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February 1, 2022
This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors.
A Congenital Anemia Reveals Distinct Targeting Mechanisms for Master Transcription Factor GATA1
Ludwig L, Lareau CA, Bao EL, Liu N, Myers SA, Verboon JM, Ulirsch JC, Luo W, Muus C, Fiorini C, Olive ME, Vockley CM, Munschauer M, Subramanian V, Chiarle R, Carr SA, Aryee MJ, Orkin S, Sankaran VG
Master regulators, such as the hematopoietic transcription factor (TF) GATA1, play an essential role in orchestrating lineage commitment and differentiation. However, the precise mechanisms by which such TFs regulate transcription through interactions with specific cis-regulatory elements remain incompletely understood. Here, we describe a form of congenital hemolytic anemia caused by missense mutations in an intrinsically disordered region of GATA1, with a poorly understood role in transcriptional regulation. Through integrative functional approaches, we demonstrate that these mutations perturb GATA1 transcriptional activity by partially impairing nuclear localization and selectively altering precise chromatin occupancy by GATA1. These alterations in chromatin occupancy and concordant chromatin accessibility changes alter faithful gene expression, with failure to both effectively silence and activate select genes necessary for effective terminal red cell production. We demonstrate how disease-causing mutations can reveal regulatory mechanisms that enable the faithful genomic targeting of master TFs during cellular differentiation.
Single Cell Analysis Reveals Immune Dysfunction from the Earliest Stages of CLL that can be Reversed by Ibrutinib
Purroy Zuriguel N, Tong YE, Cieri N, Li S, Parry EM, Zhang W, Livak KJ, Kharchenko PV, Neuberg D, Wu CJ
Chronic lymphocytic leukemia (CLL) is characterized by a clonal expansion of mature CD19+CD5+ B cells, which are highly dependent on microenvironmental cues for their survival. This common adult leukemia is preceded by a precursor phase termed monoclonal B-cell lymphocytosis (MBL) that has been characterized as indistinguishable from CLL at the genetic, transcriptomic and epigenomic level. However, how leukemia cells co-evolve with immune cells in their circulating microenvironment during the onset of MBL and upon progression to CLL remains incompletely characterized.
Attenuated Response to SARS-CoV-2 Vaccine in Patients with Asymptomatic Precursor Stages of Multiple Myeloma and Waldenström Macroglobulinemia
Konishi Y, Sklavenitis-Pistofidis R, Yue H, Ferrari F, Redd RA, Lightbody ED, Russo M, Perry J, Horowitz E, Justis AV, Shayegh NA, Savell A, Prescott J, Varmeh S, Nowak RP, Marinac CR, Trippa L, Fischer ES, Ghobrial IM
Functional Precision Oncology: Testing Tumors with Drugs to Identify Vulnerabilities and Novel Combinations
Letai A, Bhola P
Functional precision medicine is a strategy whereby live tumor cells from affected individuals are directly perturbed with drugs to provide immediately translatable, personalized information to guide therapy. The heterogeneity of human cancer has led to the realization that personalized approaches are needed to improve treatment outcomes. Precision oncology has traditionally used static features of the tumor to dictate which therapies should be used. Static features can include expression of key targets or genomic analysis of mutations to identify therapeutically targetable "drivers." Although a surprisingly small proportion of individuals derive clinical benefit from the static approach, functional precision medicine can provide additional information regarding tumor vulnerabilities. We discuss emerging technologies for functional precision medicine as well as limitations and challenges in using these assays in the clinical trials that will be necessary to determine whether functional precision medicine can improve outcomes and eventually become a standard tool in clinical oncology.
Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor-Resistant, EGFR-Mutated Non-Small Cell Lung Cancer
Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI), 26.0-52.4], and median progression-free survival was 8.2 (95% CI, 4.4-8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade 3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI-resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers. SIGNIFICANCE: In metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism. See related commentary by Lim et al., p. 16.This article is highlighted in the In This Issue feature, p. 1.
An Enhancer-Driven Stem Cell-Like Program Mediated by SOX9 Blocks Intestinal Differentiation in Colorectal Cancer
Liang X, Duronio GN, Bala P, Spisak S, Sahgal P, Singh H, Zhang Y, Xie Y, Cejas P, Long HW, Bass AJ, Sethi NS
BACKGROUND AND AIMS: Genomic alterations that encourage stem cell activity and hinder proper maturation are central to the development of colorectal cancer (CRC). Key molecular mediators that promote these malignant properties require further elucidation to galvanize translational advances. We therefore aimed to characterize a key factor that blocks intestinal differentiation, define its transcriptional and epigenetic program, and provide preclinical evidence for therapeutic targeting in CRC.
METHODS: Intestinal tissue from transgenic mice and patients were analyzed by means of histopathology and immunostaining. Human CRC cells and neoplastic murine organoids were genetically manipulated for functional studies. Gene expression profiling was obtained through RNA sequencing. Histone modifications and transcription factor binding were determined with the use of chromatin immunoprecipitation sequencing.
RESULTS: We demonstrate that SRY-box transcription factor 9 (SOX9) promotes CRC by activating a stem cell-like program that hinders intestinal differentiation. Intestinal adenomas and colorectal adenocarcinomas from mouse models and patients demonstrate ectopic and elevated expression of SOX9. Functional experiments indicate a requirement for SOX9 in human CRC cell lines and engineered neoplastic organoids. Disrupting SOX9 activity impairs primary CRC tumor growth by inducing intestinal differentiation. By binding to genome wide enhancers, SOX9 directly activates genes associated with Paneth and stem cell activity, including prominin 1 (PROM1). SOX9 up-regulates PROM1 via a Wnt-responsive intronic enhancer. A pentaspan transmembrane protein, PROM1 uses its first intracellular domain to support stem cell signaling, at least in part through SOX9, reinforcing a PROM1-SOX9 positive feedback loop.
CONCLUSIONS: These studies establish SOX9 as a central regulator of an enhancer-driven stem cell-like program and carry important implications for developing therapeutics directed at overcoming differentiation defects in CRC.
Journal of Clinical Oncology
Donor Clonal Hematopoiesis and Recipient Outcomes After Transplantation
Gibson CJ, Kim HT, Murdock HM, Ogata A, Green L, Fleharty M, Dougan T, Cheng CA, Blumenstiel B, Cibulskis C, Tsuji J, Antin JH, Nikiforow S, Chen YB, Ho VT, Lennon NJ, Walt DR, Ritz J, Soiffer RJ, Lindsley RC
PURPOSE: Clonal hematopoiesis (CH) can be transmitted from a donor to a recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain.
PATIENTS AND METHODS: We performed targeted error-corrected sequencing on samples from 1,727 donors age 40 years or older and assessed the effect of donor CH on recipient clinical outcomes. We measured long-term engraftment of 102 donor clones and cytokine levels in 256 recipients at 3 and 12 months after transplant.
