Multidisciplinary consensus statement on the clinical management of patients with pancreatic cancer.

Pancreatic cancer (PC) remains one of the most aggressive tumors with an increasing incidence rate and reduced survival. Although surgical resection is the only potentially curative treatment for PC, only 15-20% of patients are resectable at diagnosis. To select the most appropriate treatment and thus improve outcomes, the diagnostic and therapeutic strategy for each patient with PC should be discussed within a multidisciplinary expert team. Clinical decision-making should be evidence-based, considering the staging of the tumor, the performance status and preferences of the patient. The aim of this guideline is to provide practical and evidence-based recommendations for the management of PC.

Differences on metabolic behavior between intra and extrahepatic cholangiocarcinomas at 18F-FDG-PET/CT: prognostic implication of metabolic parameters and tumor markers.

BACKGROUND AND PURPOSE: Cholangiocarcinoma is an infrequent neoplasm barely studied with 18F-FDG-PET/CT. We evaluated the metabolic behavior of cholangiocarcinoma in PET/CT according to its location (intra or extrahepatic) and analyzed the relationship between metabolic parameters of the primary tumor and tumor markers (CA19-9 and CEA), determining their prognostic significance. METHODS: Retrospective study of PET/CT of 60 patients with untreated cholangiocarcinoma, divided into two groups according to tumor location. FDG uptake was evaluated visually and semiquantitatively [SUVmax and tumor-to-liver ratio (TLR)], and differences between intra and extrahepatic cholangiocarcinomas were tested, both for FDG uptake in the primary tumor and for the presence of regional or distant disease (per-patient), as well as regarding tumor marker levels. A correlation between metabolic parameters and tumor markers was performed, and prognostic value of these factors was determined (univariate and multivariate analyses). RESULTS: Intrahepatic cholangiocarcinomas were significantly more FDG-avid than extrahepatic ones (p = 0.006 for SUVmax; p = 0.002 for TLR). There were differences neither between both groups considering the capacity of PET/CT to detect regional (p = 0.261) and distant involvement (p = 0.876), nor regarding the levels of tumor markers (p = 0.160 for CA19-9; p = 0.708 for CEA). Metabolic parameters and tumor markers showed a weak positive correlation (R2 0.22-0.27). At the multivariate analysis, advanced stage (p = 0.024), increased CEA (p = 0.022), and higher TLR (p = 0.003) were significantly related with shorter overall survival. CONCLUSIONS: Intra and extrahepatic cholangiocarcinomas behave differently on PET/CT, though no differences between both groups exist in its capacity to detect regional or distant disease. Metabolic parameters and levels of tumor markers seem to relate with tumor burden, impacting in prognosis.

International geographic correlation study of the prevalence of disorders of male reproductive health.

STUDY QUESTION: Is there evidence at the population level of associations between different male genital disorders, outside Scandinavian countries? SUMMARY ANSWER: At an international scale, there is evidence for a number of correlations between rates of four male reproductive disorders (hypospadias, cryptorchidism, testicular cancer and low sperm concentration). WHAT IS KNOWN ALREADY: Some associations between these outcomes have been shown in studies focusing on individuals and mainly in Nordic European countries. These associations, together with histological evidence of a dysgenesis pattern in testicular tissue specimens, have generated the concept of the existence of a 'testicular dysgenesis syndrome' originating in utero. STUDY DESIGN, SIZE, DURATION: This is a geographical correlation study using cancer, malformations rates and sperm quality data collected between the years 1998 and 2005. PARTICIPANTS/MATERIALS, SETTING, METHODS: Incidence rates of testicular cancer were extracted from International Agency for Research on Cancer registries and Globocan, while cryptorchidism and hypospadias prevalence rates were obtained from EUROCAT and International Clearinghouse for Birth Defects Surveillance and Research registries. Sperm concentration data were extracted from recent studies using standardized methodology. A total of 39 registries and 9 sperm studies were selected. Non-parametric Spearman correlation tests were used to test the association between these four disorders. Correlations were computed for all registries together, for registries with high-quality matching coverage only and by continents. Sensitivity analyses were also conducted using data from prospective clinical studies to take into account potential bias related mainly to ascertainment of malformation rates. MAIN RESULTS AND THE ROLE OF CHANCE: We found positive correlations between testicular cancer and hypospadias (r = 0.32, P = 0.05) and between hypospadias and cryptorchidism (r = 0.70, P = 0.008). Stronger correlations were observed when using registries with high-quality matching coverage. Among these registries, differences between Europe and the rest of the world appeared (the positive correlation between testicular cancer and cryptorchidism was stronger outside Europe, r = 0.83, P = 0.01 compared with 0.40, P = 0.60 for European registries). A negative correlation between testicular cancer and sperm concentration was observed (r = -0.88, P = 0.002). These correlations support our initial hypothesis but remain only suggestive due to the intrinsic limitations in the study design (i.e. geographical correlation study) and do not allow causal inference. LIMITATIONS, REASONS FOR CAUTION: Differences in the ascertainment of malformations rates (definition, length of follow-up) make the international comparison difficult. The small number of registries for some conditions (cryptorchidism) or of studies (for sperm quality) and the absence of information about major risk factors such as ethnicity and socioeconomic status in the registries are also limitations. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are in agreement with results of studies focusing on individuals and suggest that shared risk factors are present in the populations studied.

