Citations

10520 Background: Outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are superior with pediatric-inspired therapy. CALGB 10403, the first US adult cooperative group prospective trial using a pediatric-inspired augmented BFM (ABFM)-based regimen, demonstrated feasibility and improved survival. We examined differences in drug delivery and targeted toxicities in AYAs who received the same therapy on C10403 vs the Children’s Oncology Group (COG) study AALL1131. Methods: The proportion of AYAs receiving full dose (within 10% of protocol- specified) vincristine (VCR) and pegaspargase (PEG) during induction (IND), consolidation (CON), and delayed intensification (DI); the likelihood of selected grade ≥3 adverse events (AEs); and the impact of patient characteristics were compared in AYAs 16-30 years. Targeted AEs with analogous reporting requirements in both studies included hyperbilirubinemia, pancreatitis, sensory neuropathy, and GI/intracranial hemorrhage. Thrombosis, transaminitis and hyperglycemia were not comparably captured. Fisher’s Exact test and logistic regression models were used for analyses. Results: After excluding AYAs removed from study after induction, 87 AALL1131 AYAs (accrued 2012-2016) and 188 C10403 AYAs (accrued 2007-2012) were analyzed with median ages of 17 (16-26) vs 22 (17-30) years, p < 0.001. There was no difference in the intensity of VCR delivery during IND, but in CON and DI, AALL1131 AYAs were more likely to receive all specified VCR (93.1% vs 81.9%, p = 0.02; 92.7% vs 72.1%, p = 0.01). Women were less likely to receive all specified VCR (OR 0.57, 95% CI 0.34-0.94, p = 0.03), and overweight/obese AYAs were somewhat less likely to receive all VCR compared to those considered normal weight (OR 0.88 and 0.59, p = 0.09). More C10403 AYAs were obese/overweight compared to AALL1131 AYAs (p = 0.04). There were no significant differences in dosing of PEG during IND/CON, but in DI AALL1131 AYAs were more likely to receive both doses (75.6% vs 57.1%, p = 0.03). No patient variables impacted delivery of PEG. There was no significant difference in grade ≥3 toxicities captured similarly on both studies. Conclusions: AYAs enrolled on AALL1131 were more likely to receive all protocol-specified VCR and PEG compared to those on C10403. Selected AE rates were comparable, suggesting that older AYAs do not tolerate doses of VCR and PEG for reasons other than toxicity, with body habitus as one potential variable. Further analyses to compare dose density, toxicities, and outcomes experienced by younger AYAs versus older are ongoing.

3583 Background: The novel curaxin CBL0137 intercalates into DNA, interfering with histone/DNA binding. Consequent trapping of histone chaperone FACT leads to MYC, NF-kB, and HSF1 inhibition, p53 activation, and an IFN response. CBL0137 shows broad nonclinical antitumor activity (Gasparian et al. Sci Transl Med. 2011; 3(95):95ra74). Methods: This dose-ranging study assessed the CBL0137 maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and CBL0137 safety, pharmacokinetics (PK), and efficacy in adults with advanced treatment-refractory solid tumors. CBL0137 was administered IV on Days 1, 8, and 15 of repeated 28-day cycles until progressive disease (PD) or unacceptable toxicity. Doses were escalated using a 3+3 design based on Cycle 1 dose-limiting toxicities (DLTs). PK was assessed through 168 hours after Day 1. Efficacy was evaluated every 8 weeks. Results: The study enrolled 83 pts (M/F [n] = 49/34; median [range] age = 64 [33-85] years; ECOG status [n] = 1/2 [32/51]), with cancer types (n) of colorectal (23), prostate (7), glioblastoma (6), liver (6), non-small-cell (5), and others (36) across 17 dose levels from 10 to 700 mg/m2/infusion. Durations of therapy ranged to 24 months. Cycle 1 DLTs (n type) were observed at 240 mg/m2 (1 Gr 3 