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Luteal versus follicular phase surgical oophorectomy plus tamoxifen in premenopausal women with metastatic hormone receptor-positive breast cancer
Love, Richard R; Hossain, Syed Mozammel; Hussain, Md Margub; Mostafa, Mohammad Golam; Laudico, Adriano V; Siguan, Stephen Sixto S; Adebamowo, Clement; Sun, Jing-Zhong; Fei, Fei; Shao, Zhi-Ming; Liu, Yunjiang; Akram Hussain, Syed Md; Zhang, Baoning; Cheng, Lin; Panigaro, Sonar; Walta, Fardiana; Chuan, Jiang Hong; Mirasol-Lumague, Maria Rica; Yip, Cheng-Har; Navarro, Narciso S; Huang, Chiun-Sheng; Lu, Yen-Shen; Ferdousy, Tahmina; Salim, Reza; Akhter, Chameli; Nahar, Shamsun; Uy, Gemma; Young, Gregory S; Hade, Erinn M; Jarjoura, David
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.
PMCID:5052674
PMID: 27107325
ISSN: 1879-0852
CID: 4691252
Estrogen receptor-alpha as a predictive biomarker in endometrioid endometrial cancer
Backes, Floor J; Walker, Christopher J; Goodfellow, Paul J; Hade, Erinn M; Agarwal, Garima; Mutch, David; Cohn, David E; Suarez, Adrian A
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.
PMCID:4878441
PMID: 26957478
ISSN: 1095-6859
CID: 4691242
Proteomic characterization of circulating extracellular vesicles identifies novel serum myeloma associated markers
Harshman, Sean W; Canella, Alessandro; Ciarlariello, Paul D; Agarwal, Kitty; Branson, Owen E; Rocci, Alberto; Cordero, Hector; Phelps, Mitch A; Hade, Erinn M; Dubovsky, Jason A; Palumbo, Antonio; Rosko, Ashley; Byrd, John C; Hofmeister, Craig C; Benson, Don M; Paulaitis, Michael E; Freitas, Michael A; Pichiorri, Flavia
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.
PMCID:4783258
PMID: 26775013
ISSN: 1876-7737
CID: 4691222
Oncolytic reovirus in combination with chemotherapy in metastatic or recurrent non-small cell lung cancer patients with KRAS-activated tumors
Villalona-Calero, Miguel A; Lam, Elaine; Otterson, Gregory A; Zhao, Weiqiang; Timmons, Matthew; Subramaniam, Deepa; Hade, Erinn M; Gill, George M; Coffey, Matthew; Selvaggi, Giovanni; Bertino, Erin; Chao, Bo; Knopp, Michael V
BACKGROUND:The type 3 Dearing reovirus (Reolysin) is a naturally occurring virus that preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. It induces host immunity and cell cycle arrest and acts synergistically with cytotoxic agents. METHODS:This study evaluated Reolysin combined with paclitaxel and carboplatin in patients with metastatic/recurrent KRAS-mutated or epidermal growth factor receptor (EGFR)-mutated/amplified non-small cell lung cancer. RESULTS:Thirty-seven patients were treated. Molecular alterations included 20 KRAS mutations, 10 EGFR amplifications, 3 EGFR mutations, and 4 BRAF-V600E mutations. In total, 242 cycles (median, 4; range, 1-47) were completed. The initial doses were area under the curve (AUC) 6 mg/mL/min for carboplatin, 200 mg/m(2) for paclitaxel on day 1, and 3 × 10(10) 50% tissue culture infective dose for Reolysin on days 1 to 5 of each 21-day cycle. Because of diarrhea and febrile neutropenia (in the first 2 patients), subsequent doses were reduced to 175 mg/m(2) for paclitaxel and AUC 5 mg/mL/min for carboplatin. Toxicities included fatigue, diarrhea, nausea/vomiting, neutropenia, arthralgia/myalgia, anorexia, and electrolyte abnormalities. Response Evaluation Criteria in Solid Tumors 1.0 responses included the following: partial response for 11 patients, stable disease (SD) for 20 patients, progressive disease for 4 patients, and not evaluable for 2 patients (objective response rate, 31%; 90% 1-sided lower confidence interval, 21%). Four SD patients had >40% positron emission tomography standardized uptake value reductions. The median progression-free survival, median overall survival, and 12-month overall survival rate were 4 months, 13.1 months, and 57%, respectively. Seven patients were alive after a median follow-up of 34.2 months; they included 2 patients without disease progression at 37 and 50 months. CONCLUSIONS:Reolysin in combination with paclitaxel and carboplatin was well tolerated. The observed response rate suggests a benefit of the reovirus for chemotherapy. A follow-up randomized study is recommended. The proportion of patients surviving longer than 2 years (30%) suggests a second/third-line treatment effect or possibly the triggering of an immune response after tumor reovirus infiltration.
