Association between a genetic index for digital dermatitis resistance and the presence of digital dermatitis, heel horn erosion and interdigital hyperplasia in Holstein cows.

Digital dermatitis (DD) is a polybacterial disease endemic to most UK dairy farms. It poses a major financial and welfare threat and is characterized by high incidence and recurrence rates. We aimed to investigate the association between the UK estimated breeding value for resistance to digital dermatitis, the Digital Dermatitis Index (DDI) and the frequency of DD, heel horn erosion (HHE), and interdigital hyperplasia (IH) in a population of Holstein dairy cows. We enrolled and genotyped 2,352 cows from 4 farms in a prospective cohort study. Foot lesion records were recorded by veterinary surgeons for each animal at 4 time points during a production cycle, starting at approximately 2 mo before calving and ending in late lactation. Importantly, these records were not used in the calculation of the DDI. Lesion records were matched to the animal's own DDI (n = 2,101) and their sire's DDI (n = 1,812). Digital Dermatitis Index values in our study population ranged from -1.41 to +1.2 and were transformed to represent distance from the mean expressed in standard deviations. The relationship between the DDI and the presence of DD was investigated using a logistic regression model, with farm, parity, and a farm-parity interaction fitted as covariates. A multivariable logistic regression model was fitted to evaluate the relationship between HHE and DDI with farm fitted as a covariate. Finally, a univariable logistic regression model with DDI as explanatory variable was used to investigate the relationship between IH and DDI. The odds ratio of an animal being affected by DD was 0.69 for one standard deviation (SD) increase in the animal's DDI (95% confidence interval (CI) = 0.63-0.76). The odds of HHE and IH were 0.69 (95%CI = 0.62-0.76) and 0.58 (95%CI = 0.49-0.68) respectively for one SD increase in DDI. The adjusted probability of DD was 32% (95% CI = 27-36%) for cows with mean DDI value of 0 while it was 24% (95% CI = 20-29%) in cows with a DDI value of +1. Sire DDI breeding values were standardized in the same way and then binned into terciles creating an ordinal variable representing bulls of high, medium, and low genetic merit for DD resistance. The daughters of low genetic merit bulls were at 2.05 (95% CI = 1.60-2.64), 1.96 (95% CI = 1.53-2.50), and 2.85 (95% CI = 1.64-5.16) times greater odds of being affected by DD, HHE, and IH respectively compared with the daughters of high genetic merit bulls. The results of this study highlight the potential of digital dermatitis genetic indexes to aid herd management of DD, and suggest that breeding for resistance to DD, alongside environmental and management control practices, could reduce the prevalence of the disease.

Development and validation of a fully automated 2-dimensional imaging system generating body condition scores for dairy cows using machine learning.

Monitoring body condition score (BCS) is a useful management tool to estimate the energy reserves of an individual cow or a group of cows. The aim of this study was to develop and evaluate the performance of a fully automated 2-dimensional imaging system using a machine learning algorithm to generate real-time BCS for dairy cows. Two separate datasets were used for training and testing. The training dataset included 34,150 manual BCS (MAN_BCS) assigned by 5 experienced veterinarians during 35 visits at 7 dairy farms. Ordinal regression methods and deep learning architecture were used when developing the algorithm. Subsequently, the testing dataset was used to evaluate the developed BCS prediction algorithm on 4 of the participating farms. An experienced human assessor (HA1) visited these farms and performed 8 whole-milking-herd BCS sessions. Each farm was visited twice, allowing for 30 d (±2 d) to pass between visits. The MAN_BCS assigned by HA1 were considered the ground truth data. At the end of the validation study, MAN_BCS were merged with the stored automated BCS (AI_BCS), resulting in a testing dataset of 9,657 single BCS. A total of 3,817 cows in the testing dataset were scored twice 30 d (±2 d) apart, and the change in their BCS (ΔBCS) was calculated. A subset of cows at one farm were scored twice on consecutive days to evaluate the within-observer agreement of both the human assessor and the system. The manual BCS of 2 more assessors (HA2 and HA3) were used to assess the interobserver agreement between humans. Finally, we also collected ultrasound measurements of backfat thickness (BFT) from 111 randomly selected cows with available MAN_BCS and AI_BCS. Using the testing dataset, intra- and interobserver agreement for single BCS and ΔBCS were estimated by calculating the simple percentage agreement (PA) at 3 error levels and the weighted kappa (κw) for the exact agreement. A Bland-Altman plot was constructed to visualize the systematic and proportional bias. The association between MAN_BCS and AI_BCS and the BFT was assessed with Passing-Bablok regressions. The system had an almost perfect repeatability with a κw of 0.99. The agreement between MAN_BCS and AI_BCS was substantial, with an overall κw of 0.69. The overall PA at the exact, ± 0.25-unit, and ± 0.50-unit BCS error range between MAN_BCS and AI_BCS was 44.4%, 84.6%, and 94.8%, respectively, and greater than the PA obtained between HA1 and HA3. The Bland-Altman plot revealed a minimal systematic bias of -0.09 with a proportional bias at the extreme scores. Furthermore, despite the low κw of 0.20, the overall PA at the exact and ± 0.25-unit of BCS error range between MAN_BCS and AI_BCS regarding the ΔBCS was 45.7 and 88.2%, respectively. A strong linear relationship was observed between BFT and AI_BCS (ρ = 0.75), although weaker than that between BFT and MAN_BCS (ρ = 0.91). The system was able to predict single BCS and ΔBCS with satisfactory accuracy, comparable to that obtained between trained human scorers.

