Diffuse Neuromatosis of Intrahepatic and Extrahepatic Bile Ducts as a Rare Cause of Jaundice.

BACKGROUND: Neuroma of the biliary tree is extremely rare with no more than 100 cases reported so far. They mostly present with obstructive jaundice and have been commonly described after surgery or abdominal trauma. Although involvement of the extrahepatic bile duct is far more common, occurrence in the intrahepatic ducts has not so far been reported. CASE REPORT: We describe 3 cases of diffuse biliary tree neuroma affecting 3 females aged 53-68 years. None had a history of neurofibromatosis type1. All presented with progressive obstructive jaundice with no evidence of gallstones. A history of previous surgery was noted in 2 patients. Initial impression on clinical and imaging examination was highly suspicious for bile duct carcinoma in 2 patients. Histology showed diffuse neuromatous proliferation replacing and thickening the bile duct walls. The third patient had concurrent neuroma and recurrent cholangiocarcinoma causing great clinical confusion as initial biopsy showed only benign neuroma, but CA 19-9 was steadily increasing, necessitating a second biopsy which then confirmed recurrent carcinoma. CONCLUSION: This uncommon cause of long-distance bile duct stenosis and progressive jaundice should be included in the differential diagnosis of bile duct neoplasms, in particular when there is a previous surgical history in this abdominal region.

Results of isolated limb perfusion for metastasized malignant melanoma.

BACKGROUND AND OBJECTIVES: Locoregional metastases are typical biological manifestations of advanced malignant melanomas. Treatment with hyperthermic isolated limb perfusion (HILP) should be considered in affected patients. In the present study, we have analyzed the results of HILPs performed in our department. PATIENTS AND METHODS: Eighty patients with locoregional metastases of the extremities received HILP at the Department of Surgery between January 2007 and December 2016. The mean follow-up was 38 months. RESULTS: The study included 50 men and 30 women (mean age: 63 years). The median time between melanoma diagnosis and HILP was 25 months (range: 1-219 months). HILP was performed in curative (n = 45) and palliative (n = 35) intention. Seventy-five patients received a drug combination of melphalan/dactinomycin and five patients received a drug combination of melphalan/tumor necrosis factor-alpha. Remission rates were determined in 72 of 80 patients (90%) as follows: partial response n = 28, complete response n = 25, no response n = 19. Of the 25 patients with complete response, 13 patients developed a new tumor manifestation during follow-up (locoregional recurrences n = 4; distant metastases n = 3; both n = 6). The median overall survival rate was 33 months. Tumor stage influenced the survival rate significantly (p = 0.001). Patients with complete response showed a significantly better overall survival than patients with partial or no response (p = 0.016). CONCLUSION: HILP is an effective therapeutic option in patients with locoregional metastases. This procedure carries a certain risk of side effects and adverse events but overall results in good response rates. Therefore, HILP should be offered to selected patients based on an individual discussion, considering their health status and oncological prognosis.

Cytosolic 5'-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolites.

BACKGROUND: Cytosolic 5'-nucleotidase 1A (NT5C1A) dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. Here, we investigate NT5C1A expression in pancreatic ductal adenocarcinoma (PDAC) and its impact on gemcitabine metabolism and therapeutic efficacy. METHODS: NT5C1A expression was determined by semiquantitative immunohistochemistry using tissue microarrays. Gemcitabine metabolites and response were assessed in several human and murine PDAC cell lines using crystal violet assays, Western blot, viability assays, and liquid chromatography tandem mass-spectrometry (LC-MS/MS). FINDINGS: NT5C1A was strongly expressed in tumor cells of a large subgroup of resected PDAC patients in two independent patient cohorts (44-56% score 2 and 8-26% score 3, n = 414). In contrast, NT5C1A was expressed at very low levels in the tumor stroma, and neither stromal nor tumoral expression was a prognostic marker for postoperative survival. In vitro, NT5C1A overexpression increased gemcitabine resistance by reducing apoptosis levels and significantly decreased intracellular amounts of cytotoxic dFdCTP in +NT5C1A tumor cells. Co-culture experiments with conditioned media from +NT5C1A PSCs improved gemcitabine efficacy in tumor cells. In vivo, therapeutic efficacy of gemcitabine was significantly decreased and serum levels of the inactive gemcitabine metabolite dFdU significantly increased in mice bearing NT5C1A overexpressing tumors. INTERPRETATION: NT5C1A is robustly expressed in tumor cells of resected PDAC patients. Moreover, NT5C1A mediates gemcitabine resistance by decreasing the amount of intracellular dFdCTP, leading to reduced tumor cell apoptosis and larger pancreatic tumors in mice. Further studies should clarify the role of NT5C1A as novel predictor for gemcitabine treatment response in patients with PDAC.

