A hérnia perineal é uma enfermidade que ocorre comumente em cães machos, principalmente não castrados com faixa etária entre cinco e 14 anos. A etiologia é desconhecida, sendo que vários fatores já foram associados tais como alterações hormonais, neurogênicas ou características anatômicas. Sabe-se que a atrofia muscular, principalmente do músculo elevador do ânus, está relacionada diretamente com o desenvolvimento da hérnia perineal e, de acordo com os músculos envolvidos, é classificada em caudal, dorsal, ventral ou ciática. Várias técnicas cirúrgicas foram descritas para sua correção, porém as taxas de complicações e recidivas são elevadas, sem que tenha havido avaliações comparativas das técnicas e determinação de qual é mais adequada para cada caso. Portanto, objetivou-se com o presente estudo a avaliação crítica das técnicas de herniorrafia perineal realizadas em cães machos, por meio da colimação dos resultados coligidos em trabalhos científicos observados na literatura. Para tanto foi realizada uma busca nas bases de dados referenciais eletrônicas Embase, Google Acadêmico, PubMed, SciELO, Science Direct e Web of Science. Os processos de reparação de hérnia perineal tais como a técnica de sutura padrão, transposição do músculo obturador interno; transposição do músculo glúteo superficial; transposição do músculo semitendinoso; reparação com uso de membranas sintéticas ou biológicas; e colopexia associada ou não a cistopexia foram avaliados quanto à presença de complicações e recidivas. Com a busca por meio das bases de dados referenciais eletrônicas obteve-se 5311 resultados em português e inglês. A busca manual resultou na obtenção de outros 41 artigos. Após avaliação do título e resumo, exclusão dos resultados repetidos, e leitura do texto completo, foram selecionados 30 artigos de acordo com os critérios de inclusão e exclusão. Baseando-se na comparação e avaliação dos resultados é possível concluir que existe falta de dados clínicos padronizados bem como informações sobre o tempo de acompanhamento pós-operatório e taxas de recidiva extremamente variáveis, dificultando estabelecer paralelo entre o nível de gravidade da enfermidade com as complicações advindas após realização das diferentes técnicas cirúrgicas preconizadas, dificultando a avaliação da eficácia de tais técnicas / Perineal hernia is a disease that occurs commonly in male dogs, especially uncastrated aged between five and 14 years. The etiology is unknown, and several factors have been associated such as hormonal, neurogenic or anatomical features changes. It is known that muscle atrophy, mainly of the levator ani muscle, is directly related to the development of perineal hernia and, according to the involved muscles, it is classified into caudal, dorsal, ventral or sciatica. Several surgical techniques have been described for its repair, but the complications and recurrences rates are high, without there have been comparative evaluation techniques and determination of which is more appropriate for each case. Therefore, the present study had the objective of critically evaluate the perineal hernia repair techniques performed in male dogs through collimation of the results collected in scientific studies reported in the literature. Therefore it was carried out a search in the electronic reference databases Embase, Google Scholar, PubMed, SciELO, Science Direct and Web of Science. The perineal hernia repair procedures such as standard suture technique, transposition of the internal obturator muscle; transposition of superficial gluteal muscle; transposition of semitendinosus muscle; repair with the use of synthetic or biological membranes; and colopexy with or without cistopexia were evaluated for the presence of complications and recurrences. With the search through the electronic reference databases, it was obtained 5311 results in Portuguese and English. The manual search resulted in obtaining another 41 articles. After evaluation of the title and abstract, excluding the repeated result and reading the full text, it was selected 30 articles according to the inclusion and exclusion criteria. Based on the comparison and evaluation of the results it is possible to conclude that there is a lack of standardized clinical data as well as information about the time of postoperative follow-up and extremely variable recurrences rates, making it difficult to establish a parallel between the level of the disease severity with complications arising after implementation of the various preconized surgical techniques, making it difficult to evaluate the effectiveness of such techniques

