Acalabrutinib in treatment-naive chronic lymphocytic leukemia.

Acalabrutinib has demonstrated significant efficacy and safety in relapsed chronic lymphocytic leukemia (CLL). Efficacy and safety of acalabrutinib monotherapy were evaluated in a treatment-naive CLL cohort of a single-arm phase 1/2 trial (ACE-CL-001). Adults were eligible for enrollment if chemotherapy was declined or deemed inappropriate due to comorbidities (N = 99). Patients had a median age of 64 years and 47% had Rai stage III/IV disease. Acalabrutinib was administered orally 200 mg once daily, or 100 mg twice daily until progression or intolerance. A total of 99 patients were treated; 57 (62%) had unmutated immunoglobulin heavy-chain variable gene, and 12 (18%) had TP53 aberrations. After median follow-up of 53 months, 85 patients remain on treatment; 14 discontinued treatment, mostly because of adverse events (AEs) (n = 6) or disease progression (n = 3). Overall response rate was 97% (90% partial response; 7% complete response), with similar outcomes among all prognostic subgroups. Because of improved trough BTK occupancy with twice-daily dosing, all patients were transitioned to 100 mg twice daily. Median duration of response (DOR) was not reached; 48-month DOR rate was 97% (95% confidence interval, 90-99). Serious AEs were reported in 38 patients (38%). AEs required discontinuation in 6 patients (6%) because of second primary cancers (n = 4) and infection (n = 2). Grade ≥3 events of special interest included infection (15%), hypertension (11%), bleeding events (3%), and atrial fibrillation (2%). Durable efficacy and long-term safety of acalabrutinib in this trial support its use in clinical management of symptomatic, untreated patients with CLL.

The modulation and mechanism of probiotic-derived polysaccharide capsules on the immune response in allergic diseases.

Allergic diseases, derived from the dysregulation of immune tolerance mechanisms, have been rising in the last two decades. Recently, increasing evidence has shown that probiotic-derived polysaccharide capsules exhibit a protective effect against allergic diseases, involving regulation of Th1/Th2 balance, induction of differentiation of T regulatory cells and activation of dendritic cells (DCs). DCs have a central role in controlling the immune response through their interaction with gut microbiota via their pattern recognition receptors, including Toll-like receptors and C-type-lectin receptors. This review discusses the effects and critical mechanism of probiotic-derived polysaccharide capsules in regulating the immune system to alleviate allergic diseases. We first describe the development of immune response in allergic diseases and recent relevant findings. Particular emphasis is placed on the effects of probiotic-derived polysaccharide capsules on allergic immune response. Then, we discuss the underlying mechanism of the impact of probiotic-derived polysaccharide capsules on DCs-mediated immune tolerance induction.

The role of rectal ultrasound in children with functional constipation.

AIM: The study aimed primarily to compare the transverse rectal diameter in children with functional constipation (FC) and children without constipation in different age groups, and between cases of constipation at baseline and after treatment. Secondary aim was to determine factors that could affect the transverse rectal diameter. METHODS: A controlled prospective study, including a total of 100 children between the ages of 2 and 11 years, who were divided into 50 patients suffering from constipation according to Rome IV criteria and 50 age- and sex-matched controls. Transverse rectal diameter was measured at presentation, and after 3 months of laxative therapy and behavioural modification. RESULTS: Initial rectal diameter was significantly different between cases (3.55 cm (interquartile range, IQR), 3.2-4) and controls (2.3 cm (IQR, 1.8-2.5)), P value < 0.001, and it was also significantly different between those above and below 4 years, so a separate cut-off point for diagnosis of constipation was suggested being >3 cm for the former and >2.5 cm for the latter. After 3 months of follow-up, rectal diameter significantly reduced to become 2.6 (IQR, 2-2.8), P value < 0.001. Duration of symptoms positively correlated with rectal diameter. CONCLUSIONS: Ultrasound measurement of rectal diameter is an important tool to diagnose and follow-up functional constipation in children. Different values of rectal diameter are found between those above and below 4 years of age.

