First-Line Therapy for Nodal T-cell Non-Hodgkin Lymphomas: an Unmet Need in Hematology.

PURPOSEOF REVIEW: The main aim of this review is to summarize first-line therapy of nodal T-cell non-Hodgkin lymphoma. RECENT FINDINGS: Current treatment with CHOP chemotherapy results in poor outcomes in the majority of patients. However, there are advances within the field. First breakthrough is the ECHELON-2 trial which showed that the addition of brentuximab vedotin improves outcomes in anaplastic large cell lymphoma. However, other types of peripheral T-cell non-Hodgkin lymphoma were underrepresented with optimal treatment not known. Second breakthrough is an increase of autologous stem cell transplantation usage in the first complete metabolic remission, except in ALK + anaplastic large cell lymphoma, offering better disease control. Despite advances in the field, CHOP remains the standard treatment for the majority of these lymphomas, but multiple trials are underway with the aim to improve this unmet need in hematology and, hopefully, leading us to a new era in the treatment of peripheral T-cell lymphomas.

Relationship between coffee consumption, sleep duration and smoking status with elastographic parameters of liver steatosis and fibrosis; controlled attenuation parameter and liver stiffness measurements.

AIM: our aim was to explore the association between life habits and the controlled attenuation parameter (CAP) and liver stiffness measurements (LSM) as the surrogate markers of liver steatosis and fibrosis in a large cohort of non-alcoholic fatty liver disease (NAFLD) patients. METHODS: In this prospective, cross-sectional study we had analysed 1998 patients with diagnosed NAFLD. Sleeping duration was categorised in three groups: short (S) (<6 hours), moderate (M) (6-8 hours) and long (L) (>8 hours) sleep duration. Coffee drinking was categorized into no (0), moderate (1-2) and frequent (≥3) consumption (in cups/day). Smoking was categorised as yes versus no. RESULTS: Frequent coffee consumers had the lowest prevalence of obesity, hypertension, dyslipidaemia and diabetes. Furthermore, coffee non-consumers had highest values of hepatic enzymes, CAP and LSM. Moderate sleep duration was associated with lower values of CAP and LSM. Coffee consumption was associated with lower CAP in all the multivariate models (CAP unadjusted and model 1, 2 and 3), with largest effect in most frequent coffee consumers (≥3, model 3). Also, most frequent coffee consumers were associated with lower LSM in unadjusted model, model 1 and 2, while this was not the case for model 3 and those who consumed 1-2 cups of coffee per day. Reduced sleeping was confirmed as risk factor for elevated CAP in most of the models (unadjusted and model 1 and 2). Also, negative association of LSM was also confirmed in unadjusted model and model 2. Patients which slept 6-8 hours per day were mostly associated with lower CAP and LSM. Smoking status was not associated with CAP or LSM values. CONCLUSION: Coffee consumption has beneficial effect on CAP and LSM and this effect is dose dependent since and independent of a variety of relevant confounders. We have shown that moderate sleep duration has also beneficial effect on CAP and LSM.

Small intestinal bacterial overgrowth and non-alcoholic fatty liver disease diagnosed by transient elastography and liver biopsy.

BACKGROUND: We aimed to determine if there was a higher incidence of small intestinal bacterial overgrowth (SIBO) in non-alcoholic fatty liver disease (NAFLD) than in patients without NAFLD. Moreover, we assessed whether patients with significant fibrosis (SF) had a higher incidence of SIBO compared with patients with non-significant or no liver fibrosis. METHODS: NAFLD was diagnosed in 117 patients by using Fibroscan with a controlled attenuation parameter (CAP) as well as liver biopsy (LB). SIBO was defined by esophagogastroduodenoscopy with an aspiration of the descending duodenum. RESULTS: Patients with non-alcoholic steatohepatitis (NASH) and those with SF on LB had a significantly higher incidence of SIBO than patients without NASH and those without SF, respectively (P < .05). According to histological characteristics, there was a higher proportion of patients in the SIBO group with higher steatosis and fibrosis grade, lobular and portal inflammation, and ballooning grade (P < .001). In multivariate analysis, significant predictors associated with SF and NASH were type 2 diabetes mellitus (T2DM) and SIBO. Moreover, in multivariate analysis, significant predictors that were independently associated with SIBO were T2DM, fibrosis stage and ballooning grade (OR 8.80 (2.07-37.37), 2.50 (1.16-5.37) and 27.6 (6.41-119), respectively). The most commonly isolated were gram-negative bacteria, predominantly Escherichia coli and Klebsiella pneumoniae. CONCLUSION: In this relatively large population of patients, we used a gold standard for both SIBO (quantitative culture of duodenum's descending part aspirate) and NAFLD (LB), and we demonstrated that NASH patients and those with SF had a higher incidence of SIBO. Moreover, significant predictors independently associated with SIBO were T2DM, fibrosis stage and ballooning grade. Although TE is a well-investigated method for steatosis and fibrosis detection, in our study, independent predictors of SIBO were histological characteristics of NAFLD, while elastographic parameters did not reach statistical significance.

