PRAME expression in cutaneous melanoma does not correlate with disease-specific survival.

BACKGROUND: Immunohistochemistry-based protein biomarkers can provide useful prognostic information in cutaneous melanoma. The independent prognostic value of Ki-67 has been studied with variable results. PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemistry is a useful new ancillary tool for distinguishing cutaneous nevi from melanoma; however, its prognostic value has not been well studied. We evaluated PRAME as a prognostic marker in cutaneous melanoma, compared to Ki-67. METHODS: We analyzed the immunohistochemical expression of PRAME and Ki-67 in 165 melanocytic lesions, including 92 primary melanomas, 19 metastatic melanomas, and 54 melanocytic nevi using tissue microarrays. PRAME immunostaining was scored based on the percentage of positive nuclei: 0 <1%, 1+ 1%-25%, 2+ 26%-50%, 3+ 51%-75%, and 4+ >75%. The percentage of Ki-67-positive tumor nuclei was used to calculate the proliferation index. RESULTS: PRAME and Ki-67 both showed significantly increased expression in melanomas compared to nevi (p < 0.0001 and p < 0.001, respectively). There was no significant difference in PRAME expression in primary versus metastatic melanomas. By contrast, the Ki-67 proliferation index was higher in metastatic melanoma than in primary melanoma (p = 0.013). Increased Ki-67 index correlated with ulceration (p < 0.001), increased Breslow depth (p = 0.001), and higher mitotic rate (p < 0.0001), whereas increased PRAME expression correlated with higher mitotic rate (p = 0.047) and Ki-67 index (p = 0.007). Increased Ki-67 index correlated with worse disease-specific survival in patients with primary melanoma (p < 0.001), but PRAME expression did not show prognostic significance in disease-specific survival (p = 0.63). In a multivariable analysis of patients with primary melanoma, tumor Breslow depth, ulceration, mitotic rate, and Ki-67 index were each independent predictors of disease-specific survival (p = 0.006, 0.02, 0.001, and 0.04, respectively); however, PRAME expression was not predictive of disease-specific survival (p = 0.64). CONCLUSION: Ki-67 is an independent prognostic marker; although increased PRAME expression correlates with the Ki-67 proliferation index and mitotic rate, PRAME is not an independent prognostic marker for cutaneous melanoma. PRAME and Ki-67 are useful ancillary tools for distinguishing benign from malignant melanocytic lesions.

Preventing metastatic recurrence in low-risk ER/PR + breast cancer patients-a retrospective clinical study exploring the evolving challenge of persistence with adjuvant endocrine therapy.

PURPOSE: In the genomic era, more women with low-risk breast cancer will forego chemotherapy and rely on adjuvant endocrine therapy (AET) to prevent metastatic recurrence. However, some of these patients will unfortunately relapse. We sought to understand this outcome. Preliminary work suggested that early discontinuation of AET, also known as non-persistence, may play an important role. A retrospective analysis exploring factors related to our breast cancer patients' non-persistence with AET was performed. METHODS: Women who underwent Oncotype-DX® testing between 2011 and 2014 with minimum 5 years follow-up were included. 'Low risk' was defined as Oncotype score < 26. Outcomes of recurrence and persistence were determined by chart review. Patient, tumor and treatment factors were collected, and persistent versus non-persistent groups compared using multivariable ANOVA and Fisher Chi square exact test. RESULTS: We identified six cases of distant recurrence among low-risk patients with a median follow-up of 7.7 years. Among them, five of six patients (83%) were non-persistent with AET. The non-persistence rate in our cohort regardless of recurrence was 57/228 (25%). Non-persistent patients reported more severe side effects compared with persistent patients (p = 0.002) and were more likely to be offered a switch in endocrine therapy, rather than symptom-relief (p = 0.006). In contrast, persistent patients were 10.3 times more likely to have been offered symptom-alleviating medications compared with non-persistent patients (p < 0.001). A subset analysis revealed that patients who persisted with therapy had a higher Oncotype-DX® score than patients who discontinued early (p = 0.028). CONCLUSION: Metastatic recurrence in low-risk breast cancer patients may be primarily due to non-persistence with endocrine therapy. Further work is needed to optimize care for patients who struggle with side effects. To our knowledge, these are the first published data suggesting that Oncotype-DX® score may influence persistence with AET.

