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The use of lymphoid interstitial pneumonia (LIP) as a diagnostic term has changed considerably since its introduction. Utilizing a multi-institutional collection of 201 cases from the last 20 years that demonstrate features associated with the LIP rubric, we compared cases meeting strict histologic criteria of LIP per American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus ("pathologic LIP"; n=62) with cystic cases fulfilling radiologic ATS/ERS criteria ("radiologic LIP"; n=33) and with other diffuse benign lymphoid proliferations. "Pathologic LIP" was associated with immune dysregulation including autoimmune disorders and immune deficiency, whereas "radiologic LIP" was only seen with autoimmune disorders. No case of idiopathic LIP was found. On histology, "pathologic LIP" represented a subgroup of 70% (62/88) of cases with the distinctive pattern of diffuse expansile lymphoid infiltrates. In contrast, "radiologic LIP" demonstrated a broad spectrum of inflammatory patterns, airway-centered inflammation being most common (52%; 17/33). Only 5 cases with radiologic cysts also met consensus ATS/ERS criteria for "pathologic LIP." Overall, broad overlap was observed with the remaining study cases that failed to meet consensus criteria for "radiologic LIP" and/or "pathologic LIP." These data raise concerns about the practical use of the term LIP as currently defined. What radiologists and pathologist encounter as LIP differs remarkably, but neither "radiologic LIP" nor "pathologic LIP" present with sufficiently distinct findings to delineate such cases from other patterns of diffuse benign lymphoid proliferations. As a result of this study, we believe LIP should be abandoned as a pathologic and radiologic diagnosis.

Context.— Studies of lungs in patients with COVID-19 have focused on early findings. Objective.— To systematically study histopathologic and imaging features and presence of SARS-CoV-2 RNA in lung tissue from patients in later stages of COVID-19. Design.— Autopsies, explants, surgical lung biopsies, transbronchial biopsies, cryobiopsies, and needle biopsies from patients with COVID-19 whose onset of symptoms/confirmed diagnosis was more than 28 days before the procedure were studied. Available images were reviewed. Reverse transcription droplet digital polymerase chain reaction for SARS-CoV-2 RNA was performed on lung tissue. Results.— Of 44 specimens (43 patients; median age, 59.3 years; 26 [60.5%] male) features of acute lung injury (ALI) were seen in 39 (88.6%), predominantly organizing pneumonia and diffuse alveolar damage, up to 298 days after onset of COVID-19. Fibrotic changes were found in 33 specimens (75%), most commonly fibrotic diffuse alveolar damage (n = 22) and cicatricial organizing pneumonia (n = 12). Time between acquiring COVID-19 and specimen was shorter in patients with diffuse ALI (median, 61.5 days) compared with patients with focal (140 days) or no ALI (130 days) (P = .009). Sixteen (of 20; 80%) SARS-CoV-2 reverse transcription droplet digital polymerase chain reaction tests were positive, up to 174 days after COVID-19 onset. Time between COVID-19 onset and most recent computed tomography in patients with consolidation on imaging was shorter (median, 43.0 days) versus in patients without consolidation (87.5 days; P = .02). Reticulations were associated with longer time to computed tomography after COVID-19 onset (median, 82 versus 23.5 days; P = .006). Conclusions.— ALI and SARS-CoV-2 RNA can be detected in patients with COVID-19 for many months. ALI may evolve into fibrotic interstitial lung disease.

OBJECTIVE. The purpose of this article is to characterize the appearance on CT of e-cigarette or vaping product use–associated lung injury (EVALI) in a cohort with histopathologic evidence of this ...

