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PurposeAtaxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear.MethodsFrom 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set.ResultsLOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p

Unlabelled: We performed respiratory-gated magnetic resonance imaging to evaluate airway dynamics during tidal breathing in 10 children with obstructive sleep apnea syndrome (OSAS; age, 4.3 +/- 2.3 years) and 10 matched control subjects (age, 5.0 +/- 2.0 years). We hypothesized that respiratory cycle fluctuations in upper airway cross-sectional area would be larger in children with OSAS.Methods: Studies were performed under sedation. Respiratory gating was performed automatically at 10, 30, 50, 70, and 90% of inspiratory and expiratory volume. Airway cross-sectional area was measured at four ascending oropharyngeal levels at each increment of the respiratory cycle.Results: We noted the following in subjects with OSAS compared with control subjects: (1) a smaller upper airway cross-sectional area, particularly during inspiration; (2) airway narrowing occurred during inspiration without evidence of complete airway collapse; (3) airway dilatation occurred during expiration, particularly early in the phase; and (4) magnitude of cross-sectional areas fluctuations during tidal breathing noted in OSAS at levels 1 through 4 were 317, 422, 785, and 922%, compared with 19, 15 17, and 24% in control subjects (p < 0.001, p < 0.005, p < 0.001, and p < 0.001, respectively).Conclusions: Fluctuations in airway area during tidal breathing are significantly greater in subjects with OSAS compared with control subjects. Resistive pressure loading is a probable explanation, although increased airway compliance may be a contributing factor. [ABSTRACT FROM AUTHOR]

The ethical and legal implications of decisions to withhold and withdraw life support have been widely debated. Making end-of-life decisions is never easy, and when the cultural background of doctor and patient differ, communication about these issues may become even more difficult. In this study, we examined the attitudes of people aged 65 and older from different ethnic groups toward forgoing life support. To this end, we conducted a survey of 200 respondents from each of four ethnic groups: European-American, African-American, Korean-American and Mexican-American (800 total), followed by in-depth ethnographic interviews with 80 respondents. European-Americans were the least likely to both accept and want life-support (p < 0.001). Mexican-Americans were generally more positive about the use of life-support and were more likely to personally want such treatments (p < 0.001). Ethnographic interviews revealed that this was due to their belief that life-support would not be suggested if a case was truly hopeless. Compared to European-Americans, Korean-Americans were very positive regarding life-support (RR = 6.7, p < 0.0001); however, they did not want such technology personally (RR = 1.2, p = 0.45). Ethnographic interviews revealed that the decision of life support would be made by their family. Compared to European-Americans, African-Americans felt that it was generally acceptable to withhold or withdraw life-support (RR = 1.6, p = 0.06), but were the most likely to want to be kept alive on life-support (RR = 2.1, p = 0.002). Ethnographic interviews documented a deep distrust towards the health care system and a fear that health care was based on one's ability to pay. We concluded that (a) ethnicity is strongly related to attitudes toward and personal wishes for the use of life support in the event of coma or terminal illness, and (b) this relationship was complex and in some cases, contradictory. [ABSTRACT FROM AUTHOR]