Recognized as one of the most prevalent and persistent concerns in cancer survivors, fear of cancer recurrence (FCR) is defined as the "fear, worry, or concern relating to the possibility that cancer will come back or progress" (Lebel et al., 2016). Higher FCR severity leads to poor mental health, impaired functioning and reduced quality of life. It is well established that health behaviours can help reduce the risk of cancer recurrence in cancer survivors, but little is known about their relationship with FCR. The overall thesis objectives were: 1) to identify subgroups of cancer survivors by FCR severity and corresponding patient characteristics; 2) to explore the relationship between FCR and health behaviours (physical activity and fruit and vegetable intake) over time; and 3) to further examine the relationship between FCR severity subgroups and health behaviours using the Common-Sense Model (CSM). Data analyses were conducted on 2337 survivors of ten cancer sites who completed the American Cancer Society’s Studies of Cancer Survivorship-I survey at three time points (M =1.3, 2.2, and 8.8 years post-diagnosis). In study 1, group-based trajectory analyses revealed three FCR severity groups: low, moderate, and high. FCR significantly decreased from early to long-term survivorship and remained distinct for each group. Subsequently, repeated measures analysis of variance revealed that patient characteristics prevalent in the high FCR group were being female, of younger age, Hispanic ethnicity, having more advanced cancer stage (II-III) and Non-Hodgkin lymphoma. Across FCR groups, only a minority of survivors adhered to the recommended physical activity and fruit and vegetable intake. Survivors in the high FCR group reported significantly fewer of these health behaviours than other survivors. In study 2, cross-sectional path analyses were conducted to examine the relationship between FCR and health behaviours using the CSM framework across the FCR severity groups. Results indicated good-fitting models for the low, moderate, and high FCR groups. Engaging in physical activity and fruit and vegetable intake did not influence FCR in most participants. Yet, in the low FCR group, survivors reporting more health behaviours had lower FCR severity. In the low and moderate FCR groups, health behaviours were related to control over health and self-efficacy to manage health, suggesting that cancer survivors use health behaviours to manage illness outcomes. For survivors in the high FCR group, results suggest that self-efficacy to manage health is a better predictor of FCR than engaging in physical activity and fruit and vegetable intake In conclusion, most cancer survivors fail to meet the recommended physical activity and fruit and vegetable intake throughout cancer survivorship, with survivors in the high FCR group being at greater risk of engaging in fewer health behaviours. Health behaviours appear unrelated to FCR severity for most cancer survivors, except for survivors with low FCR, who might be experiencing less FCR when engaging in more health behaviours. Findings suggests that clinical interventions should be tailored by FCR severity groups and that health behaviour research among cancer survivors should account for FCR severity groups. Further investigations are required to assess cancer survivors’ perceived usefulness of health behaviours to manage the risk of cancer recurrence by FCR severity group

