Association Between Birth Weight Z-Scores and Early Outcomes Following Truncus Arteriosus Repair.

In infants undergoing truncus arteriosus (TA) repair, we sought to determine associations between fetal growth restrictions as measured by birth weight Z-score and early outcomes. We utilized the Pediatric Health Information System (PHIS) database to identify infants < 90 days old who underwent TA repair from 2004 to 2019. The primary exposure variable was birth weight Z-score, calculated based on gestational age at birth, gender, and birth weight. The primary outcome was postoperative hospital mortality. Secondary outcomes included major complications, prolonged postoperative length of hospital stay (LOS; > 30 days), and hospital readmission within 1 year. Generalized estimating equation (GEE) models were used to identify adjusted associations between birth weight Z-score, small for gestational age (SGA) status, and mortality and included were 1039 subjects. Median birth weight was 2960 g, gestational age at birth was 38 weeks, and birth weight Z-score was - 0.47. SGA was present in 21% of subjects. Hospital mortality occurred in 104 patients (10%). By multivariable analysis, lower birth weight Z-score was associated with higher hospital mortality [for each unit decrease in birth weight Z-score below - 1.0, adjusted OR 1.71 (95% CI 1.10-4.25)]. SGA status was associated with increased hospital mortality (adjusted OR 2.17; 95% CI 1.39-3.40). Birth weight Z-scores and SGA status were not significantly associated with occurrence of cardiac arrest, ECMO use, gastrostomy tube placement, tracheostomy, seizures, infection, prolonged postoperative LOS, or hospital readmission. In infants undergoing TA repair, lower birth weight Z-scores and SGA status were strongly associated with increased hospital mortality.

Automated detection of lung nodules and coronary artery calcium using artificial intelligence on low-dose CT scans for lung cancer screening: accuracy and prognostic value.

BACKGROUND: Artificial intelligence (AI) in diagnostic radiology is undergoing rapid development. Its potential utility to improve diagnostic performance for cardiopulmonary events is widely recognized, but the accuracy and precision have yet to be demonstrated in the context of current screening modalities. Here, we present findings on the performance of an AI convolutional neural network (CNN) prototype (AI-RAD Companion, Siemens Healthineers) that automatically detects pulmonary nodules and quantifies coronary artery calcium volume (CACV) on low-dose chest CT (LDCT), and compare results to expert radiologists. We also correlate AI findings with adverse cardiopulmonary outcomes in a retrospective cohort of 117 patients who underwent LDCT. METHODS: A total of 117 patients were enrolled in this study. Two CNNs were used to identify lung nodules and CACV on LDCT scans. All subjects were used for lung nodule analysis, and 96 subjects met the criteria for coronary artery calcium volume analysis. Interobserver concordance was measured using ICC and Cohen's kappa. Multivariate logistic regression and partial least squares regression were used for outcomes analysis. RESULTS: Agreement of the AI findings with experts was excellent (CACV ICC = 0.904, lung nodules Cohen's kappa = 0.846) with high sensitivity and specificity (CACV: sensitivity = .929, specificity = .960; lung nodules: sensitivity = 1, specificity = 0.708). The AI findings improved the prediction of major cardiopulmonary outcomes at 1-year follow-up including major adverse cardiac events and lung cancer (AUCMACE = 0.911, AUCLung Cancer = 0.942). CONCLUSION: We conclude the AI prototype rapidly and accurately identifies significant risk factors for cardiopulmonary disease on standard screening low-dose chest CT. This information can be used to improve diagnostic ability, facilitate intervention, improve morbidity and mortality, and decrease healthcare costs. There is also potential application in countries with limited numbers of cardiothoracic radiologists.

Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134.

