Atrial arrhythmias following CAR-chimeric antigen receptor T-cell therapy: Incidence, risk factors and biomarker profile.

Recent reports have raised concerns about the association of chimeric antigen receptor T cell (CAR-T) with non-negligible cardiotoxicity, particularly atrial arrhythmias. First, we conducted a pharmacovigilance study to assess the reporting of atrial arrhythmias following CD19-directed CAR-T. Subsequently, to determine the incidence, risk factors and outcomes of atrial arrhythmias post-CAR-T, we compiled a retrospective single-centre cohort of non-Hodgkin lymphoma patients. Only commercial CAR-T products were considered. Atrial arrhythmias were nearly fourfold more likely to be reported after CAR-T therapy compared to all other cancer patients in the FAERS (adjusted ROR = 3.76 [95% CI 2.67-5.29]). Of the 236 patients in our institutional cohort, 23 (10%) developed atrial arrhythmias post-CAR-T, including 12 de novo arrhythmias, with most (83%) requiring medical intervention. Atrial arrhythmias frequently co-occurred with cytokine release syndrome and were associated with higher post-CAR-T infusion peak levels of IL-10, TNF-alpha and LDH, and lower trough levels of fibrinogen. In a multivariable analysis, risk factors for atrial arrhythmia were history of atrial arrhythmia (OR = 6.80 [2.39-19.6]) and using CAR-T product with a CD28-costimulatory domain (OR = 5.17 [1.72-18.6]). Atrial arrhythmias following CD19-CAR-T therapy are prevalent and associated with elevated inflammatory biomarkers, a history of atrial arrhythmia and the use of a CAR-T product with a CD28 costimulatory domain.

Multilineage involvement in KMT2A-rearranged B acute lymphoblastic leukaemia: cell-of-origin, biology, and clinical implications.

AIMS: B lymphoblastic leukaemia/lymphoma (B-ALL) is thought to originate from Pro/Pre-B cells and the genetic aberrations largely reside in lymphoid-committed cells. A recent study demonstrated that a proportion of paediatric B-ALL patients have BCR::ABL1 fusion in myeloid cells, suggesting a chronic myeloid leukaemia (CML)-like biology in this peculiar subset of B-ALL, although it is not entirely clear if the CD19-negative precursor compartment is a source of the myeloid cells. Moreover, the observation has not yet been extended to other fusion-driven B-ALLs. METHODS AND RESULTS: In this study we investigated a cohort of KMT2A-rearranged B-ALL patients with a comparison to BCR::ABL1-rearranged B-ALL by performing cell sorting via flow cytometry followed by FISH (fluorescence in situ hybridization) analysis on each of the sorted populations. In addition, RNA sequencing was performed on one of the sorted populations. These analyses showed that (1) multilineage involvement was present in 53% of BCR::ABL1 and 36% of KMT2A-rearranged B-ALL regardless of age, (2) multilineage involvement created pitfalls for residual disease monitoring, and (3) HSPC transcriptome signatures were upregulated in KMT2A-rearranged B-ALL with multilineage involvement. CONCLUSIONS: In summary, multilineage involvement is common in both BCR::ABL1-rearranged and KMT2A-rearranged B-ALL, which should be taken into consideration when interpreting the disease burden during the clinical course.

Universal germline genetic testing in patients with hematologic malignancies using DNA isolated from nail clippings.

Not available.

Acute myeloid leukemia with mixed phenotype is characterized by stemness transcriptomic signatures and limited lineage plasticity.

Mixed phenotype (MP) in acute leukemias poses unique classification and management dilemmas and can be seen in entities other than de novo mixed phenotype acute leukemia (MPAL). Although WHO classification empirically recommends excluding AML with myelodysplasia related changes (AML-MRC) and therapy related AML (t-AML) with mixed phenotype (AML-MP) from MPAL, there is lack of studies investigating the clinical, genetic, and biologic features of AML-MP. We report the first cohort of AML-MRC and t-AML with MP integrating their clinical, immunophenotypic, genomic and transcriptomic features with comparison to MPAL and AML-MRC/t-AML without MP. Both AML cohorts with and without MP shared similar clinical features including adverse outcomes but were different from MPAL. The genomic landscape of AML-MP overlaps with AML without MP but differs from MPAL. AML-MP harbors more frequent RUNX1 mutations than AML without MP and MPAL. RUNX1 mutations did not impact the survival of patients with MPAL. Unsupervised hierarchal clustering based on immunophenotype identified biologically distinct clusters with phenotype/genotype correlation and outcome differences. Furthermore, transcriptomic analysis showed an enrichment for stemness signature in AML-MP and AML without MP as compared to MPAL. Lastly, MPAL but not AML-MP often switched to lymphoid only immunophenotype after treatment. Expression of transcription factors critical for lymphoid differentiation were upregulated only in MPAL, but not in AML-MP. Our study for the first time demonstrates that AML-MP clinically and biologically resembles its AML counterpart without MP and differs from MPAL, supporting the recommendation to exclude these patients from the diagnosis of MPAL. Future studies are needed to elucidate the molecular mechanism of mixed phenotype in AML. Key points: AML-MP clinically and biologically resembles AML but differs from MPAL. AML-MP shows RUNX1 mutations, stemness signatures and limited lymphoid lineage plasticity.