Improvement in the outcomes of mantle cell lymphoma in the last decade: a real-life non interventional study of the Croatian Cooperative Group for Hematologic Diseases.

AIM: To compare the outcomes of Croatian patients with mantle cell lymphoma (MCL) who started treatment in 2007 and 2008 (historical cohort) and of those who started treatment between 2015 and 2017 (recent cohort). METHODS: The historical cohort consisted of 40 patients who started treatment with rituximab in 2007 and 2008. Data on the recent cohort, consisting of 89 patients, were collected retrospectively from the electronic databases of Croatian hospitals with hematology units. Demographic characteristics and data on induction regimens, autologous stem cell transplantation (ASCT), and rituximab maintenance in the first remission, event-free survival (EFS), and overall survival (OS) were available for both cohorts, and data on cell morphology, mantle cell international prognostic index (MIPI), and Ki67 expression only for the recent cohort. RESULTS: The recent cohort had significantly better two-year EFS and OS (EFS 58% vs 40%, P=0.014; OS 80% vs 56%, P=0.009), especially in patients below 65. In univariate analysis, induction regimen, ASCT, and maintenance were significant prognostic factors for EFS and the former two for OS. In the multivariate analysis, only ASCT remained significant. Bendamustine+rituximab (BR) induction improved the outcomes of non-transplantable patients over R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, steroid). Blastoid morphology and high MIPI were adverse prognostic factors for EFS and OS. CONCLUSION: In the last decade, the outcome of newly diagnosed MCL patients improved. ASCT in the first remission was the main contributor in transplantable patients and BR in non-transplantable. Regularly updated national guidelines may help in a timely adoption of new treatments, thus improving the results.

Vitamin D for treatment of non-alcoholic fatty liver disease detected by transient elastography: A randomized, double-blind, placebo-controlled trial.

AIM: To evaluate the effects of vitamin D on transient elastography (TE, FibroScan) indices of liver steatosis (controlled attenuation parameter [CAP]) and fibrosis (liver stiffness measurement [LSM]) in adults with non-alcoholic fatty liver disease (NAFLD). PATIENTS AND METHODS: In this randomized (2:1), double-blind, single-centre, 12-month trial, patients with NAFLD were treated with vitamin D (1000 IU/day) (n = 201) or a matching placebo (n = 110). Two co-primary outcomes were changes in CAP and LSM after 360 days of treatment versus baseline. Two main secondary outcomes were CAP/LSM changes after 180 days of treatment. RESULTS: Both CAP and LSM gradually decreased in vitamin D-treated patients and slightly increased in the placebo arm. Vitamin D was superior to placebo for both primary outcomes (mean differences in CAP and LSM changes (-49.5 dB/m [95% CI -59.5 to -39.4] and -0.72 kPa [95% CI -1.43 to 0.00], respectively) and both secondary outcomes (-22.1 dB/m [-32.1 to -12.1] and -0.89 kPa [-1.61 to -0.17], respectively). Of a number of exploratory outcomes (change at 12 months vs. baseline), vitamin D reduced serum uric acid (-17.9 µmol/L [-30.6 to -5.2]), gamma-glutamyltransferase (-8.9 IU/L [-15.5 to -2.3)] and fasting serum insulin levels (-5.1 pmol/L [-9.3 to -0.8]) as well as the homeostatic model assessment of insulin resistance index (-1.6 [-3.1 to -0.2]) (false discovery rate [5%]-adjusted P-values between .0572 and .0952). CONCLUSION: Low-medium dose supplementation of vitamin D (1000 IU/day) over 12 months reduces TE indices of liver steatosis (CAP) and fibrosis (LSM) in NAFLD patients.

