Administration In Treatment Of Patients Research Articles

Patient-Reported Experiences in Voxelotor-Treated Children and Adults with Sickle Cell Disease: A Semistructured Interview Study.

Voxelotor is a first-in-class sickle hemoglobin-polymerization inhibitor that was approved in 2019 by the US Food and Drug Administration for treatment of patients with sickle cell disease (SCD) aged ≥12 years; in 2021, the approval was extended to children with SCD aged 4 to 11 years. Additionally, both the Ministry of Health and Prevention for the United Arab Emirates and the European Commission granted marketing authorization for voxelotor in September 2021 and February 2022, respectively, for treatment of SCD in adults and pediatric patients aged ≥12 years. Thus, additional information on the patient experience with voxelotor would be useful for patients, caregivers, and healthcare professionals alike. The purpose of this study was to conduct semistructured interviews in an effort to understand the experiences and perspectives of voxelotor-treated patients with SCD. One-time semistructured interviews with adults, adolescents, and children with SCD and their primary caregivers were conducted in the United States. Twenty-three adults and adolescents were recruited across 4 clinical sites, and 10 children-caregiver dyads were recruited from a single site. The interview was designed to elicit patient perspectives on symptomatic changes with voxelotor and the impact of treatment on patients' perceived health-related quality of life. Individual interview transcripts were analyzed using a thematic analytic approach, and concept saturation was assessed in both cohorts. Most patients reported improvements in their SCD symptoms with voxelotor treatment, specifically regarding pain crises, jaundice, and fatigue. Almost all patients experienced improvements in self-reported health-related quality of life with voxelotor treatment. This study provides patient and caregiver perspectives on the symptomatic benefits of voxelotor treatment. These findings not only highlight the benefits of voxelotor treatment in improving symptoms and increasing health-related quality of life across the entire SCD population but also can inform further research on SCD-specific patient-reported outcomes.

Preoperative Plasma miRNA Levels Predict Prognosis in Early-stage Malignant Melanoma.

Non-invasive circulating tumor biomarkers in liquid biopsy, such as microRNAs (miRNA), provide for better personalization of treatment strategies. The aim of our study was to assess the prognosis of patients with melanoma undergoing tumor resection with curative intent based on analysis of selected circulating miRNAs. A total of 22 patients with stage I to III melanoma were enrolled into this prospective study. Plasma samples were obtained pre-surgery and early post-surgery from peripheral blood draws. A panel of 23 candidate miRNAs was designed and expression of miRNAs were analyzed by reverse transcription-quantitative polymerase chain reaction with exogenous reference control cel-miR-39-3p. Higher preoperative expression levels of miR-99a (p=0.008), miR-320 (p=0.009), miR-1908 (p=0.001), miR-494 (p=0.018) and miR-4487 (p=0.048) were associated with a shorter disease-free interval. Similarly, higher preoperative plasma levels of miR-99a (p=0.017), miR-221 (p=0.026), miR-320 (p=0.016), miR-494 (p=0.009), miR-1260 (p=0.026) and miR-1908 (p=0.024) were associated with worse overall survival. No significant differences between pre- and postoperative plasma miRNA levels were observed. Liquid biopsy is a minimally-invasive approach which can lead to a better understanding of cancer behavior and offers the possibility of precise patient prognosis, allowing selection of the most appropriate treatment. Our study showed that preoperative plasma levels of miR-99a, miR-221, miR-320, miR-494, miR-1908 and miR-4487 were associated with disease-free interval and overall survival of patients with early-stage melanoma. This approach may help in decision-making about the appropriateness of modern adjuvant treatment administration in patients with resectable melanoma.

Potential eligibility for Aducanumab therapy in an Irish specialist cognitive service-Utilising cerebrospinal fluid biomarkers and appropriate use criteria.

ObjectivesAducanumab is a monoclonal antibody which has recently been licenced for use by the food and drug administration for treatment of patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild AD dementia. Appropriate use criteria (AUC) for Aducanumab in clinical practice are available. We look to review patients in our specialist interdisciplinary cognitive service with positive cerebrospinal fluid (CSF) biomarkers for AD for their hypothetical eligibility for Aducanumab, or a similar anti‐amyloid agent.MethodsRetrospective analysis was undertaken of patients with positive AD‐biomarker CSF analysis. Data available at time of CSF analysis was reviewed to determine hypothetical eligibility for Aducanumab.ResultsSeventy patients had positive AD‐CSF biomarkers. Forty nine of these were seen in the Gerontology‐led service, with 21 in the neurology cohort. Average patient age was 70 years old. Forty patients (57%) met eligibility criteria for Aducanumab therapy by AUC guidelines.ConclusionWe highlight the patients within our service who would be appropriate for Aducanumab or similar anti‐amyloid agents should licencing be granted in the European Union, and the need to develop the resources and capacity to deliver this or other emerging disease modifying AD therapies. Clinical Trial Registration: All patients in the combined cognitive clinic provide consent re willingness to be contacted re research.

Combination of inhaled nitrous oxide and oral opioids induces long-lasting analgesic effects in patients with neuropathic pain: ProtoTOP study post hoc exploratory analyses.