Enlarged lymph nodes in the upper abdomen after liver transplantation: imaging features and clinical significance.

PURPOSE: Our aim was to review our single-centre experience regarding imaging features and pathological conditions arising from enlarged lymph nodes following orthotopic liver transplantation (OLD) and identify imaging features that may allow narrowing the differential diagnosis. MATERIALS AND METHODS: Between January 1997 and September 2008, 715 OLTs were performed at our Institution in 585 patients. In 19 patients (2.6 %) ultrasound (US) showed enlarged lymph nodes in the upper abdomen, and abdominal computed tomography (CT) was performed RESULTS: Histological results showed posttransplantation lymphoproliferative disorder (PTLD) in six patients (31.5 %), hepatic tumoral disease in six (31.5 %), disseminated systemic tuberculosis in one (5.2%) and sarcoidosis in one (5.2%). Histological results showed nonspecific reactive lymph node hyperplasia in five patients (26%). CONCLUSIONS: Detecting enlarged lymph nodes in the upper abdomen after liver transplantation is and infrequent occurrence; however, thorough imaging is required to detect and characterise a wide variety of disorders. Most of the time, enlarged lymph nodes will be related to posttransplantation lymphoproliferative disorder or tumoral recurrence.

Definitive diagnosis of neuroendocrine tumors using fine-needle aspiration-puncture guided by endoscopic ultrasonography.

BACKGROUND: The detection and diagnosis of neuroendocrine tumors (NETs) is challenging. Endoscopic ultrasonography (EUS) has a significant role in the detection of NETs suspected from clinical manifestations or imaging techniques, as well as in their precise localization and cytological confirmation using EUS-Fine-needle aspiration-puncture (FNA). OBJECTIVE: To assess the usefulness and precision of EUS-FNAP in the differential diagnosis and confirmation of NETs, in a retrospective review of our experience. PATIENTS AND METHODS: in a total of 55 patients with suspected NETs who underwent radial or sectorial EUS, 42 tumors were detected in 40 cases. EUS-FNA using a 22G needle was performed for 16 cases with suspected functional (hormonal disorders: 6 cases) and non-functional NETs (10 cases). Ki 67 or immunocytochemistry (ICC) testing was performed for all.There was confirmation in 9 cases (5 female and 4 male) with a mean age of 51 years (range: 41-81 years).All tumors were located in the pancreas except for one in the mediastinum and one in the rectum, with a mean size of 19 mm (range: 10-40 mm). RESULTS: There were no complications attributable to FNA. Sensitivity was 100% and both precision and PPV were 89%, as a false positive result suggested a diagnosis with NET during cytology that surgery finally revealed to be a pancreatic pseudopapillary solid tumor. CONCLUSIONS: EUS-FNA with a 22G needle for NETs has high sensitivity and PPV at cytological confirmation with few complications.

Antral mass due to cytomegalovirus infection requiring gastrectomy in a liver transplant recipient.

