Association between hepatitis B or hepatitis C virus infection and risk of pancreatic adenocarcinoma development: a systematic review and meta-analysis.

BACKGROUND: Pancreatic adenocarcinoma (PAC) is an aggressive cancer with a poor prognosis. To date, PAC causes are still largely unknown. Antigens and replicative sequences of oncogenic hepatitis B (HBV) and hepatitis C (HCV) virus were detected in different extra-hepatic tissues, including pancreas. OBJECTIVE: a systematic review and meta-analysis of epidemiological studies assessing PAC risk in patients with HBV/HCV chronic infections. METHODS: In September 2012, we extracted the articles published in Medline, Embase and the Cochrane Library, using the following search terms: "chronic HBV" and "HCV", "hepatitis", "PAC", "risk factors", "epidemiology". Only case/control (C/C), prospective/retrospective cohort studies (PCS/RCS) written in English were collected. RESULTS: four hospital-based C/C studies and one PCS, in HBV-infected patients and two hospital-based C/C studies and one RCS in HCV-infected subjects met inclusion criteria. In these studies HBsAg positivity enhanced significantly PAC risk (RR = 1.18, 95% CI:1.04-1.33), whereas HBeAg positivity (RR = 1.31, 95% CI:0.85-2.02) as well as HBsAg negative/HBcAb positive/HBsAb positive pattern (RR = 1.12, 95% CI:0.78-1.59) and HBsAg negative/HBcAb positive/HBsAb negative pattern (RR = 1.30, 95% CI:0.93-1.84) did not. Relationship between PAC risk and anti-HCV positivity was not significant, although it reached a borderline value (RR = 1.160, 95% CI:0.99-1.3). CONCLUSIONS: HBV/HCV infection may represent a risk factor for PAC, but the small number of available researches, involving mainly populations of Asian ethnicity and the substantial variation between different geographical areas in seroprevalence of HBV/HCV-antigens/antibodies and genotypes are limiting factors to present meta-analysis.

Laparoscopic trans-choledochotomy approach for common bile duct stones removal: case report.

The advent of new technologies in the 1980s allowed the increase in diagnosis and treatment of biliary diseases in the pediatric population. Nowadays, in case of pediatric common bile duct stones, the most popular procedure is laparoscopic cholecystectomy, associated to retrograde endoscopic stones removal, even if in adult age laparoscopic common bile duct clearance is a common procedure. The Authors report a case of cholelithiasis with common bile duct stones in a 10 year-old girl treated by laparoscopic cholecystectomy associated with laparoscopic trans-choledochotomy common bile duct clearance.

Campaign manufacturing of highly active or sensitizing drugs: a comparison between the GMPs of various Regulatory Agencies.

BACKGROUND: Cross-contamination and mix-ups are among the problems which could have a negative impact on the quality of the finished product during the production of highly active or sensitizing drugs with campaign manufacturing. Standardised, validated procedures ensure quality standards are maintained during production. In spite of this, the operating conditions and applicability of methods adopted by the various regulatory agencies manifest significant differences which could consequently compromise the safety of the finished product. This work has analysed and compared the GMP of various Regulatory Agencies to examine issues connected to campaign manufacturing highly active or sensitizing drugs. METHODS: The GMP of the following Regulatory Agencies have been studied: EMA, CFDA, COFEPRIS, FDA, Health Canada, ANVISA, CDSCO, PIC/S and WHO. The study was carried out for the purpose of understanding which agencies consent to the use of campaign manufacturing for the following categories of medicinal products: hormones, immunosuppressants, cytotoxic agents, highly active pharmaceutical ingredients (APIs), biological preparations, steroids, sensitizing pharmaceutical materials, antibiotics, cephalosporins, penicillins, carbapenems and beta-lactam derivatives. RESULTS: The GMP of Health Canada, EMA, PIC/S and FDA show a number of similarities, starting with the fact that they allow campaign manufacturing for similar categories of pharmaceutical products after an appropriate risk evaluation has been performed. CFDA, WHO, ANVISA authorise campaign manufacturing in "exceptional circumstances", though they do not always define what they mean by this. COFEPRIS authorises campaign manufacturing for certain classes of drugs, while there is no mention of campaign manufacturing in the CDSCO regulations. CONCLUSIONS: Quite a few significant differences have been found in the various regulations concerning the use of campaign manufacturing and the classes of drugs that can be produced with this method. In the light of this, it is obvious that efforts to harmonise legislation internationally have not yet been successful: currently, states can adopt different quality standards. The pharmaceutical industry could use this situation to its advantage by delocalising production on the basis of existing standards. The need to harmonise GMPs is a priority which must be achieved as soon as possible.

