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Most cases of indolent non-Hodgkin lymphoma (NHL) are incurable with standard chemoimmunotherapy approaches, and patients with relapsed/refractory disease have progressively shorter remissions and short survival with subsequent chemotherapy regimens. This may potentially be overcome with diversification of treatment strategies to include other modalities including radiotherapy, small molecule signaling transduction inhibitors, or highdose chemotherapy with stem cell support. Yttrium-90 ibritumomab tiuxetan (Zevalin®) is a novel treatment entity for indolent NHL. A radiolabeled antibody conjugate, it consists of a murine anti-CD20 antibody linked to a chelator molecule, tiuxetan, which is bound to radioactive yttrium. Yttrium-90 ibritumomab tiuxetan is approved for use as consolidation after initial treatment of follicular lymphoma as well as single-agent therapy in relapsed/refractory B-cell NHL. Responses are seen even in patients refractory to conventional cytotoxic chemotherapy and rituximab in both indolent and aggressive NHL subtypes. Recent clinical studies have also shown that yttrium-90 ibritumomab tiuxetan has significant activity when combined with novel targeted small molecular inhibitors as well as in autologous and allogeneic transplantation regimens. Here we review the biology underlying the efficacy of yttrium-90 ibritumomab tiuxetan in NHL and present an overview of the clinical experience with this agent in NHL. Finally, we discuss the current role of yttrium-90 ibritumomab tiuxetan in the armamentarium of treatments for NHL and possibilities for incorporating it into future NHL treatment algorithms. [ABSTRACT FROM AUTHOR]

Osmia cornifrons Radoszkowski (Hymenoptera: Megachilidae) is utilized as an alternate pollinator to Apis mellifera L. (Hymenoptera: Apidae) in early-season fruit crops. This study was conducted to investigate nesting activities and associated behaviors of O. cornifrons. Osmia cornifrons nesting activity was recorded by using a digital video recorder with infrared cameras. Nesting behavior of ten female O. cornifrons was observed, and the number of nesting trips per hour was recorded. Trends in daily activity were determined with regression analysis, and chi square analysis was used to determine if O. cornifrons spent a greater amount of time performing certain activities. The percentage of time required to gather nesting resources and complete nest construction activities was recorded from the video footage. Results of this study showed that pollen gathering was the most time-consuming gathering activity, requiring 221.6 ± 28.69 min per cell and cell provisioning was the most time-consuming intranest activity, requiring 28.9min ± 3.97 min. We also found that O. cornifrons activity was correlated with time of day, temperature, and precipitation. Various nesting behaviors, including cell provisioning and partitioning, oviposition, grooming, resting and sleeping, nest-searching, and repairing behaviors, are described in this paper. [ABSTRACT FROM AUTHOR]

Provides information on a feasibility study on reverse peristalsis for theatre automation. Criteria for selecting suitable hoses for the anticipated pressures in the system; Linear and rotary motion tests conducted for the application of the system to typical theatrical motion profiles; Cost effectiveness of a reverse peristaltic system powered by domestic water supply.

Illustrates that ecological needs and good science are necessary but not sufficient conditions for fish and wildlife management. Challenges to develop policies from a scientific and ecological perspective that will get the job done; Examination of the science of instream flow protection; Evaluation of the politics of such protections by presenting several case studies; Recommendations on how to integrate the science and politics of fish and wildlife conservation.

Background: Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes. Methods: The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases. Results: In front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p < 0.0001) and progression-free survival (PFS, p < 0.0001). P53 positive expression was the most significant pathological parameter correlating with inferior outcomes (p < 0.0001 for OS and p = 0.0021 for PFS). Based on the baseline risk factor profile, we developed a set of prognostic models incorporating clinical, laboratory, and pathological parameters that are specifically tailored for various applications. These models, when tested in the validation cohort, exhibited strong predictive power for survival and showed a stratification resembling the training cohort. Conclusions: The outcome of patients with MCL has markedly improved over the past two decades, and further enhancement is anticipated with the evolution of clinical management. The innovative prognostic models developed in this study would serve as a valuable tool to guide the selection of more suitable treatment strategies for patients with MCL. [ABSTRACT FROM AUTHOR]

MT-3724 is an engineered direct-kill immunotoxin comprised of a CD20-specific scFv fused to a Shiga-like toxin subunit. In this phase IIa study, eight patients with relapsed diffuse large B-cell lymphoma were treated with MT-3724 combined with gemcitabine and oxaliplatin (GEMOX). The objective response rate was 85.7%, with a median duration of response of 2.2 months. The 12-month overall survival and progression-free survival were 71.4% and 28.6%, respectively. Two patients experienced grade 2 capillary leak syndrome (CLS). Combination therapy with MT-3724 and GEMOX demonstrated an early efficacy signal but was limited by the incidence of CLS. [ABSTRACT FROM AUTHOR]

PURPOSE: Comprehensive genomic profiling to inform targeted therapy selection is a central part of oncology care. However, the volume and complexity of alterations uncovered through genomic profiling make it difficult for oncologists to choose the most appropriate therapy for their patients. Here, we present a solution to this problem, The Molecular Registry of Tumors (MRT) and our Molecular Tumor Board (MTB). PATIENTS AND METHODS: MRT is an internally developed system that aggregates and normalizes genomic profiling results from multiple sources. MRT serves as the foundation for our MTB, a team that reviews genomic results for all Duke University Health System cancer patients, provides notifications for targeted therapies, matches patients to biomarker-driven trials, and monitors the molecular landscape of tumors at our institution. RESULTS: Among 215 patients reviewed by our MTB over a 6-month period, we identified 176 alterations associated with therapeutic sensitivity, 15 resistance alterations, and 51 alterations with potential germline implications. Of reviewed patients, 17% were subsequently treated with a targeted therapy. For 12 molecular therapies approved during the course of this work, we identified between two and 71 patients who could qualify for treatment based on retrospective MRT data. An analysis of 14 biomarker-driven clinical trials found that MRT successfully identified 42% of patients who ultimately enrolled. Finally, an analysis of 4,130 comprehensive genomic profiles from 3,771 patients revealed that the frequency of clinically significant therapeutic alterations varied from approximately 20% to 70% depending on the tumor type and sequencing test used. CONCLUSION: With robust informatics tools, such as MRT, and the right MTB structure, a precision cancer medicine program can be developed, which provides great benefit to providers and patients with cancer. Learn how Duke University is translating complex genomic data into meaning clinical recommendations [ABSTRACT FROM AUTHOR]

GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre+ GNA13-deficient mice demonstrate disordered GC architecture and dark zone/ light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro. We also found that GNA13-deficient mice have increased numbers of GC B cells that display impaired caspase-mediated cell death and increased frequency of somatic hypermutation in the immunoglobulin VH locus. Lastly, GNA13 deficiency, combined with conditional MYC transgene expression in mouse GC B cells, promotes lymphomagenesis. Thus, GNA13 loss is associated with GC B-cell persistence, in which impaired apoptosis and ongoing somatic hypermutation may lead to an increased risk of lymphoma development. [ABSTRACT FROM AUTHOR]

Objectives: NGS tumor testing does not currently discern between germline or somatic mutations. Patients with cancer who have an incidentally discovered high-risk mutation(s) (HRMs) may have an associated underlying hereditary cancer syndrome. Referral for genetic counseling and consideration of confirmatory germline testing is recommended. We implemented a quality improvement (QI) initiative to increase referral and testing rates for patients with gynecologic cancer and HRMs identified on NGS tumor testing. Here, we report referral rates before and after this intervention. Methods: All patients with NGS testing results from January 2014 to January 2020 were obtained from an institutional database from our institution's molecular tumor board. Patients with gynecologic cancers and HRMs were identified. HRMs included MLH1, MSH2, MSH6, PMS2, SMAD4, APCI1370K, BMPR1A, EPCAM, BARD1, BRCA1, BRCA2, BRIP1, PALB2, RAD51C, RAD51D, NBN, ATM, and CHEK2 (Figure 1C). Retrospective chart review was performed for patients with HRMs to determine (1) if the patient had previous germline testing; (2) if no previous testing whether a referral for genetic counseling was recommended; and (3) completion of germline testing occurred. A QI intervention was implemented in February 2020 with weekly centralized review of NGS sequencing results at the Gynecologic Oncology Tumor Board (Figure 1A). Results and recommendations were communicated to the primary gynecologic oncology provider via the electronic medical record. Results: Of 3394 patients with solid tumors who underwent somatic NGS testing during the pre-intervention period, 465 patients (13.7%) had at least one HRM identified, and 66 of these patients (14.2%) were referred for genetic counseling. Prior to our intervention, patients with gynecologic cancer and at least one HRM (n =36) had a higher referral rate for counseling (42.6%) than patients with other solid tumors (14.2%). About 5.5% of patients with gynecologic cancer had previous germline testing prior to NGS testing. Post-intervention, we identified 10/76 (13.2%) patients with gynecologic cancer and an HRM. Of these ten patients, seven had previous germline testing (70% vs 5.5%, p<0.0001), and three patients who did not have previous germline results were referred for counseling, capturing all patients with HRMs (Figure 1B). Results from germline testing are pending. Conclusions: After implementing a QI initiative involving centralized NGS results review and communication of results to the primary gynecologic oncologist, all patients with gynecologic cancer and HRM obtained appropriate referrals to genetic testing. The overall rate of germline genetic testing prior to NGS testing increased significantly in the 2020-2021 time period compared to 2014-2020. Identification of HRMs on NGS warrants referral for genetic counseling and germline testing; our QI initiative ensured adherence to this standard. [ABSTRACT FROM AUTHOR]

Targeting tumor-specific molecular alterations has shown significant clinical benefit. Molecular tumor boards (MTBs) connect cancer patients with personalized treatments and clinical trials. However, rural cancer centers often have limited access to MTB expertise. We established an academic-community partnership expanding our academic MTB to affiliated rural community cancer centers. We developed a centralized molecular registry of tumors (MRT) to aggregate the comprehensive genomic profiling (CGP) results and facilitate multidisciplinary MTB review. Of the 151 patients included, 87 (58%) had actionable genomic biomarkers, 42 (28%) were eligible for a targeted off-label therapy, and 27 (18%) were matched to a clinical trial. Of those with a clinical trial match, only 1 of 27 (3%) was enrolled in the identified trial. One year into implementation, community oncology providers were anonymously surveyed on persistent barriers to precision treatment utilization. The primary barriers to clinical trial enrollment were the distance to the trial center (70%), lack of transportation (55%), and lack of local trials (50%). This study offers a framework to improve access to molecular expertise, but significant barriers to the equitable use of CGP and trial enrollment persist.

