Citations

Abstract The American Thoracic Society Core Curriculum updates clinicians annually in adult and pediatric pulmonary disease, medical critical care, and sleep medicine, in a 3- to 4-year recurring cycle of topics. These topics will be presented at the 2020 International Conference. Below is the adult critical care medicine core including complications of chemotherapy, acute-on-chronic liver failure, alcohol withdrawal syndrome, mechanical circulatory support, direct oral anticoagulants, upper gastrointestinal hemorrhage, and vasopressor selection.

Abstract Purpose: Intratumorally injected Clostridium novyi-NT (nontoxic; lacking the alpha toxin), an attenuated strain of C. novyi, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation. Patients and Methods: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of C. novyi-NT across 6 dose cohorts (1 × 104 to 3 × 106 spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose. Results: Among 24 patients, a single intratumoral injection of C. novyi-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 × 106 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (n = 2) and grade 4 gas gangrene (n = 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (n = 1), limb abscess (n = 1), soft-tissue infection (n = 1), respiratory insufficiency (n = 1), and rash (n = 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. C. novyi-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses. Conclusions: Single intratumoral injection of C. novyi-NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of C. novyi-NT in humans.

Abstract Objective Regulations for clinical laboratories in the United States are complex. The goal of this review is to improve the clarity of laboratory-developed test (LDT) regulation to facilitate innovation. Methods A literature and regulation review of current legislation for compliance by U.S. clinical laboratories was performed, and examples of the steps to implement LDTs within compliance with the regulatory environment are shared. Results Many federal and state jurisdictions are critical to the functionality of a laboratory in addition to upcoming potential promulgation of the Verifying Accurate Leading-Edge IVCT Development Act. Increased regulation, although imperative to maintain consistent, high-standard clinical care, could mean additional costs for developers and healthcare while also hindering innovation. Conclusion An extensive discussion of proposed regulations for LDTs needs to occur. Laboratory testing requires the sustained use of innovative methods at a cost that will permit continued, timely, uninterrupted high-quality service.

Abstract Our group has demonstrated that combinations of epigenetic modifiers produce potent synergy in pre-clinical models of PTCL, and has confirmed this data in early phase clinical studies. We showed that the combination of romidepsin and hypomethylating agents, decitabine or azacytidine, uniquely induces the expression of genes, including cancer testis antigens, gamma interferon and endogenous retrovirus. We are conducting a phase 1 study of pembrolizumab combined with pralatrexate alone (Arm A), with pralatrexate + decitabine (Arm B), or decitabine alone (Arm C) in patients with peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma. In addition, we are conducting a Phase 1/2A study of durvalumab combined with oral 5-azacitidine + romidepsin (Arm A), pralatrexate + romidepsin (Arm B), romidepsin (Arm C), or oral 5-azacitidine (Arm D) in patients with PTCL. Patient characteristics are listed in Table 1. We have treated a total of 12 patients across the 2 trials and 4 different Arms including pralatrexate plus pembrolizumab (3 patients), pralatrexate, decitabine and pembrolizumab (3 patients), decitabine and pembrolizumab (3 patients) and azacytidine, romidepsin and durvalumab (3 patients). Twelve patients out of 12 received at least one dose of drug and were evaluable for toxicity. There was a dose limiting toxicity (DLT) for each arm including prolonged grade 3 thrombocytopenia, febrile neutropenia, grade 3 hyponatremia and rash, and cytokine release syndrome, respectively. There were no treatment-related deaths. Eight patients out of 12 are evaluable for response at the time of this analysis. Three out of 8 patients achieved a complete remission, 3 out of 8 patients had a partial remission, and 2 out of 8 patients experienced progression of disease. Interestingly, all of the responses were seen in the triple combination of pralatrexate, decitabine, pembrolizumab and azacytidine, romidepsin and durvalumab. These preliminary clinical data suggest that the addition of immune-checkpoint inhibitors on an epigenetic backbone is safe and demonstrates encouraging responses in patient with PTCL and CTCL. These trials are registered at www.clinicaltrials.gov (NCT03240211, NCT03161223). Patient characteristics (n=12)Median age (range)68 (26-77)Sex, n (%) Male Female6 (50) 6 (50)Race, n (%)White/Non-Hispanic White/Hispanic Black Asian Unknown5 (42) 1 (8) 3 (25) 1 (8) 2 (17)Histology, n (%) PTCL, NOS AITL Mycosis Fungoides PTCL, NOS TFH ATLL Sezary Syndrome ALCL, ALK+2 (17) 2 (17) 2 (17) 1 (8) 1 (8) 1 (8) 1 (8)Stage at diagnosis IB II III IV Unknown1 (8) 2 (17) 3 (25) 4 (33) 2 (17)Median number of prior therapies (range) **2 unknown3 (0-5) Citation Format: Enrica Marchi, Helen Ma, Francesca Montanari, Ahmed Sawas, Jennifer K. Lue, Changchun Deng, Kareema T. Whitfield, Sandra Klein, Matthew V. Matthew, Freedy J. Loffredo, Luigi Scotto, Hyejung Lee, Hye A. Kim, Alice T. Jacobs, Aishling M. Rada, Karen A. Khan, Salvia Salvia, John Lister, Nora N. Benanni, Mark A. Francescone, Pier Luigi Zinzani, Wonseog Kim, Owen A. O'Connor. The integration of PD1 blockade with epigenetic therapy is highly active and safe in heavily treated patients with T-cell lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT160.