RESULTS: CH was present in 22.5% of donors, with DNMT3A (14.6%) and TET2 (5.2%) mutations being most common; 85% of donor clones showed long-term engraftment in recipients after transplantation, including clones with a variant allele fraction < 0.01. DNMT3A-CH with a variant allele fraction 0.01, but not smaller clones, was associated with improved recipient overall (hazard ratio [HR], 0.79; P = .042) and progression-free survival (HR, 0.72; P = .003) after adjustment for significant clinical variables. In patients who received calcineurin-based graft-versus-host disease prophylaxis, donor DNMT3A-CH was associated with reduced relapse (subdistribution HR, 0.59; P = .014), increased chronic graft-versus-host disease (subdistribution HR, 1.36; P = .042), and higher interleukin-12p70 levels in recipients. No recipient of sole DNMT3A or TET2-CH developed donor cell leukemia (DCL). In seven of eight cases, DCL evolved from donor CH with rare TP53 or splicing factor mutations or from donors carrying germline DDX41 mutations.
CONCLUSION: Donor CH is closely associated with clinical outcomes in transplant recipients, with differential impact on graft alloimmune function and potential for leukemic transformation related to mutated gene and somatic clonal abundance. Donor DNMT3A-CH is associated with improved recipient survival because of reduced relapse risk and with an augmented network of inflammatory cytokines in recipients. Risk of DCL in allogeneic hematopoietic cell transplantation is driven by somatic myelodysplastic syndrome-associated mutations or germline predisposition in donors.
Journal of Clinical Oncology
Isn't Androgen Deprivation Enough? Optimal Treatment for Newly Diagnosed Metastatic Prostate Cancer
Morgans AK, Beltran H
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
Journal of Clinical Oncology
Long-Term Outcomes with Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients with Advanced Melanoma
PURPOSE: In the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes.
PATIENTS AND METHODS: Patients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks (n = 314), nivolumab 3 mg/kg once every 2 weeks (n = 316), or ipilimumab 3 mg/kg once every 3 weeks (four doses; n = 315). Coprimary end points were progression-free survival and overall survival (OS) with nivolumab plus ipilimumab or nivolumab versus ipilimumab. Secondary end points included objective response rate, descriptive efficacy assessments of nivolumab plus ipilimumab versus nivolumab alone, and safety. Melanoma-specific survival (MSS; descriptive analysis), which excludes deaths unrelated to melanoma, was also evaluated.
RESULTS: Median OS (minimum follow-up, 6.5 years) was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median MSS was not reached, 58.7, and 21.9 months, respectively; 6.5-year OS rates were 57%, 43%, and 25% in patients with BRAF-mutant tumors and 46%, 42%, and 22% in those with BRAF-wild-type tumors, respectively. In patients who discontinued treatment, the median treatment-free interval was 27.6, 2.3, and 1.9 months, respectively. Since the 5-year analysis, no new safety signals were observed.
CONCLUSION: These 6.5-year CheckMate 067 results, which include the longest median OS in a phase III melanoma trial reported to date and the first report of MSS, showed durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and, in descriptive analyses, with the combination over nivolumab monotherapy.
Journal of Clinical Oncology
Reply to G. R. Mohyuddin et al and A. Garfall et al.
We thank Mohyuddin et al and Garfall et al for their comments on our manuscript reporting the final overall survival (OS) analysis of the TOURMALINE-MM1 phase III trial3 and associated editorial. We agree that OS remains an important end point for patients and on the need for optimal sequencing of therapies. As demonstrated by the increasingly lengthy median OS in phase III trials in relapsed or refractory multiple myeloma, physicians are using the rapidly expanding range of treatments in combination or sequentially to substantially improve outcomes for patients. This is being done in the context of a highly heterogeneous disease and patient population, and with differing global access to novel therapies, requiring individualized treatment optimization and sequencing outside the clinical-trial setting. The result is an enormous and gratifying survival benefit for patients, inconceivable 20 years ago.
Journal of Clinical Oncology
Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib With Adjuvant Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03)
Mayer EL, Burstein HJ, Winer EP, Metzger Filho O
PURPOSE: The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS.
METHODS: Patients with stage II-III HR+, HER2- disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS.
RESULTS: Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non-protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11).
CONCLUSION: Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.
Journal of Clinical Oncology
Venetoclax in Previously Treated Waldenström Macroglobulinemia
Castillo JJ, Meid K, Leventoff C, White TP, Flynn CA, Sarosiek S, Branagan AR, Demos MG, Guerrera ML, Kofides A, Liu X, Munshi M, Tsakmaklis N, Xu L, Yang G, Patterson CJ, Hunter ZR, Davids MS, Treon SP
PURPOSE: BCL2 is overexpressed and confers prosurvival signaling in malignant lymphoplasmacytic cells in Waldenstr??m macroglobulinemia (WM). Venetoclax is a potent BCL2 antagonist and triggers in vitro apoptosis of WM cells. The activity of venetoclax in WM remains to be clarified.
PATIENTS AND METHODS: We performed a multicenter, prospective phase II study of venetoclax in patients with previously treated WM (NCT02677324). Venetoclax was dose-escalated from 200 mg to a maximum dose of 800 mg daily for up to 2 years.
RESULTS: Thirty-two patients were evaluable, including 16 previously exposed to Bruton tyrosine kinase inhibitors (BTKis). All patients were MYD88 L265P-mutated, and 17 carried CXCR4 mutations. The median time to minor and major responses was 1.9 and 5.1 months, respectively. Previous exposure to BTKis was associated with a longer time to response (4.5 v 1.4 months; P < .001). The overall, major, and very good partial response rates were 84%, 81%, and 19%, respectively. The major response rate was lower in those with refractory versus relapsed disease (50% v 95%; P = .007). The median follow-up time was 33 months, and the median progression-free survival was 30 months. CXCR4 mutations did not affect treatment response or progression-free survival. The only recurring grade 3 treatment-related adverse event was neutropenia (n = 14; 45%), including one episode of febrile neutropenia. Laboratory tumor lysis without clinical sequelae occurred in one patient. No deaths have occurred.
CONCLUSION: Venetoclax is safe and highly active in patients with previously treated WM, including those who previously received BTKis. CXCR4 mutation status did not affect treatment response.
Journal of the National Cancer Institute
Smoking and Incidence of Colorectal Cancer Subclassified by Tumor-Associated Macrophage Infiltrates
Ugai T, Väyrynen JP, Haruki K, Akimoto N, Lau MC, Zhong R, Kishikawa J, Väyrynen SA, Zhao M, Fujiyoshi K, Dias Costa A, Arima K, Guerriero JL, Zhang X, Song M, Wang M, Giannakis M, Meyerhardt JA, Nowak JA, Ogino S
BACKGROUND: Biological evidence indicates that smoking can influence macrophage functions and polarization, thereby promoting tumor evolution. We hypothesized that the association of smoking with colorectal cancer incidence might differ by macrophage infiltrates.