Background: Comprehensive genomic profiling (CGP) is frequently adopted to direct the clinical care of myeloid neoplasms and solid tumors, but its utility in the care of lymphoid and histiocytic cancers is less well defined., Methods: In this study, we aimed to evaluate the frequency at which mutations identified by CGP altered management in non-myeloid hematologic malignancies. We retrospectively examined the CGP results of 105 samples from 101 patients with non-myeloid hematologic malignancies treated at an academic medical center who had CGP testing between 2014 and 2021., Results: CGP revealed one or more pathogenic or likely pathogenic variant in 92 (88%) of samples and 73 (72%) of tested patients had one or more mutations with diagnostic, prognostic, or therapeutic significance. The identification of a resistance variant resulted in the suspension of the active treatment or affected subsequent treatment choice in 9 (69%) out of 13 patients. However, the presence of a therapy sensitizing variant only led to consideration of a biomarker-directed therapy in 6 (10%) out of 61 patients., Conclusions: Overall, CGP of non-myeloid hematologic malignancies identified clinically significant variants in 72% of patients and resulted in a change in management in 22% of patients., Competing Interests: The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. C.L. has performed consulting for Rigel and ad board for Autolus and ADC Therapeutics. B.A.C. has received honoraria from Foundation Medicine and served on an ad board for Guardant. M.F.G is employed by Labcorp. J.S. performs consulting for Abbvie, Astellas, AstraZeneca, Bayer, Beigene, Daiichi-Sankyo, Eli Lilly, GE Healthcare, GSK, Ipsen, Johnson and Johnson, Jazz Pharmaceuticals, Merck, Natera, Pfizer, Roche/Genentech, Regeneron, Sanofi, Taiho, Takeda, and Xilio Therapeutics, owns stock options in Triumvira Immunologics, and receives research funding from Abbvie, Amgen, Apollo Therapeutics, AStar D3, Bayer, Beigene, Curegenix, Daiichi-Sankyo, Eli Lilly, Erasca, GSK, Leap Therapeutics, Novartis, Pfizer, Quanta Therapeutics, Revolution Medicines, and Roche/ Genentech. The remaining authors have no relevant disclosures.