Utilization of somatic healthcare in Croatian patients with schizophrenia spectrum disorder, major depression, PTSD and the general population.

BACKGROUND: Utilization of somatic healthcare services is highly predictive of the development of chronic physical illnesses and increased mortality risks. The objective of this study was to assess the differences in healthcare utilization among patients with schizophrenia spectrum disorders (SSD), major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) and the general population in Croatia. METHODS: We enrolled 566 Croatian participants from the general population, 282 with SSD, 178 with MDD, and 86 with PTSD. The primary outcome was a self-reported specialist consultation for non-psychiatric (e.g., somatic) causes within the previous 12 months. RESULTS: Although SSD patients with chronic physical illnesses were significantly more often hospitalized for physical illness than the general population, the proportion of patients who had a specialist consultation were equal in SSD and the general population. MDD and PTSD patients had significantly higher adjusted odds for specialist consultation than the general population and SSD patients (MDD compared to SSD: OR = 2.14; 95% CI 1.27-3.59; PTSD compared to SSD: OR = 2.03; 95% CI 1.00-4.10). CONCLUSIONS: SSD patients' utilization of somatic healthcare is equal to the general population, despite their increased healthcare needs. However, their utilization is lower than in MDD and PTSD patients and, therefore, probably not adequate. TRIAL REGISTRATION: The study protocol was registered at ClinicalTrials.gov ( NCT02773108 ) on May 16, 2016.

Rituximab Maintenance Strategy in Advanced Follicular Lymphoma: Facts and Controversies

Rituximab is a chimeric monoclonal CD20 antibody used in the treatment of CD20 positive non-Hodgkin lymphomas and has revolutionized treatment approach to these hematologic malignancies in the last decade. The main aim of this review is to present data on the use of rituximab in the treatment of follicular lymphoma (FL). We will focus on rituximab maintenance strategies in the first and second line treatment. This approach has improved the outcome in FL patients with better progression-free survival in all patients and better overall survival in relapsed setting. Regardless of good results, this strategy has generated controversies in medical community in the range from the lack of overall survival benefit in first line setting, adverse effects of possible overtreatment and toxicities to its unknown role in the era of novel agents. The existing data suggest that rituximab maintenance should be a rational therapeutic option for all patients with FL responding to fi rst line therapy and transplant-ineligible patients responding to reinduction.

Notch affects the prodifferentiating effect of retinoic acid and PMA on leukemic cells.

Notch proteins determine cell fate decisions in the development of diverse tissues. Notch has been initially found in T-ALL but its role has been also studied in myelopoiesis and myeloid leukemias. Studies in different model systems have led to a widespread controversy as to whether Notch promotes or blocks myeloid differentiation. In this work, we evaluated the influence of Notch activation on leukemic cell differentiation along the monocytic and myelocytic pathway induced by phorbol 12-myristate 13-acetate (PMA) or all-trans retinoic acid (ATRA). We observed that differentiation of the human myeloblastic cell line HL-60 can be retarded or blocked by Delta/Notch interaction. ATRA induces complete remission in patients with acute promyelocytic leukemia, but it cannot completely eliminate the leukemic clone and to be effective it should be combined with chemotherapy. Our findings suggest that Notch signaling may contribute to the incomplete elimination of the leukemic cells after PMA or ATRA treatment and the blockage of Notch pathway may be beneficial in the treatment of myeloid leukemia. © 2014 International Society for Advancement of Cytometry.

[AUTOLOGOUS STEM CELL TRANSPLANTATION IN REFRACTORY OR RELAPSED DIFFUSE LARGE B CELL LYMPHOMA - A SINGLE CENTRE EXPERIENCE]. / AUTOLOGNA TRANSPLANTACIJA PERIFERNIH MATICNIH STANICA U REFRAKTORNOM ILI RELAPSNOM NE-HODGKINOVU LIMFOMU DIFUZNOGA B-VELIKOSTANICNOG TIPA - ISKUSTVO JEDNOG CENTRA.

