ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor.

In this work, we have analyzed the expression of different members of the ErbB family in human samples of testicular germ cell tumors (GCTs). We observed expression of ErbB1 or ErbB2 in different tumor subtypes, but we also found high expression of ErbB3 in all GCTs tested. This pattern of expression was maintained when primary tumors were orthotopically implanted in nude mice. We have chosen a choriocarcinoma model characterized by high levels of ErbB1, but also of ErbB2 and ErbB3, to assay the in vivo effect of ErbB inhibitors on tumoral growth. Our results showed a complete lack of effect (refractoriness) to the pure ErbB1 receptor inhibitors cetuximab and gefitinib. While these inhibitors blocked ErbB1 phosphorylation, ErbB2 phosphorylation was not affected, suggesting an ErbB1-independent activation of this receptor. To confirm the importance of ErbB2 activation, animals were treated with lapatinib, a dual ErbB1 and ErbB2 inhibitor. Lapatinib treatment caused a 50% inhibition in tumor growth, an effect correlated with a blockade of both ErbB1 and ErbB2 phosphorylation levels, and of downstream signaling pathways (Akt, ERKs and Stat3). ErbB2 activation could still occur due to the formation of ErbB2/ErbB3 heterodimers, and ErbB3 activation was completely inhibited by lapatinib. Finally, combined inhibition of ErbB1 (gefitinib) and ErbB3 activities (knockdown expression by shRNA) inhibited tumoral testicular cells proliferation in a similar way to lapatinib. Our results explain why lapatinib but not anti-ErbB1 agents might be effective for treatment of testicular GCT patients.

Sensitization of retinoids and corticoids to epigenetic drugs in MYC-activated lung cancers by antitumor reprogramming.

Components of the SWI/SNF chromatin remodeling complex, including BRG1 (also SMARCA4), are inactivated in cancer. Among other functions, SWI/SNF orchestrates the response to retinoid acid (RA) and glucocorticoids (GC) involving downregulation of MYC. The epigenetic drugs SAHA and azacytidine, as well as RA and GC, are currently being used to treat some malignancies but their therapeutic potential in lung cancer is not well established. Here we aimed to determine the possible therapeutic effects of azacytidine and SAHA (A/S) alone or in combination with GC plus RA (GC/RA) in lung cancers with either BRG1 inactivation or MYC amplification. In vitro, responses to GC/RA treatment were more effective in MYC-amplified cells. These effects were mediated by BRG1 and involved a reprogramming towards prodifferentiation gene expression signatures and downregulation of MYC. In MYC-amplified cells, administration of GC/RA enhanced the cell growth inhibitory effects of A/S which, in turn, accentuated the prodifferentiation features promoted by GC/RA. Finally, these treatments improved overall survival of mice orthotopically implanted with MYC-amplified, but not BRG1-mutant, cells and reduced tumor cell viability and proliferation. We propose that the combination of epigenetic treatments with retinoids and corticoids of MYC-driven lung tumors constitute a strategy for therapeutic intervention in this otherwise incurable disease.

Prognostic value of the expression of E-cadherin and beta-catenin in bladder cancer.

The purpose of this study was to assess the prognostic effect of the expression of E-cadherin, beta-catenin and CD44 adhesion molecules in bladder carcinoma. 22 superficial and 18 invasive bladder tumour samples were studied by immunohistochemistry. The median follow-up was 24 months (range: 1-50 months). Loss of E-cadherin and beta-catenin immunoreactivity was found in 14 (35%) and 17 (43%) tumours, respectively, and was significantly associated with invasiveness, high grade and p53 overexpression. There was no correlation between CD44 variant expression and clinicopathological findings. Loss of E-cadherin expression was an independent predictor of poor survival in a multivariate analysis, when assessed with age, grade, stage and p53 status (hazards ratio adjusted (HRa)=4.45 [95% confidence interval (CI), 1.06-18.63]). This effect was particularly augmented in patients with invasive bladder cancer. When expression of E-cadherin and beta-catenin were evaluated simultaneously, loss of immunoreactivity of both proteins was a strong predictor of poor survival (HRa=13.06 [95% CI, 0.95-178.55]). The same pattern was found when progression-free survival in relation to these variables was assessed. In conclusion, assessment of E-cadherin and beta-catenin immunoreactivity may be a useful prognostic marker in bladder cancer complementary to established prognostic factors.

Cold ischemia in the absence of alloreactivity induces chronic transplant nephropathy through a process mediated by the platelet-activating factor.