Introdução: O carcinoma adenoide cístico (CAC) é uma das neoplasias de glândula salivar mais comuns para o qual não se encontra quimioterapia eficaz. Um conceito emergente na terapia do câncer é atingir proteínas especificas do tumor. MDM2 (murine double minute 2) é um importante inibidor do supressor tumoral p53, e sua expressão é aumentada em CAC. O objetivo do Artigo 1 foi avaliar o efeito de um novo inibidor da interação MDM2-p53 (MI-773) no CAC in vitro e in vivo. O Artigo 2 teve como objetivo entender o papel da combinação de MI-773 com cisplatina, além de avaliar a recorrência de CAC frente a regime neoadjuvante de MI-773. Materiais e Métodos: 3 modelos de xenoenxerto derivado de paciente (XEDP, UM-PDXHACC- 5; ACCx6; ACCx9) e 5 culturas primarias de CAC (UM-HACC-1, -2A, -2B, -5, -6) foram usados para experimentos in vitro e in vivo. Ensaio de Sulforrodamina B (SRB) foi realizado para avaliar o efeito dos agentes experimentais na viabilidade celular, além de determinar valores de IC50. Western blots revelaram a expressão de p53, fosfo-p53, MDM2, p21, PUMA, BAX, Bcl-2 e Bcl-xL. Lâminas histológicas (UMPDX- HACC-5) foram avaliadas por imunohistoquímica e imunofluorescência para determinar a localização de p53. Técnica de TUNEL in situ revelou o número de células de UM-PDX-HACC-5 no processo de apoptose. Citometria de fluxo foi realizada para determinar o efeito da terapia na proporção de células-tronco tumorais (ALDHhighCD44high) e para avaliar o ciclo celular. Para os estudos in vivo, animais transplantados com tumores (UM-PDX-HACC5, ACCx6, ou ACCx9) receberam protocolo terapêutico (MI-773 – gavagem; cisplatina – injeção intraperitoneal; ou veículo controle) conforme indicado. ANOVA, seguido de testes post-hoc (Tukey), Mann-Whitney U-test ou Student’s t-test foram usados para determinar as diferenças no crescimento tumoral, peso, volume, apoptose, viabilidade celular, expressão de TUNEL e p53. Significância estatística: p<0.05. Resultados: MI-773 causa regressão do tumor em todos os modelos préclínicos de CAC. Doses diárias de 100mg/kg de MI-773 reduziram significativamente o volume tumoral quando comparado com doses intermediárias (10 ou 50 mg/kg MI-773) ou veículo controle, em todos os modelos de CAC. Alternativamente, camundongos transplantados com tumores UM-PDX-HACC-5 receberam doses semanais de MI-773 (200 mg/kg) e/ou cisplatina (5 mg/kg) por 30 dias, a fim de se avaliar o efeito da combinação das drogas. MI-773, como agente único, causou regressão tumoral, sendo mais efetivo do que a cisplatina. Cisplatina, por outro lado, mostrou limitado efeito terapêutico, estabilizando o crescimento tumoral. Notavelmente, a combinação MI-773 + cisplatina foi mais efetiva do que os agentes isoladamente, e não foi verificada retomada do tumor no período pósoperatório. Importantemente, os protocolos experimentais não comprometeram a saúde geral dos animais. Coletivamente, estes resultados in vivo demonstram que MI-773 atua como mediador na regressão tumoral de CAC e sensibiliza os tumores à cisplatina. A inibição terapêutica da interação MDM2-p53 ativa p53 e induz apoptose. MI-773 potentemente induz expressão de p53, seu alvo p21 e proteínas relacionadas à apoptose, como PUMA, BAX, Bcl-2 e Bcl-xL in vitro e in vivo. Análise do ciclo celular mostrou que a inibição terapêutica da interação MDM2-p53 por MI- 773 causa parada no ciclo celular no primeiro ponto de checagem (G1). Marcação por TUNEL revelou número significativamente maior de células em apoptose quando tumores de UM-PDX-HACC-5 foram tratados com MI-773 em comparação com controle (p<0.05) Utilizando o mesmo modelo de xenoenxerto, a técnica de imunohistoquímica mostrou que MI-773 não somente aumentou a porcentagem de células p53-positivas (p<0.001), como causou uma translocação parcial de p53 ao citoplasma. MI-773 reduz a fração de células-tronco tumorais (CTT) e previne recorrência do CAC. Tratamento com MI-773 como agente único ou combinado com cisplatina reduziu a fração de CTT (p<0.05). Notavelmente, nenhum animal tratado com regime neoadjuvante de MI-773 apresentou recorrência tumoral mesmo após 300 dias de acompanhamento. Em contraste, em 62,5% dos animais do grupo controle houve recorrência (p=0.0097). Conclusões: Em resumo, os estudos demonstram que a inibição terapêutica da interação MDM2-p53 com MI-773 é uma estratégia antitumoral eficaz, é capaz de sensibilizar tumores à cisplatina e previne recorrência neste modelo pré-clínico de CAC. Coletivamente, os dados sugerem que pacientes com carcinoma adenoide cístico podem ser beneficiados através de terapias-alvo contra MDM2. / Introduction: Adenoid cystic carcinoma (ACC) is one of the most common salivary gland malignancies for which no effective chemotherapy is available. An emerging concept in cancer therapy is to target specific tumor-related proteins. Murine double minute 2 (MDM2) is an