Restoration of the ER stress response protein TDAG51 in hepatocytes mitigates NAFLD in mice.

Endoplasmic reticulum stress is associated with insulin resistance and the development of nonalcoholic fatty liver disease. Deficiency of the endoplasmic reticulum stress response T-cell death-associated gene 51 (TDAG51) (TDAG51-/-) in mice promotes the development of high-fat diet (HFD)-induced obesity, fatty liver, and hepatic insulin resistance. However, whether this effect is due specifically to hepatic TDAG51 deficiency is unknown. Here, we report that hepatic TDAG51 protein levels are consistently reduced in multiple mouse models of liver steatosis and injury as well as in liver biopsies from patients with liver disease compared to normal controls. Delivery of a liver-specific adeno-associated virus (AAV) increased hepatic expression of a TDAG51-GFP fusion protein in WT, TDAG51-/-, and leptin-deficient (ob/ob) mice. Restoration of hepatic TDAG51 protein was sufficient to increase insulin sensitivity while reducing body weight and fatty liver in HFD fed TDAG51-/- mice and in ob/ob mice. TDAG51-/- mice expressing ectopic TDAG51 display improved Akt (Ser473) phosphorylation, post-insulin stimulation. HFD-fed TDAG51-/- mice treated with AAV-TDAG51-GFP displayed reduced lipogenic gene expression, increased beta-oxidation and lowered hepatic and serum triglycerides, findings consistent with reduced liver weight. Further, AAV-TDAG51-GFP-treated TDAG51-/- mice exhibited reduced hepatic precursor and cleaved sterol regulatory-element binding proteins (SREBP-1 and SREBP-2). In vitro studies confirmed the lipid-lowering effect of TDAG51 overexpression in oleic acid-treated Huh7 cells. These studies suggest that maintaining hepatic TDAG51 protein levels represents a viable therapeutic approach for the treatment of obesity and insulin resistance associated with nonalcoholic fatty liver disease.

Neuroanatomical location of brain metastases from solid tumours based on pathology: An analysis of 511 patients with a comparison to the provided clinical history.

Brain metastases are a frequent occurrence in neuropathology practices. The literature on their neuroanatomical location is frequently derived from radiological analyses. This work examines brain metastases through the lens of pathology specimens. All brain surgical pathology reports for cases accessioned 2011-2020 were retrieved from a laboratory. Specimens were classified by neuroanatomical location, diagnosis and diagnostic category with a hierarchical free text string-matching algorithm (HFTSMA) and also subsequently audited. All reports classified as probable metastasis were reviewed by a pathologist. The provided history was compared to the final categorization by a pathologist. The cohort had 4,625 cases. The HFTSMA identified 854 cases (including metastases from a definite primary, metastases from primary not known and improperly classified cases). 514/854 cases had one definite primary site per algorithm and on report review 538/854 cases were confirmed as such. The 538 cases originated from 511 patients. Primaries from breast, gynecologic tract, and gastrointestinal tract not otherwise specified were most frequently found in the cerebellum. Kidney metastases were most frequently found in the occipital lobe. Lung, metastatic melanoma and colorectal primaries were most commonly found in the frontal lobe. The provided clinical history predicted the primary in 206 cases (40.3%), was discordant in 17 cases (3.3%) and non-contributory in 280 cases (54.8%). The observed distribution of the metastatic tumours in the brain is dependent on the primary site. In the majority (54.8%) of cases, the provided clinical history was non-contributory; this suggests surgeon-pathologist communication may have the potential for optimization.

Role of EBUS-TBNA/EUS-FNA and mass spectrometry for diagnosis and typing of lymph node amyloidosis: 10-year experience in two tertiary care academic centers.

