First-line avelumab for patients with PD-L1-positive metastatic or locally advanced urothelial cancer who are unfit for cisplatin.

BACKGROUND: Cisplatin-based chemotherapy is the most recommended treatment for metastatic urothelial cancer (mUC). However, about 50% of patients are considered to be cisplatin ineligible. Anti-programmed cell death protein 1/programmed death-ligand 1 (PD-L1) therapies have, nevertheless, increased the options available to clinicians and are especially valuable for treating these patients. This study therefore tested the activity and safety of avelumab as first-line therapy for mUC. PATIENTS AND METHODS: Patients with mUC who were ineligible for cisplatin-based chemotherapy were screened centrally for PD-L1 expression and only those with a tumour proportion score ≥ 5% were enrolled in the trial. The primary endpoint was 1-year overall survival (OS), and the secondary endpoints were median OS, median progression-free survival, overall response rate, duration of the response, safety and tolerability. All the survival rates were estimated with the Kaplan-Meier product-limit methodology and compared across groups using the log-rank test. RESULTS: A total of 198 patients were screened, with 71 (35.9%) whose PD-L1 expression was ≥5% enrolled in the study. The median age was 75 years, bladder cancer was the primary tumour in 73.2% of cases and 25.3% had liver metastases. The main reasons for the cisplatin ineligibility were a low rate of creatinine clearance (<60 ml/min), present in 70.4% of patients, and an Eastern Cooperative Oncology Group performance status of 2, which affected 31%. The median OS was 10.0 months (95% confidence interval 5.5-14.5 months) and 43% of patients were alive at 1 year. A complete response was achieved in 8.5% of cases, and 15.5% had a partial response. Adverse any-grade and high-grade events occurred in 49.3% and 8.5% of patients, respectively. A grade 3 infusion reaction was the only high-grade treatment-related adverse event. No treatment-related deaths were reported. CONCLUSIONS: This ARIES trial confirmed the activity and safety of avelumab for treating mUC, adding a new therapy option to the armamentarium of checkpoint inhibitors already approved for platinum-ineligible, locally advanced/mUC.

Major adverse cardiovascular events associated with VEGF-targeted anticancer tyrosine kinase inhibitors: a real-life study and proposed algorithm for proactive management.

BACKGROUND: Vascular endothelial growth factor receptor (VEGFR)-targeted tyrosine kinase inhibitors (TKIs) are widely used in cancer treatment and burdened by cardiovascular toxicity. The majority of data come from clinical trials, thus in selected populations. The aim of our study is to evaluate the cardiotoxicity profile of VEGFR-targeted TKIs and the impact of cardiovascular risk factors in a real-life population. PATIENTS AND METHODS: In this cohort, population-based study, patients treated with VEGFR-targeted TKIs, bevacizumab and trastuzumab between 2009 and 2014 were analyzed. A multi-source strategy for data retrieval through hospital, pharmaceutical and administrative databases of the Lombardy region, Italy, has been adopted. The primary endpoint was to determine the incidence and type of major adverse cardiovascular events (MACEs) along with their temporal trend. The secondary endpoint was to define the impact of cardiovascular risk factors in the occurrence of MACEs. RESULTS: A total of 829 patients were treated with VEGFR-targeted TKIs. Eighty-one MACEs occurred in the first year of follow-up [crude cumulative incidence (CCI): 9.79%] mainly consisting of arterial thrombotic events (ATEs, 31 events, CCI: 3.99%), followed by rhythm disorders (22 events, CCI: 2.66%), pulmonary embolisms and heart failures (13 events each, CCI: 1.57%). While the incidence of most MACEs showed a plateau after 6 months, ATEs kept increasing along the year of follow-up. Hypertension and dyslipidemia were associated with an increase in risk of ATEs [relative risk difference (RRD) +209.8% and +156.2%, respectively], while the presence of previous MACEs correlated with a higher risk of all MACEs in multivariate analysis (RRD 151.1%, 95% confidence interval 53.6% to 310.3%, P < 0.001). CONCLUSIONS: MACEs occur in a clinically significant proportion of patients treated with VEGFR-targeted TKIs, with ATEs being predominant, mainly associated with hypertension and dyslipidemia. A clinical algorithm for effective proactive management of these patients is warranted.

Two-dimensional echocardiographic measures of left ventricular dimensions agree with M-mode measurements in dogs.

