Microbes Contribute to Chemopreventive Efficacy, Intestinal Tumorigenesis, and the Metabolome.

Bacteria are believed to play an important role in intestinal tumorigenesis and contribute to both gut luminal and circulating metabolites. Celecoxib, a selective cyclooxygenase-2 inhibitor, alters gut bacteria and metabolites in association with suppressing the development of intestinal polyps in mice. The current study sought to evaluate whether celecoxib exerts its chemopreventive effects, in part, through intestinal bacteria and metabolomic alterations. Using ApcMin/+ mice, we demonstrated that treatment with broad-spectrum antibiotics (ABx) reduced abundance of gut bacteria and attenuated the ability of celecoxib to suppress intestinal tumorigenesis. Use of ABx also impaired celecoxib's ability to shift microbial populations and gut luminal and circulating metabolites. Treatment with ABx alone markedly reduced tumor number and size in ApcMin/+ mice, in conjunction with profoundly altering the metabolite profiles of the intestinal lumen and blood. Many of the metabolite changes in the gut and circulation overlapped and included shifts in microbially derived metabolites. To complement these findings in mice, we evaluated the effects of ABx on circulating metabolites in patients with colon cancer. This showed that ABx treatment led to a shift in blood metabolites, including several that were of bacterial origin. Importantly, changes in metabolites in patients given ABx overlapped with alterations found in mice that also received ABx. Taken together, these findings suggest a potential role for bacterial metabolites in mediating both the chemopreventive effects of celecoxib and intestinal tumor growth. PREVENTION RELEVANCE: This study demonstrates novel mechanisms by which chemopreventive agents exert their effects and gut microbiota impact intestinal tumor development. These findings have the potential to lead to improved cancer prevention strategies by modulating microbes and their metabolites.

Novel Nonproprietary Measures of Ambulatory Electronic Health Record Use Associated with Physician Work Exhaustion.

BACKGROUND: Accumulating evidence indicates an association between physician electronic health record (EHR) use after work hours and occupational distress including burnout. These studies are based on either physician perception of time spent in EHR through surveys which may be prone to bias or by utilizing vendor-defined EHR use measures which often rely on proprietary algorithms that may not take into account variation in physician's schedules which may underestimate time spent on the EHR outside of scheduled clinic time. The Stanford team developed and refined a nonproprietary EHR use algorithm to track the number of hours a physician spends logged into the EHR and calculates the Clinician Logged-in Outside Clinic (CLOC) time, the number of hours spent by a physician on the EHR outside of allocated time for patient care. OBJECTIVE: The objective of our study was to measure the association between CLOC metrics and validated measures of physician burnout and professional fulfillment. METHODS: Physicians from adult outpatient Internal Medicine, Neurology, Dermatology, Hematology, Oncology, Rheumatology, and Endocrinology departments who logged more than 8 hours of scheduled clinic time per week and answered the annual wellness survey administered in Spring 2019 were included in the analysis. RESULTS: We observed a statistically significant positive correlation between CLOC ratio (defined as the ratio of CLOC time to allocated time for patient care) and work exhaustion (Pearson's r = 0.14; p = 0.04), but not interpersonal disengagement, burnout, or professional fulfillment. CONCLUSION: The CLOC metrics are potential objective EHR activity-based markers associated with physician work exhaustion. Our results suggest that the impact of time spent on EHR, while associated with exhaustion, does not appear to be a dominant factor driving the high rates of occupational burnout in physicians.

Effects of Adiposity and Exercise on Breast Tissue and Systemic Metabo-Inflammatory Factors in Women at High Risk or Diagnosed with Breast Cancer.

