Patient-centered Outcomes in Breast Cancer: Description of EQ-5D-5L and EORTC-QLQ-BR23 Measurements in Real-world Data and Their Association With Survival.

AIMS: In recent years, major improvements in breast cancer treatments have led to a significant increase in survival. Despite that, this population's quality of life (QoL) information is lacking, especially real-world data. MATERIALS AND METHODS: This was a prospective, multicentre, observational study of female breast cancer patients, without prior systemic treatment, treated between 2012 and 2019 in private health care in Brazil. QoL was assessed by two questionnaires, the EQ-5D-5L and the EORTC-QLQ-BR23. Additional data were retrospectively collected. RESULTS: The study comprised 1372 patients, most with early-stage disease (80.2% stages 0-II). At a median follow-up of 25.6 months, the estimated 3-year overall survival was 93.6%. Patients with locally advanced and metastatic breast cancer had the lowest visual analogue scale scores and the highest symptom burden in all dimensions of EQ-5D-5L, but with the most significant improvement after treatment. With the EORTC-QLQ-BR23 questionnaire, patients undergoing lumpectomy had a better perception of body image. Axillary dissection led to greater arm symptoms after 12 months, radiotherapy enhanced breast symptoms and patients treated with chemotherapy had significant worsening in the effects of systemic therapy compared with endocrine or HER2 therapy. Staging and immunohistochemical subtype correlated with survival and with several QoL parameters, but overall survival was not independently affected by patient-reported outcomes in this cohort. CONCLUSION: Our results show that early diagnosis and access to treatments with fewer side-effects, such as endocrine or targeted therapy, and less aggressive surgeries are the best strategies to achieve a better QoL for breast cancer patients.

A genetic cluster of patients with variant xeroderma pigmentosum with two different founder mutations.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare human syndrome associated with hypersensitivity to sunlight and a high frequency of skin tumours at an early age. We identified a community in the state of Goias (central Brazil), a sunny and tropical region, with a high incidence of XP (17 patients among approximately 1000 inhabitants). OBJECTIVES: To identify gene mutations in the affected community and map the distribution of the affected alleles, correlating the mutations with clinical phenotypes. METHODS: Functional analyses of DNA repair capacity and cell-cycle responses after ultraviolet exposure were investigated in cells from local patients with XP, allowing the identification of the mutated gene, which was then sequenced to locate the mutations. A specific assay was designed for mapping the distribution of these mutations in the community. RESULTS: Skin primary fibroblasts showed normal DNA damage removal but abnormal DNA synthesis after ultraviolet irradiation and deficient expression of the Polη protein, which is encoded by POLH. We detected two different POLH mutations: one at the splice donor site of intron 6 (c.764 +1 G>A), and the other in exon 8 (c.907 C>T, p.Arg303X). The mutation at intron 6 is novel, whereas the mutation at exon 8 has been previously described in Europe. Thus, these mutations were likely brought to the community long ago, suggesting two founder effects for this rare disease. CONCLUSIONS: This work describes a genetic cluster involving POLH, and, particularly unexpected, with two independent founder mutations, including one that likely originated in Europe.

Identity of a purple dye formed by peroxidic oxidation of p-aminophenol at low pH.

The structure of a colored intermediate commonly formed in the oxidation of p-aminophenol at low pH is established by analysis of H NMR and UV/vis spectra, kinetics, and molecular modeling, following a new method for synthesizing the dye in high concentrations. The chromogen is shown to consist of two compounds with absorption maxima at 540-560 and 375-385 nm. The 2,6-dimethyl and 3,5-dimethyl analogues of p-aminophenol are found to undergo N- rather than C-substitution under similar conditions.

Increased pro-inflammatory activity and impairment of human monocyte differentiation induced by in vitro exposure to cigarette smoke.