important inhibitor of the tumor suppressor p53 and has been found overexpressed in ACC. Paper #1 aimed to evaluate the effect of a novel small molecule inhibitor of the MDM2-p53 interaction (MI-773) on ACC in vitro and in vivo. Paper #2 aimed to understand the role of combining MI-773 with cisplatin, and to evaluated ACC recurrence using a neoadjuvant regimen of MI-773. Material and Methods: 3 patient-derived xenograft (PDX) models (UM-PDX-HACC-5; ACCx6; ACCx9) and 5 low passage primary human ACC cells pools (UM-HACC-1, -2A, -2B, - 5, -6) were used for in vivo and in vitro experiments. Sulforhodamine B (SRB) assay was performed to evaluate the effect of experimental agents on ACC cell viability and to determine IC50 values. Western blots revealed the expression of p53, phosphop53, MDM2, p21, PUMA, BAX, Bcl-2 and Bcl-xL. Histological sections from UM-PDXHACC- 5 tumors were stained using immunohistochemistry and immunofluorescence techniques to determine p53 status. In situ TUNEL staining revealed the number of UM-PDX-HACC-5 cells undergoing apoptosis. Flow cytometry was carried out to determine the effect of therapy on the proportion of cancer stem cells (ALDHhighCD44high) and for cell cycle analysis. For in vivo studies, mice harboring UM-PDX-HACC5, ACCx6, or ACCx9 tumors were treated following specific therapeutic protocol (MI-773 – gavage; cisplatin – intraperitoneal injection; or vehicle control), as opportunely indicated. One-way ANOVA, followed by post-hoc tests (Tukey), Mann-Whitney U-test or Student’s t-test were used to determine significant differences in tumor growth, weight, volume, apoptosis levels, cell viability, TUNEL and p53 expression. Significance was determined at p<0.05. Results: MI-773 caused tumor regression in all ACC PDX models. Daily doses of 100 mg/kg MI- 773 significantly reduced tumor volume when compared to intermediate doses (10 or 50 mg/kg MI-773) or vehicle-treated controls in all ACC xenograft models. Alternatively, mice harboring UM-PDX-HACC-5 tumors received either weekly doses of MI-773 (200 mg/kg) and/or cisplatin (5 mg/kg) for 30 days, in order to evaluate the effect of this drug combination. MI-773 as single agent caused tumor regression, being more effective than single agent cisplatin. Cisplatin showed limited therapeutic response stabilizing tumor growth. Notably, combination of MI-773 with cisplatin was more effective than single agent therapies and no tumor rebound was observed during the follow up period. Importantly, experimental protocols did not compromise the overall health status of mice. Collectively, these in vivo results demonstrate that MI-773 mediates ACC tumor regression, and sensitizes ACC xenograft tumors to cisplatin. Therapeutic inhibition of the MDM2-p53 interaction activates p53 and induces apoptosis. MI-773 potently induced the expression of p53, its downstream target p21 and apoptosis-related proteins PUMA, BAX, Bcl-2 and Bcl-xL in vitro and in vivo. Cell cycle analysis showed that therapeutic inhibition of the MDM2-p53 interaction by MI-773 causes cell cycle arrest at the first checkpoint (G1). In situ TUNEL revealed a significant higher number of cells undergoing apoptosis in UMPDX- HACC-5 tumors treated with MI-773 compared to vehicle control (p<0.05). Using the same xenograft model, immunohistochemistry assay showed that MI-773 not only increased the percentage of p53-positive cells (p<0.001), but also caused a partial translocation of p53 to the cytoplasm. MI-773 reduces the fraction of cancer stem cells (CSC) and prevents recurrence in ACC. Treatment with MI-773 as single agent or combined with cisplatin significantly reduced the fraction of CSC (p<0.05). Notably, not a single animal treated with neoadjuvant MI-773 presented recurrence even after 300 days of follow-up. In contrast, 62,5% of mice that received vehicle control experienced tumor reappearance within this time period (p=0.0097). Conclusions: In summary, these studies demonstrate that therapeutic inhibition of the MDM2-p53 interaction with MI-773 is an effective anti-tumor strategy that mediates tumor regression, sensitizes tumors to cisplatin and prevents recurrence in this pre-clinical model of ACC. Collectively, these data suggest that patients with adenoid cystic carcinoma might benefit from MDM2-targeted therapies.

