Faculty Bibliography

OBJECTIVE:POLE mutations in high-grade endometrioid endometrial cancer (EEC) have been associated with improved survival. We sought to investigate the prevalence of POLE tumor mutation and its prognostic significance on outcomes and clinical applications in a subanalysis of women with high-grade EEC from a previously described cohort of 544 EEC patients in which POLE mutation status and survival outcomes were assessed. METHODS:Polymerase chain reaction amplification and Sanger sequencing were used to test for POLE mutations in 72 tumors. Associations between POLE mutation, demographic and clinicopathologic features, and survival were investigated with Cox proportional hazard models. RESULTS:POLE mutations were identified in 7 (9.7%) of 72 grade 3 EECs. No significant differences in the clinicopathologic features between those with POLE mutations and those without were identified. Adjusted for age, a decreased risk of recurrence was suggested in patients with a POLE mutation (adjusted hazard ratio, 0.37; 95% confidence interval, 0.09-1.55), as well as decreased risk of death (adjusted hazard ratio, 0.19; 95% confidence interval, 0.03-1.42). CONCLUSIONS:POLE mutations in tumors of women with grade 3 EEC are associated with a lower risk of recurrence and death, although not statistically significant because of high variability in these estimates. These findings, consistent with recently published combined analyses, support POLE mutation status as a noteworthy prognostic marker and may favor a change in the treatment of women with grade 3 EECs, particularly in those with early-stage disease, in which omission of adjuvant therapy and decreased surveillance could possibly be appropriate.

BACKGROUND:We sought to validate the prognostic significance of estrogen receptor alpha (ERα) expression and to investigate the relationship between ESR1 mutation status and outcomes in a large cohort of patients with endometrial cancer. We also investigated the predictive value of ERα for lymph node involvement in a large surgically staged cohort. METHODS:A tumor microarray (TMA) was constructed including only pure endometrioid adenocarcinomas, stained with ER50 monoclonal antibody, and assessed using digital image analysis. For mutation analysis, somatic DNA was extracted and sequenced for ESR1 gene hotspot regions. Differences in patient and tumor characteristics, recurrence and survival between ERα positive and negative, mutated and wild-type tumors were evaluated. RESULTS:Sixty (18.6%) tumors were negative for ERα. Absence of ERα was significantly associated with stage and grade, but not with disease-free or overall survival. ERα was a strong predictor of lymph node involvement (RR: 2.37, 95% CI: 1.12-5.02). Nineteen of 1034 tumors (1.8%) had an ESR1 hotspot mutation; twelve in hotspot 537Y, four in 538D and three in 536L. Patients with an ESR1 mutation had a significantly lower BMI, but were comparable in age, stage and grade, and progression-free survival. CONCLUSION:Patients with ERα negative endometrioid endometrial cancer are more often diagnosed with higher grade and advanced stage disease. Lymph node involvement is more common with lack of ERα expression, and may be able to help triage which patients should undergo lymphadenectomy. Mutations in ESR1 might explain why some low risk women with low BMI develop endometrial cancer.

UNLABELLED:Multiple myeloma (MM) is a hematological malignancy of clonal plasma cells in the bone marrow (BM). The microenvironment plays a key role in MM cell survival and drug resistance through release of soluble factors, expression of adhesion molecules and release of extracellular vesicles (EVs). The aim of this manuscript is to use proteomic profiling of EVs as a tool to identify circulating tumor associated markers in MM patients. First, we characterized the EV protein content obtained from different MM cell lines. Then, we established differences in protein abundance among EVs isolated from MM patient serum and BM and the serum of healthy donors. These data show that the Major Histocompatibility Complex Class I is highly enriched in EVs of MM cell lines and MM patient's serum. Next, we show that CD44 is highly expressed in the EVs isolated from the corticosteroid resistant MM cell line, MM.1R. Furthermore, CD44 was found to be differentially expressed in EVs isolated from newly diagnosed MM patients. Finally through ELISA analysis, we establish the potential of serum CD44 as a predictive biomarker of overall survival. These results support the analysis of EVs as an easily accessible source for MM biomarkers. BIOLOGICAL SIGNIFICANCE/UNASSIGNED:Extracellular vesicles are becoming a research focus due to their roles in cancer cell biology such as immune evasion, therapeutic resistance, proliferation and metastases. While numerous studies of vesicle characterization and biology have been conducted in many cancer models, the role of EV in MM remains relatively unstudied. Here we found that EVs isolated from MM cells are enriched in MHC-1 antigen presenting complex and its binding protein β2-MG, this observation is compatible with the enhanced proteasome activity of MM cells compared to other cancers and the ability of functional MHC-1 to bind and present peptides, generated from protein degradation by the proteasome. Additionally, our experiments show that CD44 is particularly enriched in the EV fraction of corticosteroid resistant MM.1R cells and is differentially expressed in the EV fraction of MM patients. This is of high significance due to the established role of CD44 in adhesion of MM cells to BMSC and induction of IL-6, the primary cytokine for MM cell survival, secretion by the BMSC. Furthermore, ELISA assays for CD44 content from the serum of 254 newly diagnosed MM patients enrolled in a Phase 3 randomized trial show highly variable CD44 levels and those patients with >280 ng/mL serum CD44 showing a reduced overall survival time. These results suggest the potential use of CD44 as a prognostic biomarker in MM.

