The epichaperome is an integrated chaperome network that facilitates tumour survival.

Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes-dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically 'rewired' to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.

Pathophysiology of SARS-CoV-2: the Mount Sinai COVID-19 autopsy experience.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe and disproportionately affected New York City between March and May 2020. Here, we report on the first 100 COVID-19-positive autopsies performed at the Mount Sinai Hospital in New York City. Autopsies revealed large pulmonary emboli in six cases. Diffuse alveolar damage was present in over 90% of cases. We also report microthrombi in multiple organ systems including the brain, as well as hemophagocytosis. We additionally provide electron microscopic evidence of the presence of the virus in our samples. Laboratory results of our COVID-19 cohort disclose elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8, and TNFα. Our autopsy series of COVID-19-positive patients reveals that this disease, often conceptualized as a primarily respiratory viral illness, has widespread effects in the body including hypercoagulability, a hyperinflammatory state, and endothelial dysfunction. Targeting of these multisystemic pathways could lead to new treatment avenues as well as combination therapies against SARS-CoV-2 infection.

Response in breast vs axilla after neoadjuvant treatment and implications for nonoperative management of invasive breast cancer.

Improved imaging and neoadjuvant chemotherapy (NAT) have led to higher pathologic complete response rates (pCR) in patients with invasive breast cancer. This has questioned the necessity of surgery and axillary lymph node (ALN) dissection in these patients. Prospective clinical trials are implementing extensive core biopsies of the tumor bed of patients with clinical complete response as a means to identify and spare them breast surgery. In addition, it is anticipated that patients with pCR are most likely going to have no or minimal disease in ALN as well. To verify the feasibility of these trials, we performed a pathologic analysis of all our patients who have undergone NAT from 2009 to present. Using pathology data base, we identified 362 patients treated with neoadjuvant chemotherapy followed by surgery. Clinical and pathologic information including gross and microscopic descriptions as well as biomarker status was collected. pCR was 50% for patients with negative ALN pretreatment but only 28% for patients with positive ALN at diagnosis. Despite achieving pCR in the breast, up to 10% of patients with positive ALN and 1% with negative ALN had persistent disease. Eight percent of patients that were presumed to have no ALN disease either clinically and or by imaging were found to have metastatic carcinoma in ALN. The metastases were predominantly (80%) <5 mm, and not palpable on physical examination and or due to biopsy sampling error. pCR in breast and ALN directly correlated with tumor size, ALN disease, and Her2 positive and triple negative receptor phenotype. In breast cancer patients who are node positive at time of diagnosis with pCR in the breast after neoadjuvant chemotherapy, residual lymph node disease was very uncommon. Further study is warranted to select patients who may avoid breast and axillary surgery post neoadjuvant chemotherapy.

Chaperome heterogeneity and its implications for cancer study and treatment.

The chaperome is the collection of proteins in the cell that carry out molecular chaperoning functions. Changes in the interaction strength between chaperome proteins lead to an assembly that is functionally and structurally distinct from each constituent member. In this review, we discuss the epichaperome, the cellular network that forms when the chaperome components of distinct chaperome machineries come together as stable, functionally integrated, multimeric complexes. In tumors, maintenance of the epichaperome network is vital for tumor survival, rendering them vulnerable to therapeutic interventions that target critical epichaperome network components. We discuss how the epichaperome empowers an approach for precision medicine cancer trials where a new target, biomarker, and relevant drug candidates can be correlated and integrated. We introduce chemical biology methods to investigate the heterogeneity of the chaperome in a given cellular context. Lastly, we discuss how ligand-protein binding kinetics are more appropriate than equilibrium binding parameters to characterize and unravel chaperome targeting in cancer and to gauge the selectivity of ligands for specific tumor-associated chaperome pools.

Evaluation of surgically excised breast tissue microstructure using wide-field optical coherence tomography.

