Evaluation of therapeutic and toxic levels of serum digoxin concentration: a cross-sectional study from a tertiary hospital.

OBJECTIVE: Digoxin is a cardiac glycoside for treating heart failure and atrial fibrillation. Despite its limited therapeutic range and complex pharmacokinetic properties, this medication continues to be frequently prescribed. This study aimed to evaluate the serum digoxin concentration (SDC) at therapeutic, subtherapeutic, and toxic levels and explore the factors affecting these levels in patients receiving digoxin therapy for heart failure. PATIENTS AND METHODS: In this descriptive and cross-sectional study, the data were obtained from the electronic system of patients who presented to Afyonkarahisar Health Sciences University. For the SDC, the reference range was accepted as 0.5-0.9 ng/mL, and the upper limit was 2.0 ng/mL. The patient's demographic characteristics, comorbidities, and laboratory findings were evaluated. The Mann-Whitney U test, Chi-square test, and logistic regression analysis were used. p<0.05 was considered statistically significant. RESULTS: The data of 419 patients (mean age: 65.9±16.1 years, 68.5% women) were evaluated. The mean SDC was 1.11±1.01 ng/mL, and it was below 0.5 ng/mL in 24.3% of the patients, 0.5-0.9 ng/mL in 23.4%, 0.9-2 ng/mL in 41.3%, and over 2 ng/mL in 11.1%. Age, male gender, the presence of diabetes mellitus, and high HbA1c values were found to be associated with greater SDC levels, but this was not statistically significant. The presence of renal failure, elevated creatinine and magnesium levels, and potassium, sodium, and calcium levels outside the normal limits significantly increased the SDC. High creatinine and low/high potassium values significantly affected the detection of SDC at the toxic level. CONCLUSIONS: The measurement of SDC levels holds significance not only in the monitoring of toxicity but also in ensuring adherence to the recommended therapeutic range during therapy. It is recommended to exercise caution in terms of risk factors such as age, kidney function test results, and blood electrolyte levels.

Harnessing the Near-Peer Effect in Anatomy Education.

Benefits of near-peer teaching are well-documented, but its time requirements can be prohibitive. We integrated the near-peer effect into a clinical anatomy course with weekly student-developed handouts vetted by faculty to provide an element of near-peer teaching without the burden of extra time.

Massive localized lymphedema with unusual presentations: report of 2 cases and review of the literature.

Massive localized lymphedema is a benign soft tissue lesion that usually presents as a large mass in morbidly obese adults. The diagnosis may be challenging as it can mimic other lesions, including well-differentiated liposarcoma. We report 2 cases of massive localized lymphedema with unusual presentation. The first case is a recurrent massive localized lymphedema in the right thigh of a 40-year-old morbidly obese woman. In addition to typical massive localized lymphedema features such as prominent edema and vascular proliferation in the adipose tissue, we observed prominent and abundant multinucleated stromal floret-like giant cells, arborizing network of capillaries, and areas of hyalinized collagen. Our second case is in a rare location (scrotum extending into penile soft tissue) in an overweight 55-year-old male. This lesion exhibits striking smooth muscle hyperplasia. Lack of staining by antibodies against murine double minute 2 protein and cyclin dependent kinase 4 and absence of high mobility group AT- hook 2 transcription factor rearrangement by fluorescence in situ hybridization support our diagnosis of massive localized lymphedema in both cases.

The many faces of pheochromocytoma.

