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Glioblastoma is the most common malignant primary central nervous system tumor in adults and is associated with a poor prognosis. The benefit of adding concomitant followed by adjuvant temozolomide to radiotherapy after maximal safe resection was demonstrated by Stupp and colleagues in 2005 and has since remained the standard of care. This regimen conferred a statistically significant benefit with a 2-year survival rate of 26.5% compared to 10.4% in patients treated with radiotherapy alone. Our primary goal was to retrospectively assess the clinical outcomes of patients with glioblastoma treated at our institution over the past 15 years by comparing the overall survival (OS) and progression-free survival (PFS) from our cohort to data from the pivotal trial. Our secondary objective was to create a comprehensive database with clinical and pathological information in order to identify predictive and prognostic factors. We reviewed the clinical records of patients treated for glioblastoma from January 2005 to November 2019 at our center. We extracted data on survival and calculated OS and PFS using the Kaplan-Meier method. 617 patient charts were reviewed, out of which 17 were excluded because of missing data. The remaining 600 patients were included. Baseline demographic information was similar to that of the Stupp cohort, with the exception of a larger proportion of patients aged 50 or above (76% versus 69%, respectively). The median OS at our center was 14.3 months, 95% confidence interval [12.8-15.2], which was comparable to that of the original trial (14.6 months [13.2-16.8]). PFS was better in our cohort at 6 months (74.2% [70.7-77.7] versus 53.9% [48.1-59.6]) and 12 months (36.3% [32.5-40.2] versus 26.9% [21.8-32.1]), and comparable thereafter. Our study confirms that the data from the Stupp trial are reproducible in a Canadian academic center setting. Our database will allow us to explore potentially new predictive factors.

Context The SELECT trial led to the approval of lenvatinib for the treatment of advanced radioiodine-refractory differentiated thyroid carcinomas (DTCs) but also revealed an important adverse event (AE) profile which may limit its use in clinical practice. Objective We aim to describe the efficacy and toxicity profiles of lenvatinib in real life. Methods We included all patients who received lenvatinib for an advanced DTC at our institution, enrolling 27 patients. We reviewed retrospectively electronic medical records to assess efficacy and AEs. Results Among the 24 patients with evaluation of tumor response during treatment, overall response rate (ORR) was 37.0% (95% CI, 19.4%-57.6%), and disease control rate was 85.2% (95% CI, 66.3%-95.8%). The median progression-free survival (PFS) was 12 months (95% CI, 7.5-16.5]. The most prevalent AEs were hypertension (77.8%), fatigue (55.6%), and weight loss (51.9%). At least one grade ≥ 3 AE was experienced by 25/27 patients (92.6%), mostly hypertension (59.3%). Lenvatinib was discontinued due to AEs in 13/27 patients (48.1%). Interestingly, 1 patient experienced a grade 4 posterior reversible encephalopathy syndrome, and another developed a Takotsubo cardiomyopathy. Conclusion The safety profile of lenvatinib in our cohort was similar to that reported in the literature, with a predominance of hypertension. Rigorous blood pressure control is therefore essential to avoid discontinuing therapy. We also report 2 severe and rarely described AEs that physicians should watch for. As for efficacy, although less than in the SELECT trial, ORR and PFS were similar to other real-life studies.

To evaluate the diagnostic accuracy of Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA) and Endoscopic Ultrasound-guided Fine Needle Aspiration (EUS-FNA) in the diagnosis of lymphoma. A retrospective analysis of patients with suspected mediastinal lymphoproliferative disorders who underwent EBUS-TBNA, EUS-FNA or combined procedures from 2009 to 2019 was conducted using a prospectively maintained interventional thoracic endoscopy database. Demographic data, imaging, needle size, surgical biopsy, complications rate and pathology reports were reviewed. Over a 10-year period, a total of 444 patients were investigated with endosonography as the first diagnostic procedure for mediastinal adenopathy suspicious for lymphoma. Lymphoma was diagnosed in 77 patients (17.3%). In total, 68 patients (88.3%) were diagnosed using endosonographic mediastinal tissue sampling. Four patients had both lymphoproliferative disorders and lung cancer. Nine patients (11.7%) required a surgical biopsy to confirm the lymphoma diagnosis (6 non-diagnostic; 3 inadequate samples from endosonographic biopsies). In patients with adequate biopsies via endosonography, the sensitivity for the diagnosis of lymphoma, was 91.9% (n = 68/74). The histopathologic subtype of lymphoma was determined by endosonographic biopsies in 61 patients (89.7%) with an increased sensitivity (92.6%) for low grade Non-Hodgkin lymphoma (NHL). No acute complication related to endosonography was observed. Endosonographic biopsy (EBUS and/or EUS) of mediastinal adenopathy in patients with suspected lymphoma is a highly sensitive and safe diagnostic test. Endosonography should be the first test in the diagnosis of suspicious mediastinal lymphoma and should be followed by surgical biopsy in cases of insufficient sampling or indefinite diagnosis.

Procarbazine, lomustine, and vincristine (pcv) significantly improve survival outcomes in lgg (low-grade gliomas). Administration of pcv to lgg patients increased tremendously over the past years as it went from 2 patients per year between 2005 and 2012 to 23 patients in 2015 only in our centre. However, serious hematological and non-hematological adverse events may occur. The purpose of this study was to evaluate the toxicity of pcv and its clinical relevance in our practice. We retrospectively reviewed the charts of 57 patients with lgg who received pcv at the Centre hospitalier de l&rsquo, Universit&eacute, de Montr&eacute, al between 1 January 2005 and 27 July 2016. Procarbazine, lomustine, and vincristine were associated with severe hematological toxicity as clinically significant grade 3 anemia, neutropenia, and thrombocytopenia occurred in 7%, 10%, and 28% of patients, respectively. Other frequent adverse events such as the increase of liver enzymes, cutaneous rash, neurotoxicity, and vomiting occurred in 65%, 26%, 60%, and 40% of patients, respectively. Patients with prophylactic trimethoprim/sulfamethoxazole had more grade 3 hematological toxicity with pcv, especially anemia (p = 0.040) and thrombocytopenia (p = 0.003) but we found no increase in pcv toxicity in patients on concurrent anticonvulsants. Patients with grade 3 neutropenia had a significantly lower survival (median survival 44.0 months vs. 114.0 months, p = 0.001). Patients who were given pcv at diagnosis had more grade 3 anemia than those who received it at subsequent lines of treatment (p = 0.042). Procarbazine, lomustine, and vincristine increase survival in lgg but were also associated with major hematologic, hepatic, neurologic, and cutaneous toxicity. Anti-Pneumocystis jiroveci pneumonia (pjp) prophylaxis, but not anticonvulsants, enhances hematologic toxicity.

