Fibrosis-free Survival Research Articles

Impact of adjuvant hormonotherapy on radiation-induced breast fibrosis according to the individual radiosensitivity: results of a multicenter prospective French trial.

BackgroundTo evaluate risk of severe breast fibrosis occurrence in patients treated by breast-conserving surgery, adjuvant radiotherapy and hormonotherapy (HT) according to individual radiosensitivity (RILA assay).ResultsHT– and RILAhigh were the two independent factors associated with improved breast-fibrosis free survival (BFFS). BFFS rate at 36 months was lower in patients with RILAlow and HT+ than in patients with RILAhigh and HT– (75.8% and 100%, respectively; p = 0.004, hazard ratio 5.84 [95% confidence interval (CI) 1.8–19.1]). Conversely, BFFS at 36 months was comparable in patients with RILAhigh and HT+ and in patients with RILAlow and HT– (89.8% and 93.5%, respectively; p = 0.39, hazard ratio 1.7 [95% CI 0.51–5.65]), showing that these two parameters influenced independently the occurrence of severe breast fibrosis. BFFS rate was not affected by the HT type (tamoxifen or aromatase inhibitor) and timing (concomitant or sequential with radiotherapy).ConclusionsHT and RILA score independently influenced BFFS rate at 36 months. Patients with RILAhigh and HT– presented an excellent BFFS at 36 months (100%).Materials and methodsBreast Fibrosis-Free Survival (BFFS) rate was assessed relative to RILA categories and to adjuvant HT use (HT+ and HT–, respectively) in a prospective multicentre study (NCT00893035) which enrolled 502 breast cancer patients (456 evaluable patients). Breast fibrosis was recorded according to CTCAE v3.0 grading scale; RILA score was defined according to two categories (<12%: RILAlow; ≥12%: RILAhigh).

Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification, and management.

Polycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. JAK2, CALR, and MPL mutations are the mutually exclusive "driver" mutations in ET with respective incidences of 55%, 25%, and 3%; approximately 17% are triple-negative. However, the same molecular markers might also be present in prefibrotic myelofibrosis, whose morphological distinction from ET is prognostically relevant. Median survivals are approximately 14 years for PV and 20 years for ET; the corresponding values for younger patients (age <60 years) are 24 and 33 years. Life-expectancy in ET is inferior to the control population. Driver mutational status has not been shown to affect survival in ET whereas the presence of JAK2/MPL mutations has been associated with higher risk of arterial thrombosis and that of MPL with higher risk of fibrotic progression. Risk factors for overall survival in both ET and PV include advanced age, leukocytosis and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Most recently, ASXL1, SRSF2, and IDH2 mutations have been associated with inferior overall, leukemia-free or fibrosis-free survival in PV; similarly adverse mutations in ET included SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2. Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis. Accordingly, PV includes two risk categories: high-risk (age >60 years or thrombosis history) and low-risk (absence of both risk factors). In ET, risk stratification includes four categories: very low risk (age ≤60 years, no thrombosis history, JAK2/MPL un-mutated), low risk (age ≤60 years, no thrombosis history, JAK2/MPL mutated), intermediate risk (age >60 years, no thrombosis history, JAK2/MPL un-mutated), and high risk (thrombosis history or age >60 years with JAK2/MPL mutation). In addition, presence of extreme thrombocytosis (platelets >1000 × 10(9)/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once-daily aspirin (81 mg). In addition, high-risk patients with PV require cytoreductive therapy. Very low risk ET patients might not require any form of therapy while low-risk patients require at least once-daily aspirin therapy. Cytoreductive therapy is also recommended for high-risk ET patients but it is not mandatory for intermediate-risk patients. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We currently do not recommend treatment with ruxolutinib or other JAK2 inhibitors in PV or ET, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis. Am. J. Hematol. 92:95-108, 2017. © 2016 Wiley Periodicals, Inc.