Sensitizing brain metastases to stereotactic radiosurgery using hyperbaric oxygen: A proof-of-principle study.

PURPOSE: Increased oxygen levels may enhance the radiosensitivity of brain metastases treated with stereotactic radiosurgery (SRS). This project administered hyperbaric oxygen (HBO) prior to SRS to assess feasibility, safety, and response. METHODS: 38 patients were studied, 19 with 25 brain metastases treated with HBO prior to SRS, and 19 historical controls with 27 metastases, matched for histology, GPA, resection status, and lesion size. Outcomes included time from HBO to SRS, quality-of-life (QOL) measures, local control, distant (brain) metastases, radionecrosis, and overall survival. RESULTS: The average time from HBO chamber to SRS beam-on was 8.3 ± 1.7 minutes. Solicited adverse events (AEs) were comparable between HBO and control patients; no grade III or IV serious AEs were observed. Radionecrosis-free survival (RNFS), radionecrosis-free survival before whole-brain radiation therapy (WBRT) (RNBWFS), local recurrence-free survival before WBRT (LRBWFS), distant recurrence-free survival before WBRT (DRBWFS), and overall survival (OS) were not significantly different for HBO patients and controls on Kaplan-Meier analysis, though at 1-year estimated survival rates trended in favor of SRS + HBO: RNFS - 83% vs 60%; RNBWFS - 78% vs 60%; LRBWFS - 95% vs 78%; DRBWFS - 61% vs 57%; and OS - 73% vs 56%. Multivariate Cox models indicated no significant association between HBO treatment and hazards of RN, local or distant recurrence, or mortality; however, these did show statistically significant associations (p < 0.05) for: local recurrence with higher volume, radionecrosis with tumor resection, overall survival with resection, and overall survival with higher GPA. CONCLUSION: Addition of HBO to SRS for brain metastases is feasible without evident decrement in radiation necrosis and other clinical outcomes.

Water hardness alleviates the stress response caused by waterborne zinc in goldfish Carassius auratus.

In this study, the combined effect of waterborne Zn and water hardness on the stress response in the goldfish Carassius auratus was investigated. Goldfish were exposed to Zn concentrations of 0.5, 1.0, and 3.0 mg/L and water hardness of 90, 270, and 450 mg/L CaCO3 for 1, 3, 7, and 14 d. After exposure, it was determined that higher the Zn concentration, the more obvious the stress response. However, the stress response reduced with increasing water hardness. An increase in the Zn concentration caused stress responses in fish according to the increase in the mRNA expressions of corticotropin-releasing hormone and adrenocorticotropic hormone and cortisol level in the hypothalamus-pituitary-interrenal axis. The expression of these factors was the highest on day 7 and decreased on day 14. Furthermore, to evaluate the stress change in the liver tissue, we analyzed alanine aminotransferase, aspartate aminotransferase, and heat shock protein 70 concentrations to determine the damage caused by Zn and the change in water hardness. Immunohistochemistry staining for Na+/K+-ATPase in the gills showed that the gill activity was inhibited by Zn, and an increase in water hardness could improve Na+/K+-ATPase. In conclusion, we found that increasing water hardness is a successful method to reduce the stress response in goldfish caused by Zn.

PRAME expression in melanocytic lesions of the nail.

BACKGROUND: Subungual melanoma can be diagnostically challenging. We evaluated the potential of PReferentially expressed Antigen for MElanoma (PRAME) immunoreactivity for differentiating benign from malignant nail melanocytic lesions. METHODS: Sixty cases were identified (10 invasive melanomas, 8 melanomas in situ, 14 nevi, 12 cases of lentigo, and 16 of melanocytic activation). Percentage of PRAME-positive melanocytes was evaluated as follows: 0 no staining, 1+ 1%-25%, 2+ 26%-50%, 3+ 51%-75%, and 4+ >75%. A combined score of both percentage and intensity was also evaluated. RESULTS: The difference in PRAME expression between malignant and benign lesions was statistically significant (p < 0.0001). The degree of PRAME expression significantly correlated with patients' age and clinical size. When based on percentage score, 61.1% of melanomas showed a 4+ score, 16.7% showed a 3+ score, 11.1% showed a 1+ score, and 11.1% was negative; 69.0% of the benign lesions was negative, 23.8% showed a 1+ score, 4.8% showed a 2+ score, and 2.4% showed a 4+ score. When the cutoff value for malignancy decreased from 4+ to 3+, the sensitivity increased from 61.1% to 77.8%, while specificity remained 97.6%. Combined score results were similar. CONCLUSIONS: PRAME is a relatively sensitive and highly specific marker in differentiating benign from malignant nail melanocytic lesions. However, correlation with morphology is imperative.

