Publications by authors named "Dilip D Giri"

36 Publications

Blood Biomarkers Reflect the Effects of Obesity and Inflammation on the Human Breast Transcriptome.

Carcinogenesis 2021 Jul 27. Epub 2021 Jul 27.

Retired, Department of Medicine, Weill Cornell Medical College, New York, New York.

Obesity is a risk factor for the development of post-menopausal breast cancer. Breast white adipose tissue (WAT) inflammation, which is commonly found in women with excess body fat, is also associated with increased breast cancer risk. Both local and systemic effects are likely to be important for explaining the link between excess body fat, adipose inflammation and breast cancer. The first goal of this cross-sectional study of 196 women was to carry out transcriptome profiling to define the molecular changes that occur in the breast related to excess body fat and WAT inflammation. A second objective was to determine if commonly measured blood biomarkers of risk and prognosis reflect molecular changes in the breast. Breast WAT inflammation was assessed by immunohistochemistry. Bulk RNA-sequencing was carried out to assess gene expression in non-tumorous breast. Obesity and WAT inflammation were associated with a large number of differentially expressed genes and changes in multiple pathways linked to the development and progression of breast cancer. Altered pathways included inflammatory response, complement, KRAS signaling, TNFα signaling via NFкB, IL6-JAK-STAT3 signaling, epithelial mesenchymal transition, angiogenesis, interferon γ response, and TGF-β signaling. Increased expression of several drug targets such as aromatase, TGF-β1, IDO-1 and PD-1 were observed. Levels of various blood biomarkers including hsCRP, IL6, leptin, adiponectin, triglycerides, HDL cholesterol and insulin were altered and correlated with molecular changes in the breast. Collectively, this study helps to explain both the link between obesity and breast cancer and the utility of blood biomarkers for determining risk and prognosis.
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http://dx.doi.org/10.1093/carcin/bgab066DOI Listing
July 2021

Toxic 'Toxo' in the heart: Cardiac toxoplasmosis following a hematopoietic stem cell transplant- a case report.

IDCases 2021 5;25:e01217. Epub 2021 Jul 5.

Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, United States.

Toxoplasmosis is a rare but potentially severe complication after allogeneic hematopoietic cell transplantation. Toxoplasma gondii-associated cardiac involvement can cause myocarditis, pericarditis, arrhythmias, and congestive heart failure. Most cases with cardiac toxoplasmosis following BMT have been fatal and diagnosed at autopsy. We present an unfortunate case of sudden onset congestive heart failure symptoms and delayed post-transplant Toxoplasma PCR testing that ultimately led to the diagnosis of cardiac toxoplasmosis on autopsy in our patient.
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http://dx.doi.org/10.1016/j.idcr.2021.e01217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267541PMC
July 2021

Integrated digital pathology at scale: A solution for clinical diagnostics and cancer research at a large academic medical center.

J Am Med Inform Assoc 2021 08;28(9):1874-1884

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Objective: Broad adoption of digital pathology (DP) is still lacking, and examples for DP connecting diagnostic, research, and educational use cases are missing. We blueprint a holistic DP solution at a large academic medical center ubiquitously integrated into clinical workflows; researchapplications including molecular, genetic, and tissue databases; and educational processes.

Materials And Methods: We built a vendor-agnostic, integrated viewer for reviewing, annotating, sharing, and quality assurance of digital slides in a clinical or research context. It is the first homegrown viewer cleared by New York State provisional approval in 2020 for primary diagnosis and remote sign-out during the COVID-19 (coronavirus disease 2019) pandemic. We further introduce an interconnected Honest Broker for BioInformatics Technology (HoBBIT) to systematically compile and share large-scale DP research datasets including anonymized images, redacted pathology reports, and clinical data of patients with consent.

Results: The solution has been operationally used over 3 years by 926 pathologists and researchers evaluating 288 903 digital slides. A total of 51% of these were reviewed within 1 month after scanning. Seamless integration of the viewer into 4 hospital systems clearly increases the adoption of DP. HoBBIT directly impacts the translation of knowledge in pathology into effective new health measures, including artificial intelligence-driven detection models for prostate cancer, basal cell carcinoma, and breast cancer metastases, developed and validated on thousands of cases.

Conclusions: We highlight major challenges and lessons learned when going digital to provide orientation for other pathologists. Building interconnected solutions will not only increase adoption of DP, but also facilitate next-generation computational pathology at scale for enhanced cancer research.
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http://dx.doi.org/10.1093/jamia/ocab085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344580PMC
August 2021

Multidimensional Diffusion Magnetic Resonance Imaging for Characterization of Tissue Microstructure in Breast Cancer Patients: A Prospective Pilot Study.

Cancers (Basel) 2021 Mar 31;13(7). Epub 2021 Mar 31.

Memorial Sloan Kettering Cancer Center, Department of Radiology, Breast Imaging Service, 300 E 66th Street, New York, NY 10065, USA.

