Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer

PURPOSE: To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC). METHODS:Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers. RESULTS:Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by (18)FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively).CONCLUSIONS:The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active

Biodiversity and the Functioning of Ecosystems in the Age of Global Change: Integrating Knowledge Across Scales

The dramatic decline of biodiversity worldwide has raised a general concern on the impacts this process could have for the well-being of humanity. Human societies strongly depend on the benefits provided by natural ecosystems, which are the result of biogeochemical processes governed by species activities and their interaction with abiotic compartments. After decades of experimental research on the biodiversity-functioning relationship, a relative agreement has been reached on the mechanisms underlying the impacts that biodiversity loss can have on ecosystem processes. However, a general consensus is still missing. We suggest that the reason preventing an integration of existing knowledge is the scale discrepancy between observations on global change impacts and biodiversity-functioning experiments. The present chapter provides an overview of global change impacts on biodiversity across various ecological scales and its consequences for ecosystem functioning, highlighting what is known and where knowledge gaps still persist. Furthermore, the reader will be introduced to a set of tools that allow a multi-scale analysis of how global change drivers impact ecosystem functioning

From micro‐ to macro‐structures in multiple sclerosis: what is the added value of diffusion imaging

Diffusion imaging has been instrumental in understanding damage to the central nervous system as a result of its sensitivity to microstructural changes. Clinical applications of diffusion imaging have grown exponentially over the past couple of decades in many neurological and neurodegenerative diseases, such as multiple sclerosis (MS). For several reasons, MS has been extensively researched using advanced neuroimaging techniques, which makes it an ‘example disease’ to illustrate the potential of diffusion imaging for clinical applications. In addition, MS pathology is characterized by several key processes competing with each other, such as inflammation, demyelination, remyelination, gliosis and axonal loss, enabling the specificity of diffusion to be challenged. In this review, we describe how diffusion imaging can be exploited to investigate micro‐, meso‐ and macro‐scale properties of the brain structure and discuss how they are affected by different pathological substrates. Conclusions from the literature are that larger studies are needed to confirm the exciting results from initial investigations before current trends in diffusion imaging can be translated to the neurology clinic. Also, for a comprehensive understanding of pathological processes, it is essential to take a multiple‐level approach, in which information at the micro‐, meso‐ and macroscopic scales is fully integrated

Transfusion of red blood cells from an HIV-RNA-positive/anti-HIV-negative donor without HIV infection in the recipient