photosensitivity), 400 mg/m2 (1 Gr 3 anemia), 700 mg/m2 (1 Gr 4 thrombocytopenia, 1 Gr 4 neutropenia/Gr 4 thrombocytopenia), and 650 mg/m2 (1 Gr 3 thrombocytopenia, 1 Gr 4 neutropenia/Gr 3 thrombocytopenia). Nausea and vomiting were successfully prevented with dexamethasone/serotonin antagonists. Photosensitization was effectively managed with sun protection. Peripheral venous thrombosis required central vein infusion in subjects with glioblastoma. PK showed dose-proportional increases in plasma CBL0137 area under the concentration-time curve (AUC), a high mean (range) volume of distribution (Vd) of 1,030 (655-1460) L/m2 consistent with extensive tissue distribution and DNA intercalation, and an average mean (range) half-life (t1/2) of 24.7 (10.3-40.7) hours without dose dependence. The best response was stable disease: 2 pts with liver cancer had tumor control for 9 and 24 months and a maximum tumor regression of 10%; 2 pts with prostate cancer had tumor regressions by 11% and 22%; 1 pt with uterine cancer had a 20% tumor regression. Conclusions: CBL0137 administered IV was generally well tolerated with manageable toxicities The MTD and RP2D were estimated at 540 mg/m2 due to myelosuppressive DLTs. PK were predictable. Preliminary evidence of antitumor activity supports Phase 2 testing. Clinical trial information: NCT01905228 .

In response to the rapidly evolving coronavirus disease 2019 (COVID-19) pandemic and the potential need for physicians to provide critical care services, the American Society of Anesthesiologists (ASA) has collaborated with the Society of Critical Care Anesthesiologists (SOCCA), the Society of Critical Care Medicine (SCCM), and the Anesthesia Patient Safety Foundation (APSF) to develop the COVID-Activated Emergency Scaling of Anesthesiology Responsibilities (CAESAR) Intensive Care Unit (ICU) workgroup. CAESAR-ICU is designed and written for the practicing general anesthesiologist and should serve as a primer to enable an anesthesiologist to provide limited bedside critical care services.

Background: Lower-dose cone-beam computed tomography protocols for image-guided radiotherapy may permit target localization while minimizing radiation exposure. We prospectively evaluated a lower-dose cone-beam protocol for central nervous system image-guided radiotherapy across a multinational pediatrics consortium. Methods: Seven institutions prospectively employed a lower-dose cone-beam computed tomography central nervous system protocol (weighted average dose 0.7 mGy) for patients ≤21 years. Treatment table shifts between setup with surface lasers versus cone-beam computed tomography were used to approximate setup accuracy, and vector magnitudes for these shifts were calculated. Setup group mean, interpatient, interinstitution, and random error were estimated, and clinical factors were compared by mixed linear modeling. Results: Among 96 patients, with 2179 pretreatment cone-beam computed tomography acquisitions, median age was 9 years (1-20). Setup parameters were 3.13, 3.02, 1.64, and 1.48 mm for vector magnitude group mean, interpatient, interinstitution, and random error, respectively. On multivariable analysis, there were no significant differences in mean vector magnitude by age, gender, performance status, target location, extent of resection, chemotherapy, or steroid or anesthesia use. Providers rated >99% of images as adequate or better for target localization. Conclusions: A lower-dose cone-beam computed tomography protocol demonstrated table shift vector magnitude that approximate clinical target volume/planning target volume expansions used in central nervous system radiotherapy. There were no significant clinical predictors of setup accuracy identified, supporting use of this lower-dose cone-beam computed tomography protocol across a diverse pediatric population with brain tumors.