Summary Despite the long history of bendamustine as treatment for indolent non-Hodgkin lymphoma, long-term efficacy and toxicity data are minimal. We reviewed long-term data from three clinical trials to characterize the toxicity and efficacy of patients receiving bendamustine. Data were available for 149 subjects at 21 sites. The median age was 60 years at the start of bendamustine (range 39–84), and patients had received a median of 3 prior therapies. The histologies included grades 1–2 follicular lymphoma (FL; n = 73), grade 3 FL (n = 23), small lymphocytic lymphoma (n = 20), marginal zone lymphoma (n = 15), mantle cell lymphoma (n = 9), transformed lymphomas (n = 5), lymphoplasmacytic lymphoma (n = 2) and not reported (n = 2). The median event-free survival was 14·1 months. Nine of 12 attempted stem cell collections were successful. With a median follow-up of 8·9 years, 23 patients developed 25 cancers, including 8 patients with myelodysplastic syndrome/acute myeloid leukaemia. These data provide important information regarding the long-term toxicity of bendamustine in previously treated patients. A small but meaningful number of patients achieved durable remissions following bendamustine. These rigorously collected, patient-level, long-term follow-up data provide reassurance that bendamustine or bendamustine plus rituximab is associated with efficacy and safety for patients with relapsed or refractory indolent non-Hodgkin lymphoma.

BACKGROUND In glioblastomas (GBM) patients the first post-radiation MRI is usually difficult to interpret given the post-radiotherapy enhancement and possible pseudo-progression which is present in almost 50% of the patients. METHODS We retrospectively analyzed all patients with GBM treated between 2006 and 2017 at the CHUM (SARDO database). If the first brain MRI done within 3 months after the systemic treatment showed progression of contrast, these patients were considered pseudoprogressors (PsP) while the patients who had stable or response to treatment were the non-progressors (nP). If progression persisted in subsequent MRI with a change of treatment within 6 months, they were considered early progressors (eP). If subsequent MRI improved or was stable, they were classified as nP (or true pseudo-progression). RESULTS In our cohort of 470 patients with GBM, 57.7% were nP and 42.3% were PsP after the first post-treatment imagery. The median follow-up was 10 months. The nP had a longer mOS 15.3m vs 11.3m, p < 0.001, regardless of subsequent evolution. After the second assessment, 67.8% of PsP patients were then considered as eP and 36.4% of nP patients also progressed within 6 months. The nP either after the first or second evaluation had the same mOS (19.9m vs 18.3m), just like the eP (9.3m vs 8.6m), independently of the subsequent treatment. No demographic, molecular or clinical factor predicted PsP, except for tumor size (> 5cm, p=0.024). PsP incidence was similar between 2006–2011 (PsP 57.8%) and 2012–2017 (42.2%). The 1y OS with pseudo progression at the first MRI was 39.7% vs 54.8% with no progression (p=0.001) which has a meaningful impact for the patient. CONCLUSION Pseudo-progression is frequent (42%) in glioblastoma and predicts a poorer prognosis with 1y OS of 39,7%. In fact, PsP patients have more than two-thirds chance to progress precociously.

BACKGROUND: Pediatric arterial ischemic stroke remains incompletely understood. Population-based epidemiological data inform clinical trial design but are scant in this condition. We aimed to determine age-specific epidemiological characteristics of arterial ischemic stroke in neonates (birth to 28 days) and older children (29 days to 18 years). METHODS: We conducted a 16-year, prospective, national population-based study, the Canadian Pediatric Ischemic Stroke Registry, across all 16 Canadian acute care children's hospitals. We prospectively enrolled children with arterial ischemic stroke from January 1992 to December 2001 and documented disease incidence, presentations, risk factors, and treatments. Study outcomes were assessed throughout 2008, including abnormal clinical outcomes (stroke-related death or neurological deficit) and recurrent arterial ischemic stroke or transient ischemic attack. RESULTS: Among 1129 children enrolled with arterial ischemic stroke, stroke incidence was 1.72/100,000/year, (neonates 10.2/100,000 live births). Detailed clinical and radiological information were available for 933 children (232 neonates and 701 older children, 55% male). The predominant clinical presentations were seizures in neonates (88%), focal deficits in older children (77%), and diffuse neurological signs (54%) in both. Among neonates, 44% had no discernible risk factors. In older children, arteriopathy (49% of patients with vascular imaging), cardiac disorders (28%), and prothrombotic disorders (35% of patients tested) predominated. Antithrombotic treatment increased during the study period (P < 0.001). Stroke-specific mortality was 5%. Outcomes included neurological deficits in 60% of neonates and 70% of older children. Among neonates, deficits emerged during follow-up in 39%. Overall, an initially decreased level of consciousness, a nonspecific systemic presentation, and the presence of stroke risk factors predicted abnormal outcomes. For neonates, predictors were decreased level of consciousness, nonspecific systemic presentation, and basal ganglia infarcts. For older children, predictors were initial seizures, nonspecific systemic presentation, risk factors, and lack of antithrombotic treatment. Recurrent arterial ischemic stroke or transient ischemic attack developed in 12% of older children and was predicted by arteriopathy, presentation without seizures, and lack of antithrombotic treatment. Emerging deficit was predicted by neonatal age at stroke and by cardiac disease. CONCLUSIONS: This national data set provides a population-based disease incidence rate and demonstrates the protective effect of antithrombotic treatment in older children, and frequent long-term emerging deficits in neonates and in children with cardiac disorders. Further clinical trials are required to develop effective age-appropriate treatments for children with acute arterial ischemic stroke.

BACKGROUND Before 2012, Temozolomide (TMZ) was used for low-grade gliomas (LGG) to avoid Lomustine toxicity. After 2012 RTOG data, Procarbazine, Lomustine and Vincristine (PCV) given sequentially with radiotherapy became standard treatment with the side effects burden associated. METHODS We retrospectively reviewed our SARDO clinical database of patients with low-grade glioma LGG grades 2 and 3 between 2006 and 2017 at CHUM University Health Center. Molecular profile for these tumors is reflex and standard in our institution since 2016. RESULTS A total of 123 patients were identified with grade 2 and grade 3 LGG; 37 (30%) treated with PCV and 86 (70%) received TMZ. Median follow up was 11mo for PCV 11mo vs 22mo TMZ. Both groups were balanced in terms of median age, sex, neurologic symptoms and surgery rate. 53% patients had tumor untested for IDH1-2 and codeletion1p19q because of diagnostic before 2016. Disparities were noted with a predominance of grade 3 in the TMZ group (74% vs 27%, p< 0.01). TMZ was the preferred regimen before 2012 (100% vs 43%) and PCV became the standard of care after 2012 (0% vs 57%). Radiation use as first line treatment was 90%. The 4y OS was not significantly longer for PCV 50% compared with TMZ 47% with mOS between both groups (PCV NR vs TMZ 39.9mo, p=0.158). When controlled for tumor grade, the 2y OS was 80% for PCV vs 64% for TMZ,p=0.542. The 4y PFS was trendly longer for PCV group 78% than TMZ group 45%, p=0.148. CONCLUSION As we are still waiting for the prospective ongoing prospective trials comparing these 2 regimens, PCV and radiation are still standard of care regimens for grade 2 and 3 LGG. This retrospective data is not reassuring for a replacement for PCV with TMZ.

