Harnessing the Power of Purple Sweet Potato Color and Myo-Inositol to Treat Classic Galactosemia.

Classic Galactosemia (CG) is a devastating inborn error of the metabolism caused by mutations in the GALT gene encoding the enzyme galactose-1 phosphate uridylyltransferase in galactose metabolism. Severe complications of CG include neurological impairments, growth restriction, cognitive delays, and, for most females, primary ovarian insufficiency. The absence of the GALT enzyme leads to an accumulation of aberrant galactose metabolites, which are assumed to be responsible for the sequelae. There is no treatment besides the restriction of dietary galactose, which does not halt the development of the complications; thus, additional treatments are sorely needed. Supplements have been used in other inborn errors of metabolism but are not part of the therapeutic regimen for CG. The goal of this study was to test two generally recognized as safe supplements (purple sweet potato color (PSPC) and myo-inositol (MI)) that may impact cellular pathways contributing to the complications in CG. Our group uses a GalT gene-trapped mouse model to study the pathophysiology in CG, which phenocopy many of the complications. Here we report the ability of PSPC to ameliorate dysregulation in the ovary, brain, and liver of our mutant mice as well as positive results of MI supplementation in the ovary and brain.

Assessment of ataxia phenotype in a new mouse model of galactose-1 phosphate uridylyltransferase (GALT) deficiency.

Despite adequate dietary management, patients with classic galactosemia continue to have increased risks of cognitive deficits, speech dyspraxia, primary ovarian insufficiency, and abnormal motor development. A recent evaluation of a new galactose-1 phosphate uridylyltransferase (GALT)-deficient mouse model revealed reduced fertility and growth restriction. These phenotypes resemble those seen in human patients. In this study, we further assess the fidelity of this new mouse model by examining the animals for the manifestation of a common neurological sequela in human patients: cerebellar ataxia. The balance, grip strength, and motor coordination of GALT-deficient and wild-type mice were tested using a modified rotarod. The results were compared to composite phenotype scoring tests, typically used to evaluate neurological and motor impairment. The data demonstrated abnormalities with varying severity in the GALT-deficient mice. Mice of different ages were used to reveal the progressive nature of motor impairment. The varying severity and age-dependent impairments seen in the animal model agree with reports on human patients. Finally, measurements of the cerebellar granular and molecular layers suggested that mutant mice experience cerebellar hypoplasia, which could have resulted from the down-regulation of the PI3K/Akt signaling pathway.

Galactose-1 phosphate uridylyltransferase (GalT) gene: A novel positive regulator of the PI3K/Akt signaling pathway in mouse fibroblasts.

The vital importance of the Leloir pathway of galactose metabolism has been repeatedly demonstrated by various uni-/multicellular model organisms, as well human patients who have inherited deficiencies of the key GAL enzymes. Yet, other than the obvious links to the glycolytic pathway and glycan biosynthetic pathways, little is known about how this metabolic pathway interacts with the rest of the metabolic and signaling networks. In this study, we compared the growth and the expression levels of the key components of the PI3K/Akt growth signaling pathway in primary fibroblasts derived from normal and galactose-1 phosphate uridylyltransferase (GalT)-deficient mice, the latter exhibited a subfertility phenotype in adult females and growth restriction in both sexes. The growth potential and the protein levels of the pAkt(Thr308), pAkt(Ser473), pan-Akt, pPdk1, and Hsp90 proteins were significantly reduced by 62.5%, 60.3%, 66%, 66%, and 50%, respectively in the GalT-deficient cells. Reduced expression of phosphorylated Akt proteins in the mutant cells led to diminished phosphorylation of Gsk-3ß (-74%). Protein expression of BiP and pPten were 276% and 176% higher respectively in cells with GalT-deficiency. Of the 24 genes interrogated using QIAGEN RT(2) Profiler PCR Custom Arrays, the mRNA abundance of Akt1, Pdpk1, Hsp90aa1 and Pi3kca genes were significantly reduced at least 2.03-, 1.37-, 2.45-, and 1.78-fold respectively in mutant fibroblasts. Both serum-fasted normal and GalT-deficient cells responded to Igf-1-induced activation of Akt phosphorylation at +15 min, but the mutant cells have lower phosphorylation levels. The steady-state protein abundance of Igf-1 receptor was also significantly reduced in mutant cells. Our results thus demonstrated that GalT deficiency can effect down-regulation of the PI3K/Akt growth signaling pathway in mouse fibroblasts through distinct mechanisms targeting both gene and protein expression levels.

