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232


Oral Complications at Six Months after Radiation Therapy for Head and Neck Cancer

Lalla, Rajesh V; Treister, Nathaniel; Sollecito, Thomas; Schmidt, Brian; Patton, Lauren L; Mohammadi, Kusha; Hodges, James S; Brennan, Michael T
OBJECTIVE: Examine oral complications 6 months after modern radiation therapy (RT) for head and neck cancer (HNC). METHODS: Prospective multi-center cohort study of HNC patients receiving Intensity-Modulated Radiation Therapy (IMRT) or more advanced RT. Stimulated whole salivary flow, maximal mouth opening, oral mucositis, oral pain, oral health-related quality of life (OH-QOL), and oral hygiene practices, were measured in 372 subjects pre-RT and 216 at 6 months from start of RT. RESULTS: Mean stimulated whole salivary flow declined from 1.09 ml/min to 0.47 ml/min at 6 months (p < 0.0001). Mean maximal mouth opening reduced from 45.58 mm to 42.53 mm at 6 months (p < 0.0001). 8.1% of subjects had some oral mucositis at 6 months, including 3.8% with oral ulceration. Mean overall pain score was unchanged. OH-QOL was reduced at 6 months, with changes related to dry mouth, sticky saliva, swallowing solid foods, and sense of taste (p
PMID: 28675770
ISSN: 1601-0825
CID: 2617062

OPRM1 Methylation Contributes to Opioid Tolerance in Cancer Patients

Viet, Chi T; Dang, Dongmin; Aouizerat, Bradley E; Miaskowski, Christine; Ye, Yi; Viet, Dan T; Ono, Kentaro; Schmidt, Brian L
Cancer patients in pain require high doses of opioids and quickly become opioid-tolerant. Previous studies have shown that both chronic cancer pain and high dose opioid use lead to mu-opioid receptor down-regulation. In this study we explore down-regulation of OPRM1, the mu-opioid receptor gene, as a mechanism f,or opioid tolerance in the setting of opioid use for cancer pain. We demonstrate in a cohort of 84 cancer patients that high dose opioid use correlates with OPRM1 hypermethylation in peripheral leukocytes of these patients. We then reverse-translate our clinical findings by creating a mouse cancer pain model; we create opioid tolerance in the mouse cancer model to mimic opioid tolerance in the cancer patients. Using this model we determine the functional significance of OPRM1 methylation on cancer pain and opioid tolerance. We focus on two main cells within the cancer microenvironment: the cancer cell and the neuron. We show that targeted re-expression of mu-opioid receptor on cancer cells inhibits mechanical and thermal hypersensitivity, and prevents opioid tolerance, in the mouse model. The resultant analgesia and protection against opioid tolerance are likely due to preservation of mu-opioid receptor expression on the cancer-associated neurons.
PMCID:5918413
PMID: 28456745
ISSN: 1528-8447
CID: 2547002

Cutaneous pigmentation modulates skin sensitivity via tyrosinase-dependent dopaminergic signalling

Ono, Kentaro; Viet, Chi T; Ye, Yi; Dang, Dongmin; Hitomi, Suzuro; Toyono, Takashi; Inenaga, Kiyotoshi; Dolan, John C; Schmidt, Brian L
We propose a new mechanism of sensory modulation through cutaneous dopaminergic signalling. We hypothesize that dopaminergic signalling contributes to differential cutaneous sensitivity in darker versus lighter pigmented humans and mouse strains. We show that thermal and mechanical cutaneous sensitivity is pigmentation dependent. Meta-analyses in humans and mice, along with our own mouse behavioural studies, reveal higher thermal sensitivity in pigmented skin relative to less-pigmented or albino skin. We show that dopamine from melanocytes activates the D1-like dopamine receptor on primary sensory neurons. Dopaminergic activation increases expression of the heat-sensitive TRPV1 ion channel and reduces expression of the mechanically-sensitive Piezo2 channel; thermal threshold is lower and mechanical threshold is higher in pigmented skin.
PMCID:5569050
PMID: 28835637
ISSN: 2045-2322
CID: 2676012