9567 Background: Functional disability degrades cancer patients' quality of life, exhausts caregivers and incurs significant expense yet little is know of the factors that contribute to disablement or whether the impact of these factors differs across functional domains. Better understanding of the influence that symptoms, physical impairments, and disease characteristics exert on disablement is needed in order to develop service delivery models that preserve function. Methods: To identify factors that influence functional performance in community dwelling people with stage IV breast cancer we conducted a cross-sectional study in a tertiary medical center outpatient cancer clinic. A consecutive sample of 163 community-dwelling patients with stage IV breast cancer were administered self- and clinician-rated functional metrics covering multiple domains including overall functioning, mobility, and self care. Self report measures included the Medical Outcomes Study Physical Function Subscale (PF-10) and the Older Americans Resource Study (OARS) Activities of Daily Living (ADL) and Instrumental ADL (IADL) subscales, and clinician report measures included the Karnofsky Performance Scale (KPS) and the Functional Independence Measure (FIM) Total and Mobility scores. Pain and mental health were assessed through administration of the Brief Pain Inventory (BPI) and Mental Health Inventory-17 (MHI-17), respectively. Electronic medical record review provided cancer-related and demographic information. The presence of physical impairments was determined through a comprehensive musculoskeletal and neurological physical examination including the 6 minute walk test. Linear and ordinal logistic regression models were constructed with function metrics as dependent variables. Results: Total number of physical impairments, BPI scores, and the presence of pleural effusions were highly significant in all models (p<0.01). Exertional intolerance and age were associated with PF-10 and OARS-ADL scores (p<0.01), while the presence of a pre-morbid disability was associated compromised mobility. Conclusions: Potentially remediable factors; pain intensity, cumulative impairment burden and pleural effusions, degrade all functional domains in patients with stage IV breast cancer. No significant financial relationships to disclose.

Abstract OBJECTIVE To determine the optimal energy profile for and to assess the feasibility and efficacy of ultrasonographic and laparoscopic guidance for microwave ablation (MWA) of clinically normal canine ovaries. SAMPLE 44 extirpated ovaries from 22 healthy dogs. PROCEDURES In the first of 2 trials, 13 dogs underwent oophorectomy by routine laparotomy. Extirpated ovaries underwent MWA at 45 W for 60 (n = 11) or 90 (12) seconds; 3 ovaries did not undergo MWA and served as histologic controls. Ovaries were histologically evaluated for cell viability. Ovaries without viable cells were categorized as completely ablated. Histologic results were used to identify the optimal MWA protocol for use in the subsequent trial. In the second trial, the ovaries of 9 dogs underwent MWA at 45 W for 90 seconds in situ. Ultrasonographic guidance for MWA was deemed unfeasible after evaluation of 1 ovary. The remaining 17 ovaries underwent MWA with laparoscopic guidance, after which routine laparoscopic oophorectomy was performed. Completeness of ablation was histologically assessed for all ovaries. RESULTS 2 ovaries were excluded from the trial 1 analysis because of equivocal cell viability. Six of 11 ovaries and 10 of 10 ovaries that underwent MWA for 60 and 90 seconds, respectively, were completely ablated. In trial 2, laparoscopic-guided MWA resulted in complete ablation for 12 of 17 ovaries. Dissection of the ovarian bursa for MWA probe placement facilitated complete ablation. CONCLUSIONS AND CLINICAL RELEVANCE Laparoscopic-guided MWA at 45 W for 90 seconds was feasible, safe, and effective for complete ablation of clinically normal ovaries in dogs.