BACKGROUND: The objectives of this study were to investigate the utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)/endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for the diagnosis of amyloidosis coupled with the feasibility of mass spectrometry (MS) for amyloid subtyping. METHODS: All patients who had amyloid diagnosed by EBUS-TBNA/EUS-FNA at two tertiary care centers from 2011 to 2020 were retrieved along with the MS subtype, clinical findings, and outcomes. RESULTS: Eight patients were included: seven underwent EBUS-TBNA of mediastinal lymph nodes, and one underwent EUS-FNA of a periportal lymph node. Ages ranged from 37 to 79 years (median, 69 years), with equal numbers of men and women. Presenting clinical history included one case each of follicular lymphoma, lymphoplasmacytic lymphoma, rheumatoid arthritis, possible sarcoid, cirrhosis, and chronic renal insufficiency, and one case each of suspected pulmonary and cardiac amyloidosis. All cases showed waxy, amorphous material on direct smears (n = 5) or ThinPrep slides (n = 3), which were confirmed as amyloid on Congo Red staining. Immunohistochemistry showed dominant lambda staining in two of three cases. MS was performed in all cases and identified five of the light-chain (AL) type, one of the heavy-chain/AL type, and two suggestive of AL amyloidosis. Bone marrow biopsy performed in seven patients demonstrated that three had monoclonal plasma cells and one had lymphoplasmacytic lymphoma. Two of four patients with systemic amyloidosis received chemotherapy and remained alive, whereas three with localized disease remained stable under observation. CONCLUSIONS: EBUS-TBNA/EUS-FNA is effective for amyloidosis diagnosis and provides adequate material for ancillary tests, including MS, which can identify the precursor amyloidogenic protein, leading to appropriate patient management.

Prevalence of Thyroid Transcription Factor-1 (TTF-1)-Negative Small Cell Carcinoma and Napsin A Positivity in Small Cell Carcinoma in a Cross-Sectional Study of Lung Core Biopsies.

Background The prevalence of thyroid transcription factor-1 (TTF-1) and napsin A expression are poorly characterized in lung core biopsies of small cell carcinoma. Locally, the TTF-1 clone is 8G7G3/1 (Agilent/Dako), and the napsin A clone is IP64 (Leica Biosystems). Methods All in-house lung core biopsy reports for cases accessioned at a regional laboratory from January 2011 to December 2020 were retrieved and analyzed using a validated hierarchical free-text string matching algorithm (HFTSMA) to establish the diagnosis. TTF-1 and napsin A were manually coded with the assistance of a logical text parsing tool. All TTF-1-negative small cell lung carcinoma (SCLC) cases had a full report review by pathologists. Results The cohort had 5,867 lung core biopsies, and 232 cases were confirmed as small cell carcinoma on pathologist review. TTF-1 immunostain results were available in 173 SCLC cases, and 16 cases of TTF-1-negative SCLC were confirmed on full report review. These 16 cases had at least one positive neuroendocrine (NE) marker and positive keratin staining; cases with mixed histology or positive CK5/6 staining were excluded. Ki-67 was done in 10/16 cases; the average Ki-67 was 75%. Napsin A was negative in 50/51 small cell carcinomas, and 0/3 TTF-1-negative SCLC had napsin A positivity. Conclusions Standardized immunostain reporting would simplify such analyses. Based on the cohort, approximately 9% (16/173) of SCLC is TTF-1 negative. Napsin A positivity in suspected small cell carcinoma should prompt consideration of an alternate diagnosis or explanation.

Myeloid-specific deletion of activating transcription factor 6 alpha increases CD11b+ macrophage subpopulations and aggravates lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease of unknown etiology. The accumulation of macrophages is associated with disease pathogenesis. The unfolded protein response (UPR) has been linked to macrophage activation in pulmonary fibrosis. To date, the impact of activating transcription factor 6 alpha (ATF6α), one of the UPR mediators, on the composition and function of pulmonary macrophage subpopulations during lung injury and fibrogenesis is not fully understood. We began by examining the expression of Atf6α in IPF patients' lung single-cell RNA sequencing dataset, archived surgical lung specimens, and CD14+ circulating monocytes. To assess the impact of ATF6α on pulmonary macrophage composition and pro-fibrotic function during tissue remodeling, we conducted an in vivo myeloid-specific deletion of Atf6α. Flow cytometric assessments of pulmonary macrophages were carried out in C57BL/6 and myeloid specific ATF6α-deficient mice in the context of bleomycin-induced lung injury. Our results demonstrated that Atf6α mRNA was expressed in pro-fibrotic macrophages found in the lung of a patient with IPF and in CD14+ circulating monocytes obtained from blood of a patient with IPF. After bleomycin administration, the myeloid-specific deletion of Atf6α altered the pulmonary macrophage composition, expanding CD11b+ subpopulations with dual polarized CD38+ CD206+ expressing macrophages. Compositional changes were associated with an aggravation of fibrogenesis including increased myofibroblast and collagen deposition. A further mechanistic ex vivo investigation revealed that ATF6α was required for CHOP induction and the death of bone marrow-derived macrophages. Overall, our findings suggest a detrimental role for the ATF6α-deficient CD11b+ macrophages which had altered function during lung injury and fibrosis.