Molecular and Clinical Characteristics of Different Toxicity Rates in Anti-CD19 Chimeric Antigen Receptor T Cells: Real-World Experience.

Commercially available anti-CD19 chimeric antigen receptor T cells (CARΤ cells) have offered long-term survival to a constantly expanding patient population. Given that novel toxicities including cytokine release syndrome (CRS) and neurotoxicity (ICANS) have been observed, we aimed to document the safety and toxicity of this treatment in a real-world study. We enrolled 31 adult patients referred to our center for CAR T therapy. Tisagenlecleucel was infused in 12 patients, axicabtagene ciloleucel in 14, and brexucabtagene autoleucel in 5. Cytokine release syndrome was noted in 26 patients while neurotoxicity was observed in 7. Tocilizumab was administered for CRS in 18 patients, along with short-term, low-dose steroid administration in one patient who developed grade III CRS and, subsequently, grade I ICANS. High-dose steroids, along with anakinra and siltuximab, were administered in only two MCL patients. With a median follow-up time of 13.4 months, nine patients were then in CR. The progression-free (PFS) and overall survival (OS) rates were 41.2% and 88.1% at one year, respectively. MCL diagnosis, which coincides with the administration of brexucabtagene autoleucel, was the only factor to be independently associated with poor OS (p < 0.001); meanwhile, increased LDH independently predicted PFS (p = 0.027).In addition, CRP at day 14 was associated with a poor OS (p = 0.001). Therefore, our real-world experience confirmed that commercial CAR T therapy can be administered with minimal toxicity.

Laparoscopic surgery in a child with a failing Fontan circulation.

A child with early failure of a Fontan circulation was listed for cardiac transplantation and then developed a subhepatic abscess. Surgical drainage was deemed necessary after the failure of an attempted percutaneous procedure. Following a multidisciplinary discussion, a laparoscopic technique was chosen to optimise postoperative recovery. To our knowledge, the literature does not describe any case of laparoscopic surgery in a patient with a failing Fontan circulation. This case report highlights the physiological variations involved with this management strategy, discusses the implications and risks, and offers some recommendations.

A study on the use of thermal imaging as a diagnostic tool for the detection of digital dermatitis in dairy cattle.

