Mantle cell lymphoma accounts for 6% of all B-cell lymphomas and is generally incurable. It is characterized by the translocation t(11;14) leading to cyclin D1 over-expression. Cyclin D1 is ...downstream of the mammalian target of rapamycin threonine kinase and can be effectively blocked by mammalian target of rapamycin inhibitors. We set out to examine the single agent activity of the orally available mammalian target of rapamycin inhibitor everolimus in a prospective, multicenter trial in patients with relapsed or refractory mantle cell lymphoma (NCT00516412).
Eligible patients who had received a maximum of three prior lines of chemotherapy were given everolimus 10 mg for 28 days (one cycle) for a total of six cycles or until disease progression. The primary endpoint was the best objective response. Adverse reactions, progression-free survival and molecular response were secondary endpoints.
Thirty-six patients (35 evaluable) were enrolled and treatment was generally well tolerated with Common Terminology Criteria grade ≥ 3 adverse events (>5%) including anemia (11%), thrombocytopenia (11%) and neutropenia (8%). The overall response rate was 20% (95% CI: 8-37%) with two complete remissions and five partial responses; 49% of the patients had stable disease. At a median follow-up of 6 months, the median progression-free survival was 5.5 months (95% CI: 2.8-8.2) overall and 17.0 (6.4-23.3) months for 18 patients who received six or more cycles of treatment. Three patients achieved a lasting complete molecular response, as assessed by polymerase chain reaction analysis of peripheral blood.
Everolimus as a single agent is well tolerated and has anti-lymphoma activity in relapsed or refractory mantle cell lymphoma. Further studies of everolimus in combination with chemotherapy or as a single agent for maintenance treatment are warranted.
In recent years the employment of implantable medical devices has increased remarkably, notwithstanding that microbial infections are a frequent complication associated with their use. Different ...strategies have been attempted to overcome this problem, including the incorporation of antimicrobial agents into the device itself. In this study a new approach to obtain intrinsically antimicrobial materials was developed. Polymer anionomers containing Ag(I), Cu(II), Zn(II), Al(III) and Fe(III) were prepared by neutralization of a carboxylated polyurethane. In the case of the PEUA-Ag, PEUA-Fe and PEUA-Cu ionomers the ion aggregates behaved as reinforcing filler particles, increasing the mechanical properties of the systems in terms of hardness and strength at break over the pristine carboxylated polymer. With the exception of the Al-containing polymer, all the other experimented ionomers showed satisfactory antimicrobial properties. The best antibacterial effect was obtained with the silver ion-containing polymer, which inhibited
Staphylococcus epidermidis growth for up to 16
days. Ciprofloxacin was also adsorbed onto the above mentioned ionomers. A synergistic effect of the antibiotic and silver ions on bacterial growth inhibition was observed for at least 25
days.
The sensitivity of lymph node core-needle biopsy under imaging guidance requires validation. We employed power Doppler ultrasonography (PDUS) to select the lymph node most suspected of malignancy and ...to histologically characterize it through the use of large cutting needle. Institutional review board approval and informed consent were obtained for this randomized clinical trial. In a single center between 1 January 2009 and 31 December 2015, patients with lymph node enlargement suspected for lymphoma were randomly assigned (1:1) to biopsy with either standard surgery or PDUS-guided 16-gauge modified Menghini needle. The primary endpoint was the superiority of sensitivity for the diagnosis of malignancy for core-needle cutting biopsy (CNCB). Secondary endpoints were times to biopsy, complications, and costs. A total of 376 patients were randomized into the two arms and received allocated biopsy. However, four patients undergoing CNCB were excluded for inadequate samples; thus, 372 patients were analyzed. Sensitivity for the detection of malignancy was significantly better for PDUS-guided CNCB 98.8%; 95% confidence interval (CI), 95.9–99.9 than standard biopsy (88.7%; 95% CI, 82.9–93;
P
< 0.001). For all secondary endpoints, the comparison was significantly disadvantageous for conventional approach. In particular, estimated cost per biopsy performed with standard surgery was 24-fold higher compared with that performed with CNCB. The presence of satellite enlarged reactive and/or necrotic lymph nodes may impair the success of an open surgical biopsy (OSB). PDUS and CNCB with adequate gauge are diagnostic tools that enable effective, safe, fast, and low-cost routine biopsy for patients with suspected lymphoma, avoiding psychological and physical pain of an unnecessary surgical intervention.