Cold‐water swimming is a recreational activity that may become a future Winter Olympic event. However, unintentional cold‐water exposure can lead to hypothermia or death. Changes in body temperature are known to diminish swimming performance in persons experiencing hypothermia, although thermal changes during recreational exposure are not well characterized. This study examined skin temperature responses to a one‐kilometer swim in normal and cold‐water. Competitive swimmers (2 male and 2 female; age 44±17 years; BMI 24±2) completed a one‐kilometer swim (22 laps × 75 foot lengths) under free‐living indoor (25.5°C water and 25.0°C air) and cold outdoor (10.9°C water and 6.5°C) conditions. Skin temperature was determined with a digital infrared camera on the center of right palm, cubital fossa of arm, lateral aspect of pectoral muscle, cheek, and average of the four locations at 8.7±1.7 minutes before the swim (pre), then 0.6±0.2 and 6.4±2.1 minutes after the swim. Data (mean±SD) was analyzed with repeated measures ANOVA with significance if P<0.05. Swimmers completed the indoor and outdoor swim events in 20.7±1.7 and 21.8±1.1 minutes respectively. Average indoor skin temperature at −8.7, +0.6 and +6.4 minutes was 94.0±1.7, 85.3±1.9, and 88.1±2.2°C. Average outdoor skin temperature at −8.7, +0.6 and +6.4 minutes was 83.0±3.6, 53.5±2.3, and 67.7±2.0°C. At all times average outdoor skin temperature was lower than indoor, with the lowest temperature 0.6 minutes post‐swim. Palm indoor temperature at −8.7, +0.6 and +6.4 minutes was 91.6±3.9, 83.1±0.5, and 87.3±5.0°C. Palm outdoor temperature at −8.7, +0.6 and +6.4 minutes was 75.1±7.9, 47.4±2.7, and 58.1±2.7°C. At all times outdoor palm temperature was lower than indoor, with the lowest temperature 0.6 minutes post‐swim. Similar thermal responses were observed in the cheek, cubital fossa and pectoral locations. While time to complete the indoor and outdoor one km swims were similar, swimming in cold water was associated with delayed rewarming in the palm and cheek relative to cubital fossa and pectoral muscle.

Cold‐water swimming is a recreational activity that may become a future Winter Olympic event. However, unintentional cold‐water exposure can lead to arrhythmias, changes in electrocardiogram (ECG) appearance, and death. This study sought to characterize cardiac responses to recreational one‐kilometer swims performed in normal and cold‐water. Competitive swimmers (2 male 2 female; age 44±17 years; BMI 24±2) completed a one‐kilometer swim (22 laps × 75‐foot lengths) under free‐living indoor (25.5°C water and 25.0°C air) and cold outdoor (10.9°C water and 6.5°C) conditions. Continuous ECGs were obtained with a waterproof recording system (Actiwave, CamNtech Inc., Boerne, TX). ECG PR‐, QT‐, and RR‐intervals (sec), ventricular diastole (sec), and heart rate (beats/minute) were measured 8.7±1.7 minutes before the swim, then 0.6±0.2, 3.0±0.0 and 6.4±2.1 minutes after the swim. Data (mean±SD) was analyzed with repeated measures ANOVA with significance if P<0.05. Swimmers completed the indoor and outdoor swim events in 20.7±1.7 and 21.8±1.1 minutes, respectively. For the indoor swim, PR‐interval (sec) at −8.7, +0.6, +3, and +6.4 minutes was 0.12±0.01, 0.12±0.01, 0.11±0.01, and 0.12±0.01, and PR‐interval for the outdoor swim at −8.7, +0.6, +3.0 and +6.4 minutes was 0.13±0.01, 0.13±0.01, 0.13±0.01, and 0.14±0.01 (sec). PR‐interval was significantly longer at +6.4 minutes post cold‐water swim. For the indoor swim, ventricular diastole (sec) at −8.7, +0.6, +3, and +6.4 minutes was 0.37±0.06, 0.22±0.04, 0.30±0.01, and 0.32±0.05 (sec), and for the outdoor swim at −8.7, +0.6, +3.0 and +6.4 minutes ventricular diastole was 0.35±0.08, 0.19±0.02, 0.30±0.04, and 0.24±0.06 (sec). Ventricular diastole was significantly shorter at +6.4 minutes post cold‐water swim. No significant changes were observed for QT‐interval, RR‐interval, and heart rate between swim conditions. These parameters were also assessed for the ECG recordings collected during the 20.7±1.7‐minute normal and 21.8±1.1‐minute cold‐water swims to characterize the physiological response during swim exercise. This study of normal and cold‐water one‐kilometer recreational swimmers determined that a waterproof ECG could generate a continuous record of changes in cardiac function. During cold‐water swim recovery (+6.4 minutes) PR interval was lengthened and ventricular diastole was shortened suggesting an influence of temperature on cardiac function.