Experimental studies have suggested that nitrous oxide-induced analgesia depends on interactions with opioids. On the basis of these results, we hypothesized that the effects of inhaled nitrous oxide/oxygen (N 2 O/O 2 ) 50%-50% equimolar mixture (EMONO) on patients with neuropathic pain would be higher in those receiving concomitant opioids. To test this hypothesis, we did exploratory post hoc analyses of our recently published ProtoTOP study to compare the effects of EMONO and placebo in patients with or without concomitant opioid treatment. A total of 92 patients of the 221 (ie, 41.6%) included in the ProtoTOP study were concomitantly treated with opioids. In contrast with our previous analyses, average pain intensity was significantly decreased in comparison with placebo one week after the last treatment administration in patients treated with opioids, but not in those treated without opioid, and this effect was maintained over the 4-week follow-up period. Neuropathic pain symptom inventory (NPSI total and subscores) was also significantly more decreased after inhalation of EMONO in comparison with placebo only in patients receiving opioids. The proportion of patients with at least 30% pain reduction and of those reporting an overall improvement with the Patient Global Impression of Change were significantly higher only in this population of patients. In conclusion, these results complement our previous analyses with the identification of a specific population of responders to EMONO inhalation in patients with neuropathic pain. As suggested by experimental studies, we hypothesized that these long-lasting analgesic effects could depend on the anti-N-methyl-D-aspartate properties of N 2 O.

Molecular and Genetic Characterization of Tumor Samples from Patients with Relapsed or Refractory Follicular Lymphoma Identifies Factors Influencing Response to Tazemetostat

Molecular and Genetic Characterization of Tumor Samples from Patients with Relapsed or Refractory Follicular Lymphoma Identifies Factors Influencing Response to Tazemetostat

Using physiologically-based pharmacokinetic modeling for predicting the effects of hepatic impairment on the pharmacokinetics of olanzapine and samidorphan given as a combination tablet.

A combination of olanzapine and samidorphan (OLZ/SAM) was recently approved by the US Food and Drug Administration for treatment of patients with schizophrenia or bipolar I disorder. The effects of moderate hepatic impairment on the pharmacokinetics (PKs) of olanzapine and samidorphan after a single dose of OLZ/SAM were characterized in a clinical study. Physiologically‐based pharmacokinetic (PBPK) modeling was used to extend the clinical findings to predict the effects of varying degrees of hepatic impairment on the PKs of olanzapine and samidorphan. A previously developed PBPK model for OLZ/SAM was refined to recover the observed pharmacokinetic differences between individuals with moderate hepatic impairment and healthy controls. The optimized model was applied to predict changes in olanzapine and samidorphan PKs after multiple once‐daily doses of OLZ/SAM in subjects with mild, moderate, and severe hepatic impairment relative to healthy controls. Modifications to model parameters, including absorption rate constant and fraction unbound to plasma protein, were made to recover the observed change in the PKs of olanzapine and samidorphan in individuals with moderate hepatic impairment. In applying the optimized model, mild, moderate, and severe hepatic impairment were predicted to increase steady‐state total systemic exposures by 1.1‐, 1.5‐, and 1.6‐fold, respectively, for olanzapine, and by 1.2‐, 1.9‐, and 2.3‐fold, respectively, for samidorphan. PBPK modeling allowed for prediction of untested clinical scenarios of varying degrees of hepatic impairment in lieu of additional clinical studies.

Health care cost impact associated with adverse events (AEs) among treatments in third-line+ (3L+) relapsed/refractory follicular lymphoma (R/R FL).

e18836 Background: Tazemetostat, a first-in-class oral, selective methyltransferase inhibitor of enhancer of zeste homolog 2 (EZH2) activity, was approved by the US Food and Drug Administration for treatment of patients with R/R FL after demonstrating single-agent antitumor activity in patients with wild-type or mutant EZH2. Phosphoinositide 3-kinase inhibitors (PI3Kis; idelalisib, duvelisib, and copanlisib) are also indicated for 3L+ R/R FL, but these drugs are associated with serious toxicities, such as neutropenia, infection, and immune-mediated toxicities. A matching-adjusted indirect comparison (MAIC) of tazemetostat with these 3 PI3Kis was previously presented in 3L+ R/R FL, showing that tazemetostat is associated with more favorable safety, and similar efficacy compared to each of the PI3Kis. The objective of this study was to estimate the difference in AE-related health care costs for each treatment. Methods: AE-related costs were sourced from a study of costs in patients hospitalized with AEs, using oncology-specific data when available. Matching-adjusted AE incidence was multiplied by costs related to each AE. Grade ≥3 AEs with incidence ≥5% for any of the evaluated treatments were included. Cost differences were estimated per treatment episode, based on duration of exposure in the tazemetostat clinical trial (9.3 months for tazemetostat, <7 months for the 3 comparators). Incidence rates were then converted to a monthly basis using an exponential curve. Results: The PI3Kis are estimated to incur $13,534 to $18,737 higher AE-related management costs per episode compared with tazemetostat. Adjusting for duration of exposure, each of the PI3Kis is project to cost $2,563 to $3,820 more per month than tazemetostat in AE-related costs. These estimates indicate that the AE-related cost impact of PI3Kis compared with tazemetostat is 3.4- to 6.1-fold higher on a per-episode basis, and 5.0- to 10.4-fold higher on a monthly basis. Conclusions: Quantifying the AE cost impact of tazemetostat based on AE incidence rates estimated by MAIC analysis adjusts for population differences and allows for more direct cost savings comparisons when accounting for duration of exposure to different treatments. Patients with 3L+ R/R FL who are treated with tazemetostat are estimated to incur substantially lower AE-related costs compared with PI3Kis (idelalisib, duvelisib, and copanlisib). [Table: see text]

