Identification of a new 2-amino acid insertion in the integrase coding region of HIV-1 subtype G isolates.

Amino acid insertions have been rarely found in the integrase (IN) coding region of Human immunodeficiency virus 1 (HIV-1), and have been considered as natural polymorphisms. It is still unclear the potential impact of these insertion mutations on the viral replication capacity and/or susceptibility to integrase strand transfer inhibitors (INSTIs). The objective of this study was to describe a previously unreported amino acid insertion in the IN coding region of HIV-1 isolates obtained from antiretroviral treatment-naïve infected individuals. Nucleotide sequences of HIV-1 isolates obtained from two infected individuals were analyzed for genotypic resistance to antiretroviral drugs. Phylogenetic inference was carried out for HIV-1 genetic variant identification. An unreported insertion of a threonine (T) and an asparagine (N) between codon 255 and 256 (S255N_TN) was identified in the IN C-terminal domain of HIV-1 subtype G isolates. No resistance-associated mutations to INSTIs were detected in the inserted sequences. Both individuals maintained undetectable HIV-1 RNA viral load, 24 months after undergoing antiretroviral treatment with an INSTI containing regimen. The results demonstrated the possibility of transmission of this insertion mutation and suggested that the codon 255 insert by itself may not affect susceptibility to INSTIs.

Clearance and persistence of SARS-CoV-2 RNA in patients with COVID-19.

Patients with coronavirus disease-2019 may be discharged based on clinical resolution of symptoms, and evidence for viral RNA clearance from the upper respiratory tract. Understanding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral clearance profile is crucial to establish a re-testing plan on discharge and ending isolation of patients. We aimed to evaluate the number of days that a patient needed to achieve undetectable levels of SARS-CoV-2 in upper respiratory tract specimens (nasopharyngeal swab and/or an oropharyngeal swab). The clearance and persistence of viral RNA was evaluated in two groups of positive patients: those who achieved two negative reverse transcription-polymerase chain reaction (RT-PCR) tests and those who kept testing positive. Patients were organized thereafter in two subgroups, mild illness patients discharged home and inpatients who had moderate to severe illness. Results from RT-PCR tests were then correlated with results from the evaluation of the immune response. The study evidenced that most patients tested positive for more than 2 weeks and that persistence of viral RNA is not necessarily associated with severe disease but may result from a weaker immune response instead.

Levels of Circulating Fibroblast Growth Factor 23 (FGF23) and Prognosis in Cancer Patients with Bone Metastases.

The fibroblast growth factor (FGF) signaling pathway plays a key role in tumorigenesis and is recognized as a potential therapeutic target. In this study, the authors aimed to assess the impact of serum FGF23 levels in the prognosis of patients with cancer and bone metastases from solid tumors. A cohort of 112 patients with cancer and metastatic bone disease were treated with bone-targeted agents (BTA). Serum baseline FGF23 was quantified by ELISA and dichotomized in FGF23high and FGF23low groups. Additionally, the association between FGF23 and overall survival (OS) and time to skeletal-related events (TTSRE) was investigated. Baseline characteristics were balanced between groups, except for the median urinary N-terminal telopeptide (uNTX) level. After a median follow-up of 26.0 months, a median OS of 34.4 and 12.2 months was found in the FGF23low and FGF23high groups, respectively (multivariate HR 0.18, 95% CI 0.07⁻0.44, p = 0.001; univariate HR 0.27, p = 0.001). Additionally, TTSRE was significantly longer for patients with FGF23low (13.0 vs 2.0 months, p = 0.04). Overall, this study found that patients with FGF23low at baseline had longer OS and TTSRE. Further studies are warranted to define its role as a prognostic biomarker and in the use of drugs targeting the FGF axis.

Corrigendum: Evaluation of PIK3CA mutations in advanced ER+/HER2-breast cancer in Portugal - U-PIK Project.

[This corrects the article DOI: 10.3389/fmolb.2023.1082915.].

Primary synovial sarcoma of the kidney with unusual follow up findings.