A Brief Historical Overview of Psychedelic Research.

Classical serotonergic psychedelics such as lysergic acid diethylamide or the naturally occurring compounds psilocybin and mescaline produce profound changes in mood, thought, intuition, sensory perception, the experience of time and space, and even the experience of self. Research examining psychedelic compounds has had a complex and turbulent evolution. Many cultures throughout the world have used psychedelic plants not only for mystical, ritualistic, or divinatory purposes but also for curing illnesses. Much of the genesis and progress of modern investigations into the effects and underlying mechanisms of action of psychedelics have been intertwined with studies of the neurotransmitter serotonin. Early hypotheses that serotonergic systems mediate psychedelic effects were supported initially by preclinical animal studies and subsequently confirmed by pharmacological studies in healthy humans. The use of psychedelic compounds as putative psychotomimetics that reproduce some features of naturally occurring psychotic disorders met with some limited success. More recent studies are exploring psychedelics as potential psychotherapeutic agents. Recent indications that even 1 or 2 psychedelic treatments produce robust and sustained reductions in clinical symptoms in a variety of psychiatric disorders have prompted an enormous resurgence of interest in the nature and mechanisms contributing to their effects.

Acute febrile neutrophilic dermatosis (Sweet syndrome) in acute myeloid leukemia patients: a 28-year institutional experience.

INTRODUCTION: Sweet syndrome (SS) is well-known to be associated with underlying hematologic malignancies. The incidence and qualities of SS among novel targeted therapies for acute myeloid leukemia (AML) have not yet been described. METHODS: Through retrospective review of 19432 patients diagnosed with acute/chronic leukemia or myelodysplastic syndromes/ myeloproliferative neoplasms (MDS+/-MPN) over 28 years, we calculated the incidence of SS in the setting of select hematologic malignancies and described the clinicopathologic characteristics of SS in patients with onset of SS after initiation of novel AML-targeted therapies. RESULTS: Overall incidence of SS was 0.36% (95% CI: 0.27% - 0.45%), which was significantly higher among patients with AML (50/5248, 0.94%; 95% CI: 0.71% - 1.25%). Nine AML patients were on 4 classes of novel targeted treatments - IDH1/2 inhibitor alone, FLT3 inhibitor, IDH2 and DOT1L inhibitor, and anti-CD33 therapy. In therapies inducing myeloid blast differentiation, SS occurred at later onset following treatment. CONCLUSIONS: In AML patients with fever and unusual skin lesions, physicians may consider SS earlier which may shorten time to diagnosis. Future assessments of SS among patients treated with novel therapies for AML and molecular studies of biopsies may help further explain this dermatologic adverse event with earlier diagnosis and management of neutrophilic dermatoses in these patients.

Expert consensus guidelines for the prophylaxis and management of tumor lysis syndrome in the United States: Results of a modified Delphi panel.

INTRODUCTION: Tumor lysis syndrome (TLS), which occurs spontaneously or in response to anticancer treatment, results in the release of intracellular potassium, phosphorus, and nucleic acids into the bloodstream, which results in secondary clinical complications that may be fatal. Prior TLS guidelines do not take into consideration potent novel oncologic agents or contemporary treatment paradigms with increased risk of TLS. Thus, a modified Delphi panel of experts was convened to provide an update for TLS management guidelines based upon a combination of supporting literature and practice consensus. METHODS: A three-round modified Delphi process was implemented. For round 1, nine expert panelists completed a web-based questionnaire developed using published literature. In round 2, panelists were asked to reconsider their answers to questions that did not reach consensus (defined as ≥ 66% agreement among voting panelists). Round 3 was an unblinded, moderated virtual meeting to discuss any remaining questions that did not reach consensus. RESULTS: Detailed recommendations are given for prophylaxis, monitoring, and management of TLS risks and complications, with hydration being a key element of TLS prophylaxis and management. Guidelines for the management of acute effects of TLS and prevention of long-term renal effects include management of hyperkalemia, hypocalcemia, hyperphosphatemia, and hyperuricemia. DISCUSSION: Although the control of uric acid levels is quite effective with currently available agents, panelists emphasize the importance of monitoring and treating other dangerous electrolyte abnormalities such as hyperkalemia and hyperphosphatemia. Guidelines from this modified Delphi panel should aid clinicians in preventing and managing TLS.