PURPOSE: Combination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4-blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600-mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy. PATIENTS AND METHODS: In a phase III trial, patients with treatment-naive BRAFV600-mutant metastatic melanoma were randomly assigned to receive either combination nivolumab/ipilimumab (arm A) or dabrafenib/trametinib (arm B) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D). The primary end point was 2-year overall survival (OS). Secondary end points were 3-year OS, objective response rate, response duration, progression-free survival, crossover feasibility, and safety. RESULTS: A total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rank P = .010). Step 1 progression-free survival favored arm A (P = .054). Objective response rates were arm A: 46.0%; arm B: 43.0%; arm C: 47.8%; and arm D: 29.6%. Median duration of response was not reached for arm A and 12.7 months for arm B (P < .001). Crossover occurred in 52% of patients with documented disease progression. Grade ≥ 3 toxicities occurred with similar frequency between arms, and regimen toxicity profiles were as anticipated. CONCLUSION: Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer.

PURPOSE: We assessed the safety, pharmacokinetics and anticancer activity of intravesical CG0070, a cancer selective, replication competent adenovirus, for the treatment of nonmuscle invasive bladder cancer. MATERIALS AND METHODS: A total of 35 patients received single or multiple (every 28 days × 3 or weekly × 6) intravesical infusions of CG0070 at 1 of 4 dose levels (1 × 10(12), 3 × 10(12), 1 × 10(13) or 3 × 10(13) viral particles). Response to treatment was based on cystoscopic assessment and biopsy or urine cytology. Urine and plasma CG0070, and granulocyte-monocyte colony-stimulating factor were measured in all patients. A subset of 18 patients was assessed for retinoblastoma phosphorylation status. RESULTS: Grade 1-2 bladder toxicities were the most common adverse events observed. A maximum tolerated dose was not reached. High levels of granulocyte-monocyte colony-stimulating factor were detected in urine after administration in all patients. Virus replication was suggested based on an increase in urine CG0070 genomes between days 2 and 5 in 58.3% of tested patients (7 of 12). The complete response rate and median duration of the complete response across cohorts was 48.6% and 10.4 months, respectively. In the multidose cohorts the complete response rate for the combined groups (every 28 days and weekly × 6) was 63.6% (14 of 22 patients). In an exploratory, retrospective assessment patients with borderline or high retinoblastoma phosphorylation who received the multidose schedules had an 81.8% complete response rate (9 of 11). CONCLUSIONS: Intravesical CG0070 was associated with a tolerable safety profile and antibladder cancer activity. Granulocyte-monocyte colony-stimulating factor transgene expression and CG0070 replication were also suggested.

Tumor burden of lung metastases at initial staging in breast cancer patients detected by artificial intelligence as a prognostic tool for precision medicine.

BACKGROUND: Determination of the total number and size of all pulmonary metastases on chest CT is time-consuming and as such has been understudied as an independent metric for disease assessment. A novel artificial intelligence (AI) model may allow for automated detection, size determination, and quantification of the number of pulmonary metastases on chest CT. OBJECTIVE: To investigate the utility of a novel AI program applied to initial staging chest CT in breast cancer patients in risk assessment of mortality and survival. METHODS: Retrospective imaging data from a cohort of 226 subjects with breast cancer was assessed by the novel AI program and the results validated by blinded readers. Mean clinical follow-up was 2.5 years for outcomes including cancer-related death and development of extrapulmonary metastatic disease. AI measurements including total number of pulmonary metastases and maximum nodule size were assessed by Cox-proportional hazard modeling and adjusted survival. RESULTS: 752 lung nodules were identified by the AI program, 689 of which were identified in 168 subjects having confirmed lung metastases (Lmet+) and 63 were identified in 58 subjects without confirmed lung metastases (Lmet-). When compared to the reader assessment, AI had a per-patient sensitivity, specificity, PPV and NPV of 0.952, 0.639, 0.878, and 0.830. Mortality in the Lmet + group was four times greater compared to the Lmet-group (p = 0.002). In a multivariate analysis, total lung nodule count by AI had a high correlation with overall mortality (OR 1.11 (range 1.07-1.15), p < 0.001) with an AUC of 0.811 (R2 = 0.226, p < 0.0001). When total lung nodule count and maximum nodule diameter were combined there was an AUC of 0.826 (R2 = 0.243, p < 0.001). CONCLUSION: Automated AI-based detection of lung metastases in breast cancer patients at initial staging chest CT performed well at identifying pulmonary metastases and demonstrated strong correlation between the total number and maximum size of lung metastases with future mortality. CLINICAL IMPACT: As a component of precision medicine, AI-based measurements at the time of initial staging may improve prediction of which breast cancer patients will have negative future outcomes.