OBJECTIVE: To recognize and manage pheochromocytomas in unusual settings. METHODS: Three case reports are presented with clinical, biochemical, imaging, and operative findings. The pitfalls in diagnosis of pheochromocytomas and management are addressed. RESULTS: We begin with a 27-yr-old gravida 2, para 1 Caucasian woman with unexplained tachycardia and hypertension during a routine pre-natal visit at 30 weeks estimated gestational age. Urinary studies revealed elevated catecholamines. Magnetic resonance imaging localized a 6.6-cm right adrenal mass with features consistent with a pheochromocytoma. She was medically managed with phenoxybenzamine and propranolol until 35 weeks, after which she underwent a combined Cesarean section, and open right adrenalectomy. Another patient, a 36-yr-old African-American woman presented to a hospital in cardiac arrest, with elevated serum troponins, and underwent cardiac catheterization, which revealed normal coronary arteries. A computed tomography (CT) scan revealed a left adrenal mass and CT-guided biopsy was consistent with a pheochromocytoma, although prior studies were negative. Finally, we present a 49-yr-old Caucasian woman who had a right adrenalectomy 10 yr prior and presented to the clinic with fluctuating blood pressures, headaches, and palpitations. Further testing revealed she had a recurrent metastatic pheochromocytoma. The challenges behind treating these patients are further explored. CONCLUSION: Antenatal diagnosis of pheochromocytoma, though challenging, is associated with lower maternal and fetal morbidity and mortality. The differential diagnosis for cardiac arrest in the presence of normal coronary arteries should include a pheochromocytoma. Finally, treatment with iodinated metaiodobenzylguanidine may be a therapeutic option for those patients with metastatic pheochromocytomas.

Nonsurgical delay of dorsal rat cutaneous flap using a long-pulsed 1064-nm Nd:YAG laser with a contact cooling device.

BACKGROUND: This study evaluated the efficiency of a long-pulsed neodymium:yttrium-aluminum-garnet laser, operating at 1064 nm and equipped with a contact cooling device, in the delay of a caudally based dorsal rat skin flap (10 x 3 cm). This laser has deeper tissue penetration and has not been used for this purpose before. METHODS: Twelve male Sprague-Dawley rats were used in each of six groups. The delay effects of three different laser treatment patterns (only longitudinal borders, cephalic and longitudinal borders, and entire surface of the 10 x 3-cm flap) were compared with an acute untreated control flap as well as two surgical delay methods (incision of longitudinal borders and incision of longitudinal borders plus flap undermining). The laser effects on the cutaneous vasculature and perfusion were assessed by intravenous fluorescein injection, histologic study, microangiography, and in vivo real-time video monitoring. RESULTS: Selective thermocoagulation of subdermal vessels was achieved using a 6-mm spot, 140-J/cm fluence, and 40-msec pulse width. In the cephalic and longitudinal borders laser-treated group, a delay effect was achieved. The maximum delay effect was achieved by the surgical delay group that used the method of incision of the longitudinal borders plus flap undermining. Laser treatment of only the longitudinal borders did not improve flap survival, whereas treatment of the entire flap surface significantly reduced flap survival. CONCLUSION: Nonsurgical delay of a dorsal rat cutaneous flap is possible by selective occlusion of the subdermal plexus at the longitudinal and cephalic borders of the planned flap using a long-pulsed 1064-nm neodymium:yttrium-aluminum-garnet laser equipped with a contact cooling device.

Comparison of ThinPrep and conventional smears in detecting carcinoma in bile duct brushings.

BACKGROUND: Bile duct brushing cytology is a common procedure for the exclusion of adenocarcinoma in the bile duct. The authors evaluated the use of ThinPrep (TP) to determine whether the information obtained is equivalent to that found with conventional smear cytology (CS). METHODS: Thirty-eight prospectively collected endoscope retrograde cholangiopancreatography-guided bile duct brushing samples were split in the following manner. First, two to four CS were prepared and immediately spray-fixed or wet-fixed. Second, the remaining sample was rinsed in PreservCyt (Cytyc Corp., Boxborough, MA). In the laboratory, one TP slide was prepared from each sample. TP and CS were stained by routine Papanicolaou stain. For the current study, TP and CS were reviewed independently by two cytopathologists. The diagnoses made by the two methods were compared with the final histology. RESULTS: The cytologic diagnoses for both TP and CS were categorized into five main groups: 1) unsatisfactory, 2) negative, 3) reactive, 4) suspicious for malignancy, and 5) malignant. The diagnoses on the 38 TP bile duct brushings and CS were categorized as follows: 1) unsatisfactory-2, 4; 2) negative-7, 4; 3) reactive-10, 14; 4) suspicious for malignancy-9, 9; and 5) malignant-10, 7, respectively. Histologic follow-up was available in 14 cases (reactive-4, suspicious for malignancy-1, and malignant-9). The sensitivity was 77% for TP and 66% for CS. The specificity was 100% for both methods. CONCLUSIONS: The two methods described in the current study detected equivalent disease on bile duct brushings. TP was found to provide better preservation and cytologic detail. However, the diagnostic criteria may require modification.

