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Supplementary Table 3: Multivariable Linear Regressions between Log Continous Serum and Tissue Hormones Stratified by Gleason Score

Background: Patient Navigation (PN) originated in Harlem as an intervention to help poor women overcome access barriers to timely breast cancer treatment. Despite rapid, nationally widespread adoption of PN, empirical evidence on its effectiveness is lacking. In 2005, National Cancer Institute initiated a multicenter PN Research Program (PNRP) to measure PN effectiveness for several cancers. The George Washington Cancer Institute, a project participant, established District of Columbia (DC)-PNRP to determine PN's ability to reduce breast cancer diagnostic time (number of days from abnormal screening to definitive diagnosis).Methods: A total of 2,601 women (1,047 navigated; 1,554 concurrent records-based nonnavigated) were examined for breast cancer from 2006 to 2010 at 9 hospitals/clinics in DC. Analyses included only women who reached complete diagnostic resolution. Differences in diagnostic time between navigation groups were tested with ANOVA models including categorical demographic and treatment variables. Log transformations normalized diagnostic time. Geometric means were estimated and compared using Tukey–Kramer P value adjustments.Results: Average—geometric mean [95% confidence interval (CI)]—diagnostic time (days) was significantly shorter for navigated, 25.1 (21.7, 29.0), than nonnavigated women, 42.1 (35.8, 49.6). Subanalyses revealed significantly shorter average diagnostic time for biopsied navigated women, 26.6 (21.8, 32.5) than biopsied nonnavigated women, 57.5 (46.3, 71.5). Among nonbiopsied women, diagnostic time was shorter for navigated, 27.2 (22.8, 32.4), than nonnavigated women, 34.9 (29.2, 41.7), but not statistically significant.Conclusions: Navigated women, especially those requiring biopsy, reached their diagnostic resolution significantly faster than nonnavigated women.Impact: Results support previous findings of PN's positive influence on health care. PN should be a reimbursable expense to assure continuation of PN programs. Cancer Epidemiol Biomarkers Prev; 21(10); 1655–63. ©2012 AACR.

Supplementary Table 2: Reproducibility of average tissue hormone assays by zone and overall from a pilot study of 30 men recruited at George Washington University Medical Center that included a total of 171 prostate biopsies.

Supplementary Table 1: Reproducibility of serum and tissue hormone assays used for the main analysis

Supplementary Table 4: Multivariable Linear Regressions between Log Continous Serum and Tissue Hormones Stratified by Race

Supplementary Table 5: Multivariable Linear Regressions between Log Continous Serum and Tissue Hormones Stratified by Median Age at Blood Draw

Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases.Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers.Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17β-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone (r2 = 0.10), and then serum estrone and tissue estrone (r2 = 0.09). There was no effect modification by Gleason score, race, or age.Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu.Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(11); 1660–6. ©2017 AACR.

PDF file - 73K, Descriptive summary statistics for diagnostic time (in days)

The survival after the diagnosis of inflammatory breast cancer (IBC) has been steadily improving for the past few decades. This has been due to advances in the knowledge of IBC in a number of fields, including epidemiology, molecular biology, and medical management. In this review we summarize some of the most important recent advances in these fields and suggest possible opportunities for continued improvement.

Background/objective Within India, chronic myeloid leukemia (CML) mean age at diagnosis is 38years. This study investigated agricultural practices and patterns corresponding to regional variations in CML epidemiology in India. Methods Multivariable linear regression and a Cox proportional hazards assessment were used to determine associations between age of CML diagnosis and crop-specific regions. Results Patients in the agriculture/fishing occupation sector from high rice-production areas developed CML earlier (2.71years) than those living in areas with lower levels of rice production (p-value=.01). Conclusions These data show a geographic relationship between crops grown and mean age of CML diagnosis. Whether crop type is a reflection of differences in specific occupational chemical uses or dietary practices, and how each of these factors relates to CML risk requires investigation at the individual level.

Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases. Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers. Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17β-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone (r2 = 0.10), and then serum estrone and tissue estrone (r2 = 0.09). There was no effect modification by Gleason score, race, or age. Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu. Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(11); 1660–6. ©2017 AACR.