Ethylmalonic encephalopathy is a recently described inborn error of metabolism characterized clinically by developmental delay and regression, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea. We describe monochorionic twins presenting with hypotonia in infancy and diagnosed with ethylmalonic encephalopathy on the basis of biochemical findings. They are compound heterozygote for missense mutations in ETHE1. Magnetic resonance imaging changes affecting the white matter, corpus callosum, and basal ganglia were seen in both patients. At 10 years of age, they have severe axial hypotonia but never displayed petechiae, orthostatic acrocyanosis, or chronic diarrhea. Their clinical courses differ markedly; one had an episode of coma when she was 3 years old and now has spastic quadraparesis and cannot speak. The other can freely use her upper extremities, her pyramidal syndrome being mostly limited to the lower extremities, and can speak 2 languages. These patients illustrate the clinical heterogeneity of ethylmalonic encephalopathy, even in monochorionic twins.

In a retrospective study, 32 patients with myotonic dystrophy, including congenital (n=17) and infantile/juvenile forms (n=15) were studied during a long follow-up lasting 7–28 years (median: 17 years). The clinical presentation was extremely variable; however, a continuum did exist between severe and less severe congenital forms, and later-onset forms, without genotype–phenotype correlation. We observed some unusual presentations, such as 3 cases of isolated club-feet during the neonatal period, and 7 patients (23%) with a completely isolated mental deficiency, language delay and school failure, who only completed the clinical picture several years later. Wechsler scale testing was performed in all cases, and repeated with 8 patients. It demonstrated a decrease in intellectual abilities in 5 patients, suggesting the possibility of a degenerative cerebral process occurring in these children. This decrease has also been reported in some adult cases. This study illustrates the extremely heterogeneous clinical presentation of myotonic dystrophy in childhood.

We compared the health-related quality-of-life of patients with newly diagnosed multiple myeloma aged over 65 years or transplant-ineligible in the pivotal, phase III FIRST trial. Patients received: i) continuous lenalidomide and low-dose dexamethasone until disease progression; ii) fixed cycles of lenalidomide and low-dose dexamethasone for 18 months; or iii) fixed cycles of melphalan, prednisone, thalidomide for 18 months. Data were collected using the validated questionnaires (QLQ-MY20, QLQ-C30, and EQ-5D). The analysis focused on the EQ-5D utility value and six domains pre-selected for their perceived clinical relevance. Lenalidomide and low-dose dexamethasone, and melphalan, prednisone, thalidomide improved patients' health-related quality-of-life from baseline over the duration of the study across all pre-selected domains of the QLQ-C30 and EQ-5D. In the QLQ-MY20, lenalidomide and low-dose dexamethasone demonstrated a significantly greater reduction in the Disease Symptoms domain compared with melphalan, prednisone, thalidomide at Month 3, and significantly lower scores for QLQ-MY20 Side Effects of Treatment at all post-baseline assessments except Month 18. Linear mixed-model repeated-measures analyses confirmed the results observed in the cross-sectional analysis. Continuous lenalidomide and low-dose dexamethasone delays disease progression versus melphalan, prednisone, thalidomide and has been associated with a clinically meaningful improvement in health-related quality-of-life. These results further establish continuous lenalidomide and low-dose dexamethasone as a new standard of care for initial therapy of myeloma by demonstrating superior health-related quality-of-life during treatment, compared with melphalan, prednisone, thalidomide. ispartof: Haematologica vol:100 issue:6 pages:826-833 ispartof: location:Italy status: published

A sensitive and accurate stable isotope dilution GC/MS assay was developed and validated for the quantification of succinylacetone (SA) in plasma and amniotic fluid (AF). SA is pathognonomic for tyrosinemia type I, a genetic disorder caused by a reduced activity of fumarylacetoacetate hydrolase (FAH). In untreated patients, SA can easily be measured in plasma and urine because the expected concentrations are in the micromol/L range. Due to a founder effect, the province of Quebec has an unusually high prevalence of tyrosinemia type I, hence, the quantification of SA in AF or plasma of treated patients in the nmol/L range becomes very useful. The method utilizes 13C5-SA as an internal standard and a three-step sample treatment consisting of oximation, solvent extraction and TMCS derivatization. The assay was validated by recording the ion intensities of m/z 620 for SA and m/z 625 for ISTD in order to demonstrate the precision of measurements, the linearity of the method, limit of quantification and detection (LOQ and LOD), specificity, accuracy, as well as metabolite stability. Values for the intra-day assays ranged from 0.2 to 3.2% while values for the inter-day assays ranged from 1.9 to 5.6% confirming that the method has good precision. A calibration plot using SA detected by GC/MS gave excellent linearity with a correlation coefficient of 0.999 over the injected concentration range of 5-2000 nmol/L. LOQ and LOD were 3 and 1 nmol/L, respectively. The usefulness of this method was demonstrated by SA quantification in an AF sample of an affected fetus and in plasma of patients treated with NTBC. The results demonstrate that this novel GC/MS method may be a valuable tool for metabolic evaluation and clinical use.

Alemtuzumab, the monoclonal anti-CD52 antibody, has clinical activity in B-cell and T-cell malignancies at the dose of 30 mg three times weekly for 9-12 weeks. This standard regimen induced responses usually shorter than 6 months. To prolong time to progression, we initialized a phase II study with an identical initial scheme until partial response, followed by a maintenance therapy lasting at least 4 months. Eleven heavily pretreated patients (8 with B-chronic lymhocytic leukemia (B-CLL) and 3 with small lymphoctyic lymphoma (SLL)) have been treated with this maintenance regimen (MR patients) and were retrospectively compared to 5 patients (3 B-CLL and 2 SLL) treated with the standard regimen (SR patients). Patients characteristics before treatment were identical in both groups. Objective response was reached by 9 (82%) MR patients and 3 (60%) SR patients (p NS). After the treatment, 8 (73%) MR patients and all SR patients progressed with a median time at 12.2 months and 3 months respectively. Survival time from alemtuzumab was significatively different (P0.005). None of the patients died in the MR group with a median follow-up at 16 months. In the SR group, the median survival from alemtuzumab was 5.9 months. We did not observe any differences in terms of hematological toxicites and infections between the two groups. In conclusion, maintenance alemtuzumab therapy seems to increase the time to progression and the survival, without adding hematological toxicities and infectious complications. More patients are needed to confirm this observation.