A fissura labiopalatina (FL/P) é uma das malformações craniofaciais mais comuns em humanos, com variação epidemiológica nas diferentes populações. Possui diferentes apresentações clínicas, divergindo de acordo com a extensão e estruturas acometidas, podendo acometer somente o lábio ou lábio e palato em conjunto, uni ou bilateralmente, de maneira completa ou incompleta ou apenas o palato (FP) tanto completa como incompletamente. Podem fazer parte de um quadro sindrômico, recebendo a denominação de FL/P sindrômica ou acontecer como um fenótipo isolado, sendo chamada de FL/P isolada ou não sindrômica. Em relação a etiologia da FL/P não sindrômica, a literatura afirma ser multifatorial com a predisposição genética associada a fatores ambientais. Apesar de se apresentarem frequentemente associadas, a FL/P e FP não sindrômicas são consideradas etiologicamente e embriologicamente distintas. Objetivo: Aprofundar e ampliar o conhecimento das FP isoladas não sindrômicas, descrevendo o fenótipo principal (FP isolada) e seus subfenótipos clínicos, investigando o fator genético relacionado à recorrência por meio do histórico familial e buscando elucidar possível fatores ambientais envolvidos por meio do histórico gestacional. Material e métodos: Foram coletados dados de 165 prontuários médicos de pacientes com FP isolada não sindrômica matriculados no Hospital de Reabilitação de Anomalias Craniofaciais da Universidade de São Paulo (HRAC-USP). Para a coleta desses dados foram analisados segmentos do prontuário referentes a atendimentos realizados no HRACUSP em diferentes setores. Resultados: Em 165 pacientes estudados, o sexo feminino foi o mais acometido com 106 casos (64,24%) encontrados. O tipo de FP predominante foi a incompleta correspondendo a 88,48% da amostra total, sendo dentre elas a fissura de palato duro parcial a mais prevalente. Em cinco casos não foi possível realizar a classificação nos grupos referentes ao tipo de fissura adotados, sendo necessária a criação de um grupo de classificação adicional. Recorrência familial positiva foi relatada em 28,47% de 144 casos em que havia informação, e na maioria das vezes havia apenas 1 outro familiar acometido. A média da idade das mães e dos pais no momento da concepção foi de 26,9 e 31,4 anos, respectivamente. A porcentagem de abortos anteriores foi de 11,95% dos 92 casos informados e a consanguinidade foi de 3,29% dos 91 casos informados. A intercorrência mais frequentemente relatada (25 em 154 casos informados) foi o uso de medicamentos, tais como, antibióticos, anti-hipertensivos e medicamentos que auxiliam na prevenção do parto prematuro. Conclusão: O fenótipo FP isolada possui variações quanto à extensão de cometimento, sendo que as fissuras incompletas foram as mais frequentes e o sexo feminino predominantemente acometido. Em relação ao histórico familial e gestacional os dados que mais chamaram atenção estão relacionados ao percentual de recorrência familial (28,47%) e o uso de medicação durante a gestação. / Cleft lip and palate (CL/P) is one of the most common craniofacial malformations in humans, with epidemiological variation in different populations. It has different clinical presentations that diverge according to the extension and affected structures, and may either affect the lip or lip and palate together, unilaterally or bilaterally, in a complete or incomplete way or just affect the palate (CP) completely or incompletely. CL/P can either be related to a syndrome, classified as syndromic CL/P or unrelated to a syndrome, occurring as an isolated phenotype, designated as isolated or nonsyndromic CL/P. Regarding the etiology of nonsyndromic CL/P, research indicates multifactorial causes with a genetic predisposition associated with environmental factors. Although it is often present in association, nonsyndromic CL/P and CP are considered embryologically and etiologically distinct. Objective: To deepen and broaden the knowledge of individual nonsyndromic CP, describing the main phenotype (isolated CP) and its clinical subphenotypes, investigating the genetic