Paquimeningitis hipertrófica y tumoración orbitaria asociada a Granulomatosis con poliangeitis: reporte de un caso clínico / Hypertrophic pachymeningitis and orbital tumour associated with Granulomatosis with polyangiitis: case report

Paciente de 65 años, con diagnóstico de Granulomatosis con Poliangeitis (GPA) de 18 años de evolución cuyo debut fue por insuficiencia respiratoria aguda asociado a hemoptisis recibiendo tratamiento con corticoides sistémicos y ciclofosfamida de inducción. Luego recibió mantenimiento con azatioprina 150 mg día, con periodos de recrudecimiento de enfermedad que respondieron al tratamiento con corticoides por períodos cortos. Acude a consulta por cefalea crónica de tres meses de evolución refractaria al tratamiento con antiinflamatorios no esteroides (AINES), asociado a proptosis ocular izquierda y dolor orbitario homolateral, presentando reactantes de fase aguda elevados (eritrosedimentación y Proteína C reactiva). Se evidencia por resonancia magnética nuclear cerebral con gadolinio, realce de la duramadre cerebral y tienda de cerebelo, presentando además una formación orbitaria izquierda.

A 65-year-old patient, with a diagnosis of Granulomatosis with Polyangeitis (GPA) of 18 years of evolution, whose debut was with respiratory failure and hemoptysis, receiving induction treatment with corticosteroids together with cyclophosphamide, and then maintenance treatment with azathioprine 150 mg per day, with periods of flare-up of the disease that responded to treatment with corticosteroids for short periods. He came to the clinic for a 3-month-long chronic headache refractory to treatment with non-steroidal anti-inflammatory drugs (NSAIDs), associated with left ocular proptosis and ipsilateral orbital pain, presenting elevated acute phase reactants (ers and c-reactive protein). It is evidenced by brain magnetic resonance with gadolinium, enhancement of the cerebral dura and cerebellum store, also presenting formation in the left orbit.

NS1 DNA vaccination protects against Zika infection through T cell-mediated immunity in immunocompetent mice.

The causal association of Zika virus (ZIKV) with microcephaly, congenital malformations in infants, and Guillain-Barré syndrome in adults highlights the need for effective vaccines. Thus far, efforts to develop ZIKV vaccines have focused on the viral envelope. ZIKV NS1 as a vaccine immunogen has not been fully explored, although it can circumvent the risk of antibody-dependent enhancement of ZIKV infection, associated with envelope antibodies. Here, we describe a novel DNA vaccine encoding a secreted ZIKV NS1, that confers rapid protection from systemic ZIKV infection in immunocompetent mice. We identify novel NS1 T cell epitopes in vivo and show that functional NS1-specific T cell responses are critical for protection against ZIKV infection. We demonstrate that vaccine-induced anti-NS1 antibodies fail to confer protection in the absence of a functional T cell response. This highlights the importance of using NS1 as a target for T cell-based ZIKV vaccines.

Leptin deficiency modulates allograft survival by favoring a Th2 and a regulatory immune profile. [corrected].

Leptin, an adipose-secreted hormone, links metabolism and immunity. Our aim was to determine whether leptin affects the alloimmune response. We used an allogeneic skin transplant model as a means to analyze the allograft immune response in Lep(ob/ob) and wild-type mice. Leptin deficiency results in an increased frequency of Treg and Th2 cells and a prolonged graft survival. These effects of leptin deficiency indicate the importance of leptin and obesity in modulating the allograft immune responses. Our data suggest a possible explanation for the increased susceptibility of hyperleptinemic obese patients to acute and chronic graft rejection.

Maximal inflammatory response benefits syngeneic skin graft acceptance.

OBJECTIVE AND DESIGN: We investigated the influence of acute inflammation in skin isograft acceptance. METHODS: Two mouse lines selected for maximal (AIRMAX) or minimal inflammatory response (AIRMIN) were transplanted with syngeneic skin. Cellular infiltrates and cytokine production were measured 1, 3, 7 or 14 days post-transplantation. The percentage of CD4+CD25+Foxp3+ cells in the lymph nodes was also evaluated. RESULTS: Grafts were totally accepted in 100% of AIRMAX and in 26% of AIRMIN mice. In the latter, partial acceptance was observed in 74% of the animals. Emigrated cells were basically PMN and were enhanced in AIRMAX transplants. IL-10 production by graft infiltrating cells showed no interline differences. IFN-gamma was increased in AIRMIN grafts at day 14 and lower percentages of CD4+CD25+Foxp3+ cells in the lymph nodes were observed in these mice. CONCLUSIONS: Our data suggest that differences in graft acceptance might be due to a lack of appropriate regulation of the inflammatory response in AIRMIN mice compromising the self/non-self recognition.

