Hemodynamic factors and atheromatic plaque rupture in the coronary arteries: from vulnerable plaque to vulnerable coronary segment

Coronary plaque disruption with superimposed thrombosis is the underlying pathology in the acute coronary syndromes and sudden death. Coronary plaques are constantly stressed by a variety of mechanical and hemodynamic forces that may precipitate or 'trigger' disruption of vulnerable or, at extreme conditions, even stable plaques. This paper reviews the exciting new evidence on the hemodynamic factors that may play a role in this process and provides the rationale for the introduction of the concept of the vulnerable coronary segment in the study of acute coronary syndromes.     

Overexpression of hUMP1/POMP proteasome accessory protein enhances proteasome-mediated antioxidant defence

The proteasome is the major cellular proteolytic machinery. It is involved in the regulation of various pathways via the selective degradation of either short-lived normal proteins or damaged proteins permitting the cellular detoxification. Proteasome has impaired function during several biological processes, including aging and diseases; however, it can be activated through overexpression of beta(5)- or beta(1)-subunits, resulting to enhanced survival and extended lifespan. In the current study, we have investigated proteasomal up-regulation via overexpression of hUMP1/POMP protein, the known accessory factor for proteasome assembly in humans. hUMP1/POMP overexpressing fibroblasts have increased levels of functional proteasome and enhanced capacity to cope better and faster with various oxidative stressors. These data highlight hUMP1/POMP role in proteasome assembly and further strengthen the prospect of genetic manipulation of the proteasomal system.     

Thalidomide in the treatment of multiple myeloma

Thalidomide--either alone or in combination with dexamethasone or chemotherapy--has shown significant activity in relapsed/refractory disease. When used in the induction regimens in untreated patients, it significantly increases the response rates as well progression-free survival. Moreover, thalidomide as a maintenance therapy has become a very attractive option. However, the toxicity profile of the drug, mainly neurotoxicity and thrombotic events, mandate careful monitoring of patients treated with thalidomide, whether as the first line, in the relapsed setting, or as maintenance. In this chapter we will review the pharmacology, mechanisms of action, and toxicity of the drug, and will focus on available data from clinical experience and randomized trials of thalidomide in the different settings of multiple myeloma: refractory/relapsed disease, upfront treatment in patients who are eligible for high-dose therapy as well as those who are not, and finally the use of thalidomide as a maintenance treatment.     

Peritoneal mesothelioma presenting as an acute surgical abdomen due to jejunal perforation

BACKGROUND: Peritoneal mesothelioma is a rare disease associated with poor prognosis. Acute abdomen as the first presentation is an extremely rare occurrence. We report an exceptional case of a patient who was found to have a jejunal perforation due to infiltration of peritoneal mesothelioma. METHODS: A 62-year-old man was admitted with clinical signs of peritonitis. Computerized tomographic scans showed a mass distal to the ligament of Treitz, thickening of the mesentery and a small amount of ascites. RESULTS: Emergency laparotomy revealed a perforated tumor 15 cm distal to the ligament of Treitz and diffuse peritoneal disease. Segmental small bowel resection and suboptimal cytoreduction were performed. Histopathology and immunohistochemistry showed infiltration of malignant mesothelioma. During the postoperative period pleural mesothelioma was also diagnosed. Despite adjuvant chemotherapy, the patient died of disseminated progressive disease 7 months after surgery. CONCLUSIONS: Peritoneal mesothelioma is a rare malignancy with grim prognosis. Small bowel involvement is a poor prognostic indicator. Our case of a small bowel perforation due to direct infiltration by peritoneal mesothelioma appears to be the first reported in the English literature.     

Therapy of the empyema thoracis. Why not thoracostoma?