Diffusion-weighted imaging is a non-invasive functional imaging modality for breast tumor characterization through apparent diffusion coefficients. Yet, it has so far been unable to intuitively inform on tissue microstructure. In this IRB-approved prospective study, we applied novel multidimensional diffusion (MDD) encoding across 16 patients with suspected breast cancer to evaluate its potential for tissue characterization in the clinical setting. Data acquired via custom MDD sequences was processed using an algorithm estimating non-parametric diffusion tensor distributions. The statistical descriptors of these distributions allow us to quantify tissue composition in terms of metrics informing on cell densities, shapes, and orientations. Additionally, signal fractions from specific cell types, such as elongated cells (bin1), isotropic cells (bin2), and free water (bin3), were teased apart. Histogram analysis in cancers and healthy breast tissue showed that cancers exhibited lower mean values of "size" (1.43 ± 0.54 × 10 mm/s) and higher mean values of "shape" (0.47 ± 0.15) corresponding to bin1, while FGT (fibroglandular breast tissue) presented higher mean values of "size" (2.33 ± 0.22 × 10 mm/s) and lower mean values of "shape" (0.27 ± 0.11) corresponding to bin3 ( < 0.001). Invasive carcinomas showed significant differences in mean signal fractions from bin1 (0.64 ± 0.13 vs. 0.4 ± 0.25) and bin3 (0.18 ± 0.08 vs. 0.42 ± 0.21) compared to ductal carcinomas in situ (DCIS) and invasive carcinomas with associated DCIS ( = 0.03). MDD enabled qualitative and quantitative evaluation of the composition of breast cancers and healthy glands.
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http://dx.doi.org/10.3390/cancers13071606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037718PMC
March 2021

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

NPJ Breast Cancer 2021 Mar 1;7(1):18. Epub 2021 Mar 1.

Departments of Medicine, Weill Cornell Medical College, New York, NY, USA.

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.
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http://dx.doi.org/10.1038/s41523-021-00226-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921427PMC
March 2021

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

Cancer Prev Res (Phila) 2021 May 1;14(5):541-550. Epub 2021 Mar 1.

Department of Medicine, Weill Cornell Medical College, New York, New York.

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 (s < 0.001). Total body fat and trunk fat correlated with B-WATi and breast aromatase levels (s < 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 ( < 0.001). Inverse relationships were observed with exercise (s < 0.05). In a subgroup of 39 women with normal BMI, body fat levels positively correlated with B-WATi and aromatase expression (s < 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.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102399PMC
May 2021

Survival Outcomes for Metaplastic Breast Cancer Differ by Histologic Subtype.

Ann Surg Oncol 2021 Aug 2;28(8):4245-4253. Epub 2021 Jan 2.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Metaplastic breast carcinoma (MBC) is a rare, aggressive subtype of breast cancer associated with poorer overall survival than other triple-negative breast cancers. This study sought to compare survival outcomes among histologic subtypes of MBC with those of non-metaplastic triple-negative breast cancer.

Methods: Clinicopathologic and treatment data for all patients with non-metastatic, pure MBC undergoing surgery from 1995 to 2017 and for a large cohort of patients with other types of triple-negative breast cancer during that period were collected from an institutional database. The MBC tumors were classified as having squamous, spindle, heterologous mesenchymal, or mixed histology. Survival outcomes were compared using the Kaplan-Meier method.

Results: Of 132 MBC patients, those with heterologous mesenchymal MBC (n = 45) had the best 5-year overall and breast cancer-specific survival (BCSS, 88%; 95% confidence interval [CI], 0.78-0.99), whereas those with squamous MBC had the worst survival (BCSS, 56%; 95% CI, 0.32-0.79). Overall survival, BCSS, and recurrence-free survival were worse for the patients with MBC than for the patients who had non-MBC triple-negative breast cancer, with a clinicopathologically adjusted recurrence hazard ratio of 2.4 (95% CI, 1.6-3.3; p < 0.001). Of the 10 MBC patients who received neoadjuvant chemotherapy, 4 progressed while receiving treatment, and 3 had no response.

Conclusions: Metaplastic breast carcinoma is associated with worse survival than other triple-negative breast cancers. The heterologous mesenchymal subtype is associated with the best survival, whereas the squamous subtype is associated with the worst survival. These data call for research to identify therapies tailored to MBC's unique biology.
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http://dx.doi.org/10.1245/s10434-020-09430-5DOI Listing
August 2021

Immunohistochemical analysis of IDH2 R172 hotspot mutations in breast papillary neoplasms: applications in the diagnosis of tall cell carcinoma with reverse polarity.

