Fangxin Hong

Background: Timely detection of chemotherapy-induced peripheral neuropathy (CIPN) is critical to effectively tailor chemotherapy dose levels and offer supportive care. The purpose of this secondary analysis was to determine the reliability and validity of the two Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) numbness and tingling severity and interference items to screen for CIPN in patients receiving taxanes, platinums, or proteasome inhibitors. Methods: Participants (N = 142) completed the two PRO-CTCAE items, a 0–10 numerical rating scale of worst CIPN pain intensity, and the Quality of Life Questionnaire–CIPN20 (QLQ-CIPN20) prior to three clinical visits (T1, T2, T3) during neurotoxic chemotherapy. Participants completed the two PRO-CTCAE items again following the T3 clinical visit (T4). In addition, study staff administered the modified Total Neuropathy Score–Clinical Version (TNSc©) at T3. We examined floor (i.e., no CIPN severity or interference) and ceiling effects, test–retest reliability, concurrent validity, longitudinal validity, construct validity of the response categories, and sensitivity and specificity of the two PRO-CTCAE items. Results: At T3, 29% of participants had PRO-CTCAE severity scores at the floor; 60.1% of participants reported interference item scores at the floor. Agreements between scores reported at T3 and T4 for PRO-CTCAE severity (ICC = 0.79) and interference (ICC = 0.73) were moderate to strong. The PRO-CTCAE severity and interference items correlated moderately-strongly with QLQ-CIPN20 sensory (Spearman’s ρ-range = 0.53–0.72) and motor (Spearman’s ρ-range = 0.50–0.58) subscale scores. The Cohen’s d from T1 to T3 for the PRO-CTCAE items were small (severity: d = 0.32, interference: d = 0.40) and comparable to the effect sizes for change observed with the QLQ-CIPN20. The PRO-CTCAE severity (0–3) and interference (0–2) response categories distinguished respondents with significantly different levels of QLQ-CIPN20 sensory and motor subscale scores (p < 0.001 via Jonckheere-Terpstra tests). The sensitivity and specificity of the PRO-CTCAE severity item (cutoff > 0) to detect probable sensory peripheral neuropathy were 95.83% and 65.22%, while the sensitivity and specificity of the PRO-CTCAE™ interference item (cutoff > 0) were 51.39% and 73.91%. Conclusion: Preliminary evidence supports the reliability and validity of the PRO-CTCAE numbness and tingling items for CIPN screening, although there may be floor effects and limitations in the capacity of the PRO-CTCAE items to identify the full range of CIPN sensory and motor features beyond numbness and tingling. Trial Registration ClinicalTrials.Gov, NCT03514680. Registered 21 April 2018. https://clinicaltrials.gov/ct2/show/NCT03514680

Decisional conflict is associated with decision quality and may affect decision outcomes. In the health sciences literature, the Decisional Conflict Scale is widely used to measure decisional conflict, yet limited research has described the psychometric properties of the Decisional Conflict Scale subscales and of the low literacy version of the scale. The purpose of this secondary data analysis was therefore to examine properties of the original (DCS-12) and low literacy (LL DCS-10) Decisional Conflict Scales using Classical Measurement Theory and Item Response Theory. Data from two multi-site trials of men with prostate cancer were used to analyze the DCS-12, LL DCS-10, and an aggregated DCS-12 dataset in which five response options were aggregated into three. Internal consistency was estimated with Cronbach’s alphas. Subscale correlations were evaluated with Pearson’s correlation coefficient. Item difficulty, item discrimination, and test information were evaluated using Graded Response Modeling (GRM). The likelihood ratio test guided model selection. Cronbach’s alphas for the total scales and three of four subscales were ≥ 0.85. Alphas ranged from 0.34–0.57 for the support subscales. Subscale correlations ranged from 0.42–0.71 (P < 0.001). Items on the DCS-12 exhibited the widest range of difficulty. Two items on the support subscale had low to moderate discrimination and contributed little information. Only the DCS-12 was informative across the full range of decisional conflict values. Lack of precision in the support subscale raises concerns about subscale validity. The DCS-12 is most capable of discriminating between respondents with high and low decisional conflict. Evaluation of interventions to reduce decisional conflict must consider the above findings.