BACKGROUND: Currently, positive margins at lumpectomy contribute to health care cost, patient anxiety, and treatment delay. Multiple technology solutions are being explored with the aim of lowering re-excision rates for breast-conserving surgery (BCS). We examined wide-field optical coherence tomography (WF-OCT), an innovative adjunct intraoperative imaging tool for tissue visualization of margins. METHODS: This IRB-approved pilot study included women with invasive or in situ carcinoma scheduled for primary BCS. Lumpectomy specimens and any final/revised margins were imaged by optical coherence tomography immediately prior to standard histological processing. The optical coherence tomography used provided two-dimensional, cross-sectional, real-time depth visualization of the margin widths around excised specimens. A volume of images was captured for 10 × 10 cm tissue surface at high resolution (sub-30 µm) to a depth of 2 mm. Integrated interpretation was performed incorporating final pathology linked with the optical image data for correlation. RESULTS: Wide-field optical coherence tomography was performed on 185 tissue samples (50 lumpectomy specimens and 135 additional margin shaves) in 50 subjects. Initial diagnosis was invasive ductal carcinoma (IDC) in 10, ductal carcinoma in situ (DCIS) in 14, IDC/DCIS in 22, invasive lobular carcinoma (ILC) in 2, ILC/DCIS in 1, and sarcoma in 1. Optical coherence tomography was concordant with final pathology in 178/185 tissue samples for overall accuracy of 86% and 96.2% (main specimen alone and main specimen + shave margins). Of seven samples that were discordant, 57% (4/7) were considered close (DCIS < 2 mm from margin) per final pathology. CONCLUSION: Wide-field optical coherence tomography demonstrated concordance with histology at tissue margins, supporting its potential for use as a real-time adjunct intraoperative imaging tool for margin assessment. Further studies are needed for comprehensive evaluation in the intraoperative setting.

Histopathologic characteristics of background parenchymal enhancement (BPE) on breast MRI.

PURPOSE: Breast fibroglandular tissue (FGT), as visualized on a mammogram (mammographic density, MD), is one of the strongest known risk factors for breast cancer. FGT is also visible on breast MRI, and increased background parenchymal enhancement (BPE) in the FGT has been identified as potentially a major breast cancer risk factor. The aim of this exploratory study was to examine the biologic basis of BPE. METHODS: We examined the unaffected contra-lateral breast of 80 breast cancer patients undergoing a prophylactic mastectomy before any treatment other than surgery of their breast cancer. BPE was classified on the BI-RADS scale (minimal/mild/moderate/marked). Slides were stained for microvessel density (MVD), CD34 (another measure of endothelial density), glandular tissue within the FGT and VEGF. Spearman correlations were used to evaluate the associations between BPE and these pathologic variables. RESULTS: In pre-menopausal patients, BPE was highly correlated with MVD, CD34 and glandular concentration within the FGT, and the pathologic variables were themselves highly correlated. The expression of VEGF was effectively confined to terminal duct lobular unit (TDLU) epithelium. The same relationships of the four pathologic variables with BPE were seen in post-menopausal patients, but the relationships were much weaker and not statistically significant. CONCLUSION: The strong correlation of BPE and MVD together with the high correlation of MVD with glandular concentration seen in pre-menopausal patients indicates that increased breast cancer risk associated with BPE in pre-menopausal women is likely to result from its association with increased concentration of glandular tissue in the FGT. The effective confinement of VEGF expression to the TDLUs shows that the signal for MVD growth arises directly from the glandular tissue. Further studies are needed to understand the basis of BPE in post-menopausal women.

Breast intraductal papillomas without atypia in radiologic-pathologic concordant core-needle biopsies: Rate of upgrade to carcinoma at excision.