Mod Pathol 2020 06 2;33(6):1056-1064. Epub 2020 Jan 2.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Tall cell carcinoma with reverse polarity is a rare subtype of breast carcinoma with solid and papillary growth and nuclear features reminiscent of those of the tall cell variant of papillary thyroid carcinoma. These tumors harbor recurrent IDH2 R172 hotspot mutations or TET2 mutations, co-occurring with mutations in PI3K pathway genes. Diagnosis of tall cell carcinomas with reverse polarity is challenging in view of their rarity and the range of differential diagnosis. We sought to determine the sensitivity and specificity of IDH2 R172 immunohistochemistry for the detection of IDH2 R172 hotspot mutations in this entity. We evaluated 14 tall cell carcinomas with reverse polarity (ten excision and five core needle biopsy specimens), 13 intraductal papillomas, 16 solid papillary carcinomas, and 5 encapsulated papillary carcinomas by Sanger sequencing of the IDH2 R172 hotspot locus and of exons 9 and 20 of PIK3CA, and by immunohistochemistry using monoclonal antibodies (11C8B1) to the IDH2 R172S mutation. The 14 tall cell carcinomas with reverse polarity studied harbored IDH2 R172 hotspot mutations, which co-occurred with PIK3CA hotspot mutations in 50% of cases. None of the other papillary neoplasms analyzed displayed IDH2 R172 mutations, however PIK3CA hotspot mutations were detected in 54% of intraductal papillomas, 6% of solid papillary carcinomas, and 20% of encapsulated papillary carcinomas tested. Immunohistochemical analysis with anti-IDH2 R172S antibodies (11C8B1) detected IDH2 R172 mutated protein in 93% (14/15) of tall cell carcinomas with reverse polarity samples including excision (n = 9/10) and core needle biopsy specimens (n = 5), whereas the remaining papillary neoplasms (n = 34) were negative. Our findings demonstrate that immunohistochemical analysis of IDH2 R172 is highly sensitive and specific for the detection of IDH2 R172 hotspot mutations, and likely suitable as a diagnostic tool in the evaluation of excision and core needle biopsy material of tall cell carcinomas with reverse polarity.
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http://dx.doi.org/10.1038/s41379-019-0442-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286791PMC
June 2020

Obesity-Associated Extracellular Matrix Remodeling Promotes a Macrophage Phenotype Similar to Tumor-Associated Macrophages.

Am J Pathol 2019 10 16;189(10):2019-2035. Epub 2019 Jul 16.

Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York; Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, New York. Electronic address:

Obesity is associated with adipose inflammation, defined by macrophages encircling dead adipocytes, as well as extracellular matrix (ECM) remodeling and increased risk of breast cancer. Whether ECM affects macrophage phenotype in obesity is uncertain. A better understanding of this relationship could be strategically important to reduce cancer risk or improve outcomes in the obese. Using clinical samples, computational approaches, and in vitro decellularized ECM models, this study quantified the relative abundance of pro-inflammatory (M1) and anti-inflammatory (M2) macrophages in human breast adipose tissue, determined molecular similarities between obesity and tumor-associated macrophages, and assessed the regulatory effect of obese versus lean ECM on macrophage phenotype. Our results suggest that breast adipose tissue contains more M2- than M1-biased macrophages across all body mass index categories. Obesity further increased M2-biased macrophages but did not affect M1-biased macrophage density. Gene Set Enrichment Analysis suggested that breast tissue macrophages from obese versus lean women are more similar to tumor-associated macrophages. These changes positively correlated with adipose tissue interstitial fibrosis, and in vitro experiments indicated that obese ECM directly stimulates M2-biased macrophage functions. However, mammographic density cannot be used as a clinical indicator of these changes. Collectively, these data suggest that obesity-associated interstitial fibrosis promotes a macrophage phenotype similar to tumor-associated macrophages, which may contribute to the link between obesity and breast cancer.
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http://dx.doi.org/10.1016/j.ajpath.2019.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880774PMC
October 2019

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

Carcinogenesis 2019 07;40(7):914-923

Department of Medicine, Weill Cornell Medicine, New York, NY, USA.

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 17β-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.
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http://dx.doi.org/10.1093/carcin/bgz088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331453PMC
July 2019

Recurrent exon 2 mutations in benign breast fibroepithelial lesions in adolescents and young adults.

J Clin Pathol 2019 Mar 22;72(3):258-262. Epub 2018 Nov 22.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA

Aims: Most benign breast fibroepithelial lesions (FEL) in adults harbour recurrent somatic exon 2 mutations and rare promoter hotspot mutations. We sought to determine the frequency of exon 2 and promoter hotspot mutations in fibroadenomas (FA) and benign phyllodes tumours (BePT) in adolescents and young adults.

Methods: DNA from 21 consecutive FAs and eight consecutive BePTs in adolescents and young adults was subjected to Sanger sequencing of the exon 2 of and the promoter hotspot locus.

Results: We identified exon 2 mutations in 62% and 88% of FAs and BePTs, respectively, and no promoter hotspot mutations. The majority of the exon 2 mutations identified were in-frame deletions (60%).

Conclusions: As in adults, benign FELs in juvenile patients harbour recurrent exon 2 mutations.
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http://dx.doi.org/10.1136/jclinpath-2018-205570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580856PMC
March 2019

Obesity-associated Breast Inflammation among Hispanic/Latina Breast Cancer Patients.

Cancer Prev Res (Phila) 2019 01 7;12(1):21-30. Epub 2018 Nov 7.

Memorial Sloan Kettering Cancer Center, New York, New York.

