Radiographic findings of space-occupying lesions in sialo-CBCT of the major salivary glands.

OBJECTIVES: When performing CBCT sialography (sialo-CBCT), space-occupying lesions may be identified incidentally. The objective was to describe their radiologic-clinical-histopathologic correlations. METHOD AND MATERIALS: The archive of sialo-CBCT scans was retrospectively searched for suspected space-occupying lesions. Based on the scan and clinical-histopathologic data, the cases were divided into "pathologic" vs "normal," "intra-parenchymal" vs "extra-parenchymal," and "benign" vs "malignant." Two precalibrated, blinded radiologists performed a survey of the radiographic features of each scan. Cohen kappa, chi-square, Kruskal-Wallis, and Mann-Whitney tests assessed inter-observer agreement and radiologic-clinical-histopathologic correlations. RESULTS: In total, 27 (1.5%) suspected space-occupying lesions were found in 1,758 reports. Full follow-up data were available for 15 cases: four were "malignant," six were "benign," and the remaining five were "normal." Kappa showed substantial inter-observer agreement (0.8 to 1.0). Constant swelling correlated with "pathologic" cases (P = .003). Lesion diameter was greater in "pathologic" than "normal" (P < .001) cases, with a cut-off of 12.6 mm. Clinical and radiographic features were similar in "benign" and "malignant" lesions. "Intra-parenchymal" and "extra-parenchymal" space-occupying lesions correlated with "no-fill-region" (P = .01) and "main-duct-displacement" (P = .002), respectively. CONCLUSIONS: Suspected space-occupying lesions in sialo-CBCT with a diameter greater than 12.6 mm are likely to be "pathologic." No radiographic features were able to differentiate between "malignant" and "benign" space-occupying lesions.

Ex-vivo activation of a liposomal prodrug of mitomycin C by human tumors.

PURPOSE: To examine the ex- vivo ability of explanted human tumors and normal tissue to activate liposomal mitomycin C lipidic prodrug (MLP) by releasing the active free drug form, mitomycin C (MMC). METHODS: We tested conversion of MLP to MMC in an ex vivo assay using explanted tissues obtained during routine surgery to remove primary tumors or metastases. Tumor and adjacent normal tissue were obtained from freshly explanted tumors and were immediately deep frozen at - 70 °C. On test day, the fragments were thawed, homogenized and incubated in the presence of a fixed amount of liposomal MLP at 37 °C for 1 h. We measured MLP and its rate of conversion to MMC by HPLC. Controls included plasma, malignant effusions, red blood cells, tumor cell lines, mouse liver, and buffer with dithiothreitol, a potent reducing agent. RESULTS: Most patients tested (16/20) were diagnosed with colo-rectal carcinoma. The average fraction of MLP cleaved per 100-mg tumor tissue (21.1%, SEM = 1.8) was greater than per 100-mg normal tissue (16.6%, SEM = 1.3). When the tumor and normal tissue samples were paired by patient, the difference was statistically significant (p = 0.022, paired t test). Biological fluids did not activate liposomal MLP, while normal liver tissue strongly does. Interestingly, the omental fatty tissue also greatly activated MLP. CONCLUSIONS: Tumor tissue homogenates activate MLP with greater efficiency than the surrounding normal tissues, but far less than liver and adipose tissue. These observations demonstrate the bioavailability of liposomal MLP in human tumors, and its pharmacologic potential in cancer therapy.

Capillaria hepatica (syn. Calodium hepaticum) as a Cause of Asymptomatic Liver Mass.

Capillaria hepatica (syn. Calodium hepaticum) is a parasitic nematode of rodents, rarely infecting humans. An asymptomatic Israeli adult male with extensive travel history was diagnosed with a liver mass on routine post-thymectomy follow-up. Imaging and computer tomography (CT) guided biopsy were inconclusive. Surgical excision revealed an eosinophilic granuloma with fragments of a nematode suspected to be C. hepatica. Molecular methods verified the diagnosis, and the patient was treated empirically. This is the first case of hepatic capillariasis described in Israel, and the first to be diagnosed using molecular methods.

Pleural-Based Intrathoracic Cystic Lymphangioma in an Infant Mimicking a Pneumonia.

