Photodynamic therapy using porfimer (P‐PDT) improves palliation and survival in nonresectable hilar bile duct cancer. Tumoricidal penetration depth of temoporfin‐PDT (T‐PDT) is twice that of P‐PDT. ...In a single‐arm phase II study we investigated the safety, efficacy, survival time, and adverse events of T‐PDT compared with previous data on P‐PDT. Twenty‐nine patients (median 71 range 47‐88 years) with nonresectable hilar bile duct cancer were treated with T‐PDT (median 1 range 1‐4 sessions) plus stenting and followed up every 3 months. The PDT was well tolerated. In patients with occluded segments at baseline (n = 28) a reopening of a median of 3 (range 1‐7) segments could be achieved: n = 16 local response and n = 11 stable local disease, one progressive disease. Cholestasis and performance significantly improved when impaired at baseline. Time to local tumor progression was a median of 6.5 (2.7‐41.0) months. Overall survival time was a median of 15.4 (range 4.4‐62.4) months. Patients died from tumor progression (55%), cholangitis (18%), pneumonia (7%), hemobilia (7%), esophagus variceal hemorrhage (3%), and vascular diseases (10%). Adverse events were cholangitis (n = 4), liver abscess (n = 2), cholecystitis (n = 2), phototoxic skin (n = 5), and injection site reactions (n = 7). Compared to previous P‐PDT, T‐PDT shows prolonged time to local tumor progression (median 6.5 versus 4.3 months, P < 0.01), fewer PDT treatments needed (median 1 versus 3, P < 0.01), a higher 6‐month survival rate (83% versus 70%, P < 0.01), and a trend for longer overall median survival (15.4 versus 9.3 months, P = 0.72) yet not significantly different. The risk of adverse events is not increased except for (avoidable) subcutaneous phototoxicity at the injection site. Conclusion: Temoporfin‐PDT can safely be delivered to hilar bile duct cancer patients and results in prolonged patency of hilar bile ducts, a trend for longer survival time, and similar palliation as with P‐PDT. (Hepatology 2015;62:1456–1465)
Hilar cholangiocarcinoma (CC) is non-resectable in the majority of patients often due to intrahepatic extension along bile duct branches/segments, and even after complete resection (R0) recurrence ...can be as high as 70%. Photodynamic therapy (PDT) is an established palliative local tumor ablative treatment for non-resectable hilar CC. We report the long-term outcome of curative resection (R0) performed after neoadjuvant PDT for downsizing of tumor margins in seven patients (median age 59 years) with initially non-resectable hilar CC. Photofrin(®) was injected intravenously 24-48 h before laser light irradiation of the tumor stenoses and the adjacent bile duct segments. Major resective surgery was done with curative intention six weeks after PDT. All seven patients had been curatively (R0) resected and there were no undue early or late complications for the neoadjuvant PDT and surgery. Six of seven patients died from tumor recurrence at a median of 3.2 years after resection, the five-year survival rate was 43%. These results are comparable with published data for patients resected R0 without pre-treatment, indicating that neoadjuvant PDT is feasible and could improve overall survival of patients considered non-curatively resectable because of initial tumor extension in bile duct branches/segments--however, this concept needs to be validated in a larger trial.
Background and Aim
Colorectal endoscopic submucosal dissection (ESD) shows higher R0 resection and lower local recurrence rates than endoscopic mucosal resection (EMR) in Japan. In Europe, ...independent learning of ESD in the colorectum is feasible, but yet to be analyzed for curative resection and recurrence rates.
Methods
After experimental training under supervision by Japanese experts (T.O., N.Y.), three endoscopists independently carried out 83 ESD procedures intention‐to‐treat for lesions in the entire colorectum of 67 patients in a prospective registry (November 2009 to June 2016).