Reducing dermal exposure to agrochemical carcinogens using a fluorescent dye-based intervention among subsistence farmers in rural Honduras.

BACKGROUND: Occupational exposure to agrochemicals, some of which are known or suspected carcinogens, is a major health hazard for subsistence agricultural workers and their families. These impacts are more prevalent in low-and-middle income countries (LMIC) due to weak regulations, lack of awareness of the risks of contamination, predominant use of handheld backpack style spraying equipment, general lack of personal protective equipment (PPE), and low literacy about proper agrochemical application techniques. Reducing exposure to agrochemicals was identified as a paramount concern by rural Hondurans working with a community-engaged research initiative. Fluorescent tracer dyes have been described as a means of visualizing and quantifying dermal exposure to agricultural chemicals, and exposure models adapted for LMIC have been developed previously. Tracer dyes have also been used in educational simulations to promote pesticide safety. However, studies evaluating the effectiveness of these educational dye interventions in reducing future exposure have been lacking. AIM: To evaluate whether observing one's own chemical contamination after applying agrochemicals changed the amount of occupational dermal exposure during a subsequent chemical application. METHODS: We employed a multi-modal community intervention in a rural village in Honduras that incorporated chemical safety education and use of a fluorescent tracer dye during pesticide application on two consecutive occasions, and compared dermal exposure between the intervention group (previous dye experience and safety education, n = 6) and the control group (safety education only, n = 7). RESULTS: Mean total visual score (TVS) of the tracer dye, which accounts for both extent and intensity of whole-body contamination, was lower among those who had previously experienced the dye intervention (mean TVS = 41.3) than among participants who were dye-naïve (mean TVS = 78.4), with a difference between means of -37.10 (95% CI [-66.26, -7.95], p = 0.02). Stratifying by body part, contamination was significantly lower for the anterior left lower extremity and bilateral feet for the dye-experienced group vs. dye-naïve, with most other segments showing a trend toward decreased contamination as well. CONCLUSION: Participants who had previously experienced the dye intervention were significantly less contaminated than the dye-naïve control group during a subsequent spraying event. The findings of this small pilot study suggest that a multi-modal, community-based approach that utilizes fluorescence-augmented contamination for individualized learning (FACIL) may be effective in reducing dermal exposure to carcinogenic agrochemicals among subsistence farmers in Honduras and other LMIC.

Aberrant expression of HMB45 and negative PRAME expression in halo nevi.

BACKGROUND: Traditionally, most cutaneous nevi show a gradient of HMB45 (human melanoma black 45) and negative PRAME (preferentially expressed antigen in melanoma) immunostaining, while melanomas often show irregularly positive, diffusely positive or completely negative HMB45 expression, and PRAME immunopositivity. However, we have occasionally observed benign halo nevi with loss of HMB45 gradient, raising diagnostic consideration for melanoma. The purpose of this study was to elucidate the expression pattern of HMB45 and PRAME in nevi with the halo phenomenon (NHP). METHODS: PRAME and HMB45 staining patterns in 20 cases of NHP and 16 cases of conventional nevi were evaluated using light microscopy. An HMB45 gradient was defined as immunopositivity in only superficial melanocytes. HMB45 aberrant expression consisted of superficial and deep immunopositivity. RESULTS: Aberrant HMB45 expression was observed in 10 of 20 NHP (50%). A gradient of HMB45 staining was seen in most conventional nevi, with only one showing focal weak expression in the deep dermis (6.3%). All cases of NHP and conventional nevi showed essentially negative immunostaining by PRAME. CONCLUSION: Aberrant HMB45 expression in NHP is not uncommon and may be a diagnostic pitfall. Negative PRAME immunostaining may be a reassuring finding to help differentiate halo nevus from malignant melanoma.

The impact of low- versus high-intensity surveillance cystoscopy on surgical care and cancer outcomes in patients with high-risk non-muscle-invasive bladder cancer (NMIBC).

