A randomized phase II study of sorafenib/gemcitabine or sorafenib/erlotinib for advanced non-small-cell lung cancer in elderly patients or patients with a performance status of 2: treatment rationale and protocol dynamics

Herein, we present a randomized phase II trial enrolling elderly patients or patients with a performance status (PS) of 2 affected by advanced non-small-cell lung cancer to receive, as first-line therapy, sorafenib/gemcitabine or sorafenib/erlotinib. The primary objective is 1-year survival, and secondary objectives include activity, toxicity, and overall survival. An additional secondary objective will be to evaluate biomarkers. Sample size is calculated on the basis of theory of selection. The study will enroll 100 patients: 58 patients aged >or= 70 years with a PS of 0-2 and 42 patients aged < 70 years with a PS of 2. The analysis will be conducted differently for the 2 groups of patients.     

Spatial patterns of matrix protein expression in dilated ascending aorta with aortic regurgitation: congenital bicuspid valve versus Marfan's syndrome

BACKGROUND AND AIM OF THE STUDY: Aortic wall stress has been shown to increase locally at the convex aspect of the ascending tract when axial root motion is increased, as occurs in aortic valve regurgitation. The study aim was to assess the expression of extracellular matrix (ECM) proteins involved in stress-induced vascular remodeling in the convexity and the concavity of dilated ascending aortas with aortic valve regurgitation. METHODS: Aortic wall specimens, harvested at the convexity and concavity of eight dilated ascending aortas with severe aortic valve regurgitation underwent morphometry, Western blot, RT-PCR and confocal immunohistochemistry. Five patients (group A) had congenital bicuspid aortic valve (BAV), and three (group B) had Marfan's syndrome. Specimens from the aorta of three multi-organ donors served as controls. RESULTS: At morphometry, medial degeneration was more severe in the convexity than in the concavity, especially in group A. Western blot, RT-PCR and immunohistochemistry disclosed an asymmetric pattern in the expression of some ECM proteins (laminin, tenascin, fibronectin). Fibronectin was increased in the convexity of both groups compared to controls at Western blot. Immunohistochemistry confirmed this pattern only in BAV. Higher levels of tenascin were found in the convexity in group A. The laminin content was greater in the concavity than in the convexity of both groups, but in group B the type of laminin was different, with the beta2 chain particularly expressed, and almost absent in non-Marfan patients. Type I and type III collagens were more markedly reduced in the convexity than in the concavity in BAV. In group B, type I collagen was decreased and type III increased, but without any significant difference between the two aspects of the aorta. CONCLUSION: A tissue remodeling response to valve disease-related wall stress may underlie aortic dilatation with BAV regurgitation. Although morphometry showed similar changes in Marfan aortas, molecular investigations differentiated this condition, qualitatively, from BAV.     

Laboratory medicine in the 2000s: programmed death or rebirth?

Changes have occurred in the organization, complexity and role of medical laboratories in healthcare, requiring a great increase in global productivity and diagnostic efficiency by enrolled professionals to withstand new challenges. Such a radical evolution, which should be very attractive for new generations of professionals, is counterbalanced by an increasing shortage of laboratory vocations worldwide, particularly in community hospital and large reference laboratories, which may lead to a serious crisis in the field of laboratory medicine in the very near future. Some reasons can be highlighted, including the decreased interaction between clinicians and laboratory professionals, centralized testing, and the development of innovative, minimally invasive techniques that can easily be handled without direct control or supervision by laboratory staff. The prospect of a professional decline in laboratory medicine can be offset by increased awareness of the radical changes occurring within clinical laboratories and re-professionalization of laboratory scientists. This will require new resources to attract young professionals, and should include reaffirmation of the role of laboratory consultants and active participation in the development, implementation and monitoring of innovative diagnostic systems. The "patient" appears to be in a serious condition; it is in our hands to let him be reborn.     

Comparison of platelet function between sedentary individuals and competitive athletes at rest

Background

For patients with a normal coagulation system, who experience serious bleeding, sound evidence for recombinant activated factor VII (rFVIIa) as an effective haemostatic agent is only scarcely available so far from controlled clinical trials. In systematic reviews on the clinical use of rFVIIa, treatment failures were only rarely reported.

Case presentation

We present a 45-year old, Caucasian male with persistent intestinal bleeding due to enterocolitis associated with cytomegalovirus infection and acute graft-versus-host-disease. He had received allogeneic peripheral blood stem cell transplantation from an unrelated HLA-identical donor because of chronic myelogenous leukaemia diagnosed two years earlier. Bleeding started at day 18 after transplantation with bloody diarrhea, which was treated with multiple transfusions of fresh frozen plasma, platelet, and red blood cell concentrates, and continued relentlessly, despite all efforts, including continued transfusions, high-dose prednisolone, broad antibiotic and antiviral coverage, and tranexamic acid. Recombinant FVIIa was started at boluses of 90–120 μg/kg every 4–8 hours. Despite more than 10 doses, recurrent severe bleeding progressed to refractory shock, multiorgan failure and death.

