Egyptian Society of Liver Cancer Recommendation Guidelines for the Management of Hepatocellular Carcinoma.

Globally, hepatocellular carcinoma (HCC) is the fourth most common cause of death from cancer. The prevalence of this pathology, which has been on the rise in the last 30 years, has been predicted to continue increasing. HCC is the most common cause of cancer-related morbidity and mortality in Egypt and is also the most common cancer in males. Chronic liver diseases, including chronic hepatitis C, which is a primary health concern in Egypt, are considered major risk factors for HCC. However, HCC surveillance is recommended for patients with chronic hepatitis B virus (HBV) and liver cirrhosis; those above 40 with HBV but without cirrhosis; individuals with hepatitis D co-infection or a family history of HCC; and Nonalcoholic fatty liver disease (NAFLD) patients exhibiting significant fibrosis or cirrhosis. Several international guidelines aid physicians in the management of HCC. However, the availability and cost of diagnostic modalities and treatment options vary from one country to another. Therefore, the current guidelines aim to standardize the management of HCC in Egypt. The recommendations presented in this report represent the current management strategy at HCC treatment centers in Egypt. Recommendations were developed by an expert panel consisting of hepatologists, oncologists, gastroenterologists, surgeons, pathologists, and radiologists working under the umbrella of the Egyptian Society of Liver Cancer. The recommendations, which are based on the currently available local diagnostic aids and treatments in the country, include recommendations for future prospects.

The Role of Interleukin 1 Beta in Differentiating Malignant from Benign Pancreatic Cysts.

Background and Aim: The frequency of detection of pancreatic cystic lesions (PCLs) in magnetic resonance imaging performed for reasons unrelated to the pancreas reaches up to 13.5%. The aim of this study was to evaluate the role of cyst fluid interleukin 1 beta (IL1ß) and different endoscopic ultrasound (EUS) features in differentiating premalignant/malignant from benign pancreatic cysts. In addition, to evaluate the role of pancreatic cyst fluid carcinoembryonic antigen (CEA) in differentiating mucinous from nonmucinous pancreatic cysts. Methods: This study was conducted on 73 patients with PCLs. EUS-guided fine-needle aspiration (EUS-FNA) was performed on all patients. Estimation of IL1ß and CEA levels in aspirated specimens were carried out. Results: Pancreatic cyst fluid IL1ß level could not differentiate between premalignant/malignant and benign pancreatic cysts. At a cutoff value of 19.81 ng/mL pancreatic cyst fluid CEA has 64.3% sensitivity and 84.4% specificity in differentiating mucinous from nonmucinous pancreatic cyst. EUS can differentiate between premalignant/malignant pancreatic cysts and benign cysts with a sensitivity of 66.7%, specificity of 69.2% Conclusions: Pancreatic cyst fluid IL1ß level cannot differentiate between premalignant/malignant and benign pancreatic cysts. CEA level can help in differentiation between mucinous and nonmucinous cysts. EUS can be useful in differentiation between premalignant/malignant pancreatic cysts and benign cysts.

Recent Approaches to Isolating and Culturing Mouse Bone Marrowderived Mesenchymal Stromal Stem Cells.

The isolation and culture of murine Bone Marrow-derived Mesenchymal stromal Stem Cells (mBMSCs) have attracted great interest in terms of the pre-clinical applications of stem cells in tissue engineering and regenerative medicine. In addition, culturing mBMSCs is important for studying the molecular mechanisms of bone remodeling using relevant transgenic mice. Several factors have created challenges in the isolation and high-yield expansion of homogenous mBMSCs; these factors include low frequencies of Bone Marrow-derived mesenchymal stromal Stem Cells (BMSCs) in bone marrow, variation among inbred mouse strains, contamination with Haematopoietic Progenitor Cells (HPCs), the replicative senescence phenotype and cellular heterogeneity. In this review, we provide an overview of nearly all protocols used for isolating and culturing mBMSCs with the aim of clarifying the most important guidelines for culturing highly purified mBMSC populations retaining in vitro and in vivo differentiation potential.

Mac-2 binding protein in non-alcoholic fatty liver disease: Is it a reliable diagnostic biomarker? A pilot study.