Background: Richter transformation usually presents as an aggressive diffuse large B-cell lymphoma, occurs in up to 10% of patients with chronic lymphocytic leukaemia, has no approved therapies, and is associated with a poor prognosis. Pirtobrutinib has shown promising efficacy and tolerability in patients with relapsed or refractory B-cell malignancies, including those who progress on covalent Bruton tyrosine kinase (BTK) inhibitors. This study aims to report the safety and activity of pirtobrutinib monotherapy in a subgroup of patients with Richter transformation from the multicentre, open-label, phase 1/2 BRUIN study., Methods: This analysis included adult patients (aged ≥18 years) with histologically confirmed Richter transformation, an Eastern Cooperative Oncology Group performance status score of 0-2, and no limit of previous therapies, with patients receiving first-line treatment added in a protocol amendment (version 9.0, Dec 15, 2021). Pirtobrutinib 200 mg was administered orally once a day in 28-day cycles. The primary endpoint of phase 1 of the BRUIN trial as a whole, which has been previously reported, was to establish the recommended phase 2 dose for pirtobrutinib monotherapy and the phase 2 primary endpoint was overall response rate. Safety and activity were measured in all patients who received at least one dose of pirtobrutinib monotherapy. This BRUIN phase 1/2 trial was registered with ClinicalTrials.gov and is closed to enrolment (NCT03740529)., Findings: Between Dec 26, 2019, and July 22, 2022, 82 patients were enrolled, of whom five were enrolled during phase 1 and 77 during phase 2. All but one patient received a starting dose of 200 mg pirtobrutinib once a day as the recommended phase 2 dose. The remaining patient received 150 mg pirtobrutinib once a day, which was not escalated to 200 mg. The median age of patients was 67 years (IQR 59-72). 55 (67%) of 82 patients were male and 27 (33%) were female. Most patients were White (65 [79%] of 82). 74 (90%) of 82 patients received at least one previous Richter transformation-directed therapy. Most patients (61 [74%] of 82) had received previous covalent BTK inhibitor therapy for chronic lymphocytic leukaemia or Richter transformation. The overall response rate was 50·0% (95% CI 38·7-61·3). 11 (13%) of 82 patients had a complete response and 30 (37%) of 82 patients had a partial response. Eight patients with ongoing response electively discontinued pirtobrutinib to undergo stem-cell transplantation. The most common grade 3 or worse adverse event was neutropenia (n=19). There were no treatment-related deaths., Interpretation: Pirtobrutinib shows promising safety and activity among patients with Richter transformation, most of whom received previous Richter transformation-directed therapy, including covalent BTK inhibitors. These data suggest that further investigation is warranted of pirtobrutinib as a treatment option for patients with relapsed or refractory Richter transformation after treatment with a covalent BTK inhibitor., Funding: Loxo Oncology., Competing Interests: Declaration of interests WGW reports research funding from Numab Therapeutics, Loxo Oncology–Lilly, Janssens Biotech, NIH P30 CA016672/MDACC Cancer Center Support Grant, GlaxoSmithKline, AbbVie, Cyclacel, Nurix Therapeutics, Juno Therapeutics, Bristol Myers Squibb (Juno & Celgene), AstraZeneca–Acerta Pharma Miragen, Oncternal Therapeutics, Janssens Biotech, Accutar Biotechnology, Sunesis, KITE Pharma, Gilead Sciences, Genentech, Pharmacyclics, GlaxoSmithKline–Novartis; consultancy fees from AbbVie, Cyclacel Nurix Therapeutics, Bristol Myers Squibb (Juno & Celgene), AstraZeneca–Acerta Pharma; a non-relevant financial relationship with the National Comprehensive Cancer Network; support from the National Institutes of Health and National Cancer Institute under award number P30 CA016672; and use of MDACC Cancer Center Support Grant shared resources. NNS reports consultancy fees from Umoja, Janssen, Bristol Myers Squibb–Juno, LOXO Oncology–Lilly, TG therapeutic, Novartis, Seattle Genetics, Gilead–Kite, Incyte, AbbVie, Lilly Oncology, and Miltenyi Biotec; research funding from Miltenyi Biotec and Lilly Oncology; having stock options in a privately-held company with Tundra Therapeutics; and travel support from Epizyme and Miltenyi Biotec. CYC reports consultancy fees, honoraria, and having an advisory role for Roche, Janssen, Gilead, AstraZenecca, Eli Lilly, BeiGene, AbbVie, Menarini, Daizai, and Genmab, and research funding from Roche, MSD, Eli Lilly, Bristol Myers Squibb, and AbbVie. DL reports consultancy fees from Kite, BeiGene, Roche, Eli Lilly, and Janssen and membership on an entity's board of directors or advisory committees with Kite, BeiGene, Roche, Eli Lilly, and Janssen. MSH reports consultancy fees and honoraria from Pharmacyclics. CCC reports consultancy fees from LOXO Oncology–Eli Lilly, BeiGene, AstraZeneca, Genentech, AbbVie, Octapharma, Allogene, Janssen, TG Therapeutics, MEI Pharma, and Mingsight; honoraria from LOXO Oncology–Eli Lilly, BeiGene, AstraZeneca, Genentech, AbbVie; research funding paid to an institution from LOXO Oncology–Eli Lilly, AbbVie, and CarnaBio; membership on an entity's board of directors or advisory committees with BeiGene, AstraZeneca, Genentech, and AbbVie; being an equity holder in a publicly-traded company with Bluebird Bio, Geron, and Pfizer; and receiving travel support from LOXO Oncology–Eli Lilly. NL reports consultancy fees from Genentech, Pharmacyclics, BeiGene, AstraZeneca, AbbVie, Adaptive Biotechnologies, Janssen, and research funding from Genentech, TG Therapeutics, BeiGene, AstraZeneca, AbbVie, MingSight, LOXO Oncology–Eli Lilly, Oncternal, and Octapharma. SM reports consultancy fees from AstraZeneca, Juno–Bristol Myers Squibb, AbbVie, Genentech, Janssen Pharmaceuticals, BeiGene; membership on a board of directors or advisory committee with AstraZeneca, Juno–Bristol Myers Squibb, Janssen Pharmaceuticals, Eli Lilly, Loxo Oncology, and BeiGene; research funding from AstraZeneca, Juno–Bristol Myers Squibb, AbbVie, Janssen Pharmaceuticals, Eli Lilly–Loxo Oncology, BeiGene; and speakers bureau with AstraZeneca, Eli Lilly–Loxo Oncology, and BeiGene. DJ reports research funding from Seagen, Trillium Pharmaceuticals, Regeneron Pharmaceuticals, MEI Pharma, Loxo Oncology, Debio Pharma, ATARA Biotherapeutics, AstraZeneca and membership on a board of directors or advisory committees with Affimed and Daiichi Sankyo. TM reports consultancy fees from BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, and AbbVie; honoraria from BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, and AbbVie; membership on a board of directors or advisory committees on BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, Abbvie; research Funding from Janssen, AbbVie; and speakers bureau for BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, and AbbVie. YW reports research funding from Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, Genmab, and AbbVie; membership on an advisory board with Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene, AstraZeneca, and Genmab; consultancy fees from Innocare and AbbVie; and honoraria from Kite. TAE reports membership on an entity's Board of Directors or advisory committees from Loxo Oncology, Incyte, BeiGene, AstraZeneca, KITE, AbbVie, Roche, Gilead, Secura Bio; speakers bureau from Loxo Oncology, Eli Lilly, Incyte, BeiGene, AstraZeneca, KITE, AbbVie, Loxo Oncology, Roche, Medscape, Janssen, Gilead, PeerView; research