Clinicogenomic characterization of inflammatory breast cancer.

Background: Inflammatory breast cancer (IBC) is a rare and poorly characterized type of breast cancer with an aggressive clinical presentation. The biological mechanisms driving the IBC phenotype are relatively undefined-partially due to a lack of comprehensive, large-scale genomic studies and limited clinical cohorts. Patients and Methods: A retrospective analysis of 2457 patients with metastatic breast cancer who underwent targeted tumor-only DNA-sequencing was performed at Dana-Farber Cancer Institute. Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV) and tumor mutational burden (TMB) comparisons were made between clinically confirmed IBC cases within a dedicated IBC center versus non-IBC cases. Results: Clinicopathologic differences between IBC and non-IBC cases were consistent with prior reports-including IBC being associated with younger age at diagnosis, higher grade, and enrichment with hormone receptor (HR)-negative and HER2-positive tumors. The most frequent somatic alterations in IBC involved TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%) and GATA3 (8%). A multivariate logistic regression analysis revealed a significant enrichment in TP53 SNVs in IBC; particularly in HER2-positive and HR-positive disease which was associated with worse outcomes. Tumor mutational burden (TMB) did not differ substantially between IBC and non-IBC cases and a pathway analysis revealed an enrichment in NOTCH pathway alterations in HER2-positive disease. Conclusion: Taken together, this study provides a comprehensive, clinically informed landscape of somatic alterations in a large cohort of patients with IBC. Our data support higher frequency of TP53 mutations and a potential enrichment in NOTCH pathway activation-but overall; a lack of major genomic differences. These results both reinforce the importance of TP53 alterations in IBC pathogenesis as well as their influence on clinical outcomes; but also suggest additional analyses beyond somatic DNA-level changes are warranted.

Severe paraquat poisoning: clinical and radiological findings in a survivor.

Paraquat is a nonselective contact herbicide of great toxicological importance, being associated with high mortality rates, mainly due to respiratory failure. We report the case of a 22-year-old male admitted to the emergency room with a sore throat, dysphagia, hemoptysis, and retrosternal pain after the ingestion of 50 mL of a paraquat solution, four days prior to admission. Chest CT scans revealed pulmonary opacities, pneumomediastinum, pneumothorax, and subcutaneous emphysema. The patient was submitted to two cycles of immunosuppressive therapy with cyclophosphamide, methylprednisolone, and dexamethasone. The pulmonary gas exchange parameters gradually improved, and the patient was discharged four weeks later. The clinical and tomographic follow-up evaluations performed at four months after discharge showed that there had been further clinical improvement. We also present a brief review of the literature, as well as a discussion of the therapeutic algorithm for severe paraquat poisoning.

Intoxicação grave por paraquat: achados clínicos e radiológicos em um sobrevivente / Severe paraquat poisoning: clinical and radiological findings in a survivor

O paraquat é um herbicida não seletivo que possui grande importância toxicológica, sendo associado a altas taxas de letalidade, devidas principalmente à insuficiência respiratória. Este é o relato do caso de um homem de 22 anos admitido no departamento de emergência com queixa de dor de garganta, disfagia, hemoptise e dor retroesternal. Ele relatava a ingestão de cerca de 50 mL de uma solução de paraquat quatro dias antes da admissão hospitalar. A TC de tórax exibia opacidades pulmonares, pneumomediastino, pneumotórax e enfisema subcutâneo. O paciente foi submetido a dois ciclos de terapia imunossupressora com ciclofosfamida, metilprednisolona e dexametasona. Os parâmetros gasométricos progressivamente melhoraram, e o paciente recebeu alta hospitalar após quatro semanas. Decorridos quatro meses da alta, o paciente foi submetido a controles clínico e tomográfico, os quais confirmaram a melhora clínica. Apresentamos também uma revisão sucinta da literatura, bem como uma discussão do processo de decisão terapêutica para intoxicação grave por paraquat.

