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Introduction Drug treatment for cancer has changed dramatically over the past decade with many new drugs often with multiple applications. More recently, the detailed pathway for approval from the National Institute for Health and Care Excellence (NICE) in the UK has been simplified. To explore how these changes have impacted on systemic anti-cancer therapy tumour site-specific prescribing and workload activities, we have reviewed the prescribing records for 2014–2018 in a UK cancer network. Methods Information about the numbers of new systemic anti-cancer therapy drugs and NICE approvals were obtained from print editions of the British National Formulary (BNF) and the NICE website. Data on the numbers of new chemotherapy courses and individual treatment-related attendances were obtained from the cancer network Chemocare electronic prescribing system. Results During the five-year study period, there were 49 new systemic anti-cancer therapy drugs for all tumour types, and a total of 65 NICE technology approvals for solid tumour indications. Overall numbers of treatment courses increased by 40.7% and total treatment-related visits by 80.6%. There was a wide variation across tumour types with the highest number of increased visits seen for melanoma (349.3%) and prostate cancer (242.3%), but in contrast, no appreciable increases were seen for lower gastrointestinal cancers or small cell lung cancer. Conclusion The study confirms the major impact of the arrival of new drug technology and positive NICE appraisals on increasing systemic anti-cancer therapy prescribing and chemotherapy unit activity. The data in this study may be of help in planning for future service delivery planning and workforce configurations.

Summary Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5′ UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor’s most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention., Graphical Abstract, Highlights • Novel hotspot of driver mutations in 5′-UTR repressor of TERT, expanding telomeres • Most common cause of 3p loss is a chromothripsis event, generating concurrent 5q gain • t(3;5) event occurs in childhood or adolescence, decades before tumor diagnosed • Initial clonal expansion after 3p loss starts from only a few hundred cells, Combination of whole-genome sequencing analysis and a multi-region sampling approach provides insights into the nature and timing of key oncogenic events in clear cell renal cell carcinoma, depicts the evolutionary trajectories of tumors in patients and highlights the opportunity for early intervention.

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with > 10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance. We thank Aida Murra, Naheed Shaikh, Justine Korteweg, Jeremy Tai, Eleanor Carlyle, Leonora Conneely, KimEdmonds, Karla Lingard, Karen O'Meara, Helen Breeze, Sarah Sarker, Lesley Cooper, Linda Shephard, Susie Slater, and Catherine Rogers for study support. We thank the patients and their families. S.T. and H.X. are funded by Cancer Research UK (CRUK) (C50947/A18176). S.T., T.C., J.L., and M.G. are funded by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at the Royal Marsden Hospital and Institute of Cancer Research (A109). J.I.L. is funded by the Ministerio de Economia y Competitividad (MINECO, SAF2016-79847-R). M.S., A.S., J. Lynch, R.F., L.A., and L.S. are funded by the Royal Marsden Cancer Charity. K.L. is funded by UK Medical Research Council (MR/P014712/1). T.B.K.W. is funded by the European Union Seventh Framework Programme (FP7-People-2013-ITN). M.J.-H. is funded by the NIHR. N.M.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation's support towards the establishment of The Francis Crick Institute. N.M.L. is additionally funded by a Wellcome Trust Joint Investigator Award (103760/Z/14/Z) and the MRC eMedLab Medical Bioinformatics Infrastructure Award (MR/L016311/1). M.K. is funded by the Danish Cancer Society grant (R90-A6213). P.C. is funded by the Wellcome Trust (WT088340MA). N.M. receives funding from CRUK, Rosetrees, and the NIHR BRC at University College London Hospitals. C.S. is a Royal Society Napier Research Professor. C.S. is funded by Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees and Stoneygate Trusts, NovoNordisk Foundation (THESEUS), Marie Curie Network PloidyNet, the NIHR BRC at University College London Hospitals, and the CRUK University College London Experimental Cancer Medicine Centre. C.S., O.P., D.R., I.C., and Z.S. are funded by NovoNordisk Foundation (16584). O.P., D.R., and I.C. are funded by the National Research, Development and Innovation Office of Hungary (NVKP_16-1-20160004). This work was supported by CRUK (Clinical Scientist Fellowship to S.T., C50947/A18176), The Francis Crick Institute, which receives its core funding from Cancer Reseach UK (FC010110), the UK Medical Research Council (FC010110), the Wellcome Trust (FC010110), and NIHR BRC at the Royal Marsden Hospital and Institute of Cancer Research (A109). High-performance computing was supported by eMedLab. The results published here are in whole or part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/.