Excess body fat and sedentary behavior are associated with increased breast cancer risk and mortality, including in normal weight women. To investigate underlying mechanisms, we examined whether adiposity and exercise impact the breast microenvironment (e.g., inflammation and aromatase expression) and circulating metabo-inflammatory factors. In a cross-sectional cohort study, breast white adipose tissue (WAT) and blood were collected from 100 women undergoing mastectomy for breast cancer risk reduction or treatment. Self-reported exercise behavior, body composition measured by dual-energy x-ray absorptiometry (DXA), and waist:hip ratio were obtained prior to surgery. Breast WAT inflammation (B-WATi) was assessed by IHC and aromatase expression was assessed by quantitative PCR. Metabolic and inflammatory blood biomarkers that are predictive of breast cancer risk and progression were measured. B-WATi was present in 56 of 100 patients and was associated with older age, elevated BMI, postmenopausal status, decreased exercise, hypertension and dyslipidemia (Ps < 0.001). Total body fat and trunk fat correlated with B-WATi and breast aromatase levels (Ps < 0.001). Circulating C-reactive protein, IL6, insulin, and leptin positively correlated with body fat and breast aromatase levels, while negative correlations were observed for adiponectin and sex hormone binding globulin (P < 0.001). Inverse relationships were observed with exercise (Ps < 0.05). In a subgroup of 39 women with normal BMI, body fat levels positively correlated with B-WATi and aromatase expression (Ps < 0.05). In conclusion, elevated body fat levels and decreased exercise are associated with protumorigenic micro- and host environments in normal, overweight, and obese individuals. These findings support the development of BMI-agnostic lifestyle interventions that target adiposity. PREVENTION RELEVANCE: We report that individuals with high body fat and low exercise levels have breast inflammation, higher breast aromatase expression, and levels of circulating metabo-inflammatory factors that have been associated with increased breast cancer risk. These findings support interventions to lower adiposity, even among normal weight individuals, to prevent tumor growth.

Effects of obesity on breast aromatase expression and systemic metabo-inflammation in women with BRCA1 or BRCA2 mutations.

Obesity is associated with an increased risk of breast cancer in post-menopausal women and decreased risk in pre-menopausal women. Conversely, in BRCA1/2 mutation carriers, pre-menopausal obesity is associated with early-onset breast cancer. Here we show that obese, pre-menopausal BRCA1/2 mutation carriers have increased levels of aromatase and inflammation in the breast, as occurs in post-menopausal women. In a prospective cohort study of 141 women with germline BRCA1 (n = 74) or BRCA2 (n = 67) mutations, leptin, and aromatase expression were higher in the breast tissue of obese versus lean individuals (P < 0.05). Obesity was associated with breast white adipose tissue inflammation, which correlated with breast aromatase levels (P < 0.01). Circulating C-reactive protein, interleukin-6, and leptin positively correlated with body mass index and breast aromatase levels, whereas negative correlations were observed for adiponectin and sex hormone-binding globulin (P < 0.05). These findings could help explain the increased risk of early-onset breast cancer in obese BRCA1/2 mutation carriers.

Dietary interventions to prevent high-fructose diet-associated worsening of colitis and colitis-associated tumorigenesis in mice.

Diet is believed to be an important factor in the pathogenesis of inflammatory bowel disease. High consumption of dietary fructose has been shown to exacerbate experimental colitis, an effect mediated through the gut microbiota. This study evaluated whether dietary alterations could attenuate the detrimental effects of a high-fructose diet (HFrD) in experimental colitis. First, we determined whether the procolitic effects of a HFrD could be reversed by switching mice from a HFrD to a control diet. This diet change completely prevented HFrD-induced worsening of acute colitis, in association with a rapid normalization of the microbiota. Second, we tested the effects of dietary fiber, which demonstrated that psyllium was the most effective type of fiber for protecting against HFrD-induced worsening of acute colitis, compared with pectin, inulin, or cellulose. In fact, supplemental psyllium nearly completely prevented the detrimental effects of the HFrD, an effect associated with a shift in the gut microbiota. We next determined whether the protective effects of these interventions could be extended to chronic colitis and colitis-associated tumorigenesis. Using the azoxymethane/dextran sodium sulfate model, we first demonstrated that HFrD feeding exacerbated chronic colitis and increased colitis-associated tumorigenesis. Using the same dietary changes tested in the acute colitis setting, we also showed that mice were protected from HFrD-mediated enhanced chronic colitis and tumorigenesis, upon either diet switching or psyllium supplementation. Taken together, these findings suggest that high consumption of fructose may enhance colon tumorigenesis associated with long-standing colitis, an effect that could be reduced by dietary alterations.

Vasovasostomy: kinetics and predictors of patency.