Paraquat is a nonselective contact herbicide of great toxicological importance, being associated with high mortality rates, mainly due to respiratory failure. We report the case of a 22-year-old male admitted to the emergency room with a sore throat, dysphagia, hemoptysis, and retrosternal pain after the ingestion of 50 mL of a paraquat solution, four days prior to admission. Chest CT scans revealed pulmonary opacities, pneumomediastinum, pneumothorax, and subcutaneous emphysema. The patient was submitted to two cycles of immunosuppressive therapy with cyclophosphamide, methylprednisolone, and dexamethasone. The pulmonary gas exchange parameters gradually improved, and the patient was discharged four weeks later. The clinical and tomographic follow-up evaluations performed at four months after discharge showed that there had been further clinical improvement. We also present a brief review of the literature, as well as a discussion of the therapeutic algorithm for severe paraquat poisoning.

Adhesion molecules and Differentiation Syndrome: phenotypic and functional analysis of the effect of ATRA, As2O3, phenylbutyrate, and G-CSF in acute promyelocytic leukemia.

BACKGROUND AND OBJECTIVES: Differentiation Syndrome (DS) is a treatment complication which can occur in patients treated with acute promyelocytic leukemia (APL) with all transretinoic acid (ATRA) or As(2)O(3), and is characterized by enhanced leukocyte transmigration. As(2)O(3), Phenylbutyrate (PB) and G-CSF are known to potentiate ATRA effects. Our aim was to analyze the changes in expression and function of adhesion molecules induced by ATRA, As(2)O(3), G-CSF and PB, and their association. DESIGN AND METHODS: APL blasts and NB4 cells were treated with ATRA, As(2)O(3), PB, G-CSF or their association and the expression of adhesion molecules was determined by flow cytometry. Cell adhesion was evaluated in vitro using Matrigel and for the in vivo analysis, Balb-c mice were injected with NB4 cells pre-treated with ATRA, As(2)O(3), ATRA+G-CSF or ATRA+As(2)O(3). In addition, CD54 and CD18 knock-out mice were injected with NB4 cells and concomitantly treated with ATRA. In both models, the MPO activity in the lungs was determined 6 hours after the injection of the cells. RESULTS: In NB4 and APL blasts, ATRA and As(2)O(3) increased CD54 expression, but no synergism was detected. CD11b and CD18 were also up-regulated by ATRA in primary cells. PB and G-CSF had no effect, but the latter potentiated ATRA-induced CD18 up-regulation. These changes were accompanied by increased adhesion to Matrigel and to lung microvasculature, and reversed by anti-CD54, anti-CD18 antibodies. In CD54 and CD18 knock-out mice the ATRA effect was canceled. INTERPRETATION AND CONCLUSIONS: The use of As(2)O(3), PB and G-CSF in association with ATRA should not aggravate DS in APL.

Sleep disturbances in patients on maintenance hemodialysis: role of dialysis shift.

OBJECTIVES: Subjective sleep complaints have been reported in up to 80% of patients with end stage renal disease (ESRD). In these patients, sleep disturbances manifesting as insomnia, sleep apnea syndrome, restless leg syndrome (RLS), periodic limb movement disorder and excessive daytime sleepiness (EDS) have been frequently reported. Moreover, studies about the role of dialysis shift on sleep abnormalities, morbidity and mortality are still scarce. The aim of this study was to investigate the influence of dialysis shift on the quality of sleep and sleep abnormalities in patients with ESRD. METHODS: We studied one hundred consecutive patients from a dialysis center. Quality of sleep was assessed by the Pittsburgh Sleep Quality Index and subjective EDS by the Epworth Sleepiness Scale. Restless leg syndrome was diagnosed using the four minimum criteria defined by the International Restless Legs Syndrome Study Group. Clinical and laboratory parameters were obtained by interview and chart review. Adequacy of dialysis was evaluated by the Kt/V index. RESULTS: Poor quality sleep (PSQI>6) was found in 75% of cases and was associated with RLS (p=0.004) and with snoring (p=0.016). EDS (ESS>10) was present in 28% of cases. Patients with EDS (1.33+/-0.29) had lower values of the Kt/v index (P=0.01) than those without EDS (1.52+/-0.32). RLS was present in 48% of cases. Irrespective of dialysis shift, poor quality sleep, EDS and RLS were not different among patients. CONCLUSION: Poor quality sleep, EDS and RLS were common and not related to dialysis shift.