Interaction between myelodysplasia-related gene mutations and ontogeny in acute myeloid leukemia.

Accurate classification and risk stratification are critical for clinical decision making in patients with acute myeloid leukemia (AML). In the newly proposed World Health Organization and International Consensus classifications of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as 1 of the diagnostic criteria for AML, AML-MR, based largely on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndrome. ICC also prioritizes MR gene mutations over ontogeny (as defined in the clinical history). Furthermore, European LeukemiaNet (ELN) 2022 stratifies these MR gene mutations into the adverse-risk group. By thoroughly annotating a cohort of 344 newly diagnosed patients with AML treated at the Memorial Sloan Kettering Cancer Center, we show that ontogeny assignments based on the database registry lack accuracy. MR gene mutations are frequently observed in de novo AML. Among the MR gene mutations, only EZH2 and SF3B1 were associated with an inferior outcome in the univariate analysis. In a multivariate analysis, AML ontogeny had independent prognostic values even after adjusting for age, treatment, allo-transplant and genomic classes or ELN risks. Ontogeny also helped stratify the outcome of AML with MR gene mutations. Finally, de novo AML with MR gene mutations did not show an adverse outcome. In summary, our study emphasizes the importance of accurate ontogeny designation in clinical studies, demonstrates the independent prognostic value of AML ontogeny, and questions the current classification and risk stratification of AML with MR gene mutations.

Payer and provider solutions to utilization management challenges in the management of rare hematologic cancers.

Patients with rare diseases such as Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), a hematologic malignancy affecting approximately 1500 new patients per year, experience barriers to care involving both clinical and administrative factors. Optimal patient outcomes depend on timely identification, diagnosis of disease, and treatment initiation. For patients living with Ph+ ALL, the process can be delayed by limited treatment options approved by the US Food and Drug Administration and administrative hurdles that often delay treatment initiation. An overhaul of utilization management processes, such as the requirement for prior authorization (PA) for treatment, are needed to ensure patients have access to appropriate treatments in a timely manner. An AJMC Roundtable in November 2022 brought together a panel of payers and providers to discuss the challenges and shortcomings of current PA processes and to present ideas for potential solutions for improving them. Panelists at the roundtable discussed approaches including the use of guideline-concordant electronic PAs and other digital solutions, expedited approval pathways for use in specific conditions, use of real-world evidence in decision-making, issuance of PA "Gold Cards" to select providers, and a shift to value-based care agreements. Roundtable attendees agreed that, regardless of the strategy for PA-process improvement, there is a need for improved communication between providers and payers to ensure that the decision-making system meets the essential need for timely patient access to optimal care. This article reviews utilization management and guideline-concordant care through the lens of rare diseases and then presents solutions to utilization.

Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients.

AIMS: Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient's immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality. METHODS AND RESULTS: From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104-647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan-Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk [hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6-4.7] after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4-8.8) after adjusting for cancer burden. CONCLUSION: Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin.

Asciminib monotherapy in patients with CML-CP without BCR::ABL1 T315I mutations treated with at least two prior TKIs: 4-year phase 1 safety and efficacy results.

Asciminib is approved for patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CML-CP) who received ≥2 prior tyrosine kinase inhibitors or have the T315I mutation. We report updated results of a phase 1, open-label, nonrandomized trial (NCT02081378) assessing the safety, tolerability, and antileukemic activity of asciminib monotherapy 10-200 mg once or twice daily in 115 patients with CML-CP without T315I (data cutoff: January 6, 2021). After ≈4-year median exposure, 69.6% of patients remained on asciminib. The most common grade ≥3 adverse events (AEs) included increased pancreatic enzymes (22.6%), thrombocytopenia (13.9%), hypertension (13.0%), and neutropenia (12.2%); all-grade AEs (mostly grade 1/2) included musculoskeletal pain (59.1%), upper respiratory tract infection (41.7%), and fatigue (40.9%). Clinical pancreatitis and arterial occlusive events (AOEs) occurred in 7.0% and 8.7%, respectively. Most AEs occurred during year 1; the subsequent likelihood of new events, including AOEs, was low. By data cutoff, among patients without the indicated response at baseline, 61.3% achieved BCR::ABL1 ≤ 1%, 61.6% achieved ≤0.1% (major molecular response [MMR]), and 33.7% achieved ≤0.01% on the International Scale. MMR was maintained in 48/53 patients who achieved it and 19/20 who were in MMR at screening, supporting the long-term safety and efficacy of asciminib in this population.

