Comparative Pharmacokinetics of Curcuminoids from Water-Dispersible Turmeric Extract Against a Curcuminoids-Piperine Combination: An Open-Label, Randomized, Balanced, 2-Treatment, 2-Sequence, 2-Period Crossover Study.

Objective: Curcuminoids, the major component of which is curcumin, are natural polyphenolic compounds from the rhizome of Curcuma longa Linn. and possess extensive biopharmacological properties that are limited in humans due to poor bioavailability. Currently, most commercial bioavailable turmeric extracts use synthetic excipients or the addition of piperine to enhance bioavailability, and are needed in multiple daily doses to achieve clinical efficacy. This study was conducted to compare the bioavailability of a natural, water-dispersible turmeric extract containing 60% natural curcuminoids, the test product, WDTE60N (1 × 250 mg per day), with the reference product, turmeric extract capsules (500 mg curcuminoids and 5 mg piperine, CPC; 3 × 500 mg per day). Methods: Sixteen healthy adult male subjects fasted overnight for 10 hours and then were dosed with either one capsule of the test product WDTE60N or three capsules of reference product CPC orally (One capsule administered at every 6 hours interval i.e. at 0.00 hrs, 6.00 hrs and at 12.00 hrs) in each study period. Blood sampling before and after dosing was carried out at defined time points at -12.00, -02.00, 00.00 (within 10 minutes prior to dosing) hours in morning before dosing and post-dose (First dose) at 00.50, 01.00, 02.00, 03.00, 04.00, 05.00, 06.50, 07.00, 08.00, 09.00, 10.00, 11.00, 12.50, 13.00, 14.00, 16.00, 18.00, 20.00 and 24.00 hours in each period. Plasma concentration of curcuminoids was determined using a validated liquid chromatography with tandem mass spectrometry bioanalytical method. Results: The Cmax (GLSM) for the test product WDTE60N was observed to be 74.56 ng/mL; and same for the reference CPC was 22.75 ng/mL. AUC0-t (GLSM) for test WDTE60N was 419.00 h∙ng/mL; and for reference CPC it was 359.86 h∙ng/mL for total curcuminoids. Conclusion: The test formulation WDTE60N showed improved relative absorption and equivalent exposure at a 10-fold-lower dose of actives than the reference formulation CPC.

The promise of combining CDK4/6 inhibition with hormonal therapy in the first-line treatment setting for metastatic or recurrent endometrial adenocarcinoma.

Metastatic or recurrent endometrioid adenocarcinoma of the uterine corpus is often incurable with limited treatment options. First-line treatment often includes cytotoxic chemotherapy, which incurs significant toxicities for many patients. Endometrial cancer, specifically endometrioid cancer, is a hormone-sensitive disease and, while single-agent hormonal therapies have demonstrated clinical benefit, resistance to these agents often leads to the use of chemotherapy. There is a lack of approved endocrine treatment options in the metastatic setting for most recurrent endometrial cancers, representing an unmet clinical need. Emerging evidence suggests that hormonal therapy in combination with other targeted treatments, such as cyclin dependent kinase (CDK)4/6 inhibitors, is well tolerated and effective in select patient populations. We discuss the clinical evidence suggesting that the combination of CDK4/6 inhibitors and hormonal therapy has the potential to represent an important addition to the first-line treatment options for patients with low-grade advanced or recurrent endometrial cancer.