AIM OF THE STUDY: This study aimed to assess the level of serum Mac-2 binding protein (Mac-2BP) as a non-invasive biomarker for the diagnosis of non-alcoholic fatty liver disease (NAFLD). MATERIAL AND METHODS: Forty patients with NAFLD and 15 healthy sex- and age-matched subjects were included in this pilot study. Serum Mac-2BP level was measured using ELISA. Liver biopsy was taken from 20 patients. RESULTS: There was no statistically significant difference between patients and controls regarding the level of Mac-2BP (p = 0.209). Mac-2BP had a statistically significant correlation with the grade of lobular inflammation (r = 0.464, p = 0.039). The Mac-2BP cut-off value used for NASH prediction was 9.55 µg/ml, with sensitivity and specificity of 100% and 91.7%, respectively. CONCLUSIONS: This study showed that Mac-2BP is not elevated in NAFLD patients compared to controls. It also demonstrated that the reliability of Mac-2BP as a biomarker for NAFLD diagnosis is still controversial and needs more investigation.

The BMP-2 mutant L51P: a BMP receptor IA binding-deficient inhibitor of noggin.

The antagonist-specific regulation in tissue engineering constitutes important attempts to achieve an improved and rapid bone regeneration by controlling the natural biological response of the natural body growth factors. L51P is molecularly engineered bone morphogentic protein-2 (BMP-2) variant with a substitution of the 51st leucine with a proline residue. L51P is deficient in BMP receptor binding, but maintains its structure and affinity for inhibitory proteins such as noggin, chordin, and gremlin. These modifications convert the BMP-2 variant L51P into a receptor-inactive inhibitor of BMP antagonists. This current approach may prevent the uncontrolled bone overgrowth using high concentration of BMPs and thus regulates the possible growth factor's high-dose side effects. Exploring of L51P biological functions is required to broad our understanding of BMP mutant biological functions and their potential clinical applications. The progress of L51P researches would hopefully lead to the development of multiple applications for using the L51P in bone and fracture healing disorders.

Establishing ultrasound based transient elastography cutoffs for different stages of hepatic fibrosis and cirrhosis in Egyptian chronic hepatitis C patients.

BACKGROUND AND STUDY AIM: Transient elastography is widely used to assess fibrosis stage in chronic hepatitis C (CHC). We aimed to establish and validate different transient elastography cut-off values for significant fibrosis and cirrhosis in CHC genotype 4 patients. PATIENTS AND METHODS: The data of 100 treatment-naive CHC patients (training set) and 652 patients (validation set) were analysed. The patients were subjected to routine pretreatment laboratory investigations, liver biopsy and histopathological staging of hepatic fibrosis according to the METAVIR scoring system. Transient elastography was performed before and in the same week as liver biopsy using FibroScan (Echosens, Paris, France). Transient elastography results were correlated to different stages of hepatic fibrosis in both the training and validation sets. RESULTS: ROC curves were constructed. In the training set, the best transient elastography cut-off values for significant hepatic fibrosis (≥F2 METAVIR), advanced hepatic fibrosis (≥F3 METAVIR) and cirrhosis (F4 METAVIR) were 7.1, 9 and 12.2 kPa, with sensitivities of 87%, 87.5% and 90.9% and specificities of 100%, 99.9% and 99.9%, respectively. The application of these cut-offs in the validation set showed sensitivities of 85.5%, 82.8% and 92% and specificities of 86%, 89.4% and 99.01% for significant hepatic fibrosis, advanced hepatic fibrosis and cirrhosis, respectively. CONCLUSION: Transient elastography performs well for significant hepatic fibrosis, advanced hepatic fibrosis and cirrhosis, with validated cut-offs of 7.1, 9 and 12.2 kPa, respectively, in genotype 4 CHC patients.

Impact of old Schistosomiasis infection on the use of transient elastography (Fibroscan) for staging of fibrosis in chronic HCV patients.

BACKGROUND AND AIM: In tropical regions, Hepatitis C virus (HCV) - Schistosomiasis coinfection remains one of the health problems. With the new era of HCV treatment and the variety of methods of assessment of liver fibrosis so we aimed to evaluate the effectiveness of FibroScan for staging hepatic fibrosis in HCV-Schistosomiasis coinfected patients. METHODOLOGY: Three groups of patients were enrolled. Group 1: chronic HCV with out antischistosomal antibody (122 patients), Group 2: chronic HCV with positive antischistosomal antibodies and without periportal tract thickening (122 patients), Group 3: chronic HCV with positive antischistosomal antibodies and ultrasonographic picture of periportal tract thickening (108 patients). Routine laboratory workup, serum Antischistosomal antibody, and Schistosomal antigen in serum were performed. Ultrasound guided liver biopsy with histopathological examination; abdominal ultrasound and fibroscan examination were done for all patients. RESULTS: The agreement between results of liver biopsy and results of fibroscan in the staging of fibrosis was the best in group 1 (55.7%), Although the agreement was higher among those with no periportal tract thickening (70.7%) and the disagreement was higher among those with positive schistosomal serology (66.5%), yet this relation was not statistically significant. Multivariate logistic regression analysis showed that disagreement is significantly associated with older age, higher BMI (≥30), and increase in anti Schistosomal antibody titer. CONCLUSION: Fibroscan is a reliable, non-invasive tool for staging hepatic fibrosis among HCV-schistosomiasis co-infected patients with no effect of the induced periportal tract thickening on the readings. Only higher antischistosomal antibody titres may cause disagreement between liver biopsy and fibroscan.

