Rucaparib in the landscape of PARP inhibition in ovarian cancer

Introduction: The landscape of poly (ADP-ribose) polymerase (PARP) inhibition in ovarian cancer is rapidly evolving and becoming increasingly complex. Ovarian cancer is leading therapeutic innovation by providing the proof of concept for DNA repair as a target. Three different PARP inhibitors have now received approvals in the US and Europe in different indications. Subtle but crucial differences can be found among the licensed indications for each PARP inhibitor in terms of histology, type of BRCA mutation (germline and/or somatic), number of prior lines of chemotherapy and whether the indication is in the treatment or maintenance settings.

Areas covered: We review the latest clinical data regarding the PARP inhibitor rucaparib in ovarian cancer, provide an update on the evolving landscape of PARP inhibition in ovarian cancer, and summarize avenues of ongoing and future research.

Expert opinion: All eligible patients should be offered a PARP inhibitor. SOLO1 trial results demonstrated an unprecedented benefit maintenance with PARP inhibitors in first line. Results from trials evaluating PARP inhibitors as maintenance in first line regardless of BRCA status and from trials evaluating combinatorial strategies are eagerly awaited.     

Treatment strategies for hypertension in patients with type 1 diabetes

ABSTRACT

Introduction

Type 1 diabetes mellitus (T1DM) is a chronic, autoimmune disease that is characterized by total absence of insulin production. Hypertension is a common comorbidity in T1DM with complex pathophysiology, while it is also a well-recognized risk factor for the development of cardiovascular disease (CVD), as well as other microvascular diabetic complications.     

The vagal nerve as a link between the nervous and immune system in the instance of polymicrobial sepsis

Background The role of the vagal nerve in the autonomic nervous system is widely well known. Recently, an additional function was revealed serving as a connector between the nervous and immune system. This connection is called the “cholinergic inflammatory pathway.” Through stimulation of the acetylcholine receptors located upon the macrophages, the “unspecific” immune system can be directly influenced. Methods The vagal nerve was completely transected directly posterior to its passage through the diaphragm. The effect of complete vagotomy was analyzed using a murine model of polymicrobial peritonitis (colon ascendens stent peritonitis, CASP). Survival and clinical course of vagotomized or sham-operated mice were analyzed in the CASP model. Results After CASP surgery, vagotomy led to a significantly increased mortality (64.7%) in comparison to sham-vagotomized animals (34%). No difference in the bacterial load of various tissues (lung, liver, spleen, blood, lavage fluid, and kidney) from septic animals with or without vagotomy was observed. Vagotomized animals reveal elevated serum cytokine levels (TNF, IL-6, IL-10, and MCP-1) 20 h after the induction of polymicrobial peritonitis. Conclusion The vagal nerve is therefore an important modulator of the immune system. W. Kessler and T. Traeger contributed equally to this work Best of Forum Papers presented at the Annual Meeting of the German Society of Surgery, 2–5 May 2006, Berlin, Germany     

Significance of lung contusion in mortality following polytrauma. Possibilities for therapeutic influence

Multiple trauma is often associated with blunt thoracic injuries. Especially lung contusion can result in respiratory insufficiency and therefore a higher mortality rate. In our prospective study comparing 8 multiple trauma patients with and without associated lung contusion, we found that respiratory function was already significantly disturbed (decrease of paO2/FiO2 and increase of AaDO2, a rise in extravascular lung water (EVLW) both early after trauma and also with a second peak following the 4th day. This group (LK) developed significantly more cases of respiratory distress (ARDS). The disturbance of respiratory function seen initially was interpreted as a consequence of the direct mechanical impact, leading to the formation of interstitial fluid and hematoma. The frequent development of ARDS in the LK-group probably results from a pronounced activation of cellular and humoral mechanisms and therefore an enforced injury of the pulmonary capillary bed. A significant increase of pulmonary infections or the development of sepsis was not seen in the LK-group and is probably not responsible for the higher ARDS-rate in this group.     

Stent fracture: an unusual cause of late restenosis after sirolimus-eluting stent placement.

Stent fracture is uncommon but may have consequences including restenosis. To date, stent fractures reported have been related to aggressive post dilation. We describe a case that involves fracture of a stent deployed to nominal pressure. Unlike most stent fractures reported that involve stent struts only our case demonstrated circumferential disruption with complete separation of the stent segments.     

Intensivmedizin aus Sicht des Unfallchirurgen

Severe injuries in patients of all ages and injuries in elderly multi-morbid subjects are a relevant medical and economic challenge. Optimal care of the polytraumatized patient can be best delivered by physicians specializing both in causal treatment of the injury or underlying disease and in intensive care. For care of critically ill injured patients, trauma surgeons with a certified specialty in intensive care medicine appear best suited. Of course, directing a surgical or trauma intensive care unit has to be full-time. Specialization of trauma surgeons (e.g., in the USA) has resulted in a considerable improvement in outcomes at least partly related to specialized trauma intensive care. Further improvement of trauma care relies on competent and innovative research not only in the fields of general intensive care, e.g., ventilation, but particularly in the complex aspects of the causality of the traumatic disease. An integrative view of the pathobiochemical, pathophysiological, and immunopathological sequelae of severe trauma under consideration of the various surgical and therapeutic strategies is the actual focus of research in surgical critical care medicine. Organ dysfunctions have to be modulated as they develop. Surgeons and trauma surgeons lead worldwide in this field of research. Obviously, competent research in polytrauma care requires competence in polytrauma intensive care.     

Soluble transferrin receptors and tissue oxygenation in non anaemic cystic fibrosis patients.

BACKGROUND: Chronic pulmonary disease and progressive tissue hypoxia are major causes of morbidity and mortality in cystic fibrosis (CF). Normally the body adapts to tissue hypoxia by increasing the red cell mass and decreasing the Hb-O(2) affinity. These adaptations are commonly observed in patients with cyanotic heart disease and individuals living at high altitude. However, patients with CF not only have an impaired erythroid response to hypoxia, but also are frequently anaemic. METHODS: In order to evaluate erythroid marrow activity and tissue oxygenation in 37 patients with CF we measured: the haematological and blood chemistry parameters; including red cell indices, ferritin, erythropoietin (Epo) and soluble transferrin receptors (sTfR) levels; arterial blood gases, P(50) and oxygen release to the tissues (O(2)(R)) and the 2,3-BPG levels. RESULTS: The main results showed that a) patients with CF have a mild degree of tissue hypoxia which is expressed by the moderately decreased of P(50) and O(2)(R) values and the relative increase of Epo level, b) 2,3-BPG synthesis in patients with CF is normal and c) sTfR levels are significantly increased (3-fold normal) in patients with CF compared to normal controls. CONCLUSIONS: The above observations indicate that erythroid marrow activity in patients with CF is increased.     

The AIDS problem in accident surgery

In trauma surgery there is a particularly high proportion of patients in the age group most at risk of infection with AIDS. The result of an epidemiological study in our patients (HIV screening of all patients scheduled for surgery at a trauma center over 18 months) showed a prevalence of 0.1%. Specific therapeutic strategies must be developed to deal with the weakened immunity of HIV-infected patients. Fracture treatment in HIV-infected hemophiliacs is a special problem. Homogenous bone transplantation is described with reference to HIV. The particular danger of injury in trauma surgery is also investigated. The chain of infection is illustrated and used to demonstrate the precautions that can be taken against nosocomial HIV infections. Following infection with fluids containing HIV, specific measures must be taken. The legal aspects of HIV-antibody testing in the Federal Republic of Germany are elucidated. Finally, the problems of general preoperative HIV-antibody testing are discussed.