Abstract Melphalan (M), Prednisone (P) and Lenalidomide (R) are active in the treatment of multiple myeloma (MM). We evaluated the toxicity and efficacy of MPR in a phase I/II trial. Results of phase I part were previously reported (Blood2006, 108(11) abst 3558). M 5 mg/m2 on days (d) 1–4, 60 mg/m2 d 1–4 and R 10 mg d 1–21 of a 28 day cycle was determined as MTD for the phase II study. Methods: Patients with previously untreated MM who were not candidates for stem cell transplantation, age ≥18 yr, ECOG PS 0–3, evaluable or measurable disease, ANC &gt;1500, platelets &gt; 100,000 and creatinine ≤ 3.0 mg/dL were eligible. All patients received aspirin 325 mg/d as DVT prophylaxis. Routine antibacterial prophylaxis was not used. G/GM-CSF was used at the discretion of the treating physician for neutropenia. Response rate (RR), confirmed on two consecutive determinations was the primary end-point. The study had 90% power to detect a RR of at least 45%. Results: Twenty-six patients were accrued between July ’06 and Feb ’08. The median age was 74 y (64 – 87y), 17 (65%) were men. Six, 13, 6, 1 (23%, 50%, 23%, and 4%) patients had ECOG PS 0, 1, 2, and 3, respectively. Three (12%), 11 (42%) and 10 (38%) patients were ISS stage 1, 2 and 3. A total of 106 cycles were administered; median 4.5 (1–13). Seventy-seven % patients experienced at least 1 grade 3 or 4 toxicity. Neutropenia (42%/8%) and thrombocytopenia (20%/8%) were the most common grade 3/4 adverse events followed by anemia (16%/0%), fatigue (8%/4%), rash (11%/0%), and hyperglycemia (4%/0%). There were 20 treatment delays in 9 patients, and 18 dose reductions (9 in R, 11 in M and 1 P) occurred in 7 patients, most commonly because of neutropenia or thrombocytopenia. Eleven patients (42%) required G-CSF treatment. Eleven patients are currently receiving treatment; 15 have gone off study (4 completed per protocol, 3 refused, 3 adverse effects, 3 unrelated illnesses, 2 other). Median follow up of survivors is 8 m (0 – 22m). Eighteen (69 %; 95%CI 48–86) patients had a PR or better according to International Myeloma Working Group Uniform Response criteria; 3 (12 %) CR, 5 (19 %) VGPR and 10 (38%) PR. Median number of cycles before achieving a response was 2 (1 – 11). Median Progression Free and Overall Survival is 16.7m (95% CI 11.2–23.0), and 23 m (95% CI: 22 – 23), respectively. Conclusions: MPR combination is feasible with a manageable toxicity profile and has significant activity in the treatment of patients with MM who are not candidates for stem cell transplant, with an overall response rate of 69%, and a CR plus VGPR rate of 31%. Grade 3 or 4 neutropenia and thrombocytopenia was the most common toxicity, seen in up to 50% of patients in this cohort of predominantly elderly patients. Dose reduction in R and/or M was required in 27% patients. No patient developed neuropathy or thromboembolic complications.