PURPOSE OF REVIEW: Despite the availability of multiple targeted therapies, the 5-year survival rate of patients with metastatic clear cell renal cell carcinoma (ccRCC) rarely exceeds 10%. Recent insights into the mutational landscape and evolutionary dynamics of ccRCC have offered up a plausible explanation for these outcomes. The purpose of this review is to link the research findings to potential changes in clinical practice. RECENT FINDINGS: Intratumour heterogeneity (ITH) dominates the evolutionary landscape in ccRCC at the genetic, transcriptomic and proteomic level. Spatial and temporal separation of tumour subclones within the primary tumour as well as between primary and metastatic sites has been demonstrated at single nucleotide resolution. In the cases analysed to date, approximately two-thirds of somatic mutations are not shared between multiple biopsies from the same primary tumour. Very few of the key disease-driving events are shared across all primary tumour regions (with the exception of VHL and loss of chromosome 3p), whereas the majority are restricted to one or more tumour regions (TP53, SETD2, BAP1, PTEN, mTOR, PIK3CA and KDM5C). SUMMARY: ITH must be considered in the management of ccRCC with respect to diagnostic procedures, prognostic and predictive biomarkers and drug development.

Background and Aim The presence of spur-cell anemia (SCA) is due to lipid disturbances of the erythrocyte membrane and may develop in patients with advanced liver cirrhosis. The accurate predicting value of SC for survival has not been clarified. The aim of this study was to evaluate SCA as a prognostic indicator in patients with cirrhosis. Methods We prospectively evaluated clinical, laboratory parameters, and survival in patients with cirrhosis, with or without SCA, during the period 2008–2011. Patients who had at admission renal failure, other causes of hemolytic anemia, hepatocellular carcinoma, sepsis, and/or active bleeding, were excluded. One hundred sixteen patients with cirrhosis were included. The presence of SCA (SC rate higher or equal to 5% [≥ 5%]) was diagnosed in 36 (31%) patients. Results Patients with SCA compared to those without had more advanced liver disease (higher Model for End-Stage Liver Disease [MELD], P

Background Testicular cancer is a rare tumor type accounting for 1% of malignancies in men. It is, however, the most common cancer in young men in Western populations. The incidence of testicular cancer is increasing globally, although a decline in mortality rates has been reported in Western countries. It is important to identify whether the variations in trends observed between populations are linked to genetic or environmental factors. Methods Age-standardized incidence rates and age-standardized mortality rates for testicular cancer were obtained for men of all ages in ten countries from the Americas, Asia, Europe, and Oceania using the Cancer Incidence in Five Continents (CI5plus) and World Health Organization (WHO) mortality databases. The annual percent change was calculated using Joinpoint regression to assess temporal changes between geographical regions. Results Testicular cancer age-standardized incidence rates are highest in New Zealand (7.8), UK (6.3), Australia (6.1), Sweden (5.6), USA (5.2), Poland (4.9), and Spain (3.8) per 100,000 men. India, China, and Colombia had the lowest incidence (0.5, 1.3, and 2.2, respectively) per 100,000 men. The annual percent changes for overall testicular cancer incidence significantly increased in the European countries Sweden 2.4%, (2.2; 2.6); UK 2.9%, (2.2; 3.6); and Spain 5.0%, (1.7; 8.4), Australia 3.0%, (2.2; 3.7), and China 3.5%, (1.9; 5.1). India had the lowest overall testicular cancer incidence −1.7%, (−2.5; −0.8). Annual percent changes for overall testicular cancer mortality rates were decreasing in all study populations, with the greatest decline observed in Sweden −4.2%, (−4.8; −3.6) and China −4.9%, (−6.5; −3.3). Conclusion Testicular cancer is increasing in incidence in many countries; however, mortality rates remain low and most men are cured. An understanding of the risks and long-term side effects of treatment are important in managing men with this disease.