funding from BeiGene and AstraZeneca; consultancy fees from Eli Lilly, Incyte, Beigene, Autolus, AstraZeneca, KITE, AbbVie, Loxo Oncology, Roche, Janssen, and Gilead; and honoraria from Eli Lilly, BeiGene, AstraZeneca, KITE, AbbVie, Loxo Oncology, Roche, Janssen, and Gilead. JMR reports consultancy fees from Pharmacyclics, Jannsen, Genentech, GenMab, AstraZeneca, Morphosys, ADC Therapeutics, Epizyme, BeiGene, and AbbVie; research funding from Pharmacyclics, Velosbio, Loxo Oncology, Acerta, Oncternal Pharmaceuticals, Epizyme, and AbbVie; and honoraria from SeaGen. MM reports consultancy from Bayer, ADC therapeutics, Epizyme, Genentech, F Hoffmann-La Roche, and Incyte; research funding from BeiGene, Janssen, F Hoffmann-La Roche– Genentech, Celgene–Bristol Myers Squibb, and Incyte; and speakers bureau with ADC therapeutics, BeiGene, and Kite–Gilead. CT reports honoraria from Loxo Oncolgy. WJ reports consultancy fees from AbbVie, AstraZeneca, BeiGene, Eli Lilly, Pfizer, Roche, SOBI, and Takeda and research funding from AbbVie, AstraZeneca, Bayer, BeiGene, Celgene, Janssen, Eli Lilly, Roche, SOBIm, and Takeda. KI reports honoraria from Eli Lilly, SymBio Pharmaceuticals, Meiji Seika, Nihon Kayaku, Takeda, AstraZeneca, Janssen, Genmab, MSD, Pfizer, AbbVie, Ono Pharmaceuticals, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Chugai Pharma, and Kyowa Kirin; consultancy fees from Takeda, AstraZeneca, Genmab, AbbVie, Otsuka, Eisai, Ono Pharmaceuticals, Nippon Shinyaku, Mitsubishi Tanabe Pharma, and Zenyaku Kogyo; and research funding from AstraZeneca, Genmab, MSD, Pfizer, AbbVie, Otsuka, Eisai, Regeneron, Loxo Oncology, BeiGene, Daiichi Sankyo, Yakult, Novartis, Bristol Myers Squibb, Incyte, Astellas Amgen, Chugai Pharma, Kyowa Kirin. AA reports membership on a board of directors or advisory committees with Genentech, Eli Lilly and Company, Amgen, TG Therapeutics, Incyte, BeiGene, Epizyme, Janssen, and SeaGen; research funding from Eli Lilly, Incyte, and BeiGene; and honoraria from Dr Reddy. MP reports consulting fees from Kura, Accutar, Mitsubishi; participating on a data safety monitoring board or advisory board with lema, Nurix, Daiichi, Kura, and Janssen; leadership with ION Pharma; honoraria from Janssen Oncology; and participating in a consulting or advisory role with Olema Pharmaceuticals, Daiichi Sankyo–UCB Japan, Kura Oncology, Accutar Biotech, and Kura. JFS reports honoraria from Hoffmann-La Roche, AbbVie, AstraZeneca, Janssen, Bristol Myers Squibb, Gilead, and BeiGene; consultancy fees from Hoffmann-La Roche, TG Therapeutics, Bristol Myers Squibb; participating on a data safety monitoring board or advisory board with Genor Bio, Hoffmann-La Roche, AbbVie, AstraZeneca, Janssen, Bristol Myers Squibb, Gilead, and BeiGene; speakers bureau with Hoffmann-La Roche, AbbVie, and BeiGene; and research funding from F Hoffmann-La Roche and AbbVie. JAW reports consultancy from Newave, Loxo Oncology, BeiGene, AstraZeneca, AbbVie, Janssen, and Pharmacyclics and research funding from Schrodinger, Morphosys, Karyopharm, Janssen, and Pharmacyclics. PAT reports consultancy and honoraria from AbbVie, Adaptive Biotechnologies, Ascentage AstraZeneca, BeiGene, Genentech, Genmab, Janssen, Lilly, Merck, Pharmacyclics; speakers bureau from AbbVie, Adaptive Biotechnologies, AstraZeneca, Janssen, and Merck; research funding from AbbVie, Pharmacyclics, Genentech, Lilly, and Adaptive Biotechnologies; and travel support from Merck. PA is a current employee of and equity holder in Eli Lilly. CH reports being an equity holder in Eli Lilly and Foundation Medicine and travel support from Eli Lilly. SCM reports current employment with, being an equity holder in, and travel support from Eli Lilly. NM reports being a current equity holder in Eli Lilly and current employment with Loxo Oncology. BN, CW, BCN, and DET reports current employment with and current equity holder in Eli Lilly. ASR reports current employment with and being equity holder in Eli Lilly and consultancy work with Telios Pharma. HL reports current employment with Loxo Oncology. LER reports serving as a consultant for AbbVie, Ascentage, AstraZeneca, BeiGene, Janssen, Loxo Oncology, Pharmacyclics, Pfizer, and TG Therapeutics; membership of a data safety monitoring committee for Ascentage; serving as a CME speaker for DAVA, Curio, Medscape, and PeerView; holding minority ownership interest in Abbott Laboratories; having received travel support from LOXO Oncology; and having received research funding (paid to the institution) from Adaptive Biotechnologies, AstraZeneca, Genentech, AbbVie, Pfizer, Loxo Oncology, Aptose Biosciences, Dren Bio, and Qilu Puget Sound Biotherapeutics. PG reports consultancy, fees, honoraria, and research funding from Janssen, Eli Lilly–Loxo Oncology, MSD, Roche, AbbVie, BMS, BeiGene, and AstraZeneca., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: It has long been established that high-dose methotrexate is an essential part of therapy for primary central nervous system lymphoma. When regimens utilizing high-dose methotrexate were first studied, a dose of 8 g/m 2 was used. More recently, reduced dosing strategies have been studied and adopted in attempts to reduce rates of adverse events. Studies utilizing 3.5 g/m 2 of methotrexate have shown promising outcomes and improved rates of adverse events but there have never been any randomized head-to-head studies of differing dose levels of high-dose methotrexate. The purpose of this study was to compare efficacy and safety of different dosing strategies of high-dose methotrexate (HD-MTX) for primary central nervous system lymphoma (PCNSL)., Methods: This single center retrospective review was conducted between 07/01/2013 to 6/3/2020. The patient population was separated into two arms based upon dose of methotrexate. The high intensity (HiHD) arm was defined as patients who received doses > 3.5 g/m 2 , while the low intensity (LiHD) arm received ≤ 3.5 g/m 2 . The primary endpoint was overall response rate (ORR) and secondary endpoints include efficacy via 2-year overall survival (OS), progression to transplant, and utilization of consolidation or salvage therapy. Safety was assessed through monitoring of relevant laboratory studies., Results: A total of 92 patients were included in this analysis. Baseline demographics were similar between groups, with the LiHD group trending toward older age. There were 78 patients eligible for assessment for ORR; there was no significant difference between the two groups (42.0% LiHD vs. 44.4% HiHD; p  = 1.0). Rates of OS, progression to transplant and progression to consolidation chemotherapy were not different between groups. There were statistically significantly higher rates of renal and/or hepatic dysfunction with the first dose in the HiHD group compared with the LiHD group (11.5% LiHD vs. 64.3% HiHD; p  ≤ 0.01)., Conclusions: In this PCNSL patient cohort, there is no difference in terms of efficacy between HiHD LiHD methotrexate, but patients in the HiHD group had higher rates of renal and hepatic dysfunction. Limitations include small sample size and disparity between group sizes., Competing Interests: Declaration of conflicting interestsDaniel P Schrum, Meredith T Moorman, Zhiguo Li, Mairead Dillon and Mallika P Patel declare they have no financial interests. Matthew McKinney has received speaker and consultant honoraria from Kite/Gilead, Seattle Genetics, Molecular Templates, BTG, Pharmacyclics, Verastem, Genentech, ADC therapeutics and Celgene.