Cigarette smoking (CS) is associated with a variety of human pathologies including cardiovascular disease and cancer. Human monocytes are prevalent in oral and respiratory mucosa and may be affected by exposure to CS, which induces oxidative stress. As a result, up-regulation of nuclear factor-kappaB (NF-kappaB) may occur. Our aims were to analyze a possible regulatory effect of CS on NF-kappaB activity in human monocytes. Human monocyte cell lines were exposed to CS in vitro. Our findings show that in vitro exposure to CS did not affect viability of human monocytes and was associated with increased production and secretion of IL-8 and up-regulation of certain C-C chemokines. Inhibition of NF-kappaB with curcumin or parthenolide resulted in a decrease of IL-8 secretion. CS also impaired the differentiation of monocytes. However, induced secretion of IL-8 from differentiated monocytes was not impaired. Our results indicate that exposure to CS stimulates pro-inflammatory activity of human monocytes through the activation of NF-kappaB pathway and also interferes with monocyte differentiation, which could play a role in the carcinogenic effects of cigarette smoking.

Efecto agudo del litio en el control de la crisis tirotoxica: reporte de un caso / Acute effect of lithium in the management of thyrotoxic storm: report of a case

La terapeutica de la crisis tirotoxic aexige una disminucion rapida de las concentraciones sericas de hormonas tiroideas para lo cual se requieren tratamiento adyuvantes a los antitiroideo. El acido iopanoico ha sido ampliamente utilizado por su capacidad de inhibir la conversion periferica de T4 a T3, sin embargo no se comercializa actualmente en nuestro pais. El litio actua inhibiendo la liberacion de T4 y T3 a la circulacion general, por lo cual puede utilizarse como droga adyuvante en el hipertiroidismo severo. Objetivo: desccribir los efectos agudos del litio en la tirotoxicosis severa. Se trata de una mujerde 39 años con antecedentes de hipertiroidismo de larga data y abandono de la medicacion, que se interno en terapia intensivapor un cuadro de neumonia severa con insuficiencia respiratoria y crisis tirotoxica. Se inicio tratamiento con hidrocortisona, metimazol y litio 600mg/dia. Las hormonas tiroideas disminuyeron mas de un 50 por ciento a las 48h y se normalizaron a los 6 dias de iniciada la terapeutica, con valores de litemia por debajo del rango terapeutico para su uso en patologia psiquiatrica. A la semana las hormonas entraron en rango subnormal coincidiendo con una desconpensacion hemodinamica de la paciente. Este efecto fue atribuido al litio y no exclusivamente a un sindrome T3 y T4 bajas dado que al suspender dicho compuesto las hormonas se elevaron nuevamente en rango de hipertirodismo sin que hubiera cambiado el cuadro clinico de la paciente. En conclusion, el uso de litio permitio en esta pciente un control rapido y reiterado de las hormonas tiroideas, a una dosis baja y alejada del rango de toxicidad. Por lo tanto consideramos que se trata de una alternativa terapeutica muy ventajosa para el control agudo del hipertiroidismo y que a su vez no posterga el tratamiento con I131

Efecto agudo del litio en el control de la crisis tirotoxica: reporte de un caso / Acute effect of lithium in the management of thyrotoxic storm: report of a case

La terapeutica de la crisis tirotoxic aexige una disminucion rapida de las concentraciones sericas de hormonas tiroideas para lo cual se requieren tratamiento adyuvantes a los antitiroideo. El acido iopanoico ha sido ampliamente utilizado por su capacidad de inhibir la conversion periferica de T4 a T3, sin embargo no se comercializa actualmente en nuestro pais. El litio actua inhibiendo la liberacion de T4 y T3 a la circulacion general, por lo cual puede utilizarse como droga adyuvante en el hipertiroidismo severo. Objetivo: desccribir los efectos agudos del litio en la tirotoxicosis severa. Se trata de una mujerde 39 años con antecedentes de hipertiroidismo de larga data y abandono de la medicacion, que se interno en terapia intensivapor un cuadro de neumonia severa con insuficiencia respiratoria y crisis tirotoxica. Se inicio tratamiento con hidrocortisona, metimazol y litio 600mg/dia. Las hormonas tiroideas disminuyeron mas de un 50 por ciento a las 48h y se normalizaron a los 6 dias de iniciada la terapeutica, con valores de litemia por debajo del rango terapeutico para su uso en patologia psiquiatrica. A la semana las hormonas entraron en rango subnormal coincidiendo con una desconpensacion hemodinamica de la paciente. Este efecto fue atribuido al litio y no exclusivamente a un sindrome T3 y T4 bajas dado que al suspender dicho compuesto las hormonas se elevaron nuevamente en rango de hipertirodismo sin que hubiera cambiado el cuadro clinico de la paciente. En conclusion, el uso de litio permitio en esta pciente un control rapido y reiterado de las hormonas tiroideas, a una dosis baja y alejada del rango de toxicidad. Por lo tanto consideramos que se trata de una alternativa terapeutica muy ventajosa para el control agudo del hipertiroidismo y que a su vez no posterga el tratamiento con I131(AU)