Uptake Rates of Novel Therapies and Survival Among Privately Insured Versus Publicly Insured Patients With Colorectal Cancer in Germany

Background: In the era of personalized medicine, cancer care is subject to major changes and innovations. It is unclear, however, to what extent implementation of such innovations and their impact on patient outcomes differ by health insurance type. This study compared provision of treatment and survival outcomes among patients with colorectal cancer (CRC) who had statutory health insurance (SHI) versus private health insurance (PHI) in Germany. Methods: We analyzed patterns of CRC treatment (surgery, chemotherapy/radiotherapy, and targeted therapy) and survival in a large cohort of patients who were diagnosed with CRC in 2003 through 2014 and were observed for an average of 6 years. Associations of type of health insurance with treatment administration and with overall, CRC-specific, and recurrence-free survival were investigated using multivariable logistic and Cox proportional hazards models, respectively. Results: Of 3,977 patients with CRC, 427 (11%) had PHI. Although type of health insurance was not associated with treatment administration in patients with stage I–III disease, those with stage IV disease with PHI more often received targeted therapy (65% vs 40%; odds ratio, 2.43; 95% CI, 1.20–4.91), with differences decreasing over time because of catch-up of uptake rates in patients with SHI. Median overall survival was longer in patients with PHI than in those with SHI (137.0 vs 114.9 months; P=.010), but survival advantages were explained to a large extent by differences in sociodemographic factors. In patients with stage IV disease, survival advantages of PHI were nonsignificant and were restricted to the early years after diagnosis. Conclusions: We observed major differences in uptake of targeted therapy between patients with PHI and those with SHI but no differences in patient survival after adjusting for relevant sociodemographic, clinical, and tumor characteristics. Further studies are needed on factors associated with the uptake of therapeutic innovations and their impact on patient survival by health insurance type.

LongShengZhi Capsule Attenuates Alzheimer-Like Pathology in APP/PS1 Double Transgenic Mice by Reducing Neuronal Oxidative Stress and Inflammation.

Alzheimer’s disease (AD) is the most common form of dementia in the elderly. It may be caused by oxidative stress, inflammation, and cerebrovascular dysfunctions in the brain. LongShengZhi Capsule (LSZ), a traditional Chinese medicine, has been approved by the China Food and Drug Administration for treatment of patients with cardiovascular/cerebrovascular disease. LSZ contains several neuroprotective ingredients, including Hirudo, Astmgali Radix, Carthami Flos (Honghua), Persicae Semen (Taoren), Acori Tatarinowii Rhizoma (Shichangpu), and Acanthopanax Senticosus (Ciwujia). In this study, we aimed to determine the effect of LSZ on the AD process. Double transgenic mice expressing the amyloid-β precursor protein and mutant human presenilin 1 (APP/PS1) to model AD were treated with LSZ for 7 months starting at 2 months of age. LSZ significantly improved the cognition of the mice without adverse effects, indicating its high degree of safety and efficacy after a long-term treatment. LSZ reduced AD biomarker Aβ plaque accumulation by inhibiting β-secretase and γ-secretase gene expression. LSZ also reduced p-Tau expression, cell death, and inflammation in the brain. Consistently, in vitro, LSZ ethanol extract enhanced neuronal viability by reducing L-glutamic acid-induced oxidative stress and inflammation in HT-22 cells. LSZ exerted antioxidative effects by enhancing superoxide dismutase and glutathione peroxidase expression, reduced Aβ accumulation by inhibiting β-secretase and γ-secretase mRNA expression, and decreased p-Tau level by inhibiting NF-κB-mediated inflammation. It also demonstrated neuroprotective effects by regulating the Fas cell surface death receptor/B-cell lymphoma 2/p53 pathway. Taken together, our study demonstrates the antioxidative stress, anti-inflammatory, and neuroprotective effects of LSZ in the AD-like pathological process and suggests it could be a potential medicine for AD treatment.

Inhaled colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria: A real-life experience in tertiary care hospitals in Saudi Arabia

BackgroundNosocomial pneumonia (NP) due to multidrug-resistant (MDR) Gram-negative pathogens, has continued to rise over the last several decades. Parenteral administration of colistin results in poor alveolar penetration and subtherapeutic concentration; therefore, direct drug deposition at site of infection may improve the effectiveness while minimizing the systemic exposure. The aim of this study is to describe the safety and effectiveness of inhaled colistin for the treatment of NP caused by MDR Gram-negative pathogens. MethodPatients who received inhaled colistin from May 2015 to May 2019 at 2 different tertiary care hospitals in Riyadh, Saudi Arabia were identified from pharmacy databases and their charts were retrospectively reviewed. Results86 patients were enrolled in this study. The mean age was 56 ± 20 years. The mean Acute Physiology and Chronic Health Evaluation (APACHE II) was 17 ± 5. The responsible pathogens for NP were Pseudomonas aeruginosa (60%) Acinetobacter baumannii (28%), and Klebsiella pneumoniae (9%). Most patients (76/86) received concomitant intravenous antibiotics. Mean colistin total daily dose was 6 ± 3 million international units divided into 2–3 doses. Mean inhaled colistin duration of therapy was 11 ± 6 days. Favorable clinical outcome was achieved in 51 (59%) patients while favorable microbiological outcome occurred in 29 (34%) patients. Death due to all causes was noted in 39 (45%) cases. Renal injury occurred in 19 (22%) patients, all received concomitant intravenous colistin. ConclusionInhaled colistin can be considered as salvage therapy as adjunct to intravenous administration for treatment of patients with NP due to MDR Gram-negative pathogens.

