Citations

AbstractBackgroundProstate‐specific membrane antigen (PSMA) is a well‐established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody‐drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti‐PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA‐positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate‐specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration‐resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy.MethodsA total of 119 (84 chemotherapy‐experienced and 35 chemotherapy‐naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed.ResultsPSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy‐naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy‐naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy‐naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy‐experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy‐naïve group had partial responses. The most common treatment‐related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis.ConclusionsPSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment‐related AEs included neutropenia and neuropathy.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Abstract Informed consent, enshrined in many of the codes of conduct of psychology and psychiatry professional organizations, is an integral component behind the ethical practice of psychotherapy. Foundationally, informed consent respects patient autonomy and should be a knowledge sharing process that allows patients greater agency and improved alliance with their clinician. Psychotherapy differs from medical and surgical interventions in that it is a longitudinal, collaborative, and interpersonal treatment. As many psychotherapists are not trained in traditional medical models of care, a medically based framework for informed consent may not be as familiar and appropriate for psychotherapy. These nuances do not diminish the need for informed consent but rather emphasize the distinctiveness of psychotherapy and necessity of adapting to this treatment modality. In this chapter, the informed consent process for psychotherapy is examined, detailing its historical development, legal and ethical foundations, as well as the subtleties and challenges regarding implementation.

AbstractBackgroundAn association between inflammatory bowel disease (IBD) and obesity has been observed. Little is known about the effect of weight loss on IBD course. Our aim was to determine the impact of bariatric surgery on long-term clinical course of obese patients with IBD, either Crohn's disease (CD) or ulcerative colitis (UC).MethodsPatients with IBD who underwent bariatric surgery subsequent to IBD diagnosis were identified from 2 tertiary IBD centers. Complications after bariatric surgery were recorded. Patients were matched 1:1 for age, sex, IBD subtype, phenotype, and location to patients with IBD who did not undergo bariatric surgery. Controls started follow-up at a time point in their disease similar to the disease duration in the matched case at the time of bariatric surgery. Inflammatory bowel disease medication usage and disease-related complications (need for corticosteroids, hospitalizations, and surgeries) among cases and controls were compared.ResultsForty-seven patients met inclusion criteria. Appropriate matches were found for 25 cases. Median follow-up among cases (after bariatric surgery) and controls was 7.69 and 7.89 years, respectively. Median decrease in body mass index after bariatric surgery was 12.2. Rescue corticosteroid usage and IBD-related surgeries were numerically less common in cases than controls (24% vs 52%; odds ratio [OR], 0.36; 95% confidence interval [CI], 0.08–1.23; 12% vs 28%; OR, 0.2; 95% CI, 0.004–1.79). Two cases and 1 control were able to discontinue biologics during follow-up.ConclusionsInflammatory bowel disease patients with weight loss after bariatric surgery had fewer IBD-related complications compared with matched controls. This observation requires validation in a prospective study design.