METHODS: Using the Nurses' Health Study and the Health Professionals Follow-up Study, we examined the association of smoking with incidence of colorectal cancer subclassified by macrophage counts. Multiplexed immunofluorescence (for CD68, CD86, IRF5, MAF, and MRC1 [CD206]) combined with digital image analysis and machine learning was used to identify overall, M1-polarized, and M2-polarized macrophages in tumor. We used inverse-probability-weighted multivariable Cox proportional hazards regression models to control for potential confounders and selection bias because of tissue data availability. All statistical tests were 2-sided.
RESULTS: During follow-up of 131 144 participants (3 648 370 person-years), we documented 3092 incident colorectal cancer cases, including 871 cases with available macrophage data. The association of pack-years smoked with colorectal cancer incidence differed by stromal macrophage densities (Pheterogeneity = .003). Compared with never smoking, multivariable-adjusted hazard ratios (95% confidence interval) for tumors with low macrophage densities were 1.32 (0.97 to 1.79) for 1-19 pack-years, 1.31 (0.92 to 1.85) for 20-39 pack-years, and 1.74 (1.26 to 2.41) for 40 or more pack-years (Ptrend = .004). In contrast, pack-years smoked was not statistically significantly associated with the incidence of tumors having intermediate or high macrophage densities (Ptrend > .009, with an ? level of .005). No statistically significant differential association was found for colorectal cancer subclassified by M1-like or M2-like macrophages.
CONCLUSION: The association of smoking with colorectal cancer incidence is stronger for tumors with lower stromal macrophage counts. Our findings suggest an interplay of smoking and macrophages in colorectal carcinogenesis.
Aiming at a Tailored Cure for ERBB2-Positive Metastatic Breast Cancer: A Review
Tarantino P, Parsons HA, Lin NU, Krop I, Mittendorf EA, Waks A, Winer EP, Tolaney SM
IMPORTANCE: Metastatic breast cancer (MBC) has traditionally been considered incurable. Accordingly, current treatment algorithms are aimed at maintaining quality of life and improving overall survival, rather than at complete eradication of the disease. Attempts to achieve cure with high-dose chemotherapy were conducted in the 1990s, with no observed long-term benefit compared with conventional chemotherapy. Nonetheless, Erb-B2 receptor tyrosine kinase 2 (ERBB2, formerly HER2)-targeted biologic treatments, developed in the past 2 decades, are currently challenging this paradigm. Indeed, a fraction of patients with ERBB2-positive MBC achieve long-lasting responses to chemotherapy and ERBB2-blockade, resembling a cure. In this setting, the challenge of identifying the optimal curable population has emerged, including identifying populations in whom treatment escalation strategies may be beneficial, while avoiding overtreatment in patients with incurable disease.
OBSERVATIONS: A number of clinical and pathologic features allow physicians to identify patients with ERBB2-positive MBC who are more likely to experience a long-lasting response to chemotherapy and ERBB2-blockade. Long-term responders tend to be de novo metastatic, have a reduced disease burden, and tend to show deep responses to systemic treatment. In pathologic terms, features associated with long-term response are high ERBB2 expression, lack of detrimental genomic aberrations, and antitumor immune activation. This population of patients may potentially derive benefit from a tailored escalation of frontline treatment with novel anti-ERBB2 drugs, such as trastuzumab deruxtecan, tucatinib, or margetuximab. Additional recent therapeutic and diagnostic advancements could further aid in the path toward a cure for ERBB2-positive MBC.
CONCLUSIONS AND RELEVANCE: Careful implementation of novel diagnostic and treatment tools could potentially expand the population of patients with ERBB2-positive MBC experiencing long-lasting disease response. Trials are in preparation to confirm this paradigm, and hopefully lead to a new era of precision therapy for breast cancer.
A DAB DUR HLA PA
Axicabtagene Ciloleucel in Relapsed or Refractory Indolent Non-Hodgkin Lymphoma (ZUMA-5): A Single-Arm, Multicentre, Phase 2 Trial
BACKGROUND: Most patients with advanced-stage indolent non-Hodgkin lymphoma have multiple relapses. We assessed axicabtagene ciloleucel autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory indolent non-Hodgkin lymphoma.
METHODS: ZUMA-5 is a single-arm, multicentre, phase 2 trial being conducted at 15 medical cancer centres in the USA and two medical cancer centres in France. Patients were eligible if they were aged 18 years or older, with histologically confirmed indolent non-Hodgkin lymphoma (follicular lymphoma or marginal zone lymphoma), had relapsed or refractory disease, previously had two or more lines of therapy (including an anti-CD20 monoclonal antibody with an alkylating agent), and an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients underwent leukapheresis and received conditioning chemotherapy (cyclophosphamide at 500 mg/m2 per day and fludarabine at 30 mg/m2 per day on days -5, -4, and -3) followed by a single infusion of axicabtagene ciloleucel (2‚106 CAR T cells per kg) on day 0. The primary endpoint was overall response rate (complete response and partial response) assessed by an independent review committee per Lugano classification. The primary activity analysis was done after at least 80 treated patients with follicular lymphoma had been followed up for at least 12 months after the first response assessment at week 4 after infusion. The primary analyses were done in the per-protocol population (ie, eligible patients with follicular lymphoma who had 12 months of follow-up after the first response assessment and eligible patients with marginal zone lymphoma who had at least 4 weeks of follow-up after infusion of axicabtagene ciloleucel). Safety analyses were done in patients who received an infusion of axicabtagene ciloleucel. This study is registered with ClinicalTrials.gov, NCT03105336, and is closed to accrual.
FINDINGS: Between June 20, 2017, and July 16, 2020, 153 patients were enrolled and underwent leukapheresis, and axicabtagene ciloleucel was successfully manufactured for all enrolled patients. As of data cutoff (Sept 14, 2020), 148 patients had received an infusion of axicabtagene ciloleucel (124 [84%] who had follicular lymphoma and 24 [16%] who had marginal zone lymphoma). The median follow-up for the primary analysis was 17¬?5 months (IQR 14¬?1-22¬?6). Among patients who were eligible for the primary analysis (n=104, of whom 84 had follicular lymphoma and 20 had marginal zone lymphoma), 96 (92%; 95% CI 85-97) had an overall response and 77 (74%) had a complete response. The most common grade 3 or worse adverse events were cytopenias (104 [70%] of 148 patients) and infections (26 [18%]). Grade 3 or worse cytokine release syndrome occurred in ten (7%) patients and grade 3 or 4 neurological events occurred in 28 (19%) patients. Serious adverse events (any grade) occurred in 74 (50%) patients. Deaths due to adverse events occurred in four (3%) patients, one of which was deemed to be treatment-related (multisystem organ failure).