OBJECTIVE: To assess the timing of patency and late failure (secondary azoospermia) after vasovasostomy (VV) using standardized kinetics definitions. DESIGN: Retrospective cohort study. SETTING: University-affiliated hospital. PATIENT(S): Patients with obstructive azoospermia. INTERVENTION(S): Vasovasostomy. MAIN OUTCOME MEASURE(S): Univariate and multivariate logistic regression assessed predictors of patency and late failure. Patency was defined as any sperm return to the ejaculate; and >2 million total motile sperm (TMS) in ejaculate. Late failure after VV was defined as azoospermia; or <2 million TMS in ejaculate. RESULT(S): 429 men underwent VV, with median follow up of 242 days. Mean time to patency was 3.25 months versus 5.29 months in the "any sperm" versus ">2 million TMS" groups. Finding sperm intraoperatively during VV significantly improved patency rates in multivariable analysis (odds ratio [OR] 4.22). This association was further boosted when sperm was found bilaterally (OR 6.70). Late failure rate (azoospermia) was 10.6% at mean time of 14.1 months and 23% for <2 million, at mean time of 15.7 months. When assessing predictors of late failure, intraoperative motile sperm bilaterally was a statistically significant protective factor on multivariate analysis (hazard ratio 0.22). CONCLUSION(S): Vasovasostomy remains highly efficacious in treating obstructive azoospermia. Young patients, shorter obstructive intervals, and sperm identified intraoperatively predict improved outcomes. Clinicians can expect VV patency in 3 months and late failure within the first 2 years after surgery. However, patency rates, late failure rates, and kinetics vary by definition.

Lenvatinib promotes antitumor immunity by enhancing the tumor infiltration and activation of NK cells.

Based on previous reports, the efficacy of lenvatinib against cancer is mainly attributed to its antiangiogenic activity and its ability to suppress tumor proliferation, which are mediated by targeting receptor tyrosine kinases (RTKs). However, the effects of lenvatinib on tumor immune modulation have rarely been explored. Here, we show that lenvatinib effectively inhibited murine melanoma and renal cancer, and this inhibition was associated with enhanced tumor infiltration by natural killer (NK) cells. Critically, lenvatinib-induced tumor growth inhibition was attenuated by antibody-mediated NK cell depletion or the blockade of NK cell chemotaxis with an anti-CXCR3 blocking antibody. In addition, the expression of natural cytotoxicity receptors (NCRs) by tumor-infiltrating NK cells and the expression of cytotoxic cytokines in the tumor tissue were also augmented by lenvatinib. These data thus suggest that lenvatinib may be used not only as a direct cytotoxic drug against tumor angiogenesis and proliferation but also as a potent adjunct for enhancing the efficacy of immune-based cancer therapies by enhancing the tumor infiltration and activation of NK cells.

Supplemental estrogen and caloric restriction reduce obesity-induced periprostatic white adipose inflammation in mice.

Obesity is associated with an increased incidence of high-grade prostate cancer (PC) and worse prognosis for PC patients. Recently, we showed in men that obesity-related periprostatic white adipose tissue (WAT) inflammation, characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures, was associated with high-grade PC. Possibly, interventions that suppress periprostatic WAT inflammation will improve outcomes for men with PC. Here, we tested the hypothesis that supplemental 17ß-estradiol (E2) could decrease periprostatic WAT inflammation in obese male mice. Mice were fed a high-fat diet to induce periprostatic WAT inflammation before being treated with supplemental E2. E2 supplementation suppressed caloric intake, induced weight loss, decreased periprostatic WAT inflammation and downregulated the expression of genes linked to inflammation including Cd68, Mcp1 and Tnf. Similar to the effects of E2 supplementation, treatment with diethylstilbestrol, a synthetic estrogen, also suppressed caloric intake and reduced periprostatic WAT inflammation. To determine whether the observed effects of supplemental estrogen could be reproduced by caloric restriction (CR) alone, obese mice were put on a 30% CR diet. Like estrogen treatment, CR was effective in reducing body weight, periprostatic WAT inflammation and the expression of pro-inflammatory genes. Transcriptomic analyses of periprostatic fat showed that obesity was associated with enrichment in inflammatory response pathways, which were normalized by both supplemental E2 and CR. Taken together, these findings strengthen the rationale for future efforts to determine whether either CR or supplemental estrogen will decrease periprostatic WAT inflammation and thereby improve outcomes for men with PC.

Colonoscopic-Guided Pinch Biopsies in Mice as a Useful Model for Evaluating the Roles of Host and Luminal Factors in Colonic Inflammation.