Breast white adipose tissue inflammation (BWATi) is associated with obesity and higher breast cancer risk among non-Hispanic white women. Obesity is prevalent in Hispanic/Latina patients with breast cancer, and the occurrence of BWATi in this population is not well-characterized. The association between BWATi and body mass index (BMI) was evaluated in Hispanic/Latina patients with breast cancer who underwent mastectomy. BWATi was defined as the presence of crown-like structures of the breast (CLS-B), detected by CD68 IHC in nontumor breast tissue. BWATi severity was quantified as number of CLS-B/cm Adipocyte diameter was measured using hematoxylin and eosin-stained breast tissue sections. Preoperative BMI (within 1 week prior to mastectomy) was categorized as normal (18.5-<25.0 kg/m), overweight (25.0-<30.0 kg/m), class I obesity (30.0-<35.0 kg/m), and class II-III obesity (35.0 kg/m or above). Patient charts were abstracted to record clinicopathologic features and liver function tests <90 days before mastectomy. The study included 91 women (mean age 69 years; range 36-96 years). Prevalence of BWATi increased with BMI (24% in normal weight, 34% in overweight, 57% in class I obesity, and 65% in class II-III obesity; <0.01). Severe BWATi (>0.27 CLS-B/cm) was associated with higher BMI ( = 0.046) and greater adipocyte diameter ( = 0.04). Adjusting for BMI, neoadjuvant chemotherapy, and elevated alanine aminotransferase were associated with severe BWATi, and current smoking was associated with mild BWATi (all < 0.05). BWATi was associated with higher BMI in Hispanic/Latina patients with breast cancer, consistent with previously described associations in other populations.
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http://dx.doi.org/10.1158/1940-6207.CAPR-18-0207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663483PMC
January 2019

Lobular Carcinomas Display Intralesion Genetic Heterogeneity and Clonal Evolution in the Progression to Invasive Lobular Carcinoma.

Clin Cancer Res 2019 01 5;25(2):674-686. Epub 2018 Sep 5.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Lobular carcinoma (LCIS) is a preinvasive lesion of the breast. We sought to define its genomic landscape, whether intralesion genetic heterogeneity is present in LCIS, and the clonal relatedness between LCIS and invasive breast cancers. We reanalyzed whole-exome sequencing (WES) data and performed a targeted amplicon sequencing validation of mutations identified in 43 LCIS and 27 synchronous more clinically advanced lesions from 24 patients [9 ductal carcinomas (DCIS), 13 invasive lobular carcinomas (ILC), and 5 invasive ductal carcinomas (IDC)]. Somatic genetic alterations, mutational signatures, clonal composition, and phylogenetic trees were defined using validated computational methods.

Results: WES of 43 LCIS lesions revealed a genomic profile similar to that previously reported for ILCs, with mutations present in 81% of the lesions. Forty-two percent (18/43) of LCIS were found to be clonally related to synchronous DCIS and/or ILCs, with clonal evolutionary patterns indicative of clonal selection and/or parallel/branched progression. Intralesion genetic heterogeneity was higher among LCIS clonally related to DCIS/ILC than in those nonclonally related to DCIS/ILC. A shift from aging to APOBEC-related mutational processes was observed in the progression from LCIS to DCIS and/or ILC in a subset of cases.

Conclusions: Our findings support the contention that LCIS has a repertoire of somatic genetic alterations similar to that of ILCs, and likely constitutes a nonobligate precursor of breast cancer. Intralesion genetic heterogeneity is observed in LCIS and should be considered in studies aiming to develop biomarkers of progression from LCIS to more advanced lesions.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726436PMC
January 2019

Solid papillary breast carcinomas resembling the tall cell variant of papillary thyroid neoplasms (solid papillary carcinomas with reverse polarity) harbour recurrent mutations affecting IDH2 and PIK3CA: a validation cohort.

Histopathology 2018 Aug 1;73(2):339-344. Epub 2018 Jun 1.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Aims: Solid papillary breast carcinoma resembling the tall cell variant of papillary thyroid neoplasms (BPTC), also known as solid papillary carcinoma with reverse polarity, is a rare histological type of breast cancer that resembles morphologically the tall cell variant of papillary thyroid carcinoma. BPTCs are characterised by IDH2 R172 hotspot somatic mutations or mutually exclusive TET2 somatic mutations, concurrently with mutations affecting PI3K pathway-related genes. We sought to characterise their histology and investigate the frequency of IDH2 and PIK3CA mutations in an independent cohort of BPTCs, as well as in conventional solid papillary carcinomas (SPCs).

Methods And Results: Six BPTCs, not previously analysed molecularly, and 10 SPCs were reviewed centrally. Tumour DNA was extracted from microdissected histological sections and subjected to Sanger sequencing of the IDH2 R172 hotspot locus and exons 9 and 20 of PIK3CA. All six BPTCs were characterised by solid, papillary and follicular architecture with circumscribed, invasive tumour nodules composed of epithelial cells with reverse polarity. IDH2 mutations were identified in all six BPTCs (three R172S, two R172T and one R172G), four of which also harboured PIK3CA mutations (two H1047R, one Q546K and one Q546R). By contrast, all SPCs lacked IDH2 mutations, while one of 10 harboured a PIK3CA mutation (H1047R).

