AN ECONOMIC ANALYSIS OF THE ADDITION OF BEVACIZUMAB TO STANDARD CHEMOTHERAPY IN PATIENTS WITH MALIGNANT PLEURAL MESOTHELIOMA

Thesis (Master's)--University of Washington, 2016-08

Synchronous primary malignant tumors of the breast, caecum and sigma. Case report

We present the case of a patient with a double adenocarcinoma of the right colon and sigma associated with a bilateral infiltrating ductal breast carcinoma. Sigma and caecum bowel cancers were diagnosed at colonoscopy, with computerized tomography staging, while breast cancer was found with screening mammography. Following right hemicolectomy , sigmoidectomy and bilateral mastectomy the histology confirmed the presence of colonic adenocarcinoma and infiltrating and in situ lobular cancer. This case report reviews the treatment of synchronous neoplasia.

CYR61 and TAZ Upregulation and Focal Epithelial to Mesenchymal Transition May Be Early Predictors of Barrett’s Esophagus Malignant Progression

Barrett's esophagus is the major risk factor for esophageal adenocarcinoma. It has a low but non-neglectable risk, high surveillance costs and no reliable risk stratification markers. We sought to identify early biomarkers, predictive of Barrett's malignant progression, using a meta-analysis approach on gene expression data. This in silico strategy was followed by experimental validation in a cohort of patients with extended follow up from the Instituto Português de Oncologia de Lisboa de Francisco Gentil EPE (Portugal). Bioinformatics and systems biology approaches singled out two candidate predictive markers for Barrett's progression, CYR61 and TAZ. Although previously implicated in other malignancies and in epithelial-to-mesenchymal transition phenotypes, our experimental validation shows for the first time that CYR61 and TAZ have the potential to be predictive biomarkers for cancer progression. Experimental validation by reverse transcriptase quantitative PCR and immunohistochemistry confirmed the up-regulation of both genes in Barrett's samples associated with high-grade dysplasia/adenocarcinoma. In our cohort CYR61 and TAZ up-regulation ranged from one to ten years prior to progression to adenocarcinoma in Barrett's esophagus index samples. Finally, we found that CYR61 and TAZ over-expression is correlated with early focal signs of epithelial to mesenchymal transition. Our results highlight both CYR61 and TAZ genes as potential predictive biomarkers for stratification of the risk for development of adenocarcinoma and suggest a potential mechanistic route for Barrett's esophagus neoplastic progression.