Tolvaptan for Autosomal Dominant Polycystic Kidney Disease: Pharmacokinetics and Implications for Practice

Autosomal dominant polycystic kidney disease (ADPKD) is incurable and occurs once in every 1,000 births. Confirmation of AKPKD is made through imaging and a positive family history. Symptoms typically appear in mid-life and include kidney, side, and/or back pain related to the rupture of kidney cysts, renal stones, infection, pressure of cysts against other organs, and stretching of the renal capsule. In addition to end stage renal disease, cerebral aneurysm may also be a threat to individuals with this diagnosis. Recent clinical trials have shown that tolvaptan, a vasopressin-2 receptor antagonist, produced a moderate to significant reduction in total kidney volume and improved function, leading to its recent approval by the U.S. Federal Drug Administration for treatment of patients with ADPKD. This article provides a comprehensive look at the pathophysiology of ADPKD, pharmacokinetics and pharmacodynamics of tolvaptan, and tolvaptan's clinical implications, effects, and contraindications. In addition, we present a case study discussing tolvaptan's clinical usefulness and address patient concerns in an adult presenting with rapidly progressing ADPKD.

The Combination of CUDC-907 and Gilteritinib Shows Promising Antileukemic Activity in Vitro and In Vivo in Preclinical Models of FLT3-ITD AML

Introduction FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations are found in approximately one quarter of acute myeloid leukemia (AML) cases. Its presence results in constitutive activation of the FLT3 receptor tyrosine kinase and its downstream growth/pro-survival pathways including MAPK/ERK, PI3K/AKT, and JAK/STAT, and confers a poor prognosis. Gilteritinib is a selective inhibitor of FLT3 recently approved by the Food and Drug Administration for treatment of patients with relapsed/refractory AML and a FLT3 mutation. However, gilteritinib exposure induces upregulation of FLT3 - a mechanism of resistance. Previously, we showed that CUDC-907, a dual PI3K/histone deacetylase inhibitor, downregulates FLT3 expression (Li X, et al. Haematologica. 2019; epub ahead of print). We therefore hypothesized that combining CUDC-907 with gilteritinib would abrogate FLT3 upregulation and expression, resulting in synergistic antileukemic activities against FLT3-mutated AML. Methods FLT3-ITD AML cell lines and primary patient samples were treated with gilteritinib or CUDC-907, alone or in combination at clinically achievable concentrations, and subjected to annexin V/propidium iodide staining and flow cytometry analysis to quantify apoptosis. Protein levels of FLT3, Bcl-2 family proteins, and key components of the MAPK/ERK, PI3K/AKT, and JAK/STAT pathways were examined using western blotting. The impact of the observed alterations upon apoptosis were confirmed via overexpression, knockdown, and targeted inhibitor experiments. Real-time RT-PCR was used to determine FLT3 transcript levels. The FLT3-ITD AML cell line MV4-11 was used to generate a xenograft mouse model to assess in vivo efficacy of the two agents. Results CUDC-907 and gilteritinib demonstrated potent synergistic antileukemic effects in FLT3-ITD AML cell lines in vitro and patient samples ex vivo, with combined therapy. CUDC-907 abolished gilteritinib-induced expression of FLT3 in both cell lines and primary patient samples. Gilteritinib treatment reduced p-AKT, p-S6, and p-STAT5 and increased p-ERK, while CUDC-907 reduced p-AKT and p-ERK, and upregulated p-STAT5. The combination of gilteritinib and CUDC-907 decreased not only p-AKT and p-S6, but also p-ERK and p-STAT5. Targeted inhibition of ERK and JAK2/STAT5 signaling by SCH772984 and AZD1480, respectively, confirmed their roles in resistance to gilteritinib and CUDC-907 monotherapies, respectively. Combined gilteritinib and CUDC-907 treatment reduced expression of the anti-apoptotic BCL-2 family member Mcl-1 and increased expression of the pro-apoptotic protein Bim. MCL-1 overexpression and BIM knockdown partially rescued FLT3-ITD AML cells upon drug treatment, confirming their role in the antileukemic activity of combined gilteritinib and CUDC-907. To determine in vivo efficacy of the two agents, NSGS mice were injected with MV4-11 cells. Three days later, the mice were randomized into vehicle control (n=5), 40 mg/kg gilteritinib (oral gavage; n=5), 100 mg/kg CUDC-907 (oral gavage; n=5) or combination (40 mg/kg gilteritinib + 100 mg/kg CUDC-907; n=6) groups. CUDC-907 was given daily for 5 days on, 2 days off, for a total of 4 cycles. Gilteritinib was administered daily for 28 days. Both agents were well tolerated; maximal weight loss was 5.5%, 0.9%, and 6.7% in the CUDC-907, gilteritinib, and combination groups, respectively. Median survival of mice in the vehicle control group was 43 days. Median survival in the CUDC-907 monotherapy and gilteritinib monotherapy arm was 40.5 days and 104 days, respectively. One mouse in the combination therapy arm died on day 138, while the remaining 5 mice in the combination therapy arm continue to survive, as of time of writing (day 168), and are asymptomatic (Figure 1). Conclusion We confirmed that the combination of CUDC-907 plus gilteritinib synergistically induces apoptosis in both FLT3-ITD AML cell lines and primary patient samples, and that gilteritinib-induced FLT3 expression is abolished by CUDC-907. Cooperative inhibition of the PI3K-AKT, JAK-STAT, and RAS-RAF pathways, as well as upregulation of Bim/downregulation of Mcl-1 all appear to contribute to this observed antileukemic synergy. Our cell line-derived xenograft mouse model provides strong evidence of in vivo efficacy and robust grounds for clinical translation of this therapeutic combination. Disclosures No relevant conflicts of interest to declare.