High proliferative activity and chromosomal instability in oral lichen planus.

The study aimed to assess the proliferative activity and karyotype in Oral Lichen Planus (OLP) lesions. G-banding chromosomal analysis of short-term primary cultures, and immunohistochemical expression of Ki67 and p53 were applied in 30 consecutive OLP patients divided into two groups according to clinical presentation of the lesions, and in nine subjects as negative controls. Mean values of Ki67 and p53 expression differed significantly (P<.01) between controls and patients groups with reticular or atrophic-erosive forms of OLP, whereas there was no significant difference between the two groups of patients with reticular or atrophic-erosive lesions. Six OLP patients showed clonal chromosome alterations, four of them associated with p53 overexpression. In conclusion, OLP is characterized by a high cellular turnover in most patients irrespective of clinical disease presentation. The genetic instability found in some patients should be interpreted as a consequence of the enhanced epithelial turnover, although we cannot rule out the possibility that some of the cytogenetic non-random anomalies observed represent early steps in cancer development.

Preliminary experience with laparoscopic repair of associated inguinal and umbilical hernias in children.

PURPOSE: The authors report their preliminary experience in laparoscopic repair of associated inguinal and umbilical hernias in children. METHODS: Twenty-six patients affected by the association of inguinal and umbilical hernia with an umbilical defect larger than 5 mm underwent a laparoscopic procedure. A 5-mm trocar was placed through the umbilical defect for the optic. To fix the trocar to avoid loss of carboperitoneum, we fashioned and tightened a purse-string non-absorbable suture with a sliding knot around the defect. In this manner, we ensured the trocar, fixing it and avoiding any loss of CO2, proceeding safely to the laparoscopic IH repair, by means of two additional 3 mm operative trocars. At the end of the inguinal herniorrhaphy, the previously fashioned purse-string suture was tightened to repair the umbilical defect. RESULTS: The mean operative time for the repair of associated inguinal and umbilical hernias was 30.1 ± 7.4 min in cases of unilateral inguinal hernia and 39.5 ± 10.6 for bilateral inguinal hernia. Follow-up ranged from 8 to 32 months. Neither intra- nor post-operative complications nor recurrences were seen. CONCLUSION: This small sample suggests that this simple method is safe, effective and might be useful for pediatric surgeons performing laparoscopic repair for inguinal hernia in presence of an associated UH with a statistically significant decrease of operative time.

In vitro testing of the potential for orthopedic bone cements to cause apoptosis of osteoblast-like cells.

The purpose of this study was to investigate in vitro the apoptosis- and/or necrosis-inducing potential of polymethylmethacrylate (PMMA)-based bone cements for prosthetic surgery. Four bone cements widely used in orthopedics were tested as extracts onto osteoblast-like MG-63 cells and for comparison, HL-60 cells, which are remarkably sensitive to apoptotic stimuli. Neutral red uptake (NRU) was used to measure cell viability while Hoechst 33258 staining was used to detect DNA content. Apoptosis was characterized using a BrdU-based ELISA assay for DNA fragmentation and examined by fluorescence microscopy using acridine orange and propidium iodide staining of nuclei. The generation of reactive oxygen species (ROS), which could mediate apoptosis, was verified using dichlorofluorescein-diacetate (DCFH-DA) oxidation to DCF. After 24 h of challenge of the cells with the four cement extracts, the viability of either MG-63 or HL-60 cells was found to be unaltered, as recorded by NRU. Apoptotic cell death was induced by three cements in HL-60, whereas MG-63 cells were significantly affected by the four cements tested: the finding of DNA fragments both in the cytoplasm and supernatants of MG-63 after 24 h demonstrated that these cells underwent late-apoptosis secondary necrosis. Fluorescent staining of the nuclei confirmed the results obtained with the ELISA test. Oxygen free radicals were elicited by two cements in HL-60 cells, while MG-63 did not generate ROS in response to cements. This study helps to gain more insight into the mechanism of cell death induced by PMMA-based cements and suggests apoptosis of osteoblasts as a part of the tissue reaction around cemented prostheses.

G-CSF in an infant donor: a method of reducing harvest volume in bone marrow transplantation.

