Investigating the role of Class Ia phosphoinositide-3 kinase isoforms in Mantle Cell Lymphoma.

PhDMantle Cell Lymphoma (MCL) is a rare but aggressive Non-Hodgkin Lymphoma (NHL). Although t(11;14) is a hallmark of MCL, it is insufficient for lymphomagenesis. The phosphoinositide-3 kinase (PI3K) pathway is thought to play an important role in MCL pathogenesis and the PI3K p110δ isoform is enriched in leucocytes making it an attractive target. Early phase trials evaluating the p110δ selective inhibitor GS-1101 however demonstrate inferior responses in MCL compared to chronic lymphocytic leukaemia and indolent NHL. The relative contribution of the class Ia PI3K isoforms p110α (PIK3CA), p110β (PIK3CB) and p110δ (PIK3CD) was therefore evaluated in MCL. Immunohistochemistry on MCL tissue microarrays revealed that while p110δ was highly expressed, p110α showed wide variation and p110β expression was the weakest. A significant increase in p110α expression was found with disease progression. Although GS-1101 was sufficient to abolish B-cell receptor mediated PI3K activation, additional p110α inhibition was necessary to abolish constitutive PI3K activation in MCL exhibiting high p110α expression. Compared to GS-1101, GDC-0941 (p110α and p110δ inhibitor) had greater in vitro toxicity and a high PIK3CA/PIK3CD mRNA ratio (> twice ratio in healthy B-cells) was able to identify primary MCL samples that were resistant to GS-1101 but significantly more sensitive to GDC—0941. This ratio also increased with disease progression. No PIK3CA or PIK3R1 activating mutations were found. In summary, blockade of both p110α and p110δ appears to be necessary for effective PI3K inhibition in MCL, particularly with relapse. The PIK3CA/PIK3CD mRNA ratio may help identify those patients that are most likely to respond. Finally, a disseminated xenograft model of human primary MCL was established in NSG mice. Engraftment of primary MCL was demonstrated by peripheral blood flow cytometry, tissue immunohistochemistry and FISH for t(11;14). This model is potentially valuable for pre-clinical in vivo testing of novel drugs for this incurable disease.Roger Counter Foundation Early Stage Research Grant awarded by the British Society of Haematology

To read or not to read: A question of national consequence

In 2004, the US National Endowment for the Arts published \u27Reading at Risk: A Survey of Literary Reading in America\u27. This detailed study showed that Americans in almost every demographic group were reading fiction, poetry, and drama?and books in general?at significantly lower rates than 10 or 20 years earlier, i.e. declines were steepest among young adults. More recent findings attest to the diminished role of voluntary reading in American life. These new statistics come from a variety of reliable sources, including large, nationally representative studies conducted by other federal agencies. Brought together here for the first time, the data prompt three unsettling conclusions: ? Americans are spending less time reading. ? Reading comprehension skills are eroding. ? These declines have serious civic, social, cultural, and economic implications. Americans are reading less - teens and young adults read less often and for shorter amounts of time compared with other age groups and with Americans of previous years. ? Less than one-third of 13-year-olds are daily readers, a 14 percent decline from 20 years earlier. Among 17-year-olds, the percentage of non-readers doubled over a 20-year period, from nine percent in 1984 to 19 percent in 2004. ? On average, Americans ages 15 to 24 spend almost two hours a day watching TV, and only seven minutes of their daily leisure time on reading. Americans are reading less well ? reading scores continue to worsen, especially among teenagers and young males. By contrast, the average reading score of 9-year-olds has improved. ? Reading scores for 12th-grade readers fell significantly from 1992 to 2005, with the sharpest declines among lower-level readers. ? 2005 reading scores for male 12th-graders are 13 points lower than for female 12th-graders, and that gender gap has widened since 1992. ? Reading scores for American adults of almost all education levels have deteriorated, notably among the best-educated groups. From 1992 to 2003, the percentage of adults with graduate school experience who were rated proficient in prose reading dropped by 10 points, a 20 percent rate of decline. The declines in reading have civic, social, and economic implications ? Advanced readers accrue personal, professional, and social advantages. Deficient readers run higher risks of failure in all three areas. ? Nearly two-thirds of employers ranked reading comprehension \u27very important\u27 for high school graduates. Yet 38 percent consider most high school graduates deficient in this basic skill. ? American 15-year-olds ranked fifteenth in average reading scores for 31 industrialized nations, behind Poland, Korea, France, and Canada, among others. ? Literary readers are more likely than non-readers to engage in positive civic and individual activities ? such as volunteering, attending sports or cultural events, and exercising