BackgroundHuman herpesvirus-6 (HHV-6) is a ubiquitous double-stranded DNA virus that can cause roseola infantum, encephalitis, and seizure disorders. Several studies have shown an association between HHV-6 and cancer but confirmation of an etiologic role is lacking. We reviewed the criteria for viral causation of cancer used by The International Agency for Research on Cancer (IARC) for six oncogenic viruses and applied criteria to published reports of HHV-6 and its association with Hodgkin lymphoma and brain tumors.MethodsOur major criteria for oncogenicity were finding evidence of the virus in every tumor cell and prevention of the tumor by an antiviral vaccine. Our six minor criteria included: 1) suggestive serologic correlation, such as higher virus antibody levels in cases compared to controls; 2) evidence of the virus in some but not all tumor cells, and 3) time space clustering. We focused on Epstein-Barr virus (EBV) as the primary virus for comparison as HHV-6 and EBV are both Herpesviridae, ubiquitous infections, and EBV is well-accepted as a human oncovirus. Particular attention was given to Hodgkin lymphoma (HL) and brain cancer as these malignancies have been the most studied.ResultsNo studies reported HHV-6 satisfying either of the major criteria for oncogenicity. Of the minor criteria used by IARC, serologic studies have been paramount in supporting EBV as an oncogenic agent in all EBV-associated tumors, but not for HHV-6 in HL or brain cancer. Clustering of cases was suggestive for both HL and brain cancer and medical intervention suggested by longer survival in patients treated with antiviral agents was reported for brain cancer.ConclusionThere is insufficient evidence to indicate HHV-6 is an etiologic agent with respect to HL and brain cancers. We suggest that methods demonstrating EBV oncogenicity be applied to HHV-6. It is important that one study has found HHV-6 in all cancer cells in oral cancer in a region with elevated HHV-6 antibodies and therefore HHV-6 can still be considered a possible human oncogenic virus.

Background/objectives We have found that chronic myelocytic leukemia (CML) is diagnosed at an earlier age in poorer populations than in more affluent populations. We had used data from the Glivec® Patient Assistance Program (GIPAP) involving 33,985 patients from 94 participating countries and documented the geographic variation in CML age of onset, with low income identified as a major risk factor for early age of onset. As India is the largest cohort within GIPAP, we studied several demographic factors in this population to investigate other possible contributors to early age at onset. Methods We analyzed data collected 2002-2008 from 14,167 Indian patients to investigate demographic factors related to age at diagnosis focusing on income and occupation as risk factors. Results As in the first study, patients with an earlier age at diagnosis of CML were more likely to be in families with lower annual income. In addition, we found age at diagnosis varied across different occupations; patients who were self-employed and worked in agriculture/fishing were more likely to be diagnosed at a younger age than patients working in the government. Geographic variation in age at CML diagnosis was also observed, possibly reflecting the influence of environmental and socioeconomic factors on the pathogenesis of CML. Conclusions Environmental factors apparently play a major role in determining age of diagnosis of CML. Analytic studies are needed to determine the relative importance of various exposures such as to herbicides/pesticides, dietary habits and other factors related to income to identify specific contributory factors in the pathogenesis of CML.

BACKGROUND Patient navigation was developed to address barriers to timely care and reduce cancer disparities. The current study explored navigation and racial and ethnic differences in time to the diagnostic resolution of a cancer screening abnormality. METHODS The authors conducted an analysis of the multisite Patient Navigation Research Program. Participants with an abnormal cancer screening test were allocated to either navigation or control. The unadjusted median time to resolution was calculated for each racial and ethnic group by navigation and control. Multivariable Cox proportional hazards models were fit, adjusting for sex, age, cancer abnormality type, and health insurance and stratifying by center of care. RESULTS Among a sample of 7514 participants, 29% were non-Hispanic white, 43% were Hispanic, and 28% were black. In the control group, black individuals were found to have a longer median time to diagnostic resolution (108 days) compared with non-Hispanic white individuals (65 days) or Hispanic individuals (68 days) (P

We used male pattern baldness as a proxy for long-term androgen exposure and investigated the association of dermatologist-assessed hair loss with prostate cancer–specific mortality in the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. From the baseline survey (1971–1974), we included 4,316 men who were 25–74 years of age and had no prior cancer diagnosis. We estimated hazard ratios and used Cox proportional hazards regressions with age as the time metric and baseline hazard stratified by baseline age. A hybrid framework was used to account for stratification and clustering of the sample design, with adjustment for the variables used to calculate sample weights. During follow-up (median, 21 years), 3,284 deaths occurred; prostate cancer was the underlying cause of 107. In multivariable models, compared with no balding, any baldness was associated with a 56% higher risk of fatal prostate cancer (hazard ratio = 1.56; 95% confidence interval: 1.02, 2.37), and moderate balding specifically was associated with an 83% higher risk (hazard ratio = 1.83; 95% confidence interval: 1.15, 2.92). Conversely, patterned hair loss was not statistically significantly associated with all-cause mortality. Our analysis suggests that patterned hair loss is associated with a higher risk of fatal prostate cancer and supports the hypothesis of overlapping pathophysiological mechanisms.