Multicenter analysis of outcomes in blastic plasmacytoid dendritic cell neoplasm offers a pretargeted therapy benchmark.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an uncommon hematologic malignancy with poor outcomes. Existing data on the clinical behavior of BPDCN are limited because reported outcomes are from small retrospective series, and standardized treatment guidelines are lacking. The interleukin-3 cytotoxin conjugate tagraxofusp was recently tested in phase 1/2 trials that led to US Food and Drug Administration approval, the first ever for BPDCN. However, because there was no matched internal comparator in this or any clinical study to date, results of BPDCN trials testing new drugs are difficult to compare with alternative therapies. We therefore sought to define the clinical characteristics and outcomes of a group of patients with BPDCN treated at 3 US cancer centers in the modern era but before tagraxofusp was available. In 59 studied patients with BPDCN, the median overall survival from diagnosis was 24 months, and outcomes were similar in patients with "skin only" or with systemic disease at presentation. Intensive first-line therapy and "lymphoid-type" chemotherapy regimens were associated with better outcomes. Only 55% of patients received intensive chemotherapy, and 42% of patients underwent stem cell transplantation. Clinical characteristics at diagnosis associated with poorer outcomes included age >60 years, abnormal karyotype, and terminal deoxynucleotidyltransferase (TdT) negativity in the BPDCN cells. We also identified disease responses to pralatrexate and enasidenib in some patients. This study highlights poor outcomes for patients with BPDCN in the modern era and the need for new treatments. Outcomes from ongoing clinical trials for BPDCN can be evaluated relative to this contemporary cohort.

Deaths and complications associated with the management of acute immune thrombotic thrombocytopenic purpura.

BACKGROUND: The introduction of therapeutic plasma exchange (TPE) dramatically decreased mortality in patients with immune thrombotic thrombocytopenic purpura (iTTP). However, there are few modern descriptions of residual causes of death from iTTP and complications associated with TPE. STUDY DESIGN AND METHODS: This was a retrospective study in a multi-institutional cohort of 109 patients with iTTP between 2004 and 2017. Complications of TPE were analyzed in a subset of this cohort (74 patients representing 101 treatment courses). RESULTS: Death occurred in 8 of 109 patients (7.3%) and in 8 of 219 captured episodes of acute iTTP (mortality rate per episode: 3.7%). Neither the number of TPE treatments nor length of hospitalization predicted mortality. The majority of deaths (5/8) were associated with delay in the diagnosis of iTTP or initiation of TPE or presentation to the hospital in a moribund state. A subset of patients (N = 74) was analyzed for TPE-related complications. Most patients (56/74; 76%) had at least one minor or major complication of TPE. Seven of 101 (6.9%) discrete treatment courses were associated with one or more severe complications, including anaphylaxis and line-associated infections and thrombosis. Overall, the most frequent adverse events were mild allergic (urticarial) transfusion reactions, which affected 34 of 101 (34%) treatment courses. One patient died from a TPE-related complication, line-associated bacteremia. CONCLUSION: Early identification of patients with iTTP and the rapid initiation of TPE are paramount in preventing mortality. While TPE was associated with a high rate of adverse events, the vast majority were treatable and TPE-related mortality is low.

Utilizing a PLASMIC score-based approach in the management of suspected immune thrombotic thrombocytopenic purpura: a cost minimization analysis within the Harvard TMA Research Collaborative.

The PLASMIC score is a recently described clinical scoring algorithm that rapidly assesses the probability of severe ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency among patients presenting with microangiopathic haemolytic anaemia. Using a large multi-institutional cohort, we explored whether an approach utilizing the PLASMIC score to risk-stratify patients with suspected immune thrombotic thrombocytopenic purpura (iTTP) could lead to significant cost savings. Our consortium consists of institutions with an unrestricted approach to ADAMTS13 testing (Group A) and those that require pre-approval by the transfusion medicine service (Group B). Institutions in Group A tested more patients than those in Group B (P < 0·001) but did not identify more cases of iTTP (P = 0·29) or have lower iTTP-related mortality (P = 0·84). Decision tree cost analysis showed that applying a PLASMIC score-based strategy to screen patients for ADAMTS13 testing in Group A would have reduced costs by approximately 27% over the 12-year period of our study compared to the current approach. Savings were primarily driven by a reduction in unnecessary therapeutic plasma exchanges, but lower utilization of ADAMTS13 testing and subspecialty consultations also contributed. Our data indicate that using the PLASMIC score to guide ADAMTS13 testing and the management of patients with suspected iTTP could be associated with significant cost savings.