Cystic lymphangioma is an uncommon benign tumor that occurs primarily in children in the cervical region. We report the first case of a pleural-based cystic lymphangioma in an infant. The patient was admitted for RUL pneumonia. Because of the persistence of the radiographic findings despite clinical improvement, a computed tomography (CT) and a magnetic resonance imaging (MRI) scan were performed. They showed a multiloculated cystic lesion in the superior posterior right hemithorax. A surgical procedure was performed with complete resection of the tumor. Histopathological examination showed a pleural-based intrathoracic multicystic lymphangioma. One year after the surgery, the patient feels well without any sign of recurrence.

[INTRACHOLECYSTIC PAPILLARY-TUBULAR NEOPLASM: A NEW PATHOLOGY OF THE GALLBLADDER?]

INTRODUCTION: The clinicopathologic characterization of tumoral intra-epithelial neoplasms of the gallbladder is fairly limited compared to that of similar tumors of the pancreatobiliary system. Until recently, pre-malignant lesions of the gallbladder were mostly reported as adenomas, which were microscopic and therefore regarded as benign and clinically inconsequential, whereas papillary lesions have been largely regarded as a papillary subtype of gallbladder invasive adenocarcinoma. In an attempt to create a unified terminology for these tumors, the term Intracholecystic papillary-tubular neoplasm (ICPN) was proposed to include all exophytic intra-epithelial tumors of the gallbladder measuring ≥1 cm under one category. A few studies which have retrospectively analyzed tumors fulfilling this category found them to be remarkable analogous to the more well-characterized intra-epithelial tumors of the pancreato-biliary system such as IPMN of the pancreas and IPNB of the bile ducts and as such they also represent an 'adenoma-carcinoma' sequence in the gallbladder. Since then a number of case series have been published which attempted to characterize the clinical and pathological features of these tumors and their relationship with invasive carcinoma. In this paper we report three cases of ICPN which represent different stages of the 'adenoma-carcinoma' sequence.

Combining chloroquine with RAD001 inhibits tumor growth in a NEN mouse model.

Patients with neuroendocrine neoplasms (NENs) often require systemic treatment, which is frequently limited by the emergence of drug resistance. mTOR inhibitors (mTORi), such as RAD001 (everolimus), have been shown to inhibit neoplasm progression. mTORi stimulates autophagy, a degradation pathway that might promote the survival of neoplasm cells that are exposed to anti-cancer therapy. Chloroquine (CQ), a well-known anti-malarial and anti-rheumatic drug, suppresses autophagy. Based on our previous results, we hypothesized that CQ may enhance the anti-tumorigenic effects of mTORi by inhibiting autophagy and we aimed to examine the anti-tumorigenic effect of CQ, alone or in combination with RAD001. We established a NEN subcutaneous xenograft mouse model and evaluated the effect of the drugs on tumor growth, mTOR pathway, autophagy and apoptosis. CQ alone and in combination with RAD001 significantly decreased neoplasm volume. Histopathological analysis revealed that the combination of CQ and RAD001 markedly inhibited mTOR activity and neoplasm cell growth, along with accumulation of autophagosomes and increased apoptosis. In conclusion, CQ enhances the anti-tumorigenic effect of RAD001 in vivo by inhibiting autophagy. Clinical trials addressing the effects of CQ therapy on neoplasm progression in patients with NENs, mainly in those treated with mTORi, are warranted.

New ARCHITECT plasma pro-gastrin-releasing peptide assay for diagnosing and monitoring small-cell lung cancer.