PURPOSE: To assess the association of low- vs. guideline-recommended high-intensity cystoscopic surveillance with outcomes among patients with high-risk non-muscle invasive bladder cancer (NMIBC). MATERIALS & METHODS: A retrospective cohort study of Veterans Affairs patients diagnosed with high-risk NMIBC between 2005 and 2011 with follow-up through 2014. Patients were categorized by number of surveillance cystoscopies over two years following diagnosis: low- (1-5) vs. high-intensity (6 or more) surveillance. Propensity score adjusted regression models were used to assess the association of low-intensity cystoscopic surveillance with frequency of transurethral resections, and risk of progression to invasive disease and bladder cancer death. RESULTS: Among 1,542 patients, 520 (33.7%) underwent low-intensity cystoscopic surveillance. Patients undergoing low-intensity surveillance had fewer transurethral resections (37 vs. 99 per 100 person-years; p<0.001). Risk of death from bladder cancer did not differ significantly by low (cumulative incidence [CIn] 8.4% [95% CI 6.5-10.9) at 5 years) vs. high-intensity surveillance (CIn 9.1% [95% CI 7.4-11.2) at 5 years, p = 0.61). Low vs. high-intensity surveillance was not associated with increased risk of bladder cancer death among patients with Ta (CIn 5.7% vs. 8.2% at 5 years p = 0.24) or T1 disease at diagnosis (CIn 10.2% vs. 9.1% at 5 years, p = 0.58). Among patients with Ta disease, low-intensity surveillance was associated with decreased risk of progression to invasive disease (T1 or T2) or bladder cancer death (CIn 19.3% vs. 31.3% at 5 years, p = 0.002). CONCLUSIONS: Patients with high-risk NMIBC undergoing low- vs. high-intensity cystoscopic surveillance underwent fewer transurethral resections, but did not experience an increased risk of progression or bladder cancer death. These findings provide a strong rationale for a clinical trial to determine whether low-intensity surveillance is comparable to high-intensity surveillance for cancer control in high-risk NMIBC.

Health Through Activity: Initial Evaluation of an In-Home Intervention for Older Adults With Cancer.

OBJECTIVE: The objective of this study was to assess the feasibility of conducting a future full-scale trial to test the efficacy of an in-home occupational therapy intervention designed to reduce disability in older adult cancer survivors. METHOD: Participants reporting activity limitations during or after cancer treatment were enrolled in a Phase 1 pilot randomized controlled trial comparing the 6-wk intervention (n = 30) to usual care (n = 29). Descriptive data on retention rates were collected to assess feasibility of intervention and study procedures. Potential efficacy was explored through participants' self-reported disability, quality of life, activity level, and behavioral activation at 0, 8, and 16 wk after enrollment. RESULTS: Retention rates were high regarding completion of the intervention (90%) and outcome assessments (90% of usual-care participants and 80% of intervention participants). Outcomes consistently favored the intervention group, although group differences were small. CONCLUSION: The procedures were feasible to implement and acceptable to participants.

Small and Isolated Immunohistochemistry-positive Cells in Melanoma Sentinel Lymph Nodes Are Associated With Disease-specific and Recurrence-free Survival Comparable to that of Sentinel Lymph Nodes Negative for Melanoma.

Although immunohistochemistry (IHC) has improved our ability to detect melanoma metastases in sentinel lymph nodes (SLN), the American Joint Committee on Cancer (AJCC) does not provide a lower threshold for determining if a SLN is positive for metastasis. Existing literature suggests that even a small aggregate or an enlarged, abnormal cell detectable by IHC can be associated with an adverse outcome. In our experience, however, some SLNs contain small solitary cells the size of neighboring lymphocytes demonstrable only by IHC. We sought to determine their clinical significance. A total of 821 patients underwent a SLN biopsy at our institution over a 12-year period. In all, 639 (77.8%) were SLN-negative, 125 (15.2%) were SLN-positive, and 57 (6.9%) had rare IHC-positive cells of undetermined clinical significance with no disease progression over a mean 59-month follow-up. Kaplan-Meier method with pair-wise comparisons revealed no significant difference in disease-specific survival and recurrence-free survival between SLN-negative and rare IHC-positive groups. There were significant differences in survival and recurrence between patients in the rare IHC-positive group and those with melanoma metastases, including those with solitary melanoma cells and those with tumor burdens ≤0.2 mm. While the lower diagnostic threshold for metastatic melanoma on IHC-stained sections needs to be studied further, our data suggest that rare IHC-positive cells lacking cytomorphologic features of overt malignancy are equivocal for melanoma and could impart a similar prognosis as patients with no evidence of SLN involvement.

