Primary and metastatic brain cancer genomics and emerging biomarkers for immunomodulatory cancer treatment.

Recent studies with immunomodulatory agents targeting both cytotoxic T-lymphocyte protein 4 (CTLA4) and programmed cell death 1 (PD1)/programmed cell death ligand 1 (PDL1) have shown to be very effective in several cancers revealing an unexpected great activity in patients with both primary and metastatic brain tumors. Combining anti-CTLA4 and anti-PD1 agents as upfront systemic therapy has revealed to further increase the clinical benefit observed with single agent, even at cost of higher toxicity. Since the brain is an immunological specialized area it's crucial to establish the specific composition of the brain tumors' microenvironment in order to predict the potential activity of immunomodulatory agents. This review briefly summarizes the basis of the brain immunogenicity, providing the most updated clinical evidences in terms of immune-checkpoint inhibitors efficacy and toxicity in both primary and metastatic brain tumors with the final aim of defining potential biomarkers for immunomodulatory cancer treatment.

Forestier syndrome and obstructive sleep apnea: Surgical treatment.

INTRODUCTION: We report a case of obstructive sleep apnea that occurred as a result of Forestier disease and describe the surgical treatment that was performed. SUMMARY: The patient is a 56-year-old man who presented dysphagia for solids and liquids, snoring (score 10) and excessive daytime sleepiness for 5 years. On fiber optic laryngoscopy examination, there was interarytenoid edema and protrusion of the posterior wall of the larynx. The cervical X-Ray showed protrusion of intervertebral disc between C3-C5 (skeletal hyperostosis) and the polysomnography revealed apnea-hypopnea index (AHI) of 56 events/h. Surgery was performed by the otorhinolaryngology and orthopedic teams. The patient evolved with complete symptom resolution and an AHI of 3,9 events/h on the control polysomnography. DISCUSSIONS: This is the first reported case of Forestier Syndrome (FS) associated with Obstructive Sleep Apnea (OSA) that was proposed surgical treatment and the patient evolved with complete symptom improvement.

Doctors' awareness concerning primary immunodeficiencies in Brazil.

BACKGROUND: PIDs are a heterogeneous group of genetic illnesses, and delay in their diagnosis is thought to be caused by a lack of awareness among physicians concerning PIDs. The latter is what we aimed to evaluate in Brazil. METHODS: Physicians working at general hospitals all over the country were asked to complete a 14-item questionnaire. One of the questions described 25 clinical situations that could be associated with PIDs and a score was created based on percentages of appropriate answers. RESULTS: A total of 4026 physicians participated in the study: 1628 paediatricians (40.4%), 1436 clinicians (35.7%), and 962 surgeons (23.9%). About 67% of the physicians had learned about PIDs in medical school or residency training, 84.6% evaluated patients who frequently took antibiotics, but only 40.3% of them participated in the immunological evaluation of these patients. Seventy-seven percent of the participating physicians were not familiar with the warning signs for PIDs. The mean score of correct answers for the 25 clinical situations was 48.08% (±16.06). Only 18.3% of the paediatricians, 7.4% of the clinicians, and 5.8% of the surgeons answered at least 2/3 of these situations appropriately. CONCLUSIONS: There is a lack of medical awareness concerning PIDs, even among paediatricians, who have been targeted with PID educational programmes in recent years in Brazil. An increase in awareness with regard to these disorders within the medical community is an important step towards improving recognition and treatment of PIDs.

Severe combined immunodeficiency in Brazil: management, prognosis, and BCG-associated complications.

BACKGROUND: Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency. The objectives of this study were to analyze the diagnosis, treatment, and prognosis of SCID in Brazil and to document the impact of BCG vaccine. METHODS: We actively searched for cases by contacting all Brazilian referral centers. RESULTS: We contacted 23 centers and 70 patients from 65 families. Patients were born between 1996 and 2011, and 49 (70%) were male. More than half (39) of the diagnoses were made after 2006. Mean age at diagnosis declined from 9.7 to 6.1 months (P = .058) before and after 2000, respectively, and mean delay in diagnosis decreased from 7.9 to 4.2 months (P = .009). Most patients (60/70) were vaccinated with BCG before the diagnosis, 39 of 60 (65%) had complications related to BCG vaccine, and the complication was disseminated in 29 of 39 (74.3%). Less than half of the patients (30, 42.9%) underwent hematopoietic stem cell transplantation (HSCT). Half of the patients died (35, 50%), and 23 of these patients had not undergone HSCT. Disseminated BCG was the cause of death, either alone or in association with other causes, in 9 of 31 cases (29%, no data for 4 cases). CONCLUSIONS: In Brazil, diagnosis of SCID has improved over the last decade, both in terms of the number of cases and age at diagnosis, although a much higher number of cases had been expected. Mortality is higher than in developed countries. Complications of BCG vaccine are an important warning sign for the presence of SCID and account for significant morbidity during disease progression.

