Cytokeratin 7 and Copper Stains Facilitate Diagnosis of Small Duct Primary Sclerosing Cholangitis

Introduction/Objective Classic primary sclerosing cholangitis (PSC) involves extrahepatic and/or intrahepatic biliary ducts with segmental biliary strictures and dilatations that often allow the diagnosis to be made via cholangiogram. Small duct PSC (sdPSC) is a rare subtype that presents similarly with a cholestatic pattern of injury, yet due to the small size of involved ducts, a cholangiogram is non-diagnostic and diagnosis is dependent on clinical suspicion and liver biopsy. The histopathological features of sdPSC are often subtle and may easily be overlooked. Diagnosis of this entity- though difficult- is important, as early recognition can facilitate the identification of associated disease processes and life-threatening complications. Methods/Case Report We encountered a 33-year-old female presenting with intermittent pruritis, episodes of jaundice, and persistently elevated alkaline phosphatase who was misdiagnosed with only fatty liver at an outside institution. Evaluation with MRCP showed no abnormalities within the biliary tract and a liver biopsy was performed to aid in the diagnosis. The H&E and trichrome findings of atrophic bile ducts and some peribiliary sclerosis were extremely subtle and may have been overlooked without clinical suspicion. Cytokeratin 7 (CK7) highlighted cholangiolar metaplasia in hepatocytes and the bile ductular reaction that occurs in cholestatic disease states. A Rhodamine copper stain showed periportal deposition suggestive of chronic biliary obstruction. Use of CK7 and copper stains supported the presence of chronic biliary injury and suboptimal bile flow, confirming the diagnosis of sdPSC. Results (if a Case Study enter NA) NA Conclusion Diagnosis of sdPSC has historically relied on H&E and trichrome stains. In this case, the findings on H&E and trichrome stains were non-diagnostic, while the use of CK7 and copper stains confirmed the diagnosis of sdPSC. We recommend using CK7 and copper stains to evaluate for sdPSC.

Turkish cases of Mabry Syndrome with a novel homozygous mutation in PGAP2 gene

Hyperphosphatasia with mental retardation syndrome is a genetic disorder. We report two siblings aged three years and fourteen years who were investigated for global development delays, seizures and dysmorphic features. A novel missense variant, c.1003G>A (p. Ala335 Thr chr11.3,846,572 NM_001256236.1), in PGAP2 gene was identified using whole-exome sequencing. We highlight the significance of elevated alkaline phosphatase in patients with certain dysmorphic features, can lead to the diagnosis of hyperphosphatasia with mental retardation syndrome using exome sequencing.

Turkish cases of Mabry Syndrome with a novel homozygous mutation in PGAP2 gene

Hyperphosphatasia with mental retardation syndrome is a genetic disorder. We report two siblings aged three years and fourteen years who were investigated for global development delays, seizures and dysmorphic features. A novel missense variant, c.1003G>A (p. Ala335 Thr chr11.3,846,572 NM_001256236.1), in PGAP2 gene was identified using whole-exome sequencing. We highlight the significance of elevated alkaline phosphatase in patients with certain dysmorphic features, can lead to the diagnosis of hyperphosphatasia with mental retardation syndrome using exome sequencing.

Cytology and Radiology as a Diagnostic Tool to Detect Metastasis in Mammary Tumor Affected Dogs

Background: Malignant mammary gland tumors can metastasize to various organs; of which, lungs and regional lymph nodes are most frequently affected. Chest radiographs and regional lymph node FNAs are important diagnostic tool to detect metastasis as per oncology practice guidelines. The present study was aimed to develop suitable diagnostic tool to detect metastasis in mammary tumor affected dogs. Methods: Between September 2017 to July 2018, thirty three dogs (n=33) affected with mammary tumors were included in the study. Out of thirty three dogs, three dogs (n=3) showed swollen regional lymph nodes and pulmonary metastases. Different parameters such as haematology, serum biochemistry, radioimmunoassay, radiology, cytology, histopathology and immunohistochemistry were analysed. Result: TNM clinical staging revealed that all the three dogs showed stage IV tumors which were usually malignant and showed frequent metastases. Haematological abnormalities such as anemia, leucocytosis and reduced platelet count were noticed. Serum biochemistry showed reduced protein and electrolyte level with elevated alkaline phosphatase and alanine transaminase. Radioimmunoassay showed many-fold elevation of estradiol and progesterone. Radiography of lungs revealed severe pulmonary metastasis. Cytological examination of swollen accessory lymph node revealed mixed population of lymphocytes and neoplastic cells. Grossly, the lymph nodes were found to be enlarged, blood tinged and covered with subcutaneous adipose tissue. Histopathology of tumor masses from three dogs revealed cystic papillary carcinoma, ductal carcinoma and anaplastic carcinoma. Immunohistochemistry revealed that dogs were affected with triple negative tumors which were highly malignant, poor prognosis and not responding to therapy.