Lenalidomide-associated B-cell ALL: clinical and pathologic correlates and sensitivity to lenalidomide withdrawal.

Lenalidomide is an effective component of induction and maintenance therapy for multiple myeloma, though with a risk of secondary malignancies, including acute lymphoblastic leukemia (ALL). In contrast to therapy-related myeloid neoplasia, lenalidomide-associated lymphoblastic neoplasia remains poorly characterized. We conducted a dual institution retrospective study of 32 ALL cases that arose after lenalidomide maintenance (all B-lineage, 31/32 BCR::ABL-negative). B-cell ALL (B-ALL) was diagnosed at median 54 months (range, 5-119) after first exposure to lenalidomide and after median 42 months of cumulative lenalidomide exposure (range, 2-114). High incidence of TP53 mutations (9/19 evaluable cases) and low hypodiploidy (8/26 patients) were identified. Despite median age of 65 years and poor-risk B-ALL features observed in the cohort, rates of complete response (CR) or CR with incomplete hematologic recovery were high (25/28 patients receiving treatment). Median event-free survival was 35.4 months among treated patients (not reached among those undergoing allogeneic hematopoietic cell transplantation [HCT]). Sixteen patients remain alive without evidence of B-ALL after HCT or extended maintenance therapy. We also describe regression of B-ALL or immature B-cell populations with B-ALL immunophenotype after lenalidomide discontinuation in 5 patients, suggesting lenalidomide may drive leukemic progression even after initiation of lymphoblastic neoplasia and that lenalidomide withdrawal alone may be an appropriate first-line intervention in selected patients. Monitoring for early B-ALL-like proliferations may offer opportunities for lenalidomide withdrawal to prevent progression. Established combination chemotherapy regimens, newer surface antigen-targeted approaches, and allogeneic HCT are effective in many patients with lenalidomide-associated B-ALL and should be offered to medically fit patients.

Molecular predictors of immunophenotypic measurable residual disease clearance in acute myeloid leukemia.

Measurable residual disease (MRD) is a powerful prognostic factor in acute myeloid leukemia (AML). However, pre-treatment molecular predictors of immunophenotypic MRD clearance remain unclear. We analyzed a dataset of 211 patients with pre-treatment next-generation sequencing who received induction chemotherapy and had MRD assessed by serial immunophenotypic monitoring after induction, subsequent therapy, and allogeneic stem cell transplant (allo-SCT). Induction chemotherapy led to MRD- remission, MRD+ remission, and persistent disease in 35%, 27%, and 38% of patients, respectively. With subsequent therapy, 34% of patients with MRD+ and 26% of patients with persistent disease converted to MRD-. Mutations in CEBPA, NRAS, KRAS, and NPM1 predicted high rates of MRD- remission, while mutations in TP53, SF3B1, ASXL1, and RUNX1 and karyotypic abnormalities including inv (3), monosomy 5 or 7 predicted low rates of MRD- remission. Patients with fewer individual clones were more likely to achieve MRD- remission. Among 132 patients who underwent allo-SCT, outcomes were favorable whether patients achieved early MRD- after induction or later MRD- after subsequent therapy prior to allo-SCT. As MRD conversion with chemotherapy prior to allo-SCT is rarely achieved in patients with specific baseline mutational patterns and high clone numbers, upfront inclusion of these patients into clinical trials should be considered.

iTat transgenic mice exhibit hyper-locomotion in the behavioral pattern monitor after chronic exposure to methamphetamine but are unaffected by Tat expression.