Our aims were to (1) determine how interdigital skin temperature (IST), measured using infrared thermography, was associated with different stages of digital dermatitis (DD) lesions and (2) develop and validate models that can use IST measurements to identify cows with an active DD lesion. Between March 2019 and March 2020, infrared thermographic images of hind feet were taken from 2,334 Holstein cows across 4 farms. We recorded the maximum temperature reading from infrared thermographic images of the interdigital skin between the heel bulbs on the hind feet. Pregnant animals were enrolled approximately 1 to 2 mo precalving, reassessed 1 wk after calving, and again at approximately 50 to 100 d postpartum. At these time points, IST and the clinical stage of DD (M-stage scoring system: M1-M4.1) were recorded in addition to other data such as the ambient environmental temperature, height, body condition score, parity, and the presence of other foot lesions. A mixed effect linear regression model with IST as the dependent variable was fitted. Interdigital skin temperature was associated with DD lesions; compared to healthy feet, IST was highest in feet with M2 lesions, followed by M1 and M4.1 lesions. Subsequently, the capacity of IST measurements to detect the presence or absence of an active DD lesion (M1, M2, or M4.1) was explored by fitting logistic regression models, which were tested using 10-fold validation. A mixed effect logistic regression model with the presence of active DD as the dependent variable was fitted first. The average area under the curve for this model was 0.80 when its ability to detect presence of active DD was tested on 10% of the data that were not used for the model's training; an average sensitivity of 0.77 and an average specificity of 0.67 was achieved. This model was then restricted so that only explanatory variables that could be practically recorded in a nonresearch, external setting were included. Validation of this model demonstrated an average area under the curve of 0.78, a sensitivity of 0.88, and a specificity of 0.66 for 1 of the time points (precalving). Lower sensitivity and specificity were achieved for the other 2 time points. Our study adds further evidence to the relationship between DD and foot skin temperature using a large data set with multiple measurements per animal. Additionally, we highlight the potential for infrared thermography to be used for routine on-farm diagnosis of active DD lesions.

Outcome in patients with diffuse large B-cell lymphoma who relapse after autologous stem cell transplantation and receive active therapy. A retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) who relapse/progress after first line chemoimmunotherapy. Long-term outcome of those who relapse after transplant is poor. We present the results of a retrospective study of 256 adult patients reported to the EBMT registry with DLBCL who relapsed after auto-HSCT performed between 2003 and 2013, and who received active salvage strategies. One hundred and fifty-four (60%) were male; median age was 53 years. Median time to relapse was 7 months, 65% relapsed during the first year. Overall response rate after salvage therapy was 46%. Median follow-up after first salvage therapy was 40 months (IQR 23-63 months). Overall survival (OS) at 3 years was 27% (95% CI 22-33). OS at 3 years of patients relapsing longer than 1 year after auto-HSCT was 41% (95% CI 31-53) compared with 20% (95% CI 14-24) in those who relapsed in less than 1 year. Eighty-two patients (32%) had a second HSCT, an allogeneic HSCT (allo-HSCT) in 69 cases, at a median time of 6.5 months after relapse. OS at 3 years after allo-HSCT was 36% (95% CI 25-51). In conclusion, the prognosis of patients with DLBCL that relapse after auto-HSCT is dismal. Patients who relapse in less than 1 year remain an unmet need, and should be considered for CAR T cell therapy or clinical trials. Patients who relapse after 1 year can be rescued with salvage therapies and a second HSCT. These results provide a benchmark to compare data of new prospective studies.

Synovial C-reactive protein features high negative predictive value but is not useful as a single diagnostic parameter in suspected periprosthetic joint infection (PJI).

OBJECTIVES: Synovial fluid C-reactive protein (syCRP) has been recently described as a new biomarker in preoperative diagnostics to identify periprosthetic joint infections (PJI). The aim of this study was to evaluate syCRP in a large cohort of patients with suspected PJI and to calculate the optimal cut-off to diagnose PJI. METHODS: Between September 2015 and June 2017, we prospectively included patients with suspected PJI, in which syCRP was additionally measured along with routine preoperative diagnostic serum and synovial biomarkers. We analysed the sensitivity and specificity of syCRP using receiver operating characteristic curves. RESULTS: We included 192 cases (hip n = 80, knee n = 91, shoulder n = 21) with a final diagnosis of PJI in 26 cases (14.0%). Combined for all joints, the syCRP values were significantly higher in the PJI group than in the no PJI group (median: 13.8 vs. 0 mg/l; p < 0.001). The optimal cut-off (Youden Index: 0.71) for the PJI diagnosis combined for all joints was at a syCRP value of 2.9 mg/l with a sensitivity of 88%, a specificity of 82%, and a negative predictive value of 98%. CONCLUSIONS: SyCRP features high negative predictive value but is not useful as a single diagnostic parameter in suspected periprosthetic joint infection (PJI).

[Painful lymphadenopathy after an insect bite-a case report]. / Schmerzhafte Lymphadenopathie nach Insektenstich ­ ein Fallbericht.

Tularemia is a bacterial zoonosis which is commonly transmitted through tick or insect bites or contact with meat of infected animals. We report the case of a 36-year-old man who developed fever, chills, headaches, and a painful, unilateral, inguinal lymphadenopathy with a red-livid skin discoloration after an insect bite on his abdomen. Ulceroglandular tularemia was diagnosed through polymerase chain reaction (PCR) and serology. Treatment with doxycycline for 21 days resulted in an excellent outcome.

