Faculty Bibliography

BACKGROUND: Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. METHODS: In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks. RESULTS: Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60-80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. CONCLUSIONS: In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00957359.

OBJECTIVE: The purpose of this study was to evaluate trajectories of and predictors for changes in upper extremity (UE) function in women (n = 396) during the first year after breast cancer treatment. DESIGN: Prospective, longitudinal assessments of shoulder range of motion (ROM), grip strength, and perceived interference of function were performed before and for 1 year after surgery. Demographic, clinical, and treatment characteristics were evaluated as predictors of postoperative function. RESULTS: Women had a mean (SD) age of 54.9 (11.6) years, and 64% were white. Small but statistically significant reductions in shoulder ROM were found on the affected side over 12 months (P < 0.001). Predictors of interindividual differences in ROM at the 1-month assessment were ethnicity, neoadjuvant chemotherapy, type of surgery, axillary lymph node dissection, and preoperative ROM. Predictors of interindividual differences in changes over time in postoperative ROM were living alone, type of surgery, axillary lymph node dissection, and adjuvant chemotherapy. Declines in mean grip strength from before through 1 month after surgery were small and not clinically meaningful. Women with greater preoperative breast pain interference scores had higher postoperative interference scores at all postoperative assessments. CONCLUSION: Some of the modifiable risk factors identified in this study can be targeted for intervention to improve UE function in these women.

In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state-of-the-science regarding mTOR inhibitor-associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2-78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR-associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high-dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop.

Moderate-to-severe fatigue occurs in up to 94% of oncology patients undergoing active treatment. Current interventions for fatigue are not efficacious. A major impediment to the development of effective treatments is a lack of understanding of the fundamental mechanisms underlying fatigue. In the current study, differences in phenotypic characteristics and gene expression profiles were evaluated in a sample of breast cancer patients undergoing chemotherapy (CTX) who reported low (n = 19) and high (n = 25) levels of evening fatigue. Compared to the low group, patients in the high evening fatigue group reported lower functional status scores, higher comorbidity scores, and fewer prior cancer treatments. One gene was identified as upregulated and 11 as downregulated in the high evening fatigue group. Gene set analysis found 24 downregulated and 94 simultaneously up- and downregulated pathways between the two fatigue groups. Transcript origin analysis found that differential expression (DE) originated primarily from monocytes and dendritic cell types. Query of public data sources found 18 gene expression experiments with similar DE profiles. Our analyses revealed that inflammation, neurotransmitter regulation, and energy metabolism are likely mechanisms associated with evening fatigue severity; that CTX may contribute to fatigue seen in oncology patients; and that the patterns of gene expression may be shared with other models of fatigue (e.g., physical exercise and pathogen-induced sickness behavior). These results suggest that the mechanisms that underlie fatigue in oncology patients are multifactorial.

Tumor necrosis factor-alpha (TNF-alpha) is a proalgesic cytokine that is commonly expressed following tissue injury. TNF-alpha expression not only promotes inflammation but can also lead to pain hypersensitivity in nociceptors. With the established link between TNF-alpha and inflammatory pain, we identified its increased expression in the teeth of patients affected with caries and pulpitis. We generated a transgenic mouse model (TNF-alphaglo) that could be used to conditionally overexpress TNF-alpha. These mice were bred with a dentin matrix protein 1 (DMP1)-Cre line for overexpression of TNF-alpha in both the tooth pulp and bone to study oral pain that would result from subsequent development of pulpitis and bone loss. The resulting DMP1/TNF-alphaglo mice show inflammation in the tooth pulp that resembles pulpitis while also displaying periodontal bone loss. Inflammatory infiltrates and enlarged blood vessels were observed in the tooth pulp. Pulpitis and osteitis affected the nociceptive neurons innervating the orofacial region by causing increased expression of inflammatory cytokines within the trigeminal ganglia. With this new mouse model morphologically mimicking pulpitis and osteitis, we tested it for signs of oral pain with an oral function assay (dolognawmeter). This assay/device records the time required by a mouse to complete a discrete gnawing task. The duration of gnawing required by the DMP1/TNF-alphaglo mice to complete the task was greater than that for the controls; extended gnaw time in a dolognawmeter indicates reduced orofacial function. With the DMP1/TNF-alphaglo mice, we have shown that TNF-alpha expression alone can produce inflammation similar to pulpitis and osteitis and that this mouse model can be used to study dental inflammatory pain.

Raf Kinase Inhibitory Protein (RKIP) expression has been profiled for a number of unique tissue cancers. However, certain tissues have not been explored, and oral and oropharyngeal cancers stand out as high priority targets, given their relatively high incidence, high morbidity rate, and in many cases, preventable nature. The purpose of this study was to examine changes in RKIP expression and phosphorylation in tissues resected from oral cancer patients, and compare to results generated from immortalized cell lines raised from primary oral cancer tissues, including oral squamous cell carcinoma line 4 (SCC4) and human squamous cell carcinoma line 3 (HSC3). Out of 4 human samples collected from male and female patients across various ages with variable risk factors, we observed an across the board reduction in RKIP expression. Two human samples demonstrated a significant increase in phosphorylated RKIP when normalized to total RKIP, however all 4 were increased when normalized to total cellular protein. The immortalized oral cancer cell culture HSC3 revealed significant increases in phosphorylated RKIP with no change in total RKIP expression, while line SCC4 demonstrated an increase in both total and phosphorylated RKIP. Results presented here indicate that oral cancers behave similarly to other cancers in terms of changes in RKIP expression and phosphorylation, although immortalized cell line expression profiles significantly differ from human tissue biopsies.

Functional analysis of a clinical microbiome facilitates the elucidation of mechanisms by which microbiome perturbation can cause a phenotypic change in the patient. The direct approach for the analysis of the functional capacity of the microbiome is via shotgun metagenomics. An inexpensive method to estimate the functional capacity of a microbial community is through collecting 16S rRNA gene profiles then indirectly inferring the abundance of functional genes. This inference approach has been implemented in the PICRUSt and Tax4Fun software tools. However, those tools have important limitations since they rely on outdated functional databases and uncertain phylogenetic trees and require very specific data pre-processing protocols. Here we introduce Piphillin, a straightforward algorithm independent of any proposed phylogenetic tree, leveraging contemporary functional databases and not obliged to any singular data pre-processing protocol. When all three inference tools were evaluated against actual shotgun metagenomics, Piphillin was superior in predicting gene composition in human clinical samples compared to both PICRUSt and Tax4Fun (p<0.01 and p<0.001, respectively) and Piphillin's ability to predict disease associations with specific gene orthologs exhibited a 15% increase in balanced accuracy compared to PICRUSt. From laboratory animal samples, no performance advantage was observed for any one of the tools over the others and for environmental samples all produced unsatisfactory predictions. Our results demonstrate that functional inference using the direct method implemented in Piphillin is preferable for clinical biospecimens. Piphillin is publicly available for academic use at http://secondgenome.com/Piphillin.