Context.— Diffuse parenchymal lung disease (DPLD) is a well-recognized complication of systemic connective tissue disease (CTD) but rarely arises in patients with psoriasis or psoriatic arthritis, a poorly understood phenomenon. Objective.— To characterize DPLD associated with psoriasis or psoriatic arthritis, with or without prior immunomodulation. Design.— Pathology consultation files were searched for patients having psoriasis or psoriatic arthritis and DPLD. After excluding cases with active infection or smoking-related DPLD only, 44 patients (22 women; median age, 60 years; range, 23–81 years) were enrolled. Clinical history and pathology slides were reviewed. Results.— Twenty-seven of 44 patients (61%) had psoriatic arthritis; the remainder had psoriasis alone. Most presented many years later with nonspecific respiratory symptoms. Nearly one-third had no prior immunosuppression, and most had no concomitant CTD. Radiographically, ground-glass opacities, consolidation, and/or reticulation were typical. Histologically, nonspecific interstitial pneumonia and unclassifiable fibrosis were seen in 24 patients (55%) and 8 patients (18%), respectively; usual interstitial pneumonia and airway-centered fibrosis were rare. Superimposed acute lung injury was common, usually manifesting as organizing pneumonia. Lymphoplasmacytic infiltrates, lymphoid aggregates, and chronic pleuritis were frequent. Interstitial granulomas were seen in 17 patients (39%) but were usually rare, poorly formed, and nonnecrotizing. No histologic differences were apparent among patients with or without concomitant CTDs or prior therapy. Conclusions.— Some patients with psoriasis or psoriatic arthritis develop clinically significant DPLD, even without prior therapy. Histopathologic findings mirror changes seen with other CTDs. Additional studies are warranted to clarify the association between psoriasis or psoriatic arthritis and DPLD.

PURPOSE: Bronchoalveolar lavage and transbronchial biopsy can be a useful tool in the evaluation of interstitial lung disease (ILD), but patient selection for this procedure remains poorly defined. Determining clinical characteristics that help with patient selection for bronchoscopy may improve confidence of ILD classification while limiting potential adverse outcomes associated with surgical lung biopsy. The purpose of this study is to identify factors that were associated with change in multidisciplinary ILD diagnosis (MDD) before and after incorporation of BAL and TBBx data. METHODS: We conducted a retrospective cohort study of ILD patients at a single center who underwent bronchoscopy in the diagnostic workup of ILD. We performed sequential MDD both pre- and post-bronchoscopy to calculate the frequency of change in diagnosis after incorporating information from BAL and TBBx and identify features associated with change in diagnosis. RESULTS: 245 patients were included in the study. Bronchoscopy led to a change in diagnosis in 58 patients (23.7%). The addition of TBBx to BAL increased diagnostic yield from 21.8 to 34.1% (p = 0.027). Identification of antigen, HRCT scan inconsistent with UIP, and absence of a pre-bronchoscopy diagnosis of CTD-ILD or IPAF were associated with a change in diagnosis after bronchoscopy. CONCLUSION: Our study suggests clinical features that may assist with patient selection for bronchoscopy. We suggest bronchoscopy in patients with identified antigen or an HRCT that is consistent with a non-IPF diagnosis. Appropriate patient selection for bronchoscopy may improve ILD diagnostic confidence and avoid potential complications from more invasive and higher risk procedures.

No abstract available. Article truncated after 150 words. Clinical History: A 25-year-old man with no previous medical history presented to the Emergency Room with complaints of worsening non-productive cough and fever to 102°F over the previous 7 days. The patient also complained of some nausea, vomiting, and generalized muscle aches. The patient denies rhinorrhea, sore throat, congestion, and diarrhea. The patient also illicit drug use, and drinks alcohol only occasionally. He said he previously smoked 1-2 packs-per day, having quit 6 months earlier. The patient’s physical examination showed normal vital signs, although his respiration rate was approximately 18/minute. The physical examination showed some mild basilar crackles bilaterally, but was otherwise entirely within normal limits. Basic laboratory data showed a white blood cell count near the upper of normal= 10.3 x 109 / L (normal, 4–10.8 x 109/L) with a normal platelet count and no evidence of anemia, normal serum chemistries and renal function parameters, and normal liver …

Pathologic antibody-mediated rejection (pAMR) occurs in 10% of cardiac transplant patients and is associated with increased mortality. The endomyocardial biopsy remains the primary diagnostic tool to detect and define pAMR. However, certain challenges arise for the pathologist. Accurate identification of >10% of intravascular macrophages along with endothelial swelling, which remains a critical component of diagnosing pAMR, is one such challenge. We used double labeling with an endothelial and histiocytic marker to improve diagnostic accuracy. Twenty-two cardiac transplant endomyocardial biopsies were screened using a CD68/CD31 immunohistochemical (IHC) double stain. To determine whether pAMR diagnosis would change using the double stain, intravascular macrophage staining was compared to using CD68 alone. Twenty-two cardiac pAMR cases from patients were included. Fifty-nine percent of cases previously called >10% intravascular macrophage positive by CD68 alone were called