Although antiretroviral therapy (ART) has increased the quality of life and lifespan in people living with HIV (PWH), millions continue to suffer from the neurobehavioral effects of the virus. Additionally, the abuse of illicit drugs (methamphetamine in particular) is significantly higher in PWH compared to the general population, which may further impact their neurological functions. The HIV regulatory protein, Tat, has been implicated in the neurobehavioral impacts of HIV and is purported to inhibit dopamine transporter (DAT) function in a way similar to methamphetamine. Thus, we hypothesized that a combination of Tat expression and methamphetamine would exert synergistic deleterious effects on behavior and DAT expression. We examined the impact of chronic methamphetamine exposure on exploration in transgenic mice expressing human Tat (iTat) vs. their wildtype littermates using the behavioral pattern monitor (BPM). During baseline, mice exhibited sex-dependent differences in BPM behavior, which persisted through methamphetamine exposure, and Tat activation with doxycycline. We observed a main effect of methamphetamine, wherein exposure, irrespective of genotype, increased locomotor activity and decreased specific exploration. After doxycycline treatment, mice continued to exhibit drug-dependent alterations in locomotion, with no effect of Tat, or methamphetamine interactions. DAT levels were higher in wildtype, saline-exposed males compared to all other groups. These data support stimulant-induced changes of locomotor activity and exploration, and suggest that viral Tat and methamphetamine do not synergistically interact to alter these behaviors in mice. These findings are important for future studies attempting to disentangle the effect of substances that impact DAT on HAND-relevant behaviors using such transgenic animals.

Modulation of ventromedial orbitofrontal cortical glutamatergic activity affects the explore-exploit balance and influences value-based decision-making.

The balance between exploration and exploitation is essential for decision-making. The present study investigated the role of ventromedial orbitofrontal cortex (vmOFC) glutamate neurons in mediating value-based decision-making by first using optogenetics to manipulate vmOFC glutamate activity in rats during a probabilistic reversal learning (PRL) task. Rats that received vmOFC activation during informative feedback completed fewer reversals and exhibited reduced reward sensitivity relative to rats. Analysis with a Q-learning computational model revealed that increased vmOFC activity did not affect the learning rate but instead promoted maladaptive exploration. By contrast, vmOFC inhibition increased the number of completed reversals and increased exploitative behavior. In a separate group of animals, calcium activity of vmOFC glutamate neurons was recorded using fiber photometry. Complementing our results above, we found that suppression of vmOFC activity during the latter part of rewarded trials was associated with improved PRL performance, greater win-stay responding and selecting the correct choice on the next trial. These data demonstrate that excessive vmOFC activity during reward feedback disrupted value-based decision-making by increasing the maladaptive exploration of lower-valued options. Our findings support the premise that pharmacological interventions that normalize aberrant vmOFC glutamate activity during reward feedback processing may attenuate deficits in value-based decision-making.

Chronic methamphetamine exposure exerts few effects on the iTat mouse model of HIV, but blocks Tat expression-induced slowed reward retrieval.

Human immunodeficiency virus (HIV) continues to infect millions worldwide, negatively impacting neurobehavioral function. Further understanding of the combined effects of HIV and methamphetamine use is crucial, as methamphetamine use is prevalent in people with HIV. The HIV-associated protein Tat may contribute to cognitive dysfunction, modeled preclinically in mice using doxycycline (DOX)-inducible Tat expression (iTat). Tat may exert its effects on cognitive function via disruption of the dopamine transporter, similar to the action of methamphetamine. Additionally, Tat and methamphetamine both decrease interneuron populations, including those expressing calbindin. It is important to understand the combined effects of Tat and methamphetamine in preclinical models of HIV infection. Here, we used iTat transgenic mice and a chronic binge regimen of methamphetamine exposure to determine their combined impact on reward learning and motivation. We also measured calbindin expression in behavior-relevant brain regions. Before induction with DOX, iTat mice exhibited no differences in behavior. Chronic methamphetamine exposure before Tat induction impaired initial reward learning but did not affect motivation. Furthermore, DOX-induced Tat expression did not alter behavior, but slowed latencies to retrieve rewards. This effect of Tat, however, was not observed in methamphetamine-treated mice, indicative of a potential protective effect. Finally, Tat expression was associated with an increase in calbindin-expressing cells in the VTA, while methamphetamine exposure did not alter calbindin numbers. These findings may indicate a protective role of methamphetamine in HIV neuropathology, which in turn may help in our understanding of why people with HIV use methamphetamine at disproportionately higher rates.

Prospective longitudinal assessment of sensorimotor gating as a risk/resiliency factor for posttraumatic stress disorder.

