Oro-Respiratory Dysbiosis and Its Modulatory Effect on Lung Mucosal Toxicity during Exposure or Co-Exposure to Carbon Nanotubes and Cigarette Smoke.

The oro-respiratory microbiome is impacted by inhalable exposures such as smoking and has been associated with respiratory health conditions. However, the effect of emerging toxicants, particularly engineered nanoparticles, alone or in co-exposure with smoking, is poorly understood. Here, we investigated the impact of sub-chronic exposure to carbon nanotube (CNT) particles, cigarette smoke extract (CSE), and their combination. The oral, nasal, and lung microbiomes were characterized using 16S rRNA-based metagenomics. The exposures caused the following shifts in lung microbiota: CNT led to a change from Proteobacteria and Bacteroidetes to Firmicutes and Tenericutes; CSE caused a shift from Proteobacteria to Bacteroidetes; and co-exposure (CNT+CSE) had a mixed effect, maintaining higher numbers of Bacteroidetes (due to the CNT effect) and Tenericutes (due to the CSE effect) compared to the control group. Oral microbiome analysis revealed an abundance of the following genera: Acinetobacter (CNT), Staphylococcus, Aggregatibacter, Allobaculum, and Streptococcus (CSE), and Alkalibacterium (CNT+CSE). These proinflammatory microbial shifts correlated with changes in the relative expression of lung mucosal homeostasis/defense proteins, viz., aquaporin 1 (AQP-1), surfactant protein A (SP-A), mucin 5b (MUC5B), and IgA. Microbiota depletion reversed these perturbations, albeit to a varying extent, confirming the modulatory role of oro-respiratory dysbiosis in lung mucosal toxicity. This is the first demonstration of specific oro-respiratory microbiome constituents as potential modifiers of toxicant effects in exposed lungs.

Evaluation of the SmartClip™ Nonradioactive Seed, a Novel Wireless Localization Method for the Breast: Initial Clinical Experience and Surgical Outcome.

INTRODUCTION: Wire localization has been the gold standard for breast localization of non-palpable lesions for decades. This technique remains robust but has disadvantages relative to scheduling, complications of vasovagal reactions in placement, wire migration, or transection. With more modern technologies available, several implantable markers have been developed to allow uncoupling of localization by radiology and the surgical procedure on the same day. This study summarizes our experience with the EnVisio Navigation System™ utilizing SmartClip™ as the implantable tissue localization marker. METHODS: An IRB-approved retrospective database of benign and malignant breast disease was used to perform a review of 100 consecutive patients who underwent SmartClip™ localized breast and axillary procedures in 2021. Demographic information, localization accuracy, associated surgical procedure(s) with resultant pathology findings, margin status for malignancies, and re-excision rate were collected. RESULTS: The localized breast lesion or lymph node was excised and SmartClip™ retrieved in all cases, confirmed by intraoperative specimen radiograph. The distribution of gender and race/ethnicity among the patients who underwent surgery reflects the community population and frequency of breast cancer development among men versus women. 45.1% of the cases involved malignancy, as determined pre-operatively. Positive margins requiring re-excision constituted 18.2% of cases. In twenty-six patients, two or three SmartClips™ were placed per case for either a bracketed lesion, two separate breast lesions, and/or a breast lesion and lymph node. CONCLUSION: Although this study is limited in patient number, it demonstrates safety of this technique and its reliability in guiding the surgeon directly to the lesion(s) of concern.

RESNA position on the application of power mobility devices for pediatric users.

This paper serves as an update to the previous RESNA Position on the Application of Power Wheelchairs for Pediatric Users with more current and additional scientific literature. This document contains typical clinical applications and best evidence from the literature supporting the application of power mobility (PM) for young children and to assist practitioners in decision-making and justification. It is RESNA' s position that age, limited vision or cognition, behavioral issues, and the ability to walk or propel a manual wheelchair short distances should not, in and of themselves, be used as discriminatory factors against providing PM for children. RESNA recommends early utilization of PM for children with mobility limitations as medically necessary, to promote integration and psycho-social development, reduce passive dependency, and to enhance participation, function, and independence.