BACKGROUND: Progastrin-releasing peptide (ProGRP) is a potential marker for small-cell lung cancer (SCLC) in serum; however, it may be more stable in plasma. We investigated a new plasma assay (ProGRPp) and its usefulness in diagnosing and monitoring SCLC. METHODS: The marker concentrations were determined on the ARCHITECT i system. RESULTS: The assay could distinguish SCLC from non-small-cell lung cancer (NSCLC: area under the curve 0.931, 95% CI 0.893-0.969; cross-validated accuracy 0.813; sensitivity 84.0%, specificity 96.3%; at 140 pg ml(-1) cutoff). The probability of SCLC when ProGRPp was >140 pg ml(-1) was 91.8%, after adjusting for age, gender, and renal dysfunction. The NSCLC patients with ProGRPp >140 pg ml(-1) were at high risk (odds ratio=37.0, P<0.001) for tumours with neuroendocrine features. False negatives in SCLC were associated with a lack of thyroid transcription factor-1 (P<0.001). A decrease of ProGRPp to <140 pg ml(-1) during chemotherapy was significantly associated with the image-based response (P<0.001), and independently affected progression-free survival (PFS, relative risk=2.51, P=0.04) and overall survival (OS, relative risk=4.38, P=0.003), after adjustment for imaging response, performance status, and stage. CONCLUSIONS: The ProGRPp assay is specific and sensitive for diagnosing SCLC. Changes in ProGRPp during chemotherapy are significantly associated with image-based response, PFS, and OS.

Diagnostic and therapeutic approach to obscure gastrointestinal bleeding in a patient with a jejunal gastrointestinal stromal tumor: a case report.

BACKGROUND: Gastrointestinal stromal tumors of the alimentary tract may present with severe bleeding. Localization and treatment of obscure gastrointestinal bleeding is challenging in cases of negative bi-directional endoscopy. CASE PRESENTATION: A previously healthy 64-year-old Caucasian female presented with clinical signs of active gastrointestinal bleeding. Esophagogastroduodenoscopy was normal, and colonoscopy revealed passage of blood from the small bowel. Computerized tomography angiography demonstrated a hypervascular lesion with active extravasation located in the jejunum. Angiography of the superior mesenteric artery revealed a focal hypervascular mass in the jejunum, and super selective distal coil embolization of the feeding vessel was performed. When the patient was taken for laparoscopic exploration, a 2.5 cm tumor arising from the anti-mesenteric border of the proximal jejunum was identified and resected with primary anastomosis. Pathological results demonstrated a gastrointestinal stromal tumor with a low proliferation index of 1%. Small erosions in the adjacent mucosa confirmed the locus of bleeding. CONCLUSIONS: Computerized tomography is a useful tool for initial diagnosis of submucosal alimentary tumors in patients with obscure but clinically overt gastrointestinal bleeding. Selective angiography, following positive computerized tomography findings, is an important modality to allow both localization and hemostasis in actively bleeding small bowel tumors, but the procedure carries the risk of bowel necrosis. Complete surgical resection remains the mainstay for treatment of gastrointestinal stromal tumors.

Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is closely associated with colon cancer. Expression of the enzyme heparanase is clearly linked to colon carcinoma progression, but its role in UC is unknown. Here we demonstrate for what we believe to be the first time the importance of heparanase in sustaining the immune-epithelial crosstalk underlying colitis-associated tumorigenesis. Using histological specimens from UC patients and a mouse model of dextran sodium sulfate-induced colitis, we found that heparanase was constantly overexpressed and activated throughout the disease. We demonstrate, using heparanase-overexpressing transgenic mice, that heparanase overexpression markedly increased the incidence and severity of colitis-associated colonic tumors. We found that highly coordinated interactions between the epithelial compartment (contributing heparanase) and mucosal macrophages preserved chronic inflammatory conditions and created a tumor-promoting microenvironment characterized by enhanced NF-κB signaling and induction of STAT3. Our results indicate that heparanase generates a vicious cycle that powers colitis and the associated tumorigenesis: heparanase, acting synergistically with the intestinal flora, stimulates macrophage activation, while macrophages induce production (via TNF-α-dependent mechanisms) and activation (via secretion of cathepsin L) of heparanase contributed by the colon epithelium. Thus, disruption of the heparanase-driven chronic inflammatory circuit is highly relevant to the design of therapeutic interventions in colitis and the associated cancer.

Glucagonoma and the glucagonoma syndrome - cumulative experience with an elusive endocrine tumour.