Background: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition of somatic mutations that leads to an expanded blood cell clone, has been associated with development of a pro-inflammatory state. An enhanced or dysregulated inflammatory response may contribute to rejection after lung transplantation, however the prevalence of CHIP in lung recipients and influence of CHIP on allograft outcomes is unknown., Methods: We analyzed whole-exome sequencing data in 279 lung recipients to detect CHIP, defined by pre-specified somatic mutations in 74 genes known to promote clonal expansion of hematopoietic stem cells. We compared the burden of acute rejection (AR) over the first post-transplant year in lung recipients with vs. without CHIP using multivariable ordinal regression. Multivariate Cox proportional hazards models were used to assess the association between CHIP and CLAD-free survival. An exploratory analysis evaluated the association between the number of CHIP-associated variants and chronic lung allograft dysfunction (CLAD)-free survival., Results: We detected 64 CHIP-associated mutations in 45 individuals (15.7%), most commonly in TET2 (10.8%), DNMT3A (9.2%), and U2AF1 (9.2%). Patients with CHIP tended to be older but did not significantly differ from patients without CHIP in terms of race or native lung disease. Patients with CHIP did not have a higher incidence of AR over the first post-transplant year (p = 0.45) or a significantly increased risk of death or CLAD (adjusted HR 1.25, 95% CI 0.88-1.78). We did observe a significant association between the number of CHIP variants and CLAD-free survival, specifically patients with 2 or more CHIP-associated variants had an increased risk for death or CLAD (adjusted HR 3.79, 95% CI 1.98-7.27)., Conclusions: Lung recipients have a higher prevalence of CHIP and a larger variety of genes with CHIP-associated mutations compared with previous reports for the general population. CHIP did not increase the risk of AR, CLAD, or death in lung recipients., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Parsaclisib, a potent and highly selective PI3Kδ inhibitor, has shown clinical benefit in patients with relapsed or refractory (R/R) B-cell malignancies. This phase 2 study (CITADEL-203; NCT03126019, EudraCT 2017-001624-22) assessed efficacy and safety of parsaclisib monotherapy in patients with R/R follicular lymphoma (FL)., Methods: Patients ≥18 years of age with histologically confirmed R/R FL (grade 1-3a) and prior treatment with ≥2 systemic therapies received parsaclisib 20 mg once daily (QD) for 8 weeks then parsaclisib 20 mg once weekly (weekly dosing group [WG]) or parsaclisib 20 mg QD for 8 weeks then parsaclisib 2.5 mg QD (daily dosing group [DG]); DG was selected for further assessment. Primary endpoint was objective response rate (ORR)., Findings: At data cut-off (January 15, 2021), 126 patients had been treated (WG: n = 23; DG: n = 103). ORR (95% confidence interval [CI]) was 77.7% (68.4-85.3) with a complete response rate (95% CI) of 19.4% (12.3-28.4) in DG; median (95% CI) duration of response was 14.7 months (10.4-not estimable [NE]), median progression-free survival was 15.8 months (11.0-NE), and median overall survival was not reached. The most common any-grade treatment-emergent adverse events (TEAEs) among all treated patients included diarrhoea (n = 48, 38.1%), nausea (n = 31, 24.6%), and cough (n = 28, 22.2%); the most common grade ≥3 TEAEs were diarrhoea (n = 15, 11.9%), neutropenia (n = 13, 10.3%), and colitis (n = 7, 5.6%). Dose interruption, reduction, and discontinuation from TEAEs occurred in 46.8% (n = 59), 17.5% (n = 22), and 23.8% (n = 30) of patients, respectively., Interpretation: Treatment with parsaclisib demonstrated rapid and durable responses, and a manageable safety profile in patients with R/R FL., Funding: Incyte Corporation., Competing Interests: Marek Trněný—Consultancy: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Gilead Sciences, Incyte Corporation, Janssen, MorphoSys, Roche, and Takeda. Honoraria: AbbVie, Amgen, Bristol Myers Squibb, Gilead Sciences, Incyte Corporation, Janssen, MorphoSys, Roche, and Takeda. Travel, accommodations, or expenses: AbbVie, Bristol Myers Squibb, Gilead Sciences, Janssen, Roche, and Takeda. Research funding: Roche. Abraham Avigdor—Consultancy: Gilead Sciences, Pfizer, and Takeda. Honoraria: Gilead Sciences, Pfizer, and Takeda. Research funding: Bristol Myers Squibb and Janssen. Matthew S. McKinney—Consultancy: BTG Specialty Pharmaceuticals, Celgene, Genentech, Molecular Templates, Pharmacyclics, and Verastem Oncology. Honoraria: Genentech and Kite Pharma/Gilead Sciences. Research funding: BeiGene, Celgene, Genentech, Incyte Corporation, Molecular Templates, Nordic Nanovector, and Novartis. Speakers bureau: Kite Pharma/Gilead Sciences. Shankara Paneesha—Honoraria: AbbVie, Bristol Myers Squibb, Celgene, Gilead Sciences, and Janssen. Björn E. Wahlin—Consultancy: Roche. Research funding: Gilead Sciences and Roche. David Cunningham—Advisory committee: OVIBIO. Research funding: 4SC, Amgen, AstraZeneca, Bayer, Celgene, Clovis Oncology, Eli Lilly & Company, Janssen, MedImmune, Merck, Merrimack Pharmaceuticals, and Sanofi. Nicholas Morley—Advisory board: Roche. Honoraria: Kite Pharma and Janssen. Conference support: AbbVie, Roche, and Takeda. Miguel Canales—Honoraria: BeiGene, Celgene, Gilead Sciences, Incyte Corporation, Janssen, Karyopharm, Kyowa, Novartis, Sandoz, and Takeda. Speakers' bureau: Amgen, Janssen, Kyowa, Roche, Sandoz, and Takeda. Mariana Bastos-Oreiro—Honoraria: Bristol Myers Squibb/Celgene, Gilead Sciences, Janssen, Novartis, and Roche. Research funding: Roche. Speakers’ bureau: Bristol Myers Squibb/Celgene, Janssen, Kite Pharma, Roche, Novartis, and Takeda. David Belada—Consultancy: Gilead Sciences, Janssen, Roche, and Takeda. Board of Directors or Advisory committee: Gilead Sciences, Janssen, Roche, and Takeda. Travel expenses: Gilead Sciences, Roche, and Takeda. Research funding: Celgene, Gilead Sciences, Janssen, Roche, and Takeda. Fred Zheng—Employment and stock ownership: Incyte Corporation. Douglas J. DeMarini—Former employment and stock ownership: Incyte Corporation. Wei Jiang—Former employment and stock ownership: Incyte Corporation. Ping Jiang—Former employment and stock ownership: Incyte Corporation. Ryan C. Lynch—Consultancy: MorphoSys. Research funding: Bayer, Cyteir Therapeutics, Genentech, Incyte Corporation, Juno Pharmaceuticals, Rhizen Pharmaceuticals, Takeda, and TG Therapeutics. John S. Hrom and Liliana Devizzi—No relevant financial relationships to disclose., (© 2023 The Authors.)