Exploiting the advantages of a wireless seed localization system that differentiates between the seeds: Breast cancer resection following neoadjuvant chemotherapy.

BACKGROUND: Most wireless localization methods utilize only one means of detection for the surgeon, sufficient to localize a single small breast lesion for excision. Complex cases requiring bracketing of a larger lesion or localization of two or more close lesions can superimpose the signal from separate "seeds" with such methods. The lack of discernment between the localization "seeds" can disorient the surgeon, risking a missed lesion on excision and longer operative times. with the use of neoadjuvant chemotherapy prior to breast surgery, the necessity of localizing both a breast lesion and an axillary lymph node previously biopsied is becoming frequent. CASE: A 44 year-old woman underwent neoadjuvant chmotherapy for a breast cancer the did not express estrogen receptor, progesterone receptor, or HER2 receptor. In establishing the extent of disease, a suspicious ipsilateral lymph node was biopsied and found to contain metastatic disease. She had an excellent response to the chemotherapy, with decreased size of the primary tumor and the previously biopsied lymph node. The patient desired breast conservation. The primary tumor and associated calcifications were bracketed using two different Smartclips™, with a third localizing the lymph node biopsied. CONCLUSION: This report illustrates how the use of three SmartClips™, within the EnVisioTM system, allowed for separate tracking of each "seed" throughout a complex surgery in a patient following neoadjuvant chemotherapy. This resulted in successful resection of both the tumor and the tagged lymph node.

Differential modulation of lung aquaporins among other pathophysiological markers in acute (Cl2 gas) and chronic (carbon nanoparticles, cigarette smoke) respiratory toxicity mouse models.

Inhaled toxic chemicals and particulates are known to disrupt lung homeostasis causing pulmonary toxicity and tissue injury. However, biomarkers of such exposures and their underlying mechanisms are poorly understood, especially for emerging toxicants such as engineered nanoparticles and chemical threat agents such as chlorine gas (Cl2). Aquaporins (AQPs), commonly referred to as water channels, are known to play roles in lung homeostasis and pathophysiology. However, little is known on their regulation in toxicant-induced lung injuries. Here, we compared four lung toxicity models namely, acute chemical exposure (Cl2)-, chronic particulate exposure (carbon nanotubes/CNT)-, chronic chemical exposure (cigarette smoke extract/CSE)-, and a chronic co-exposure (CNT + CSE)- model, for modulation of lung aquaporins (AQPs 1, 3, 4, and 5) in relation to other pathophysiological endpoints. These included markers of compromised state of lung mucosal lining [mucin 5b (MUC5B) and surfactant protein A (SP-A)] and lung-blood barrier [protein content in bronchoalveolar lavage (BAL) fluid and, cell tight junction proteins occludin and zona-occludens]. The results showed toxicity model-specific regulation of AQPs measured in terms of mRNA abundance. A differential upregulation was observed for AQP1 in acute Cl2 exposure model (14.71-fold; p = 0.002) and AQP3 in chronic CNT exposure model (3.83-fold; p = 0.044). In contrast, AQP4 was downregulated in chronic CSE model whereas AQP5 showed no significant change in any of the models. SP-A and MUC5B expression showed a decreasing pattern across all toxicity models except the acute Cl2 toxicity model, which showed a highly significant upregulation of MUC5B (25.95-fold; p = 0.003). This was consistent with other significant pathophysiological changes observed in this acute model, particularly a compromised lung epithelial-endothelial barrier indicated by significantly increased protein infiltration and expression of tight junction proteins, and more severe histopathological (structural and immunological) changes. To our knowledge, this is the first report on lung AQPs as molecular targets of the study toxicants. The differentially regulated AQPs, AQP1 in acute Cl2 exposure versus AQP3 in chronic CNT nanoparticle exposure, in conjunction with the corresponding differentially impacted pathophysiological endpoints (particularly MUC5B) could potentially serve as predictive markers of toxicant type-specific pulmonary injury and as candidates for future investigation for clinical intervention.