CCN4/WISP-1 positively regulates chondrogenesis by controlling TGF-ß3 function.

The CCN family of proteins plays important roles in development and homeostasis of bone and cartilage. To understand the role of CCN4 in chondrogenesis, human bone marrow stromal cells (hBMSCs) were transduced with CCN4 adenovirus (adCCN4) or siRNA to CCN4 (siCCN4) in the presence or absence of transforming growth factor-ß3 (TGF-ß3). Overexpression of CCN4 enhanced TGF-ß3-induced SMAD2/3 phosphorylation and chondrogenesis of hBMSCs in an in vitro assay using a micromass culture model. On the other hand, knockdown of CCN4 inhibited the TGF-ß3-induced SMAD2/3 phosphorylation and synthesis of cartilage matrix in micromass cultures of hBMSCs. Immunoprecipitation-western blot analysis revealed that CCN4 bound to TGF-ß3 and regulated the ability of TGF-ß3 to bind to hBMSCs. In vivo analysis confirmed there was a significant decrease in the gene expression levels of chondrocyte markers in cartilage samples from Ccn4-knock out (KO) mice, compared to those from wild type (WT) control. In order to investigate the regenerative properties of the articular cartilage in Ccn4-KO mice, articular cartilage defects were surgically performed in the knee joints of young mice, and the results showed that the cartilage was partially repaired in WT mice, but not in Ccn4-KO mice. In conclusion, these results show, for the first time, that CCN4 has a positive influence on chondrogenic differentiation by modulating the effects of TGF-ß3.

Relation of ALT and AST levels to the histopathological changes in liver biopsies of patients with chronic hepatitis C genotype 4.

BACKGROUND AND STUDY AIMS: Worldwide, Egypt has a high prevalence of adult hepatitis C virus (HCV) infection. Serum alanine aminotransferase (ALT) activity is most commonly measured to assess hepatic disease. The revision of the definition of the normal limits for the ALT level is advisable. The aim of this work was to compare the histopathological changes in the liver tissue biopsies of HCV-infected patients, clinically presenting with ALT levels below normal, based on the conventional, previously used upper limit of normal (ULN) of ALT (40U/L for men and 30U/L for women) with the proposed new ULN (30U/L for men, and 19U/L for women). PATIENTS AND METHODS: This is a retrospective cross-sectional study. A total of 668 cases of chronic hepatitis C genotype 4 were included. Patients were classified according to grades of histological activity and fibrosis stages (by the Metavir scoring system). They were also classified into normal and high groups according to the old and new cutoffs of both aspartate transaminase (AST) and ALT levels. RESULTS: The results of our study showed that the serum AST level in our study showed a better correlation with the histopathological changes in liver biopsy rather than ALT, especially when using the old cutoff of the ULN for AST. The serum ALT level in our study (both the old and the new cutoffs) did not show a significant correlation with the histopathological status in the liver biopsies of our patients. CONCLUSION: This study concluded that the old cutoff of the ULN AST is a better predictor of fibrosis.

Physical interaction of CCN2 with diverse growth factors involved in chondrocyte differentiation during endochondral ossification.