Colonic inflammation, a hallmark of inflammatory bowel disease, can be influenced by host intrinsic and extrinsic factors. There continues to be a need for models of colonic inflammation that can both provide insights into disease pathogenesis and be used to investigate potential therapies. Herein, we tested the utility of colonoscopic-guided pinch biopsies in mice for studying colonic inflammation and its treatment. Gene expression profiling of colonic wound beds after injury showed marked changes, including increased expression of genes important for the inflammatory response. Interestingly, many of these gene expression changes mimicked those alterations found in inflammatory bowel disease patients. Biopsy-induced inflammation was associated with increases in neutrophils, macrophages, and natural killer cells. Injury also led to elevated levels of sphingosine-1-phosphate (S1P), a bioactive lipid that is an important mediator of inflammation mainly through its receptor, S1P1. Genetic deletion of S1P1 in the endothelium did not alter the inflammatory response but led to increased colonic bleeding. Bacteria invaded into the wound beds, raising the possibility that microbes contributed to the observed changes in mucosal gene expression. In support of this, reducing bacterial abundance markedly attenuated the inflammatory response to wounding. Taken together, this study demonstrates the utility of the pinch biopsy model of colonic injury to elucidate the molecular underpinnings of colonic inflammation and its treatment.

A Randomized Multicenter Phase II Study of Docosahexaenoic Acid in Patients with a History of Breast Cancer, Premalignant Lesions, or Benign Breast Disease.

Obesity, a cause of subclinical inflammation, is a risk factor for the development of postmenopausal breast cancer and is associated with poorer cancer outcomes. Docosahexaenoic acid (DHA), an omega-3 fatty acid, possesses anti-inflammatory properties. We hypothesized that treatment with DHA would reduce the expression of proinflammatory genes and aromatase, the rate-limiting enzyme for estrogen biosynthesis, in benign breast tissue of overweight/obese women. A randomized, placebo-controlled, double-blind phase II study of DHA given for 12 weeks to overweight/obese women with a history of stage I-III breast cancer, DCIS/LCIS, Paget's disease, or proliferative benign breast disease was carried out. In this placebo controlled trial, the primary objective was to determine whether DHA (1,000 mg by mouth twice daily) reduced breast tissue levels of TNFα. Secondary objectives included evaluation of the effect of DHA on breast tissue levels of COX-2, IL1ß, aromatase, white adipose tissue inflammation, and gene expression by RNA-seq. Red blood cell fatty acid levels were measured to assess compliance. From July 2013 to November 2015, 64 participants were randomized and treated on trial (32 women per arm). Increased levels of omega-3 fatty acids in red blood cells were detected following treatment with DHA (P < 0.001) but not placebo. Treatment with DHA did not alter levels of TNFα (P = 0.71), or other biomarkers including the transcriptome in breast samples. Treatment with DHA was overall well-tolerated. Although compliance was confirmed, we did not observe changes in the levels of prespecified biomarkers in the breast after treatment with DHA when compared with placebo. Cancer Prev Res; 11(4); 203-14. ©2018 AACRSee related editorial by Fabian and Kimler, p. 187.

Adiposity, Inflammation, and Breast Cancer Pathogenesis in Asian Women.

Obesity is associated with white adipose tissue (WAT) inflammation in the breast, elevated levels of the estrogen biosynthetic enzyme, aromatase, and systemic changes that predispose to breast cancer development. We examined whether WAT inflammation and its associated systemic effects correlate with body fat levels in an Asian population where body mass index (BMI) is not an accurate assessment of obesity and cancer risk. We also investigated whether biologic differences could account for the greater proportion of premenopausal estrogen receptor (ER)-positive breast cancer in Asian versus Western countries. Breast WAT and fasting blood were prospectively collected from Taiwanese women undergoing mastectomy for breast cancer treatment. Body composition was measured in a subgroup using bioelectrical impedance analysis. WAT inflammation was defined by the presence of crown-like structures of the breast, which are composed of dead or dying adipocytes surrounded by macrophages. Findings were compared with U.S. Caucasian women. In the Taiwanese cohort (n = 72), breast WAT inflammation was present in 31 (43%) women and was associated with elevated BMI (P < 0.01) and increased levels of body fat (P < 0.01), C-reactive protein (P = 0.02), triglycerides (P < 0.01), insulin resistance scores (P = 0.04), and lower HDL cholesterol (P < 0.01). ER+ tumors were associated with greater body fat versus other subtypes (P = 0.03). Compared with U.S. Caucasians (n = 267), Taiwanese women had larger breast adipocytes despite lower BMI after adjusting for BMI and menopausal status (P = 0.01). A subclinical inflammatory state associated with increased adiposity and metabolic dysfunction could contribute to breast cancer pathogenesis in Asian women. Cancer Prev Res; 11(4); 227-36. ©2017 AACR.