Abstract Background A meta-analysis by our group has shown an elevated risk of lymphoma with thiopurine therapy for IBD (Kandiel 2005 Gut). It summed referral data and population (pop) data, but the risk of lymphoma in referral centers may be skewed higher due to referral bias (Ang 2006 PMID 16531538). Since a previous meta-analysis presented in 2012 (Kotlyar 2012, DDW), there have been two large population based studies published (Pasternak 2013 Am J of Epidemiol, Abbas 2013 Gastroenterology). The latter study reported on a nationwide database of patients from the Veterans Affairs (VA) Hospitals from the United States. Aims Calculate the standard incidence rate of lymphoma in pts exposed to AZA/6-MP in population cohort studies and contrast these results to referral center studies. Methods We searched MEDLINE and the Cochrane Database for: “lymphoproliferative and thiopurines”; and “azathioprine and lymphoma”. Included citations were IBD cohort studies, evaluated cancer as an outcome, and pts. received AZA and/or 6-MP. Additionally a comprehensive search of the literature and abstracts from international meetings (2005-2013) was done. In our study additional data were extracted from the Spanish collaborative registry ENEIDA. Pooled standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were estimated. CIs assumed a Poisson distribution. To examine for heterogeneity, the deviance statistic from Poisson regression models was examined. Results There were 507 citations, and fifteen citations were included. Two studies (Korelitz and Kinlen) were obtained from Kandiel 2005, and Lewis 2001 was replaced by Armstrong 2010 as data were of the GPRD database. In referral studies (n=7), the SIR = 6.47 (95% CI: 3.77-10.36). In pop studies (n=8), the SIR = 2.27 (95% CI: 1.76-2.88). Overall the SIR was = 2.61 (95% CI: 2.08-3.23). Data from referral centers did not show significant heterogeneity (p=0.052), while pop studies did show significant heterogeneity (p=0.003). Results between referral and pop centers showed a significant difference (p<0.01). Conclusion Pts with IBD who are treated with thiopurines have approximately a 3-fold increased risk of lymphoma as compared to the general pop. The SIR of referral studies were seen to be significantly higher than those of population based studies, consistent with possible referral bias. Also, the addition of two population based studies have added 58,349 person-years of follow-up to our analysis.With a total of 84 lymphomas observed, and with total pt-years being 184,085, this study shows 2,191 pt-yrs per lymphoma in the exposed group. Meta-analysis of Standardized Incidence Ratios (SIR) Disclosures: Lewis: Pfizer: Consultancy; Centocor: Consultancy; Allos: Research Funding; Shire: Consultancy; Takeda: Research Funding; Amgen: Research Funding; Millenium: Consultancy; AstraZeneca: Consultancy; GlaxoSmithKline: Consultancy; Dark Canyon Labs: Consultancy; Roche Pharma AG: Consultancy. Beaugerie:Ferring : Speakers Bureau; Schering-Plough: Speakers Bureau; Merck : Speakers Bureau. Loftus:Pfizer: Consultancy; Genentech: Research Funding; Braintree: Research Funding; Abbott: Consultancy, Research Funding; UCB: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Shire: Membership on an entity’s Board of Directors or advisory committees; Centocor: Research Funding; Takeda: Research Funding; Amgen: Research Funding. Lichtenstein:Abbott: Research Funding; BristolMyers: Consultancy; Centocor: Consultancy, Research Funding; Elan: Research Funding; Ferring: Consultancy; MilleniumResearch: Consultancy; Procter and Gamble: Consultancy, Research Funding; Prometheus: Consultancy, Research Funding; Salix: Consultancy, Research Funding; Warner-Chilcotte: Consultancy, Research Funding; Schering-Plough: Consultancy; Shire: Consultancy, Research Funding; Wyeth: Consultancy; UCB: Consultancy.

AbstractObjectiveTo characterize the natural history and clinical features of myopathies caused by mono‐allelic, dominantly acting pathogenic variants in COL12A1.MethodsPatients with dominant COL12A1‐related myopathies were characterized by history and clinical examination, muscle imaging, and genetic analysis. Pathogenicity of the variants was assessed by immunostaining patient‐derived dermal fibroblast cultures for collagen XII.ResultsFour independent families with childhood‐onset weakness due to novel, dominantly acting pathogenic variants in COL12A1 were identified. Adult patients exhibited distal‐predominant weakness. Three families carried dominantly acting glycine missense variants, and one family had a heterozygous, intragenic, in‐frame deletion of exon 52 of COL12A1. All pathogenic variants resulted in increased intracellular retention of collagen XII in patient‐derived fibroblasts as well as loss of extracellular, fibrillar collagen XII deposition. Since haploinsufficiency for COL12A1 is largely clinically asymptomatic, we designed and evaluated small interfering RNAs (siRNAs) that specifically target the mutant allele containing the exon 52 deletion. Immunostaining of the patient fibroblasts treated with the siRNA showed a near complete correction of collagen XII staining patterns.InterpretationThis study characterizes a distal myopathy phenotype in adults with dominant COL12A1 pathogenic variants, further defining the phenotypic spectrum and natural history of COL12A1‐related myopathies. This work also provides proof of concept of a precision medicine treatment approach by proposing and validating allele‐specific knockdown using siRNAs specifically designed to target a patient’s dominant COL12A1 disease allele.