Conclusion: We validated the presence of IDH2 R172 hotspot mutations and PIK3CA hotspot mutations in 100% and 67% BPTCs tested, respectively, and documented absence of IDH2 R172 mutations in SPCs. These findings confirm the genotypical-phenotypical correlation reported previously in BPTC, which constitutes an entity distinct from conventional SPC.
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http://dx.doi.org/10.1111/his.13522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783257PMC
August 2018

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

Cancer Prev Res (Phila) 2018 04 16;11(4):203-214. Epub 2018 Feb 16.

Department of Medicine, Weill Cornell Medical College, New York, New York.

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, IL1β, 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 ( < 0.001) but not placebo. Treatment with DHA did not alter levels of TNFα ( = 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. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-17-0354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290902PMC
April 2018

Effects of Rapid Weight Loss on Systemic and Adipose Tissue Inflammation and Metabolism in Obese Postmenopausal Women.

J Endocr Soc 2017 Jun 25;1(6):625-637. Epub 2017 Apr 25.

Department of Medicine, Weill Cornell Medical College, New York, New York 10065.

Context: Obesity is associated with subclinical white adipose tissue inflammation, as defined by the presence of crown-like structures (CLSs) consisting of dead or dying adipocytes encircled by macrophages. In humans, bariatric surgery-induced weight loss leads to a decrease in CLSs, but the effects of rapid diet-induced weight loss on CLSs and metabolism are unclear.

Objective: To determine the effects of rapid very-low-calorie diet-induced weight loss on CLS density, systemic biomarkers of inflammation, and metabolism in obese postmenopausal women.

Design: Prospective cohort study.

Setting: Rockefeller University Hospital, New York, NY.

Participants: Ten obese, postmenopausal women with a mean age of 60.6 years (standard deviation, ±3.6 years).

Main Outcome Measures: Effects on CLS density and gene expression in abdominal subcutaneous adipose tissue, cardiometabolic risk factors, white blood count, circulating metabolites, and oxidative stress (urinary isoprostane-M) were measured.

Results: Obese subjects lost approximately 10% body weight over a mean of 46 days. CLS density increased in subcutaneous adipose tissue without an associated increase in proinflammatory gene expression. Weight loss was accompanied by decreased fasting blood levels of high-sensitivity C-reactive protein, glucose, lactate, and kynurenine, and increased circulating levels of free fatty acids, glycerol, -hydroxybutyrate, and 25 hydroxyvitamin D. Levels of urinary isoprostane-M declined.

Conclusion: Rapid weight loss stimulated lipolysis and an increase in CLS density in subcutaneous adipose tissue in association with changes in levels of circulating metabolites, and improved systemic biomarkers of inflammation and insulin resistance. The observed change in levels of metabolites (, lactate, -hydroxybutyrate, 25 hydroxyvitamin D) may contribute to the anti-inflammatory effect of rapid weight loss.
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http://dx.doi.org/10.1210/js.2017-00020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686624PMC
June 2017

Pioglitazone Inhibits Periprostatic White Adipose Tissue Inflammation in Obese Mice.

Cancer Prev Res (Phila) 2018 04 8;11(4):215-226. Epub 2017 Dec 8.

Department of Medicine, Weill Cornell Medical College, New York, New York.

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, TGFβ, and the chemokine monocyte chemoattractant protein-1 (MCP-1). Importantly, the ability of pioglitazone to suppress periprostatic WAT inflammation was abrogated in 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. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-17-0296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882568PMC
April 2018

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

Cancer Prev Res (Phila) 2018 04 8;11(4):227-236. Epub 2017 Dec 8.

Department of Medicine, Weill Cornell Medical College, New York, New York.

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 ( = 72), breast WAT inflammation was present in 31 (43%) women and was associated with elevated BMI ( < 0.01) and increased levels of body fat ( < 0.01), C-reactive protein ( = 0.02), triglycerides ( < 0.01), insulin resistance scores ( = 0.04), and lower HDL cholesterol ( < 0.01). ER tumors were associated with greater body fat versus other subtypes ( = 0.03). Compared with U.S. Caucasians ( = 267), Taiwanese women had larger breast adipocytes despite lower BMI after adjusting for BMI and menopausal status ( = 0.01). A subclinical inflammatory state associated with increased adiposity and metabolic dysfunction could contribute to breast cancer pathogenesis in Asian women. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-17-0283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882588PMC
April 2018

Somatic mutations reveal asymmetric cellular dynamics in the early human embryo.

Nature 2017 03 22;543(7647):714-718. Epub 2017 Mar 22.

Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway.

Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.
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http://dx.doi.org/10.1038/nature21703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169740PMC
March 2017

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

J Clin Endocrinol Metab 2017 05;102(5):1692-1701

Department of Medicine, Weill Cornell Medical College, New York, New York 10065.

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.
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http://dx.doi.org/10.1210/jc.2016-3606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443335PMC
May 2017

Fibroepithelial Lesions in the Breast of Adolescent Females: A Clinicopathological Study of 54 Cases.

