Breast Density Lacks Influence on Upgrade Rates to High Risk Lesions and Cancer Among Proliferative Breast Lesion Excisions.

INTRODUCTION: Breast density is an independent risk factor for the development of breast cancer. We assessed if upgrade rates to high-risk lesions and cancer were influenced by density when evaluating proliferative complex sclerosing lesions and intraductal papillomas. METHODS: This is a retrospective single institution study. We evaluated 168 women aged 18-86 who received a core needle biopsy revealing a breast proliferative lesion of complex sclerosing lesion (CSL) or intraductal papilloma. We analyzed the upgrade rate to high-risk atypia (HRL) and cancer. Subgroup analysis based on age and breast density was performed. RESULTS: The patient collective was well balanced-51% had dense breasts and 42% were under 50 years old. Half were diagnosed with papilloma based on CNB and the other half with CSL. For those proliferative lesions without atypia, the upgrade rate to cancer was 1.6%. CNB showed concomitant HRL in 23% of patients with non-dense breasts and in 22% with dense tissue. In 24 cases, the pathology was considered an upgrade by showing either a not prior noted HRL or carcinoma. Most patients with upgrade following surgical excision were over 50 years old. Dense breasts did not show a higher risk of upgrade following surgical excision (P = .975). CONCLUSION: Our data did not reveal a difference between upgrade rates of proliferative lesions excised in dense and non-dense breasts. Further evaluation is warranted to establish whether density should be considered as a meaningful factor in excision vs observation of CSL and papillomas.

Magnetic Seeds: An Alternative to Wire Localization for Nonpalpable Breast Lesions.

INTRODUCTION: Magnetic seeds have emerged as an alternative to wires for localization of nonpalpable breast lesions. The purpose of this study was to evaluate the utility of magnetic seeds compared to wires for preoperative localization. MATERIALS AND METHODS: A retrospective cohort analysis of magnetic seed localization (MSL) and wire localization (WL) excisional biopsies and lumpectomies performed at a single institution was conducted. Indication, age, BMI, number of markers, procedure type, operative time, and postoperative opioid administration were reviewed. Impact of localization method on operative time, specimen volume, postoperative opioid administration, and re-excision rate were assessed. RESULTS: A total of 608 MSL procedures in 601 patients were compared to 628 WL procedures in 620 patients. MSL excisional biopsies were significantly longer (37.0 minutes) than WL excisional biopsies (31.9 minutes, P< .001), but in lumpectomies without axillary surgery, MSL procedures (42.3 minutes) were significantly shorter than WL procedures (46.9 minutes, P = .017). Significantly less tissue was excised during MSL lumpectomies (68.5 cm3) and excisional biopsies (32.3 cm3) than WL lumpectomies (78.1 cm3, P = .039) and excisional biopsies (38.7 cm3, P = .018). Postoperative opioid administration was similar for MSL and WL procedures (P = .076). Re-excision rates for MSL lumpectomies were significantly higher for ductal carcinoma in situ (35.3% MSL vs. 18.5% WL, P = .013), but were similar for invasive carcinoma (14.4% MSL vs. 17.7% WL, P = .290). Logistic regression analysis showed no association between localization method and re-excision (OR 1.007, 95% CI 0.681-1.488; P = .973). CONCLUSION: MSL is a feasible alternative to WL for excision of nonpalpable breast lesions with regard to surgical outcomes.

Benefit of regional anaesthesia on postoperative pain following mastectomy: the influence of catastrophising.