Phase I study of paclitaxel and day 1/day 8 gemcitabine in patients with solid malignancies.

A phase I study was designed to evaluate the toxicity of escalating doses of gemcitabine along with fixed-dose paclitaxel in patients heavily pretreated with chemotherapy or radiotherapy. All patients had no prior therapy with the study drugs and possessed both adequate performance and end organ function. Eighteen patients were entered in the study. Characteristics included a median age of 66 years (range, 41 to 77) and stage IV disease in all patients; there were six patients with colon cancer, two with bladder cancer, three with non-small-cell lung cancer, two with esophageal cancer, three with pancreatic cancer, and two with cancer of unknown primary. Paclitaxel (150 mg/m2 over 3 hours) was given on day 1 and gemcitabine (800, 900, and 1,000 mg/m2 over 15 minutes) was given in three separate dose-escalating cohorts (1-3) on days 1 and 8. The treatment cycled every 21 days. The dose-limiting toxicity (DLT) proved to be neutropenia. All nonhematologic toxicities were mild and included gastrointestinal (nausea, vomiting, and diarrhea), dermatologic (rash), and neurologic (paresthesias) disturbances along with transient elevations of liver function tests. The combination of gemcitabine and paclitaxel seems to be well tolerated, and the recommended starting dose for a phase II study, in pretreated patients using a day 1/day 8 treatment schedule, should be 900 mg/m2 for gemcitabine (days 1 and 8) along with 150 mg/m2 for paclitaxel (day 1).

Unilateral external and internal ophthalmoplegia caused by intracranial meningioma in a dog.

Unilateral internal and external ophthalmoplegia caused by an intracranial meningioma occurred in a 15-year-old Belgian Sheepdog. The dog initially presented with ventro-lateral strabismus of the left eye, and ptosis of the left upper eyelid. Anisocoria was present with the left pupil fixed and dilated. Both eyes were visual. Neuro-ophthalmic evaluation revealed a lesion located in the left oculomotor nerve. Pharmacological testing with dilute pilocarpine (0.1% in artificial tears) revealed evidence of parasympathetic denervation of the left eye. Further evaluation via magnetic resonance imaging (MRI) revealed a well-defined mass to the left of midline and lateral to the sella turcica. An attempt was made to excise/debulk the mass due to worsening conditions and the dog died the following day. Necropsy revealed a mass of randomly arranged bundles and streams of spindle cells. Immunohistochemistry demonstrated a strong avidity for vimentin and a negative response for S-100 protein. These findings suggest a diagnosis of meningioma.

Eosinophilic conjunctivitis, herpes virus and mast cell tumor of the third eyelid in a cat.

A 3-year-old Himalayan cat was diagnosed with concurrent eosinophilic conjunctivitis, herpes virus, and a conjunctival mast cell tumor. Eosinophilic conjunctivitis was verified via cytology from a conjunctival scraping, which revealed 50% eosinophils and 50% neutrophils. Herpes virus was verified via a positive polymerase chain reaction (PCR). Conjunctival scrapings for chlamydia immmunofluorescent antibody (IFA) and herpes IFA were negative. A mycoplasma was detected by a general mycoplasma PCR but the organism did not grow on the available mycoplasma media. The mass was excised and microscopic evaluation revealed a histiocytic mast cell tumor. The mast cell did not recur following local excision (at 1 year follow-up). The eosinophilic conjunctivitis was treated with both topical steroids and systemic megesterol acetate (Ovaban). When topical steroids were used, the herpes virus flared up and resulted in dendritic and geographic corneal ulceration. Therefore, the cat was treated with megesterol acetate and the eosinophilic conjunctivitis was well controlled. Treatment of eosinophilic conjunctivitis in the cat with megesterol acetate may be the treatement of choice due to the possibility of herpes virus.

Suppository administration of chemotherapeutic drugs with concomitant radiation for rectal cancer.