Differences between glycogen biogenesis in fast- and slow-twitch rabbit muscle.

Skeletal muscle glycogen is an essential energy substrate for muscular activity. The biochemical properties of the enzymes involved in de novo synthesis of glycogen were analysed in two types of rabbit skeletal muscle fiber (fast- and slow-twitch). Glycogen concentration was higher in fast-twitch muscle than in slow-twitch muscle, but the latter contained many more small intermediate-acceptor molecules that could act as glycogen synthase substrates. The enzymes involved in de novo synthesis of glycogen in fast-twitch muscle were strongly stimulated by Glc-6-P, but those in slow-twitch muscle were not.

Nrl and Sp nuclear proteins mediate transcription of rod-specific cGMP-phosphodiesterase beta-subunit gene: involvement of multiple response elements.

cGMP-phosphodiesterase (PDE) is the key effector in rod photoreceptor signal transduction. Mutations in the gene encoding its catalytic beta-subunit (beta-PDE) cause retinal degenerations leading to blindness. We report that the short -93 to +53 sequence in the upstream region of this gene is sufficient for beta-PDE transcription in both Y79 human retinoblastoma cells and Xenopus embryo heads maintained ex vivo. This sequence also functions as a minimal rod-specific promoter in transgenic Xenopus tadpoles. The Nrl transcription factor binds in vitro to the betaAp1/NRE regulatory element located within this region and transactivates it when overexpressed in nonretinal 293 embryonic kidney cells. We also found a G/C-rich activator element, beta/GC, important for promoter activity in Y79 retinoblastoma cells and Xenopus embryos. Both the ubiquitous Sp1 and the central nervous system-specific Sp4 transcription factors are expressed in retina and interact with this element in vitro. Electrophoretic mobilities of beta/GC-Y79 nuclear protein complexes are altered by antibodies against Sp1 and Sp4. Thus, our results implicate Nrl, Sp1, and Sp4 in transcriptional regulation of the rod-specific minimal beta-PDE promoter. We also conclude that Xenopus laevis is an efficient system for analyzing the human beta-PDE promoter and may be used to study other human retinal genes ex vivo and in vivo.

Outbreak of sternal surgical site infections due to Pseudomonas aeruginosa traced to a scrub nurse with onychomycosis.

From 19 February 1999 through 31 October 1999, 16 (8.6%) of 185 patients who underwent median sternotomy developed infections with Pseudomonas aeruginosa. Seven patients had mediastinitis, 5 had deep sternal wound infection, 2 had superficial sternal wound infection, 1 had prosthetic valve endocarditis, and 1 had sepsis. Pulsed-field gel electrophoresis confirmed that all 13 isolates that were available for typing were the same strain. Cultures of hand specimens identified 1 nurse from whom the same strain of P. aeruginosa was repeatedly isolated; the nurse had been in contact with all 16 infected patients. Investigation revealed that the nurse had severe onycholysis and onychomycosis of the right thumbnail. Cultures of samples of this nail's subungual region and of multiple cosmetic products from the nurse's home yielded the identical P. aeruginosa strain. This outbreak of surgical site infections due to P. aeruginosa was caused by wound contamination from the thumbnail of this nurse, despite her appropriate use of latex surgical gloves.

