Metabolic Status Influences Probiotic Efficacy for Depression-PRO-DEMET Randomized Clinical Trial Results.

Probiotics may represent a safe and easy-to-use treatment option for depression or its metabolic comorbidities. However, it is not known whether metabolic features can influence the efficacy of probiotics treatments for depression. This trial involved a parallel-group, prospective, randomized, double-blind, controlled design. In total, 116 participants with depression received a probiotic preparation containing Lactobacillus helveticus Rosell®-52 and Bifidobacterium longum Rosell®-175 or placebo over 60 days. The psychometric data were assessed longitudinally at five time-points. Data for blood pressure, body weight, waist circumference, complete blood count, serum levels of C-reactive protein, cholesterol, triglycerides, and fasting glucose were measured at the beginning of the intervention period. There was no advantage of probiotics usage over placebo in the depression score overall (PRO vs. PLC: F(1.92) = 0.58; p = 0.45). However, we found a higher rate of minimum clinically important differences in patients supplemented with probiotics than those allocated to placebo generally (74.5 vs. 53.5%; X2(1,n = 94) = 4.53; p = 0.03; NNT = 4.03), as well as in the antidepressant-treated subgroup. Moreover, we found that the more advanced the pre-intervention metabolic abnormalities (such as overweight, excessive central adipose tissue, and liver steatosis), the lower the improvements in psychometric scores. A higher baseline stress level was correlated with better improvements. The current probiotic formulations may only be used as complementary treatments for depressive disorders. Metabolic abnormalities may require more complex treatments. ClinicalTrials.gov identifier: NCT04756544.

First-year follow-up costs of myocardial infarction management in Poland from the payer's perspective.

BACKGROUND: Myocardial infarction (MI) remains a major burden for healthcare systems. Therefore, we intended to analyze the determinants of cost management of patients hospitalized for MI in Poland. METHODS: Data on patients hospitalized and discharged with the diagnosis of acute MI were derived from the public payer claims database. Adult patients, reported between October 1, 2017 and December 31, 2019, were included. Costs of hospitalization for acute MI and cumulative one-year follow-up were analyzed. RESULTS: The median (IQR) of the total direct cost was €3804.7 (2674.1-5712.7) per patient and 29% (€1113.6 [380.5-2490.4]) of these were costs related to the use of post-hospitalization healthcare resources. The median cost of cardiovascular disease management was €3624.7 (2582.1-5258.5), and 26% of this sum were follow-up costs. The analysis of the total cost for individual years showed a slight increase in median costs in subsequent years: €3450.7 (2407.8-5205.2) in 2017, €3753.8 (2642.6-5681.9) in 2018, and €3944.9 (2794.8-5844.4) in 2019. Male sex, heart failure, atrial fibrillation, diabetes, kidney disease, chronic obstructive pulmonary disease, and history of stroke in addition to hospitalization in a department other than cardiology or internal disease were independently related to the cost of MI patient management. CONCLUSIONS: The high cost of management of MI patients was independently related to sex, heart failure, atrial fibrillation, diabetes, kidney disease, chronic obstructive pulmonary disease, and history of stroke as well as hospitalization in other than cardiology or internal disease department.

PRO-DEMET Randomized Controlled Trial on Probiotics in Depression-Pilot Study Results.