BACKGROUND: Ischemia-reperfusion injury is considered a risk factor for the development of chronic transplant nephropathy (CTN) although the mechanisms that mediate its effects have not been completely established. We have previously shown that treatment with a platelet-activating factor (PAF) receptor antagonist (UR12670) protected kidneys from the progression to chronic nephropathy induced by warm ischemia. Here we examine the contribution of cold ischemia to the development of late functional and structural kidney changes in rats subjected to syngeneic renal transplantation and the role of PAF in this chronic nephropathy. SUBJECTS AND METHODS: Lewis rats were used as kidney donors and recipients, which were transplanted either immediately or after a cold ischemia period of 5 hr. Contralateral nephrectomy was performed on the seventh day after transplantation. Cyclosporine was administered for 15 days after transplantation. Groups were as follows: Sy, immediate transplantation; SyI, transplantation after 5 hr of cold ischemia; SyIUr, transplantation after 5 hr of cold ischemia plus UR12670 from the transplantation day to the end of the study, at 24 weeks. Serum creatinine, creatinine clearance, and proteinuria were determined every 4 weeks. Urinary

Protocol renal allograft biopsies and the design of clinical trials aimed to prevent or treat chronic allograft nephropathy.

BACKGROUND: The minimum sample size to perform a clinical trial aimed to modify the natural history of chronic allograft nephropathy (CAN) is very large. Since the presence of chronic tubulointerstitial damage in renal protocol biopsy specimens is an independent predictor of late outcome, we evaluated whether protocol biopsies could facilitate the design of trials aimed to prevent or treat CAN. METHODS: Two hundred eighty-two protocol biopsy specimens were obtained 3 months after transplantation in 280 patients with serum creatinine levels <300 micromol/L, proteinuria <1000 mg/day, and stable function. The specimens were evaluated according to the Banff criteria. RESULTS: Graft survival depended on the presence of CAN and renal transplant vasculopathy (RTV). Thus, biopsy specimens were classified as: (a) no CAN (n=174); (b) CAN without RTV (n=87); and (c) CAN with RTV (n=21). Graft survival at 10 years was 95%, 82%, and 41%, respectively (P=0.001). Total serum cholesterol before transplantation was 4.5+/-1.1, 4.6+/-1.1, and 5.3+/-1.6 mmol/L, respectively (P=0.009) and it was the only predictor of RTV. Power analysis (beta=20%, alpha=5%) was done to evaluate whether protocol biopsies can facilitate the design of clinical trials aimed either to prevent or treat CAN. We showed that the most feasible approach would be to use the presence of CAN as the primary efficacy end point in a prevention trial. To demonstrate a 50% reduction in the incidence of CAN at 3 months, 570 patients would be required. CONCLUSIONS: Protocol biopsies may allow a reduction of sample size and especially the time of follow-up in a trial aimed to prevent CAN.

Cardiac hemangioma with papillary endothelial hyperplasia: report of a resected case and review of the literature.

A case of left atrial hemangioma with papillary endothelial hyperplasia in a 42-year-old man is reported. With the aid of cardiopulmonary bypass, the tumor was resected, and the patient is well 22 months after operation. The clinical symptoms at initial examination, operative procedure, and pathological findings are reported, and the diagnostic and therapeutic approaches to cardiac tumors are described briefly. A review of surgically treated hemangiomas is also given.

Adhesion molecule expression and endothelial cell activation in cutaneous leukocytoclastic vasculitis. An immunohistologic and clinical study in 42 patients.