TRIB2 in normal and malignant hematopoiesis - a transcription factor network

Hematopoiesis is the tightly controlled and complex process in which the entire blood system is formed and maintained by a rare pool of hematopoietic stem cells (HSCs), and its dysregulation results in the formation of leukaemia. TRIB2, a member of the Tribbles family of serine/threonine pseudokinases, has been implicated in a variety of cancers and is a potent murine oncogene that induces acute myeloid leukaemia (AML) in vivo via modulation of the essential myeloid transcription factor CCAAT-enhancer binding protein α (C/EBPα). C/EBPα, which is crucial for myeloid cell differentiation, is commonly dysregulated in a variety of cancers, including AML. Two isoforms of C/EBPα exist - the full-length p42 isoform, and the truncated oncogenic p30 isoform. TRIB2 has been shown to selectively degrade the p42 isoform of C/EBPα and induce p30 expression in AML. In this study, overexpression of the p30 isoform in a bone marrow transplant (BMT) leads to perturbation of myelopoiesis, and in the presence of physiological levels of p42, this oncogene exhibited weak transformative ability. It was also shown by BMT that despite their degradative relationship, expression of C/EBPα was essential for TRIB2 mediated leukaemia. A conditional mouse model was used to demonstrate that oncogenic p30 cooperates with TRIB2 to reduce disease latency, only in the presence of p42. At the molecular level, a ubiquitination assay was used to show that TRIB2 degrades p42 by K48-mediated proteasomal ubiquitination and was unable to ubiquitinate p30. Mutation of a critical lysine residue in the C-terminus of C/EBPα abrogated TRIB2 mediated C/EBPα ubiquitination suggesting that this site, which is frequently mutated in AML, is the site at which TRIB2 mediates its degradative effects. The TRIB2-C/EBPα axis was effectively targeted by proteasome inhibition. AML is a very difficult disease to target therapeutically due to the extensive array of chromosomal translocations and genetic aberrations that contribute to the disease. The cell from which a specific leukaemia arises, or leukaemia initiating cell (LIC), can affect the phenotype and chemotherapeutic response of the resultant disease. The LIC has been elucidated for some common oncogenes but it is unknown for TRIB2. The data presented in this thesis investigate the ability of the oncogene TRIB2 to transform hematopoietic stem and progenitor cells in vitro and in vivo. TRIB2 overexpression conferred in vitro serially replating ability to all stem and progenitor cells studied. Upon transplantation, only TRIB2 overexpressing HSCs and granulocyte/macrophage progenitors (GMPs) resulted in the generation of leukaemia in vivo. TRIB2 induced a mature myeloid leukaemia from the GMP, and a mixed lineage leukaemia from the HSC. As such the role of TRIB2 in steady state hematopoiesis was also explored using a Trib2-/- mouse and it was determined that loss of Trib2 had no effect on lineage distribution in the hematopoietic compartment under steady-state conditions. The process of hematopoiesis is controlled by a host of lineage restricted transcription factors. Recently members of the Nuclear Factor 1 family of transcription factors (NFIA, NFIB, NFIC and NFIX) have been implicated in hematopoiesis. Little is known about the role of NFIX in lineage determination. Here we describe a novel role for NFIX in lineage fate determination. In human and murine datasets the expression of Nfix was shown to decrease as cells differentiated along the lymphoid pathway. NFIX overexpression resulted in enhanced myelopoiesis in vivo and in vitro and a block in B cell development at the pre-pro-B cell stage. Loss of NFIX resulted in disruption of myeloid and lymphoid differentiation in vivo. These effects on stem and progenitor cell fate correlated with changes in the expression levels of key transcription factors involved in hematopoietic differentiation including a 15-fold increase in Cebpa expression in Nfix overexpressing cells. The data presented support a role for NFIX as an important transcription factor influencing hematopoietic lineage specification. The identification of NFIX as a novel transcription factor influencing lineage determination will lead to further study of its role in hematopoiesis, and contribute to a better understanding of the process of differentiation. Elucidating the relationship between TRIB2 and C/EBPα not only impacts on our understanding of the pathophysiology of AML but is also relevant in other cancer types including lung and liver cancer. Thus in summary, the data presented in this thesis provide important insights into key areas which will facilitate the development of future therapeutic approaches in cancer treatment.

Schwannoma of the Lower Leg with Malignant Transformation. A Case Report

Background: Peripheral nerve sheath tumours are benign or malignant. Schwannoma is a benign peripheral nerve sheath tumour originating from Schwann cells that slowly grows eccentrically to the nerve axis. Malignant transformation of a schwannoma is rare. Case presentation: A 73-year-old woman who presented to our medical service with other medical problems was diagnosed with a tumour of the lower leg (a small mass neglected by the patient for about 10 years). The ultrasound features of the tumour suggested it was a schwannoma. The tumour was resected and histopathological assessment revealed a schwannoma with areas of malignant peripheral nerve sheath tumour transformation.

More Than Just a Case of Polymyalgia Rheumatica

Malignant neoplasms are associated with a wide range of paraneoplastic rheumatological syndromes. These can be defined as remote effects of cancer, which are not caused by the tumor and its metastasis. The authors describe the case of an 82-year-old man, who presented with a one-month history of pain, stiffness, and functional limitation of the scapular and pelvic girdles. Blood tests showed raised levels of inflammatory markers. He was diagnosed with Polymyalgia Rheumatica, but the lack of response to corticosteroids led to the suspicion of an alternative diagnosis, like, for example, an occult neoplasm. Although patient evaluation was initially normal, five months later he developed macroscopic haematuria and was diagnosed with bladder and prostate carcinomas. After surgical treatment, the patient fully recovered from his rheumatological syndrome.

