Publications by authors named "Katherine A Guthrie"

123 Publications

Vaginal microbiota and genitourinary menopausal symptoms: a cross-sectional analysis.

Menopause 2017 Oct;24(10):1160-1166

1Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA 2Fred Hutchinson Cancer Research Center, Seattle, WA 3Department of Obstetrics & Gynecology, University of Washington, Seattle, WA 4Department of Family Medicine and Public Health, University of California at San Diego, La Jolla, CA 5Department of Laboratory Medicine, University of Washington, Seattle, WA 6Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 7Group Health Research Institute, Seattle, WA 8Department of Obstetrics & Gynecology and Psychiatry, University of Pennsylvania, Philadelphia, PA 9Brigham and Women's Hospital and Dana Farber Cancer Center, Boston, MA 10Department of Psychiatry, Massachusetts General Hospital, Boston, MA.

Objective: To examine associations between the composition of the vaginal microbiota and genitourinary menopausal symptoms, serum estrogen, and vaginal glycogen.

Methods: For this cross-sectional study, 88 women aged 40 to 62 years, enrolled in a hot flash treatment trial, provided vaginal swabs and a blood sample at enrollment. Bacterial communities were characterized using 16S rRNA PCR and deep sequencing targeting the V3-V4 region. Quantities of Lactobacillus crispatus and Lactobacillus iners were measured using qPCR. Self-reported genitourinary symptoms included: presence and severity of individual symptoms and identification of most bothersome symptom. Glycogen was measured fluorometrically in swab eluate. Serum estradiol (E2) and estrone (E1) were measured by liquid chromatography/mass spectrometry. Associations between bacteria, symptoms, glycogen, and serum estrogens were tested by linear regression or Wilcoxon signed-rank test, adjusted for multiple comparisons. Comparisons between groups used Kruskall-Wallis or Fisher's exact test.

Results: Of the 88 women, 33 (38%) had a majority of Lactobacillus species, whereas 58 (66%) had any Lactobacillus detected. Over half (53%) reported at least one vulvovaginal symptom (most commonly dryness), but symptoms were not associated with the presence of Lactobacillus species. Women with Lactobacillus-dominant communities had higher unconjugated serum estrone, but no difference in vaginal glycogen levels, compared with those with non-Lactobacillus-dominant communities. Higher serum E2 and E1 were not associated with either higher vaginal glycogen or detection of individual genera.

Conclusions: Presence of Lactobacillus-dominant vaginal microbiota was not associated with fewer vulvovaginal symptoms. Serum estrone was higher in women with Lactobacillus dominance, but vaginal-free glycogen was not associated with composition of the vaginal microbiota.
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http://dx.doi.org/10.1097/GME.0000000000000904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607086PMC
October 2017

Validity, cut-points, and minimally important differences for two hot flash-related daily interference scales.

Menopause 2017 Aug;24(8):877-885

1School of Nursing, Indiana University, Indianapolis, IN 2Department of Biostatistics, Fairbanks School of Public Health, School of Medicine, Indiana University, Indianapolis, IN 3Department of Psychology, School of Science, Indiana University-Purdue University Indianapolis, IN 4University of Washington School of Nursing, Seattle, WA 5Group Health Research Institute, Seattle, WA 6Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 7Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and Harvard School of Public Health, Boston, MA 8Departments of Obstetrics/Gynecology and Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 9MsFLASH Data Coordinating Center, Fred Hutchinson Cancer Research Center, Seattle, WA.

Objectives: To conduct psychometric analyses to condense the Hot Flash-Related Daily Interference Scale (HFRDIS) into a shorter form termed the Hot Flash Interference (HFI) scale; evaluate cut-points for both scales; and establish minimally important differences (MIDs) for both scales.

Methods: We analyzed baseline and postrandomization patient-reported data pooled across three randomized trials aimed at reducing vasomotor symptoms (VMS) in 899 midlife women. Trials were conducted across five MsFLASH clinical sites between July 2009 and October 2012. We eliminated HFRDIS items based on experts' content validity ratings and confirmatory factor analysis, and evaluated cut-points and established MIDs by mapping HFRDIS and HFI to other measures.

Results: The three-item HFI (interference with sleep, mood, and concentration) demonstrated strong internal consistency (alphas of 0.830 and 0.856), showed good fit to the unidimensional "hot flash interference factor," and strong convergent validity with HFRDIS scores, diary VMS, and menopausal quality of life. For both scales, cut-points of mild (0-3.9), moderate (4-6.9), and severe (7-10) interference were associated with increasing diary VMS ratings, sleep, and anxiety. The average MID was 1.66 for the HFRDIS and 2.34 for the HFI.

Conclusions: The HFI is a brief assessment of VMS interference and will be useful in busy clinics to standardize VMS assessment or in research studies where response burden may be an issue. The scale cut-points and MIDs should prove useful in targeting those most in need of treatment, monitoring treatment response, and interpreting existing and future research findings.
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http://dx.doi.org/10.1097/GME.0000000000000871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002749PMC
August 2017

Phase III Prospective Randomized Comparison Trial of Depot Octreotide Plus Interferon Alfa-2b Versus Depot Octreotide Plus Bevacizumab in Patients With Advanced Carcinoid Tumors: SWOG S0518.

J Clin Oncol 2017 May 6;35(15):1695-1703. Epub 2017 Apr 6.

James C. Yao and Cesar Moran, MD Anderson Cancer Center, Houston, TX; Katherine A. Guthrie and Shannon McDonough, Fred Hutchinson Cancer Research Center, Seattle, WA; Jonathan R. Strosberg, H. Lee Moffitt Cancer Center, Tampa, FL; Matthew H. Kulke and Jennifer A. Chan, Dana Farber Cancer Institute, Boston, MA; Noelle LoConte, University of Wisconsin, Carbone Cancer Center, Madison, WI; Robert R. McWilliams, Mayo Clinic College of Medicine, Rochester, MN; Edward M. Wolin, University of Kentucky, Lexington, KY; Edward M. Wolin, Montifiore Einstein Cancer Center, New York, NY; Bassam Mattar, Wichita NCORP/Cancer Center of Kansas, Wichita, KS; Helen Chen, NCI Cancer Therapy Evaluation Program, Bethesda, MD; Charles D. Blanke, Oregon Health & Science University, Portland, OR; and Howard S. Hochster, Yale Cancer Center, New Haven, CT.

Purpose Treatment options for neuroendocrine tumors (NETs) remain limited. This trial assessed the progression-free survival (PFS) of bevacizumab or interferon alfa-2b (IFN-α-2b) added to octreotide among patients with advanced NETs. Patients and Methods Southwest Oncology Group (SWOG) S0518, a phase III study conducted in a US cooperative group system, enrolled patients with advanced grades 1 and 2 NETs with progressive disease or other poor prognostic features. Patients were randomly assigned to treatment with octreotide LAR 20 mg every 21 days with either bevacizumab 15 mg/kg every 21 days or 5 million units of IFN-α-2b three times per week. The primary end point was centrally assessed PFS. This trial is registered with ClinicalTrials.gov as NCT00569127. Results A total of 427 patients was enrolled, of whom 214 were allocated to bevacizumab and 213 to IFN-α-2b. The median PFS by central review was 16.6 months (95% CI, 12.9 to 19.6 months) in the bevacizumab arm and was 15.4 months (95% CI, 9.6 to 18.6 months) in the IFN arm (hazard ratio [HR], 0.93; 95% CI, 0.73 to 1.18; P = .55). By site review, the median PFS times were 15.4 months (95% CI, 12.6 to 17.2 months) for bevacizumab and 10.6 months (95% CI, 8.5 to 14.4 months) for interferon (HR, 0.90; 95% CI, 0.72 to 1.12; P = .33). Time to treatment failure was longer with bevacizumab than with IFN (HR, 0.72; 95% CI, 0.58 to 0.89; P = .003). Confirmed radiologic response rates were 12% (95% CI, 8% to 18%) for bevacizumab and 4% (95% CI, 2% to 8%) for IFN. Common adverse events with bevacizumab and octreotide included hypertension (32%), proteinuria (9%), and fatigue (7%); with IFN and octreotide, they included fatigue (27%), neutropenia (12%), and nausea (6%). Conclusion No significant differences in PFS were observed between the bevacizumab and IFN arms, which suggests that these agents have similar antitumor activity among patients with advanced NETs.
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http://dx.doi.org/10.1200/JCO.2016.70.4072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455764PMC
May 2017

Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial.

JAMA Oncol 2017 Apr;3(4):516-522

Yale Cancer Center, New Haven, Connecticut.

Importance: KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer.

Objective: To compare selumetinib and MK-2206 vs modified FOLFOX (mFOLFOX) in patients with metastatic pancreatic cancer for whom gemcitabine-based therapy had failed.