OBJECTIVES: To investigate the sequential expression of adhesion molecules on endothelium and inflammatory cells in cutaneous leukocytoclastic vasculitis, and the relation of these adhesive molecules with clinical and histologic variables. DESIGN: An immunohistochemical analysis (streptavidin-biotin-peroxidase technique) of 42 vasculitic lesions of up to 96 hours was performed using a panel of monoclonal antibodies specific for different adhesion molecules. Twenty normal skin samples and 3 perilesional specimens served as control samples. A clinical protocol was also performed, and patients were followed up for 1 to 5 years. SETTING: A clinicopathologic research unit of a university hospital. PATIENTS: Forty-two patients, 21 women and 21 men, aged 22 to 79 years, with cutaneous leukocytoclastic vasculitis. INTERVENTIONS: Three skin biopsy specimens of vasculitic lesions from each patient were obtained for histopathologic examination on paraffin, direct immunofluorescence, and immunohistochemical analysis on cryostatic tissue sections. MAIN OUTCOME MEASURES: The histologic characteristics and the immunohistochemical-stained specimens were evaluated by 3 independent investigators, using a semiquantitative method. RESULTS: Increased endothelial expression of very late activation antigen-1, HLA-DR, and intercellular adhesion molecule-1 was observed. The induction of E-selectin expression was more marked in recent lesions (P < .001) and correlated with the proportion of infiltrating neutrophils (P = .03). Endothelial expression of vascular cell adhesion molecule-1 was restricted to developed lesions. Most infiltrating cells were neutrophils expressing Mac-1. In 1 patient, lymphocyte function associated antigen-1 expression was also up-regulated. No significant increase in CD3, CD8, or CD71 immunoreactivity was found. An up-regulation of perivascular cells expressing HLA-DR and vascular cell adhesion molecule-1 was observed in vasculitic lesions. This cellular staining correlated with long-term evolution of the disease (P = .04). CONCLUSIONS: Adhesion molecules are sequentially upregulated in cutaneous leukocytoclastic vasculitis. The results of this study support the possible involvement of E-selectin in mediating recruitment of neutrophils expressing Mac-1.

Prognostic factors in leukocytoclastic vasculitis: a clinicopathologic study of 160 patients.

OBJECTIVE: To analyze risk factors for systemic involvement and long-term course in leukocytoclastic vasculitis. DESIGN: A clinicopathological study of 160 patients with leukocytoclastic vasculitis followed up for at least 3 years. Univariate and multivariate analysis were conducted by logistic regression methods. SETTING: The Bellvitge Hospital, a referral center in Barcelona, Spain. PATIENTS: One hundred sixty patients with cutaneous leukocytoclastic vasculitis. Patients in the categories cutaneous/systemic vasculitis and acute/chronic cutaneous vasculitis were selected for comparative analysis. MAIN OUTCOME MEASURES: Clinical, laboratory, and histopathological findings. RESULTS: Of 89 females and 71 males, aged 14 to 89 years, systemic involvement was documented in 20% of cases. Perinuclear-staining antineutrophil cytoplasmic autoantibodies were found in 21% of patients and cryoglobulins in 25.4%. Of the patients, 1.9% died of systemic vasculitis. The average duration of cutaneous lesions was 27.9 months. In 67.2%, a cause or associated condition was identified. Of the skin specimens, 59.6% showed vasculitis limited to superficial dermal vessels. Direct immunofluorescence was positive in 84.3% of cases. In the multivariate analysis, paresthesia, fever, and absence of painful lesions were found to be risk factors for systemic involvement. Cryoglobulins, arthralgia, and normal temperature were risk factors for chronic cutaneous disease. CONCLUSION: Our results identify prognostic factors in leukocytoclastic vasculitis and may provide some aid in the management of this heterogeneous group of patients.

Increased expression of bcl-2 immunoreactivity in the developing cerebral cortex of the rat.

Bcl-2 proto-oncogene encodes a protein which may cancel the cell death programme in normal development and experimentally induced conditions. Strong bcl-2 immunoreactivity occurs in the neocortex and hippocampus of the developing rat during the 1st postnatal week. Bcl-2 immunoreactivity rapidly decreases from this age onwards to steady very low levels in adulthood. Since increased expression of bcl-2 immunoreactivity during cortical neurogenesis is coincidental in time with a special vulnerability of cortical neurons to naturally occurring cell death, it is suggested that bcl-2 may have a role in regulating cell death and survival during cortical morphogenesis.

Spinal cord compression by a unifocal eosinophilic granuloma: a case report of an adult with unusual roentgenological features.

We describe an unusual case of unifocal eosinophilic granuloma of the spine in a 38-year-old woman who presented with spinal cord compression. After 2 years of back pain, x-ray films of the spine were normal, but computed tomography and magnetic resonance imaging demonstrated a lytic lesion of the 1st lumbar vertebral body with cephalic extension in the epidural space. The lesion was later confirmed at operation to be an eosinophilic granuloma spreading into the surrounding tissues.

Ferritin immunohistochemical localization in normal and neoplastic colonic mucosa.