Induction chemotherapy in acute myeloid leukaemia: origins and emerging directions.

PURPOSE OF REVIEW: This review summarizes the hallmark developments in induction chemotherapy for acute myeloid leukaemia and further describes future directions in its evolution. RECENT FINDINGS: We describe the origin of induction chemotherapy. We also describe notable modifications and adjustments to 7+3 induction chemotherapy since its development. Finally, we describe new efforts to modify and add new agents to induction therapy, including '7+3 Plus' combinations. SUMMARY: Induction chemotherapy remains the standard of care for the majority of patients with acute myeloid leukaemia. However, its success is limited in a subset of patients by toxicity, failure to achieve remission and potential for subsequent relapse. Novel agents such as mutant fms like tyrosine kinase 3 inhibitors, mutant isocitrate dehydrogenase inhibitors, CD33-antibody drug conjugates and liposomal formulations have demonstrated significant potential as modifications to traditional induction chemotherapy.

Shedding LIGHT (TNFSF14) on the tumor microenvironment of colorectal cancer liver metastases.

BACKGROUND: T-cell infiltration in primary colon tumors is associated with improved patient survival. Preliminary data supports a similar association in colorectal liver metastases (CRLM), and we previously identified increased CRLM expression of the immunostimulatory cytokine LIGHT (TNFSF14) to be related to improved patient prognosis. Therefore, mechanisms to augment the T-cell response in CRLM may be a promising treatment modality, however, the tumor immune microenvironment and LIGHT expression in CRLM remains to be characterized. METHODS: Utilizing a syngeneic and immunocompetent model of CRLM, the immune microenvironment was characterized for lymphocyte phenotype, function, and location utilizing flow cytometry, immunoassays, and immunofluorescence microscopy. RESULTS: CD3+ and CD4+ lymphocytes were decreased, and CD8+ cells were increased in CRLM compared to control liver. When present, greater populations of tumor infiltrating lymphocytes (TIL) were found peritumoral than intratumoral. The TIL expressed significantly higher levels of CD69 and CD107a, but lower levels of LIGHT. Cytokine expression profiles revealed increased levels of the T-helper 1 (Th1) cytokines IFN gamma, IL-12, IL-1b, and IL-8 in CRLM compared to control liver tissue. There was no difference in T-helper 2 (Th2) cytokines between the groups. CONCLUSIONS: Characterization of the tumor microenvironment of CRLM revealed that although a limited number of activated T-cells infiltrate the tumor and initiate an immune response, the number of LIGHT + T cells infiltrating the tumor were very low. Techniques to decrease suppressive influences or augment the cytotoxic T-cell response are needed and may be possible through mechanisms that can increase intratumoral TIL LIGHT expression.

Improving depression and perceived social support enhances overall quality of life among myocardial infarction survivors: necessity for integrating mental health care into cardiac rehabilitation programs.

Background: Depression and low perceived social support (PSS) have been found to deleteriously affect quality of life (QoL) among myocardial infarction (MI) survivors. The complex relationship between these variables has not been assessed. We wanted to assess first the prevalence of depression among MI survivors and whether depression mediates the effect of PSS on QoL and, second, whether the physical and social domains of QoL mediated the effect of depression and PSS on the emotional domain. This cross-sectional study was done among MI survivors using Cardiac Depression Scale, MacNew Quality of Life After Myocardial Infarction Questionnaire and Multidimensional Scale of Perceived Social Support to assess for depression, QoL and PSS respectively. Results: A total of 103 MI survivors were included in the study, and the mean age was 59.66 (± 10.42) years. Depression was found in 21.36% of the participants. The indirect effect of PSS on QoL with depression as a mediator was significant (b = 0.15, p < 0.001, 95% CI 0.12, 0.18). The direct effect of PSS on QoL controlling for depression was also significant (b = 0.05, p < 0.001, 95% CI = 0.02, 0.07). Depression as a mediator in the relationship explained 75.3% of the effect of PSS on QoL. PSS and depression did not have a significant direct effect on emotional QoL, but it became significant when the physical and social domains were included in the model. The total indirect effects of PSS and depression on emotional QoL were b = 0.16, p < 0.001, 95% CI = 0.05, 0.17 and b = - 0.05, p < 0.001, 95% CI = 0.06, - 0.03, respectively. Conclusion: Depression and poor PSS impair physical and social domains, which impairs the emotional domain of QoL; as such, overall QoL is undermined. As limited physical and social activity because of depression and poor PSS may increase the risk of further cardiovascular events, a holistic approach which includes mental health care is warranted.