Design, Setting, And Participants: SWOG S1115 was a randomized phase 2 clinical trial. Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed were randomized to selumetinib plus MK-2206 or mFOLFOX. Patients were randomized in a 1:1 fashion and stratified according to duration of prior systemic therapy and presence of liver metastases.

Interventions: Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin, 85 mg/m2 intravenous, and fluorouracil, 2400 mg/m2 intravenous infusion over 46-48 hours) on days 1 and 15 of a 28-day cycle.

Main Outcomes And Measures: The primary end point of the study was overall survival. Secondary objectives included evaluating toxic effects, objective tumor response, and progression-free survival.

Results: There were 58 patients in the selumetinib plus MK-2206 (experimental) arm (60% male; median [range] age, 69 [54-88] years) and 62 patients in the mFOLFOX arm (35% male; median [range] age, 65 [34-82] years). In the experimental arm, median overall survival was shorter (3.9 vs 6.7 months; HR, 1.37; 95% CI, 0.90-2.08; P = .15), as was median progression-free survival (1.9 vs 2.0 months; HR, 1.61; 95% CI, 1.07-2.43; P = .02). One vs 5 patients had a partial response and 12 vs 14 patients had stable disease in the experimental arm vs mFOLFOX arm. Grade 3 or higher toxic effects were observed in 39 patients treated with selumetinib and MK-2206 vs 23 patients treated with mFOLFOX. More patients in the experimental arm discontinued therapy due to adverse events (13 vs 7 patients).

Conclusions And Relevance: Dual targeting of the MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed. This was the first randomized prospective evaluation of mFOLFOX in the US population that showed comparable results to CONKO-003 and PANCREOX.

Trial Registration: clinicaltrials.gov Identifier: NCT01658943.
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http://dx.doi.org/10.1001/jamaoncol.2016.5383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665683PMC
April 2017

Statistical Methods for Unusual Count Data: Examples From Studies of Microchimerism.

Am J Epidemiol 2016 11;184(10):779-786

Natural acquisition of small amounts of foreign cells or DNA, referred to as microchimerism, occurs primarily through maternal-fetal exchange during pregnancy. Microchimerism can persist long-term and has been associated with both beneficial and adverse human health outcomes. Quantitative microchimerism data present challenges for statistical analysis, including a skewed distribution, excess zero values, and occasional large values. Methods for comparing microchimerism levels across groups while controlling for covariates are not well established. We compared statistical models for quantitative microchimerism values, applied to simulated data sets and 2 observed data sets, to make recommendations for analytic practice. Modeling the level of quantitative microchimerism as a rate via Poisson or negative binomial model with the rate of detection defined as a count of microchimerism genome equivalents per total cell equivalents tested utilizes all available data and facilitates a comparison of rates between groups. We found that both the marginalized zero-inflated Poisson model and the negative binomial model can provide unbiased and consistent estimates of the overall association of exposure or study group with microchimerism detection rates. The negative binomial model remains the more accessible of these 2 approaches; thus, we conclude that the negative binomial model may be most appropriate for analyzing quantitative microchimerism data.
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http://dx.doi.org/10.1093/aje/kww093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141948PMC
November 2016

Effects of Yoga and Aerobic Exercise on Actigraphic Sleep Parameters in Menopausal Women with Hot Flashes.

J Clin Sleep Med 2017 01 15;13(1):11-18. Epub 2017 Jan 15.

Division of Epidemiology and Community Health, Department of Medicine, University of Minnesota, Minneapolis, MN.

Study Objectives: To determine effects of yoga and aerobic exercise compared with usual activity on objective assessments of sleep in midlife women.

Methods: Secondary analyses of a randomized controlled trial in the Menopause Strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH) network conducted among 186 late transition and postmenopausal women aged 40-62 y with hot flashes. Women were randomized to 12 w of yoga, supervised aerobic exercise, or usual activity. The mean and coefficient of variation (CV) of change in actigraph sleep measures from each intervention group were compared to the usual activity group using linear regression models.

Results: Baseline values of the primary sleep measures for the entire sample were mean total sleep time (TST) = 407.5 ± 56.7 min; mean wake after sleep onset (WASO) = 54.6 ± 21.8 min; mean CV for WASO = 37.7 ± 18.7 and mean CV for number of long awakenings > 5 min = 81.5 ± 46.9. Changes in the actigraphic sleep outcomes from baseline to weeks 11-12 were small, and none differed between groups. In an exploratory analysis, women with baseline Pittsburgh Sleep Quality Index higher than 8 had significantly reduced TST-CV following yoga compared with usual activity.

Conclusions: This study adds to the currently scant literature on objective sleep outcomes from yoga and aerobic exercise interventions for this population. Although small effects on self-reported sleep quality were previously reported, the interventions had no statistically significant effects on actigraph measures, except for potentially improved sleep stability with yoga in women with poor self-reported sleep quality.
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http://dx.doi.org/10.5664/jcsm.6376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5181601PMC
January 2017

Female Sexual Function Index Short Version: A MsFLASH Item Response Analysis.

Arch Sex Behav 2016 11 8;45(8):1897-1905. Epub 2016 Aug 8.

Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.

The Female Sexual Function Index (FSFI) is a psychometrically sound and popular 19-item self-report measure, but its length may preclude its use in studies with multiple outcome measures, especially when sexual function is not a primary endpoint. Only one attempt has been made to create a shorter scale, resulting in the Italian FSFI-6, later translated into Spanish and Korean without further psychometric analysis. Our study evaluated whether a subset of items on the 19-item English-language FSFI would perform as well as the full-length FSFI in peri- and postmenopausal women. We used baseline data from 898 peri- and postmenopausal women recruited from multiple communities, ages 42-62 years, and enrolled in randomized controlled trials for vasomotor symptom management. Goals were to (1) create a psychometrically sound, shorter version of the FSFI for use in peri- and postmenopausal women as a continuous measure and (2) compare it to the Italian FSFI-6. Results indicated that a 9-item scale provided more information than the FSFI-6 across a spectrum of sexual functioning, was able to capture sample variability, and showed sufficient range without floor or ceiling effects. All but one of the items from the Italian 6-item version were included in the 9-item version. Most omitted FSFI items focused on frequency of events or experiences. When assessment of sexual function is a secondary endpoint and subject burden related to questionnaire length is a priority, the 9-item FSFI may provide important information about sexual function in English-speaking peri- and postmenopausal women.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053877PMC
http://dx.doi.org/10.1007/s10508-016-0804-5DOI Listing
November 2016

Validity of Adjuvant! Online in older patients with stage III colon cancer based on 2967 patients from the ACCENT database.

J Geriatr Oncol 2016 11 25;7(6):422-429. Epub 2016 Jul 25.

Mayo Clinic, Rochester, MN, United States.

Background: Adjuvant! Online is a tool used for clinical decision making in patients with early stage colon cancer. As details of the tool's construction are not published, the ability of Adjuvant! Online to accurately predict outcomes for older patients (age 70+) with node positive colon cancer receiving adjuvant chemotherapy is unclear.

Methods: Individual data from older patients with stage III colon cancer who enrolled into multiple trials within the ACCENT database were entered into the Adjuvant! Online program to obtain predicted probabilities of 5-year overall survival (OS) and recurrence-free survival (RFS). Median predictions were compared with known rates. As co-morbidities were not known for ACCENT patients, but required for calculator entry, patients were assumed to have either "minor" or "average for age" co-morbidities.

Results: 2967 older patients from 10 randomized studies were included. When "minor" co-morbidities were assumed, the median predicted 5-year OS rate of 64% nearly matched the actual rate of 65%; when "average for age" co-morbidities were assumed, the median prediction dropped to 58%, outside the CI for the actual rate. On the other hand, assuming "minor" co-morbidities gave a median 5-year RFS prediction of 62%, outside the 95% CI for the actual rate of 58%, while assuming "average for age" co-morbidities yielded a better median prediction of 57%.

Conclusion: Adjuvant! Online is reasonably accurate overall for predicting outcomes in older trial patients with stage III colon cancer, though accuracy may differ between 5-year RFS and 5-year OS predictions when a fixed degree of co-morbidities is assumed.
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http://dx.doi.org/10.1016/j.jgo.2016.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159186PMC
November 2016

A yoga & exercise randomized controlled trial for vasomotor symptoms: Effects on heart rate variability.

Complement Ther Med 2016 Jun 4;26:66-71. Epub 2016 Mar 4.

Group Health Research Institute, 1730 Minor Ave, Seattle, WA 98101, United States.