More than 90 percent of recipients of HIV-1-containing blood components acquire HIV infection.1 We report the case of a recipient of red blood cells (RBCs), collected from an HIV-1-infected donor in the HIV-RNA positive/anti-HIV negative window phase, who did not develop HIV infection. In September 2004, HIV-1-specific antibodies(HIV1-2 Ab-Capture EIA, Ortho Diagnostic System,Raritan, NJ) and p24 antigen (Genescreen Plus HIV Ag-Ab, Bio-Rad Laboratories, Hercules, CA) were detected in a 44-year-old male blood donor who denied HIV-related risk behavior. The HIV-RNA assay (Cobas Amplicor HIV-1 Monitor Test, v. 1.5, Roche Diagnostics, Indianapolis, IA)confirmed HIV infection (56,000 copies/ml). Viral genotyping(AbbottViroseqTM HIV1 Genotyping SystemVersion 2.0, Abbott Molecular, Des Plaines, IL) showed an HIV-1 subtype B virus, not resistant to anti-retroviral medications. A routine blood donation 6 months earlier tested anti-HIV-negative. At that time, nucleic acid testing (NAT)for HIV was not performed in our Blood Service, and the components were released for transfusion. The RBCs were transfused 7 days after collection to the patient of this report. The plasma was transferred for processing(Kedrion, Lucca, Italy). Retrospectively, a sample that had been retained from this donation tested positive for HIVRNA(98 copies/mL). However, a sample retained from a blood donation on December 22, 2003, tested repeatedly HIV-RNA negative. Notice of the HIV-infected plasma unit was communicated immediately to Kedrion and to the recipient, a 54-year-old woman who had laparoscopic surgery. She has remained negative for HIV\u2013RNA, p24Ag and anti-HIV when tested at 6, 12, and 14 months after transfusion. In vitro studies showed that the recipient\u2019s peripheral blood mononuclear cells (PBMCs) could be infected with the donor\u2019s HIV isolate. The recipient was genotyped by PCR as wild-type CCR5. Because exposure to HIV in the absence of seroconversion can be inferred by the detection of HIV-specific T lymphocytes,2,3 an in-depth immunologic analysis on the recipient was performed 14 months after the RBCs transfusion. Recipient\u2019s PBMCs were stimulated with pools of antigens from env and gag regions of HIV. A higher than normal percentage of env-specific, IL-2-expressing CD4+ T lymphocytes (0.9%) was observed, whereas neither envspecific CD8+ nor gag-specific CD4+ or CD8+ T lymphocytes were detected. Na\uefve (CCR7+/CD45RA+), as well as central (CCR7+/CD45RA-) and effector (CCR7-/CD45RA-)memory CD4+ and CD8+ T lymphocytes, were measured. Both CD4+ and CD8+ na\uefve lymphocytes were reduced(11.3% vs. 23.4% and 10.1% vs. 22.2%) whereas CD8+ terminally-differentiated lymphocytes were augmented(22.7% vs. 7.0%) compared to results obtained in sex- and age-matched controls. These results strongly suggest that exposure to HIV antigens in the absence of replicating virus occurred in this patient. Thus, only actual infection with live and replicating virus would result in presentation of viral antigens in association with HLA class Imolecules, and elicitation of a CD8-mediated immune response. Additionally, responses to env, but not to gag, would be detected in the case of exposure toviral antigens in the absence of viral replication within the host cells. Finally, the observation that na\uefve cells were decreased in this patient is suggestive of a massive antigenic exposure, possibly HIV antigen-driven. Of importance, the donor\u2019s HIV isolate was able to infect the recipient\u2019s PBMCs and a CCR5D32 deletion was not present in either the donor or the recipient. Other investigators have reported cases illustrating that blood components may differ in their ability to transmit HIV infection.1,4 In one report, platelets from an HIVpositive donor transmitted infection, while RBCs from the same blood collection did not.5 There are several possible explanations for exposure to HIV without infection,including: 1) the presence of a low viral load at the time of donation; 2) a sub-infective volume of plasma in the RBCs; 3) loss of infectivity during storage of the component before transfusion; and 4) recipient\u2019s resistance related to genetic background (other than the CCR5D32 deletion,which was not present in our patient). We believe that our results indicate that the presence of a strong cell-mediated immune response, possibly secondary to the exposure to a low amount of HIV, plays a role in resistance to HIV infection

Different Levels of Exhaled Nasal Nitric Oxide in Patients Diagnosed with Primary Dyskinesia

Background:Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormally beating cilia. In&nbsp; these patients levels of nasal nitric oxide (nNO) are lower than those observed in healthy subjects.&nbsp; Objectives:We recorded the nNO levels in PCD patients in order to use those nNO measurements in the screening and identification of patients with symptoms suggestive of disease PCD disease.Methods:We measured nasal NO in 36 PCD patients (3 uncooperative younger children and 33 cooperative adult patients) and did a nNO re-evaluation after 12 months in patients with higher levels of nNO.Results:Twenty-seven PCD patients showed very low nNO levels (29.1 ppb) and nine cooperative patients had high nNO levels (583.3 ppb, p&lt;0.001) (T0); the PCD patients with high nNO levels were re-evaluated after 12 months (T1). The median T0 and T1 nNO values of the seven PCD patients were 360 ppb and 324&nbsp; ppb(p=0.0180), respectively; in 6 patients with high levels of nNO the diagnosis of PCD was confirmed byelectron microscopy, and in one subject the diagnosis was confirmed for secondary ciliary dyskinesia.Conclusions:Low levels of&nbsp; nNO remain&nbsp; indicative of&nbsp; PCD&nbsp; disease; high levels of nNO are supportive of PCD, but cannot be used to exclude diagnosis.These results suggest that repeated measures are warranted when nNO is occasionally high inpatients with symptoms suggestive of PCD disease, and at present electron microscopy is still the only valid evaluation tool in unclear cases of PCD.</p

Screening mammography interpretation test: more frequent mistakes.