Abstract: The ACE-536-MF-001 trial enrolled patients with myelofibrosis (n = 95) into 4 cohorts: patients in cohorts 1 and 3A were non-transfusion dependent (NTD) and had anemia; patients in cohorts 2 and 3B were transfusion dependent (TD); and patients in cohort 3A/3B had stable ruxolitinib treatment before and during the study. All patients received luspatercept (1.0-1.75 mg/kg, 21-day cycles). Treatment was extended if clinical benefit was observed at day 169. The primary end point was anemia response rate (NTD, ≥1.5 g/dL hemoglobin increase from baseline; TD, transfusion-independence) over any 12-week period during the primary treatment period (weeks 1-24). Overall, 14% of patients in cohorts 1 and 3A, 10% in cohort 2, and 26% in cohort 3B met the primary end point. In cohorts 1 and 3A (NTD), 27% and 50% of patients, respectively, had mean hemoglobin increase of ≥1.5 g/dL from baseline. Among TD patients, ∼50% had ≥50% reduction in transfusion burden. Reduction in total symptom score was observed in all cohorts, with the greatest response rate seen in cohort 3A. Overall, 94% of patients had ≥1 adverse event (AE); 47% had ≥1 treatment-related AE (TRAE; 11% grade ≥3), most frequently hypertension (18%), managed with medical intervention. One patient had a serious TRAE leading to luspatercept discontinuation. Nine patients died on treatment (unrelated to study drug). In most patients, ruxolitinib dose and spleen size remained stable. In patients with myelofibrosis, luspatercept improved anemia and transfusion burden across cohorts; the safety profile was consistent with previous studies. This trial was registered at www.ClinicalTrials.gov as #NCT03194542., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: To report the clinicopathological features and epidemiology of iris melanoma in Queensland, Australia., Methods: This was a retrospective study of 86 patients with iris melanoma treated between 2001 and 2022 at the Queensland Ocular Oncology Service, Brisbane, Australia. Main outcome measures included demographics, clinical and phenotypic features, age-adjusted incidence and relative survival., Results: Eighty-six patients (63% female) were included. Mean age was 54 years (range 17-82 years). The majority of patients (97%) were Caucasian, with blue eyes, fair skin and Fitzpatrick Skin Type I or II. Demographic features and clinical history showed a tendency for high ultraviolet radiation (UVR) exposure in the cohort. Histopathology was available in 69 cases (82%), and of these, 77% tumours were of spindle cell origin, with low-risk genetic profiles. Patients were followed for a mean of 8 years (median 7, range 1-21 years) after diagnosis, and only one case of metastasis was documented., Conclusions: The association of iris freckles, history of UVR exposure and dermatologic findings supports the role of UVR in iris melanoma. Occupation and avocation history, as well as evaluation of iris freckles may offer an easily accessible way of stratifying the risk of an individual for development of UVR-related uveal melanoma., (© 2024 The Author(s). Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Ophthalmologists.)

Not available.

Objective: The objective of this study was to determine whether combining verteporfin-based photodynamic therapy (PDT) and transpupillary thermotherapy (TTT) achieves adequate tumour control while maintaining visual acuity in individuals with small choroidal melanoma of amelanotic, melanotic, and variable pigmentation., Design: Individuals with posterior choroidal melanomas up to 3 mm in height underwent verteporfin-based PDT followed by immediate TTT. Further combined laser therapy was performed if a poor response was noted at 12 weeks or beyond. Tumours that demonstrated significant further growth were treated with brachytherapy or enucleation. A total of 37 eyes of 37 patients from the Terrace Eye Centre in Brisbane, Australia were studied. Average age of participants was 59.62 ± 12.45 years, and 17 of 37 participants were female (46%)., Methods: This was a retrospective, noncomparative interventional study., Results: Seven of the 37 participants (19%) had recurrence of their tumour requiring further brachytherapy or enucleation. There was no statistically significant difference in visual acuity before and after treatment. There were no baseline characteristics that predicted treatment outcome. Ten individuals developed complications including epiretinal membrane (16%), scotoma (8%), cataract (3%), and macular edema (3%). No individuals experienced extraocular extension or progressed to metastatic disease. The mean follow-up time was 49 months., Conclusion: Combined PDT and TTT achieved 81% tumour control in this study while preserving visual acuity. However, higher rates of local recurrence compared with brachytherapy warrant close follow-up to identify recurrences early., (Copyright © 2024 Canadian Ophthalmological Society. All rights reserved.)

