Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma.

We report follow-up results from the randomized, placebo-controlled, phase 3 HELIOS trial of ibrutinib+bendamustine and rituximab (BR) for previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without deletion 17p. Overall, 578 patients were randomized 1:1 to either ibrutinib (420 mg daily) or placebo, in combination with 6 cycles of BR, followed by ibrutinib or placebo alone. Median follow-up was 34.8 months (range: 0.1-45.8). Investigator-assessed median progression-free survival (PFS) was not reached for ibrutinib+BR, versus 14.3 months for placebo+BR (hazard ratio [HR] [95% CI], 0.206 [0.159-0.265]; P < 0.0001); 36-month PFS rates were 68.0% versus 13.9%, respectively. The results are consistent with the primary analysis findings (HR = 0.203, as assessed by independent review committee, with 17-month median follow-up). Median overall survival was not reached in either arm; HR (95% CI) for ibrutinib+BR versus placebo: 0.652 (0.454-0.935; P = 0.019). Minimal residual disease (MRD)-negative response rates were 26.3% for ibrutinib+BR and 6.2% for placebo+BR (P < 0.0001). Incidence of treatment-emergent adverse events (including grades 3-4) were generally consistent with the initial HELIOS report. These long-term data support improved survival outcomes and deepening responses with ibrutinib+BR compared with BR in relapsed CLL/SLL.

Synergistic effect of Si-hydroxyapatite coating and VEGF adsorption on Ti6Al4V-ELI scaffolds for bone regeneration in an osteoporotic bone environment.

The osteogenic and angiogenic responses to metal macroporous scaffolds coated with silicon substituted hydroxyapatite (SiHA) and decorated with vascular endothelial growth factor (VEGF) have been evaluated in vitro and in vivo. Ti6Al4V-ELI scaffolds were prepared by electron beam melting and subsequently coated with Ca10(PO4)5.6(SiO4)0.4(OH)1.6 following a dip coating method. In vitro studies demonstrated that SiHA stimulates the proliferation of MC3T3-E1 pre-osteoblastic cells, whereas the adsorption of VEGF stimulates the proliferation of EC2 mature endothelial cells. In vivo studies were carried out in an osteoporotic sheep model, evidencing that only the simultaneous presence of both components led to a significant increase of new tissue formation in osteoporotic bone. STATEMENT OF SIGNIFICANCE: Reconstruction of bones after severe trauma or tumors extirpation is one of the most challenging tasks in the field of orthopedic surgery. This scenario is even more complicated in the case of osteoporotic patients, since their bone regeneration capability is decreased. In this work we present a porous implant that promotes bone regeneration even in osteoporotic bone. By coating the implant with osteogenic bioceramics such as silicon substituted hydroxyapatite and subsequent adsorption of vascular endothelial growth factor, these implants stimulate the bone ingrowth when they are implanted in osteoporotic sheep.

Interimplant femoral fractures: risk factors, treatment and evolution. / Fracturas interimplante de fémur: factores de riesgo, tratamiento y evolución.

OBJECTIVE: The aim of this study is to determine the risk factors involved in the development of these fractures and analyze the treatments used as well as their influence on the clinical and functional prognosis of patients. MATERIALS AND METHODS: We made an observational, retrospective case-control study, with a sample of 38 patients (40 femoral bones) operated in our hospital, who had two femoral ipsilateral implants, proximal and distal. We found 10 cases of interimplant fracture and 28 patients who had not suffered a fracture (2 of them had bilateral implants). We analyzed the influence of different variables, such as age, gender, comorbidities, radiological variables, type of treatments employed, clinical evolution, etc. RESULTS: the female sex was predominant in both groups, 80.7 was the average age. Osteoporosis was statistically significant (P=.007) for the development of these fractures. We did not find statistical significance in the radiological variables. Surgical treatment was the most frequent, and the plate of osteosynthesis the most employed option. We found a death rate of 40% at 4 years. Although all fractures healed, the survivors' ambulation ability was reduced. CONCLUSIONS: interimplant fractures are predominant in elderly women. Osteoporosis is a statistically significant risk factor. Despite optimal treatment and fracture healing, functional outcomes were decreased. Specific classification systems and therapeutic algorithms are necessary to improve the management and prognosis of these patients.