BACKGROUND: Previous studies suggest that truncal regional anaesthesia (TRA), including techniques such as paravertebral block, may contribute significantly to analgesia after mastectomy. However, the severity and impact of postoperative pain varies markedly amongst individuals, making the identification of patients who would benefit most from TRA a potentially important step toward personalised perioperative care. METHODS: In this prospective observational study, mastectomy patients (n=122) were recruited and systematically assessed for psychosocial characteristics including pain catastrophising before surgery, and either received preoperative TRA (n=57) or no block (n=65). RESULTS: Age, baseline pain, and psychosocial traits did not differ between these groups. TRA was associated with lower overall pain scores and opioid consumption perioperatively, with a larger proportion of patients without block (50% vs 28%) reporting moderate-severe pain (more than three/10) on the day of surgery. Mixed model analysis of variance revealed a significant interaction between catastrophising and TRA, such that amongst patients with high baseline catastrophising, TRA was associated with substantially lower pain severity score (58% lower), while amongst patients with low baseline catastrophising, TRA was associated with only 18% lower pain severity. At 2 weeks, this interaction between baseline catastrophising and TRA was also observed when examining surgical pain burden, with higher baseline catastrophising patients who had received TRA reporting lower pain and less frequent opioid use (40% vs 70% of patients). CONCLUSIONS: TRA provided immediate analgesic benefit for patients undergoing mastectomy on the day of surgery, but this effect appeared more pronounced and sustained amongst patients with higher baseline catastrophising. CLINICAL TRIAL REGISTRATION: NCT02329574.

Radiofrequency identification tag localization is comparable to wire localization for non-palpable breast lesions.

PURPOSE: Radiofrequency identification (RFID) tag localization (TL) is a technique of localizing non-palpable breast lesions that can be performed prior to surgery. We sought to evaluate whether TL is comparable to wire localization (WL) in regard to specimen size, operative time, and re-excision rate. METHODS: A retrospective cohort analysis was performed on TL and WL excisional biopsies and lumpectomies performed by 5 surgeons at 2 institutions. Cases were stratified by surgery type and surgical indication. Associations between localization technique and specimen volume, operative time, and re-excision rate were assessed by univariate and multivariate analyses. RESULTS: A total of 503 procedures were included, 147 TL (29.2%) and 356 WL (70.8%). Nineteen (12.9%) RFID tags were placed before surgery, ranging 1-22 days. All intended targets were removed. TL and WL excisional biopsy and lumpectomy specimen volumes were similar (p = 0.560 and 0.494). TL and WL excisional biopsy and lumpectomy + SLNB operative times were similar (p = 0.152 and 0.158), but TL lumpectomies without SLNB took longer than WL (57 min vs 49 min; p = 0.027). Re-excision rates were similar by surgical procedure (p = 0.615), surgical indication (DCIS p = 0.145; invasive carcinoma p = 0.759), and confirmed by multivariable analysis (OR 0.754, 95% CI 0.392-1.450; p = 0.397). CONCLUSIONS: TL has similar surgical outcomes to WL with added benefit that TL can occur prior to the day of surgery. TL is an acceptable alternative to WL and should be considered for non-palpable breast lesions.

Preoperative Psychosocial and Psychophysical Phenotypes as Predictors of Acute Pain Outcomes After Breast Surgery.

The severity and impact of acute pain after breast surgery varies markedly among individuals, underlining the importance of comprehensively identifying specific risk factors, including psychosocial and psychophysical traits. In this prospective observational study, women (n = 234) undergoing breast-conserving surgery, mastectomy, or mastectomy with reconstruction completed a brief bedside quantitative sensory testing battery, along with measures of psychosocial characteristics. Postoperative pain severity, impact, and opioid use at 2 weeks were assessed using Brief Pain Inventory and procedure-specific breast cancer pain questionnaires. Moderate-severe average pain (>3/10) was reported by 29% of patients at 2 weeks. Regression analysis of pain outcomes revealed that pain severity was independently predicted by axillary dissection, pre-surgical pain, temporal summation of pain (TSP), (-)positive affect, and behavioral coping style. Pain impact was predicted by age, education, axillary dissection, reconstruction, but also by negative affect and depression scores. Lastly, opioid use was predicted by age, education, axillary dissection, reconstruction, TSP, and reinterpreting coping style. Our findings suggest that, individuals with certain phenotypic characteristics, including high TSP and negative affect, may be at greater risk of significant pain and continued opioid use at 2 weeks after surgery, independent of known surgical risk factors. PERSPECTIVE: We measured differences in the psychosocial and psychophysical processing of pain amongst patients before breast surgery using simple validated questionnaires and brief quantitative sensory testing. Independent of younger age and procedural extent (axillary surgery and reconstruction), affect and greater temporal summation of pain predicted acute postoperative pain and opioid use.