Fas deficiency exacerbates cerulein-induced pancreatitis.

Acute pancreatitis results in many deaths each year. Our understanding of pathophysiology is limited. To better understand the impact of apoptosis versus necrosis, we compared cerulein-induced pancreatitis in Fas-deficient (MRL lpr/lpr) versus Fas-sufficient (MRL +/+) mice. Average amylase values in Fas-deficient mice were substantially greater than in Fas-sufficient mouse. Histology graded on edema, inflammation, vacuolization, and necrosis showed greater injury in the Fas-deficient mouse. This finding suggests that the Fas pathway is important in controlling cerulein-induced pancreatitis.

Symptomatic nephrogenic metaplasia of ureter: a morphologic and immunohistochemical study of four cases.

Nephrogenic metaplasia of the bladder and urethra has been the subject of extensive studies in recent years. However, information about ureteral involvement is still limited because of the rarity of the lesion. We described four cases of nephrogenic metaplasia of the ureter. They occurred in two men and two women whose ages ranged from 46 to 69 years. Three patients had stones, and one had multiple episodes of cystitis and chronic pyelonephritis. The lesions led to ureteral obstruction that in two patients was radiographically suspicious for carcinoma. Microscopically, three lesions were composed of tiny mucin-containing microcysts and medium-sized tubular structures lined by cuboidal cells that showed cytologic atypia characterized by enlarged vesicular nuclei and prominent nucleoli. However, there were no mitotic figures. Two lesions invaded the full thickness of the wall of the ureter and exhibited an infiltrative growth pattern highlighted by cytokeratin stains. The remaining two lesions were confined to the lamina propria. The cells of nephrogenic metaplasia were immunoreactive to cytokeratin 7 and AE1-AE3. They lacked reactivity for monoclonal and polyclonal CEA and p53. The MIB-1-labeling index was <5%. The cytologic atypia and infiltrative growth pattern of ureteral nephrogenic metaplasia should not be misinterpreted as evidence of malignancy. All four patients are alive and symptom free 8 months to 7 years after diagnosis.

Diagnostic utility of the HepPar1 antibody to differentiate hepatocellular carcinoma from metastatic carcinoma in fine-needle aspiration samples.

BACKGROUND: The cytopathologic distinction between hepatocellular carcinoma (HCC) and metastatic carcinoma (MC) in the liver can be problematic, especially in patients with poorly differentiated HCC, in whom a trabecular pattern, bile production, and Mallory bodies may not be apparent on small fine-needle aspiration (FNA) samples. HepPar1 (OCH1E5) is a monoclonal antibody specifically developed to react with hepatocytes. It rarely reacts with bile duct and nonparenchymal liver cells. METHODS: FNA samples (cell blocks) from 75 liver tumors were selected. These included 50 moderate to poorly differentiated HCC cases, 5 cholangiocarcinoma (CC) cases, and 20 MC cases (4 from the breast, 4 from the stomach, 4 from the pancreas, and 8 from the colon). Immunohistochemical staining for HepPar1 was performed to differentiate HCC from MC. RESULTS: The HepPar1 antibody was positive in 50 of 50 HCC cases (100%). The positivity was cytoplasmic, diffuse, and granular. All 5 cases of CC were found to be negative (0%). Although focal positivity within tumor cells was noted in one case, cytologically these were entrapped normal hepatocytes between the tumor cells. In addition, 3 of 20 MC cases (15%) also were positive for HepPar1. All three cases originated from gastric primary tumors and exhibited diffuse, granular cytoplasmic staining. CONCLUSIONS: The results of the current study demonstrate that HepPar1 is an effective marker with which to differentiate between HCC and CC and/or MC. HepPar1 was found to demonstrate 100% positivity in HCC cases, compared with 0% and 15% positivity, respectively, in CC and MC cases. In addition, HepPar1 is extremely helpful in limited tissue samples from FNA. Although 15% of the MC cases in the current study were found to be positive, with the help of clinical correlation and other immunohistochemical stains a definite diagnosis could be rendered. Potential pitfalls include residual benign hepatocyte staining within a non-HCC malignancy, as was observed in one of the CC cases in the current study.