Prefibrotic Primary Myelofibrosis As an Entity Distinct from Other Philadelphia-Chromosome Negative Myeloproliferative Neoplasms - Data from the Austrian Reclassification Project

Introduction:The distinction between essentialthrombocythemia(ET) and early, prefibrotic primary myelofibrosis (prePMF) by strictly applying the criteria of the WHO classification results in a newly defined subgroup of myeloproliferative neoplasm (MPN) in which the frequency and severity of clinical features are currently poorly characterized.Since prePMF was usually summarized under the subgroup of ET in previous classifications, little is known about the frequency of prePMFamong MPN. The importance of accurate diagnosis, however, is underlined by various publications that could demonstrate a significant impact on management and outcome of these patients.Aims:The aim of this study was to describe the clinical characteristics and symptoms at diagnosis of prePMF as a distinct entity and to evaluate the course of the disease in regard to survival, transformation into overt myelofibrosis and acute leukemia.Methods:All patients with representative bone marrow biopsies at presentation and complete clinical data at time of diagnosis and follow up were included in this study. All patients included were recruited from the MPN cohort of the Medical University of Vienna.Results:In total, 807 MPN patients diagnosed according to the WHO 2008 criteria were analyzed. The relative frequency of prePMF in our cohort was 17.6% (n=142) as opposed to 27.4% (221) in ET (Fig. 1). The median age for prePMF patients was 63.4 years (range 26.9-88.1) and 55.1% were female. The majority showed an elevated platelet count (median 770 G/l, range 78-2869), hemoglobin levels were on the lower end of the normal range in both genders (median 13.9, range 8.1-18.4 and 13.2, range 7.9-16.2 in men and women respectively). Leukocyte counts in the upper range of normal were common (median 9.87, range 4.0-46.0). The lactate dehydrogenase levels (LDH) were markedly elevated (median 303, range 153-729 with an institutional cut-off of 250 U/L). Therewasalso a considerate proportion of patients with splenomegaly (39.8%). Further, 22.6% of patients reported constitutional symptoms such as night sweats and weight loss. Fiber grade of 1 of a three-graded score in the bone marrow biopsy was reported in 26.2% of cases. 27.0% of patients presented withleftshiftingwith a few peripheral blasts. JAK2 positivity was found in 57.1%, CALR in 32.7 and MPL in 3.3% of cases. Only 5.9% were triple negative. 5-, 10- and 20-year survival rates were 87.6%, 67.0% and 28.8% respectively (38.2% of patients followed to death). Cumulative rate of progression into overt fibrosis was 34.2% after 10 and 58.8% after 20 years (Fig. 2).Discussion:Our data highlight important features of prePMF. Firstly, compared to ET, it has a later onset. More importantly, thrombocytosis is not a feature limited to ET, but is also frequently seen in prePMF and is therefore not suitable to accurately characterize MPN at time of diagnosis. However, leukocytosis and elevated LDH levels are features uncommon for ET as is fiber grade > 0 that is almost never seen in the WHO-defined ET, but relatively common in prePMF. Splenomegaly and presence of a few blasts are generally signs of beginningextramedullaryhematopoiesis are therefore more commonly associated with early stages primary myelofibrosis. Lastly, overall survival and fibrosis-free survival is substantially impaired in prePMF in comparison to data previously published for ET and similar to polycythemiavera.In conclusion, prePMF is a distinct entity, that while sharing some features of ET, most notably thrombocytosis, shows several striking features that should be regarded when investigating newly diagnosed MPN patients. [Display omitted] [Display omitted] DisclosuresGisslinger:Baxalta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria.

Clinical Impact of Bone Marrow Morphology for the Diagnosis of Essential Thrombocythemia: Comparison Between the British Standards (BCSH) and the WHO Criteria