Real-World Analysis of Off-Label Use of Molecularly Targeted Therapy in a Large Academic Medical Center Cohort.

PURPOSE: The primary objective of this study is to quantify the use of off-label molecularly targeted therapy and describe the clinical situations in which off-label targeted therapy are used. A key secondary objective is to report the outcomes of patients treated with off-label use of targeted therapy. PATIENTS AND METHODS: We searched the electronic health record between 2000 and 2020 at our center to characterize the volume, clinical settings, and outcomes associated with off-label use of targeted therapies in different types of solid tumors. RESULTS: Among 46,712 patients who received targeted therapies, we identified 119 instances of off-label use of targeted therapy. Colon cancer was the most common cancer type to receive off-label targeted therapy in 18 patients (15.1%), followed by 13 with non-small-cell lung cancer (10.9%), eight with cholangiocarcinoma (6.7%), and seven with glioblastoma (5.9%). The most frequent molecular rationale for off-label therapy came from a comprehensive next-generation sequencing test (53.7%). The most frequently mutated gene that provided the rationale for targeted therapy was BRAF (20.1%), with BRAFV600E being the most common molecular alteration overall (15.1%). The median duration of off-label targeted therapy was 3.58 months, and the overall survival of treated patients was 7.59 months. There were 37 patients (31.1%) treated for longer than 6 months, 23 patients (19.3%) who survived ≥ 2 years, and 13 patients who were still on therapy as of June 2020. CONCLUSION: In this large cohort study of patients with solid tumors, off-label use of targeted therapy was uncommon. With that said, a notable proportion of patients had treatment durations ≥ 6 months and survivals of ≥ 2 years.

Landscape Analysis of Oncology Mobile Health Applications.

PURPOSE: More than 325,000 mobile health (mhealth) applications (apps) have been developed. We sought to describe the state of oncology-specific apps and to highlight areas of strength and opportunities for future development. METHODS: We searched for oncology apps in the Apple iOS and Google Play app stores in January 2020. Apps were classified by English language support, date of last update, downloads, intended audience, intended purpose, and developer type. RESULTS: We identified 794 oncology-specific, English language applications; only 257 (32%) met basic recency standards and were considered evaluable. Of evaluable apps, almost half (47%) were found in the Medical Store Category and the majority were free (88%). The most common intended audience was health care professionals (45%), with 28% being geared toward the general public and 27% being intended for patients. The intended function was education for 36%, clinical decision support for 19.5%, and patient support for 18%. Only 23% of education apps and 40% of clinical decision support apps reported any formal app content review process. Web developers created 61.5% of apps, scientific societies created 10%, and hospitals or health care organizations created just 6%. Of 54 studies that used mobile apps in oncology identified by a recent meta-analysis, only two could be matched to commercially available apps from our study, suggesting a substantial divide between investigation and product dissemination. CONCLUSION: Relatively few oncology-related apps exist in the commercial marketplace, up-to-date apps are uncommon, and there is a notable absence of key oncology stakeholders in app development. Meaningful development opportunities exist.

Comparative bioavailability of curcuminoids from a water-dispersible high curcuminoid turmeric extract against a generic turmeric extract: a randomized, cross-over, comparative, pharmacokinetic study.