Crosstalk between gut microbiota and lung inflammation in murine toxicity models of respiratory exposure or co-exposure to carbon nanotube particles and cigarette smoke extract.

Carbon nanotubes (CNTs) are emerging environmental and occupational toxicants known to induce lung immunotoxicity. While the underlying mechanisms are evolving, it is yet unknown whether inhaled CNTs would cause abnormalities in gut microbiota (dysbiosis), and if such microbiota alteration plays a role in the modulation of CNT-induced lung immunotoxicity. It is also unknown whether co-exposure to tobacco smoke will modulate CNT effects. We compared the effects of lung exposure to multi-wall CNT, cigarette smoke extract (CSE), and their combination (CNT + CSE) in a 4-week chronic toxicity mouse model. The exposures induced differential perturbations in gut microbiome as evidenced by altered microbial α- and ß- diversity, indicating a lung-to-gut communication. The gut dysbiosis due to CNTs, unlike CSE, was characterized by an increase in Firmicutes/Bacteroidetes ratio typically associated with proinflammatory condition. Notably, while all three exposures reduced Proteobacteria, the CNT exposure and co-exposure induced appearance of Tenericutes and Cyanobacteria, respectively, implicating them as potential biomarkers of exposure. CNTs differentially induced certain lung proinflammatory mediators (TNF-α, IL-1ß, CCL2, CXCL5) whereas CNTs and CSE commonly induced other mediators (CXCL1 and TGF-ß). The co-exposure showed either a component-dominant effect or a summative effect for both dysbiosis and lung inflammation. Depletion of gut microbiota attenuated both the differentially-induced and commonly-induced (TGF-ß) lung inflammatory mediators as well as granulomas indicating gut-to-lung communication and a modulatory role of gut dysbiosis. Taken together, the results demonstrated gut dysbiosis as a systemic effect of inhaled CNTs and provided the first evidence of a bidirectional gut-lung crosstalk modulating CNT lung immunotoxicity.

Adenoid Cystic Carcinoma of the Breast: Radiologic-Pathologic Correlation.

Adenoid cystic carcinoma (ACC) is an uncommon malignancy occurring most frequently in the salivary glands. Breast ACC is rare. Pain is common at the site of ACC; otherwise, presentation is similar to other primary breast cancers. Adenoid cystic carcinomas classically lack calcifications; the imaging manifestations of ACC are otherwise highly variable, likely related to multiple pathologic growth patterns. While ACC in other regions of the body tends to be more aggressive, ACC involving the breast typically has less aggressive biologic characteristics. Classic-type breast ACC has a lower tendency to recur locally with radiation, metastasize to regional lymph nodes, and spread to other parts of the body. Perineural spread of disease can be seen but is not common. The rarer solid basaloid-type has a higher tendency for local or distant spread and recurrence. Although ACC is usually triple receptor-negative (estrogen receptor, progesterone receptor, human epidermal growth factor-2 receptor), the indolent nature of this tumor dictates its management. With classic-type ACC, the inclusion of axillary surgery has no consensus and the use of chemotherapy or hormonal therapy is rare. Axillary nodal surgery and chemotherapy are often included in management of the more aggressive solid basaloid-type. An understanding of the breast imaging, histopathology, and clinical course is key for appropriate treatment and follow-up of ACC.

Clinicopathologic features of unexpectedly HER2 positive breast carcinomas: An institutional experience.