The incidence of cytomegalovirus (CMV) infection after liver transplantation (LT) has decreased in recent years. Advances in immunosuppression and CMV prophylaxis have improved the management of CMV disease. Organ involvement is infrequent and gastrointestinal CMV disease is quite rare. Few cases of an antral mass due to CMV infection have been described; those reported to date have mostly been in patients with acquired immunodeficiency syndrome. We describe a case of a CMV-seronegative liver transplant patient who received a seropositive liver graft. Owing to gastrointestinal complaints, CMV prophylaxis was stopped one month after LT. The patient developed an antral mass due to CMV infection and an anastomotic biliary stricture. Antigenemia became negative with ganciclovir, but this treatment did not eliminate the mass. Ganciclovir resistance was ruled out as well as other causes of antral mass, especially malignancy. The patient finally required gastrectomy and hepaticojejunostomy. We conclude that CMV disease is less common today but should be included in the diagnosis of gastrointestinal mass after transplantation.

Preliminary results of treatment with pegylated interferon alpha 2A for chronic hepatitis C virus in kidney transplant candidates on hemodialysis.

INTRODUCTION: At present, there is little published information on the outcome of treatment with pegylated interferon (Peg-IF alpha 2a) in hepatitis C virus (HCV)-infected hemodialysis patients awaiting renal transplantation. The objective of this study was to assess the efficacy and tolerance of Peg-IF alpha 2a in this population. PATIENTS AND METHODS: Twelve noncirrhotic HCV-infected patients (10 men, 50 +/- 8 years of age, genotype 1b 84%), were prescribed Peg-IF alpha 2a, at 135 microg/wk for 48 weeks. Liver biopsy was performed in 11 of 12 cases. RESULTS: Six patients completed 48 weeks of treatment, with one end of treatment response (ETR), two sustained viral responses (SVRs), and three HCV relapses. Treatment was shorter in the six remaining patients: two cases 24 weeks (one due to medical reasons with relapse, one due to nonresponse), one patient chose to discontinue at 14 weeks (with relapse), one patient died of stroke at 10 weeks, and in two additional patients interferon was withdrawn at 18 weeks because of severe anemia (SVR) and at 26 weeks due to prolonged fever (relapse). Other secondary treatment-related events included anemia (requiring transfusion in two patients and major erythropoietin administration in six), and fever in four patients. CONCLUSIONS: Peg-IF had limited efficacy in this group, with ETR in 83%, SVR in only 25%, and recurrence in 50%. Tolerance was moderate, with 4/12 (33%) discontinuing treatment due to adverse events, personal decision, or death. Large randomized controlled studies are needed to determine the role of Peg-IF treatment in this population.

[Changes in nerve growth factor levels related to age and neurotrophic treatment in non-human primate]. / Cambios en los niveles de factor de crecimiento nervioso con el envejecimiento y el tratamiento neurotrófico en primates no humanos.

INTRODUCTION: To examine the amounts and role of growth factors in different tissues and corporal fluid, new sensitive techniques have to be developed. A major problem is that the normal concentration of trophic substances, such as nerve growth factor (NGF), in central and peripheral nervous system and in fluids is very low (ng pg/ml). A valuable method of research is the sensitive two site enzyme immunoassay using the monoclonal antibody 27/21 to mouse NGF. Materials and methods. The present work applied this enzyme immunoassay to examine the NGF levels in normal non human primate sera (n= 94) and applied this assay to study of NGF levels in two non human primate receiving NGF infusion: one young and one aged. Two groups of non human primate sera were studied one young adult (n= 69) and one aged (n= 25). The serum samples NGF treated non human primate were taken before the infusion and at the 1st week and 1st, 3rd, 6th and 12th month after infusion. RESULTS: To further test the specificity of conjugate binding, dilutions of the non human primate sera were preincubated with an excess of monoclonal NGF antibody 27/21 in solution. With this strategy it was possible to completely block the signal obtained using the enzyme immunoassay. We found very low levels of NGF in aged monkeys (0.054 ng/ml) when compared with young adult group (0.152 ng/ml) (p> 0.01). The NGF levels in aged non human primate treatment with NGF was very low before (0.50 ng/ml) and during NGF treatment evolution time, whereas at the the 12th month showed an increase in NGF levels (0.180 ng/ml). We found normal values of NGF in the young monkey before and during the first year after NGF infusion. CONCLUSIONS: Using the enzyme immunoassay described it is possible to know the serum concentration of NGF immunoreactive in non human primate and this assay is able to detect peripheral changes in NGF levels after intracerebral infusion of NGF.

Risk factors for development of de novo neoplasia after liver transplantation.