Encapsulated Papillary Oncocytic Neoplasm: A Newly Recognized Hurthle Cell Neoplasm With Unique Morphology.

Diagnosis of oncocytic neoplasm of the thyroid gland can be challenging especially on fine needle aspiration biopsy (FNAB), given the wide differential diagnoses. In this report, we present the case of a 66-year-old male with an incidental thyroid nodule identified on imaging. In this case, identification of the distinctive cytologic features leads to the diagnosis of papillary oncocytic neoplasm on FNAB and helped to decide the appropriate surgical management. To date, the cytomorphologic features of this lesion are not well studied and established, with only a single case report in the literature. Herein, we describe the characteristic cytomorphologic and immunophenotypic features of this neoplasm. The recognition of the unique cytomorphologic features and awareness of the non-classic expression of the thyroid lineage markers will help in accurate diagnosis and management of this entity.

Uterine Sarcoma Presenting as Hypercapnic Respiratory Failure.

Thyroid cancer is a type of malignancy that is considered to have a low morbidity and an indolent disease course in most patients. Though some of its pathologic variants such as anaplastic carcinoma may present with advanced disease staging, it is important to consider the possibility of metastasis to thyroid which may present like a thyroid primary. Solid organ carcinomas form the bulk of the uncommon metastasis to the thyroid, though sarcomas from various organs also rarely exhibit this activity. Literature demonstrating sound diagnostic criteria for these occurrences is sparse. We present a case of uterine sarcoma with distant metastasis to the thyroid gland that initially presented as hypercapnic respiratory failure. Only an inpatient episode of uterine bleeding prompted our team to explore the potential of a metastatic process. Our diagnosis was made utilizing a multidisciplinary approach that we feel is important for clinicians dealing with metastatic disease to the thyroid. In addition to sound physical exam, and use of appropriate imaging modality, we feel it is essential to utilize a detailed cytohistologic specimen evaluation, immunohistochemistry, and genetic sequencing to effectively work up such patients. Although our patient did not survive her hospital stay, we hope this paper brings greater awareness of this malignancy and acts as a benchmark for diagnosing such an unusual remote primary.

Concomitant Gastric Malignancy and Hepatocellular Carcinoma.

Multiple primary malignant tumors (MPMTs) are two or more separate malignancies found at different sites concurrently. Prior studies have shown that the most common tumor associations in MPMTs are typically between two tumors in the digestive system. We present a case of a male patient in his 60s who initially presented with melena and was found to have a clean-based gastric ulcer on initial endoscopic evaluation. Repeat endoscopy on later admission revealed persistent ulceration. Biopsy showed Epstein-Barr virus (EBV) positive lymphoepithelioma-like gastric carcinoma (LELGC), a rare gastric malignancy. The patient underwent endoscopic ultrasound (EUS) for assessment of tumor depth and involvement of perigastric lymph nodes, but was incidentally found to have a liver lesion. Biopsy of the liver lesion was positive for hepatocellular carcinoma (HCC) with no morphologic similarity to the gastric malignancy. This case highlights a rare finding of MPMTs. In addition to the diagnosis of a rare gastric malignancy, the patient developed a well-known but uncommon phenomenon of non-cirrhotic HCC associated with hepatitis C virus (HCV). Due to an increasing number of advances in cancer therapy that are leading to increased survival times, clinicians can expect for a patient to develop MPMTs in their lifetime. A high index of suspicion must exist for the possibility of MPMTs because treatment options and outcomes can be vastly affected by their findings.

Toward realization of remote controlled telecytopathology-a validation study from a large academic medical center from the southeast United States.

INTRODUCTION: With increase in the number and types of biopsies requiring rapid on-site evaluation for adequacy, telecytopathology is one of the solutions. MATERIALS AND METHODS: Using a microscope camera with MS Surface Pro, a live telecytopathology audio video feed for the adequacy of 55 study set validation cases was sent over Zoom from the satellite hospital over 10 miles away with cytopathologists at the main hospital. The study set cases included Diff-Quik-stained smears and core imprints. RESULTS: The overall percent of positive agreement (accuracy) for adequacy during rapid on-site evaluation via telecytopathology was 96%. Core imprint percentage for positive agreement was slightly higher (96.2%), than fine-needle aspiration smears (95.8%). CONCLUSIONS: Use of telecytopathology is the best solution for optimizing the cytopathologist's time for evaluating biopsy adequacy from distant sites.