OBJECTIVE: Glucagonoma is a pancreatic neuroendocrine tumour that arises from alpha cells in the pancreas and is often accompanied by a characteristic clinical syndrome. DESIGN: In this report, we present the cumulative experience and clinical characteristics of six patients diagnosed with glucagonoma and the glucagonoma syndrome and treated at our centre during the past 25 years. RESULTS: Although the course of the disease was variable, some features were similar. The median age at diagnosis was 53·5 years; the median time from onset of symptoms to diagnosis was 39 months. Presenting symptoms were as follows: weight loss 5/6 (83%), necrotizing migratory erythema (NME) 5/6 (83%), diabetes mellitus 4/6 (66%) and diarrhoea, weakness and thrombosis 2/6 (33%). Plasma glucagon was elevated in all patients upon diagnosis (range 200-10,000 pm; N < 50). Skin biopsy was diagnostic only in 1/6 specimens obtained, even after revision. Metastatic disease developed in all patients; 4/6 initially presented with hepatic metastasis. All patient symptoms responded to somatostatin analogue therapy. In 4/6, the NME responded to amino acid solutions. Other modes of therapy were as follows: surgery in 3/6 patients, peptide receptor radioligand therapy with (90) Y-DOTATOC (PRRT) in 3/6 patients (two responses) and chemotherapy in three patients (two responded). Four out of six patients died of the disease, and median survival time was 6·25 years (range 2-11) from diagnosis and 8 years (range 8-16) from initial symptoms. Five-year survival was 66%. CONCLUSION: Our data indicate that somatostatin analogues and an aggressive surgical approach offer symptom relief and tumour control. Among other available treatment modalities, PRRT seems to hold the most promise.

Malignant pheochromocytoma: predictive factors of malignancy and clinical course in 16 patients at a single tertiary medical center.

Metastases appear in approximately 10% of patients with pheochromocytoma. There is no predictive marker of malignancy. The aim is to describe clinical course of patients with malignant pheochromocytoma and to identify predictive features of malignancy. The method involves retrospective analysis of patients files diagnosed with malignant pheochromocytoma at our institution between January 1, 1980 and December 31, 2008. We identified 16 patients with malignant pheochromocytoma. There were more men than women (10/6). Mean age of patients at time of diagnosis was 37.75-year-old. Time of occurrence of metastases ranged from 0 to 22 years after first diagnosis of pheochromocytoma. The mean size of the primary tumor was 12.1 cm. High levels of chromogranin A at the time of diagnosis were associated with the presence of metastases. The pheochromocytoma of the adrenal gland scoring scale (PASS) histological evaluation in adrenal primary tumors was above four in all cases but one. All patients had initial surgery, followed in most cases by palliative therapy: chemotherapy (streptozocin, cyclophosphamide-vincristine-dacarbazine, thalidomide, imatinib, everolimus) or (131)I-MIBG; only the latter had replicable encouraging response evaluation criteria in solid tumor response rates. We observed a 10-year survival rate of 50% after initial diagnosis of pheochromocytoma, and 25% after diagnosis of metastasis. Metastasis can occur very late after the initial diagnosis of pheochromocytoma. High chromogranin A levels may be associated with the presence of metastases and poor prognosis. Histological adrenal PASS higher than 4 appears to be suggestive of malignancy. The best therapeutic approach remains to be established.

Short homologous peptides based on C-terminal sequences of fibrinogen ß- and γ-chains (Haptides) affect cardiovascular function by eNOS inhibition.

Haptides are a family of 19-21-mer cell-binding and permeating peptides homologous to sequences in the C termini on both fibrinogen ß- and γ-chain (Cß and preCγ, respectively). The effect of the Haptides on the cardiovascular system was studied by different assays, including the activity of isolated perfused rat heart and blood vessels in the organ bath. Haptides (50-80 µg/ml) decreased the hemodynamic functions of perfused rat hearts by up to 60% (p < 0.05) in a dose-dependent manner. Whole fibrinogen or a control nonrelated peptide (Cα) did not show such an effect. The NO donor, sodium nitroprusside, reversed the inhibitory effects of Haptides. L-NAME, an endothelial nitric oxide synthase (eNOS) inhibitor, did not further augment the effect of the Haptides. Perfused (FITC)Haptides were attached to the coronary endothelium. In myocardial homogenates and HUVEC, Haptides significantly decreased eNOS activity, but had no effect on the contraction of isolated cultured adult cardiomyocytes. Haptides also significantly enhanced the contraction of rings of rat aorta and human mammary artery vessels ex vivo only when the endothelium was intact. Haptides seem to affect the coronary endothelium, but not the cardiomyocytes, by inhibiting eNOS activity, causing vasoconstriction, temporary ischemia and impaired myocardial function that seem to be related to the amino acid composition of the Haptides.