Breast J 2017 Mar 4;23(2):182-192. Epub 2016 Nov 4.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Fibroepithelial lesions (FELs) are the most frequent breast tumors in adolescent females. The pubertal hormonal surge could impact the growth and microscopic appearance of FELs in this age group. In this study, we evaluate the morphology and clinical behavior of FELs in adolescents. We searched the 1992-2012 pathology data base for FELs in females 18 years old or younger (F ≤18 years). Seven FELs from 1975 to 1983 were also included. Three pathologists reviewed all available material. Patient (pt) characteristics and follow-up information were obtained from electronic medical records. Forty-eight F ≤18 years had 54 FELs with available slides. Thirty (67%) pts were Caucasian, 12 (27%) African-American, two (4%) Hispanic, one (2%) Asian; three were of unknown race/ethnicity. Median age at diagnosis was 16 years. Median age at menarche was 12 years; most (96%) FELs occurred after menarche (median interval 48 months). All patients underwent lumpectomy; one required subsequent mastectomy. The FELs were 34 fibroadenomas (FAs) (11 usual, 23 juvenile), and 20 phyllodes tumors (PTs) (16 benign, one borderline and three malignant). Eight (35%) juvenile FAs showed slight intratumoral heterogeneity. The mean mitotic rate was 1.3 mitoses/10 high-power fields (HPFs) (range, 0-6) in usual FAs, 1.8/10 HPFs in juvenile FAs, 3.1/10 HPFs in benign PTs, 10/10 HPFs in the borderline PT and 17/10 HPFs in malignant PTs. The mean follow-up for 29 pts with 33 FELs was 44 months. Two (10%) PTs recurred locally (a benign PT at 18 months, and a borderline PT at 11 months). Both recurrent PTs had microscopic margins <1 mm. Mitotic activity in FAs from adolescents can be substantial and this finding should be interpreted cautiously. Awareness of the morphologic features of FELs in adolescents is important to avoid overdiagnosis of PTs, which can lead to additional unnecessary and potentially disfiguring surgery.
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http://dx.doi.org/10.1111/tbj.12706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356480PMC
March 2017

Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer.

J Pathol 2017 06 27;242(2):165-177. Epub 2017 Apr 27.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Homologous recombination (HR) DNA repair-deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51-based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression, and whole-exome sequencing was employed to ascertain the aetiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large-scale state transitions and specific mutational signatures. Somatic and/or germline genetic alterations resulting in bi-allelic loss-of-function of HR genes underpinned functional HRD in 89% of cases, and were observed in only one of the 15 HR-proficient samples tested. These findings indicate the importance of a comprehensive genetic assessment of bi-allelic alterations in the HR pathway to deliver a precision medicine-based approach to select patients for therapies targeting tumour-specific DNA repair defects. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516531PMC
June 2017

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

Cancer Prev Res (Phila) 2017 Apr 7;10(4):235-243. Epub 2017 Mar 7.

Department of Medicine, Weill Cornell Medical College, New York, New York.

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/m) 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/cm 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/m (range, 18.4-24.9 kg/m) in women with breast WAT inflammation versus 21.8 kg/m (range, 17.3-24.6 kg/m) in those without inflammation ( = 0.04). Breast WAT inflammation was associated with elevated aromatase expression and activity, which increased with severity of inflammation ( < 0.05). Breast WAT inflammation correlated with larger adipocytes ( = 0.01) and higher circulating levels of C-reactive protein, leptin, insulin, and triglycerides ( ≤ 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. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-16-0314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380584PMC
April 2017

Docosahexaenoic Acid Supplementation is Not Anti-Inflammatory in Adipose Tissue of Healthy Obese Postmenopausal Women.

Int J Nutr 2017 21;1(4):31-49. Epub 2017 Jul 21.

The Rockefeller University.

Adipose tissue inflammation is associated with obesity comorbidities. Reducing such inflammation may ameliorate these comorbidities. n-3 fatty acids have been reported to have anti-inflammatory properties in obesity, which may modulate this inflammatory state. In the current study a 1 gram per day oral supplement of the n-3 fatty acid docosahexaenoic acid (DHA) was administered for 12 weeks to 10 grade 1-2 obese postmenopausal women and markers of adipose tissue and systemic inflammation measured and compared before and after supplementation. DHA administration resulted in approximately a doubling of plasma and red cell phospholipid and adipose tissue DHA content but no change in systemic markers of inflammation, such as circulating C-reactive protein (CRP) or interleukins (IL) 6, 8 and 10 (IL-6, IL-8, IL-10). DHA supplementation did not alter the adipose tissue marker of inflammation crown-like structure density nor did it affect any gene expression pathways, including anti-inflammatory, hypoxic and lipid metabolism pathways. The obese postmenopausal women studied were otherwise healthy, which leads us to suggest that in such women DHA supplementation is not an effective means for reducing adipose tissue or systemic inflammation. Further testing is warranted to determine if n-3 fatty acids may ameliorate inflammation in other, perhaps less healthy, populations of obese individuals.
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http://dx.doi.org/10.14302/issn.2379-7835.ijn-17-1636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909688PMC
July 2017

Quantitative apparent diffusion coefficient measurement obtained by 3.0Tesla MRI as a potential noninvasive marker of tumor aggressiveness in breast cancer.