Sleep disturbances in patients on maintenance hemodialysis: role of dialysis shift

OBJECTIVES: Subjective sleep complaints have been reported in up to 80 percent of patients with end stage renal disease (ESRD). In these patients, sleep disturbances manifesting as insomnia, sleep apnea syndrome, restless leg syndrome (RLS), periodic limb movement disorder and excessive daytime sleepiness (EDS) have been frequently reported. Moreover, studies about the role of dialysis shift on sleep abnormalities, morbidity and mortality are still scarce. The aim of this study was to investigate the influence of dialysis shift on the quality of sleep and sleep abnormalities in patients with ESRD. MÉTHODS: We studied one hundred consecutive patients from a dialysis center. Quality of sleep was assessed by the Pittsburgh Sleep Quality Index and subjective EDS by the Epworth Sleepiness Scale. Restless leg syndrome was diagnosed using the four minimum criteria defined by the International Restless Legs Syndrome Study Group. Clinical and laboratory parameters were obtained by interview and chart review. Adequacy of dialysis was evaluated by the Kt/V index. RESULTS: Poor quality sleep (PSQI>6) was found in 75 percent of cases and was associated with RLS (p=0.004) and with snoring (p=0.016). EDS (ESS>10) was present in 28 percent of cases. Patients with EDS (1.33±0.29) had lower values of the Kt/v index (P=0.01) than those without EDS (1.52±0.32). RLS was present in 48 percent of cases. Irrespective of dialysis shift, poor quality sleep, EDS and RLS were not different among patients. CONCLUSION: Poor quality sleep, EDS and RLS were common and not related to dialysis shift.

OBJETIVOS: Alterações do sono têm sido relatadas em até 80 por cento dos pacientes com Insuficiência renal crônica dialítica (IRCD). Insônia, síndrome da apnéia do sono, síndrome das pernas inquietas (SPI), movimentos periódicos de extremidades e sonolência excessiva diurna (SED) têm sido descritos. A influência que o turno da diálise exerce sobre as alterações do sono e sobre a morbidade e mortalidade ainda é desconhecida. O objetivo deste estudo foi avaliar a influência do turno da diálise sobre as anormalidades do sono em pacientes com IRCD. MÉTODOS: Estudamos 100 pacientes consecutivos provenientes de um centro de diálise. A qualidade do sono foi avaliada através do Índice de Qualidade do Sono de Pittsburgh (IQSP) e a SED através da Escala de sonolência de Epworth (ESE). A SPI foi avaliada utilizando os quatro critérios mínimos definidos internacionalmente pela International Restless Legs Syndrome Study Group. Os parâmetros clínicos e laboratoriais foram obtidos através de entrevistas e revisão de prontuários. A qualidade da diálise foi avaliada pelo índice Kt/V. RESULTADOS: Má qualidade do sono (IQSP>6), encontrada em 75 por cento dos casos, associou-se à SPI (P= 0.004) e à presença de ronco (P= 0.016). Pacientes com SED (ESE>10) (1.33±0.29) apresentaram valores do índice Kt/v menores (P=0.01) do que aqueles sem SED (1.52±0.32). Observou-se a presença de SPI em 48 por cento dos pacientes. Má qualidade do sono, SED e SPI não diferiram entre os pacientes agrupados quanto ao turno de diálise. CONCLUSÃO: Má qualidade do sono, SED e SPI são freqüentes e não se relacionam com o turno da diálise.