Introduction: Frequently reported symptoms and treatment side effects may not be the most bothersome issues to patients with cancer. The purpose of this study was to investigate patient-reported symptom distress and bothersome issues among participants with cancer. Methods: Participants completed the Symptom Distress Scale-15 before treatment (T1) and during cancer treatment (T2) and reported up to two most bothersome issues among symptoms rated with moderate-to-severe distress. We compared symptom ratings and perceived bother and explored two approaches predicting patients’ most bothersome issues: worst absolute symptom score or worst change from pretreatment. Results: Significantly, (P≤0.0002) more patients reported moderate-to-severe distress at T2 for eight of 13 symptoms. At T1, 81% of patients reported one and 56% reported multiple symptoms with moderate-to-severe distress, while at T2, 89% reported one and 69% reported multiple symptoms with moderate-to-severe distress. Impact on sexual activity/interest, pain, fatigue, and insomnia were the most prevalent symptoms with moderate-to-severe distress. Fatigue, pain, and insomnia were perceived most often as bothersome. When one symptom was rated moderate-to-severe, predictive accuracy of the absolute score was 46% and 48% (T1 & T2) and 38% with the change score (T2–T1). When two or more symptoms were rated moderate-to-severe, predictive accuracy of the absolute score was 76% and 79% (T1 & T2) and 70% with the change score (T2–T1). Conclusion: More patients experienced moderate-to-severe symptom distress after treatment initiation. Patient identification of bothersome issues could not be assumed based on prevalence of symptoms reported with moderate-to-severe distress. The absolute symptom distress scores identified patients’ most bothersome issues with good accuracy, outperforming change scores.

Evaluate baseline factors that may explain the influence of study site on decisional conflict (DC) in men from the Personal Patient Profile: Prostate (P3P) randomized trial. 476 cases from 5 P3P sites were included. Participants completed baseline demographic assessments, 4 subscales of the DC scale at baseline (uncertainty, informed, values clarity, and support), the Expanded Prostate Cancer Index Composite (short form) and the State-Trait Anxiety Inventory. Site data regarding typical practices were collected. Linear regressions were used to model the relation between baseline DC scores and study site adjusting for the list of variables. Baseline decisional uncertainly (p?=?0.001) and informed (p?=?0.03) subscales were significantly different across sites. Participant demographic and baseline measures were significantly different (p?<?0.05) between sites except for trait anxiety. We identified participant level factors that explained study site differences at baseline for the decisional uncertainty and values clarity subscales: a preferred treatment choice at study entry, whether the study program was accessed at home vs. in clinic, number of doctors consulted pre-study, working status, state anxiety, information from the media or a health care provider, and perceived knowledge level. State anxiety was associated with higher DC across all subscales. Individual characteristics of men seeking consultation for LPC were associated with DC at baseline, not the site alone; anxiety contributed to higher conflict. These findings will inform future development and implementation of the P3P and other decision support interventions. NCT00692653.

The electronic self report assessment - cancer (ESRA-C), has been shown to reduce symptom distress during cancer therapy The purpose of this analysis was to evaluate aspects of how the ESRA-C intervention may have resulted in lower symptom distress (SD).

