Detecting HLA loss of heterozygosity within a standard diagnostic sequencing workflow for prognostic and therapeutic opportunities.

To enable interrogation of tumor HLA LOH as a clinical diagnostic for precision oncology, we developed and validated an assay that detects HLA LOH within the context of an FDA-approved clinical diagnostic test, Tempus xT CDx. Validation was conducted via: (1) analytical evaluation of 17 archival patient samples and 42 cell line admixtures and (2) independent clinical evaluation of LOH prevalence in the HLA-A gene (HLA-A LOH) across 10,982 patients. To evaluate the prognostic relevance of HLA-A LOH we assessed 256 immunotherapy-treated non-small cell lung cancer (NSCLC) patients. To determine the feasibility of prospectively identifying and enrolling HLA-A LOH patients into a clinical trial, we established BASECAMP-1 (NCT04981119). We observed a positive predictive agreement of 97% and a negative predictive agreement of 100% in samples with ≥ 40% tumor purity. We observed HLA-A LOH in 16.1% of patients (1771/10,982), comparable to previous reports. HLA-A LOH was associated with longer survival among NSCLC adenocarcinoma patients (HR = 0.60, 95% CI [0.37, 0.96], p = 0.032) with a trend towards shorter survival among squamous cell patients (HR = 1.64, 95% CI [0.80, 3.41], p = 0.183). In 20 months, we prospectively screened 1720 subjects using the Tempus AWARE program, identifying 26 HLA-A*02 LOH patients at 8 sites, with 14 (54%) enrolled into BASECAMP-1. In conclusion, we developed and validated an investigational assay that detects tumor HLA LOH within an FDA-approved clinical diagnostic test, enabling HLA LOH utilization in diagnostic, prognostic, and therapeutic applications.

Dynamic Changes in Circulating Tumor Fraction as a Predictor of Real-World Clinical Outcomes in Solid Tumor Malignancy Patients Treated with Immunotherapy.

INTRODUCTION: A dynamic molecular biomarker that can identify early efficacy of immune checkpoint inhibitor (ICI) therapy remains an unmet clinical need. Here we evaluate if a novel circulating tumor DNA (ctDNA) assay, xM, used for treatment response monitoring (TRM), that quantifies changes in ctDNA tumor fraction (TF), can predict outcome benefits in patients treated with ICI alone or in combination with chemotherapy in a real-world (RW) cohort. METHODS: This retrospective study consisted of patients with advanced cancer from the Tempus de-identified clinical genomic database who received longitudinal liquid-based next-generation sequencing. Eligible patients had a blood sample ≤ 40 days prior to the start of ICI initiation and an on-treatment blood sample 15-180 days post ICI initiation. TF was calculated via an ensemble algorithm that utilizes TF estimates derived from variants and copy number information. Patients with molecular response (MR) were defined as patients with a ≥ 50% decrease in TF between tests. In the subset of patients with rw-imaging data between 2 and 18 weeks of ICI initiation, the predictive value of MR in addition to rw-imaging was compared to a model of rw-imaging alone. RESULTS: The evaluable cohort (N = 86) was composed of 14 solid cancer types. Patients received either ICI monotherapy (38.4%, N = 33) or ICI in combination with chemotherapy (61.6%, N = 53). Patients with MR had significantly longer rw-overall survival (rwOS) (hazard ratio (HR) 0.4, P = 0.004) and rw-progression free survival (rwPFS) (HR 0.4, P = 0.005) than patients with molecular non-response (nMR). Similar results were seen in the ICI monotherapy subcohort; HR 0.2, P = 0.02 for rwOS and HR 0.2, P = 0.01 for rwPFS. In the subset of patients with matched rw-imaging data (N = 51), a model incorporating both MR and rw-imaging was superior in predicting rwOS than rw-imaging alone (P = 0.02). CONCLUSIONS: xM used for TRM is a novel serial quantitative TF algorithm that can be used clinically to evaluate ICI therapy efficacy.