Combined treatment of dendritoma vaccine and low-dose interleukin-2 in stage IV renal cell carcinoma patients induced clinical response: A pilot study.

Vaccination using dendritic/tumor cell hybrids represents a novel and promising cancer immunotherapy. We have developed a technology that can instantly purify the hybrids (dendritomas) from the fusion mixture of dendritic cells (DCs) and tumor cells. Our animal studies and a phase I study of stage IV melanoma patients demonstrated that dendritoma vaccination could be conducted without major toxicity and induced tumor cell-specific immunological and clinical responses. In this pilot study, ten stage IV renal cell carcinoma patients were studied. Dendritomas were made from autologous DCs and tumor cells and administered by subcutaneous injection. After initial vaccination, three escalating doses of IL-2 (3, 6, and 9 million units each) were followed within five days. This treatment regimen was tolerated well without severe adverse events directly related to the dendritoma vaccine. Most adverse events were related to IL-2 administration or pre-existing disease. Patient-specific immune responses were evaluated by flow cytometric measurement of interferon-gamma-producing T-cells before and after vaccination in response to stimulation with tumor antigens. Nine out of nine patients eligible for the analysis showed an increase of IFN-gamma-expressing CD4+ T cells after vaccination(s); while five out of eight patients eligible for the analysis showed an increase of IFN-gamma-expressing CD8+ T cells. Clinical responses were documented in 40% of the patients, three with stabilization of disease and one with a partial response documented by a reduction in tumor size. This pilot study demonstrated that dendritoma vaccines could be administered safely to patients with metastatic renal cell carcinoma, while producing both clinical and immunologic evidence of response.

Dendritoma vaccination combined with low dose interleukin-2 in metastatic melanoma patients induced immunological and clinical responses.

A pilot clinical trial using dendritomas, purified hybrids from the fusion of dendritic/tumor cells combined with a low dose of IL-2, in metastatic melanoma patients was conducted in order to determine its safety and potential immunological and clinical responses. Ten metastatic melanoma patients were enrolled into this study. Dendritoma vaccines were created by fusing dendritic cells stained with green fluorescent dye with irradiated autologous tumor cells stained with red fluorescent dye and purifying the hybrids using immediate fluorescent-activated cell sorting. Initial vaccine was given subcutaneously and followed by IL-2 in serially elevated doses from 3-9 million units/m2 for 5 days. Repeated vaccinations were administered without IL-2, at 3-month intervals for a maximum of 5 times. Immune reactions were measured by the increase of interferon-gamma (IFN-gamma) expressing T cells. Vaccine doses ranged from 250,000 to 1,000,000 dendritomas. There was no grade 2 or higher toxicity directly attributable to the vaccine. All patients experienced toxicity due to IL-2 administration (9-grade 2, 3-grade 3, 1-grade 4). Eight of nine evaluable patients demonstrated immunologic reactions by increased IFN-gamma expressing T cells. One patient developed partial response at 12 weeks after the first vaccine. Nine months later, this patient achieved a complete response. In addition, two patients had stable disease for 9 and 4 months, respectively; one patient had a mixed response. Our findings demonstrated that dendritoma vaccines with a low dose of IL-2 can be safely administered to patients with metastatic melanoma and induce immunological and clinical responses.

Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration-Resistant Prostate Cancer.

PURPOSE: Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study. EXPERIMENTAL DESIGN: In ARMOR1, 49 patients received increasing doses (650-2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700-3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed. RESULTS: In ARMOR1, across all doses, 49.0% (24/49) achieved a ≥30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a ≥50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events. CONCLUSIONS: The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition.

