To assess whether prediagnostic metabolites were associated with incident pancreatic ductal adenocarcinoma (PDAC) in a prospective cohort study.
We conducted an untargeted analysis of 554 known ...metabolites measured in prediagnostic serum (up to 24 years) to determine their association with incident PDAC in a nested case-control study of male smokers (372 matched case-control sets) and an independent nested case-control study that included women and non-smokers (107 matched sets). Metabolites were measured using Orbitrap Elite or Q-Exactive high-resolution/accurate mass spectrometers. Controls were matched to cases by age, sex, race, date of blood draw, and follow-up time. We used conditional logistic regression adjusted for age to calculate ORs and 95% CIs for a 1 SD increase in log-metabolite level separately in each cohort and combined the two ORs using a fixed-effects meta-analysis.
Thirty-one metabolites were significantly associated with PDAC at a false discovery rate <0.05 with 12 metabolites below the Bonferroni-corrected threshold (p<9.04×10
). Similar associations were observed in both cohorts. The dipeptides glycylvaline, aspartylphenylalanine, pyroglutamylglycine, phenylalanylphenylalanine, phenylalanylleucine and tryptophylglutamate and amino acids aspartate and glutamate were positively while the dipeptides tyrosylglutamine and α-glutamyltyrosine, fibrinogen cleavage peptide DSGEGDFXAEGGGVR and glutathione-related amino acid cysteine-glutathione disulfide were inversely associated with PDAC after Bonferroni correction. Five top metabolites demonstrated significant time-varying associations (p<0.023) with the strongest associations observed 10-15 years after participants' blood collection and attenuated thereafter.
Our results suggest that prediagnostic metabolites related to subclinical disease, γ-glutamyl cycle metabolism and adiposity/insulin resistance are associated with PDAC.
BACKGROUND There are limited data of outcomes in patients who require anticoagulation interruption for a surgical procedure shortly after an acute VTE, especially in patients with cancer who are at ...higher risk for both hemorrhage and recurrent thrombosis. Our goal was to assess the incidence of recurrent thrombosis or major hemorrhage at 60-days following an urgent surgical procedure in patients with acute VTE (within one month prior to surgery). METHODS We performed a retrospective cohort study of patients with cancer at Memorial Sloan Kettering Cancer Center (from January 1 st 2021 to December 31 st 2022). Patients were eligible for inclusion if they were diagnosed with a new acute deep vein thrombosis or pulmonary embolism and underwent surgical procedure within 30-days following the acute VTE diagnosis. Recurrent VTE was defined as symptomatic new deep-vein thrombosis or pulmonary embolism, incidental new deep-vein thrombosis or pulmonary embolism involving segmental or more proximal pulmonary arteries, or fatal pulmonary embolism or unexplained death for which pulmonary embolism could not be ruled out as the cause. Major hemorrhage was characterized according to ISTH definition. Competing risk framework was used to estimate cumulative incidences of major hemorrhage, VTE and death at 30 and 60-days. RESULTS A total of 90 patients were included in this analysis. The median age was 73 years and 62% were female (Table 1). Surgical procedures were classified by their risk of bleeding with 64 patients undergoing lower bleeding risk procedures and 26 high-risk procedures (Table 1). There were 10 recurrent or new VTE within 60-days of surgery (60-day cumulative incidence of 8.9%, 95% CI 4.1-16%). The recurrent sites were deep venous (N=7) and new PE (N=3). There were 12 major hemorrhagic events within 60 days (cumulative incidence of 12%, 95% CI 6.5-20%). The most common sites of hemorrhage were the lower gastrointestinal tract and genitourinary system. The competing risk framework is shown graphically in Figure 1. Among patients who received IVC filters the incidence of recurrent VTE was 1.1% and major hemorrhage was 2.2%. The 60-day cumulative incidence of death following surgical procedure was 19% (95% 12-28%). There were no fatal VTE and 3 fatal hemorrhagic events. CONCLUSION Among patients with cancer undergoing surgical procedures within 30-days of an acute VTE, the rates of recurrent VTE and major hemorrhage are substantively higher than reported in non-surgical acute VTE cohorts. Placement of temporary IVC filters may improve short-term bleeding and thrombotic outcomes.
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Coronavirus-2019 (COVID-19) mortality is higher in patients with cancer than in the general population, yet the cancer-associated risk factors for COVID-19 adverse outcomes are not fully ...characterized.
We reviewed clinical characteristics and outcomes from patients with cancer and concurrent COVID-19 at Memorial Sloan Kettering Cancer Center until March 31, 2020 (n = 309), and observed clinical end points until April 13, 2020. We hypothesized that cytotoxic chemotherapy administered within 35 days of a COVID-19 diagnosis is associated with an increased hazard ratio (HR) of severe or critical COVID-19. In secondary analyses, we estimated associations between specific clinical and laboratory variables and the incidence of a severe or critical COVID-19 event.
Cytotoxic chemotherapy administration was not significantly associated with a severe or critical COVID-19 event (HR, 1.10; 95% CI, 0.73 to 1.60). Hematologic malignancy was associated with increased COVID-19 severity (HR, 1.90; 95% CI, 1.30 to 2.80). Patients with lung cancer also demonstrated higher rates of severe or critical COVID-19 events (HR, 2.0; 95% CI, 1.20 to 3.30). Lymphopenia at COVID-19 diagnosis was associated with higher rates of severe or critical illness (HR, 2.10; 95% CI, 1.50 to 3.10). Patients with baseline neutropenia 14-90 days before COVID-19 diagnosis had worse outcomes (HR, 4.20; 95% CI, 1.70 to 11.00). Findings from these analyses remained consistent in a multivariable model and in multiple sensitivity analyses. The rate of adverse events was lower in a time-matched population of patients with cancer without COVID-19.
Recent cytotoxic chemotherapy treatment was not associated with adverse COVID-19 outcomes. Patients with active hematologic or lung malignancies, peri-COVID-19 lymphopenia, or baseline neutropenia had worse COVID-19 outcomes. Interactions among antineoplastic therapy, cancer type, and COVID-19 are complex and warrant further investigation.
In the search for genetic factors that are associated with complex heritable human traits, considerable attention is now being focused on rare variants that individually have small effects. In ...response, numerous recent papers have proposed testing strategies to assess association between a group of rare variants and a trait, with competing claims about the performance of various tests. The power of a given test in fact depends on the nature of any association and on the rareness of the variants in question. We review such tests within a general framework that covers a wide range of genetic models and types of data. We study the performance of specific tests through exact or asymptotic power formulas and through novel simulation studies of over 10,000 different models. The tests considered are also applied to real sequence data from the 1000 Genomes project and provided by the GAW17. We recommend a testing strategy, but our results show that power to detect association in plausible genetic scenarios is low for studies of medium size unless a high proportion of the chosen variants are causal. Consequently, considerable attention must be given to relevant biological information that can guide the selection of variants for testing.
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7045 Background: Venetoclax (ven) is a BCL2 inhibitor used for the treatment (tx) of chronic lymphocytic leukemia (CLL) which can cause clinical or laboratory (lab) tumor lysis syndrome (TLS). A dose ...ramp-up schedule and prophylaxis strategies are incorporated into NCCN guidelines and prescribing information. Prior reports have of TLS focused mostly on patients (pts) with relapsed/refractory CLL receiving ven as monotherapy. Methods: We included pts >18y who were diagnosed with CLL or small lymphocytic lymphoma (SLL) and received tx with commercial ven in any line of therapy at our institution from 1/1/2016 to 12/31/2020. TLS was defined using the modified Cairo Bishop Criteria. TLS risk was based on the size of the largest lymph node (LN) on imaging or examination and the absolute lymphocyte count (ALC) as defined by ven prescribing information. Results: We included 616 ven escalations among 136 pts with CLL. Median age was 70 years and 86% were white. Ven was part of first line of tx for 48 pts (35%). 11% had high TLS risk at baseline; 37% among those escalated exclusively inpatient (IP) and 2% among those escalated exclusively outpatient (OP). Among those treated with ven, 47 pts (35%) received ven monotherapy. 74 (54%) of pts were escalated exclusively OP, 35 (26%) had at least one prophylactic hospitalization and 27 (20%) were escalated exclusively IP. During ven initiation, 86% of pts received allopurinol, 71% intravenous hydration, 18% phosphate binders, and 10% prophylactic rasburicase. Among the entire cohort, 8 pts (5.9%) developed lab TLS and zero developed clinical TLS. There were 11 TLS events; 2 pts developed TLS in more than one escalation. Incidence of TLS was 15% for those escalated exclusively IP, 5.7% for those with any prophylactic hospitalization and 2.7% for those escalated exclusively OP. Those who developed TLS were more likely to have a higher TLS risk at baseline, preceding isolated hyperuricemia, or CrCl measurement < 60 mL/min (Table). Conclusions: In this single institution retrospective cohort study, lab TLS was observed, though clinical TLS was not. Baseline hyperuricemia and impaired renal function were more common among those who developed lab TLS compared to those who did not. Prophylactic measures, including use of IV hydration, may have contributed to low rates of observed TLS in the outpatient setting. Table: see text
Many association tests have been proposed for rare variants, but the choice of a powerful test is uncertain when there is limited information on the underlying genetic model. Proposed methods use ...either linear statistics, which are powerful when most variants are causal and have the same direction of effect, or quadratic statistics, which are more powerful in other scenarios. To achieve robustness, it is natural to combine the evidence of association from two or more complementary tests. To this end, we consider the minimum‐p and Fisher's methods of combining P‐values from linear and quadratic statistics. Extensive simulation studies show that both methods are robust across models with varying proportions of causal, deleterious, and protective rare variants, allele frequencies, and effect sizes. When the majority (>75%) of the causal effects are in the same direction (deleterious or protective), Fisher's method consistently outperforms the minimum‐p and the individual linear and quadratic tests, as well as the optimal sequence kernel association test, SKAT‐O. When the individual test has moderate power, Fisher's test has improved power for 90% of the ∼5000 models considered, with >20% relative efficiency gain for 40% of the models. The maximum absolute power loss is 8% for the remaining 10% of the models. An application to the GAW17 quantitative trait Q2 data based on sequence data of the 1000 Genomes Project shows that, compared with linear and quadratic tests, Fisher's test has comparable power for all 13 functional genes and provides the best power for more than half of them.
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Background and Significance: Patients (pts) with primary or secondary myelofibrosis (MF) experience variable degrees of constitutional symptoms, cytopenias and risk of progression to acute myeloid ...leukemia leading to a reduced life-expectancy compared to age-matched controls. Although several oral Janus Kinase (JAK) inhibitors such as ruxolitinib (RUX) have been approved by the US FDA based on improvements in symptom burden and spleen volume compared to physician's choice of best available therapy, the duration of response to these agents is generally time-limited and treatment with JAK inhibitors is not considered to have disease-modifying potential. Furthermore, the median overall survival after RUX discontinuation is only 11-14 months highlighting the need for novel mechanism-based therapies for pts with disease progression on RUX. JAK2 V617F mutations promote transition from the G1 to S-phase of the cell cycle via increased expression of CDC25A, which is also upregulated in primary MPN patient samples. Additional cell cycle regulators such as CDK6 and Cyclin D have also been implicated in MF pathogenesis and contribute to myeloproliferation. Finally, we and others have shown synergistic effects of the combination of CDK4/6 inhibitors and RUX in murine models of MF (Rampal et al., CCR 2021) including improvement in bone marrow fibrosis suggesting the potential for disease-modifying activity. Several CDK4/6 inhibitors have been approved by the US FDA for the treatment of hormone receptor-positive metastatic breast cancer establishing a robust record of safety data. These preclinical data and known safety profile of CDK4/6 and RUX as single agents, provide rationale for combining CDK4/6 and JAK inhibition in pts with MF. Methods: This multicenter, phase I dose-escalation trial (NCT05714072) evaluates the safety of RUX + the CDK4/6 inhibitor abemaciclib in primary or secondary MF pts with intermediate-1/2 or high-risk disease by DIPSS who require treatment and had an inadequate response to RUX. Inadequate response to RUX is defined by (I) palpable splenomegaly ≥5 cm below the left costal margin at study entry AND/OR (II) active MPN symptoms, as defined by the presence of one symptom score ≥5 or two symptom scores ≥3 using the screening MPN-SAF TSS. Pts must have been on a stable dose of 10 mg or 15 mg BID of RUX for at least 4 weeks prior to enrollment with adequate platelet (≥75 x 10 9/L) and neutrophil counts (≥1.5 x 10 9/L). Key exclusion criteria include prior treatment with a CDK4/6 inhibitor, accelerated- or blast-phase MPN, platelet count <50 x 10 9/L in the 4 weeks before screening or platelet transfusion(s) within 8 weeks before screening, and absolute neutrophil count <0.5 x 10 9/L in the 4 weeks before screening. Among the currently FDA-approved CDK4/6 inhibitors, abemaciclib was chosen for combination therapy due to less myelosuppressive effects compared with other CDK4/6 inhibitors. This trial uses a conventional “3+3” dose-escalation design ( Figure), pts will be treated with increasing doses of abemaciclib added to a stable dose of RUX (10 mg or 15 mg BID). The pre-study dose of RUX will be maintained to determine the maximum tolerated dose of the combination of RUX and abemaciclib. The primary endpoint is to determine the maximum tolerated dose of RUX + abemaciclib. Secondary endpoints include measures of efficacy such as overall response rate, duration of response and survival endpoints. Exploratory endpoints include changes in allele fraction of driver mutations, gene expression profiling, and clonal architecture to identify biomarkers of response, mechanisms of resistance, and to assess for any disease-modifying effects of the combination therapy. At this time, 2 pts have been enrolled at dose level 0 without any dose-limiting toxicities observed. In line with the known adverse event profile of abemaciclib, grade 1 diarrhea occurred in one patient. One patient developed grade 3 neutropenia which promptly resolved with holding abemaciclib. No unexpected safety signal was noted and enrollment continues. This trial is open to enrollment at Memorial Sloan Kettering Cancer Center and will commence at MD Anderson Cancer Center later this year.
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*JPB and NSC contributed equally. Background and Significance: Mutations in RNA splicing factor genes ( SF3B1, SRSF2 U2AF1 and ZRSR2)are common in patients with acute myeloid leukemia (AML) and ...myelodysplastic syndromes (MDS). We and others have previously shown that pharmacologic degradation of the RNA splicing factor RBM39 preferentially kills splicing factor mutant cells. These preclinical data provided the rationale for a recently completed phase II clinical trial (NCT05024994) of the oral RBM39 degrader E7820 in patients with relapsed or refractory splicing factor mutant MDS or AML. The safety and efficacy data of this trial have been presented previously (Bewersdorf et al ASH 2022). The generally favorable safety profile and correlative studies confirming target engagement and induction of mis-splicing events support the further exploration of E7820 in the context of combination therapies. Recent clinical data show that treatment with venetoclax can overcome the negative prognostic impact of splicing factor mutations in AML (Senapati et al, Blood 2023). Additionally, preclinical data from our laboratory show synergy between E7820 and venetoclax in SF3B1-mutant isogenic cell lines leading to enhanced RBM39 degradation and blunting of MCL-1 expression, a common cause of venetoclax resistance ( Figure 1). Dynamic BH3 profiling of E7820 in myeloid leukemia cell lines suggests an E7820 dose-dependent priming for BAD which implies forced reliance on BCL2. Furthermore, adding venetoclax to E7820 further increased mitochondrial priming. Preclinical animal modeling with patient-derived xenografts (PDX) is ongoing. Based on these preclinical data, we are amending the study to include a separate arm of E7820 in combination with venetoclax. Methods and Study Design: This is an investigator-initiated, phase II trial (NCT05024994) that is being conducted at Memorial Sloan Kettering Cancer Center and Sylvester Comprehensive Cancer Center at the University of Miami of adult (≥18 years) patients with relapsed or refractory AML, MDS, or chronic myelomonocytic leukemia (CMML). Patients must have a hotspot splicing factor mutation in SF3B1, SRSF2, U2AF1 or U2AF2 (with hotspot mutations as defined by OncoKB) or