Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis.

OBJECTIVE: Caspase-2 is an initiator caspase involved in multiple apoptotic pathways, particularly in response to specific intracellular stressors (eg, DNA damage, ER stress). We recently reported that caspase-2 was pivotal for the induction of cell death triggered by excessive intracellular accumulation of long-chain fatty acids, a response known as lipoapoptosis. The liver is particularly susceptible to lipid-induced damage, explaining the pandemic status of non-alcoholic fatty liver disease (NAFLD). Progression from NAFLD to non-alcoholic steatohepatitis (NASH) results, in part, from hepatocyte apoptosis and consequential paracrine-mediated fibrogenesis. We evaluated the hypothesis that caspase-2 promotes NASH-related cirrhosis. DESIGN: Caspase-2 was localised in liver biopsies from patients with NASH. Its expression was evaluated in different mouse models of NASH, and outcomes of diet-induced NASH were compared in wild-type (WT) and caspase-2-deficient mice. Lipotoxicity was modelled in vitro using hepatocytes derived from WT and caspase-2-deficient mice. RESULTS: We showed that caspase-2 is integral to the pathogenesis of NASH-related cirrhosis. Caspase-2 is localised in injured hepatocytes and its expression was markedly upregulated in patients and animal models of NASH. During lipotoxic stress, caspase-2 deficiency reduced apoptosis, inhibited induction of profibrogenic hedgehog target genes in mice and blocked production of hedgehog ligands in cultured hepatocytes. CONCLUSIONS: These data point to a critical role for caspase-2 in lipid-induced hepatocyte apoptosis in vivo for the production of apoptosis-associated fibrogenic factors and in the progression of lipid-induced liver fibrosis. This raises the intriguing possibility that caspase-2 may be a promising therapeutic target to prevent progression to NASH.

Spindle-cell lesions of the liver: diagnosis by fine-needle aspiration biopsy.

Rarely, spindle-cell lesions in liver fine-needle aspiration biopsies (FNABs) are encountered. A retrospective review of our experience with lesions that are mesenchymal in origin or appearance was undertaken to elucidate the frequency and spectrum of these lesions. Image-guided liver FNABs performed over a 3-year period (n = 585) at our institution (1996-1998) were retrospectively evaluated. Cytologic smears, cell block preparations, and clinical follow-up of lesions with spindle-cell morphology were reviewed. Twenty-nine of 585 cases were of spindle-cell morphology (5%). Hemangiomas (n = 12, 41%) and metastatic sarcomas (n = 6, 21%) comprised the largest categories, followed by granulomatous inflammation (n = 3, 10%). Other cases included primary angiosarcoma and fibrolamellar hepatocellular carcinoma. The most frequent spindle-cell liver lesion encountered is hemangioma, followed by metastatic leiomyosarcoma and granulomatous hepatitis. Awareness of diagnostic possibilities, special attention to specimen adequacy, and use of ancillary procedures can maximize diagnostic yield.

Long term response in a patient with neoplastic meningitis secondary to melanoma treated with (131)I-radiolabeled antichondroitin proteoglycan sulfate Mel-14 F(ab')(2): a case study.

Even with novel chemotherapeutic agents and external beam radiation therapy, the prognosis of neoplastic meningitis secondary to malignant melanoma is still dismal. The authors report a case study of a 46-year-old white female who presented with progressive hearing loss, severe headaches, nausea, vomiting, and a rapid decline in neurologic status. She was referred to Duke University Medical Center after conventional chemotherapy for malignant melanoma failed. She was enrolled in a Phase I trial of (131)I-labeled monoclonal antibody Mel-14 F(ab')(2) fragment administered intrathecally. Within a year after her treatment, she recovered, having a normal neurologic exam except for residual bilateral hearing loss. The authors discuss dosimetry, preclinical, and clinical studies conducted with Mel-14 F(ab')(2) and introduce a potentially promising therapy option in the treatment of neoplastic meningitis in patients with malignant melanoma. Currently, the patient remains neurologically normal except for a mild bilateral hearing loss more than 4 years after treatment and has no radiographic evidence of neoplastic meningitis.

Abdominal fat pad aspiration biopsy for tissue confirmation of systemic amyloidosis: specificity, positive predictive value, and diagnostic pitfalls.