The physician factor and anatomical site in 8846 consecutive mediastinal lymph node aspirations in a cross-sectional study.

Mediastinal lymph node fine needle aspiration (MLN-FNA) is a common procedure; however, the physician factor in pathological category, and anatomical site are not routinely assessed. Cytology reports for endobronchial ultrasound (EBUS)/endoscopic ultrasound (EUS) MLN-FNA specimens (8846) were retrieved for July 2012-Dec 2019, classified by hierarchical free text string match algorithm into 51 diagnostic categories, four mutually exclusive diagnostic groups (benign |suspicious |malignant |insufficient), and 24 anatomical sites. Pathologist and submitting physician/surgeon bias were assessed using logistic regression and funnel plots|control charts centered on the group median (diagnostic/capture) rate. Eleven pathologists and seven submitting physician/surgeon were involved in more than 250 specimens each. Overall, the MLN-FNAs were benign|suspicious|malignant|insufficient in 46%|4%|25%|24% of specimens. Percent malignant (number of samples) varied by station; 7| 4R| 4L| 2R| 10R| 11R| 11L were respectively 21%(3,101), 27%(2,453), 19%(1,289), 41%(435), 27%(497), 24%(357), 26%(229). The number of outlier (P < 0.05/P < 0.001) pathologists of 11 from the group median rate for benign|suspicious|malignant|insufficient was 0/0| 3/1| 0/0| 3/0 respectively. The outlier (P < 0.05/P < 0.001) submitting physicians/surgeons of 7 for benign|suspicious|malignant|insufficient was 3/2| 2/2| 3/2| 3/2 respectively. The physician and anatomical site are significant predictors of MLN-FNA pathology.

Routine Pathological Examination of Clinically Presumed Dupuytren Disease: Does It Add Value?

BACKGROUND: In surgery for Dupuytren disease (DD), palmar fascia specimens are routinely submitted for pathological evaluation. The purpose of this study was to determine the rate of discordant diagnosis and the value of, and costs associated with, routine pathological analysis of palmar fascia tissue extracted in surgery for clinically diagnosed DD. METHODS: All pathology reports for in-house palmar fascia specimens obtained in surgery for clinically diagnosed DD (time period: January 2001 to December 2020) were retrieved from one academic institution. All specimens were classified by a hierarchical free-text string matching algorithm (HFTSMA) and searched for evidence of malignancy. The primary outcome was percentage of concordant, discrepant, and discordant diagnoses. Secondary outcomes included anatomical location and costs. The HFTSMA was used to capture the anatomical location. Costs included professional, laboratory processing, and ancillary fees based on the Ontario Schedule of Benefits. RESULTS: The search retrieved 1323 pathology reports, with 1480 palmar fascia specimens, from 1078 individual patients. By diagnosis, 96.1% of specimens (1422/1480) were concordant (fibromatosis), 3.9% (58/1480) were discrepant (scarring/fibrosis, benign fascia/connective tissue, or other benign findings), and 0% (0/1480) were discordant. The most common location was ring finger (n = 381, 48.7%). Ancillary testing was minimal. The cost per palmar fascia specimen was estimated to be CAD $34.57. The institutional costs were approximately CAD $2558.18/year. CONCLUSIONS: Routine pathological examination of specimens in cases of clinically diagnosed DD does not yield additional clinically important findings and may not warrant their costs.

The histologic effects of neoadjuvant stereotactic body radiation therapy (SBRT) followed by pulmonary metastasectomy-rationale and protocol design for the Post SBRT Pulmonary Metastasectomy (PSPM) trial.