There is a pressing need to identify new treatment options for depression and its comorbidities. Depression often coexists with metabolic complications, and the two may share a pathophysiological overlap, including inflammation and microbiota changes. Microbiota interventions (e.g., probiotics) may represent a safe and easy-to-use treatment option as an adjunctive therapy in patients only partially responsive to pharmacologic treatment. (1) Objective: The paper presents the results of a feasibility and pilot study. The study is an internal part of a randomized controlled trail (RCT) of the effect of probiotic supplementation on psychometric, anthropometric, metabolic, and inflammatory parameters in adult patients with depressive disorders depending on the presence of metabolic syndrome. (2) Methods: The trial has a four-arm, parallel-group, prospective, randomized, double-blind, controlled design. Sixty participants received a probiotic preparation containing Lactobacillus helveticus Rosell®-52 and Bifidobacterium longum Rosell®-175 over 60 days. The feasibility of the study design was assessed, as well as the rates of recruitment, eligibility, consent, and study completion. The following were assessed: depressive, anxiety and stress symptoms, quality of life, blood pressure, body mass index and waist circumference, complete blood count with differential, serum levels of C-reactive protein, high-density lipoprotein cholesterol, triglycerides, fasting glucose, some secondary markers of inflammation and metabolic health, as well as noninvasive biomarkers of liver fibrosis (APRI and FIB-4). (3) Results: The study was found to be generally feasible. The eligibility rate was 52% of recruited participants with 80% completing the study protocol. No differences in sociodemographic or anthropometric factors or basic laboratory findings were found between the placebo and probiotic group at the start of the intervention period. Importantly, the proportion of recruited participants fulfilling the criteria of metabolic syndrome was too low. (4) Conclusions: Whilst the whole study protocol was feasible, some different timepoint procedures require modification. The major weakness of the recruitment methods was that the percentage of metabolic arms participants was insufficient. Overall, the full RCT design on probiotics in depression with vs. without metabolic syndrome was shown to be feasible with little modification.

The Influence of Probiotic Supplementation on the Severity of Anxiety and Depressive Symptoms; Function and Composition of Gut Microbiota; and Metabolic, Inflammation, and Oxidative Stress Markers in Patients with Depression-A Study Protocol.

This article aims to present the theoretical basis, methodology, and design of a clinical trial we will conduct. The study will be prospective, randomized, placebo-controlled, and double-blind. Each intervention period will last 8 weeks and the trial will be conducted on 100 patients in total, who will be randomly divided into two groups consisting of 50 patients each. We plan to investigate the impact of Lactobacillus helveticus Rosell and Bifidobacterium longum Rosell on the depressive, anxiety, and stress levels in patients with depressive disorders with possible comorbid anxiety. In addition to assessing the influence of probiotics on the clinical condition, we also plan to study the clinical and biochemical parameters of metabolic syndrome, which often coexists with depression. Both depressive and metabolic issues may have part of their etiopathology in common, e.g., inflammation, oxidative stress, and dysbiosis. This is why we will additionally investigate the parameters related to gut microbiota, inflammatory, and oxidative statuses. Thus, the primary endpoint of the study will be the change in depression score measured with the Montgomery-Åsberg Depression Rating Scale. The secondary endpoints will include changes in anxiety and stress levels, as well as metabolic, inflammation, and oxidative stress parameters.

Etiological factors of bloodstream infections in oncological patients, who was hospitalized at the National Institute of Maria Sklodowska-Curie - National Research Institute in Warsaw in 2020-2022.