PCN137 COST COMPARISON OF ADVERSE EVENTS AND TREATMENT ADMINISTRATION OF LURBINECTEDIN VERSUS INTRAVENOUS TOPOTECAN FOR RELAPSED SMALL CELL LUNG CANCER IN SPAIN AND THE UNITED KINGDOM

To conduct an economic analysis comparing the costs of managing adverse events (AEs) and treatment administration in patients with relapsed small cell lung cancer (SCLC) treated either with lurbinectedin or intravenous (IV) topotecan. A cost analysis was conducted comparing the costs of managing Grade ≥3 AEs and treatment administration with lurbinectedin and topotecan. The incidence of AEs was obtained from the Basket trial for lurbinectedin (n=105) and from three randomised controlled trials (RCTs) for topotecan (1.5mg/m2/day): Von Pawel 1999 (n=107), Von Pawel 2001 (n=54) and Eckardt 2007 (n=151). Trials were identified via targeted literature review; RCTs permitting granulocyte-colony stimulating factor and/or antibiotic as primary prophylaxis were excluded. AEs affecting >1% of patients in either treatment were included in the analysis and the time horizon was in line with median treatment duration (4 cycles). Where AEs were reported as percentage of cycles (this was the case for febrile neutropenia in von Pawel 2001 and Eckardt 2007) they were converted to percentage of patients. Spanish and UK costs were obtained from the literature and local costs databases. In the UK and Spain, the mean total costs per patient were higher for topotecan than lurbinectedin. In Spain, mean total costs: lurbinectedin = €3,042 and topotecan = €11,447 (range: €11,155- €11,727). In UK, mean total costs: Lurbinectedin = £3,973 and topotecan = £14,383 (range: £13,697 - £15,271). This resulted in a total cost saving of €8,406 in Spain and £10,409 in the UK for lurbinectedin vs topotecan. Spain disaggregated results showed a cost saving of €5,103 and €3,302 for administration and AEs, respectively. UK disaggregated results showed a cost saving of £4,629 and £5,780 for administration and AEs, respectively. Lurbinectedin demonstrated consistent cost savings in terms of both treatment administration and management of AEs in Spain and the UK.

Role of interferon-γ in immune-mediated graft failure after allogeneic hematopoietic stem cell transplantation.

Pathophysiology of graft failure (GF) occurring after allogeneic hematopoietic stem cell transplantation (HSCT) still remains elusive. We measured serum levels of several different cytokines/chemokines in 15 children experiencing GF, comparing their values with those of 15 controls who had sustained donor cell engraftment. Already at day +3 after transplantation, patients developing GF had serum levels of interferon (IFN)-γ and CXCL9 (a chemokine specifically induced by IFNγ) significantly higher than those of controls (8859±7502 vs. 0 pg/mL, P=0.03, and 1514.0±773 vs. 233.6±50.1 pg/mlL, P=0.0006, respectively). The role played by IFNγ in HSCT-related GF was further supported by the observation that a rat anti-mouse IFNγ-neutralizing monoclonal antibody promotes donor cell engraftment in Ifngr1−/−mice receiving an allograft. In comparison to controls, analysis of bone marrow-infiltrating T lymphocytes in patients experiencing GF documented a predominance of effector memory CD8+ cells, which showed markers of activation (overexpression of CD95 and downregulation of CD127) and exhaustion (CD57, CD279, CD223 and CD366). Finally, we obtained successful donor engraftment in 2 out of 3 children with primary hemophagocytic lymphohistiocytosis who, after experiencing GF, were re-transplanted from the same HLA-haploidentical donor under the compassionate use coverage of emapalumab, an anti-IFNγ monoclonal antibody recently approved by the US Food and Drug Administration for treatment of patients with primary hemophagocytic lymphohistiocytosis. Altogether, these results suggest that the IFNγ pathway plays a major role in GF occurring after HSCT. Increased serum levels of IFNγ and CXCL9 represent potential biomarkers useful for early diagnosis of GF and provide the rationale for exploring the therapeutic/preventive role of targeted neutralization of IFNγ.

