Clonal and subclonal TP53 molecular impairment is associated with prognosis and progression in multiple myeloma.

Aberrations on TP53, either as deletions of chromosome 17p (del17p) or mutations, are associated with poor outcome in multiple myeloma (MM), but conventional detection methods currently in use underestimate their incidence, hindering an optimal risk assessment and prognostication of MM patients. We have investigated the altered status of TP53 gene by SNPs array and sequencing techniques in a homogenous cohort of 143 newly diagnosed MM patients, evaluated both at diagnosis and at first relapse: single-hit on TP53 gene, either deletion or mutation, detected both at clonal and sub-clonal level, had a minor effect on outcomes. Conversely, the coexistence of both TP53 deletion and mutation, which defined the so-called double-hit patients, was associated with the worst clinical outcome (PFS: HR 3.34 [95% CI: 1.37-8.12] p = 0.008; OS: HR 3.47 [95% CI: 1.18-10.24] p = 0.02). Moreover, the analysis of longitudinal samples pointed out that TP53 allelic status might increase during the disease course. Notably, the acquisition of TP53 alterations at relapse dramatically worsened the clinical course of patients. Overall, our analyses showed these techniques to be highly sensitive to identify TP53 aberrations at sub-clonal level, emphasizing the poor prognosis associated with double-hit MM patients.

Opposite activation of the Hedgehog pathway in CD138+ plasma cells and CD138-CD19+ B cells identifies two subgroups of patients with multiple myeloma and different prognosis.

Hyperactivation of the Hedgehog (Hh) pathway, which controls refueling of multiple myeloma (MM) clones, might be critical to disease recurrence. Although several studies suggest the Hh pathway is activated in CD138- immature cells, differentiated CD138+ plasma cells might also be able to self-renew by producing themselves the Hh ligands. We studied the gene expression profiles of 126 newly diagnosed MM patients analyzed in both the CD138+ plasma cell fraction and CD138-CD19+ B-cell compartment. Results demonstrated that an Hh-gene signature was able to cluster patients in two subgroups characterized by the opposite Hh pathway expression in mature plasma cells and their precursors. Strikingly, patients characterized by Hh hyperactivation in plasma cells, but not in their B cells, displayed high genomic instability and an unfavorable outcome in terms of shorter progression-free survival (hazard ratio: 1.92; 95% confidence interval: 1.19-3.07) and overall survival (hazard ratio: 2.61; 95% confidence interval: 1.26-5.38). These results suggest that the mechanisms triggered by the Hh pathway ultimately led to identify a more indolent vs a more aggressive biological and clinical subtype of MM. Therefore, patient stratification according to their molecular background might help the fine-tuning of future clinical and therapeutic studies.

Current and emerging triplet combination therapies for relapsed and refractory multiple myeloma.

Despite significant improvement in outcomes have been observed for multiple myeloma (MM) patients over the past 10-15 years, mainly due to the introduction of novel agents targeting the tumor clone and the bone marrow microenvironment, treatment of refractory and/or relapsed (RR) disease remains a challenge, particularly for patients who have failed prior bortezomib- and lenalidomide-based therapies. More recently, new drugs with different mechanisms of action, including second generation proteasome inhibitors, third generation immunomodulatory drugs, histone deacetylase inhibitors and monoclonal antibodies, have been developed and are under investigation, further increasing treatment options for RRMM patients. Overall, novel agent-based triplet combinations demonstrated superior response rates and prolonged disease control when compared with two-drug regimens in several randomized clinical trials, without adding any relevant additional toxicity. Salvage triplet therapies are likely to play a key role in overcoming drug-resistance and hold promise to further improve long-term outcomes of RRMM patients.

18F-FDG PET/CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease.