The introduction of our voluntary mass screening programme in 1971, in the province of Quebec, has permitted us to detect different inborn errors of metabolism in the newborn population using a thin-layer chromatographic (TLC) technique with sequential use of different sprays on the same plate. Abnormalities in amino acids and organic acids are detected in urine filter paper specimens of 21-day-old babies. Initial parental compliance is 90% and climbs to 99.25% for repeat sample requests. Screening is centralized in one laboratory, while diagnosis, counselling, management and follow-up are done in four regional centres. Over 25 inherited Mendelian disorders can be identified. There have been certain modifications in our programme throughout the years in order to increase efficiency, screen for a larger number of disorders, improve the quality of the collection of the urine filter paper samples, increase parental compliance and better manage the data bank. However, one goal has remained a priority: early prevention of genetic diseases. We present an overall view of our screening programme with an add-on technique to detect different organic acidurias, our recent statistics and the modifications implemented over the years.

Using a protein truncation assay, we have identified a new mutation in the neurofibromatosis type 1 (NF1) gene that causes a severe defect in NF1 pre-mRNA splicing. The mutation, which consists of a G to A transition at position +1 of the 5' splice site of exon 12a, is associated with the loss of both exons 11 and 12a in the NF1 mRNA. Through the use of in vivo and in vitro splicing assays, we show that the mutation inactivates the 5' splice site of exon 12a, and prevents the definition of exon 12a, a process that is normally required to stimulate the weak 3' splice site of exon 12a. Because the 5' splice site mutation weakens the interaction of splicing factors with the 3' splice site of exon 12a, we propose that exon 11/exon 12a splicing is also compromised, leading to the exclusion of both exons 11 and 12a. Our results provide in vivo support for the importance of the exon definition model during NF1 splicing, and suggest that the NF1 region containing exons 11 and 12a plays an important role in the activity of neurofibromin.

Decreased bone mineral density (BMD) has been reported in patients with celiac disease in association with secondary hyperparathyroidism. The present study investigated whether basal parathyroid hormone (PTH) remained elevated and whether abnormalities of parathyroid function were still present in celiac disease patients treated with a gluten-free diet. Basal seric measurements of calcium and phosphate homeostasis and BMD were obtained in 17 biopsy-proven patients under treatment for a mean period of 5.7±3.7 years (range 1.1 to 15.9). In addition, parathyroid function was studied with calcium chloride and sodium citrate infusions in seven patients. Basal measurements of patients were compared with those of 26 normal individuals, while parathyroid function results were compared with those of seven sex- and age-matched controls. Basal results were similar in patients and controls except for intact PTH (I-PTH) (3.77±0.88 pmol/L versus 2.28±0.63 pmol/L, P

Department of Genetics, The McGill University-Montreal Children’s Hospital Research Institute, Montreal, CanadaWe genotyped 19 NF1 families from theFrench Canadians of the Que´bec populationwith six intragenic polymorphic markersincluding 2 RFLPs (EcoRI and RsaI) and 4microsatellites (IVS26-2.3, IVS27AC28.4, IVS27AC33.1, and IVS38GT53.0). Genotype ana-lysis indicated families 7610 and 7473 beardeletions. In Family 7610 the deletionremoved the entire NF1 gene except exons1 to 4b. The breakpoint of the deletion islocated between exons 4a and 4b. The dele-tion 7473 was derived from the maternalchromosome and exons 1 to 5 were deleted.The breakpoint of the deletion is locatedbetween exons 7 and 13. Their phenotypesare reported. The allele frequencies of mi-crosatellites IVS27AC28.4 and IVS38GT 53.0are compared to previously reported datafrom Caucasians, including Spanish andItalians. The difference is statistically sig-nificant(P

Neuroblastoma exhibits many characteristics which would suggest that preclinical detection may improve outcome. The Quebec Neuroblastoma Screening Project was initiated to determine whether mass screening could reduce mortality in a large cohort of infants. All 476,603 children born in the province of Quebec during a 5-year period of time (1 May 1989 to 30 April 1994) were eligible for determinations of urinary catecholamine metabolites at 3 weeks and 6 months of age. Children with positive screening were referred to one of four paediatric cancer centres in Quebec for uniform evaluation and treatment. Standardised incidence ratios (SIRs) were calculated for neuroblastoma in Quebec and two comparable population-based controls during the same period of time using similar ascertainment procedures. Compliance with screening in Quebec was 91% at 3 weeks (n = 425,816) and 74% at 6 months (n = 349,706). Up to 31 July 1995 with a follow-up of the birth cohort of 15-75 months, 118 cases of neuroblastoma were diagnosed, 43 detected preclinically by screening, 20 detected clinically prior to screening at 3 weeks of age and 55 detected clinically after 3 weeks of age having normal screens (n = 52) or never screened (n = 3). Based on data from concurrent control populations, 54.5 cases of neuroblastoma would have been expected in Quebec during the study period for an SIR of 2.17 (95% CI 1.79-2.57, P < 0.0001). For the two control groups, the overall SIR was 1.00 (NS). SIRs for Quebec by age at diagnosis in yearly intervals show a marked increased incidence under 1 year of age (SIR = 2.85, 95% CI 2.26-3.50), with no reduction in incidence in subsequent years. We conclude that screening for neuroblastoma markedly increases the incidence in infants without decreasing the incidence of unfavourable advanced stage disease in older children. It is unlikely that screening for neuroblastoma in infants will reduce the mortality of this disease.

The study examined the stability of HVA and VMA in 1-ml aliquots of a single urine sample stored on filter paper at different temperatures for 2 years. The results showed that HVA and VMA were stable in dried filter paper when stored at 4 °C or lower temperature. Storage at room temperature resulted in degradation of the sample.

We studied genotype-phenotype correlations in a group of 100 patients with typical Friedreich ataxia (FRDA), and in three groups of patients with atypical clinical presentations, including 44 Acadian FRDA, 8 late-onset FRDA (LOFA), and 6 FRDA with retained reflexes (FARR). All patients, except 3 with typical FRDA, carried two copies of the FRDA-associated GAA triplet repeat expansion. Overall, the phenotypic spectrum of FRDA appeared to be wider than defined by the currently used diagnostic criteria. Our study indicated the existence of several sources of variability in FRDA. Patients with larger GAA expansions tended to have earlier onset and were more likely to show additional manifestations of the disease. Mitotic instability of the expanded GAA repeats may partially account for the limited degree of correlation between expansion sizes as determined in lymphocytes and clinical parameters. Some clinical variants associated with specific FRDA haplotypes, such as Acadian FRDA and FARR, turned out to be unrelated to expansion sizes. No polymorphism in the frataxin coding sequence could be associated with these clinical variants.