PURPOSE: Preoperative radiation with combined chemotherapy is effective in shrinking advanced rectal cancer locally and facilitating subsequent surgery. Suppository delivery of 5-fluorouracil is associated with less toxicity and higher rectal tissue concentrations than intravenous administration. This prompted us to evaluate suppository and intravenous administration of 5-fluorouracil and mitomycin C with concomitant radiation to determine associated toxicity. METHODS: Rectal, liver, lymph node, and lung tissue and systemic and portal blood were collected serially from male Sprague Dawley rats to determine drug concentrations following suppository or intravenous delivery of 5-fluorouracil or mitomycin C. Thirty-six animals were randomly assigned to treatment groups and received 5-fluorouracil suppositories, mitomycin C suppositories, or an equivalent intravenous dose of 5-fluorouracil or mitomycin C 30 minutes before radiation therapy. Before and 3, 6, 10, and 15 days following this treatment, blood was collected, colonoscopy was performed, and rectal tissue was harvested for histologic examination. RESULTS: Mitomycin C suppository was significantly less toxic compared with intravenous delivery, and higher rectal tissue concentrations were observed from 10 to 30 minutes (P < 0.05). Compared with intravenous 5-fluorouracil administration and radiation, 5-fluorouracil suppository and radiation resulted in additive myelosuppression at day 6 (P < 0.05) with rapid recovery. CONCLUSIONS: 5-Fluorouracil and mitomycin C suppository delivery combined with radiation causes less systemic toxicity and is more effective than intravenous administration.

Suppository delivery of 5-fluorouracil in rectal cancer.

BACKGROUND: Preoperative radiotherapy with concomitant intravenous 5-fluorouracil (5-FU-i.v.) is effective in shrinking locally advanced rectal cancers and facilitating subsequent surgery. Topical 5-FU application may enhance its radiosensitizing and cytotoxic effects. Suppository and intravenous 5-FU administration were compared with respect to myelo-suppression and tissue concentrations. METHODS: Rats received 120 mg/kg 5-FU-i.v. or via suppository (5-FU-S). White blood cell count, serum albumin, alkaline phosphatase, creatinine, and aspartate aminotransferase (AST) were determined before and serially after 5-FU administration. In a separate experiment, rats received 5-FU-S or 5-FU-i.v. as already described. Portal and systemic blood, rectal, iliac lymph node, liver, and lung tissue were harvested for high-performance liquid chromatography determination of 5-FU concentrations 30 min, 1, 3, 6, and 12 h after drug administration. RESULTS: No toxicity was observed in 5-FU-S animals, whereas 63% of 5-FU-IV animals had diarrhea. Weight loss and myelosuppression occurred only in 5-FU-i.v. animals. Rectal drug concentrations were significantly higher in the 5-FU-S animals compared with 5-FU-i.v. animals, 0.5-6 h after drug administration. Blood, liver, and lung 5-FU concentrations with 5-FU-S were comparable to those with 5-FU-i.v. CONCLUSIONS: 5-FU suppositories are associated with fewer systemic side effects and higher rectal 5-FU concentrations than with 5-FU-i.v. administration.

Evaluation of multiple doses of 4 and 6% timolol, and timolol combined with 2% pilocarpine in clinically normal beagles and beagles with glaucoma.

Topically applied 4% timolol, 4% timolol combined with 2% pilocarpine, 6% timolol, and 6% timolol combined with 2% pilocarpine were evaluated in clinically normal Beagles and Beagles with glaucoma. The drugs were instilled twice daily for 5 days. Changes in intraocular pressure (IOP), pupil size, and heart rate were recorded on days 1, 3, and 5 at 0, 2, 5, and 8 hours, starting at 8:30 AM. In clinically normal dogs, 4 and 6% topically administered timolol did not cause consistent reductions in IOP; however, with addition of 2% pilocarpine, IOP was consistently lower. In the Beagles with glaucoma, 4 and 6% timolol and, to a greater extent, 4 and 6% timolol combined with 2% pilocarpine lowered IOP. The combinations lowered IOP and reduced pupil size consistently. In all test groups, either 4 or 6% topically applied timolol caused approximately 10% decrease in mean heart rate.

Suramin interference with transforming growth factor-beta inhibition of human renal cell carcinoma in culture.

Suramin is a polyanionic compound used clinically for the treatment of trypanosomiasis, which is known to inhibit the action of many protein factors in vitro. Transforming growth factor-beta (TGF-beta) is a multifunctional regulatory protein which inhibits the growth of renal cell carcinoma in culture. While suramin at 50-500 micrograms/ml had no significant effect on the growth of renal cell carcinoma in culture in our experiments, it did partially reverse the growth inhibition induced by TGF-beta in the two cell lines tested. This effect apparently is caused by suramin's direct interference with 125I-labeled TGF-beta's ability to bind to the cell, and not by any effect of suramin on the TGF-beta receptor. Furthermore, suramin dissociates TGF-beta bound to the cell with a t1/2 of less than 30 min. These results are consistent with those previously reported regarding suramin's interaction with other protein growth factors, and suggest that suramin may interact with the TGF-beta protein itself to inactivate it.

Suramin: a novel growth factor antagonist with activity in hormone-refractory metastatic prostate cancer.