BACKGROUND AND OBJECTIVES--Autonomic dysfunction seems to be involved in the progression and prognosis of severe congestive heart failure. Parasympathetic activity can still be abnormal 4-8 weeks ...after haemodynamic improvement by heart transplantation. To identify patients in heart failure with a more pronounced neural derangement and to analyse the changes in sympathetic and parasympathetic activity soon after heart transplantation, spectral indices of heart rate variability were assessed in 30 patients in severe heart failure and in 13 patients after heart transplantation; a group of 15 age-matched subjects served as controls. METHODS AND RESULTS--Heart rate variability was assessed by standard electrocardiography (ECG) in patients in heart failure and by oesophageal ECG in patients after heart transplantation. Compared with controls, the mean RR interval and total power were reduced in heart failure. The 30 patients showed two different patterns of heart rate variability: in 14 no power was detected in the low frequency band (0.03-0.15 Hz) (LF) and total power was mainly concentrated in the high frequency band (0.15-0.45 Hz) (HF), whereas in the remaining 16 patients power in the LF band was increased and power in HF band was reduced compared with the controls. Patients with undetectable LF had a lower mean RR interval and total power (745(25) v 864(36) ms, p < 0.05; 118(16) v 902(202) ms2, p < 0.001), higher concentration of plasma noradrenaline (635(75) v 329(54) pg/ml, p < 0.05), and worse clinical status and prognosis (4 deaths v no deaths at 6 month follow up) than patients with a dominant LF band. In the post-transplant patients both the mean PP interval of the remnant atrium and total power resembled results in the patients with heart failure; in 7 of the 13 post-transplant patients no power was detectable in the LF band: when both HF and LF power were present the results resembled those in the 16 patients in heart failure. CONCLUSIONS--These data suggest that in more advanced stages of congestive heart failure, power spectral analysis of heart rate variability allows identification of a subgroup of patients with higher sympathetic activation and poorer clinical status who are at major risk of adverse events. In the short term after cardiac transplantation the spectral profile of the rhythm variability of the remnant atrium was not improved, suggesting that parasympathetic withdrawal and sympathetic hyperactivity persist, despite the restoration of ventricular function.
The functional activity of the organic cation transporter 1 (OCT-1) protein (OCT-1 activity) is an excellent predictor of molecular response and progression-free survival in patients with newly ...diagnosed chronic phase chronic myeloid leukemia treated with imatinib as front-line therapy.
In this study the predictive value of OCT-1 activity in patients treated with imatinib 400 mg/day or 800 mg/day was evaluated in relation to trough imatinib plasma levels assessed in 100 patients enrolled in the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial.
The rate of major molecular responses by 24 months in patients on imatinib 400 mg/day was significantly higher in those with high OCT-1 activity than in those with low OCT-1 activity (low OCT-1 activity, 57% of patients; high OCT-1 activity, 100%; P < 0.001); the corresponding difference in patients treated with imatinib 800 mg/day did not reach statistical significance (low OCT-1 activity, 68%; high OCT-1 activity, 95%; P = 0.073). In addition, the combination of low trough imatinib levels (< 1200 ng/mL) and low OCT-1 activity defined a group of patients who had the lowest rates of major molecular response (47%) by 24 months compared to all other patients (81%, P = 0.009). These patients were also at the highest risk of failed imatinib therapy when compared to all other patients (P<0.001).
High-dose imatinib leads to superior molecular responses in patients with low OCT-1 activity. In this group trough imatinib levels may define a group with inferior outcomes. Among patients with high OCT-1 activity, neither higher imatinib dose nor monitoring imatinib trough levels was found to be of significant clinical value. Hence OCT-1 activity determined prior to the start of therapy in newly diagnosed CML patients provides a valuable prognostic tool to determine the optimal up-front dose of imatinib in patients with newly diagnosed chronic phase chronic myeloid leukemia.
The autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is an entity that includes different autoimmune conditions observed after exposure to an adjuvant. Patients with undifferentiated ...connective tissue disease (UCTD) present many signs and symptoms of ASIA, alluding to the idea that an exposure to adjuvants can be a trigger also for UCTD. The aim of this case-control study was to investigate exposure to adjuvants prior to disease onset in patients affected by UCTD. Ninety-two UCTD patients and 92 age- and sex-matched controls with no malignancy, chronic infections, autoimmune disease nor family history of autoimmune diseases were investigated for exposure to adjuvants. An ad hoc-created questionnaire exploring the exposure to vaccinations, foreign materials and environmental and occupational exposures was administered to both cases and controls. Autoantibodies were also analyzed (anti-nuclear, anti-extractable nuclear antigens, anti-double-stranded DNA, anti-cardiolipin, anti-β2 glycoprotein I). UCTD patients displayed a greater exposure to HBV (
p
= 0.018) and tetanus toxoid (
p
< 0.001) vaccinations, metal implants (
p
< 0.001), cigarette smoking (
p
= 0.006) and pollution due to metallurgic factories and foundries (
p
= 0.048) as compared to controls. UCTD patients exposed to major ASIA triggers (vaccinations, silicone implants) (
n
= 49) presented more frequently with chronic fatigue (
p
< 0.001), general weakness (
p
= 0.011), irritable bowel syndrome (
p
= 0.033) and a family history for autoimmunity (
p
= 0.018) in comparison to non-exposed UCTDs. ASIA and UCTD can be considered as related entities in the “mosaic of autoimmunity”: the genetic predisposition and the environmental exposure to adjuvants elicit a common clinical phenotype characterized by signs and symptoms of systemic autoimmunity.