Abdominal aortic aneurysm (AAA) is a prevalent vascular disease with high mortality rates upon rupture. Despite its prevalence in elderly populations, there remain limited treatment options; invasive surgical repair, while risky, is the only therapeutic intervention with proven clinical benefits. Dietary factors have long been suggested to be closely associated with AAA risks, and dietary therapies recently emerged as promising avenues to achieve non-invasive management of a wide spectrum of diseases. However, the role of dietary therapies in AAA remains elusive. In this article, we will summarize the recent clinical and pre-clinical efforts in understanding the therapeutic and mechanistic implications of various dietary patterns and therapeutic approaches in AAA., Competing Interests: Author BW is the corresponding author, the coordinator for this research topic, and has recused from the peer-review and editorial processes. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yin, Gregg, Riccio, Hoyt, Islam, Ahn, Le, Patel, Zhang, He, McKinney, Kent and Wang.)

Joint and muscle pain, including arthralgia, myalgia, and musculoskeletal pain, are among the common adverse events (AEs) reported for ibrutinib, a once-daily Bruton's tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). This pooled analysis from nine clinical trials of ibrutinib in CLL and MCL ( N  = 1178) evaluated patterns of these AEs. Any grade arthralgia, myalgia, and musculoskeletal pain occurred in 18%, 10%, and 6% of patients, respectively. AEs were primarily low-grade (grade 1/2: 97‒99%) and occurred during the first year of treatment; most resolved (67%-80%) at first occurrence. Few (<5%) patients required ibrutinib dose modification; no patients discontinued ibrutinib due to these AEs. Among patients evaluated for concomitant medication use, all those receiving concomitant medications after the first AE occurrence experienced AE resolution. These data suggest that these AEs were not treatment-limiting during ibrutinib therapy.

Purpose: Diagnosing primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is challenging because it is a clinicopathologic entity that shares characteristics with other lymphomas and lacks pathognomonic features. We sought to investigate the fidelity between a working diagnosis of PMBCL at our institution and the clinicopathologic criteria established within the 2017 World Health Organization (WHO) classification., Patients and Methods: Medical records and archived tissue of patients treated for stage I-II PMBCL from 1998 to 2018 were retrospectively reviewed for clinical and pathologic conformity with current WHO criteria. Disease was characterized as definitely PMBCL if all of the following were present: anterior mediastinal mass with or without lymph node involvement, no extranodal disease, B-cell antigen expression, Epstein-Barr virus negativity, and at least one supportive feature: female gender under age 40, bulky primary tumor, CD30 weakly positive, compartmentalizing alveolar fibrosis, lack of surface immunoglobulin expression, and MUM1 or CD23 positivity. Disease without supportive features or other pathologic findings more suggestive of other entities was characterized as equivocal for PMBCL. Lack of an anterior mediastinal mass, presence of distant lymph node involvement or extranodal disease, lack of B-cell antigen expression, or Epstein-Barr virus positivity were characterized as definitely not PMBCL. Clinical management and outcomes were also assessed., Results: Of 63 patients treated for presumed stage I-II PMBCL, 58 (92%) met the criteria for PMBCL. The most common reason for a discordant diagnosis was lack of an anterior mediastinal mass (n = 3). Two additional patients were characterized as having disease equivocal for PMBCL. In retrospect, one patient most likely had a mediastinal gray zone lymphoma due to CD15 positivity and another diffuse large B cell, not otherwise specified, at pathologic review. Five-year progression-free and overall survival were 67% (95% confidence interval, 54-77) and 81% (95% confidence interval, 68-89), respectively, for all patients., Conclusion: Despite the complexity of the clinicopathologic criteria of PMBCL, most patients (92%) who were treated for stage I-II PMBCL at our institution appear to have been accurately diagnosed., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Recent advances in next-generation sequencing have allowed for an increase in molecular tumor profiling., Objective: We sought to assess the actionability and clinical utilization of molecular tumor profiling results obtained via Foundation Medicine tumor sequencing tests in uterine and ovarian cancers., Patients and Methods: We performed a single-institution retrospective chart review to obtain demographic and clinical information in patients with uterine and ovarian cancer whose tumors were submitted to Foundation Medicine for molecular tumor profiling over a 7-year period. Alterations identified on testing were stratified according to the OncoKB database actionability algorithm. Descriptive statistics were primarily used to analyze the data., Results: Tumors from 185 women with gynecologic cancer were submitted for molecular tumor profiling between 2013 and 2019. The majority of tests (144/185; 78%) were ordered after a diagnosis of recurrence. In 60 (32%), no actionable molecular alteration was identified. Thirteen (7%) identified an alteration that directed to a US Food and Drug Administration-approved therapy in that tumor type, while 112 (61%) had alterations with investigational or hypothetical treatment implications. In patients with any actionable finding, treatment was initiated in 27 (15%) based on these results., Conclusions: The majority of uterine and ovarian cancers (93%) did not have molecular alterations with corresponding Food and Drug Administration-approved treatments. Even in patients with a potentially actionable alteration, gynecologic oncologists were more likely to choose an alternative therapy. Further investigation is warranted to determine which patients with uterine and ovarian cancer are most likely to benefit from molecular tumor profiling and the ideal timing of testing. The potential to identify effective therapeutic options in a minority of patients needs to be balanced with the current limited clinical applicability of these results in most cases.