BACKGROUND: The surgical management of mammary intraductal papilloma without atypia (IDP) identified at core-needle biopsy (CNB) is controversial. This study assessed the rate of upgrade to carcinoma at surgical excision (EXC). METHODS: This study identified women with a CNB diagnosis of intraductal papilloma without atypia or carcinoma at a cancer center between 2003 and 2013. Radiologic-pathologic concordance was assessed for all cases, and discordant cases were excluded. The radiologic and clinicopathologic features of patients with a CNB diagnosis of IDP were correlated with an upgrade to carcinoma at EXC. RESULTS: The study population consists of 189 women with 196 IDPs; 166 women (171 IDPs) underwent EXC. The upgrade rate was 2.3% (4 of 171). The upgraded lesions were 2 invasive lobular carcinomas and 2 cases of ductal carcinoma in situ (DCIS). One case of DCIS involved the residual IDP, whereas the other 3 carcinomas were ≥ 8 mm away. Twenty-four women (25 IDPs) did not undergo EXC and had stable imaging on follow-up (median, 23.5 months). CONCLUSIONS: The upgrade rate at EXC for IDPs diagnosed at CNB with radiologic-pathologic concordance was 2.3%. These findings suggest that observation is appropriate for patients with radiologic-pathologic concordant CNB yielding IDP, regardless of its size. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2819-2827. © 2016 American Cancer Society.

Breast Carcinoma in Young Women: No Evidence of Increasing Rates of Metastatic Breast Carcinoma in a Single Tertiary Center Review.

Breast carcinoma in young women aged less than 40 years attracts a high level of mainstream media coverage, and there is a gap between societal perceptions of the disease as a growing problem and epidemiological trends. Several population studies have reported that the overall incidence of breast carcinoma in young women is stable, while one recent article suggested that the relative proportion of breast carcinoma in young women that is metastatic at diagnosis is growing. We sought to establish whether these trends were apparent at our institution. In this study, the clinical database at a breast carcinoma tertiary center was reviewed in terms of clinicopathologic data on patient age, diagnosis, clinical and pathologic stage, hormone receptor status, and HER-2 overexpression status for the period 2000-2011. Over the study period, young patients represented a decreasing proportion of all breast carcinoma cases (10.8% [2000-2003] to 8.7% [2008-2011]; p < 0.0001) treated at our institution. Young patients were more likely than patients aged 40 years or older to present with metastatic (M1) disease (5.4% versus 4.4%; p = 0.009), to be triple negative (21.6% versus 13%; p < 0.001), or to be HER-2 positive (24.3% versus 14.8%; p < 0.01). Young patients with HER-2-positive cancers were significantly more likely to present with metastatic disease (8.3% versus 4.8%; p = 0.004). This study showed no demonstrable increase in the relative proportion of breast cancer occurring in patients aged <40 years over the 12-year period 2000-2011 and no increase in the proportion of young patients presenting with metastatic disease.

Appearance of untreated bone metastases from breast cancer on FDG PET/CT: importance of histologic subtype.

PURPOSE: To determine if the histology of a breast malignancy influences the appearance of untreated osseous metastases on FDG PET/CT. METHODS: This retrospective study was performed under IRB waiver. Our Hospital Information System was screened for breast cancer patients who presented with osseous metastases, who underwent FDG PET/CT prior to systemic therapy or radiotherapy from 2009 to 2012. Patients with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), or mixed ductal/lobular (MDL) histology were included. Patients with a history of other malignancies were excluded. PET/CT was evaluated, blinded to histology, to classify osseous metastases on a per-patient basis as sclerotic, lytic, mixed lytic/sclerotic, or occult on CT, and to record SUVmax for osseous metastases on PET. RESULTS: Following screening, 95 patients who met the inclusion criteria (74 IDC, 13 ILC, and 8 MDL) were included. ILC osseous metastases were more commonly sclerotic and demonstrated lower SUVmax than IDC metastases. In all IDC and MDL patients with osseous metastases, at least one was FDG-avid. For ILC, all patients with lytic or mixed osseous metastases demonstrated at least one FDG-avid metastasis; however, in only three of seven patients were sclerotic osseous metastases apparent on FDG PET. CONCLUSION: The histologic subtype of breast cancer affects the appearance of untreated osseous metastases on FDG PET/CT. In particular, non-FDG-avid sclerotic osseous metastases were more common in patients with ILC than in patients with IDC. Breast cancer histology should be considered when interpreting non-FDG-avid sclerotic osseous lesions on PET/CT, which may be more suspicious for metastases (rather than benign lesions) in patients with ILC.