PURPOSE: Suramin is known to inhibit the growth of malignant prostate carcinoma cells in vitro. This led us to evaluate the effectiveness of suramin in the treatment of 38 patients with prostate carcinoma refractory to hormone therapy. PATIENTS AND METHODS: Suramin was administered by continuous infusion at a rate designed to reach a peak of 300 micrograms/mL at the end of 14 days. Patients were given 8 weeks to recover from any toxicity before beginning the second cycle. Subsequent cycles were administered in the same manner except the starting dose rate was 280 mg/m2. RESULTS: In 17 patients with measurable soft tissue disease, three had complete disappearance of soft tissue disease for 4, 5, and 11 months, whereas three patients had a greater than or equal to 50% decrease in the sum of the products of the diameters of all measurable disease for greater than or equal to 1 month. Of these 17 patients, pretreatment prostate-specific antigen (PSA) decreased by 75% or more in five (29%) and normalized in one (6%). The remaining 21 patients had disease limited to bone, and only one of these experienced resolution of more than 50% of all lesions on bone scan. Of these 21 patients, pretreatment PSA decreased by 75% or more in eight (38%) and normalized in five (25%). Median time to progression for all patients was 26.3 weeks, and median survival was 42.3 weeks. Patients with bone involvement alone exhibited a better survival than patients with soft tissue involvement (P2 = .02). Survival was strongly correlated (P2 = .0001) with a decline in the pretreatment PSA of greater than or equal to 75% by the eighth week on therapy, with nearly an 85% survival at 1 year compared with a 20% survival for those whose pretreatment PSA did not decline by that amount. CONCLUSION: We conclude that suramin is an active agent in hormone-refractory prostate carcinoma.

Suramin in advanced platinum-resistant ovarian cancer.

10 patients with ovarian cancer, whose disease had progressed while receiving platinum-based therapy, were entered onto a phase II clinical trial of the antiproliferative agent suramin. Suramin was administered in a fashion that is associated with durable objective disease response in patients with hormonally resistant metastatic prostate cancer. No individual had an objective response to therapy in this study, but 3 of 9 evaluable patients (33%) experienced disease stabilisation and subjective clinical improvement for periods ranging from 2 to 5 months. Disease stabilisation was associated with prolonged periods of comparatively high plasma levels of drug, which appeared to be determined primarily by reduced drug clearance. We conclude that suramin has potential activity in platinum-resistant ovarian cancer, and we have initiated a second clinical trial using pharmacological information derived from this study.

Effect of Evans blue and trypan blue on syncytia formation and infectivity of human immunodeficiency virus type I and type II in vitro.

Polyanionic compounds were used to inhibit infectivity of human immunodeficiency virus in vitro. Suramin, Evans blue, and Trypan blue were shown to inhibit syncytia formation normally observed when HIV-1-infected cells are cocultured with CD4+ cells. The inhibition was more pronounced with Evans blue than with any of the other polyanions studied. The inhibitory effect was significantly weaker in HIV-2 systems. However, the reverse transcriptase activities of both types of viruses were inhibited by Evans blue. Another polyanionic compound, phosphorothioate 28-mer cytidine homopolymer (SdC28) was shown to inhibit syncytium formation induced by HIV-1-and HIV-2-infected cells in an identical manner. Evans blue showed partial blocking of gp120 binding to CD4 in a solid-phase enzyme-linked immunosorbent assay (ELISA). These results suggest that the polyanionic dyes may exert their antiviral effects, at least in part, by interfering with the binding and fusion of HIV with susceptible T cells.

Use of suramin in treatment of prostatic carcinoma refractory to conventional hormonal manipulation.

Suramin and related compounds, in view of their growth factor and enzyme binding properties, represent in many respects a novel approach to the treatment of cancer. Although in this preliminary analysis of suramin use in the treatment of metastatic prostate cancer, the objective response rate does not appear impressive, much work still needs to be done to optimize suramin's administration to patients and to elucidate its various postulated mechanisms of action. The development of related compounds with more specific enzyme and growth factor antagonist properties is under way.

Characteristics of cell lines established from human gastric carcinoma.