CCN family member 2 (CCN2) has been shown to promote the proliferation and differentiation of chondrocytes, osteoblasts, osteoclasts, and vascular endothelial cells. In addition, a number of growth factors and cytokines are known to work in harmony to promote the process of chondrogenesis and chondrocyte differentiation toward endochondral ossification. Earlier we showed that CCN2 physically interacts with some of them, suggesting that multiple effects of CCN2 on various differentiation stages of chondrocytes may be attributed to its interaction with these growth factors and cytokines. However, little is known about the functional interaction occurring between CCN2 and other growth factors and cytokines in promoting chondrocyte proliferation and differentiation. In this study we sought to shed light on the binding affinities between CCN2 and other essential growth factors and cytokines known to be regulators of chondrocyte differentiation. Using the surface plasmon resonance assay, we analyzed the dissociation constant between CCN2 and each of the following: TGF-ß1, TGF-ß3, IGF-I, IGF-II, PDGF-BB, GDF5, PTHrP, and VEGF. We found a strong association between CCN2 and VEGF, as well as a relatively high association with TGF-ß1, TGF-ß3, PDGF-BB, and GDF-5. However, the sensorgrams obtained for possible interaction between CCN2 and IGF-I, IGF-II or PTHrP showed no response. This study underlines the correlation between CCN2 and certain other growth factors and cytokines and suggests the possible participation of such interaction in the process of chondrogenesis and chondrocyte differentiation toward endochondral ossification.

CCN2 enhances RANKL-induced osteoclast differentiation via direct binding to RANK and OPG.

CCN family protein 2/connective tissue growth factor (CCN2/CTGF) is a multi-potent factor for mesenchymal cells such as chondrocytes, osteoblasts, osteoclasts, and endothelial cells. CCN2 is also known as a modulator of other cytokines and receptors via direct molecular interactions with them. We screened additional factors binding to CCN2 and found receptor activator of NF-kappa B (RANK) as one of them. RANK is also known as TNF-related activation-induced cytokine (TRANCE) receptor, and its signaling plays a critical role in osteoclastogenesis. Notable affinity between CCN2 and RANK was confirmed by using surface plasmon resonance (SPR) analysis. In fact, CCN2 enhanced the RANK-mediated signaling, such as occurs in NF-kappa B, p38 and JNK pathways, in pre-osteoclastic RAW264.7 cells; whereas CCN2 had no influence on RANK-RANK ligand (RANKL) binding. Moreover, CCN2 also significantly bound to osteoprotegerin (OPG), which is a decoy receptor of RANKL. Of note, OPG markedly inhibited the binding between CCN2 and RANK; and CCN2 canceled the inhibitory effect of OPG on osteoclast differentiation. These findings suggest CCN2 as a candidate of the fourth factor in the RANK/RANKL/OPG system for osteoclastogenesis, which regulates OPG and RANK via direct interaction.

The BMP2 antagonist inhibitor L51P enhances the osteogenic potential of BMP2 by simultaneous and delayed synergism.

Bone morphogenetic protein 2 (BMP2) is a potent osteoinductive cytokine that plays crucial roles in bone repair. However, large amounts of BMP2 are required to induce sufficient bone formation in humans possibly due to a feedback response of BMP antagonists. The engineered BMP2 variant L51P is deficient in BMP receptor type I activation but maintains affinity for BMP antagonists and can allow for the inactivation of BMP antagonists, and eventually enhance BMP2 action. As hypothesized, simultaneous addition of L51P enhanced the BMP2-induced osteogenesis. To test the ability of L51P to competitively inactivate BMP antagonists, cell binding affinity of BMP2 ligands was investigated in the presence or absence of L51P. Because the BMP antagonists were highly expressed 3 days after exogenous BMP2 stimulation, we collected supernatants from 3-day stimulated cell cultures and used as condition culture media (CM). The results showed a significant decrease in the cell binding of BMP2 ligands when cells were incubated with exogenous BMP2 and CM, whereas L51P addition competitively rescued the suppression of BMP2-to-cell binding induced by CM incubation. In a delayed experimental model, L51P was applied 3 days after exogenous BMP2 stimulation and we could observe a striking enhancement of the BMP2-induced SMAD-1/5/8 phosphorylation and luciferase activity of the Id1 promoter compared to the simultaneous addition of the two factors. These findings provide a deeper insight into the cellular and molecular mechanisms involved in the effect of L51P in suppressing the BMP antagonists and enhancing BMP activity. Additionally, these results demonstrate that L51P is a promising down regulator of BMP-induced negative feedback, which could have a significant impact in future applications of BMP2 in research and clinical settings.

Role of high resolution ultrasound/endosonography and elastography in predicting lymph node malignancy.