INTERPRETATION: Axicabtagene ciloleucel showed high rates of durable responses and had a manageable safety profile in patients with relapsed or refractory indolent non-Hodgkin lymphoma.
FUNDING: Kite, a Gilead Company.
Dabrafenib Plus Trametinib in Patients with BRAF V600E-Mutant Low-Grade and High-Grade Glioma (ROAR): A Multicentre, Open-Label, Single-Arm, Phase 2, Basket Trial
BACKGROUND: Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma.
METHODS: This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity, disease progression, or death. In the high-grade glioma cohort, patients were required to have measurable disease at baseline using the Response Assessment in Neuro-Oncology high-grade glioma response criteria and have been treated previously with radiotherapy and first-line chemotherapy or concurrent chemoradiotherapy. Patients with low-grade glioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma) at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade glioma and complete response plus partial response plus minor response for low-grade glioma). This trial is ongoing, but is closed for enrolment, NCT02034110.
FINDINGS: Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12¬?7 months (IQR 5¬?4-32¬?3) and 15 (33%; 95% CI 20-49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32¬?2 months (IQR 25¬?1-47¬?8). Nine (69%; 95% CI 39-91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]).
INTERPRETATION: Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAFV600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma.
Durvalumab Plus Tremelimumab Alone or in Combination with Low-Dose or Hypofractionated Radiotherapy in Metastatic Non-Small-Cell Lung Cancer Refractory to Previous PD(L)-1 Therapy: An Open-Label, Multicentre, Randomised, Phase 2 Trial
Schoenfeld JD, Giobbie-Hurder A, Ranasinghe S, Kao KZ, Lako A, Tsuji J, Liu Y, Brennick RC, Lyon H, Cibuskis C, Lennon N, Jhaveri A, Yang L, Altreuter J, Gunasti L, Weirather JL, Mak RH, Awad MM, Rodig SJ, Wu CJ, Hodi FS
BACKGROUND: Patients with non-small-cell lung cancer (NSCLC) that is resistant to PD-1 and PD-L1 (PD[L]-1)-targeted therapy have poor outcomes. Studies suggest that radiotherapy could enhance antitumour immunity. Therefore, we investigated the potential benefit of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) inhibition alone or combined with radiotherapy.
METHODS: This open-label, multicentre, randomised, phase 2 trial was done by the National Cancer Institute Experimental Therapeutics Clinical Trials Network at 18 US sites. Patients aged 18 years or older with metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression during previous PD(L)-1 therapy were eligible. They were randomly assigned (1:1:1) in a web-based system by the study statistician using a permuted block scheme (block sizes of three or six) without stratification to receive either durvalumab (1500 mg intravenously every 4 weeks for a maximum of 13 cycles) plus tremelimumab (75 mg intravenously every 4 weeks for a maximum of four cycles) alone or with low-dose (0¬?5 Gy delivered twice per day, repeated for 2 days during each of the first four cycles of therapy) or hypofractionated radiotherapy (24 Gy total delivered over three 8-Gy fractions during the first cycle only), 1 week after initial durvalumab-tremelimumab administration. Study treatment was continued until 1 year or until progression. The primary endpoint was overall response rate (best locally assessed confirmed response of a partial or complete response) and, along with safety, was analysed in patients who received at least one dose of study therapy. The trial is registered with ClinicalTrials.gov, NCT02888743, and is now complete.
FINDINGS: Between Aug 24, 2017, and March 29, 2019, 90 patients were enrolled and randomly assigned, of whom 78 (26 per group) were treated. This trial was stopped due to futility assessed in an interim analysis. At a median follow-up of 12¬?4 months (IQR 7¬?8-15¬?1), there were no differences in overall response rates between the durvalumab-tremelimumab alone group (three [11¬?5%, 90% CI 1¬?2-21¬?8] of 26 patients) and the low-dose radiotherapy group (two [7¬?7%, 0¬?0-16¬?3] of 26 patients; p=0¬?64) or the hypofractionated radiotherapy group (three [11¬?5%, 1¬?2-21¬?8] of 26 patients; p=0¬?99). The most common grade 3-4 adverse events were dyspnoea (two [8%] in the durvalumab-tremelimumab alone group; three [12%] in the low-dose radiotherapy group; and three [12%] in the hypofractionated radiotherapy group) and hyponatraemia (one [4%] in the durvalumab-tremelimumab alone group vs two [8%] in the low-dose radiotherapy group vs three [12%] in the hypofractionated radiotherapy group). Treatment-related serious adverse events occurred in one (4%) patient in the durvalumab-tremelimumab alone group (maculopapular rash), five (19%) patients in the low-dose radiotherapy group (abdominal pain, diarrhoea, dyspnoea, hypokalemia, and respiratory failure), and four (15%) patients in the hypofractionated group (adrenal insufficiency, colitis, diarrhoea, and hyponatremia). In the low-dose radiotherapy group, there was one death from respiratory failure potentially related to study therapy.
INTERPRETATION: Radiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD(L)-1 therapy. However, PD-L1 plus CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting.
FUNDING: The US National Institutes of Health and the Dana-Farber Cancer Institute.
HLA-A*03 and Response to Immune Checkpoint Blockade in Cancer: An Epidemiological Biomarker Study
Naranbhai V, Groha S, Braun DA, Labaki C, Shukla SA, Gusev A, Choueiri TK
BACKGROUND: Predictive biomarkers could allow more precise use of immune checkpoint inhibitors (ICIs) in treating advanced cancers. Given the central role of HLA molecules in immunity, variation at the HLA loci could differentially affect the response to ICIs. The aim of this epidemiological study was to determine the effect of HLA-A*03 as a biomarker for predicting response to immunotherapy.
METHODS: In this epidemiological study, we investigated the clinical outcomes (overall survival, progression free survival, and objective response rate) after treatment for advanced cancer in eight cohorts of patients: three observational cohorts of patients with various types of advanced tumours (the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] cohort, the Dana-Farber Cancer Institute [DFCI] Profile cohort, and The Cancer Genome Atlas) and five clinical trials of patients with advanced bladder cancer (JAVELIN Solid Tumour) or renal cell carcinoma (CheckMate-009, CheckMate-010, CheckMate-025, and JAVELIN Renal 101). In total, these cohorts included 3335 patients treated with various ICI agents (anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitors) and 10‚Äâ917 patients treated with non-ICI cancer-directed therapeutic approaches. We initially modelled the association of HLA amino-acid variation with overall survival in the MSK-IMPACT discovery cohort, followed by a detailed analysis of the association between HLA-A*03 and clinical outcomes in MSK-IMPACT, with replication in the additional cohorts (two further observational cohorts and five clinical trials).
