Methodological Challenges for Epidemiologic Studies of Deprescribing at the End of Life

Purpose of Review: To describe approaches to measuring deprescribing and associated outcomes in studies of patients approaching end of life (EOL). Recent Findings: We reviewed studies published through 2020 that evaluated deprescribing in patients with limited life expectancy and approaching EOL. Deprescribing includes reducing the number of medications, decreasing medication dose(s), and eliminating potentially inappropriate medications. Tools such as STOPPFrail, OncPal, and the Unnecessary Drug Use Measure can facilitate deprescribing. Outcome measures vary and selection of measures should align with the operationalized deprescribing definition used by study investigators. Summary: EOL deprescribing considerations include medication appropriateness in the context of patient goals for care, expected benefit from medication given life expectancy, and heightened potential for medication-related harm as death nears. Additional data are needed on how EOL deprescribing impacts patient quality of life, caregiver burden, and out-of-pocket medication-related costs to patients and caregivers. Investigators should design deprescribing studies with this information in mind

Measurement of the open-charm contribution to the diffractive proton structure function

Production of D*+/-(2010) mesons in diffractive deep inelastic scattering has been measured with the ZEUS detector at HERA using an integrated luminosity of 82 pb^{-1}. Diffractive events were identified by the presence of a large rapidity gap in the final state. Differential cross sections have been measured in the kinematic region 1.5 < Q^2 < 200 GeV^2, 0.02 < y < 0.7, x_{IP} < 0.035, beta 1.5 GeV and |\eta(D*+/-)| < 1.5. The measured cross sections are compared to theoretical predictions. The results are presented in terms of the open-charm contribution to the diffractive proton structure function. The data demonstrate a strong sensitivity to the diffractive parton densities.Comment: 35 pages, 11 figures, 6 table

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The impact of depression on patient outcomes among older adults with lung cancer

Thesis (Ph.D.)--University of Washington, 2016-06Background: Depression is a common malady among older adults, and as the incidence of cancer increases with age, older adults may be living with both cancer and depression. Previous studies have assessed the impact of depression on patient outcomes when depression is measured around the time of a cancer diagnosis or during cancer treatment, but we know very little about how depression preceding the cancer diagnosis affects patient outcomes during the course of cancer treatment. Using the example of lung cancer, the most common cause of cancer death among older adults, we examined the association between pre-existing depression and cancer stage at diagnosis, survival, and health care utilization. Methods: We used the national Surveillance, Epidemiology, and End Results (SEER) database, linked to Medicare healthcare and prescription claims, to examine the association between pre-existing depression and patient outcomes for older adults with non-small cell lung cancer (NSCLC) diagnosed between 2008-2011 with claims from 2007-2013. We used multivariate logistic regression models to investigate the association of pre-existing depression, advanced NSCLC stage at diagnosis, and receipt of aggressive end-of-life care. We estimated multivariate Cox proportional hazards models to examine the association of pre-existing depression and overall survival. We utilized competing risk regression models to examine the relationship between pre-existing depression and time to anticancer therapy or hospice enrollment. Results: We included 24,666 people in our analysis. Older adults with pre-existing depression were less likely to be diagnosed with advanced stage NSCLC (OR 0.76, 95% CI 0.68-0.85). Of the 8,873 older adults with stages 1-3A NSCLC, persons with pre-existing depression and stage 1 NSCLC had a higher risk of death compared to those without depression (OR 1.19, 95% CI 1.01-1.41). We found similar patterns of anticancer therapy receipt between older adults with or without pre-existing depression, and no significant difference in time to first anticancer treatment, accounting for the competing risk of death. Among 14,385 decedents with stage 3B or 4 NSCLC, those with pre-existing depression were more likely to enroll in hospice than persons without depression (SHR 1.16, 95% CI 1.06-1.28). We found no difference in utilization of inpatient hospitalizations, emergency room use, or chemotherapy receipt in the last 30 days of life, comparing those with versus those without pre-existing depression. Discussion: In a national sample of older adults with NSCLC, pre-existing depression was associated with earlier stage at cancer diagnosis, shorter survival among those with early stage NSCLC and higher hospice utilization among persons with advanced NSCLC. These findings indicate the importance of screening for and treating depression during cancer therapy. As people with pre-existing depression are more likely to enroll in hospice, it is important that hospice organizations and caregivers have sufficient support to address cancer and mental health concerns at end-of-life

Level of HIV DNA in peripheral blood mononuclear cells correlates with efficacy of antiretroviral therapy

A novel colorimetric assay was developed and validated for accurate quantitation of HIV DNA in PBMCs. We tested 318 sequential samples from 56 subjects, 53 of whom were undergoing dual or triple therapy. Patients were considered responders when viremia levels were below 5,000 HIV RNA copies/ml: 3,492 and 1,242 were mean RNA copy number of responders, while 55,916 and 34,880 were of nonresponders. The mean DNA copy number for untreated and responder subjects were similar (72 and 75, respectively), while it was 4.54-fold higher for nonresponders (339). Moreover, it was higher for dual-therapy nonresponders than for triple therapy nonresponders, 390 and 288, respectively. This report (J Clin Microb, in press) provides strong evidence that HIV DNA levels in PBMCs correlate with therapeutic efficacy and suggests that DNA quantitation is a useful tool to monitor the decay of the HIV reservoir towards disease remission, especially when viremia is undetectable. Since both unintegrated and integrated HIV DNA forms were measured, the 2LTR circular unintegrated form was amplified in 91 samples from 15 patients. 2LTR DNA correlates with viral replication, but was also present in samples from patients with persistently undetectable viremia suggesting residual or cryptic HIV replication

Level of Human Immunodeficiency Virus DNA in Peripheral Blood Mononuclear Cells Correlates with Efficacy of Antiretroviral Therapy

A novel colorimetric assay was developed and validated for accurate quantitation of human immunodeficiency virus (HIV) DNA in peripheral blood mononuclear cells (PBMCs). We tested 318 sequential samples from 56 subjects, 53 of whom were undergoing dual or triple therapy. Patients were considered responders when viremia levels were below 5,000 HIV RNA copies/ml. The mean DNA copy numbers for untreated and responder subjects were similar (72 and 75, respectively), while it was 4.54-fold higher for nonresponders (339). This report provides strong evidence that HIV DNA levels in PBMCs correlate with therapeutic efficacy and suggests that DNA quantitation is a useful tool to monitor the decay of the HIV reservoir toward disease remission, especially when viremia is undetectable

New aspects and perspectives in AIDS diagnosis

Discovenes on the efficacy of antiretroviral drug have changed the management of HIV patients. More information on viral load is needed with accurate markers of remission and/or eradication. First objective: to evaluete the sensitivity of an innovative protocol for p24 antigen(3 Plus). The p24 assay has a sensitivity of 70 fg/reaction correlates with viral replication,viral load,CD4+cell numbers and therapy efficacy. Thuss it is a useful and inexpensive marker in AIDS management. Second objective: to develop and evaluate assays for total HIV DNA and non-integrated circular DNA. Total HIV DNA was detected in 96.9% of 548 samples from HIV-infected individuals. High levels of total HIV DNA in sequential samples correlated with therapy inefficacy and subsequent HIV replication,confirmed by the detection of non-integrated DNA. In absence of NI-DNA, total HIV DNA contrains only proviral DNA and is the only marker of remission and/or eradication