FDG-PET/CT in the management of lymphomas: current status and future directions.

FDG-PET/CT is the current state-of-the-art imaging in lymphoma and plays a central role in treatment decisions. At diagnosis, accurate staging is crucial for appropriate therapy selection: FDG-PET/CT can identify areas of lymphoma missed by CT alone and avoid under-treatment of patients with advanced disease stage who would have been misclassified as having limited stage disease by CT. Particularly in Hodgkin lymphoma, positive interim FDG-PET/CT scans are adversely prognostic for clinical outcomes and can inform PET-adapted treatment strategies, but such data are less consistent in diffuse large B-cell lymphoma. The use of quantitative FDG-PET/CT metrics using metabolic tumour volume, possibly in combination with other biomarkers, may better define prognostic subgroups and thus facilitate better treatment selection. After chemotherapy, FDG-PET/CT response is predictive of outcome and may identify a subgroup who benefit from consolidative radiotherapy. Novel therapies, in particular immunotherapies, exhibit different response patterns than conventional chemotherapy, which has led to modified response criteria that take into account the risk of transient pseudo-progression. In relapsed lymphoma, FDG-PET/CT after second-line therapy and prior to high-dose therapy is also strongly associated with outcome and may be used to guide intensity of salvage therapy in relapsed Hodgkin lymphoma. Currently, FDG-PET/CT has no role in the routine follow-up after complete metabolic response to therapy, but it remains a powerful tool for excluding relapse if patients develop clinical features suggestive of disease relapse. In conclusion, FDG-PET/CT plays major roles in the various phases of management of lymphoma and constitutes a step towards the pursuit of personalized treatment.

Observation as the initial management strategy in patients with mantle cell lymphoma.

BACKGROUND: Patients with mantle cell lymphoma (MCL) follow a heterogeneous clinical course. While they generally require treatment initiation shortly after diagnosis, it is unclear whether deferring treatment in selected patients with an indolent clinical behavior affects their overall outcome. PATIENTS AND METHODS: In this population-based study, all patients diagnosed with MCL during 1998-2014 were identified in the British Columbia Cancer Agency Lymphoid Cancer Database. The associations between clinico-pathologic characteristics, including the expression of Ki67, SOX11, and TP53, and time to treatment (TtT) and OS were analyzed. RESULTS: A total of 440 patients with MCL were evaluated: 365 (83%) received early treatment and 75 (17%) were observed ≥3 months. In the observation group, 54 (72%) patients had a nodal presentation, 16 (21%) a non-nodal presentation, and 5 (7%) had only gastrointestinal involvement. Characteristics associated with deferred treatment included good performance status, no B symptoms, low LDH, non-bulky disease, non-blastoid morphology, and lower Ki67 values. The median TtT in the observation group was 35 months (range 5-79), and 60 (80%) patients were observed beyond 12 months. The median OS was significantly longer in the observation group than in the early treatment group (72 versus 52.5 months, respectively, P = 0.041). In multivariable analysis, treatment decision was not associated with OS [HR 0.804 (95% CI 0.529-1.221), P = 0.306]. CONCLUSIONS: A subgroup of patients with MCL may be safely observed from diagnosis without negatively impacting their outcomes, including patients with non-nodal presentation as well as asymptomatic patients with low burden nodal presentation and a low proliferative rate.

Complete Genome Sequences of Zika Virus Strains Isolated from the Blood of Patients in Thailand in 2014 and the Philippines in 2012.