We present a case report of a 17-year-old patient with a large renal mass that was detected on a computed tomography scan during investigation for secondary hypertension. Radical nephrectomy was performed and the morphologic and immunocytochemical findings were compatible with a diagnosis of monophasic synovial sarcoma of the kidney. A cytogenetic search for t(X;18) translocation was performed, which was negative. The patient underwent an ifosfamide-based chemotherapy regimen. During follow up, a positron emission tomography scan showed increased 18F-fluorodeoxyglucose metabolism at the right femur. Although cancer cells were expected in the biopsy specimen, only fibrous dysplasia of the bone was found. The patient was disease free at his 29 month follow up check up.

Evaluation of PIK3CA mutations in advanced ER+/HER2-breast cancer in Portugal - U-PIK Project.

Background: Around 40% of ER+/HER2-breast carcinomas (BC) present mutations in the PIK3CA gene. Assessment of PIK3CA mutational status is required to identify patients eligible for treatment with PI3Kα inhibitors, with alpelisib currently the only approved tyrosine kinase inhibitor in this setting. U-PIK project aimed to conduct a ring trial to validate and implement the PIK3CA mutation testing in several Portuguese centers, decentralizing it and optimizing its quality at national level. Methods: Eight Tester centers selected two samples of patients with advanced ER+/HER2- BC and generated eight replicates of each (n = 16). PIK3CA mutational status was assessed in two rounds. Six centers used the cobas® PIK3CA mutation test, and two used PCR and Sanger sequencing. In parallel, two reference centers (IPATIMUP and the Portuguese Institute of Oncology [IPO]-Porto) performed PIK3CA mutation testing by NGS in the two rounds. The quality of molecular reports describing the results was also assessed. Testing results and molecular reports were received and analyzed by U-PIK coordinators: IPATIMUP, IPO-Porto, and IPO-Lisboa. Results: Overall, five centers achieved a concordance rate with NGS results (allele frequency [AF] ≥5%) of 100%, one of 94%, one of 93%, and one of 87.5%, considering the overall performance in the two testing rounds. NGS reassessment of discrepancies in the results of the methods used by the Tester centers and the reference centers identified one probable false positive and two mutations with low AF (1-3%, at the analytical sensitivity threshold), interpreted as subclonal variants with heterogeneous representation in the tissue sections processed by the respective centers. The analysis of molecular reports revealed the need to implement the use of appropriate sequence variant nomenclature with the identification of reference sequences (HGVS-nomenclature) and to state the tumor cell content in each sample. Conclusion: The concordance rates between the method used by each tester center and NGS validate the use of the PIK3CA mutational status test performed at these centers in clinical practice in patients with advanced ER+/HER2- BC.

Parechovirus Genotype 3 Outbreak Among Young Infants in Portugal.

INTRODUCTION: Human parechovirus type 3 has been recognized as a cause of pediatric infection, occasionally associated with serious illness, including sepsis and meningitis, particularly among young infants. The aim of this study is to report the first known human parechovirus type 3 outbreak in Portugal. MATERIAL AND METHODS: Descriptive study of an outbreak that occurred between the 8th June to the 12th August 2016. Laboratory diagnosis was made by reverse transcription - polymerase chain reaction in the cerebrospinal fluid and/or in stools. Genotyping was made by reverse transcription - polymerase chain reaction and sequencing in stool samples from infants and family members. RESULTS: Human parechovirus type 3 infection was detected in seven infants, of which six were male. Median age was 23 days (5 - 52). One had seizures, with a magnetic resonance imaging scan showing white matter diffusion restriction. The mean duration of admission was 5.6 days (3 - 11), with favourable outcome in all. In three cases there were symptomatic close family members. Human parechovirus type 3 was identified in the stools of three mothers. DISCUSSION: Even though human parechovirus type 3 infection has been well described in the presented age group, most Portuguese hospitals do not have this laboratory diagnosis. Our results are comparable to those obtained in other countries. Besides detection of the virus in the cerebrospinal fluid, there were no raised local or systemic inflammatory markers. CONCLUSION: This study reports the first known outbreak, in infants, of human parechovirus type 3 in Portugal. Although there is no specific treatment, this diagnosis can avoid unnecessary empirical antibiotic treatment and prolonged admissions.