Human epidermal growth factor receptor 2 (HER2) overexpression occurs in 15-20 % of all breast carcinomas. These tumors are usually high-grade which often correlates with reduced overall survival and increased rates of recurrence. In a retrospective review, we identified 19 cases of unexpectedly HER2 positive (by immunohistochemistry and/or fluorescence in-situ hybridization) invasive breast carcinomas on core needle biopsies from a registry at Northwestern Memorial Hospital. These cases included low-grade tumors, invasive lobular carcinomas, classic type, and invasive carcinomas with special subtype features. Twelve of the tumors were histologic grade 1 and 7 were histologic grade 2. One of the grade 1 tumors had tubular features (8 %), 1 had cribriform features (8 %), 2 had mucinous features (17 %), 2 were invasive lobular carcinomas, classic type (17 %), and the rest were invasive carcinoma, no special type (50 %). The histologic grade 2 tumors included 5 invasive lobular carcinomas, classic type (71 %) and 2 invasive ductal carcinomas with mucinous features (29 %). By immunohistochemistry, 13 (65 %) were HER2 score 3+, 7 were score 2+ (35 %), and reflex fluorescence in-situ hybridization (FISH) testing showed amplification in 6 cases, with 1 equivocal case amplified on excision. Despite the HER2 positive status in the selected cases, no unique morphologic features that would indicate aggressive behavior were identified. In clinical follow up, two patients were found to have recurrences, five had lymph node metastasis, and one had distant metastasis. None of the patients with recurrent disease were treated with trastuzumab, despite their positive HER2 results. These findings support that our population of HER2 positive carcinomas showed a similar rate of lymph node metastases and recurrence as poorly-differentiated tumors, supporting HER2 positivity as a poor prognostic indicator, irrespective of morphologic features. We recommend continuing to test all breast cancers, regardless of grade or special subtype features, to provide the most comprehensive treatment and prognostic information for both clinicians and patients.

Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study.

A recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014. Nuclear grade was computed combining nuclear atypia and mitotic count into a grade of I-III using the published system. Nuclear grade was assessed by one pathologist for three institutions, the remaining were scored independently. The presence or absence of necrosis and predominant growth pattern were also evaluated. Two additional scoring systems were evaluated, one combining nuclear grade and necrosis and the other mitotic count and necrosis. Median overall survival was the primary endpoint. A total of 776 cases were identified including 301 (39%) nuclear grade I tumors, 354 (45%) grade II tumors and 121 (16%) grade III tumors. The overall survival was 16 months, and correlated independently with age (P=0.006), sex (0.015), necrosis (0.030), mitotic count (0.001), nuclear atypia (0.009), nuclear grade (<0.0001), and mitosis and necrosis score (<0.0001). The addition of necrosis to nuclear grade further stratified overall survival, allowing classification of epithelioid malignant pleural mesothelioma into four distinct prognostic groups: nuclear grade I tumors without necrosis (29 months), nuclear grade I tumors with necrosis and grade II tumors without necrosis (16 months), nuclear grade II tumors with necrosis (10 months) and nuclear grade III tumors (8 months). The mitosis-necrosis score stratified patients by survival, but not as well as the combination of necrosis and nuclear grade. This study confirms that nuclear grade predicts survival in epithelioid malignant pleural mesothelioma, identifies necrosis as factor that further stratifies overall survival, and validates the grading system across multiple institutions and among both biopsy and resection specimens. An alternative scoring system, the mitosis-necrosis score is also proposed.

Programmed death-ligand 1 testing of lung cancer cytology specimens obtained with bronchoscopy.

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression testing is recommended by guidelines for patients with advanced non-small cell lung cancer (NSCLC). The primary objective of the current study was to determine the success rate of PD-L1 testing from cytology cell block samples obtained by bronchoscopic needle aspiration. The secondary objective was the assessment of the difference in specimen adequacy acquired via needles of different gauges. METHODS: Patients with NSCLC who underwent bronchoscopic needle aspirations for which PD-L1 testing was requested between November 1, 2016, and February 6, 2017, were included in the current analysis. Patients underwent needle aspiration from intrathoracic adenopathy or a pulmonary lesion. Rapid on-site cytology evaluation was performed in all cases. PD-L1 immunohistochemistry was performed using the Abcam anti-PD-L1 antibody 28.8 clone on cell block specimen. RESULTS: A total of 22 patients had PD-L1 testing requested on needle cytology samples obtained via bronchoscopy at the time of initial diagnosis (81.8%) and for progression of disease (18.2%). Twenty patients (90.9%) underwent successful PD-L1 testing. Sample acquisition was via endobronchial ultrasound-guided transbronchial needle aspiration in 72.7% of patients, endobronchial needle aspiration in 18.2% of patients, and peripheral nodule needle aspiration in 9.1% of patients. There was no statistical difference in PD-L1 test success rates between sample methods (P = .99) or needle sizes (P = 1.00). CONCLUSIONS: Bronchoscopically obtained cytology needle-based samples are adequate for PD-L1 testing in patients with NSCLC. There was no difference noted between different needle sizes with regard to adequacy for PD-L1 testing. These findings are relevant for clinicians caring for patients with lung cancer because a vast majority of patients with advanced NSCLC are diagnosed by bronchoscopic needle-based techniques using a variety of commercially available needles. Cancer Cytopathol 2018;126:122-8. © 2017 American Cancer Society.