PMCID:5068485
PMID: 26709987
ISSN: 1097-0142
CID: 4691212
Long-term visual acuity outcomes in patients with uveal melanoma treated with 125I episcleral OSU-Nag plaque brachytherapy
Wisely, C Ellis; Hadziahmetovic, Mersiha; Reem, Rachel E; Hade, Erinn M; Nag, Subir; Davidorf, Frederick H; Martin, Douglas; Cebulla, Colleen M
PURPOSE/OBJECTIVE:To report our experience in long-term follow-up of ocular melanoma patients treated with custom OSU-Nag eye plaques using (125)I sources. METHODS:A retrospective chart review was conducted for 113 consecutive ocular melanoma patients with follow-up visual acuity data who were treated with OSU-Nag plaque episcleral brachytherapy at The Ohio State University Medical Center from 1994 to 2009. Visual acuity, complication data, and recurrence rates were recorded up to 120Â months after brachytherapy. RESULTS:Median age at presentation was 63.0Â years (range, 22-93). Median follow-up was 65.5Â months (range, 2-180). Median radiation dose at the prescription point was 85.8Â Gy (range, 51.8-103.7). Preservation of useful visual acuity, defined as better than 20/200, was noted in 43 of 74 (58%) of patients in the present study at 36Â months compared with 50.1% of Collaborative Ocular Melanoma Study participants. By 120Â months, 17 of 30 (57%; 95% confidence interval, 45-69%) progressed to visual acuity worse than 20/200, whereas 9 of 30 (30%) retained visual acuity of 20/40 or better, and 4 of 30 (13%) were 20/50-20/200. The rate of retinopathy after radiation was approximately 40% of all those observed by 60Â months. Baseline visual acuity, apical tumor height, American Joint Committee on Cancer tumor category, and distance between the tumor and the fovea were all significantly associated with loss of visual acuity. The local tumor control rate by 60Â months of follow-up was 93% (95% confidence interval, 85-97%). CONCLUSIONS:The OSU-Nag custom (125)I plaque is an effective treatment for uveal melanoma, with preservation of useful visual acuity in 58% of eyes 3Â years after treatment and 43% of eyes 10Â years after treatment.
PMCID:4990815
PMID: 26525215
ISSN: 1873-1449
CID: 4691202
Serum adipocytokines and adipose weight gain: a pilot study in adolescent females initiating depot medroxyprogesterone acetate
Bonny, Andrea E; Lange, Hannah L H; Hade, Erinn M; Kaufman, Bram; Reed, Michael D; Mesiano, Sam
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.
PMCID:4575860
PMID: 26071674
ISSN: 1879-0518
CID: 4691182
Setting the bar: compliance with ovarian cancer quality indicators at a National Cancer Institute-designated Comprehensive Cancer Center
Liang, Margaret I; ElNaggar, Adam C; Nekkanti, Silpa; O'Malley, David M; Hade, Erinn M; Copeland, Larry J; Fowler, Jeffrey M; Salani, Ritu; Backes, Floor J; Cohn, David E
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.