INTRODUCTION: Clinicians measure left ventricular dimensions in dogs from both M-mode and two-dimensional images. Little information currently exists as to whether these two methods provide measurements similar enough to be interchangeable. ANIMALS: The animals included in this study are 206 client-owned dogs: 68 healthy, 105 with myxomatous mitral valve disease, 33 with other cardiac or extracardiac disease. MATERIALS AND METHODS: Investigators measured left ventricular diastolic and systolic dimensions from archived M-mode and two-dimensional images obtained from the right parasternal short-axis view. Agreement between the pairs of measurements was examined using limits of agreement (Bland-Altman) plots. RESULTS: Left ventricular diastolic dimensions showed no fixed or proportional bias but did show heteroscedasticity. Ninety-five percent limits of agreement for normalized differences approximated ±10%; 95% of the absolute differences for any pair of measurements were <3.9 mm regardless of bodyweight and <2.7 mm for dogs <15 kg. Left ventricular systolic dimensions showed slight proportional bias, with two-dimensional measurements being progressively larger than M-mode measurements as ventricular size increased. Ninety-five percent limits of agreement for normalized differences approximated ±20%; 95% of the absolute differences for any pair of measurements were <4.6 mm regardless of bodyweight and <3.5 mm for dogs <15 kg. Mitral valve disease did not appreciably affect these findings. CONCLUSIONS: Left ventricular internal dimensions in dogs with and without cardiac disease measured from two-dimensional right parasternal short-axis images are interchangeable with those measured from M-mode images using the same view.

Early reduction of serum TARC levels may predict for success of ABVD as frontline treatment in patients with Hodgkin Lymphoma.

BACKGROUND: Many efforts have been made to predict prognosis of newly diagnosed Hodgkin Lymphoma (HL) patients. Objective of this study was to investigate the association between early reduction of Thymus and Activation-Regulated Chemokine after the first ABVD cycle (TARC-1) and prognosis of HL patients. METHODS: Serum samples of 116 HL patients were collected at baseline, after every ABVD cycle and during follow-up. The 99th centile of TARC distribution in a group of 156 independent healthy subjects (800pg/ml) was considered as cut-off for discriminating between abnormal and normal TARC values. FINDINGS: 101 patients out of 116 had baseline TARC above 800pg/ml (median value 27515pg/ml (IQR, 11001-68139)) and were the object of this analysis. TARC-1 significantly decreased to a median value of 556pg/ml (IQR, 378-977pg/ml). TARC-1 values below 800pg/ml were associated with success of therapy (p=0.0003) and PET-2 negativity (p=0.001). TARC-1≤800pg/ml identified a population with a significantly higher 5-years PFS in the whole cohort (90.1% vs 55.6%; p<0.0001) and in both subgroups of advanced (p=0.003) and early stage patients (p=0.021). At multivariable analysis, TARC-1 was significant independent predictor of PFS (p=0.0035). INTERPRETATION: Early reduction of TARC serum levels can predict success of treatment, being associated with achievement of interim PET-2 negative and favorable long-term outcome in HL patients receiving ABVD as front-line therapy.

Feasibility of allogeneic stem-cell transplantation after azacitidine bridge in higher-risk myelodysplastic syndromes and low blast count acute myeloid leukemia: results of the BMT-AZA prospective study.

BACKGROUND: Allogeneic stem-cell transplantation (HSCT) is the only curative treatment in myelodysplastic syndromes (MDS). Azacitidine (AZA) is increasingly used prior to HSCT, however in Europe it is only approved for patients who are not eligible for HSCT. PATIENTS AND METHODS: We conducted a phase II multicenter study to prospectively evaluate the feasibility of HSCT after treatment with AZA in 70 patients with a myelodysplastic syndrome (MDS), 19 with acute myeloid leukemia (AML), and 8 with chronic myelomonocytic leukemia (CMML). After a median of four cycles (range 1-11): 24% of patients achieved complete remission, 14% partial remission, 8% hematologic improvement, 32% had stable and 22% progressive disease. Ten patients discontinued treatment before the planned four cycles, due to an adverse event in nine cases. RESULTS: A HSC donor was identified in 73 patients, and HSCT was performed in 54 patients (74% of patients with a donor). Main reasons for turning down HSCT were lack of a donor, an adverse event, or progressive disease (9, 12, and 16 patients, respectively). At a median follow-up of 20.5 months from enrolment, response to AZA was the only independent prognostic factor for survival. Compared to baseline assessment, AZA treatment did not affect patients' comorbidities at HSCT: the HCT-CI remained stable in 62% patients, and worsened or improved in 23% and 15% of patients, respectively. CONCLUSIONS: Our study shows that HSCT is feasible in the majority of patients with HR-MDS/AML/CMML-2 after AZA treatment. As matched unrelated donor was the most frequent source of donor cells, the time between diagnosis and HSCT needed for donor search could be 'bridged' using azacitidine. These data show that AZA prior to HSCT could be a better option than intensive chemotherapy in higher-risk MDS. The trial has been registered with the EudraCT number 2010-019673-1.