Background: For the local management of pulmonary malignancies, surgical resection and stereotactic body radiation therapy (SBRT) are mutually exclusive treatments. This study aims to assess the effectiveness of SBRT on reducing tumor viability at a histologic level in the context of pulmonary metastases. Methods: This protocol describes an open-label unblinded single-arm prospective Phase 2 trial to determine the effects of dual treatment of pulmonary metastasis amenable to curative resection using neoadjuvant SBRT followed by surgical resection, the Post SBRT Pulmonary Metastasectomy (PSPM) trial. Sample size require 39 patients, with an anticipated study duration of 30-36 months. Following completion of SBRT, eligible patients will be assessed at the 4-6-week mark by the treating radiation oncologist and thoracic surgeon with a post-treatment computed tomography (CT) of the chest. Patients with no disease progression will undergo scheduled surgical resection of all metastatic tumors at 8-12 weeks post SBRT. Patients will then be evaluated postoperatively at 30 days, and every 6 months for a total of 36 months with surveillance CT scans. Patients will also undergo sequential serologic evaluation of circulating tumor DNA (ctDNA) levels throughout their respective treatment pathway. The primary outcome of this study is the rate of complete pathologic response (pCR) following SBRT, assess using the International Association for the Study of Lung Cancer (IASLC) multidisciplinary recommendations for pathologic assessment of lung cancer resection specimens after neoadjuvant therapy. Secondary outcomes include overall survival (OS), disease free survival (DFS), local recurrence rates, cancer histology effects on pCR and treatment related complications, and treatment effect on ctDNA levels. Primary and secondary outcomes will be analyzed using Fisher's Exact test and Student's t-test based on data type. Cox-proportional hazard ratios will be used to evaluate OS and DFS, using the log rank test. Discussion: In evaluating the effect of SBRT on pulmonary metastasis at a histologic level, this trial may increase the use of this modality in selected patients who would otherwise only undergo surgery for disease that has already metastasized. Also, the trial provides secondary benefits of evaluating the abscopal effects of radiation on pulmonary metastatic disease, and serves as a platform for more comprehensive large-scale research in this field. Trial Registration: ClinicalTrials.gov identifier: NCT04160143 (HiREB: 7925).

Stability of diagnostic rate in a cohort of 38,813 colorectal polyp specimens and implications for histomorphology and statistical process control.

This work sought to quantify pathologists' diagnostic bias over time in their evaluation of colorectal polyps to assess how this may impact the utility of statistical process control (SPC). All colorectal polyp specimens(CRPS) for 2011-2017 in a region were categorized using a validated free text string matching algorithm. Pathologist diagnostic rates (PDRs) for high grade dysplasia (HGD), tubular adenoma (TA_ad), villous morphology (TVA + VA), sessile serrated adenoma (SSA) and hyperplastic polyp (HP), were assessed (1) for each pathologist in yearly intervals with control charts (CCs), and (2) with a generalized linear model (GLM). The study included 64,115 CRPS. Fifteen pathologists each interpreted > 150 CRPS/year in all years and together diagnosed 38,813. The number of pathologists (of 15) with zero or one (p < 0.05) outlier in seven years, compared to their overall PDR, was 13, 9, 9, 5 and 9 for HGD, TVA + VA, TA_ad, HP and SSA respectively. The GLM confirmed, for the subset where pathologists/endoscopists saw > 600 CRPS each(total 52,760 CRPS), that pathologist, endoscopist, anatomical location and year were all strongly correlated (all p < 0.0001) with the diagnosis. The moderate PDR stability over time supports the hypothesis that diagnostic rates are amendable to calibration via SPC and outcome data.

Evolution of anatomic pathology workload from 2011 to 2019 assessed in a regional hospital laboratory via 574,093 pathology reports.