Identification of patient sub-groups with smoldering multiple myeloma (SMM) at high risk of progression to active disease (MM) is an important goal. 18F-FDG PET/CT (positron emission tomography (PET) integrated with computed tomography (PET/CT) using glucose labelled with the positron-emitting radionuclide (18)F) allows for assessing early skeletal involvement. Identification of osteolytic lesions by this technique has recently been incorporated into the updated International Myeloma Working Group criteria for MM diagnosis. However, no data are available regarding the impact of focal lesions (FLs) without underlying osteolysis on time to progression (TTP) to MM. We hence prospectively studied a cohort of 120 SMM patients with PET/CT. PET/CT was positive in 16% of patients (1 FL: 8, 2 FLs: 3, >3 FLs: 6, diffuse bone marrow involvement: 2). With a median follow-up of 2.2 years, 38% of patients progressed to MM, in a median time of 4 years, including 21% with skeletal involvement. The risk of progression of those with positive PET/CT was 3.00 (95% confidence interval 1.58-5.69, P=0.001), with a median TTP of 1.1 versus 4.5 years for PET/CT-negative patients. The probability of progression within 2 years was 58% for positive versus 33% for negative patients. In conclusion, PET/CT positivity significantly increased the risk of progression of SMM to MM. PET/CT could become a new tool to define high-risk SMM.

Successful mobilization of PBSCs predicts favorable outcomes in multiple myeloma patients treated with novel agents and autologous transplantation.

Incorporation of novel agents into auto-SCT for patients with multiple myeloma has led to improvement in their outcomes. However, the effects of new drugs, either single or combined, on PBSC mobilization have not been fully evaluated, particularly in phase 3 clinical studies. We analyzed the impact of two novel agent-based induction treatments in patients enrolled in the GIMEMA MMY-3006 study comparing bortezomib, thalidomide and dexamethasone (VTD) versus thalidomide and dexamethasone (TD) in preparation for double auto-SCT. Results showed that a short-term induction therapy with VTD did not adversely affect CD34(+) cell yields as compared with TD (9.75 vs 10.76 × 10(6) CD34(+) cells/kg, P=0.220). For poor mobilizers (<4 × 10(6) CD34(+) cells/kg), 5-year rates of time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were significantly shorter than for successful mobilizers (TTP:17 vs 48%, P<0.0001; PFS: 16 vs 46%, P<0.0001; OS: 50 vs 80%, P<0.0001). These differences were retained across patients randomized to the TD arm; conversely, no differences in outcomes were seen in patients treated with VTD, irrespective of the number of harvested CD34(+) cells. The number of collected PBSCs predicted better outcomes after auto-SCT and VTD overcame the negative impact of a poor stem cell mobilization.

Role of consolidation therapy in transplant eligible multiple myeloma patients.

The role of high-dose therapy and autologous stem-cell transplantation (ASCT) in the treatment of multiple myeloma (MM) has continued to evolve in recent years. The novel agents thalidomide, bortezomib, and lenalidomide have been successfully incorporated into induction therapy in preparation for ASCT and are currently being investigated also as post-ASCT consolidation and maintenance therapy. Consolidation treatment is generally short term and aims to increase the frequency and depth of response obtained with the previous treatment phases, including novel agent-based induction therapy and ASCT. This review will focus on recent trials of novel agents as post-ASCT consolidation therapy, offering an overview of pros and cons of this new treatment strategy in the ASCT sequence for MM patients.

A study of unusual Rayleigh matches in deutan deficiency.

Rayleigh match data were modeled with the aim of explaining the locations of match midpoints and matching ranges, both in normal trichromats and in subjects with congenital color deficiency. Model parameters included the wavelength of peak sensitivity of cone photopigments, the effective photopigment optical density, and the noise amplitude in the red-green color channel. In order to avoid the suprathreshold, perceptual effects of extreme L:M cone ratios on color vision, selective post-receptoral amplification of cone signals is needed. The associated noise is also amplified and this causes corresponding changes in red-green threshold sensitivity. We propose that the noise amplitude and hence the size of the matching range in normal trichromats relates to the known inter-subject variation in the relative numbers of L and M cones. If this hypothesis can be shown to account for the extremes of the red-green matching range measured in normal trichromats, it is of interest to establish the extent to which it also predicts the unexpected, small matching ranges that are observed in some subjects with red-green color deficiency. A subset of subjects with deutan deficiency that exhibited less common Nagel matches were selected for genetic analysis of their cone pigment genes in order to confirm the type of deficiency, and to predict the corresponding peak wavelength separation (delta lambda(max)) of their two, long-wavelength cone pigments. The Rayleigh match model predicted accurately the midpoint and the range for the spectral differences specified by the genes. The prediction also required plausible selection of effective optical density of the cone pigments and noise. The noise needed varied, but the estimates were confined to lie within the limits established from the matching ranges measured in normal trichromats. The model predicts correctly the small matching ranges measured in some deuteranomalous subjects, principally accounted for by a low estimate of noise level in the red-green channel. The model also predicts the "normal" matches made by some subjects that rely on two hybrid genes and therefore exhibit red-green thresholds outside the normal range, typical of mild deuteranomaly.