Purpose Previous studies have reported that survivors of non-Hodgkin lymphoma (NHL) have an increased risk of developing cutaneous melanoma; however, risks associated with specific treatments and immune-related risk factors have not been quantified. Patients and Methods We evaluated second melanoma risk among 44,870 1-year survivors of first primary NHL diagnosed at age 66 to 83 years from 1992 to 2009 and included in the Surveillance, Epidemiology, and End Results-Medicare database. Information on NHL treatments, autoimmune diseases, and infections was derived from Medicare claims. Results A total of 202 second melanoma cases occurred among survivors of NHL, including 91 after chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 111 after other NHL subtypes (cumulative incidence by age 85 years: CLL/SLL, 1.37%; other NHL subtypes, 0.78%). Melanoma risk after CLL/SLL was significantly increased among patients who received infused fludarabine-containing chemotherapy with or without rituximab (n = 18: hazard ratio [HR], 1.92; 95% CI, 1.09 to 3.40; n = 10: HR, 2.92; 95% CI, 1.42 to 6.01, respectively). Significantly elevated risks also were associated with T-cell activating autoimmune diseases diagnosed before CLL/SLL (n = 36: HR, 2.27; 95% CI, 1.34 to 3.84) or after CLL/SLL (n = 49: HR, 2.92; 95% CI, 1.66 to 5.12). In contrast, among patients with other NHL subtypes, melanoma risk was not associated with specific treatments or with T-cell/B-cell immune conditions. Generally, infections were not associated with melanoma risk, except for urinary tract infections (CLL/SLL), localized scleroderma, pneumonia, and gastrohepatic infections (other NHLs). Conclusion Our findings suggest immune perturbation may contribute to the development of melanoma after CLL/SLL. Increased vigilance is warranted among survivors of NHL to maximize opportunities for early detection of melanoma.

Objective Two groups of Gulf War era veterans, one exhibiting blurred vision, balance problems/dizziness, tremors/shaking, and speech difficulty and a second group with post-traumatic stress disorder (PTSD), but not the neurologic syndrome, were assessed for organophosphate-detoxifying enzyme paraoxonase/arylesterase (PON1) and its Q/R isoforms, butyrylcholinesterase (BuChE) and its U/A isoforms and cytokines. Methods Defibrinated peripheral blood was evaluated for enzymes and cytokines. Results Trends toward elevation of Th2 cytokines interleukin-4 (IL-4) and IL-13 were observed in subjects with neurologic syndrome. Neither the activities nor isoforms of the enzyme, the neurologic symptoms, nor PTSD had any relationship to wartime deployment to the theater of combat. Conclusion The negative outcomes described above suggest that exposure to organophosphates or other agents normally detoxified by PON1 and BuChE may not have contributed significantly to neurologic components of Gulf War Illness.

BACKGROUND Prospective cohort studies of circulating sex steroid hormones and prostate cancer risk have not provided a consistent association, despite evidence from animal and clinical studies. However, studies using male pattern baldness as a proxy of early-life or cumulative androgen exposure have reported significant associations with aggressive and fatal prostate cancer risk. Given that androgens underlie the development of patterned hair loss and chest hair, we assessed whether these two dermatological characteristics were associated with circulating and intraprostatic concentrations of sex steroid hormones among men diagnosed with localized prostate cancer. METHODS We included 248 prostate cancer patients from the NCI Prostate Tissue Study, who answered surveys and provided a pre-treatment blood sample as well as fresh frozen adjacent normal prostate tissue. Male pattern baldness and chest hair density were assessed by trained nurses before surgery. General linear models estimated geometric means and 95% confidence intervals (95%CIs) of each hormone variable by dermatological phenotype with adjustment for potential confounding variables. Subgroup analyses were performed by Gleason score (

BACKGROUND Male pattern baldness and prostate cancer may share common pathophysiological mechanisms in terms of advancing age, heritability, and endogenous hormones. Results from previous epidemiologic studies are inconsistent. Therefore, we investigated the association of prostate cancer risk with male pattern baldness at age 30 years, age 45 years, and baseline (median age=60.5 years) in the VITamins And Lifestyle (VITAL) cohort study.

Nasopharyngeal carcinoma (NPC) is a non-lymphomatous, squamous-cell carcinoma that occurs in the epithelial lining of the nasopharynx. Nasopharyngeal carcinoma has a geographically well-defined distribution worldwide, with the highest prevalence in China, Southeast Asia, and Northern Africa. Symptoms of nascent NPC may be unapparent or trivial, with diagnosis based on the histopathology of biopsied tissue following endoscopy of the nasopharynx. The tumor node metastasis (TNM) staging system is the benchmark for the prognosis of NPC and guides treatment strategy. However, there is a consensus that the TNM system is not sufficiently specific for the prognosis of NPC, as it does not reflect the biological heterogeneity of this tumor, making another biomarker for the detection of NPC a priority. We have previously reported on different approaches for microRNA (miRNA) biomarker discovery for Formalin Fixed Paraffin Embedded (FFPE) NPC tissue samples by both a targeted (microarray) and an untargeted (small RNA-Seq) discovery platform. Both miRNA discovery platforms produced similar results, narrowing the miRNA signature to 1–5% of the known mature human miRNAs, with untargeted (small RNA-Seq approach) having the advantage of indicating “unknown” miRNAs associated with NPC. Both miRNA profiles strongly associated with NPC, providing two potential discovery platforms for biomarker signatures for NPC. Herein, we provide a detailed description of the methods that we used to interrogate FFPE samples to discover biomarkers for NPC.