The impact of frequent cystoscopy on surgical care and cancer outcomes among patients with low-risk, non-muscle-invasive bladder cancer.

BACKGROUND: Surveillance recommendations for patients with low-risk, non-muscle-invasive bladder cancer (NMIBC) are based on limited evidence. The objective of this study was to add to the evidence by assessing outcomes after frequent versus recommended cystoscopic surveillance. METHODS: This was a retrospective cohort study of patients diagnosed with low-risk (low-grade Ta (AJCC)) NMIBC from 2005 to 2011 with follow-up through 2014 from the Department of Veterans Affairs. Patients were classified as having undergone frequent versus recommended cystoscopic surveillance (>3 vs 1-3 cystoscopies in the first 2 years after diagnosis). By using propensity score-adjusted models, the authors estimated the impact of frequent cystoscopy on the number of transurethral resections, the number of resections without cancer in the specimen, and the risk of progression to muscle-invasive cancer or bladder cancer death. RESULTS: Among 1042 patients, 798 (77%) had more frequent cystoscopy than recommended. In adjusted analyses, the frequent cystoscopy group had twice as many transurethral resections (55 vs 26 per 100 person-years; P < .001) and more than 3 times as many resections without cancer in the specimen (5.7 vs 1.6 per 100 person-years; P < .001). Frequent cystoscopy was not associated with time to progression or bladder cancer death (3% at 5 years in both groups; P = .990). CONCLUSIONS: Frequent cystoscopy among patients with low-risk NMIBC was associated with twice as many transurethral resections and did not decrease the risk for bladder cancer progression or death, supporting current guidelines.

Diagnostic and prognostic value of glucose transporters in melanocytic lesions.

We have previously reported increased glucose transporter 1 (GLUT1) expression in melanoma compared to benign nevi, associated with a significantly lower survival rate. GLUT1 upregulation was highly specific for distinguishing melanoma from benign nevi, yet poorly sensitive, likely because of expression of other GLUT isoforms. The purpose of this study was to evaluate GLUT2 and GLUT3, as melanoma biomarkers. A tissue microarray, consisting of 91 primary melanomas, 18 melanoma metastases, and 56 nevi, was examined using GLUT2 and GLUT3 immunohistochemistry. A semiquantitative scoring method was used to determine the percentage of positive tumor cells and staining intensity. GLUT2 was negative in all melanomas and benign nevi examined. Increased GLUT3 expression was more frequent in melanoma than in nevi (P < 0.0001), and in metastatic melanoma than in primary melanomas (P < 0.001). Of melanoma cases, 85.3% expressed either GLUT1 or GLUT3 or both, 39.4% of melanoma cases coexpressed GLUT1 and GLUT3, 17.4% of melanoma cases only expressed GLUT1, 28.4% of melanoma cases only expressed GLUT3, and 14.7% of melanoma cases were negative for both markers. Patients whose melanoma exhibited a high level of GLUT3 had significantly lower survival rates than those with low GLUT3 expression (P = 0.002). Evaluating both GLUT1 and GLUT3 increased the diagnostic value by increasing the sensitivity while the specificity remained high. In conclusion, GLUT2 was not expressed in melanocytes. GLUT3 expression was upregulated in melanoma compared with nevi, especially in those with worse prognosis. Similar to GLUT1, GLUT3 may serve as a useful diagnostic and prognostic marker.

Effect of Uric Acid Control on Serum Creatinine.