Background Accurate diagnosis of essential thrombocythemia (ET) continues to be a challenging issue for both hematopathologists and clinicians. Diagnosis is usually performed by applying either the 2014 British Committee for Standards in Haematology (BCSH) guidelines or the 2008 World Health Organization (WHO) criteria. While the WHO classification requires bone marrow morphology (BM) as a major criterion, the BCSH guidelines allow diagnosis also based solely on clinical symptoms and is more focused on exclusion of the other subtypes of myeloproliferative neoplasia (MPN). However, prefibrotic/early stages of primary myelofibrosis (prePMF) may also present with thrombocytosis, while failing to meet the diagnostic signs and symptoms characterizing overt PMF. Moreover, a small fraction of polycythemia vera (PV) patients may present with low hemoglobin and hematocrit levels, but a platelet count in keeping with BCSH- and WHO-defined ET, thus mimicking phenotypically ET at onset (masked PV). Clinical outcome in prePMF patients is considerably worse than in ET patients, while treatment strategies are likely to change for prePMF patients with the use of interferon-alpha or JAK1/2-inhibitors.Aims The aim of this study was to investigate the prognostic relevance of BM morphology for ET diagnosis as underscored by the WHO classification versus the first set of the BCSH criteria that do not include BM evaluation.Methods A clinic-pathological database including 450 MPN patients was created by clinicians and hematopathologists from a major Austrian center. Treatment-naive BM biopsies were centrally re-reviewed by three of the authors, who were completely blinded to initial data (except for age and gender). Follow-up data, including clinical course and mutation status, were analyzed after the completion of the histopathology review. For purpose of this study we selected two cohorts of ET patients presenting with a sustained platelet count > 450x10^9/L: (1) 209 ET patients in accordance with the diagnostic requirements of the BCSH (A1-A3) that included no BM biopsy examination. (2) 152 patients in strict agreement with the diagnostic guidelines of the WHO including BM biopsy evaluation as major criterion. Both cohorts were compared and analyzed to regarding their presenting clinico-pathological data, driver mutation status, and follow-up. Diagnosis of post-ET myelofibrosis or progression into overt myelofibrosis with myeloid metaplasia was made according to previously published criteria.Results Following the BCSH criteria, 209 patients were diagnosed as ET. When reclassifying those cases according to the WHO criteria including BM morphology examination, 80 (38.3%) patients were diagnosed as prePMF and 14 (6.7%) as PV and two were diagnosed as PMF (0.9%). Comparison of clinical features of BCSH-ET and WHO-ET revealed significant differences in LDH levels and palpable splenomegaly at diagnosis. Fibrosis-free survival was significantly shorter in BCSH-ETs (Fig. 1A) as was overall survival (Fig. 1B). When reclassifying the BCSH cohort according to WHO criteria, progression-free and overall survival were significantly shorter in WHO-confirmed prePMF (Fig. 1C and 1D).Summary/Conclusion The striking differences in outcome are certainly linked with the entry of many prePMF cases in the BCSH-confirmed cohort. The inclusion of these cases, as well as cases with masked PV demonstrates, that BCSH criteria A1-3 may lead clinicians to refrain from performing BM biopsy in patients with elevated thrombocyte counts, which impairs accurate diagnosis with subsequent inadequate management and inferior prognosis. Our results highlight the central role of BM biopsy to achieve accurate diagnosis and differentiation of ET and prePMF. [Display omitted] DisclosuresGisslinger:Geron: Consultancy; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Consultancy; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau.

Survival Trends in Essential Thrombocythemia in the Face of Changing Treatment Practices

Background:Hydroxyurea has been the mainstay of cytoreductive therapy in essential thrombocythemia (ET) for over four decades. In 1988, anagrelide was first reported as an effective drug in ET (Silverstein et al. NEJM 1988;318:1292) and hundreds of patients were enrolled in clinical trials, which subsequently led to FDA approval in 1997. As a result, an increasing number of patients with ET were being treated with anagrelide until a subsequent controlled study suggested an inferior treatment outcome with anagrelide compared to hydroxyurea (Harrison et al. NEJM 2005;353:33). In the current study, we examined the impact of the corresponding practice changes on overall, myelofibrosis-free and leukemia-free survival, by comparing patients with ET diagnosed before 1988, between 1988 and 1997, and between 1998 and 2005Methods:More than 45,000 patient charts with "thrombocytosis" were reviewed to identify those who met either PVSG (older patient cohort) or WHO criteria for diagnosis of ET. Survival was calculated from time of initial diagnosis to the time of last follow-up or death. For leukemia- or fibrosis-free survival, the time of the transformation events was considered as the uncensored variable. Conventional statistics was utilized for all analyses. Patients were divided into three groups commensurate with changes in treatment practices, corresponding to the aforementioned publications; Group 1 patients were diagnosed prior to 1988 (n =222), Group 2 1988 to 1997 (n =253), and Group 3 1998 to 2005 (n =264).Results:A total of 739 patients met the above-stipulated criteria (median age 57 years; 65% females). At a median follow-up of 12.2 years (range: 0.01-43.6 years), 368 (50%) deaths, 48 (6.5%) fibrotic transformations and 23 (3%) leukemic transformations were documented. Median overall survival (OS) was 18.6 years. On multivariable analysis, older age (P <0.001), increased leukocyte count (P <0.001), thrombosis history (P =0.04), and male sex (P<0.0001) were identified as predictors of inferior OS. Myelofibrosis-free survival (MFS) was predicted by platelet count <100 x 10(9)/L and lower hemoglobin level (multivariate P values 0.03 and <0.001, respectively). Leukemia-free survival (LFS) was predicted by increased leukocyte count, on multivariable analysis (P =0.002).Comparison of presenting features and outcome by period of diagnosis:Significant differences, in presenting features, between groups 1, 2, and 3 included age (median 55, 56, and 59 years, respectively; P =0.003), female preponderance (68, 69, and 58%, respectively; P =0.02), platelet count (1080, 995, and 890 x 10(9)/L, respectively; P <0.001), and leukocyte count (10, 9.6, and 8.4 x 10(9)/L, respectively; P <0.001). Median survival was 20.7 years, 19 years and 14.3 years, in groups 1, 2 and 3, respectively (P =0.02) (Figure 1). However, the difference in survival was no longer apparent during multivariable analysis that included age as a covariate (P=0.88). In univariate analysis, MFS was significantly shorter in group 3 patients (P=0.02; Figure 2); borderline significance was retained during multivariable analysis (p=0.13). LFS was similar among the three groups (P = 0.27).Conclusions:The results from the current retrospective study suggest increased rate of progression to myelofibrosis in ET patients diagnosed in the anagrelide era, an observation that is consistent with the results from a previous controlled study (Harrison et al. NEJM 2005;353:33). Regardless, survival in ET in the last four decades remains unchanged. [Display omitted] [Display omitted] DisclosuresPardanani:Stemline: Research Funding.