Curative effect of different routes of mesalazine administration in treatment of patients with ulcerative colitis

Curative effect of different routes of mesalazine administration in treatment of patients with ulcerative colitis

Sociodemographic Disparities in Chemotherapy and Hematopoietic Cell Transplantation Utilization Among Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia Patients

Introduction:Chemotherapy and hematopoietic cell transplantation (HCT) are cornerstones of therapy for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Identifying sociodemographic factors affecting utilization of chemotherapy and HCT may help improve outcomes for more patients with acute leukemia.Methods: Using the California Cancer Registry, we performed a retrospective population-based study of treatment administration in patients ≥15 years of age diagnosed with ALL (n=3,221) or AML (n=10,029) between 1/2003 and 12/2012. The effect of age, sex, race/ethnicity, marital status, neighborhood socioeconomic status (nSES), and distance from nearest transplant center on the receipt of no treatment, chemotherapy alone, or chemotherapy followed by HCT was assessed. Chemotherapy and HCT were common events ensuring that odds ratios for treatment would overestimate relative risk (RR). Log-binomial and negative binomial regression models did not converge so Poisson regression with robust confidence intervals was used to estimate crude and adjusted RR with 95 percent confidence interval limits (CIs). Model fitness assumption using Pearson’s chi-squared tests did not reveal over dispersion. Testing for multicollinearity showed no highly correlated covariates. Influence analysis did not identify influential observations or critical outliers. The Cochran-Armitage test for trend was used to assess changes in treatment utilization over time. Predictors were selected a priori based on published studies. Google maps API was used to compute the shortest driving distance between place of residence and nearest transplant centers. All statistical tests were 2-sided and conducted at a significance level of 0.05.Results: Patients <60 years of age comprised 75.5% of ALL and 31.5% of AML patients. Females represented 43% of ALL and 45% of AML patients. ALL represented 47.3% of acute leukemia cases in Hispanics versus 20.5%, 19.0% and 15.6% in Asian/other, non-Hispanic blacks, and non-Hispanic whites, respectively. Among ALL patients, 11%, 75% and 14% received no treatment, chemotherapy, or chemotherapy followed by HCT, respectively. For AML patients, 36% received no treatment while 53% and 11% were treated with chemotherapy or chemotherapy followed by HCT, respectively. HCT rates were highest in 40-59 year-old (yo) ALL patients (21.3%) and 15-39 yo AML patients (31.3%). Only 3.4% of ALL patients and 3.6% of AML patients over ≥60 yo underwent HCT. Covariate-adjusted findings showed a decreasing RR of chemotherapy with increasing age for ALL (trend p <0.001) and AML (trend p <0.001). Compared to 40-59 yos, those ≥60 years of age had reduced utilization of chemotherapy and HCT [ALL, RR 0.20 (95% CI=0.14-0.29); AML, RR 0.23 (95% CI=0.20-0.26)]. Overall, older acute leukemia patients showed increasing utilization of chemotherapy and HCT over the study period. For ALL patients ≥60 yo, chemotherapy utilization was stable (p=0.38) while HCT utilization increased from 5% in 2005 to 9% in 2012 (p=0.03). Among AML patients ≥60 yo, chemotherapy utilization increased from 39% in 2003 to 58% in 2012 (p<0.001) and HCT utilization from 5% in 2003 to 9% in 2012 (p<0.001). Relative to non-Hispanic whites, lower HCT utilization was observed in Hispanic white [ALL, RR=0.80 (95% CI =0.65-0.98); AML, RR=0.86 (95% CI =0.75-0.99)] and non-Hispanic black patients [ALL, RR=0.40 (95% CI =0.18-0.89); AML, RR=0.60 (95% CI =0.44-0.83)]. Compared to married patients, never married patients had a lower RR of receiving chemotherapy [ALL, RR=0.96 (95% CI=0.92-0.99); AML, RR=0.94 (95% CI=0.90-0.98)] or HCT [ALL, RR=0.58 (95% CI=0.47-0.71); AML, RR=0.80 (95% CI=0.70-0.90)]. Lower nSES quintiles predicted lower chemotherapy and HCT utilization for ALL and AML (Trend p <0.001).For ALL and AML, the lowest SES quintile had a lower RR of chemotherapy [ALL, RR= 0.95 (95% CI 0.90-0.99); AML, RR=0.89 (95% CI 0.84-0.94)] and HCT [ALL, RR=0.63 (95% CI 0.47-0.84); AML, RR=0.52 (95% CI 0.43-0.64)] compared to the highest nSES quintile. Distance from a transplant center had no impact on the receipt of chemotherapy or HCT.Conclusions: Older age, lower neighborhood SES, and being unmarried predicted lower utilization of both chemotherapy and HCT among ALL and AML patients. Addressing these disparities may increase utilization of known curative therapies and improve survival in underserved acute leukemia patients. DisclosuresNo relevant conflicts of interest to declare.

Bortezomib-mediated downregulation of S-phase kinase protein-2 (SKP2) causes apoptotic cell death in chronic myelogenous leukemia cells.

