5-lipoxygenase-dependent recruitment of neutrophils and macrophages by eotaxin-stimulated murine eosinophils.

The roles of eosinophils in antimicrobial defense remain incompletely understood. In ovalbumin-sensitized mice, eosinophils are selectively recruited to the peritoneal cavity by antigen, eotaxin, or leukotriene(LT)B4, a 5-lipoxygenase (5-LO) metabolite. 5-LO blockade prevents responses to both antigen and eotaxin. We examined responses to eotaxin in the absence of sensitization and their dependence on 5-LO. BALB/c or PAS mice and their mutants (5-LO-deficient ALOX; eosinophil-deficient GATA-1) were injected i.p. with eotaxin, eosinophils, or both, and leukocyte accumulation was quantified up to 24 h. Significant recruitment of eosinophils by eotaxin in BALB/c, up to 24 h, was accompanied by much larger numbers of recruited neutrophils and monocytes/macrophages. These effects were abolished by eotaxin neutralization and 5-LO-activating protein inhibitor MK886. In ALOX (but not PAS) mice, eotaxin recruitment was abolished for eosinophils and halved for neutrophils. In GATA-1 mutants, eotaxin recruited neither neutrophils nor macrophages. Transfer of eosinophils cultured from bone-marrow of BALB/c donors, or from ALOX donors, into GATA-1 mutant recipients, i.p., restored eotaxin recruitment of neutrophils and showed that the critical step dependent on 5-LO is the initial recruitment of eosinophils by eotaxin, not the secondary neutrophil accumulation. Eosinophil-dependent recruitment of neutrophils in naive BALB/c mice was associated with increased binding of bacteria.

Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms of the Rectum: A Case Report.

Introduction: Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) represent roughly 1-2% of all colorectal malignancies. Given the rareness and heterogeneity of these mixed tumors, recognition and accurate diagnosis remain a challenge. In the absence of established guidelines, they are treated according to the standard of care for pure neuroendocrine carcinomas or adenocarcinomas from similar sites of origin. Case Presentation: We herein report a case of a rectal MiNEN in a 55-year-old male. He underwent colonoscopy for rectal bleeding and mucus emission, which revealed a vegetating lesion located approximately 8 cm from the anal verge, corresponding to a moderately differentiated low-grade adenocarcinoma of the rectum. Computed tomography scan and magnetic resonance imaging uncovered the presence of lung, lymph node, and subcutaneous implant metastases. The biopsy of the cutaneous implant showed neuroendocrine carcinoma Ki-67 90%. The patient underwent systemic chemotherapy. Conclusion: High-grade MiNEN tumors are the most commonly encountered in clinical practice and have an aggressive biological behavior. Little is known about the genetic drivers of this neoplasm and its pathogenesis remains controversial. Clinical and pathological awareness of this rare entity is a key step to design future targeted therapies and improve treatment options. The aim of this case report is to further our understanding regarding the clinical presentation, radiological features, pathology, management, and prognosis of MiNEN.

Essential roles of PKA, iNOS, CD95/CD95L, and terminal caspases in suppression of eosinopoiesis by PGE2 and other cAMP-elevating agents.

Up- and downregulation of eosinopoiesis control pulmonary eosinophilia in human asthma. In mice, eosinopoiesis is suppressed in vitro by prostaglandin E2 (PGE2) and in vivo by diethylcarbamazine, through a proapoptotic mechanism sequentially requiring inducible NO synthase (iNOS) and the ligand for death receptor CD95 (CD95L). We examined the roles of iNOS, cAMP-mediated signaling, caspases, and CD95L/CD95 in suppression of eosinopoiesis by PGE2 and other agents signaling through cAMP. Bone-marrow collected from BALB/c mice, or from iNOS-, CD95-, or CD95L-deficient mutants (and wild-type controls), was cultured with interleukin-5 (IL-5), alone or associated with PGE2, cAMP-inducing/mimetic agents, caspase inhibitor zVAD-fmk, iNOS inhibitor aminoguanidine, or combinations thereof, and eosinopoiesis was evaluated at various times. PGE2, added up to 24 hours of culture, dose-dependently suppressed eosinopoiesis, by inducing apoptosis. This effect was (a) paralleled by induction of iNOS in eosinophils; (b) duplicated by sodium nitroprusside, isoproterenol, and cAMP-inducing/mimetic agents; (c) prevented by protein kinase A inhibition. NO was produced through iNOS by dibutyryl-cAMP-stimulated bone-marrow. Overall, PGE2 and isoproterenol shared a requirement for four effector elements (iNOS, CD95L, CD95, and terminal caspases), which together define a pathway targeted by several soluble up- and downmodulators of eosinopoiesis, including drugs, mediators of inflammation, and cytokines.