Assessment of HER-2/neu status in breast cancer. Automated Cellular Imaging System (ACIS)-assisted quantitation of immunohistochemical assay achieves high accuracy in comparison with fluorescence in situ hybridization assay as the standard.

This retrospective study of formalin-fixed infiltrating breast cancer specimens compared manual immunohistochemical assay with a new image analyzer-assisted immunohistochemical quantitation method, using fluorescence in situ hybridization assay (FISH) as the standard. Following the manual immunohistochemical assay, 189 cases, including most manual immunohistochemically positive and some random negative cases, were analyzed by FISH assay for Her-2/neu gene amplification and by the Automated Cellular Imaging System (ACIS) for immunohistochemical staining. Using the FISH standard, the ACIS immunohistochemical assay attained a higher concordance rate and sensitivity than the manual immunohistochemical assay (91.0% and 88% vs 85.7% and 71%, respectively), with only a slight decrease in specificity (93% vs 96%, respectively). In particular, the ACIS immunohistochemical assay resulted in a higher correlation with the FISH assay in the manual immunohistochemical assay 2+ cases. The ACIS immunohistochemical assay achieved higher accuracy than the manual method according to receiver operating characteristic curve analysis. The ACIS method represents a substantial improvement over the manual method for objective evaluation of the HER-2/neu status.

Solitary cylindroma (dermal analog tumor) of the breast: a previously undescribed neoplasm at this site.

The authors report a previously undescribed small, well-demarcated breast tumor similar to a dermal cylindroma in a 63-year-old woman. The tumor was an incidental finding in a lumpectomy specimen for infiltrating lobular carcinoma. The cylindroma was surrounded by normal-appearing breast parenchyma and had the typical "jigsaw" pattern of epithelial basaloid islands. The islands showed focal squamous and myoepithelial differentiation. A notable number of reactive dendritic Langerhans cells permeated the epithelial cell islands, a feature considered to be characteristic of dermal cylindroma. There was also ductal differentiation. Thick bands of hyaline periodic acid-Schiff (PAS) stain and collagen IV-positive basement membrane material bordered the cell islands, and PAS-collagen IV-positive hyaline globules were seen within the cell islands. There was no nuclear pleomorphism or mitotic figures. The cylindroma did not express gross cystic disease fluid protein 15, carcinoembryonic antigen, estrogen and progesterone receptors, or cytokeratin 20 (CK20). There was diffuse and strong immunoreactivity to CK AE1/AE3, and focal reactivity for CK7 and smooth muscle actin. Cylindroma of the breast should be distinguished from adenoid cystic carcinoma and basal cell carcinoma. Although clearly epithelial, the exact histogenesis and cell phenotype of this unusual dermal type cylindroma of the breast are unknown.

The utility of transbronchial (Wang) fine needle aspiration in lung cancer diagnosis.

We evaluated our experience with transbronchial fine needle aspiration (TBNA) in cancer diagnosis over a period of 1 year. A total of 51 aspirates were performed by specialist chest physicians in the presence of a cytopathologist who made on spot evaluation of Diff-Quik smears for adequacy and guided the aspirator for additional sampling if necessary. Two clusters of at least 10 malignant cells were required on the Diff-Quik smears to render an on the spot positive diagnosis of malignancy. Aspirates showing atypical cells or few malignant cells not fulfilling the above criteria were placed in a suspicious category and additional material was requested. The TBNA results were correlated with the transbronchial biopsy when available.

Laboratory assessment of the status of Her-2/neu protein and oncogene in breast cancer specimens: comparison of immunohistochemistry assay with fluorescence in situ hybridisation assays.