The importance of pancreatic inflammation in endosonographic diagnostics of solid pancreatic masses.

AIMS: Endosonography (EUS) is one of the main diagnostic tools for the differential diagnosis of pancreatic masses. The aim of our study was to describe the value of this technique in the work-up of solid pancreatic lesions, considering the influence of the morphological evidence of pancreatic inflammation in the diagnostic process. MATERIAL AND METHODS: Retrospective analysis of prospectively collected data in our tertiary University center. From March 2007 to October 2015, 218 patients underwent EUS for a suspected solid pancreatic neoplasm (based on previous cross-sectional imaging results, idiopatic acute pancreatitis, weight loss, pancreatic hyperenzymemia, painless jaundice or elevated Ca 19-9 values). RESULTS: Malignant lesions were diagnosed in 98 (45%) patients. Sensitivity of EUS for malignancy was 91% and specificity 89.2%. Signs of pancreatic inflammation in the surrounding pancreatic parenchyma around the focal lesion were present in 97 patients (44.4%)(more often in men, smokers and drinkers, and the most common etiology was focal chronic pancreatitis) and in these patients the sensitivity and sensibility dropped to 44% and 87.1%, respectively. In patients without signs of pancreatic inflammation, the pancreatic focal lesions were adenocarcinoma, neuroendocrine tumor, ventral/dorsal split, non-pancreatic pathology, pancreatic lipomatosis and autoimmune pancreatitis. CONCLUSION: Pancreatic inflammation (either focal or involving the whole gland) lowers the diagnostic sensibility of EUS in the work- up of pancreatic masses suspected for cancer, requiring further invasive diagnostic methods. Focal autoimmune pancreatitis and paraduodenal pancreatitis are still confused with pancreatic cancer, even in the absence of pancreatic inflammation.

Successful Multidisciplinary Treatment with Secondary Metastatic Liver Resection after Downsizing by Palliative Second-Line Treatment of Colorectal Cancer: A Curative Option.

INTRODUCTION: The prognostic outcome following progression after palliative first-line treatment for patients suffering from metastatic colorectal adenocarcinoma is generally poor. Long-term relapse-free survival with palliative second-line treatment may be achieved in only a limited number of individual cases. CASE REPORT: A 37-year-old patient presented with bilobar liver metastases of colon cancer confirmed by histology with wild-type K-RAS (exon 2). Due to progressive disease after eight cycles of first-line therapy with FOLFIRI plus cetuximab, second-line chemotherapy with modified FOLFOX4 (mFOLFOX4) plus bevacizumab was initiated. During four cycles of mFOLFOX4 plus bevacizumab (2 months), no higher-grade toxicity occurred. Liver MRI with contrast medium revealed downsizing of the segment II/III metastases, as well as regressive, small, faint, hardly definable lesions in segments VI and IVb. The interdisciplinary tumor board of the University of Erlangen thus decided to perform resection of the liver metastases. Segments II and III were resected, and the liver metastases in segments IVa and VI were excised (R0). Histopathology confirmed three of the R0-resected metastases to be completely necrotic, with residual scarring. As perioperative therapy, four additional cycles of mFOLFOX4 plus bevacizumab were administered postoperatively. No higher-grade toxicity was observed. Three years after the initial diagnosis, the patient is relapse free, professionally fully reintegrated, and has an excellent performance status. CONCLUSION: Patients suffering from metastatic colorectal cancer may benefit from multidisciplinary treatment with secondary metastatic liver resection after downsizing by palliative second-line treatment. In individual cases, patients may even have a curative treatment option, provided that close interdisciplinary collaboration exists.