Background Chronic myeloid leukemia (CML) is a rare disease in children and represents approximately 2% of all childhood leukemia. This results in difficulty creating large cohorts of patients for pediatric CML research. The Glivec International Patient Assistance Program (GIPAP) is a patient-access program sponsored by Novartis Oncology and administered by The Max Foundation (MAX) that provides imatinib free of charge to patients in resource-restricted countries who are not able to afford this treatment. Procedures GIPAP highlights a cohort of children (n = 3,188) with CML that provides novel insight into international trends in diagnosis, treatment, and survival. These trends can be compared to outcomes in developed nations to crudely assess the impact of an extended access program for CML treatment such as GIPAP. Results Overall survival values for children treated for CML within the GIPAP (89%) suggest that imatinib is very effective in middle and low-income countries. Conclusions This may allow for increased international awareness within the scientific community to consider possible reasons for the differences in overall survival in pediatric CML within the United States versus other nations with fewer resources. Pediatr Blood Cancer 2014; 61:1774–1778. © 2014 Wiley Periodicals, Inc.

Background: We recently evaluated four laboratory assays, vascular endothelial growth factor D (VEGF-D), E-cadherin, lymphatic vessel density (LVD) measured by podoplanin, and intra-lymphatic tumor emboli (ILTE), which showed notable differences between inflammatory breast cancer (IBC) and non-inflammatory locally advanced breast cancer (LABC). In this study we investigated the potential of the three most quantitatively measured markers, E-cadherin, LVD and VEGF-D, to predict survival in the IBC patients. Materials and Methods: This study involved the 100 cases identified in the Inflammatory Breast Cancer Registry (IBCR) whose tumors were previously evaluated for the four assays noted above. Living patients were recontacted and survival data were available for up to 17 years. Overall survival (OS) was analyzed through the Kaplan-Meier method stratified by E-cadherin, LVD, VEGF-D, and response to chemotherapy. The differences in OS curves were compared using the log-rank test. Results: The median OS for patients with high LVD was 6.63 years (95% CI: 4.06 to 10.14), compared to median at 10 years not reached in those with low LVD (p = 0.03). There was a trend towards a longer median OS in patients with high E-cadherin (10.14, 95% CI: 6.63 to 11.67), compared with those with low E-cadherin (6.26, 95% CI: 3.42 to undeterminable). VEGF-D levels showed no correlation with survival. Conclusion: Low LVD significantly predicts better survival. High E-cadherin expression, as with non-IBC breast cancer and several other malignancies, tends to be associated with a better prognosis.

Introduction: Inflammatory breast cancer (IBC) is a rare but extraordinarily aggressive disease with a number of studies indicating that environmental factors play the most important role. We have identified four reported clusters of IBC and our investigations thus far suggest that local toxic or infectious agents could be involved in the pathogenesis of the disease. IBC, like Burkitt's lymphoma (BL) has been reported to cluster and both have been implicated with infectious agents. Since BL has been reported to have a seasonal variation attributed to acute malaria symptoms as the precipitating agent, we decided to investigate the seasonality of IBC in two populations. Methods: For our analysis we used the datasets of two IBC referral groups. The first group consisted of a series of 163 consecutive cases of patients seen at Fox Chase Cancer Center (FCCC) almost all being from the Northeast U.S. (NE) and Canada. At the time of initial visit a detailed series of questions was specifically directed at identifying the accurate time of the first onset of symptoms/signs including skin rash, swelling, pain, nipple retraction and palpable mass. The second was the IBC registry (IBCR), established at the George Washington University with the purpose of collecting standardized clinical and epidemiologic data (including a detailed interview) and biospecimens from patients with IBC in the U.S and Canada. Complete data on patients in both groups were evaluated, including diagnostic workup, pathologic findings and treatment. Results: Of the 163 FCCC patients, 156 had the month of onset of symptoms clearly delineated. Of the 161 patients in the IBCR, 153 had month of symptomatic onset defined. In the combined groups, 181 NE patients were compared with 63 from the South. A seasonal pattern was noted in the NE patients, a bimodal pattern showing most patients with onset in March and July-Sept. No seasonal pattern was noted in patients from the South. Conclusion: The reports of IBC clusters are consistent with an acute triggering factor, possibly an infection. The seasonality we observed in NE patients but not in southern patients is consistent with this hypothesis. We are currently continuing to investigate clusters of IBC and are testing for specific candidate infectious agents as well as candidate environmental toxic agents to further understand possible triggers for this disease. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-06.