The extent of extracapsular extension may influence the need for axillary lymph node dissection in patients with T1-T2 breast cancer.

BACKGROUND: Whether extracapsular extension (ECE) of tumor in the sentinel lymph node (SLN) is an indication for axillary lymph node dissection (ALND) in patients managed by American College of Surgeons Oncology Group Z0011 criteria is controversial. Here we examine the correlation between ECE in the SLN and disease burden in the axilla. METHODS: Patients meeting Z0011 clinicopathologic criteria (pT1-2, cN0 with <3 positive SLNs) were selected from a prospectively maintained database (2006-2013). Chart review documented the presence and extent of ECE. Neoadjuvant chemotherapy patients were excluded. Comparisons were made by presence and extent (≤2 vs. >2 mm) of ECE. RESULTS: Of 11,730 patients, 778 were pT1-2, cN0 with <3 positive SLNs without ECE, and 331 (2.8 %) had ECE. Of these, 180 had ≤2 mm and 151 had >2 mm of ECE. Patients with ECE were older (57 vs. 54 years; p = 0.001) and had larger (2.0 vs. 1.7 cm; p < 0.0001), multifocal (p = 0.006), hormone receptor-positive tumors (p = 0.0164) with lymphovascular invasion (p < 0.0001). Presence and extent of ECE were associated with greater axillary disease burden; 20 and 3 % of patients with and without ECE, respectively, had ≥4 additional positive nodes at completion ALND (p < 0.0001), and 33 % of patients with >2 mm ECE had ≥4 additional positive nodes at completion ALND, compared with 9 % in the <2 mm group (p < 0.0001). On multivariate analysis, >2 mm of ECE was the strongest predictor of ≥4 positive nodes at completion ALND (odds ratio 14.2). CONCLUSIONS: Presence and extent of ECE were significantly correlated with nodal tumor burden at completion ALND, thus suggesting that >2 mm of ECE may be an indication for ALND or radiotherapy when applying Z0011 criteria to patients with metastases in <3 SLNs. ECE reporting should be standardized to facilitate future studies.

Antitumorigenic potential of STAT3 alternative splicing modulation.

Signal transducer and activator of transcription 3 (STAT3) plays a central role in the activation of multiple oncogenic pathways. Splicing variant STAT3ß uses an alternative acceptor site within exon 23 that leads to a truncated isoform lacking the C-terminal transactivation domain. Depending on the context, STAT3ß can act as a dominant-negative regulator of transcription and promote apoptosis. We show that modified antisense oligonucleotides targeted to a splicing enhancer that regulates STAT3 exon 23 alternative splicing specifically promote a shift of expression from STAT3α to STAT3ß. Induction of endogenous STAT3ß leads to apoptosis and cell-cycle arrest in cell lines with persistent STAT3 tyrosine phosphorylation compared with total STAT3 knockdown obtained by forced splicing-dependent nonsense-mediated decay (FSD-NMD). Comparison of the molecular effects of splicing redirection to STAT3 knockdown reveals a unique STAT3ß signature, with a down-regulation of specific targets (including lens epithelium-derived growth factor, p300/CBP-associated factor, CyclinC, peroxisomal biogenesis factor 1, and STAT1ß) distinct from canonical STAT3 targets typically associated with total STAT3 knockdown. Furthermore, similar in vivo redirection of STAT3 alternative splicing leads to tumor regression in a xenograft cancer model, demonstrating how pharmacological manipulation of a single key splicing event can manifest powerful antitumorigenic properties and validating endogenous splicing reprogramming as an effective cancer therapeutic approach.

Phosphorylation-Driven Epichaperome Assembly: A Critical Regulator of Cellular Adaptability and Proliferation.