OBJECTIVE: Hyperuricemia has been epidemiologically associated with multiple comorbidities including chronic renal failure and cardiovascular disease. Cause and effect are difficult to address, given comorbidities associated with and prevalence of metabolic syndrome. One impediment to achieving serum uric acid (sUa) levels less than or equal to 6.0 mg/DL is the concept that allopurinol might be nephrotoxic. We examined the relation of sUa less than or equal to 6.0 mg/dL to renal function over time. METHODS: This is a medical records review study of 348 hyperuricemia patients identified in 2015, as having been followed with serial uric acid measurements. After 1 year of serial urate levels, to allow for treatment, patient cohorts were defined: sUa less than or equal to 6.0 mg/dL and sUa greater than 6.0 mg/dL. A repeated measure model was used to test for an association between uric acid level and serum creatinine, while adjusting for covariates. RESULTS: There was a significant difference in the least square means of serum creatinine comparing those who achieved an sUa less than or equal to 6.0 mg/dL versus sUa greater than 6.0 mg/dL (1.39 mg/dL [95% confidence interval, 1.30-1.48] vs 1.57 mg/dL [95% confidence interval, 1.46-1.69]; p = 0.0015). This is a between-group difference in creatinine of 0.18 mg/dL. If a change in serum creatinine of 0.2 is considered significant, this short-term between-group progression of renal failure approaches clinical significance. CONCLUSIONS: Given that most serial measures were within the first few years of follow-up, and change in renal function occurs slowly over time, the between group difference of sUa of 0.18 mg/dL is close to a clinically significant creatinine difference of 0.2 mg/dL.

VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival.

Adaptive immune responses contribute to the pathogenesis of melanoma by facilitating immune evasion. V-domain Ig suppressor of T-cell activation (VISTA) is a potent negative regulator of T-cell function and is expressed at high levels on monocytes, granulocytes, and macrophages, and at lower densities on T-cell populations within the tumor microenvironment. In this study, 85 primary melanoma specimens were selected from pathology tissue archives and immunohistochemically stained for CD3, PD-1, PD-L1, and VISTA. Pearson's correlation coefficients identified associations in expression between VISTA and myeloid infiltrate (r = 0.28, p = 0.009) and the density of PD-1+ inflammatory cells (r = 0.31, p = 0.005). The presence of VISTA was associated with a significantly worse disease-specific survival in univariate analysis (hazard ratio = 3.57, p = 0.005) and multivariate analysis (hazard ratio = 3.02, p = 0.02). Our findings show that VISTA expression is an independent negative prognostic factor in primary cutaneous melanoma and suggests its potential as an adjuvant immunotherapeutic intervention in the future.

Immediate Symptom Relief After a First Session of Massage Therapy or Reiki in Hospitalized Patients: A 5-Year Clinical Experience from a Rural Academic Medical Center.

OBJECTIVES: There is an increasing demand for and use of alternative and complementary therapies, such as reiki and massage therapy, in hospital-based settings. Most controlled studies and practice-based reports include oncology and surgical patient populations; thus the effect in a more heterogeneous hospitalized patient population is hard to estimate. We examined the immediate symptom relief from a single reiki or massage session in a hospitalized population at a rural academic medical center. DESIGN: Retrospective analysis of prospectively collected data on demographic, clinical, process, and quality of life for hospitalized patients receiving massage therapy or reiki. SETTINGS/LOCATION: A 396-bed rural academic and tertiary medical center in the United States. SUBJECTS: Hospitalized patients requesting or referred to the healing arts team who received either a massage or reiki session and completed both a pre- and post-therapy symptom questionnaire. INTERVENTIONS: First session of routine reiki or massage therapy during a hospital stay. OUTCOME MEASURES: Differences between pre- and postsession patient-reported scores in pain, nausea, fatigue, anxiety, depression, and overall well-being using an 11-point Likert scale. RESULTS: Patients reported symptom relief with both reiki and massage therapy. Analysis of the reported data showed reiki improved fatigue (-2.06 vs. -1.55 p < 0.0001) and anxiety (-2.21 vs. -1.84 p < 0.001) statistically more than massage. Pain, nausea, depression, and well being changes were not statistically different between reiki and massage encounters. Immediate symptom relief was similar for cancer and noncancer patients for both reiki and massage therapy and did not vary based on age, gender, length of session, and baseline symptoms. CONCLUSIONS: Reiki and massage clinically provide similar improvements in pain, nausea, fatigue, anxiety, depression, and overall well-being while reiki improved fatigue and anxiety more than massage therapy in a heterogeneous hospitalized patient population. Controlled trials should be considered to validate the data.

What happens during early outpatient palliative care consultations for persons with newly diagnosed advanced cancer? A qualitative analysis of provider documentation.