BackgroundProteasome inhibitors are attractive cancer therapeutic agents because they can regulate apoptosis-related proteins. Bortezomib also known as Velcade®, a proteasome inhibitor that has been approved by the food and drug administration for treatment of patients with multiple myeloma, and many clinical trials are ongoing to examine to the efficacy of bortezomib for the treatment of other malignancies. Bortezomib has been shown to induce apoptosis and inhibit cell growth of many cancer cells. In current study, we determine whether bortezomib induces cell death/apoptosis in CML.MethodsCell viability was measured using MTT assays. Apoptosis was measured by annexin V/PI dual staining and DNA fragmentation assays. Immunoblotting was performed to examine the expression of proteins. Colony assays were performed using methylcellulose.ResultsTreatment of CML cells with bortezomib results in downregulation of S-phase kinase protein 2 (SKP2) and concomitant stabilization of the expression of p27Kip1. Furthermore, knockdown of SKP2 with small interference RNA specific for SKP2 caused accumulation of p27Kip1. CML cells exposed to bortezomib leads to conformational changes in Bax protein, resulting in loss of mitochondrial membrane potential and leakage of cytochrome c to the cytosol. In the cytosol, cytochrome c causes sequential activation of caspase-9, caspase-3, PARP cleavage and apoptosis. Pretreatment of CML cells with a universal inhibitor of caspases, z-VAD-fmk, prevents bortezomib-mediated apoptosis. Our data also demonstrated that bortezomib treatment of CML downregulates the expression of inhibitor of apoptosis proteins. Finally, inhibition of proteasome pathways by bortezomib suppresses colony formation ability of CML cells.ConclusionsAltogether, these findings suggest that bortezomib suppresses the cell proliferation via induction of apoptosis in CML cells by downregulation of SKP2 with concomitant accumulation of p27Kip1, suggesting that proteasomal pathway may form novel therapeutic targets for better management of CML.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0823-y) contains supplementary material, which is available to authorized users.

Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer

Heparanase (HPSE) is the dominant mammalian endoglycosidase and important tumorigenic, angiogenic, and pro-metastatic molecule. Highest levels of HPSE activity have been consistently detected in cells possessing highest propensities to colonize the brain, emphasizing the therapeutic potential for targeting HPSE in brain metastatic breast cancer (BMBC). Lapatinib (Tykerb) is a small-molecule and dual inhibitor of human epidermal growth factor receptor1 and 2 (EGFR and HER2, respectively) which are both high-risk predictors of BMBC. It was approved by the US Food and Drug Administration for treatment of patients with advanced or metastatic breast cancer. However, its role is limited in BMBC whose response rates to lapatinib are significantly lower than those for extracranial metastasis. Because HPSE can affect EGFR phosphorylation, we examined Roneparstat, a non-anticoagulant heparin with potent anti-HPSE activity, to inhibit EGFR signaling pathways and BMBC onset using lapatinib-resistant clones generated from HER2-transfected, EGFR-expressing MDA-MB-231BR cells. Cell growth, EGFR pathways, and HPSE targets were assessed among selected clones in the absence or presence of Roneparstat and/or lapatinib. Roneparstat overcame lapatinib resistance by inhibiting pathways associated with EGFR tyrosine residues that are not targeted by lapatinib. Roneparstat inhibited the growth and BMBC abilities of lapatinib-resistant clones. A molecular mechanism was identified by which HPSE mediates an alternative survival pathway in lapatinib-resistant clones and is modulated by Roneparstat. These results demonstrate that the inhibition of HPSE-mediated signaling plays important roles in lapatinib resistance, and provide mechanistic insights to validate the use of Roneparstat for novel BMBC therapeutic strategies.

Responses to Romidepsin in Patients with Cutaneous T-Cell Lymphoma (CTCL) and Prior Treatment with Systemic Chemotherapy: Subanalysis from the Pivotal Phase 2 Study