Background: Hyalinizing clear cell carcinomas of tracheobronchial origin are very rare salivary gland type tumors accounting for less than 1% of lung tumors with only 13 cases reported to date. Their radiological features, morphological spectrum, and molecular features are not well described. Aim: To perform a clinicopathological analysis of primary pulmonary hyalinizing clear cell carcinomas. Method: A retrospective search of primary pulmonary hyalinizing clear cell carcinomas was conducted from authors’ institutions and the clinicopathological features including details of molecular testing were analyzed. Results: Five primary pulmonary hyalinizing clear cell carcinomas were identified. The mean patient age at diagnosis was 48.2 years (range: 33-64 years). Three patients were women. All patients were nonsmokers and 3 were symptomatic; 2 were detected incidentally during health screening. The tumors were located in the main lobar bronchi ranging from 1.3 to 4.9 cm in maximum dimension. Microscopy showed cords and nests of at least, focally clear tumor cells. Mucin cysts lacking goblet cells were seen. All tumors were uniformly positive for p40, p63, AE1/AE3, keratin 7, and epithelial membrane antigen but negative for TTF1, KIT, neuroendocrine markers, and other myoepithelial markers. All cases showed Ewing sarcoma breakpoint region 1 ( EWSR1) gene rearrangement. Perineural invasion and lymph node metastases were detected in patient 5. Two patients with available follow-up data were recurrence-free until 4 years (patient 1) and 9 months (patient 5) after resection. Conclusion: The present series adds to the scant available literature on primary pulmonary hyalinizing clear cell carcinomas highlighting the characteristic histomorphology, immunoprofiles, and benign outcomes of these rare tumors.

Electronic cigarette or vaping product use-associated lung injury most frequently presents with an acute lung injury pattern at CT, manifesting as multifocal ground-glass opacity and/or consolidation, typically multifocal and multilobar, possibly with subpleural sparing. Areas of organization, manifesting as contracting consolidation, mild architectural distortion, intralobular lines, lobular distortion, and traction bronchiectasis may occur as the illness evolves. A CT appearance resembling hypersensitivity pneumonitis, reflecting the exquisitely bronchiolocentric micronodular lesions of organizing pneumonia and acute lung injury seen at histopathologic findings in these patients, may be encountered. Less common CT appearances include organizing pneumonia or acute eosinophilic pneumonia patterns, the latter consisting of multifocal opacity and smooth interlobular septal thickening, possibly with small effusions, but without clinical evidence of volume overload. Patients may present with pneumothorax or pneumomediastinum, or these conditions may develop during their illness course. Most patients improve clinically and at imaging on follow-up, particularly following exposure cessation and corticosteroid therapy, but the time course to improvement is variable and most likely related to the severity of the lung injury. Radiologists should be familiar with the imaging manifestations of vaping-associated pulmonary injury, and the possibility of this condition should be considered when the imaging findings reviewed in this article are encountered. © RSNA, 2020.

Pathology of Vaping-Associated Lung Injury This letter describes findings in 17 patients with a history of vaping who had lung biopsies after presenting with symptoms and bilateral pulmonary opacit...

By nature, idiopathic interstitial pneumonias have been diagnosed in a multidisciplinary manner. As classifications have been subject to significant refinement over the last decade, the importance of correlating clinical, radiologic, and pathologic information to arrive at a diagnosis, which will predict prognosis in any given patient, has become increasingly recognized. In 2013, the American Thoracic Society and European Respiratory Society updated the idiopathic interstitial pneumonias classification scheme, addressing the most recent updates in the field. The purpose of this review is to highlight the correlations between radiologic and pathologic findings in idiopathic interstitial pneumonias while using updated classification schemes and naming conventions.

We report the case of a 78-year-old woman who presented with cardiovascular risk factors and a history of an atypical transient ischaemic attack. She was referred by her primary care physician to the vascular surgery department at our institution for evaluation of progressive weakness, fatigue, arm claudication and difficulty assessing the blood pressure in her right arm. She was being considered for surgical revascularisation, but a careful history and review of her imaging studies raised suspicion for vasculitis, despite her normal inflammatory markers. She was eventually diagnosed with biopsy-proven giant cell arteritis with diffuse large-vessel involvement. Her symptoms improved with high-dose glucocorticoids.

