Paclitaxel is a powerful chemotherapeutic drug, used for the treatment of many cancer types, including esophageal adenocarcinomas (EAC). Autophagy is a lysosome-dependent degradation process ...maintaining cellular homeostasis. Defective autophagy has been implicated in cancer biology and therapy resistance. We aimed to assess the impact of autophagy on chemotherapy response in EAC, with a special focus on paclitaxel. Responsiveness of EAC cell lines, OE19, FLO-1, OE33 and SK-GT-4, to paclitaxel was assessed using Alamar Blue assays. Autophagic flux upon paclitaxel treatment in vitro was assessed by immunoblotting of LC3B-II and quantitative assessment of WIP1 mRNA. Immunohistochemistry for the autophagy markers LC3B and p62 was applied on tumor tissue from 149 EAC patients treated with neoadjuvant chemotherapy, including pre- and post-therapeutic samples (62 matched pairs). Tumor response was assessed by histology. For comparison, previously published data on 114 primary resected EAC cases were used. EAC cell lines displayed differing responsiveness to paclitaxel treatment; however this was not associated with differential autophagy regulation. High p62 cytoplasmic expression on its own (p ≤ 0.001), or in combination with low LC3B (p = 0.034), was associated with nonresponse to chemotherapy, regardless of whether or not the regiments contained paclitaxel, but there was no independent prognostic value of LC3B or p62 expression patterns for EAC after neoadjuvant treatment. p62 and related pathways, most likely other than autophagy, play a role in chemotherapeutic response in EAC in a clinical setting. Therefore p62 could be a novel therapeutic target to overcome chemoresistance in EAC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To determine benefits of conservative versus surgical treatment in patients with necrotizing pancreatitis.
Infection of pancreatic necrosis is the most important risk factor contributing to death in ...severe acute pancreatitis, and it is generally accepted that infected pancreatic necrosis should be managed surgically. In contrast, the management of sterile pancreatic necrosis accompanied by organ failure is controversial. Recent clinical experience has provided evidence that conservative management of sterile pancreatic necrosis including early antibiotic administration seems promising.
A prospective single-center trial evaluated the role of nonsurgical management including early antibiotic treatment in patients with necrotizing pancreatitis. Pancreatic infection, if confirmed by fine-needle aspiration, was considered an indication for surgery, whereas patients without signs of pancreatic infection were treated without surgery.
Between January 1994 and June 1999, 204 consecutive patients with acute pancreatitis were recruited. Eighty-six (42%) had necrotizing disease, of whom 57 (66%) had sterile and 29 (34%) infected necrosis. Patients with infected necrosis had more organ failures and a greater extent of necrosis compared with those with sterile necrosis. When early antibiotic treatment was used in all patients with necrotizing pancreatitis (imipenem/cilastatin), the characteristics of pancreatic infection changed to predominantly gram-positive and fungal infections. Fine-needle aspiration showed a sensitivity of 96% for detecting pancreatic infection. The death rate was 1.8% (1/56) in patients with sterile necrosis managed without surgery versus 24% (7/29) in patients with infected necrosis (P <.01). Two patients whose infected necrosis could not be diagnosed in a timely fashion died while receiving nonsurgical treatment. Thus, an intent-to-treat analysis (nonsurgical vs. surgical treatment) revealed a death rate of 5% (3/58) with conservative management versus 21% (6/28) with surgery.
These results support nonsurgical management, including early antibiotic treatment, in patients with sterile pancreatic necrosis. Patients with infected necrosis still represent a high-risk group in severe acute pancreatitis, and for them surgical treatment seems preferable.
Esophageal adenocarcinoma (EAC) is a highly lethal cancer type with an overall poor survival rate. Twenty to thirty percent of EAC overexpress the human epidermal growth factor receptor 2 (Her2), a ...transmembrane receptor tyrosine kinase promoting cell growth and proliferation. Patients with Her2 overexpressing breast and gastroesophageal cancer may benefit from Her2 inhibitors. Therapy resistance, however, is well documented. Since autophagy, a lysosome-dependent catabolic process, is implicated in cancer resistance mechanisms, we tested whether autophagy modulation influences Her2 inhibitor sensitivity in EAC. Her2-positive OE19 EAC cells showed an induction in autophagic flux upon treatment with the small molecule Her2 inhibitor Lapatinib. Newly generated Lapatinib-resistant OE19 (OE19 LR) cells showed increased basal autophagic flux compared to parental OE19 (OE19 P) cells. Based on these results, we tested if combining Lapatinib with autophagy inhibitors might be beneficial. OE19 P showed significantly reduced cell viability upon double treatment, while OE19 LR were already sensitive to autophagy inhibition alone. Additionally, Her2 status and autophagy marker expression (LC3B and p62) were investigated in a treatment-naïve EAC patient cohort (
= 112) using immunohistochemistry. Here, no significant correlation between Her2 status and expression of LC3B and p62 was found. Our data show that resistance to Her2-directed therapy is associated with a higher basal autophagy level, which is not per se associated with Her2 status. Therefore, we propose that autophagy may contribute to acquired resistance to Her2-targeted therapy in EAC, and that combining Her2 and autophagy inhibition might be beneficial for EAC patients.
Esophageal adenocarcinomas (EAC) are aggressive tumors with considerable rates of chemoresistance. Autophagy is a lysosome-dependent degradation process, characterized by the formation of vesicles ...called autophagosomes, and has been implicated in cancer. Protein light chain 3 B (LC3B) and p62 are associated with autophagosomal membranes and degraded. We aimed to assess the impact of basal autophagy on EAC. In EAC cell lines, an increase in LC3B and p62 was observed with increasing concentrations of the autophagy inhibitor chloroquine, which indicates functional basal autophagy. LC3B and p62 immunohistochemistry was performed on primary resected EAC. High LC3B and p62 expression was associated with earlier tumor stages (p < 0.05). High nuclear and cytoplasmic p62 staining were associated with a better prognosis (p = 0.006; p = 0.028). Various combinations of p62 expression with or without LC3B expression identified different prognostic groups. Tumors with low total p62 (p = 0.007) or low LC3B/low p62 expression had the worst outcome (p = 0.007; p = 0.005). A combination score of dot-like/cytoplasmic p62 and nuclear p62 staining was an independent prognostic parameter (p = 0.033; HR = 0.6). This study highlights the potential significance of basal autophagy in EAC biology. Tumors with low LC3B and p62 expression show the most aggressive behavior and may be candidates for autophagy regulating therapeutics.
Summary Tumor budding has prognostic significance in many carcinomas and is defined as the presence of detached isolated single cells or small cell clusters up to five cells at the invasion front ...(peritumoral budding=PTB) or within the tumor (intratumoral budding=ITB). For esophageal adenocarcinomas (EAC) there are currently only few data about the impact of this morphological feature. We investigated tumor budding in a large collective of 200 primarily resected EAC. Pancytokeratin staining was demonstrated to be superior to Hematoxylin & Eosin staining for the detection of buds with substantial to excellent interobserver agreement and used for subsequent analysis. PTB and ITB were scored across 10-high-power-fields (HPF). The median count of tumor buds was 130/10 HPF for PTB (range 2-593) and 80/10 HPF for ITB (range 1-656). PTB and ITB correlated significantly with each other (r=0.9; p<0.001). High PTB and ITB rates were seen in more advanced tumor categories (p<.001 each), tumors with lymph node metastases (p<0.001/p=0.002), lymphatic, vascular and perineural invasion and higher tumor grading (p<0.001 each). Survival analysis showed an association with worse survival for high grade ITB (p=0.029), but not PTB (p=0.385). However, in multivariate analysis, lymph node and resection status, but not ITB were independent prognostic parameters. In conclusion, PTB and ITB can be observed in EAC to various degrees. High grade budding is associated with aggressive tumor phenotype. Assessment of tumor budding, especially ITB may provide additional prognostic information about tumor behavior and may be useful in specific cases for risk stratification of EAC patients
Esophageal carcinoma (EC) is one of the most aggressive human malignancies with high rates of resistance to conventional anticancer treatment. Cancer-associated fibroblasts (CAFs) are an important ...part of the tumor microenvironment and associated with tumor progression. COL11A1, SPARC, and CD90 have been identified as rather specific CAF markers, with COL11A1 expression particularly shown to influence response to chemotherapy. We investigated the impact of CAFs in esophageal cancer with a special focus on response to neoadjuvant treatment (nTX). Two collections of esophageal carcinomas were investigated: 164 cases treated with primary resection and 256 cases receiving nTX before resection. The expression of CAF markers was determined using next-generation tissue microarray (ngTMA®) technology and immunohistochemistry. The presence of COL11A1 and SPARC in fibroblasts within both primary resected cases and nTX-treated cases was associated with unfavorable clinicopathological variables such as higher (y)pT category and lymphatic invasion (p<0.001 each). The presence of COL11A1-positive CAFs was associated with worse overall survival in primary resected cases (HR: 2.162, p = 0.004, CI 95% 1.275–3.686). While in tumors showing regression after nTX, COL11A1-positive CAFs were detected less frequently, SPARC-positive CAFs were enriched after nTX, in both responding and non-responding patients (
p
< 0.001). Our results support the concept of CAFs as an important factor of tumor promotion and maintenance in EC. The population of CAFs increases with tumor progression and decreases, partly depending on the subtype, after regression following nTX. CAFs may serve as potential target for future therapeutic approaches for these highly aggressive tumors.