Goals: Comparison of nitric oxide (NO) levels in cirrhotic patients with and without hepatic encephalopathy (HE), evaluation of possible correlation between HE and other clinical or laboratory characteristics, and estimation of utilization of NO levels in clinical practice. Background: HE is a neuropsychiatric complication of cirrhosis. The exact pathogenetic mechanisms underlying the presence of HE are not known. However, dysfunction of the NO pathway and ammonia detoxification are thought to play a major role. Study: Sixty-seven cirrhotic patients, 36 (53.7%) without HE, and 31 (46.3%) with HE were included in the study. Eighteen healthy individuals were used as control group. Clinical and laboratory data, including ammonia and stable end products of NO using Griess reaction, were collected. Results: NOx levels were statistically significantly higher in cirrhotic patients (225.5 μmol/L) than in control group [(67.94 μmol/L) (P = 0.000)]. NOx levels were, also, statistically significantly higher in patients with HE compared with patients without HE (324.67 μmol/L vs. 141.96 μmol/L, P = 0.000). Significant correlation between the presence of HE and NOx, ammonia, C-reactive protein, albumin, Model for End-Stage Liver Disease score, and Child-Pugh classification revealed. NOx levels also correlated with severity of HE. NOx and ammonia are independent factors predicting HE according to regression analysis. Diagnostic accuracy for the diagnosis of HE using a combination of NOx and ammonia was superior compared with standalone NOx or ammonia utilization. Conclusions: NOx levels are correlated with the presence and severity of HE. NOx levels determination, in addition to ammonia levels, could contribute in diagnosis of HE.

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases. S.T. and H.X. are funded by Cancer Research UK (CRUK) (C50947/A18176). S.T., T.C., J.L., and M.G. are funded by the NIH Research (NIHR) Biomedical Research Centre (BRC) at the Royal Marsden Hospital and Institute of Cancer Research (A109). J.I.L. is funded by the Ministerio de Economia y Competitividad (MINECO, SAF2016-79847-R). M.S., A.S., J.L., R.F., L.A., and L.S. are funded by the Royal Marsden Cancer Charity. K.L. is funded by UK Medical Research Council (MR/P014712/1). N.M. receives funding from CRUK, Rosetrees, and the NIHR BRC at University College London Hospitals. C.S is Royal Society Napier Research Professor. C.S. is funded by Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees and Stoneygate Trusts, NovoNordisk Foundation (ID 16584), the Breast Cancer Research Foundation (BCRF), the European Research Council (THESEUS), Marie Curie Network PloidyNet, the NIHR BRC at University College London Hospitals, and the CRUK University College London Experimental Cancer Medicine Centre. The work presented in this manuscript was funded by Cancer Research UK (grant reference number C50947/A18176), Ventana Medical Systems (grant reference numbers 10467 and 10530), the Kidney Cancer Fund of The Royal Marsden Cancer Charity, NIHR BRC at the Royal Marsden Hospital and Institute of Cancer Research (grant reference number A109), and the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202), and the Wellcome Trust (FC001202). In particular, we acknowledge the support of the Advanced Sequencing Facility and the High-Performance Computing at the Francis Crick Institute. This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (grant number MR/L016311/1).