The role of body mass index (BMI) in survival outcomes is controversial among lymphoma patients. We evaluated the association between BMI at study entry and failure-free survival (FFS) and overall survival (OS) in three phase III clinical trials, among patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin's lymphoma (HL). A total of 537, 730 and 282 patients with DLBCL, HL and FL were included in the analysis. Baseline patient and clinical characteristics, treatment received and clinical outcomes were compared across BMI categories. Among patients with DLBCL, HL and FL, the median age was 70, 33 and 56; 29%, 29% and 37% were obese and 38%, 27% and 37% were overweight, respectively. Age was significantly different among BMI groups in all three studies. Higher BMI groups tended to have more favorable prognosis factors at study entry among DLBCL and HL patients. BMI was not associated with clinical outcome with P-values of 0.89, 0.30 and 0.40 for FFS, and 0.64, 0.67 and 0.09 for OS, for patients with DLBCL, HL and FL, respectively. The association remains non-significant after adjusting for other clinical factors in the Cox model. A subset analysis of males with DLBCL treated on R-CHOP revealed no differences in FFS (P = 0.48) or OS (P = 0.58). BMI was not significantly associated with clinical outcomes among patients with DLBCL, HD or FL, in three prospective phase III clinical trials. The findings contradict some previous reports of similar investigations. Further work is required to understand the observed discrepancies.

Clinical interpretation of health related quality of life (HRQOL) scores is challenging. The purpose of this analysis was to interpret score changes and identify minimal clinically important differences (MCID) on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) before (T1) and during (T2) cancer treatment.

T-cell leukemia/lymphoma 1 (TCL1) is an oncogene overexpressed in T-cell prolymphocytic leukemia and in B-cell malignancies including B-cell chronic lymphocytic leukemia and lymphomas. To date, only a limited number of Tcl1-interacting proteins that regulate its oncogenic function have been identified. Prior studies used a proteomic approach to identify a novel interaction between Tcl1 with Ataxia Telangiectasia Mutated. The association of Tcl1 and Ataxia Telangiectasia Mutated leads to activation of the NF-κB pathway. Here, we demonstrate that Tcl1 also interacts with heat shock protein (Hsp) 70. The Tcl1-Hsp70 complex was validated by coimmunoprecipitation experiments. In addition, we report that Hsp70, a protein that plays a critical role in the folding and maturation of several oncogenic proteins, associates with Tcl1 protein and stabilizes its expression. The inhibition of the ATPase activity of Hsp70 results in ubiquitination and proteasome-dependent degradation of Tcl1. The inhibition of Hsp70 significantly reduced the growth of lymphoma xenografts in vivo and down-regulated the expression of Tcl1 protein. Our findings reveal a functional interaction between Tcl1 and Hsp70 and identify Tcl1 as a novel Hsp70 client protein. These findings suggest that inhibition of Hsp70 may represent an alternative effective therapy for chronic lymphocytic leukemia and lymphomas via its ability to inhibit the oncogenic functions of Tcl1.

Motivation: The proliferation of public data repositories creates a need for meta-analysis methods to efficiently evaluate, integrate and validate related datasets produced by independent groups. A t-based approach has been proposed to integrate effect size from multiple studies by modeling both intra- and between-study variation. Recently, a non-parametric ‘rank product’ method, which is derived based on biological reasoning of fold-change criteria, has been applied to directly combine multiple datasets into one meta study. Fisher's Inverse χ² method, which only depends on P-values from individual analyses of each dataset, has been used in a couple of medical studies. While these methods address the question from different angles, it is not clear how they compare with each other. Results: We comparatively evaluate the three methods; t-based hierarchical modeling, rank products and Fisher's Inverse χ² test with P-values from either the t-based or the rank product method. A simulation study shows that the rank product method, in general, has higher sensitivity and selectivity than the t-based method in both individual and meta-analysis, especially in the setting of small sample size and/or large between-study variation. Not surprisingly, Fisher's χ² method highly depends on the method used in the individual analysis. Application to real datasets demonstrates that meta-analysis achieves more reliable identification than an individual analysis, and rank products are more robust in gene ranking, which leads to a much higher reproducibility among independent studies. Though t-based meta-analysis greatly improves over the individual analysis, it suffers from a potentially large amount of false positives when P-values serve as threshold. We conclude that careful meta-analysis is a powerful tool for integrating multiple array studies. Contact:fxhong@jimmy.harvard.edu Supplementary information: Supplementary data are available at Bioinformatics online.