Antibody-Drug Conjugates in Prostate Cancer: A Systematic Review.

The prognosis in the setting of metastatic castration-resistant prostate cancer patients (mCRPC) remains limited. Therefore, novel treatment strategies remain an unmet need. Antibody-drug conjugates (ADC) emerged as a new drug concept with the potential to deliver a cytotoxic payload with limited off-target toxicity and potentially bystander effect. Following the success of ADCs in breast cancer and urothelial tumours, their activity in prostate cancer is now under investigation. Thus, the aim of this systematic review was to identify published and ongoing prospective clinical trials regarding ADC treatment in prostate cancer. A systematic search of PubMed, MEDLINE, and Web of Science was conducted as per PRISMA guidelines to identify prospective clinical trials of ADCin prostate cancer. Trials are currently ongoing on ClinicalTrials.gov and in the EU. The Clinical Trials Register was also identified. Abstracts, publications in languages other than English, review articles, retrospective analyses, and phase I trials were excluded. A total of six phase I/II prospective clinical trials already published were included. Seven ongoing trials were also identified. All studies were in the refractory/advanced tumour setting, and two included only mCRPC patients. The ADC targets were prostate-specific membrane antigen (PSMA), trophoblast cell surface antigen-2 (TROP-2), six-transmembrane epithelial antigen of prostate-1 (STEAP-1), tissue factor (TF), delta-like protein 3 (DLL-3), B7-H3 family of proteins (B7-H3), and human epidermal growth factor receptor 2 (HER2). Regarding the efficacy of PSMA ADC treatment in the second-line or beyond mCRPC setting, a PSA ≥ 50% decline rate in 14% of all treated patients was reported. One patient achieved a complete response with TROP-2 ADC. Overall, a wide range of safety issues were raised, particularly in connection with neuropathy and hematologic toxicity. Novel therapies have been changing the scope of treatment in mCRPC. ADCs seem to provide efficacy benefits, even with potential toxicity. The results of most prospective ongoing studies are still awaited, and a longer follow-up time is warranted to evaluate the real impact of ADCs in PCa.

Bispecific T-Cell Engagers Therapies in Solid Tumors: Focusing on Prostate Cancer.

Over the past decade, immunotherapy has demonstrated an impressive improvement in treatment outcomes for multiple cancers. Following the landmark approvals for use of immune checkpoint inhibitors, new challenges emerged in various clinical settings. Not all tumor types harbor immunogenic characteristics capable of triggering responses. Similarly, many tumors' immune microenvironment allows them to become evasive, leading to resistance and, thus, limiting the durability of responses. To overcome this limitation, new T-cell redirecting strategies such as bispecific T-cell engager (BiTE) have become attractive and promising immunotherapies. Our review provides a comprehensive perspective of the current evidence of BiTE therapies in solid tumors. Considering that immunotherapy has shown modest results in advanced prostate cancer to date, we review the biologic rationale and promising results of BiTE therapy in this clinical setting and discuss potential tumor-associated antigens that may be integrated into BiTE construct designs. Our review also aims to evaluate the advances of BiTE therapies in prostate cancer, illustrate the major obstacles and underlying limitations, and discuss directions for future research.

The Large-Scale Implementation of a Health Information System in Brazilian University Hospitals: Process and Outcomes.

Governments around the globe are paving the way for healthcare services that can have a profound impact on the overall well-being and development of their nations. However, government programs to implement health information technologies on a large-scale are challenging, especially in developing countries. In this article, the process and outcomes of the large-scale implementation of a hospital information system for the management of Brazilian university hospitals are analyzed. Based on a qualitative approach, this research involved 21 hospitals and comprised a documentary search, interviews with 24 hospital managers and two system user focus groups, and a questionnaire of 736 respondents. Generally, we observed that aspects relating to the wider context of system implementation (macro level), the managerial structure, cultural nuances, and political dynamics within each hospital (meso level), as well as the technology, work activities, and individuals themselves (micro level) acted as facilitators and/or obstacles to the implementation process. The dynamics and complex interactions established between these aspects had repercussions on the process, including the extended time necessary to implement the national program and the somewhat mixed outcomes obtained by hospitals in the national network. Mostly positive, these outcomes were linked to the eight emerging dimensions of practices and work processes; planning, control, and decision making; transparency and accountability; optimization in the use of resources; productivity of professionals; patient information security; safety and quality of care; and improvement in teaching and research. We argued here that to maximize the potential of information technology in healthcare on a large-scale, an integrative and cooperative vision is required, along with a high capacity for change management, considering the different regional, local, and institutional contexts.

