that bilateral lower lobe/middle lobe and lingula ground glass opacification with distribution suggestive of COVID-19 pneumonia and right renal infarction. In addition, it demonstrated SMA occlusion with intestinal ischemia suggesting extensive necrosis from the jejunum to the transverse colon. The patient underwent an emergency exploratory laparotomy with implementing institutional COVID-19 precaution guideline. Upon exploration, the intestine from jejunum at 100 cm from Treitz ligament to middle of transverse colon appeared necrotic. Necrotic bowel resection was performed with constructing jejunostomy and transverse colon mucous fistula. We performed second surgery to close the jejunostomy and transverse colon mucous fistula with end-to-end anastomosis on postoperative day 22. The postoperative course was uneventful and he moved to another hospital for rehabilitation to improve activities of daily living (ADLs) on postoperative day 45. As of 6 months after the surgery, his ADLs have completely improved and he has returned to social life without any intravenous nutritional supports.
Conclusions
Intensive treatment including surgical procedures allowed the patient with SMA occlusion in COVID-19 pneumonia to return to social life with completely independent ADLs. Although treatment for COVID-19 involves many challenges, including securing medical resources and controlling the spread of infection, when severe abdominal pain occurs in patients with COVID-19, physicians should consider SMA occlusion and treat promptly for life-saving from this deadly combination.
In patients with pancreatic ductal adenocarcinoma (PDAC), optimal treatment selection, including multimodality regimens such as neoadjuvant chemoradiotherapy (NACRT), can be clinically ...transformative. Unfortunately, currently no predictive biomarkers are available that can guide the use of NACRT in PDAC patients. Accordingly, herein we developed a novel gene signature that can preoperatively predict NACRT‐sensitivity in PDAC patients. Herein, we evaluated the performance of a 10‐gene panel in 749 PDAC cases, which included two public datasets (The Cancer Genome Atlas and International Cancer Genome Consortium; n = 276), and three clinical specimen cohorts (n = 417), and a pre‐NACRT endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) biopsy cohort (n = 56). The potential predictive performance of this signature was evaluated and compared to CA‐19‐9 levels and key clinicopathological factors. We first evaluated the prognostic potential of a 10‐gene panel which significantly predicted overall survival in both public datasets (P < .01, P < .01), and two in‐house patient cohorts (P < .01, P = .04). In the pre‐NACRT EUS‐FNA cohort, we established a radio‐sensitivity gene panel (RSGP) which yielded highly robust (area under the curve AUC = 0.91; 95% CI: 0.81‐0.97) for predicting response to gemcitabine‐based NACRT. Multivariate logistic regression analysis revealed that RSGP was an independent predictor for response to NACRT (OR = 2.70; 95% CI: 1.25‐5.85), and this response‐prediction was even more robust when CA‐19‐9 levels were included into the model. In conclusion, we have validated and developed a novel gene signature that is highly robust in predicting response to NACRT, even in preoperative settings, highlighting its clinical significance for optimizing and personalizing treatment strategies in PDAC patients.
What's new?
While the benefits of radiation treatment have been well established in solid cancers, the criteria for optimal indication of radiotherapy in pancreatic ductal adenocarcinoma and the best regimens for its clinical application remain unclear. The availability of biomarkers that could help predict response to radio‐sensitivity before treatment could lead to better‐informed decision‐making. Here, the authors report developing and validating a novel gene expression signature that is highly robust in predicting patient response to neoadjuvant chemoradiotherapy, even in preoperative settings. The results highlight the clinical significance of this gene signature for optimizing and personalizing treatment strategies in patients with pancreatic cancer.
Background
Organ/space surgical site infection (SSI) is one of the most common complications of liver resection, with significant impact on morbidity and mortality, so patients at high risk should be ...identified early. This study aimed to determine whether pre- and postoperative C-reactive protein (CRP) levels could predict organ/space SSIs.
Methods
The hospital records of consecutive patients who underwent hepatectomy without biliary reconstruction at our institutions between 2008 and 2015 were reviewed retrospectively. Preoperative, intraoperative, and postoperative variables were compared between patients with or without organ/space SSIs. Its risk factors were also determined.
Results
Among 443 identified patients, 55 cases (12.5%) developed organ/space SSIs; they more frequently experienced other complications and bile leakage (47.3% vs. 16.6%,
p
= 0.001; 40.0% vs. 8.5%,
p
< 0.001, respectively). Postoperative CRP elevation from postoperative day (POD) 3 to 5 was significantly more frequent in the SSI group (21.8% vs. 4.9%,
p
< 0.001). Multivariate analysis identified preoperative CRP ≥ 0.2 mg/dL (odds ratio (OR), 2.01,
p
= 0.044, preoperative cholangitis (OR, 15.7;
p
= 0.020), red cell concentrate (RCC) transfusion (OR, 2.61,
p
= 0.018), bile leakage (OR, 9.51;
p
< 0.001), and CRP level elevation from POD 3 to 5 (OR, 3.81,
p
= 0.008) as independent risk factors for organ/space SSIs.
Conclusions
Preoperative CRP elevation and postoperative CRP trajectory are risk factors for organ/space SSIs after liver resection. A prolonged CRP level elevation at POD 5 indicates its occurrence. If there were no risk factors and no CRP elevation at POD 5, its presence could be excluded.
Background
The optimal stent type in patients receiving preoperative neoadjuvant chemoradiotherapy (NACRT) is uncertain. The present study aimed to compare the clinical effectiveness of biliary ...metallic stent (MS) and plastic stent (PS) in patients undergoing preoperative NACRT for resectable pancreatic cancer.
Methods
This retrospective study included 43 patients who required either biliary MS or PS before initiating NACRT for resectable or borderline resectable pancreatic head cancer. Seventeen patients had MS (MS group), while 23 patients had PS (PS group). All patients received preoperative NACRT, including gemcitabine and concomitant three-dimensional radiation of 54 Gy, and underwent pancreatectomy. Stent patency, surgery postponement, postoperative outcomes, and cost-effectiveness were compared between these groups.
Results
There were no significant differences in baseline demographic or tumor characteristics between the groups. Stent patency was significantly longer in the MS group than in the PS group (
p
= 0.042). There were no differences in time to surgery, intraoperative characteristics, surgical complications, margin positivity, and pathological response between the groups. Furthermore, the medical cost of maintenance of biliary drainage during NACRT was similar between the groups.
Conclusions
MS placement compared to PS in patients receiving preoperative NACRT provided no significant benefits during the postoperative course of pancreatectomy. However, MS placement was associated with long stent patency while showing no economic disadvantage. Therefore, MS placement may be recommended in patients receiving preoperative NACRT for resectable pancreatic cancer.
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