Introdução: O parechovirus humano tipo 3 tem sido reconhecido como causa de infeção em idade pediátrica, ocasionalmente associado a doença grave, incluindo sépsis e meningite, particularmente em pequenos lactentes. Foi objectivo deste estudo descrever o primeiro surto conhecido de infeção por parechovirus humano tipo 3 em Portugal. Material e Métodos: Estudo descritivo de um surto ocorrido entre 8 de junho a 12 de agosto de 2016. O diagnóstico laboratorial foi realizado por transcriptase reversa - reação em cadeia da polimerase no líquido cefalorraquidiano e/ou nas fezes. A genotipagem foi efetuada no Instituto Nacional de Saúde Doutor Ricardo Jorge, por transcriptase reversa - reação em cadeia da polimerase e sequenciação, em amostras de fezes dos lactentes e seus familiares. Resultados: Foi detetada infeção por parechovirus humano tipo 3 em sete lactentes, seis dos quais do sexo masculino, mediana de idade de 23 dias (5 - 52). Uma lactente apresentou convulsões, com múltiplas lesões da substância branca na ressonância magnética nuclear. A duração média de internamento foi de 5,6 dias (3 - 11), com evolução favorável em todos. Em três casos havia familiares próximos sintomáticos. Em três mães foi identificado parechovirus humano tipo 3 nas fezes. Discussão: Embora a infeção por parechovirus humano tipo 3 esteja bem descrita neste grupo etário, a maior parte dos hospitais portugueses não dispõe deste diagnóstico laboratorial. Os resultados obtidos foram semelhantes aos verificados noutros países. Apesar da deteção do vírus no líquido cefalorraquidiano, destaca-se a ausência de resposta inflamatória local ou sistémica. Conclusão: Este estudo reporta o primeiro surto conhecido de infeção por parechovirus humano tipo 3 ocorrido em Portugal em pequenos lactentes. Apesar de não existir tratamento específico, este diagnóstico poderá evitar poderá evitar antibioterapia e internamentos prolongados.

Secondary hypertension due to a juxtaglomerular cell tumor.

Juxtaglomerular cell tumors are rare, generally benign, and they are one of the secondary surgically treatable causes of arterial hypertension. There are about 100 reported cases on literature, and the diagnosis is usually carried out based on a high clinic suspicion index, mostly in patients with hypokalemia and arterial hypertension. The diagnosis involves blood tests and imaging studies, but it is only definite with histopathological exam after surgical treatment. We present a case of a 22-year-old woman with resistant arterial hypertension and renal and cardiovascular target-organ lesions. High plasmatic renin and a nodular renal mass on magnetic resonance imaging were present. A tumorectomy was performed and the histological exam confirmed a reninoma. After surgery, blood pressure and serum renin values returned to normal without medication. This work focuses on the need to exclude rare secondary causes of hypertension in young patients with resistant forms of this disease.

Treatment adoption and relative effectiveness of aromatase inhibitors compared to tamoxifen in early breast cancer: A multi-institutional observational study.

BACKGROUND: Since 2005, aromatase inhibitors (AIs) have been the adjuvant treatment of choice for postmenopausal women with early breast cancer (BC). In this study we characterize the adoption of AIs in Portugal, variables associated with treatment administration, and compare its effectiveness (either in monotherapy or sequential therapy) to tamoxifen monotherapy (TAM). PATIENTS AND METHODS: This was a retrospective cohort study that included postmenopausal women with stage I-III hormone receptor (HR) positive BC diagnosed from 2006 to 2008 and treated with adjuvant endocrine therapy in four participating institutions. RESULTS: Of the 1283 eligible patients, 527 (41%) received an AI (16% as monotherapy, 25% as sequential therapy) and 756 (59%) TAM. Patients treated with AI had less differentiated tumors, with higher TNM stage, and were more frequently HER2-positive. Use of AI also differed by center (use range from 33% to 75%, p < 0.001). With a median follow-up of 6.3 years and controlling for clinicopathological and treatment characteristics, treatment with AI had a better overall survival (OS) when compared with TAM (adjusted-HR 0.55, 95% CI 0.37-0.81). CONCLUSION: AIs were successfully introduced as adjuvant treatment for HR-positive BC in Portuguese hospitals. Its use was influenced by tumor and patient characteristics, but also center of care. In this large cohort, AI use was associated with an OS benefit.