Pioglitazone Inhibits Periprostatic White Adipose Tissue Inflammation in Obese Mice.

Obesity is associated with an increased incidence of high-grade prostate cancer and poor prognosis for prostate cancer patients. Recently, we showed that obesity-related periprostatic white adipose tissue (WAT) inflammation, characterized by crown-like structures (CLS) consisting of dead or dying adipocytes surrounded by macrophages, was associated with high-grade prostate cancer. It is possible, therefore, that agents that suppress periprostatic WAT inflammation will alter the development or progression of prostate cancer. Pioglitazone, a ligand of PPARγ, is used to treat diabetes and possesses anti-inflammatory properties. Here, our main objectives were to determine whether pioglitazone inhibited obesity-related periprostatic WAT inflammation in mice and then to elucidate the underlying mechanism. Treatment with pioglitazone reduced the density of CLS in periprostatic fat and suppressed levels of TNFα, TGFß, and the chemokine monocyte chemoattractant protein-1 (MCP-1). Importantly, the ability of pioglitazone to suppress periprostatic WAT inflammation was abrogated in MCP-1 knockout mice. Pioglitazone caused dose-dependent induction of both adiponectin, an anti-inflammatory adipokine, and its receptor AdipoR2 in cultured 3T3-L1 cells and in periprostatic WAT of obese mice. Pioglitazone blocked TNFα-mediated induction of MCP-1 in 3T3-L1 cells, an effect that was attenuated when either adiponectin or AdipoR2 were silenced. Taken together, pioglitazone-mediated induction of adiponectin suppressed the elevation in MCP-1 levels, thereby attenuating obesity-related periprostatic WAT inflammation. These findings strengthen the rationale for future efforts to determine whether targeting the PPARγ-adiponectin-MCP-1 axis will decrease periprostatic adipose inflammation and thereby reduce the risk of high-grade prostate cancer or improve outcomes for men with prostate cancer. Cancer Prev Res; 11(4); 215-26. ©2017 AACR.

Metabolic Obesity, Adipose Inflammation and Elevated Breast Aromatase in Women with Normal Body Mass Index.

Obesity is associated with breast white adipose tissue (WAT) inflammation, elevated levels of the estrogen biosynthetic enzyme, aromatase, and systemic changes that have been linked to the pathogenesis of breast cancer. Here, we determined whether metabolic obesity, including changes in breast biology and systemic effects, occurs in a subset of women with normal body mass index (BMI). Breast WAT and fasting blood were collected from 72 women with normal BMI (<25 kg/m2) undergoing mastectomy for breast cancer risk reduction or treatment. WAT inflammation was defined by the presence of crown-like structures of the breast (CLS-B) which are composed of dead or dying adipocytes surrounded by macrophages. Severity of inflammation was measured as CLS-B/cm2 The primary objective was to determine whether breast WAT inflammation is associated with aromatase expression and activity. Secondary objectives included assessment of circulating factors and breast adipocyte size. Breast WAT inflammation was present in 39% of women. Median BMI was 23.0 kg/m2 (range, 18.4-24.9 kg/m2) in women with breast WAT inflammation versus 21.8 kg/m2 (range, 17.3-24.6 kg/m2) in those without inflammation (P = 0.04). Breast WAT inflammation was associated with elevated aromatase expression and activity, which increased with severity of inflammation (P < 0.05). Breast WAT inflammation correlated with larger adipocytes (P = 0.01) and higher circulating levels of C-reactive protein, leptin, insulin, and triglycerides (P ≤ 0.05). A subclinical inflammatory state associated with elevated aromatase in the breast, adipocyte hypertrophy, and systemic metabolic dysfunction occurs in some normal BMI women and may contribute to the pathogenesis of breast cancer. Cancer Prev Res; 10(4); 235-43. ©2017 AACRSee related article by Berger, p. 223-25.

Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers.