Autologous stem cell transplantation represents the gold standard in chemosensitive diffuse B large cell lymphoma in relapse or in refractory setting. The aim of this study was to present the outcome of peripheral autologous stem cell transplantation in patients with refractory or relapsed diffuse large B cell lymphoma. We retrospectively analysed the data of 62 patients, who underwent this procedure for the period 2000-2013. The majority of patients (71%) were treated with miniBEAM salvage chemotherapy and all received BEAM myeloablative protocol followed by the stem cell reinfusion. The overall response rate for autologous transplantation was 75.8%. Median overall survival was 37.2 months. Median event-free survival was 16.9 months. Factors associated with overall survival were state of disease prior to salvage chemotherapy, chemosensitivity of disease, International prognostic index, disease activity at the relapse, response to autologous transplantation and post-transplantation radiotherapy. The use of rituximab was not significantly correlated to the outcome. In this patient group autologous stem cell transplantation was found to be effective in achieving remission and survival showing the adequate role of this procedure in this clinical setting. We stress out that autologous stem cell transplantation was effective in 32.5% patients with chemorefractory disease after salvage therapy.

Analysis of Primary Chronic Lymphocytic Leukemia Cells' Signaling Pathways.

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by a specific expansion of mature B-cell clones. We hypothesized that the disease has a heterogeneous clinical outcome that depends on the genes and signaling pathways active in the malignant clone of the individual patient. It was found that several signaling pathways are active in CLL, namely, NOTCH1, the Ikaros family genes, BCL2, and NF-κB, all of which contribute to cell survival and the proliferation of the leukemic clone. Therefore, we analyzed primary CLL cells for the gene and protein expression of NOTCH1, DELTEX1, HES1, and AIOLOS in both peripheral blood lymphocytes (PBLs) and the bone marrow (BM) of patients, as well as the expression of BCL2 and miRNAs to see if they correlate with any of these genes. BCL2 and AIOLOS were highly expressed in all CLL samples as previously described, but we show here for the first time that AIOLOS expression was higher in the PBLs than in the BM. On the other hand, NOTCH1 activation was higher in the BM. In addition, miR-15a, miR-181, and miR-146 were decreased and miR-155 had increased expression in most samples. The activation of the NOTCH pathway in vitro increases the susceptibility of primary CLL cells to apoptosis despite high BCL2 expression.

Clinical Dilemmas in the Treatment of Elderly Patients Suffering from Hodgkin Lymphoma: A Review.

Elderly patients make up a significant number of cases of newly diagnosed Hodgkin lymphoma. However, unlike in young patients, the outcomes of elderly patients are poor, and they are under-represented in phase III trials. Prior to treatment initiation, geriatric assessment should ideally be performed to address the patient's fitness and decide whether to pursue a curative or palliative approach. The ABVD regimen is poorly tolerated in unfit patients, with high treatment-related mortality. Alternative chemotherapy approaches have been explored, with mixed results obtained concerning their feasibility and toxicity in phase II trials. The introduction of brentuximab vedotin-based regimens led to a paradigm shift in first- and further-line treatment of elderly Hodgkin lymphoma patients, providing adequate disease control within a broader patient population. As far as checkpoint inhibitors are concerned, we are only just beginning to understand the role in the treatment of this population. In relapsed/refractory settings there are few options, ranging from autologous stem cell transplantation in selected patients to pembrolizumab, but unfortunately, palliative care is the most common modality. Importantly, published studies are frequently burdened with numerous biases (such as low numbers of patients, selection bias and lack of geriatric assessment), leading to low level of evidence. Furthermore, there are few ongoing studies on this topic. Thus, elderly Hodgkin lymphoma patients are hard to treat and represent an unmet need in hematologic oncology. In conclusion, treatment needs to be personalized and tailored on a case-by-case basis. In this article, we outline treatment options for elderly Hodgkin lymphoma patients.

[Extramedullary multiple myeloma of the colon--case presentation and literature review]. / Ekstramedularna infiltracija kolona u bolesnika s multiplim mijelomom--prikaz bolesnika i pregled literature.