Interferons are cytokines with immunomodulatory properties and disease-modifying effects that have been used to treat myeloproliferative neoplasms (MPNs) for more than 35 years. The initial use of interferons was limited due to difficulties with administration and a significant toxicity profile. Many of these shortcomings were addressed by covalently binding polyethylene glycol to the interferon structure, which increases the stability, prolongs activity, and reduces immunogenicity of the molecule. In the current therapeutic landscape, pegylated interferons are recommended for use in the treatment of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We review recent efficacy, molecular response, and safety data for the two available pegylated interferons, peginterferon alfa-2a (Pegasys) and ropeginterferon alfa-2b-njft (BESREMi). The practical management of interferon-based therapies is discussed, along with our opinions on whether to and how to switch from hydroxyurea to one of these therapies. Key topics and questions related to use of interferons, such as their safety and tolerability, the significance of variant allele frequency, advantages of early treatment, and what the future of interferon therapy may look like, will be examined. Pegylated interferons represent an important therapeutic option for patients with MPNs; however, more research is still required to further refine interferon therapy., Competing Interests: PV: Consulting fees (AbbVie, Amgen, Blueprint Medicines, Cogent Biosciences, Incyte, CTI BioPharma Corp, Daiichi Sankyo, GlaxoSmith Kline, Karyopharm, Novartis, Pfizer, Genentech, Servier, Stemline, MorphoSys, LAVA Therapeutics); honoraria for lectures/advisory boards (Incyte, Blueprint Medicines, CTI Biopharma). JM: Grants (PharmaEssentia, Novartis, Roche, Geron, Abbie, Kartos, Karyopharm); consulting fees (PharmaEssentia, CTI, Incyte, Roche, Novartis, Merck, Geron, AbbVie, BMS, Kartos, MorphoSys, Galecto, Imago); honoraria for lectures/advisory boards (BMS); monitoring or advisory board (Incyte, Galecto); meeting/travel support (Kartos). PB: Grants (Incyte, CTI, MorphoSys, Kartos, Telios, Ionis, Disc, Blueprint, Cogent, Geron, Janssen, Sumitomo, BMS, Karyopharm); consulting fees (Incyte, BMS, CTI, GSK, AbbVie, MorphoSys, Karyopharm, PharmaEssentia, Blueprint, Cogent, Novartis, Jubilant, Morphic, Ono, Sumitomo); honoraria for lectures/advisory boards (Incyte, Blueprint, GSK, CTI, AbbVie, Sumitomo, PharmaEssentia). GH: Grants (Incyte); consulting fees (PharmaEssentia, Protagonist, AbbVie, GSK, Pfizer, Novartis, MorphoSys, Cogent, Pharmaxis); monitoring or advisory board (PharmaEssentia, Protagonist, AbbVie, GSK, Pfizer, Novartis, MorphoSys); stock/stock options (Regeneron Pharmaceuticals). AY: Consulting fees (Incyte, CTI Pharma, PharmaEssentia, Pfizer, Novartis, Acceleron Pharma, Servier, AbbVie, Apellis, Gilead, Notable Labs); meeting/travel support (Incyte). JMP: Consulting fees (Sierra Oncology, MorphoSys, CTI, Protagonist). ATG: Consulting fees (PharmaEssentia, MorphoSys, CTI, Biopharma, Bristol-Meyers Squibb, Sierra Oncology/GSK, Kartos, AbbVie, Imago Biosciences). LM: Advisory board (MorphoSys). ATK: Grants (BMS, Protagonist, Janssen, GSK, MorphoSys); consulting fees (GSK, AbbVie, Incyte); honoraria for lectures/advisory boards (PharmaEssentia, Novartis, BMS); monitoring or advisory board (Incyte). RKR: Grants (Incyte, Ryvu, MorphoSys, Zentalis); consulting fees (MorphoSys, CTI, GSK, Stemline, Blueprint, SDP, Servier, Zentalis, BMS, Galectco, AbbVie, PharmaEssentia, Cogent, Kartos); honoraria for lectures/advisory boards (Protagonist, Karyopharm, GSK); monitoring or advisory board (Kartos). RM: Consulting fees (Incyte, PharmaEssentia, CTI, AbbVie, GSK, BMS, Genentech). SV: The author declares that there is no conflict of interest., (© The Author(s), 2024.)