Malignant Müllerian Adenocarcinoma Manifesting With Cardiac Tamponade and Pleural Effusion.

A 54-year-old woman with a past medical history of untreated stage IV Müllerian adenocarcinoma presented for dyspnea. She was found to have a large right-sided pleural effusion through basic radiology and clinically improved after a CT-guided therapeutic thoracocentesis. However, the patient rapidly deteriorated shortly afterward. A broader workup that included echocardiography revealed a large pericardial effusion with tamponade physiology. The patient underwent an emergent pericardiocentesis, which briefly improved hemodynamics, but her clinical status kept declining until she eventually expired. Subsequent cytology of the pleural and pericardial fluid revealed malignant cells of Müllerian origin.

"Complex" Vasovagal Syncope: A Zebra Among Horses.

Background: Vasovagal syncope (VVS) occurs due to cerebral hypoperfusion from a fall in blood pressure, with accompanying bradycardia in most cases. Seizure and/or asystole may accompany VVS, though their prediction within the VVS cohort remains elusive. Objective: To further characterize VVS and to find predictive features of "complex" VVS (defined as VVS associated with seizures and/or asystole). Methods: We reviewed medical records of all patients who were referred for orthostatic intolerance and had a definite VVS during the head-up tilt table testing (HUTT). The following variables were recorded: cardiovascular indices during HUTT, autonomic testing results, and semiology of asystole and/or seizure when present. Simple frequency and correlation analysis were performed using the ANOVA. Results: A total of 78 independent VVS were recorded in 60 patients of which 24% were not preceded by presyncope. Vasodepressor (45%) and mixed (38%) VVS were the most prevalent types. Eighteen (23%) were complex VVS; five had an associated seizure (SySz), nine were accompanied by asystole (SyAs), and four had both (SySzAs). Males were significantly more likely to have complex VVS. Mean asystole duration was somewhat longer in the SyAsSz group. The severity of bradycardia significantly correlated with complex VVS and was a predictor of SySz. Autonomic abnormalities were frequent but did not distinguish the two VVS subgroups. Seizures had multiple distinguishing features from those typically associated with epileptic seizures. Conclusions: The underlying pathophysiologic mechanisms of complex VVS remain unclear, but the severity of cerebral hypoperfusion due to bradycardia likely plays a key role in seizure generation.

A Rare Case of Metastatic Hepatocellular Carcinoma Masquerading as a Forehead Hematoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and can arise from any form of chronic liver disease or cirrhosis. With increasing rates of metabolic syndrome and obesity, it is not surprising that NASH is quickly becoming a leading cause of chronic liver disease and HCC in the western hemisphere (Wang and Malhi, 2018). Metastasis is usually found in advanced stages of the disease, owing to its poor prognosis. The lung, bone, and lymph nodes are the most frequent sites of metastasis (Balogh et al., 2016, and Becker et al., 2014). On the other hand, metastasis to the skin and cranium is relatively rare. Literature review reveals less than 10 reported cases in the last 10 years. Herein, we report an unusual case of a "forehead hematoma" leading to the formal diagnosis of metastatic HCC.

Prevalence of epithelial abnormalities and high-risk human papilloma virus in cervicovaginal Pap smears of population subgroups as a guide toward evidence-based best practice.

BACKGROUND: The 2012 American Society for Colposcopy and Cervical Pathology Consensus Guidelines provide information for managing abnormal cervical cancer screening tests and cancer precursors. According to these guidelines for Pap smear diagnosis of Atypical squamous cells of undetermined significance, reflex high risk (HR) human papilloma virus (HPV) genotyping is required among women 21 years of age or older. Whereas, in women of 30 to 65 years of age, HR-HPV can be ordered by the clinicians as part of co-testing with any diagnosis and every 5 years with a negative Cervico-Vaginal Pap test (CVPT). METHODS: A retrospective review of the CoPath database of the Pathology Department at the University of Florida, College of Medicine Jacksonville, FL, was performed to identify North Florida (NF) women who underwent CVPT and HR-HPV testing between 2006 and 2014. The women were stratified by race and age, respectively. RESULTS: The study included 19,933 CVPTs. Significant differences in the outcomes' distributions were found among age and race groups, respectively. Highest prevalence of HPV positivity was found in African American women, and in 14- to 20-year-old women, respectively. Twenty- to 30-year-old women had the highest percentage (59%) of epithelial abnormality. The most common HR-HPV genotypic distribution was other HR-HPV. CONCLUSIONS: This study underscores the importance of using both HR-HPV and CVPT for screening for cervical cancer, and confirms the need for special focus on managing high-risk populations subgroups, such as African American women, and women of ages 14 to 20 years especially in high-risk populations.