Chronic Pain After Breast Surgery: A Prospective, Observational Study.

BACKGROUND: Chronic pain is an important complication of breast surgery, estimated to affect 20-30% of patients. We prospectively examined surgical, demographic, and psychosocial factors associated with chronic pain 6 months after breast surgery. METHODS: Patients undergoing breast surgery for benign and malignant disease preoperatively completed validated questionnaires to assess baseline pain and psychosocial characteristics. Pain at 6 months was quantified as the Pain Burden Index (PBI), which encompasses pain locations, severity, and frequency. Surgical type was categorized as breast-conserving surgery (BCS), mastectomy, and mastectomy with reconstruction; axillary procedure was categorized as no axillary surgery, sentinel lymph node biopsy (SLNB), and axillary dissection. PBI was compared between groups using one-way analysis of variance (ANOVA) or Kruskal-Wallis ANOVA, and the relationship between baseline demographic and psychosocial factors and PBI was assessed using Spearman's Rank Correlation. p < 0.05 was considered significant. RESULTS: PBI was variable amongst patients reporting this endpoint (n = 216) at 6 months, but no difference was found between primary breast surgical types (BCS, mastectomy, and mastectomy with reconstruction) or with surgical duration. However, axillary dissection was associated with higher PBI than SLNB and no axillary procedure (p < 0.001). Younger age (< 0.001) and higher BMI (p = 0.010), as well as higher preoperative anxiety (p = 0.017), depression (p < 0.001), and catastrophizing scores (p = 0.005) correlated with higher 6-month PBI. CONCLUSIONS: Amongst surgical variables, only axillary dissection was associated with greater pain at 6 months after surgery. Patient characteristics that were associated with higher PBI included lower age and higher BMI, as well as higher baseline anxiety, depression, and catastrophizing.

Breast Imaging Second Opinions Impact Surgical Management.

BACKGROUND: Breast surgeons often see women for second opinions for abnormalities found on breast imaging. For second opinions, these images are submitted for review and interpretation by dedicated breast imagers. This study evaluated the conformity of results among interpretation of imaging submitted from outside hospitals both from tertiary care centers, as well as community programs, in an attempt to evaluate the utility of this practice for the sake of clinical management and resource utilization. METHODS: A retrospective chart review was conducted on all breast patients that submitted outside imaging films for the years 2011 to 2013 at Rush University Medical Center (RUMC). The radiologic diagnosis and each patient's proposed management plan was collected and evaluated for concordance between the outside institutions and RUMC. RESULTS: A total of 380 patients who presented for second opinions with an interpretation of outside exams were evaluated. In 47.4 % [95 % confidence interval (CI) 42.4-52.4] of cases there was distinct variance in radiologic impression. For 53.5 % (95 % CI 48.4-58.5) of patients, there was a change in recommended management plan, which included recommendations for either additional imaging or need for additional biopsy. In total, this changed the overall surgical management in 27.1 % (95 % CI 22.8-31.9) of cases. In six patients, the reinterpretation of outside imaging detected new malignancies not previously identified. Overall, 83.7 % (95 % CI 79.7-87.1) of patients who submitted imaging from outside institutions chose to complete the remainder of their treatment at RUMC. CONCLUSIONS: The practice of second opinion review changed overall definitive management at our specialty center in more than one in four cases. In addition, the review identified six previously unrecognized malignancies. Given this data, the practice of second opinions and interpretation of outside exams should continue despite the additional resources required.

Melanoma NOS1 expression promotes dysfunctional IFN signaling.