Context: Most estrogen-dependent breast cancers occur after menopause, despite low levels of circulating estrogens. Breast expression of the estrogen-biosynthetic enzyme, aromatase, is proposed to drive breast cancer development after menopause. However, the effects of menopause on breast aromatase expression are unknown. Objective: To determine the effect of menopause on breast aromatase expression in relation to body mass index (BMI), white adipose tissue inflammation (WATi), and systemic markers of metabolic dysfunction. Design, Setting, and Participants: Cross-sectional study of 102 premenopausal (age 27 to 56) and 59 postmenopausal (age 45 to 74) women who underwent mastectomy for breast cancer treatment/prevention. Outcome: Breast tissue was assessed for the presence of crown-like structures and the expression and activity of aromatase. Systemic markers examined include interleukin (IL)-6, insulin, glucose, leptin, adiponectin, high-sensitivity C-reactive protein (hsCRP), cholesterol, and triglycerides. Multivariable analysis was performed for aromatase messenger RNA (mRNA) in relation to BMI, WATi, and blood markers. Results: Postmenopausal women had higher BMI and more breast WATi than premenopausal women. Fasting levels of IL-6, glucose, leptin, hsCRP, and homeostatic model assessment 2 insulin resistance score were higher in the postmenopausal group. BMI was positively correlated with aromatase mRNA in both pre- and postmenopausal women. Aromatase levels were higher in breast tissue of postmenopausal women, with levels being higher in inflamed vs noninflamed, independent of BMI. Adipocyte diameter and levels of leptin, hsCRP, adiponectin, and high-density lipoprotein cholesterol were more strongly correlated with aromatase in postmenopausal than premenopausal women. Conclusions: Elevated aromatase in the setting of adipose dysfunction provides a possible mechanism for the higher incidence of hormone-dependent breast cancer in obese women after menopause.

Elevated Levels of Urinary PGE-M Are Found in Tobacco Users and Indicate a Poor Prognosis for Oral Squamous Cell Carcinoma Patients.

Cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) plays a role in the development and progression of epithelial malignancies. Measurements of urinary PGE-M, a stable metabolite of PGE2, reflect systemic PGE2 levels. Here, we investigated whether urinary PGE-M levels were elevated in healthy tobacco users and in patients with oral squamous cell carcinoma (OSCC). Median urinary PGE-M levels were increased in healthy tobacco quid chewers [21.3 ng/mg creatinine (Cr); n = 33; P = 0.03] and smokers (32.1 ng/mg Cr; n = 31; P < 0.001) compared with never tobacco quid chewers-never smokers (18.8 ng/mg Cr; n = 30). Urinary PGE-M levels were also compared in OSCC patients versus healthy tobacco users. An approximately 1-fold increase in median urinary PGE-M level was found in OSCC patients (48.7 ng/mg Cr, n = 78) versus healthy controls (24.5 ng/mg Cr, n = 64; P < 0.001). We further determined whether baseline urinary PGE-M levels were prognostic in OSCC patients who underwent treatment with curative intent. A nearly 1-fold increase in baseline urinary PGE-M levels (64.7 vs. 33.8 ng/mg Cr, P < 0.001) was found in the group of OSCC patients who progressed (n = 37) compared with the group that remained progression free (n = 41). Patients with high baseline levels of urinary PGE-M had both worse disease-specific survival [HR, 1.01 per unit increase; 95% confidence interval (CI), 1.01-1.02; P < 0.001] and overall survival (HR, 1.01 per unit increase; 95% CI, 1.00-1.02; P = 0.03). Taken together, our findings raise the possibility that NSAIDs, prototypic inhibitors of PGE2 synthesis, may be beneficial for reducing the risk of tobacco-related aerodigestive malignancies or treating OSCC patients with high urinary PGE-M levels. Cancer Prev Res; 9(6); 428-36. ©2016 AACR.

Allogeneic Transplantation for Patients With Advanced Myelofibrosis: Splenomegaly and High Serum LDH are Adverse Risk Factors for Successful Engraftment.