Oncogenic osteomalacia secondary to glomus tumor

Summary Oncogenic osteomalacia secondary to glomus tumor is extremely rare. Localization of causative tumors is critical as surgical resection can lead to a complete biochemical and clinical cure. We present a case of oncogenic osteomalacia treated with resection of glomus tumor. A 39-year-old woman with a history of chronic sinusitis presented with chronic body ache and muscle weakness. Biochemical evaluation revealed elevated alkaline phosphatase hypophosphatemia, increased urinary phosphate excretion, low calcitriol, and FGF23 was unsuppressed suggestive of oncogenic osteomalacia. Diagnostic studies showed increase uptake in multiple bones. Localization with MRI of paranasal sinuses revealed a sinonasal mass with concurrent uptake in the same area on the octreotide scan. Surgical resection of the sinonasal mass was consistent with the glomus tumor. The patient improved both clinically and biochemically postoperatively. Along with the case of oncogenic osteomalacia secondary to a glomus tumor, we have also discussed in detail the recent development in the diagnosis and management of oncogenic osteomalacia. Learning points Tumor-induced osteomalacia is a rare cause of osteomalacia caused by the secretion of FGF23 from mesenchymal tumors. Mesenchymal tumors causing TIO are often difficult to localize and treat. Resection of the tumor can result in complete resolution of biochemical and clinical manifestations in a very short span of time. Glomus tumor can lead to tumor induced osteomalacia and should be surgically treated.

Epidemiology, Clinical and Laboratory Manifestations, and Outcomes of Brucellosis Among 104 Patients in Referral Hospitals of Tehran, Iran

Background: Brucellosis is the most common zoonotic disease in Iran, imposing a significant financial burden on the healthcare system. The diversity of non-specific clinical manifestations of this disease can lead to misdiagnosis or delayed diagnosis. Therefore, it is important to pay attention to other aspects of this disease. Objectives: This study aimed to determine the epidemiology, clinical and laboratory manifestations, and outcomes of brucellosis. Methods: In this cross-sectional study, brucellosis patients, admitted to three hospitals, affiliated to Shahid Beheshti University of Medical Sciences (Tehran, Iran) from April 2015 to September 2020, were examined. The patients' medical records were reviewed for epidemiological, clinical, and laboratory findings. The outcomes of the disease were evaluated by phone calls. Results: Of the 104 patients included in this study, 53.8% were male, and 46.2% were female. The mean age of the patients was 43.07 ± 18.521 years. Unpasteurized dairy consumption and contact with livestock were reported in 60.6 and 27.9% of the patients, respectively. Also, 23.1% of the patients had high-risk occupations. The most common symptoms included fever (80.8%), chills (58.7%), backache (55.8%), and sweating (51%). The most common complication was osteoarticular involvement (21.2%), followed by neurobrucellosis (6.7%). Elevated alkaline phosphatase (89.7%), anemia (67.3%), increased C-reactive protein (57.7%), and increased erythrocyte sedimentation rate (48.1%) were common laboratory findings. The rates of improvement, treatment failure, and relapse were 86.9, 9.1, and 4%, respectively. There was no significant relationship between the rate of improvement and the antibiotic regimen. However, the most common cause of treatment failure was the patient’s poor compliance with treatment. Conclusions: The diversity of non-specific clinical manifestations of brucellosis is a diagnostic challenge. Therefore, physicians must request laboratory tests to evaluate brucellosis after taking a precise epidemiological and clinical history of suspected cases.