We report the case of a 4-year-old female with high-risk ALL in first CR who received a BMT from an 11-month-old matched sibling treated with G-CSF in order to obtain an adequate number of mononuclear cells in a limited volume of bone marrow. The absence of toxicity, efficacy of the procedure and quality of the post-transplant clinical outcome suggest such treatments are feasible and useful to overcome problems caused by donor age and/or body weight. In view of this experience we demonstrate how such an approach leads to a notable reduction in risks and in bone marrow donation costs.

G-CSF-primed peripheral blood progenitor cells (PBPC) support in high-risk Ewing sarcoma of childhood.

Since 1993 pediatric patients affected by high-risk Ewing sarcoma for the presence at onset of a large pelvic mass and/or metastatic disease, were enrolled in a national pilot study comprehensive, finally, of a high-dose chemotherapy (HDCT) procedure with hemopoietic stem cell support. The HDCT procedure considered as consolidation of the disease status obtained after the first-line therapy was followed by the reinfusion of granulokine colony-stimulating factor-primed (G-CSF) peripheral blood progenitor cell (PBPCT). Here we present the results in terms of treatment-related toxicity, hospitalization and rescue of the bone marrow function, in 17 pediatric patients enrolled in such a pilot protocol and submitted to HDCT and PBPCT at the end of first-line therapy.

Effect of butyrate analogues on proliferation and differentiation in human neuroblastoma cell lines.

Butyric acid has been shown in vitro to produce cytodifferentiation of a wide variety of neoplastic cells. The potential clinical use of this compound as a therapeutic agent is limited by its rapid metabolism. This has led to the examination, as potential antineoplastic agents, of compounds structurally correlated to butyrate, with longer biological half lives. In this study we investigated the effect in vitro of two butyrate analogues, tributyrin and butyramide, on inducing growth inhibition and expression of morphological and immunophenotypic properties, in human neuroblastoma cell lines. Treatment with tributyrin resulted in a strong inhibition of cell proliferation and in induction of extensive differentiation; on the contrary butyramide was scarcely effective or quite ineffective. These results demonstrate that tributyrin retains the effectiveness of butyrate and suggest that this analogue could have utility for cytodifferentiation therapy.

Inhibitors of protein kinases induce differentiation in human neuroblastoma cell lines.

We investigated the effect on differentiation of genistein, an inhibitor of tyrosine protein kinase, and 1-(-5 isoquinolinylsulfonyl)-2-methylpiperazine (H7), an inhibitor of protein kinase C, in neuroblastoma cell lines. Growth inhibition and expression of morphological and biochemical properties were examined in the human neuroblastoma cell lines TS12 and SJNKP. Genistein and H7 induced neurite outgrowth, increased acetylcholinesterase activity and cell growth inhibition in both cell lines. These results underline that tyrosine protein kinase and protein kinase C may play a key role in the control of differentiation and proliferation of neural cells.

Effect of a new derivative of retinoic acid on proliferation and differentiation in human neuroblastoma cells.

Neuroblastoma, a tumor originating from the sympathetic nervous system, is the most common extracranial malignant solid tumor of childhood. Human neuroblastoma cells may differentiate in vitro under treatment with a variety of biological agents and drugs. Among these, retinoic acid (RA) is quite potent and its effectiveness as a therapeutic agent is now being evaluated in clinical trials. As its pleiotropic biological activities may produce side-effects limiting clinical use, it is important to find new compounds that present the same effectiveness together with few side-effects. In this study we have explored the action of IIF, (pat. WIPO W0 00/17143) a new derivative of RA, as a differentiation inducer in the human neuroblastoma cell line TS12. In the same cell line, we have also compared the effect of IIF with that of all trans RA (ATRA) and of 9 cis RA (9cRA), with respect to morphological and biochemical differentiation and growth inhibition. Treatment with IIF resulted in a strong inhibition of proliferation and in a marked induction of neuronal differentiation as revealed by neurite extension, increase of actylcholinesterase (AchE) specific activity and tyrosine hydroxylase (TH) expression. The results demonstrate the effectiveness of this new retinoid as a differentiation inducer on neuroblastoma cells TS12. Furthermore, the differentiation-promoter and antimitotic activities of IIF were on the whole more pronounced than those of ATRA and 9cRA. Therefore our study suggests the evaluation of the new retinoid IIF as a therapeutic approach in the treatment of neuroblastoma.

[Choroid plexus tumours: cytogenetic analysis of a single case and literature review]. / Papilloma dei plessi corioidei: analisi citogenetica di un caso e revisione della letteratura.