Lung cancer is the leading cause of cancer-related mortality in the United States, and accurate staging plays a vital role in determining prognosis and treatment. The recently revised eighth edition of the TNM staging system for lung cancer defines new T and M descriptors and updates stage groupings on the basis of substantial differences in survival. There are new T descriptors that are based on the findings at histopathologic examination, and T descriptors are reassigned on the basis of tumor size and extent. No changes were made to the N descriptors in the eighth edition of the TNM staging of lung cancer, because the four N categories that are based on the location of the diseased nodes can be used to consistently predict prognosis. The eighth edition includes a new M1b descriptor for patients with a single extrathoracic metastatic lesion in a single organ (M1b), because they have better survival and different treatment options, compared with those with multiple extrathoracic lesions (M1c). Examination with fluorine 18 fluorodeoxyglucose (FDG) PET/CT is the standard of care and is an integral part of the clinical staging of patients with lung cancer. To provide the treating physicians with accurate staging information, radiologists and nuclear medicine physicians should be aware of the updated classification system and should be cognizant of the site-specific strengths and limitations of FDG PET/CT. In this article, the eighth edition of the TNM staging system is reviewed, as well as the role of FDG PET/CT in the staging of non-small cell lung carcinoma. ©RSNA, 2018.

Malignant mesothelioma is an uncommon form of neoplastic transformation of the mesothelial cells that line the serosal surfaces of the body. It most commonly affects the pleura and is often associated with pleural effusions and pleural-based masses. The annual incidence in the United States is only 3300 cases, representing less than 0.3% of all cancers worldwide, although this is likely underestimated. We present a case of diffuse epithelioid malignant pleural mesothelioma in a patient with remote, short-term asbestos exposure complicated by recurrent left-sided hydropneumothoraces and pleural-based invasion of the T12 vertebral body, which represent two rare coexisting complications. This case illustrates the importance of maintaining a broad differential for hydropneumothorax, particularly as the risk factors may be decades removed and the degree of asbestos exposure to induce a malignant mesothelioma may be smaller than has been traditionally thought.

Diffuse parenchymal lung diseases (DPLDs) encompass a variety of restrictive and obstructive lung pathologies. In this article, the authors discuss a series of rare pulmonary entities and their high-resolution computed tomography imaging appearances, which can mimic more commonly encountered patterns of DPLDs. These cases highlight the importance of surgical lung biopsies in patients with imaging findings that do not show typical imaging features of usual interstitial pneumonia.

Pleuroparenchymal fibroelastosis (PPFE) is a rare condition currently described as an upper lobe subpleural and interstitial proliferation of predominantly elastic fibers. The etiology is unknown, and no specific diagnostic criteria have been reported. Here we report 5 cases of PPFE, 1 man and 4 women, 3 of them diagnosed at the time autopsy, 1 diagnosed in an explanted lung, and 1 diagnosed on a surgical wedge biopsy. The average age of diagnosis among this series is 73 years, and the duration of pulmonary symptoms ranged from 14 months to at least 9 years. Two patients had been exposed to specific medications (daptomycin and dapsone) preceding the development of pulmonary symptoms, and 1 patient developed eosinophilic pneumonia in the course of the disease. Four patients had clinical evidence of fibrous interstitial pneumonia. We found evidence of diffuse parenchymal fibroelastosis involving both upper and lower lobes in all 5 cases, suggesting that the disease may be a more diffuse condition than previously reported. PPFE may actually represent a pattern of chronic lung injury rather than a specific entity and may be seen in association with a variety of clinicoradiologic conditions. Based on our findings in this series and the most recent publications of the subject, we propose the following set of diagnostic criteria for PPFE: multilobar subpleural and/or centrilobular fibrous interstitial pneumonia characterized by an extensive (>80%) proliferation of elastic fibers in nonatelectatic lung, along with absent to mild chronic inflammation, and absent to rare granulomas.