Endemic Burkitt lymphoma (eBL) is linked to Plasmodium falciparum (Pf) infection geographically, but evidence from individual-level studies is limited. We investigated this issue among 354 childhood eBL cases and 384 age-, sex-, and location-matched controls enrolled in Ghana from 1965 to 1994. Immunoglobulin G1 (IgG1) and immunoglobulin G3 (IgG3) antibodies to antigens diagnostic of recent infection Pf histidine-rich protein-II (HRP-II) and 6NANP, Pf-vaccine candidates SE36 and 42-kDa region of the 3D7 Pf merozoite surface protein-1 (MSP-1), and tetanus toxoid were measured by indirect enzyme-linked immunoassay. Odds ratios (ORs) and 95% confidence intervals (CIs) for association with eBL were estimated using unconditional logistic regression. After adjustments, eBL was positively associated with HRP-IIIgG3 seropositivity (adjusted OR: 1.60; 95% CI 1.08-2.36) and inversely associated with SE36IgG1 seropositivity (adjusted OR: 0.37; 95% CI 0.21-0.64) and with tetanus toxoidIgG3 levels equal or higher than the mean (adjusted OR: 0.46; 95% CI 0.32-0.66). Anti-MSP-1IgG3 and anti-6NANPIgG3 were indeterminate. eBL risk was potentially 21 times higher (95% CI 5.8-74) in HRP-IIIgG3-seropositive and SE36IgG1-seronegative responders compared with HRP-IIIgG3-seronegative and SE36IgG1-seropositive responders. Our results suggest that recent malaria may be associated with risk of eBL but long-term infection may be protective.

Background: Light and/or intermittent smokers have been the fastest growing segment of cigarette smokers in the United States over the past two decades. Defining their behavioral characteristics is a critical public health priority. Methods: Our sample included 78,229 U.S. adults from three pooled contemporary population-based surveys: the 2012 NHIS, 2012 NSDUH, and 2011–2012 NHANES. We classified current smokers into four categories (light and intermittent [LITS], light-daily, heavier-intermittent, and heavier-daily) and assessed smoking behaviors, illicit drug use, and mental health indicators using weighted analyses. Results: Analyses associated smoking categories with nicotine dependence, age of smoking initiation, race/ethnicity, and other demographic and behavioral factors. Compared with heavier-daily smokers, smokers who were LITS were most likely to have mild or no nicotine dependence (weighted odds ratio [OR], 16.92; 95% confidence interval [CI], 13.10–21.85), to start smoking cigarettes regularly after age 21 (OR, 3.42; 95% CI, 2.84–4.12), and to be Hispanic (OR, 5.38; 95% CI, 4.38–6.61). Additional significant results were found for other categories of smokers. Conclusions: Based on pooled data from three large national surveys, light and/or intermittent smokers differed in smoking, drug use, and mental health behaviors from heavier-daily, former, and never smokers. Notable differences by level of smoking frequency and intensity were observed for nicotine dependence, age of smoking initiation, and race/ethnicity. Impact: Our results may help focus preventive measures and policies for the growing number of light and/or intermittent smokers in the United States because smoking patterns vary by behavioral and socioeconomic factors. Cancer Epidemiol Biomarkers Prev; 26(2); 228–39. ©2016 AACR.

Inflammatory breast cancer (IBC) accounts for a small fraction but aggressive form of epithelial breast cancer. Although the role of thrombin in cancer is beginning to be unfolded, its impact on the biology of IBC remains unknown. The purpose of this study was to establish the role of thrombin on the invasiveness of IBC cells. The IBC SUM149 cell line was treated with thrombin in the absence or presence of the epidermal growth factor receptor (EGFR) inhibitor erlotinib and protease-activated receptor 1 (PAR1) inhibitor. The effects of pharmacological inhibitors on the ability of thrombin to stimulate the growth rate and invasiveness were examined. We found that the inhibition of putative cellular targets of thrombin action suppresses both the growth and invasiveness of SUM149 cells in a concentration-dependent manner. In addition, thrombin-mediated increased invasion of SUM149 cells was routed through EGFR phosphorylation, and in turn, stimulation of the p21-activated kinase (Pak1) activity in a EGFR-sensitive manner. Interestingly, thrombin-mediated activation of the Pak1 pathway stimulation was blocked by erlotinib and PAR1 inhibitor. For proof-of-principle studies, we found immunohistochemical evidence of Pak1 activation as well as expression of PAR1 in IBC. Thrombin utilizes EGFR to relay signals promoting SUM149 cell growth and invasion via the Pak1 pathway. The study provides the rationale for future therapeutic approaches in mitigating the invasive nature of IBC by targeting Pak1 and/or EGFR.

The phenomenon of accelerated tumor growth following surgery has been observed repeatedly and merits further study. Inflammatory breast carcinoma (IBC) is widely recognized as an extremely aggressive malignancy characterized by micrometastasis at the time of diagnosis, with one interesting subgroup defined as secondary IBC where pathologically identifiable IBC appears after surgical treatment of a primary non-inflammatory breast cancer. One possible mechanism can be related to the stimulation of dormant micrometastasis through local angiogenesis occurring as part of posttraumatic healing. In this report, we review cases of secondary IBC and others where localized trauma was followed by the appearance of IBC at the traumatized site that have been identified by our IBC Registry (IBCR) and hypothesize that angiogenesis appearing as part of the healing process could act as an accelerant to an otherwise latent breast malignancy. It is therefore possible that secondary IBC can be used as a model to support local angiogenesis as an important contributor to the development of an aggressive cancer.