We report the establishment and characterization of four continuous cell lines derived from human primary and metastatic gastric carcinomas, and we compare their properties with a panel of colorectal carcinoma cell lines previously established and reported by us. Our success rate in culturing gastric carcinomas was relatively low, especially from primary tumors, compared to colorectal carcinoma. These observations may reflect the relatively modest number of gastric carcinoma cell lines established (mainly from Japan), compared to the abundance of colorectal carcinoma lines established worldwide. All four gastric lines expressed the surface glycoproteins carcinoembryonic antigen and TAG-72 and three lines expressed CA 19-9. Two of the lines expressed aromatic amino acid decarboxylase but lacked other markers for neuroendocrine differentiation. All four lines were positive for vasoactive intestinal peptide receptors but lacked gastrin receptors. In addition, two lines expressed receptors for muscarinic/cholinergic receptors but not beta-adrenergic receptors. Cytogenetic evidence for gene amplification was present in the cell lines. All four lines contained varying numbers of double-minute chromosomes. One line, SNU-16, was amplified for the c-myc proto-oncogene and contained four homogeneously staining regions. While c-myc and c-erb-B-2 RNA were expressed by all lines, there was no evidence of amplification or overexpression of several other proto-oncogenes and growth factors. The multiple properties we have described in our gastric carcinoma cell lines are remarkably similar to those found in the panel of colorectal carcinoma cell lines. These properties include morphology, growth characteristics, expression of surface glycoproteins, partial expression of neuroendocrine cell markers, frequent chromosomal evidence of gene amplification, and occasional amplification of the c-myc proto-oncogene. Our four well characterized cell lines should provide useful additions to the modest number currently available for in vitro studies of gastric carcinoma.

Patterns of proto-oncogene expression in human glioma cell lines.

Previously reported studies have suggested that variations in the pattern of proto-oncogene expression within a specific tumor type may denote an underlying difference in the biology and clinical behavior of those tumors. To more sensitively characterize malignant tumors of the central nervous system, we have used Northern blot hybridization analysis to determine the patterns of expression of seven proto-oncogenes in 20 cell lines established from biopsy specimens of patients with malignant glioma. The following proto-oncogenes are expressed at detectable levels in 30 micrograms of total RNA from most glioma cell lines examined: c-myc (20/20), c-mil/raf-1 (18/18), neu (19/20), c-erbB (19/20), and c-myb (17/20). In contrast, only half of the cell lines expressed detectable c-sis (10/20). In none of the cell lines tested was N-myc (0/20) mRNA detected. Morphologic analysis of these 20 cell lines revealed three different growth patterns: bipolar, epithelial, and pleomorphic-glial. Detectable levels of c-sis mRNA typically occurred with either an epithelial or pleomorphic-glial morphology. The pleomorphic-glial subgroup was also characterized by the expression of glial fibrillary acidic protein.

Genetic changes in human adrenocortical carcinomas.

Recent studies have suggested that loss of heterozygosity at loci on the short arm of human chromosome 11 (11p) may be important in the pathogenesis of benign and malignant adrenal cortical tumors. To test this concept, adrenocortical carcinomas from nine patients and benign adrenal cortical lesions from eight patients were tested for loss of alleles at loci on human chromosomes 11, 13, and 17. All patients with adrenocortical carcinoma whose normal somatic tissues were heterozygous for a locus on chromosome 17p had lost alleles in the tumor. Four of six patients with adrenocortical carcinoma who were heterozygous for one or more alleles on chromosome 11p in normal tissues had lost 11p alleles in the tumor. Three of six patients with adrenocortical carcinoma showed loss of 13q alleles in the tumor. Loss of alleles on chromosomes 11p, 13q, and 17p was observed in primary tumors and metastases but not in adrenocortical adenomas or hyperplastic lesions of the adrenal cortex. One patient with adrenocortical carcinoma had a somatic mutation in the HRAS1 gene in the normal adrenal gland. The consistency of the genetic changes on chromosomes 11p, 13q, and 17p suggests that they are important in the pathogenesis of adrenocortical carcinoma.

Suramin: an anticancer drug with a unique mechanism of action.

We administered suramin, an anti-parasitic drug and reverse transcriptase inhibitor, to 15 patients with metastatic cancer. This compound is known to inhibit the binding of growth factors (eg, epidermal growth factor [EGF], platelet-derived growth factor [PDGF], tumor growth factor-beta [TGF-beta]) to their receptors and thus antagonize the ability of these factors to stimulate growth of tumor cells in vitro. There were no complete responses (CRs), four partial responses (PRs) (two of ten adrenal cortex, one of four renal, one of one adult T-cell leukemia-lymphoma [HTLV-1]), and two minimal responses (MRs) (two of ten adrenal cortex). Toxicity included proteinuria (14 patients), reversible liver function test abnormalities (eight), vortex keratopathy (five), adrenal insufficiency (three), coagulopathy secondary to increased circulating levels of glycosaminoglycans (11), and one case of a reversible acute demyelinating polyneuropathy resembling the Guillain-Barrè syndrome. We conclude that suramin is an active agent in the treatment of metastatic cancer, and further work is necessary to define its scope.