Cross-protection to new drifted influenza A(H3) viruses and prevalence of protective antibodies to seasonal influenza, during 2014 in Portugal.

INTRODUCTION: Immune profile for influenza viruses is highly changeable over time. Serological studies can assess the prevalence of influenza, estimate the risk of infection, highlight asymptomatic infection rate and can also provide data on vaccine coverage. The aims of the study were to evaluate pre-existing cross-protection against influenza A(H3) drift viruses and to assess influenza immunity in the Portuguese population. MATERIALS AND METHODS: We developed a cross-sectional study based on a convenience sample of 626 sera collected during June 2014, covering all age groups, both gender and all administrative health regions of Portugal. Sera antibody titers for seasonal and new A(H3) drift influenza virus were evaluated by hemagglutination inhibition assay (HI). Seroprevalence to each seasonal influenza vaccine strain virus and to the new A(H3) drift circulating strain was estimated by age group, gender and region and compared with seasonal influenza-like illness (ILI) incidence rates before and after the study period. RESULTS: Our findings suggest that seroprevalences of influenza A(H3) (39.9%; 95% CI: 36.2-43.8) and A(H1)pdm09 (29.7%; 95% CI: 26.3-33.4) antibodies were higher than for influenza B, in line with high ILI incidence rates for A(H3) followed by A(H1)pdm09, during 2013/2014 season. Low pre-existing cross-protection against new A(H3) drift viruses were observed in A(H3) seropositive individuals (46%). Both against influenza A(H1)pdm09 and A(H3) seroprotection was highest in younger than 14-years old. Protective antibodies against influenza B were highest in those older than 65years old, especially for B/Yamagata lineage, 33.3% (95% CI: 25.7-41.9). Women showed a high seroprevalence to influenza, although without statistical significance, when compared to men. A significant decreasing trend in seroprotection from north to south regions of Portugal mainland was observed. CONCLUSIONS: Our results emphasize that low seroprotection increases the risk of influenza infection in the following winter season. Seroepidemiological studies can inform policy makers on the need for vaccination and additional preventive measures.

Advanced Stage Hepatocellular Carcinoma with Multiple Metastasis and Vascular Thrombosis: A Case of Complete Response to Sorafenib.

Sorafenib is a multi-targeted tyrosine kinase inhibitor, with antiangiogenic and antiproliferative properties, approved for the treatment of advanced hepatocellular carcinoma. It induces a significant increase in the median overall survival, despite a complete response to treatment being rare. We report a clinical case of a 60-year-old male with hepatic cirrhosis, Child-Pugh class A and performance status 0, and advanced hepatocellular carcinoma. The primary tumor measured 17 x 8 cm and had diffuse intrahepatic metastization, extensive lung and left adrenal invasion, as well as thrombosis of inferior vena cava, with projection to the right atrium. This patient showed a rapid and complete response to sorafenib, evaluated by mRECIST (modified Response Evaluation Criteria in Solid Tumors), that remains after three years of treatment.