Long-Term Follow-up in Interferon-Alpha Treated Polycythemia Vera Patients - a Single Center Analysis

▪Introduction: Interferon-alpha (IFNα) has been successfully used to treat myeloproliferative neoplasms (MPN) for 30 years, although never officially registered for this indication. Studies with new pegylated interferons are underway to finally achieve IFNα registration for MPN.Aims: The aim of this retrospective analysis was to investigate the long-term survival of polycythemia vera (PV) patients that received IFNα while being treated at the outpatient clinic of the Medical University of Vienna, a center that has been treating MPN with IFNα since 1984, and to compare it to patients that received best available therapy (BAT). All treatments were based on international recommendations and standardized center specific guidelines.Methods: The medical histories of patients diagnosed with PV according to the PVSG- or WHO-criteria were investigated and information on the course of the disease and on cytoreductive treatment was collected. For a patient to be included in the analysis, IFNα (conventional or pegylated IFNα2a, -2b, or IFNα2c, or lymphoblastoid IFNα) had to be given for at least 365 days, or, in patients who were followed for more than 10 years, for at least 10% of the observation period after the diagnosis of PV. IFNα-patients who did not fulfill these criteria were not included. The IFNα-patients were compared to patients who received BAT consisting of other cytoreductive agents and/or phlebotomy. A portion of IFNα-patients also received other cytoreductive agents. The patients were then divided into three risk groups based on a previously published score based on age at diagnosis (<57, 57-66, ≥67), venous thromboembolism at baseline and leukocyte counts at diagnosis ≥15 G/L (Fig. 1A). Kaplan-Meier plots were used to compute overall, fibrosis- and AML-free survival.Results: Of 129 patients, 67 received IFNα, 62 BAT (22 received no cytoreductive therapy). Median duration of IFNα treatment was 1981 days. Overall survival was generally better in patients treated with IFNα in all three risk groups. While the difference in the intermediate risk group did not reach significance (Fig. 1C), the survival benefit in the low risk group narrowly missed significance (p=0.127, Fig. 1B). More importantly, IFN-patients in the highest risk group lived significantly longer than patients receiving BAT (p=0.005, Fig. 1D). Median age in all three risk groups did not differ between the two groups, ruling out age as a possible confounder. Also, there were no other relevant differences between any of the groups. Although fibrosis-free survival differed in the low and intermediate risk group, no significant differences were observed. There was no benefit in leukemia-free survival in this analysis.Discussion: This study supports the theory that IFNα can have a beneficial impact not only on symptoms and blood counts of PV-patients, but also on the long-term outcome in regard of overall survival, even in high risk patients. However, due to the retrospective nature of this study, the low case number in some subgroups and the lack of information on the fitness of the individual patients, our results can only serve as an impulse on future studies investigating the long-term outcome of IFNα-patients in MPN. [Display omitted] DisclosuresOff Label Use: Interferon-alpha, use in myeloproliferative neoplasms. Gisslinger:AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy.