Empyema toracis can be defined as a purulent pleural effusion. From 1998 to 2003 we treated 106 patients (87 men and 19 women), aged between 23 and 82 years, affected by localized empyema toracis. All of them received initially a chest tube and 73 of them (60 men and 13 women), in combination with selected antibiotics, had an uneventful recovery. Twenty three patients (17 men and 5 women) underwent thoracotomy and pleural decortication, and 7 patients (6 men and 1 woman) underwent open drainage, that means a thoracostoma. All these 7 patients were affected by chronic empyema: 3 of them with residual post-pneumectomy empyema (1 for lung cancer and 2 for tubercular lung disease); 3 had destroyed lung and 1 was suffering for multiorgan deficiency (respiratory, cardiac and chronic renal insufficiency). The thoracostoma procedure was under general tube anaesthesia with tracheal intubation. The mean surgical time was 26 minutes. The mean postoperative hospital stay was 10 days. In this period of time no death has been recorded or any kind of complication. Before the dismission all of them were teached with their familiars how to take care of the remaining thoracostoma. After the dismission all the patients were followed as outpatients for a variable period, for 14 and 36 months. During this period there were neither complications nor recidives, and all the patients have accepted the "thoracostoma" as a new way of life. Therefore thoracostoma appears as an acceptable, useful and no dangerous solution for the treatment of the chronic thoracic empyema.     

Comparative immunohistochemical analysis of aurora-A and aurora-B expression in human glioblastomas. Associations with proliferative activity and clinicopathological features

In the present study, we carried out a comparative immunohistochemical analysis of aurora-A and aurora-B expression in 40 patients with primary glioblastomas, and attempted to identify any associations with Ki-67 index and the patients’ clinical features. The impact of various treatment modalities and proliferative activity on patient outcome was also assessed.Immunohistochemistry was carried out using formalin-fixed and paraffin-embedded tissue sections.Aurora-A expression was higher in tumors with high Ki-67 expression (p=0.01) and was positively, though marginally, related to aurora-B expression (p=0.085). Aurora-B expression was not linked to Ki-67 expression (p=0.182). Lower aurora-A immunohistochemical expression, chemotherapy administration, and tumor localization in one lobe of the brain implied a greater probability of patient survival in univariate analysis (p=0.044, p=0.008, p=0.041, respectively). Ki-67 and aurora-B immunoreactivities were not associated with patient survival (p=0.918 and p=0.539, respectively).To our knowledge, for the first time, the association between aurora-A and aurora-B expression, the correlation of aurora-A with Ki-67 index, and the prognostic impact of aurora-A expression were assessed in glioblastomas. Although we addressed a prognostic connotation of aurora-A, we presume that aurora-A and aurora-B play a complicated role within glioblastomas. Further examinations of larger series are required, so that definite conclusions can be drawn.     

Masking and triggered unmasking of targeting ligands on nanocarriers to improve drug delivery to brain tumors

Long-circulating nanocarriers have been extensively studied to deliver chemotherapeutics; however, the inclusion of targeting agents compromises circulation times thereby offsetting the benefits of active targeting. Here, we formulated cysteine-cleavable phospholipid–polyethylene glycol (PEG) to ‘mask’ nanocarrier bound targeting ligands from RES clearance and prolong circulation times of liposomes to allow passive targeting to tumors. This detachable polymer coating can be removed after nanocarrier extravasation to tumor is achieved to expose targeting ligands and promote active targeting to tumor cells. In vivo studies on folate receptor-targeted liposomes demonstrated our ability to prolong circulation in the bloodstream using this system thereby verifying the ‘masking’ capacity of cleavable phospholipid–PEG₅₀₀₀. Controlled modulation of uptake and cytotoxicity of targeted nanocarriers using cleavable phospholipid–PEG was demonstrated through in vitro studies. Finally, studies analyzing uptake by tumor cells in vivo confirmed enhanced intracellular delivery when tumor-inoculated animals received targeted liposomes containing cleavable phospholipid–PEG₅₀₀₀ followed by a cysteine infusion to expose folate after liposomes had extravasated to tumor. These results indicate that cleavable phospholipid–PEG can be used in nanocarrier formulations for controlled exposure of targeting ligands to ensure that circulation times remain uncompromised by the inclusion of targeting agents while enabling active targeting to tumors after removal of the polymer coating.     

Prognostication of the high-risk WM patient

Waldenström's macroglobulinemia is characterized by a protracted course in most patients and the median survival may be long. However, a subset of patients may present with more aggressive disease that is associated with short survival. In order to better characterize these “poor-risk” patients, we identified patients who died within 2 years from the initiation of front-line treatment. These patients were older and had more often features of aggressive disease, such as elevated LDH and low serum albumin than the standard-risk population. Furthermore, only a minority of poor-risk patient had a response to initial therapy. However, conventional clinical factors or even the lack on response could not adequately identify poor-risk patients, indicating the need for novel molecular or other markers that would be able to effectively recognize patients at greatest need for aggressive therapies.