OBJECTIVES: The therapeutic utility of turmeric (Curcuma longa L., Zingiberaceae) is limited due to low bioavailability of its active principal curcuminoids. This study evaluates the pharmacokinetic characteristics of a natural, water-dispersible turmeric extract containing 60% curcuminoids (TurmXtra 60N), referred to as WDTE60N, compared to standard turmeric extract 95% (STE95). METHODS: This open-label, two-way crossover, single oral dose, comparative pharmacokinetic study, randomized 14 subjects to receive one capsule of WDTE60N (150 mg curcuminoids) or three capsules of STE95 (500 mg curcuminoids each). The resulting dose ratio of actives for WDTE60N:STE95 was 1:10. KEY FINDINGS: Peak plasma levels of free curcumin, total curcuminoids, tetrahydrocurcumin and demethoxycurcumin were similar (P > 0.05). Cmax of total curcumin was higher (P = 0.0253) for WDTE60N at a 10-fold lower dose compared to STE95 (43.5 ± 28.5 vs. 21.3 ± 10.7 ng/ml). Mean AUC0-t was higher (P < 0.001) for free curcumin and comparable for total curcumin and total curcuminoids with WDTE60N than with STE95. Five adverse events were reported in three subjects (mild in severity) and were unrelated to study products. CONCLUSION: WDTE60N showed higher absorption and comparable exposure for free curcumin, total curcumin and total curcuminoids at a 10-fold lower dose than STE95.

Genomic Profiling of Combined Hepatocellular Cholangiocarcinoma Reveals Genomics Similar to Either Hepatocellular Carcinoma or Cholangiocarcinoma.

PURPOSE: Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a rare, aggressive primary liver carcinoma, with morphologic features of both hepatocellular carcinomas (HCC) and liver cholangiocarcinomas (CCA). METHODS: The genomic profiles of 4,975 CCA, 1,470 HCC, and 73 cHCC-CCA cases arising from comprehensive genomic profiling in the course of clinical care were reviewed for genomic alterations (GA), tumor mutational burden, microsatellite instability status, genomic loss of heterozygosity, chromosomal aneuploidy, genomic ancestry, and hepatitis B virus status. RESULTS: In cHCC-CCA, GA were most common in TP53 (65.8%), TERT (49.3%), and PTEN (9.6%), and 24.6% cHCC-CCA harbored potentially targetable GA. Other GA were predominantly associated with either HCC or CCA, including, but not limited to, TERT, FGFR2, IDH1, and presence of hepatitis B virus. On the basis of these features, a machine learning (ML) model was trained to classify a cHCC-CCA case as CCA-like or HCC-like. Of cHCC-CCA cases, 16% (12/73) were ML-classified as CCA-like and 58% (42/73) cHCC-CCA were ML-classified as HCC-like. The ML model classified more than 70% of cHCC-CCA as CCA-like or HCC-like on the basis of genomic profiles, without additional clinico-pathologic input. CONCLUSION: These findings demonstrate the use of ML for classification as based on a targeted exome panel used during routine clinical care. Classification of cHCC-CCA by genomic features alone creates insights into the biology of the disease and warrants further investigation for relevance to clinical care.

A Space-Time Continuum for Immunotherapy Biomarkers in Gastroesophageal Cancer?

In an annotated series of gastroesophageal adenocarcinomas differences in PD-L1 expression and tumor mutation burden occur between both paired contemporaneous primary and metastatic biopsies and pre/posttreatment samples. This work has implications for optimizing patient selection, serial testing, need for mechanistic understanding, and may underlie variable responses to checkpoint inhibitors in gastroesophageal cancers.See related article by Zhou et al., p. 6453.

Predictors of relapse and efficacy of rituximab in immune thrombotic thrombocytopenic purpura.

Patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) often experience life-threatening relapses of the disease, and rituximab (RTX) can be used to mitigate relapse risk. However, the predictors of relapse in iTTP and the magnitude and duration of effect of RTX remain key unanswered questions. Using a multi-institutional cohort of consecutive adult patients with iTTP, we used survival analysis to compare relapse rates between patients who received RTX during the index presentation with acute iTTP and those who did not. Of 124 patients, 60 (48%) received RTX and 34 (27%) experienced relapse. Median time to relapse was 3.71 (interquartile range, 1.75-4.9) and 1.33 (interquartile range, 0.43-2.35) years for RTX-treated and untreated patients, respectively. RTX conferred protection from relapse at 1 year of follow-up (P = .01) but not at 5 years of follow-up. Extended Cox regression was then used to identify predictors of relapse and to estimate the protective effect of RTX. The following parameters were independently associated with increased risk for subsequent relapse: presenting in iTTP relapse (hazard ratio [HR], 2.97; 95% confidence interval [CI], 1.4-6.4), age younger than 25 years (HR, 2.94; 95% CI, 1.2-7.2), and non-O blood group (HR, 2.15; 95% CI, 1.06-4.39). RTX initially provided protection from relapse (HR, 0.16; 95% CI, 0.04-0.70), but this effect gradually diminished, returning to the baseline risk for untreated patients at approximately 2.6 years. Patients who are young, have non-O blood group, or present with relapsed iTTP are at increased risk for subsequent relapse. RTX appears to confer short-term protection from relapse.

Automated liquid-liquid extraction based on 96-well plate format in conjunction with ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for the quantitation of methoxsalen in human plasma.

A sensitive, specific and high throughput bioanalytical method using automated sample processing via 96-well plate liquid-liquid extraction and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) has been developed for the determination of methoxsalen in human plasma. Plasma samples with ketoconazole as internal standard (IS) were prepared by employing 0.2 mL human plasma in ethyl acetate:dichloromethane (80:20, v/v). The chromatographic separation was achieved on a Waters Acquity UPLC BEH C18 column using isocratic mobile phase, consisting of 10 mM ammonium formate and acetonitrile (60:40, v/v), at a flow rate of 0.5 mL/min. The linear dynamic range was established over the concentration range 1.1-213.1 ng/mL for methoxsalen. The method was rugged and rapid with a total run time of 1.5 min. It was successfully applied to a pivotal bioequivalence study in 12 healthy human subjects after oral administration of 10 mg extended release methoxsalen formulation under fasting condition.

Isocitrate dehydrogenase (IDH) inhibition as treatment of myeloid malignancies: Progress and future directions.

Isocitrate dehydrogenase (IDH) is an essential metabolic enzyme. Over the last two decades, there has been a growing focus on the metabolic derangements that occur with IDH1 and IDH2 mutations. The altered IDH protein leads to accumulation of 2-hydroxyglutarate (2-HG), a metabolite with oncogenic activity via epigenetic mechanisms. The advent of IDH inhibitors has engendered hope in novel and targeted therapies in IDH1/2 mutant myeloid malignancies. We here summarize the basic physiology of IDH, the metabolic and oncogenic consequences of mutant IDH1/2, and the clinical significance of IDH inhibition in hematologic malignancies. We also discuss completed and ongoing clinical trials focusing on the inhibition of IDH proteins, which have demonstrated preliminary indications of efficacy. The promise of IDH inhibition is now being further investigated as a novel therapeutic approach for AML and other myeloid malignancies.

Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study.