What Has Changed During the COVID-19 Pandemic? - The Effect on an Academic Breast Department in Portugal.

INTRODUCTION: One year ago, Portugal entered its first lockdown because of the coronavirus disease-2019 (COVID-19) pandemic. The impact of this on delays in cancer diagnosis and treatment is a major concern, which may negatively affect the outcomes of these patients. MATERIALS AND METHODS: This retrospective, single-center analysis compared the clinical and pathological characteristics of breast cancer (BC) patients referred to a medical oncology first appointment between March 2020 and 2021, with the same period in the previous year. RESULTS: Strikingly, there was a 40% reduction in the number of BC patients during lockdown. However, there was a statistically significant increase in the proportion of metastatic BC patients admitted for the first time for systemic therapy (13.6% vs. 28.9%, p = 0.003). Additionally, a statistically significant increase in the number of patients with bilateral early BC at diagnosis after March 2020 was found (7.2% vs. 1.9%, p = 0.043). CONCLUSION: These findings support international recommendations for an accelerated restoration of BC screening, to reduce incidence of advanced breast cancer at diagnosis and mitigate the expected impact of the COVID-19 pandemic on patients with cancer. Further work is needed to examine in detail the impact of measures to manage the COVID-19 pandemic on breast cancer outcomes.

Prognostic Impact of Baseline Neutrophil-to-Eosinophil Ratio in Patients With Metastatic Renal Cell Carcinoma Treated With Nivolumab Therapy in Second or Later Lines.

Background Inflammation is a crucial component in carcinogenesis. The neutrophil-to-eosinophil ratio (NER) has been studied as a biomarker of prognosis and predictive of response in metastatic renal cell carcinoma (mRCC). In the present study, we evaluated the relevance of baseline NER on the progression-free survival (PFS) and overall survival (OS) outcomes in real-world patients with mRCC treated with nivolumab in second or subsequent lines. We also assessed the association of baseline NER with objective response, as well as with toxicity and histology. Methods In this multicenter retrospective analysis of patients with mRCC treated with nivolumab, the last systemic absolute neutrophil and eosinophil count before treatment with nivolumab was used to calculate the NER. An additive Cox proportional hazards model was used to identify the cut-off point for NER considering PFS and the patients were allocated into low and high NER groups. Median OS and median PFS were estimated using the Kaplan-Meier estimator, and survival curves of groups were compared using the log-rank test. Univariable and multivariable Cox regression models were used to study OS and PFS and Fisher's exact test was performed to evaluate the association of NER with the response, toxicity, and histology. Results The 49 analyzed patients had a median follow-up of nine months. The NER cut-off was established at 48, locating 29 patients in the low NER group (NER < 48) and 20 in the high NER group (NER ≥ 48). Median PFS and median OS were significantly shorter in patients with high NER versus low NER (3 vs. 30 months (p < 0.001) and 6 vs. 24 months (p = 0.002), respectively). Multivariable analyses showed that NER (HR 3.92 (95% CI: 1.66-9.23), p = 0.002) was an independent factor for PFS and that NER (HR 3.85 (95% CI: 1.33-11.17), p = 0.013) and progressive disease (HR 5.62 (95% CI: 1.88-16.83), p = 0.002) were independent factors for OS. NER was significantly associated with objective response rate (ORR) (NER ≥ 48-12.5% vs. NER < 48-87.5%, p = 0.003), immune-related adverse events (irAEs) (NER ≥ 48-10.0% vs. NER < 48-42.9%, p = 0.014), and tumor's histology as patients of high NER group had more non-clear cell carcinoma than low NER group (35.0% vs. 7.4%, p = 0.017). Conclusion Our real-world data analysis of NER in patients with mRCC confirmed the prognostic value of this biomarker, supporting clinical utility in predicting survival. Results also suggested an association between lower NER and better ORR, and that irAEs occur more frequently in patients with a lower NER. However, further large-scale prospective studies are needed to confirm these findings and to validate this biomarker.