Possible association between NOD2 variants and joint surgery in psoriatic arthritis.

BACKGROUND: Psoriatic arthritis (PsA) has been inconsistently associated with common NOD2 gene variants, although some of these studies did not include patient stratification by clinical phenotype. OBJECTIVES: To analyse the association between the three common NOD2 variants (R702W, G908R and L1007fs) and clinical phenotypes of PsA, particularly with surrogate markers of severe joint destruction. PATIENTS AND METHODS: A total of 183 unrelated PsA patients and 187 controls were included. Demographic, clinical, biological and immunological characteristics were collected. Genotypes for the three common NOD2 gene variants were obtained by PCR and direct sequencing. RESULTS: NOD2 variants in PsA patients (7.6%) are just as prevalent as in healthy controls (7.5%). 18.5% of PsA patients carrying at least one NOD2 variant underwent joint surgery compared with 4.5% of those without these variants (p=0.019). Multivariate analysis confirmed this finding (OR 8.82, CI 1.7-46.3). There was no requirement for early surgery in patients carrying the NOD2 variants but there was an increased possibility of requiring surgery at similar times of disease duration. No other association with clinical features and NOD2 status carrier was found. CONCLUSIONS: Common NOD2 gene variants are not associated with PsA, but might increase the risk of undergoing joint replacement surgery, suggesting that this autoinflammatory-associated gene could act as a phenotypic modifier gene in PsA patients by increasing the risk of joint destruction. Given the small number of PsA patients with joint surgery included, we consider our findings a new hypothesis that will need further testing.

Influence of variants of Fc gamma receptors IIA and IIIA on the American College of Rheumatology and European League Against Rheumatism responses to anti-tumour necrosis factor alpha therapy in rheumatoid arthritis.

OBJECTIVE: Fc gamma receptor (Fc gammaR) polymorphism influences the affinity of the receptor for Ig, which may, in turn, affect the efficacy of Ig-based therapies. The relationship between functional single nucleotide polymorphisms (SNP) of the FCGR2A and FCGR3A genes and the response to anti-tumour necrosis factor (TNF)alpha therapy (infliximab) in patients with rheumatoid arthritis (RA) was assessed. METHODS: A total of 91 patients with RA (89% female; 76.7% rheumatoid factor (RF) positive) starting therapy with infliximab were evaluated at 0, 6 and 30 weeks using the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria and the 28-joint Disease Activity Score (DAS28) was evaluated using three parameters, including C-reactive protein (CRP) (DAS28 3v-CRP) changes during the follow-up. Genotyping of FCGR2A-R131H and FCGR3A-F158V polymorphisms was performed by allele-specific PCR and PCR sequence-based typing, respectively. The chi(2) and Fisher exact tests were used to show differences in the outcome variables, and analysis of variance (ANOVA) to analyse the evolution of DAS28 3v-CRP. A generalised linear models multivariable analysis was also performed. RESULTS: At week 6 of follow-up, the proportion of patients achieving 50% improvement as per ACR criteria (ACR50) and EULAR good responses were significantly higher among homozygotes of the low affinity FCGR3A allele (FF: 24.1% and VV-VF:2.2%; p = 0.003 and FF: 44.8% and VV-VF: 22.9%; p = 0.040, respectively). At week 30, homozygotes of the low affinity FCGR2A allele had a better ACR20 response (RR: 60% and HH-RH: 33.3%; p = 0.035). Changes in DAS28 3v-CRP during follow-up were consistent with those observed in ACR and EULAR responses. CONCLUSIONS: The response to anti-TNFalpha treatment with infliximab in patients with RA is influenced by the FCGR2A and FCGR3A genotypes. This effect is observed at different times in the follow-up (6 and 30 weeks, respectively) indicating the dynamic nature of the Fc gammaR versus Ig interaction.

Further description of early clinically silent lupus nephritis.