Studying genetic determinants of natural variation in human gene expression using Bayesian ANOVA

Standard genetic mapping techniques scan chromosomal segments for location of genetic linkage and association signals. The majority of these methods consider only correlations at single markers and/or phenotypes with explicit detailing of the genetic structure. These methods tend to be limited by their inability to consider the effect of large numbers of model variables jointly. In contrast, we propose a Bayesian analysis of variance (ANOVA) method to categorize individuals based on similarity of multidimensional profiles and attempt to analyze all variables simultaneously. Using Problem 1 of the Genetic Analysis Workshop 15 data set, we demonstrate the method's utility for joint analysis of gene expression levels and single-nucleotide polymorphism genotypes. We show that the method extracts similar information to that of previous genetic mapping analyses, and suggest extensions of the method for mining unique information not previously found

Compliance with Home-based Fortification Strategies for Delivery of Iron and Zinc: Its Effect on Haematological and Growth Markers among 6-24 months Old Children in North India

Compliance is a key component in successful implementation of the delivery of micronutrients among children. The present study evaluates the compliance with two home-based food fortification strategies (fortified complementary food or sprinkle) for providing iron and zinc among children aged 6-24 months. A total of 292 children were randomly allocated to receive either rice-based fortified complementary food and nutrition education (Cf=101), sprinkle and nutrition education (Mp=97), or nutrition education alone as control (Ed=94). All the enrolled children were breastfed at the beginning of the study and were advised to continue breastfeeding. Biweekly information on compliance and anthropometry was collected. Complete haemogram estimation was conducted at baseline and end of the study. Compliance with the fortified complementary food was higher compared to sprinkle (Cf=81%, Mp=64% child-days). Consumption of the fortified complementary food for 6 months resulted in a significant increase in mean haemoglobin in the intervention group compared to control group (Cf 1.29\ub11.6 g/dL; Ed 0.23\ub11.3 g/dL; p<0.001). Our results showed that fortified complementary food had higher compliance than sprinkle and is a suitable delivery mechanism for iron and zinc in preschool children

Effective bridging therapy can improve CD19 CAR-T outcomes while maintaining safety in patients with large B-cell lymphoma

The impact of bridging therapy (BT) on CD19-directed chimeric antigen receptor T-cell (CD19CAR-T) outcomes in large B-cell lymphoma (LBCL) is poorly characterised. Current practice is guided by physician preference rather than established evidence. Identification of effective BT modalities and factors predictive of response could improve CAR-T intention to treat and clinical outcomes. We assessed BT modality and response in 375 adult LBCL patients in relation to outcomes following axicabtagene ciloleucel (Axi-cel) or tisagenlecleucel (Tisa-cel). The majority of patients received BT with chemotherapy (57%) or radiotherapy (17%). We observed that BT was safe for patients, with minimal morbidity/mortality. We showed that complete or partial response to BT conferred a 42% reduction in disease progression and death following CD19CAR-T therapy. Multivariate analysis identified several factors associated with likelihood of response to BT, including response to last line therapy, the absence of bulky disease, and the use of Polatuzumab-containing chemotherapy regimens. Our data suggested that complete/partial response to BT may be more important for Tisa-cel than Axi-cel, as all Tisa-cel patients with less than partial response to BT experienced frank relapse within 12 months of CD19CAR-T infusion. In summary, BT in LBCL should be carefully planned towards optimal response and disease debulking, to improve CD19CAR-T patient outcomes. Polatuzumab-containing regimens should be strongly considered for all suitable patients, and failure to achieve complete/partial response to BT pre-Tisa-cel may prompt consideration of further lines of BT where possible

Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in the United Kingdom: A real‐world intention‐to‐treat analysis

Brexucabtagene autoleucel (brexu‐cel) is an autologous CD19 CAR T‐cell product, approved for relapsed/refractory (r/r) mantle cell lymphoma (MCL). In ZUMA‐2, brexu‐cel demonstrated impressive responses in patients failing ≥2 lines, including a bruton's tyrosine kinase inhibitor, with an overall and complete response rate of 93% and 67%, respectively. Here, we report our real‐world intention‐to‐treat (ITT) outcomes for brexu‐cel in consecutive, prospectively approved patients, from 12 institutions in the United Kingdom between February 2021 and June 2023, with a focus on feasibility, efficacy, and tolerability. Of 119 approved, 104 underwent leukapheresis and 83 received a brexu‐cel infusion. Progressive disease (PD) and/or manufacturing (MF) were the most common reasons for failure to reach harvest and/or infusion. For infused patients, best overall and complete response rates were 87% and 81%, respectively. At a median follow‐up of 13.3 months, median progression‐free survival (PFS) for infused patients was 21 months (10.1–NA) with a 6‐ and 12‐month PFS of 82% (95% confidence interval [CI], 71–89) and 62% (95% CI, 49–73), respectively. ≥Grade 3 cytokine release syndrome and neurotoxicity occurred in 12% and 22%, respectively. On multivariate analysis, inferior PFS was associated with male sex, bulky disease, ECOG PS > 1 and previous MF. Cumulative incidence of non‐relapse mortality (NRM) was 6%, 15%, and 25% at 6, 12, and 24 months, respectively, and mostly attributable to infection. Outcomes for infused patients in the UK are comparable to ZUMA‐2 and other real‐world reports. However, ITT analysis highlights a significant dropout due to PD and/or MF. NRM events warrant further attention

Effective bridging therapy can improve CD19 CAR-T outcomes while maintaining safety in patients with large B-cell lymphoma

The impact of bridging therapy (BT) on CD19-directed chimeric antigen receptor T-cell (CD19CAR-T) outcomes in large B-cell lymphoma (LBCL) is poorly characterized. Current practice is guided through physician preference rather than established evidence. Identification of effective BT modalities and factors predictive of response could improve both CAR-T intention to treat and clinical outcomes. We assessed BT modality and response in 375 adult patients with LBCL in relation to outcomes after axicabtagene ciloleucel (Axi-cel) or tisagenlecleucel (Tisa-cel) administration. The majority of patients received BT with chemotherapy (57%) or radiotherapy (17%). We observed that BT was safe for patients, with minimal morbidity or mortality. We showed that complete or partial response to BT conferred a 42% reduction in disease progression and death after CD19CAR-T therapy. Multivariate analysis identified several factors associated with likelihood of response to BT, including response to last line therapy, the absence of bulky disease, and the use of polatuzumab-containing chemotherapy regimens. Our data suggested that complete or partial response to BT may be more important for Tisa-cel than for Axi-cel, because all patients receiving Tisa-cel with less than partial response to BT experienced frank relapse within 12 months of CD19CAR-T infusion. In summary, BT in LBCL should be carefully planned toward optimal response and disease debulking, to improve patient outcomes associated with CD19CAR-T. Polatuzumab-containing regimens should be strongly considered for all suitable patients, and failure to achieve complete or partial response to BT before Tisa-cel administration may prompt consideration of further lines of BT where possible

The evolving landscape of COVID‐19 and post‐COVID condition in patients with chronic lymphocytic leukemia: A study by ERIC, the European research initiative on CLL

In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations