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T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53 -wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53 -wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models. T- and NK-cell lymphomas (TCL) are a group of lymphoid malignancies characterized by poor prognosis, but the absence of appropriate pre-clinical models has hampered the development of effective therapies. Here the authors establish several pre-clinical models and identify vulnerabilities that could be further exploited to treat patients afflicted by these diseases.

In patients with sickle cell disease (SCD), poor outcome measures compromise the potential success of clinical trials. Contrast-enhanced ultrasound (CEUS) is a technique that can non-invasively quantify deep tissue microvascular blood flow. We tested the hypothesis that CEUS of forearm skeletal muscle could be used to: 1) assess microvascular abnormalities that occur during vaso-occlusive crisis; and 2) test new therapies for SCD that are targeted to improving the status of the microcirculation. We performed a prospective study, CEUS perfusion imaging of resting forearm muscle was performed in adults with SCD: 1) during and after a pain episode, and 2) before, during, and after a 24-hour infusion of the investigative agent, regadenoson, an adenosine A2A agonist. CEUS destruction-replenishment time-intensity data were analyzed to measure microvascular blood flow, as well as its components, microvascular blood volume and flux rate. Serial CEUS measurements were obtained in 32 adults with SCD. For the studies during crisis, there was a 30% reduction in microvascular blood flow compared to steady-state (p = 0.031), a reduction that was largely due to microvascular flux rate. For the regadenoson group, a non-significant 25% increase in flux rate and 9% increase in microvascular blood flow compared to baseline were detected during infusion. In a study of adults with SCD, CEUS detected changes in microvascular blood flow associated with vaso-occlusive crises. No changes were found during an infusion of the adenosine A2A agonist, regadenoson. This study provides preliminary evidence that CEUS could detect blood flow changes consistent with SCD physiology.

Intracranial hemorrhage (ICH) is a common and often devastating outcome in patients with brain tumors. Despite this, there is little evidence to guide anticoagulation management following an initial ICH event. To analyze the risk of recurrent hemorrhagic and thrombotic outcomes after an initial ICH event in patients with brain tumors and prior venous thromboembolism (VTE). A retrospective cohort study was performed. Radiographic images obtained after initial ICH were reviewed for the primary outcomes of recurrent ICH and VTE. A total of 79 patients with brain tumors who developed ICH on anticoagulation for VTE were analyzed. Fifty‐four patients (68.4%) restarted anticoagulation following ICH. The cumulative incidence of recurrent ICH at 1 year was 6.1% (95% confidence interval [CI], 1.5‐15.3) following reinitiation of anticoagulation. Following a major ICH (defined as an ICH >10 mL in size, causing symptoms, or requiring intervention), the rate of recurrent ICH upon reexposure to anticoagulation was 14.5% (95% CI, 2.1‐38.35), whereas the rate of recurrent ICH following smaller ICH was 2.6% (95% CI, 0.2%‐12.0%). Mortality following a recurrent ICH on anticoagulation was 67% at 30 days. The cumulative incidence of recurrent VTE was significantly lower in the restart cohort compared to patients who did not restart anticoagulation (8.1% vs 35.3%; P = .003). We conclude that resumption of anticoagulation is lowest among patients with metastatic brain tumors with small initial ICH. Following an initial major ICH, resumption of anticoagulation was associated with a high rate of recurrent ICH.

Background As use of oral cancer therapies increases, patient adherence has become critical when evaluating the effectiveness of therapy. In a phase III trial for renal cell carcinoma, we: (a) characterized adherence to sorafenib, sunitinib, and/or placebo and (b) identified factors associated with non‐adherence. Methods ECOG‐ACRIN E2805 was a double‐blind, placebo‐controlled, randomized trial comparing adjuvant sorafenib or sunitinib in patients with resected primary renal cell carcinoma at high risk for recurrence. We used patient‐completed pill diaries to measure adherence as the number of pills taken divided by the number of pills prescribed. Log‐binomial regression was used to identify correlates of non‐adherence (<80% of prescribed pills reported as taken). Results Mean adherence was 90.7% among those assigned to sunitinib (n = 613) and 84.8% among those assigned to sorafenib (n = 616). Among those assigned to placebo, mean adherence was 94.9% and 92.4% to sunitinib and sorafenib placebo, respectively. Non‐adherence was associated with race/ethnicity (non‐Hispanic Black: prevalence ratio [PR] 2.22, 95% CI 1.63, 3.01; Hispanic: PR 1.54, 95% CI 1.05, 2.26), high volume enrollment (≥10 patients: PR 1.30, 95% CI 1.03, 1.64), treatment group (sunitinib: PR 2.24, 95% CI 1.66, 3.02; sorafenib: PR 2.37, 95% CI 1.74, 3.22), and skin rash (PR 1.36, 95% CI 1.03, 1.80). Conclusion Among patients participating in a randomized clinical trial, adherence to oral cancer therapies was lower compared to placebo. Adherence was also worse in racial/ethnic minorities, those experiencing toxicities, and high volume enrolling sites. Our findings highlight several challenges to address in clinical practice as use of oral therapies continues to increase. Clinical trial registration number This trial is registered with ClinicalTrials.gov, number NCT00326898. In a randomized clinical trial for renal cell carcinoma, adherence to oral therapy was lower (85%) than adherence to placebo (95%). Adherence was also worse among racial/ethnic minorities, patients experiencing certain toxicities, and high volume enrolling sites, highlighting several challenges to address in clinical practice as oral therapies become increasingly common.