Background: The phenomenon of accelerated tumor growth following surgery has been observed repeatedly and merits further study. Inflammatory breast carcinoma (IBC) is widely recognized as an extremely aggressive malignancy characterized by micrometastasis at the time of diagnosis. It is fast growing, highly angiogenic and angioinvasive, features that are present from its inception. The idea of a dormant cancer cell and awakening of metastatic disease following a surgical/traumatic event may well be exemplified by secondary IBC, a term used to describe the IBC appearing following surgery for a noninflammatory primary breast carcinoma. One possible mechanism can be related to the stimulation of dormant micrometastasis through local angiogenesis occurring as part of posttraumatic healing. It is therefore possible that secondary IBC can be used as a model to support local angiogenesis as an important contributor to the development of an aggressive cancer. Materials and Methods: Cases of secondary IBC were identified in a review of patients referred to the IBC Registry (IBCR). In this report we document the histories of three patients with secondary IBC as well as two additional patients whose disease presentation also supports the possible occurrence of IBC secondary to breast trauma. Secondary IBC cases were defined as women who had surgery for non-inflammatory breast cancer with recurrence at the previous mastectomy site manifest as skin erythema shown to be associated with pathologically confirmed tumor emboli in the dermal lymphatics. Results: Two of the patients with secondary IBC developed pathologically confirmed dermal lymphatic invasion two and 42 months after partial mastectomy for non-inflammatory breast cancer. The third had been apparently free of recurrence for seven years when she had reconstructive surgery, which was followed by IBC seven months later. Two additional cases are presented, one in which IBC manifested one month following ductogram procedure and had a contralateral breast IBC recurrence 2 years later. The other patient was diagnosed with IBC one year following nipple piercing and ring removal. Discussion: Recent publications have focused on the role of surgery in the subsequent development of metastatic breast cancer, many of them focusing on a hormonal mechanism triggered by removal of the primary tumor. We propose local angiogenesis as another possible mechanism for post-surgical dissemination of cancer. In view of the hypothesis that trauma can stimulate angiogenesis which can accelerate tumor growth, the documentation of IBC appearing at the site of a traumatic event merits consideration. Our experience with IBC, noted in the case reports above suggest that local trauma probably mediated in large part by angiogenesis can be an important trigger of IBC. We would therefore suggest that secondary IBC be considered for investigation of one possible mechanism for post-surgical tumor dissemination. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-05-09.

BACKGROUND: Delays in follow-up after breast cancer screening contribute to disparities in breast cancer outcomes. The objective of this research was to determine the impact of race/ethnicity and health insurance on diagnostic time, defined as number of days from suspicious finding to diagnostic resolution. METHODS: This retrospective cohort study of 1538 women examined for breast abnormalities between 1998-2010 at 6 hospitals/clinics in the District of Columbia measured mean diagnostic times between non-Hispanic whites (NHWs), non-Hispanic blacks (NHBs), and Hispanics with private, government, or no health insurance by using a full-factorial ANOVA model. RESULTS: Respective average—geometric mean (95% CI)—diagnostic times (in days) for NHWs, NHBs, and Hispanics were 16 (12, 21), 27 (23, 33), and 51 (35, 76) among privately insured; 12 (7, 19), 39 (32, 48), and 71 (48, 105) among government insured; 45 (17, 120), 60 (39, 92), and 67 (56, 79) among uninsured. Government insured NHWs had significantly shorter diagnostic times than government insured NHBs (P = .0003) and Hispanics (P < .0001). Privately insured NHWs had significantly shorter diagnostic times than privately insured NHBs (P = .03) and Hispanics (P < .0001). Privately insured NHBs had significantly shorter diagnostic times than uninsured NHBs (P = .03). CONCLUSIONS: Insured minorities waited >2 times longer to reach their diagnostic resolution than insured NHWs. Having private health insurance increased the speed of diagnostic resolution in NHBs; however, their diagnostic time remained significantly longer than for privately insured NHWs. These results suggest diagnostic delays in minorities are more likely caused by other barriers associated with race/ethnicity than by insurance status. Cancer 2011;. © 2011 American Cancer Society.

Transfer factor (TF) is a lymphocyte extract of low molecular weight capable of transferring antigen-specific information to T-lymphocytes. A number of reports have documented its efficacy in the control of acute viral infections, particularly those associated with herpes viruses. There have been also several reports of clinical trials utilizing Epstein-Barr Virus-specific TF in associated malignancies, particularly Burkitt's lymphoma and nasopharyngeal carcinoma. One of the more important advances in the field has been the ability to produce standardized TF in tissue culture or by animal immunization, allowing the opportunity to develop well-controlled clinical trials, and the possibility to replicate them in independent studies. This review discusses the studies that have provided the best information regarding the efficacy of TF in fighting viral infections and suggests areas where clinical trials could be most useful, such as the prevention of human papilloma virus induced cervical cancer and human T-cell lymphotropic virus induced adult T-cell leukemia/lymphoma.