a nonsense or frameshift mutation in ZRSR2 detected within 6 months of study screening for enrollment. Patients are required to have adequate end-organ function and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤3. Prior treatment with venetoclax is permitted. Patients enrolled in the new combination arm will receive E7820 100mg by mouth once daily + venetoclax orally once daily on days 1-28 of cycle 1 on days 1-21 of subsequent cycles. The study design is shown in Figure 2. As this combination has never been studied in human AML and MDS patients previously, the study will include a 6-patient safety run-in phase with an optional dose de-escalation of E7820 to 70mg orally once daily. The sample size is based on a Minimax Simon 2-stage design. Assuming a type I error rate of 0.05, power of 0.8, a response rate of 10% in the historical control group and 30% with E7820 + venetoclax, 15 patients will be enrolled in stage 1. If there are at least 2 responses among the first 15 patients, we will enroll another 10 patients. The null hypothesis will be rejected if there are at least 6 responses in the 25 patients. The primary endpoint of this trial is to evaluate the efficacy of E7820 + venetoclax in patients with relapsed/refractory myeloid malignancies with mutations in splicing factor genes as measured by the response rate within 6 cycles of therapy (AML: complete remission (CR) + complete remission with partial hematologic recovery (CRh); MDS: CR + CRh + CR with limited hematologic recovery (CR-L) + partial remission (PR); CMML: CR + PR). Secondary endpoints include overall and event-free survival. Correlative biomarker and pharmacodynamic parameters will be assessed as exploratory endpoints including effects on RBM39 protein levels, changes in global and key target splicing events, and evaluation of DCAF15 mRNA levels and response to therapy.
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Immunity may play a role in preventing cancer progression. We studied associations of immune‐related conditions with cancer‐specific mortality among older adults in the United States. We evaluated 1 ...229 443 patients diagnosed with 20 common cancer types (age 67‐99, years 1993‐2013) using Surveillance Epidemiology and End Results‐Medicare data. With Medicare claims, we ascertained immune‐related medical conditions diagnosed before cancer diagnosis (4 immunosuppressive conditions n = 3380 affected cases, 32 autoimmune conditions n = 155 766, 3 allergic conditions n = 101 366). For each cancer site, we estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for cancer‐specific mortality associated with each condition, applying a Bonferroni cutoff for significance (P < 5.1 × 10−5). Bayesian metaanalysis methods were used to detect patterns across groups of conditions and cancers. We observed 21 associations with cancer‐specific mortality at the Bonferroni threshold. Increased cancer‐specific mortality was observed with rheumatoid arthritis for patients with melanoma (aHR 1.51, 95% CI 1.31‐1.75) and breast cancer (1.24, 1.15‐1.33)), and with hemolytic anemia for bladder cancer (2.54, 1.68‐3.82). Significant inverse associations with cancer‐specific mortality were observed for allergic rhinitis (range of aHRs: 0.84‐0.94) and asthma (0.83‐0.95) for cancers of the lung, breast, and prostate. Cancer‐specific mortality was nominally elevated in patients with immunosuppressive conditions for eight cancer types (aHR range: 1.27‐2.36; P‐value range: 7.5 × 10−5 to 3.1 × 10−2) and was strongly associated with grouped immunosuppressive conditions using Bayesian metaanalyses methods. For older patients with several cancer types, certain immunosuppressive and autoimmune conditions were associated with increased cancer‐specific mortality. In contrast, inverse associations with allergic conditions may reflect enhanced immune control of cancer.
What's new?
Little is known about the impact of immune‐related medical conditions on outcomes following a cancer diagnosis. In this population‐based study involving 1.2 million older cancer patients in the United States, individuals with certain previously diagnosed immunosuppressive and autoimmune conditions were found to be at increased risk for cancer‐specific mortality. Meanwhile, inverse associations were detected between cancer‐specific mortality and allergic conditions. The findings highlight the biological importance of immunity in controlling cancer and suggest that conditions that alter immunity can significantly affect therapeutic responses, relapse risk, and mortality.
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