Laminin, gamma 2 (LAMC2): a promising new putative pancreatic cancer biomarker identified by proteomic analysis of pancreatic adenocarcinoma tissues.

In pancreatic cancer, the incidence and mortality curves coincide. One major reason for this high mortality rate in pancreatic ductal adenocarcinoma (PDAC) patients is the dearth of effective diagnostic, prognostic, and disease-monitoring biomarkers. Unfortunately, existing tumor markers, as well as current imaging modalities, are not sufficiently sensitive and/or specific for early-stage diagnosis. There is, therefore, an urgent need for improved serum markers of the disease. Herein, we performed Orbitrap® mass spectrometry proteomic analysis of four PDAC tissues and their adjacent benign tissues and identified a total of 2190 nonredundant proteins. Sixteen promising candidates were selected for further scrutiny using a systematic scoring algorithm. Our preliminary serum verification of the top four candidates (DSP, LAMC2, GP73, and DSG2) in 20 patients diagnosed with pancreatic cancer and 20 with benign pancreatic cysts, showed a significant (p < 0.05) elevation of LAMC2 in pancreatic cancer serum. Extensive validation of LAMC2 in healthy, benign, and PDAC sera from geographically diverse cohorts (n = 425) (Japan, Europe, and USA) demonstrated a significant increase in levels in early-stage PDAC compared with benign diseases. The sensitivity of LAMC2 was comparable to CA19.9 in all data sets, with an AUC value greater than 0.85 in discriminating healthy patients from early-stage PDAC patients. LAMC2 exhibited diagnostic complementarity with CA19.9 by showing significant (p < 0.001 in two out of three cohorts) elevation in PDAC patients with clinically low CA19.9 levels.

Identification and validation of colorectal neoplasia-specific methylation markers for accurate classification of disease.

Aberrant DNA methylation occurs early in oncogenesis, is stable, and can be assayed in tissues and body fluids. Therefore, genes with aberrant methylation can provide clues for understanding tumor pathways and are attractive candidates for detection of early neoplastic events. Identification of sequences that optimally discriminate cancer from other diseased and healthy tissues is needed to advance both approaches. Using well-characterized specimens, genome-wide methylation techniques were used to identify candidate markers specific for colorectal neoplasia. To further validate 30 of these candidates from genome-wide analysis and 13 literature-derived genes, including genes involved in cancer and others with unknown functions, a high-throughput methylation-specific oligonucleotide microarray was used. The arrays were probed with bisulfite-converted DNA from 89 colorectal adenocarcinomas, 55 colorectal polyps, 31 inflammatory bowel disease, 115 extracolonic cancers, and 67 healthy tissues. The 20 most discriminating markers were highly methylated in colorectal neoplasia (area under the receiver operating characteristic curve > 0.8; P < 0.0001). Normal epithelium and extracolonic cancers revealed significantly lower methylation. Real-time PCR assays developed for 11 markers were tested on an independent set of 149 samples from colorectal adenocarcinomas, other diseases, and healthy tissues. Microarray results could be reproduced for 10 of 11 marker assays, including eight of the most discriminating markers (area under the receiver operating characteristic curve > 0.72; P < 0.009). The markers with high specificity for colorectal cancer have potential as blood-based screening markers whereas markers that are specific for multiple cancers could potentially be used as prognostic indicators, as biomarkers for therapeutic response monitoring or other diagnostic applications, compelling further investigation into their use in clinical testing and overall roles in tumorigenesis.