To evaluate the prevalence and clinical burden of serendipitously discovered abnormalities in hospitalized patients, unrelated to their presenting symptoms and physical signs.A total of 478 patients consecutively admitted in the Department of Medicine were enrolled in the study. In the end of first diagnostic work-up, the previously undetected imaging or endoscopic asymptomatic abnormalities termed as incidental findings (IFs) were recorded and some of them were further investigated.One hundred thirty eight (28.8%) patients had IFs. The most common IFs were located in the kidney and genitourinary system followed by liver and gallbladder. The most common method of detection of IFs was ultrasonography (US) of the abdomen. The patients with IFs compared with those without, were older (P=0.007), had no previous hospitalizations (P0.001) and stayed longer in the hospital (P0.001). The 25 (18.1%) patients with IFs were not evaluated further. One hundred seventy seven IFs discovered in 113 patients were further evaluated by medical specialists and additional tests were performed if warranted. In the end of the diagnostic work-up, in a total of 113 patients with IFs, 78.7% had insignificant and 21.2% potentially significant IFs. The latter group had higher rate of IFs compared with the former group, usually more than 3 (P=0.017).IFs were prevalent in a hospital population. Hospitalized patients with IFs were more than 60 years old and had no previous hospitalization. A large number of IFs were potentially significant deserving further clinical management.

Autoimmune thyroid diseases have been correlated with a variety of autoimmune diseases also affecting the skin. A 56-year-old patient with a history of vitiligo is presented who was admitted for hyperthyroidism (Graves disease) and a blistering eruption. Clinical and histological appearance of the skin disorder, rapid response to corticosteroids, recurrence and remission of the lesions with discontinuation and reintroduction of corticosteroids, respectively, were all suggestive of an autoimmune blistering disease accompanying autoimmune hyperthyroidism and vitiligo.

TO THE EDITOR: A randomized phase II trial suggests improved outcome with the addition of onartuzumab to erlotinib in patients with advanced non–small-cell lung cancer (NSCLC) expressing MET. Overall survival (OS) is improved disproportionately in the combination arm compared with progression-free survival (PFS). Median OS improvement of 8.8 months compares with a 1.4-month improvement for median PFS, and response rates in both groups were low and not significantly different. In considering the current understanding of MET biology, the authors suggest that the therapeutic benefit of onartuzumab may arise from inhibition of migration and invasion rather than direct inhibition of tumor growth. Upregulation of oncogenic MET signaling results in features of epithelial to mesenchymal transition, including increased protease production, cell dissociation, and increased motility. This can contribute to cellular invasion through extracellular matrix, enabling tumor invasion and metastasis. In mouse models, silencing of endogenous overexpressed MET gene in tumor cells suppresses tumor growth and metastasis. Onartuzumab may have had a similar effect in the patients on this trial. We suggest that clinical support for this mechanism of action may be available in the data collected by Spigel et al. Review of computed tomography scans documenting progression could categorize patients according to increase in size of target lesions identified at baseline, or detection of new metastatic sites. If, compared with erlotinib controls, MET-positive patients who experience disease progression in the combination arm are less likely to have new distant metastases, indirect clinical support for their hypothesis would be provided. In addition, if confirmed, this finding would provide a possible explanation for the observed impressive survival benefit with the addition of onartuzumab to erlotinib, despite a low response rate and the absence of significant PFS difference seen with the combination. In an era of individualized treatment with expensive targeted therapies, early prediction of clinical benefit is of great value. However, current radiological tools, including response, may not be sufficient to evaluate the complex biology that underlies the mode of action of these drugs. The results presented by Spigel et al offer an exciting new perspective for patients with MET-positive NSCLC, but further exploration of the mode of disease progression, as suggested above, is warranted.

Although autopsy series report liver granulomas in up to 70% of patients, computed tomography detection of hepatic and splenic lesions is described in 5% and 15% of sarcoidosis cases, respectively. A rather rare case of liver sarcoidosis mimicking macronodular cirrhosis is presented by this current article. Imaging findings in our patient were in compliance with the diagnosis of liver cirrhosis, although liver biopsy findings eventually revealed sarcoid granulomas located in the portal and lobular areas without fibrotic lesions. Histological and imaging modalities in liver sarcoidosis are discussed.

