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One of most challenging issues in tumor immunology is a better understanding of the dynamics in the accumulation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TIME), as this would lead to the development of new cancer therapeutics. Here, we show that translationally controlled tumor protein (TCTP) released by dying tumor cells is an immunomodulator crucial to full-blown MDSC accumulation in the TIME. We provide evidence that extracellular TCTP mediates recruitment of the polymorphonuclear MDSC (PMN-MDSC) population in the TIME via activation of Toll-like receptor-2. As further proof of principle, we show that inhibition of TCTP suppresses PMN-MDSC accumulation and tumor growth. In human cancers, we find an elevation of TCTP and an inverse correlation of TCTP gene dosage with antitumor immune signatures and clinical prognosis. This study reveals the hitherto poorly understood mechanism of the MDSC dynamics in the TIME, offering a new rationale for cancer immunotherapy. Cell death in the context of cancer therapies is often associated with immunogenicity. Taniguchi and colleagues instead find that release of the cellular protein TCTP following cell death triggers an immunosuppressive pathway in the tumor microenvironment.

BackgroundEndoscopic management of hepaticojejunostomy anastomotic strictures is technically demanding due to surgically altered anatomy. The promise of double-balloon endoscope-assisted endoscopic retrograde cholangiopancreatography (DB-ERCP) has been reported in this setting. No large study has examined long-term outcomes of this new treatment modality and predictive factors for the stricture resolution.MethodsWe included 102 patients who received DB-ERCP for a hepaticojejunostomy anastomotic stricture between 2008 and 2018. Balloon dilation was performed as a first-line treatment, and plastic stent(s) were placed for refractory cases. Potential predictive factors for the stricture resolution were examined using multivariable logistic regression analyses.ResultsDB-ERCP was technically successful in 91 patients (89.2%). Overall, stricture resolution was achieved in 70 patients (76.9%) with a median follow-up period of 30.9 months (range 1–118.5 months). Among 64 patients (71.9%) who underwent successful re-canalization via balloon dilation, anastomotic stricture recurred in 22 patients (34.4%). In cases with refractory or recurrent stricture after balloon dilation, 20 patients (52.6%) underwent stricture resolution via plastic stent placement, and the recurrence was observed in two patients (10%). Post-operative time to DB-ERCP of > 12 months and the scar-like appearance around the anastomosis were associated with a higher rate of stricture resolution (odds ratios, 5.59 [95% CI 1.69–18.5] and 5.22 [95% CI 1.29–21.1], respectively).ConclusionsTreatment of hepaticojejunostomy anastomotic strictures via DB-ERCP was technically feasible, providing a reasonably high rate of stricture resolution. Alternative treatment should be explored for refractory cases.

Macroautophagy (hereafter autophagy) is a catabolic process through which cytosolic components are captured in the autophagosome and degraded in the lysosome. Autophagy plays two major roles: nutrient recycling under starvation or stress conditions and maintenance of cellular homeostasis by removing the damaged organelles or protein aggregates. In established cancer cells, autophagy-mediated nutrient recycling promotes tumor progression, whereas in normal/premalignant cells, autophagy suppresses tumor initiation by eliminating the oncogenic/harmful molecules. Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is refractory to most currently available treatment modalities, including immune checkpoint blockade and molecular-targeted therapy. One prominent feature of PDAC is its constitutively active and elevated autophagy-lysosome function, which enables PDAC to thrive in its nutrient-scarce tumor microenvironment. In addition to metabolic support, autophagy promotes PDAC progression in a metabolism-independent manner by conferring resistance to therapeutic treatment or facilitating immune evasion. Besides to cell-autonomous autophagy in cancer cells, host autophagy (autophagy in non-cancer cells) supports PDAC progression, further highlighting autophagy as a promising therapeutic target in PDAC. Based on a growing list of compelling preclinical evidence, there are numerous ongoing clinical trials targeting the autophagy-lysosome pathway in PDAC. Given the multifaceted and context-dependent roles of autophagy in both cancer cells and normal host cells, a deeper understanding of the mechanisms underlying the tumor-promoting roles of autophagy as well as of the consequences of autophagy inhibition is necessary for the development of autophagy inhibition-based therapies against PDAC.

BackgroundIn patients with unresectable hilar malignant biliary obstruction (MBO), bilateral metal stent placement is recommended. However, treatment selection between partially stent-in-stent (SIS) and side-by-side (SBS) methods is still controversial.StudyClinical outcomes of bilateral metal stent placement by SBS and SIS methods for hilar MBO were retrospectively studied in four Japanese centers. While large-cell-type uncovered metal stents were placed above the papilla in SIS, braided-type uncovered metal stents were placed across the papilla in SBS.ResultsA total of 64 patients with hilar MBO (40 SIS and 24 SBS) were included in the analysis. Technical success rate was 100% in SIS and 96% in SBS. Functional success rate was 93% in SIS and 96% in SBS. Early adverse event rates were higher in SBS (46%) than in SIS (23%), though not statistically significant (P = 0.09). Post-procedure pancreatitis was exclusively observed in SBS group (29%). Recurrent biliary obstruction rates were 48% and 43%, and the median time to recurrent biliary obstruction was 169 and 205 days in SIS and SBS, respectively.ConclusionsOther than a trend to higher adverse event rates including post-procedure pancreatitis in SBS, clinical outcomes of SIS and SBS methods were comparable in patients with unresectable hilar MBO.

BackgroundAutoimmune pancreatitis (AIP) is frequently complicated by diabetes mellitus (DM), but DM associated with AIP is reported to improve after steroid therapy. The aim of this study is to investigate glucose intolerance during steroid therapy according to the onset of DM.MethodsSixty-one patients who underwent steroid therapy for AIP were included into this study. We evaluated C peptide index (CPI), homeostasis model assessment for insulin resistance (HOMA-R), and the pancreatic diameter at AIP diagnosis and after 4 weeks, 1 year, and 2 years of steroid therapy. Patients were categorized into three groups according to DM onset: Pre-existing DM (pDM), concurrent DM (cDM), and non-DM (nDM).ResultsForty-three patients (71%) had DM: 15 pDM and 28 cDM. At AIP diagnosis, CPI was lower in patients with pDM (0.7, P = 0.007) and cDM (0.9, P = 0.018) than nDM (1.3). After 4 weeks of steroid therapy, CPI improved in cDM (P < 0.001) and in nDM (P = 0.021). After 2 years of steroid therapy, HOMA-R increased (2.1–3.0, P = 0.007) but CPI gradually improved (1.0–2.1, P = 0.004). DM improved in 23% of cDM, and 55% of insulin users in cDM discontinued using insulin. Pancreatic atrophy was seen in 30%, and was associated with DM.ConclusionDM in patients with AIP was associated with impaired insulin secretion rather than insulin resistance. Insulin secretion improved during steroid therapy for AIP in patients with concurrent DM. Thus, glucose intolerance can be an indication for AIP treatment.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with only a few effective therapeutic options. A characteristic feature of PDAC is its unique tumor microenvironment (TME), termed desmoplasia, which shows extensive fibrosis and extracellular matrix deposition, generating highly hypoxic and nutrient-deprived conditions within the tumor. To thrive in this harsh TME, PDAC undergoes extensive metabolic rewiring that includes the altered use of glucose and glutamine, constitutive activation of autophagy-lysosomal pathways, and nutrient acquisition from host cells in the TME. Notably, these properties support PDAC metabolism and mediate therapeutic resistance, including immune suppression. A deeper understanding of the unique metabolic properties of PDAC and its TME may aid in the development of novel therapeutic strategies against this deadly disease.

Interstitial lung disease (ILD) is an adverse event associated with gemcitabine administration. Gemcitabine plus nab‐paclitaxel, which is now a first‐line chemotherapy regimen for pancreatic cancer (PC), may increase the risk of ILD; however, large‐scale clinical data on this are limited. Thus, this study aimed to elucidate the incidence and risk factors of ILD in patients with PC receiving gemcitabine plus nab‐paclitaxel. Through the Diagnosis Procedure Combination database, a Japanese nationwide inpatient database with outpatient data, we identified consecutive patients with PC who received gemcitabine‐based chemotherapy between July 2010 and March 2019 at 205 hospitals. Competing‐risk analysis was used to examine the cumulative incidence and risk factors of ILD. Among the 6163 patients who received gemcitabine plus nab‐paclitaxel, we documented 168 patients (2.7%) who developed ILD with cumulative incidence rates (95% confidence intervals [CIs]) of 2.0% (1.6%–2.4%), 2.7% (2.2%–3.1%), and 3.1% (2.6%–3.6%) at 3, 6, and 12 months, respectively. Compared with patients with PC who received gemcitabine monotherapy, those who received gemcitabine plus nab‐paclitaxel had an adjusted subdistribution hazard ratio (SHR) for ILD of 1.93 (95% CI: 1.51–2.47). Older age was associated with a high risk of ILD in patients receiving gemcitabine plus nab‐paclitaxel (adjusted SHR comparing ≥75 to ≤74 years, 1.61; 95% CI: 1.16–2.24). In conclusion, this study demonstrated the clinical course of gemcitabine plus nab‐paclitaxel‐associated ILD in patients with PC. When gemcitabine plus nab‐paclitaxel is administered to elderly patients with PC, symptoms associated with ILD must be monitored.