Neuroblastoma has many characteristics which suggest that preclinical detection might improve outcome. The Quebec Neuroblastoma Screening Project was initiated to determine whether mass screening could reduce mortality in a large cohort of infants. As an early endpoint, we report whether screening could reduce the incidence of poor-prognosis neuroblastoma in children with advanced-stage disease over 1 year of age.All 476,603 children born in the province of Quebec during the 5-year period of May 1, 1989, to April 30, 1994, were eligible for urinary assay of homovanillic acid and vanillylmandelic acid at 3 weeks and 6 months of age. Children with a positive screen were referred to one of four paediatric cancer centres in the province for uniform evaluation and treatment if necessary. Standardised incidence ratios (SIRs) were calculated for neuroblastoma in the province and two similar population-based controls, the state of Minnesota and the province of Ontario, during the same period of time and with similar ascertainment procedures.Compliance with screening in Quebec province was 91% at 3 weeks (n = 425,816) and 74% at 6 months (n = 349,706). Through July 31, 1995, with a follow-up of the birth cohort of 15-75 months, 118 cases of neuroblastoma were diagnosed, 43 detected preclinically by screening, 20 detected clinically before screening at 3 weeks of age, and 55 detected clinically after 3 weeks of age having normal screens (52) or never screened (3). Retrospective analysis of stored samples confirmed that 49 of 52 patients missed by screening had levels of catecholamine metabolites that were too low to be detected at 6 months or earlier. Based on US Surveillance, Epidemiology and End Results data, 54.5 cases of neuroblastoma would have been expected in Quebec province during the study period, for an SIR of 2.17 (95% CI 1.79-2.57, p0.0001). For the two control groups, 43 and 80 cases of neuroblastoma were detected, respectively, compared with 37.9 and 85.4 expected, overall SIR 1.00 (not significant). SIRs for Quebec province by age at diagnosis in yearly intervals show a marked increased incidence under 1 year of age (SIR 2.85, 2.26-3.50), with no reduction in incidence in subsequent years. Limiting analysis to only patients diagnosed over 1 year of age with advanced-stage disease, 22 cases were detected in Quebec province versus 14.4 expected (SIR 1.52, 0.95-2.23). Data in the two control groups show no significant increase or decrease in any-stage disease in children under or over the age of 1 year, except for an increase in early-stage disease in Minnesota children over 1 year: 10 versus 3.8 expected (SIR 2.67, 1.27-4.58).Screening for neuroblastoma increases the incidence in infants without decreasing the incidence of unfavourable advanced-stage disease in older children. It is unlikely that screening for neuroblastoma in infants will reduce mortality for this disease.

Neuroblastoma is the most common extra-cranial solid tumor of childhood 1. It originates in cells of the neural crest, and so can be found anywhere along the paravertebral sympathetic chain or in the adrenal gland. In the last 15 years, new developments in the genetics and biology of neuroblastoma , have led to a better understanding of the natural history and prognostic features of this cancer. The presence of identifying biochemical markers detectable in the urine of patients with neuroblastoma, as well as the remarkably inferior survival of children diagnosed at more than 12 months of age, have led some groups to screen infants for neuroblastoma, in the hope of decreasing both overall mortality, as well as the incidence of advanced stage disease. This article reviews some clinical aspects of neuroblastoma , but emphasizes the genetic and biologic features in relation to prognosis and treatment. Finally, we discuss the different screening experiences for this disease, in particular from the Quebec Neuroblastoma Screening Project.

Background Use of combination antiretroviral therapy (cART) and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) with or without rituximab for treatment of diffuse large B-cell lymphoma (DLBCL) in HIV substantially increases response rates but may also increase toxicity, possibly due to antiretroviral– antineoplastic drug interactions. The objective of this study was to evaluate the frequency of complete remission (CR) of DLBCL in patients treated with CHOP while receiving a protease inhibitor (PI) versus a non-PI-based cART. Methods A retrospective multicentre pilot study was conducted in HIV-infected patients on cART treated for DLBCL with CHOP between 2002–2010 in three academic hospitals. Results A total of 34 patients were included with 65% and 35% of patients receiving a PI and non-PI-based cART, respectively. Baseline characteristics between groups were similar; overall 85% were male, median age was 43 years, 50% had an International Prognostic Index (IPI) of 2–3 and median CD4+ T-cell count was 225 cells/mm3. CR was achieved in 77% and 58% of patients in the PI and non-PI groups, respectively ( P=0.21), with 65% and 63% of patients achieving 2-year overall survival ( P=1.00). A multivariate analysis showed that lower IPI score alone was significantly associated with higher CR rates ( P=0.05). Toxicity was similar between both groups. Conclusions Similar efficacy and toxicity of CHOP was observed in patients receiving a PI and non-PI-based cART.

Background. The Quebec Neuroblastoma Screening Project was initiated to assess clinical and biologic aspects of neuroblastomas detected by screening infants born in the province of Quebec from May 1, 1989, to April 30, 1994. Methods. Infants were screened for preclinical detection of neuroblastoma by determination of catecholamine metabolites, vanillylmandelic acid (VMA), and homovanillic acid (HVA). Patients with tumors discovered through this screening as well as patients in the same birth cohort with clinically detected tumors were referred to Quebec Oncology Centers for further investigation, diagnosis, and treatment. Pathology specimens were submitted to Childrens Hospital Los Angeles for central review. Tumors were histopathologically classified according to the Shimada system. Results. As of August, 1993, 340,000 infants were screened at 3 weeks and 245,000 of them were retested at 6 months of age. Thirty-one tumors were detected through this screening and removed. Histologic material was available for 27 cases: 14 were detected at 3 weeks of age and 13 at 6 months of age. Twenty-six patients had tumors with favorable histology (FH), and one patient had a Stage I tumor with unfavorable histology (UH). At the time of this writing, all mass screening patients are alive, including one child with relapsed disease. During this period, 48 tumors were detected clinically in the same birth cohort, 40 of which were evaluated histologically. Of these 40 cases, 28 of 29 tumors diagnosed in patients up to age 12 months indicated an FH, whereas 9 of 11 tumors diagnosed in patients older than age 12 months indicated a UH. All patients with FH tumors are alive including a child with relapsed disease. The single patient with UH diagnosed before age 12 months died of disease. Of the nine patients with UH diagnosed after age 12 months, four died of disease, one relapsed, and four are alive (including one treated with bone marrow transplantation) after variable follow-up periods. Conclusions. The tumors detected by mass screening, similar to those tumors detected through clinical examination before age 12 months, were predominantly FH with good prognosis. However, those tumors that were missed by screening and were detected clinically after the patient was 12 months of age were predominantly UH, with serious clinical problems. This subgroup of patients not detectable by the current screening system presents an immediate and important clinical challenge that should be addressed in future studies. Cancer 1995; 76:2363–71.

Brain metastases from colorectal cancer (crc) are quite rare. Here, we review the characteristics, presentation, and clinical course of such patients at our institution. We reviewed the medical records of patients with brain metastases from crc treated during 2000&ndash, 2009. Associations between patient, tumour characteristics, treatment modality, and survival were assessed using the Kaplan&ndash, Meier method. We identified 48 patients (25 men, 23 women) who developed brain metastases from crc. The median age at diagnosis of the brain metastases was 63 years (range: 37&ndash, 84 years). In 23 of the patients (48%), the primary tumour occurred in the rectum. At diagnosis of brain metastases, 43 patients (90%) also had other systemic metastases (mainly pulmonary and hepatic). The median interval between diagnosis of the primary tumour and of the brain metastases was 24 months. Median survival after a diagnosis of brain metastasis from crc was 4 months (range: 1&ndash, 13 months). We observed substantially better survival (13 months, p < 0.001) in patients treated with surgery followed by whole-brain radiotherapy (wbrt) than in those treated with radiotherapy or surgery alone. Sex, age, location and number of brain metastases, and timing of diagnosis did not affect survival. Brain metastases from crc develop late in the course of the disease, given that most patients already have other secondary lesions. Prognosis in these patients is poor, with those receiving treatment with surgery and wbrt having the best overall survival. Early detection and treatment of brain metastases with new systemic therapies may improve outcomes.