Objectives: Heart rate variability (HRV) reflects the integration of the parasympathetic nervous system with the rest of the body. Studies on the effects of yoga and exercise on HRV have been mixed but suggest that exercise increases HRV. We conducted a secondary analysis of the effect of yoga and exercise on HRV based on a randomized clinical trial of treatments for vasomotor symptoms in peri/post-menopausal women.

Design: Randomized clinical trial of behavioral interventions in women with vasomotor symptoms (n=335), 40-62 years old from three clinical study sites.

Interventions: 12-weeks of a yoga program, designed specifically for mid-life women, or a supervised aerobic exercise-training program with specific intensity and energy expenditure goals, compared to a usual activity group.

Main Outcome Measures: Time and frequency domain HRV measured at baseline and at 12 weeks for 15min using Holter monitors.

Results: Women had a median of 7.6 vasomotor symptoms per 24h. Time and frequency domain HRV measures did not change significantly in either of the intervention groups compared to the change in the usual activity group. HRV results did not differ when the analyses were restricted to post-menopausal women.

Conclusions: Although yoga and exercise have been shown to increase parasympathetic-mediated HRV in other populations, neither intervention increased HRV in middle-aged women with vasomotor symptoms. Mixed results in previous research may be due to sample differences. Yoga and exercise likely improve short-term health in middle-aged women through mechanisms other than HRV.
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http://dx.doi.org/10.1016/j.ctim.2016.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893767PMC
June 2016

Telephone-Based Cognitive Behavioral Therapy for Insomnia in Perimenopausal and Postmenopausal Women With Vasomotor Symptoms: A MsFLASH Randomized Clinical Trial.

JAMA Intern Med 2016 Jul;176(7):913-20

Department of Family Medicine and Public Health, University of California-San Diego, La Jolla.

Importance: Effective, practical, nonpharmacologic therapies are needed to treat menopause-related insomnia symptoms in primary and women's specialty care settings.

Objective: To evaluate the efficacy of telephone-based cognitive behavioral therapy for insomnia (CBT-I) vs menopause education control (MEC).

Design, Setting, And Participants: A single-site, randomized clinical trial was conducted from September 1, 2013, to August 31, 2015, in western Washington State among 106 perimenopausal or postmenopausal women aged 40 to 65 years with moderate insomnia symptoms (Insomnia Severity Index [ISI] score, ≥12) and 2 or more daily hot flashes. Blinded assessments were conducted at baseline, 8, and 24 weeks postrandomization. An intent-to-treat analysis was conducted.

Interventions: Six CBT-I or MEC telephone sessions in 8 weeks. Participants submitted weekly electronic sleep diaries and received group-specific written educational materials. The CBT-I sessions included sleep restriction, stimulus control, sleep hygiene education, cognitive restructuring, and behavioral homework; MEC sessions provided information about menopause and women's health.

Main Outcomes And Measures: Primary outcome was scores on the ISI (score range, 0-28; scores ≥15 indicate moderate to severe insomnia). Secondary outcome was scores on the Pittsburgh Sleep Quality Index (score range, 0-21; higher scores indicate worse sleep quality). Additional outcomes included sleep and hot flash diary variables and hot flash interference.

Results: At 8 weeks, ISI scores had decreased 9.9 points among 53 women receiving CBT-I (mean [SD] age, 55.0 [3.5] years) and 4.7 points among 53 women receiving MEC (age, 54.7 [4.7] years), a mean between-group difference of 5.2 points (95% CI, -6.1 to -3.3; P < .001). Pittsburgh Sleep Quality Index scores decreased 4.0 points in women receiving CBT-I and 1.4 points in women receiving MEC, a mean between-group difference of 2.7 points (95% CI, -3.9 to -1.5; P < .001). Significant group differences were sustained at 24 weeks. At 8 and 24 weeks, 33 of 47 women (70%) and 37 of 44 (84%) in the CBT-I group, respectively, had ISI scores in the no-insomnia range compared with 10 of 41 (24%) and 16 of 37 (43%) in the MEC group, respectively. The CBT-I group also had greater improvements in diary-reported sleep latency, wake time, and sleep efficiency. There were no between-group differences in frequency of daily hot flashes, but hot flash interference was significantly decreased at 8 weeks for the CBT-I group (-15.7; 95% CI, -20.4 to -11.0) compared with the MEC group (-7.1; 95% CI, -14.6 to 0.4) (P = .03), differences that were maintained at 24 weeks for the CBT-I group (-22.8; 95% CI, -28.6 to -16.9) and MEC group (-11.6; 95% CI, -19.4 to -3.8) (P = .003).

Conclusions And Relevance: Telephone-based CBT-I improved sleep in perimenopausal and postmenopausal women with insomnia and hot flashes. Results support further development and testing of centralized CBT-I programs for treating menopausal insomnia.

Trial Registration: clinicaltrials.gov Identifier: NCT01936441.
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http://dx.doi.org/10.1001/jamainternmed.2016.1795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935624PMC
July 2016

Determinants of Early Mortality Among 37,568 Patients With Colon Cancer Who Participated in 25 Clinical Trials From the Adjuvant Colon Cancer Endpoints Database.

J Clin Oncol 2016 Apr 8;34(11):1182-9. Epub 2016 Feb 8.

Winson Y. Cheung, British Columbia Cancer Agency, Vancouver, British Columbia; Chris O'Callaghan, Queen's University, Kingston, Ontario, Canada; Lindsay A. Renfro, Axel Grothey, Steven R. Alberts, and Daniel J. Sargent, Mayo Clinic, Rochester, MN; David Kerr, University of Oxford, Oxford; Chris Twelves, University of Leeds and St James Institute of Oncology, Leeds, United Kingdom; Aimery de Gramont, Franco-British Institute, Levallois-Perret; Thierry Andre, Hospital Saint-Antoine and Pierre and Marie Curie University, Paris; Jean-Francois Seitz, La Timone Hospital, Aix-Marseille University, Marseille, France; Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; Katherine A. Guthrie, Fred Hutchinson Cancer Center, Seattle, WA; Roberto Labianca, Ospedale Giovanni XXIII, Bergamo; Guido Francini, University of Siena, Siena, Italy; Eric Van Cutsem, University Hospital Leuven, Leuven, Belgium; Daniel G. Haller, University of Pennsylvania, Philadelphia; and Greg Yothers, University of Pittsburgh, Pittsburgh, PA.

Purpose: Factors associated with early mortality after surgery and treatment with adjuvant chemotherapy in colon cancer are poorly understood. We aimed to characterize the determinants of early mortality in a large cohort of colon cancer trial participants.

Methods: A pooled analysis of 37,568 patients in 25 randomized trials of adjuvant systemic therapy was conducted. Multivariable logistic regression models with several definitions of early mortality (30, 60, and 90 days, and 6 months) were constructed, adjusting for clinically and statistically significant variables. A nomogram for 6-month mortality was developed and validated.

Results: Median age among patients was 61 years, patient demographics included 54% men and 90% White, 29% and 71% had stage II and III disease, respectively, and 79%, 20%, and 1% had an Eastern Cooperative Oncology Group performance status (PS) of 0, 1, and ≥ 2, respectively. Early mortality was low: 0.3% at 30 days, 0.6% at 60 days, 0.8% at 90 days, and 1.4% at 6 months. Of those patients who died by 6 months post-random assignment, 40% had documented disease recurrence prior to death. Early disease recurrence was associated with a markedly increased risk of death during the first 6 months post-treatment (hazard ratio, 82.6; 95%CI, 66.9 to 102.1). In prognostic analyses, advanced age, male sex, poorer PS, increasing ratio of positive to examined lymph nodes, earlier decade of enrollment, and higher tumor stage and grade predicted a greater likelihood of early mortality, whereas treatment received was not strongly predictive. A multivariable model for 6-month mortality showed strong optimism-adjusted discrimination (concordance index, 0.73) and calibration.

Conclusion: Early mortality was infrequent but more prevalent in patients with advanced age and a PS of ≥ 2, underscoring the need to carefully consider the risk-to-benefit ratio when making treatment decisions in these subgroups.
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http://dx.doi.org/10.1200/JCO.2015.65.1158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933130PMC
April 2016

Is heart rate variability associated with frequency and intensity of vasomotor symptoms among healthy perimenopausal and postmenopausal women?

Clin Auton Res 2016 Feb 21;26(1):7-13. Epub 2015 Dec 21.

Group Health Research Institute, 1730 Minor Ave, Seattle, WA, 98101, USA.

Objective: Research has suggested that the autonomic nervous system (ANS) is involved in the experience of vasomotor symptoms (VMS) during menopause. We examined the relationship of VMS intensity and heart rate variability (HRV), a measure of ANS function.