Aim of the study: The purpose of the study was the microbiological analysis of bloodstream infections in patients hospitalized at the National Institute of Oncology, Maria Sklodowska-Curie - National Research Institute in the period from 01/01/2020 to 31/10/2022. Material and methods: In the period from 01/01/2020 to 31/10/2022, 18,420 blood cultures obtained from patients hospitalized at the NIO-PIB were analysed in the Department of Clinical Microbiology (total for the presence of bacteria and fungi). Culture for the presence of bacteria was carried out in the BactAlert automatic system by bioMerieux, and for fungi in the Bactec FX automatic system by Becton Dickinson. Results: 1,184 strains of bacteria and 32 strains of fungi considered to be the etiological factor of the infection were cultured from clinical samples. Gram-positive bacteria accounted for 61.57%, while Gram-negative bacteria accounted for 32.26% of all isolated bacterial strains. The most frequently cultured strains were Escherichia coli - 13.77% (including 22.1% of ESBL strains), Klebsiella penumoniae - 4.6% (44.4% of ESBL strains, 1.85% of NDM strains), Enterobacter cloacae - 2 .7% (including 40.6% of multi-resistant strains: ESBL (15.6%) or with AmpC derepression (25%), among the non-fermenting bacilli, Pseudomonas aeruginosa was the most frequently cultured - 4.18% (including 3.8% MBL) and Acinetobacter baumannii - 0.8% (including CRAB strains 50%, MBL 10%). Anaerobic microorganisms were responsible for 3.46% of blood infection cases. Yeast- like fungi were a factor in 2.7% of all fungemia cases. From blood samples taken Staphylococci were more frequently isolated directly from a vein or through a central venous catheter than aerobic Gram-negative bacilli (44.7% and 25.3% and 55.6% and 12.5%, respectively). The opposite situation occurred in the case of samples taken simultaneously directly from vein and through a central venous catheter, in which a higher share of aerobic Gram-negative bacilli (46.6%) than staphylococci (32.8%) in causing blood infections was observed. Conclusions: Gram-positive bacteria are the major contributors to bloodstream infections in cancer patients. There is a growing tendency to develop BSI caused by multi-resistant strains.

The Impact of Diabetes and Glucose-Lowering Therapies on Hepatocellular Carcinoma Incidence and Overall Survival.

PURPOSE: The incidence of hepatocellular carcinoma (HCC) in the United Kingdom has increased 60% in the past 10 years. The epidemics of obesity and type 2 diabetes are contributing factors. In this article, we examine the impact of diabetes and glucose-lowering treatments on HCC incidence and overall survival (OS). METHODS: Data from 1064 patients diagnosed with chronic liver disease (CLD) (n = 340) or HCC (n = 724) were collected from 2007 to 2012. Patients with HCC were followed up prospectively. Univariate and multivariate logistic regression determined HCC risk factors. Kaplan-Meier curves were used to examine survival and Cox proportional hazards analysis estimated hazard ratios (HRs) for death according to use of glucose-lowering therapies. FINDINGS: Diabetes prevalence was 39.6% and 10.6% within the HCC and CLD cohorts, respectively. The odds ratio for having HCC in patients with diabetes was 5.55 (P < 0.001). Univariate analysis found an increased association of HCC with age, sex, cirrhosis, hemochromatosis, alcohol abuse, diabetes, and Child's Pugh score. In multivariate analysis age, sex, cirrhosis, Child's Pugh score, diabetes status, and insulin use retained significance. Diabetes status did not significantly affect OS in HCC; however, in people with diabetes and HCC, metformin treatment was associated with improved OS (mean survival, 31 vs 24 months; P =0.016; HR for death = 0.75; P = 0.032). IMPLICATIONS: Diabetes is significantly associated with HCC in the United Kingdom. Metformin treatment is associated with improved OS after HCC diagnosis. Treatment of diabetes should be appropriately reviewed in high-risk populations, with specific consideration of the potential hepatoprotective effects of metformin in HCC.

The Influence of Probiotic Supplementation on Depressive Symptoms, Inflammation, and Oxidative Stress Parameters and Fecal Microbiota in Patients with Depression Depending on Metabolic Syndrome Comorbidity-PRO-DEMET Randomized Study Protocol.

There is a huge need to search for new treatment options and potential biomarkers of therapeutic response to antidepressant treatment. Depression and metabolic syndrome often coexist, while a pathophysiological overlap, including microbiota changes, may play a role. The paper presents a study protocol that aims to assess the effect of probiotic supplementation on symptoms of depression, anxiety and stress, metabolic parameters, inflammatory and oxidative stress markers, as well as fecal microbiota in adult patients with depressive disorders depending on the co-occurrence of metabolic syndrome. The trial will be a four-arm, parallel-group, prospective, randomized, double-blind, controlled design that will include 200 participants and will last 20 weeks (ClinicalTrials.gov identifier: NCT04756544). The probiotic preparation will contain Lactobacillus helveticus Rosell®-52, Bifidobacterium longum Rosell®-175. We will assess the level of depression, anxiety and stress, quality of life, blood pressure, body mass index and waist circumference, white blood cells count, serum levels of C-reactive protein, high-density lipoprotein (HDL) cholesterol, triglycerides, fasting glucose, fecal microbiota composition and the level of some fecal microbiota metabolites, as well as serum inflammatory markers and oxidative stress parameters. The proposed trial may establish a safe and easy-to-use adjunctive treatment option in a subpopulation of depressive patients only partially responsive to pharmacologic therapy.