Expression analysis of programmed death-ligand 1 (PD-L1) may be helpful in guiding clinical decisions for immune checkpoint inhibition therapy, but testing by immunohistochemistry may be hampered by ...heterogeneous staining patterns within tumors and expression changes during metastatic course. PD-L1 expression (clone SP142) was investigated in esophageal adenocarcinomas using tissue microarrays (TMA) from 112 primary resected tumors, preoperative biopsies and full slide sections from a subset of these cases (
n
= 24), corresponding lymph node (
n
= 55) and distant metastases (
n
= 17). PD-L1 expression was scored as 0.1–1, >1, >5, >50% positive membranous staining of tumor cells and any positive staining of tumor-associated inflammatory infiltrates and/or stroma cells. There was a significant correlation with overall PD-L1 expression between the full slide sections and the TMA (
p
= 0.001), but not with the corresponding biopsies. PD-L1 expression in tumor cells >1% was detected in 8.0% of cases (9/112) and 51.8% of cases (58/112) in tumor-associated inflammatory infiltrates and/or stroma cells of primary tumors. Epithelial expression in metastases was found in 5.6% of cases (4/72) and immune cell expression in 18.1% of cases (13/72), but did not correlate with the expression pattern in the primary tumor. Overall PD-L1 expression in the primary tumor did not influence survival. However, PD-L1 expression was correlated with the number of CD3
+
tumor-infiltrating lymphocytes in the tumor center, and a combinational score of PD-L1 status/CD3
+
tumor-infiltrating lymphocytes was correlated with patients’ overall survival.
Multiple therapies are currently available for patients with neuroendocrine tumors (NETs), yet many therapies have not been compared head-to-head within randomized clinical trials (RCTs).
To assess ...the relative safety and efficacy of therapies for NETs.
PubMed, Embase, the Cochrane Central Register of Controlled Trials, trial registries, meeting abstracts, and reference lists from January 1, 1947, to March 2, 2018, were searched. Key search terms included neuroendocrine tumors, gastrointestinal neoplasms, therapy, and randomized controlled trial.
Randomized clinical trials comparing 2 or more therapies in patients with NETs (primarily gastrointestinal and pancreatic) were evaluated. Thirty RCTs met the selection criteria.
Pairs of independent reviewers screened studies, extracted data, and assessed the risk of bias. A network meta-analysis with a frequentist approach was used to compare the efficacy of therapies; the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used.
Disease control, progression-free survival, overall survival, adverse events, and quality of life.
The systematic review identified 30 relevant RCTs comprising 3895 patients (48.4% women) assigned to 22 different therapies for NETs. These therapies showed a broad range of risk for serious and nonserious adverse events. The network meta-analyses included 16 RCTs with predominantly a low risk of bias; nevertheless, precision-of-treatment estimates and estimated heterogeneity were limited. The network meta-analysis found 7 therapies for pancreatic NETs: everolimus (hazard ratio HR, 0.35 95% CI, 0.28-0.45), everolimus plus somatostatin analogue (HR, 0.35 95% CI, 0.25-0.51), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.44 95% CI, 0.26-0.75), interferon (HR, 0.37 95% CI, 0.16-0.83), interferon plus somatostatin analogue (HR, 0.31 95% CI, 0.13-0.71), somatostatin analogue (HR, 0.46 95% CI, 0.33-0.66), and sunitinib (HR, 0.42 95% CI, 0.26-0.67), and 5 therapies for gastrointestinal NETs: bevacizumab plus somatostatin analogue (HR, 0.22 95% CI, 0.05-0.99), everolimus plus somatostatin analogue (HR, 0.31 95% CI, 0.11-0.90), interferon plus somatostatin analogue (HR, 0.27 95% CI, 0.07-0.96), Lu 177-dotatate plus somatostatin analogue (HR, 0.08 95% CI, 0.03-0.26, and somatostatin analogues (HR, 0.40 95% CI, 0.21-0.78) with higher efficacy than placebo and suggests an overall superiority of combination therapies.
The findings from this study suggest that a range of efficient therapies with different safety profiles is available for patients with NETs.
Background
High-volume caseload in thyroid surgery is associated with lower postoperative complication rates resulting to better outcomes. The aim of the present study was to investigate the ...correlation of the departments’ annual number of thyroid surgeries on the adherence to consensus guidelines and on the implementation of measures for quality assurance.
Methods
In 2016, we sent an anonymous electronic survey with questions related to the perioperative management in thyroid surgery to all directors of departments in operative medicine in Switzerland and Austria. We compared the pre- and postoperative management with the summarized recommendations of the four most frequently used consensus guidelines. Analogously, we analyzed the implementation of six measures for quality assurance related to thyroid surgery for each participating department. Using logistic regression analysis, we evaluated the correlation of number of guidelines respected and number of measures for quality assurance with the departments’ annual number of surgeries performed. Furthermore, we evaluated the number of departments providing thyroid cancer surgery and their experience in neck dissection.
Results
The management corresponded in 64.0% to the summarized recommendations. Adherence to the summarized recommendations and implementation of measures for quality assurance were significantly more likely with increasing numbers of surgeries performed (
p
= 0.049 and
p
< 0.001). Ninety-two departments provided thyroid cancer surgery, whereas 12/92 (13.0%) were not able to perform central and/or lateral neck dissection.
Conclusion
Consensus guidelines are insufficiently implemented within thyroid surgery, and quality management is associated with surgical volume.
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