Background
Neuronal signaling has been implicated in the pathophysiology of multiple malignancies. In biliary tract cancers (BTCs), tumor cell expression of nerve growth factor (NGF) and its receptor ...neurotrophic tropomyosin receptor kinase (NTRK) has been reported in Asian patients and linked to inferior clinical outcome. Furthermore, NTRK fusions have emerged as a promising target in various cancers. Expression patterns of these markers in Caucasian patients remain unknown.
Methods
In this study, 106 patients with BTCs were included. Immunohistochemistry for pan-NTRK and NGF-beta was performed on > 90 samples of this cohort. Additionally, samples from two independent cohorts, incorporating 254 cases, were used to confirm the findings of the original cohort.
Results
While expression of pan-NTRK and NGF-beta was readily detectable in peri-tumoral nerves, these markers were not detectable in malignant epithelial cells in our cohort.
Conclusions
In a large cohort of Caucasian patients with BTC, NTRK and NGF-beta were not detectable, underscoring potential differences between Caucasian and Asian patient populations.
Background and study aims
Radiofrequency ablation (RFA) is a new endoscopic palliation therapy for malignant biliary obstruction. The aim of this study was to compare the short-term effects of ...biliary drainage and adverse events of this technique with the standard of endoscopical treatment of hilar cholangiocarcinoma, photodynamic therapy (PDT).
Patients and methods
We retrospectively and since December 2012 prospectively investigated the efficacy and adverse events of RFA in patients with hilar cholangiocarcinoma in two tertiary referral centers between November 2011 and January 2013. The approach of the study was prospective, but because of the large amount of retrospectively included patients, the design of the study is overall retrospective. A group of 20 patients treated with PDT between April 2005 and May 2011 served as a historical control.
Results
Fourteen patients received 31 biliary RFAs and 20 patients received 36 PDTs. Within the RFA group, a significant decrease (p = 0.046) of the bilirubin level was seen 14 days after the first RFA (3.3 ± 3.9 (mg/dl) versus 2.3 ± 2.6 (mg/dl)). In the PDT group no significant decrease (p = 0.67) of the bilirubin level was obtained (4.1 ± 6.9 (mg/dl) versus 3.5 ± 5.3 (mg/dl)). In the PDT group (13/20, 65%) a significantly higher number of premature stent replacements (<3 months) after the first intervention was noticed in comparison with the RFA group (four of 14, 29%) (p < 0.01). Between the first and fifth procedure, post-interventional adverse events tend to occur more frequently in patients with PDT (eight of 20, 40%) than with RFA (three of 14, 21%) (p = 0.277).
Conclusions
Looking at the short-term effects, we conclude that RFA may present a therapeutic alternative to PDT for palliative treatment of malignant biliary obstruction because of its simple feasibility and moderate adverse event rate. To provide a definitive evaluation of the long-term effects and of overall median survival, a controlled trial with PDT must follow.
Background: Prominent fibroinflammatory response and reduced perfusion are hallmarks of pancreatic ductal adenocarcinoma (PDAC). Ineffective delivery of therapy agents to the tumor side is one of the ...reasons for therapeutic resistance of PDAC. Here we investigate vascular function in PDAC with different cellularity and stroma content developed in genetically engineered mouse models (GEM). In addition, we use GEM to assess perfusion changes under the standard palliative treatment with gemcitabine. Material and Methods: A cohort of mice (N = 48) with genotypes Ptf1awt/cre(C)Kraswt/G12D(K)Ela-Tgfa(T), CK;p53(P)wt/fl, CKPfl/fl, CKTPwt/R172H and CKTPwt/flwas subjected to final Dynamic Contrast Enhanced (DCE)-MRI employing a 1.5T Achieva, Philips with a 47-mm microscopy surface coil. Tumor perfusion was measured by single-shot Look-Locker based radial T1 mapping technique using the golden cut principle with a bolus of 0.04mmol/kg of Gd-DTPA (Magnevist®). In a subset of CKPfl/fl mice therapy response to gemcitabine (Gem, twice per week, 120mg/kg by intraperitoneal injection, NNaCl = 10, Ngem = 12) was monitored pre and 2 weeks post treatment. Imaging data were validated by histopathology using H&E, Movat and CD31 staining. Results: Relative area under the curve of the first 60s (AUC60. tumor/muscle ratio) derived from measured Gadolinium concentration curves correlated positively with open vascular spaces (r = 0.68, CI: 0.28,0.88) and stroma content (r = 0.46, CI: 0.2,0.66) and negatively with the amount of tumor cell (r = -0.42, CI: -0.63.-0.17) in murine PDAC. Significant differences were noted in AUC60 between stroma rich, low cellular (PDAClow, 2.06±0.1, n = 27) and stroma poor, moderately cellular lesions (PDACmed, 1.21 ±0.1. n = 25) albeit an overlap in individual tumors. PDACmed tumors reveal significantly reduced perfusion after 14 days independent of the treatment and analysis method. PDAClow tumors showed impaired perfusion under gemcitabine treatment (AUC60pre = 2.7±0.6, AUC60post = 2.0±0.2, P = 0.012), whereas no significant changes were noted in the vehicle group. Conclusions: Murine PDAC lesions with low amount of tumor cells reveal higher perfusion compared to tumors with intermediate cellularity and reduce their vascular function under gemcitabine treatment.