In multiple forms of cancer, constitutive activation of type I IFN signaling is a critical consequence of immune surveillance against cancer; however, PBMCs isolated from cancer patients exhibit depressed STAT1 phosphorylation in response to IFN-α, suggesting IFN signaling dysfunction. Here, we demonstrated in a coculture system that melanoma cells differentially impairs the IFN-α response in PBMCs and that the inhibitory potential of a particular melanoma cell correlates with NOS1 expression. Comparison of gene transcription and array comparative genomic hybridization (aCGH) between melanoma cells from different patients indicated that suppression of IFN-α signaling correlates with an amplification of the NOS1 locus within segment 12q22-24. Evaluation of NOS1 levels in melanomas and IFN responsiveness of purified PBMCs from patients indicated a negative correlation between NOS1 expression in melanomas and the responsiveness of PBMCs to IFN-α. Furthermore, in an explorative study, NOS1 expression in melanoma metastases was negatively associated with patient response to adoptive T cell therapy. This study provides a link between cancer cell phenotype and IFN signal dysfunction in circulating immune cells.

Longitudinal study of recurrent metastatic melanoma cell lines underscores the individuality of cancer biology.

Recurrent metastatic melanoma provides a unique opportunity to analyze disease evolution in metastatic cancer. Here, we followed up eight patients with an unusually prolonged history of metastatic melanoma, who developed a total of 26 recurrences over several years. Cell lines derived from each metastasis were analyzed by comparative genomic hybridization and global transcript analysis. We observed that conserved, patient-specific characteristics remain stable in recurrent metastatic melanoma even after years and several recurrences. Differences among individual patients exceeded within-patient lesion variability, both at the DNA copy number (P<0.001) and RNA gene expression level (P<0.001). Conserved patient-specific traits included expression of several cancer/testis antigens and the c-kit proto-oncogene throughout multiple recurrences. Interestingly, subsequent recurrences of different patients did not display consistent or convergent changes toward a more aggressive disease phenotype. Finally, sequential recurrences of the same patient did not descend progressively from each other, as irreversible mutations such as homozygous deletions were frequently not inherited from previous metastases. This study suggests that the late evolution of metastatic melanoma, which markedly turns an indolent disease into a lethal phase, is prone to preserve case-specific traits over multiple recurrences and occurs through a series of random events that do not follow a consistent stepwise process.

The stable traits of melanoma genetics: an alternate approach to target discovery.

BACKGROUND: The weight that gene copy number plays in transcription remains controversial; although in specific cases gene expression correlates with copy number, the relationship cannot be inferred at the global level. We hypothesized that genes steadily expressed by 15 melanoma cell lines (CMs) and their parental tissues (TMs) should be critical for oncogenesis and their expression most frequently influenced by their respective copy number. RESULTS: Functional interpretation of 3,030 transcripts concordantly expressed (Pearson's correlation coefficient p-value < 0.05) by CMs and TMs confirmed an enrichment of functions crucial to oncogenesis. Among them, 968 were expressed according to the transcriptional efficiency predicted by copy number analysis (Pearson's correlation coefficient p-value < 0.05). We named these genes, "genomic delegates" as they represent at the transcriptional level the genetic footprint of individual cancers. We then tested whether the genes could categorize 112 melanoma metastases. Two divergent phenotypes were observed: one with prevalent expression of cancer testis antigens, enhanced cyclin activity, WNT signaling, and a Th17 immune phenotype (Class A). This phenotype expressed, therefore, transcripts previously associated to more aggressive cancer. The second class (B) prevalently expressed genes associated with melanoma signaling including MITF, melanoma differentiation antigens, and displayed a Th1 immune phenotype associated with better prognosis and likelihood to respond to immunotherapy. An intermediate third class (C) was further identified. The three phenotypes were confirmed by unsupervised principal component analysis. CONCLUSIONS: This study suggests that clinically relevant phenotypes of melanoma can be retraced to stable oncogenic properties of cancer cells linked to their genetic back bone, and offers a roadmap for uncovering novel targets for tailored anti-cancer therapy.

Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis.