factors related to recurrence through family history and to elucidate possible environmental factors involving gestational history. Material and Methods: Data were collected from 165 medical patients records with isolated nonsyndromic CP enrolled at the Hospital de Reabilitação de Anomalias Craniofaciais da Universidade de São Paulo (HRAC-USP). For data collection, segments of the records pertaining to care provided by HRAC-USP in different sectors were analyzed. Results: In the 165 patients studied, females were the most affected with 106 cases (64.24%) found. The predominant type of CP was incomplete corresponding to 88.48% of the total sample, and among these incomplete CP, the clefts involving partial hard palate were the most prevalent. In five cases it was impossible to classify the type of cleft, and the creation of an additional classification group was required. Positive familial recurrence was reported in 28.47% of 144 cases where information was available and in most cases there was only one other affected family member. The average age of mothers and fathers at conception was 26.9 and 31.4 years respectively. The percentage of previous miscarriages was 11.95% of the 92 reported cases and consanguineous marriage was found in 3.29% of the 91 reported cases. The most frequently reported complication (25 in 154 reported cases) was the use of drugs such as antibiotics, antihypertensives drugs, and drugs used to prevent premature birth. Conclusion: The phenotype Isolated CP presents variations in the extent of involvement, and incomplete clefts were the most frequent, with females predominantly affected. Regarding family history and gestational data what calls more attention were the percentage of familial recurrence (28.47%) and the use of medication during pregnancy.

The public use version of the National Comorbidity Survey - Replication (NCS-R) dataset was used (N = 995) to investigate risk factors for recurrent major depressive disorder (MDD) that are evident before recovery from the first major depressive episode (MDE) by comparing persons diagnosed with MDD who experienced a single MDE to persons with recurrent MDD. Multiple logistic regression analyses assessed the independent risk of recurrent MDD for each of the following risk factors: an early age of onset (old), absence of a life stress trigger, chronic first episode, childhood parental loss, parental maltreatment, parental depression, comorbid anxiety disorder, and comorbid substance disorder. The relative excess risk due to interaction (RERI) assessed the risk of recurrent MDD associated with the interaction of an early onset with three childhood-based vulnerabilities: a) parental depression, b) parental loss, and c) parental maltreatment. There was a statistically significant risk of recurrent MDD found for the following risk factors: early onset, stress trigger absent, childhood parental loss, parental maltreatment, parental depression, and anxiety disorder; marginally significant results suggested an increased risk of recurrent MDD for substance disorder. There was a significant increased risk found for the interaction of an early onset with parental depression and similar non-significant trends were found for the interactions of early onset with parental loss and early onset with parental maltreatment. An early onset, the absence of a life stress trigger, and the presence of parental loss, parental maltreatment, parental depression, a comorbid anxiety disorder, and a comorbid substance disorder each confer greater risk of recurrent MDD among persons that have not yet recovered from their first lifetime MDE. The presence of an early onset combined with a childhood-based vulnerability such as parental depression, parental loss, or parental maltreatment, indicate an especially high risk of recurrent MDD. These findings may inform the development of a screening tool to assess risk for recurrent MDD and early intervention to prevent recurrent MDD. Future research should employ a longitudinal research design to replicate and expand upon these findings.