Abdominal fat pad fine-needle aspiration biopsy (FNAB) is considered the method of choice for confirmation of systemic amyloidosis. Due to our impression that positive results are rare in our FNA service, we retrospectively analyzed our results. Forty-five samples collected from 45 patients over 3 yr were reviewed. Of the 7 patients with positive Congo red-stained FNAB specimens, all 7 (100%) had documented amyloidosis. Of the 33 patients with negative Congo red fat samples, 28 (85%) were disease-free. Of the 5 patients with inadequate samples, 2 (40%) were later diagnosed with disease. We demonstrate excellent specificity (100%). The positive predictive value, documented in only a few previous studies, is likewise excellent (100%). Sensitivity is low (58%) and inadequacy is high (11%). Improvement in technique, such as concurrent cell block preparation, may help avoid inadequate specimens. Difficulties in confirming amyloidosis also include interpretation of the Congo red stain (pale-stained amyloid fibrils and collagen birefringence).

Percutaneous fine-needle aspiration of gastrointestinal wall lesions with image guidance.

The fear of complications related to transgression of the bowel wall has limited the application of fine-needle aspiration (FNA) in gastrointestinal wall masses. We have undertaken a study examining our use of image-guided FNA in this setting, and evaluated diagnostic outcome and procedural risk. Twenty patients underwent percutaneous computed topography (CT) or ultrasound (U/S)-guided FNA biopsy of gastrointestinal wall masses over a 3-yr period. Hollow-bore needles were used to aspirate 8 gastric wall masses, 5 perirectal/distal sigmoid masses, 4 colonic masses, and 3 small-bowel masses. Lesions ranged in size from 1.5-13.0 cm (mean, 3.9 cm). One to five passes were made into each lesion (mean, 2.4). Immediate assessment for adequacy by a cytopathologist was performed in all cases. Neoplastic processes were identified in 15 cases (8 primary adenocarcinomas, 2 gastrointestinal stromal tumors, 3 metastases to the bowel wall, 1 Kaposi's sarcoma, and 1 primary lymphoma). Eleven of these 15 patients had histologic confirmation (all neoplastic lesions, excepting patients with metastases or Kaposi's sarcoma). Negative diagnoses (no evidence of malignancy) were obtained in the remaining 5 patients (2 benign colonic epithelium, 1 benign lymphoid population, 1 benign stroma, and 1 acute inflammatory process). A benign clinical course was followed in 4 patients, with 1 patient lost to follow-up. No acute or chronic postprocedural complications were identified. The earlier literature as well as this current study suggest that complications of FNA in this setting are rare. Diagnostic material may be obtained in a less invasive manner than open surgical biopsy.

Fine needle aspiration biopsy of the liver.

The liver is a commonly targeted deep-seated organ in which fine-needle aspiration biopsy (FNAB) is performed. By far, the most frequently encountered lesions on FNAB of the liver are metastases; however, a wide variety of other lesions have been described and are likely to be encountered. Because of this wide variety, attention to architectural as well as cytologic features on smears and cell block preparations, ancillary techniques, and special studies are often required. In the setting of proper specimen handling and judicious use of ancillary procedures, FNAB of hepatic lesions can be an accurate diagnostic procedure.

Rhabdoid tumors of the kidney in children: CT findings.

OBJECTIVE: The purpose of this study was to identify CT characteristics of rhabdoid tumor of the kidney, a rare, aggressive, malignant neoplasm of unknown origin that occurs mainly in infants and young children. MATERIALS AND METHODS: CT scans of eight children (newborn to 13 years old; mode, 4 months old; six boys and two girls) with histopathologic diagnosis of rhabdoid tumor of the kidney were evaluated retrospectively by two of the authors, who were not blinded to the diagnosis. All eight CT scans were performed with intravenous and oral contrast, and noncontrast intravenous CT scans were available in four cases. The following CT characteristics were evaluated: location of tumor within the kidney; presence of calcification, subcapsular hematoma, multiple tumor lobules, enlarged vessels, vascular invasion, or central tumor necrosis or hemorrhage; visibility of tumor margin; distant metastasis; and primary tumor size. RESULTS: All eight primary tumors (five on the left, one of which had contralateral renal nodules) were central in location and involved the hilum. Calcification outlining the tumor lobule was present in two of the four tumors on noncontrast CT scans. Subcapsular hematoma was seen in five children. Tumor necrosis and hemorrhage were seen in seven children. Tumors were well defined from the renal cortex in four children. Lobules of tumor were seen in seven children. CONCLUSION: CT findings of calcification, subcapsular hematoma, and lobular appearance in a large, centrally located, and heterogeneous renal mass in a child suggest a rhabdoid tumor of the kidney.