Previous studies utilizing data from the Nevada Cancer Registry suggested a transient increase in non-Hodgkin’s lymphoma (NHL) and brain cancer in northern Nevada following an outbreak of Chronic Fatigue Syndrome (CFS) in that area which was not seen in southern Nevada which had no reported CFS outbreaks. A subsequent study from the National Cancer Institute (NCI) using data from the NCI’s Surveillance, Epidemiology and End Results (SEER) Program and Medicare documented the association between CFS and NHL on a national basis but no other cancer association was seen. Since brain cancer has a younger age distribution than NHL, we returned to the Nevada Cancer Registry and used ten more years of data and additional analyses to determine if there was an association between CFS and brain cancer by age. This study confirmed the increased incidence of brain cancer following the outbreak in northern Nevada but not southern Nevada with the increase limited to the under 65 age group, thus explaining why the SEER-Medicare analysis only analyzing data in the 65 and above age group did not detect this association.

The case definition for inflammatory breast cancer (IBC) is controversial. The American Joint Committee on Cancer defines IBC as redness, warmth and edema involving at least half the breast. The SEER program relies on a pathologic finding of dermal lymphatic invasion and recently added those with clinical involvement of more than 3/4 of the breast. We established a registry to collect information and specimens from IBC patients to clarify the epidemiology and biology of these tumors. The goals of this report are to suggest improvements regarding case definitions and provide data on the variety of presentations relevant to early diagnosis.

(2010). Longitudinal Network Patient Navigation. Oncology Issues: Vol. 25, No. 2, pp. 28-35.

Our previous studies revealed that beta protein 1 (BP1) was barely detectable in normal human breasts, but was seen in 21%, 46%, and 81% of hyperplastic, in situ, and invasive breast lesions, respectively. Our current study attempted to assess BP1 expression in inflammatory breast cancer (IBC), a very aggressive subtype of breast cancers characterized by extensive lympho-vascular invasion and involvement of dermal lymphatics. Paraffin-embedded tissue sections from 45 cases of IBC (nine with paired metastatic lymph nodes) and different controls were assayed immunohistochemically for BP1 expression. Positive BP1 immunoreactivities were present in all IBC cases. Strikingly, all cancer cells metastasized to lymph nodes and cells within lymphatic channels were uniformly and strongly immunoreactive to BP1. The percentage of BP1 positive cells and the intensity of BP1 immunostaining in IBC cases were significantly greater than those in non-IBC cases. Our findings suggest that BP1 may possess properties of onco-proteins that promote tumor progression, invasion, and metastasis, representing a putative signature marker for IBC and tumor aggressiveness.

Earlier studies have suggested an association between breast cancer aggressiveness and the presence of viral sequences resembling mouse mammary tumor virus (MMTV). This study was to determine if inflammatory breast cancer (IBC) in the United States had a higher proportion of cases with these viral sequences than non-IBC patients and if specific risk factors for the sequences could be identified. Biospecimens from 67 patients in the North American IBC Registry were selected for sequencing of MMTV env- like sequences. The presence or absence of the viral sequences was compared to progression free survival (PFS), risk factors including exogenous hormones, and tumor markers. Of the 67 cases, 44 were positive for viral sequences (VSP), 17 were negative (VSN) and six were excluded from analysis because of insufficient DNA to perform replicates. The 72% of VSP cases was significantly more than the 40% in non-IBC U.S. breast cancer patients (p < 0.0001). Non-significant trends suggested that VSP patients were more likely to be HER-2 neu positive and ER negative, have a stronger exposure to exogenous hormones, and have a shorter PFS than VSN patients. MMTV-related sequences appear to be related to the aggressiveness of breast cancer with a higher incidence in North American IBC than in non-IBC breast cancer.

Risk factors for second acute myeloid leukemia/myelodysplastic syndrome among survivors of non-Hodgkin lymphoma