Clinical and biological implications of target occupancy in CLL treated with the BTK inhibitor acalabrutinib.

Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Target occupancy is a measure of covalent binding to BTK and has been applied as a pharmacodynamic parameter in clinical studies of BTK inhibitors. However, the kinetics of de novo BTK synthesis, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remain undefined. This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily (BID) or 200 mg once daily (QD) in 48 patients with relapsed/refractory or high-risk treatment-naïve CLL. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% confidence interval [CI], 78.9-99.9) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI, 70.0-97.8) with BID dosing and an ORR of 79.2% (95% CI, 57.9-92.9) and an estimated PFS rate at 24 months of 87.2% (95% CI, 57.2-96.7) with QD dosing. BTK resynthesis was faster in patients with CLL than in healthy volunteers. BID dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared with QD dosing. Small increments in occupancy attained by BID dosing relative to QD dosing compounded over time to augment downstream biological effects. The impact of BTK occupancy on long-term clinical outcomes remains to be determined. This trial was registered at www.clinicaltrials.gov as #NCT02337829.

Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results.

Therapeutic targeting of Bruton tyrosine kinase (BTK) has dramatically improved survival outcomes for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Acalabrutinib is an oral, highly selective BTK inhibitor that allows for twice-daily dosing due to its selectivity. In this phase 1b/2 study, 134 patients with relapsed/refractory CLL or SLL (median age, 66 years [range, 42-85 years]; median prior therapies, 2 [range, 1-13]) received acalabrutinib 100 mg twice daily for a median of 41 months (range, 0.2-58 months). Median trough BTK occupancy at steady state was 97%. Most adverse events (AEs) were mild or moderate, and were most commonly diarrhea (52%) and headache (51%). Grade ≥3 AEs (occurring in ≥5% of patients) were neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status). Median duration of response and progression-free survival (PFS) have not been reached; the estimated 45-month PFS was 62% (95% confidence interval, 51% to 71%). BTK mutation was detected in 6 of 9 patients (67%) at relapse. This updated and expanded study confirms the efficacy, durability of response, and long-term safety of acalabrutinib, justifying its further investigation in previously untreated and treated patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.

Ursodeoxycholic acid for the prevention of gall stones after laparoscopic sleeve gastrectomy: a prospective controlled study.

BACKGROUND: Obesity is a risk factor for cholelithiasis. Besides, rapid weight loss after bariatric surgery upsurges the rate of cholelithiasis and acute cholecystitis. This study aimed to compare gallstone development frequency after LSG under ursodeoxycholic acid (UDCA) prophylaxis. METHODS: This prospective controlled study included 332 patients scheduled for LSG randomized to receive 500 mg UDCA daily for 12 months (UDCA Group) or no treatment (Control Group). Ultrasonography was done 6 and 12 months after surgery to detect gallstones. Cholecystectomy was done for complicated cases of cholelithiasis. RESULTS: Seventy-one patients were lost to follow-up, and 3 developed severe adverse effects of UDCA and excluded. Data are presented for 130 patients in the UDCA group and 128 in the Control group. Collectively, 11 patients (8.5%) of the UDCA group and 41 (32.0%) of the Control group developed gall stones during the first postoperative year (p < 0.001). Cholecystectomy was indicated in 3 patients (2.3%) of the UDCA group and 9 (7.0%) of the Control group (p = 0.072). On multivariate analysis, higher BMI, dyslipidemia, and lacking UDCA prophylaxis were the independent factors significantly associated with stone development. Also, stone development was associated with higher weight loss after 6 and 12 months. CONCLUSION: UDCA 500 mg once daily for 12 months after LSG is effective in reducing gallstone formation at 1 year. UDCA administration reduced the frequency of cholecystectomies from 7 to 2.3%. High BMI and dyslipidemia are the independent preoperative factors significantly associated with stone development.