Methods: Women (n = 282) were recruited from three American states for a clinical trial of yoga, exercise, and omega-3 fatty acid supplements for VMS. To be eligible, women had to report at least 14 VMS per week, with some being moderate to severe. Sitting electrocardiograms were recorded for 15 min using Holter monitors at both baseline and 12-week follow-up. Time and frequency domain HRV measures were calculated. Women completed daily diary measures of VMS frequency and intensity for 2 weeks at baseline and for 1 week at the follow-up assessment 12 weeks later. Multivariable linear regression was used to assess the relationship between VMS and baseline HRV measures and to compare change in HRV with change in VMS over the 12 weeks.

Results: Baseline HRV was not associated with either VMS frequency or intensity at baseline. Change in HRV was not associated with change in VMS frequency or intensity across the follow-up.

Interpretation: Heart rate variability (HRV) was not associated with basal VMS frequency or intensity in perimenopausal and postmenopausal women experiencing high levels of VMS. Autonomic function may be associated with the onset or presence of VMS, but not with the number or intensity of these symptoms.
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http://dx.doi.org/10.1007/s10286-015-0322-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742392PMC
February 2016

Symptom clusters among MsFLASH clinical trial participants.

Menopause 2016 Feb;23(2):158-65

1Biobehavioral Nursing, University of Washington 2Fred Hutchinson Cancer Research Center, Seattle, WA 3Science of Nursing Care, School of Nursing, Indiana University, Indianapolis, IN 4Center for Women's Mental Health; Perinatal and Reproductive Psychiatry Clinical Research Program, Massachusetts General Hospital, Boston, MA 5Department of Medicine and Division of Epidemiology and Community Health, University of Minnesota 6Center for Chronic Disease Outcomes Research, Minneapolis VA Health Care System, Minneapolis, MN 7Departments of Obstetrics/Gynecology and Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 8Harvard Medical School, Department of Psychiatry, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, MA 9Department of Family Medicine and Public Health, University of California San Diego, San Diego, CA.

Objective: Our objective was to identify symptom clusters using standardized measures completed by participants in the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health clinical trial at baseline, including hot flash interference, and sleep, depressive, anxiety, and pain symptoms.

Methods: Data from all women randomized to interventions and controls from Menopausal Strategies: Finding Lasting Answers to Symptoms and Health studies 1, 2, and 3 (N = 899) were included; 797 with complete data were used in the analyses. Scores from standardized measures obtained at baseline included the following: Hot Flash-Related Daily Interference Scale, Insomnia Severity Index, Pittsburgh Sleep Quality Index, Patient Health Questionnaire-9 measure of depressed mood, Generalized Anxiety Disorder, and Brief Pain Inventory PEG scores (pain intensity [P], interference with enjoyment of life [E], and interference with daily activity [G]). Latent class analysis was used to identify symptom clusters using standardized scale scores and their established cut points.

Results: We identified five classes using the Bayesian Information Criterion and the Akaike Information Criterion. Women in classes 1 and 2 had high hot flash interference levels relative to the others, and class 1 (10.5% of total) included severe hot flash interference, severe sleep symptoms, and moderately severe pain symptoms (hot flash, sleep, pain). In class 2 (14.1%), severe hot flash interference was paired with the severe sleep symptoms, and moderate to severe depressed and anxious mood symptoms and pain (hot flash, sleep, mood, pain). In class 3 (39.6%), women reported moderately severe sleep symptoms with moderate hot flash interference, and low severity mood and pain symptoms (hot flash, sleep). Those in class 4 (7.0%) reported moderate hot flash interference with severe levels of anxiety and depressed mood symptoms, but low levels of other symptoms (hot flash, mood). Women in class 5 (28.7%) reported the lowest levels of all the five symptoms (low severity symptoms).

Conclusions: Women meeting hot flash frequency criteria for inclusion in clinical trials exhibited multiple co-occurring symptoms that clustered into identifiable groups according to symptom interference and severity. Variability of symptom profiles between the classes was evident, indicating that the classes were composed of differing symptom types and not simply differing severity levels. These symptom clusters may be useful phenotypes for differentiating treatment effects or evaluating associations with biomarkers or genes.
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http://dx.doi.org/10.1097/GME.0000000000000516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731298PMC
February 2016

Pooled Analysis of Six Pharmacologic and Nonpharmacologic Interventions for Vasomotor Symptoms.

Obstet Gynecol 2015 Aug;126(2):413-422

MsFLASH Data Coordinating Center, Fred Hutchinson Cancer Research Center, the Group Health Research Institute, and the University of Washington School of Medicine, Seattle, Washington; the Department of Family and Preventive Medicine, University of California, San Diego, San Diego, and the Division of Research, Kaiser Permanente, Oakland, California; the VA Medical Center/University of Minnesota, Minneapolis, Minnesota; Brigham and Women's Hospital, Dana Farber Cancer Institute, and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; the School of Nursing and the Department of Medicine, Division of Clinical Pharmacology, Indiana University, Indianapolis, Indiana; and the Departments of Obstetrics and Gynecology and Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

Objective: To describe the effects of six interventions for menopausal vasomotor symptoms relative to control in a pooled analysis, facilitating translation of the results for clinicians and symptomatic women. The Menopause Strategies: Finding Lasting Answers for Symptoms and Health network tested these interventions in three randomized clinical trials.

Methods: An analysis of pooled individual-level data from three randomized clinical trials is presented. Participants were 899 perimenopausal and postmenopausal women with at least 14 bothersome vasomotor symptoms per week. Interventions included 10-20 mg escitalopram per day, nonaerobic yoga, aerobic exercise, 1.8 g per day omega-3 fatty acid supplementation, 0.5 mg low-dose oral 17-beta-estradiol (E2) per day, and 75 mg low-dose venlafaxine XR per day. The main outcome measures were changes from baseline in mean daily vasomotor symptom frequency and bother during 8-12 weeks of treatment. Linear regression models estimated differences in outcomes between each intervention and corresponding control group adjusted for baseline characteristics. Models included trial-specific intercepts, effects of the baseline outcome measure, and time.

Results: The 8-week reduction in vasomotor symptom frequency from baseline relative to placebo was similar for escitalopram at -1.4 per day (95% confidence interval [CI] -2.7 to -0.2), low-dose E2 at -2.4 (95% CI -3.4 to -1.3), and venlafaxine at -1.8 (95% CI -2.8 to -0.8); vasomotor symptom bother reduction was minimal and did not vary across these three pharmacologic interventions (mean -0.2 to -0.3 relative to placebo). No effects on vasomotor symptom frequency or bother were seen with aerobic exercise, yoga, or omega-3 supplements.

Conclusion: These analyses suggest that escitalopram, low-dose E2, and venlafaxine provide comparable, modest reductions in vasomotor symptom frequency and bother among women with moderate hot flushes.

Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00894543 (MsFLASH 01), NCT01178892 (MsFLASH 02), and NCT01418209 (MsFLASH 03).
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http://dx.doi.org/10.1097/AOG.0000000000000927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526122PMC
August 2015

Phase I trial of sorafenib following liver transplantation in patients with high-risk hepatocellular carcinoma.

Liver Cancer 2015 Mar;4(2):115-25

Columbia University Medical Center Departments of Medicine and Surgery, New York, N.Y., USA.

Liver transplantation offers excellent long-term survival for hepatocellular carcinoma (HCC) patients who fall within established criteria. For those outside such criteria, or with high-risk pathologic features in the explant, HCC recurrence rates are higher. We conducted a multicenter phase I trial of sorafenib in liver transplantation patients with high-risk HCC. Subjects had HCC outside the Milan criteria (pre- or post-transplant), poorly differentiated tumors, or vascular invasion. We used a standard 3+3 phase I design with a planned duration of treatment of 24 weeks. Correlative studies included the number of circulating endothelial cells (CECs), plasma biomarkers, and tumor expression of p-Erk, p-Akt, and c-Met in tissue micro-arrays. We enrolled 14 patients with a median age of 63 years. Of these, 93% were men and 71% had underlying hepatitis C virus (HCV) and 21% had HBV. The maximum tolerated dose of sorafenib was 200 mg BID. Grade 3-4 toxicities seen in >10% of subjects included leukopenia (21%), elevated gamma-glutamyl transferase (21%), hypertension (14%), hand-foot syndrome (14%) and diarrhea (14%). Over a median follow-up of 953 days, one patient died and four recurred. The mean CEC number at baseline was 21 cells/4 ml for those who recurred, and 80 cells/4 ml for those who did not (p=0.10). Mean soluble vascular endothelial growth factor receptor-2 levels decreased after 1 month on sorafenib (p=0.09), but did not correlate with recurrence. There was a trend for tumor c-Met expression to correlate with increased risk of recurrence. Post-transplant sorafenib was found to be feasible and tolerable at 200 mg PO BID. The effect of post-transplant sorafenib on recurrence-free survival is potentially promising but needs further validation in a larger study.
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http://dx.doi.org/10.1159/000367734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439789PMC
March 2015

SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma.