Preliminary results using rituximab in extranodal marginal zone (MALT) non-Hodgkin's lymphoma (NHL) patients seem to indicate a relevant clinical activity. Aim of the present study is to investigate ...the efficacy of conventional weekly treatment using rituximab in gastric MALT NHL patients resistant/refractory or not suitable for eradication treatment, and to evaluate the relevance of the t(11; 18)(q21; q21) translocation and its possible role as a predictive criteria of response.
Twenty-seven patients presenting with gastric MALT NHL at any stage, relapsed/refractory to initial treatment or not suitable for eradication were treated with rituximab in a weekly conventional schedule and evaluated for response and relapse. Flourescence in situ hybridization (FISH) analysis for the presence of 18q21 translocation was performed in 21 patients and was evaluated with clinical outcome.
Among the 26 evaluated patients, 20 (77%) achieved an objective response. Twelve patients (46%) had a pathological and clinical complete remission, and eight (31%) had a partial response. With a median follow-up of 33 months, only two patients relapsed at 26 and 14 months, respectively. No correlation was founded between FISH analysis and response or relapse.
Our experience seems to confirm the clinical activity of rituximab in gastric MALT NHL patients resistant/refractory to antibiotics treatment or not presenting with clinical evidence of Helicobacter pylori infection. The t(11; 18)(q21; q21) translocation seems not to be a predictive marker to response or to subsequent relapse.
Hypothesis/Gap Statement.
The impacts of increased biomarker testing on antifungal prescribing have not yet been fully examined in a real-life setting.
Objectives.
Biomarkers for invasive fungal ...disease (IFD) have been shown to reduce antifungal prescriptions in neutropaenic haemato-oncology patients. Our study aimed to assess the real-life impacts of introducing a novel biomarker-based pathway, incorporating serum galactomannan and
Aspergillus
PCR, for pyrexial haemato-oncology admissions.
Methods.
Patients with neutropaenic fever were identified prospectively after introduction of the new pathway from 2013–2015. A historical group of neutropaenic patients who had blood cultures taken from 2009–2012 was generated for comparison. Clinical details, including demographics, underlying diagnosis, investigations, radiology and antimicrobial treatment were obtained.
Results.
Prospective data from 308 patients were compared to retrospective data from 302 patients. The proportion of patients prescribed an antifungal medication was unchanged by the pathway (
P
=0.79), but the pattern was different, with more patients receiving targeted antifungals (
P
=0.04). A negative serum galactomannan test was not sufficient evidence to withhold therapy, with 17.2% of these episodes felt to have possible or probable IFD using the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. There was no difference in 30-day mortality (
P
=0.21) or 1-year mortality (
P
=0.57) following introduction of the pathway.
Conclusions.
Biomarkers can be used safely as part of a multidisciplinary approach to the diagnosis of IFD in neutropaenic haemato-oncology patients. Whilst they do not necessarily result in antifungal therapy being withheld, they can allow more confident diagnosis of IFD and more specific antifungal therapy in selected cases.
Context.
In metric theories of gravity with photon number conservation, the luminosity and angular diameter distances are related via the Etherington relation, also known as the distance duality ...relation (DDR). A violation of this relation would rule out the standard cosmological paradigm and point to the presence of new physics.
Aims.
We quantify the ability of
Euclid
, in combination with contemporary surveys, to improve the current constraints on deviations from the DDR in the redshift range 0 <
z
< 1.6.
Methods.
We start with an analysis of the latest available data, improving previously reported constraints by a factor of 2.5. We then present a detailed analysis of simulated
Euclid
and external data products, using both standard parametric methods (relying on phenomenological descriptions of possible DDR violations) and a machine learning reconstruction using genetic algorithms.
Results.
We find that for parametric methods
Euclid
can (in combination with external probes) improve current constraints by approximately a factor of six, while for non-parametric methods
Euclid
can improve current constraints by a factor of three.
Conclusions.
Our results highlight the importance of surveys like
Euclid
in accurately testing the pillars of the current cosmological paradigm and constraining physics beyond the standard cosmological model.
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