AIM: To evaluate the clinical usefulness of three commercially available assays for Her-2/neu oncogene and protein measurements. The Her-2/neu protein is overexpressed, mostly as a result of gene amplification, in 20-30% of human breast cancers, and has been shown to have prognostic and predictive value for treatment with chemotherapy or the new monoclonal antibody, Herceptin. METHODS: An immunohistochemistry (IHC) assay using the Dako polyclonal antibody A0485, which measures the Her-2/neu protein, was compared with two new Food and Drug Administration (FDA) approved fluorescence in situ hybridisation (FISH) assays--INFORM and PathVysion, in a cohort of 52 formalin fixed, paraffin wax embedded breast tissues. These tissues were selected randomly from 84 consecutive infiltrating breast cancer specimens, which were first stratified according to the Her-2/neu protein levels as measured by IHC. RESULTS: The two FISH assays achieved a 98% concordance rate: 14 specimens (27%) showed Her-2/neu gene amplification and 37 specimens (71%) showed no Her-2/neu gene amplification. The PathVysion assay had certain advantages over the INFORM assay. In contrast, the IHC assay detected Her-2/neu overexpression in a high percentage of cases, including 13 high positive specimens (25%) and 13 medium positive specimens (25%). Although 10 of these 13 IHC high positive specimens showed gene amplification by FISH, nine of 13 IHC medium positive specimens showed no gene amplification. Statistical analyses showed that the differences between IHC and FISH assays were primarily in the specimens with medium positive IHC, but negative FISH results. CONCLUSIONS: Because of the increasing importance of the Her-2/neu oncogene and oncoprotein in the clinical management of patients with breast cancer, the accurate and consistent evaluation of Her-2/neu status is crucial. This study suggests that the best approach is to combine both IHC and FISH assays; that is, to use the IHC assay as a triage step, followed by the PathVysion FISH assay to analyse the IHC medium and high positive cases.

The role of fine-needle aspiration biopsy in the primary diagnosis of mesenchymal lesions: a community hospital-based experience.

BACKGROUND: The objective of this study was to determine the utility of fine-needle aspiration biopsy (FNAB) in the primary diagnosis of mesenchymal lesions. A total of 162 cases with a diagnosis of benign or malignant mesenchymal lesion (excluding lipoma) on FNAB were retrieved from the cytopathology archives for the years 1990-1997. METHODS: Patients selected for inclusion in this study underwent FNAB as the primary diagnostic modality without a previous tissue diagnosis and had a subsequent surgical procedure for definitive histologic correlation. Seventy-two patients were selected on the basis of the above criteria. RESULTS: Cytologic diagnoses were categorized as benign, malignant, or suspicious for malignancy. Among the 72 cases selected, 42 (58%) benign, 18 (25%) malignant, and 12 (16%) suspicious diagnoses were rendered. Of the patients with benign FNAB diagnoses, 39 of 42 (93%) had a benign lesion on histologic follow-up, and 3 of 42 (7%) had a malignancy. Of the patients with malignant FNAB diagnoses, 17 of 18 (94%) had a malignant lesion and 1 of 17 (6%) proved to be benign. In the subset of suspicious lesions, subsequent histology was benign in 5 of 12 (42%) and malignant in 7 of 12 (58%). CONCLUSIONS: Based on our study, FNAB has excellent accuracy (88%), sensitivity (89%), and specificity (87%) for classifying a mesenchymal tumor as benign or malignant. FNAB can be a rapid and effective tool for the primary categorization of mesenchymal lesions and provide reliable information to the clinician for triage of patients.

Endometrioid carcinoma arising in pericecal endometriosis clinically mimicking Crohn's disease.

A case of endometrioid carcinoma arising in pericecal endometriosis that clinically and radiologically mimicked Crohn's disease is presented. After developing several complications of steroid therapy for presumed Crohn's disease, a 48-year-old woman developed intestinal obstruction and underwent a right hemicolectomy. A pericecal mass composed of endometriosis and endometrioid carcinoma and a locally metastatic ileal carcinoid tumor were resected. The patient recovered fully and is clinically free of tumor at 36 months. The pertinent literature is reviewed and the etiologic, therapeutic, and prognostic implications of this case are discussed.

Signet-ring cell variant of small lymphocytic lymphoma with a prominent sinusoidal pattern.

