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Late-onset combined immunodeficiency (LOCID), considered now a subset of common variable immunodeficiency (CVID) disorders, is characterized by a predominantly T-cell immune defect. LOCID has a distinct phenotype from CVID with a greater risk of lymphoproliferative complications. As compared to the CVID cohort, LOCID patients also have increased rates of splenomegaly and granulomatous disease. We report a case of central nervous system (CNS) T-cell lymphoma in a 67-year-old male as the presenting manifestation of LOCID. The patient achieved a complete response to therapy after 4 cycles of MATRix (methotrexate, cytarabine, and thiotepa) and 2 cycles of ICE (etoposide, carboplatin, and ifosfamide) chemotherapy followed by CNS-directed autologous stem cell transplantation. Intravenous immunoglobulin replacement was commenced to address the underlying immunodeficiency. Pulmonary lesions consistent with a diagnosis of granulomatous and lymphocytic interstitial lung disease (GLILD) were identified as a second noninfectious complication of LOCID. The pulmonary lesions resolved after chemotherapy and immunoglobulin replacement. The patient remains well with no evidence of disease recurrence now more than 18 months after completion of therapy. This is the first reported case of T-cell lymphoma in an adult patient with LOCID. Further study is needed to elucidate the mechanisms of transformation of B- or T-cells to lymphoproliferation in primary immunodeficiency patients as well as research to inform evidence-based therapeutic strategies for this challenging cohort of patients. [ABSTRACT FROM AUTHOR]

We have built a quantitative systems toxicology modeling framework focused on the early prediction of oncotherapeutic‐induced clinical intestinal adverse effects. The model describes stem and progenitor cell dynamics in the small intestinal epithelium and integrates heterogeneous epithelial‐related processes, such as transcriptional profiles, citrulline kinetics, and probability of diarrhea. We fitted a mouse‐specific version of the model to quantify doxorubicin and 5‐fluorouracil (5‐FU)‐induced toxicity, which included pharmacokinetics and 5‐FU metabolism and assumed that both drugs led to cell cycle arrest and apoptosis in stem cells and proliferative progenitors. The model successfully recapitulated observations in mice regarding dose‐dependent disruption of proliferation which could lead to villus shortening, decrease of circulating citrulline, increased diarrhea risk, and transcriptional induction of the p53 pathway. Using a human‐specific epithelial model, we translated the cytotoxic activity of doxorubicin and 5‐FU quantified in mice into human intestinal injury and predicted with accuracy clinical diarrhea incidence. However, for gefitinib, a specific‐molecularly targeted therapy, the mice failed to reproduce epithelial toxicity at exposures much higher than those associated with clinical diarrhea. This indicates that, regardless of the translational modeling approach, preclinical experimental settings have to be suitable to quantify drug‐induced clinical toxicity with precision at the structural scale of the model. Our work demonstrates the usefulness of translational models at early stages of the drug development pipeline to predict clinical toxicity and highlights the importance of understanding cross‐settings differences in toxicity when building these approaches. [ABSTRACT FROM AUTHOR]

Myeloid sarcoma (MS), also termed 'chloroma' or 'granulocytic sarcoma', is a tumour mass consisting of myeloid blasts occurring at an anatomical site other than the bone marrow. MS occurs in up to 8% of patients with acute myeloid leukaemia. While MS typically involves the skin or lymph nodes, almost any tissue can be affected, and symptoms largely depend on the organ involved and subsequent mass effect. We present a case series of patients that presented to a tertiary hospital with MS affecting the central nervous system over a 4‐month period. These three cases demonstrate the vast spectrum of clinical presentations of MS and, furthermore, show rare examples of intramedullary spinal cord involvement and disseminated intraparenchymal brain disease. [ABSTRACT FROM AUTHOR]