Here, we present the complete genome sequences of two Zika virus (ZIKV) strains, Zika virus/Homo sapiens-tc/THA/2014/SV0127-14 and Zika virus/H. sapiens-tc/PHL/2012/CPC-0740, isolated from the blood of patients collected in Thailand, 2014, and the Philippines, 2012, respectively. Sequencing and phylogenetic analysis showed that both strains belong to the Asian lineage.

The value of routine bone marrow biopsy in patients with diffuse large B-cell lymphoma staged with PET/CT: a Danish-Canadian study.

BACKGROUND: The added diagnostic and prognostic value of routine bone marrow biopsy (BMB) in patients with diffuse large B-cell lymphoma (DLBCL) undergoing positron emission tomography combined with computed tomography (PET/CT) staging is controversial. PATIENTS AND METHODS: Patients with newly diagnosed DLBCL who underwent both staging PET/CT and BMB were retrospectively identified in British Columbia, Aalborg, and Copenhagen. Original written PET/CT and pathology reports were retrospectively reviewed to determine Ann Arbor stage and outcomes, with and without the contribution of BMB. RESULTS: A total of 530 patients were identified: 146 (28%) had focal bone marrow (BM) lesions on PET/CT and 87 (16%) had positive BMB. Fifty-two of 146 patients (36%) with positive PET/CT had a positive BMB [39 DLBCL, 13 indolent non-Hodgkin lymphoma (iNHL)], while 35 of 384 patients (9%) with negative PET/CT had positive BMB (12 DLBCL, 23 iNHL). BMB upstaged 12/209 (6%) of stage I/II patients to stage IV, although this was the case for only 3 (1%) patients with DLBCL in the BMB. PET/CT identified BM involvement by BMB with sensitivity 60%, specificity 79%, positive predictive value 36%, and negative predictive value 91%. Concordant histological involvement of the BM by DLBCL was associated with worse overall survival and progression-free survival than discordant or no involvement in univariate and multivariate analyses. CONCLUSIONS: In patients with DLBCL, staging PET/CT can miss BM involvement with concordant DLBCL (less common) or discordant iNHL (more common). Routine BMB does not add relevant diagnostic or prognostic value over PET/CT alone in the majority of patients with DLBCL.

Outcome of patients with primary refractory diffuse large B cell lymphoma after R-CHOP treatment.

Primary refractory diffuse large B cell lymphoma (DLBCL) following R-CHOP chemotherapy is a major concern. We identified 1126 patients with DLBCL treated with R-CHOP from 2000 to 2009, of whom 166 (15 %) had primary refractory disease. Of the 75/166 (45 %) who were age <70 years and had been planned for stage-directed curative therapy, 43 (57 %) were primary nonresponders and 32 (43 %) relapsed within 3 months of completing R-CHOP. Thirty of 75 (40 %) patients had serious comorbidity and organ dysfunction precluding intensive treatment and had palliative treatment only. Twelve of 45 (27 %) patients responded to second-line treatment and underwent ASCT. The median overall survival for the 75 patients was 10 months with only seven patients alive without evidence of disease at follow-up ranging from 14 to 106 months. Primary refractory DLBCL after R-CHOP has a very poor outcome with only anecdotal survivors independent of the intended treatment approach.

Influence of cardiovascular risk factors on levels of matrix metalloproteinases 2 and 9 in human abdominal aortic aneurysms.