H syndrome: recently defined genodermatosis with distinct histologic features. A morphological, histochemical, immunohistochemical, and ultrastructural study of 10 cases.

This study analyzes the histopathological findings in H syndrome, a recently recognized autosomal recessive genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin in well-defined anatomical areas accompanied by various systemic manifestations. So far, descriptions of the histopathological skin changes in this disorder, as reported in a few small case series, were inconsistent, leading to diverse clinical interpretations. In an attempt to define standardized, diagnostic, morphological criteria that will distinguish this disorder from other fibrosing conditions, we studied skin biopsies from 10 patients with H syndrome. The characteristic morphology included widespread fibrosis (moderate in dermis and severe in subcutis); striking mononuclear infiltrates consisting mainly of monocyte-derived cells (small CD68 histiocytes and CD34 and FXIIIa dendrocytes) and plasma cells; and thickened, fragmented, and partially calcified elastic fibers, admixed with well-formed psammoma bodies, a previously unrecognized feature in nonneoplastic skin and subcutaneous conditions. In addition, the ultrastructure of CD68 small histiocytes exhibited distended endoplasmic reticulum and scarcity of lysosomes, features typical for fibroblasts but unusual for histiocytes. These unusual findings in the histiocytes pose a question as to their possible role in the fibrotic cascade in this disorder. We conclude that the above findings are essential for the diagnosis of H syndrome and that incisional biopsies are mandatory for recognition of the full spectrum of histopathological findings.

Nested (ossifying) stromal epithelial tumor of the liver: case report.

Nested stromal-epithelial tumor (NSET) of the liver is an extremely rare primary hepatic tumor with uncertain malignant potential. To date, only 11 cases have been described. We describe the case of a 2 1/2-year-old girl with an incidental liver mass. The mass was discovered on follow-up abdominal imaging for asymptomatic hydronephrosis diagnosed on antenatal ultrasound. Needle biopsy showed a mixed stromal and epithelial process in a nested pattern, with foci of ossification and no significant pleomorphism or necrosis. The nest cells stained with WT-1, cytokeratin 18, and CD56. Ossifying stromal epithelial tumor of the liver was strongly suspected. The findings were confirmed in the subsequent partial hepatectomy specimen. To our knowledge, this is the 12th case of NSET in the English-language literature and the 3rd case of NSET associated with genitourinary system abnormalities. Possible associations with dysregulated WT-1 expression are discussed.

The H syndrome: a genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin with systemic manifestations.

BACKGROUND: The association of cutaneous hyperpigmented, hypertrichotic, and indurated patches associated with hearing loss, short stature, cardiac anomalies, hepatosplenomegaly, scrotal masses, and hypogonadism has not, to our knowledge, been previously recognized as a disease entity. OBJECTIVE: We describe 10 patients with the above-mentioned findings. METHODS: Patients were clinically examined and extensive laboratory evaluation was performed. RESULTS: We describe 10 patients from 6 Arab consanguineous families with hyperpigmented, hypertrichotic, and indurated cutaneous patches involving the middle and lower parts of their bodies. In addition, patients displayed short stature, sensorineural hearing loss, cardiac anomalies, hepatosplenomegaly, and scrotal masses. Laboratory evaluation revealed growth hormone deficiency and hypergonadotropic hypogonadism with azoospermia. Cutaneous histopathologic examination showed hyperpigmentation of the basal layer with seborrheic-keratosis-like acanthosis, histiocytic infiltration, and a perivascular mononuclear infiltrate with plasma cells and mast cells throughout the dermis and subcutaneous fat. Comparison with several patients, recently reported in the medical literature, with similar cutaneous findings is made. LIMITATIONS: Laboratory evaluation in some patients was incomplete because of lack of cooperation. CONCLUSIONS: We suggest that our patients represent a novel multisystemic autosomal recessive inherited disorder. We call this constellation of symptoms the "H syndrome."