Survival of patients with hepatocellular carcinoma in cirrhosis: a comparison of BCLC, CLIP and GRETCH staging systems

Background  A major problem in assessing the likelihood of survival of patients with hepatocellular carcinoma (HCC) arises from a lack of models capable of predicting outcome accurately.
Aim  To compare the ability of the Italian score (CLIP), the French classification (GRETCH) and the Barcelona (BCLC) staging system in predicting survival in patients with HCC.
Methods  We included 406 consecutive patients with cirrhosis and HCC. Seventy-eight per cent of patients had hepatitis C. Independent predictors of survival were identified using the Cox model.
Results  One-hundred and seventy-eight patients were treated, while 228 were untreated. The observed mortality was 60.1% in treated patients and 84.9% in untreated patients. Among treated patients, albumin, bilirubin and performance status were the only independent variables significantly associated with survival. Mortality was independently predicted by bilirubin, alpha-fetoprotein and portal vein thrombosis in untreated patients. CLIP achieved the best discriminative capacity in the entire HCC cohort and in the advanced untreatable cases, while BCLC was the ablest in predicting survival in treated patients.
Conclusions  Overall predictive ability of BCLC, CLIP and GRETCH staging systems was not satisfactory, and was not uniform for treated patients and untreated patients. None of the scoring systems provided confident prediction of survival in individual patients.     

Epidemiology of Crohn's disease in Israel: a survey of Israeli kibbutz settlements

OBJECTIVE: The prevalence of Crohn's disease ranges from 10 to 70 cases per 100,000 population, and is 3-8 times more common among Jews. However, this excess risk is not evident in the Jewish population of Israel. Recently we have described a significant increase in the prevalence and incidence of Crohn's disease in the south of Israel. The aim of this study was to confirm this trend in a stable population found in communal (kibbutz) settlements. METHODS: We repeated a community-based survey in 124,400 kibbutz residents, 10 yr after our first study. This population represents 5% of the Jewish population of Israel. All Crohn's disease patients were located by contacting the kibbutz clinics of the 269 kibbutz settlements (100% compliance). Data was updated to December 31st, 1997, which was designated the point prevalence date, and included information on gender, age, origin, education, profession, extent of the inflammatory process, clinical spectrum of the disease, therapy, complications of the disease, and treatment. The average annual incidence for the 10 yr was calculated from the prevalence data. Only cases with a definite diagnosis of Crohn's disease made in a recognized gastroenterology unit were accepted into the study. RESULTS: There were 81 confirmed cases of Crohn's disease and the prevalence rate rose from 25.5/100,000 in 1987 to 65.1/100,000 in 1997 (p < 0.001). The mean annual incidence rate for this period (1987-1997) is 5.0/100,000/yr. Prevalence rates were higher in women than men, and in those born in Israel or Europe/America than in Asia/Africa. The mean age at presentation of the disease was lower in 1997 than in 1987, 37.4 +/- 17.0 and 45.0 +/- 17.0 yr, respectively (p = 0.041). Prevalence was highest in men with > 16 yr of education, and in women with 11-12 yr education, 119.7 and 100.3/100,000, respectively. CONCLUSIONS: During the decade 1987-1997, the prevalence of Crohn's disease has increased in Israel and is approaching the rates in Europe and America.     

Increased surface phosphatidylserine is an early marker of neuronal apoptosis

Neuronal apoptosis is the subject of intense investigation and is beginning to be understood in some molecular detail. In the present study, we show that PC12 cells, like certain other cell types, redistribute phosphatidylserine (PS) from the inner leaflet to the outer leaflet of the plasma membrane early in the process of apoptosis. The externalised PS can be readily visualised by incubating intact cells with a fluorescent derivative of the protein annexin V. When apoptosis is blocked with an inhibitor of interleukin-1β-converting-enzyme-like proteases, the increased annexin binding is also blocked. Fluorescent annexin V binding provides a rapid and convenient way to identify apoptotic neurones. J. Neurosci. Res. 48:563–570, 1997. © 1997 Wiley-Liss Inc.     

Quantification of human serum procollagen C-proteinase enhancer (hsPCPE) glycopattern

BackgroundProcollagen C-proteinase enhancer 1 (PCPE1), a glycoprotein secreted from differentiating osteoblast, enhances the rate-limiting step of collagen type I fibrillar formation. It is expressed and secreted by cells that produce collagen type I and has the potential to be a marker for bone pathologies.MethodsWe developed an assay to quantify PCPE glycopattern based on isoelectric focusing (IEF) and detection with a bio-imaging camera (coefficient of variation within and between assays, 15% and 20%, respectively).ResultsPCPE was quantified in 39 serum samples from healthy subjects (17 females and 22 males). The concentration in the serum was 305(274) ng/ml, median(IQR). The level of the PCPE isoforms and their relative distribution were altered in patients with bone disorders.ConclusionsThe data generated by our system, support our hypothesis that combined data on PCPE concentration and isoforms may be useful for the diagnosis and follow-up of bone diseases. Further research, on larger cohorts of both normal subjects and patients, must be done.     