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that typically manifests with debilitating symptoms that progressively worsen, negatively impacting patients' quality of life. Fatigue is a multifactorial and burdensome MF-related symptom due to its severity, persistence, and prevalence, with anemia a contributing factor and major unmet need. Clinical trials of the Janus kinase (JAK)1/JAK2/activin A receptor type 1 inhibitor momelotinib have shown consistent anemia benefits, in addition to improvements in MF-related symptoms. The phase 3 MOMENTUM trial in symptomatic and anemic patients met its primary end point, with a greater proportion having a Myelofibrosis Symptom Assessment Form (MFSAF) Total Symptom Score (TSS) reduction ≥50% at week 24 with momelotinib versus danazol. To support the positive primary end point result, we conducted longitudinal, responder, and time-to-event analyses of patient-reported outcomes from MOMENTUM, as measured by the MFSAF, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Patient-Reported Outcomes Measurement Information System (PROMIS) assessments. These analyses demonstrated rapid and durable response benefits with momelotinib, with achievement of first TSS response by day 29 and continued improvement over time. Improvements favored momelotinib versus danazol for each MFSAF individual item, and greater improvements were observed for disease- and cancer-related fatigue and physical functioning at week 24, with significant results for multiple items/domains across the 3 assessments. These findings are consistent in demonstrating that momelotinib provides substantial symptom benefit., Competing Interests: RAM has consulted and received honoraria from Novartis, Sierra Oncology, Gentech, Blueprint, Geron, Telios, CTI, Incyte, BMS, AbbVie, GSK and Morphosys. CH has consulted for Galecto DISC and Keros and received compensation; received honoraria from Novartis, CTI, BMS, Sierra, and GSK; participated on an Ad Board for AOP, Telios, Sumitomo, and Keros; and had a leadership role in EHA, HemaSphere, and MPN Voice. VG has consulted for Novartis, BMS Celgene, Sierra Oncology, AbbVie, Constellation Biopharma, Pfizer, GSK Pharma, and CTI Biopharma and received compensation; received honoraria from Novartis and BMS Celgene; and received compensation for participation on an Ad Board for BMS Celgene, Roche, AbbVie, Pfizer, Sierra Oncology, and CTI Biopharma. DPM received a research grant from Imago Biosciences; received honoraria from JAZZ Pharma, AbbVie, and Novartis; participated in the UK ALL RIC TRIAL – DSM board and is an EBMT Scientific Council Member Chair of the EBMT CMWP. MFM received honoraria from Novartis, Abbvie, and AOP; and received compensation for participation on an Ad Board from Novartis, BMS, AbbVie, CTI, Sierra Oncology, and GSK. J-JK received compensation and participated in Ad Boards for Novartis, AbbVie, BMS, GSK, Incyte, and AOP Health. LF received honoraria from Novartis and BMS and participated in Ad Boards for Incyte and GS. MLF has consulted for Novartis, GSK, AbbVie, and Sierra Oncology and received compensation; and received honoraria from Novartis and BMS and attended meetings for AbbVie. DMR has consulted for Keros, and the institution received compensation; received honoraria from Novartis personally and to the institution; received compensation from Novartis to attend a meeting; received compensation to the institution for participation on an Ad Board from Novartis, Menarini, and Takeda. STO has consulted for AbbVie, Constellation, CTI BioPharma, BMS, Geron, Sierra Oncology, Cogent, Protagonist, and Incyte and received compensation. JK owned stock in Sierra Oncology and owns stock in Gilead. SR and RD owned stock in Sierra Oncology. SD is an employee at Sierra Oncology. BG received compensation from GSK for attending meetings and owns stock in GSK. SV received compensation for participation on an Ad Board. UP received honoraria and research support from Geron, GSK, Novartis, Abbvie, and Curis. JMP received honoraria to the institution from CTI; and received compensation to the institution for participation in an Ad Board for Morphosys. AJM received support from Abbvie for the present article; received grants or contracts from Celgene/BMS; received royalties or licenses from Alethiomics; received consulting fees from Celgene/BMS paid to the Sierra Oncology, Novartis paid to Karyopharm, Abbvie paid to Sensyn, and CTI paid to Incyte, Galecto, Pfizer, and Gilead; received honoraria from Celgene/BMS, Novartis, and Abbvie; received support to attend meetings from Celgene/BMS and Novartis; and participated on an Ad Board for Celgene/BMS and Abbvie. All authors received medical writing support for this article funded by Sierra Oncology, a GSK company. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

The apolipoprotein ε4 (APOE ε4) allele is most commonly associated with increased risk for late-onset Alzheimer's disease (AD). However, recent longitudinal studies suggest that these risks are overestimated; most ε4 carriers will not develop dementia in their lifetime. In this article, we review new evidence regarding the impact of APOE ε4 on cognition among healthy older adults. We discuss emerging work from animal models suggesting that ε4 impacts brain structure and function in multiple ways that may lead to age-related cognitive impairment, independent from AD pathology. We discuss the importance of taking an individualized approach in future studies by incorporating biomarkers and neuroimaging methods that may better disentangle the phenotypic influences of APOE ε4 on the aging brain from prodromal AD pathology., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines., Patients and Methods: In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas., Results: Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up., Conclusions: Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued., (©2023 American Association for Cancer Research.)

Objective: On continuous recognition tasks, changing the context objects are embedded in impairs memory. Older adults are worse on pattern separation tasks requiring identification of similar objects compared to younger adults. However, how contexts impact pattern separation in aging is unclear. The apolipoprotein (APOE) ϵ4 allele may exacerbate possible age-related changes due to early, elevated neuropathology. The goal of this study is to determine how context and APOE status affect pattern separation among younger and older adults., Method: Older and younger ϵ4 carriers and noncarriers were given a continuous object recognition task. Participants indicated if objects on a Repeated White background, Repeated Scene, or a Novel Scene were old, similar, or new. The proportions of correct responses and the types of errors made were calculated., Results: Novel scenes lowered recognition scores compared to all other contexts for everyone. Younger adults outperformed older adults on identifying similar objects. Older adults misidentified similar objects as old more than new, and the repeated scene exacerbated this error. APOE status interacted with scene and age such that in repeated scenes, younger carriers produced less false alarms, and this trend switched for older adults where carriers made more false alarms., Conclusions: Context impacted recognition memory in the same way for both age groups. Older adults underutilized details and over relied on holistic information during pattern separation compared to younger adults. The triple interaction in false alarms may indicate an even greater reliance on holistic information among older adults with increased risk for Alzheimer's disease.