Case Report: Children with Severe Nutritional Rickets in the Naga Region in Northwest Myanmar, on the border with India

Rickets is an often-neglected, painful, and disabling childhood condition of impaired bone mineralization. In this case series we describe a cluster of 29 children with severe, painful bone deformities who live in the very remote region of Nagaland in northwest Myanmar. Children were found to have low 25-hydroxyvitamin D, elevated parathyroid hormone, and elevated alkaline phosphatase levels, consistent with nutritional rickets secondary to vitamin D deficiency, calcium deficiency, or a combination of the two. After treatment with vitamin D3 and calcium carbonate, significant improvement was seen in symptoms, biochemistry, and radiography. This is the first report of nutritional rickets in Myanmar in more than 120 years. Vitamin D and calcium supplementation, and food fortification for pregnant women and young children may be required to prevent this potentially devastating disease.

Older woman with abdominal pain and bilateral sequential vision loss due to syphilis

A 62-year-old woman presented with non-specific abdominal pain, elevated alkaline phosphatase levels and bilateral sequential visual loss. Visual acuity was counting fingers in right eye (RE) and 20/400 in left eye (LE). She was noted to have optic nerve pallor in RE and mildly elevated optic disc with signs of ocular inflammation in LE. After 2 weeks, vision deteriorated to light perception bilaterally with now extensive vitreal inflammation present in both eyes. Positive rapid plasma reagen and Treponema pallidum’s antibody tites confirmed syphilis infection. Unfortunately, as the diagnosis was delayed by many months, her visual acuity remained poor (hand motions in RE and 20/50 in LE) despite treatment with intravenous penicillin. This case reminds us of the re-emergence of this ‘great masquerader’ and highlights the importance of maintaining high suspicion for syphilis in patients with unexplained visual loss and systemic symptoms, even in older adults without identifiable risk factors.

Prostate cancer intensive, non-cross reactive therapy (PRINT) for CRPC: Interim analysis of efficacy endpoints.

e17027 Background: The standard mCRPC treatment paradigm, with sequential single agents administered until resistance, may be limited due to heterogenous tumors comprised of clones differentially sensitive to available therapies. An alternative approach involves rapid cycling of non-cross resistant therapies in an attempt to efficiently eradicate sensitive clones, mitigate resistance, and minimize toxicity. Methods: Patients with mCRPC received 3 consecutive treatment modules, each lasting 12 weeks: 1. abiraterone acetate 1000 mg PO daily + prednisone 5 mg PO BID; 2. cabazitaxel 20 mg/m2 IV + carboplatin AUC 4 IV q3 weeks; 3. enzalutamide 160 mg PO daily + radium-223 55 kBq/kg IV q4 weeks (in those with bone metastases). Upon completion of the 9-month study regimen, patients continued ADT alone. The primary endpoint is time to progression (TTP). A sample size of 33 patients will provide 90% power for a one-sided test at the 5% level to detect increase in TTP compared with historical control. Secondary endpoints include PSA response (>90%, >50%) with each module, and changes to alkaline phosphatase levels. Results: From 3/2017 to 11/2020, 40 mCRPC patients were enrolled. As of the data cut-off of 1/03/2021, 31 patients have completed the 9-month study regimen and are evaluable for TTP analysis. With a median follow up of 20.7 months, the median time to PSA progression is 3.8 months (95%CI; 2.1-6.3 mo). PSA declines >90% from baseline was achieved in 35.5% after module 1, 41.9% after module 2, 58.1% after module 3. Of the patients with bone metastasis and elevated alkaline phosphatase levels at baseline (9/31), 78% had normalization of alkaline phosphatase upon completion of study regimen. Five of 31 patients (16%) were able to be maintained on ADT alone for over a year during the post-study surveillance period: three patients were subsequently restarted on a mCRPC agent at time of disease progression (14.4 mo, 17.0 mo, 24.8 mo), two patients demonstrate sustained disease control and remain on ADT alone (16.3+ mo, 21.5+ mo). Shared baseline clinical features of the 5 patients with prolonged control include PSA of <10 ng/mL and normal alkaline phosphatase levels (< 126 IU/L); Gleason score and presence of bone and nodal metastases varied. Conclusions: Treatment of mCRPC with a rapidly-cycling non-cross resistant regimen is feasible and a subset of patients achieve prolonged disease control on ADT alone after completion of study treatment. Rapid cycling of available CRPC therapies may eliminate castration-resistant clones in a subset of patients, a concept warranting further preclinical and clinical evaluation. Clinical trial information: NCT02903160. [Table: see text]