Creation of genome-wide protein expression libraries using random activation of gene expression.

Here we report the use of random activation of gene expression (RAGE) to create genome-wide protein expression libraries. RAGE libraries containing only 5 x 10(6) individual clones were found to express every gene tested, including genes that are normally silent in the parent cell line. Furthermore, endogenous genes were activated at similar frequencies and expressed at similar levels within RAGE libraries created from multiple human cell lines, demonstrating that RAGE libraries are inherently normalized. Pools of RAGE clones were used to isolate 19,547 human gene clusters, approximately 53% of which were novel when tested against public databases of expressed sequence tag (EST) and complementary DNA (cDNA). Isolation of individual clones confirmed that the activated endogenous genes can be expressed at high levels to produce biologically active proteins. The properties of RAGE libraries and RAGE expression clones are well suited for a number of biotechnological applications including gene discovery, protein characterization, drug development, and protein manufacturing.

Transient transfection of human retinoblastoma cells : application to the analysis of the regulatory regions of photoreceptor-specific genes.

Retinoblastoma (Rb) is an intraocular tumor usually diagnosed in children under four years of age (1). The tumor rises when both alleles of the Rb tumor suppressor gene become inactivated in a retinal precursor cell during development (2,3). The first retinoblastoma cell line to be established in culture, Y-79 (4), has been shown to originate from neuroectodermal cells that express both neuronal and glial cell markers (3). Both Y-79 cells and Rb tumor cells produce mRNAs encoding several proteins unique to the photoreceptors (5), including different subunits of cone- and rod-specific cGMP-phosphodiesterases (6). Therefore, cultured Y-79 cells, which have a human retinal origin, could be particularly useful for studying the regulatory mechanisms of photoreceptor-specific gene expression (7).

Pigmented purpuric eruption associated with injection medroxyprogesterone acetate.

Pigmented purpuric eruptions are characterized clinically by purpura, most commonly petechial, and brownish pigmentation. Although there are several idiopathic variants, several drugs have been associated with these eruptions. We present a patient who experienced pigmented purpura on her lower extremities several months after initiating medroxyprogesterone acetate injection. The eruption cleared several weeks after discontinuation of the medication.

Progression to invasive melanoma from malignant melanoma in situ, lentigo maligna type.

We have previously hypothesized that lesions that have been termed lentigo maligna can be divided into 2 categories: 1 represents a pigmented lesion that is a precursor to melanoma, and the other melanoma in situ. We and others have hypothesized that there is a progressive acquisition of attributes in pigmented lesions that results in malignant melanoma. Based on these 2 hypotheses, we have predicted that the intraepidermal component of invasive malignant melanomas, lentigo maligna type, should be similar to those lesions that we have termed malignant melanoma in situ, lentigo maligna type rather than lentigo maligna. The intraepidermal component of 42 consecutive cases of invasive malignant melanoma, lentigo maligna type was evaluated by all of the authors. Malignant melanoma in situ, lentigo maligna type is characterized by pagetoid spread, confluence, and nesting of atypical melanocytes. All of the cases evaluated showed features diagnostic of malignant melanoma in situ, lentigo maligna type, in the epidermis overlying the invasive dermal component. We conclude that invasive lentigo maligna melanoma arises in association with those lesions that we have termed malignant melanoma in situ, lentigo maligna type, which may represent a step in the progression between atypical melanocytic hyperplasia (lentigo maligna) and invasive melanoma. This finding supports the distinction of these entities and may have therapeutic implications.

Nitric oxide synthase in toxic epidermal necrolysis and Stevens-Johnson syndrome.