Results
ESD was feasible in 80 (96%) colorectal neoplasias (mean diameter 33.6 ± 1.8 mm), and three more required conversion to piecemeal EMR. The lesions were adenomas in 66% with low‐grade intraepithelial neoplasia (LGIN), 29% with high‐grade intraepithelial neoplasia, and 5% with carcinomas (G2, pT1). ESD had to be facilitated by the final use of snaring (hybrid‐ESD, n = 45), especially in the initial learning period. En‐bloc resection rate was 85%. Complications were microperforations (7%, conducive to one hemicolectomy), and delayed bleeding (1%) without mortality or long‐term morbidity. Residual adenomas with LGIN (5%) after hybrid‐ESD did not recur after endoscopic ablation. All malignant neoplasias (34%) were curatively resected without recurrence after a mean follow up of 19.5 (± 3.2) months.
Conclusions
During independent ESD learning in the colorectum, ESD intention‐to‐treat showed a low recurrence rate after appropriate training, and hybrid‐ESD showed acceptable complication and recurrence rates, justifying hybrid‐ESD as a strategy for self‐completion and rescue.
Photodynamic therapy (PDT) has been established for palliation of non-resectable hilar bile duct cancer (hBDC). Ablation of hBDC using porfimer (P-PDT) improves cholestasis and survival. However, the ...tumoricidal effect is confined to the inner 4 mm of the tumor wall. Here, we have studied whether temoporfin PDT (T-PDT) shows an efficient local response and an increased tumoricidal penetration depth. In the first stage of a phase-II trial (NCT01016002), eleven patients with hBDC (Bismuth III-IV) were treated with T-PDT plus stenting and 10 could be analyzed for local tumor response. T-PDT resulted in complete local response in n = 1 of 10 patients, partial response in n = 8 and no response in one patient (occluded right hepatic duct re-opened but positive for residual tumor cells) - indicating a tumoricidal efficacy of 90%. Four patients showed a tumoricidal depth of ≥7.5 mm. Cholestasis and palliation improved in 8 patients with an overall median survival of 18 (4.4-32.0) months after the first T-PDT. Adverse events were phototoxic skin reaction (n = 4), cholangitis (n = 3), and liver abscess (n = 3). T-PDT doubles the depth of the local tumor-ablative effect of P-PDT, is highly tumoricidal and is associated with similar rates of infectious complications and grade I and II skin phototoxicity.
The aim of this study was to investigate the molecular and protein expression pattern of markers of stemness phenotype and its clinicopathological significance in human biliary tract cancer (BTC). ...Human BTC cell lines (CCLP-1, Egi-1, MzChA-1, MzChA-2, SkChA-1, TFK-1 and GBC) were analyzed in vitro and in xenotransplanted animals for expression of markers of stemness and compared to tissue microarrays (TMA) of 34 cases of human BTC with complete pathomorphological and clinical data (survival). Molecular analyses on the mRNA and protein level included makers of stemness and progenitor (Bmi-1, Sox-2, Nestin, CD133, CD44 and Nanog), proliferation and differentiation (cell cycle proteins, intermediate filaments). The investigated BTC samples showed a low to moderate and partially significantly different expression pattern of the stem cell markers in vitro, in vivo and in TMA. Hierarchical cluster analysis identified subgroups with homogenous expression of stem cell markers significantly differing with respect to cytokeratin expression in xenografts and Ki67 proliferation marker in human TMA, respectively - thus indicating possible heterogeneous carcinogenesis pathways in BTC. Additionally, these stem cell markers could be linked to morphology and molecular markers of proliferation and differentiation on the mRNA and protein level. Finally, survival analysis identified the combination of CD133 and CD44 as an independent prognostic factor yet their value as prognostic factors need testing in prospective study design.
The underlying etiological cause of non-hereditary colorectal cancer has yet to be determined. The adenoma-carcinoma sequence is widely accepted, however, a sole trigger has not been specified. ...Therefore, we sought to further define genotypic and phenotypic parameters that could be involved in promoting a possible infection, inflammation and hyper-proliferation, followed by the adenoma-carcinoma sequence. Expression of phenotype-related parameters for MHC class I (HLA-A N-20 and β2 microglobulin) and class II (HLA-DRα and HLA-DR) as well as CD45 and carcinoembryonic antigen (CEA) were investigated immunohistochemically in a series of 93 colorectal cancers. Additionally, in 49 of the tumours the MHC class II genotype was analysed. MHC class II genotype analyses revealed a tendency towards DRB1*08 and DQB1*04. A significant association among the MHC class I markers or the MHC class II markers was found. No difference in marker expression could be detected between tumour and stromal tissue, however a significant inverse expression existed for markers of the functionally different class I or II systems. With the exception of CEA, there was no correlation between expression of any marker and tumour grade. Only 2% of tumours expressed no markers for MHC class I and II. Further studies on MHC class I and II genotype and phenotype relation in colorectal cancer may help to identify trigger mechanisms for tumourigenesis, involved markers and possible mechanisms of subsequent immune escape.