Troxacitabine, an L-stereoisomeric nucleoside analog, on a five-times-daily schedule: a phase I and pharmacokinetic study in patients with advanced solid malignancies.

PURPOSE: To assess the feasibility of administering troxacitabine, a unique L-nucleoside that is not a substrate for deoxycytidine deaminase-mediated catabolism, as a 30-minute intravenous (IV) infusion daily for 5 days. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of troxacitabine as a 30-minute IV infusion daily for 5 days. Plasma and urine sampling was performed to characterize the pharmacokinetics and pharmacodynamics of troxacitabine. RESULTS: Thirty-nine patients received 124 courses of troxacitabine at eight dose levels ranging from 0.12 to 1.8 mg/m(2)/d. Severe neutropenia that was protracted (> 5 days) and/or associated with fever, and skin rashes were consistently experienced by heavily (HP) and minimally pretreated (MP) patients at doses exceeding 1.2 and 1.5 mg/m(2)/d, respectively. At troxacitabine doses > or = 1.2 mg/m(2)/d, treatment was often delayed 1 additional week for complete resolution of hematologic effects, resulting in lengthening of the treatment interval from every 3 to 4 weeks. Skin rash, palmar-plantar erythrodysesthesia, and thrombocytopenia were also observed and were occasionally severe, particularly at the highest doses. A patient with metastatic ocular melanoma experienced a partial response. Pharmacokinetics of troxacitabine were dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance (Cl(s)) were 60 (32) L and 161 (33) mL/min, respectively, on day 1. After treatment on the fifth day, terminal half-life values averaged 39 (63) hours, and Cl(s) was reduced by approximately 20%, averaging 127 (27) mL/min. The principal mode of drug elimination was renal. CONCLUSION: Recommended doses for phase II studies of troxacitabine as a 30-minute infusion daily for 5 days every 4 weeks are 1.5 and 1.2 mg/m(2)/d for MP and HP patients, respectively. Broad disease-directed evaluations of troxacitabine on this schedule and possibly less frequent schedules are warranted.

Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors.

PURPOSE: The metabolism of pazopanib is primarily mediated by CYP3A4. The solubility of pazopanib is pH-dependent, and an elevated gastric pH may decrease its bioavailability. This study evaluated the effect of a potent CYP3A4 inhibitor, ketoconazole, and the proton pump inhibitor esomeprazole on the pharmacokinetics and safety of pazopanib and its metabolites. METHODS: In Arm A, patients received pazopanib 400 mg alone once daily for 7 days followed by pazopanib 400 mg plus ketoconazole 400 mg once daily for 5 days. In Arm B, patients received pazopanib 800 mg once daily for 7 days, followed by pazopanib 800 mg plus esomeprazole 40 mg once daily for 5 days, and then pazopanib alone on the last day. RESULTS: Arm A enrolled 21 patients. In the presence of ketoconazole, mean area under the plasma concentration-time curve 24 h post-dose (AUC(0-24)) and mean maximum observed concentration (C max) of pazopanib increased by 66 and 45 %, respectively; mean AUC(0-24) and C max for pazopanib metabolites were lower or remained unchanged. Arm B enrolled 13 patients. In the presence of esomeprazole, mean pazopanib AUC(0-24) and C max decreased by 40 and 42 %, respectively; mean values of those parameters for metabolites of pazopanib also decreased. CONCLUSIONS: Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If coadministration is necessary, pazopanib should be reduced to 400 mg. Concomitant use of pazopanib and proton pump inhibitors should also be avoided. Alternative dosing regimens that do not increase gastric pH at the time of pazopanib dosing should be considered.

Phase I clinical study of Seneca Valley Virus (SVV-001), a replication-competent picornavirus, in advanced solid tumors with neuroendocrine features.

