Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to ...the tumor.
To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system.
In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis.
Patients were randomized 2:1 to TTFields plus maintenance temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz frequency, alternating electric fields, was delivered (≥ 18 hours/d) via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both groups (150-200 mg/m2) for 5 days per 28-day cycle (6-12 cycles).
Progression-free survival (tested at α = .046). The secondary end point was overall survival (tested hierarchically at α = .048). Analyses were performed for the intent-to-treat population. Adverse events were compared by group.
Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men 68%), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields-temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone.
In the final analysis of this randomized clinical trial of patients with glioblastoma who had received standard radiochemotherapy, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the previous interim analysis.
clinicaltrials.gov Identifier: NCT00916409.
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative neuromuscular disease that presents primarily in children. Abnormalities in the
gene cause reduced levels of the survival ...motor neuron (SMN) protein, while a second gene,
, produces low levels of functional SMN protein. Currently available drugs do not cure, so a significant unmet need remains for patients treated after symptom onset.
Drugs available in the clinic, investigational agents and key questions for researchers are discussed. A pragmatic search of the literature was performed to identify therapies in late stages of preclinical, or in early stages of clinical development. This list was compared to the CureSMA pipeline for completeness. Drugs approved for indications that have potential for impact for SMA were included. These drugs target the primary deficiency in SMN protein or other pathways involved in SMA pathophysiology that are not SMN-protein dependent.
Children treated after the onset of symptoms continue to have significant disability. Given the heterogeneity of the population phenotype evidenced by variable response to initial therapy, age at treatment onset and the need to demonstrate added value beyond approved therapeutics, the clinical development of new drugs will be challenging.
Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared ...first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC.
We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more.
Among the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval CI, 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy.
Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533 .).
To examine population-based improvements in survival and the impact of clinical covariates on outcome among children and adolescents with acute lymphoblastic leukemia (ALL) enrolled onto Children's ...Oncology Group (COG) clinical trials between 1990 and 2005.
In total, 21,626 persons age 0 to 22 years were enrolled onto COG ALL clinical trials from 1990 to 2005, representing 55.8% of ALL cases estimated to occur among US persons younger than age 20 years during this period. This period was divided into three eras (1990-1994, 1995-1999, and 2000-2005) that included similar patient numbers to examine changes in 5- and 10-year survival over time and the relationship of those changes in survival to clinical covariates, with additional analyses of cause of death.
Five-year survival rates increased from 83.7% in 1990-1994 to 90.4% in 2000-2005 (P < .001). Survival improved significantly in all subgroups (except for infants age ≤ 1 year), including males and females; those age 1 to 9 years, 10+ years, or 15+ years; in whites, blacks, and other races; in Hispanics, non-Hispanics, and patients of unknown ethnicity; in those with B-cell or T-cell immunophenotype; and in those with National Cancer Institute (NCI) standard- or high-risk clinical features. Survival rates for infants changed little, but death following relapse/disease progression decreased and death related to toxicity increased.
This study documents ongoing survival improvements for children and adolescents with ALL. Thirty-six percent of deaths occurred among children with NCI standard-risk features emphasizing that efforts to further improve survival must be directed at both high-risk subsets and at those children predicted to have an excellent chance for cure.
Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for ...mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease.
Fifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three of the patients received a low dose (6.7×10
vg per kilogram of body weight), and 12 received a high dose (2.0×10
vg per kilogram). The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilatory assistance. In exploratory analyses, we compared scores on the CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale of motor function (ranging from 0 to 64, with higher scores indicating better function) in the two cohorts and motor milestones in the high-dose cohort with scores in studies of the natural history of the disease (historical cohorts).
As of the data cutoff on August 7, 2017, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone.
In patients with SMA1, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts. Further studies are necessary to confirm the safety and efficacy of this gene therapy. (Funded by AveXis and others; ClinicalTrials.gov number, NCT02122952 .).
Real-world data inform the outcome comparisons and help the development of new therapeutic strategies. To this end, we aimed to describe the full characteristics and outcomes in the Epidemiological ...Strategy and Medical Economics (ESME) cohort, a large national contemporary observational database of patients with metastatic breast cancer (MBC).
Women aged ≥18 years with newly diagnosed MBC and who initiated MBC treatment between January 2008 and December 2016 in one of the 18 French Comprehensive Cancer Centers (N = 22,109) were included. We assessed the full patients’ characteristics, first-line treatments, overall survival (OS) and first-line progression-free survival, as well as updated prognostic factors in the whole cohort and among the 3 major subtypes: hormone receptor positive and HER2-negative (HR+/HER2−, n = 13,656), HER2-positive (HER2+, n = 4017) and triple-negative (n = 2963) tumours.