Multiple myeloma with gastrointestinal infiltration is rare, and it has been usually described in some case reports or case series. Stomach and small intestine are mostly involved, while large bowell involvement is very rare. Multiple myeloma should be considered in the differential diagnosis of some other diseases of the large bowel associated with weight loss, diarrhoea, malabsorption, frequent lumbar pain, effort intolerance. Colonoscopic biopsy followed by histopathological examination is essential for the diagnosis of multiple myeloma. Multiple myeloma with extramedullary infiltration of the colon has no well defined treatment guideline. Localised infiltration of gastrointestinal tract could be treated by surgical resection, but as these tumors are radiosensitive, radiotherapy has also been used. Chemotherapy with pulsed dexamethasone and afterwards a combination of cyclophosphamide, vincristine, melphalan and prednisone has been described in some case studies. Some patients were treated with other therapies incuding thalidomide, bortezomib, autologous or allogeneic stem cell transplantation. The clinical presentation, diagnosis and therapy may be challenging, so we present a 66-year old patient with extramedullary multiple myeloma of the colon who was treated at our Department.

[Multiple myeloma in a patient with chronic lymphocytic leukemia--case report and literature review]. / Multipli mijelom u bolesnika s dugogodisnjom kronicnom limfocitnom leukemijom--prikaz bolesnika i pregled literature.

The occurrence of B-cell chronic lymphocytic leukemia (B-CLL) and another B-cell neoplasm in the same patient is a rare event and is mostly described in the literature as single case reports. In most cases reported in the literature, CLL was diagnosed several years before multiple myeloma. Some patients were only observed for CLL without therapy, whereas others had already been treated for CLL when the diagnosis of myeloma was established. Some authors came to a conclusion that therapy used for treating CLL can induce some secondary neoplasms, like multiple myeloma. We present a male patient who was diagnosed with multiple myeloma 11 years after B-CLL had been diagnosed. Two hematologic neoplasms in one patient could be a diagnostic problem, but also a therapeutic challenge.

[Billateral pleural effusion as first manifestation of multiple myeloma]. / Bilateralni pleuralni izljev kao prva manifestacija multiplog mijeloma.

Multiple myeloma is clonal malignancy of plasma cells with overproduction of monoclonal antibodies and destruction of bones. Hypercalcemia, anemia and renal disfunction are common manifestations of the disease. Billateral pleural effusion is rare multiple myeloma presentation with unfavorable prognosis so it is important to recognizze it for better diagnostic and therapy approach. 59-year old woman was admitted to Hematology Department with history of severe caugh, dyspnea and left chest pain. Physical examination and chest X-ray showed billateral pleural effusion while cytologic examination of pleural aspirate found plasma cells. Bone marrow examination and skeleton X-ray confirmed diagnosis of multiple myeloma. Serum and urine immunoelectrophoresis detected lambda Bence Jones protein. This case is rare manifestation of multiple myeloma.

[Association of CD34 cell surface antigen expression with cytomorphological characteristics of acute promyelocytic leukemia blasts and clinical characteristics of patients: one center experience]. / Povezanost izrazaja biljega CD34 s morfoloskim znacajkama blasta u akutnoj promijelocitnoj leukemiji i klinickim znacajkama oboljelih: iskustvo jednog centra.

The aims of the study were to investigate the association between cytomorphology and immunophenotypic expression of CD34 cell surface antigen of blasts and their relationship with clinical and laboratory characteristics of patients with acute promyelocytic leukemia (APL). Sixteen consecutive patients (male 69% and female 31%) diagnosed with APL at Department of Hematology, Merkur University Hospital between August 1998 and December 2010 were included in the study. The mean age of patients was 43.9 (range: 18-78, SD 14.9). The patients' clinical and laboratory features, cytomorphological characteristics of APL-blasts and their immunophenotype determined by flow cytometry were analyzed. Patients were divided into two groups, CD34- and CD34+, and were then compared according to clinical and laboratory characteristics. There was no difference according to age, sex or white blood cell count between two groups. The mean value of hypogranular/agranular APL-blasts was markedly higher in CD34+ group than CD34- group (34%, range 9-60, SD 24.4 vs. 11.5%, range 0-38, SD 13.7), with borderline statistical significance (P=0.055). CD34- patients had significantly better overall survival than CD34+ ones (P=0.02). Patients without Auer rods detected in APL-blasts had higher CD34 expression (69.4% +/- 33.8) compared to patients with detected Auer rods (7.3% +/- 24.8), but statistical significance was not reached (p=0.053). Our results are consistent with the results of other published studies and point to the fact that higher CD34 expression and lower cytoplasmic granularity of APL-blasts are factors that seem to define a specific subgroup of APL patients. Together with other diagnostic tools currently available, they could be of value in planning treatment of APL patients.