To present the mammographic cases most commonly misinterpreted by the participants in the mammography self-test proposed by the Italian Society of Medical Radiology (SIRM) National Congress in Rimini, Italy, 2002, by analysing the findings responsible for errors, suggesting reasons for the errors, and assessing possible inadequacies in the format of the test.The self-test was performed on the mammograms of 160 cases (32 positive and 128 negative for cancer as confirmed by histology). The mammograms had been taken in the four standard projections and placed on four multi-panel diaphanoscopes, each displaying a set of 40 cases comprising benign and malignant cases in equal proportions. The participants were given pre-printed forms on which to note down their diagnostic judgement. We evaluated a total of 134 fully-completed forms. Among these, we identified the 23 cases most frequently misread by over 15 participants in percentages varying between 40-90\%. Of these cases, 10 were malignancies and 13 were negative mammograms. On review, we also assessed the diagnostic contribution of complementary investigations (not available the participants).The 134 fully-completed forms (all of the 40 cases) yielded a total of 5360 responses, 1180 of which (22.01\%) were incorrect. Of these, 823 out of the 4288 cases expected to be negative (19.2\%) were false positive, and 357 out of the 1072 cases expected to be positive (33.3\%) were false negative. As regards the 23 most frequently misread cases, these were 10/32 (31.25\%) mammograms positive for malignancy and 13/128 (10.15\%) negative mammograms or mammograms showing benign disease. The 10 malignancies included 7 infiltrating ductal carcinomas, 1 infiltrating cribriform carcinoma, 1 infiltrating tubular carcinoma, and 1 carcinoma in situ. The 13 cases of benign disease--as established by histology or long-term follow-up--mistaken for malignancies by the test participants were fibrocystic breast disease in 5 cases, surgical scar in 1 case, ABBI scar in 1 case, radial scar in 2 cases, microcalcifications that had remained stable for years in 2 cases, focal sclero-adenosis in 1 case and sclero-elastosis in 1 case.The errors were due to microcalcifications, benign disease simulating a neoplasm, overlapping tissue, visibility of a lesion in one projection only, lesion site in relation to the corpus mammae, missed areas of asymmetry. Attention must be paid to these signs of focal breast disease since, if correctly evaluated, they enable the early diagnosis of low-grade carcinomas that frequently carry a favourable prognosis

Accuracy of mammography and echography versus clinical palpation in the assessment of response to primary chemotherapy in breast cancer patients with operable disease.

The response to primary chemotherapy is an important prognostic factor in patients with non metastatic breast cancer. In this study we compared the assessment of response performed by clinical palpation to that performed by echography and mammography in 141 out of 157 consecutive breast cancer patients (T2-4, N0-1, M0) submitted to primary chemotherapy. A low relationship was recorded between tumor size assessed clinically and that evaluated by either mammography: Spearman R = 0.38 or echography: R = 0.24, while a greater correlation was found between the tumor dimension obtained by the two imaging techniques (R = 0.62). According to the WHO criteria, the grade of response of breast cancer to primary chemotherapy, showed by mammography and echography, was less marked than the grade of response seen at clinical examination. Residual tumor size assessed clinically depicted a stronger correlation with pathological findings (R = 0.68) than the residual disease assessed by echography (R = 0.29) and mammography (R = 0.33). Post-chemotherapy histology evaluation revealed pathological complete response in three cases (2.1%). Two of these cases were judged as complete responders by clinical palpation but only one was recognized by mammography, and none by echography. Clinical response, but not the response obtained by the two imaging techniques, was a significant predictor for longer disease free survival (p = 0.04). To conclude, physical examination measurements remain the method of choice in evaluating preoperatively the disease response in trials of primary chemotherapy. Prediction of pathological outcome is not improved by echography and mammography