Allogeneic stem cell transplantation (alloSCT) is the only known curative treatment for myelofibrosis (MF). Risk assessment remains important for patient counseling and predicting survival outcomes for relapse and nonrelapse mortality (NRM). Outcome-prediction tools can guide decision-making. Their use in MF has relied on their extrapolation from other malignancies. The primary objective of this study was to assess the performance of the Hematopoietic cell Transplantation Comorbidity Index (HCT-CI), the augmented HCT-CI (aHCT-CI), and the Endothelial Activation and Stress Index (EASIX) in predicting NRM in patients with MF undergoing alloSCT. We retrospectively reviewed patients with MF undergoing alloSCT between 2012 and 2020 at the Mayo Clinic. Data were abstracted from the electronic medical record. EASIX score was calculated before starting conditioning therapy and analyzed based on log2- transformed values. We evaluated the log2-EASIX scores by quartiles to assess the effect of increasing values on NRM. NRM was evaluated using competing risk analyses. We used the Kaplan-Meier and log-rank methods to evaluate OS. The Fine-Gray model was used to determine risk factors for NRM. The performance of HCT-CI and aHCT-CI was compared by evaluation of model concordance given the high correlation between HCT-CI and aHCT-CI (r = .75). A total of 87 patients were evaluated. The median duration of follow-up after alloSCT was 5 years (95% confidence interval [CI], 4.4 to 6.31 years). Patients with a high HCT-CI score had significantly increased cumulative incidence of NRM at 3 years (35.5% versus 11.6%; P = .011) after alloSCT. A progressively increasing 3-year NRM was observed with increasing aHCT-CI risk category, and patients with a high or very high aHCT-CI score had significantly higher 3-year NRM compared to those with intermediate-risk or low-risk aHCT-CI scores at 3 years post-alloSCT (31.9% versus 6.52%; P = .004). An increasing log2-EASIX score quartile was not associated with 3-year NRM (19.0% versus 10.1% versus 25% versus 14.3%; P = .59), and the EASIX score was not found to be a predictor of post-transplantation NRM. A high HCT-CI was associated with significantly worse 3-year overall survival (OS) (hazard ratio [HR], 4.41; 95% CI, 1.97 to 9.87; P < .001). A high or very high aHCT-CI was significantly associated with poor 3-year OS (HR, 3.99; 95% CI, 1.56 to 10.22; P = .004). An increasing log2-EASIX score quartile group was not associated with 3-year OS (3-year OS rate, 66.7% versus 80.4% versus 64.6% versus 76.2%; P = .57). The EASIX score should not be used routinely in patients with MF. Both the HCT-CI and the aHCT-CI are accurate in predicting long-term survival outcomes in this patient population. Further studies are important to validate our findings of the role of EASIX in predicting NRM in patients with MF or other myeloproliferative neoplasms undergoing alloSCT. © 2023 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