Society for Cardiovascular Magnetic Resonance 2019 Case of the Week series.

The Society for Cardiovascular Magnetic Resonance (SCMR) is an international society focused on the research, education, and clinical application of cardiovascular magnetic resonance (CMR). The SCMR web site ( https://www.scmr.org ) hosts a case series designed to present case reports demonstrating the unique attributes of CMR in the diagnosis or management of cardiovascular disease. Each clinical presentation is followed by a brief discussion of the disease and unique role of CMR in disease diagnosis or management guidance. By nature, some of these are somewhat esoteric, but all are instructive. In this publication, we provide a digital archive of the 2019 Case of the Week series as a means of further enhancing the education of those interested in CMR and as a means of more readily identifying these cases using a PubMed or similar search engine.

EGFR-Targeted Pentacyclic Triterpene Analogues for Glioma Therapy.

Glioma, particularly its most malignant form, glioblastoma multiforme (GBM), is the most common and aggressive malignant central nervous system tumor. The drawbacks of the current chemotherapy for GBM have aroused curiosity in the search for targeted therapies. Aberrantly overexpressed epidermal growth factor receptor (EGFR) in GBM results in poor prognosis, low survival rates, poor responses to therapy and recurrence, and therefore EGFR-targeted therapy stands out as a promising approach for the treatment of gliomas. In this context, a series of pentacyclic triterpene analogues were subjected to in vitro and in silico assays, which were conducted to assess their potency as EGFR-targeted anti-glioma agents. In particular, compound 10 was the most potent anti-glioma agent with an IC50 value of 5.82 µM towards U251 human glioblastoma cells. Taking into account its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), compound 10 exerts selective antitumor action towards Jurkat human leukemic T-cells. This compound also induced apoptosis and inhibited EGFR with an IC50 value of 9.43 µM compared to erlotinib (IC50 = 0.06 µM). Based on in vitro and in silico data, compound 10 stands out as a potential orally bioavailable EGFR-targeted anti-glioma agent endowed with the ability to cross the blood-brain barrier (BBB).

Antenatal perineal massage benefits in reducing perineal trauma and postpartum morbidities: a systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION AND HYPOTHESIS: Most vaginal births are associated with trauma to the perineum. The morbidity associated with perineal trauma can be significant, especially when it leads to third- and fourth-degree perineal tears. We hypothesized that antenatal perineal massage could decrease the incidence of perineal trauma, particularly severe perineal tears and other postpartum complications. METHODS: We searched four different databases from inception until August 2019 for the available trials. We included randomized controlled trials (RCTs) which assessed the effect of antenatal perineal massage (intervention group) versus control group (no antenatal perineal massage) in perineal trauma patients. Data were extracted from eligible studies and meta-analyzed using RevMan software. Primary outcomes were the risk of episiotomies and perineal tears. Secondary outcomes were perineal pain, second stage of labor duration, wound healing, anal incontinence, and Apgar scores at 1 and 5 min. RESULTS: Eleven RCTs with 3467 patients were analyzed. Women who received antenatal perineal massage had significantly lower incidence of episiotomies (RR = 0.79, 95% CI [0.72, 0.87], p < 0.001) and perineal tears (RR = 0.79, 95% CI [0.67, 0.94], p = 0.007), particularly the risk of third- and fourth-degree perineal tears (p = 0.03). Better wound healing and less perineal pain were evident in the antenatal perineal massage group. Antenatal perineal massage reduced the second stage of labor duration (p = 0.005) and anal incontinence (p = 0.003) with significant improvement in Apgar scores at 1 and 5 min (p = 0.01 and p = 0.02). CONCLUSIONS: Antenatal perineal massage is associated with a lower risk of severe perineal trauma and postpartum complications.

Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial.