BACKGROUND: Thirty consecutive patients underwent hematopoietic stem cell transplantation for myelofibrosis (MF) at our institution. The median age at the time of transplant was 49 (range, 18-68) years, 74% of patients had advanced Dynamic International Prognostic Scoring System (DIPSS) scores, and 83% received reduced-intensity conditioning. PATIENTS AND METHODS: With a long follow-up of our patients, we analyzed disease and transplant variables that contributed to engraftment and outcomes. RESULTS: Neutrophil engraftment was achieved in 27 patients (90%) at a median time of 15 (range, 10-44) days, and 19 patients (63%) achieved platelet recovery at a median time of 18 (range, 8-100) days. Splenomegaly was associated with poor neutrophil engraftment (subdistributional hazard ratio [SHR], 0.42; 95% confidence interval [CI], 0.21-0.83; P = .01) and platelet engraftment (SHR, 0.18; 95% CI, 0.07-0.48; P < .001). Increased levels of lactate dehydrogenase (LDH) was associated with poor platelet engraftment (SHR, 0.39; 95% CI, 0.16-0.94; P = .04). The median follow-up for surviving patients was 49 (range, 3-155) months. The 1-year cumulative incidence of nonrelapse mortality (NRM) and relapse were respectively, 57% (95% CI, 29%-76%) and 25% (95% CI, 7%-48%). Increased levels of LDH was associated with high NRM (SHR, 2.82; 95% CI, 1.08-7.35; P = .03). The 4-year overall survival (OS) and relapse-free survival (RFS) were 44% (95% CI, 29%-67%) and 37% (95% CI, 23%-61%), respectively. In the multivariable model, splenomegaly and Eastern Cooperative Oncology Group (ECOG) performance status (PS) > 1 were associated with worse OS (hazard ratio [HR], 5.40; 95% CI, 1.19-24.56); P = .03) and RFS (HR, 3.78; 95% CI, 1.01-14.06; P < .05), respectively. ECOG PS > 1 was also associated with worse RFS (HR, 5.00; 95% CI, 1.31-19.14; P = .02). In this patient group with advanced disease, DIPPS score, Lille score, Janus-Associated Kinase V617F (JAK2 V617F) mutation status, and donor type did not predict transplant outcome. CONCLUSION: We confirm curative potential, but high NRM of allogeneic transplant for advanced MF.

Early human herpes virus type 6 reactivation in umbilical cord blood allogeneic stem cell transplantation.

Human herpes virus type 6 can reactivate in patients after allogeneic stem cell transplantation and has been associated with serious sequelae such as delayed engraftment and an increased risk of developing acute graft-versus-host disease (GVHD). This study investigated human herpes virus type 6 (HHV-6) reactivation within 60 days of transplantation in stem cell transplants utilizing single umbilical cord blood, double umbilical cord blood, or umbilical cord blood plus haploidentical stem cells. Of 92 patients, 60 (65%) had HHV-6 reactivation. Reactivation was not significantly influenced by any patient characteristics, disease characteristics, or by stem cell source (umbilical cord blood only versus haploidentical plus umbilical cord blood). We did not observe any impact of HHV-6 reactivation on neutrophil or platelet count recovery or on relapse-free survival. HHV-6 reactivation was associated with subsequent development of prerelapse acute GVHD (HR = 3.00; 95% CI, 1.4 to 6.4; p = 0.004).

Systemic Correlates of White Adipose Tissue Inflammation in Early-Stage Breast Cancer.

PURPOSE: Obesity, insulin resistance, and elevated levels of circulating proinflammatory mediators are associated with poorer prognosis in early-stage breast cancer. To investigate whether white adipose tissue (WAT) inflammation represents a potential unifying mechanism, we examined the relationship between breast WAT inflammation and the metabolic syndrome and its prognostic importance. EXPERIMENTAL DESIGN: WAT inflammation was defined by the presence of dead/dying adipocytes surrounded by macrophages forming crown-like structures (CLS) of the breast. Two independent groups were examined in cross-sectional (cohort 1) and retrospective (cohort 2) studies. Cohort 1 included 100 women undergoing mastectomy for breast cancer risk reduction (n = 10) or treatment (n = 90). Metabolic syndrome-associated circulating factors were compared by CLS-B status. The association between CLS of the breast and the metabolic syndrome was validated in cohort 2, which included 127 women who developed metastatic breast cancer. Distant recurrence-free survival (dRFS) was compared by CLS-B status. RESULTS: In cohorts 1 and 2, breast WAT inflammation was detected in 52 of 100 (52%) and 52 of 127 (41%) patients, respectively. Patients with breast WAT inflammation had elevated insulin, glucose, leptin, triglycerides, C-reactive protein, and IL6 and lower high-density lipoprotein cholesterol and adiponectin (P < 0.05) in cohort 1. In cohort 2, breast WAT inflammation was associated with hyperlipidemia, hypertension, and diabetes (P < 0.05). Compared with patients without breast WAT inflammation, the adjusted HR for dRFS was 1.83 (95% CI, 1.07-3.13) for patients with inflammation. CONCLUSIONS: WAT inflammation, a clinically occult process, helps to explain the relationship between metabolic syndrome and worse breast cancer prognosis. Clin Cancer Res; 22(9); 2283-9. ©2015 AACR.