In two randomized trials, the use of gantenerumab (an anti-Aβ monoclonal antibody) did not lead to slower clinical decline than placebo over 116 weeks among persons with early Alzheimer’s disease.
Background/Aims
In oncology, new combined treatments make it difficult to order dose levels according to monotonically increasing toxicity. New flexible dose-finding designs that take into account ...uncertainty in dose levels ordering were compared with classical designs through simulations in the setting of the monotonicity assumption violation. We give recommendations for the choice of dose-finding design.
Methods
Motivated by a clinical trial for patients with high-risk neuroblastoma, we considered designs that require a monotonicity assumption, the Bayesian Continual Reassessment Method, the modified Toxicity Probability Interval, the Bayesian Optimal Interval design, and designs that relax monotonicity assumption, the Bayesian Partial Ordering Continual Reassessment Method and the No Monotonicity Assumption design. We considered 15 scenarios including monotonic and non-monotonic dose–toxicity relationships among six dose levels.
Results
The No Monotonicity Assumption and Partial Ordering Continual Reassessment Method designs were robust to the violation of the monotonicity assumption. Under non-monotonic scenarios, the No Monotonicity Assumption design selected the correct dose level more often than alternative methods on average. Under the majority of monotonic scenarios, the Partial Ordering Continual Reassessment Method selected the correct dose level more often than the No Monotonicity Assumption design. Other designs were impacted by the violation of the monotonicity assumption with a proportion of correct selections below 20% in most scenarios. Under monotonic scenarios, the highest proportions of correct selections were achieved using the Continual Reassessment Method and the Bayesian Optimal Interval design (between 52.8% and 73.1%). The costs of relaxing the monotonicity assumption by the No Monotonicity Assumption design and Partial Ordering Continual Reassessment Method were decreases in the proportions of correct selections under monotonic scenarios ranging from 5.3% to 20.7% and from 1.4% to 16.1%, respectively, compared with the best performing design and were higher proportions of patients allocated to toxic dose levels during the trial.
Conclusions
Innovative oncology treatments may no longer follow monotonic dose levels ordering which makes standard phase I methods fail. In such a setting, appropriate designs, as the No Monotonicity Assumption or Partial Ordering Continual Reassessment Method designs, should be used to safely determine recommended for phase II dose.
Background:
Diffuse intrinsic pontine glioma (DIPG) is a fatal disease with a median overall survival (OS) of less than 12 months after diagnosis. Radiotherapy (RT) still remains the mainstay ...treatment. Several other therapeutic strategies have been attempted in the last years without a significant effect on OS. Although radiological imaging is the gold standard for DIPG diagnosis, the urgent need to improve the survival has led to the reconsideration of biopsy with the aim to better understand the molecular profile of DIPG and support personalized treatment.
Methods:
In this study, we present a single-center experience in treating DIPG patients at disease progression combining targeted therapies with standard of care. Biopsy was proposed to all patients at diagnosis or disease progression. First-line treatment included RT and nimotuzumab/vinorelbine or temozolomide. Immunohistochemistry-targeted research included study of mTOR/p-mTOR pathway and BRAFv600E. Molecular analyses included polymerase chain reaction, followed by Sanger sequences and/or next-generation sequencing.
Results:
Based on the molecular profile, targeted therapy was administered in 9 out of 25 patients, while the remaining 16 patients were treated with standard of care. Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (5/9), PI3K/AKT/mTOR pathway and BRAFv600E (1/9), ACVR1 (2/9) and PDGFRA (1/9); no severe side effects were reported during treatment. Response to treatment was evaluated according to Response Assessment in Pediatric Neuro-Oncology criteria, and the overall response rate within the cohort was 66%. Patients treated with targeted therapies were compared with the control cohort of 16 patients. Clinical and pathological characteristics of the two cohorts were homogeneous. Median OS in the personalized treatment and control cohort was 20.26 and 14.18 months, respectively (p = 0.032). In our experience, the treatment associated with the best OS was everolimus.
Conclusion:
Despite the small simple size of our study, our data suggest a prognostic advantage and a safe profile of targeted therapies in DIPG patients, and we strongly advocate to reconsider the role of biopsy for these patients.