COVID-19 adversely affects individuals with cancer. Several studies have found that seroconversion rates among patients with hematologic malignancies are suboptimal when compared to patients without cancer. Patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are immunocompromised due to impaired humoral and cellular immunity in addition to prescribed immunosuppressive therapy. Chimeric antigen receptor T-cell (CAR T) therapy is now widely used for NHL and MM, but little is known about seroconversion rates after COVID-19 vaccination among these populations. We evaluated SARS-CoV-2 spike-binding IgG antibody levels following COVID-19 vaccination among NHL and MM CAR T therapy recipients. Out of 104 CAR T infusions, 19 patients developed known COVID-19 infection post-CAR T. We tested 17 patients that received CAR T for antibody spike titers post COVID-19 vaccination, only 29 % (n = 5) were able to mount a clinically relevant antibody response (>250 IU/mL)., Competing Interests: Disclosure JM receives consulting fees from Pharmacyclics/Abbvie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Fosunkite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, Servier, Novartis, Morphosys/Incyte, Secura Bio, TG Therapeutics, MEI, Lilly/Loxo; research funding from Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium; Honoraria from Targeted Oncology, OncView, Curio, Kyowa, Physicians' Education Resource, and Seattle Genetics. Speaker's bureau from Gilead/Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche. PV receives funds from DSMB from AbbVie, Vanda, Algernon; research from Cidara, Scynexis and fees paid to Mayo Clinic. PLB receives consulting and honoraria funding from Pfizer, Novartis, Janssen, Clgene, GSK, Genetech, and Oncopeptides. YW has financial research funding from InnoCare, Novartis, Genentech, MorphoSys and Membership on an entity's Board of Directors or advisory committees and research Funding with Incyte, LOXO Oncology, Eli Lilly, and TG Therapeutics. RF is a consultant for Amgen, BMS, Celgene, Takeda, Bayer, Janssen, Novartis, Pharcyclics, Sanofi, Merck, Juno, Kite, Aduro, OncoTracker, GSK, AbbVie, Patents and Royalties from Patent: Prognostication of myeloma via FISH and Membership on an entity's Board of Directors or advisory committees from OncoTracker, Adaptive Biotechnologies, and Caris Life Sciences. JMP receives research funding from PharmaEssentia, Incyte and consultancy and research funding from Protagonist, CTI BioPharma, and Sierra Oncology. DD receives consultancy fees from Alexion, Apellis, GSK, Sanofi, Janssen and research funding from Novartis. SK receives consultancy and research funding from BMS, Abbvie, Amgen, Takeda, Janssen, KITE, Astra-Zeneca, Roche-Genentech; consultancy fees from Beigene, Oncopeptides, and Bluebird Bio, and research funding from Tenebio, Carsgen, Merck, and Novartis. JP receives research funding from Karyopharm. SMA receives research funding from Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium, and Takeda. YL receives consultancy fees from Novartis, Juno, Legend, Sorrento, Gamida Cell; research funding from Merck and Takeda and consultancy and research funding from Kite, Janssen, Celgene, and Bluebird Bio. HSM receives research funding from CRISPR therapeutics., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Myeloid/lymphoid neoplasms with FLT3 gene fusions have recently been included among myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) in the World Health Organization classification and International Consensus Classification. As this entity remains remarkably rare, its scope and phenotypic features are evolving. In this report, we describe a 33-yr-old male with MLN-TK. Conventional chromosome analysis revealed a t(13;14)(q12;q32). Further analysis with mate-pair sequencing (MPseq) confirmed a TRIP11::FLT3 gene fusion. A diagnosis of MLN-TK was rendered. To the best of our knowledge, we report the third case of MLN-TK with a TRIP11::FLT3 gene fusion. In contrast to previously described cases, our case exhibited distinctly mild clinical features and disease behavior, emphasizing the diverse spectrum of MLN-TK at primary presentation and variability in disease course. MLN-TK with FLT3 gene fusions are a genetically defined entity which may be targetable with tyrosine kinase inhibitors with anti-FLT3 activity. Accordingly, from diagnostic and therapeutic viewpoints, genetic testing for FLT3 rearrangements using fluorescence in situ hybridization (FISH) or sequencing-based assays should be pursued for patients with chronic eosinophilia., (© 2023 Venable et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Spitzoid morphology in familial melanoma has been associated with germline variants in POT1 , a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid differentiation., Objective: To assess if familial melanoma cases associated with germline variants in TMG ( POT1 , ACD , TERF2IP , and TERT ) commonly exhibit spitzoid morphology., Methods: In this case series, melanomas were classified as having spitzoid morphology if at least 3 of 4 dermatopathologists reported this finding in ≥25% of tumor cells. Logistic regression was used to calculate odds ratios (OR) of spitzoid morphology compared to familial melanomas from unmatched noncarriers that were previously reviewed by a National Cancer Institute dermatopathologist., Results: Spitzoid morphology was observed in 77% (23 of 30), 75% (3 of 4), 50% (2 of 4), and 50% (1 of 2) of melanomas from individuals with germline variants in POT1 , TERF2IP , ACD , and TERT , respectively. Compared to noncarriers ( n  = 139 melanomas), POT1 carriers (OR = 225.1, 95% confidence interval: 51.7-980.5; P  < .001) and individuals with TERF2IP, ACD, and TERT variants (OR = 82.4, 95% confidence interval: 21.3-494.6; P  < .001) had increased odds of spitzoid morphology., Limitations: Findings may not be generalizable to nonfamilial melanoma cases., Conclusion: Spitzoid morphology in familial melanoma could suggest germline alteration of TMG., Competing Interests: None disclosed.