Synchronous and Metastatic Papillary and Follicular Thyroid Carcinomas with Unique Molecular Signatures.

Despite the relatively high prevalence of thyroid cancer, the occurrence of multiple synchronous, distinct subtypes of primary thyroid carcinoma is uncommon. The incidental finding of papillary thyroid microcarcinoma in a gland with a biologically relevant follicular or medullary carcinoma is more frequent than the synchronous occurrence of multiple clinically significant carcinomas. We report a case of synchronous papillary and follicular thyroid carcinomas metastatic to lymph node and bone, respectively. Next generation sequencing showed BRAF V600E mutation in the primary papillary carcinoma and NRAS Q61R mutation in the primary follicular carcinoma and bony metastasis. To our knowledge, this is the first reported case of synchronous and metastatic primary papillary and follicular carcinomas, and the first report of synchronous BRAF V600E mutated papillary and NRAS mutated follicular carcinoma.

Neuroendocrine Tumors of the Breast.

Primary neuroendocrine tumors of the breast are a rare and underrecognized subtype of mammary carcinoma. Neuroendocrine tumors of the breast occur predominately in postmenopausal women. The tumors are subclassified into well-differentiated and poorly differentiated neuroendocrine tumors, and invasive breast carcinoma with neuroendocrine features. Well-differentiated tumors show architectural similarity to carcinoids of other sites but lack characteristic neuroendocrine nuclei. Poorly differentiated neuroendocrine tumors are morphologically identical to small cell carcinoma of the lung. Neuroendocrine differentiation, seen in up to 30% of invasive breast carcinomas, is most commonly associated with mucinous and solid papillary carcinomas. The diagnosis of neuroendocrine differentiation requires expression of the neuroendocrine markers synaptophysin or chromogranin. The main differential diagnosis is a metastatic neuroendocrine tumor from an extramammary site. Neuroendocrine tumors of the breast are treated similarly to other invasive breast carcinomas. Although no consensus has been reached on the prognosis, most studies suggest a poor outcome.

Prognostic Markers and Histologic Subtypes in Patients with Meningeal Carcinomatosis in Breast Cancer.

OBJECTIVE: Meningeal carcinomatosis (MC) is a rare complication in breast cancer patients. It is defined as a diffuse or multifocal leptomeningeal metastasis. STUDY DESIGN: From our institution database, we retrospectively studied 19 patients diagnosed with MC in the cerebrospinal fluid (CSF) in 1997-2015, in order to evaluate tumor prognostic markers, histologic subtypes, and clinical outcome. RESULTS: All patients were female, with a mean age of 53 years (range 36-75 years). The mean interval between diagnosis of breast carcinoma and MC was 28 months (range 6-62 months). The median survival from the time of diagnosis was 2 months (1-51 months). Sixteen cases (84%) were the ductal phenotype, 62% of which were of a high grade (grade 3), and 3 cases (16%) were lobular. Estrogen and progesterone receptors were positive on immunohistochemistry (IHC) in 53 and 33% of patients, respectively. HER2 IHC was positive (3+) in 20% of the cases; all were amplified by fluorescence in situ hybridization. The incidence of MC in triple-negative tumors was 40%. Twelve patients (63%) already had known metastasis at the time of diagnosis. CONCLUSIONS: Most cases of MC are high-grade ductal. MC is more common in triple-negative breast cancers. The outcome of these breast cancer patients with MC was poor. There was no survival difference according to age, histologic subtype, grade, or hormonal or HER2 status.