Choroid plexus tumours are intraventricular papillary lesions that are observed in typical papillomas, atypical papillomas and carcinomas. They usually occur in childhood, and can result in hydrocephalus and increased intracranial pressure. The present paper describes a case of choroid plexus papilloma in an adult woman; cytogenetic analysis of the lesion is also presented, which demonstrated the presence of tumour mosaicism. Compared to the chromosomal aberrations observed in previous cases, those in the present tumour do not show significant differences between papillomas harboured in adults and paediatric patients. Moreover, there was no apparent correlation between genetic alternations in typical and atypical papillomas and prognosis or recurrence.

Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).

To investigate the role of gefitinib in patients with high-grade gliomas (HGGs), a phase II trial (1839IL/0116) was conducted in patients with disease recurrence following surgery plus radiotherapy and first-line chemotherapy. Adult patients with histologically confirmed recurrent HGGs following surgery, radiotherapy and first-line chemotherapy, were considered eligible. Patients were treated with gefitinib (250 mg day(-1)) continuously until disease progression. The primary end point was progression-free survival at 6 months progression-free survival at 6 months (PFS-6). Tissue biomarkers (epidermal growth factor receptor (EGFR) gene status and expression, phosphorylated Akt (p-Akt) expression) were assessed. Twenty-eight patients (median age, 55 years; median ECOG performance status, 1) were enrolled; all were evaluable for drug activity and safety. Sixteen patients had glioblastoma, three patients had anaplastic oligodendrogliomas and nine patients had anaplastic astrocytoma. Five patients (17.9%, 95% CI 6.1-36.9%) showed disease stabilisation. The overall median time to progression was 8.4 (range 2-104+) weeks and PFS-6 was 14.3% (95% CI 4.0-32.7%). The median overall survival was 24.6 weeks (range 4-104+). No grade 3-4 gefitinib-related toxicity was found. Gefitinib showed limited activity in patients affected by HGGs. Epidermal growth factor receptor expression or gene status, and p-Akt expression do not seem to predict activity of this drug.

Insulin-like growth factor receptor 1 (IGFR-1) is significantly associated with longer survival in non-small-cell lung cancer patients treated with gefitinib.

BACKGROUND: The aim of the study was to assess whether loss of PTEN and expression of insulin-like growth factor receptor 1 (IGFR-1) could be responsible for intrinsic resistance to the tyrosine kinase inhibitor (TKI) gefitinib. PATIENTS AND METHODS: One hundred and twenty-four gefitinib-treated patients with advanced non-small-cell lung cancer (NSCLC) were analyzed for PTEN and IGFR-1 expression by immunohistochemistry. RESULTS: IGFR-1 was evaluated in 77 patients and resulted positive in 30 (39.0%). IGFR-1 expression was not significantly associated with clinical or biological characteristics. No difference in response to gefitinib treatment (16.7% versus 12.8%, P = 0.74) and time to progression (2.6 versus 3.06 months, P = 0.83) was observed between IGFR-1+ and IGFR-1-. Median survival was significantly longer in IGFR-1+ patients (17.8 versus 7.3 months, P = 0.013). PTEN expression was successfully evaluated in 93 cases. Loss of PTEN was detected in 19 tumors (20.4%) and was not associated with any clinical or biological characteristic. No difference in terms of response, time to progression and survival was observed between PTEN+ and PTEN- patients. In multivariable analysis IGFR-1 negative status was significantly associated with higher risk of death (hazard ratio 2.21, P = 0.012). CONCLUSIONS: IGFR-1 expression and loss of PTEN are not associated with intrinsic resistance to gefitinib. Clinical relevance of these two biomarkers as determinant for acquired resistance, and the prognostic role of IGFR-1 expression in patients not exposed to TKIs should be evaluated further.

HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients.

In non-small-cell lung cancer (NSCLC), sensitivity to tyrosine kinase inhibitors (TKIs) is associated with activating mutations and genomic gain of the epidermal growth factor receptor (EGFR). Preclinical data suggested that HER3 overexpression increases sensitivity to TKIs. A total of 82 NSCLC patients treated with gefitinib (250 mg), and previously evaluated for EGFR and HER2 status by fluorescence in situ hybridisation (FISH) and DNA sequencing, and for Phospho-Akt status by immunohistochemistry, were investigated for HER3 genomic gain by FISH. Patients with high polysomy and gene amplification were considered as HER3 FISH positive (+). HER3 FISH+ pattern was significantly associated with female gender (P=0.02) and never smoking history (P=0.02). Patients with HER3+ tumours (26.8%) had a significantly longer time to progression (3.7 vs 2.7, P=0.04) than patients with HER3- tumours, but not a significantly better response rate or survival. Patients with EGFR+/HER3+ tumours had higher objective response rate (36.4 vs 9.9%, P=0.03) and time to progression (7.7 vs 2.7 months, P=0.03) than patients with EGFR- and/or HER3- tumours, but no significantly longer survival. No difference in response was observed according to HER3 status in patients with EGFR+ tumours. Patients with HER2+/HER3+ tumours had similar outcome as patients with HER2- and/or HER3- tumours. Significantly different clinical end points were not observed between patients with HER3+/P-Akt+ and HER3- and/or P-Akt- tumours. Genomic gain for HER3 is not a marker for response or resistance to TKI therapy in advanced NSCLC patients.