The intricate protein-chaperone network is vital for cellular function. Recent discoveries have unveiled the existence of specialized chaperone complexes called epichaperomes, protein assemblies orchestrating the reconfiguration of protein-protein interaction networks, enhancing cellular adaptability and proliferation. This study delves into the structural and regulatory aspects of epichaperomes, with a particular emphasis on the significance of post-translational modifications in shaping their formation and function. A central finding of this investigation is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 situated within an intrinsically disordered region, as critical determinants in epichaperome assembly. Our data demonstrate that the phosphorylation of these serine residues enhances HSP90's interaction with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Furthermore, this study establishes a direct link between epichaperome function and cellular physiology, especially in contexts where robust proliferation and adaptive behavior are essential, such as cancer and stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone complexes in diseases characterized by epichaperome dysregulation, bridging the gap between fundamental research and precision medicine.

Non-mammary metastases to the breast and axilla: a study of 85 cases.

Non-mammary metastases to the breast and axilla are rare occurrences. However, they are important diagnostic considerations as their treatment and prognosis differ significantly from primary breast cancer. Between 1990 and 2010, we identified a total of 85 patients, 72 women and 13 men, with non-mammary malignancies involving the breast, axilla, or both. The tumor types consisted of carcinoma (58%), melanoma (22%) and sarcoma (20%). Ovary was the most common site of origin for carcinoma, and metastatic high-grade ovarian serous carcinoma was most frequently misdiagnosed as a primary breast carcinoma. Melanoma was the single most common non-carcinomatous tumor type to involve the breast and/or axilla, and uterine leiomyosarcoma was the most common type of sarcoma. Most patients (77%) had other metastases at the time of diagnosis of the tumor, but in 11% the breast or axillary lesion was the first presentation. Without a clinical history, non-mammary metastases were difficult to diagnose because the majority of cases presented with a solitary nodule and lacked pathognomonic pathologic features. There were, however, certain recurrent histological findings identified, such as the often relatively well-circumscribed growth pattern of the metastatic lesion surrounded by a fibrous pseudocapsule, and the absence of an in situ carcinoma. Overall, these patients had poor survival; 96% of patients with follow-up available are dead of disease, with a median survival of 15 months after the diagnosis of the breast or axillary lesion. This finding emphasizes the need to accurately identify these tumors as metastases in order to avoid unnecessary procedures and treatments in these patients.

Focal extravasated mucin in breast core needle biopsies: is surgical excision always necessary?

Focal extravasated mucin (EM) with benign or atypical epithelium is a rare finding at breast core needle biopsy (CNB) and usually prompts surgical excision to rule out mucin-producing carcinoma. In the largest detailed series to date, we assessed surgical outcomes in lesions yielding EM with atypical or nonatypical epithelium at CNB. With IRB approval, we retrospectively reviewed 28 consecutive atypical and nonatypical CNBs with EM that underwent surgical excision at our center over a 22-year period. CNB imaging and pathologic findings were concordant if pathology sufficiently explained the radiologic features of the lesions. Pathologic findings in CNB and excision specimens were correlated. Statistical analysis was performed. CNBs sampled mammographic calcifications in 25/28 (89%) women and a mass in 3/28 (11%). All cases had concordant pathologic and imaging findings. At CNB, the epithelium associated with EM was atypical in 18/28 (64%) lesions and nonatypical in 10 (36%). Cancer (one mucinous carcinoma; three ductal carcinoma in situ) was present in 4/28 excision specimens (14%; 95% confidence intervals [CI], 4%-33%). All carcinomas were in lesions with epithelial atypia at CNB (4/18; 22%; 95% CI, 6%-48%) versus none (0/10; 0%; 95% CI, 0%-31%) in nonatypical lesions at CNB; this difference was not statistically significant (p = 0.3). Surgery is warranted for lesions yielding EM with atypia at CNB due to the high (22%) prevalence of cancer. Our data suggest that surgical excision of lesions yielding EM without epithelial atypia at CNB may not be necessary provided that imaging and pathologic findings are concordant.

Wide-field optical coherence tomography for microstructural analysis of key tissue types: a proof-of-concept evaluation.