A Systematic Review of Immune Checkpoint Inhibitors in Non-Clear-Cell Renal Cancer.

BACKGROUND: Immune checkpoint inhibitors (ICI) have emerged as active therapies in the management of advanced RCC. While multiple studies have shown clinical activity of ICIs in clear cell histologies, the evidence to support their use in non-clear cell (ncc) subtypes is based on smaller prospective trials and retrospective analyses. OBJECTIVE: The objective of this review is to summarize the clinical outcomes of ICI-based therapies in ncc-subtypes and in tumors with sarcomatoid/rhabdoid features. METHODS: We performed a systematic literature search using PubMed, Google Scholar and ASCO databases. The keywords "renal cell cancer" and "immune checkpoint inhibitors" and equivalents were used and all original publications between July 2016 and July 2021 were included. RESULTS: We included a total of 14 publications, including two clinical trials and 12 case series. The most frequent histologies were papillary (up to 75-100%), unclassified (up to 34%) and chromophobe (up to 28%). ICI monotherapy showed some activity in both 1st and 2nd line with response rates up to 27%. ICI combination regimens yielded better activity than ICI monotherapy but, overall, a heterogeneous efficacy was noted across histologies. Overall, outcomes of ICIs were superior in tumors with sarcomatoid/rhabdoid features. CONCLUSION: The observed activity of ICI-based therapies was heterogeneous. Combination regimens, papillary subtype and sarcomatoid/rhabdoid features were associated with higher responses. These findings might help treatment decisions and require further validation.

Fibrolamellar Carcinoma: A Multimodal Approach.

Fibrolamellar carcinoma is a rare variant of hepatocellular carcinoma not associated with cirrhosis or viral hepatitis. Serum alpha-fetoprotein levels are usually normal; the histology is of a well-differentiated tumor, and the staging is the same as for hepatocellular carcinoma. We describe the case of a female patient in her 4th decade of life with a diagnosis of fibrolamellar hepatocellular carcinoma with a multimodal approach. The rare incidence of this cancer and its unusual clinical presentation justifies reporting this case and highlights the importance of multidisciplinary teams in the treatment of cancer patients.

O Carcinoma fibrolamelar é uma variante rara de hepatocarcinoma, não associado a cirrose ou hepatites virais. Os níveis séricos de alfafetoproteína são geralmente normais; A histologia é de um tumor bem diferenciado e o estadiamento é o mesmo do hepatocarcinoma. Descrevese o caso clínico de um doente do sexo feminino, na sua 4a década de vida com diagnóstico de Hepatocarcinoma fibrolamelar com abordagem multimodal. A rara incidência desta neoplasia e a sua apresentação clínica incomum justificam a notificação deste caso e destacam a importância de equipas multidisciplinares no tratamento dos doentes oncológicos.

Full recovery of a stage IV cancer patient facing COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19), first recognized in Wuhan, China, was recently declared a global pandemic by the World Health Organization (WHO). Advanced age and comorbid disease, well-known characteristics in the solid tumor population, have been reported as risk factors for severe disease and death. Cancer-related immunosuppression and its treatments also seem to play an active role in the prognosis, response, and clinical outcomes of these patients. The most effective combination therapy for COVID-19 is still under investigation, and the use of corticosteroids is controversial. Although, as a group, metastatic cancer patients are often considered not to be good candidates for ICU treatment, the individual prognosis should always come into consideration, even in a context of high pressure on medical facilities. We report the case of a stage IV prostate cancer patient infected with SARS-CoV-2 who required ICU admission and recovered from COVID-19 infection. Further studies are needed in order to identify accurate clinical prognostic criteria and provide the best treatment for these challenging patients.

Three-dimensional speckle-tracking echocardiography for the global and regional assessments of left ventricle myocardial deformation in breast cancer patients treated with anthracyclines.