Inflammatory disorders mimicking periprosthetic joint infections may result in false-positive α-defensin.

OBJECTIVES: The antimicrobial peptide α-defensin has recently been introduced as a potential 'single' biomarker with a high sensitivity and specificity for the preoperative diagnosis of periprosthetic joint infections (PJIs). However, most studies assessed the benefits of the test with exclusion of patients with rheumatic diseases. We aimed to evaluate the α-defensin test in a cohort study without exclusion of people with inflammatory diseases. METHODS: Between June 2016 and June 2017, we prospectively included cases with a suspected PJI and an available lateral flow test α-defensin (Synovasure®) in synovial fluid. We compared the test result to the diagnostic criteria for PJIs published by an International Consensus Group in 2013. RESULTS: We included 109 cases (49 hips, 60 knees) in which preoperative α-defensin tests had been performed. Among these, 20 PJIs (16 hips, four knees) were diagnosed. Preoperative α-defensin tests were positive in 25 cases (22.9%) with a test sensitivity and specificity of 90% and 92.1% (95% CI 68.3%-98.8% and 84.5%-96.8%, respectively), and a high negative predictive value of 97.6% (95% CI 91.7%-99.4%). We interpreted seven α-defensin tests as false positive, mainly in cases with inflammatory rheumatic diseases, including crystal deposition diseases. CONCLUSIONS: A negative synovial α-defensin test can reliably rule out a PJI. However, the test can be false positive in conjunction with an underlying non-infectious inflammatory disease. We therefore propose to use the α-defensin test only in combination with Musculoskeletal Infection Society criteria and assessment for crystals in synovial aspirates.

Pediatric brain tumors: Update of proteome-based studies.

Pediatric brain tumors (PBTs) are the most common solid malignancies in childhood and continue to pose a serious burden to modern societies. Existing treatments impose debilitating effects on the developing child, highlighting the need for molecularly targeted treatments with reduced toxicity, as well as the necessity of markers that reliably assess efficacy of, and tumor response to targeted-therapies of PBTs. On this regard advances in technologies of protein identification and quantification, the large-scale, high-throughput investigation of the proteome, as well the newly-emerging field of "proteogenomics" aim to further our knowledge towards understanding the molecular pathophysiology of PBTs. This mini review article presents all updates on knowledge produced and published during the last years on PBT research derived from "omics" technologies, mainly involving protein research and proteomics.

[Long-term results of the compatibility of a coralline hydroxyapatite implant as eye replacement]. / Langzeitergebnisse zur Verträglichkeit eines korallinen Hydroxylapatitimplantats als Bulbusersatz.

BACKGROUND: Coralline hydroxyapatite has been used since 1983 as volume replacement. Through 2001, a total of 200 hydroxyapatite implants were used in our department. OBJECTIVE: This prospective study was undertaken to measure the subjective and objective long-term tolerance of this implant. MATERIALS AND METHODS: In 2012, a total of 20 patients were examined, who were enucleated or eviscerated between 1993 and 2001 (average follow-up 16.2 years) and had an hydroxyapatite implant placed with a scleral sheath. We evaluated the subjective tolerance and measured the motility, the prominence of the globe, lid positions, changes of the conjunctiva and postoperative complications. RESULTS: The subjective long-term tolerance was reported to be good. All patients had a ptosis; an ectropion was found in 50% of patients. In 40% of the patients additional surgery was performed. The motility was better in primary than in secondary placed implants. Volume replacement was successful in 10 patients, 9 patients had a retraction and 1 patient a prominent prosthesis. DISCUSSION: Hydroxyapatite implants with sclera sheathing were well tolerated and showed good motility on long-term follow-up over more than 16 years. Lid malpositions such as ptosis or ectropion are common but might be due to mechanical stress through the prosthesis and atrophy of the orbital fat.

Protein expression during early stages of bone regeneration under hydrophobic and hydrophilic titanium domes. A pilot study.