The presence of spur-cell anemia (SCA) is due to lipid disturbances of the erythrocyte membrane and may develop in patients with advanced liver cirrhosis. The accurate predicting value of SC for survival has not been clarified. The aim of this study was to evaluate SCA as a prognostic indicator in patients with cirrhosis.We prospectively evaluated clinical, laboratory parameters, and survival in patients with cirrhosis, with or without SCA, during the period 2008-2011. Patients who had at admission renal failure, other causes of hemolytic anemia, hepatocellular carcinoma, sepsis, and/or active bleeding, were excluded. One hundred sixteen patients with cirrhosis were included. The presence of SCA (SC rate higher or equal to 5% [≥ 5%]) was diagnosed in 36 (31%) patients.Patients with SCA compared to those without had more advanced liver disease (higher Model for End-Stage Liver Disease [MELD], P0.001), higher total bilirubin (P0.001), and International Normalized Ratio (P0.001). Patients with SCA had worse survival (log rank P0.001). Survival of patients with SCA at the first, second, and third month of follow-up was 77%, 45%, and 33%, respectively. In multivariate Cox's regression analysis, the presence of SCA was an independent predictor of mortality (hazard ratio = 3.17 [95% CI 1.55-6.48]).The presence of spur-cell anemia is not uncommon in cirrhosis and seems to be strongly associated with mortality. SCA can be used in combination with MELD as an additional predictor of early mortality.

Despite the available prevention and early detection strategies, squamous-cell carcinoma of the uterine cervix is still diagnosed as locally advanced disease in a considerable proportion of patients. As a potent sensitizer of cancer cells, cisplatin has been the “traditional partner” of external beam irradiation in this setting for more than two decades. Induction chemotherapy strategies followed by concurrent chemoradiation or surgery and preoperative concurrent chemoradiation have been recently implemented in clinical trials in an effort to optimize local control and to minimize the risk of distant metastases. In this context, cisplatin has been combined with a number of other potential radiosensitizers, including 5-fluorouracil, capecitabine, and gemcitabine. In patients resistant or intolerant to platinum compounds, numerous non-platinum-containing regimens have been developed, implementing various antimetabolites, taxanes, antineoplastic antibiotics, and topoisomerase II inhibitors. More recently, molecular agents targeting critical pathways in cervical malignant transformation are being assessed in early clinical trials in combination with external-beam irradiation. In the current work, we review the evolving role of cisplatin and other platinum compounds, either alone or in combination regimens, in the context of other potent radiosensitizers. The emerging role of molecular targeted agents, as candidate partners of external beam irradiation, is also discussed.

Patients with brain metastases from malignant melanoma historically have a very poor outcome. Surgery and radiotherapy can be used, but for the majority of patients the disease will progress quickly. In the recent past, patients with brain metastases derived only minimal benefit from cytotoxic chemotherapy. Novel therapies that have been shown to be superior to chemotherapy in metastatic melanoma have made their way in clinic and data regarding their use in patients with treated or untreated brain metastases are encouraging. In this paper we describe the use of vemurafenib, dabrafenib, and ipilimumab in patients with melanoma disseminated to the brain in addition to other treatments currently in development.

TPS4583Background: Cytoreductive nephrectomy may be beneficial in patients with metastatic clear cell renal cell carcinoma (mccRCC). However, there are currently no standard pre-operative systemic ...

In cancer biology angiogenesis plays a vital role in tumour growth and its subsequent metastatic potential. By targeting the angiogenic process, a new treatment strategy was added in the clinician's therapeutic armamentarium. On the other hand, numerous classic cytotoxic agents are currently considered as potential angiogenesis inhibitors, although they were not originally developed as such, representing the so-called "accidental" anti-angiogenic drugs. The discovery of these new properties of classic cytotoxic agents led to the re-evaluation of their effect on vascular cells, rendering thus the endothelium an appealing target for therapeutic intervention, either with chemotherapy alone or with combination of cytotoxics with molecular angiogenesis inhibitors. Moreover, current evidence supports that chemotherapy-induced endothelial dysfunction constitutes an integrating predictive marker of future cardiovascular events and correlates well with traditional cardiovascular risk factors. It has therefore been suggested that evaluation of endothelial function may be useful in identifying asymptomatic subjects at high risk for cardiovascular events as well as for risk stratification of patients with established cardiovascular disease. Integration of the assessment of endothelial function in the clinical setting will thus enable effective intervention strategies to prevent or minimize the impact of these late adverse effects and design accurate follow-up protocols focused on cardiovascular complications. In the current review we provide a comprehensive overview of the effects of cytotoxic chemotherapeutic agents on endothelial function and the clinical implications of chemotherapy-associated endothelial toxicity in patients with cancer.