Mental practice (MP) is a promising adjuvant to physical practice that involves many of the same mechanisms and takes on many of the same properties as physical practice. This study compared efficacy of a "massed" MP regimen versus a "distributed" MP regimen on upper extremity (UE) motor impairment and functional limitation. Twenty-seven chronic stroke survivors were administered the UE section of the Fugl-Meyer (FM) and Action Research Arm Test (ARAT), followed by standardized physical practice and MP regimens. One group was administered "massed" MP (60 min of MP during a single daily session) and a second group administered distributed MP (20 min of MP occurring three times/day). After intervention, changes in FM and ARAT scores of subjects in the distributed condition were significantly higher than those of subjects in the massed condition (FM 3.65, 95 % CI 0.82-6.49, p value = 0.01; ARAT 3.95, 95 % CI 1.24-6.67, p value = 0.006). Likewise, at POST 3, subjects in the distributed group showed significantly higher change in ARAT scores (ARAT 4.90, 95 % CI 0.57-9.22, p value = 0.03); the change in FM scores at POST 3 was 3.18 points higher among subjects in the distributed condition, but only approached significance (95 % CI -1.27 to 7.63, p value = 0.15). Results suggest that a distributed MP schedule is more efficacious in bringing about paretic UE changes than a massed practice schedule, especially in terms of reducing UE functional limitation.

PURPOSE:In premenopausal women with metastatic hormone receptor-positive breast cancer, hormonal therapy is the first-line therapy. Gonadotropin-releasing hormone analogue + tamoxifen therapies have been found to be more effective. The pattern of recurrence risk over time after primary surgery suggests that peri-operative factors impact recurrence. Secondary analyses of an adjuvant trial suggested that the luteal phase timing of surgical oophorectomy in the menstrual cycle simultaneous with primary breast surgery favourably influenced long-term outcomes. METHODS:Two hundred forty-nine premenopausal women with incurable or metastatic hormone receptor-positive breast cancer entered a trial in which they were randomised to historical mid-luteal or mid-follicular phase surgical oophorectomy followed by oral tamoxifen treatment. Kaplan-Meier methods, the log-rank test, and multivariable Cox regression models were used to assess overall and progression-free survival (PFS) in the two randomised groups and by hormone-confirmed menstrual cycle phase. RESULTS:Overall survival (OS) and PFS were not demonstrated to be different in the two randomised groups. In a secondary analysis, OS appeared worse in luteal phase surgery patients with progesterone levels <2 ng/ml (anovulatory patients; adjusted hazard ratio 1.46, 95% confidence interval [CI]: 0.89-2.41, p = 0.14) compared with those in luteal phase with progesterone level of 2 ng/ml or higher. Median OS was 2 years (95% CI: 1.7-2.3) and OS at 4 years was 26%. CONCLUSIONS:The history-based timing of surgical oophorectomy in the menstrual cycle did not influence outcomes in this trial of metastatic patients. ClinicalTrials.gov number NCT00293540.

Only a minority of patients with high risk lymphoma will be cured with autologous transplant, so maintenance with vorinostat, an oral agent with activity in relapsed lymphoma, was studied starting day + 60 for 21 consecutive days followed by a week off for up to 11 cycles. Twenty-three patients with lymphoma were treated. Ten patients completed the full 11-cycle treatment plan per protocol, four patients were removed due to progressive disease and seven withdrew or were removed from the study due to toxicities. Despite Prevnar vaccine administration every 2 months for three injections, the mean antibody concentration never reached protective levels (> 0.35 μg/mL). Fatigue and functional well-being measured by Brief Fatigue Inventory and Functional Assessment of Cancer Therapy-General improved significantly from cycle 1 to cycle 7, but depression scores from the Center for Epidemiologic Studies Depression scale did not change. Given the toxicities observed, this broad-spectrum deacetylase inhibitor at this schedule is not optimal for prolonged maintenance therapy.

OBJECTIVE:To evaluate whether serum adipocytokine concentrations, controlling for baseline adiposity, are predictive of adipose weight gain in adolescents initiating depot medroxyprogesterone acetate (DMPA). METHODS:Percent body fat was measured at baseline and 6 months. Baseline serum adipocytokine concentrations were quantified. RESULTS:Mean percent body fat was 31.6% (±7.6) at baseline and 33.5% (±7.6) at 6 months. In multivariable linear regression modeling (adjusted for baseline percent body fat), Hispanic ethnicity and baseline serum adiponectin concentration were inversely associated (p≤.05) with absolute change in percent body fat at 6 months. CONCLUSIONS:Serum adiponectin concentration may be useful for assessing risk of DMPA-associated adipose gains.