Malignant seeding of percutaneous endoscopic gastrostomy tract in patient with head and neck cancer.

Malignant seeding of the percutaneous endoscopic gastrostomy (PEG) stoma is a rare and unusual complication of PEG performed in patients with head and neck cancer. Direct seeding of PEG stoma is believed to be the culprit. We present one such case of metastasis that lends support to an alternate hypothesis of vascular spread. First responders in such cases are usually not gastroenterologists and may include dieticians, primary care physicians, and radiologists. As such, we also provide pictures that would help the health care providers recognize this rare entity and manage appropriately and promptly.

Solitary fibrous tumor of the lung: a case report with a study of the aspiration biopsy, histopathology, immunohistochemistry, and autopsy findings.

Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm of ubiquitous location. In addition to its classic presentation as a pleural-based mass, it can be encountered in a variety of other sites. A pleural-based lung lesion can be easily accessed by radiologic guidance for cytologic study. Several reports have described the cytologic findings of SFT at various locations, including the lung. However, diagnostic difficulties can occur due to unusual clinical, radiologic, atypical cytomorphologic, and histologic features. We describe a case of intrapulmonary SFT in which a false-positive malignant diagnosis was rendered on fine-needle aspiration biopsy and concurrent surgical core biopsy prior to radiofrequency ablation. The patient died of procedural complications, and an autopsy was performed. Retrospective study of the case, especially correlation of cytologic, histologic, autopsy findings, and immunohistochemistry results were helpful in correctly diagnosing the case as SFT. We are reporting this case with emphasis on avoiding diagnostic pitfalls by being familiar with the accepted cytohistologic features and appropriate immunohistochemical results.

Brace yourself: an unusual case of knee pain, an extradigital glomangioma of the knee.

The differential diagnosis for knee pain is extensive. Glomus tumors comprise approximately 1.6% of soft-tissue tumors in the extremities. Classic subungual tumors occur more frequently in women, whereas ectopic locations are more common in men. Unusual locations include the stomach; lungs; trachea; bones; intestines; fallopian tubes; and intraneural, neuromal, and intravenous locations. We present the case of a 50-year-old man with a 12-year history of enlarging right knee mass found to be a glomangioma. This case report discusses the incidence, presentation, imaging characteristics, histology, and management of glomus tumors of the knee.

Fine needle aspiration biopsy of vertebral and paravertebral lesions: retrospective study of 124 cases.

OBJECTIVE: To evaluate the diagnostic value of image-guided fine needle aspiration biopsy (FNAB) in the diagnosis and management of vertebral and paravertebral lesions and to review similar studies in the literature. STUDY DESIGN: One hundred twenty-four FNAB cases (113 [corrected] patients) of vertebral and paravertebral lesions occurring over a 10-year period were retrieved from the archives of the University of Mississippi Medical Center for review and clinico-radiologic correlation. Thirty-four of the cases included a concurrent core needle biopsy sample, 15 cases had subsequent surgical specimens, while 32 cases had previously established malignancy. The age range was 11 days to 91 years (mean, 46 years), with 57 male patients and 56 female. RESULTS: One hundred five cases were vertebral lesions, and 19 cases were paravertebral lesions. FNAB diagnosis were malignant in 33.87% of cases, benign in 5.64%, suspicious in 4.03%, infectious/inflammatory and degenerative in 12.91%, unsatisfactory in 16.13% and negative in 27.42%. The overall sensitivity of the procedure was 89.3% and the specificity, 93.8%. The positive predictive value was 95.7% and negative predictive value, 85.2%. CONCLUSION: FNAB is an effective means of establishing a definitive diagnosis of vertebral and paravertebral lesions, allowing appropriate patient management. Cell blocks, core biopsies and ancillary studies are useful adjuncts in rendering the diagnosis.