Abstract Background: Therapeutic blockade of the signaling axis between PD-1 and its ligand programmed cell death ligand-1 (PD-L1) with monoclonal antibodies has shown remarkable clinical success in the treatment of cancer and demonstrated impressive activity across a broad set of cancer subtypes, even at advanced and metastatic stages of disease. Contrary to treatment with monoclonal antibodies, chimeric B-cell cancer vaccines have the advantage of producing a specific immune response that can potentially induce memory B & T cell responses, while reducing immune evasion and suppression. Methods: We have translated two HER-2 combination peptide vaccines (B-Vaxx) to the clinic in a Phase 1/2b trial to safely deliver curative and transformative cancer immunotherapies to advanced cancer patients. We have created and established the development of a novel B-cell peptide vaccine (Key-Vaxx) with high immunogenicity that binds to human PD-1 and produces tumor inhibition in vivo in an animal model of colon cancer. Here, we describe the transferable CT-26-HER2 neu tumor model in Balb/c was used to test for synergistic effects of anti-PD1 immunization therapy in combination with anti-HER2 immunization therapy to determine whether this combination could increase immunogenicity, enhance anti-tumor responses and provide synergistic benefit in inhibiting tumor growth. Results: We show robust HER-2 and PD-1 antibody responses in all vaccinated mice indicating that the combined vaccination is effective in reducing tumor growth in a Balb/c syngeneic model of colon carcinoma versus either the PD-1 vaccine or more importantly the positive control gold standard that is anti-mouse PD-1 monoclonal antibody. The vaccine combination was found to be safe and did not appear to exhibit toxicity or autoimmunity. Conclusion: Development of a novel PD-1 vaccine in combination with two Chimeric HER-2 peptide vaccine provides synergistic inhibition of tumor growth with no evidence of toxicity or autoimmunity. A clinical trial with the combination is under planning. Citation Format: Tanios Bekaii-Saab, Jay Overholser, Yuhong Yang, Manuel Penichet, Pravin Kaumaya. Development of a novel PD-1 vaccine and in combination with two Chimeric HER-2 peptide vaccine provides synergistic inhibition of tumor growth in a syngeneic Balb/c model challenged with CT26/HER-2 carcinoma cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1453.

AbstractContrary to common perception, modern palliative care (PC) is applicable to all people with an incurable disease, not only cancer. PC is appropriate at every stage of disease progression, when PC needs emerge. These needs can be of physical, emotional, social, or spiritual nature. This document encourages the use of validated assessment tools to recognize such needs and ascertain efficacy of management. PC interventions should be provided alongside cardiologic management. Treating breathlessness is more effective, when cardiologic management is supported by PC interventions. Treating other symptoms like pain or depression requires predominantly PC interventions. Advance Care Planning aims to ensure that the future treatment and care the person receives is concordant with their personal values and goals, even after losing decision-making capacity. It should include also disease specific aspects, such as modification of implantable device activity at the end of life. The Whole Person Care concept describes the inseparability of the physical, emotional, and spiritual dimensions of the human being. Addressing psychological and spiritual needs, together with medical treatment, maintains personal integrity and promotes emotional healing. Most PC concerns can be addressed by the usual care team, supported by a PC specialist if needed. During dying, the persons’ needs may change dynamically and intensive PC is often required. Following the death of a person, bereavement services benefit loved ones. The authors conclude that the inclusion of PC within the regular clinical framework for people with heart failure results in a substantial improvement in quality of life as well as comfort and dignity whilst dying.

Abstract Background The aetiology of Crohn’s disease [CD] involves immune dysregulation in a genetically susceptible individual. Genome-wide association studies [GWAS] have identified 200 loci associated with CD, ulcerative colitis, or both, most of which fall within non-coding DNA regions. Long non-coding RNAs [lncRNAs] regulate gene expression by diverse mechanisms and have been associated with disease activity in inflammatory bowel disease. However, disease-associated lncRNAs have not been characterised in pathogenic immune cell populations. Methods Terminal ileal samples were obtained from 22 CD patients and 13 controls. RNA from lamina propria CD4+ T cells was sequenced and long intergenic non-coding RNAs [lincRNAs] were detected. Overall expression patterns, differential expression [DE], and pathway and gene enrichment analyses were performed. Knockdown of novel lincRNAs XLOC_000261 and XLOC_000014 was performed. Expression of Th1 or Th17-associated transcription factors, T-bet and RORγt, respectively, was assessed by flow cytometry. Results A total of 6402 lincRNAs were expressed, 960 of which were novel. Unsupervised clustering and principal component analysis showed that the lincRNA expression discriminated patients from controls. A total of 1792 lincRNAs were DE, and 295 [79 novel; 216 known] mapped to 267 of 5727 DE protein-coding genes. The novel lincRNAs were enriched in inflammatory and Notch signalling pathways [p &lt;0.05]. Furthermore, DE lincRNAs in CD patients were more frequently found in DNA regions with known inflammatory bowel disease [IBD]-associated loci. The novel lincRNA XLOC_000261 negatively regulated RORγt expression in Th17 cells. Conclusions We describe a novel set of DE lincRNAs in CD-associated CD4+ cells and demonstrate that novel lincRNA XLOC_000261 appears to negatively regulate RORγt protein expression in Th17 cells.