Publications

We previously demonstrated an association between decreased expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate the clinical relevance of SMAD4 loss in HNSCC. SMAD4 expression was assessed by IHC in 130 newly diagnosed and 43 patients with recurrent HNSCC. Correlative statistical analysis with clinicopathologic data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines and Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of prosurvival and antiapoptotic pathways that were commonly dysregulated in -low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that depletion in an HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss. Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors. .

Household air pollution (HAP) and chronic HIV infection are each associated with significant respiratory morbidity. Little is known about relationships between HAP and respiratory symptoms among people living with HIV. The objective of this study was to investigate the relationship between cooking fuel type and chronic respiratory symptoms in study participants from the Uganda AIDS Rural Treatment Outcomes Study. Study participants were enrolled at the time of antiretroviral therapy initiation and seen quarterly from 2005 to 2014 for health-focused questionnaires, CD4 count and HIV viral load. We used multivariable logistic regression and generalised estimating equations, with each study visit as a unit of observation, to investigate relationships between cooking fuel type and chronic respiratory symptoms. We observed an association between cooking with firewood ( charcoal) and chronic cough among HIV-infected females in rural Uganda (adjusted OR 1.41, 95% CI 1.00-1.99; p=0.047). We did not observe an association between cooking fuel type and respiratory symptoms among males (adjusted OR 0.88, 95% CI 0.47-1.63; p=0.658). Associations between cooking fuel and chronic cough in this HIV-infected cohort may be influenced by sex-based roles in meal preparation. This study raises important questions about relationships between household air pollution, HIV infection and respiratory morbidity.

The purpose of this prospective study was to estimate the effect of Ga-labeled prostate-specific membrane antigen (PSMA)-11 PET on the intended management of patients with biochemically recurrent prostate cancer. Pre- and postimaging surveys were filled out by the referring providers for patients with biochemical recurrence who were imaged using Ga-PSMA-11 PET. The inclusion criterion for this study was a prostate-specific antigen (PSA) doubling time of less than 12 mo after initial treatment (NCT02611882). Of the 150 consecutive patients imaged, 126 surveys were completed (84% response rate). The responses were categorized as major change, minor change, no change, or unknown change. There were 103 patients (82%) with disease detected on Ga-PSMA-11 PET. On the basis of the survey results, there were 67 patients (53.2%) with major changes in management and 8 patients (6.4%) with minor changes. The proportion of cases resulting in a change in management did not significantly differ by baseline PSA level. In patients with PSA levels below 0.2 ng/dL, 7 of 12 patients had disease detected on Ga-PSMA-11 PET, 5 of whom had a major change in management. Ga-PSMA-11 PET resulted in a major change in management in 53% of patients with biochemical recurrence. Further studies are warranted to investigate whether PSMA-based management strategies result in improved outcomes for patients.

BACKGROUND

Optimal management of chronic medications for patients with life-limiting illness is uncertain. Medication deprescribing may improve outcomes in this population, but patient concerns regarding deprescribing are unclear.

OBJECTIVE

The aim of this study was to quantify the perceived benefits and concerns of statin discontinuation among patients with life-limiting illness.

DESIGN

Baseline data from a multicenter, pragmatic clinical trial of statin discontinuation were used.

SETTING/SUBJECTS

Cognitively intact participants with a life expectancy of 1-12 months receiving statin medications for primary or secondary prevention were enrolled.

MEASUREMENTS

Responses to a 9-item questionnaire addressing patient concerns about discontinuing statins were collected. We used Pearson chi-square tests to compare responses by primary life-limiting diagnosis (cancer, cardiovascular disease, other).

RESULTS

Of 297 eligible participants, 58% had cancer, 8% had cardiovascular disease, and 30% other primary diagnoses. Mean (standard deviation) age was 72 (11) years. Fewer than 5% of participants expressed concern that statin deprescribing indicated physician abandonment. About one in five participants reported being told to take statins for the rest of their life (18%) or feeling that discontinuation represented prior wasted effort (18%). Many participants reported benefits of stopping statins, including spending less money on medications (63%), potentially stopping other medications (34%), and having a better quality of life (25%). More participants with cardiovascular disease as a primary diagnosis perceived that quality-of-life benefits related to statin discontinuation (52%) than participants with cancer (27%) or noncardiovascular disease diagnoses (27%) [p = 0.034].

CONCLUSION

Few participants expressed concerns about discontinuing statins; many perceived potential benefits. Cardiovascular disease patients perceived greater potential positive impact from statin discontinuation.

Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance. Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system. Monoclonal antibodies that block the interaction between PD-1 and PD-L1, by binding to either the ligand or receptor, have shown notable clinical efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small-cell lung cancer and Hodgkin's lymphoma. Although it is well established that PD-1-PD-L1 blockade activates T cells, little is known about the role that this pathway may have in tumour-associated macrophages (TAMs). Here we show that both mouse and human TAMs express PD-1. TAM PD-1 expression increases over time in mouse models of cancer and with increasing disease stage in primary human cancers. TAM PD-1 expression correlates negatively with phagocytic potency against tumour cells, and blockade of PD-1-PD-L1 in vivo increases macrophage phagocytosis, reduces tumour growth and lengthens the survival of mice in mouse models of cancer in a macrophage-dependent fashion. This suggests that PD-1-PD-L1 therapies may also function through a direct effect on macrophages, with substantial implications for the treatment of cancer with these agents.