Diagnostic value and accuracy of imprint cytology evaluation during image-guided core needle biopsies: Review of our experience at a large academic center.

BACKGROUND: Several studies have emphasized the value of on-site evaluation of imprint cytology (IC) performed on core needle biopsies (CNB) of breast, prostate, and lung, in terms of adequacy. The aim of this study was to investigate the diagnostic value and accuracy of rapid on-site IC of CNB specimens performed for liver, lung, lymph node, bone, and soft tissue masses to evaluate whether on-site preliminary diagnosis is sufficiently accurate to allow earlier, more efficient planning of ancillary studies with decreased turnaround time. METHODS: This morphology-based, retrospective study was approved by our Institutional Review Board. A total of 252 consecutive CNBs with on-site IC on masses of liver, lung, lymph node, bone, and soft tissue were included in this study. IC was reviewed by two cytopathology fellows and two board-certified cytopathologists who gave a categorical diagnosis (malignant/benign/atypical) and exact diagnosis when possible. Preliminary diagnoses were compared with corresponding histological CNB diagnoses. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. RESULTS: Of the 252 cases reviewed, 30 cases were classified as atypical by IC and evaluated separately. Of the remaining 222 cases, IC classified an average of 154 (70%) as malignant, 54 (24%) as benign, and 14 (6%) as nondiagnostic. The corresponding distribution of histological diagnoses was 151 (68%) malignant and 71 (32%) benign. Overall correlation of correct IC diagnoses was 80%, with a correlation of 91% in malignant cases and 59% in benign cases. Sensitivity, specificity, PPV, and NPV were 96, 74, 92, and 87%, respectively. Diagnostic accuracy was 91%. There was no statistically significant difference in the accuracy of categorical diagnoses between IC and final histologic diagnosis. Atypical cases by IC were more likely to be malignant in lung and liver lesions (71% and 58%, respectively), than in lymph node, bone, or soft tissue lesions (17%, 0%, 0%, respectively). An exact diagnosis on IC was rendered in 113 (51%) cases, with an accuracy of 73%. Sensitivity, specificity, PPV, and NPV were 94, 41, 70, and 83%, respectively. CONCLUSION: Rapid on-site IC is a useful and valuable tool for evaluating adequacy of CNB as well as providing accurate information on a categorical basis (malignant versus benign), with greater diagnostic accuracy in cases of malignancy than for benign lesions. IC provides high sensitivity with high PPV in lung, liver, lymph node, bone, and soft tissue lesions. Exact preliminary diagnoses have good diagnostic accuracy. Considering the fundamentally different diagnostic and therapeutic approach based on histologic tumor type (e.g., in lung malignancies), on-site preliminary diagnosis may allow appropriate triaging of tissue for early planning of ancillary studies with decreased turnaround times. In addition, early diagnosis may reduce anxiety in patients and expedite treatment planning.

Atypical Endobronchial Carcinoid with Postobstructive Pneumonia Obscuring the Diagnosis of Granulomatosis with Polyangiitis.

Granulomatosis with polyangiitis (GPA), previously termed Wegener's Granulomatosis, is an autoimmune small vessel vasculitis which is highly associated with antineutrophil cytoplasmic antibodies (ANCA) and has varied clinical manifestations. Diagnosis hinges on identifying a combination of clinical features of systemic vasculitis, positive ANCA serology, and histological evidence of necrotizing vasculitis, necrotizing glomerulonephritis, or granulomatous inflammation from a relevant organ biopsy. The American College of Rheumatology has also developed a classification criteria focusing specifically on nasal or oral inflammation, abnormal chest radiograph, and abnormal urinary sediment, along with granulomatous inflammation, which helps to distinguish GPA from other forms of systemic vasculitis. In the case presented below, the diagnosis of GPA was delayed as the patient had a concomitant atypical endobronchial carcinoid which predisposed to postobstructive pneumonia. Fortunately, the papular lesions that developed across her lower limbs prompted further investigations. The return of appropriate serology coincided with progression to alveolar hemorrhage, offering a more complete clinical picture, and when she responded to the combination of steroid, cyclophosphamide, and plasma exchange, the diagnosis of GPA was cinched.