OBJECTIVES/OBJECTIVE:Ovarian cancer quality measures are being developed to improve health care delivery and outcomes. Our objective is to evaluate compliance with 8 quality indicators proposed by the Society of Gynecologic Oncology. METHODS:A review of 123 ovarian cancer patients who underwent primary surgical staging/cytoreduction and chemotherapy from 2010-2012 was undertaken. Medical records were reviewed, and descriptive statistics were performed to determine compliance. RESULTS:A timely operative report documenting residual disease was dictated for 121/123 (98.4%) patients. Complete surgical staging was performed in 33/55 (60.0%) stage I-IIIB patients, with lymphadenectomy most frequently omitted. For optimally debulked stage III patients, 52/56 (92.9%) were offered intraperitoneal chemotherapy. Ultimately, 29/56 (51.8%) received this route and 19/56 (33.9%) within 42 days (range 18-48, median 40 days). Clinical trial randomization and co-morbidities accounted for most cases of non-compliance. All 105 patients for whom chemotherapy was indicated received platin/taxane therapy, and 79/105 (75.2%) within 42 days (range 4-82, median 37days). Venous thromboembolism prophylaxis was provided mechanically in 122/123 (99.2%) and pharmacologically in 99/123 (80.5%) patients within 24h of surgery. Prophylactic parenteral antibiotics were administered within 60 min of cytoreduction in 119/123 (96.7%) and discontinued within 24h after surgery in 120/123 (97.6%) cases. CONCLUSIONS:Compliance with strict definitions of ovarian cancer quality indicators varies depending on the care delivered and documentation of that care. Increased attention to comprehensive surgical staging and timely initiation of chemotherapy appears warranted. With the move toward value-based payment models, quality indicators will play a significant role in health care delivery.

BACKGROUND:There remains a need for a quickly administered, stroke-specific, bedside measure of active wrist and finger movement for the expanding stroke population. The wrist stability and hand mobility scales of the upper extremity Fugl-Meyer Assessment (w/h UE FM) constitute a valid, reliable measure of paretic UE impairment in patients with active wrist and finger movement. OBJECTIVE:The aim of this study was to determine performance on the w/h UE FM in a stable cohort of survivors of stroke with only palpable movement in their paretic wrist flexors. DESIGN/METHODS:A single-center cohort study was conducted. METHOD/METHODS:Thirty-two individuals exhibiting stable, moderate upper extremity hemiparesis (15 male, 17 female; mean age=56.6 years, SD=10.1; mean time since stroke=4.6 years, SD=5.8) participated in the study, which was conducted at an outpatient rehabilitation clinic in the midwestern United States. The w/h UE FM and Action Research Arm Test (ARAT) were administered twice. Intraclass correlation coefficients (ICCs), Cronbach alpha, and ordinal alpha were computed to determine reliability, and Spearman rank correlation coefficients and Bland-Altman plots were computed to establish validity. RESULTS:Intraclass correlation coefficients for the w/h UE FM and ARAT were .95 and .99, respectively. The w/h UE FM intrarater reliability and internal consistency were greater than .80, and concurrent validity was greater than .70. This also was the first stroke rehabilitative study to apply ordinal alpha to examine internal consistency values, revealing w/h UE FM levels greater than .85. Concurrent validity findings were corroborated by Bland-Altman plots. CONCLUSIONS:It appears that the w/h UE FM is a promising tool to measure distal upper extremity movement in patients with little active paretic wrist and finger movement. This finding widens the segment of patients on whom the w/h UE FM can be effectively used and addresses a gap, as commonly used measures necessitate active distal upper extremity movement.

BACKGROUND:For women with hormone receptor-positive, operable breast cancer, surgical oophorectomy plus tamoxifen is an effective adjuvant therapy. We conducted a phase III randomized clinical trial to test the hypothesis that oophorectomy surgery performed during the luteal phase of the menstrual cycle was associated with better outcomes. METHODS:Seven hundred forty premenopausal women entered a clinical trial in which those women estimated not to be in the luteal phase of their menstrual cycle for the next one to six days (n = 509) were randomly assigned to receive treatment with surgical oophorectomy either delayed to be during a five-day window in the history-estimated midluteal phase of the menstrual cycles, or in the next one to six days. Women who were estimated to be in the luteal phase of the menstrual cycle for the next one to six days (n = 231) were excluded from random assignment and received immediate surgical treatments. All patients began tamoxifen within 6 days of surgery and continued this for 5 years. Kaplan-Meier methods, the log-rank test, and multivariable Cox regression models were used to assess differences in five-year disease-free survival (DFS) between the groups. All statistical tests were two-sided. RESULTS:The randomized midluteal phase surgery group had a five-year DFS of 64%, compared with 71% for the immediate surgery random assignment group (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 0.91 to 1.68, P = .18). Multivariable Cox regression models, which included important prognostic variables, gave similar results (aHR = 1.28, 95% CI = 0.94 to 1.76, P = .12). For overall survival, the univariate hazard ratio was 1.33 (95% CI = 0.94 to 1.89, P = .11) and the multivariable aHR was 1.43 (95% CI = 1.00 to 2.06, P = .05). Better DFS for follicular phase surgery, which was unanticipated, proved consistent across multiple exploratory analyses. CONCLUSIONS:The hypothesized benefit of adjuvant luteal phase oophorectomy was not shown in this large trial.