Male Breast Carcinoma: A Clinical and Pathological Review.

Male breast carcinomas (MBCs) are rare neoplasms that account for 0.1% of all male cancers. Still, there are 2000 new cases of MCB diagnosed annually in the United States. Because of its rarity, data regarding the etiology, risk factors, diagnosis, management, and prognosis of MBC are limited. MBC shares some similarities with female breast carcinoma (FBC). This review will address the important clinical, histopathological, immunohistochemical and molecular features, genetics, management, and prognosis of MBC.

Rehabilitation Engineering & Assistive Technology Society (RESNA) position on the application of wheelchair standing devices: 2013 current state of the literature.

This article, approved by the Rehabilitation Engineering & Assistive Technology Society of North America Board of Directors on December 23, 2013, shares typical clinical applications and provides evidence from the literature supporting the use of wheelchair standers.

Concurrent angiomyolipomas and renal cell neoplasms in patients without tuberous sclerosis: a retrospective study.

Synchronous renal cell neoplasms (RCNs) and angiomyolipomas (AML) occurring in the same kidney are rare. The aim of this retrospective study is to investigate the incidence and clinicopathological features of concurrent AML and RCN in patients without tuberous sclerosis complex (TSC). Partial and radical nephrectomy specimens with a diagnosis of RCN and AML from 1995 to May 2013 were reviewed. Cases were assessed for histological subtype of AML and RCN, topographic relationship between the AML and the RCN, and clinical characteristics. A total of 565 RCNs and 19 AMLs were identified. Of 19 cases of AML, 9 (47%) were associated with renal tumors. Clear-cell renal cell carcinoma (RCC) was the most common malignancy associated with AML (56%). The mean age of patients with concomitant AML and RCN was higher than the mean age of patients with only AML (58.6 vs 55.5 years). The majority of patients with concomitant AML and RCN were female (78%). All concurrent sporadic AMLs were benign. We identified one case of bilateral clear-cell RCC with concomitant multiple bilateral AMLs in a patient with TSC.

Myoepithelial carcinoma of the lung: a review.

Primary myoepithelial carcinoma of the lung is a rare neoplasm with only 8 cases reported in the English literature to date. Myoepithelial carcinomas of the lung are thought to arise from submucosal bronchial glands and have morphologic features similar to their salivary gland counterparts. The pathologic features and immunohistochemical profile of this tumor have not yet been summarized in the literature. Our objective is to review the clinicopathologic features and immunohistochemistry of these tumors.

Myocardial hydrophilic polymer emboli following cardiac catheterization: a case report and literature review.

BACKGROUND: Intravascular polymer emboli have been reported in the skin, lungs, and brain following vascular procedures utilizing hydrophilic polymer coated devices. The Cook arterial introducer sheath was the first of these devices to be introduced, after which case reports followed documenting sterile inflammation at the sheath access site, characterized histologically by perivascular granulomas containing hydrophilic polymer. More recently, hydrophilic polymer emboli have been reported in the vessels of the lungs and brain in association with ischemia and infarct following vascular procedures using polymer coated devices. METHODS: We report a case of intravascular myocardial emboli associated with acute myocardial infarction following cardiac catheterization. The patient was a 65-year-old man who received cardiac catheterization with placement of a bare metal stent following myocardial infarction. One month later, the patient presented with angina and died shortly after admission. RESULTS: Autopsy revealed hemopericardium with rupture of the left ventricle through an aneurismal defect within the area of prior infarction. Microscopically, an area of acute infarction was present within the aneurismal defect. Numerous small and medium-sized vessels within the left ventricle were occluded by basophilic amorphous granular material with an inflammatory giant cell response. CONCLUSION: The emboli were most frequent in the area of acute infarction, suggesting that the emboli may have resulted in ischemia leading to the patient's death. This is the third documented case of intramyocardial polymer emboli following cardiac catheterization and the first case to our knowledge to document an association between intravascular myocardial polymer emboli and acute myocardial infarction.