[Isolated myeloid sarcoma involving the mediastinum]. / Izolirani mijeloidni sarkom medijastinuma.

Myeloid sarcoma is a rare extramedullary solid tumor consisting of immature myeloid cells and most commonly involving the bone, skin, lymph nodes, soft tissue, gastrointestinal tract and testis. Mediastinal myeloid sarcoma is very rare. There are two major types of myeloid sarcoma: granulocytic sarcoma and monoblastic sarcoma, according to immature cell type. Myeloid sarcoma is found in 2%-8% of patients with acute myeloid leukemia (AML). Myeloid sarcoma may develop before or concurrently with AML, or may be the initial manifestation of AML relapse in previously treated patients. Blast transformation of some form of myeloproliferative neoplasm or myelodysplastic syndrome may also manifest as myeloid sarcoma. A major differential diagnostic problem is isolated primary myeloid sarcoma without bone marrow and peripheral blood involvement, which may precede leukemic stage for months or years, and which is frequently misdiagnosed, mostly as malignant lymphoma. A case is presented of a 56-year-old female patient complaining of weakness, vertigo, dry cough and breathing difficulties. Clinical examination revealed enhanced vascular pattern on the right chest and right arm edema. Computed tomography (CT) of the thorax showed an expansive growth measuring 11 cm craniocaudally in the anterior mediastinum. Fine needle aspiration cytology of tumor mass yielded a scarcely cellular sample with individual atypical immature cells, fine chromatin structure and scarce cytoplasm with occasional granules and Auer rods. Considering the morphological, cytochemical and immunocytochemical characteristics of immature cells, the diagnosis of myeloid sarcoma was made and verified by histopathology of tumor biopsy sample. Immature cells were not found by analysis of bone marrow puncture sample, immunophenotyping of bone marrow cells and bone biopsy analysis. As immature cell proliferation was not detected in bone marrow and peripheral blood, while spread of the disease beyond the mediastinum was ruled out by imaging methods (CT, ultrasonography), it was decided to be a primary non-leukemic form of mediastinal myeloid sarcoma. Myeloid sarcoma should be taken in consideration on differential diagnosis of solid tumors because making an accurate diagnosis is necessary for timely initiation of appropriate therapy. Weakly expressed or lacking clear signs of myeloid differentiation may hamper morphological diagnosis. As isolated myeloid sarcoma is a very rare entity frequently resembling lymphoma in clinical presentation, it poses a major diagnostic challenge for both morphologists and clinicians.

Liver disease in the era of COVID-19: Is the worst yet to come?

The global social, economic and political crises related to coronavirus disease 2019 (COVID-19) presumably had more indirect than direct negative impacts on health systems. Drastic lifestyle changes, social isolation and distancing, and individual and global financial crises resulted in robust populations forfeiting healthy habits and seeking comfort in alcoholic beverages, drugs and unhealthy diets. The inevitable consequences are increases in the incidence of nonalcoholic fatty liver disease, viral hepatitis, acute alcoholic hepatitis, liver cirrhosis decompensation and ultimately liver-related mortality. The inaccessibility of regular clinical and sonographic monitoring systems has caused difficulties in the treatment of patients with chronic liver disease (CLD) and has prevented prompt hepatocellular carcinoma detection and treatment. A dramatic reduction in the number of liver donors and the transformation of numerous transplantation centers into COVID-19 units drastically decreased the rate of orthotopic liver transplantation. The indirect, unavoidable effects of the COVID-19 pandemic in the following years have yet to be determined. Substantial efforts in the management of patients with liver disease in order to overcome the inevitable COVID-19-related morbidity and mortality that will follow have yet to be initiated. Several questions regarding the impact of the COVID-19 pandemic on liver disease remain. The most important question for general CLD patients is: How will the modification of clinical practice during this pandemic affect the outcomes of CLD patients? This article reviews the influence of COVID-19 on patients with liver disease during the pandemic, with particular emphasis on the disease course associated with pandemic resolution.

Noninvasive markers of liver steatosis and fibrosis after liver transplantation - Where do we stand?