J Clin Oncol 2015 Aug 11;33(24):2617-22. Epub 2015 May 11.

Edgar Ben-Josef, University of Pennsylvania, Philadelphia, PA; Katherine A. Guthrie, Fred Hutchinson Cancer Research Center, Seattle, WA; Anthony B. El-Khoueiry, University of Southern California Norris Comprehensive Cancer Center, Los Angeles; Andrew M. Lowy, University of California San Diego Moores Cancer Center, La Jolla, CA; Christopher L. Corless, Oregon Health and Science University Knight Diagnostic Laboratories; Charles R. Thomas Jr and Charles D. Blanke, Oregon Health and Science University Knight Cancer Institute, Portland, OR; Mark M. Zalupski, University of Michigan, Ann Arbor, MI; Steven R. Alberts, Mayo Clinic, Rochester, MN; Laura A. Dawson, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada; Kenneth C. Micetich, Loyola University Medical Center, Maywood, IL; Melanie B. Thomas, Medical University of South Carolina, Charleston, SC; and Abby B. Siegel, Columbia University, New York, NY.

Purpose: The role of postoperative therapy in extrahepatic cholangiocarcinoma (EHCC) or gallbladder carcinoma (GBCA) is unknown. S0809 was designed to estimate 2-year survival (overall and after R0 or R1 resection), pattern of relapse, and toxicity in patients treated with this adjuvant regimen.

Patients And Methods: Eligibility criteria included diagnosis of EHCC or GBCA after radical resection, stage pT2-4 or N+ or positive resection margins, M0, and performance status 0 to 1. Patients received four cycles of gemcitabine (1,000 mg/m(2) intravenously on days 1 and 8) and capecitabine (1,500 mg/m(2) per day on days 1 to 14) every 21 days followed by concurrent capecitabine (1,330 mg/m(2) per day) and radiotherapy (45 Gy to regional lymphatics; 54 to 59.4 Gy to tumor bed). With 80 evaluable patients, results would be promising if 2-year survival 95% CI were > 45% and R0 and R1 survival estimates were ≥ 65% and 45%, respectively.

Results: A total of 79 eligible patients (R0, n = 54; R1, n = 25; EHCC, 68%; GBCA, 32%) were treated (86% completed). For all patients, 2-year survival was 65% (95% CI, 53% to 74%); it was 67% and 60% in R0 and R1 patients, respectively. Median overall survival was 35 months (R0, 34 months; R1, 35 months). Local, distant, and combined relapse occurred in 14, 24, and nine patients. Grade 3 and 4 adverse effects were observed in 52% and 11% of patients, respectively. The most common grade 3 to 4 adverse effects were neutropenia (44%), hand-foot syndrome (11%), diarrhea (8%), lymphopenia (8%), and leukopenia (6%). There was one death resulting from GI hemorrhage.

Conclusion: This combination was well tolerated, has promising efficacy, and provides clinicians with a well-supported regimen. Our trial establishes the feasibility of conducting national adjuvant trials in EHCC and GBCA and provides baseline data for planning future phase III trials.
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http://dx.doi.org/10.1200/JCO.2014.60.2219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534524PMC
August 2015

Uterine rupture risk after periviable cesarean delivery.

Obstet Gynecol 2015 May;125(5):1095-1100

Department of Obstetrics and Gynecology, University of Washington, the Public Health Sciences Division and the Clinical Research Division, Fred Hutchinson Cancer Research Center, and Swedish Medical Center, Seattle, Washington.

Objective: To investigate the risk of uterine rupture in women with prior periviable cesarean delivery and prior term cesarean delivery independent of initial incision type.

Methods: We conducted a retrospective longitudinal cohort study using Washington state birth certificate data and hospital discharge records, identifying primary cesarean deliveries performed at 20-26 weeks and 37-41 weeks of gestation with subsequent delivery between 1989 and 2008. We compared subsequent uterine rupture risk in the two groups considering both primary incision type and subsequent labor induction and augmentation.

Results: We identified 456 women with index periviable cesarean delivery and 10,505 women with index term cesarean delivery. Women with index periviable cesarean delivery were younger, more frequently of nonwhite race, more likely to smoke, and more likely to have hypertension. Women in the periviable group had more index classical incisions (42% compared with 1%, P<.001) and fewer subsequent inductions and augmentations (8% compared with 16%, P<.001). Uterine rupture in the subsequent pregnancy occurred more frequently among women in the index periviable group than those in the index term group (8/456 [1.8%] compared with 38/10,505 [0.4%], odds ratio [OR] 4.9, 95% confidence interval [CI] 2.3-10.6). This relationship persisted among women with a low transverse incision (4/228 [1.8%] compared with 36/9,558 [0.4%], OR 4.7, 95% CI 1.7-13.4).

Conclusion: Cesarean delivery at periviability compared with term is associated with an increased risk for uterine rupture in a subsequent pregnancy, even after low transverse incision. These data support judicious use of cesarean delivery at periviable gestational ages and inform subsequent counseling.

Level Of Evidence: II.
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http://dx.doi.org/10.1097/AOG.0000000000000832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418026PMC
May 2015

Clinical outcomes associated with respiratory virus detection before allogeneic hematopoietic stem cell transplant.

Clin Infect Dis 2015 Jul 5;61(2):192-202. Epub 2015 Apr 5.

Fred Hutchinson Cancer Research Center University of Washington, Seattle.

Background: The management of respiratory virus infections prior to hematopoietic cell transplant (HCT) is difficult. We examined whether respiratory virus detection before HCT influenced the requirement for bronchoscopy, hospitalization, and overall survival following HCT.

Methods: Pre-HCT and weekly post-HCT nasal washes were collected through day 100 from patients with and without symptoms. Samples were tested by multiplex polymerase chain reaction for respiratory syncytial virus, parainfluenza viruses 1-4, influenza A and B, human metapneumovirus, adenovirus, and human rhinoviruses, coronaviruses, and bocavirus.

Results: Of 458 patients, 116 (25%) had respiratory viruses detected pre-HCT. Overall, patients with viruses detected pre-HCT had fewer days alive and out of the hospital and lower survival at day 100 (adjusted hazard ratio [aHR], 2.4; 95% confidence interval [CI], 1.3-4.5; P = .007) than patients with negative samples; this risk was also present with rhinovirus alone (aHR for mortality, 2.6; 95% CI, 1.2-5.5; P = .01). No difference in bronchoscopy incidence was seen in patients with and without respiratory viruses (aHR, 1.3; 95% CI, .8-2.0; P = .32). In symptomatic patients, those with respiratory viruses detected had increased overall mortality compared with patients without viruses detected (unadjusted HR, 3.5; 95% CI, 1.0-12.1; P = .05); among asymptomatic patients, detection of respiratory viruses was not associated with increased mortality.

Conclusions: These data support routine testing for respiratory viruses among symptomatic patients before HCT, and delay of transplant with virus detection when feasible, even for detection of rhinovirus alone. Further study is needed to address whether asymptomatic patients should undergo screening for respiratory virus detection before HCT.
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http://dx.doi.org/10.1093/cid/civ272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565994PMC
July 2015

Using an FSDS-R Item to Screen for Sexually Related Distress: A MsFLASH Analysis.

Sex Med 2015 Mar;3(1):7-13

Harvard Medical School Boston, MA, USA.

Introduction: The Female Sexual Distress Scale-Revised (FSDS-R) was created and validated to assess distress associated with impaired sexual function, but it is lengthy for use in clinical practice and research when assessing sexual function is not a primary objective.

Aim: The study aims to evaluate whether a single item from the FSDS-R could be identified to use to screen midlife women for bothersome diminution in sexual function based on three criteria: (i) highly correlated with total scores; (ii) correlated with commonly assessed domains of female sexual functioning; and (iii) able to differentiate between women reporting high and low sexual concerns during the prior month.

Methods: Data from 93 midlife women were collected by the Menopause Strategies Finding Lasting Answers to Symptoms and Health (MsFLASH) research network.

Main Outcome Measures: Women completed the FSDS-R, Female Sexual Function Index (FSFI), and Menopausal Quality of Life Scale (MENQOL). Those who reported a change in the past month on the MENQOL sexual were categorized into a high sexual concerns group, while all others were categorized into a low sexual concerns group.