OBJECTIVE: The objective of this study is to evaluate the role of high resolution ultrasonography (US) and endoscopic ultrasound (EUS)-elastography in predicting malignant lymphadenopathy. PATIENTS AND METHODS: This prospective study included 88 patients who underwent EUS or US examination of different groups of lymph nodes (LNs). The classification as benign or malignant based on the real time elastography pattern and the B-mode US/EUS images was compared with the final diagnosis obtained by EUS or US guided fine-needle aspiration cytology (FNAC), tru-cut biopsy or excisional biopsy and follow-up in benign lesions not indicated for biopsy for at least 12 months. RESULTS: Regarding the echogenicity, 98.3% of the benign LNs were hyperechoic, 1.7% was hypoechoic while 89.7% of the malignant LNs were hypoechoic, 3.4% were heterogenous and 6.9% were hyperechoic. With cut-off value of 1.93, the sensitivity of longitudinal to transverse ratio was 73% and the specificity was 100%. Score 1 elastography had specificity of 100% in diagnosis of benign LNs, sensitivity was 76.3%, positive predictive value (PPV) was 100%, negative predictive value (NPV) was 84.7% while score 2 had a sensitivity of 60%, specificity of 31.5%, PPV of 15.3%, NPV of 79.3%. Score 3 had a sensitivity of 70.2%, specificity of 100%, PPV of 13.8%, NPV of 100% in detecting malignancy while score 4 had a sensitivity of 85.5%, specificity of 100%, PPV of 100%, NPV of 65.5%. CONCLUSION: Elastography is a promising diagnostic modality that may complement standard ultrasound and EUS and help guide FNAC during staging of LNs.

Fibroscan of chronic HCV patients coinfected with schistosomiasis.

BACKGROUND AND STUDY AIMS: Both hepatitis C virus (HCV) and schistosomiasis are highly endemic in Egypt and coinfection is frequently encountered. Such coinfection is responsible for leading to a more severe liver disease. Hence, the aim of the study was to assess the fibroscan in chronic HCV patients coinfected with Schistosoma. PATIENTS AND METHODS: This study included 231 chronic HCV patients. Routine pre-treatment work-up was done including anti-schistosomal antibodies. Liver stiffness measurements using fibroscan and reference needle-liver biopsy were done. Patients were categorised into two groups: HCV patients with positive schistosomal serology and HCV patients with negative schistosomal serology. RESULTS: Anti-schistosomal antibody was positive in 29% of the studied population. Positive schistosomal serology status was significantly associated with the disagreement between the results of liver biopsy (Metavir) and the fibroscan results (p value=0.02), which was more obvious in F2 and F3 fibrosis stages. The sensitivity of fibroscan for the detection of the F2 stage decreased from 64% among negative schistosomal serology patients to 30.8% among positive schistosomal serology patients, and for the F3 stage it decreased from 43.8% to 21.4%, respectively. Multivariate logistic regression showed that fibrosis stages (F0-F1 and F4) were the most independent factors that were associated with the agreement between fibroscan and liver biopsy (odds ratio (OR) 3.4, 7.12 and p value <0.001, <0.001, respectively). CONCLUSION: Although the sensitivity of fibroscan for the detection of fibrosis stages (F2 and F3) was impaired in patients with positive schistosomal serology, fibrosis stages (F0-F1 and F4) were the most independent factors associated with the agreement between fibroscan and liver biopsy.

Coinfection with hepatitis C virus and schistosomiasis: fibrosis and treatment response.

AIM: To assess whether schistosomiasis coinfection with chronic hepatitis C virus (HCV) influences hepatic fibrosis and pegylated-interferon/ribavirin (PEG-IFN/RIB) therapy response. METHODS: This study was designed as a retrospective analysis of 3596 chronic HCV patients enrolled in the Egyptian National Program for HCV treatment with PEG-IFN/RIB. All patients underwent liver biopsy and anti-schistosomal antibodies testing prior to HCV treatment. The serology results were used to categorize the patients into group A (positive schistosomal serology) or group B (negative schistosomal serology). Patients in group A were given oral antischistosomal treatment (praziquantel, single dose) at four weeks prior to PEG-IFN/RIB. All patients received a 48-wk course of PEG-IFN (PEG-IFNα2a or PEG-IFNα2b)/RIB therapy. Clinical and laboratory follow-up examinations were carried out for 24 wk after cessation of therapy (to week 72). Correlations of positive schistosomal serology with fibrosis and treatment response were assessed by multiple regression analysis. RESULTS: Schistosomal antibody was positive in 27.3% of patients (15.9% females and 84.1% males). The patients in group A were older (P = 0.008) and had a higher proportion of males (P = 0.002) than the patients in group B. There was no significant association between fibrosis stage and positive schistosomal serology (P = 0.703). Early virological response was achieved in significantly more patients in group B than in group A (89.4% vs 86.5%, P = 0.015). However, significantly more patients in group A experienced breakthrough at week 24 than patients in group B (36.3% vs 32.3%, P = 0.024). End of treatment response was achieved in more patients in group B than in group A (62.0% vs 59.1%) but the difference did not reach statistical significance (P = 0.108). Sustained virological response occurred in significantly more patients in group B than in group A (37.6% vs 27.7%, P = 0.000). Multivariate logistic regression analysis of patient data at treatment weeks 48 and 72 showed that positive schistosomal serology was associated with failure of response to treatment at week 48 (OR = 1.3, P = 0.02) and at week 72 (OR = 1.7, P < 0.01). CONCLUSION: Positive schistosomal serology has no effect on fibrosis staging but is significantly associated with failure of response to HCV treatment despite antischistosomal therapy.