BACKGROUND: Assessment of 2D/3D left ventricular ejection fraction (LVEF) and 2D global longitudinal strain (GLS) is the gold standard for diagnosing cancer therapeutics-related cardiac dysfunction (CTRCD). Although 3D speckle-tracking echocardiography (STE) has several advantages, it is not used in this setting. METHODS: 105 breast cancer patients who underwent serial echocardiographic assessment during anthracycline therapy were included. STE was used to estimate 2D GLS, 3D GLS, 3D global circumferential strain (GCS), 3D global radial strain (GRS), and 3D global area strain (GAS). CTRCD was defined as an absolute decrease in 2D/3D LVEF > 10% to a value < 54% or a relative decrease in 2D GLS > 15%. RESULTS: 24 patients developed CTRCD. There was a significant worsening of all 3D strain parameters during chemotherapy. 3D strain regional analysis showed impaired contractility in the anterior, inferior, and septal walls. Variations of 3D GRS and 3D GCS were associated with a higher incidence of CTRCD and the variation of 3D GRS was an independent predictor of CTRCD. Variations of 3D GCS and 3D GRS had a good discrimination for predicting CTRCD, with optimal cutoff values of - 34.2% for 3D GCS and - 34.4% for 3D GRS. These variations were observed 45 and 23 days before the diagnosis of CTRCD, respectively. CONCLUSION: Variations of 3D strain parameters were predictive of and preceded CTRCD, and thus have added value over currently recommended 2D/3D LVEF and 2D GLS. Routine application of this technique should be considered to offer targeted monitoring and timely initiation of cardioprotective treatment.

Full recovery of a stage IV cancer patient facing COVID-19 pandemic

Coronavirus disease 2019 (COVID-19), first recognized in Wuhan, China, was recently declared a global pandemic by the World Health Organization (WHO). Advanced age and comorbid disease, well-known characteristics in the solid tumor population, have been reported as risk factors for severe disease and death. Cancer-related immunosuppression and its treatments also seem to play an active role in the prognosis, response, and clinical outcomes of these patients. The most effective combination therapy for COVID-19 is still under investigation, and the use of corticosteroids is controversial. Although, as a group, metastatic cancer patients are often considered not to be good candidates for ICU treatment, the individual prognosis should always come into consideration, even in a context of high pressure on medical facilities. We report the case of a stage IV prostate cancer patient infected with SARS-CoV-2 who required ICU admission and recovered from COVID-19 infection. Further studies are needed in order to identify accurate clinical prognostic criteria and provide the best treatment for these challenging patients.

Quantification and localization of platelet-derived growth factor in gingiva of periodontitis patients.

BACKGROUND: Platelet-derived growth factor (PDGF) is a mitogen and chemoattractant for cells of mesenchymal origin. Over-expression of PDGF-B can promote formation of inflammatory lesions in the lungs of transgenic mice. Moreover, continuous exposure to PDGF inhibits collagen production by osteoblastic cells. Thus, the expression of mitogenic factors in an inflammatory context may limit the differentiated function of cells, and thereby limit repair following periodontal attachment and bone loss. The goals of the present study were to test whether PDGF is present at increased levels in inflamed gingiva and to localize its expression in gingival biopsies from individuals with chronic periodontitis. METHODS: Tissues obtained during therapeutic procedures from inflamed and control sites of 9 patients were subjected to protein extraction, descriptive histology by hematoxylin and eosin, or immunohistochemistry assays. Quantification was calculated with an enzyme-linked immunosorbent assay (ELISA) kit specific for PDGF-AB. For the immunolocalization, anti-PDGF-A and -B antibodies were employed. RESULTS: PDGF concentration in the total protein extract was approximately 3 times higher in the inflamed sites (0.60 +/- 0.18 ng/mg versus 0.20 +/- 0.05 ng/mg; P = 0.03). Immunohistochemistry revealed prominent expression of PDGF in the pocket epithelial cells as well as the adjacent connective tissue. In contrast, little or no expression was detected in control biopsies devoid of the pocket epithelium and granulation tissue. CONCLUSIONS: PDGF is present in increased levels in the human inflamed gingiva and is mainly localized to the pocket epithelium. It is possible that chronic expression of PDGF contributes to the inflammatory changes that occur during periodontal diseases.

[Primary and secondary outcomes in oncology clinical trials: definitions and uses]. / Indicadores (outcomes) primários e secundários em ensaios clínicos oncológicos: definição e usos.

INTRODUCTION: The proof of efficacy from a therapeutic intervention in oncology must be defined through well conducted clinical trials. One of the most important methodological issue is the outcome selection needed to calculate measures of association allowing definition of clinical efficacy. MATERIAL AND METHODS: We designed a narrative revision based on some of the international regulatory instructions from drug agencies, as well as consensus papers from scientific oncology societies, listing and critically assessing each outcome used in oncology clinical trials. RESULTS: We identified as being the most important outcomes in oncology trials the overall survival, the progression free survival/ disease-free survival, the toxicity, the quality of life/patient-reported outcomes and the objective response rate. DISCUSSION: The selection of the primary outcome must be based on therapeutic efficacy as well as toxicity, expected survival, alternative drug regimens and even disease prevalence. CONCLUSION: The selection of efficacy outcomes for clinical trials in oncology is very important and its selection must be well justified, and depends on the type of disease, the patients and the drug being studied.