Lymphocytic neoplasm involving the heart is not common and usually presents with pericardial effusion or focal myocardial infiltration. Myocardial infarctions due to leukemic infiltration of the coronary arteries are rarely reported. We present the case of a 52-year-old Guatemalan man with a one-year history of untreated T-cell prolymphocytic leukemia. He was admitted to our hospital for chemotherapy and evaluation of a pulmonary cavitary lesion by wedge resection. During sedation, the patient experienced acute respiratory failure and hypovolemic shock, from which he could not be resuscitated. Autopsy revealed that leukemic cells extensively infiltrated the aorta, myocardium, and coronary arteries. The lumina of the 3 major coronary artery branches showed 70% to 95% stenosis, with multifocal remote myocardial infarctions. Tumor cells were also detected in the lungs and other organs. The acute cardiorespiratory insufficiency secondary to leukemia—particularly the extensive infiltration of the coronary arteries and myocardium, and the multiple myocardial infarctions—eventually resulted in cardiac death.

Summary Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small-cell lung cancers (NSCLCs) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here, we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high 18 fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with 13 C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell-autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo .

Organizing pneumonia (OP) is a common pattern of lung injury that can be associated with a wide range of etiologies. Typical and not-so-typical imaging features of OP occur, as both common and rare lung pathologies can mimic the same imaging pattern as that of OP. This article will attempt to describe the difference between confusing terminologies that have been used in the past for OP and existence of primary versus secondary OP. The role of a multidisciplinary approach as an essential component to correctly diagnose and effectively manage challenging cases of OP will be highlighted. Additionally, we will discuss the limitation of transbronchial and importance of open lung biopsy to make the correct diagnosis. One example of an emerging diagnosis in the spectrum of OP and diffuse alveolar damage is acute fibrinous and organizing pneumonia. Ultimately, the reader should feel comfortable recognizing the many variable presentations of OP and be able to participate knowledgeably in a multidisciplinary team after reading this article. OP is a disease entity with variable radiographic and distinct histological characteristics that requires a multidisciplinary approach to correctly diagnose cryptogenic OP. Classic radiologic findings of OP occur in as low as 60% of cases. Secondary causes include infections, neoplasms, inflammatory disorders, and iatrogenic. Acute fibrinous and organizing pneumonia can appear similarly, but miliary nodules are a clue to diagnosis.

Context.—The utility of immunohistochemistry (IHC) in breast lesions needs to be updated with exceptions among these lesions. Biomarker studies with IHC in triple-negative breast carcinoma may help develop targeted therapies for this aggressive breast cancer. The distinction of metastatic lung adenocarcinoma to the breast and invasive breast carcinoma has significant prognostic and therapeutic implications. The determination can be challenging because both primary tumors can express estrogen receptor and/or HER2 by IHC, creating a diagnostic dilemma.Objectives.—To provide a practical update on the use of IHC markers in differential diagnoses in breast lesions, including benign, atypical, precancerous, and malignant tumors; to highlight recently published research findings on novel IHC markers in triple-negative breast carcinoma cases; and to reinforce the importance of IHC use as an ancillary tool in distinguishing metastatic lung adenocarcinoma to the breast from primary breast carcinoma using real case examples.Data Sources.—PubMed (US National Library of Medicine, Bethesda, Maryland) literature review and authors' research data and personal experiences were used in this review.Conclusions.—Immunohistochemistry has an important role in making differential diagnoses in breast lesions in morphologically equivocal settings; recognizing IHC expression status in the exceptions among these lesions will aid in the correct diagnosis of challenging breast cases. Studies suggest that androgen receptor, p16, p53, GATA3, and PELP1 may have potential diagnostic, prognostic, and predictive value in triple-negative breast carcinoma cases; these findings may provide insight and a greater understanding of the tumor biology in triple-negative breast carcinomas. In distinguishing metastatic estrogen receptor–positive or HER2+ lung adenocarcinoma to the breast from primary breast carcinoma, napsin A, TTF-1, and GATA3 comprise a useful IHC panel.