O sorafenib, um inibidor de múltiplas cinases com propriedades antiangiogénicas e antiproliferativas foi aprovado para o tratamento de carcinoma hepatocelular em estádio avançado por induzir um prolongamento da sobrevivência global estatisticamente significativo, sendo a resposta completa rara. Relata-se o caso clínico de um homem de 60 anos com cirrose hepática classe A de Child-Pugh e performance status 0 e carcinoma hepatocelular em estádio avançado (com tumor primitivo medindo 17 X 8 cm, metastização intra-hepática difusa, pulmonar maciça e da suprarrenal esquerda e ainda trombose da veia cava inferior com extensão e projeção na c'mara da aurícula direita), que apresentou resposta completa com sorafenib, avaliada pelos critérios mRECIST (modified Response Evaluation Criteria in Solid Tumors). Esta resposta mantem-se após três anos de tratamento.

The prognostic role of RANK SNP rs34945627 in breast cancer patients with bone metastases.

Receptor activator of NF-kB (RANK) pathway regulates bone remodeling and is involved in breast cancer (BC) progression. Genetic polymorphisms affecting RANK-ligand (RANKL) and osteoprotegerin (OPG) have been previously associated with BC risk and bone metastasis (BM)-free survival, respectively. In this study we conducted a retrospective analysis of the association of five missense RANK SNPs with clinical characteristics and outcomes in BC patients with BM. SNP rs34945627 had an allelic frequency of 12.5% in BC patients, compared to 1.2% in the control group (P = 0.005). SNP rs34945627 was not associated with any clinicopathological characteristics, but patients presenting SNP rs34945627 had decreased disease-free survival (DFS) (log-rank P = 0.039, adjusted HR 2.29, 95% CI 1.04-5.08, P = 0.041), and overall survival (OS) (log-rank P = 0.019, adjusted HR 4.32, 95% CI 1.55-12.04, P = 0.005). No differences were observed regarding bone disease-free survival (log-rank P = 0.190, adjusted HR 1.68, 95% CI 0.78-3.66, P = 0.187), time to first skeletal-related event (log-rank P = 0.753, adjusted HR 1.28, 95% CI 1.42-3.84; P = 0.665), or time to bone progression (log-rank P = 0.618, adjusted HR 0.511, 95% CI 0.17-1.51; P = 0.233). Our analysis shows that RANK SNP rs34945627 has a high allelic frequency in patients with BC and BM, and is associated with decreased DFS and OS.

Variation in type of adjuvant chemotherapy received among patients with stage I breast cancer: A multi-institutional Portuguese cohort study.

BACKGROUND: A contemporary US study showed an increase in the use of chemotherapy in the last decade for some patients with stage-I breast cancer; with a rise in more intensive regimens, and declining use of anthracyclines. Nevertheless, there is still uncertainty on the absolute benefit of chemotherapy for these patients and the optimal regimen. In this study we compare those findings with the patterns of care among a Portuguese cohort of stage-I breast cancers. METHODS: Retrospective cohort study of patients with stage-I breast cancer diagnosed from 2006 to 2008 at four Portuguese institutions. The use and type of chemotherapy was evaluated. RESULTS: Among patients with stage I-III breast cancer 39.4% (n = 682) had stage I disease. Of the 595 eligible patients, 22.4% were treated with chemotherapy, 33.9% aged <55 years vs. 12.7% aged >65 years (p < 0.001). Thirteen percent of patients with hormone receptor (HR)+/HER2- tumors, 52.7% of patients with HER2+ and 66.0% of patients with HR-/HER2- received chemotherapy (p < 0.001). In addition, we found inter-institutional variability, with the use of chemotherapy ranging from 0.0% to 43.4% (p < 0.001). Eighty-five percent of patients treated with chemotherapy received less-intensive regimens with anthracycline-based regimens, such as doxorubicin and cyclophosphamide, being the most frequently used, while docetaxel and cyclophosphamide was only used in 1.5% of cases. CONCLUSIONS: Overall, almost one-quarter of patients received chemotherapy with institutional variability. When treated, mostly less-intensive associations including anthracyclines were used, which contrasts with contemporary US practice. This study highlights the need for health-services research to understand local practices and tailor quality improvement interventions.

[Metallosis: A Rare Cause of Autoimmune Hemolytic Anemia]. / Metalose: Causa Rara de Anemia Hemolítica Autoimune.