OBJECTIVE: Quantify changes in workload in relation to the anatomic pathologist workforce. METHODS: In house pathology reports for cytology and surgical specimens from a regional hospital laboratory over a nine- year period (2011-2019) were analyzed, using custom computer code. Report length for the diagnosis+microscopic+synoptic report, number of blocks, billing classification (L86x codes), billings, national workload model (L4E 2018), regional workload model (W2Q), case count, and pathologist workforce in full-time equivalents (FTEs) were quantified. Randomly selected cases (n = 1,100) were audited to assess accuracy. RESULTS: The study period had 574,093 pathology reports that could be analyzed. The coding accuracy was estimated at 95%. From 2011 to 2019: cases/year decreased 6% (66,056 to 61,962), blocks/year increased 20% (236,197 to 283,751), L4E workload units increased 23% (165,276 to 203,894), W2Q workload units increased 21% (149,841 to 181,321), report lines increased 19% (606,862 to 723,175), workforce increased 1% (30.42 to 30.77 FTEs), billings increased 13% ($6,766,927 to $7,677,109). W2Q in relation to L4E underweights work in practices with large specimens by up to a factor of 2x. CONCLUSIONS: Work by L4E for large specimens is underrated by W2Q. Reporting requirements and pathology work-up have increased workload per pathology case. Work overall has increased significantly without a commensurate workforce increase. The significant practice changes in the pathology work environment should prompt local investment in the anatomic pathology workforce.

Russell Body Typhlitis: A Case Report and Literature Review.

Russell bodies are accumulation of immunoglobulin in plasma cells forming intracytoplasmic inclusions. Russell body colitis is rare with only 3 cases described in the English literature up to date. We report a 78-year-old male with cirrhosis showing prominent cecal infiltration of Russell body containing plasma cells. Plasma cells showed no nuclear atypia or mitoses, and no evidence of light chain restriction. In this article, we report a fourth case of Russell body colitis, that is unique in being localized to the cecum in contrast to the other 3, 1 of which was in an inflammatory polyp in the sigmoid colon, 1 in a rectal tubulovillous adenoma and 1 as part of diffuse gastrointestinal disease. This is therefore the first report of localized Russell body typhlitis, occurring in a cirrhotic patient in whom an adjacent erosion was likely nonsteroidal anti-inflammatory drug-associated, a combination that may have facilitated the formation of Russell bodies.

Application of Next Generation Quality/Statistical Process Control and Expert-Led Case Review to Increase the Consistency of Diagnostic Rates in Precancerous Colorectal Polyps.

BACKGROUND: Prior work suggests high interrater variability in the pathologist diagnostic rate (PDR) of the precancerous polyp sessile serrated adenoma (SSA). OBJECTIVES: To improve the diagnostic consistency in the pathological evaluation of colorectal polyp specimens with diagnostic rate awareness, using funnel plots (FPs)/control charts (CCs), and a focused group case review. METHODS: All colorectal polyp specimen (CRPS) reports September 2015 to August 2017 were analyzed at one institution. PDRs were extracted using a hierarchical free-text string matching algorithm and visualized using FPs, showing pathologist specimen volume versus PDR, and CCs, showing pathologist versus normed PDR. The FPs/CCs were centered on the group median diagnostic rate (GMDR). Pathologists were shown their baseline SSA diagnostic rate in relation to the practice, and in January 2017, there was a focused group case review/open discussion of approximately 40 sequential cases signed as SSA with a gastrointestinal pathology expert. RESULTS: Nine pathologists interpreted more than 250 CRPSs per year. FPs/CCs for the first and second years showed 6/4 and 3/1 P < .05/P < .001 pathologist outliers, respectively, in relation to the GMDR for SSA and 0/0 and 0/0 P < .05/P < .001 pathologist outliers, respectively, in relation to the GMDR for tubular adenoma (TA). An in silico kappa (ISK) for SSA improved from 0.52 to 0.62. CONCLUSION: Diagnostic rate awareness facilitated by FPs/CCs coupled with focused expert-led reviews may help calibrate PDR. Variation in SSA PDRs still remains high in relation to TA. ISK represents an intuitive, useful metric and Next Generation Quality/Statistical Process Control a promising approach for objectively increasing diagnostic consistency.

FK506-Binding Protein 13 Expression Is Upregulated in Interstitial Lung Disease and Correlated with Clinical Severity. A Potentially Protective Role.

