Low-power photodynamic therapy induces survival signaling in perihilar cholangiocarcinoma cells.

BACKGROUND: Photodynamic therapy (PDT) of solid cancers comprises the administration of a photosensitizer followed by illumination of the photosensitizer-replete tumor with laser light. This induces a state of local oxidative stress, culminating in the destruction of tumor tissue and microvasculature and induction of an anti-tumor immune response. However, some tumor types, including perihilar cholangiocarcinoma, are relatively refractory to PDT, which may be attributable to the activation of survival pathways in tumor cells following PDT (i.e., activator protein 1 (AP-1)-, nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB)-, hypoxia-inducible factor 1-alpha (HIF-1α)-, nuclear factor (erythroid-derived 2)-like 2 (NFE2L2)-, and unfolded protein response-mediated pathways). METHODS: To assess the activation of survival pathways after PDT, human perihilar cholangiocarcinoma (SK-ChA-1) cells were subjected to PDT with zinc phthalocyanine (ZnPC)-encapsulating liposomes. Following 30-minute incubation with liposomes, the cells were either left untreated or treated at low (50 mW) or high (500 mW) laser power (cumulative light dose of 15 J/cm(2)). Cells were harvested 90 min post-PDT and whole genome expression analysis was performed using Illumina HumanHT-12 v4 expression beadchips. The data were interpreted in the context of the survival pathways. In addition, the safety of ZnPC-encapsulating liposomes was tested both in vitro and in vivo. RESULTS: PDT-treated SK-ChA-1 cells exhibited activation of the hypoxia-induced stress response via HIF-1α and initiation of the pro-inflammatory response via NF-кB. PDT at low laser power in particular caused extensive survival signaling, as evidenced by the significant upregulation of HIF-1- (P < 0.001) and NF-кB-related (P < 0.001) genes. Low-power PDT was less lethal to SK-ChA-1 cells 90 min post-PDT, confirmed by annexin V/propidium iodide staining. In vitro toxicogenomics and toxicological testing in chicken embryos and mice revealed that the ZnPC-encapsulating liposomes are non-toxic. CONCLUSIONS: PDT-treated perihilar cholangiocarcinoma cells exhibit extensive survival signaling that may translate to a suboptimal therapeutic response and possibly tumor recurrence. These findings encourage the development of photosensitizer delivery systems with co-encapsulated inhibitors of survival pathways.

The value of 99mTc-labeled galactosyl human serum albumin single-photon emission computerized tomography/computed tomography on regional liver function assessment and posthepatectomy failure prediction in patients with hilar cholangiocarcinoma.

BACKGROUND: The aim was to evaluate the value of Tc-labeled galactosyl human serum albumin (Tc-GSA) with single-photon emission computerized tomography (SPECT) in the preoperative assessment of regional liver function and prediction of posthepatectomy liver failure (PHLF) in patients with hilar cholangiocarcinoma (hCCA). METHODS: Patients with hCCA who underwent Tc-GSA SPECT/computed tomography (CT) before hepatectomy were included. The liver functional parameters of functional liver density (FLD) and predictive residual index (PRI) were calculated based on Tc-GSA SPECT/CT. PHLF was defined according to the International Study Group of Liver Surgery criteria. Univariate and multivariate analyses were used to analyze the risk factors for PHLF. The prediction of PHLF was calculated using receiver operating characteristic curve. RESULTS: A total of 34 patients were included, 23 of whom underwent preoperative biliary drainage. FLD was significantly higher in patients with drained lobes than that in patients with undrained lobes (0.615 ± 0.190 versus 0.500 ± 0.211, P < 0.05). Sixteen patients suffered PHLF. The ratio of future remnant to total morphological liver volume, future remnant FLD, and PRI differed significantly in patients with and without PHLF according to univariate analysis. PRI was identified as the only independent factor for prediction of PHLF according to multivariate analysis. With a PRI of 0.78, it was possible to predict PHLF with a sensitivity of 83% and a specificity of 93%. CONCLUSIONS: Tc-GSA SPECT/CT can accurately assess regional liver function and is better able to predict PHLF than conventional methods in patients with hCCA.

Hepatic tuberculosis mimicking Klatskin tumor: a diagnostic dilemma.

Tubercular involvement of liver is rare and usually occurs in association with pulmonary or miliary tuberculosis, as diffuse involvement without recognizable pulmonary tuberculosis or rarely in a localized form, which presents as a tuberculoma or tubercular abscess. We report the case of a 22-year-old boy presenting with features of obstructive jaundice and a clinico-radiological picture highly suggestive of a perihilar cholangiocarcinoma (Klatskin tumor), but found to have tubercular involvement of porta hepatis. We review the literature on this unusual presentation, highlight the considerable diagnostic challenge such cases can pose, and also emphasize the need to consider tuberculosis in differential diagnosis of lesions involving the porta hepatis, particularly in areas endemic for the disease.

Resected biliary tract cancers: a novel clinical-pathological score correlates with global outcome.

BACKGROUND: Biliary tract cancer presents a poor prognosis. AIMS: The objective of this study is to find clinical-laboratory parameters like prognostic factors to select patients who can benefit from surgery and post-operative treatments. METHODS: Between 2005 and 2010, 41 patients underwent radical surgery at our Institution. A novel score was retrospectively calculated assigning a grade to the clinical-laboratory findings at diagnosis. 0 and 1 point were respectively assigned to the normal or abnormal parameter. Two groups were identified: SCORE 0 and SCORE 1. RESULTS: Patients with cholangiocarcinoma or Klatskin tumours or asymptomatic at diagnosis presented a significantly better overall survival (OS) than patients with different primary sites or who presented pain, jaundice or cholangitis. At univariate analysis, high levels of aspartate aminotransferase, alanine aminotransferase and CA19-9 before surgery, hyperbilirubinemia before and after surgery had a negative correlation with OS. A worse OS was observed in patients with a higher score (median OS in the "score 0" group=30.79 months vs. median OS in the "score 1"=17.98 months). CONCLUSION: Our results suggest that pre and post-surgery clinical-laboratory parameters and the novel score, could be useful, especially for intrahepatic tumours, in predicting the outcome in patients undergoing surgery and in selecting patients to receive adjuvant therapy.