Personalized management of essential thrombocythemia—application of recent evidence to clinical practice

The World Health Organization (WHO) classification system has recently strengthened the diagnostic criteria for essential thrombocythemia (ET) by lowering the threshold platelet count, underscoring its morphological distinction from early/prefibrotic myelofibrosis (MF) and incorporating molecular markers of clonality. The International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) examined the clinical relevance of this process in 1104 cases of locally diagnosed ‘ET' and showed worse overall, leukemia-free and fibrosis-free survival, and a higher risk of bleeding in early/prefibrotic MF (n=180) vs WHO-defined ET (n=891). The risk of thrombosis was similar between the two entities and, in WHO-defined ET, was predicted by thrombosis history, older age, cardiovascular risk factors and JAK2V617F. A prognostic model based on these risk factors identified patient groups in ET with residual risk of thrombosis, despite treatment with conventional therapy. The main objectives of the current perspective are to underscore the prognostic importance of morphological confirmation in the diagnosis of ET and provide management recommendations, in both WHO-defined ET and early/prefibrotic MF, based on observations from the aforementioned IWG-MRT and other studies. In so doing, we are fully cognizant and sympathetic of the fact that some of our recommendations need to be tested in prospective controlled studies.

Explanted liver inflammatory grade predicts fibrosis progression in hepatitis C recurrence

Factors present prior to liver transplantation (LT) that predict fibrosis progression in recurrent hepatitis C infection (HCV) after LT would be important to identify. This study sought to determine if histologic grade of HCV in the explant predicts fibrosis progression in recurrent HCV. The clinical and histologic data of all 159 patients undergoing their first LT for HCV at our center from 1998 to 2001 were retrospectively reviewed with follow-up through June 2008. Twenty-five cases were excluded for: non-HCV-related graft loss <90 days (19), recidivism (4), or unavailable explant or follow-up biopsies (2). A single pathologist scored (Ishak) explants in a blinded fashion. Patients were grouped by explant inflammatory grade ≤ 4 (group1) and >4 (group 2). Prospectively scored liver biopsies (protocol months 1 and 4, annually, and as indicated clinically) were reviewed for development of advanced fibrosis (bridging or cirrhosis). Cox proportional hazard regression was used to analyze the association of explant grade, donor, viral and LT factors with progression to advanced fibrosis. The groups were well-matched for patient, viral, donor, and transplant factors. Five-year advanced fibrosis-free survival in group 1 versus group 2 was 63% versus 28%, P < 0.001. Explant grade >4 was associated with increased HCV-related graft loss at 1 (6% versus 3%) and 5 (36% versus 14%) years post-LT (P = 0.003). On univariate and multivariate Cox regression analysis, predictors of advanced fibrosis were explant grade >4 (hazard ratio [HR] = 3.3, 95% confidence interval [CI] = 1.9-5.6, P < 0.001) donor age >50 (HR = 3.3, 95% CI = 1.9-5.7, P < 0.001) and viral load at LT of >158,730 IU/mL (HR = 1.8, 95% CI = 1.05-3.1, P = 0.03). Explant histologic grade can identify patients requiring more aggressive monitoring and intervention for HCV recurrence post-LT.

Influence of steroids on HCV recurrence after liver transplantation: A prospective study

To assess the effect of long-term maintenance of steroids on HCV recurrence after liver transplantation (LT), that is still controversial, a prospective multicentre trial was conducted at the centres of Bologna and Padua, Italy. From September 2002, 47 eligible HCV positive LT recipients were randomized to receive 2 different steroid schedules in association with tacrolimus: group A: rapid tapering and withdrawal 91 days after LT group B: slow tapering and withdrawal 25 months after LT. Thirty-nine patients were assessable: 23 in group A and 16 in group B. Donor and recipient characteristics were similar in the two groups. Median follow-up was 841 days (130-1376). One hundred liver biopsies were performed, and every patient had a biopsy at month 12. Twenty-two out of 23 (95, 65%) patients in group A and 15 out of 16 (93, 75%) in group B had histologically-confirmed HCV recurrence. Twelve-month histology showed advanced fibrosis (score 3 or 4) in 42.1% of the patients in group A versus 7.6% in group B (P=0.03). One-and 2-year advanced fibrosis-free survival were 65.2 and 60.8 in group A and 93.7% in group B (P=0.03 and =0.02, respectively). Slow tapering of steroids reduced the progression of recurrent hepatitis C after LT.