Pulmonary fibrosis is a progressive lung disease characterized by myofibroblast accumulation and excessive extracellular matrix deposition. We sought to investigate the role of FKBP13 (13-kD FK506-binding protein), an endoplasmic reticulum-resident molecular chaperone, in various forms of pulmonary fibrosis. We first characterized the gene and protein expression of FKBP13 in lung biopsy specimens from 24 patients with idiopathic pulmonary fibrosis and 17 control subjects. FKBP13 expression was found to be elevated in the fibrotic regions of idiopathic pulmonary fibrosis lung tissues and correlated with declining forced vital capacity and dyspnea severity. FKBP13 expression was also increased in lung biopsy specimens of patients with hypersensitivity pneumonitis, rheumatoid arthritis, and sarcoidosis-associated interstitial lung disease. We next evaluated the role of this protein using FKBP13-/- mice in a bleomycin model of pulmonary fibrosis. Animals were assessed for lung function and histopathology at different stages of lung injury including the inflammatory (Day 7), fibrotic (Day 21), and resolution (Day 50) phases. FKBP13-/- mice showed increased infiltration of inflammatory cells and cytokines at Day 7, increased lung elastance and fibrosis at Day 21, and impaired resolution of fibrosis at Day 50. These changes were associated with an increased number of cells that stained positive for TUNEL and cleaved caspase 3 in the FKBP13-/- lungs, indicating a heightened cellular sensitivity to bleomycin. Our findings suggest that FKBP13 is a potential biomarker for severity of interstitial lung diseases and that it has a biologically relevant role in protecting mice against bleomycin-induced injury, inflammation, and fibrosis.

Langerhans Cell Histiocytosis Associated With Renal Cell Carcinoma Is a Neoplastic Process: Clinicopathologic and Molecular Study of 7 Cases.

Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder composed of Langerhans cells admixed with reactive mononuclear and granulocytic cells, associated with prominent eosinophils. LCH is considered a neoplasm, driven in most cases by oncogenic RAS/RAF/MEK/ERK pathway mutations. The disease predominantly affects children. Urinary system involvement has rarely been reported in a multisystem disease setting. We describe 7 patients who presented with LCH occurring within (6 cases) or after (1 case) a resected clear cell (n=6) or clear cell papillary (n=1) renal cell carcinoma (RCC), identified prospectively in our routine and consultation files (2012 to 2019). The patients included 5 women and 2 men, with a median age of 54 years (range, 39 to 73 y), none with a history of LCH or LCH manifestations before the time of RCC diagnosis. The median size of the RCC was 3.5 cm (range, 1.8 to 8.3 cm). Treatment included partial (5 cases), or radical (2 cases) nephrectomy. All RCCs on gross examination showed at least focal cystic changes and were low grade (World Health Organization [WHO]/International Society of Urologic Pathologists [ISUP] grade 1 to 2). The LCH foci were detected as incidental histological finding within the resected RCC in all six cases and they were limited to few high-power fields (<2 mm) in 5 of 6 cases, but in the sixth case, they occupied almost the entire clear cell papillary RCC (2 cm nodule). No LCH manifestations were detected in the normal kidney or in perinephric fat. The seventh patient developed LCH within inguinal deep soft tissue followed by systemic manifestations 6 years after clear cell RCC. Langerhans cell immunophenotype was supported by the reactivity for S-100, CD1a, and langerin and by the negative pankeratin. Successful pyrosequencing of microdissected LCH DNA revealed the V600E BRAF mutation in all 6 cases of LCH within RCC. To our knowledge, only 3 similar cases were published since 1980; the only case tested for BRAF mutation showed wild-type BRAF. This is the first study analyzing the morphologic and genetic features of a cohort of LCH associated with RCC. In our experience, these cases may be underrecognized in practice, or may erroneously be diagnosed as RCC dedifferentiation or high-grade sarcomatoid transformation. Finally, the detection of BRAF mutation further confirms that LCH in this setting is indeed a neoplasm, rather than a reactive lesion.

SDH-deficient renal cell carcinoma - clinical, pathologic and genetic correlates: a case report.