Pancreatic cancer is characterized by a microenvironment suppressing immune responses. RIG-I-like helicases (RLH) are immunoreceptors for viral RNA that induce an antiviral response program via the ...production of type I interferons (IFN) and apoptosis in susceptible cells. We recently identified RLH as therapeutic targets of pancreatic cancer for counteracting immunosuppressive mechanisms and apoptosis induction. Here, we investigated immunogenic consequences of RLH-induced tumor cell death. Treatment of murine pancreatic cancer cell lines with RLH ligands induced production of type I IFN and proinflammatory cytokines. In addition, tumor cells died via intrinsic apoptosis and displayed features of immunogenic cell death, such as release of HMGB1 and translocation of calreticulin to the outer cell membrane. RLH-activated tumor cells led to activation of dendritic cells (DCs), which was mediated by tumor-derived type I IFN, whereas TLR, RAGE or inflammasome signaling was dispensable. Importantly, CD8α(+) DCs effectively engulfed apoptotic tumor material and cross-presented tumor-associated antigen to naive CD8(+) T cells. In comparison, tumor cell death mediated by oxaliplatin, staurosporine or mechanical disruption failed to induce DC activation and antigen presentation. Tumor cells treated with sublethal doses of RLH ligands upregulated Fas and MHC-I expression and were effectively sensitized towards Fas-mediated apoptosis and cytotoxic T lymphocyte (CTL)-mediated lysis. Vaccination of mice with RLH-activated tumor cells induced protective antitumor immunity in vivo. In addition, MDA5-based immunotherapy led to effective tumor control of established pancreatic tumors. In summary, RLH ligands induce a highly immunogenic form of tumor cell death linking innate and adaptive immunity.
A 69-year-old man presented for endoscopic examination of the upper gastrointestinal tract because of dysphagia for solid food and unintended weight loss. Several months before, he had noticed ...brownish-gray skin lesions in the neck, in the thorax and in both axillae. A dermatological consultant expressed the suspicion of a paraneoplastic disease. Endoscopic examination revealed an adenocarcinoma of the esophagogastric junction as well as multiple small polyps in the middle and the lower thirds of the esophagus. Histological examination showed papilloma-like proliferations without atypia, which were diagnosed as acanthosis nigricans of the esophagus. After completion of the staging investigation regarding the cardiac carcinoma, combination chemotherapy was started because of the presence of liver metastases. Subsequently, partial regression of the carcinoma as well as of the dermal and esophageal lesions was noted. Acanthosis nigricans is a rare paraneoplastic disease of the esophagus. As an indicator lesion, its detection should prompt a search for a malignant tumor in the gastrointestinal tract.
VEGF inhibition in gastric cancer has a proven benefit in the second line setting. Pazopanib, an oral tyrosine kinase inhibitor, selectively inhibits VEGFR‐1, ‐2 and ‐3, c‐kit and PDGF‐R resulting in ...inhibition of angiogenesis. This open‐label randomized phase II trial (2:1) investigated the efficacy of combining pazopanib with FLO (5‐fluorouracil, oxaliplatin) vs FLO alone (internal control arm) as first‐line treatment in patients with advanced adenocarcinoma of the stomach and gastroesophageal junction (GEJ). Eighty‐seven patients were randomized and 78 patients were eligible and evaluable (PaFLO arm 51 patients, FLO arm 27 patients). The PFS rate at 6 months (primary endpoint) was 34% in the PaFLO arm vs 30% in the FLO arm. Comparing PaFLO with FLO median PFS was 4.66 months (95% confidence interval CI 2.87‐6.46) vs 4.47 months (95% CI 1.79‐7.14) (95% CI, hazard ratio HR 0.96 (0.60‐1.55), P = .882 exploratory); median OS was 10.19 months (95% CI 5.46‐14.92) vs 7.33 months (95% CI 4.93‐9.73), (95% CI HR 1.01 0.62‐1.65, P = .953, exploratory), disease control rate was 72% vs 59%. PaFLO was well tolerable, toxicities were slightly higher in the PaFLO arm. Major adverse events were loss of appetite, nausea, fatigue, diarrhea, neutropenia and thrombocytopenia. Adding pazopanib to chemotherapy shows signs of efficacy but no major improvement in this randomized phase 2 trial. The PFS at 6 months in both arms was lower than expected from the literature. Biomarkers identifying subgroups who benefit and novel combinations are needed. ClinicalTrials.gov: NCT01503372.
What's new?
Pazopanib is an oral angiogenesis inhibitor. In this randomized, phase II clinical trial, the authors added pazopanib to standard chemotherapy as a first‐line treatment in patients with advanced gastro‐esophageal cancer. This combination was compared to chemotherapy alone. The results indicated that the addition of pazopanib to 5‐FU/oxaliplatin was well tolerated and showed some efficacy, but didn't yield a major benefit over standard therapy. Further research into other novel treatment combinations, as well as into biomarkers to identify subgroups who might benefit, are urgently needed.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide with a median 5-year survival of about 10%. Although specic therapies for distinct subtypes of NSCLC have ...been developed, treatment options for the majority of patients are unsatisfactory. In order to identify new therapeutic options and targets, a better understanding of the pathogenesis of NSCLC is necessary. Notch receptors belong to a family of evolutionary conserved transmembrane proteins that are critical for cell fate decisions, tissue homeostasis and tumorigenesis. In mammals, there are four known Notch receptors (Notch14). Upon binding to its ligands Notch receptors are proteolytically processed by metalloproteases and the g-secretase complex. This process releases the intracellular domain of Notch (NIC), which then translocates into the nucleus to modulate expression of its target genes including the basic helix-loop-helix transcriptional repressors of the HES and HEY families. Notch1 was rst identied as an oncogene in T-cell acute lymphoblastic leukemia. Although chromosomal rearrangement of Notch receptors seems to be rare in solid tumors, aberrant expression of Notch receptors and Notch ligands have been linked to a variety of tumors such as carcinomas of the lung, skin, pancreas, breast and cervix.
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