FINDINGS: HLA-A*03 was associated in an additive manner with reduced overall survival after ICI treatment in the MSK-IMPACT cohort (HR 1¬?48 per HLA-A*03 allele [95% CI 1¬?20-1¬?82], p=0¬?00022), the validation DFCI Profile cohort (HR 1¬?22 per HLA-A*03 allele, 1¬?05-1¬?42; p=0¬?0097), and in the JAVELIN Solid Tumour clinical trial for bladder cancer (HR 1¬?36 per HLA-A*03 allele, 1¬?01-1¬?85; p=0¬?047). The HLA-A*03 effect was observed across ICI agents and tumour types, but not in patients treated with alternative therapies. Patients with HLA-A*03 had shorter progression-free survival in the pooled patient population from the three CheckMate clinical trials of nivolumab for renal cell carcinoma (HR 1¬?31, 1¬?01-1¬?71; p=0¬?044), but not in those receiving control (everolimus) therapies. Objective responses were observed in none of eight HLA-A*03 homozygotes in the ICI group (compared with 59 [26¬?6%] of 222 HLA-A*03 non-carriers and 13 (17¬?1%) of 76 HLA-A*03 heterozygotes). HLA-A*03 was associated with shorter progression-free survival in patients receiving ICI in the JAVELIN Renal 101 randomised clinical trial for renal cell carcinoma (avelumab plus axitinib; HR 1¬?59 per HLA-A*03 allele, 1¬?16-2¬?16; p=0¬?0036), but not in those receiving control (sunitinib) therapy. Objective responses were recorded in one (12¬?5%) of eight HLA-A*03 homozygotes in the ICI group (compared with 162 [63¬?8%] of 254 HLA-A*03 non-carriers and 40 [55¬?6%] of 72 HLA-A*03 heterozygotes). HLA-A*03 was associated with impaired outcome in meta-analysis of all 3335 patients treated with ICI at genome-wide significance (p=2¬?01‚10-8) with no evidence of heterogeneity in effect (I2 0%, 95% CI 0-0¬?76)
INTERPRETATION: HLA-A*03 is a predictive biomarker of poor response to ICI. Further evaluation of HLA-A*03 is warranted in randomised trials. HLA-A*03 carriage could be considered in decisions to initiate ICI in patients with cancer.
FUNDING: National Institutes of Health, Merck KGaA, and Pfizer.
Patient-Reported Outcomes with First-Line Nivolumab Plus Cabozantinib Versus Sunitinib in Patients with Advanced Renal Cell Carcinoma Treated in CheckMate 9ER: An Open-Label, Randomised, Phase 3 Trial
BACKGROUND: In the CheckMate 9ER trial, patients with advanced renal cell carcinoma who received first-line nivolumab plus cabozantinib had significantly better progression-free survival compared with those given sunitinib. In this study, we aimed to describe the patient-reported outcome (PRO) results from CheckMate 9ER.
METHODS: In this open-label, randomised, phase 3 trial done in 125 cancer centres, urology centres, and hospitals across 18 countries, patients aged 18 years or older with previously untreated advanced renal cell carcinoma with a clear-cell component, a Karnofsky performance status of 70% or more, and available tumour tissue were randomly assigned (1:1) via interactive response technology to nivolumab 240 mg intravenously every 2 weeks plus oral cabozantinib 40 mg per day, or oral sunitinib 50 mg per day monotherapy for 4 weeks in 6-week cycles. The primary endpoint of progression-free survival was reported previously. PROs were analysed as prespecified exploratory endpoints at common timepoints (at baseline and every 6 weeks) until week 115. Disease-related symptoms were evaluated using the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and global health status was assessed with the three-level EQ-5D (EQ-5D-3L) visual analogue scale (VAS) and UK utility index. PRO analyses were done in the intention-to-treat population. Change from baseline was assessed using mixed-model repeated measures. A time-to-deterioration analysis was done for first and confirmed deterioration events. This study is registered with ClinicalTrials.gov, NCT03141177, and is closed to recruitment .
FINDINGS:Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to nivolumab plus cabozantinib and 328 to sunitinib. Median follow-up was 23¬?5 months (IQR 21¬?0-26¬?5). At baseline, patients in both groups reported low symptom burden (FKSI-19 disease-related symptoms version 1 mean scores at baseline were 30¬?24 [SD 5¬?19] for the nivolumab plus cabozantinib group and 30¬?06 [5¬?03] for the sunitinib group). Change from baseline in PRO scores indicated that nivolumab plus cabozantinib was associated with more favourable outcomes versus sunitinib (treatment difference 2¬?38 [95% CI 1¬?20-3¬?56], nominal p<0¬?0001, effect size 0¬?33 [95% CI 0¬?17-0¬?50] for FKSI-19 total score; 1¬?33 [0¬?84-1¬?83], nominal p<0¬?0001, 0¬?45 [0¬?28-0¬?61] for FKSI-19 disease-related symptoms version 1; 3¬?48 [1¬?58-5¬?39], nominal p=0¬?0004, 0¬?30 [0¬?14-0¬?47] for EQ-5D-3L VAS; and 0¬?04 [0¬?01-0¬?07], nominal p=0¬?0036, 0¬?25 [0¬?08-0¬?41] for EQ-5D-3L UK utility index), reaching significance at most timepoints. Nivolumab plus cabozantinib was associated with decreased risk of clinically meaningful deterioration for FKSI-19 total score compared with sunitinib (first deterioration event hazard ratio 0¬?70 [95% CI 0¬?56-0¬?86], nominal p=0¬?0007; confirmed deterioration event 0¬?63 [0¬?50-0¬?80], nominal p=0¬?0001).
INTERPRETATION: PROs were maintained or improved with nivolumab plus cabozantinib versus sunitinib. Compared with sunitinib, nivolumab plus cabozantinib significantly delayed time to deterioration of patient-reported outcome scores. These results suggest a benefit for nivolumab plus cabozantinib compared with sunitinib in the treatment of patients with advanced renal cell carcinoma.
FUNDING: Bristol Myers Squibb.