BACKGROUND: Bruton tyrosine kinase is a clinically validated target in mantle cell lymphoma. Acalabrutinib (ACP-196) is a highly selective, potent Bruton tyrosine kinase inhibitor developed to minimise off-target activity. METHODS: In this open-label, phase 2 study, oral acalabrutinib (100 mg twice per day) was given to patients with relapsed or refractory mantle cell lymphoma, until disease progression or unacceptable toxicity. The primary endpoint was overall response assessed according to the Lugano classification, and safety analyses were done in all participants. This trial is registered with ClinicalTrials.gov, number NCT02213926. FINDINGS: From March 12, 2015, to Jan 5, 2016, 124 patients with relapsed or refractory mantle cell lymphoma were enrolled and all patients received treatment; median age 68 years. Patients received a median of two (IQR 1-2) previous therapies. At a median follow-up of 15·2 months, 100 (81%) patients achieved an overall response and 49 (40%) patients achieved a complete response. The Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached; the 12-month rates were 72% (95% CI 62-80), 67% (58-75), and 87% (79-92%), respectively. The most common adverse events were primarily grade 1 or 2 and were headache (47 [38%]), diarrhoea (38 [31%]), fatigue (34 [27%]), and myalgia (26 [21%]). The most common grade 3 or worse adverse events were neutropenia (13 [10%]), anaemia (11 [9%]), and pneumonia (six [5%]). There were no cases of atrial fibrillation and one case of grade 3 or worse haemorrhage. The median duration of treatment was 13·8 months. Treatment was discontinued in 54 (44%) patients, primarily due to progressive disease (39 [31%]) and adverse events (seven [6%]). INTERPRETATION: Acalabrutinib treatment provided a high rate of durable responses and a favourable safety profile in patients with relapsed or refractory mantle cell lymphoma. These findings suggest an important role for acalabrutinib in the treatment of this disease population. FUNDING: Acerta Pharma, a member of the AstraZeneca Group.

Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia.

BACKGROUND: Irreversible inhibition of Bruton's tyrosine kinase (BTK) by ibrutinib represents an important therapeutic advance for the treatment of chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromises its therapeutic index. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors. METHODS: In this uncontrolled, phase 1-2, multicenter study, we administered oral acalabrutinib to 61 patients who had relapsed CLL to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib. Patients were treated with acalabrutinib at a dose of 100 to 400 mg once daily in the dose-escalation (phase 1) portion of the study and 100 mg twice daily in the expansion (phase 2) portion. RESULTS: The median age of the patients was 62 years, and patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletion, and 75% had unmutated immunoglobulin heavy-chain variable genes. No dose-limiting toxic effects occurred during the dose-escalation portion of the study. The most common adverse events observed were headache (in 43% of the patients), diarrhea (in 39%), and increased weight (in 26%). Most adverse events were of grade 1 or 2. At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response with lymphocytosis; the remaining 5% of patients had stable disease. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%. No cases of Richter's transformation (CLL that has evolved into large-cell lymphoma) and only one case of CLL progression have occurred. CONCLUSIONS: In this study, the selective BTK inhibitor acalabrutinib had promising safety and efficacy profiles in patients with relapsed CLL, including those with chromosome 17p13.1 deletion. (Funded by the Acerta Pharma and others; ClinicalTrials.gov number, NCT02029443.).

Perfusion CT to Assess Response to Neoadjuvant Chemotherapy and Radiation Therapy in Pancreatic Ductal Adenocarcinoma: Initial Experience.