Comparative diagnostic study of biomarkers using FibroMax™ and pathology for prediction of liver steatosis in patients with chronic hepatitis C virus infection: an Egyptian study.

BACKGROUND: Steatosis is common in patients with hepatitis C virus (HCV) infection and may be a major determinant of progression of liver injury. This study evaluated FibroMax™ for noninvasive diagnosis of steatosis in patients with chronic HCV. METHODS: This cross-sectional study included 44 patients naïve to treatment who were referred to our hepatology clinic for assessment of fitness for antiviral therapy. Chronic HCV infection was diagnosed by viral markers. Investigations included assessment of abdominal ultrasonography, liver biopsy, calculation of body mass index, and biomarker parameters in serum using FibroMax. RESULTS: Histopathology of liver biopsies showed steatosis in 30 of 44 (68%) patients. FibroMax results were positively correlated with viral load by quantitative polymerase chain reaction and histopathological findings. Body mass index was significantly higher in steatotic patients (P = 0.003) and was significantly associated with the results on FibroMax (P = 0.005). CONCLUSION: FibroMax was correlated with histopathology and body mass index in patients with HCV. Abdominal ultrasonography could not be used as a single tool to diagnose steatosis with HCV. Steatosis is correlated with viral load, which suggests a direct viral effect. We recommend FibroMax assessment in a larger number of patients to assess its applicability in patients with HCV and steatosis.

Nodular fasciitis of the external auditory canal in six Egyptian children.

OBJECTIVE: Nodular fasciitis of external auditory canal may mimic a malignant tumor due to its progressive course, so it was the aim of this study to focus on a new etiology for aural masses to avoid unnecessary aggressive treatment. STUDY DESIGN: Retrospective study on six children presented with aural masses that were diagnosed pathologically to have nodular fasciitis. METHODS: Presentation of the cases clinically, radiologically and pathologically was carried out. Surgical excision of the lesions was done through the external canal with follow up of the cases for 1 year. RESULTS: Recurrence was detected in two cases, one after 2 months and the other after 4 months. Re-excision was carried out without recurrence till the end of the follow up period. CONCLUSIONS: Proper diagnosis of this lesion is mandatory to avoid aggressive treatment (radical surgery and/or radiotherapy) as the disease has favorable prognosis with local excision.

Host susceptibility to schistosomes: effect of host sera on cell proliferation of Schistosoma mansoni schistosomula.

To determine effects of the sera on cell proliferation, schistosomula of Schistosoma mansoni (20-days-old) were incubated in medium containing fetal calf serum plus hamster (highly susceptible host) portal or peripheral venous serum, or rat (poorly susceptible host) portal or peripheral venous serum in the presence of bromodeoxyuridine (BrdU). Compared with schistosomula cultured in presence of control medium containing fetal calf serum alone, BrdU labeling indices (BLIs) were increased by 39% in the presence of portal, but not in peripheral, serum of hamsters. In contrast, no significant differences were observed in the BLIs in rat portal, or peripheral, sera or in control media. In vivo BrdU labeling results revealed that there was no detectable cell proliferation in S. mansoni schistosomula (6 days old) in the lungs. However, cell proliferation was detected in schistosomula beginning at 17 days. The results indicated that portal venous serum from a highly susceptible host, but not from a poorly susceptible host, stimulated schistosome cell proliferation in vitro. The timing of the increase in cell proliferation in terms of development corresponded to liver portal-mesenteric localization of schistosomula. Together, the data support the conclusion that in susceptible hosts, portal serum may play a role in schistosome cell proliferation, possibly resulting in termination of schistosome migration. This may explain the colocalization of adults, and the known organ selectivity of disease.