Purpose Bortezomib has demonstrated promising activity in patients with follicular lymphoma (FL). This is the first study to evaluate the safety and efficacy of bortezomib added to rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) in previously untreated advanced-stage FL. Patients and Methods This is a phase II multicenter trial adding bortezomib (1.3 mg/m2 days 1 and 8) to standard-dose R-CVP (BR-CVP) for up to eight cycles in patients with newly diagnosed stage III/IV FL requiring therapy. Two co-primary end points, complete response rate (complete response [CR]/CR unconfirmed [CRu]) and incidence of grade 3 or 4 neurotoxicity, were assessed. Results Between December 2006 and March 2009, 94 patients were treated with BR-CVP. Median patient age was 57 years (range, 29 to 84 years), and the majority had a high (47%) or intermediate (43%) Follicular Lymphoma International Prognostic Index score. BR-CVP was extremely well tolerated, with 90% of patients completing the intended eight cycles. No patients developed grade 4 neurotoxicity, and only five of 94 patients (5%; 95% CI, 0.8% to 9.9%) developed grade 3 neurotoxicity, which was largely reversible. On the basis of an intention-to-treat analysis, 46 of 94 patients (49%; 95% CI, 38.8% to 59.0%) achieved a CR/CRu, and 32 of 94 patients (34%) achieved a partial response, for an overall response rate of 83% (95% CI, 75.4% to 90.6%). Conclusion The addition of bortezomib to standard-dose R-CVP for advanced-stage FL is feasible and well tolerated with minimal additional toxicity. The complete response rate in this high-risk population compares favorably to historical results of patients receiving R-CVP. Given these results, a phase III trial comparing BR-CVP with R-CVP is planned.

BACKGROUND Neuroblastoma has several characteristics that suggest that preclinical diagnosis might improve outcome. Therefore, the Quebec Neuroblastoma Screening Project was undertaken from 1989 to 1994 to examine infants at 3 weeks and 6 months by measuring urinary catecholamine metabolites. PROCEDURE Over the 5-yr period, 45 tumors were detected by screening, 20 were identified clinically prior to the third week, and 64 were identified clinically at a later time. We analyzed available tumors for Shimada histopathology, tumor ploidy, MYCN copy number and serum ferritin. RESULTS Of the tumors detected by screening, only 2 of 45 tested had unfavorable histology, 2 of 45 had diploid or tetraploid DNA content, 0 of 43 had MYCN amplification, and 4 of 44 had elevated serum ferritin. All of these patients are alive and well. The 20 patients detected prior to the 3-week screen had similar biological characteristics. In contrast, of the patients detected clinically after 3 weeks of age, 19 of 51 testedhad unfavorable histology, 25 of 66 had diploid or tetraploid tumors, 12 of 56 had MYCN amplification, and 14 of 54 had elevated ferritin. CONCLUSIONS The difference between the screened and clinically detected cases was highly significant for each biological variable. Preliminary data on other biological variables, such as neurotrophin expression and allelic loss on 1 p in these patients are consistent with the above findings. These data suggest that mass screening for neuroblastoma at or before 6 months of age detects almost exclusively tumors that have favorable biological characteristics, many of which might have regressed spontaneously. Thus, continued mass screening for neuroblastoma at 6 months is unlikely to accomplish its intended goal, and should probably be discontinued.

Purpose Bendamustine HCl is a bifunctional mechlorethamine derivative with clinical activity in the treatment of non-Hodgkin's lymphoma. This study evaluated bendamustine plus rituximab in 67 adults with relapsed, indolent B-cell or mantle cell lymphoma without documented resistance to prior rituximab. Patients and Methods Patients received rituximab 375 mg/m2 intravenously on day 1 and bendamustine 90 mg/m2 intravenously on days 2 and 3 of each 28-day cycle for four to six cycles. An additional dose of rituximab was administered 1 week before the first cycle and 4 weeks after the last cycle. Sixty-six patients (median age, 60 years) received at least one dose of both drugs. Results Overall response rate was 92% (41% complete response, 14% unconfirmed complete response, and 38% partial response). Median duration of response was 21 months (95% CI, 18 to 24 months). Median progression-free survival time was 23 months (95% CI, 20 to 26 months). Outcomes were similar for patients with indolent or mantle cell histologies. The combination was generally well tolerated; the primary toxicity was myelosuppression (grade 3 or 4 neutropenia, 36%; grade 3 or 4 thrombocytopenia, 9%). Conclusion Bendamustine plus rituximab is an active combination in patients with relapsed indolent and mantle cell lymphoma.

A large neuroblastoma screening study was recently started in the province of Quebec, Canada. This project, a collaboration between the Quebec Network for Genetic Medicine and the University of Minnesota, is studying the impact of screening infants for the preclinical detection of neuroblastoma on the population-based mortality caused by this tumor. All infants born in Quebec during a 5-year period will be screened twice, at 3 weeks and at 6 months. Urinary homovanillic acid and vanillylmandelic acid determination from dried filter paper samples is used for screening. Initial qualitative screening is done by means of thin-layer chromatography with confirmatory quantitative screening by gas chromatography-mass spectrometry (GC-MS). During the initial 6 months of 3-week screening, 41 673 neonates (92% compliance rate) were screened and 10.6% of them were tested also by GC-MS. Nine of these neonates had positive results on two GC-MS tests and were referred for evaluation to rule out the presence of neuroblastoma. Four had the tumor, 1 had a calcified adrenal gland, and 4 had no tumor detected. Three additional neonates had clinical diagnosis of neuroblastoma before they reached the screening age of 3 weeks. A neuroblastoma that did not secrete homovanillic acid or vanillylmandelic acid was diagnosed clinically in 1 additional patient who tested negative by screening.

In a retrospective study, 32 patients with myotonic dystrophy, including congenital (n=17) and infantile/juvenile forms (n=15) were studied during a long follow-up lasting 7-28 years (median: 17 years). The clinical presentation was extremely variable; however, a continuum did exist between severe and less severe congenital forms, and later-onset forms, without genotype-phenotype correlation. We observed some unusual presentations, such as 3 cases of isolated club-feet during the neonatal period, and 7 patients (23%) with a completely isolated mental deficiency, language delay and school failure, who only completed the clinical picture several years later. Wechsler scale testing was performed in all cases, and repeated with 8 patients. It demonstrated a decrease in intellectual abilities in 5 patients, suggesting the possibility of a degenerative cerebral process occurring in these children. This decrease has also been reported in some adult cases. This study illustrates the extremely heterogeneous clinical presentation of myotonic dystrophy in childhood.