Refeeding syndrome as treatment complication of anorexia nervosa. / Zespól realimentacyjny jako powiklanie leczenia jadlowstretu psychicznego.

Refeeding syndrome (RS) is one of the serious complications during treatment of anorexia nervosa. It includes hormonal and metabolic changes that occur during the process of refeeding in chronically malnourished patient when nutrition is introduced in an excessive and improper amount. RS manifests in water-electrolyte imbalances, including hypophosphatemia (the mostimportant diagnosticmarker), hypokalemia, hyponatremia, hypomagnesaemia, fluid retention, vitamin deficiency and metabolic acidosis. It applies to either oral and parenteral supplementation. In the treatment of malnourished patients with anorexia nervosa, it is essential to establish an initial caloric amount that will stimulate weight gain from the beginning of treatment, increase its effectiveness while minimizing the risk of RS. Recent research suggests that the current recommendations may be too stringent in this respect and require further updating. Awareness of the risks associated with RS, including significant mortality, appears to be currently insufficient also among physicians. There is a need for far more specialized multidisciplinary centers for patients with anorexia nervosa and also appropriate algorithms and standards of care for that population. The aim of this paper is to systematize the current knowledge about RS and RS prevention, to increase awareness of its occurrence and present the results of the latest research on safe resupplementation of patients suffering from anorexia nervosa.

Accuracy of the European Thyroid Imaging Reporting and Data System (EU-TIRADS) in the valuation of thyroid nodule malignancy in reference to the post-surgery histological results.

PURPOSE: To assess the clinical usefulness of the European Thyroid Imaging and Reporting Data System (EU-TIRADS) in the valuation of thyroid nodules malignancy in reference to post-surgery histological results. MATERIAL AND METHODS: Pre-operative ultrasound was performed in consecutive patients admitted for thyroid surgery between June 2017 and January 2018. Thyroid nodules were classified according to EU-TIRADS to five groups: 1-5. At least one fine-needle aspiration biopsy (FNAB)/patient (dominant or suspected nodule) was performed in an outpatient clinic. The final diagnosis was based on the histological result. The percentage of cancers in each EU-TIRADS group was evaluated. Finally, sensitivity, specificity, accuracy, as well as positive and negative predictive values for malignancy were assessed. RESULTS: Fifty-two patients with a total of 140 thyroid nodules (median: 3 nodules/thyroid [minimum-maximum: 1-6]) were enrolled in the study. Thyroid cancer was diagnosed in 0% (0/6) in EU-TIRADS 2; 0% (0/92) in EU-TIRADS 3; 5.9% (2/34) in EU-TIRADS 4, and 75% (6/8) in EU-TIRADS 5. In nodules assessed as EU-TIRADS ≥ 4 sensitivity, specificity, positive and negative predictive values for malignancy were, respectively: 75% (CI 95%: 40.7-93.5), 94.1% (CI 95%: 86.0-98.5), 75% (CI 95%: 40.7-93.5), and 94.1% (CI 95%: 86.0-98.5). CONCLUSIONS: EU-TIRADS is a valuable and simple tool for assessment of the risk of malignancy of thyroid nodules and demonstrates a high ultrasound correlation with histological post-surgery results. FNAB should be performed in all nodules assessed as EU-TIRADS ≥ 4, due to higher risk of malignancy.