Results: Women were an average of 54.6 years old (SD 3.1) and mostly Caucasian (77.4%), college educated (60.2%), married/living as married (64.5%), and postmenopausal (79.6%). The FSDS-R item number 1 "Distressed about sex life" was: (i) highly correlated with FSDS-R total scores (r = 0.90); (ii) moderately correlated with FSFI total scores (r = -0.38) and FSFI desire (r = -0.37) and satisfaction domains (r = -0.40); and (iii) showed one of the largest mean differences between high and low sexual concerns groups (P < 0.001). Other FSDS-R items met one or two, but not all three of the prespecified criteria (i, ii, iii).

Conclusions: A single FSDS-R item may be a useful screening tool to quickly identify midlife women with sexually related distress when it is not feasible to administer the entire scale, though further validation is warranted. Carpenter JS, Reed SD, Guthrie KA, Larson JC, Newton KM, Lau RJ, Learman LA, and Shifren JL. Using an FSDS-R item to screen for sexually related distress: A MsFLASH analysis. Sex Med 2015;3:7-13.
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http://dx.doi.org/10.1002/sm2.53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380908PMC
March 2015

Reduced Mortality of Cytomegalovirus Pneumonia After Hematopoietic Cell Transplantation Due to Antiviral Therapy and Changes in Transplantation Practices.

Clin Infect Dis 2015 Jul 16;61(1):31-9. Epub 2015 Mar 16.

Division of Vaccine and Infectious Disease Division of Clinical Research Department of Medicine, University of Washington, Seattle.

Background: Despite major advances in the prevention of cytomegalovirus (CMV) disease, the treatment of CMV pneumonia in recipients of hematopoietic cell transplant remains a significant challenge.

Methods: We examined recipient, donor, transplant, viral, and treatment factors associated with overall and attributable mortality using Cox regression models.

Results: Four hundred twenty-one cases were identified between 1986 and 2011. Overall survival at 6 months was 30% (95% confidence interval [CI], 25%-34%). Outcome improved after the year 2000 (all-cause mortality: adjusted hazard ratio [aHR], 0.7 [95% CI, .5-1.0]; P = .06; attributable mortality: aHR, 0.6 [95% CI, .4-.9]; P = .01). Factors independently associated with an increased risk of all-cause and attributable mortality included female sex, elevated bilirubin, lymphopenia, and mechanical ventilation; grade 3/4 acute graft-vs-host disease was associated with all-cause mortality only. An analysis of patients who received transplants in the current preemptive therapy era (n = 233) showed only lymphopenia and mechanical ventilation as significant risk factors for overall and attributable mortality. Antiviral treatment with ganciclovir or foscarnet was associated with improved outcome compared with no antiviral treatment. However, the addition of intravenous pooled or CMV-specific immunoglobulin to antiviral treatment did not seem to improve overall or attributable mortality.

Conclusions: Outcome of CMV pneumonia showed a modest improvement over the past 25 years. However, advances seem to be due to antiviral treatment and changes in transplant practices rather than immunoglobulin-based treatments. Novel treatment strategies for CMV pneumonia are needed.
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http://dx.doi.org/10.1093/cid/civ215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542910PMC
July 2015

Placebo improvement in pharmacologic treatment of menopausal hot flashes: time course, duration, and predictors.

Psychosom Med 2015 Feb-Mar;77(2):167-75

From the Department of Obstetrics/Gynecology and Psychiatry (Freeman), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Epidemiology and Community Health (Ensrud), Department of Medicine, Veterans Affairs Health System, Minneapolis, Minnesota; Department of Medicine (Ensrud), University of Minnesota, Minneapolis, Minnesota; MsFlash Data Coordinating Center (Larson, Guthrie), Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; School of Nursing (Carpenter), Indiana University, Indianapolis, Indiana; Department of Psychiatry (Joffe), Brigham and Women's Hospital and Massachusetts General Hospital, Boston, Massachusetts; Department of Psychosocial (Joffe) Dana Farber Institute, Harvard Medical School, Boston, Massachusetts; Group Health Research Institute (Newton), Seattle, Washington; Division of Research (Sternfeld), Kaiser Permanente of Northern California, Oakland, California; Women's Health Center, Family and Preventive Medicine (LaCroix), University of California San Diego, La Jolla, California.

Objectives: To characterize the time course, duration of improvement, and clinical predictors of placebo response in treatment of menopausal hot flashes.

Methods: Data were pooled from two trials conducted in the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health network, providing a combined placebo group (n = 247) and a combined active treatment group (n = 297). Participants recorded hot flash frequency in diaries twice daily during treatment (Weeks 0-8) and subsequent follow-up (Weeks 9-11). The primary outcome variable was clinically significant improvement, defined as a 50% or greater decrease in hot flash frequency from baseline and calculated for each week in the study. Subgroups were defined a priori using standard clinical definitions for significant improvement and partial improvement. Clinical and demographic characteristics of the participants were evaluated as predictors of improvement.

Results: Clinically significant improvement with placebo accrued each treatment week, with 33% significantly improved at Week 8. Of placebo responders who were improved at both Weeks 4 and 8, 77% remained clinically improved at Week 11 after treatment ended. Independent predictors of significant placebo improvement in the final multivariable model were African American race (odds ratio [OR] = 5.61, 95% confidence interval [CI] = 2.41-13.07, p < .001), current smokers (OR = 2.30, 95% CI = 1.05-5.06, p = .038), and hot flash severity in screening (OR = 1.45, 95% CI = 1.00-2.10, p = .047).

Conclusions: Clinically significant improvement with placebo accrued throughout treatment with a time course similar to improvement with active drug. A meaningful number of participants in the placebo group sustained a clinically significant response after stopping placebo pills. The results suggest that nonspecific effects are important components of treatment and warrant further studies to optimize their contributions in clinical care.
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http://dx.doi.org/10.1097/PSY.0000000000000143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333078PMC
November 2015

Long-term outcomes of patients with persistent indolent B cell malignancies undergoing nonmyeloablative allogeneic transplantation.

Biol Blood Marrow Transplant 2015 Feb 1;21(2):281-7. Epub 2014 Nov 1.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington. Electronic address:

Relapse is least common in patients with indolent B cell (iB) malignancies (ie, iB non-Hodgkin lymphoma [NHL]) who undergo nonmyeloablative allogeneic transplantation (NMAT) in complete remission (CR). However, for the many patients unable to achieve this state, outcomes are poorly described and methods to improve results are unknown. We sought to describe the long-term follow-up and predictive factors for these poor-risk patients unable to achieve CR before NMAT. We identified and evaluated patients with iB-NHL including chronic lymphocytic leukemia treated with fludarabine/total body irradiation-based NMAT that had evidence of persistent disease before NMAT. From December 1998 to April 2009, 89 patients were identified, most commonly with small/chronic lymphocytic lymphoma (n = 62) and follicular lymphoma (n = 24). Pretransplant anti-CD20 radioimmunotherapy (RIT) using standard yttrium-90-ibritumomab tiuxetan was administered to 18 patients (20%) who more frequently had chemoresistant disease (81% versus 39%, P = .003), disease bulk > 5 cm (61% versus 15%, P < .001), thrombocytopenia < 25k/μL (33% versus 7%, P = .002), and Hematopoietic Cell Transplant Comorbidity Index scores ≥ 3 (72% versus 37%, P = .006). After adjusting for these imbalances, RIT-treated patients had improved rates of progression-free survival (PFS) (hazard ratio [HR] = .4; 95% confidence interval [CI], .2 to .9, P = .02) and overall survival (OS) (HR = .3; 95% CI, .1 to .8, P = .008) compared with the non-RIT group. The 3-year adjusted estimates of PFS and OS for the RIT and non-RIT groups were 71% and 87% versus 44% and 59%, respectively. The use of RIT was the only factor independently associated with improved PFS and OS. Rates of nonrelapse mortality and graft-versus-host disease (GVHD) were similar between the 2 groups, although over 70% of patients developed clinically significant acute or chronic GVHD. In conclusion, despite relatively high rates of GVHD, patients with persistent iB-NHL can derive durable benefit from NMAT.
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http://dx.doi.org/10.1016/j.bbmt.2014.10.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408880PMC
February 2015

Effects of estrogen and venlafaxine on menopause-related quality of life in healthy postmenopausal women with hot flashes: a placebo-controlled randomized trial.

Menopause 2015 Jun;22(6):607-15

From the 1Division of Research, Kaiser Permanente of Northern California, Oakland, CA; 2University of California, San Diego, CA; 3Brigham and Women's Hospital, Boston, MA; 4Dana Farber Cancer Institute, Boston, MA; 5MsFLASH Coordinating Center, Fred Hutchinson Cancer Research Center, Seattle, WA; 6School of Nursing, Indiana University, Indianapolis, IN; 7Massachusetts General Hospital, Boston, MA; 8Harvard Medical School, Boston, MA; 9Departments of Obstetrics/Gynecology and Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA; 10Group Health Research Institute, Seattle, WA; 11University of Washington School of Medicine, Seattle, WA; and 12VA Medical Center/University of Minnesota, Minneapolis, MN.