AAPT Diagnostic Criteria for Chronic Cancer Pain Conditions

Paice, Judith A; Mulvey, Matt; Bennett, Michael; Dougherty, Patrick M; Farrar, John T; Mantyh, Patrick W; Miaskowski, Christine; Schmidt, Brian; Smith, Thomas J
Chronic cancer pain is a serious complication of malignancy or its treatment. Currently, no comprehensive, universally accepted cancer pain classification system exists. Clarity in classification of common cancer pain syndromes would improve clinical assessment and management. Moreover, an evidence-based taxonomy would enhance cancer pain research efforts by providing consistent diagnostic criteria, ensuring comparability across clinical trials. As part of a collaborative effort between the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) and the American Pain Society (APS), the ACTTION-APS Pain Taxonomy (AAPT) initiative worked to develop the characteristics of an optimal diagnostic system.59, 65 Following the establishment of these characteristics, a working group consisting of clinicians and clinical and basic scientists with expertise in cancer and cancer-related pain was convened to generate core diagnostic criteria for an illustrative sample of 3 chronic pain syndromes associated with cancer (i.e., bone pain and pancreatic cancer pain as models of pain related to a tumor) or its treatment (i.e., chemotherapy-induced peripheral neuropathy). A systematic review and synthesis was conducted to provide evidence for the dimensions that comprise this cancer pain taxonomy. Future efforts will subject these diagnostic categories and criteria to systematic empirical evaluation of their feasibility, reliability and validity and extension to other cancer-related pain syndromes. PERSPECTIVE: The ACTTION-APS chronic cancer pain taxonomy provides an evidence-based classification for 3 prevalent syndromes, namely malignant bone pain, pancreatic cancer pain, and chemotherapy-induced peripheral neuropathy. This taxonomy provides consistent diagnostic criteria, common features, co-morbidities, consequences, and putative mechanisms for these potentially serious cancer pain conditions that can be extended and applied with other cancer-related pain syndromes.
PMCID:5439220
PMID: 27884691
ISSN: 1528-8447
CID: 2314732

Clinical registry of dental outcomes in head and neck cancer patients (OraRad): rationale, methods, and recruitment considerations

Lalla, Rajesh V; Long-Simpson, Leslie; Hodges, James S; Treister, Nathaniel; Sollecito, Thomas; Schmidt, Brian; Patton, Lauren L; Brennan, Michael T
BACKGROUND: Most head and neck (H&N) cancer patients receive high-dose external beam radiation therapy (RT), often in combination with surgery and/or chemotherapy. Unfortunately, high-dose RT has significant adverse effects on the oral and maxillofacial tissues, some of which persist for the life of the patient. However, dental management of these patients is based largely on individual and expert opinion, as few studies have followed patients prospectively to determine factors that predict adverse oral sequelae. In addition, many previous studies were conducted before wide-spread adoption of intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy. The objective of this multi-center study is to systematically evaluate the oral health of subjects for 2 years after commencement of RT, with the goal of identifying risk factors that predict adverse oral outcomes post-RT. METHODS: This is a prospective multi-center longitudinal cohort study of H&N cancer patients who receive high-dose RT with curative intent. Planned enrollment is 756 subjects at 6 primary clinical sites (and their affiliated sites) in the USA. A baseline visit is conducted prior to the beginning of RT. Follow-up visits are conducted at 6, 12, 18 and 24 months from the start of RT. The primary outcome measure is the 2-year rate of tooth loss in patients who have received at least one session of external beam RT for H&N cancer. Secondary outcome measures include the incidence of exposed intraoral bone; incidence of post-extraction complications; change in Decayed Missing and Filled Surfaces (DMFS); change in periodontal measures; change in stimulated whole salivary flow rates; change in mouth opening; topical fluoride utilization; chronic oral mucositis incidence; changes in RT-specific quality of life measures; and change in oral pain scores. DISCUSSION: This study will contribute to a better understanding of the dental complications experienced by these patients. It will also enable identification of risk factors associated with adverse outcomes such as tooth loss and osteoradionecrosis. These findings will support the development of evidence-based guidelines and inform the planning of future interventional studies, with the goal of advancing improvements in patient care and outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02057510 , registered 5 February 2014.
PMCID:5327511
PMID: 28241807
ISSN: 1472-6831
CID: 2472412

Ex vivo nonviral gene delivery of mu-opioid receptor to attenuate cancer-induced pain

Yamano, Seiichi; Viet, Chi T; Dang, Dongmin; Dai, Jisen; Hanatani, Shigeru; Takayama, Tadahiro; Kasai, Hironori; Imamura, Kentaro; Campbell, Ron; Ye, Yi; Dolan, John C; Kwon, William Myung; Schneider, Stefan D; Schmidt, Brian L
Virus-mediated gene delivery shows promise for the treatment of chronic pain. However, viral vectors have cytotoxicity. To avoid toxicities and limitations of virus-mediated gene delivery, we developed a novel nonviral hybrid vector: HIV-1 Tat peptide sequence modified with histidine and cysteine residues combined with a cationic lipid. The vector has high transfection efficiency with little cytotoxicity in cancer cell lines including HSC-3 (human tongue squamous cell carcinoma) and exhibits differential expression in HSC-3 ( approximately 45-fold) relative to HGF-1 (human gingival fibroblasts) cells. We used the nonviral vector to transfect cancer with OPRM1, the mu-opioid receptor gene, as a novel method for treating cancer-induced pain. After HSC-3 cells were transfected with OPRM1, a cancer mouse model was created by inoculating the transfected HSC-3 cells into the hind paw or tongue of athymic mice to determine the analgesic potential of OPRM1 transfection. Mice with HSC-3 tumors expressing OPRM1 demonstrated significant antinociception compared with control mice. The effect was reversible with local naloxone administration. We quantified beta-endorphin secretion from HSC-3 cells and showed that HSC-3 cells transfected with OPRM1 secreted significantly more beta-endorphin than control HSC-3 cells. These findings indicate that nonviral delivery of the OPRM1 gene targeted to the cancer microenvironment has an analgesic effect in a preclinical cancer model, and nonviral gene delivery is a potential treatment for cancer pain.
PMCID:5584564
PMID: 28092646
ISSN: 1872-6623
CID: 2412132