Abstract Objectives A matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) method (Mass-Fix) as a replacement for gel-based immunofixation (IFE) has been recently described. To utilize Mass-Fix clinically, a validated automated method was required. Our aim was to automate the pre-analytical processing, improve positive specimen identification and ergonomics, reduce paper data storage and increase resource utilization without increasing turnaround time. Methods Serum samples were batched and loaded onto a liquid handler along with reagents and a barcoded sample plate. The pre-analytical steps included: (1) Plating immunopurification beads. (2) Adding 10 μl of serum. (3) Bead washing. (4) Eluting the immunoglobulins (Igs), and reducing to separate the heavy and light Ig chains. The resulting plate was transferred to a second low-volume liquid handler for MALDI plate spotting. MALDI-TOF mass spectra were collected. Integrated in-house developed software was utilized for sample tracking, driving data acquisition, data analysis, history tracking, and result reporting. A total of 1,029 residual serum samples were run using the automated system and results were compared to prior electrophoretic results. Results The automated Mass-Fix method was capable of meeting the validation requirements of concordance with IFE, limit of detection (LOD), sample stability and reproducibility with a low repeat rate. Automation and integrated software allowed a single user to process 320 samples in an 8 h shift. Software display facilitated identification of monoclonal proteins. Additionally, the process maintains positive specimen identification, reduces manual pipetting, allows for paper free tracking, and does not significantly impact turnaround time (TAT). Conclusions Mass-Fix is ready for implementation in a high-throughput clinical laboratory.

Pediatric aggressive mature B-cell lymphomas are the most common types of non-Hodgkin lymphoma in children, and they include Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). These diseases are highly aggressive but curable, the treatment is complex, and patients may have many complicated supportive care issues. The NCCN Guidelines for Pediatric Aggressive Mature B-Cell Lymphomas provide guidance regarding pathology and diagnosis, staging, initial treatment, disease reassessment, surveillance, therapy for relapsed/refractory disease, and supportive care for clinicians who treat sporadic pediatric BL and DLBCL.

AbstractObjectivesFailure to produce sufficient quantities of functional α1-antitrypsin (AAT) can result in AAT deficiency (AATD) and significant comorbidities. Laboratory testing plays a vital role in AATD, with diagnosis requiring documentation of both a low AAT level and a mutated allele. This retrospective evaluation examines the efficacy of a liquid chromatography–tandem mass spectrometry (LC-MS/MS) (proteotyping)–based algorithm for AATD detection.MethodsA 16-month retrospective data analysis was performed on two cohorts: 5,474 samples tested with the proteotype-based algorithm and 16,147 samples directly tested by isoelectric focusing (IEF) phenotyping.ResultsLC-MS/MS reduced the rate of IEF testing by 97%. The 3% of cases reflexed to IEF resulted in 12 (0.2%) additional phenotype findings. Retrospectively applying the proteotype-based algorithm to the IEF cohort demonstrated a 99.9% sensitivity for the detection of deficiency-associated phenotypes. Most deficiency phenotypes missed by the proteotyping algorithm would come from heterozygous patients with an F, I, or P paired to an S or Z. In all of these cases, patient AAT levels were greater than 70 mg/dL, above the threshold for AAT augmentation therapy.ConclusionsThe proteotype algorithm is a sensitive and cost-effective approach for the diagnosis of clinical AAT deficiency.

Abstract Background Parity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated. Methods A pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses. Results Ever having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend &lt; .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer. Conclusions Incomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.