Deriving the Transdiagnostic Scales From the Personality Assessment Inventory and SPECTRA: Indices of Psychopathology: A Demonstration.

Transdiagnostic models of psychopathology address many of the shortcomings common to categorical diagnostic systems. These empirically derived models conceptualize psychopathology as a few broad interrelated and hierarchically arranged dimensions, with an overarching general psychopathology dimension, the p-factor, at the apex. While transdiagnostic models are gaining prominence in mental health research, the lack of available tools has limited their clinical translation. The present study explored the potential of creating transdiagnostic scales from the joint factor structure of the Personality Assessment Inventory, Alternative Model of Personality Disorder trait scales (AMPD), and the clinical scales of the SPECTRA: Indices of Psychopathology (SPECTRA). Exploratory factor analysis in a clinical sample (n = 212) identified five factors corresponding to the Negative Affect/Internalizing, Detachment, Antagonism/Externalizing, Disinhibition/Externalizing, and Thought Disorder transdiagnostic dimensions. Goldberg's "Bass-Ackward" method supported a hierarchical structure. Five composite transdiagnostic scales were created by summing each factor's highest loading PAI and SPECTRA scales. A global psychopathology scale was created by summing the five composite scales. All the composite scales demonstrated adequate internal consistency. Correlations between the composite scales and the NEO Five-Factor Inventory-3 provide initial validity evidence for four composite and global scales. The composite thought disorder scale had no conceptually corresponding NEO domain. Clinical implications and study limitations are discussed.

Via subcutânea: segunda opção em cuidados paliativos / Subcutaneous route: second option in palliative care

A via subcutânea é indicada como via de segunda opção para a administração de fármacos de forma contínua ou intermitente nos pacientes em cuidados paliativos que não podem utilizar a via oral. No entanto, há controvérsias e pouca aderência ao seu uso. A dissecção venosa e/ou punção de subclávia ainda são procedimentos frequentes nos pacientes com doença avançada, vivenciando a fase final da vida. A via subcutânea é um método consensualmente reconhecido como seguro internacionalmente, não produzindo nenhuma complicação grave quando comparado ao intravenoso e, tecnicamente, a aplicação do cateter subcutâneo é mais fácil. No Brasil, os relatos científicos da administração de fármacos por via subcutânea são incipientes e, na prática clínica, ainda pouco utilizada. Uma discussão sobre essa técnica é premente no meio hospitalar. O objetivo deste estudo é realizar uma revisão teórica sobre o uso da via subcutânea na prática clínica com pacientes em cuidados paliativos. A busca foi realizada nas bases de dados no período de 1998 a 2010, nos meses de setembro e outubro de 2011. A análise do material encontrado apontou que é uma técnica de fácil aplicabilidade e manutenção em ambiente hospitalar ou domiciliar; melhora a autonomia e a qualidade de vida do paciente, sendo esse o objetivo primordial em cuidados paliativos.

Subcutaneous route is the second option for continuous or intermittent administration of medication to patients in need of palliative care who cannot receive oral medication. However, there is controversy over the use of the subcutaneous route and, thus, poor adherence to it. Vein dissection and/or subclavian puncture are frequent procedures in patients with advanced diseases during their terminal phase of life. Subcutaneous route is considered to be a safe method that does not cause severe complications when compared with the intravenous route. In addition, the technique used for subcutaneous catheter placement is much simpler. In Brazil, there are few reports on the administration of medication using the subcutaneous route, and this technique is seldom used in clinical practice. Therefore, there is urgent need for discussing the use of this technique in hospitals. The objective of this review of the literature was to investigate the use of the subcutaneous route in palliative care. We searched the databases in September and October of 2011. The studies included in our search were published between 1998 and 2010. The analysis of the articles selected suggests that the subcutaneous route is easy to use and maintain in both hospital and home environments. This technique improves the patients’ autonomy and quality of life, which is the main goal of palliative care.