PURPOSE: Seneca Valley Virus (SVV-001) is a novel naturally occurring replication-competent picornavirus with potent and selective tropism for neuroendocrine cancer cell types, including small cell lung cancer. We conducted a first-in-human, first-in-class phase I clinical trial of this agent in patients with cancers with neuroendocrine features, including small cell lung cancer. EXPERIMENTAL DESIGN: Clinical evaluation of single intravenous doses in patients with cancers with neuroendocrine features was performed across five log-increments from 10(7) to 10(11) vp/kg. Toxicity, viral titers and clearance, neutralizing antibody development, and tumor response were assessed. RESULTS: A total of 30 patients were treated with SVV-001, including six with small cell carcinoma at the lowest dose of 10(7) vp/kg. SVV-001 was well tolerated, with no dose-limiting toxicities observed in any dose cohort. Viral clearance was documented in all subjects and correlated temporally with development of antiviral antibodies. Evidence of in vivo intratumoral viral replication was observed among patients with small cell carcinoma, with peak viral titers estimated to be >10(3)-fold higher than the administered dose. One patient with previously progressive chemorefractory small cell lung cancer remained progression-free for 10 months after SVV-001 administration, and is alive over 3 years after treatment. CONCLUSIONS: Intravenous SVV-001 administration in patients is well tolerated at doses up to 10(11) vp/kg, with predictable viral clearance kinetics, intratumoral viral replication, and evidence of antitumor activity in patients with small cell lung cancer. Phase II clinical evaluation in small cell lung cancer is warranted, and has been initiated.

Pilot study using molecular profiling of patients' tumors to find potential targets and select treatments for their refractory cancers.

PURPOSE: To compare the progression-free survival (PFS) using a treatment regimen selected by molecular profiling (MP) of a patient's tumor with the PFS for the most recent regimen on which the patient had experienced progression (ie, patient as his own control). PATIENTS AND METHODS: Patients with refractory metastatic cancer had tissue samples submitted for MP in two formats including formalin-fixed tissue for immunohistochemistry and fluorescent in situ hybridization assays and immediately frozen tissue for oligonucleotide microarray (MA) gene expression assays (all performed in a Clinical Laboratory Improvement Amendments [CLIA]-certified laboratory). The MP approach was deemed of clinical benefit for the individual patient who had a PFS ratio (PFS on MP-selected therapy/PFS on prior therapy) of ≥ 1.3. RESULTS: In 86 patients who had MP attempted, there was a molecular target detected in 84 (98%). Sixty-six of the 84 patients were treated according to MP results. Eighteen (27%) of 66 patients had a PFS ratio of ≥ 1.3 (95% CI, 17% to 38%; one-sided, one-sample P = .007). Therefore, the null hypothesis (that ≤ 15% of this patient population would have a PFS ratio of ≥ 1.3) was rejected. CONCLUSION: It is possible to identify molecular targets in patients' tumors from nine different centers across the United States. In 27% of patients, the MP approach resulted in a longer PFS on an MP-suggested regimen than on the regimen on which the patient had just experienced progression. Issues to be considered in interpretation of this study include limited prior experience with patients as their own controls as a study end point and overall patient attrition.

Complete remissions observed in acute myeloid leukemia following prolonged exposure to lintuzumab: a phase 1 trial.

A multi-institutional, phase 1 dose-escalation trial of lintuzumab (humanized anti-CD33 antibody; SGN-33, HuM195) was performed in patients with CD33-positive myeloid malignancies. In this study, higher doses than previously tested and prolonged duration of treatment for responding patients were evaluated. Over the dose range of 1.5-8 mg/kg/week, lintuzumab was well tolerated, and a maximum tolerated dose was not defined. The most common adverse event was transient chills with the initial lintuzumab infusion (39%). Responses were observed in 7 of 17 patients with acute myeloid leukemia: morphologic complete remission (n = 4), partial remission (n = 2), and morphologic leukemia-free state (n = 1). Of 14 patients with myelodysplastic syndrome or myeloproliferative diseases, 1 patient had major hematologic improvement and 9 patients had stable disease. In contrast to aggressive conventional chemotherapy, lintuzumab was administered in an ambulatory clinic setting with acceptable toxicity.