Signet-ring cell lymphoma is a rare morphologic variant of non-Hodgkin's lymphoma characterized by neoplastic lymphoid cells with cytoplasmic vacuoles or eosinophilic globules that impart a signet-ring cell morphology. Although most cases are variants of follicular center B-cell lymphomas, this pattern also can be seen in T-cell lymphomas. An indolent clinical course and prolonged survival have characterized the majority of published cases. We document the case of a 62-year-old African-American woman with diffuse small lymphocytic signet-ring lymphoma having a predominant sinusoidal growth pattern, which, to our knowledge, has not been previously reported. The prominent sinusoidal pattern of signet-ring lymphocytes contributes to its confusion with metastatic signet-ring cell adenocarcinoma. The correct diagnosis is greatly facilitated by the use of appropriate immunohistochemical stains for lymphoid markers.

Low grade fibromyxoid sarcoma: fine-needle aspiration cytology with histologic, cytogenetic, immunohistochemical, and ultrastructural correlation.

BACKGROUND: Although the histologic features of the recently described low grade fibromyxoid sarcoma are well established, to the authors' knowledge there are no reports in the literature describing the cytologic features of this tumor by fine-needle aspiration. Recognition of this lesion is important because of its indolent but metastasizing nature. METHODS: The authors retrospectively reviewed their surgical pathology files for cases of low grade fibromyxoid sarcoma with a preoperative fine-needle aspiration biopsy (FNAB); three such cases were found. Immunohistochemical studies were performed in all three tumors, ultrastructural examination was performed in two tumors, and fresh tissue for cytogenetic analysis was obtained in one tumor. RESULTS: All FNABs showed similar features. The aspirates were relatively hypocellular with an abundant myxoid background; the neoplastic cells contained oval to spindle shaped nuclei with minimal pleomorphism. No capillaries or areas of fibrous tissue were identified. Cytogenetic study of one case revealed no chromosomal abnormalities. The histologic findings were characteristic for this lesion. By immunohistochemistry the tumor cells showed diffuse and strong reactivity for vimentin only; at the ultrastructural level the neoplastic spindle cells had characteristics of fibroblasts. CONCLUSIONS: The cytologic features of low grade fibromyxoid sarcoma are not specific enough for a definitive diagnosis based on FNAB alone; however, correlating the cytologic and clinical findings can narrow the range of diagnosis. The differential diagnosis includes other myxoid lesions, in particular superficial or intramuscular myxoma and myxofibrosarcoma. In addition, the immunohistochemical and ultrastructural findings support a fibroblastic origin for this neoplasm.

Fine-needle aspiration findings in patients with polymorphous low grade adenocarcinoma of the salivary glands.

BACKGROUND: Polymorphous low grade adenocarcinoma of the salivary glands (PLAC) is a low grade neoplasm that predominantly occurs in the minor salivary glands. In this site it is amenable to biopsy and histologic diagnosis. However, experience with fine-needle aspiration (FNA) biopsy findings in these tumors is limited. The authors describe the FNA cytology of this entity. METHODS: Fine-needle aspirates from two primary parotid and three metastatic PLACs were reviewed and correlated with their histology. RESULTS: All aspirates showed similar cytologic features, with hypercellular smears showing branching papillae, sheets and clusters composed of bland uniform cells with round-to-oval nuclei, dispersed chromatin, and absent or inconspicuous nucleoli. The cells generally had a scant-to-moderate amount of eosinophilic cytoplasm. Mitoses and nuclear pleomorphism were absent. These cells formed tubular structures containing hyaline globules in all cases and often a dispersed myxohyaline stroma. Bare nuclei also frequently appeared in the background. Two cases, which had prior histologic diagnoses, were diagnosed on FNA as metastatic PLAC. One metastatic case was diagnosed as benign metastasizing pleomorphic adenoma. One primary case was diagnosed as adenoid cystic carcinoma and one case as PLAC on FNA. CONCLUSIONS: The cytologic differential diagnosis of PLAC includes adenoid cystic carcinoma, pleomorphic adenoma, and monomorphic adenoma. PLAC should be considered in the differential diagnosis of head and neck masses, where the cytology suggests one of these tumors, even when the clinical context (involvement of a major salivary gland, lymph node metastasis) is not typical of PLAC.