OBJECTIVE: To evaluate the influence of cardiovascular risk factors on levels of matrix metalloproteinases (MMP) 2 and 9 in human abdominal aortic aneurysms (AAA). METHODS: Aortic samples were collected from patients who underwent AAA repair (n = 89). Patients were stratified according to the maximum transverse aorta diameter: small diameter (<55 mm), moderate diameter (55-69.9 mm) and large diameter (≥70 mm). Aortic walls were studied using real-time PCR and immunohistochemistry. MMP-2, MMP-9, α-actin, CD45, and CD68 transcript levels were determined relative to ß-actin. Quantitative data were expressed as median (IQ-range). RESULTS: No differences were found in MMP-2 expression between the patient groups, which was mainly associated with vascular smooth muscle cells (VSMC); however, MMP-9 displayed the maximum level in the moderate-diameter group, associated with infiltrating macrophages. Current smoking (CS) and renal insufficiency (RI) significantly increased local levels of MMP-2 (CS 349.5 [219.5-414.1] vs. no-CS 184.4 [100.0-320.5]; p < .008; RI 286.8 [189.6-410.8] vs. no-RI 177.3 [99.3-326.9]; p = .047). Nevertheless, after stepwise linear regression analysis only CS remained as an independent variable predicting local levels of MMP-2 (p = .002). No risk factors influenced local levels of MMP-9. CONCLUSIONS: The results show that local levels of MMP-2, an important factor for AAA development, were increased in current smoking AAA patients. MMP-2 was mainly associated with VSMC. It is suggested that MMP-2 could contribute significantly to the increased AAA growth rate observed in current smoking patients. These findings support inclusion of smokers in screening for aneurysmal disease, and emphasize the need for more aggressive monitoring of aneurysmal disease outside the surgical range in patients who smoke at the time of diagnosis and in those who continue to smoke during follow-up.

A prospective clinical utility and pharmacoeconomic study of the impact of the 21-gene Recurrence Score® assay in oestrogen receptor positive node negative breast cancer.

PURPOSE: The primary purpose of this study was to measure the impact of the 21-gene Recurrence Score® result on systemic treatment recommendations and to perform a prospective health economic analysis in stage I-II, node-negative, oestrogen receptor positive (ER+) breast cancer. METHODS: Consenting patients with ER+ node negative invasive breast cancer and their treating medial oncologists were asked to complete questionnaires about treatment preferences, level of confidence in those preferences and a decisional conflict scale (patients only) after a discussion of their diagnosis and risk without knowledge of the Recurrence Score. At a subsequent visit, the assay result and final treatment recommendations were discussed prior to both parties completing a second set of questionnaires. A Markov health state transition model was constructed, simulating the costs and outcomes experienced by a hypothetical 'assay naïve' population and an 'assay informed' population. RESULTS: One hundred and fifty-six patients across two cancer centres were enrolled. Of the 150 for whom successful assay results were obtained, physicians changed their chemotherapy recommendations in 45 cases (30%; 95% confidence interval (CI) 22.8-38.0%); either to add (10%; 95% CI 5.7-16.0%) or omit (20%; 95% CI 13.9-27.3%) adjuvant chemotherapy. There was an overall significant improvement in physician confidence post-assay (p<0.001). Patient decisional conflict also significantly decreased following the assay (p<0.001). The simulation model found an incremental cost-effectiveness ratio of Canadian Dollars (CAD) $6630/quality-adjusted life years (QALY). CONCLUSION: Within the context of a publicly funded health care system, the Recurrence Score assay significantly affects adjuvant treatment recommendations and is cost effective in ER+ node negative breast cancer.

Discrimination training reduces high rate social approach behaviors in Angelman syndrome: proof of principle.

This proof of principle study was designed to evaluate whether excessively high rates of social approach behaviors in children with Angelman syndrome (AS) can be modified using a multiple schedule design. Four children with AS were exposed to a multiple schedule arrangement, in which social reinforcement and extinction, cued using a novel stimulus, were alternated. Twenty-five to 35 discrimination training sessions were conducted and levels of approach behaviors were measured before and after the discrimination training for two children. All four participants evidenced discrimination between conditions of reinforcement and extinction after 16-20 teaching sessions as indicated by lower rates of social approach behaviors in the presence of the S(Δ) for extinction. Reversal effects for the two children for whom this design was implemented were evident. The results demonstrate that after repeated training, the use of a novel stimulus can serve as a cue for children with AS to discriminate adult availability. This is a potentially effective component of a broader intervention strategy but highlights the need for sustained teaching procedures within this population.

Outcome of patients with transformed indolent non-Hodgkin lymphoma referred for autologous stem-cell transplantation.