Background Given the widespread use of bendamustine, data on long-term outcomes are essential for patients and clinicians to understand potential risks and benefits of therapy. Despite a long history as treatment for indolent non-Hodgkin lymphoma (iNHL), such information has been limited. We retrospectively reviewed the registration SDX-105-01 and SDX-105-03 trials (bendamustine 120 mg/m2 days 1+2 q21 days) and SDX-105-02 trial (bendamustine 90 mg/m2 days 1+2 plus rituximab 375 mg/m2 day 1 q28 days) to characterize long-term toxicity and efficacy of patients treated with bendamustine. Methods Patient level data was retrospectively collected from patients treated on the SDX-01, 02, and 03 trials. Descriptive statistics were used to summarize patient characteristics and events. The Kaplan-Meier method was used to report time-to-event outcomes. Wilcoxon Rank sum test was used to test the difference between events for continuous variables. Results Out of the total 245 subjects at 45 sites, data were available for 149 subjects (60 men, 89 women; SDX-01 N = 40, SDX-02 N = 43, SDX-03 N = 66) at 21 sites (included based on willingness to participate). The median age was 60 years at the start of bendamustine (range 39-84). The histologies included grade 1-2 follicular lymphoma (FL; N = 73), grade 3 FL (N = 23), SLL (N = 20), marginal zone lymphoma (N = 15), mantle cell lymphoma (N = 9), transformed lymphomas (N = 5), lymphoplasmacytic lymphoma (N = 2), and not reported (N = 2). The average time from diagnosis to study entry was 41 months (range 2-229). The median number of therapies prior to bendamustine was 2.5 (range 1-8). Patients received a median of 6 cycles and a median total dose of bendamustine of 1408 mg (max 5216, min 240). With a median follow up of 8.8 years after study entry, 80 patients had experienced progression. The median PFS was 18.4 months (95% C.I. 11.9-27.8); the 3-year PFS was 37%. During follow up, 93 patients had died at a median time of 22.3 months after the start of bendamustine. The median OS after start of bendamustine was 65.9 months (95% C.I. 38.8-91.8). The causes of death were lymphoma (N = 45), bendamustine toxicity (N = 2), subsequent treatment toxicity (N = 8), MDS/AML (N = 5), other cancer (N = 2), other (N = 6), and unknown (N = 25). A total of 98 patients received a median of 2 therapies following bendamustine (range 1-9), with the first treatment occurring a median of 13.2 months (range 0-111.3) following the final dose of bendamustine. The reported best response to the first subsequent treatment was CR (N = 11), PR (N = 6), SD (N = 21), PD (N = 12), not evaluable (N = 25), and unknown (N = 22) and the median OS of these patients was 51.3 months (95% C.I. 33.4-80.3). Fourteen patients had attempted stem cell collection following bendamustine, 10 of which had stem cells collected successfully. Eight patients had stem cells collected with GCSF alone (N = 7) or GCSF plus chemotherapy (N = 1). Twenty-three patients developed 25 cancers following bendamustine. Six patients developed MDS and 2 more developed AML. The median time to MDS/AML following bendamustine was 24 months (range 10-103) with an annualized incidence rate of 0.52%/year. One of patient had a prior myeloid neoplasm and one had a prior germ cell tumor. In univariate analysis, neither age at lymphoma diagnosis (P=0.438), nor total number of systemic regimens (P=0.443), nor total dose of bendamustine (P=0.291) was associated with MDS/AML. Other cancers included adenocarcinoma (colon N = 2; prostate N = 2; lung N = 2; breast N = 1), non-melanoma skin cancer (N = 6), squamous cell carcinoma (N = 2), hepatocellular carcinoma (N = 1), and bladder cancer (N = 1). None of these occurred in the 12 patients with a history of solid tumor before bendamustine. Conclusions With a median follow up of survivors of > 8 years, there was no evidence that bendamustine in the setting of previously treated iNHL was associated with a high rate of long-term bone marrow toxicity. Rates of MDS/AML and failure to collect stem cells were lower than expected. However, roughly half of all patients died within 5 years of starting bendamustine, thereby limiting the long-term follow up. A small but meaningful number of patients achieved durable remissions following bendamustine. These rigorously collected, patient-level, long-term follow up data provide reassurance that bendamustine or bendamustine plus rituximab is associated with efficacy and safety for many patients with relapsed or refractory iNHL. Disclosures Martin: Janssen: Consultancy, Honoraria; Acerta: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bayer: Consultancy. Cheson:AstraZeneca: Consultancy; Ascenta: Research Funding; Spectrum: Consultancy; Astellas: Consultancy; MedImmune: Research Funding; Pharmacyclics: Consultancy, Research Funding; Teva: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding. Williams:Celgene: Consultancy, Other: Research funding to my institution; Takeda: Consultancy, Other: Research Funding to my institution; Genentech: Other: Research funding to my institution. Bartlett:Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; Seattle Genetics: Consultancy, Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Szer:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Australia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Smith:celegene, spectrum, genentech: Honoraria. Leonard:Weill Cornell Medical College: Employment; Genentech: Consultancy; Medimmune: Consultancy; AstraZeneca: Consultancy; Spectrum: Consultancy; Boehringer Ingelheim: Consultancy; Vertex: Consultancy; ProNAI: Consultancy; Biotest: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Mirati Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy.

e13556 Background: The combination of epigenetic drug decitabine with genistein, a natural isoflavone, produces synergistic responses in preclinical studies with particular activity shown in lung c...

Background: Well-designed evaluations of health services are frequently made today. However, the extent of the evaluations’ benefi ts and costs is not well documented, creating uncertainty whether their use is optimal from society’s perspective. We examined these costs and benefi ts using data from one well-designed evaluation, the Quebec Neuroblastoma Screening Project (QNSP). It screened most Quebec newborns between 1989 and 1994 for neuroblastoma. As previously reported, the screening did not reduce neuroblastoma mortality and caused adverse health effects. Methods: We compared the cost of doing the QNSP with its benefi ts. Had the QNSP not been undertaken, neuroblastoma screening would have been implemented throughout North America. We assume that screening would have started in 1989 and ended in 2002. The QNSP’s benefi ts include the health costs and adverse health effects averted by not using ineffective screening during those 14 years. In our calculations we used neuroblastoma incidence data for the QNSP and for Ontario where there was no screening, detailed data describing the health services used by the patients, and Quebec cost data for those services. Results: The QNSP cost $8.77 million (2002 US dollars). By not implementing similar screening programs between 1989 and 2002, the United States and Canada avoided $574.1 million in health costs, the unnecessary treatment of 9223 children, and false-positive fi ndings for 5003 children screened. Conclusions: The health care costs and adverse health effects averted by the QNSP justify its costs. These results show that well-designed evaluations can yield — at least sometimes — benefi ts substantially greater than their high costs. This raises an important policy issue: are these evaluations now being under- or over used? [J Natl Cancer Inst 2005;97:1118 – 24]