Introdução: A prova de eficácia de uma intervenção terapêutica em oncologia consegue-se através de ensaios clínicos rigorosamente conduzidos. Um dos factores metodológicos mais importantes é a selecção de indicadores clínicos de eficácia (outcomes), necessários ao cálculo das chamadas medidas de associação que permitem a definição de eficácia terapêutica. Material e Métodos: Foi feita uma revisão narrativa baseada em alguns dos documentos de agências reguladoras internacionais, assim como documentos de consenso entre as sociedades científicas oncológicas, procurando listar e avaliar criticamente cada um dos indicadores utilizados em ensaios clínicos oncológicos. Resultados: Identificaram-se como indicadores mais importantes a sobrevivência global, a sobrevivência livre de progressão/sobrevivência livre de doença, a toxicidade/qualidade de vida e taxa objectiva de resposta tumoral. Discussão: A selecção do outcome primário deve basear-se no conceito de eficácia terapêutica, mas também na toxicidade relativa da terapêutica experimental, na sobrevivência esperada após progressão da doença, na existência de fármacos alternativos já estudados com indicações idênticas e até a prevalência da patologia em causa. Conclusão: A selecção de indicadores em ensaios clínicos oncológicos reveste-se de especial importância e a sua selecção deve ser bem fundamentada, dependendo da doença, dos doentes e do fármaco em estudo.

Essential roles of endogenous glucocorticoids and TNF/TNFR1 in promoting bone-marrow eosinopoiesis in ovalbumin-sensitized, airway-challenged mice.

AIMS: Stress mechanisms paradoxically contribute to allergic episodes in humans and mice. Glucocorticoids (GC) and interleukin (IL)-5 synergically upregulate murine bone-marrow eosinophil production. Here we explored the role of endogenous GC in allergen-stimulated bone-marrow eosinophil production in ovalbumin-sensitized/challenged mice. MAIN METHODS: In BALB/c or C57BL/6 mice, sensitized and intranasally challenged with ovalbumin, we monitored eosinophil numbers in freshly harvested or cultured bone-marrow, and plasma corticosterone levels. Metyrapone (MET) was used to inhibit GC synthesis, and RU486 to block GC actions. In sensitized mice challenged intraperitoneally, we examined the relationship between eosinophilia of bone-marrow and peritoneal cavity, in the absence or presence of RU486. In experiments involving in vivo neutralization of tumor necrosis factor-α (TNF) by specific antibodies, or using mice which lack functional type I TNF receptors (TNFRI), we evaluated the relationship between TNF blockade, corticosterone levels, RU486 or MET treatment and challenge-induced bone-marrow eosinophilia. KEY FINDINGS: RU486 or MET pretreatments abolished challenge-induced increases in eosinophil numbers in bone-marrow (in vivo and ex vivo), and in the peritoneal cavity. MET, but not RU486, prevented the challenge-induced increase in corticosterone levels. Challenge-induced bone-marrow eosinophilia and corticosterone surge were abolished in TNFRI-deficient mice. Anti-TNF-treatment very effectively prevented challenge-induced bone-marrow eosinophilia, in the absence of RU486 or MET, but had no independent effect in the presence of either drug. SIGNIFICANCE: Endogenous GC was essential for allergen challenge-induced increases in eosinophil numbers inside bone-marrow. This effect required TNF and TNFRI, which suggests an immunoendocrine mechanism.

Prediction of sepsis-related outcomes in neonates through systematic genotyping of polymorphisms in genes for innate immunity and inflammation: a narrative review and critical perspective.