BACKGROUND: The proportion of potentially eligible patients with transformed indolent non-Hodgkin lymphoma who undergo autologous stem-cell transplantation (ASCT) is unknown. There are limited data describing their outcome in the rituximab era. PATIENTS AND METHODS: We reviewed 105 consecutive patients with biopsy-proven transformation referred to Princess Margaret Hospital for consideration of ASCT during 1996-2009. Patients received anthracycline or platinum-based chemotherapy with or without rituximab. Responders proceeded to stem-cell mobilization and ASCT. RESULTS: The median age at transformation was 54 (range 30-65) years. Patients received a median of two chemotherapy regimens for transformation, including rituximab in 39%. Fifty patients (48%) proceeded with ASCT and 55 (52%) did not, mainly due to progressive disease (n = 42). Three-year overall (OS) and progression-free survival (PFS) post-ASCT were 54% and 42%, respectively. Patients receiving rituximab with chemotherapy before transplant had a 3-year post-ASCT OS of 71% versus 47% in those who received chemotherapy alone (P = 0.046). Patients transplanted after 2004 had a 3-year post-ASCT OS of 69% versus 39% in those receiving ASCT earlier (P = 0.009). CONCLUSIONS: About half of transplant-eligible patients with transformation are able to undergo ASCT. Outcomes following ASCT appear to have improved over recent years, although the role of rituximab in this patient population requires further evaluation.

Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy.

BACKGROUND: The addition of rituximab to CHOP (R-CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy improves outcome in patients with diffuse large B-cell lymphoma (DLBCL). We evaluated the risk of central nervous system (CNS) relapse in the R-CHOP in a population-based cohort of patients with DLBCL. METHODS: Patients with DLBCL diagnosed from 1 September 1999 to 14 January 2005 at the British Columbia Cancer Agency (BCCA) were identified. Patients were included if they were > or =16 years old with advanced stage or any stage with testicular involvement and were treated with CHOP (1999-2001) or R-CHOP (2001-2005) with curative intent. RESULTS: Four hundred and thirty-five patients were identified; 126 (29%) were treated with CHOP and 309 (71%) with R-CHOP. With a median follow-up of 5.7 years, there were 31 CNS relapses in total with a trend to a reduced likelihood of CNS relapse in R-CHOP-treated patients (3-year risk 9.7% versus 6.4, P = 0.085). In multivariate analysis, the use of rituximab significantly reduced the risk of CNS relapse [hazard ratio (HR) 0.45, P = 0.034]; this benefit was more striking in patients who achieved a complete response (HR 0.18, P = 0.005). CONCLUSION: The use of R-CHOP appears to reduce the overall risk of CNS relapse in patients with DLBCL particularly in patients who achieve a complete response.

Survey of Argentinean human plasma for ochratoxin A.

The presence of ochratoxin A (OTA) in human blood has been reported for many countries, especially in Europe. However, so far no report exists concerning such a presence in Argentina. The aim of this study was to assess OTA concentration in human plasma in two different areas of Buenos Aires province. OTA was determined by high-performance liquid chromatography (HPLC) in 199 plasma samples from blood donors in Mar del Plata and 236 from General Rodriguez. Solid-phase extraction with Bakerbond C-18 cartridge and a final purification with Ochraprep immunoaffinity columns was employed. The limit of quantification of ochratoxin A was 0.019ngml(-1) and the confirmation of OTA was by formation of ochratoxin A methyl ester. The results showed that 63.8% of human plasma samples from Mar del Plata and 62.3% from General Rodriguez were positive for OTA, with Winsorized means of 0.15 and 0.43ngml(-1), respectively. It is important to continue the research to detect the foods responsible of the presence of OTA in plasma.

IL-1beta induces VEGF, independently of PGE2 induction, mainly through the PI3-K/mTOR pathway in renal mesangial cells.