Objective: This study aims to evaluate the effects of low-dose estradiol (E2) or venlafaxine on menopause-related quality of life and associated symptoms in healthy perimenopausal and postmenopausal women with hot flashes.

Methods: A double-blind, placebo-controlled, randomized trial of low-dose oral 17β-E2 0.5 mg/day and venlafaxine XR 75 mg/day, versus identical placebo, was conducted among 339 women (aged 40-62 y) experiencing two or more vasomotor symptoms (VMS) per day (mean [SD], 8.07 [5.29]) who were recruited at three clinical sites from November 2011 to October 2012. The primary trial outcome, as reported previously, was frequency of VMS at 8 weeks. Here, we report on secondary endpoints of total and domain scores from the Menopause-Specific Quality of Life Questionnaire (MENQOL) and from measures of pain (Pain, Enjoyment in life, and General activity scale), depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder Questionnaire-7), and perceived stress (Perceived Stress Scale).

Results: Treatment with both E2 and venlafaxine resulted in significantly greater improvement in quality of life, as measured by total MENQOL scores, compared with placebo (E2: mean difference at 8 wk, -0.4; 95% CI, -0.7 to -0.2; P < 0.001; venlafaxine: mean difference at 8 wk, -0.2; 95% CI, -0.5 to 0.0; P = 0.04). Quality-of-life domain analyses revealed that E2 had beneficial treatment effects on all domains of the MENQOL except for the psychosocial domain, whereas venlafaxine benefits were observed only in the psychosocial domain. Neither E2 nor venlafaxine improved pain, anxiety, or depressive symptoms, although baseline symptom levels were low. Modest benefits were observed for perceived stress with venlafaxine.

Conclusions: Both low-dose E2 and venlafaxine are effective pharmacologic agents for improving menopause-related quality of life in healthy women with VMS.
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http://dx.doi.org/10.1097/GME.0000000000000364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610378PMC
June 2015

Effects of estradiol and venlafaxine on insomnia symptoms and sleep quality in women with hot flashes.

Sleep 2015 Jan 1;38(1):97-108. Epub 2015 Jan 1.

Department of Psychiatry, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, MA.

Study Objectives: Determine effects of low-dose estradiol and low-dose venlafaxine on self-reported sleep measures in menopausal women with hot flashes.

Design: 3-arm double-blind randomized trial. Participants assigned in a 2:2:3 ratio to 17β estradiol 0.5 mg/day (n = 97), venlafaxine XR 75 mg/day (n = 96), or placebo (n = 146) for 8 weeks.

Setting: Academic research centers.

Participants: 339 community-dwelling perimenopausal and postmenopausal women with ≥2 bothersome hot flashes per day.

Measurements And Results: Insomnia symptoms (Insomnia Severity Index [ISI]) and sleep quality (Pittsburgh Sleep Quality Index [PSQI]) at baseline, week 4 and 8; 325 women (96%) provided ISI data and 312 women (92%) provided PSQI data at baseline and follow-up. At baseline, mean (SD) hot flash frequency was 8.1/day (5.3), mean ISI was 11.1 (6.0), and mean PSQI was 7.5 (3.4). Mean (95% CI) change from baseline in ISI at week 8 was -4.1 points (-5.3 to -3.0) with estradiol, -5.0 points (-6.1 to -3.9) with venlafaxine, and -3.0 points (-3.8 to -2.3) with placebo (P overall treatment effect vs. placebo 0.09 for estradiol and 0.007 for venlafaxine). Mean (95% CI) change from baseline in PSQI at week 8 was -2.2 points (-2.8 to -1.6) with estradiol, -2.3 points (-2.9 to -1.6) with venlafaxine, and -1.2 points (-1.7 to -0.8) with placebo (P overall treatment effect vs. placebo 0.04 for estradiol and 0.06 for venlafaxine).

Conclusions: Among perimenopausal and postmenopausal women with hot flashes, both low dose oral estradiol and low-dose venlafaxine compared with placebo modestly reduced insomnia symptoms and improved subjective sleep quality.

Clinical Trial Registration: NCT01418209 at www.clinicaltrials.gov.
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http://dx.doi.org/10.5665/sleep.4332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262961PMC
January 2015

Impact of donor age on outcome after allogeneic hematopoietic cell transplantation.

Biol Blood Marrow Transplant 2015 Jan 30;21(1):105-12. Epub 2014 Sep 30.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Oncology, University of Washington, School of Medicine, Seattle, Washington. Electronic address:

As older patients are eligible for allogeneic hematopoietic cell transplantation (HCT), older siblings are increasingly proposed as donors. We studied the impact of donor age on the tempo of hematopoietic engraftment and donor chimerism, acute and chronic graft-versus-host disease (GVHD), and nonrelapse mortality (NRM) among 1174 consecutive patients undergoing myeloablative and 367 patients undergoing nonmyeloablative HCT from HLA-matched related or unrelated donors with granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell allografts. Sustained engraftment rates were 97% and 98% in patients undergoing myeloablative and nonmyeloablative conditioning, respectively, for grafts from donors < 60 years old (younger; n = 1416) and 98% and 100%, respectively, for those from donors ≥ 60 years old (older; n = 125). No significant differences were seen in the tempo of neutrophil and platelet recoveries and donor chimerism except for an average 1.3-day delay in neutrophil recovery among myeloablative patients with older donors (P = .04). CD34(+) cell dose had an independent effect on the tempo of engraftment. Aged stem cells did not convey an increased risk of donor-derived clonal disorders after HCT. Myeloablative and nonmyeloablative recipients with older sibling donors had significantly less grade II to IV acute GVHD than recipients with grafts from younger unrelated donors. Rates of grade III and IV acute GVHD, chronic GVHD, and NRM for recipients with older donors were not significantly different from recipients with younger donors. In conclusion, grafts from donors ≥ 60 years old do not adversely affect outcomes of allogeneic HCT compared with grafts from younger donors.
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http://dx.doi.org/10.1016/j.bbmt.2014.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286386PMC
January 2015

Effects of escitalopram on markers of bone turnover: a randomized clinical trial.

J Clin Endocrinol Metab 2014 Sep 11;99(9):E1732-7. Epub 2014 Jul 11.

University of Minnesota (S.J.D., K.E.E.), Minneapolis, Minnesota 55415; Brigham and Women's Hospital and Dana Farber Cancer Institute (H.J.), Boston, Massachusetts 02115; Fred Hutchinson Cancer Research Center (J.C.L., A.Z.L.), Seattle, Washington 98109; Massachusetts General Hospital (J.N.T., B.Z.L.), Boston, Massachusetts 02114; Minneapolis Veterans Affairs Health Care System (K.E.E.), Minneapolis, Minnesota 55417; and Perelman School of Medicine (E.W.F.), University of Pennsylvania, Philadelphia, Pennsylvania 19104.

Context: Recent observational studies have suggested that the use of selective serotonin reuptake inhibitors is associated with an increased fracture risk and an accelerated bone loss, although conflicting results have been reported. Furthermore, because many of these studies have been performed in depressed women, confounding by indication may influence these findings.

Objective: The objective of the study was to determine whether selective serotonin reuptake inhibitors affect bone metabolism Design: This was a randomized controlled trial.

Setting: The study was conducted in four US clinical sites.

Participants: Healthy peri- and postmenopausal women participated in the study.

Intervention: The intervention was escitalopram (10-20 mg/d) for the treatment of vasomotor symptoms.

Main Outcome Measures: Serum carboxyterminal collagen crosslinks (CTX) and serum amino-terminal propeptide of type I collagen (P1NP) were measured.

Results: One hundred forty-one peri- or postmenopausal nondepressed women (mean age 53.7 y, SD 4.1) had baseline and 8-week follow-up samples available for analysis and were included in the study (69 escitalopram, 72 placebo). The groups were balanced across a broad range of baseline characteristics, including age, race, body mass index, smoking status, and mood symptoms. The between-group differences in the change in CTX and P1NP from baseline to week 8 were compared by a repeated-measures linear regression model adjusted for race, clinical center, and baseline measurement. Treatment with escitalopram reduced serum P1NP by 1.02 ng/mL on average [95% confidence interval (CI) -5.17, 3.12] compared with a reduction of 1.88 ng/mL (95% CI -4.82, 1.06) in the placebo group (P = .65). Similarly, serum CTX decreased 0.02 ng/mL on average (95% CI -0.05, 0.01) in the escitalopram group compared with 0.00 ng/mL (95% CI -0.02, 0.02) in the placebo group (P = .24). The results were similar when the analysis was restricted to those women whose adherence to study medication was 70% or greater.