BackgroundChange in tumor size at CT is insufficient for reliable assessment of treatment response after neoadjuvant chemotherapy and radiation therapy (CRT) and shows poor correlation with histologic grading of response.PurposeTo investigate the use of perfusion CT to predict the response of pancreatic ductal adenocarcinoma (PDA) to CRT.Materials and MethodsBetween June 2016 and May 2018, study participants with biopsy-proven PDA were prospectively recruited to undergo perfusion CT before and after planned CRT. Blood flow (BF), blood volume (BV), and permeability-surface area product (PSP) were quantified from CT images. Participants were categorized into responders and nonresponders according to therapy response. The Mann-Whitney test was used to compare the baseline perfusion values between responders and nonresponders, and the Wilcoxon matched-pairs signed rank test was used to compare perfusion values before and after CRT.ResultsThe final cohort of 21 participants (median age, 68 years; interquartile range [IQR], 65-72 years; eight men) underwent dynamic perfusion (dual-source) CT before neoadjuvant CRT. All participants underwent pancreatectomy. Eighteen participants underwent post-CRT perfusion CT. Baseline BF was higher in responders (n = 10) than in nonresponders (n = 11) (median, 44 [IQR, 39-56] vs 28 [IQR, 16-52] mL/100 g/min; P = .04), while BV and PSP were similar between groups (median BV, 4.3 [IQR, 3.5-6.9] vs 2.0 [IQR, 1.6-6.5] mL/100 g, P = .15; median PSP, 25 [IQR, 21-30] vs 20 [IQR, 10-34] mL/100 g/min, P = .31). Response Evaluation Criteria in Solid Tumors (RECIST) and carbohydrate antigen (CA) 19-9 showed no correlation with perfusion parameters (eg, RECIST and BF: r = 0.05, P = .84, 95% confidence interval [CI]: -0.40, 0.48; CA 19-9 and BF: r = 0.06, P = .78, 95% CI: -0.39, 0.49) or histopathologic response (r = 0.16, P = .47, 95% CI: -0.3, 0.57 and r = 0.09, P = .71, 95% CI: -0.37, 0.51, respectively). For responders, perfusion parameters increased after CRT (eg, median BF, 54 [IQR, 42-73] vs 43 [IQR, 28-53] mL/100 g/min; P = .04). The perfusion change in nonresponders was not significant (median BF, 43 [IQR, 28-53] vs 33 [IQR, 16-52] mL/100 g/min; P = .06).ConclusionPerfusion CT may be useful in helping predict the histopathologic response to therapy in pancreatic ductal adenocarcinoma.© RSNA, 2019See also the editorial by Sinitsyn in this issue.

Outcome of sirolimus-based immunosuppression, fifteen years post-live-donor kidney transplantation: Single-center experience.

In a prospective randomized controlled trial, between May 2001 and January 2003, 132 live-donor kidney transplant recipients were randomized to receive sirolimus primary immunosuppression, either in combination with low dose tacrolimus (Tac group) or in combination with mycophenolate mofetil (MMF group). We have previously reported on 2- and 5-year follow-up results, with favorable patient and graft outcomes obtained in both groups. In view of recent published reports of increased risk of inferior outcomes among sirolimus-treated patients, we herein present results of an observational extension of the previously randomized patients 15 years post-transplantation. Mortality rates were 10.8% and 3% in Tac and MMF groups respectively after mean follow-up period of 11.2-11.8 years. Comparable graft survival rates were obtained in both groups ranging from 60% to 62.7%. The (MMF) group continued to have the advantage of remaining on primary plan of immunosuppression (56.7% of patients) as well as to maintain better graft function in terms of serum creatinine level. Herein, we presented longest term published data for sirolimus-based immunosuppression among live-donor kidney transplants with favorable outcome in terms of survival and graft function.

Comparative study and multiple linear regression analysis for assessment of chromatographic behavior of structurally related ß-blockers on different stationary phases.

A quantitative structure-retention relationship study was performed by thin layer chromatography on a number of ß-blockers using 315 molecular descriptors of which nine were selected to be having the most important physicochemical properties. These descriptors provide good correlations with chromatographic behavior of the studied structurally related drugs. This research was completed on three pretreated silica gel plates via impregnation in urea, sodium dodecyl sulfate, and dimethylformamide, hence it possesses varying interplay mechanisms and polarities. The retention parameters were obtained by utilizing four solvent systems of two additives of variable ratios, consequently specific polarities in addition to imparted different pH values using either glacial acetic acid or liquid ammonia. Calculated theoretical approaches prove good correlations between investigated descriptors and retention factors. Some correlations show excellent predicting models, which might be critical for toning better know-how relationships between chemical structures and retention of ß-blockers.