CONTEXT AND OBJECTIVE: Neonatal sepsis is associated with premature birth and maternal infection. Large-scale studies seek to define markers that identify neonates at risk of developing sepsis. Here, we examine whether the scientific evidence supports systematic use of polymorphism genotyping in cytokine and innate immunity genes, to identify neonates at increased risk of sepsis. DESIGN AND SETTING: Narrative literature review conducted at Fernandes Figueira Institute, Brazil. METHODS: The literature was searched in PubMed, Embase (Excerpta Medica Database), Lilacs (Literatura Latino-Americana e do Caribe em Ciências da Saúde), SciELO (Scientific Electronic Library Online) and Cochrane Library. From > 400,000 references, 548 were retrieved based on inclusion/exclusion criteria; 22 were selected for detailed analysis after quality assessment. RESULTS: The studies retrieved addressed the impact of gene polymorphisms relating to immune mechanisms (most often TNF-a, LT-a, IL-6, IL-1ß, IL-1ra, L-selectin, CD14 and MBL) or inflammatory mechanisms (ACE and angiotensin II receptors; secretory PLA2; and hemostatic factors). Despite initial reports suggesting positive associations between specific polymorphisms and increased risk of sepsis, the accumulated evidence has not confirmed that any of them have predictive power to justify systematic genotyping. CONCLUSIONS: Sepsis prediction through systematic genotyping needs to be reevaluated, based on studies that demonstrate the functional impact of gene polymorphisms and epidemiological differences among ethnically distinct populations.

G-CSF suppresses allergic pulmonary inflammation, downmodulating cytokine, chemokine and eosinophil production.

AIMS: Granulocyte Colony-Stimulating Factor (G-CSF), which mobilizes hemopoietic stem cells (HSC), is believed to protect HSC graft recipients from graft-versus-host disease by enhancing Th2 cytokine secretion. Accordingly, G-CSF should aggravate Th2-dependent allergic pulmonary inflammation and the associated eosinophilia. We evaluated the effects of G-CSF in a model of allergic pulmonary inflammation. MAIN METHODS: Allergic pulmonary inflammation was induced by repeated aerosol allergen challenge in ovalbumin-sensitized C57BL/6J mice. The effects of allergen challenge and of G-CSF pretreatment were evaluated by monitoring: a) eosinophilia and cytokine/chemokine content of bronchoalveolar lavage fluid, pulmonary interstitium, and blood; b) changes in airway resistance; and c) changes in bone-marrow eosinophil production. KEY FINDINGS: Contrary to expectations, G-CSF pretreatment neither induced nor enhanced allergic pulmonary inflammation. Instead, G-CSF: a) suppressed accumulation of infiltrating eosinophils in bronchoalveolar, peribronchial and perivascular spaces of challenged lungs; and b) prevented ovalbumin challenge-induced rises in airway resistance. G-CSF had multiple regulatory effects on cytokine and chemokine production: in bronchoalveolar lavage fluid, levels of IL-1 and IL-12 (p40), eotaxin and MIP-1a were decreased; in plasma, KC, a neutrophil chemoattractant, was increased, while IL-5 was decreased and eotaxin was unaffected. In bone-marrow, G-CSF: a) prevented the increase in bone-marrow eosinophil production induced by ovalbumin challenge of sensitized mice; and b) selectively stimulated neutrophil colony formation. SIGNIFICANCE: These observations challenge the view that G-CSF deviates cytokine production towards a Th2 profile in vivo, and suggest that this neutrophil-selective hemopoietin affects eosinophilic inflammation by a combination of effects on lung cytokine production and bone-marrow hemopoiesis.

[Thyroid carcinoma with thymus-like differentiation (CASTLE): case report and review of the literature]. / Carcinoma da tireóide com diferenciação semelhante a timo (CASTLE): relato de caso e revisão da literatura.

Carcinoma with thymus-like differentiation (CASTLE) is a rare malignant epithelial tumor which arises on soft tissue of the neck or thyroid gland. It is important to differentiate CASTLE from primary or metastatic squamous cell carcinoma of head and neck, and from squamous cell thyroid carcinoma, because it has a different prognosis. CD5 immunoreactivity might be helpful in CASTLE diagnosis. CASTLE behaves generally in an indolent fashion, even though it has a high relapse rate, while the other have a dismal prognosis due its high dissemination rate. Treatment includes surgical excision and radiotherapy. Chemotherapy can be offered, although its efficacy is not clear. Authors present a case of a 52 year-old male that complaints with cough, disphony, asthenia, and thyroid mass. Thyroidectomy was performed and the pathology revealed a CASTLE. After radiotherapy and chemotherapy, minimal response was obtained. The authors intend to discuss the differential pathologic diagnosis and the best therapy of this indolent but recurrent neoplasm, that demands strict long term follow-up.