KRD (carfilzomib and lenalidomide plus dexamethasone) for the treatment of relapsed or refractory multiple myeloma in the real-life: a retrospective survey in 123 patients.

From April 2016, carfilzomib, in combination with lenalidomide and dexamethasone (KRD), became available for use in the daily practice in Italy for patients with relapsed or refractory multiple myeloma (RRMM). We performed a retrospective survey at 14 different institutions from Southern Italy in order to evaluate patient characteristics and treatment results from an unselected series of patients treated accordingly so far. One hundred and twenty-three consecutive patients were included, with a median of 2 previous lines of therapy (range 1-9) and a median age of 63 years (range 39-82). At the time of analysis, median number of courses administered is 11 (range 1-34), and all patients are evaluable for response. Overall response rate including complete remission, very good partial remission, and partial remission is 85%. After a median follow-up of 27 months, median overall and progression-free survival are 33 and 23 months, respectively. Sixty-three patients are alive and between them, 45 (37%) are in continuous remission. Sixty patients have died (49%), mainly from progressive disease. There were 6 treatment-related deaths (5% of the whole patient population). Overall, hematological and non-hematological toxicity were manageable, mostly on outpatient basis. Arterial hypertension has been observed in 43 cases (35%) but did not lead to treatment interruption. Our data demonstrate that in real life, KRD is highly effective and well tolerated in the majority of patients with RRMM.

Cyberknife® system: a new therapeutic strategy for sinonasal solitary extramedullary plasmacytomae.

Sino-nasal solitary extramedullary plasmacytoma (EMP) is a rare neoplasm with unpredictable progression to multiple myeloma. To improve the precision of irradiation delivery, preserving the healthy surrounding tissue and critical structures we used a CyberKnife® for the treatment of sinonasal solitary extramedullary plasmacytoma. We present the first case of sinonasal-EMP treated with CyberKnife®-stereotactic radiotherapy (SRT) with a complete remission without adverse events. Based on the post-therapeutic results and healthy tissue preservation, we believe that CyberKnife®-SRT represents a good therapeutic option for the treatment of sinonasal-EMP.

First Report of 'Candidatus Liberibacter asiaticus' Associated with Huanglongbing in Sweet Orange in Ethiopia.

Huanglongbing (HLB) is a serious disease of citrus worldwide. Three different 'Candidatus Liberibacter' species are associated with HLB: 'Ca. Liberibacter asiaticus', 'Ca. L. africanus', and 'Ca. L. americanus' (1). 'Ca. L. africanus' and its vector, Trioza erytreae, are both heat sensitive, and when present, occur in citrus when temperatures remain below 30 to 32°C. In Africa, 'Ca. L. africanus' and T. erytreae have been reported in South Africa, Zimbabwe, Malawi, Burundi, Kenya, Somalia, Ethiopia, Cameroon, and Madagascar (1). Inspection of citrus trees in orchards and budwood sources in nurseries located in the warmer citrus-growing areas of Tigray and North Wollo in northern Ethiopia revealed nearly 100 trees with symptoms of leaf yellowing with a blotchy mottle pattern, dead branches, and decreased fruit quality and yield. Two symptomatic sweet orange budwood trees and three symptomatic orchard plants were sampled in April 2009, along with three healthy-looking sweet orange plants. DNA was extracted from 200 mg of desiccated leaf midribs using the CTAB method (4) and subjected to conventional PCR using the primer pairs A2/J5 (2) and OI2/23S1 (3) that amplify the ribosomal protein gene in the rplKAJL-rpoBC operon and the 16S/23S ribosomal intergenic regions, respectively, of 'Ca. L. africanus' and 'Ca. L. asiaticus'. Positive PCR reactions were obtained for all five symptomatic samples with both primer pairs. PCR amplicons of 703 bp (A2/J5) and 892 bp (OI2/23S) recovered from two of these samples were purified, cloned, and sequenced. BLAST analysis revealed that the nucleotide sequences we obtained for the ribosomal protein (GenBank Accessions Nos. GQ890155 and GQ890156) shared 100% identity with each other and 99% identity with sequences of 'Ca. L. asiaticus' from Brazil (DQ471904), Indonesia (AB480161), China (DQ157277), and Florida (CP001677). Similarly, the 16S/23S ribosomal intergenic sequences (GU296538 and GU296539) shared 100% identity with each other and 99% identity with homologous 'Ca. L. asiaticus' sequences from Brazil (DQ471903), Indonesia (AB480102), China (DQ778016), and Florida (CP001677) and contained two tRNA genes as occurs in 'Ca. L. asiaticus' but not in 'Ca. L. africanus' (3). To our knowledge, this is the first report of 'Ca. L. asiaticus' in Africa. The presence of 'Ca. L. asiaticus' is a threat for warmer citrus-growing areas of Africa that are less favorable for 'Ca. L. africanus' and T. erytreae. In areas where 'Ca. L. asiaticus' was confirmed, symptomatic trees must be promptly eradicated and surveys to determine spread of the disease and its vectors are necessary. References: (1) J. M. Bove. J. Plant Pathol. 88:7, 2006. (2) A. Hocquellet et al. Mol. Cell. Probes 13:373, 1999. (3) S. Jagoueix et al. Int. J. Syst. Bacteriol. 47:224, 1997. (4) M. G. Murray and W. F Thompson. Nucleic Acids Res. 8:4321, 1980.