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder. Lenalidomide, especially in conjunction with dexamethasone, has been shown to be highly active in patients with multiple myeloma. We previously reported a hematologic response rate of 41% and an organ response rate of 23% among 22 AL patients treated with lenalidomide and on-demand dexamethasone (Dispenzieri et al, Blood 2007). Long term outcomes of AL patients treated with lenalidomide have not yet been described. Methods: Thirty-seven patients were treated on an IRB approved treatment trial with single agent lenalidomide, starting doses of 25 mg in 22 and reduced dose of 15 mg in the last 15. If progression within or no evidence of hematologic response after 3 cycles, dexamethasone was added. Patients were classified according to cardiac biomarker stage (cut-offs for serum troponin T &lt;0.035 ng/ml and NT-proBNP &lt;332 pg/ml--Stage I neither above cutoff; Stage III, both above cut-off; and Stage II, any one above cut-off). Survival estimates were done according to the methods of Kaplan and Meier. Results: Median age was 64 years (range 44–88), with 70% male. Sixty-five percent of patients were previously treated, and the median time from diagnosis to study entry was 8.9 months (range 0.4–237). The biomarker staging breakdown was: I, 16%; II, 43%; and III, 41%. As of 7/11/08, 5 patients remain on active therapy. The overall hematologic response rate was 43% (1 CR and 15 PR), with only one patient responding to single agent lenalidomide, and the overall organ response rate was 20%. If one excludes the 13 patients who did not complete 3 months of therapy and have the opportunity of having dexamethasone added to their program, the respective hematologic and organ response rates were 62% and 32%. With a median follow-up of 33.6 months (range 14.4–42), twenty-two patients (59%) have died, but only 2 had deaths possibly related to treatment. Median duration of response, progression free survival and overall survival were 31 months, 14.8 months (95%CI: 5.7–28.1), and 18.8 months (95%CI: 11.7-not reached), respectively. Overall survival from diagnosis was 48 months (95%CI: 21.6–153.6). As shown in Table below, outcomes were dependent on underlying risk stratification and ability to stay on therapy. High risk patients were more likely to drop out early and less likely to respond. High risk patients had shorter OS All Patients Outcome Stage I Stage II Stage III p N 6 16 15 Survival from enrollment, mo NR 18.8 (11.7–33.6) 5.7 (3.2–18.3) 0.01 Survival from Diagnosis, mo NR 48.4 (20.4–62) 21.1 (11.2–31.7) 0.005 Progression Free Survival, mo 34.7 (33.7–NR) 18.3 (6.2–28.1) 4.4 (3–8.6) NS Drop out by cycle 4, % 17 31 60 NS Median # of cycles administered 31 6 3 0.04 Time to response, mo 6.2 (3.6–9.3) 6.4 (5.2–NR) 4.7 (3.8–NR) NS Hematologic response rate, % 83 38 27 0.05 Organ response rate, % 40 20 13 NS Duration of Response, mo NR 27.2 (13.6–NR) NR NS Subgroup analysis of patients receiving &gt;3 cycles of therapy (i.e getting Len and Dex) N 5 12 7 Time on therapy, mo 35.2 8 10.5 Hematologic Response Rate, % 100 50 56 Organ response rate, % 50 27 25 Conclusions: Based on these data, single agent lenalidomide is not recommended for patients with AL; however, lenalidomide in combination with dexamethasone can be associated with good progression free and overall survival rates, even among patients with relapsed or refractory disease.