Zero-valent iron nanoparticles for methylene blue removal from aqueous solutions and textile wastewater treatment, with cost estimation.

Nanoscale zero-valent iron (nZVI) particles were investigated for the removal of methylene blue (MB) from aqueous solutions and the treatment of textile industry effluents. The nZVI material was characterized by XRD, TEM, EDS, FTIR, and SEM. It was demonstrated that several functional groups such as C-H, C = C, C-C, and C-O contributed to MB reduction. At initial MB concentration of 70 mg/L, the optimum pH was 6, achieving a removal efficiency of 72.1% using an nZVI dosage of 10 g/L, stirring rate of 150 rpm, and temperature of 30 °C within 30 min. The adsorption isotherm was described by the Langmuir model with monolayer coverage of 5.53 mg/g, and the Freundlich equation with multilayer adsorption capacity of 1.59 (mg/g)·(L/mg)1/n. The removal mechanisms of MB included reduction into colorless leuco-MB, precipitation as Fe(II)-MB, adsorption as ZVI-MB or FeOOH-MB, and/or degradation using •OH radicals. The synthesized nZVI particles were applied to reduce various organic and inorganic compounds, as well as heavy metal ions from real textile wastewater samples. The removal efficiencies of COD, BOD, TN, TP, Cu2+, Zn2+, and Pb2+ reached up to 91.9%, 87.5%, 65.2%, 78.1%, 100.0%, 29.6%, and 99.0%, respectively. The treatment cost of 1 m3 of textile wastewater was estimated as 1.66 $USD.

Relationship between matrix metalloproteinase-9 and common carotid artery intima media thickness.

Atherosclerosis causes significant morbidity and mortality. Carotid intima media thickness (IMT) predicts future ischaemic strok e incidence. Matrix metalloproteinases (MMPs) play a considerable role in atherosclerosis and hold therapeutic promise as well. To investigate the relationship between serum level of matrix metalloproteinase-9 (MMP-9) and common carotid artery intima media thickness (CCA-IMT) in patients with ischaemic stroke and asymptomatic subjects. Thirty patients with a previous ischaemic stroke and 30 asymptomatic volunteers were recruited. Assessment of vascular risk factors, serum level of MMP-9 and CCA-IMT on both sides was performed. The IMT of both CCAs correlated positively with the serum MMP-9 level in asymptomatic subjects (p = 0.000), even after adjustment for other risk factors. In the patients group, this positive correlation was significant for the right but not for the left CCA (right CCA: p = 0.023, left CCA: p = 0.0284). Fasting blood sugar correlated positively with serum levels of MMP-9 in asymptomatic subjects (p = 0.005) but did not correlate positively in patients. There was no significant correlation between MMP-9 and age or other investigated laboratory risk factors in either the patient or asymptomatic groups. MMP-9 is positively correlated with CCA-IMT both in stroke patients and asymptomatic subjects. This may indicate that MMP-9 is a possible therapeutic target for stroke prevention.

Native Myocardial T1 Mapping, Are We There Yet?

T1 or longitudinal relaxation time is one of the very fundamental magnetic resonance imaging (MRI) time constants and a tissue characterizing parameter. Only during the last decade did it become possible to quantify T1 values of the myocardium through T1 mapping. Evolving from only region of interest analysis and long acquisition times to the pixel-based parametric mapping and short breath-hold sequences, T1 mapping is reaching maturity among cardiac magnetic resonance (CMR) techniques. Both inversion recovery methods such as MOdified Look-Locker Inversion (MOL-LI) and Shortened MOLLI (ShMOLLI) and saturation recovery methods such as Saturation recovery Single-Shot Acquisition (SASHA) are available for T1 quantification with variable degrees of accuracy, precision, and reproducibility. Native (non-contrast) T1 values increase with edema, amyloid deposition, and fibrosis, while they decrease in fat or iron deposition in the myocardium. These features enabled significant expansion of the clinical applications of native T1 mapping where it provides high sensitivity and specificity and even acts as a disease biomarker or a predictor of prognosis. It is of particular usefulness in diffuse myocardial diseases where conventional CMR techniques might be deceiving. A brighter future for the technique is expected if certain challenges are to be faced, examples of which are the need for standardization of normal values, acquisition techniques, and improving analysis tools.