Background: Vaccines for SARS-CoV-2 have been considerably effective in reducing rates of infection and severe COVID-19. However, many patients, especially those who are immunocompromised due to cancer or other factors, as well as individuals who are unable to receive vaccines or are in resource-poor countries, will continue to be at risk for COVID-19. We describe clinical, therapeutic, and immunologic correlatives in two patients with cancer and severe COVID-19 who were treated with leflunomide after failing to respond to standard-of-care comprising remdesivir and dexamethasone. Both patients had breast cancer and were on therapy for the malignancy., Methods: The protocol is designed with the primary objective to assess the safety and tolerability of leflunomide in treating severe COVID-19 in patients with cancer. Leflunomide dosing consisted of a loading dose of 100 mg daily for the first three days, followed by daily dosing, at the assigned dose level (Dose Level 1: 40 mg, Dose Level -1, 20 mg; Dose Level 2, 60 mg), for an additional 11 days. At defined intervals, serial monitoring of blood samples for toxicity, pharmacokinetics, and immunologic correlative studies were performed, as well as nasopharyngeal swabs for PCR analysis of SARS-CoV-2., Results: Preclinically, leflunomide impaired viral RNA replication, and clinically, it led to a rapid improvement in the two patients discussed herein. Both patients completely recovered, with minimal toxicities; all adverse events experienced were considered unrelated to leflunomide. Single-cell mass-cytometry analysis showed that leflunomide increased levels of CD8+ cytotoxic and terminal effector T cells and decreased naïve and memory B cells., Conclusions: With ongoing COVID-19 transmission and occurrence of breakthrough infections in vaccinated individuals, including patients with cancer, therapeutic agents that target both the virus and host inflammatory response would be helpful despite the availability of currently approved anti-viral agents. Furthermore, from an access to care perspective, especially in resource-limited areas, an inexpensive, readily available, effective drug with existing safety data in humans is relevant in the real-world setting., Competing Interests: Conflict of Interest The authors declare that they have no competing interests that are relevant to this study.

Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation; uveal melanoma occurs in the eyes; mucosal melanoma occurs in internal mucous membranes; and acral melanoma occurs on the palms, soles, and nail beds. Here, we present the largest whole-genome sequencing study of melanoma to date, with 570 tumors profiled, as well as methylation and RNA sequencing for subsets of tumors. Uveal melanoma is genomically distinct from other melanoma subtypes, harboring the lowest tumor mutation burden and with significantly mutated genes in the G-protein signaling pathway. Most cutaneous, acral, and mucosal melanomas share alterations in components of the MAPK, PI3K, p53, p16, and telomere pathways. However, the mechanism by which these pathways are activated or inactivated varies between melanoma subtypes. Additionally, we identify potential novel germline predisposition genes for some of the less common melanoma subtypes., Significance: This is the largest whole-genome analysis of melanoma to date, comprehensively comparing the genomics of the four major melanoma subtypes. This study highlights both similarities and differences between the subtypes, providing insights into the etiology and biology of melanoma. This article is highlighted in the In This Issue feature, p. 2711., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: IgA and its secretory form sIgA impact protection from infection and necrotising enterocolitis but little is known about quantities in preterm mums own milk (MOM) or infant stool, onset of endogenous production in the preterm gut, and what affects these., Methods: We measured by ELISA in MOM and stool from healthy preterm infants total IgA and sIgA longitudinally and additionally in MOM fresh, refrigerated, frozen, and after traversing feeding systems., Results: In 42 MOM (median gestation 26 weeks), we showed total IgA levels and sIgA were highest in colostrum, fell over 3 weeks, and were not impacted by gestation. Median IgA values matched previous term studies (700 mcg/ml). In MOM recipients stool IgA was detected in the first week, at around 30% of MOM quantities. Formula fed infants did not have detectable stool IgA until the third week. Levels of IgA and sIgA were approximately halved by handling processes., Conclusions: MOM in the 3 weeks after preterm delivery contains the highest concentrations of IgA and sIgA. Endogenous production after preterm birth occurs from the 3 week meaning preterm infants are dependent on MOM for IgA which should be optimised. Routine NICU practices halve the amount available to the infant., Impact: (Secretory) Immunoglobulin A (IgA) is present in colostrum of maternal milk from infants as preterm as 23-24 weeks gestational age, falling over the first 3 weeks to steady levels similar to term. Gestation at birth does not impact (secretory) IgA levels in breast milk. IgA is present in very preterm infant stools from maternal milk fed infants from the first week of life, but not in formula milk fed preterm infants until week three, suggesting endogenous production from this point. Refrigeration, freezing, and feeding via plastic tubing approximately halved the amount of IgA available., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