BACKGROUND: Among the syndromes characterised by thrombotic microangiopathy, thrombotic thrombocytopenic purpura is distinguished by a severe deficiency in the ADAMTS13 enzyme. Patients with this disorder need urgent treatment with plasma exchange. Because ADAMTS13 activity testing typically requires prolonged turnaround times and might be unavailable in resource-poor settings, a method to rapidly assess the likelihood of severe ADAMTS13 deficiency is needed. METHODS: All consecutive adult patients presenting to three large academic medical centres in Boston, MA, USA, with thrombotic microangiopathy and a possible diagnosis of thrombotic thrombocytopenic purpura between Jan 8, 2004, and Dec 6, 2015, were included in an ongoing multi-institutional registry (the Harvard TMA Research Collaborative). Univariate analysis was used to identify covariates for a logistic regression model predictive of severe ADAMTS13 deficiency (≤10% activity). A clinical point score was generated, and its diagnostic performance was assessed using internal and external validation cohorts and compared to clinical assessment alone. FINDINGS: 214 patients with thrombotic microangiopathy were included in the derivation cohort. A seven-component clinical prediction tool, termed the PLASMIC score, was developed and found to reliably assess the pretest probability of severe ADAMTS13 deficiency (C statistic 0·96, 95% CI 0·92-0·98). Our diagnostic model was reproducibly accurate in both the internal (0·95, 0·91-0·98) and external (0·91, 0·85-0·95) validation cohorts. The scoring system also more consistently diagnosed thrombotic microangiopathy due to severe ADAMTS13 deficiency than did standard clinical assessment, as measured by C statistic (0·96, 95% CI 0·92-0·98 for PLASMIC vs 0·83, 0·77-0·88 for clinical assessment; p<0·0001) and mean Brier score (0·065 for PLASMIC vs 0·111 for clinical assessment; mean paired difference 0·05, 95% CI 0·01-0·08; p<0·0001). When utilised in addition to clinical assessment, the PLASMIC score contributed significant discriminatory power (integrated discrimination improvement 0·24, 95% CI 0·11-0·37). INTERPRETATION: We have developed and validated a clinical prediction tool-the PLASMIC score-to stratify patients with thrombotic microangiopathy according to their risk of having severe ADAMTS13 deficiency. We have shown that this scoring system is superior to standard clinical assessment in addressing the diagnostic challenge presented by thrombotic microangiopathy. Its use, together with clinical judgment, may facilitate treatment decisions in patients for whom timely results of ADAMTS13 activity testing are unavailable. FUNDING: The Luick Family Fund of Massachusetts General Hospital.

The Approach to Acute Lymphoblastic Leukemia in Older Patients: Conventional Treatments and Emerging Therapies.

Acute lymphoblastic leukemia (ALL) among older adult patients presents significant clinical challenges. As opposed to pediatric populations, in whom long-term outcomes are markedly superior, those for adults remain grim. Nevertheless, younger adults with ALL have experienced a steady improvement in long-term survival in the last few decades. This is significantly different for older ALL patients, for whom long-term outcomes remain poor. Conventional chemotherapies are associated with sub-optimal outcomes and increased toxicity in this population. However, several emerging therapies, including antibody-drug conjugates, bi-specific engagers, and chimeric antigen receptor (CAR) T cells, have demonstrated much promise and are either incorporated into the existing therapeutic paradigms or being actively investigated to improve outcomes.

Impact of electrospray ion source platforms on matrix effect due to plasma phospholipids in the determination of rivastigmine by LC-MS/MS.

BACKGROUND: This study evaluates the performance of three electrospray ionization source designs to monitor the interference of plasma phospholipids for reliable estimation of rivastigmine by LC-MS/MS for method ruggedness. The variation in the area response due to matrix effects was assessed by post-column infusion, post-extraction spiking and standard-line slope methods. RESULTS: The observed interference due to coeluting phospholipids (m/z: 524.0/184.0) at the retention time of rivastigmine was 39.5, 12.9 and 0.4% using angular spray, orthogonal spray and dual orthogonal ion source spray design, respectively. Similarly, %CV for standard line slopes was 6.9, 4.6 and 2.0, respectively. CONCLUSION: Z-spray source design provided better and efficient transfer of gas phase ions into the mass analyzer compared with angular and orthogonal spray. The study showed that Z-spray ion source provided minimum interference from phospholipids compared with other ion source designs.