Liver transplant recipients are at greater risk for de novo neoplasia, especially lymphoma and nonmelanoma skin cancer; however, risk factors for this complication have not been well studied. Clinical and pathological records of 137 consecutive liver transplant recipients who had survived for at least 1 year were reviewed to register de novo neoplasia. Ten variables were analyzed for their association with the development of de novo malignancies by means of a log-rank test and stepwise selection in a multivariate analysis using the Cox proportional hazard model. Thirty de novo neoplasias appeared in 22 of 137 transplant recipients between 12 and 104 months after orthotopic liver transplantation (OLT; median follow-up, 69 months): 14 patients had 21 skin cancers, 6 patients had solid-organ cancer, and 3 patients developed a lymphoproliferative disease. Probabilities of de novo neoplasia were 13% at 5 years post-OLT and 26% at 8 years post-OLT. The only associated risk factor for any neoplasia was age. Age and hepatocarcinoma were independent risk factors associated with skin cancer. That hepatocarcinoma in the explanted liver is an independent risk factor for skin cancer suggests there is individual susceptibility to both neoplasias.

Influence of donor post-reperfusion changes on graft evolution after liver transplant.

INTRODUCTION: The increase in indications for liver transplantation has meant that waiting lists are growing ever longer. For this reason, broadening the donor pool is a priority for most groups. OBJECTIVE: The objective of this study was to analyze the predictive value of post-reperfusion biopsy in the evolution of graft function after liver transplantation. PATIENTS: One hundred and forty-eight liver biopsies, obtained after graft reperfusion, were analyzed. Eight pathological variables and thirty-seven clinical variables of the donors were recorded. Risk factors for presenting primary graft non-function or dysfunction were studied with logistic regression models. Factors associated to the long-term graft failure were studied using Cox analysis and actuarial survival curves. RESULTS: Microvesicular steatosis greater than 50% was the only risk factor associated to graft dysfunction in the multivariate logistic regression model. Microvesicular steatosis greater than 30%, severe hepatocyte necrosis and presence of abundant neutrophilic leukocytes were risk factors associated to graft failure in the univariate study. Only steatosis remained as an independent risk factor in the multivariate study. These grafts also presented poorer long-term survival. Abundant polymorphonuclear infiltrate was associated to a higher frequency of biliary complications. CONCLUSIONS: Microvesicular steatosis implies a better evolution than macrovesicular steatosis. Neutrophilic infiltrate and hepatocellular necrosis lead to poorer initial graft function and reduced long-term survival.

A phase I clinical trial of a multi-epitope polypeptide TAB9 combined with Montanide ISA 720 adjuvant in non-HIV-1 infected human volunteers.

A phase I clinical trial was performed to examine the safety and immunogenicity of a multi-epitope polypeptide comprising the central 15 amino acids of the V3 loop from six HIV-1 isolates. This protein called TAB9 was emulsified in Montanide ISA720 (Seppic, Paris) and administered intramuscularly at doses of 0, 0.2 and 1 mg to 24 healthy, HIV-1 seronegative adult males. Three immunisations were given at months 0, 1 and 6 in a randomised, double blind, placebo controlled clinical trial. The placebo was generally well tolerated. However, severe local reactions were observed in TAB9 vaccinated subjects after the second and third inoculations. Seven out of eight volunteers from the lower dose group showed moderate or severe local inflammation, while four out of eight subjects from the higher dose group developed granulomas and sterile abscesses. In general, the reactogenicity depended on the number of inoculations given and the dose of TAB9. Both doses were immunogenic, all immunised volunteers seroconverted and antibodies were broadly reactive against the V3 peptides included in the protein. All vaccine's sera reacted against gp120 in Western blot and 50% of them also neutralised at least one out of five laboratory isolates tested. No differences between doses were found. Anti TAB9 lymphoproliferative responses were observed, being more intense in the high dose group. Due to the strong local reactions that were found in this study, a change in the formulation will be required for further trials with this vaccine candidate in humans.

Postreperfusion biopsies are useful in predicting complications after liver transplantation.