Thirty silent lupus nephritis (SLN) patients were compared to 16 individuals bearing overt lupus nephritis (OLN). Results included: years of systemic lupus erythematosus (SLE) diagnosis were significantly earlier (4.6 +/- 2.8 years) in SLN than in OLN (7.18 +/- 3.61) (P < 0.05). Neurological compromise, hypertension, normocitic anemia and lymphopenia were significantly prevalent in OLN than in SLN (P < 0.05). Beside normal urinary sediment and renal function tests, the SLN group showed a moderate increase of both activity (AI) and chronicity (CI) renal pathology index when compared to highly increased AI and CI in OLN (P < 0.05). Seventy percent of SLN patients were ISN/RPS Classes I (6.6%) and II (63.3%) while 81% of OLN cases were Classes III, IV (37.5%) and V. IgG, IgA, IgM, lambda chain, C3 and fibrinogen immune deposits were found in 90% or over in both SLN and OLN individuals while in 60% or over, both groups also showed kappa chain, Clq and C4 deposits. While prevalence of ANA, anti-dsDNA and anti-C1q antibodies were similar in both groups, anti-histone, anti-RNP, CIC and CH50 serum levels were significantly different in OLN versus SLN (P < 0.05). We strongly suggest that indeed SLN is the earliest stage in the natural history of lupus nephritis.

Riñón trasplantado: aspectos históricos, inmunológicos e histopatológicos / Renal transplantation: histopathology and immunological history aspects

El trasplante renal es el tratamiento sustitutivo de elección en todo el mundo, para pacientes con insuficiencia renal crónica terminal. Históricamente sus comienzos se sitúan a principios del siglo XX en Europa. Su éxito y permanencia como tratamiento electivo hasta ahora es la consecuencia principalmente de los adelantos de las técnicas quirúrgicas, del conocimiento de los fenómenos inmunológicos que se relacionan con la colocación de injertos y del descubrimiento de nuevas drogas inmunosupresoras, ya de uso corriente, como lo es la Ciclosporina A, que tiene gran efectividad en controlar los fenómenos de rechazo. La mejoría en la supervivencia de los injertos ha motivado también el desarrollo de una activa clínica de trasplante renal para encarar las alteraciones del funcionamiento de los injertos, cuyo diagnóstico definitivo descansa en el estudio morfológico de la biopsia renal, que se considera el estándar de oro y cuyos hallazgos histopatológicos fundamentales se muestran en la presente revisión

Immunochemotherapy in American cutaneous leishmaniasis: immunological aspects before and after treatment.

In this study, we evaluated the immune response of patients suffering from cutaneous leishmaniasis treated with two distinct protocols. One group was treated with conventional chemotherapy using pentavalent antimonium salts and the other with immunochemotherapy where a vaccine against cutaneous leishmaniasis was combined with the antimonium salt. Our results show that, although no differences were observed in the necessary time for complete healing of the lesions between the two treatments, peripheral blood mononuclear cells from patients treated by chemotherapy showed smaller lymphoproliferative responses at the end of the treatment than those from patients in the immunochemotherapy group. Furthermore, IFN-gamma production was also different between the two groups. While cells from patients in the chemotherapy group produced more IFN-gamma at the end of treatment, a significant decrease in this cytokine production was associated with healing in the immunochemotherapy group. In addition, IL-10 production was also less intense in this latter group. Finally, an increase in CD8+ -IFN-gamma producing cells was detected in the chemotherapy group. Together these results point to an alternative treatment protocol where healing can be induced with a decreased production of a potentially toxic cytokine.

Immunochemotherapy in American cutaneous leishmaniasis: immunological aspects before and after treatment

In this study, we evaluated the immune response of patients suffering from cutaneous leishmaniasis treated with two distinct protocols. One group was treated with conventional chemotherapy using pentavalent antimonium salts and the other with immunochemotherapy where a vaccine against cutaneous leishmaniasis was combined with the antimonium salt. Our results show that, although no differences were observed in the necessary time for complete healing of the lesions between the two treatments, peripheral blood mononuclear cells from patients treated by chemotherapy showed smaller lymphoproliferative responses at the end of the treatment than those from patients in the immunochemotherapy group. Furthermore, IFN-gamma production was also different between the two groups. While cells from patients in the chemotherapy group produced more IFN-gamma at the end of treatment, a significant decrease in this cytokine production was associated with healing in the immunochemotherapy group. In addition, IL-10 production was also less intense in this latter group. Finally, an increase in CD8+ -IFN-gamma producing cells was detected in the chemotherapy group. Together these results point to an alternative treatment protocol where healing can be induced with a decreased production of a potentially toxic cytokine

Ductal cell carcinoma of the kidney with extensive signet ring cell mucosecreting areas. A case report with immunohistochemical analysis.