BACKGROUND AND OBJECTIVES: There is significant evidence that, during the early stages of osseointegration, moderately rough hydrophilic (SLActive) surfaces can accelerate osteogenesis and increase bone-to-implant contact in comparison to hydrophobic (SLA) surfaces. However, very little is known regarding the molecular mechanisms behind the influence that surface chemistry modifications to increase hydrophilicity determine on bone healing. The aim of this study was to describe for the first time the proteins and related signalling pathways expressed during early osseous healing stages under SLA and SLActive titanium domes for guided bone regeneration. MATERIAL AND METHODS: One SLA and 1 SLActive dome with an internal diameter of 5.0 mm and a height of 3.0 mm were secured to the parietal bones of nine 6-month-old male New Zealand rabbits. Three animals were randomly euthanized at 4, 7 and 14 days and the newly formed tissues retrieved under the domes were analysed with liquid chromatography-mass spectrometry/mass spectrometry. STRING and KEGG databases were applied for Gene Ontology and pathway analyses. RESULTS: A different modulation of several pathways was detected between the 2 groups at all healing times. The main differences in the osseous healing response associated to the 2 surfaces were related to pathways involved in regulating the inflammatory response, differentiation of osteoblast precursors and skeletogenesis. At day 7, the highest number of proteins and the highest cellular activity were observed in both groups, although a more complex and articulated proteome in terms of cellular metabolism and signal transduction was observed in SLActive samples. CONCLUSION: This is the first study describing the proteome expressed during early healing stages of guided bone regeneration and osseointegration. A combination of enhanced early osteogenic response and reduced inflammatory response were suggested for the hydrophilic group. Future studies are needed to corroborate these findings and explore the molecular effects of different titanium surfaces on the cascade of events taking place during bone formation.

Transplant-associated thrombotic microangiopathy: opening Pandora's box.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an early complication of hematopoietic cell transplantation (HCT). A high mortality rate is documented in patients who are refractory to calcineurin inhibitor cessation. Estimates of TA-TMA prevalence vary significantly and are higher in allogeneic compared with autologous HCT. Furthermore, our understanding of the pathophysiology that is strongly related to diagnosis and treatment options is limited. Recent evidence has linked TA-TMA with atypical hemolytic uremic syndrome, a disease of excessive activation of the alternative pathway of complement, opening the Pandora's box in treatment options. As conventional treatment management is highly inefficient, detection of complement activation may allow for early recognition of patients who will benefit from complement inhibition. Preliminary clinical results showing successful eculizumab administration in children and adults with TA-TMA need to be carefully evaluated. Therefore, realizing the unmet needs of better understanding TA-TMA in this complex setting, we aimed to summarize current knowledge focusing on (1) critical evaluation of diagnostic criteria, (2) epidemiology and prognosis, (3) recent evidence of complement activation and endothelial damage and (4) treatment options.

Safety and Cost Considerations during the Introduction Period of Laparoscopic Radical Hysterectomy.

Objective. To compare the safety, efficacy, and direct cost during the introduction of laparoscopic radical hysterectomy within an enhanced recovery pathway. Methods. A 1 : 1 single centre retrospective case control study of 36 propensity matched pairs of patients receiving open or laparoscopic surgery for early cervical cancer. Results. There were no significant differences in the baseline characteristics of the two cohorts. Open surgery cohort had significantly higher intraoperative blood loss (189 versus 934 mL) and longer postoperative hospital stay (2.3 versus 4.1 days). Although no significant difference in the intraoperative or postoperative complications was found more urinary tract injuries were recorded in the laparoscopic cohort. Laparoscopic surgery had significantly longer duration (206 versus 159 minutes), lower lymph node harvest (12.6 versus 16.9), and slower bladder function recovery. The median direct hospital cost was £4850 for laparoscopic radical hysterectomy and £4400 for open surgery. Conclusions. Laparoscopic radical hysterectomy can be safely introduced in an enhanced recovery environment without significant increase in perioperative morbidity. The 10% higher direct hospital cost is not statistically significant and is expected to even out when indirect costs are included.

The effect of experimental osteoporosis on bone regeneration: part 2, proteomics results.