In humans, the role and relationship between molecular pathways that lead to tissue destruction during acute allograft rejection are not fully understood. Based on studies conducted in humans, we recently hypothesized that different immune-mediated tissue destruction processes (i.e. cancer, infection, autoimmunity) share common convergent final mechanisms. We called this phenomenon the "Immunologic Constant of Rejection (ICR)." The elements of the ICR include molecular pathways that are consistently described through different immune-mediated tissue destruction processes and demonstrate the activation of interferon-stimulated genes (ISGs), the recruitment of cytotoxic immune cells (primarily through CXCR3/CCR5 ligand pathways), and the activation of immune effector function genes (IEF genes; granzymes A/B, perforin, etc.). Here, we challenge the ICR hypothesis by using a meta-analytical approach and systematically reviewing microarray studies evaluating gene expression on tissue biopsies during acute allograft rejection. We found the pillars of the ICR consistently present among the studies reviewed, despite implicit heterogeneity. Additionally, we provide a descriptive mechanistic overview of acute allograft rejection by describing those molecular pathways most frequently encountered and thereby thought to be most significant. The biological role of the following molecular pathways is described: IFN-γ, CXCR3/CCR5 ligand, IEF genes, TNF-α, IL-10, IRF-1/STAT-1, and complement pathways. The role of NK cell, B cell and T-regulatory cell signatures are also addressed.

An immunologic portrait of cancer.

The advent of high-throughput technology challenges the traditional histopathological classification of cancer, and proposes new taxonomies derived from global transcriptional patterns. Although most of these molecular re-classifications did not endure the test of time, they provided bulk of new information that can reframe our understanding of human cancer biology. Here, we focus on an immunologic interpretation of cancer that segregates oncogenic processes independent from their tissue derivation into at least two categories of which one bears the footprints of immune activation. Several observations describe a cancer phenotype where the expression of interferon stimulated genes and immune effector mechanisms reflect patterns commonly observed during the inflammatory response against pathogens, which leads to elimination of infected cells. As these signatures are observed in growing cancers, they are not sufficient to entirely clear the organism of neoplastic cells but they sustain, as in chronic infections, a self-perpetuating inflammatory process. Yet, several studies determined an association between this inflammatory status and a favorable natural history of the disease or a better responsiveness to cancer immune therapy. Moreover, these signatures overlap with those observed during immune-mediated cancer rejection and, more broadly, immune-mediated tissue-specific destruction in other immune pathologies. Thus, a discussion concerning this cancer phenotype is warranted as it remains unknown why it occurs in immune competent hosts. It also remains uncertain whether a genetically determined response of the host to its own cancer, the genetic makeup of the neoplastic process or a combination of both drives the inflammatory process. Here we reflect on commonalities and discrepancies among studies and on the genetic or somatic conditions that may cause this schism in cancer behavior.

Genomic scale analysis of racial impact on response to IFN-alpha.

Limited responsiveness to IFN-alpha in hepatitis C virus (HCV)-infected African-Americans compared to European Americans (AAs vs. EAs) hinders the management of HCV. Here, we studied healthy non-HCV-infected AA and EA subjects to test whether immune cell response to IFN-alpha is determined directly by race. We compared baseline and IFN-alpha-induced signal transducer and activator of transcription (STAT)-1, STAT-2, STAT-3, STAT-4, and STAT-5 protein and phosphorylation levels in purified T cells, global transcription, and a genomewide single-nucleotide polymorphism (SNP) profile of healthy AA and EA blood donors. In contrast to HCV-infected individuals, healthy AAs displayed no evidence of reduced STAT activation or IFN-alpha-stimulated gene expression compared to EAs. Although >200 genes reacted to IFN-alpha treatment, race had no impact on any of them. The only gene differentially expressed by the two races (NUDT3, P < 10(-7)) was not affected by IFN-alpha and bears no known relationship to IFN-alpha signaling or HCV pathogenesis. Genomewide analysis confirmed the self-proclaimed racial attribution of most donors, and numerous race-associated SNPs were identified within loci involved in IFN-alpha signaling, although they clearly did not affect responsiveness in the absence of HCV. We conclude that racial differences observed in HCV-infected patients in the responsiveness to IFN-alpha are unrelated to inherent racial differences in IFN-alpha signaling and more likely due to polymorphisms affecting the hosts' response to HCV, which in turn may lead to a distinct disease pathophysiology responsible for altered IFN signaling and treatment response.