Vascular endothelial growth factor (VEGF) could play a relevant role in angiogenesis associated with chronic allograft nephropathy. Interleukin-1beta (IL-1beta) has a key role in inflammatory response. It induces prostaglandin (PG) E2, which is involved in VEGF release by some normal and tumor cells. In the present work, we studied the effect of IL-1beta on VEGF release by rat mesangial cells, the transduction signal, and whether or not PGE2 is involved in this effect. IL-1beta induced a time-dependent formation of VEGF (analyzed by enzyme-linked immunosorbent assay) and PGE2 (analyzed by enzyme immunoassay). The latter correlated with microsomal-PGE-synthase (mPGES)-1 expression rather than with cyclooxygenase (COX)-2 in terms of protein, determined by Western blotting. No effect of IL-1beta on COX-1, cytosolic PGES, or mPGES-2 expression was observed. Indomethacin exerted a nonsignificant effect on IL-1beta-induced VEGF, and exogenously added PGE2 exhibited a nonsignificant stimulatory effect on VEGF formation. SB 203580, a p38 mitogen-activated protein kinase inhibitor, weakly inhibited the induction of VEGF by IL-1beta in a concentration-dependent manner, whereas LY 294002, a phosphoinoside 3-kinase (PI3-K) inhibitor, and rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, strongly inhibited both IL-1beta- and tumor necrosis factor-alpha-induced VEGF formation in a concentration-dependent manner. Rapamycin also decreased glomerular VEGF levels in the anti-Thy1.1 model of experimental glomerulonephritis. In conclusion, the PI3-K-mTOR pathway seems to be essential in cytokine-induced release of VEGF in mesangial cells.

Dermoscopy in black people.

BACKGROUND: Little is known about the use of dermoscopy in nonwhite-skinned populations and whether it can influence diagnostic performance. OBJECTIVES: To evaluate for the first time the utility and efficacy of dermoscopy in a black population for the diagnosis of pigmented cutaneous lesions. METHODS: In total, 100 consecutive clinically doubtful or equivocal pigmented skin lesions in black patients were submitted to dermoscopic examination. The lesions were observed using dermoscopy by two groups of dermatologists, one in Brazil (in vivo) and the other in Italy (on slide images). Besides diagnosis, each group recorded on the same type of form the dermoscopic features present. RESULTS: Of 100 clinically suspicious cases, 79 were Clark naevi, 15 seborrhoeic keratoses, four blue naevi, one dermatofibroma and one melanoma. The two groups of observers succeeded in identifying and classifying all the lesions to such a margin of diagnostic accuracy that only a few cases (three Clark naevi) were subjected to surgical excision to confirm diagnosis. CONCLUSIONS: Darker pigmentation of the skin does not impede the identification of single dermoscopic features. As in lighter-skinned populations, dermoscopy in black people can also lead to early and accurate diagnosis of melanoma, thereby significantly reducing the number of unnecessary excisions.

Resveratrol interference with the cell cycle protects human neuroblastoma SH-SY5Y cell from paclitaxel-induced apoptosis.

In previous studies we demonstrated that resveratrol acts in an antiapoptotic manner on the paclitaxel-treated human neuroblastoma (HN) SH-SY5Y cell line inhibiting the apoptotic pathways induced by the antineoplastic drug. In the present study we evaluated the antiapoptotic effect of resveratrol, studying its activity on cell cycle progression. We determined the mitotic index of cultures exposed to resveratrol and paclitaxel alone or in combination, the cell cycle distribution by flow cytometric analysis (FACS), and the modulation of some relevant cell cycle regulatory proteins. Resveratrol is able to induce S-phase cell arrest and this interference with the cell cycle is associated with an increase of cyclin E and cyclin A, a downregulation of cyclin D1, and no alteration in cyclin B1 and cdk 1 activation. The resveratrol-induced S-phase block prevents SH-SY5Y from entering into mitosis, the phase of the cell cycle in which paclitaxel exerts its activity, explaining the antiapoptotic effect of resveratrol.