Background: Infection by Helicobacter pylori has been linked to monoclonal gammopathy of undetermined significance (MGUS). MGUS is thought to develop due to chronic antigenic stimulation in people ...with a specific genetic predisposition.
Methods and Results: We describe a patient presenting with dyspepsia associated with H. pylori‐related erosive gastritis. Histopathologic findings revealed infiltration with plasma cells containing accumulated condensed intercisternal immunoglobulins, the so‐called ‘Russell bodies’. In addition, MGUS was present with total immunoglobulins within the normal range but a significantly decreased serum concentration of IgG subtype 3. Molecular analyses demonstrated IgH formation, T‐cell receptor γ rearrangement, and alterations within the IgHG3 gene sequence. Following H. pylori eradication, gastritis and dyspepsia gradually resolved but MGUS persisted for at least 22 months.
Conclusions: This is the first report to demonstrate that upon infection with H. pylori, an impaired secretory capacity of plasma cells due to specific molecular changes can present as Russell body gastritis. The molecular findings question a pathogenetic link between Russell bodies and H. pylori, but suggest genetic alterations in the immunoglobulin locus as the possible cause for both MGUS and Russell body gastritis.
Activation of developmental pathways has been recognized as a key mechanism for tumourigenesis and, hence, might be a valuable target for otherwise difficult to treat tumour entities such as biliary ...tract cancer (BTC). Therefore, we performed a comprehensive analysis of the Wnt signalling pathway in 9 BTC cell lines on cell blocks, xenograft tumours and on human tissue microarrays by real-time reverse transcription PCR and by immunochemistry. Furthermore, the effects of pharmacological pathway inhibition were investigated. As a result we found a significant positive correlation of Wnt pathway activation with cyclin D1 expression and the proliferation parameters Ki67, cell cycle distribution, and growth kinetics as well as the mesenchymal marker vimentin and an inverse correlation with E-cadherin in BTC cell lines in vitro and in vivo. In human BTC samples loss of membranous beta-catenin, an indicator of active Wnt signalling, correlated with vimentin expression and advanced tumour stage or metastasis, whereas membranous localisation of beta-catenin was associated with the differentiation marker cytokeratin-8/18 and differentiated tumour morphology (ductal or mixed type BTC). In addition, Wnt pathway inhibition by DMAT effectively reduced viability in all cancer cell lines, most effectively in those showing cytoplasmatic beta-catenin localisation, i.e. active Wnt signalling. In summary, activation of the Wnt pathway is associated with high proliferation, dedifferentiation and a solid morphology in human biliary tract cancer cell lines both in vitro and in vivo, and in human BTC tissues. Further investigation of the mechanism(s) of Wnt pathway activation and its inhibition may provide new molecular treatment strategies for biliary tract cancer.
The prognosis of patients with nonresectable hilar biliary tract cancer (hBTC) is poor. Responsiveness to chemotherapy or radiochemotherapy is moderate at best, and patients are at a high risk of ...dying early from complications of local tumor infiltration (e.g., cholestasis, septic cholangitis, empyema or liver failure) rather than systemic disease. Therefore, palliative local therapy for the prevention of tumor complications plays a central role and still yields the longest survival times. Photodynamic therapy (PDT) is a local-ablative, tumor tissue-specific treatment currently representing the standard of care for nonresectable hBTC. Throughout the literature, PDT plus biliary drainage achieves median survival times in the range of 9-21 months (average 14-16 months), compared with approximately 6 months for drainage only. This article summarizes the recent advances in preclinical and clinical experience of PDT for hBTC, including experimental in vitro and in vivo studies, clinical studies and an overview of the ongoing clinical trials.
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