Eur J Radiol 2016 Sep 28;85(9):1651-8. Epub 2016 Jun 28.

Department of Radiology, Memorial Sloan-Kettering Cancer Center, 300 East, 66th street, NY 10065, USA; Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NY 10065, USA. Electronic address:

Purpose: To assess the association between apparent diffusion coefficient (ADC), and histological prognostic parameters in malignant breast lesions. The ability of ADC to identify lesions with the presence of Lymphovascular invasion (LVI) in breast carcinoma was also examined.

Materials And Methods: This HIPAA-compliant retrospective study consisted of 212 consecutive patients with known cancers who underwent 3.0T MRI between January 2011 and 2013. In this study, a total of 126 malignant lesions in 114 women, who had undergone DWI (b-values of 0 and 1000s/mm(2)) in addition to diagnostic MRI, were included. Patients with less than 0.8cm lesions, or those who underwent neoadjuvant chemotherapy or suboptimal DW images were excluded. Classical prognostic factors [lesion size, histopathological type and grade, lymph node (LN) status and lymphovascular invasion (LVI)], molecular prognostic markers [estrogen receptor (ER), progesterone receptor (PR) and human epidermal grow factor receptor 2 (HER2)] were reviewed and recorded. A region of interest (ROI) was drawn within the lesions to measure ADC values. Statistical analyses were performed by the Wilcoxon rank sum test (statistical significance at P<0.05). Adjusted p values from multiple comparison analysis were also calculated.

Results: This study demonstrates an inverse correlation between ADC and LVI in malignant lesions and the ability of ADC to identify aggressiveness in lesions with positive LVI. Tumor size, grade, ER, PR, HER2 and lymph node status did not impact tumor ADC value. However, tumors with LVI showed significantly lower ADC values when compared to tumors without LVI, regardless of the enhancement type, histological grade, histological type, and LN status.

Conclusion: Our study shows that ADC could be a potential clinical adjunct in the evaluation of prognostic factors related to malignant lesion aggressiveness such as LVI.
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http://dx.doi.org/10.1016/j.ejrad.2016.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505563PMC
September 2016

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

Clin Cancer Res 2016 05 28;22(9):2283-9. Epub 2015 Dec 28.

Department of Medicine, Weill Cornell Medical College, New York, New York.

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.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854755PMC
May 2016

Case report of malignant pulmonary parenchymal glomus tumor: imaging features and review of the literature.

Clin Imaging 2016 Jan-Feb;40(1):144-7. Epub 2015 Sep 30.

Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Electronic address:

Glomus tumor is rare tumor which arises from glomus body and is most frequently found in the soft tissue of the extremities. The lung is a rare ectopic site, and a malignant glomus tumor arising from pulmonary parenchyma is particularly uncommon. To deepen our understanding on their imaging features, we report a case of malignant glomus tumor of pulmonary parenchyma confirmed with surgical histopathology and immunochemistry and review the medical literature on pulmonary parenchymal glomus tumors with emphasis on their imaging features.
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http://dx.doi.org/10.1016/j.clinimag.2015.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688063PMC
August 2016

Intravoxel incoherent motion diffusion-weighted MRI at 3.0 T differentiates malignant breast lesions from benign lesions and breast parenchyma.

J Magn Reson Imaging 2014 Oct 22;40(4):813-23. Epub 2013 Nov 22.

Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Purpose: To study the differentiation of malignant breast lesions from benign lesions and fibroglandular tissue (FGT) using apparent diffusion coefficient (ADC) and intravoxel incoherent motion (IVIM) parameters.

Materials And Methods: This retrospective study included 26 malignant and 14 benign breast lesions in 35 patients who underwent diffusion-weighted MRI at 3.0T and nine b-values (0-1000 s/mm(2) ). ADC and IVIM parameters (perfusion fraction fp , pseudodiffusion coefficient Dp , and true diffusion coefficient Dd ) were determined in lesions and FGT. For comparison, IVIM was also measured in 16 high-risk normal patients. A predictive model was constructed using linear discriminant analysis. Lesion discrimination based on ADC and IVIM parameters was assessed using receiver operating characteristic (ROC) and area under the ROC curve (AUC).

Results: In FGT of normal subjects, fp was 1.1 ± 1.1%. In malignant lesions, fp (6.4 ± 3.1%) was significantly higher than in benign lesions (3.1 ± 3.3%, P = 0.0025) or FGT (1.5 ± 1.2%, P < 0.001), and Dd ((1.29 ± 0.28) × 10(-3) mm(2) /s) was lower than in benign lesions ((1.56 ± 0.28) × 10(-3) mm(2) /s, P = 0.011) or FGT ((1.86 ± 0.34) × 10(-3) mm(2) /s, P < 0.001). A combination of Dd and fp provided higher AUC for discrimination between malignant and benign lesions (0.84) or FGT (0.97) than ADC (0.72 and 0.86, respectively).