Introduction: The presence of positive margins following tumor resection is a frequent cause of re-excision surgery. Nondestructive, real-time intraoperative histopathological imaging methods may improve margin status assessment at the time of surgery; optical coherence tomography (OCT) has been identified as a potential solution but has not been tested with the most common tissue types in surgical oncology using a single, standardized platform. Methods: This was a proof-of-concept evaluation of a novel device that employs wide-field OCT (WF-OCT; OTIS 2.0 System) to image tissue specimens. Various cadaveric tissues were obtained from a single autopsy and were imaged with WF-OCT then processed for permanent histology. The quality and resolution of the WF-OCT images were evaluated and compared to histology and with images in previous literature. Results: A total of 30 specimens were collected and tissue-specific microarchitecture consistent with previous literature were identified on both WF-OCT images and histology slides for all specimens, and corresponding sections were correlated. Application of vacuum pressure during scanning did not affect specimen integrity. On average, specimens were scanned at a speed of 10.3 s/cm2 with approximately three features observed per tissue type. Conclusion: The WF-OCT images captured in this study displayed the key features of the most common human tissue types encountered in surgical oncology with utility comparable to histology, confirming the utility of an FDA-cleared imaging platform. With further study, WF-OCT may have the potential to bridge the gap between the immediate information needs of the operating room and the longer timeline inherent to histology workflow.

Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation.

Systems-level assessments of protein-protein interaction (PPI) network dysfunctions are currently out-of-reach because approaches enabling proteome-wide identification, analysis, and modulation of context-specific PPI changes in native (unengineered) cells and tissues are lacking. Herein, we take advantage of chemical binders of maladaptive scaffolding structures termed epichaperomes and develop an epichaperome-based 'omics platform, epichaperomics, to identify PPI alterations in disease. We provide multiple lines of evidence, at both biochemical and functional levels, demonstrating the importance of these probes to identify and study PPI network dysfunctions and provide mechanistically and therapeutically relevant proteome-wide insights. As proof-of-principle, we derive systems-level insight into PPI dysfunctions of cancer cells which enabled the discovery of a context-dependent mechanism by which cancer cells enhance the fitness of mitotic protein networks. Importantly, our systems levels analyses support the use of epichaperome chemical binders as therapeutic strategies aimed at normalizing PPI networks.

Papilloma diagnosed at MRI-guided vacuum-assisted breast biopsy: is surgical excision still warranted?

OBJECTIVE: The objective of our study was to determine the frequency of cancer at surgery in breast lesions yielding papilloma at MRI-guided 9-gauge vacuum-assisted biopsy (VAB) and to determine whether any features are associated with cancer upgrade. MATERIALS AND METHODS: For this study, 1487 MRI-guided vacuum-assisted biopsies performed from January 2004 to March 2011 were reviewed. Lesions yielding papilloma were identified and classified as papilloma with or without atypia. Surgical findings were reviewed to determine the cancer rate. Statistical analysis was performed and 95% CIs were calculated. RESULTS: Papilloma was identified in 75 of the 1487 MRI-guided vacuum-assisted biopsies (5%). These 75 papillomas occurred in 73 women with a median age of 49 years (age range, 27-70 years). Of the 75 papillomas, 25 (33%) had atypia and 50 (67%) did not on core needle biopsy. Subsequent surgery of 67 of the 75 papillomas (89%) yielded ductal carcinoma in situ (DCIS) in four (6%; 95% CI, 2-15%). Surgery yielded DCIS in two of 23 papillomas with atypia (9%; 95% CI, 1-28%) at MRI-guided VAB and in two of 44 papillomas without atypia (5%; 95% CI, 0.4-16%) at MRI-guided VAB; these cancer rates did not differ significantly (p=0.6). Postmenopausal status (p=0.04) and histologic size of less than 0.2 cm (p=0.04) had a significant association with the cancer upgrade rate. CONCLUSION: Papilloma with or without atypia was found in 5% of patients who underwent MRI-guided VAB during the study period. Surgery revealed cancer in 6%. DCIS was found at surgery in 9% of lesions yielding papilloma with atypia versus 5% of lesions yielding papilloma without atypia. For lesions yielding papilloma with or without atypia at MRI-guided VAB, surgical excision is warranted.