BACKGROUND: Succinate dehydrogenase (SDH)- deficient renal cell carcinoma (RCC) is a newly identified rare subtype of RCC, having only gained acceptance from the World Health Organization in 2016. To the best of our knowledge, there are only 55 reported cases worldwide. Here, we report a new case of SDH-deficient RCC. CASE PRESENTATION: A 49-year-old male patient was incidentally found to have a large right renal mass. He had no personal or family history of paragangliomas (PGL), pheochromocytomas (PC), or gastrointestinal stromal tumors (GIST). The neoplasm was unilateral and unifocal. He underwent an open partial nephrectomy. Detailed pathological analysis was conducted to confirm the diagnosis. Genetic testing revealed a pathogenic mutation in the SDHB gene. He has been followed for 24 months now and has remained well without any evidence of local or distant recurrence. In this report we describe our experience with this diagnosis and review the relevant clinical, pathological, and genetic features. CONCLUSIONS: Without the identification of SDHB deficiency, this patient's personal and familial predisposition to PC, PGL, GIST and metachronous RCCs may have gone undetected despite his RCC diagnosis. When faced with an eosinophilic RCC, pathologists should routinely search for vacuoles or flocculent cytoplasmic inclusions. When these are present, or in cases of difficult eosinophilic renal tumors, staining for SDHB is recommended. For tumours without adverse pathologic features (i.e. high nuclear grade, coagulative necrosis, or sarcomatoid differentiation) excision alone may be a reasonable option, with the addition of regular surveillance for PC and PGLs in those found to harbor germline SDH mutations.

Pulmonary Intravascular B-Cell Lymphoma with Angiotropism/Angioinvasion Mimicking Interstitial Lung Disease: A Clinical Dilemma and Potential Diagnostic Challenge.

Intravascular large B cell lymphoma (IVLBCL) is a rare type of extranodal diffuse large B-cell lymphoma. Patients typically present with nonspecific findings, particularly bizarre neurologic symptoms, fever, and skin lesions. IVLBCL with primary lung presentation is very rare and difficult to diagnose. The authors report a case of a 75-year-old male who presented with neurological symptoms and showed diffuse pulmonary ground glass opacities on computed tomography scan (CT scan). Surgical lung biopsy was performed. Light microscopic examination of the specimen showed diffuse alveolar septal widening caused by neoplastic lymphocytes, which were positive for CD20. These atypical lymphoid cells also demonstrated angiotropism/angioinvasion of the medium sized pulmonary vessels. The patient was diagnosed with IVLBCL and underwent chemotherapy. The patient is still alive 12 months after diagnosis.

A Case of Patch Stage of Kaposi's Sarcoma and Discussion of the Differential Diagnosis.

A 55 year old HIV positive male had a skin lesion biopsy which showed atypical vascular proliferation within the superficial and deep dermis with mild atypia of lining endothelial cells. A sparse lymphoplasmacytic infiltrate surrounding the irregular vascular channels was noted. Immunohistochemistry highlighted the atypical blood vessels with the vascular markers CD31, CD34 and Factor VIII. The differential diagnosis included unusual vascular or lymphatic proliferations, stasis dermatitis, kaposiform hemangioendothelioma, progressive lymphangioma and angiosarcoma with focal Kaposi's sarcoma features. Characteristic human herpes virus-8 positive staining helped support the diagnosis of patch stage of Kaposi's sarcoma. Herein, we discuss the case findings, differential diagnosis and characteristic histological findings associated with the patch stage of Kaposi's sarcoma which can be an elusive diagnosis.

Erythrocyte saturated fatty acids and systemic inflammation in adults.