Conclusion: The IVIM parameters provide accurate identification of malignant lesions.
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http://dx.doi.org/10.1002/jmri.24462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786009PMC
October 2014

Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer.

Clin Cancer Res 2013 Oct 21;19(19):5505-12. Epub 2013 Aug 21.

Authors' Affiliations: Breast Cancer Medicine Service, Departments of Pathology, Biostatistics, and Radiology, Memorial Sloan-Kettering Cancer Center; Weill Medical College of Cornell University, New York; Dana-Farber Cancer Institute; Massachusetts General Hospital, Boston, Massachusetts; Mayo Clinic, Rochester, Minnesota; Georgetown Lombardi Comprehensive Cancer Center, Washington, District of Columbia; University of North Carolina at Chapel Hill, Chapel Hill; Duke University Medical Center, Durham, North Carolina; University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California; University of Alabama at Birmingham, Birmingham, Alabama; and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland.

Purpose: Patients with hormone receptor-negative breast cancer generally do not benefit from endocrine-targeted therapies. However, a subset with androgen receptor (AR) expression is predicted to respond to antiandrogen therapies. This phase II study explored bicalutamide in AR-positive, estrogen receptor (ER), and progesterone receptor (PgR)-negative metastatic breast cancer.

Experimental Design: Tumors from patients with ER/PgR-negative advanced breast cancer were tested centrally for AR [immunohistochemistry (IHC) > 10% nuclear staining considered positive]. If either the primary or a metastatic site was positive, patients were eligible to receive the AR antagonist bicalutamide at a dose of 150 mg daily. Clinical benefit rate (CBR), the primary endpoint, was defined as the total number of patients who show a complete response (CR), partial response (PR), or stable disease (SD) > 6 months; secondary endpoints included progression-free survival (PFS) and toxicity. Correlative studies included measurement of circulating endocrine markers and IHC surrogates for basal-like breast cancer.

Results: Of 424 patients with ER/PgR-negative breast cancer, 12% tested AR-positive. The 6-month CBR was 19% [95% confidence interval (CI), 7%-39%] for bicalutamide. The median PFS was 12 weeks (95% CI, 11-22 weeks). Bicalutamide was well-tolerated with no grade 4/5 treatment-related adverse events observed.

Conclusion: AR was expressed in 12% of patients with ER/PgR-negative breast cancer screened for this trial. The CBR of 19% observed with bicalutamide shows proof of principle for the efficacy of minimally toxic androgen blockade in a select group of patients with ER/PgR-negative, AR-positive breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-3327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086643PMC
October 2013

Expression of androgen receptor and its phosphorylated forms in breast cancer progression.

Cancer 2013 Jul 19;119(14):2532-40. Epub 2013 Apr 19.

Department of Urology, New York University School of Medicine, New York, NY.

Background: Androgen receptor (AR) expression in breast cancers may serve as a prognostic and predictive marker. We examined the expression pattern of AR and its phosphorylated forms, Ser-213 (AR-Ser[P]-213) and Ser-650 (AR-Ser[P]-650), in breast cancer and evaluated their association with clinicopathological parameters.

Methods: Immunohistochemistry was performed on primary and distant metastatic breast cancers and benign breast tissue using antibodies against AR, AR-Ser(P)-213, and AR-Ser(P)-650. The levels of cytoplasmic and nuclear expression were scored semiquantitatively using a histoscore.

Results: Nuclear staining of AR was observed in all benign breast tissue and 67% of cancer cases. Nuclear and cytoplasmic AR-Ser(P)-213 was increased in breast cancers 2-fold (P = .0014) and 1.7-fold (P = .05), respectively, compared with benign controls, whereas nuclear and cytoplasmic AR-Ser(P)-650 expression was decreased in tumors by 1.9-fold and 1.7-fold (both P < .0001), respectively. Increased expression of nuclear or cytoplasmic AR-Ser(P)-213 was observed in metastatic breast cancers (1.3-fold, P = .05), ER-negative (2.6-fold, P = .001), and invasive ductal carcinoma (6.8-fold, P = .04). AR-Ser(P)-650 expression was downregulated in lymph node-positive breast cancers (1.4-fold, P = .02) but was upregulated in invasive ductal carcinomas (3.2-fold, P < .0001) and metastases (1.5-fold, P = .003). Moreover, in ER-negative breast cancers, nuclear AR-Ser(P)-650 was decreased (1.4-fold, P = .005), and cytoplasmic AR-Ser(P)-650 was increased (1.4-fold, P = .003).

Conclusions: AR and its phosphorylation at serines 213 and 650 are differentially expressed in breast cancer tumorigenesis and progression. Phosphorylation of AR at serines 213 and 650 is increased in ER-negative breast cancers, ductal carcinomas, and metastases and may have predictive value in breast cancer prognosis.
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http://dx.doi.org/10.1002/cncr.28092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3874891PMC
July 2013
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