Human leukocyte antigen II expression in sperm cells: comparison between fertile and infertile men.

Human leukocyte antigens (HLA) class II transcripts in mature spermatozoa of healthy volunteers have recently been demonstrated using reverse transcription polymerase chain reaction (RT-PCR). HLA II expression was investigated on ejaculated sperm cells in fertile and infertile men by RT-PCR and flow cytometry. Among 22 fertile and 20 infertile men, 18 were selected for the study because they showed no contamination with non-sperm cells. HLA II mRNA transcripts were expressed in all but 1 of 8 infertile subjects and in only 2 of 10 fertile ones. The cytofluorometric analysis on three RT-PCR positive samples confirmed the presence of class II antigens on cell surfaces. These data clearly confirm the presence of both HLA II mRNA and surface molecules on human sperm cells. In addition, an interesting nonrandom distribution of positivity among fertile and infertile samples regarding HLA II expression (p < .025) suggests a possible correlation with infertility.

Human leucocyte antigen I expression in spermatozoa from infertile men.

The expression of class I human leucocyte antigen (HLA) has been investigated by reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry on human purified ejaculated spermatozoa from an infertile population. Similar investigation in a control fertile population has been performed. Among 22 fertile and 20 infertile men, 17 were selected for the study because they showed no contamination with non-sperm cells. HLA I molecules were expressed in four of nine fertile subjects (44.4%) and three of eight infertile subjects (37.5%), with no significant difference between groups. These data demonstrate for the first time the presence of class I HLA antigens on spermatozoa of infertile subjects. In addition, considering that similar results have been obtained in both fertile and infertile populations, the hypothesis that the fertilizing capacity of the spermatozoon is independent of class I HLA-antigen expression on their surface may be advanced.

CD38: a multi-lineage cell activation molecule with a split personality.

This review reports the characteristics of the human surface molecule CD38, a structure not linked to a definite line and predominantly expressed in early and activated phenotypes. The CD38 molecule consists of a single chain of 46 kDa, spanning the membrane and with the carboxyl terminus located in the extracellular compartment. The CD38 molecule is also involved in the transduction of activation and proliferation signals, which are line unrestricted. The gene coding for the CD38 antigen has been cloned and used for the construction of simian and mouse transfectants expressing the human molecule. These cell models are used for the analysis of several unanswered issues, mainly concerning the in vivo function of CD38, the existence of a natural ligand and of polymorphism in the population.

Phase II trial of carboplatin and etoposide for patients with recurrent high-grade glioma.

We present the results of a phase II trial of carboplatin and etoposide (CE) combination as first-line chemotherapy in patients with recurrent glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA) after surgery and radiotherapy. We assess the activity and the tolerability of this combination. 30 patients with GBM (25) and AA (5) were treated with VP-16 (etoposide) 120 mg m(-2) and CBCDA (carboplatin) 100 mg m(-2) for 3 days every 4 weeks. Moreover, we performed a retrospective analysis of topoisomerase IIalpha gene status using chromogenic in situ hybridisation. The median age was 54 years (21-73 years); Eastern Cooperative Oncology Group performance score was 0-1 in 25 patients and 2 in five patients. All patients had been previously treated with surgical resection (21 radical resections) followed by radiation therapy (40-60 Gy). We observed six (20%) complete responses, three (10%) partial responses and 12 (40%) stable diseases, with a response rate of 30%. The median time to progression was 4 months, while progression-free survival at 6 months was 33.3%. The median survival time was 10 months. Neutropenia occurred in 9 patients: four patients had grade 4, two patients grade 3 and three patients grade 2. In the conclusion of this clinical trial, the CE combination has shown activity in recurrent GBM and AA, with a good toxicity profile. Alterations in the copy number of topoisomerase IIalpha gene seem to be a rare event and in our series do not influence response to the CE combination.