We present the case of a 45-year-old patient with a renal ductal cell carcinoma arising in the Bellini ducts that was composed of histologically well-differentiated tubulopapillary and cystic areas with desmoplastic stroma, extensive mucosecreting areas, and regions depicting a transition between these two constituents. The mucosecreting component was mostly formed by signet ring tumor cells containing cytoplasmic Alcian blue-PAS-stainable mucins. The tubulopapillary and cystic areas of the tumor showed the immunohistochemical staining for low and high molecular weight cytokeratin, EMA, vimentin and Ulex europaeus, characteristic of ductal cell carcinoma. The mucosecreting cells also presented intense positive staining for cytokeratin and vimentin, and this is quite similar to observations reported in some forms of gastrointestinal cancer with rhabdoid features that are indicative of poor prognosis. Our findings suggest that mucosecreting areas with signet ring cells represent an extreme metaplastic change that can seldom occur in certain forms of renal tumors.

Well differentiated gastric adenocarcinoma with rhabdoid areas: a case report with immunohistochemical analysis.

We describe the case of a 73-year-old patient with gastric adenocarcinoma composed of histologically well differentiated glandular areas, extensive rhabdoid zones and regions depicting a transition between these two constituents. The rhabdoid component showed typical features such as abundant eosinophilic cytoplasm, eccentric nuclei, prominent nucleoli, intense positive immunohistochemical cytoplasmic reaction for vimentin and less evident immunohistochemical for cytokeratin and epithelial membrane antigen (EMA). Our findings strongly suggest that the rhabdoid areas probably represent a phenotypic variant of a gastric adenocarcinoma, otherwise fairly well differentiated, a combination that to the best of our knowledge has not been previously reported.

Tratamento cirúrgico do pé torto equinovaro congênito idiopático: avaliaçäo pó-operatória de 164 pés / Surgical treatment of congenital clubfoot: postoperative evaluation of 164 feet

A via de acesso de Cincinnati foi utilizada em 111 pacientes (164 pés) portadores de pé torto eqüinovaro congênito (PTC) no período de 1985 a 1994. Os autores descrevem a técnica cirúrgica empregada e as facilidades que envolvem a abordagem das regiöes medial, posterior e lateral através dessa via de acesso. Os resultados säo analisados por um sistema de avaliaçäo funcional que permite, por meio de exame clínico e radiográfico, classificá-los em excelentes, bons, regulares e ruins. Os autores, entretanto, sugerem que os resultados excelentes e bons sejam denominados satisfatórios e os regulares e ruins, insatisfatórios. A análise comparativa entre duas faixas etárias é submetida ao estudo estatístico. Dessa forma, foi possível concluir que a idade influenciou significantemente os resultados obtidos.

Síndrome da apnéia do sono obstrutiva: um novo desafio médico - odontológico / Obstrutive sleep apnea syndrome: a new medical - odontologic defiance

Este artigo destina-se a informaçäo do cirurgiäo dentista, em particular do ortodontista, a respeito de uma nova síndrome que desperta interesse no meio médico e que em seu tratamento e o ortodontista terá importante participaçäo

The value of CT-scanning in supratentorial haemangioblastomas.

The authors describe a case of supratentorial haemangioblastoma, presenting with epileptic fits, without association with polycythemia, or Von Hippel-Lindau syndrome, which, if present, would have given a clinical clue as to the nature of the lesion.

Microsurgery in severe posterior epistaxis.

A brief review of surgery for severe posterior epistaxis has been outlined. Hundred and forty-five (27.3%) patients were treated by transnasal microsurgery in order to undergo ligation of the branches of the sphenopalatine artery in the nasal cavity. The rate of failure was 6.1%. It seems that by using this kind of operation, we can significantly decrease the morbidity in relation to other methods of controlling the posterior epistaxis.

Immune complex disease complicating diabetic glomerulosclerosis.

We report immunopathologic findings observed in renal biopsies of 18 patients with diabetic glomerulosclerosis and associated glomerulonephritis. 10 patients had nodular and 8 patients diffuse diabetic glomerulosclerosis. Focal proliferative glomerulonephritis (4 patients), membranous glomerulonephritis (3 patients), postinfectious glomerulonephritis, Henoch-Schönlein nephritis, IgA nephropathy of Berger (1 patient each), and mesangiopathic glomerulonephritis (8 patients) were the superimposed conditions. In patients with diabetic renal disease, a rapid loss of renal function or an atypical urinalysis could be the expression of a superimposed immune complex disease. Because of functional and biochemical alterations, the glomeruli of diabetic patients may be more susceptible to immune-mediated injury.