The currently available genetic tests for identification of the RET proto-oncogene mutation offer the possibility of prospective successful therapy before the hyperplasia of C-cells evolve to Medullary Thyroid Carcinoma. We present our experience regarding the preventive thyroidectomy of family members with history of Medullary Thyroid Carcinoma, who were found to be heterozygote for mutant RET proto-oncogene. We have retrospectively reviewed 19 members of 6 families with history of Medullary Thyroid Carcinoma, who were heterozygote for mutant RET protooncogene and underwent prophylactic thyroidectomy. All patients included in this series were below twenty years of age. The Medullary Thyroid Carcinoma was asymptomatic and the mutation of RET protooncogene has been also documented pre-operatively in all of them. All patients had undergone total thyroidectomy, while 1 with pheochromocytoma had undergone also left epinephridectomy. Fourteen patients (73.68%) had undergone lymph-nodes resection (in 10 of them the resection was central, in 3 unilateral and in 1 bilateral). Although none of our patients suffered from hyperparathyroidism, 7 parathyroid glands have been also resected from 3 patients, while auto-transfusion has been performed in one. In all patients, preoperative measurement of the calcitonin blood levels before and after stimulation with pentagastrin has been performed.

Perioperative use of a cell saver device can serve as a cost-beneficial alternative to the transfusion method, especially in countries where the cost of a single unit of blood is high. The purpose of this study, conducted in a Greek hospital, was to calculate the cost benefit of using a cell saver device to salvage intraoperative blood during open surgical abdominal aortic aneurysm repair or open aortofemoral bypass for occlusive disease. This retrospective study measured the amounts of salvaged blood and reinfused blood encountered during the procedure and then calculated the cost benefit of cell saver use. With the cost of a unit of blood purchased in Greece about €450 ($585), the blood units salvaged and reinfused were calculated at a mean cost benefit of €754 ($980) per case.

AIM: To evaluate survival rate and clinical outcome of cholangiocarcinoma. METHODS: The medical records of 34 patients with cholangiocarcinoma, seen at a single hospital between the years 1999-2006, were retrospectively reviewed. RESULTS: Thirty-four patients with a median age of 75 years were included. Seventeen (50%) had painless jaundice at presentation. Sixteen (47.1%) were perihilar, 15 (44.1%) extrahepatic and three (8.8%) intrahepatic. Endoscopic retrograde cholangiography (ERCP) and/or magnetic resonance cholangiography (MRCP) were used for the diagnosis. Pathologic confirmation was obtained in seven and positive cytological examination in three. Thirteen patients had co-morbidities (38.2%). Four cases were managed with complete surgical resection. All the rest of the cases (30) were characterized as non-resectable due to advanced stage of the disease. Palliative biliary drainage was performed in 26/30 (86.6%). The mean follow-up was 32 mo (95% CI, 20-43 mo). Overall median survival was 8.7 mo (95% CI, 2-16 mo). The probability of 1-year, 2-year and 3-year survival was 46%, 20% and 7%, respectively. The survival was slightly longer in patients who underwent resection compared to those who did not, but this difference failed to reach statistical significance. Patients who underwent biliary drainage had an advantage in survival compared to those who did not (probability of survival 53% vs 0% at 1 year, respectively, P = 0.038). CONCLUSION: Patients with cholangiocarcinoma were usually elderly with co-morbidities and/or advanced disease at presentation. Even though a slight amelioration in survival with palliative biliary drainage was observed, patients had dismal outcome without resection of the tumor.