[Figure][1] A 33-year-old African American man with end-stage renal disease on hemodialysis for 5 years presented with anemia and splenomegaly. His peripheral blood smear demonstrated anemia (hemoglobin 77 g/L) with anisopoikilocytosis including occasional teardrop cells (panel A, green

Cobalt exposure in the hard metal and bonded diamond tool industry is a well-established cause of ILD. The primary theories regarding the underlying mechanism of cobalt related ILD include an immunologic mechanism and an oxidant injury mechanism. Cobalt related ILD may present in subacute and chronic forms and often has associated upper respiratory symptoms. The evaluation begins with a thorough occupational history and includes PFTs, HRCT, and bronchoalveolar lavage. HRCT findings are nonspecific and may resemble NSIP, UIP, sarcoidosis, or HP. The finding of cannibalistic multinucleated giant cells is diagnostic provided there is a history of exposure and appropriate changes on imaging; however, when these cells are not found on lavage, lung biopsy is required for diagnosis. Giant cell interstitial pneumonia is the classic pathologic pattern, but cobalt related ILD may also present with pathologic findings of UIP, DIP, or HP. When cobalt related ILD is suspected, removal from exposure is the most important step in treatment. Case reports suggest that treatment with steroids results in symptomatic, physiologic, and radiographic improvement.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are a continuum of lung changes arising from a wide variety of lung injuries, frequently resulting in significant morbidity and frequently in death. Research regarding the molecular pathophysiology of ALI/ARDS is ongoing, with the aim toward developing prognostic molecular biomarkers and molecular-based therapy.Context.—To review the clinical, radiologic, and pathologic features of ALI/ARDS; and the molecular pathophysiology of ALI/ARDS, with consideration of possible predictive/prognostic molecular biomarkers and possible molecular-based therapies.Objective.—Examination of the English-language medical literature regarding ALI and ARDS.Data Sources.—ARDS is primarily a clinicoradiologic diagnosis; however, lung biopsy plays an important diagnostic role in certain cases. A significant amount of progress has been made in the elucidation of ARDS pathophysiology and in predicting patient response, however, currently there is no viable predictive molecular biomarkers for predicting the severity of ARDS, or molecular-based ARDS therapies. The proinflammatory cytokines TNF-α (tumor necrosis factor α), interleukin (IL)–1β, IL-6, IL-8, and IL-18 are among the most promising as biomarkers for predicting morbidity and mortality.Conclusions.—

ContextBronchioloalveolar carcinoma is a term that has served lung pathology well for almost a century; however, more accurate terms have recently been suggested to better characterize the various lesions that have formerly all been considered bronchioloalveolar carcinoma.ObjectivesTo evaluate the origin and history of the term bronchioloalveolar carcinoma and to compare the term's traditional uses with current understanding and terminology of lung lesions formerly termed bronchioloalveolar carcinoma.Data SourcesReview of the literature pertaining to bronchioloalveolar carcinoma.ConclusionsBronchioloalveolar carcinoma has been an extremely useful term for many decades; however, it has now obtained respected obsolescence. Novel, more medically appropriate terms have been suggested for the group of lesions formerly termed bronchioloalveolar carcinoma, and these newer terms should now be routinely used.

Although mitochondrial fatty acid beta-oxidation (FAO) is considered to be well understood, further elucidation of the pathway continues through evaluation of patients with FAO defects. The FAO pathway can be examined by measuring the 3-hydroxy-fatty acid (3-OHFA) intermediates. We present a unique finding in the study of this pathway: the addition of medium-chain fatty acids to the culture media of fibroblasts results in generation of 3-OHFAs which are two carbons longer than the precursor substrate. Cultured skin fibroblasts from normal and LCHAD-deficient individuals were grown in media supplemented with various chain-length fatty acids. The cell-free medium was analyzed for 3-OHFAs by stable-isotope dilution gas-chromatography/mass-spectrometry. Our finding suggests that a novel carbon chain-length elongation process precedes the oxidation of medium-chain fatty acids. This previously undescribed metabolic step may have important implications for the metabolism of medium-chain triglycerides, components in the dietary treatment of a number of disorders.