A Fatal Case of Neuroleptic Malignant Syndrome After Paralytic Bowel in a Patient Taking Antiparkinson Medication

Objectives: We report a fatal case of neuroleptic malignant-like syndrome, which occurred as a consequence of paralytic bowel in a 72-year-old woman on treatment with antiparkinson medication. Case description: Contrast enhanced computerized tomography of the chest and abdomen demonstrated the presence of paralytic bowel. Results: The patient died. Conclusions: Physicians involved in the treatment of patients affected by Parkinson’s disease should take into consideration the possibility of dopaminergic drug malabsorption due to paralytic bowel as a possible cause of neuroleptic malignant-like syndrome.

Malignant Otitis Externa and Stroke

Malignant otitis externa (MOE) is an aggressive but benign entity which evolves into skull base osteomyelitis. An 81-year-old female patient was admitted for left hemiparesis and homonymous hemianopia. She complained of headache radiating to the right cervical area. A recent history of recurrent otitis media was present. Head and neck imaging showed an ischemic infarction (right temporo-occipital) and a parapharyngeal soft tissue mass originating in an external and medial ear infection. Culture samples revealed Pseudomonas aeruginosa infection leading to the diagnosis of Malignant otitis externa (MOE). Parenteral antibacterial therapy and hyperbaric oxygen therapy resulted in improvement.

Superparamagnetic Liposomes for MRI Monitoring and External Magnetic Field-Induced Selective Targeting of Malignant Brain Tumors

International audience

Osteomyelitis of the maxilla in a patient with Malignant Infantile Osteopetrosis

Osteopetrosis is characterized by a considerable increase in bone density resulting in defective remodeling, caused by failure in the normal function of osteoclasts, and varies in severity. It is usually subdivided into three types: benign autosomal dominant osteopetrosis; intermediate autosomal recessive osteopetrosis; and malignant autosomal recessive infantile osteopetrosis, considered the most serious type. The authors describe a case of chronic osteomyelitis in the maxilla of a 6-year-old patient with Malignant Infantile Osteopetrosis. The treatment plan included pre-maxilla sequestrectomy and extraction of erupted upper teeth. No surgical procedure was shown to be the best to prevent the progression of oral infection. Taking into account the patient's general condition, if the patient develops severe symptomatic and refractory osteomyelitis surgery should be considered. The patient and his family are aware of the risks and benefits of surgery and its possible complications.

Algoritmo de abordagem das lesões anexiais indeterminadas na ecografia

O esclarecimento do órgão de origem, ou principalmente da natureza benigna ou maligna de um tumor anexial ecograficamente indeterminado surge com frequência na prática clínica e obriga a uma investigação complementar da sua natureza de modo a evitar cirurgias inúteis, sem deixar de diagnosticar precocemente a patologia maligna. Neste trabalho apresentamos um algoritmo de diagnóstico por Ressonância Magnética (RM), que recentemente foi proposto pela European Society of Urogenital Radiology (ESUR), o qual permite um diagnóstico preciso dos casos indeterminados à ecografia e uma intervenção responsável na abordagem clínica destas doentes.

Comparison of covered and uncovered self-expandable stents in the treatment of malignant biliary obstruction

Background and objective: Drainage with metallic stents is the treatment of choice in malignant obstructive jaundice. Technical and clinical success with metallic stents is obtained in over 90% and 80% of cases, respectively. There are self-expandable metallic stents designed to increase permeability. The aim of this study was to describe the results obtained with totally covered self-expandable and uncovered self-expandable metallic stents in the palliative treatment of malignant biliary obstruction. Patients and methods: Sixty eight patients with malignant obstructive jaundice secondary to pancreatobiliary or metastatic disease not amenable to surgery were retrospectively included. Two groups were created: group A (covered self-expandable metallic stents) (n = 22) and group B (uncovered self-expandable metallic stents) (n = 46). Results: Serum total bilirubin, direct bilirubin, alkaline phosphatase and gamma glutamyl transferase levels decreased in both groups and no statistically significant difference was detected (p = 0.800, p = 0.190, p = 0.743, p = 0.521). Migration was greater with covered stents but it was not statistically significant either (p = 0.101). Obstruction was greater in the group with uncovered stents but it was not statistically significant either (p = 0.476). Conclusion: There are no differences when using covered self-expandable stents or uncovered self-expandable stents in terms of technical and clinical success or complications in the palliative treatment of malignant obstructive jaundice.