Biliary complications after orthotopic liver transplantation (OLT) may occur because of preservation injury (PI). In this study, we examine findings on routine reperfusion biopsy specimens in relation to the occurrence of biliary complications and graft outcome. From 1997 to 2000, a total of 193 OLTs were performed in our center. Postreperfusion biopsy specimens were analyzed and histological lesions were graded. For analysis, grafts were grouped into 2 categories: the presence or absence of PI (severe to moderate lesions versus mild or no lesions). Histological evidence of PI was present in 17% of the biopsy specimens. The incidence of grafts with PI and ischemia time longer than 12 hours was 38% compared with 14% in PI and short ischemia time (P =.02). Biliary complications were also more frequent in the PI group (28% v 14%; P =.03). Study of risk factors by means of logistic regression analysis confirmed that the PI group had a greater risk for biliary complications (relative risk, 2.8; 95% confidence interval, 1 to 7.4; P =.03). Moreover, moderate macrovesicular steatosis was found in 6% of the grafts, resulting in a 40% graft loss rate. We found that an increased presence of neutrophilic infiltrates in the postreperfusion biopsy specimen, indicating PI, was related to an increased incidence of biliary complications. Moreover, moderate macrovesicular steatosis was associated with increased graft loss. Therefore, postreperfusion biopsies are useful in anticipating post-OLT complications.

Efficacy of interferon for chronic hepatitis C virus-related hepatitis in kidney transplant candidates on hemodialysis: results after transplantation.

OBJECTIVES: Interferon-alpha (IFN) may have undesirable effects on a functioning graft. The aim of this study was to evaluate IFN treatment in kidney transplant candidates during the hemodialysis period as well as the results after transplantation. METHODS: A total of 29 noncirrhotic hemodialysis patients with chronic hepatitis C virus (HCV) infection (based on long-term rise in ALT, HCV serology, HCV RNA by polymerase chain reaction methods, and histological evidence) were included. Tolerability to IFN treatment, pre- and posttransplantation therapeutic results, and long-term outcome were recorded. IFN regimen consisted of 3 million units (MU) times per week after hemodialysis sessions for 6 months, followed by 1.5 MU after each hemodialysis session for an additional 6 months. All patients gave informed consent for participation. RESULTS: IFN therapy was fairly well tolerated. Adverse effects due to IFN toxicity, renal disease, or causes related to the immunological properties of IFN were observed in 24% of patients. At the end of treatment, ALT had normalized in 23/28 patients (82.1%), and HCV RNA had cleared in 23/28 patients (82.1%). During follow-up, HCV RNA was persistently negative in 18 patients (64%, including transplant recipients). A total of 14 patients (nine HCV RNA-negative) received a kidney transplant. Mean follow-up after the procedure was 41 +/- 28 months. In all, 12 patients had a functioning graft, one had acute vascular rejection, and one died of carcinoma. All transplanted patients maintained normal ALT levels, and eight remained HCV RNA-negative. CONCLUSIONS: Treatment results in our study population were better than those observed in the general population. The long-term response achieved, which was maintained after transplantation, supports the use of IFN for HCV hepatitis in kidney transplant candidates under hemodialysis.

Hepatic metastases from colorectal cancer: preoperative detection and assessment of resectability with helical CT.

PURPOSE: To prospectively evaluate helical computed tomography (CT) in the preoperative detection of hepatic metastases and assessment of resectability with surgical, intraoperative ultrasonographic (US), and histopathologic correlation. MATERIALS AND METHODS: Between October 1995 and December 1998, preoperative staging with helical CT (5-mm collimation; reconstruction interval, 5 mm) was performed in 157 patients with hepatic metastases. Iodinated contrast material was injected intravenously (160-170 mL; rate, 2.5-3.0 mL/sec); acquisition began at 60-70 seconds. Four radiologists prospectively assessed the metastatic involvement of the liver by indicating the number and location of the lesions; resection was indicated in 113 patients (119 instances). Helical CT findings were correlated with pathologic and surgical findings on a lesion-by-lesion basis. RESULTS: Intraoperative US, palpation, and histopathologic examination revealed 290 liver metastases; helical CT correctly depicted 247. Helical CT results were the following: overall detection rate, 85.1% (95% CI: 80.8%, 89.3%); positive predictive value, 96.1% (95% CI: 92.9%, 98.1%); and false-positive rate, 3.9% (10 of 257 findings; 95% CI: 1.9%, 7.1%). False-positive findings were related to hemangioendothelioma, hemangioma, hepatic peliosis, biliary adenoma, centrilobar hemorrhage, biliary hamartoma, periportal fibrosis, and normal liver parenchyma. Curative resection was performed in 112 instances with a resectability rate of 94.1%. Four-year patient survival rate was 58.6%. CONCLUSION: Helical CT is a noninvasive, reliable, and accurate technique for imaging the liver and should be considered as the standard preoperative work-up of hepatic metastases from colorectal cancer.