INTRODUCTION: Hemolytic anemia may be associated with multiple etiologies, including toxic substances, such as metals, which is a rare cause. CASE STUDY: 55-year-old male, who underwent a total arthroplasty of the right hip (uncemented prostheses with ceramic-ceramic articulation with an acetabular component consisting of a dome composed of an alloy of titanium, aluminum and vanadium into which fitted a ceramic 'insert'). Approximately 4 years after surgery the patient complained of noise originating from the prosthesis which occurred on movement. A surgical revision was performed and showed the presence of dark thick intracapsular fluid, fracture of the ceramic acetabular 'insert' and signs of wear of the acetabular metal dome. Extensive washing was carried out and the fractured ceramic 'insert' was replaced for a polyethylene 'insert'. Two months later he was referred to the Emergency Room due to worsening of his general health, floating in the right hip and mucocutaneous jaundice. Laboratory tests suggested autoimmune hemolytic anemia. Arthrocentesis was performed and a large volume of metal fluid was drained off. The CT scan showed a large heterogeneous pelvic cystic collection seeded with prosthesis fragments, suggestive of metallosis. Hemolytic anemia was explained as toxicity of the particles and metal ions caused by the wear of the prosthesis. The patient was started on a high-dose steroid treatment. Afterwards, when he was stable, prosthesis components replacement and drainage of pelvic debris fluid were carried out. DISCUSSION: After the fracture of the ceramic 'insert' the ceramic head began to articulate directly with the metallic acetabular component, causing noise and wear with release of particles and ions. This caused a cystic pelvic abscess, which went unnoticed on the first surgical revision. Surgical debridement lead to the cystic collection extending into the adjacent tissues and the systemic circulation, triggering serious systemic effects, such as autoimmune hemolytic anemia. The potential toxicity of each of the metal elements of this prosthesis is unknown, and there are still no available laboratory tests for its detection. CONCLUSION: Metallosis is a rare cause of autoimmune hemolytic anemia.

Introdução: A anemia hemolítica pode estar associada a múltiplas etiologias, nomeadamente a tóxicos, como os metais, sendo esta uma causa rara.Caso Clínico: Homem de 55 anos de idade, sujeito a artroplastia total da anca direita (prótese não cimentada com articulação cerâmica-cerâmica, cujo componente acetabular era constituído por uma cúpula metálica composta por uma liga de titânio, vanádio e alumínio na qual encaixava um insert cerâmico). Cerca de quatro anos após esta intervenção cirúrgica referia ruídos na prótese com os movimentos. Foi sujeito a revisão cirúrgica tendo-se constatado a presença de líquido espesso intracapsular de cor escura, fractura do insert acetabular cerâmico e sinais de desgaste da cúpula metálica acetabular. Procedeu-se a lavagem abundante e substituição do insert cerâmico fracturado por um insert de polietileno. Dois meses depois recorreu ao Serviço de Urgência por degradação do estado geral, flutuação na anca direita e icterícia muco-cutânea. Analiticamente evidenciava valores compatíveis com anemia hemolítica autoimune. Foi feita punção articular com saída de abundante líquido metalótico. A tomografia computorizada revelou extensa colecção heterogénea quística intrapélvica com múltiplos fragmentos de prótese no seu interior, sugestivos de metalose. A anemia hemolítica foi interpretada como consequência da toxicidade das partículas e iões metálicos oriundos do desgaste da prótese. Iniciou corticoterapia em altas doses e posteriormente quando houve condições procedeu-se à substituição de todos os componentes da prótese e drenagem do material acumulado intra-pélvico.Discussão: Após a fractura do insert cerâmico a cabeça cerâmica passou a articular directamente com o componente acetabular metálico, originando os ruídos e desgaste com libertação de partículas e iões. Este material formou uma coleção quística intrapélvica, que passou despercebida na primeira revisão cirúrgica. O desbridamento cirúrgico pôs em comunicação esta coleção com os tecidos adjacentes e com a circulação sistémica, desencadeando efeitos sistémicos graves, como anemia hemolítica auto-imune. Desconhece-se o potencial de toxicidade de cada um dos elementos metálicos desta prótese, não estando ainda disponíveis testes laboratoriais de detecção.Conclusão: A metalose é uma causa rara de anemia hemolítica auto-imune.