USP7 inhibition alters homologous recombination repair and targets CLL cells independently of ATM/p53 functional status.

The role of deubiquitylase ubiquitin-specific protease 7 (USP7) in the regulation of the p53-dependent DNA damage response (DDR) pathway is well established. Whereas previous studies have mostly focused on the mechanisms underlying how USP7 directly controls p53 stability, we recently showed that USP7 modulates the stability of the DNA damage responsive E3 ubiquitin ligase RAD18. This suggests that targeting USP7 may have therapeutic potential even in tumors with defective p53 or ibrutinib resistance. To test this hypothesis, we studied the effect of USP7 inhibition in chronic lymphocytic leukemia (CLL) where the ataxia telangiectasia mutated (ATM)-p53 pathway is inactivated with relatively high frequency, leading to treatment resistance and poor clinical outcome. We demonstrate that USP7 is upregulated in CLL cells, and its loss or inhibition disrupts homologous recombination repair (HRR). Consequently, USP7 inhibition induces significant tumor-cell killing independently of ATM and p53 through the accumulation of genotoxic levels of DNA damage. Moreover, USP7 inhibition sensitized p53-defective, chemotherapy-resistant CLL cells to clinically achievable doses of HRR-inducing chemotherapeutic agents in vitro and in vivo in a murine xenograft model. Together, these results identify USP7 as a promising therapeutic target for the treatment of hematological malignancies with DDR defects, where ATM/p53-dependent apoptosis is compromised.

T-cell number and subtype influence the disease course of primary chronic lymphocytic leukaemia xenografts in alymphoid mice.

Chronic lymphocytic leukaemia (CLL) cells require microenvironmental support for their proliferation. This can be recapitulated in highly immunocompromised hosts in the presence of T cells and other supporting cells. Current primary CLL xenograft models suffer from limited duration of tumour cell engraftment coupled with gradual T-cell outgrowth. Thus, a greater understanding of the interaction between CLL and T cells could improve their utility. In this study, using two distinct mouse xenograft models, we investigated whether xenografts recapitulate CLL biology, including natural environmental interactions with B-cell receptors and T cells, and whether manipulation of autologous T cells can expand the duration of CLL engraftment. We observed that primary CLL xenografts recapitulated both the tumour phenotype and T-cell repertoire observed in patients and that engraftment was significantly shorter for progressive tumours. A reduction in the number of patient T cells that were injected into the mice to 2-5% of the initial number or specific depletion of CD8(+) cells extended the limited xenograft duration of progressive cases to that characteristic of indolent disease. We conclude that manipulation of T cells can enhance current CLL xenograft models and thus expand their utility for investigation of tumour biology and pre-clinical drug assessment.

Targeting the Ataxia Telangiectasia Mutated-null phenotype in chronic lymphocytic leukemia with pro-oxidants.

Inactivation of the Ataxia Telangiectasia Mutated gene in chronic lymphocytic leukemia results in resistance to p53-dependent apoptosis and inferior responses to treatment with DNA damaging agents. Hence, p53-independent strategies are required to target Ataxia Telangiectasia Mutated-deficient chronic lymphocytic leukemia. As Ataxia Telangiectasia Mutated has been implicated in redox homeostasis, we investigated the effect of the Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia genotype on cellular responses to oxidative stress with a view to therapeutic targeting. We found that in comparison to Ataxia Telangiectasia Mutated-wild type chronic lymphocytic leukemia, pro-oxidant treatment of Ataxia Telangiectasia Mutated-null cells led to reduced binding of NF-E2 p45-related factor-2 to antioxidant response elements and thus decreased expression of target genes. Furthermore, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia cells contained lower levels of antioxidants and elevated mitochondrial reactive oxygen species. Consequently, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia, but not tumors with 11q deletion or TP53 mutations, exhibited differentially increased sensitivity to pro-oxidants both in vitro and in vivo. We found that cell death was mediated by a p53- and caspase-independent mechanism associated with apoptosis inducing factor activity. Together, these data suggest that defective redox-homeostasis represents an attractive therapeutic target for Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia.

Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade.

PURPOSE: Most patients with hepatocellular carcinoma (HCC) have associated chronic liver disease, the severity of which is currently assessed by the Child-Pugh (C-P) grade. In this international collaboration, we identify objective measures of liver function/dysfunction that independently influence survival in patients with HCC and then combine these into a model that could be compared with the conventional C-P grade. PATIENTS AND METHODS: We developed a simple model to assess liver function, based on 1,313 patients with HCC of all stages from Japan, that involved only serum bilirubin and albumin levels. We then tested the model using similar cohorts from other geographical regions (n = 5,097) and other clinical situations (patients undergoing resection [n = 525] or sorafenib treatment for advanced HCC [n = 1,132]). The specificity of the model for liver (dys)function was tested in patients with chronic liver disease but without HCC (n = 501). RESULTS: The model, the Albumin-Bilirubin (ALBI) grade, performed at least as well as the C-P grade in all geographic regions. The majority of patients with HCC had C-P grade A disease at presentation, and within this C-P grade, ALBI revealed two classes with clearly different prognoses. Its utility in patients with chronic liver disease alone supported the contention that the ALBI grade was indeed an index of liver (dys)function. CONCLUSION: The ALBI grade offers a simple, evidence-based, objective, and discriminatory method of assessing liver function in HCC that has been extensively tested in an international setting. This new model eliminates the need for subjective variables such as ascites and encephalopathy, a requirement in the conventional C-P grade.

ATM mutation rather than BIRC3 deletion and/or mutation predicts reduced survival in 11q-deleted chronic lymphocytic leukemia: data from the UK LRF CLL4 trial.

ATM mutation and BIRC3 deletion and/or mutation have independently been shown to have prognostic significance in chronic lymphocytic leukemia. However, the relative clinical importance of these abnormalities in patients with a deletion of 11q encompassing the ATM gene has not been established. We screened a cohort of 166 patients enriched for 11q-deletions for ATM mutations and BIRC3 deletion and mutation and determined the overall and progression-free survival among the 133 of these cases treated within the UK LRF CLL4 trial. SNP6.0 profiling demonstrated that BIRC3 deletion occurred in 83% of 11q-deleted cases and always co-existed with ATM deletion. For the first time we have demonstrated that 40% of BIRC3-deleted cases have concomitant deletion and mutation of ATM. While BIRC3 mutations were rare, they exclusively occurred with BIRC3 deletion and a wild-type residual ATM allele. In 11q-deleted cases, we confirmed that ATM mutation was associated with a reduced overall and progression-free survival comparable to that seen with TP53 abnormalities, whereas BIRC3 deletion and/or mutation had no impact on overall and progression-free survival. In conclusion, in 11q-deleted patients treated with first-line chemotherapy, ATM mutation rather than BIRC3 deletion and/or mutation identifies a subgroup with a poorer outcome.

The role of ATM mutations and 11q deletions in disease progression in chronic lymphocytic leukemia.

Abstract ATM gene alteration is a frequent event in pathogenesis of chronic lymphocytic leukemia (CLL) and occurs as monoallelic loss in the form of 11q23 deletion, with and without mutation in the remaining ATM allele. ATM is a principal DNA damage response gene and biallelic ATM alterations lead to ATM functional loss and chemoresistance. The introduction of new therapies, such as intensive chemoimmunotherapy and inhibition of B-cell receptor (BCR) signaling, has changed clinical responses for the majority of CLL tumors including those with 11q deletion, but it remains to be determined whether these strategies can prevent clonal evolution of tumors with biallelic ATM alterations. In this review we discuss ATM function and the consequences of its loss during CLL pathogenesis, differences in clinical behavior of tumors with monoallelic and biallelic ATM alterations, and we outline possible approaches for targeting the ATM null CLL phenotype.

Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 trial.

PURPOSE: The prognostic significance of ATM mutations in chronic lymphocytic leukemia (CLL) is unclear. We assessed their impact in the context of a prospective randomized trial. PATIENTS AND METHODS: We analyzed the ATM gene in 224 patients treated on the Leukemia Research Fund Chronic Lymphocytic Leukemia 4 (LRF-CLL4) trial with chlorambucil or fludarabine with and without cyclophosphamide. ATM status was analyzed by denaturing high-performance liquid chromatography and was related to treatment response, survival, and the impact of TP53 alterations for the same patient cohort. RESULTS: We identified 36 ATM mutations in 33 tumors, 16 with and 17 without 11q deletion. Mutations were associated with advanced disease stage and involvement of multiple lymphoid sites. Patients with both ATM mutation and 11q deletion showed significantly reduced progression-free survival (median, 7.4 months) compared with those with ATM wild type (28.6 months), 11q deletion alone (17.1 months), or ATM mutation alone (30.8 months), but survival was similar to that in patients with monoallelic (6.7 months) or biallelic (3.4 months) TP53 alterations. This effect was independent of treatment, immunoglobulin heavy chain variable gene (IGHV) status, age, sex, or disease stage. Overall survival for patients with biallelic ATM alterations was also significantly reduced compared with those with ATM wild type or ATM mutation alone (median, 42.2 v 85.5 v 77.6 months, respectively). CONCLUSION: The combination of 11q deletion and ATM mutation in CLL is associated with significantly shorter progression-free and overall survival following first-line treatment with alkylating agents and purine analogs. Assessment of ATM mutation status in patients with 11q deletion may influence the choice of subsequent therapy.

ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but influences rapid disease progression through loss of the remaining ATM allele.

Ataxia telangiectasia patients, with constitutional bi-allelic ATM mutations, have a marked risk of lymphoid tumors and ATM mutation carriers have a smaller risk of cancer. Sporadic ATM mutations occur in 10-20% of chronic lymphocytic leukemia and are often associated with chromosome 11q deletions which cause loss of an ATM allele. The role of constitutional ATM mutations in the pathogenesis of chronic lymphocytic leukemia is unknown. Here we investigated the frequency of constitutional ATM mutations in either of two chronic lymphocytic leukemia cohorts, those with and without a chromosome 11q deletion. We found that in comparison to controls, constitutional pathogenic ATM mutations were increased in patients with chromosome 11q deletions (6 of 140 vs. 0 of 281, P = 0.001) but not in those without 11q deletions (2 of 178 vs. 0 of 281, P = 0.15). These results suggest that ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but rather influences rapid disease progression through ATM loss.

The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo.

The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia (CLL), T-prolymphocytic leukemia (T-PLL), and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues. ATM mutant cells exhibit impaired DNA double strand break repair. Poly (ADP-ribose) polymerase (PARP) inhibition that imposes the requirement for DNA double strand break repair should selectively sensitize ATM-deficient tumor cells to killing. We investigated in vitro sensitivity to the poly (ADP-ribose) polymerase inhibitor olaparib (AZD2281) of 5 ATM mutant lymphoblastoid cell lines (LCL), an ATM mutant MCL cell line, an ATM knockdown PGA CLL cell line, and 9 ATM-deficient primary CLLs induced to cycle and observed differential killing compared with ATM wildtype counterparts. Pharmacologic inhibition of ATM and ATM knockdown confirmed the effect was ATM-dependent and mediated through mitotic catastrophe independently of apoptosis. A nonobese diabetic/severe combined immunodeficient (NOD/SCID) murine xenograft model of an ATM mutant MCL cell line demonstrated significantly reduced tumor load and an increased survival of animals after olaparib treatment in vivo. Addition of olaparib sensitized ATM null tumor cells to DNA-damaging agents. We suggest that olaparib would be an appropriate agent for treating refractory ATM mutant lymphoid tumors.