Common antigen in meningioma-derived cell cultures.

Serums of patients with intracranial meningiomas reacted in immunofluorescence assays with cell cultures and tumor imprints prepared from human meningiomas. Antibody in these serums appears to be specific for antigens in meningioma tissue and shows some cross-reactivity with neoplastic tissue of glial origin.

Genital herpesvirus hominis type 2 infection: an experimental model in cebus monkeys.

Genital infection with herpesvirus hominis type 2 was established in ten female cebus monkeys. Clinical and laboratory findings in the cebus mimic closely those observed in humans, thus providing an experimental model which may be used in the study of the possible role of genital herpetic infection in cervical cancer and in perinatal and chronic neurological diseases.

Propranolol causes a paradoxical enhancement of cardiomyocyte foetal gene response to hypertrophic stimuli.

BACKGROUND AND PURPOSE: Pathological cardiac hypertrophy is associated with the expression of a gene profile reminiscent of foetal development. The non selective beta-adrenoceptor antagonist propranolol is able to blunt cardiomyocyte hypertrophic response in pressure-overloaded hearts. It remains to be determined whether propranolol also attenuates the expression of hypertrophy-associated foetal genes. EXPERIMENTAL APPROACH: To address this question, the foetal gene programme, of which atrial natriuretic peptide (ANP), the beta-isoform of myosin heavy chain (beta-MHC), and the alpha-skeletal muscle isoform of actin (skACT) are classical members, was induced by thoracic aortic coarctation (TAC) in C57BL/6 mice, or by phenylephrine, a selective alpha(1)-adrenoceptor agonist, in cultured rat neonatal cardiomyocytes. KEY RESULTS: In TAC mice, the left ventricular weight-to-body weight (LVW/BW) ratio increased by 35% after 2 weeks. Levels of ANP, beta-MHC and skACT mRNA in the left ventricles increased 2.2-fold, 2.0-fold and 12.1-fold, respectively, whereas alpha-MHC and SERCA mRNA levels decreased by approximately 50%. Although propranolol blunted cardiomyocyte growth, with approximately an 11% increase in the LVW/BW ratio, it enhanced the expression of ANP, beta-MHC and skACT genes (10.5-fold, 27.7-fold and 22.7-fold, respectively). Propranolol also enhanced phenylephrine-stimulated ANP and beta-MHC gene expression in cultured cardiomyocytes. Similar results were obtained with metoprolol, a selective beta(1)-adrenoceptor antagonist, but not with ICI 118551, a beta(2)-adrenoceptor antagonist. CONCLUSIONS AND IMPLICATIONS: Propranolol enhances expression of the hypertrophy-associated foetal genes mainly via the beta(1)-adrenoceptor blockade. Our results also suggest that, in pressure-overloaded hearts, cardiomyocyte growth and foetal gene expression occur as independent processes.

Superfluorinated and NIR-luminescent gold nanoclusters.

A novel class of superfluorinated and NIR-luminescent gold nanoclusters were obtained starting from a branched thiol, bearing 27 equivalent 19F atoms per molecule. These unprecedented clusters combine in a unique nanosystem both NIR photoluminescence and 19F NMR properties, thus representing a promising multimodal platform for bioimaging applications.

Autologous transplant vs oral chemotherapy and lenalidomide in newly diagnosed young myeloma patients: a pooled analysis.

In newly diagnosed myeloma patients, upfront autologous transplant (ASCT) prolongs progression-free survival 1 (PFS1) compared with chemotherapy plus lenalidomide (CC+R). Salvage ASCT at first relapse may still effectively rescue patients who did not receive upfront ASCT. To evaluate the long-term benefit of upfront ASCT vs CC+R and the impact of salvage ASCT in patients who received upfront CC+R, we conducted a pooled analysis of 2 phase III trials (RV-MM-209 and EMN-441). Primary endpoints were PFS1, progression-free survival 2 (PFS2), overall survival (OS). A total of 268 patients were randomized to 2 courses of melphalan 200 mg/m2 and ASCT (MEL200-ASCT) and 261 to CC+R. Median follow-up was 46 months. MEL200-ASCT significantly improved PFS1 (median: 42 vs 24 months, HR 0.53; P<0.001), PFS2 (4 years: 71 vs 54%, HR 0.53, P<0.001) and OS (4 years: 84 vs 70%, HR 0.51, P<0.001) compared with CC+R. The advantage was noticed in good and bad prognosis patients. Only 53% of patients relapsing from CC+R received ASCT at first relapse. Upfront ASCT significantly reduced the risk of death (HR 0.51; P=0.007) in comparison with salvage ASCT. In conclusion, these data confirm the role of upfront ASCT as the standard approach for all young myeloma patients.

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.

Trisomy 13 in a patient with leukemic progression of myelodysplasia.

Four months after the diagnosis of refractory anemia, a 60-year-old patient developed acute leukemia with blast cells that were poorly differentiated by morphology and clearly myeloid by immunophenotyping. Cytogenetic analysis performed at leukemization showed trisomy 13. An extra copy of chromosome 13 has already been reported in a few cases of acute leukemia and myelodysplastic syndrome.

Displaced intra-articular fractures of the distal aspect of the radius. Long-term results in young adults after open reduction and internal fixation.

The purpose of this retrospective study was to determine the long-term functional and radiographic outcomes in a series of young adults (less than forty-five years old) in whom an acute displaced intra-articular fracture of the distal aspect of the radius had been treated with operative reduction and stabilization. Twenty-six fractures in twenty-six patients met the initial inclusion criteria for the study. Twenty-one patients returned for a physical examination, imaging (plain radiographs and computerized tomography scans), and completion of a validated musculoskeletal function assessment questionnaire at a minimum of 5.5 years. The physical examinations were performed by the same observer, who was not involved in the initial care of the patients. The plain radiographs and computerized tomography scans were assessed in a blinded fashion by two independent observers who measured the radiographic parameters with standardized methods. At an average of 7.1 years, osteoarthrosis of the radiocarpal joint was evident on the plain radiographs and computerized tomography scans of sixteen (76 per cent) of the twenty-one wrists. A strong association was found between the development of osteoarthrosis of the radiocarpal joint and residual displacement of articular fragments at the time of osseous union (p < 0.01). However, the functional status at the time of the most recent follow-up, as determined by physical examination and on the basis of the responses on the questionnaire, did not correlate with the magnitude of the residual step and gap displacement at the time of fracture-healing. All patients had a good or excellent functional outcome irrespective of radiographic evidence of osteoarthrosis of the radiocarpal or the distal radio-ulnar joint or non-union of the ulnar styloid process. It appears prudent therefore to base the indications for salvage operative procedures on the presence of severe symptoms or a loss of function rather than on radiographic evidence of osteoarthrosis of the radiocarpal joint.