Severe hyponatremia in older patients at admission in an internal medicine department.

Hyponatremia is common in older people, most often of multifactorial origin, and can be associated with poor clinical outcomes. The aim was to analyze the frequency of severe hyponatremia (sodium concentration below 125 mmol/L), risk factors and mortality association in hospitalized older patients. A retrospective study was performed in older patients (over 65 years) with hyponatremia, diagnosed at admission in an Internal Medicine Department during one year. A control group of 127 older patients without hyponatremia was considered. Statistical analysis of the data gathered was made with SPSS Statistics 20. The main results were: a group of 1060 patients with age superior to 65 years was identified (representing 72.26% of total admissions); incidence of hyponatremia in those patients was 27.55% and severe hyponatremia was 5.94%; diagnosis of hyponatremia was mentioned in the discharge note in 66.67% of cases; mortality was 27.0%, against 16.0% in the control group (p=0.057, Odds Ratio (OR)=1.940); drugs were a significant risk factor (p<0.001), specially thiazide diuretics (p=0.029, OR=2.774), angiotensin receptor blockers (ARB) (p=0.001, OR=4.097), proton-pump inhibitors (PPI) (p=0.007, OR=2.561) and spironolactone (p=0.011, OR=4.473); other relevant risk factors were: increased water intake (p=0.004), tube feeding (p<0.001), vomiting (p=0.032, OR=2.492), cirrhosis (p=0.008, OR=10.862) and hyperhidrosis (p=0.017, OR=2.542). We conclude that, although this group of patients had a high mortality, hyponatremia is often not investigated and not always mentioned as a diagnosis. Clinicians should have a clear appreciation of the roles that iatrogenic interventions and lapses in nutrition frequently play in upsetting the homeostatic balance in older patients.

Analysis of a bone metastasis gene expression signature in patients with bone metastasis from solid tumors.

Bone is a major target for metastases in the most frequent solid tumors, which result in severe complications and are a major cause of pain. A bone metastasis gene expression signature was identified using human breast cancer cells in a mouse model. The bone metastasis-related genes encode secretory and cell surface proteins implicated in bone-homing (CXCR4), angiogenesis (CTGF and FGF5), invasion (MMP-1 and ADAMTS1), and osteoclast recruitment (IL11). This signature superimposes on the 70-gene poor prognosis gene expression signature for breast cancer, and only ADAMTS1, CTGF and IL11 were found to be overexpressed in human primary breast cancers with bone relapse. We analyzed the expression of the six bone metastasis-related genes in bone metastases from patients with different types of solid tumors, to assess its relevance in human clinical samples. MMP-1, CXCR4, FGF5 and CTGF were found to be overexpressed in tumor cells of human bone metastases when compared to a human normal epithelial cell line. All the analyzed genes were overexpressed in the tumor cells of breast cancer bone metastases when compared to normal breast tissue. We did not detect any differences between the expression of these genes in bone metastases from breast cancer or from other types of solid tumors. Importantly, there was a significant correlation between the expressions of IL11/CTGF, IL11/ADAMTS1, CTGF/CXCR4, CTGF/ADAMTS1, and MMP-1/ADAMTS1, supporting the cooperative function of these proteins in the bone microenvironment, and the potential functional role of these genes in the establishment of bone metastases in vivo.

[Negative paraquaturia does not exclude paraquat fatal poisoning]. / Paraquatúria negativa não exclui intoxicação fatal por paraquat.

The authors present a case report of fatal paraquat poisoning demonstrating persistently negative urine paraquat test. A brief review is also made, concerning the importance of blood test for paraquat, the false negative results in urine test and the need for new effective therapeutic approaches that can change the tragic course of most of these poisoning cases.