Reproductive ecology of coypu (Myocastor coypus Molina, 1782) in the Middle Delta of the Paraná River, Argentina / Ecología reproductiva do coipo (Myocastor coypus) no Delta Meio do Río Paraná (Entre Ríos. Argentina)

The objective of this study was to estimate and compare some important reproductive parameters of Myocastor coypus over time (June 2006-May 2008), in wetlands of the Middle Delta of the Paraná River (MD) Entre Ríos province, R. Argentina. Within the original coypu distribution range, the MD is among the areas of highest habitat suitability for the species. Coypus were captured and the following reproductive parameters were estimated on a monthly, seasonal and annual basis: pregnancy rate (PR), litter size (LS), gross productivity (GP) and annual production (AP). Statistical non-parametric tests were used for comparisons. Additionally, the expected birth date of each embryo and fetus was estimated by assigning it to a developmental stage category and considering the gestation period of the species. All the parameters showed high values and PR and LS differed significantly between the dry (2006) and humid years (2007). Two peaks of birth were detected, one in spring and another one in mid-autumn. The implications of these results for ensuring the sustainable management of this rodent are discussed.

O objetivo deste trabalho é a descripção e comparação ao longo do tempo (junho 2006 – maio 2008), de diversos parámetros da ecologia reprodutiva de Myocastor coypus nas terras úmidas do Delta Meio do Río Paraná (DM), una das zonas de maior aptidão de hábitat para a espécie dentro da sua área de distribuição original. Com base em capturas de exemplares estimaram-se en forma mensal, sazonal y anual, a taxa de prenhez (TP); o tamanho da camada (TC), a produtividade bruta (PB) e a produção anual (PA) e foram realizadas as comparações correspondentes mediante provas estatísticas não paramétricas. Alem disso, com base no estádio de desenvolvimento dos fetos y embriões observados, levando em consideração a duração do período de gestação, estimou-se quais teriam sido as datas de nascimento mais prováveis. Observaram-se valores relativamente altos para todos os parámetros e diferenças significativas entre as TP y os TC de anos secos (2006) e anos úmidos (2007). Também foram detectados dois picos de parição, um em plena primavera e o outro a meados do outono. Discutem-se as implicâncias destes resultados para assegurar o manejo sustentável do coipo, o principal recurso de fauna silvestre argentina.

Allogeneic transplantation following a reduced-intensity conditioning regimen in relapsed/refractory peripheral T-cell lymphomas: long-term remissions and response to donor lymphocyte infusions support the role of a graft-versus-lymphoma effect.

Rescue chemotherapy or autologous stem cell transplantation (autoSCT) gives disappointing results in relapsed peripheral T-cell lymphomas (PTCLs). We have retrospectively evaluated the long-term outcome of 52 patients receiving allogeneic SCT for relapsed disease. Histologies were PTCL-not-otherwise specified (n=23), anaplastic large-cell lymphoma (n=11), angioimmunoblastic T-cell lymphomas (n=9) and rare subtypes (n=9). Patients were allografted from related siblings (n=33, 64%) or alternative donors (n=13 (25%) from unrelated and 6 (11%) from haploidentical family donors), following reduced-intensity conditioning (RIC) regimens including thiotepa, fludarabine and cyclophosphamide. Most of the patients had chemosensitive disease (n=39, 75%) and 27 (52%) failed a previous autoSCT. At a median follow-up of 67 months, 27 of 52 patients were found to be alive (52%) and 25 (48%) were dead (n=19 disease progression, n=6 non-relapse mortality (NRM)). The cumulative incidence (CI) of NRM was 12% at 5 years. Extensive chronic graft-versus-host disease increased the risk of NRM (33% versus 8%, P=0.04). The CI of relapse was 49% at 5 years, influenced by disease status at the time of allografting (P=0.0009) and treatment lines (P=0.007). Five-year overall survival and progression-free survival (PFS) were 50% (95% CI, 36 - 63%) and 40% (95% CI, 27 - 53%), respectively. The current PFS was 44% (95% CI, 30-57%). In all, 8 out of 12 patients (66%) who received donor-lymphocytes infusions for disease progression had a response. At multivariable analysis, refractory disease and age over 45 years were independent adverse prognostic factors. RIC allogeneic SCT is an effective salvage treatment with a better outcome for younger patients with chemosensitive disease.