BACKGROUND: Early outpatient palliative care consultations are recommended by clinical oncology guidelines globally. Despite these recommendations, it is unclear which components should be included in these encounters. AIM: Describe the evaluation and treatment recommendations made in early outpatient palliative care consultations. DESIGN: Outpatient palliative care consultation chart notes were qualitatively coded and frequencies tabulated. SETTING/PARTICIPANTS: Outpatient palliative care consultations were automatically triggered as part of an early versus delayed randomized controlled trial (November 2010 to April 2013) for patients newly diagnosed with advanced cancer living in the rural Northeastern US. RESULTS: In all, 142 patients (early = 70; delayed = 72) had outpatient palliative care consultations. The top areas addressed in these consultations were general evaluations-marital/partner status (81.7%), spirituality/emotional well-being (80.3%), and caregiver/family support (79.6%); symptoms-mood (81.7%), pain (73.9%), and cognitive/mental status (68.3%); general treatment recommendations-counseling (39.4%), maintaining current medications (34.5%), and initiating new medication (23.9%); and symptom-specific treatment recommendations-pain (22.5%), constipation (12.7%), depression (12.0%), advanced directive completion (43.0%), identifying a surrogate (21.8%), and discussing illness trajectory (21.1%). Compared to the early group, providers were more likely to evaluate general pain ( p = 0.035) and hospice awareness ( p = 0.005) and discuss/recommend hospice ( p = 0.002) in delayed group participants. CONCLUSION: Outpatient palliative care consultations for newly diagnosed advanced cancer patients can address patients' needs and provide recommendations on issues that might not otherwise be addressed early in the disease course. Future prospective studies should ascertain the value of early outpatient palliative care consultations that are automatically triggered based on diagnosis or documented symptom indicators versus reliance on oncologist referral.

The role of a palliative care intervention in moderating the relationship between depression and survival among individuals with advanced cancer.

OBJECTIVE: Randomized controlled trials (RCTs) of early palliative care interventions in advanced cancer have positively impacted patient survival, yet the mechanisms remain unknown. This secondary analysis of 2 RCTs assessed whether an early palliative care intervention moderates the relationship between depressive symptoms and survival. METHOD: The relationships among mood, survival, and early palliative care intervention were studied among 529 advanced cancer patients who participated in 2 RCTs. The first (N = 322) compared intervention versus usual care. The second (N = 207) compared early versus delayed intervention (12 weeks after enrollment). The interventions included an in-person consultation, weekly nurse coach-facilitated phone sessions, and monthly follow-up. Mood was measured using the Center for Epidemiologic Studies-Depression (CES-D) scale. Cox proportional hazard analyses were used to examine the effects of baseline CES-D scores, the intervention, and their interaction on mortality risk while controlling for demographic variables, cancer site, and illness severity. RESULTS: The combined sample was 56% male (M = 64.7 years). Higher baseline CES-D scores were significantly associated with greater mortality risk (hazard ratio [HR] = 1.042, 95% confidence interval [CI] [1.017, 1.067], p = .001). However, participants with higher CES-D scores who received the intervention had a lower mortality risk (HR = .963, CI [0.933, 0.993], p = .018) even when controlling for demographics, cancer site, and illness-related variables. CONCLUSION: This study is the first to demonstrate that patients with advanced cancer who also have depressive symptoms benefit the most from early palliative care. Future research should be devoted to exploring the mechanisms responsible for these relationships. (PsycINFO Database Record

"There were more decisions and more options than just yes or no": Evaluating a decision aid for advanced cancer patients and their family caregivers.