5-Fluorouracil (5-FU) is a widely used chemotherapeutical that induces acute toxicity in the small and large intestine of patients. Symptoms can be severe and lead to the interruption of cancer treatments. However, there is limited understanding of the molecular mechanisms underlying 5-FU-induced intestinal toxicity. In this study, well-established 3D organoid models of human colon and small intestine (SI) were used to characterize 5-FU transcriptomic and metabolomic responses. Clinically relevant 5-FU concentrations for in vitro testing in organoids were established using physiologically based pharmacokinetic simulation of dosing regimens recommended for cancer patients, resulting in exposures to 10, 100 and 1000 µM. After treatment, different measurements were performed: cell viability and apoptosis; image analysis of cell morphological changes; RNA sequencing; and metabolome analysis of supernatant from organoids cultures. Based on analysis of the differentially expressed genes, the most prominent molecular pathways affected by 5-FU included cell cycle, p53 signalling, mitochondrial ATP synthesis and apoptosis. Short time-series expression miner demonstrated tissue-specific mechanisms affected by 5-FU, namely biosynthesis and transport of small molecules, and mRNA translation for colon; cell signalling mediated by Rho GTPases and fork-head box transcription factors for SI. Metabolomic analysis showed that in addition to the effects on TCA cycle and oxidative stress in both organoids, tissue-specific metabolic alterations were also induced by 5-FU. Multi-omics integration identified transcription factor E2F1, a regulator of cell cycle and apoptosis, as the best key node across all samples. These results provide new insights into 5-FU toxicity mechanisms and underline the relevance of human organoid models in the safety assessment in drug development. [ABSTRACT FROM AUTHOR]

We present a retrospective multicenter study of pralatrexate treatment outcomes in an Australian practice setting for patients with relapsed/refractory T-cell lymphoma who had failed 1+ systemic therapies, treated via a compassionate access program. Endpoints assessed included response rates, toxicities, and subsequent therapies. Progression-free survival (PFS), time to next treatment (TTNT), event-free survival (EFS), overall survival (OS), and time to best response, were assessed by Kaplan–Meier analysis. The study included 31 patients, with median age 69 years. We demonstrated ORR of 35.5% (n = 11), including 4 complete responses (13%) and 7 partial responses (23%). The predicted median OS was 10 months, with EFS of 9 months, and PFS of 9 months. Median TTNT was 8 months. Mucositis was the most commonly observed toxicity. This study – the second largest real-world cohort reported to date – underscores the importance of pralatrexate in relapsed/refractory T-cell lymphoma, as well as its acceptable toxicity profile. [ABSTRACT FROM AUTHOR]

Roughly, 30-50% of patients with R/R DLBCL who achieve disease remission with salvage therapies relapse within 1 year of treatment [[3]]. The results of this pooled analysis suggest treatment with blinatumomab salvage therapy may lead to durable CR and survival benefit in patients with R/R DLBCL. Outcomes of diffuse large B-cell lymphoma patients relapsing after autologous stem cell transplantation: an analysis of patients included in the CORAL study. [Extracted from the article]

The phase 2 portion of this open-label phase 2/3 study assessed the efficacy and safety of blinatumomab as second salvage for aggressive relapsed or refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL) following platinum-based first salvage chemotherapy. Forty-one patients with aggressive disease (32% relapsed; 68% refractory) enrolled and received stepwise blinatumomab (9–28–112 μg/day) in a 70-day cycle 1 and an optional 28-day cycle 2; 19 (46%) completed cycle 1 and 3 (7%) completed cycle 2. The overall response rate after 12 weeks was 37%, including 9 (22%) complete metabolic responses. Eight (20%) patients (all responders) subsequently received stem cell transplants. Grade ≥3 adverse events were reported in 29 (71%) patients. Grade 3 cytokine release syndrome occurred in one patient. Grade 3 neurologic events occurred in 10 (24%) patients; all resolved. Blinatumomab monotherapy appears effective as second salvage therapy in patients with r/r aggressive B-NHL. Trial registration: NCT02910063. [ABSTRACT FROM AUTHOR]

The prognosis of AML in elderly patients is poor and research into novel therapeutic approaches is urgently needed. This study examined the use of low-dose chemotherapy with cytarabine and thioguanine administered in repetitive cycles in 62 elderly patients with newly diagnosed or relapsed/refractory AML. The overall response rate was 58% in the total cohort. Response rates (CR/CRi) were significantly higher in patients with newly diagnosed AML (74%) compared to patients with relapsed/refractory disease (25%, p =.0004). Kaplan–Meier estimate of overall survival was 289 days (95% CI; 183–395 days) with a relapse rate of 65.7%. The induction mortality rate was 16.1% with treatment successfully undertaken in the outpatient setting. Similar clinical outcomes were observed in a retrospective analysis of a second cohort of 25 AML patients treated at a different site. These results support the use of a sustained low intensity chemotherapy approach as a therapeutic option for elderly patients with AML. [ABSTRACT FROM AUTHOR]