High levels of ferritin have been detected in serum and tumoral extracts of gastrointestinal neoplasms. However, its histological localization is not well known. An immunoperoxidase technique (PAP) was used for detecting ferritin in 30 colorectal carcinomas, 20 polyps and 8 cases of non-neoplastic mucosae. Ferritin staining was detected in stromal cells (98%) much more than in epithelial cells (21%). Connective cells were positive in 5 cases of normal mucosae (62%), 19 polyps (95%) and all carcinomas (100%). The number of positive cells gradually rose from normal mucosa to carcinoma with an intermediate score in adenomas. However, no relation could be found between the stromal ferritin score and dysplasia in polyps. Likewise, no relation was found between the stromal ferritin score and the differentiation grade, invasion or metastases in carcinomas. The positive epithelial pattern seen in 12 cases (21%) suggests non-specific staining due to passive diffusion from the stroma. Thus, these immunohistochemical findings suggest that in colonic neoplasms, ferritin could be a tumor marker produced mainly by stromal cell reaction more than by the epithelial cells.

Expression of cytokeratins in squamous cell carcinomas of the larynx: immunohistochemical analysis and correlation with prognostic factors.

The expression of distinct cytokeratin subtypes in squamous cell carcinomas (SQCC) of the larynx was examined by immunohistochemistry with a panel of monoclonal antibodies (MABs) and different immunophenotypes were correlated with known prognostic factors, such as tumor site, local extension, degree of morphologic differentiation and lymph node metastasis. Among 50 cases of laryngeal SQCC tested, all 22 low grade tumors (Broders I and II) reacted strongly with MABs AE1, AE3 and KB.12, which corresponds to the phenotype of non-neoplastic squamous epithelium of the larynx. MABs K8.13 and K8.60 were negative only in 1 and 4 cases respectively. In these tumors CAM5.2 was either negative (18 cases) or weakly positive (4 cases). In contrast, we found that of 28 high grade SQCC (Broders III and IV) tested, strong reactivity with MABs AE1, AE3, K8.12 and K8.13 was restricted to smaller subsets, whereas CAM5.2 immunoreactivity was seen in 16 cases (57%). By morphological criteria 31 out of 50 cases in our series of SQCC showed keratinization and 30 of these 31 showed coexpression of cytokeratins identified by MABs AE3, K8.12, K8.13 and K8.60 and 29 cases by MAB AE1. The remaining non-keratinizing SQCC showed heterogeneous immunoreactivity for AE1, AE3 and K8.12 in 13 cases, for K8.13 in 12 cases and for K8.60 in 5 cases. Thirty of the 50 SQCC tested had no known lymph node metastasis and of these, 29 reacted with MABs AE1, AE3, K8.12 and K8.13 respectively, the remaining cases being either unreactive or only weakly reactive. Statistical analysis showed no significant differences between cytokeratins expression in SQCC and either anatomical location or local extension (pT).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal myelolipoma in a woman with congenital 17-hydroxylase deficiency.

A case of adrenal myelolipoma, which to our knowledge is the first case to be associated with 17-hydroxylase deficiency, is reported. This rare, benign lesion is known to occur in association with other endocrinopathies. Discussion focuses on the possible role of continued stimulation by corticotropin and/or steroids as pathogenic factors. The present case adds evidence supporting this view.

Adenomyoepithelioma of the breast. A report of two cases.

We describe two cases of adenomyoepithelioma of the breast. The two tumors reported herein were well-circumscribed lesions that showed ducts lined by inner epithelial and outer myoepithelial cells and solid areas made up of fasciculated spindle myoepithelial cells. This dual differentiation was corroborated by immunohistochemical studies and electron microscopy.

Importance of tumoral markers in donors: study of prostate-specific antigen.

UNLABELLED: We established a protocol to determine the serum prostate-specific antigen (PSA) in male donors of 50 years or older, and to histologically examine the prostate glands. From January 1997 to December 2002 we analysed serum PSA in 51 cases, of which it was normal in 34 and high in 17. Prostate glands were examined histologically in 13 of the high PSA cases. Donors were classified according to the PSA level and histology: donors with high PSA values and adenocarcinoma or high-grade PIN (group A, n=6); donors with elevated PSA but no malignancy (group B, n=7); and donors with normal PSA (group C, n=34). The ages, days in hospital, and causes of death were similar among the 3 groups. The levels of PSA were significantly higher among group A than group B or group C, but were similar between group B and C. The list of transplanted organs is as follows: 5 organs of group A; 8 organs of group B; and 59 organs of group C. CONCLUSIONS: High PSA levels seem show 2 patterns: (1) small increases of PSA related to donors with no prostate cancer, and (2) high levels of PSA related to the presence of prostate cancer, as is the case in the general population. The incidence of prostate cancer in overall male donors was 3.1%. Due to this high incidence, we believe it is important to determine PSA levels to diagnose prostate cancer in older donors. A separate consideration is what to do with the organs of those donors.