OBJECTIVE: Few decision aids are available for patients with a serious illness who face many treatment and end-of-life decisions. We evaluated the Looking Ahead: Choices for Medical Care When You're Seriously Ill® patient decision aid (PtDA), one component of an early palliative care clinical trial. METHOD: Our participants included individuals with advanced cancer and their caregivers who had participated in the ENABLE (Educate, Nurture, Advise, Before Life Ends) early palliative care telehealth randomized controlled trial (RCT) conducted in a National Cancer Institute-designated cancer center, a U.S. Department of Veterans Affairs medical center, and affiliated outreach clinics in rural New England. ENABLE included six weekly patient and three weekly family caregiver structured sessions. Participants watched the Looking Ahead PtDA prior to session 3, which covered content on decision making and advance care planning. Nurse coaches employed semistructured interviews to obtain feedback from consecutive patient and caregiver participants approximately one week after viewing the Looking Ahead PtDA program (booklet and DVD). RESULTS: Between April 1, 2011, and October 31, 2012, 57 patients (mean age = 64), 42% of whom had lung and 23% gastrointestinal cancer, and 20 caregivers (mean age = 59), 80% of whom were spouses, completed the PtDA evaluation. Participants reported a high degree of satisfaction with the PtDA format, as well as with its length and clarity. They found the format of using patient interviews "validating." The key themes were: (1) "the earlier the better" to view the PtDA; (2) feeling empowered, aware of different options, and an urgency to participate in advance care planning. SIGNIFICANCE OF RESULTS: The Looking Ahead PtDA was well received and helped patients with a serious illness realize the importance of prospective decision making in guiding their treatment pathways. We found that this PtDA can help seriously ill patients prior to the end of life to understand and discuss future healthcare decision making. However, systems to routinely provide PtDAs to seriously ill patients are yet not well developed.

Epithelial-Mesenchymal Expression Phenotype of Primary Melanoma and Matched Metastases and Relationship with Overall Survival.

E-Cadherin and N-cadherin are important components of epithelial-mesenchymal transition (EMT). The majority of studies on EMT in melanoma have been performed with cultured cell lines or pooled melanoma samples. The goal of our study was to evaluate the expression of E-cadherin and N-cadherin in matched tissue samples from primary and metastatic sites of melanoma and to determine the correlation with survival outcome. We analyzed tissues from 42 melanoma primary lesions and their corresponding metastases, as well as 53 benign nevi, for expression levels of E-cadherin and N-cadherin using immunohistochemical methods. There were heterogenous expression patterns of E- and N-cadherin in both primary and metastatic melanomas. Overall, metastatic tumor showed a decrease in E-cadherin expression and an increase in N-cadherin expression compared to the primary tumor, although the difference did not reach statistical significance (p=0.24 and 0.28 respectively). A switch of membranous expression from E-cadherin to N-cadherin from primary to metastatic melanoma was seen in eight patients (19%). Aberrant E-cadherin expression (defined as negative to weak membranous E-cadherin or positive nuclear E-cadherin expression) was more frequently observed in metastatic than in primary melanomas (p=0.03). Multivariate analysis showed that absence of N-cadherin expression in primary melanomas and the presence of aberrant E-cadherin expression in primary melanomas and metastatic melanomas was associated with a significantly worse overall survival. Our data support the importance of E-cadherin and N-cadherin proteins in melanoma progression and patient survival.

Diagnostic and Prognostic Value of ProEx C and GLUT1 in Melanocytic Lesions.

BACKGROUND: Melanoma is one of the most aggressive types of skin cancer. The purpose of this study was to evaluate the use of two biomarkers, ProEx C and glucose transporter isoform 1 (GLUT1), in the diagnosis and prognostication of melanoma. MATERIALS AND METHODS: We analyzed 129 melanomas and 59 benign nevi in a tissue microarray using immunohistochemical method with antibodies to topoisomerase IIα (TOP2A) and minichromosome maintenance complex component 2 (MCM2) using ProEx C and to GLUT1. RESULTS: The average proliferative index by ProEx C immunostain was significantly higher in melanomas (37.5%) compared to benign nevi (1.9%) as was the expression of GLUT1 (p<0.0001 respectively). Dermal mitosis was found to correlate positively with both ProEx C and GLUT1 (p=0.003 and p<0.001, respectively). Ulceration and tumor thickness positively correlated with GLUT1 expression (p=0.013 and p=0.033, respectively), but not with ProEx C staining. There was a significant association between increasing ProEx C index and stronger expression of GLUT1 (p<0.001). Kaplan-Meier disease-specific survival analyses indicated that patients whose melanoma exhibited expression of GLUT1 had a significantly lower rate of disease-specific survival than patients whose melanoma did not (p=0.039). However, staining by ProEx C did not show a prognostic significance in disease-specific survival. CONCLUSION: ProEx C and GLUT1 are potentially useful markers in differentiation of melanoma from nevi. Absence of GLUT1 expression in patients with primary melanoma predicts better survival.