1. Two experiments were conducted to investigate whether the use of phytase in the pre-experimental or experimental phases of true pre-caecal phosphorus digestibility (TPD) assay influenced the assayed TPD values. In experiments 1 and 2, broiler chickens were randomly allocated to 12 treatments in a 2 × 2 × 3 factorial arrangement. The factors were pre-experimental phytase supplementation (+ or -), experimental phase phytase supplementation (+ or -) with varying soybean meal inclusion levels (450, 560, or 670 g/kg).2. The diets in the pre-experimental phase were based on maize-soybean meal, whereas the diet used during the experimental phase was semi-purified, with soybean meal as the only source of P. Both TPD and true phosphorus retention (TPR) were determined using regression for the P output (g/kg, dry matter basis), pre-caecal or total tract, against P intake (g/kg). Data for TPD and TPR were analysed as a 2 × 2 factorial (with or without pre-experimental or experimental phase phytase).3. In both experiments 1 and 2, there were no significant effects for pre-experimental phytase supplementation nor interaction of pre- and experimental phytase supplementation on any of the pre-caecal digestibility responses. Phytase supplementation during the experimental phase increased (P < 0.01) pre-caecal P digestibility and retention, as well as digestible and retained P intake, and decreased (P < 0.01) P output.4. In experiment 1, pre- and experimental phytase supplementation increased (P < 0.01) the coefficient of TPR. In experiment 2, there was no significant effect of pre-experimental phytase supplementation on coefficient of pre-caecal TPD. However, phytase supplementation in the experimental phase increased (P < 0.01) the coefficient of pre-caecal TPD.5. In conclusion, whether or not phytase was supplemented to a P-adequate diet in the pre-experimental phase of the TPD assay, it had no influence on assayed TPD or TPR value.

Graft-versus-host disease (GVHD) has remained the main cause of post-transplantation mortality and morbidity after allogeneic hematopoietic cell transplantation (alloHCT), adding significant economic burden and affecting quality of life. It would be desirable to reduce the rate of GVHD among patients in complete remission (CR) without increasing the risk of relapse. In this study, we have tested a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 2000 cGy, together with post-transplantation cyclophosphamide (PTCy) for patients with acute myeloid leukemia in first or second CR, to attenuate the risk of chronic GVHD by using PTCy, while using escalated targeted radiation conditioning before allografting to offset the possible increased risk of relapse. The primary objective was to evaluate the safety/feasibility of combining a TMLI transplantation conditioning regimen with a PTCy-based GVHD prophylaxis strategy, through the assessment of adverse events in terms of type, frequency, severity, attribution, time course, duration, and complications, including acute GVHD, infection, and delayed neutrophil/platelet engraftment. Secondary objectives included estimation of non-relapse mortality (NRM), overall survival (OS), relapse-free survival, acute and chronic GVHD, and GVHD-relapse-free survival (GRFS). A patient safety lead-in was first conducted to ensure there were no unexpected toxicities and was expanded on the basis of lack of dose-limiting toxicities. The patient safety lead-in segment followed 3 + 3 dose expansion/(de-)escalation rules based on observed toxicity through day 30; the starting dose of TMLI was 2000 cGy, and a de-escalation to 1800 cGy was considered. After the safety lead-in segment, an expansion cohort of up to 12 additional patients was to be studied. TMLI was administered on days -4 to 0, delivered in 200 cGy fractions twice daily. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Cyclophosphamide was given on days 3 and 4 after alloHCT, 50 mg/kg each day for GVHD prevention; tacrolimus was given until day 90 and then tapered. Among 18 patients with a median age of 40 years (range 19-56), the highest grade toxicities were grade 2 Bearman bladder toxicity and stomatitis. No grade 3 or 4 Bearman toxicities or toxicity-related deaths were observed. The cumulative incidence of acute GVHD grade 2 to 4 and moderate-to-severe chronic GVHD were 11.1% and 11.9%, respectively. At a median follow up of 24.5 months, two-year estimates of OS and relapse-free survival were 86.7% and 83.3%, respectively. Disease relapse at 2 years was 16.7%. The estimates of NRM at 2 years was 0%. The GVHD/GRFS rate at 2 years was 59.3% (95% confidence interval, 28.8-80.3). This chemotherapy-free conditioning regimen, together with PTCy and tacrolimus, is safe, with no NRM. Preliminary results suggest an improved GRFS rate., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)