Although Epidermal Growth Factor Receptor (EGFR) overexpression is observed frequently in hepatocellular carcinomas (HCC), specific gene deregulation mechanisms remain unknown. Our aim was to investigate the prognostic significance of the combined protein and gene/chromosome 7 numerical alterations. Using tissue microarray technology, thirty-five (n = 35) paraffin embedded histologically confirmed HCCs were cored and re-embedded in a paraffin block. Immunohistochemistry was performed for the determination of EGFR protein levels and evaluated by the performance of digital image analysis. Chromogenic in situ hybridization was also performed based on the use of EGFR gene and chromosome 7 centromeric probes, respectively. EGFR overexpression was observed in 26/35 (74.2%) cases and was correlated to the grade of the tumors and also to the history of the patients (p = 0.013, p = 0.036, respectively). Numerical alterations regarding gene and chromosome 7 were identified in 4/35 (11.4%) and 12/35 (43.2%) cases associated to the grade of the tumors (p = 0.019, p = 0.001, respectively) and to the survival rate of the patients (p = 0.037, p = 0.001, respectively). EGFR overall expression was also correlated to the gene copies (p = 0.020). EGFR gene numerical alterations -although rare- and also chromosome 7 aneuploidy maybe affect prognosis in HCC patients. To our knowledge this is the first chromogenic in situ hybridization analysis based on tissue microarrays in hepatocellular carcinoma.

Classical interferon-alpha has been shown to be correlated with the development of a variety of autoimmune disorders. A 38 year-old female patient developed simultaneously diabetic ketoacidosis and hyperthyroidism 5 mo following initiation of treatment with pegylated interferon-alpha and ribavirin for chronic hepatitis C. High titers of glutamic acid decarboxylase, antinuclear and thyroid (thyroid peroxidase and thyroglobulin) antibodies were detected. Antiviral treatment was withdrawn and the patient was treated with insulin for insulin-dependent diabetes mellitus and propranolol for hyperthyroidism. Twelve months after cessation of pegylated interferon-alpha therapy the patient was euthyroid without any medication but remained insulin-dependent.

HCC infrequently metastasize to the right atrium via the IVC. A 75-year-old patient is presented who was admitted with dyspnea, edema of the lower extremities, weakness and osteodynia. Magnetic resonance imaging revealed a large mass in the right lobe of the liver infiltrating the intrahepatic part of the inferior vena cava (IVC) and expanding into the right atrium of the heart. A liver biopsy was conducted establishing the diagnosis of hepatocellular carcinoma (HCC) invading the IVC and expanding to the right atrium. Magnetic resonance images are presented and a brief review of diagnostic modalities available in such cases is attempted.

Cyproterone acetate (CPA) is a steroidal synthetic progestagen and anti-androgenic compound widely administered in prostate cancer which has been evidentially correlated with a severe hepatotoxic potency. Three male patients aged 78-83 years are presented, in whom severe hepatotoxic reactions emerged after CPA administration. Patients were treated with CPA at the doses of 200-300 mg/d for malignant prostate disease for 3-12 mo prior to the acute manifestation of the hepatic disease. Clinical features compatible with mixed hepatocellular and cholestatic liver disease including jaundice, white stools and dark urine, manifested in all three cases whereas encephalopathy and ascites were present in two of the patients. Other primary causes of hepatotoxicity (alcohol consumption and viral hepatitis) were also verified in two cases, and in those patients biopsy findings revealed the presence of cirrhotic lesions in liver parenchyma. Discontinuation of the therapeutic agent led to the amelioration of the clinical profile in all the patients whereas a patient died 40 d after hospital admission due to sepsis, despite acute liver disease improvement. The current article highlights the hepatotoxic potency of a widely administered therapeutic agent and illustrates the importance of clinical surveillance especially in patients with previous hepatic diseases. Three relevant cases are reported and a review of the published literature is made.