A Cyclosporine-Based Immunosuppressive Regimen May Be Better Than Tacrolimus for Long-Term Liver Allograft Survival in Recipients Transplanted for Hepatitis C

Rapid recurrence of severe hepatitis C (HCV) after liver transplantation is a major barrier to survival of the transplanted liver. While cyclosporine (CsA) in vitro has been shown to suppress HCV replication, an effect is not seen with tacrolimus (Tac). Evidence is inconsistent whether or how this translates to clinical practice. To expand the evidence on this issue, we analyzed graft survival and histological outcomes after liver transplantation for HCV hepatitis. Methods Using our longitudinal database (1991 onward) graft outcomes for all liver transplant recipients with HCV were evaluated (105 grafts in 97 patients). Severe activity, severe fibrosis, and graft survival were analyzed. All liver biopsies were scored (blinded) according to the Ludwig scale. Immunosuppression was based on prednisone and a calcineurin inhibitor (Tac n = 89, 85%; CsA n = 15, 14%). Comparisons of outcomes using CsA versus Tac therapy were done using survival analysis via the log-rank test. Results Graft survival was significantly better in the CsA group. Although there was no apparent difference in severe activity (grade 2), there was a statistically significant difference in graft survival without fibrosing cholestatic hepatitis ( P = .01) and a trend toward a difference in fibrosis-free survival ( P = 0.1). The rate of sustained response to antiviral therapy was twice as high in the CsA group, 50% versus 22% ( P = 0.16; NS). Conclusions Graft survival in liver transplant recipients with HCV may be greater with CsA-based immunosuppression. There may also be a lower rate of fibrosing cholestatic hepatitis in this group.

Positive Serum Cryoglobulin Is Associated with Worse Outcome after Liver Transplantation for Chronic Hepatitis C

Recurrent hepatitis C virus (HCV) infection in patients after liver transplantation is an important clinical problem. Because serum cryoglobulins (CG) are known to be associated with an increased incidence of cirrhosis in nontransplant patients, the authors tested the hypothesis that CG would also predict aggressive recurrent HCV in patients after liver transplantation. Using a longitudinal database, the outcomes of 105 allografts transplanted into 97 HCV-positive patients from 1991 through 2002 were analyzed on the basis of CG status using a retrospective cohort design. Fifty-nine CG-negative and 38 CG-positive patients were identified. Histologic outcomes and graft survival were analyzed using Kaplan-Meier estimates and Cox univariate and multivariate analyses. Both overall survival and HCV-specific survival (non-HVC-related deaths and graft losses censored) were analyzed. By Kaplan-Meier estimates, CG-positive patients showed earlier graft failure with decreased time to severe histologic activity and fibrosis as compared with CG-negative patients (P<0.05 for all outcomes). By univariate analysis, CG-positive patients had significantly higher risk ratios for shortened HCV-specific graft survival, severe activity-free survival, and severe fibrosis-free survival as compared with CG-negative patients (P<0.05 for all outcomes). In the multivariate model, CG was an independent predictor for severe activity-free, severe fibrosis-free, and HCV-specific graft survival (P<0.05 for all outcomes). CG-positivity is associated with severe recurrent HCV disease in liver transplant recipients.

Progression of liver fibrosis in patients with chronic hepatitis C after orthotopic liver transplantation.

Hepatitis C virus (HCV)-related cirrhosis is the leading indication for orthotopic liver transplantation (OLTx). HCV recurrence is universal after OLTx, with a highly variable course. This study aimed to find factors that affect progression of fibrosis in recurrent HCV. Fifty-eight HCV patients underwent OLTx at our center who were selected on the basis of available preOLTx serum or explanted liver sample and liver biopsy obtained at least 6 months postOLTx. All liver biopsies were performed when clinically indicated and were scored using the modified Hepatitis Activity Index (HAI). Primary immunosuppression consisted of tacrolimus and prednisone. The group included 41 males (mean age 49.6 years). HCV genotype distribution was 1a, 31 (53%); 1b, 16 (28%), and others 11 (19%). The mean follow-up was 53.1 months. Patients with genotype 1a (n=31; mean 46.3 months) had significantly lower fibrosis-free survival analyzed by the presence of fibrosis stages 5 and 6 when compared with other genotypes (n=27; mean 60.1 months; P=0.0088, log rank test). Mean HAI scores were significantly higher in HCV genotype 1a, although there were no differences in survival between genotypes. Similarly, patients with cytomegalovirus (CMV) infection postOLTx (n=4) had a higher fibrosis progression rate compared with those without CMV (n=54) (mean fibrosis-free survival 29.0 vs. 53.0 months P=0.0004, log-rank test). Human leukocyte antigen matching and rate of acute rejection did not influence progression of fibrosis. Patients with HCV genotype 1a and those developing CMV postOLTx have a higher rate of hepatic fibrosis progression after OLTx for HCV-related chronic liver disease.