Cathepsin B inhibition limits bone metastasis in breast cancer

Metastasis to bone is a major cause of morbidity in breast cancer patients, emphasizing the importance of identifying molecular drivers of bone metastasis for new therapeutic targets. The endogenous cysteine cathepsin inhibitor stefin A is a suppressor of breast cancer metastasis to bone that is coexpressed with cathepsin B in bone metastases. In this study, we used the immunocompetent 4T1.2 model of breast cancer which exhibits spontaneous bone metastasis to evaluate the function and therapeutic targeting potential of cathepsin B in this setting of advanced disease. Cathepsin B abundancy in the model mimicked human disease, both at the level of primary tumors and matched spinal metastases. RNA interference-mediated knockdown of cathepsin B in tumor cells reduced collagen I degradation in vitro and bone metastasis in vivo. Similarly, intraperitoneal administration of the highly selective cathepsin B inhibitor CA-074 reduced metastasis in tumor-bearing animals, a reduction that was not reproduced by the broad spectrum cysteine cathepsin inhibitor JPM-OEt. Notably, metastasis suppression by CA-074 was maintained in a late treatment setting, pointing to a role in metastatic outgrowth. Together, our findings established a prometastatic role for cathepsin B in distant metastasis and illustrated the therapeutic benefits of its selective inhibition in vivo.     

Localization of PKCη in Cell Membranes as a Predictor for Breast Cancer Response to Treatment

Background: Successful treatment of breast cancer is frequently limited by the resistance of tumors to chemotherapy. Recent studies suggested a role for protein kinase C (PKC) in the resistance to chemotherapy. Here we used retrospective analysis of breast cancer biopsies of neoadjuvantly treated patients to investigate the correlation of PKC expression with aggressiveness and resistance to chemotherapy. Patients and Methods: Our cohort (n = 25) included patients with advanced and aggressive breast cancers, who underwent neoadjuvant therapy with the CAF regimen (cyclophosphamide, doxorubicin, fluorouracil). Core biopsies (pre-chemotherapy) and surgical biopsies of primary tumors and lymph node metastases (post-chemotherapy) were scored for PKCeta (PKCh) and PKCepsilon (PKCe) expression in the cytoplasm, cell membrane, nuclear membrane, and the nucleus. Results: Our results showed increased expression of PKCh (not PKCe) in the cytoplasm and cell membranes of post-chemotherapy biopsies (p = 0.03). PKCh presence in cell membranes, indicating activation, was in correlation with poor survival (p = 0.007). Conclusion: PKCh staining in cell and nuclear membranes is an indicator for poor survival and a predictor for the effectiveness of neoadjuvant treatment. Other avenues of treatment should be considered for these patients. PKCh presents a target for therapy where inhibition of its activity and/or translocation to membranes could interfere with the resistance to chemotherapy.     

Severe combined immunodeficiency (SCID): From the detection of a new mutation to preimplantation genetic diagnosis

Purpose

To describe the identification of a new mutation responsible for causing human severe combined immunodeficiency syndrome (SCID). In a large consanguineous Israeli Arab family, this served as a diagnostic tool and enabled us to carry out preimplantation genetic diagnosis (PGD). We also demonstrated that PGD for homozygosity alleles is feasible.

Methods

We carried out genome-wide screening followed by fine mapping and linkage analysis in order to identify the candidate genes. We then sequenced DCLRE1C in order to find the familial mutation. The family was anxious to avoid the birth of an affected child, and therefore, because of their religious beliefs, PGD was the only option open to them. The embryos were biopsied at day 3, and a single blastomere from each embryo was analyzed by multiplex polymerase chain reaction for the SCID mutation and 5 additional polymorphic markers flanking DCLRE1C.

Results

Linkage analysis revealed linkage to chromosome 10p13, which harbors the DNA Cross-Link Repair Protein 1 C (DCLRE1C) ARTEMIS gene. Sequencing identified an 8 bp insertion in exon 14 (1306ins8) of DCLRE1C in all the affected patients; this causes an alteration in amino acid 330 of the protein from cysteine to a stop codon (p.C330X). One cycle of PGD was performed and two embryos were transferred, one homozygous wild-type and one a heterozygous carrier, and healthy twins were born.

Conclusions

Identifying the familial mutation enabled us to design a reliable and accurate PGD protocol, even in this case of a consanguineous family.