Measuring Invasive Breast Carcinoma on Core Biopsy-Is It Necessary?

CONTEXT.­: Pathologic tumor size is significant in the treatment of breast carcinoma and is routinely measured on excision. OBJECTIVE.­: To analyze the need for measuring size of invasive mammary carcinoma on biopsy. DESIGN.­: Nine hundred twenty-two cases of invasive carcinoma whose size was measured (greatest linear measurement) on biopsy and excision was correlated, including imaging when available (110 cases). RESULTS.­: Patient mean age was 62 years. Most (90%; 830 of 922) carcinomas were ductal and sampled by ultrasound and graded as follows: well, 13% (113 of 922); moderately, 58% (532 of 922), and poorly differentiated, 28% (258 of 922); 19 microinvasive not graded. Tumor mean size was 7.5 mm on biopsy and 14.4 mm on excision. Biopsy modality was as follows: ultrasound, 7.8 mm (92%, 844 of 922); mammotome, 3.3 mm (7%, 65 of 922); and magnetic resonance imaging, 5.9 mm (1%, 13 of 922). Size comparison on biopsy versus excision was biopsy > excision: 8% (72 of 922), biopsy = excision: 10% (95 of 922), and biopsy < excision: 82% (755 of 922). Half (36 of 72) of the biopsy > excision tumors were less than 5 mm, 96% (726 of 755) of biopsy < excision tumors were greater than 5 mm, while those equal on both were predominantly (88%, 84 of 95) less than 10 mm, 20% (19 of 95) of which were microinvasive. Stage changed in 600 cases, staging based on excision in 581 (63%), and staging based on biopsy in 19 (2%). Radiologic-pathologic correlation (n = 110) showed perfect concordance in 11 (10%), 83 (75%) were ±1 to 2 mm, and 16 (15%) were ± more than 3 mm. Difference between the biopsy and excision ranged from a lower limit of 1.3 mm for T1a tumors to 18 mm for T2. CONCLUSIONS.­: While most carcinomas are larger on excision, 18% (167 of 922) are larger or equal on biopsy. Factors predictive of biopsy > excision tumors include stage 1 tumors (P < .001), especially less than 5 mm, and sampled by mammotome. We recommend measuring invasive carcinoma on biopsy and excision.

Chemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system.

Diseases are a manifestation of how thousands of proteins interact. In several diseases, such as cancer and Alzheimer's disease, proteome-wide disturbances in protein-protein interactions are caused by alterations to chaperome scaffolds termed epichaperomes. Epichaperome-directed chemical probes may be useful for detecting and reversing defective chaperomes. Here we provide structural, biochemical, and functional insights into the discovery of epichaperome probes, with a focus on their use in central nervous system diseases. We demonstrate on-target activity and kinetic selectivity of a radiolabeled epichaperome probe in both cells and mice, together with a proof-of-principle in human patients in an exploratory single group assignment diagnostic study (ClinicalTrials.gov Identifier: NCT03371420). The clinical study is designed to determine the pharmacokinetic parameters and the incidence of adverse events in patients receiving a single microdose of the radiolabeled probe administered by intravenous injection. In sum, we introduce a discovery platform for brain-directed chemical probes that specifically modulate epichaperomes and provide proof-of-principle applications in their use in the detection, quantification, and modulation of the target in complex biological systems.

Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer.

Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours. Further, we can essentially force tumours into interactome hyperconnectivity and maximal protein-protein interaction capacity, a state whereby no rebound pathways can be deployed and where alternative signalling is supressed. This approach therefore primes interactomes to enhance vulnerability and improve treatment efficacy, enabling therapeutics with traditionally poor performance to become highly efficacious. These findings provide proof-of-principle for a paradigm to overcome drug resistance through pharmacologic manipulation of proteome-wide protein-protein interaction networks.