The treatment for patients with genetic disorders of mitochondrial long-chain fatty acid beta-oxidation is directed toward providing sufficient sources of energy for normal growth and development, and at the same time preventing the adverse effects that precipitate or result from metabolic decompensation. Standard of care treatment has focused on preventing the mobilization of lipids that result from fasting and providing medium-chain triglycerides (MCT) in the diet in order to bypass the long-chain metabolic block. MCTs that are currently available as commercial preparations are in the form of even-chain fatty acids that are predominately a mixture of octanoate and decanoate. Recently, the use of odd-chain fatty acids has been proposed as an alternative treatment. We have shown previously that the even-numbered medium-chain fatty acids (MCFAs) that are found in MCT preparations can reduce the accumulation of potentially toxic long-chain metabolites of fatty acid oxidation (FAO). In the current study, we undertook to determine if the same is true of odd-numbered MCFAs. We found that provision of odd-chain species does decrease the build-up of long-chain FAO intermediates in our in vitro skin fibroblast model, but to a lesser extent than even-numbered MCFAs.

We present a rare of case of a carcinoid tumor-causing Cushing syndrome. Cushing syndrome, if left untreated, can result in severe morbidity and even mortality. Common causes of endogenous Cushing include pituitary gland adenomas and excess cortisol produced from various adrenal gland pathologies. Rarely, tumors such as pulmonary neuroendocrine tumors can produce adrenocorticotropic hormone (ACTH) and cause …

Although pilocytic astrocytoma (PA) is the most common brain tumor diagnosed in children, few prognostic variables have been delineated that stratify the risk of clinical progression in patients with this tumor. In this study, the MIB-1 labeling index was compared with 2 other immunohistochemical markers of cell proliferation, phospho-histone H3 (PHH3) and mini-chromosomal maintenance protein 2 (MCM2) in 80 incompletely resected PAs to see which was best able to identify patients at risk for tumor progression. 0(6)-Methylguanine-DNA methyltransferase (MGMT) protein expression, which has been predictive of progression-free survival (PFS) in high-grade gliomas in children, was also evaluated in these cases. The mean follow-up period was 7.81 ± 3.9 years, and 42.8% of tumors have shown progression at the time of censoring. A MIB-1 labeling index ≥2.0 was associated with shortened PFS as a grouped variable by log-ranked analysis (P = .03) and by Cox regression analysis as a continuous variable (P = .007). None of the other potential biomarkers was significantly predictive of PFS. Although the amount of MCM2 staining correlated with the MIB-1 labeling index (P < .001), MCM2 reactivity was not independently associated with outcome. We conclude that MIB-1 labeling remains the best predictor of PFS in pediatric PAs.

The mechanism of insulin dysregulation in children with hyperinsulinism associated with inactivating mutations of short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) was examined in mice with a knock-out of the hadh gene (hadh(-/-)). The hadh(-/-) mice had reduced levels of plasma glucose and elevated plasma insulin levels, similar to children with SCHAD deficiency. hadh(-/-) mice were hypersensitive to oral amino acid with decrease of glucose level and elevation of insulin. Hypersensitivity to oral amino acid in hadh(-/-) mice can be explained by abnormal insulin responses to a physiological mixture of amino acids and increased sensitivity to leucine stimulation in isolated perifused islets. Measurement of cytosolic calcium showed normal basal levels and abnormal responses to amino acids in hadh(-/-) islets. Leucine, glutamine, and alanine are responsible for amino acid hypersensitivity in islets. hadh(-/-) islets have lower intracellular glutamate and aspartate levels, and this decrease can be prevented by high glucose. hadh(-/-) islets also have increased [U-(14)C]glutamine oxidation. In contrast, hadh(-/-) mice have similar glucose tolerance and insulin sensitivity compared with controls. Perifused hadh(-/-) islets showed no differences from controls in response to glucose-stimulated insulin secretion, even with addition of either a medium-chain fatty acid (octanoate) or a long-chain fatty acid (palmitate). Pull-down experiments with SCHAD, anti-SCHAD, or anti-GDH antibodies showed protein-protein interactions between SCHAD and GDH. GDH enzyme kinetics of hadh(-/-) islets showed an increase in GDH affinity for its substrate, α-ketoglutarate. These studies indicate that SCHAD deficiency causes hyperinsulinism by activation of GDH via loss of inhibitory regulation of GDH by SCHAD.