Author Correction: A Neuroanatomical Basis for Electroacupuncture to Drive the Vagal-Adrenal Axis
Liu S, Wang Z, Su Y, Qi L, Yang W, Fu M, Ma Q
Somatosensory autonomic reflexes allow electroacupuncture stimulation (ES) to modulate body physiology at distant sites1-6 (for example, suppressing severe systemic inflammation6-9). Since the 1970s, an emerging organizational rule about these reflexes has been the presence of body-region specificity1-6. For example, ES at the hindlimb ST36 acupoint but not the abdominal ST25 acupoint can drive the vagal-adrenal anti-inflammatory axis in mice10,11. The neuroanatomical basis of this somatotopic organization is, however, unknown. Here we show that PROKR2Cre-marked sensory neurons, which innervate the deep hindlimb fascia (for example, the periosteum) but not abdominal fascia (for example, the peritoneum), are crucial for driving the vagal-adrenal axis. Low-intensity ES at the ST36 site in mice with ablated PROKR2Cre-marked sensory neurons failed to activate hindbrain vagal efferent neurons or to drive catecholamine release from adrenal glands. As a result, ES no longer suppressed systemic inflammation induced by bacterial endotoxins. By contrast, spinal sympathetic reflexes evoked by high-intensity ES at both ST25 and ST36 sites were unaffected. We also show that optogenetic stimulation of PROKR2Cre-marked nerve terminals through the ST36 site is sufficient to drive the vagal-adrenal axis but not sympathetic reflexes. Furthermore, the distribution patterns of PROKR2Cre nerve fibres can retrospectively predict body regions at which low-intensity ES will or will not effectively produce anti-inflammatory effects. Our studies provide a neuroanatomical basis for the selectivity and specificity of acupoints in driving specific autonomic pathways.
Identification of RIOK2 as a Master Regulator of Human Blood Cell Development
Ghosh S, Raundhal M, Myers SA, Carr SA, Petsko GA, Glimcher LH
Anemia is a major comorbidity in aging, chronic kidney and inflammatory diseases, and hematologic malignancies. However, the transcriptomic networks governing hematopoietic differentiation in blood cell development remain incompletely defined. Here we report that the atypical kinase RIOK2 (right open reading frame kinase 2) is a master transcription factor (TF) that not only drives erythroid differentiation, but also simultaneously suppresses megakaryopoiesis and myelopoiesis in primary human stem and progenitor cells. Our study reveals the previously uncharacterized winged helix-turn-helix DNA-binding domain and two transactivation domains of RIOK2 that are critical to regulate key hematopoietic TFs GATA1, GATA2, SPI1, RUNX3 and KLF1. This establishes RIOK2 as an integral component of the transcriptional regulatory network governing human hematopoietic differentiation. Importantly, RIOK2 mRNA expression significantly correlates with these TFs and other hematopoietic genes in myelodysplastic syndromes, acute myeloid leukemia and chronic kidney disease. Further investigation of RIOK2-mediated transcriptional pathways should yield therapeutic approaches to correct defective hematopoiesis in hematologic disorders.
A Functional Subdivision within the Somatosensory System and its Implications for Pain Research
Somatosensory afferents are traditionally classified by soma size, myelination, and their response specificity to external and internal stimuli. Here, we propose the functional subdivision of the nociceptive somatosensory system into two branches. The exteroceptive branch detects external threats and drives reflexive-defensive reactions to prevent or limit injury. The interoceptive branch senses the disruption of body integrity, produces tonic pain with strong aversive emotional components, and drives self-caring responses toward to the injured region to reduce suffering. The central thesis behind this functional subdivision comes from a reflection on the dilemma faced by the pain research field, namely, the use of reflexive-defensive behaviors as surrogate assays for interoceptive tonic pain. The interpretation of these assays is now being challenged by the discovery of distinct but interwoven circuits that drive exteroceptive versus interoceptive types of behaviors, with the conflation of these two components contributing partially to the poor translation of therapies from preclinical studies.
Bacterial Gasdermins Reveal an Ancient Mechanism of Cell Death
Johnson AG, Mayer ML, Duncan-Lowey B, Kranzusch PJ
Gasdermin proteins form large membrane pores in human cells that release immune cytokines and induce lytic cell death. Gasdermin pore formation is triggered by caspase-mediated cleavage during inflammasome signaling and is critical for defense against pathogens and cancer. We discovered gasdermin homologs encoded in bacteria that defended against phages and executed cell death. Structures of bacterial gasdermins revealed a conserved pore-forming domain that was stabilized in the inactive state with a buried lipid modification. Bacterial gasdermins were activated by dedicated caspase-like proteases that catalyzed site-specific cleavage and the removal of an inhibitory C-terminal peptide. Release of autoinhibition induced the assembly of large and heterogeneous pores that disrupted membrane integrity. Thus, pyroptosis is an ancient form of regulated cell death shared between bacteria and animals.
CDK4 and CDK6 kinases: From Basic Science to Cancer Therapy
Fassl A, Geng Y, Sicinski P
Cyclin-dependent kinases (CDKs), in complex with their cyclin partners, modulate the transition through phases of the cell division cycle. Cyclin D–CDK complexes are important in cancer progression, especially for certain types of breast cancer. Fassl et al. discuss advances in understanding the biology of cyclin D–CDK complexes that have led to new concepts about how drugs that target these complexes induce cancer cell cytostasis and suggest possible combinations to widen the types of cancer that can be treated. They also discuss progress in overcoming resistance to cyclin D–CDK inhibitors and their possible application to diseases beyond cancer.
CAR Keys to Unlock the Intracellular Immunopeptidome
Chimeric antigen receptor T cells (CAR-T) have emerged as effective and flexible cell-based therapies for cancer. However, design of CAR-T cells typically requires the identification of immunoglobulin variable chain sequences that (i) recognize a target protein uniquely expressed on the cancer cell-surface and (ii) are amenable to engineering as a single-chain variable fragment (scFv) capable of triggering CAR-T activation. The identification of suitable cell-surface proteins that enable selective targeting of tumor cells has represented a major challenge in the development of CAR-T therapies, especially in the space of solid tumors.
AJR American Journal of Roentgenology
Imaging of Oncologic Treatment-Related Pneumonitis: A Focused Review on Emerging Issues of Immune Checkpoint Inhibitor Pneumonitis, From the AJR Special Series on Inflammation
American Journal of Gastroenterology
Long-Term Statin Use, Total Cholesterol Level, and Risk of Colorectal Cancer: A Prospective Cohort Study
Zhang Y, Wu K, Chan AT, Meyerhardt JA, Giovannucci EL
American Journal of Kidney Diseases
Combined Nephrology and Palliative Medicine Fellowship Training: A Breath of Fresh AIRE
Annals of Surgical Oncology
Racial and Socioeconomic Disparities in Breast Cancer Outcomes within the AJCC Pathologic Prognostic Staging System
Kantor O, Wang ML, Freedman RA, King TA, Mittendorf EA
Defibrotide: Real-World Management of Veno-Occlusive Disease/Sinusoidal Obstructive Syndrome After Stem Cell Transplant
Kim HT, Richardson PG, Soiffer RJ, Antin JH, Cutler C, Nikiforow S, Gooptu M, Koreth J, Romee R, Ho VT
Orthopedic Toxicities Among Adolescents and Young Adults Treated in DFCI ALL Consortium Trials
Valtis YK, Stevenson KE, Place AE, Silverman LB, Vrooman LM, Gotti G, Brunner AM, DeAngelo DJ, Luskin MR
Effect of Dose Reductions on Clinical Outcomes, or of Outcomes on Dose Reductions?