Conclusions: Although the study was limited to 8 weeks, these results suggest that escitalopram does not significantly alter bone metabolism in the short term.
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http://dx.doi.org/10.1210/jc.2014-2288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154080PMC
September 2014

Sexual function in women on estradiol or venlafaxine for hot flushes: a randomized controlled trial.

Obstet Gynecol 2014 Aug;124(2 Pt 1):233-241

Departments of Obstetrics and Gynecology and Epidemiology, University of Washington School of Medicine, the Group Health Research Institute, and the Data Coordinating Center, Fred Hutchinson Cancer Research Center, Seattle, Washington; the Departments of Psychiatry and Medicine, Brigham and Women's Hospital, the Departments of Psychiatry and Obstetrics and Gynecology, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts; and the Departments of Obstetrics and Gynecology and Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

Objective: To evaluate sexual function in midlife women taking low-dose oral estradiol or venlafaxine for hot flushes.

Methods: In an 8-week randomized controlled trial among women aged 40-62 years, sexual function was compared between 0.5 mg oral estradiol per day or 75 mg venlafaxine per day (both compared with a placebo). Measures included composite and six domain scores from the Female Sexual Function Index and sexually related personal distress.

Results: Participants were aged 54.6 years (standard deviation [SD] 3.8) years, 59% white, with 8.1 (SD 5.3) daily hot flushes. Median composite baseline Female Sexual Function Index score was 16.3 (SD 11.9, n=256) for all women and 21.7 (SD 9.3, n=198) among sexually active women. Composite mean Female Sexual Function Index change from baseline to week 8 was 1.4 (95% confidence interval [CI] -0.4 to 3.2) for estradiol, 1.1 (95% CI -0.5 to 2.7) for venlafaxine, and -0.3 (95% CI -1.6 to 1.0) for placebo. Composite Female Sexual Function Index and sexually related distress change from baseline did not differ between estradiol and placebo (P=.38, P=.30) or venlafaxine and placebo (P=.79, P=.48). Among sexually active women, Female Sexual Function Index domain score change from baseline differences (active compared with placebo) in desire was 0.3 (95% CI 0.0-0.6) for estradiol, -0.6 (95% CI -1.2 to 0.0) in orgasm for venlafaxine, and 0.9 (95% CI 0.2-1.6) in penetration pain for venlafaxine. No women reported adverse events related to sexual dysfunction.

Conclusion: Overall sexual function among nondepressed midlife women experiencing hot flushes did not change over 8 weeks with low-dose oral estradiol or venlafaxine (compared with placebo), although a subtle increase in desire (estradiol) and decreases in orgasm and pain (venlafaxine) may exist.

Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01418209.

Level Of Evidence: I.
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http://dx.doi.org/10.1097/AOG.0000000000000386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113909PMC
August 2014

Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms: a randomized clinical trial.

JAMA Intern Med 2014 Jul;174(7):1058-66

Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston.

Importance: Estrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine hydrochloride is used widely as a nonhormonal treatment. While the clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial to date.

Objective: To determine the efficacy and tolerability of low-dose oral 17β-estradiol and low-dose venlafaxine extended release in alleviating vasomotor symptoms (VMS).

Design, Setting, And Participants: In total, 339 perimenopausal and postmenopausal women with at least 2 bothersome VMS per day (mean, 8.1 per day) were recruited from the community to MsFLASH (Menopause Strategies: Finding Lasting Answers for Symptoms and Health) clinical network sites between December 5, 2011, and October 15, 2012.

Interventions: Participants were randomized to double-blind treatment with low-dose oral 17β-estradiol (0.5 mg/d) (n = 97), low-dose venlafaxine hydrochloride extended release (75 mg/d) (n = 96), or placebo (n = 146) for 8 weeks.

Main Outcomes And Measures: The primary outcome was the mean daily frequency of VMS after 8 weeks of treatment. Secondary outcomes were VMS severity, bother, and interference with daily life. Intent-to-treat analyses compared the change in VMS frequency between each active intervention and placebo and between the 2 active treatments.

Results: Compared with baseline, the mean VMS frequency at week 8 decreased to 3.9 (95% CI, 2.9-4.9) VMS per day (52.9% reduction) in the estradiol group, to 4.4 (95% CI, 3.5-5.3) VMS per day (47.6% reduction) in the venlafaxine group, and to 5.5 (95% CI, 4.7-6.3) VMS per day (28.6% reduction) in the placebo group. Estradiol reduced the frequency of symptoms by 2.3 more per day than placebo (P < .001), and venlafaxine reduced the frequency of symptoms by 1.8 more per day than placebo (P = .005). The results were consistent for VMS severity, bother, and interference. Low-dose estradiol reduced the frequency of symptoms by 0.6 more per day than venlafaxine (P = .09). Treatment satisfaction was highest (70.3%) for estradiol (P < .001 vs placebo), lowest (38.4%) for placebo, and intermediate (51.1%) for venlafaxine (P = .06 vs placebo). Both interventions were well tolerated.

Conclusions And Relevance: Low-dose oral estradiol and venlafaxine are effective treatments for VMS in women during midlife. While the efficacy of low-dose estradiol may be slightly superior to that of venlafaxine, the difference is small and of uncertain clinical relevance.

Trial Registration: clinicaltrials.gov Identifier: NCT01418209.
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http://dx.doi.org/10.1001/jamainternmed.2014.1891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4179877PMC
July 2014

Late-onset colitis after cord blood transplantation is consistent with graft-versus-host disease: results of a blinded histopathological review.

Biol Blood Marrow Transplant 2014 Jul 3;20(7):1008-13. Epub 2014 Apr 3.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Departments of Pediatrics, Pathology, and Medicine, University of Washington School of Medicine, Seattle, Washington.

Cord colitis syndrome after umbilical cord blood transplantation (UCBT) involves late-onset diarrhea, absence of infection or GVHD, chronic active colitis, and granulomatous inflammation that responds to antibiotics. We tested the hypothesis that Seattle recipients of UCBT had late-occurring colitis distinct from GVHD and colitis in other allograft recipients. We conducted a blinded histological review of 153 colon biopsy specimens from 45 UCBT recipients and 45 matched allografted controls obtained between day +70 and day +365 post-transplantation. Diarrhea was the primary indication for biopsy in 10 UCBT recipients and 11 controls. No histological differences were seen between UCBT recipients and controls with diarrhea or between the entire cohort of UCBT recipients and their controls. Distorted mucosal architecture and apoptotic crypt cells typical of GVHD were common in both groups; Paneth cell metaplasia and granulomas were rare findings. Chronic active colitis was present in 58% of the UCBT recipients and in 62% of controls. No UCBT recipient with diarrhea was treated with antibiotics, and all recipients responded to systemic corticosteroids. Colitis occurring after day +70 in allografted controls was related to acute GVHD, independent of the source of donor cells. We could not identify a histologically distinct cord colitis syndrome in either the UCBT or the non-cord blood allograft recipients.
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http://dx.doi.org/10.1016/j.bbmt.2014.03.020DOI Listing
July 2014

Peripheral blood hematopoietic stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced-intensity conditioning.

Biol Blood Marrow Transplant 2014 Jun 18;20(6):890-5. Epub 2014 Mar 18.

Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington, Seattle. Electronic address:

In a multicenter collaboration, we carried out T cell-replete, peripheral blood stem cell (PBSC) transplantations from related, HLA-haploidentical donors with reduced-intensity conditioning (RIC) and post-transplantation cyclophosphamide (Cy) as graft-versus-host disease (GVHD) prophylaxis in 55 patients with high-risk hematologic disorders. Patients received 2 doses of Cy 50 mg/kg i.v. on days 3 and 4 after infusion of PBSC (mean, 6.4 × 10(6)/kg CD34(+) cells; mean, 2.0 × 10(8)/kg CD3(+) cells). The median times to neutrophil (500/μL) and platelet (>20,000/μL) recovery were 17 and 21 days respectively. All but 2 of the patients achieved full engraftment. The 1-year cumulative incidences of grade II and grade III acute GVHD were 53% and 8%, respectively. There were no cases of grade IV GVHD. The 2-year cumulative incidence of chronic GHVD was 18%. With a median follow-up of 509 days, overall survival and event-free survival at 2 years were 48% and 51%, respectively. The 2-year cumulative incidences of nonrelapse mortality and relapse were 23% and 28%, respectively. Our results suggest that PBSC can be substituted safely and effectively for bone marrow as the graft source for haploidentical transplantation after RIC.
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http://dx.doi.org/10.1016/j.bbmt.2014.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451937PMC
June 2014
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