Objectives: To assess therapeutic levels, safety and tolerability of a novel formulation SUBA-itraconazole (where SUBA stands for SUper BioAvailability) when compared with conventional itraconazole liquid when used as antifungal prophylaxis in patients undergoing allogeneic HSCT or in haematological malignancy patients with an intermediate/high risk of invasive fungal infection (IFI).Methods: This was a single-institution, prospective cohort study using a historical control group as the comparator.Results: A total of 57 patients were assessed: 27 in the SUBA-itraconazole cohort and 30 in the liquid itraconazole cohort. Therapeutic concentrations were achieved significantly more quickly in the SUBA-itraconazole group: median of 6 (95% CI 5-11) days versus 14 (95% CI 12-21) days in the liquid itraconazole group (P < 0.0001). At day 10, therapeutic concentrations were achieved in 69% (95% CI 44%-81%) of the SUBA-itraconazole group versus 21% (95% CI 7%-33%) of the liquid itraconazole group (P < 0.0001). The mean trough serum concentrations at steady-state of SUBA-itraconazole were significantly higher, with less interpatient variability [1577 ng/mL, coefficient of variation (CV) 35%] versus liquid itraconazole (1218 ng/mL, CV 60%) (P < 0.001). There were two (7.4%) treatment failures in the SUBA-itraconazole group, both due to cessation of therapy for mucositis, compared with seven (23.3%) treatment failures in the liquid itraconazole group, due to subtherapeutic levels (five), mucositis (one) and gastrointestinal intolerance (one) (P = 0.096).Conclusions: The use of the SUBA-itraconazole formulation was associated with more rapid attainment of therapeutic levels with less interpatient variability compared with conventional liquid itraconazole when used as IFI prophylaxis in allogeneic HSCT or intermediate-/high-IFI risk haematological malignancy patients. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cell–derived cardiomyocytes (hiPS-CMs) are capable of detecting drug-induced clinical arrhythmia, Torsade de Pointes (TdP), and QT prolongation. Efforts herein employ a broad set of structurally diverse drugs to optimize the predictive algorithm for applications in discovery toxicology and cardiac safety screening. The changes in the beat rhythm and rate of a confluent monolayer of hiPS-CMs by 88 marketed and 30 internal discovery compounds were detected with real-time cellular impedance measurement and quantified by measures of arrhythmic beating (IB20, lowest concentration inducing ≥ 20% arrhythmic [irregular, atypical] beats in 3 consecutive 20-s sweeps, and predicted proarrhythmic score [PPS]-IB20) or changes in beat rate (BR20, the lowest concentration inducing a reduction in beat rate of ≥ 20% at 3 consecutive sweeps compared with the time-matched vehicle control group, and PPS-BR20). Drug-induced arrhythmic beats and reductions in beat rates are predictive of clinical arrhythmia and QT prolongation, respectively. A threshold of ≤ 10μM for class determination results in 82% in vitro-in vivo concordance for TdP prediction and 91% sensitivity for non-TdP arrhythmia detection, or 83% and 91% if clinically efficacious plasma (effective serum therapeutic concentration [Ceff]) values are incorporated. This human cardiomyocyte arrhythmic risk (hCAR) model provides greater predictivity for torsadogenicity in humans compared with either human ether-a-go-go-related gene (hERG) inhibition (75%) or QT prolongation (81%). The concordance of beat rate reductions to predict clinical QT prolongation is 86%, or 87% when Ceff is considered, which is greater than a hERG signal (80%). Further, arrhythmic beats resulting from cytotoxicity were identified by a distinct arrhythmic beating pattern, which occurred after the onset of cytolethality. This hCAR assay showed increased performance over existing preclinical tools in predicting clinical QT prolongation, arrhythmia, and TdP. Thus, hiPS-CMs are a relevant cell system to improve evaluating cardiac safety liabilities of drug candidates. [ABSTRACT FROM PUBLISHER]