共著者あり。共著者名:Asaka Masahiro, Kudo Mineo, Sukegawa Makoto, Katagiri Masaki, Koshiyama Tatsumi, Kagaya Hidetoshi, Nishikawa Keiko, Hokari Kaku, Takeda Hiroshi, Sugiyama Toshiro. / Hokkaido University (北海道大学) / 博士 / 医学

Background - Current guidelines suggest that all cancer patients with venous thrombosis be treated with long-term low molecular weight heparin. Whether treatment strategies should vary according to clinical characteristics remains unknown. // Systematic review - A systematic review was performed to determine current understanding of the association between malignancy characteristics in patients with cancer-associated VTE and the risk of VTE recurrence. Four retrospective and 6 prospective studies were included. They suggest that lung cancer, metastases, and adenocarcinomas confer an increased the risk of recurrence and breast cancer a low risk. // Survey - I performed survey to evaluate thrombosis experts’ opinion about the low risk of VTE recurrence they would consider acceptable for patients with cancer- associated thrombosis 103 specialists participated. 80% of respondents agreed that a risk of recurrent VTE during anticoagulation below 7% is low enough. 92% agreed that a CPR that categorizes risk of recurrence is relevant. // Retrospective Study - I performed a single retrospective cohort study to assess the feasibility of derivation of a CPR that stratifies VTE recurrence risk in patients with cancer–associated thrombosis. The study included 543 patients. A multivariate analysis selected female, lung cancer and prior history of VTE as high risk predictors and breast cancer and stage I disease as low risk. // Conclusion - Patients with cancer-associated thrombosis do have varying risks of recurrent VTE depending on clinical characteristics.

Women with breast cancer without local metastasis to the axillary lymph nodes (axillary lymph node-negative, ANN) have a good prognosis. However, 20 to 30% of patients with ANN breast cancer will still experience recurrence and distant metastases. Lymphatic invasion (LVI) is an important prognostic factor for ANN breast cancer. Zinc fingers and homeoboxes 1 (ZHX1) was identified as a candidate gene involved in LVI and associated with early recurrence of ANN breast cancer. I examined expression of ZHX1 in breast cancer cell lines and ANN breast tumour samples and discovered that it is expressed at variable levels. I also investigated ZHX1 copy number and determined that amplification does not appear to be a mechanism of its over-expression. From bioinformatic and proteomic analyses, ZHX1 was discovered to potentially be phosphorylated. Overall, these studies suggest that ZHX1 may be involved in ANN breast cancer.

Women with breast cancer without local metastasis to the axillary lymph nodes (axillary lymph node-negative, ANN) have a good prognosis. However, 20 to 30% of patients with ANN breast cancer will still experience recurrence and distant metastases. Lymphatic invasion (LVI) is an important prognostic factor for ANN breast cancer. Zinc fingers and homeoboxes 1 (ZHX1) was identified as a candidate gene involved in LVI and associated with early recurrence of ANN breast cancer. I examined expression of ZHX1 in breast cancer cell lines and ANN breast tumour samples and discovered that it is expressed at variable levels. I also investigated ZHX1 copy number and determined that amplification does not appear to be a mechanism of its over-expression. From bioinformatic and proteomic analyses, ZHX1 was discovered to potentially be phosphorylated. Overall, these studies suggest that ZHX1 may be involved in ANN breast cancer.

Background - Current guidelines suggest that all cancer patients with venous thrombosis be treated with long-term low molecular weight heparin. Whether treatment strategies should vary according to clinical characteristics remains unknown. // Systematic review - A systematic review was performed to determine current understanding of the association between malignancy characteristics in patients with cancer-associated VTE and the risk of VTE recurrence. Four retrospective and 6 prospective studies were included. They suggest that lung cancer, metastases, and adenocarcinomas confer an increased the risk of recurrence and breast cancer a low risk. // Survey - I performed survey to evaluate thrombosis experts’ opinion about the low risk of VTE recurrence they would consider acceptable for patients with cancer- associated thrombosis 103 specialists participated. 80% of respondents agreed that a risk of recurrent VTE during anticoagulation below 7% is low enough. 92% agreed that a CPR that categorizes risk of recurrence is relevant. // Retrospective Study - I performed a single retrospective cohort study to assess the feasibility of derivation of a CPR that stratifies VTE recurrence risk in patients with cancer–associated thrombosis. The study included 543 patients. A multivariate analysis selected female, lung cancer and prior history of VTE as high risk predictors and breast cancer and stage I disease as low risk. // Conclusion - Patients with cancer-associated thrombosis do have varying risks of recurrent VTE depending on clinical characteristics.