OBJECTIVE: The role of saturated fatty acids (SFAs) in chronic disease remains controversial; inflammation is one pathway by which SFAs influence the risk for chronic disease. The aim of this study was to investigate the associations between red blood cell (RBC) phospholipid SFAs and systemic inflammation. METHODS: As part of a randomized controlled trial, we measured RBC phospholipid FA composition in 55 generally healthy adults twice at 3-mo intervals. We estimated associations of RBC total SFAs and two major SFA subtypes, palmitic and stearic acids, with C-reactive protein (CRP), interleukin (IL)-6, white blood count (WBC), and a composite inflammation measure using generalized estimating equations in multivariable FA substitution models. RESULTS: Mean (±SD) SFA level across both visits was 45% ± 3% of the total RBC FAs, mainly palmitic (21% ± 1%) and stearic (17% ± 3%) acids. In models adjusted for age, sex, race, smoking, body mass index, statin use, aspirin use, transunsaturated FAs, and ω-3 FAs, SFAs were significantly associated with IL-6 (20% increase per 1 SD increment; 95% confidence interval [CI], 0.03%-43%; P = 0.05) and the composite inflammation measure (P = 0.05) and marginally associated with CRP (34% increase; 95% CI, -1% to 81%; P = 0.06), but not associated with WBC. Stearic acid was positively associated with CRP (35% increase; 95% CI, 2%-79%; P = 0.04). Palmitic acid was marginally associated with the composite inflammation measure (P = 0.06) and, upon additional ω-6 FA adjustment, significantly associated with IL-6 (15% increase; 95% CI, 0.4%-27%; P = 0.006). CONCLUSIONS: RBC SFAs, which represent longer-term dietary intake, are positively associated with inflammation. In particular, palmitic acid was associated with IL-6, and stearic acid was associated with CRP after multivariable adjustment.

Nutrient intake and peripheral artery disease in adults: key considerations in cross-sectional studies.

BACKGROUND & AIMS: There are limited studies of nutrient intake and peripheral artery disease (PAD). Some studies have not accounted for the functional consequences of PAD, potentially leading to biased results. To determine the associations between intakes of dietary fiber, folate, vitamins A, C, E, and B6 and PAD. METHODS: Cross-sectional analysis of 6534 adults aged 40 years and older in the U.S. National Health and Nutrition Examination Survey between 1999 and 2004, including measurement of ankle-brachial index (ABI) and nutrient intake by 24-h dietary recall. Weighted multivariable logistic regression models to determine odds ratios and 95% confidence intervals. RESULTS: The prevalence of PAD (ABI < 0.9) was 5.3% (4.7-5.9). Inverse associations between PAD and intakes of fiber, folate, and vitamins A, B6, C, and E were statistically significant when adjusting for age, sex, hypertension, diabetes and smoking. In models further adjusted for energy intake and physical activity, these odds ratios all became null (p ≥ 0.1). CONCLUSIONS: In this sample, dietary fiber, folate, and vitamins B6, C, and E were not associated with PAD after accounting for energy intake and activity. Adjustment for energy and physical activity are essential to avoid bias due to reverse causation in cross-sectional studies of diet and PAD.

n-3 fatty acids and periodontitis in US adults.

BACKGROUND: Periodontitis is a common, chronic inflammatory disease. Although n-3 fatty acids have anti-inflammatory properties, it is unclear whether n-3 fatty acids can treat or prevent periodontitis. METHOD: We studied 9,182 adults aged 20 years and older who participated in the National Health and Nutrition Examination Survey between 1999 and 2004. Periodontitis was assessed by dental exam and was defined as >4 mm pocket depth and >3 mm attachment loss in any one tooth. Intake of n-3 fatty acids was assessed by 24-hour dietary recall. We used multivariable logistic regression to estimate the associations between periodontitis and intakes of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and linolenic acid (LNA). RESULTS: The weighted prevalence and 95% confidence interval (CI) of periodontitis was 8.2% (95% CI 7.0 to 9.4). Compared with the lowest tertiles, the adjusted odds ratios for periodontitis associated with the highest tertiles of dietary n-3 intake were 0.78 (95% CI 0.61 to 1.00; P=0.009) for DHA, 0.85 (95% CI 0.67 to 1.08; P=0.10) for EPA, and 0.86 (95% CI 0.60 to 1.23; P=0.28) for LNA. The associations were little changed by multivariable adjustment or exclusion of individuals reporting use of dietary supplements containing DHA, EPA, or LNA. CONCLUSIONS: In this nationally representative sample, higher dietary intakes of DHA and, to a lesser degree, EPA, were associated with lower prevalence of periodontitis. Interventional studies are needed to confirm the potential protective effects of n-3 fatty acids on periodontitis.