It is well documented in animal and human studies that therapy with the anti-cancer drug doxorubicin (DOX) induces fibrosis, cardiac dysfunction, and cell death. The most widely accepted mechanism of cardiac injury is through production of reactive oxygen species (ROS), which cause mitochondrial damage, sarcomere structural alterations, and altered gene expression in myocytes and fibroblasts. Here we investigated the effects of acetaminophen (APAP, N-acetyl- para-aminophenol) on DOX-induced cardiac injury and fibrosis in the presence or absence of osteopontin (OPN). H9c2 rat heart-derived embryonic myoblasts were exposed to increasing concentrations of DOX ± APAP; cell viability, oxidative stress, and OPN transcript levels were analyzed. We found a dose-dependent decrease in cell viability and a corresponding increase in intracellular oxidants at the tested concentrations of DOX. These effects were attenuated in the presence of APAP. RT-PCR analysis revealed a small increase in OPN transcript levels in response to DOX, which was suppressed by APAP. When male 10-12-week-old mice (OPN+/+ or OPN−/−) were given weekly injections of DOX ± APAP for 4 weeks there was substantial cardiac fibrosis in OPN+/+ and, to a lesser extent, in OPN−/− mice. In both groups, APAP decreased fibrosis to near baseline levels. Activity of the pro-survival GATA4 transcription factor was diminished by DOX in both mouse genotypes, but retained baseline activity in the presence of APAP. These effects were mediated, in part, by the ability of APAP, acting as an anti-inflammatory agent, to decrease intracellular ROS levels, consequently diminishing the injury-induced increase in OPN levels. J. Cell. Physiol. 228: 2006-2014, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Hepatitis B reactivation in patients receiving immunosuppressive therapy or chemotherapy may be associated with acute hepatitis, liver failure and/or death. Aim To audit the efficacy of entecavir as compared to lamivudine for the prophylaxis of HBV reactivation in patients with haematological disease receiving immunosuppression or chemotherapy. Methods Patients treated for haematological disease with pretreatment serological evidence of chronic hepatitis B (CHB) (HBV surface antigen, HBsAg positive) or resolved HBV infection (HBsAg negative but HBV core antibody positive) are included in this study. Patients received lamivudine 100 mg or entecavir 0.5 mg daily. Hepatitis B serology, HBV DNA and ALT were audited at baseline, 6 months, year 1, 2 and 3. HBV reactivation was defined as a 1 log increase in HBV DNA from baseline or reversion to sAg positivity. The occurrence of jaundice, symptomatic hepatitis, liver failure or death were audited. Results Of the 40 patients included in the study, 65% (4 CHB and 22 resolved HBV) received entecavir and 35% (11 CHB and 3 resolved HBV) received lamivudine. One patient with resolved HBV experienced HBV seroreversion related to premature cessation of entecavir. Eight patients with CHB (two from entecavir group and six from lamivudine group) had detectable HBVDNA levels at baseline; one case of HBV reactivation related to probable lamivudine resistance was identified. No HBV related deaths occurred. Conclusion Lamivudine and entecavir are both efficacious in the prophylaxis of hepatitis B reactivation. Entecavir should be used in preference to lamivudine in patients CHB with detectable baseline HBV DNA levels. [ABSTRACT FROM AUTHOR]

Gefitinib is a tyrosine kinase inhibitor (TKI) that selectively inhibits the epidermal growth factor receptor (EGFR), hampering cell growth and proliferation. Due to its action, gefitinib has been used in the treatment of cancers that present abnormally increased expression of EGFR. However, side effects from gefitinib therapy may occur, among which diarrhoea is most common, that can lead to interruption of the planned therapy in the more severe cases. The mechanisms underlying intestinal toxicity induced by gefitinib are not well understood. Therefore, this study aims at providing insight into these mechanisms based on transcriptomic responses induced in vitro. A 3D culture of healthy human colon and small intestine (SI) organoids was exposed to 0.1, 1, 10 and 30 µM of gefitinib, for a maximum of three days. These drug concentrations were selected using physiologically-based pharmacokinetic simulation considering patient dosing regimens. Samples were used for the analysis of viability and caspase 3/7 activation, image-based analysis of structural changes, as well as RNA isolation and sequencing via high-throughput techniques. Differential gene expression analysis showed that gefitinib perturbed signal transduction pathways, apoptosis, cell cycle, FOXO-mediated transcription, p53 signalling pathway, and metabolic pathways. Remarkably, opposite expression patterns of genes associated with metabolism of lipids and cholesterol biosynthesis were observed in colon versus SI organoids in response to gefitinib. These differences in the organoids' responses could be linked to increased activated protein kinase (AMPK) activity in colon, which can influence the sensitivity of the colon to the drug. Therefore, this study sheds light on how gefitinib induces toxicity in intestinal organoids and provides an avenue towards the development of a potential tool for drug screening and development. [ABSTRACT FROM AUTHOR]