Context.— Vaping is the inhalation of heated aerosol from a small battery-powered device as a method to deliver nicotine or other substances. A recent outbreak of severe respiratory illness primarily in the United States has put a spotlight on vaping and its potential risks. Objective.— To familiarize pathologists with vaping, the cytologic and histopathologic features of vaping-associated acute lung injury, and the role of pathology in this diagnosis. Data Sources.— A targeted literature review was performed. Conclusions.— Most cases of vaping-associated lung injury have been linked to vaping products containing tetrahydrocannabinol or other cannabinoids. Lung biopsies show a spectrum of nonspecific acute lung injury patterns (organizing pneumonia, diffuse alveolar damage, acute fibrinous, and organizing pneumonia, or combinations of the above), accompanied by prominent, foamy macrophage accumulation. Injury is usually accentuated around small airways. Lipid-laden macrophages can be identified in bronchioloalveolar lavage fluid in most patients and these can be highlighted using lipid stains, such as oil red O, but the clinical utility of this finding remains unclear, as lipid-laden macrophages can be seen in a wide variety of processes and should not be relied upon to make the diagnosis. Classic histologic features of exogenous lipoid pneumonia have not been identified in tissue samples. Lightly pigmented macrophages, similar to those seen with traditional cigarette smoking, are present in some cases but are usually a minor feature. To date, no specific pathologic features for vaping-related injury have been identified, and it remains a diagnosis of exclusion that requires clinicopathologic correlation.

Preeclampsia is a multifactorial pregnancy-specific disease. In some cases, severe preeclampsia and related disorders of acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, low platelets syndrome are associated with inherited defects in mitochondrial β-oxidation of fatty acids, especially a deficiency of long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD). Recently, an unexplained increase in the incidence of preeclampsia has been documented in human immunodeficiency virus (HIV)–infected pregnant women on treatment with highly active antiretroviral therapy (HAART). We performed this study to determine if antiretroviral drugs affect mitochondrial β-oxidation fatty acids in vitro. Two normal and 1 heterozygous LCHAD-deficient cell lines were exposed to up to 5 times the therapeutic concentrations of the following antiretroviral drugs: nevirapine, didanosine, lamivudine, and a combination of nelfinavir, zidovudine, and lamivudine. One homozygous LCHAD-deficient cell line served as the positive control. After exposure of the fibroblasts to these drugs for periods ranging from 2 to 10 days, accumulations of even-chain 3-hydroxy fatty acids (3-OH-C6 to 3-OH-C18) in the culture media were measured by stable-isotope dilution gas chromatography/mass spectrometry. Compared to the respective unexposed fibroblasts, there was no significant build-up of 3-hydroxy fatty acids in the culture media of normal or heterozygous LCHAD-deficient fibroblasts exposed to antiretroviral drugs. Our results show that the commonly used antiretroviral drugs do not adversely affect fatty acid oxidation in fibroblasts. Therefore, an altered fatty acid oxidation may not be the mechanism for the reported increased risk of preeclampsia in HIV-infected pregnant women on HAART.

Dietary management of long-chain l-3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency involves a regimen that contains adequate carbohydrate, protein, and essential lipids, and supplementation with medium-chain fatty acids in the form of medium-chain triglycerides, providing energy from fats that bypasses the long-chain metabolic block. This study analyzes the effects of dietary treatment of LCHAD deficiency in an in vitro model. Cultured skin fibroblasts from LCHAD-deficient and normal individuals were grown in media supplemented with physiologic combinations of medium-chain fatty acids octanoate and decanoate, and the long-chain palmitate. Medium was removed from the cells after various incubation times, and assayed for 3-hydroxy-intermediates of fatty acid oxidation. The 3-hydroxy-fatty acids were measured by stable-isotope dilution gas chromatography/mass spectrometry. We found that the addition of medium-chain fatty acids caused a decrease in the accumulation of long-chain fatty acid oxidation intermediates in LCHAD-deficient cells when the cells were incubated in untreated medium, and also when they were incubated in this medium with palmitate added. Medium with decanoate alone was better at achieving this effect than medium with only octanoate added. A 1:3 ratio of octanoate to decanoate worked best over an extended time period in LCHAD-deficient cells in untreated medium, whereas a 1:1 ratio of octanoate to decanoate worked best in the same cells incubated in medium containing palmitate. In all dietary medium-chain triglyceride preparations, the ratio of octanoate was greater than that of decanoate. Our results suggest that a medium-chain triglyceride preparation that is higher in decanoate may be more effective in reducing the accumulation of potentially toxic long-chain 3-hydroxy-fatty acids in LCHAD deficiency.