An anatomic classification of the ethmoidal bulla.

OBJECTIVE: The ethmoid bone is arguably the most complex and varied osseous structure in the human body. The partitions within form a unique labyrinth of lamellae and spaces from specimen to specimen or, as in this study, from patient to patient. The surgical anatomy of the ethmoid bone, and the ethmoidal bulla in particular, is ill-defined and heretofore largely unclassified. In an attempt to better understand the ethmoid labyrinth, a prospective anatomic study of 107 patients undergoing primary intranasal endoscopic ethmoidectomy was undertaken. STUDY DESIGN: Two hundred fourteen ethmoidal bullae were dissected intraoperatively with video-documentation obtained in over 90% of cases. Based on these dissections, the compartments or cells formed by the partitioning within the ethmoidal bulla and the respective communication with adjacent spaces were the parameters used to develop the classification system. SETTING: Private midwestern rhinologic referral practice. RESULTS: Three main categories of ethmoidal development were identified: simple, compound, and complex. Forty-seven percent of bullae were of the simple type, 26% were compound, and 27% complex. Sixty-eight percent of ethmoidal bullae had a single opening into the hiatus semilunaris superior; 6 (2.8%) ethmoidal bullae had a single anterior opening to the ethmoidal infundibulum. The remaining 28.7% had multiple cells with multiple openings, at least 1 of which opened into the hiatus semilunaris superior 98.4% of the time. There was a cell in the complex bulla opening anteriorly to the ethmoidal infundibulum in 46.5%. In 58% of cases, there was symmetry from side to side. CONCLUSION: A novel anatomic classification for the ethmoidal bulla is presented, with examples of the 3 types of sinus development encountered. We believe that understanding ethmoid sinus anatomy and potential drainage pathways is a core principle to functional sinus surgery.

Elevation of serum immunoglobulin M (IgM) level in patients with brain tumors.

Sera of 43 brain tumor patients were analyzed along with various other control groups for serum immunoglobulin, cold and sheep cell hemagglutinin and a heterophile type antibody. Serum IgM and heterophile antibody (non-Forssman type) were found elevated in brain tumor and various acute viral meningoencephalitis groups. Serum IgA and IgG levels were essentially unchanged. IgM levels appear to be particularly stimulated by the meningioma class because the removal of tumor from the host was accompanied by its return to normal range. This system of IgM measurement may prove to be a valuable tool in preliminary diagnosis of brain tumors.

Tc-99m sestamibi scintigraphy in multiple myeloma.

Tc-99m sestamibi imaging was performed in two patients with multiple myeloma. Focal areas of increased uptake in one patient and diffuse skeletal uptake in the second patient were found. Tc-99m sestamibi appears to identify bone marrow and osteolytic involvement in multiple myeloma.

Stem cell mobilization in patients with newly diagnosed multiple myeloma after lenalidomide induction therapy.

Lenalidomide has raised concerns regarding its potential impact on the ability to collect stem cells for autologous stem cell transplantation, especially after prolonged exposure. The use of cyclophosphamide plus granulocyte colony-stimulating factor (G-CSF) to mobilize peripheral blood stem cells may overcome this concern. In newly diagnosed multiple myeloma (MM) patients, we investigated the influence of lenalidomide on stem cell collection. In a prospective study, 346 patients received four cycles of lenalidomide-dexamethasone (Rd). Stem cells were mobilized with cyclophosphamide and G-CSF. Patients failing to collect a minimum of 4 × 10(6) CD34(+)/kg cells received a second mobilization course. After mobilization, a median yield of 8.7 × 10(6) CD34(+)/kg was obtained from patients receiving Rd induction. After first mobilization, inadequate yield was observed in 21% of patients, whereas only 9% of patients failed to collect the target yield after the second mobilization attempt. In conclusion, we confirm that a short induction with lenalidomide allowed sufficient stem cells collection to perform autologous transplantation in 91% of newly diagnosed patients.