Doxorubicin is widely used in the treatment of different cancers, and its side effects can be severe in many tissues, including the intestines. Symptoms such as diarrhoea and abdominal pain caused by intestinal inflammation lead to the interruption of chemotherapy. Nevertheless, the molecular mechanisms associated with doxorubicin intestinal toxicity have been poorly explored. This study aims to investigate such mechanisms by exposing 3D small intestine and colon organoids to doxorubicin and to evaluate transcriptomic responses in relation to viability and apoptosis as physiological endpoints. The in vitro concentrations and dosing regimens of doxorubicin were selected based on physiologically based pharmacokinetic model simulations of treatment regimens recommended for cancer patients. Cytotoxicity and cell morphology were evaluated as well as gene expression and biological pathways affected by doxorubicin. In both types of organoids, cell cycle, the p53 signalling pathway, and oxidative stress were the most affected pathways. However, significant differences between colon and SI organoids were evident, particularly in essential metabolic pathways. Short time-series expression miner was used to further explore temporal changes in gene profiles, which identified distinct tissue responses. Finally, in silico proteomics revealed important proteins involved in doxorubicin metabolism and cellular processes that were in line with the transcriptomic responses, including cell cycle and senescence, transport of molecules, and mitochondria impairment. This study provides new insight into doxorubicin-induced effects on the gene expression levels in the intestines. Currently, we are exploring the potential use of these data in establishing quantitative systems toxicology models for the prediction of drug-induced gastrointestinal toxicity. [ABSTRACT FROM AUTHOR]

Lymphomatoid granulomatosis (LYG) is a rare Epstein Barr virus (EBV)-associated lymphoproliferative disease. Even with combination chemotherapy, mortality is high. There is no standard therapy for relapsed or refractory disease. There is only one report in the literature of a complete remission with high-dose chemotherapy and autologous stem cell transplantation. This study presents the case of a patient with progressive LYG, who was successfully treated with autologous stem cell transplantation after conditioning with high-dose chemotherapy and total body irradiation. After transplantation, maintenance therapy with interferon alpha 2a was administered for 3.75 years. The patient remains well and in remission 8 years post-transplantation. This is the first report of a durable (>1 year) complete remission after high-dose chemotherapy and autologous stem cell transplantation in LYG. The role of high-dose chemotherapy and autologous stem cell transplantation in relapsed or refractory cases merits further evaluation. The exact place of interferon in treatment of LYG remains to be clarified but is promising. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: Acquired and hereditary amyloidosis can cause peripheral neuropathy, but the mechanisms by which this occurs have not been established. Threshold tracking techniques allow in vivo assessment of the properties of the axonal membrane and may shed light on pathogenetic mechanisms underlying neuropathic disorders. Methods: We studied 10 subjects with primary amyloidosis using conventional nerve conduction studies and quantitative sensory, autonomic, and axonal excitability testing of median motor and sensory fibers. Results: As expected, subjects with amyloidosis had evidence of small- and large-fiber neuropathy on conventional testing. There was no significant difference in axonal excitability between subjects and controls apart from the stimulus required to activate sensory fibers. Conclusions: Amyloid-related neuropathy does not produce a change in membrane potential as either a primary or secondary event. This suggests that ischemia and axonal compression are unlikely mechanisms for the neuropathy. Muscle Nerve 51: 443-445, 2015 [ABSTRACT FROM AUTHOR]

The article describes the clinical case of a 68-year-old woman who was taken to the emergency department due to partial seizures of her left hand and mild left hemiparesis. It notes that the non-enhancing lesion found in the brain has increased in size within two months. The patient has been diagnosed with progressive multifocal leukoencephalopathy (PML). The diagnosis has been associated with immunosuppression resulting from undetected HIV infection.

The article presents an abstract on a case study of a 40 year-old man with severe fatigue, footdrop and ascending weakness who was diagnosed with POEMS syndrome.