"Liquid biopsy" approaches analyzing cell-free DNA (cfDNA) from the blood of patients with cancer are increasingly utilized in clinical practice. However, it is not yet known whether cfDNA sequencing from large cohorts of patients with cancer can detect genomic alterations at frequencies similar to those observed by direct tumor sequencing, and whether this approach can generate novel insights. Here, we report next-generation sequencing data from cfDNA of 1,397 patients with colorectal cancer. Overall, frequencies of genomic alterations detected in cfDNA were comparable to those observed in three independent tissue-based colorectal cancer sequencing compendia. Our analysis also identified a novel cluster of extracellular domain (ECD) mutations in EGFR , mediating resistance by blocking binding of anti-EGFR antibodies. Patients with EGFR ECD mutations displayed striking tumor heterogeneity, with 91% harboring multiple distinct resistance alterations (range, 1-13; median, 4). These results suggest that cfDNA profiling can effectively define the genomic landscape of cancer and yield important biological insights. Significance: This study provides one of the first examples of how large-scale genomic profiling of cfDNA from patients with colorectal cancer can detect genomic alterations at frequencies comparable to those observed by direct tumor sequencing. Sequencing of cfDNA also generated insights into tumor heterogeneity and therapeutic resistance and identified novel EGFR ectodomain mutations. Cancer Discov; 8(2); 164-73. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 127 ., (©2017 American Association for Cancer Research.)

Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1 , JAK3 , STAT3 , and SOCS1 We also identified mutations in KRAS , TP53 , and TERT Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell-specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes., (© 2017 Moffitt et al.)

Chaetodactylus krombeini (Baker) (Acari: Chaetodactylidae) is a cleptoparasitic mite that negatively affects propagation of Osmia spp. (Hymenoptera: Megachilidae) for orchard pollination in the USA. This study was conducted to determine the effect of C. krombeini on mortality of male and female Osmia cornifrons, the Japanese hornfaced bee. A total of 107 O. cornifrons nests were examined to determine within-nest distribution of C. krombeini with regression analyses. A total of 30 mite-free O. cornifrons nests were observed and within-nest distribution of male and female O. cornifrons was determined with non-linear regression analyses. In addition, cocoons from 20 mite-infested O. cornifrons cells were examined to determine whether C. krombeini could be found inside cocoons of O. cornifrons. The results of this study showed that female O. cornifrons and C. krombeini were found more frequently in the inner part of the nest, and male O. cornifrons were found mostly in the center of the nest. No C. krombeini were found inside O. cornifrons cocoons. These results indicate that C. krombeini have a greater negative impact on mortality in the egg and larval stages of female O. cornifrons than in male O. cornifrons. Implications for management of C. krombeini and O. cornifrons populations for orchard pollination are discussed in this article.

Recombinant human erythropoietin (rhEPO), the prototype erythropoiesis-stimulating agent developed in the 1980s, was among the first recombinant human proteins to be marketed for clinical use in the oncology setting. Anemia is a frequent concern in patients with cancer receiving myelosuppressive chemotherapy and the availability of rhEPO as an alternative to red blood cell transfusions to treat symptomatic anemia created excitement among clinicians, particularly during an era of mounting concern for transfusion-transmissible infections. Early studies of rhEPO for chemotherapy-induced anemia in patients with non-myeloid malignancies showed these agents improved hemoglobin levels and reduced transfusion rates. rhEPO therapy was reported to decrease fatigue and improve quality of life, although the magnitude and clinical meaningfulness of these effects have been debated. More recent clinical trials since 2003 linking rhEPO therapy to increased risk of tumor progression, thrombo-vascular events and mortality prompted implementation of use restrictions to minimize potential for harm. Scientific research to understand the basic mechanisms of the biologic effects of erythropoietin at the cellular receptor and signaling level has revealed pleiotropic cytokine effects extending beyond erythropoiesis regulation. The importance of erythropoietin receptor signaling in normal, non-erythroid tissues and in pre-clinical tumor models has been under intense investigation and scrutiny, as potential mechanisms of the adverse outcomes associated with rhEPO therapy have been debated. Further research will be required to clarify the complex interplay between the diverse hematopoietic and non-hematopoietic effects of erythropoietin in normal and malignant tissues and to optimize the clinical use of rhEPO in the supportive care of cancer patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)