Patients with high-risk renal cell carcinoma (RCC) experience high rates of recurrence despite definitive surgical resection. Recent trials of adjuvant tyrosine kinase inhibitor therapy have provided conflicting efficacy results at the cost of significant adverse events. PD-1 blockade via monoclonal antibodies has emerged as an effective disease-modifying treatment for metastatic RCC. There is emerging data across other solid tumors of the potential efficacy of neoadjuvant PD-1 blockade, and preclinical evidence supporting a neoadjuvant over adjuvant approach. PROSPER RCC is a Phase III, randomized trial evaluating whether perioperative nivolumab increases recurrence-free survival in patients with high-risk RCC undergoing nephrectomy. The neoadjuvant component, intended to prime the immune system for enhanced efficacy, distinguishes PROSPER from other purely adjuvant studies and permits highly clinically relevant translational studies. While many patients with early stage kidney cancer can be cured by removal of the tumor and kidney (‘nephrectomy’), upward of 40% of patients can recur due to microscopic spread of the cancer prior to surgery. Adding anticancer drugs that are effective in the metastatic setting to surgery has potential to eliminate the microscopic disease and increase cure rates. The PROSPER renal cell carcinoma study is testing whether adding nivolumab, a drug that engages the immune system to better recognize, fight and eliminate the cancer, will improve disease control over surgery alone. Nivolumab will be given before and after surgery to see if it reduces the chance of the disease returning and decreases death from kidney cancer compared with patients receiving surgery only.

Reduced emphasis on early postoperative bridging anticoagulation is one explanation for the increased incidence of HeartMate II (HM II) pump thrombosis. We conducted a single-center analysis of initial postoperative anticoagulation practices and their impact on the incidence of HM II pump thrombosis. Data was collected on 105 patients undergoing primary HM II implant from 2009 to 2014. A parenteral bridge was defined as use of parenteral anticoagulation prior to attainment of an international normalized ratio ≥ 2 on warfarin. A parenteral bridge was further characterized as early if initiated ≤ 3 days of implant and therapeutic if a manufacturer-specified goal partial thromboplastin time (PTT) was achieved during each of the first 3 days of administration. Pump thrombosis was “suspected” based upon suggestive clinical parameters leading to hospital admission with parenteral anticoagulant administration and “confirmed” by direct visualization of thrombus in the device. A majority of patients (70%) were treated with an initial parenteral bridge, which was started within 3 days of device implantation in 68% of cases. Therapeutic PTT levels were achieved in 52% of patients treated with a parenteral bridge. Patients who were bridged had lower Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles (p = 0.039) and longer intensive care unit stay (p = 0.005). Pump thrombosis was suspected in 25% and confirmed in 13% of patients within 6 months of implant. Point estimates of pump thrombosis incidence demonstrated a lower event rate at 6 months in patients who received a therapeutic bridge (15.8%, 95% CI 6.3–29.1% for suspected; 7.9%, 95% CI 2.0–19.3% for confirmed) compared to those who did not receive a therapeutic bridge (29.9%, CI 19.3–41.1% for suspected; 16.4%, 95% CI 8.7–26.3% for confirmed). This trend was not sustained at 12 and 24 months. Cumulative incidence analyses showed no significant difference in the overall incidence of pump thrombosis between patients who did and did not receive a parenteral bridge. In patients undergoing HM II implantation, the use of initial postoperative parenteral bridging anticoagulation is common but frequently sub-therapeutic. Use of a parenteral bridge reaching therapeutic targets may decrease the 6-month but not the overall incidence of pump thrombosis.