Epidural analgesia for cephalic version: a randomized trial.

OBJECTIVE: To determine if epidural analgesia improves the success rate of external cephalic version. METHODS: Women with singleton fetuses in breech or transverse presentation of at least 37 weeks' gestation were offered enrollment in a randomized trial. Inclusion criteria included maternal age of 18 years or older, nonvertex presentation confirmed by ultrasound, intact membranes, reactive fetal nonstress test, and estimated fetal weight (EFW) between 2000 and 4000 g. Women in the epidural group had lumbar epidural catheters inserted, through which 2% lidocaine and 100 microg of fentanyl were infused. External cephalic version attempts were done with ultrasound guidance in a standard fashion for both groups. The primary outcome variable was the successful version of the fetus to a cephalic presentation. RESULTS: There were no statistically significant differences between groups in gestation at time of procedure, placental location, fetal lie, gravity, parity, EFW, or amniotic fluid index. External cephalic version was successful in 32 of 54 women (59%) with epidural anesthesia compared with 18 of 54 (33%) with no anesthesia (relative risk [RR] 1.8, 95% confidence interval [CI] 1.2, 2.8, P <.05). Vaginal delivery occurred in 29 of 54 women (54%) in the epidural group and 16 of 54 women (30%) in the control group (RR 1.9, 95% CI 1.2, 2.9, P <.05). CONCLUSION: Epidural analgesia increased the success rate of external cephalic version and the likelihood of subsequent vaginal delivery.

A prospective randomized trial of the use of epidural anesthesia during external cephalic version.

Objective: To determine if the use of epidural anesthesia improves the success rate of external cephalic version (ECV).Design: Women identified with a singleton fetus in a breech or transverse presentation at a gestational age of >/=37 weeks gestation were offered enrollment in this prospective randomized trial. Inclusion criteria included maternal age of 18 years or older, a non-vertex presentation confirmed by ultrasound, a reactive fetal non-stress test, and an estimated fetal weight of 2,000-4,000 g. A 1:1 randomization was accomplished through a computer-generated random numbers table with group assignments sealed in sequentially numbered opaque envelopes. Women in the epidural ECV group had a lumbar epidural catheter inserted through which 2% lidocaine and 100 µg of fentanyl were infused.Results: There were no statistically significant differences between the two groups in gestational age at ECV, placental location, fetal lie, gravidity or parity, estimated fetal weight, or amniotic fluid index. The ECV was successful in 26 of 45 (58%) women with epidural anesthesia compared to 16 of 48 (33%) with no anesthesia (relative risk 1.7, 95% confidence interval 1.1-2.8, P <.05). Fetal bradycardia resulting in discontinuation of the version efforts occurred in two patients in the epidural group and three women in the control population, a non-statistically significant difference. There were no maternal complications noted in the study population related to the epidural anesthesia.Conclusions: The use of epidural anesthesia increases the success rate of external cephalic version.

Absorption and retention of uranium from drinking water by rats and rabbits.

Uranium in the form of uranyl nitrate hexahydrate was administered in drinking water to Sprague-Dawley rats for periods of 28 and 91 d and New Zealand White rabbits for 91 d. The animals consumed food and water ad libitum. Subgroups of rabbits were followed for recovery periods of up to 91 d; 24-h collections of urine and feces were performed for some of the rabbits at various times during the exposure and recovery periods. At the end of the experiment, all animals were sacrificed and femur and kidney samples were analyzed for uranium residues. The results show that both rats and rabbits absorb about 0.06% of ingested uranium in the gastrointestinal (GI) tract. The distribution and retention of uranium in the skeleton and kidneys of rats are comparable to parameters reported for humans. The retention half-time in rabbit bone is substantially longer than for humans. The implications of extrapolating from animal data to effects on humans are discussed.