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.
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.
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/cm
with approximately three features observed per tissue type.
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.
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.
Signal transducer and activator of transcription 3 (STAT3) plays a central role in the activation of multiple oncogenic pathways. Splicing variant STAT3β uses an alternative acceptor site within exon ...23 that leads to a truncated isoform lacking the C-terminal transactivation domain. Depending on the context STAT3β 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 STAT3β. Induction of endogenous STAT3β 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 STAT3β signature, with a down-regulation of specific targets (including lens epithelium-derived growth factor, p300/CBP-assodated factor, CyclinC, peroxisomal biogenesis factor 1, and STAT1β) 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.
Heat shock protein 90 (HSP90) serves as a critical facilitator for oncogene addiction. There has been augmenting enthusiasm in pursuing HSP90 as an anticancer strategy. In fact, since the initial ...serendipitous discovery that geldanamycin (GM) inhibits HSP90, the field has rapidly moved from proof-of-concept clinical studies with GM derivatives to novel second-generation inhibitors.
The authors highlight the current status of the second-generation HSP90 inhibitors in clinical development. Herein, the authors note the lessons learned from the completed clinical trials of first- and second-generation inhibitors and describe various assays attempting to serve for a more rational implementation of these agents to cancer treatment. Finally, the authors discuss the future perspectives for this promising class of agents.
The knowledge gained thus far provides perhaps only a glimpse at the potential of HSP90 for which there is still much work to be done. Lessons from the clinical trials suggest that HSP90 therapy would advance at a faster pace if patient selection and tumor pharmacokinetics of these drugs were better understood and applied to their clinical development. It is also evident that combining HSP90 inhibitors with other potent anticancer therapies holds great promise not only due to synergistic antitumor activity but also due to the potential of prolonging or preventing the development of drug resistance.
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.
Abstract
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.
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.
Summary Mucinous micropapillary carcinoma of the breast, also described as “pure mucinous carcinoma with micropapillary pattern,” has recently come to attention as an unusual form of invasive breast ...cancer exhibiting dual mucinous and micropapillary differentiation. Despite increasing awareness of this morphologic variant, its clinical significance has not yet been elucidated. Here, we present 15 additional examples of these rare tumors to highlight some important differences between mucinous micropapillary carcinoma of the breast and ordinary pure mucinous carcinomas. The key features of mucinous micropapillary carcinoma of the breast included ( a ) largely or entirely mucinous appearance (>90% mucinous morphology), ( b ) distinctive micropapillary arrangement of the neoplastic cells, ( c ) intermediate to high nuclear grade, ( d ) “hobnail” cells, and ( e ) frequent psammomatous calcifications. In contrast to ordinary pure mucinous carcinomas, 20% of mucinous micropapillary carcinomas of the breast were characterized by human epidermal growth factor receptor 2 positivity, and 23% were p53 positive. More than half of mucinous micropapillary carcinomas of the breast (60%) demonstrated lymphovascular invasion, sometimes extensive. Synchronous axillary lymph node metastases were detected in 33% of patients and, on 2 occasions, involved more than 10 nodes. With a median follow-up of 4.5 years, we identified 1 patient (7%) with chest wall recurrence of mucinous micropapillary carcinoma of the breast after mastectomy. We conclude that mucinous micropapillary carcinomas of the breast constitute a clinically aggressive subset of mucin-producing breast carcinomas characterized by an increased capacity for lymphatic invasion and regional lymph node metastasis, reflective of their dual phenotype. Recognition of the morphologic and biologic heterogeneity within breast cancer subtypes should allow for a more accurate classification of the individual tumors and better patient stratification for treatment.
Optimal management of a lesion yielding radial scar (RS) without epithelial atypia on breast biopsy is controversial. In this single-institution study spanning 17 years, 53 patients with this biopsy ...diagnosis were evaluated in terms of clinical, radiologic, and pathologic features and outcomes. RSs were categorized as either "incidental" or as the "targeted" lesion according to defined criteria. Of 48 patients who underwent surgical excision after a diagnosis of RS on biopsy, only 1 had an "upgrade" diagnosis of malignancy (2%). No "incidental" RS was associated with the presence of malignancy on surgical excision. Meta-analysis of 20 RS excision studies demonstrated an overall upgrade rate of 10.4%, with a higher rate in patients with a diagnosis of RS with atypia (26%). The upgrade rate for RS without atypia was 7.5% overall. The lower rate of upgrade to malignancy in this study (2%) is likely related to the thorough radiologic-pathologic review undertaken. In the setting of multidisciplinary agreement and careful radiologic-pathologic correlation, it may be appropriate for patients with a biopsy diagnosis of RS without atypia to forego surgical excision in favor of imaging follow-up.
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