Background: CTCL is a primarily indolent, heterogeneous group of non-Hodgkin lymphomas that arise in the skin but can progress to systemic disease (blood, lymph nodes, viscera). For patients who require systemic treatment, nonchemotherapeutic agents are currently preferred, and multiagent chemotherapies are typically reserved for patients with disease that is particularly aggressive or relapsed/refractory to multiple prior systemic therapies. Durable clinical responses are difficult to achieve, and selection of the best treatment following chemotherapy is unclear. Romidepsin is a potent, bicyclic class 1 selective HDAC inhibitor approved by the US Food Drug Administration for treatment of patients with CTCL who had received ≥ 1 prior systemic therapy as well as patients with peripheral T-cell lymphoma who have received ≥ 1 prior therapy. In the pivotal phase 2 study for the treatment of relapsed/refractory CTCL (GPI-04-0001), romidepsin resulted in rapid and durable responses, with an objective response rate (ORR) of 34% (33/96), including 6% (6/96) with complete response (CR), and median duration of response (DOR) of 15 months. Reduction in pruritus (a common and often debilitating symptom of CTCL) with romidepsin treatment was seen in both clinical responders and nonresponders. Here, we present data for patients with prior systemic chemotherapy from GPI-04-0001.Methods: Adult patients with stage IB-IVA CTCL, including mycosis fungoides and Sézary syndrome, in whom ≥ 1 prior systemic therapy had failed received romidepsin 14 mg/m2as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for patients with stable disease or response. The primary endpoint was ORR (CR + partial response) using a rigorous composite endpoint based on the sum of changes in the skin, lymph nodes, and blood. DOR was a key secondary endpoint, and reduction in pruritus (by patient-assessed 100-mm visual analog scale [VAS]) was analyzed as an additional indicator of clinical benefit. Concomitant use of antipruritic medications (eg steroids, antihistamines) was not allowed. Responses were assessed at patient screening, on day 1 of each treatment cycle, at end-of-study visit, and every 2 months thereafter for patients off study without disease progression (PD). In this analysis, efficacy and safety of romidepsin in patients with CTCL and prior systemic chemotherapy is assessed.Results: Patients (N = 96) had received a median of 2 (range, 1-8) prior systemic therapies, and 73 of 96 patients (76%) had been previously treated with systemic chemotherapy. The most common prior single-agent chemotherapy and multiagent regimens were methotrexate, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and COP (CHOP without doxorubicin). Patients with all stages of CTCL (IB-IVA) had been previously treated with chemotherapy, including 10 of 15 patients with stage IB disease and 21 of 25 patients with skin disease only. The ORR in patients with prior chemotherapy was 34% (25/73), including all 6 patients who achieved CR (8%). The median time to response was 57 days, and the median DOR was 15 months, with the longest response ongoing at 19 months. Response rates to romidepsin for patients with 1, 2, 3, or > 3 total prior systemic therapies were 32% (8/25), 43% (6/14), 27% (4/15), and 37% (7/19), respectively. The mean best change in pruritus VAS for the 50 patients with prior chemotherapy and moderate to severe pruritus at baseline was −39 mm; 24 of 50 patients (48%) experienced clinically meaningful pruritus reduction, defined as a reduction of ≥ 30 mm for ≥ 2 consecutive treatment cycles. The most common (≥ 10%) treatment-emergent adverse events in patients with prior chemotherapy were nausea (52%), asthenic conditions (51%), anorexia (26%), vomiting (26%), pyrexia (22%), anemia (19%), thrombocytopenia (19%), diarrhea (15%) and headache (15%), and most events were grade 1/2.Conclusions: Patients in the pivotal study of romidepsin for the treatment of relapsed/refractory CTCL were heavily pretreated, and the majority—even those with early-stage disease—had received prior systemic chemotherapy. Romidepsin resulted in durable responses with manageable toxicity in patients with prior chemotherapy, supporting the use of romidepsin irrespective of the number of prior therapies. DisclosuresDuvic:Celgene: Consultancy, Research Funding. Kim:Celgene : Advisory Board Other. Robak:Celgene: Research Funding; Gloucester Pharmaceuticals: Research Funding. McCulloch:Celgene, Inc. : Consultancy, Equity Ownership. Waksman:Brightech International, LLC: Consultancy. Whittaker:Millennium Pharmaceuticals: Advisory Board, Advisory Board Other, Consultancy, Honoraria, Research Funding; Actelion: Advisory Board Other, Consultancy.

FTY720 (fingolimod) modulates the severity of viral-induced encephalomyelitis and demyelination.

BackgroundFTY720 (fingolimod) is the first oral drug approved by the Food and Drug Administration for treatment of patients with the relapsing-remitting form of the human demyelinating disease multiple sclerosis. Evidence suggests that the therapeutic benefit of FTY720 occurs by preventing the egress of lymphocytes from lymph nodes thereby inhibiting the infiltration of disease-causing lymphocytes into the central nervous system (CNS). We hypothesized that FTY720 treatment would affect lymphocyte migration to the CNS and influence disease severity in a mouse model of viral-induced neurologic disease.MethodsMice were infected intracranially with the neurotropic JHM strain of mouse hepatitis virus. Infected animals were treated with increasing doses (1, 3 and 10 mg/kg) of FTY720 and morbidity and mortality recorded. Infiltration of inflammatory virus-specific T cells (tetramer staining) into the CNS of FTY720-treated mice was determined using flow cytometry. The effects of FTY720 treatment on virus-specific T cell proliferation, cytokine production and cytolytic activity were also determined. The severity of neuroinflammation and demyelination in FTY720-treated mice was examined by flow cytometry and histopathologically, respectively, in the spinal cords of the mice.ResultsAdministration of FTY720 to JHMV-infected mice resulted in increased clinical disease severity and mortality. These results correlated with impaired ability to control viral replication (P < 0.05) within the CNS at days 7 and 14 post-infection, which was associated with diminished accumulation of virus-specific CD4+ and CD8+ T cells (P < 0.05) into the CNS. Reduced neuroinflammation in FTY720-treated mice correlated with increased retention of T lymphocytes within draining cervical lymph nodes (P < 0.05). Treatment with FTY720 did not affect virus-specific T cell proliferation, expression of IFN-γ, TNF-α or cytolytic activity. FTY720-treated mice exhibited a reduction in the severity of demyelination associated with dampened neuroinflammation.ConclusionThese findings indicate that FTY720 mutes effective anti-viral immune responses through impacting migration and accumulation of virus-specific T cells within the CNS during acute viral-induced encephalomyelitis. FTY720 treatment reduces the severity of neuroinflammatory-mediated demyelination by restricting the access of disease-causing lymphocytes into the CNS but is not associated with viral recrudescence in this model.