Abstract Background: The plasma cell labeling index (LI), a slide-based measure of the percentage of bone marrow plasma cells in the S-phase of cell cycle, is a powerful prognostic tool in multiple myeloma (MM). A high LI is a marker of poor outcome, and is a useful adjunct to cytogenetics and fluorescent in-situ hybridization to risk-stratify MM patients. It has been shown to provide additional prognostic information in International Staging System (ISS) stages 1 and 2 patients treated with conventional chemotherapy ± autologous stem cell transplantation. However, the impact of a high LI is not known in patients receiving novel agents that have been integrated into the current treatment paradigm of newly diagnosed MM. The objective of this study was to determine the value of LI in patients treated with thalidomide-dexamethasone (Thal/Dex) or lenalidomide-dexamethasone (Len/Dex). Patients and Methods : Data from 125 newly diagnosed MM patients enrolled in clinical trials with either thalidomide (200mg/d) plus dexamethasone (Thal-Dex; n=50), or lenalidomide (25 mg/d on days 1–21 of a 4-week cycle) plus dexamethasone (Len-Dex; n=75) as initial therapy, were utilized. Patients within both the studies were categorized into 2 LI groups based on baseline LI: high (≥1%) vs. low (&lt;1%) LI. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan Meier method, and compared between the two LI groups within the Thal Dex and Len-Dex studies using log rank tests. Results : The median follow-up for patients on Thal-Dex and Len-Dex was 7.5 and 3 years, respectively. 36% (18/50) of patients in the Thal-Dex study and 35% (26/75) in the Len-Dex study had high LI. The baseline patient-characteristics, including age, stage (ISS), lactate dehydrogenase, calcium, hemoglobin and creatinine were comparable between the 2 studies. The median OS for patients receiving Thal-Dex was 4.7 years (95% CI 3.1–8.1); 2.3 years (95% CI 1.3–4.6) for patients with LI ≥1 compared to 6.9 years (95% CI: 3.9–NA) for those with LI &lt;1 (P=0.02). The median OS for patients on Len-Dex was not reached for either the high or low LI group (P=0.80). The median PFS for all Thal-Dex patients was 1.7 years (95% CI: 1.4–3.1); 1.3 years (95% CI: 0.2–2.0) for patients with high LI vs.2.3 years (95% CI: 1.3–3.3) for patients with low LI; P = 0.01. The median PFS for Len-Dex patients was 2.6 years (95% CI: 1.8–3.1) years, and no significant difference was observed between the 2 LI groups, with PFS of 2.3 years (95% CI: 1.4–3.1) for patients with high LI, and 3.1 years for patients in the low LI group. Due to a shorter median follow-up of Len-Dex patients, a separate analysis censoring all patients in both the studies at 3 years was performed with similar results. Conclusion : LI remains a significant determinant of PFS and OS in newly diagnosed MM patients treated with Thal-Dex, with high baseline LI predicting poorer outcome. In contrast, during first 3 years of follow-up, the unfavorable prognostic effect of LI is not apparent with Len-Dex therapy, and longer follow-up is needed to determine if Len-Dex therapy overcomes the poor prognostic effect of high LI. Figure Figure

ABSTRACT Epithelial cells, such as liver-resident hepatocytes, rely heavily on the Rab family of small GTPases to perform membrane trafficking events that dictate cell physiology and metabolism. Not surprisingly, disruption of several Rab proteins can manifest in metabolic diseases or cancer. Rab32 is expressed in many secretory epithelial cells but its role in cellular metabolism is virtually unknown. In this study, we find that Rab32 associates with lysosomes and regulates proliferation and cell size of Hep3B hepatoma and HeLa cells. Specifically, we identify that Rab32 supports the mechanistic target of rapamycin complex 1 (mTORC1) signaling under basal and amino acid-stimulated conditions. Consistent with inhibited mTORC1, an increase in nuclear TFEB localization and lysosome biogenesis is also observed in Rab32-depleted cells. Finally, we find that Rab32 interacts with mTOR kinase, and that loss of Rab32 reduces the association of mTOR and mTORC1 pathway proteins with lysosomes, suggesting that Rab32 regulates lysosomal mTOR trafficking. In summary, these findings suggest that Rab32 functions as a novel regulator of cellular metabolism through supporting mTORC1 signaling. This article has an associated First Person interview with the first author of the paper.