OBJECTIVES: To identify and describe protein expression in a Wistar rat calvarial critical size defect (CSD) model following treatment with guided bone regeneration in healthy and osteoporotic conditions. MATERIAL AND METHODS: Thirty-six 10-month-old female Wistar rats were used. Half of them were ovariectomized (OVX) and fed with a low-calcium diet to induce an osteoporotic-like status. In each animal of both groups, two 5-mm calvarial CSDs were treated with deproteinized bovine bone mineral graft particles and a bilayer collagen membrane. Six OVX and six control rats were randomly euthanized at 7, 14, and 30 days. One defect/animal was randomly chosen for proteomic analysis. Differently expressed proteins between the two groups were identified with matrix-assisted laser desorption time-of-flight mass spectrometry and liquid chromatography-mass spectrometry/mass spectrometry. RESULTS: At 7 days, 29 and 27 proteins were, respectively, identified in the healthy and OVX animals. At 14 days, 103 proteins were detected in the healthy controls and 20 proteins in the OVX rats, while at 30 days, 31 and 75 proteins were identified, respectively. Only limited proteins known to play a role in the later stages of bone formation and maturation were identified within the animals 'proteomes. DISCUSSION: The osseous formation process was quite immature even at 30 days of healing. An overexpression of inflammatory and stress response pathways was detected in the OVX animals, as well as a tendency toward a delayed maturation of the osseous wound and a reduced/delayed differentiation of osteoblast cell precursors.

Restrictions in the T-cell repertoire of chronic lymphocytic leukemia: high-throughput immunoprofiling supports selection by shared antigenic elements.

Immunoglobulin (IG) gene repertoire restrictions strongly support antigen selection in the pathogenesis of chronic lymphocytic leukemia (CLL). Given the emerging multifarious interactions between CLL and bystander T cells, we sought to determine whether antigen(s) are also selecting T cells in CLL. We performed a large-scale, next-generation sequencing (NGS) study of the T-cell repertoire, focusing on major stereotyped subsets representing CLL subgroups with undisputed antigenic drive, but also included patients carrying non-subset IG rearrangements to seek for T-cell immunogenetic signatures ubiquitous in CLL. Considering the inherent limitations of NGS, we deployed bioinformatics algorithms for qualitative curation of T-cell receptor rearrangements, and included multiple types of controls. Overall, we document the clonal architecture of the T-cell repertoire in CLL. These T-cell clones persist and further expand overtime, and can be shared by different patients, most especially patients belonging to the same stereotyped subset. Notably, these shared clonotypes appear to be disease-specific, as they are found in neither public databases nor healthy controls. Altogether, these findings indicate that antigen drive likely underlies T-cell expansions in CLL and may be acting in a CLL subset-specific context. Whether these are the same antigens interacting with the malignant clone or tumor-derived antigens remains to be elucidated.

Recurrent mutations refine prognosis in chronic lymphocytic leukemia.

Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.

Efficacy of lead-in silibinin and subsequent triple therapy in difficult-to-treat HIV/hepatitis C virus-coinfected patients.

OBJECTIVES: The efficacy of current hepatitis C virus (HCV) triple therapy, including a protease inhibitor, is limited in HIV/HCV-coinfected patients with advanced liver fibrosis and nonresponse to previous peginterferon-ribavirin. These patients have a low chance (only 30%) of achieving a sustained virological response (SVR) during triple therapy and cannot wait for next-generation anti-HCV drugs. In a pilot study, we investigated the efficacy of a lead-in therapy with silibinin before triple therapy in difficult-to-treat patients. METHODS: Inclusion criteria were HIV/HCV coinfection with advanced liver fibrosis and documented failure of previous peginterferon-ribavirin treatment. Intervention was lead-in therapy with intravenous silibinin 20 mg/kg/day for 14 days. Subsequently, peginterferon-ribavirin combined with telaprevir was initiated for 12 weeks, followed by peginterferon-ribavirin dual therapy until week 48 after initiation of triple therapy. The outcome measurements were HCV RNA after silibinin lead-in, at weeks 2, 4 and 12 of triple therapy, and SVR at week 24 after the end of treatment. RESULTS: We examined six HIV/HCV-coinfected patients (four infected with genotype 1a). All had fibrosis grade METAVIR ≥F3 and were on fully suppressive antiretroviral therapy. Mean HCV RNA decline after silibinin therapy was 2.6 log10 IU/mL (range 2-3 log10 IU/mL). Five of the six patients were virologically suppressed at weeks 2 and 4, and all six at week 12 of triple therapy. One experienced a viral breakthrough thereafter. Four of five patients (80%) showed an SVR 24. One patient had an SVR 12 but has not yet reached week 24. CONCLUSIONS: A lead-in with silibinin before triple therapy is highly effective and increases the probability of HCV treatment success in difficult-to-treat HIV/HCV-coinfected patients with advanced liver fibrosis and previous failure of peginterferon-ribavirin.