The hematopoietic cell transplantation comorbidity index (HCT-CI) predicts clinical outcomes in lymphoma and myeloma patients after reduced-intensity or non-myeloablative allogeneic stem cell transplantation.

The hematopoietic cell transplantation specific comorbidity index (HCT-CI) has been developed to identify patients at high risk of mortality after an allograft. Reduced-intensity/non-myeloablative regimens have decreased the non-relapse mortality (NRM) in elderly and/or heavily pretreated patients. We performed a retrospective study to assess whether HCT-CI may predict clinical outcomes in a cohort of 203 patients with non-Hodgkin's (NHL; n=108), Hodgkin's lymphomas (HL; n=26), and multiple myeloma (MM; n=69), who were transplanted from a human leucocyte antigen (HLA)-matched sibling (n=121) or an unrelated donor (n=82) after a reduced-intensity regimen (n=154) or a low-dose total body irradiation-based non-myeloblative regimen (n=49). Cumulative incidence of NRM was 5, 16 and 20% at 1 year and 6, 24 and 27% at 2 years, for patients with an HCT-CI of 0, 1-2 and > or =3, respectively. By multivariate analysis, HCT-CI significantly predicted NRM (hazard ratio (HR)=1.6, P=0.03), overall survival (OS; HR=1.62, P<0.001) and progression-free survival (PFS; HR=1.43, P=0.002). Moreover, the Karnofsky performance status was also significantly associated with OS and NRM (HR=1.62, P<0.001 and HR=2.12, P=0.04, respectively). Conditioning type did not affect outcome after stratifying patients by HCT-CI. In the light of our study, all future prospective trials of the Gruppo Italiano Trapianti di Midollo (GITMO) will include the HCT-CI to stratify patients.

Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial.

Patients with high-risk endometrial carcinoma (stage IcG3, IIG3 with myometrial invasion >50%, and III) receive adjuvant therapy after surgery but it is not clear whether radiotherapy (RT) or chemotherapy (CT) is better. We randomly assigned 345 patients with high-risk endometrial carcinoma to adjuvant CT (cisplatin (50 mg m(-2)), doxorubicin (45 mg m(-2)), cyclophosphamide (600 mg m(-2)) every 28 days for five cycles, or external RT (45-50 Gy on a 5 days week(-1) schedule). The primary end points were overall and progression-free survival. After a median follow-up of 95.5 months women in the CT group as compared with the RT group, had a no significant hazard ratio (HR) for death of 0.95 (95% confidence interval (CI), 0.66-1.36; P = 0.77) and a nonsignificant HR for event of 0.88 (95% CI, 0.63-1.23; P = 0.45). The 3, 5 and 7-year overall survivals were 78, 69 and 62% in the RT group and 76, 66 and 62% in the CT group. The 3, 5 and 7-year progression-free survivals were, respectively, 69, 63 and 56 and 68, 63 and 60%. Radiotherapy delayed local relapses and CT delayed metastases but these trends did not achieve statistical significance. Overall, both treatments were well tolerated. This trial failed to show any improvement in survival of patients treated with CT or the standard adjuvant radiation therapy. Randomised trials of pelvic RT combined with adjuvant cytotoxic therapy compared with RT alone are eagerly awaited.

A rare case of basosquamous carcinoma of the orbit invading the maxillary sinus.

A rare case of basosquamous carcinoma of the orbit invading the maxillary sinus is presented. The authors discuss clinical and pathological findings. Techniques for removal and reconstructive plastic surgery are reported.