Background To assess the importance of heredity in the etiology of inflammatory breast cancer (IBC), we compared IBC patients to several carefully chosen comparison groups with respect to the prevalence of first-degree family history of breast cancer. Methods IBC cases (n = 141) were compared to non-inflammatory breast cancer cases (n = 178) ascertained through George Washington University (GWU) with respect to the prevalence of first-degree family history of breast cancer and selected environmental/lifestyle risk factors for breast cancer. Similar comparisons were conducted with subjects from three case–control studies: breast cancer cases (n = 1145) and unaffected controls (n = 1142) from the Cancer Genetic Markers of Susceptibility (CGEMS) study, breast cancer cases (n = 465) and controls (n = 9317) from the Women’s Health Initiative (WHI) study, and ovarian cancer cases (n = 260) and controls (n = 331) from a study by University of Toronto (UT). Results The frequency of first-degree breast cancer family history among IBC cases was 17.0 % compared to 24.4 % for GWU breast cancer cases, 23.9 % and 17.9 % for CGEMS breast cancer cases and controls, respectively, 16.9 % and 12.6 % for WHI breast cancer cases and controls, respectively, and 24.2 % and 11.2 % for UT ovarian cancer cases and controls, respectively. IBC cases had a significantly lower prevalence of parous women than WHI breast cancer cases (OR = 0.46, 95 % CI:0.27–0.81) and controls (OR = 0.31, 95 % CI:0.20–0.49). Oral contraceptive use was significantly higher among IBC cases compared to WHI breast cancer cases (OR = 7.77, 95 % CI:4.82–12.59) and controls (OR = 8.14, 95 % CI:5.28–12.61). IBC cases had a significantly higher frequency of regular alcohol consumption (≥1 drink per day) compared to WHI controls (OR = 1.84, 95 % CI:1.20–2.82) and UT controls (OR = 1.86, 95 % CI:1.07–3.22) and higher (statistically non-significant) prevalence (21.3 %) compared to breast cancer cases from GWU (18.2 %) and WHI (15.2 %). Conclusions The prevalence of first-degree breast cancer family history among IBC cases was lower compared to breast and ovarian cancer cases but higher than unaffected individuals. Our multiple-case inflammatory and non-inflammatory breast cancer families may reflect aggregation of common genetic and/or environmental factors predisposing to both types of breast cancer. Our findings that oral contraceptive use and regular alcohol consumption may be associated with IBC warrant further investigations.

Developing countries have a younger population of CML patients than developed countries. Patterns of age at diagnosis and incidence by geography and gross national income (GNI) are not well understood. A population-based descriptive study was conducted using data from the International Agency for Research on Cancer's population-based registry compilation. Geographical regions were classified according to the United Nations World Macro Regions and Components. Age-Standardized Incidence Rates (ASR) were adjusted to the World Standard Population. Poisson regression was used to assess age-specific interactions. 57.2% were male among 33,690 diagnoses. Median age at diagnosis was lowest in Africa and Asia (47 years) and highest in Oceania (72 years). ASR was lowest in African males (0.61 per 100,000) and Asian females (0.55 per 100,000) and highest in Oceania males and females (1.78 and 0.96 per 100,000, respectively). A significant interaction (p0.0001) between age (50 years and50 years) and region exists; no significant differences were seen by region in the50 age-group while significant differences by region exist in the50 age group. Population-based estimates suggest that the median age at diagnosis and incidence varies by region. Geographic and income heterogeneity suggest an important effect of environment that warrants further studies.

Washington, DC (DC), has among the highest AIDS prevalence and cancer incidence in the USA. This study compared cancer diagnoses and survival among AIDS cases with AIDS-defining cancers (ADCs) to those with non-AIDS-defining cancers (NADCs) in DC from 1996 to 2006. Survival by cancer type and time period was also examined for 300 individuals diagnosed with AIDS who developed cancer; 49% of AIDS cases developed an ADC. ADC cases were younger at both AIDS and cancer diagnosis and had significantly lower median CD4 counts at AIDS diagnosis than NADC cases. The most frequent cancers were non-Hodgkin lymphoma (NHL; 44% of ADC), Kaposi's sarcoma (40% of ADC), and lung cancer (20% of NADC). There was no significant difference in distribution of cancers when comparing ADCs to NADCs, or over time (1996-2001 vs. 2002-2006). Survival among NHL, oral cavity, and lung cancer cases was 0.4, 0.8, and 0.3 years, respectively; the risk of death was approximately two times higher for each of these cancers when compared to other cancers. Given the high burden of cancer and HIV in DC, early highly active antiretroviral therapy initiation, routine cancer screening, and risk reduction through behavioral modification should be emphasized to prevent cancer among HIV-infected persons.

A previous symptom-based survey of veterans of the 1990-1991 Persian Gulf War suggested a neurological syndrome (blurred vision, loss of balance/dizziness, tremors/shaking, and speech difficulty). The authors conducted the present study to determine whether specific findings could indicate an organic basis for this possible syndrome. They completed an extensive clinical and laboratory evaluation on Gulf War veterans with all 4 symptoms, using 3 comparison groups. A single clinically based neurological syndrome could not be identified. No deployment-related exposure appeared to explain the pattern of symptoms, but this evaluation suggested comorbidities and possibly multiple vaccines as important contributors. Many of the neurological symptoms reported by the studied veterans appear to have an organic basis, but comorbidities must be excluded before researchers can conclude that a definitive syndrome exists.

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer with unknown etiology and generally poor outcome. It is characterized by diffuse edema (peau d'orange) and redness (erythema), although either the disease itself or case definitions have varied over time and place, confounding temporal trends and geographic variations. In this review, we discuss case definitions for IBC and its clinical characteristics; describe its geographic variation, age and racial distribution, incidence and survival patterns, and summarize the very limited information on its epidemiologic risk factors. We also incorporate emerging data from the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) Program.