Trajectories of Fear of Cancer Recurrence in Young Breast Cancer Survivors
Zheng Y, Gelber SI, Poorvu P, Peppercorn J, Come SE, Partridge AH, Rosenberg SM
Precision Medicine in Aggressive Thyroid Cancer: Moving Beyond Multitargeted Tyrosine Kinase Inhibitors
Mahmood U, Lorch JH
EGFR Inhibition Enhances the Cellular Uptake and Antitumor-Activity of the HER3 Antibody-Drug Conjugate HER3-DXd
Haikala HM, Lopez T, Köhler J, Eser PO, Xu M, Zeng Q, Teceno TJ, Ngo K, Zhao Y, Ivanova EV, Bertram AA, Leeper BA, Chambers ES, Adeni AE, Taus LJ, Kuraguchi M, Kirschmeier PT, Paweletz CP, Gokhale PC, Jänne PA
Cysteine 253 of UCP1 Regulates Energy Expenditure and Sex-Dependent Adipose Tissue Inflammation
Mills EL, Harmon C, Jedrychowski MP, Xiao H, Bradshaw GA, Tran N, Garrity R, Laznik-Bogoslavski D, Szpyt J, Lynch L, Gygi SP, Spiegelman BM, Chouchani ET
Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma
Bakouny Z, Sadagopan A, Ravi P, Metaferia NY, Li J, AbuHammad S, Tang S, Denize T, Garner ER, Gao X, Braun DA, Hirsch L, Steinharter JA, Bouchard G, Walton E, West D, Labaki C, Sethunath V, Carvalho FLF, Imamovic A, Ricker C, Nyman J, Berchuck JE, Park J, Hirsch MS, Haq R, Mary Lee GS, McGregor BA, Chang SL, Feldman AS, Wu CJ, McDermott DF, Heng DYC, Signoretti S, Van Allen EM, Choueiri TK, Viswanathan SR
Clinical Cancer Research
Real-World Evidence in Support of Oncology Product Registration: A Systematic Review of New Drug Application and Biologics License Application Approvals from 2015-2020
European Journal of Haematology
Pomalidomide, Bortezomib, and Dexamethasone at First Relapse in Lenalidomide-Pretreated Myeloma: A Subanalysis of OPTIMISMM by Clinical Characteristics
Leveraging Real World Genomic Data to Advance Prostate Cancer Precision Oncology
Beltran H, Morgans AK
Gastrointestinal Endoscopy Clinics of North America
Lynch Syndrome-Associated Cancers Beyond Colorectal Cancer
Biller LH, Creedon SA, Klehm M, Yurgelun MB
Genes and Development
Transcription Factor-Mediated Intestinal Metaplasia and the Role of a Shadow Enhancer
Singh H, Seruggia D, Madha S, Saxena M, Nagaraja AK, Wu Z, Zhou J, Huebner AJ, Maglieri A, Hochedlinger K, Orkin SH, Bass AJ, Hornick JL, Shivdasani RA
Health and Quality of Life Outcomes
More Often Than Not, We're in Sync: Patient and Caregiver Well-Being Over Time in Stem Cell Transplantation
Sannes TS, Yusufov M, Jacobs JM
Immunology and Cell Biology
More Often Than Not, We're in Sync: Patient and Caregiver Well-Being Over Time in Stem Cell Transplantation
Yang C, Lin J, Xue L, Kwart A, Jiang M, Munshi NC
International Journal of Radiation Oncology, Biology, Physics
Local Therapy Outcomes and Toxicity from the (Anonymized for Review) Trial: A Phase II Randomized Trial of Adjuvant Trastuzumab Emtansine vs. Paclitaxel in Combination with Trastuzumab in Women with Stage I HER2-Positive Breast Cancer
Bellon JR, Tayob N, Yang DD, Isakoff SJ, DeMeo M, Burstein HJ, Partridge AH, Winer EP, Krop IE, Tolaney SM
International Journal of Radiation Oncology, Biology, Physics
Radiation Dose to the Intraprostatic Urethra Correlates Strongly with Urinary Toxicity After Prostate Stereotactic Body Radiation Therapy: A Combined Analysis of 23 Prospective Clinical Trials
Leeman JE, Chen YH, Catalano P, Bredfeldt J, King M, Mouw KW, D'Amico AV, Orio P, Nguyen PL, Martin N
Journal of General Internal Medicine
ACO Spending and Utilization Among Medicare Patients at the End of Life: An Observational Study
Lam MB, Friend TH, Erfani P, Orav EJ, Figueroa JF
Journal of Genetic Counseling
Risk assessment and genetic counseling for Lynch syndrome - Practice Resource of the National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer
Journal of Medical Chemistry
Development of PDE6D and CK1 Degraders through Chemical Derivatization of FPFT-2216
Teng M, Donovan KA, Sun J, Krupnick NM, Nowak RP, Li YD, Sperling AS, Ebert BL, Fischer ES, Gray NS
Journal of Medical Internet Research
Designing Effective eHealth Interventions for Underserved Groups: Five Lessons from a Decade of eHealth Intervention Design and Deployment
McCloud RF, Viswanath K
Journal of the National Comprehensive Cancer Network
Letter to the Editor: Lapatinib Confounds Post-Hoc Weight Loss Analysis in the ALTTO Trial
Journal of Nuclear Medicine
Imaging Androgen Receptors in Breast Cancer with (18)F-Fluoro-5-Dihydrotestosterone PET: A Pilot Study
Jacene H, Liu M, Cheng SC, Abbott A, Dubey S, McCall K, Van den Abbeele AD, Overmoyer B
Journal of Pain and Symptom Management
International Standards for Pediatric Palliative Care: From IMPaCCT to GO-PPaCS
Journal of Pain and Symptom Management
Natural Language Processing to Identify Advance Care Planning Documentation in a Multisite Pragmatic Clinical Trial
Lindvall C, Deng CY, Moseley E, Agaronnik N, El-Jawahri A, Lakin JR, Volandes A, Tulsky TAIJA
Journal of Pain and Symptom Management
Normalization of symptoms in advanced child cancer: the PediQUEST-Response Case Study
Avery M, Feraco AM, Wolfe J, Dussel V
Journal of Pain and Symptom Management