Oralcomplicationsafterradiationtherapy for head and neck cancer [Meeting Abstract]

Lalla, R; Treister, N; Sollecito, T; Schmidt, B; Patton, L; Mohammadi, K; Hodges, J; Brennan, M
Introduction Radiation Therapy (RT) for Head and Neck Cancer (HNC) can cause significant oral complications. However, modern techniques such as Intensity Modulated RT (IMRT) may reduce their incidence/severity. Objectives To assess severity of oral complications 6 months after modern RT for HNC. Methods OraRad is an ongoing 6-center prospective cohort study. Oral outcomes are evaluated before start of RT (baseline), and 6, 12, 18, 24 months after RT. For this analysis, we compared baseline vs. 6 month data using mixed linear models for continuous measures and generalized estimating equations for categorical measures. Data are presented as outcome mean (SD, number of subjects), unless otherwise stated. Results Stimulated whole salivary flow declined from 1.09 ml/min (0.67, 354) at baseline to 0.47 (0.47, 216) at 6 months (p < 0.0001). Maximal mouth opening reduced from 45.58 mm (10.40, 371) to 42.53 (9.52, 208) (p < 0.0001). 17 of 203 subjects (8.4%) had persistent oral mucositis at 6 months. Overall oral health-related quality of life score (1-4 scale) worsened from 1.48 (0.42, 371) to 1.86 (0.47, 211) (p < 0.0001). Contributing to this decline were subject-reported negative changes related to swallowing solid food, choking when swallowing, opening the mouth wide, dry mouth, sticky saliva, smell, and taste (p < 0.0001). At 6 months, there was greater frequency of using dental floss, and greater proportion using supplemental fluoride (p < 0.0001). Conclusions Despite use of IMRT, HNC patients continue to suffer significant oral complications of cancer therapy, with negative impact on oral health, function, and quality of life
EMBASE:616191438
ISSN: 1433-7339
CID: 2580392

Dental disease prior to radiation therapy for head and neck cancer [Meeting Abstract]

Brennan, M; Sollecito, T; Treister, N; Schmidt, B; Patton, L; Mohammadi, K; Long-Simpson, L; Voelker, H; Hodges, J; Lalla, R
Introduction No evidence-based guidelines exist for preventive dental care before ra-diation therapy (RT) in head and neck cancer (HNC) patients. An ongoing multi-center, prospective cohort study, Clinical Registry of Dental Outcomes in HNC patients (OraRad) (1U01DE022939-01), is addressing this knowledge gap. Objectives Evaluate dental disease and associated factors pre-RT. Methods OraRad enrolls patients at six U.S. clinical centers pre-RT; follows them every 6 months for 2 years post-RT with primary outcome of tooth loss. Calibrated examiners assess caries and periodontal disease using validated scales and standardized procedures. Results Baseline measures were reported for 356 participants with mean (SD) age 59.9 (11.0) years; 77% male. Pre-RT dental disease parameters (means) include: number of teeth 22.9; decayed, missing, filled surfaces (DMFS) 33.3 with 1.6 decayed surfaces; clinical attachment level 1.8mm; and probing depth 2.4 mm with 13.5% of tooth sites >=4mm. Participants with at least a high school diploma had more teeth and fewer tooth sites with PD >=4mm compared to those with less education. Patients who received routine dental care had more total teeth pre-RT vs. those without (24.0 vs. 19.8, respectively). We found 37.2% of patients had at least 1 decayed surface and 47.4% had a least one tooth with a probing depth >4mm. Conclusions A high proportion of patients have dental disease at the start of RT for HNC. Observing dental outcomes post-RT, OraRad has the potential to determine the risk of dental disease at the start of RT and determine the best treatment recommendations for HNC patients pre-and post-RT
EMBASE:616191265
ISSN: 1433-7339
CID: 2580402

Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial

Ross, Stephen; Bossis, Anthony; Guss, Jeffrey; Agin-Liebes, Gabrielle; Malone, Tara; Cohen, Barry; Mennenga, Sarah E; Belser, Alexander; Kalliontzi, Krystallia; Babb, James; Su, Zhe; Corby, Patricia; Schmidt, Brian L
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.
PMCID:5367551
PMID: 27909164
ISSN: 1461-7285
CID: 2329512

Predictors of Altered Upper Extremity Function During the First Year After Breast Cancer Treatment

Smoot, Betty; Paul, Steven M; Aouizerat, Bradley E; Dunn, Laura; Elboim, Charles; Schmidt, Brian; Hamolsky, Deborah; Levine, Jon D; Abrams, Gary; Mastick, Judy; Topp, Kimberly; Miaskowski, Christine
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.
PMCID:4967035
PMID: 26829093
ISSN: 1537-7385
CID: 1933422