In the last two decades, advances in immunosuppressive regimens have led to fewer complications of acute rejection crisis and consequently improved short-term graft and patient survival. In parallel with this great success, long-term post-transplantation complications have become a focus of interest of doctors engaged in transplant medicine. Metabolic syndrome (MetS) and its individual components, namely, obesity, dyslipidemia, diabetes, and hypertension, often develop in the post-transplant setting and are associated with immuno-suppressive therapy. Nonalcoholic fatty liver disease (NAFLD) is closely related to MetS and its individual components and is the liver manifestation of MetS. Therefore, it is not surprising that MetS and its individual components are associated with recurrent or "de novo" NAFLD after liver transplantation (LT). Fibrosis of the graft is one of the main determinants of overall morbidity and mortality in the post-LT period. In the assessment of post-LT steatosis and fibrosis, we have biochemical markers, imaging methods and liver biopsy. Because of the significant economic burden of post-LT steatosis and fibrosis and its potential consequences, there is an unmet need for noninvasive methods that are efficient and cost-effective. Biochemical scores can overestimate fibrosis and are not a good method for fibrosis evaluation in liver transplant recipients due to frequent post-LT thrombocytopenia. Transient elastography with controlled attenuation parameter is a promising noninvasive method for steatosis and fibrosis. In this review, we will specifically focus on the evaluation of steatosis and fibrosis in the post-LT setting in the context of de novo or recurrent NAFLD.

Metabolism of Direct-acting Antiviral Agents (DAAs) in Hepatitis C Therapy: A Review of the Literature.

BACKGROUND: Hepatitis C virus (HCV) infection is still one of the leading causes of chronic liver disease, with chronically infected making up approximately 1% of the global population. Of those infected, 70% (55-85%) will develop chronic HCV infection. Chronic HCV infection causes substantial morbidity and mortality, with complications including cirrhosis, end-stage liver disease, hepatocellular carcinoma, and eventually death. OBJECTIVE: Therapeutic options for chronic HCV infection have evolved dramatically since 2014, with a translation from pegylated interferon and ribavirin (associated with suboptimal cure and high treatment-related toxicity) to oral direct-acting antiviral treatment. There are four classes of direct-acting antivirals which differ by their mechanism of action and therapeutic target. They are all pointed to proteins that form the cytoplasmic viral replication complex. Multiple studies have demonstrated that direct-acting antiviral therapy is extremely well tolerated, highly efficacious, with few side effects. METHODS: We performed an indexed MEDLINE search with keywords regarding specific direct-acting antiviral regimes and their pharmacokinetics, drug-drug interactions, and metabolism in specific settings of pregnancy, lactation, liver cirrhosis, liver transplantation and HCC risk, kidney failure and kidney transplantation. RESULTS: We present a comprehensive overview of specific direct-acting antiviral metabolism and drug-drug interaction issues in different settings. CONCLUSION: Despite its complex pharmacokinetics and the possibility of drug-drug interactions, direct-acting antivirals are highly efficacious in providing viral clearance, which is an obvious advantage compared to possible interactions or side effects. They should be administered cautiously in patients with other comorbidities, and with tight control of immunosuppressive therapy.

Accuracy of Controlled Attenuation Parameter and Liver Stiffness Measurement in Patients with Non-alcoholic Fatty Liver Disease.

We evaluated the diagnostic accuracy of the controlled attenuation parameter (CAP) and liver stiffness measurements (LSM) measured with either an M or XL probe against liver biopsy (LB) in patients with non-alcoholic fatty liver disease (NAFLD). This study was a cross-sectional prospective study that included 179 NAFLD patients. With a cutoff value for CAP ≥345, we can exclude significant steatosis in 87% (79.4%-92.5%) of our population. With respect to the LSM, the highest accuracy was obtained for F ≥ F3 (area under the receiver operating characteristic curve [AUROC] = 0.98) and F = F4 (AUROC = 0.98). In a multivariable linear regression model, significant predictors influencing LSM were fibrosis stage (ß = 2.6, p < 0.001) as a positive predictor and lobular inflammation (ß = -0.68, p = 0.04) as a negative predictor, without significant influence after adjustment for CAP and probe type. We found that CAP is a satisfactory method for excluding advanced steatosis, while LSM is a good non-invasive marker for the exclusion of fibrosis.