Parent and Adolescent Perspectives on the Impact of COVID on the Care of Seriously Ill Children
Beight LJ, Helton G, Avery M, Dussel V, Wolfe J
Journal of Palliative Medicine
Missing Voices: Lessons Learned from Nonparticipating Caregivers in Palliative Care Research
Umaretiya PJ, Ilowite M, Fisher L, Mack JW, Bona K
Journal of Thoracic Oncology
Axillary Lymphadenopathy After Coronavirus Disease 2019 Vaccinations in Patients with Thoracic Malignancy: Incidence, Predisposing Factors, and Imaging Characteristics
Nishino M, Hatabu H, Ricciuti B, Vaz V, Michael K, Awad MM
JCO Clinical Cancer Informatics
eSyM: An Electronic Health Record-Integrated Patient-Reported Outcomes-Based Cancer Symptom Management Program Used by Six Diverse Health Systems
Hassett MJ, Cronin C, McCleary N
JCO Oncology Practice
Prostate Cancer Disparities in Risk Group at Presentation and Access to Treatment for Asian Americans, Native Hawaiians, and Pacific Islanders: A Study with Disaggregated Ethnic Groups
Jain B, Muralidhar V, Trinh QD, Nguyen PL, Dee EC
JCO Oncology Practice
Sharing Decisions About Systemic Therapy for Advanced Cancers
Tarbi EC, Pirl WF
Cell-Free DNA for the Detection of Emerging Treatment Failure in Relapsed/Refractory Multiple Myeloma
Waldschmidt JM, Yee AJ, Vijaykumar T, Pinto RA, Frede J, Anand P, Bianchi G, Guo G, Potdar S, Seifer C, Nair MS, Kokkalis A, Kloeber JA, Shapiro S, Budano L, Mann M, O'Donnell EK, Zhang CZ, Laubach JP, Munshi NC, Richardson PG, Anderson KC, Raje NS, Knoechel B, Lohr JG
Small Molecule Inhibition of Deubiquitinating Enzyme JOSD1 as a Novel Targeted Therapy for Leukemias with Mutant JAK2
Yang J, Weisberg EL, Liu X, Magin RS, Chan WC, Hu B, Schauer NJ, Zhang S, Lamberto I, Doherty L, Meng C, Sattler M, Cabal-Hierro L, Winer E, Stone R, Marto JA, Griffin JD, Buhrlage SJ
Targeting LAG3/GAL-3 to Overcome Immunosuppression and Enhance Anti-Tumor Immune Responses in Multiple Myeloma
Bae J, Accardi F, Hideshima T, Tai YT, Prabhala R, Shambley A, Wen K, Rowell S, Richardson PG, Munshi NC, Anderson KC
Mayo Clinic Proceedings
Coffee Intake of Colorectal Cancer Patients and Prognosis According to Histopathologic Lymphocytic Reaction and T-Cell Infiltrates
Ugai T, Haruki K, Vayrynen JP, Fujiyoshi K, Lau MC, Akimoto N, Zhong R, Kishikawa J, Arima K, Shi SS, Zhao M, Zhang X, Giannakis M, Song M, Meyerhardt JA, Wang M, Nowak JA, Ogino S
Design and Synthesis of Gold Nanostars-Based SERS Nanotags for Bioimaging Applications
Andreiuk B, Nicolson F, Clark LM, Panikkanvalappil SR, Kenry, Rashidian M, Kircher MF
Nature Reviews Clinical Oncology
Single-Cell Profiling of Tumour Evolution in Multiple Myeloma - Opportunities for Precision Medicine
Dutta AK, Alberge JB, Sklavenitis-Pistofidis R, Lightbody ED, Getz G, Ghobrial IM
Activity of PD-1 Blockade with Nivolumab Among Patients with Recurrent Atypical/Anaplastic Meningioma: Phase II Trial Results
Bi WL, Nayak L, Meredith DM, Driver J, Hoffman S, Li Y, Lee EQ, Beroukhim R, Rinne M, McFaline-Figueroa R, Chukwueke U, McCluskey C, Gaffey S, Cherniack AD, Stefanik J, Doherty L, Taubert C, Cifrino M, LaFrankie D, Wen PY, Ligon KL, Al-Mefty O, Huang RY, Muzikansky A, Chiocca EA, Santagata S, Reardon DA
Liquid Biopsy Detection of Genomic Alterations in Pediatric Brain Tumors from Cell-Free DNA in Peripheral Blood, CSF, and Urine
Pages M, Rotem D, Gydush G, Reed S, Rhoades J, Ha G, Lo C, Fleharty M, Duran M, Jones R, Becker S, Haller M, Sinai CE, Goumnerova L, Golub TR, Ligon KL, Wright K, Adalsteinsson VA, Beroukhim R, Bandopadhayay P
Liquid Biopsy in Gliomas: A RANO Review and Proposals for Clinical Applications
Warren KE, Wen PY
Multimodal Platform for Assessing Drug Distribution and Response in Clinical Trials
Lopez BGC, Du Z, Korsunsky I, Abdelmoula WM, Dai Y, Stopka SA, Gaglia G, Randall EC, Regan MS, Basu SS, Clark AR, Supko JG, Raychaudhuri S, Ligon KL, Wen PY, Alexander B, Lee EQ, Santagata S, Agar NYR
Predictors of Long-Term Survival Among Patients with Brain Metastases
Lamba N, Catalano PJ, Bi WL, Wen PY, Haas-Kogan DA, Cagney DN, Aizer AA
Nucleic Acids Research
TISMO: Syngeneic Mouse Tumor Database to Model Tumor Immunity and Immunotherapy Response
Zeng Z, Wong CJ, Yang L, Ouardaoui N, Li D, Zhang W, Gu S, Zhang Y, Liu Y, Wang X, Fu J, Zhou L, Zhang B, Kim S, Yates KB, Brown M, Freeman GJ, Uppaluri R, Manguso R, Liu XS
Practical Radiation Oncology
A Tribute to Dr Larissa Lee
Importance of 68Ga-FAPI PET/CT for Detection of Cancer
Jacobson FL, Van den Abbeele AD
Deletion of Murine Rhoh Leads to De-Repression of Bcl-6 via Decreased KAISO Levels and Accelerates a Malignancy Phenotype in a Murine Model of Lymphoma
Horiguchi H, Xu H, Duvert B, Ciuculescu F, Yao Q, McGuinness M, Harris C, Brendel C, Chiarle R, Williams DA
Prevalence of Pathogenic Germline Cancer Risk Variants in Testicular Cancer Patients: Identifying High Risk Groups
Nassar AH, Abou Alaiwi S, Adib E, Akl EW, Sonpavde GP
The Risk of Death from Prostate Cancer in Men with Gleason Score 3+4 Prostate Cancer Treated Using Brachytherapy with or Without a Short Course of Androgen Deprivation Therapy
Yang DD, D'Amico AV