PMID: 26216728
ISSN: 1095-6859
CID: 4691192
Evaluation of the Hematologic Safety of Same Day Versus Standard Administration (24- to 72-Hour Delay) of Pegfilgrastim in Gynecology Oncology Patients Undergoing Cytotoxic Chemotherapy
Billingsley, Caroline C; Jacobson, Samuel N; Crafton, Sarah M; Crim, Aleia K; Li, Quan; Hade, Erinn M; Cohn, David E; Fowler, Jeffrey M; Copeland, Larry J; Salani, Ritu; Backes, Floor J; O'Malley, David M
OBJECTIVE:We assessed the safety and efficacy of administration of pegfilgrastim on the same day compared with standard administration 24 to 72 hours after chemotherapy in patients with gynecologic malignancies. METHODS:A retrospective review was conducted on patients undergoing pegfilgrastim to mitigate the myelosuppressive consequences of chemotherapy. The primary outcome was incidence of grade 3 to 4 neutropenia following pegfilgrastim for same-day administration (D1) versus standard administration (D2+). Secondary outcomes included dose delay, regimen change, hospitalization due to neutropenia, and incidence of febrile neutropenia. RESULTS:Four hundred twenty-one patients with 2071 administrations of pegfilgrastim were included. Five hundred six administrations of pegfilgrastim were given on D1 compared with 1565 administrations on D2+. The most common malignancy was ovarian cancer (79.1%), followed by endometrial (14.5%). Comparing the D1 and D2+ cohorts, noninferiority was not established for the incidence of grade 3 to 4 neutropenia (2.6% vs 1.8%, adjusted relative risk [aRR], 1.6; 90% confidence interval [CI], 0.87-3.2) or dose modification (6.5% vs 4.9%; aRR, 1.3; 90% CI, 0.9-1.8). However, the rate of treatment delays (7.3% vs 9.4%; aRR, 0.8; 90% CI, 0.6-1.1) in the D1 and D2+ groups suggested that delays in the D1 group were not more common than in the D2+ group. CONCLUSIONS:The incidence of hematologic toxicities and dose modification in patients receiving same-day pegfilgrastim were not as low as in those undergoing standard administration. However, treatment delays were found to be no more frequent in those receiving same-day pegfilgrastim versus standard administration. Same-day administration of pegfilgrastim is a reasonable option.
PMID: 26067861
ISSN: 1525-1438
CID: 4691172
Relation of body mass index to frequency of recurrent preterm birth in women treated with 17-alpha hydroxyprogesterone caproate
Co, Aila L; Walker, Hetty C; Hade, Erinn M; Iams, Jay D
OBJECTIVE:The standard weekly dose of 17-alpha hydroxyprogesterone caproate (17OHP-C; 250 mg/wk) to reduce the risk of recurrent preterm birth was adopted without regard to patient characteristics. We examined the relationship between prepregnancy body mass index (BMI) and gestational age at birth after 17OHP-C prophylaxis. We hypothesized that rates of births before 32, 35, and 37 weeks of gestation would be increased in women with a BMI of 25 kg/m(2) or greater. STUDY DESIGN/METHODS:A retrospective cohort study was conducted from a deidentified database of women treated with 17OHP-C for prior spontaneous preterm birth. The frequency of recurrent preterm delivery before 32, 35, and 37 weeks of gestation was investigated for women with a BMI less than 25 kg/m(2) compared with women with a BMI of 25 kg/m(2) or greater. The adjusted relative risk of preterm delivery was estimated through a modified Poisson regression approach. RESULTS:Of 390 women who met inclusion criteria, 60 (15.4%) delivered before 32 weeks, 89 (22.8%) before 35 weeks, and 156 (40.0%) before 37 weeks. A total of 174 women had a BMI less than 25 kg/m(2) (mean [SD], 21.2 [2.5]) and 216 had a BMI of 25 kg/m(2) or greater (mean [SD], 33.5 [6.7]). Risk of birth before 32 weeks was 1.7 times higher on average (adjusted relative risk, 1.7; 95% confidence interval, 1.05-2.77) in overweight women than in women with a BMI less than 25 kg/m(2), adjusting for age, race, smoking, and short cervix. There was no difference in the risk of preterm birth before 35 or 37 weeks. CONCLUSION/CONCLUSIONS:Among pregnant women receiving 17OHP-C prophylaxis for a prior preterm birth, recurrent preterm birth before 32 weeks was significantly more common in those women whose prepregnancy BMI was 25 kg/m(2) or greater than in women with BMI less than 25 kg/m(2). This observation is consistent with pharmacological studies suggesting that dosing regimens of 17OHP-C may affect efficacy.
PMID: 25912300
ISSN: 1097-6868
CID: 4691162
Timing of adjuvant surgical oophorectomy in the menstrual cycle and disease-free and overall survival in premenopausal women with operable breast cancer
Love, Richard R; Laudico, Adriano V; Van Dinh, Nguyen; Allred, D Craig; Uy, Gemma B; Quang, Le Hong; Salvador, Jonathan Disraeli S; Siguan, Stephen Sixto S; Mirasol-Lumague, Maria Rica; Tung, Nguyen Dinh; Benjaafar, Noureddine; Navarro, Narciso S; Quy, Tran Tu; De La Peña, Arturo S; Dofitas, Rodney B; Bisquera, Orlino C; Linh, Nguyen Dieu; To, Ta Van; Young, Gregory S; Hade, Erinn M; Jarjoura, David
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.
PMCID:4838061
PMID: 25794890
ISSN: 1460-2105
CID: 4691152