Toxic epidermal necrolysis and Stevens-Johnson syndrome are severe cutaneous drug reactions of unknown mechanism. Nitric oxide can cause apoptosis and necrosis. The inducible form of nitric oxide synthase generates large amounts of nitric oxide and has been described in human skin. We propose that a large burst of nitric oxide in toxic epidermal necrolysis and Stevens-Johnson syndrome may cause the epidermal apoptosis and necrosis. Skin biopsies were taken from seven patients with actively progressing Stevens-Johnson syndrome or toxic epidermal necrolysis. Expression of inducible nitric oxide synthase was examined by reverse transcription-polymerase chain reaction and by immunoperoxidase staining for inducible nitric oxide synthase protein. Messenger RNA for inducible nitric oxide synthase was detected by reverse transcription-polymerase chain reaction and confirmed by the sequencing of polymerase chain reaction products. Strong staining for inducible nitric oxide synthase was observed in inflammatory cells in the lower epidermis and upper dermis. Diffuse, weaker staining was observed in keratinocytes. Expression of inducible nitric oxide synthase is consistent with the hypothesis that nitric oxide mediates the epidermal necrosis in toxic epidermal necrolysis and provides a potential target for therapeutic intervention.

Clinical, epidemiological, and microbiological features of Vibrio vulnificus biogroup 3 causing outbreaks of wound infection and bacteraemia in Israel. Israel Vibrio Study Group.

BACKGROUND: Vibrio vulnificus is a gram-negative bacterium that causes septicaemia and wound infection. Cases occur sporadically, and no previous outbreaks due to a common source or a clonal strain have been reported. In the summer and autumn of 1996 and 1997, an outbreak of invasive V. vulnificus infection occurred in Israel in people who had recently handled fresh, whole fish purchased from artificial fish-ponds. METHODS: We reviewed clinical and epidemiological information, and undertook an environmental investigation to assess disease characteristics, modes of transmission, phenotypic characteristics of the bacterium, and fish-marketing policy. The clonal nature of 19 isolates was studied by biotyping, pulsed-field gel electrophoresis, and restriction-fragment length polymorphism (RFLP) analysis of a PCR fragment. FINDINGS: During 1996-97, 62 cases of wound infection and bacteraemia occurred. 57 patients developed cellulitis, four had necrotising fasciitis, and one developed osteomyelitis. In all cases, the fish were cultivated in inland fish-ponds. In the summer of 1996, fish-pond managers initiated a new marketing policy, in which fish were sold alive instead of being packed in ice. Phenotypically, the isolates had five atypical biochemical test results. The isolates were non-typeable by pulsed-field gel electrophoresis, and all had the same PCR-RFLP pattern which had not been seen previously. INTERPRETATION: The cause of the outbreak was a new strain of V. vulnificus, classified as biogroup 3. A new fish-marketing policy that began in 1996 may have exposed susceptible people to the organism.

Vulvar metastases secondary to transitional cell carcinoma of the bladder. A case report.

BACKGROUND: Gynecologists are frequently asked to evaluate patients with vulvar lesions. Although the differential diagnosis of a vulvar lesion is varied, the main concern is to rule out a vulvar malignancy. Primary vulvar carcinoma is uncommon, and a metastatic cancer from an extragenital site involving the vulva is even more rare. CASE: A 78-year-old woman with a history of a transitional cell carcinoma (TCC) of the bladder presented with two painful vulvar lesions, which represented the first manifestation of metastatic disease. This is the fifth reported case of TCC from the bladder with metastases to the vulva. CONCLUSION: The differential diagnosis of a vulvar lesion, especially in a woman with a prior history of renal tract malignancy, should include metastatic lesions.

Tools of the trade: statistical analysis in dermatopathology articles.

Statistical analysis of research results provides powerful tools for understanding the data from projects. A prospective review of the statistical methods utilized in 100 consecutive articles in the recent literature relevant to dermatopathology was performed. The majority of papers, 75%, did not contain statistical analyses. A wide variety of methods were utilized in the papers that did have statistical analyses including methods in the following categories: t-test, contingency tables, multiple regression, multiple comparisons, nonparametric tests, life tables, and survival tests. Nine of the 25 papers utilizing statistical analysis had problems in the methods. These problems included treating categorical data as a continuous variable, multiple comparisons, subgroup analysis, and discordance of statistics and conclusions. It is important to understand the underlying assumptions of statistical methods to use the appropriate tets. These are tools of the trade for dermatopathology investigators.