[Myocardial infarction in a young woman with left atrial myxoma]. / Infarto de miocardio en una mujer joven con un mixoma auricular izquierdo.

A 38 year old female patient without coronary risk factors suffered an acute myocardial infarction. Echocardiographic and cardiac catheterization was undertaken and a left atrial mass with normal coronary arteries was assessed. The tumor mass was successfully resected and pathological examination of the specimen disclosed a myxoma. Three months after the operation the patient is symptom-free and an echocardiogram taken at this time showed no evidence of tumor. A bibliographic review of the association cardiac myxoma and coronary artery occlusion or myocardial infarction is done.

Oncogenic osteomalacia: case report and review of head and neck associated tumours.

Oncogenic osteomalacia is an uncommon syndrome characterized by mineral metabolism abnormalities that disappear after the resection of an associated tumour. Head and neck is the second most frequent location of these tumours. We describe a case with an ethmoido-frontal phosphaturic mesenchymal tumour and review oncogenic osteomalacia-associated tumours. Among 21 cases found, 57 per cent affected the sinonasal area and 20 per cent the mandible. The diagnosis of the tumour lasted a mean of 4.7 years from the onset of osteomalacia, and most of them showed a significant vascular component. An aggressive surgical approach is recommended.

[Superficial gastric cancer in Barcelona. Importance of the detection of severe epithelial dysplasia in biopsies obtained under endoscopic control in the diagnosis of early gastric cancer]. / Cáncer gástrico superficial en Barcelona. Importancia de la detección de displasia epitelial acusada en las biopsias obtenidas bajo control endoscópico para el diagnóstico del cáncer gástrico incipiente.

BACKGROUND: Severe mucosal dysplasia (SMD) in endoscopic gastric biopsies is a controversial lesion because some authors consider it as an histologic lesion associated to superficial gastric cancer (SCG). This study is aimed to asses the prevalence of SCG in Barcelona; if the presence of SMD is associated to SCG and, the clinical and endoscopic manifestations which induced the diagnosis. METHODS: We studied a total of 4,800 patients who had been submitted to gastroscopy during 1.5 years. A total of 79 patients suffered gastric cancer, 56 of them were submitted to resection. Ten of these 56 patients (17%) had SCG. The most frequent first clinical manifestation of SCG was gastrointestinal haemorrhage. RESULTS: Endoscopic aspect suggested malignancy in five cases. Biopsies during endoscopy allow diagnosis of gastric cancer in five. In four histologic studies showed SMD. In the tenth patient, the first endoscopy with biopsies showed a gastric peptic ulcer. A later endoscopic control showed the persistence of the macroscopically benign lesion but one among seven biopsies showed adenocarcinoma. The four patients with SMD had gastric cancer in further endoscopic procedures, except in one which was operated after two endoscopies demonstrating SMD. CONCLUSIONS: This study suggests: 1) prevalence of SGC in Barcelona is similar than the other European countries. 2) haemorrhage is a frequent first manifestation of SCG, and 3) the finding of SMD in endoscopic biopsy strongly suggests the presence of SCG in the stomach.

[Solitary plasmacytoma of the upper respiratory and digestive tracts. Report of 3 cases]. / Plasmocytome solitaire des voies aéro-digestives supérieures. Présentation de trois observations.

Three cases of plasmocytoma of cervicofacial localization are reported and diagnostic and therapeutic methods and prognostic factors reviewed. One patient had localized cervicofacial amyloidosis. A literature review confirmed the rarity of this tumor and its marked oncologic differences from epithelial type tumors and multiple myeloma.

[Thornwaldt's cyst. The experience of a decade]. / Quiste de Thornwaldt. La experiencia de una decada.

The cyst of the Thornwaldt's bursa is a bulge on the postero-superior wall of the rhinopharynx, due to the closure of the sac's drainage duct. The bursa pharyngea being an embryologic remnant occurring in 3 percent of healthy adults. It is a process well known since a century, but only 11 cases (in 9 several publications) have been quoted in the last 20 years. Perusal of the cases seen at the ENT Department of the Clinic and Provincial Hospital of Barcelona during the latter decade.