Little is understood about cognitive mechanisms that confer risk and resiliency for posttraumatic stress disorder (PTSD). Prepulse Inhibition (PPI) is a measure of pre-attentional response inhibition that is a stable cognitive trait disrupted in many neuropsychiatric disorders characterized by poor behavioral or cognitive inhibition, including PTSD. Differentiating between PTSD-related phenotypes that are pre-existing factors vs. those that emerge specifically after trauma is critical to understanding PTSD etiology and can only be addressed by prospective studies. This study tested the hypothesis that sensorimotor gating performance is associated with risk/resiliency for combat-related PTSD. As part of a prospective, longitudinal study, 1226 active duty Marines and Navy Corpsman completed a PPI test as well as a clinical interview to assess PTSD symptoms both before,  and 3 and 6 months after a combat deployment. Participants that developed PTSD 6 months following deployment (N=46)  showed lower PPI across pre and post-deployment time points compared to participants who did not develop PTSD (N=1182) . Examination of the distribution of PTSD across PPI performance revealed a lower than expected number of cases in the highest performing quartile compared to the rest of the distribution (p < 0.04). When controlling for other factors that predict PTSD in this population, those in the top 25% of PPI performance showed a >50% reduction in chance to develop PTSD (OR = 0.32). Baseline startle reactivity and startle habituation were not significantly different between PTSD risk and control groups. These findings suggest that robust sensorimotor gating may represent a resiliency factor for development of PTSD following trauma.

Combining targeted and systematic prostate biopsy improves prostate cancer detection and correlation with the whole mount histopathology in biopsy naïve and previous negative biopsy patients.

Objective: Guidelines for previous negative biopsy (PNB) cohorts with a suspicion of prostate cancer (PCa) after positive multiparametric (mp) magnetic-resonance-imaging (MRI) often favour the fusion-guided targeted prostate-biopsy (TB) only approach for Prostate Imaging-Reporting and Data System (PI-RADS) ≥3 lesions. However, recommendations lack direct biopsy performance comparison within biopsy naïve (BN) vs. PNB patients and its prognostication of the whole mount pathology report (WMPR), respectively. We suppose, that the combination of TB and concomitant TRUS-systematic biopsy (SB) improves the PCa detection rate of PI-RADS 2, 3, 4 or 5 lesions and the International Society of Urological Pathology (ISUP)-grade predictability of the WMPR in BN- and PNB patients. Methods: Patients with suspicious mpMRI, elevated prostate-specific-antigen and/or abnormal digital rectal examination were included. All PI-RADS reports were intramurally reviewed for biopsy planning. We compared the PI-RADS score substratified TB, SB or combined approach (TB/SB) associated BN- and PNB-PCa detection rate. Furthermore, we assessed the ISUP-grade variability between biopsy cores and the WMPR. Results: According to BN (n = 499) vs. PNB (n = 314) patients, clinically significant (cs) PCa was detected more frequently by the TB/SB approach (62 vs. 43%) than with the TB (54 vs. 34%) or SB (57 vs. 34%) (all p < 0.0001) alone. Furthermore, we observed that the TB/SB strategy detects a significantly higher number of csPCa within PI-RADS 3, 4 or 5 reports, both in BN and PNB men. In contrast, applied biopsy techniques were equally effective to detect csPCa within PI-RADS 2 lesions. In case of csPCa diagnosis the TB approach was more often false-negative in PNB patients (BN 11% vs. PNB 19%; p = 0.02). The TB/SB technique showed in general significantly less upgrading, whereas a higher agreement was only observed for the total and BN patient cohort. Conclusion: Despite csPCa is more frequently found in BN patients, the TB/SB method always detected a significantly higher number of csPCa within PI-RADS 3, 4 or 5 reports of our BN and PNB group. The TB/SB strategy predicts the ISUP-grade best in the total and BN cohort and in general shows the lowest upgrading rates, emphasizing its value not only in BN but also PNB patients.

NCCN Guidelines® Insights: Hematopoietic Growth Factors, Version 1.2022.

The NCCN Guidelines for Hematopoietic Growth Factors provide recommendations for the appropriate use of growth factors in the clinical management of febrile neutropenia (FN), chemotherapy-induced thrombocytopenia (CIT), and chemotherapy-induced anemia (CIA). Management and prevention of these sequelae are an integral part of supportive care for many patients undergoing cancer treatment. The purpose of these guidelines is to operationalize the evaluation, prevention, and treatment of FN, CIT, and CIA in adult patients with nonmyeloid malignancies and to enable the patient and clinician to assess management options for FN, CIT, and CIA in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for Hematopoietic Growth Factors, with particular emphasis on the incorporation of a newly developed section on CIT.