Introduction Subcutaneous (SC) injection of bortezomib is more convenient for patients and staff. In September 2012, we standardised all bortezomib containing-protocols at our centre and changed the route of administration form intravenous to SC. Hematologic toxicity is commonly reported with these protocols. Currently, in our protocols, a complete blood count (CBC) is needed before every injection. Objectives This retrospective study aimed to analyse the rate of neutropenia and thrombocytopenia with Vel-Dex, VMP and CyBorD based on a threshold at day 1 to see if a CBC is needed before every injection in all patients. Blood pressure (BP) was measured before and after each SC injection to evaluate the risk of hypotension. Methods This retrospective study included all patients who received SC bortezomib in Vel-Dex, VMP and CyBorD protocols for multiple myeloma or amyloidosis at the Centre hospitalier de l'Université de Montréal (CHUM) between June 1, 2012 and May 31, 2013. Data was collected through medical and pharmaceutical patient records. Our local ethics board approved this study. Our main outcome is defined as the presence of neutropenia and thrombocytopenia for CyBorD (days 1, 8, 15 and 22 q 28 days), Vel-Dex (days 1, 4, 8 and 11 q 21 days) and VMP (days 1, 8, 22 and 29 q 42 days or days 1, 8, 15, 22 q 35 days) dichotomized at a threshold of ≥ 1.5 x 109 and ≥ 75 x 109respectively. A McNemar Test was used to estimate the association between the neutropenia and thrombocytopenia based on the dichotomized value on day 1. Results A total of 69 patients received bortezomib for MM (65 patients) or amyloidosis (4 patients). Median age was 67 years (SD ± 9.1) and 58 % of patients were male. Patients received Vel-Dex (23.2%), VMP (36.2%) and CyBorD (40.6%) protocols in 1st line eligible to stems cells transplant (26.2%), 1st line non-eligible (40.0%) or ≥ 2nd line (33.8%) for a total of 349 cycles. The median starting dose of bortezomib was 1.3 mg/m2 (SD ± 0.14). As shown in tables I and II, there is a statistical evidence of association when neutrophils ≥ 1.5 x 109 and platelets ≥ 75 x 109 at day 1 with the minimum of neutrophils and platelets on the CBC for the rest of the cycle of CyBorD and VMP. For Vel-Dex no significant association was seen because the incidence of neutropenia and thrombocytopenia is very low and doesn’t depend on a threshold at day 1. A patient, who has values above this threshold at day 1, could receive the rest of the cycle (Vel-Dex, CyBorD or VMP) without additional CBCs. When patients had blood counts below this threshold, chemotherapy was delayed 18 times (generally at day 1) or cancelled 39 times (other days). Patient previously exposed to many lines of therapy tend to have lower neutrophils or platelets counts. Also, a total of 1224 BP values before after SC bortezomib were analysed. No significant difference was detected between the average systolic (122 vs 122; p=0.43) and diastolic BP (70 vs 71; p=0.33) before and after treatment. Hypotension, defined as a drop of 20 mmHg of systolic BP, occurred 37 times (3.0%) but systolic BP was never below 90 mmHg and treatment was not necessary. A small increase of heart rate (82 vs 84; p Table I: Rate of neutropenia during the cycle according to day-1 neutrophil counts Protocols CyBorD VMP Vel-Dex Neutrophils at day 1 of each cycle n ≥ 1.5 n < 1.5 p value n ≥ 1.5 n < 1.5 p value n ≥ 1.5 n < 1.5 p value Neutrophils ≥ 1.5 for the rest of the cycle 81.8 % 20 % p Table II: Rate of thrombocytopenia during the cycle according to day-1 platelet counts Protocols CyBorD VMP Vel-Dex Platelets at day 1 of each cycle Plt ≥ 75 Plt < 75 p value Plt ≥ 75 Plt < 75 p value Plt ≥ 75 Plt < 75 p value Platelets ≥ 75 for the rest of the cycle 97.7 % 15.4 % p Conclusion Our results demonstrate that the rate of thrombocytopenia and neutropenia was very low in patients who have neutrophils and platelets ≥ 1.5 x 109 and ≥ 75 x 109 at day 1 of each cycle of Vel-Dex, VMP and CyBorD. In these patients, no CBC seems necessary for the rest of cycle. Decreasing the number of CBC will use less resources, decrease costs and most importantly, improve the patient’s care by minimising interventions without increasing risk of adverse events. Disclosures Adam: Janssen: Honoraria. Lemieux-Blanchard:Celgene: Honoraria. Lemieux:Janssen: Honoraria.

8516^ Background: In the pivotal FIRST trial, continuous lenalidomide plus low-dose dexamethasone (Rd; [N = 535]) improved progression-free survival (PFS) and overall survival (OS) compared with 18 cycles of Rd (Rd 18; [N = 541] for and 12 cycles of melphalan-prednisone-thalidomide (MPT; [N = 547] for 72 weeks) (Facon, Blood 2013). This analysis evaluates HRQOL changes in these NDMM pts. Methods: HRQOL was assessed using the EORTC-QLQ-C30, QLQ-MY20, and EQ-5D validated questionnaires at baseline, end of cycle 1, then 3, 6, 12, 18 months (mos), and at study discontinuation. Cross sectional and longitudinal analyses were performed. Changes from baseline at each time-point were estimated with a focus on seven pre-selected and clinically-relevant domains (Global QOL, Physical Functioning, Pain, Fatigue, Disease Symptoms, Side Effects of Treatment, and Health Utility). Results: Questionnaire compliance was high (≥ 84%) at Cycle 1, 3 and 6 mos across treatment arms. At 12 and 18 mos, the compliance rates were l...

Background: The clinical spectrum of methylmalonic aciduria (MMAuria) ranges from severe, neonatal acidosis to benign asymptomatic organic aciduria. In 1975, screening for MMAuria was established in the province of Quebec. Although newborn screening programs facilitate presymptomatic detection and treatment and also detect asymptomatic variants, uncertainties about potential long-term hazards of mild to moderate elevations of MMA create concern. The objective of this study was to examine the outcome of individuals excreting low to intermediate quantities of MMA, ascertained by a newborn screening program. Results and study design: One hundred and thirty-six individuals with elevations of urinary MMA were initially identified by the screening program; 122 individuals were noted to have excretion of urinary MMA

The debate about whether to implement screening for neuroblastoma in North America is ongoing. Those in favor of implementing mass screening are quoting results from programs in Japan where the government has mandated neuroblastoma screening for infants.1-7 In North America, the Quebec Neuroblastoma Screening Study (QNS) has been established as a result of the collaboration between the Quebec Network for Genetic Medicine and the University of Minnesota. This controlled research project is studying the impact of screening infants for the preclinical detection of neuroblastoma on changes in population-based mortality caused by this tumor as well as on various biologic parameters and their relation to prognosis.8