The median OS of the whole cohort was 39.5 months (95% confidence interval CI, 38.7–40.3). Five-year OS was 33.8%. OS differed significantly between the 3 subtypes (p < 0.0001) with a median OS of 43.3 (95% CI, 42.5–44.5) in HR+/HER2−; 50.1 (95% CI, 47.6–53.1) in HER2+; and 14.8 months (95% CI, 14.1–15.5) in triple-negative subgroups, respectively. Beyond performance status, the following variables had a constant significant negative prognostic impact on OS in the whole cohort and among subtypes: older age at diagnosis of metastases (except for the triple-negative subtype), metastasis-free interval between 6 and 24 months, presence of visceral metastases and number of metastatic sites ≥ 3.
The ESME program represents a unique large-scale real-life cohort on MBC. This study highlights important situations of high medical need within MBC patients.
clinicaltrials.gov Identifier NCT032753.
•ESME provides a full picture of the real-life overall survival (OS) of women diagnosed with metastatic breast cancer from 2008 till 2016.•The median OS of the whole population over this 9-year period was 39.5 months (95% confidence interval, 38.7–40.3).•Prognostic factors on OS were age, tumour subtype, metastasis-free interval, presence of visceral metastases and number of metastatic sites.
Long-Term Survival after Kidney Transplantation Hariharan, Sundaram; Israni, Ajay K; Danovitch, Gabriel
The New England journal of medicine,
08/2021, Letnik:
385, Številka:
8
Journal Article
Spinal muscular atrophy (SMA), which results from the loss of expression of the survival of motor neuron-1 (SMN1) gene, represents the most common genetic cause of pediatric mortality. A duplicate ...copy (SMN2) is inefficiently spliced, producing a truncated and unstable protein. We describe herein a potent, orally active, small-molecule enhancer of SMN2 splicing that elevates full-length SMN protein and extends survival in a severe SMA mouse model. We demonstrate that the molecular mechanism of action is via stabilization of the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex. The binding affinity of U1 snRNP to the 5' splice site is increased in a sequence-selective manner, discrete from constitutive recognition. This new mechanism demonstrates the feasibility of small molecule-mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases.
This large population‐based study compared breast‐conserving surgery with radiation therapy (BCT) with mastectomy on (long‐term) breast cancer‐specific (BCSS) and overall survival (OS), and ...investigated the influence of several prognostic factors. Patients with primary T1‐2N0‐2M0 breast cancer, diagnosed between 1999 and 2012, were selected from the Netherlands Cancer Registry. We investigated the 1999–2005 (long‐term outcome) and the 2006–2012 cohort (contemporary adjuvant systemic therapy). Cause of death was derived from the Statistics Netherlands (CBS). Multivariable analyses, per time cohort, were performed in T1‐2N0‐2, and separately in T1‐2N0‐1 and T1‐2N2 stages. The T1‐2N0‐1 stages were further stratified for age, hormonal receptor and HER2 status, adjuvant systemic therapy and comorbidity. In total, 129,692 patients were included. In the 1999–2005 cohort, better BCSS and OS for BCT than mastectomy was seen in all subgroups, except in patients < 40 years with T1‐2N0‐1 stage. In the 2006–2012 cohort, superior BCSS and OS were found for T1‐2N0‐1, but not for T1‐2N2. Subgroup analyses for T1‐2N0‐1 showed superior BCSS and OS for BCT in patients >50 years, not treated with chemotherapy and with comorbidity. Both treatments led to similar BCSS in patients <50 years, without comorbidity and those treated with chemotherapy. Although confounding by severity and residual confounding cannot be excluded, this study showed better long‐term BCSS for BCT than mastectomy. Even with more contemporary diagnostics and therapies we identified several subgroups that may benefit from BCT. Our results support the hypothesis that BCT might be preferred in most breast cancer patients when both treatments are suitable.
What's new?
While breast‐conserving therapy (BCT) and mastectomy have long been considered equivalent in terms of survival in early‐stage breast cancer, recent studies suggest BCT offers superior survival over mastectomy. The findings of this study support that idea, showing that breast cancer‐specific survival and overall survival were greater for BCT than mastectomy in analyses of 129,692 patients diagnosed with breast cancer in The Netherlands between 1999 and 2012. Subgroup analyses revealed better survival for BCT in most instances, with survival being similar for BCT and mastectomy primarily among patients under age 50, patients without comorbidity, and those treated with chemotherapy.
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