Conclusions

Little can be concluded from single case reports of clinical improvement, because publication bias in favour of positive effects is likely. Our case suggests that rFVIIa is not a panacea, in particular for severe bleeding after bone-marrow transplantation. As long as rigorous, controlled studies or comprehensive registries are lacking, conventional interventions remain the standard of care in non-haemophilic patients with severe bleeding.     

Plasma D-dimer concentration in patients with systemic sclerosis

Background

Systemic sclerosis (SSc) is an autoimmune disorder of the connective tissue characterized by widespread vascular lesions and fibrosis. Little is known so far on the activation of the hemostatic and fibrinolytic systems in SSc, and most preliminary evidences are discordant.

Methods

To verify whether SSc patients might display a prothrombotic condition, plasma D-dimer was assessed in 28 consecutive SSc patients and in 33 control subjects, matched for age, sex and environmental habit.

Results and discussion

When compared to healthy controls, geometric mean and 95% confidence interval (IC95%) of plasma D-dimer were significantly increased in SSc patients (362 ng/mL, IC 95%: 361–363 ng/mL vs 229 ng/mL, IC95%: 228–231 ng/mL, p = 0.005). After stratifying SSc patients according to disease subset, no significant differences were observed between those with limited cutaneous pattern and controls, whereas patients with diffuse cutaneous pattern displayed substantially increased values. No correlation was found between plasma D-dimer concentration and age, sex, autoantibody pattern, serum creatinine, erythrosedimentation rate, nailfold videocapillaroscopic pattern and pulmonary involvement.

Conclusion

We demonstrated that SSc patients with diffuse subset are characterized by increased plasma D-dimer values, reflecting a potential activation of both the hemostatic and fibrinolytic cascades, which might finally predispose these patients to thrombotic complications.     

Specific polymorphisms of cytokine genes are associated with different risks to develop single-system or multi-system childhood Langerhans cell histiocytosis

Cytokines and chemokines determine mobilisation of Langerhans cells and their dysregulation is implicated in the pathogenesis of Langerhans cell histiocytosis (LCH). Twenty point mutations of 12 different cytokine genes were studied in 41 Italian children, 15 with single-system (SS) and 26 with multi-system disease. The allele and genotype distributions of interleukin-4 (IL-4) and interferon-gamma (IFNgamma) were significantly different in patients vs. 140 controls (P = 0.007, and P = 0.018). Older children with single-system disease shared the 'anti-inflammatory profile' determined by the intermediate producer genotype IFNgamma +874A/T (P = 0.029) and the high-producer genotypes IL-4 -590C/T and T/T (P = 0.029). Our findings suggest that specific cytokine gene variants affect susceptibility to LCH and its clinical heterogeneity.     

Estimation of bulky lymph nodes by power Doppler ultrasound scanning in patients with Hodgkin's lymphoma: a prospective study

The accuracy of standard methods in estimating bulky lesions requires validation. We used clinical/computed tomography (CT) evaluation and power Doppler ultrasound (US) to detect bulky disease in 137 consecutive Hodgkin's lymphoma patients, and analyzed the prognostic relevance of each method. Bulky disease was detected by clinical/CT evaluation in 47% of the patients and by power Doppler US in 20%. After treatment, at multivariate analysis power Doppler US-selected bulky disease was the parameter that best correlated with freedom from treatment failure (p<0.001). Power Doppler US, a readily available imaging technique, provides a better prognostic classification by detecting true bulky disease more accurately.     

Impact of occult hepatitis B virus infection in HIV patients naive for antiretroviral therapy

OBJECTIVE: To study the impact of occult hepatitis B virus (HBV) infection in 115 consecutive anti-HIV-positive, hepatitis B surface antigen-negative patients, naive for antiretroviral treatment. METHODS: Of these 115, 86 patients were followed for at least 6 months (range 6-36) with serial determinations of HIV RNA and HBV DNA by polymerase chain reaction and other laboratory tests. RESULTS: Of the 86 patients having a follow-up, plasma HBV DNA was detected in 17 (19.8%), 13 on admission and four during follow-up. HBV DNA was more frequently found in patients with isolated anti-hepatitis B core (HBc; 35.5% of 31 cases) than in those lacking anti-HBc and anti-hepatitis B surface (8.8% of 41, P < 0.005), or showing both (21.4% of 14). Twenty-eight patients (32.5%) experienced a hepatic flare during the follow-up; this event was more frequent in the 17 HBV-DNA-positive patients than in the 69 negative (64.7% versus 24.6%, P < 0.005). Of the 13 HBV-DNA-positive patients on admission, 11 receiving HAART containing lamivudine became HBV-DNA negative, but two of these again became positive and experienced a hepatic flare during treatment and two both during and after lamivudine treatment. A hepatic flare also occurred under lamivudine treatment in two of the four patients in whom HBV DNA became detectable during follow-up. The role of immune reconstitution inflammatory syndrome and HAART in inducing a hepatic flare was found to be marginal in 49 patients with no HBV or hepatitis C virus marker. CONCLUSION: The study suggests that HBV occult infection, relatively frequent in anti-HIV-positive patients, is associated with hepatic flares.