Modeling absolute lymphocyte counts after treatment of chronic lymphocytic leukemia with ibrutinib.

The objective in this study was to characterize the pattern of the treatment-related lymphocytosis curve in chronic lymphocytic leukemia (CLL) patients treated with ibrutinib, and assess the relationship between the baseline factors and absolute lymphocyte counts (ALC). The PCYC-1102-CA study was a five-arm phase Ib/II open-label, nonrandomized, multicenter study in CLL/SLL. The arms and accruals were 420 and 840 mg/day treatment-naive elderly CLL/SLL (N = 27 and N = 4, respectively), 420 and 840 mg/day relapsed/refractory CLL/SLL (N = 27 and N = 34, respectively), and 420 mg/day high-risk CLL/SLL (N = 24). The results were generated through statistical modeling using data from a clinical trial (PCYC-1102) in five cohorts of treatment-naïve or relapsed/refractory CLL patients treated at 420 and 840 mg daily of ibrutinib. In cases in which the initial increase in ALC doubles by day 28, it takes patients longer to reach their maximum ALC when compared with those with a lower rate of increase. Our models show that all of the cohorts exhibited the same pattern of treatment-related lymphocytosis from ibrutinib, and there are no significant differences between cohorts, including no detectable dose effect. The ALC of the majority of patients return to baseline ALC values by the end of cycle 5.

Anti-C1q in chronic hepatitis C virus genotype IV infection: association with autoimmune rheumatologic manifestations.

A growing body of evidence suggests that anti-complement-1q (anti-C1q) antibodies are elevated in a variety of autoimmune disease. Therefore, we investigated their prevalence and clinical significance in plasma of patients with hepatitis C virus (HCV) genotype IV in the presence and absence of autoimmune extra hepatic manifestations in comparison to normal healthy individuals. Plasma Anti-C1q Abs levels were assessed by an Enzyme Linked Immunosorbant Assay in 91 chronic HCV-infected patients (51 with and 40 without autoimmune rheumatic manifestations) and 40 healthy volunteers matched for age and gender. Epidemiological, clinical, immunochemical and virological data were prospectively collected. Positive Anti-C1q antibodies were more frequent among HCV patients with extra-hepatic autoimmune involvement, than those without and healthy control subjects. No significant correlations were found between Anti-C1q levels with either the liver activity or the fibrosis scores. In HCV-patients with autoimmune involvements, plasma Anti-C1q levels were significantly higher in patients with positive cryoglobulin, and in those with lymphoma than in those without. These results were confirmed by multivariate analysis. Further large scale longitudinal studies are required to assess and clarify the significance and the pathogenic role of anti-C1q antibodies among HCV infected patients with positive cryoglobulinaemia and lymphoma.

Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial.

BACKGROUND: Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia. METHODS: In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247. FINDINGS: Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65-84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1-2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one developed grade 4 thrombocytopenia. After a median follow-up of 22.1 months (IQR 18.4-23.2), 22 (71%) of 31 patients achieved an objective response (95% CI 52.0-85.8); four patients (13%) had a complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had a partial response. INTERPRETATION: The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic lymphocytic leukaemia, or small lymphocytic lymphoma is encouraging, and merits further investigation in phase 3 trials. FUNDING: Pharmacyclics, Leukemia and Lymphoma Society, D Warren Brown Foundation, Mr and Mrs Michael Thomas, Harry Mangurian Foundation, P50 CA140158 to Prof J C Byrd MD.