Cardiovascular disease (CVD) is the main cause of death in systemic lupus erythematous (SLE) patients. The Framingham score underestimates the risk for CVD in this population. Our study aimed to ...determine whether serum high-sensitivity cardiac troponin T (HS-cTnT) might help to identify SLE patients at risk for CVD.
The presence of carotid plaques was prospectively assessed by ultrasound in 63 consecutive SLE patients asymptomatic for CVD and 18 controls. Serum HS-cTnT concentration was measured using the electrochemiluminescence method. Factors associated with carotid plaques were identified and multivariate analysis was performed.
Framingham score was low in both SLE patients (median 1 (range 1-18%)) and controls (1 (1-13%)). Nevertheless, 23 (36.5%) SLE patients, but only 2 (11.1%) controls (p = 0.039), had carotid plaque detected by vascular ultrasound. In the multivariate analysis, only age (p = 0.006) and SLE status (p = 0.017) were independently associated with carotid plaques. Serum HS-cTnT concentration was detectable (i.e. >3 ng/L) in 37 (58.7%) SLE patients and 6 (33.3%) controls (p = 0.057). Interestingly, 87% of SLE patients with carotid plaques, but only 42.5% of SLE patients without plaques (p < 0.001), had detectable HS-cTnT. Conversely, 54.5% of SLE patients with detectable HS-cTnT, but only 11.5% with undetectable HS-cTnT (p < 0.001), had a carotid plaque. In the multivariate analysis, only body mass index (p = 0.006) and HS-cTnT (p = 0.033) were statistically associated with carotid plaques in SLE patients. Overall, the risk of having a carotid plaque was increased by 9 (odds ratio 9.26, 95% confidence interval 1.55-90.07) in SLE patients in whom HS-cTnT was detectable in serum.
Serum HS-cTnT level is high and associated with carotid plaques in SLE patients who are at an apparently low risk for CVD according to the Framingham score. HS-cTnT may be a useful biomarker for SLE-associated atherosclerosis.
Since the online publication of the above article, the authors have noted an error with the name of the co-author Dr Liang (Last name) Hong (first name).
Background
Germ cell tumors (GCT) account for a minority of central nervous system (CNS) malignancies, highly prevalent in adolescents and young adults. Despite their aggressive biological behavior, ...prognosis is excellent in most cases with risk stratified treatment, consisting in a combination of chemotherapy and radiotherapy. Whole ventricular irradiation (WVI) and craniospinal irradiation, the treatment of choice for localized and metastatic disease, pose significant risk of collateral effects, therefore proton beam radiation (PBT) has been recently proposed for its steep dose fallout.
Materials and methods
We report our experience in a consecutive series of 17 patients treated for CNS GCT at our Institution from 2015 to 2021.
Results
Most frequent lesion location were sellar/suprasellar (35%) and bifocal germinoma (35%), followed by pineal (18%) and thalamic (12%). Two patients (12%), had evidence of disseminated disease at the time of diagnosis. At the latest follow-up all but one patient showed complete response to treatment. The only relapse was successfully rescued by additional chemotherapy and PBT. PBT was well tolerated in all cases. No visual, neurological or endocrinological worsening was documented during and after treatment. Neuropsychological evaluation demonstrated preservation of cognitive performance after PBT treatment.
Conclusions
Our data, albeit preliminary, strongly support the favourable therapeutic profile of PBT for the treatment of CNS germ cell tumors.
To evaluate the influence of automated visual field (VF) testing on intraocular pressure (IOP) in patients with ocular hypertension (OHT) or glaucoma.
We conducted a prospective observational study ...in the glaucoma department at Quinze-Vingts National Ophthalmology Hospital in Paris. Ninety-five right eyes of 95 patients followed for glaucoma or OHT were included. IOP was measured three times using a Nidek NT-510 non-contact tonometer within a maximum of 5 min before and after VF testing. Sub analyses using logistic regression analysis were performed to evaluate the impact of gender, age, central corneal thickness (CCT), mean deviation (MD) of the VF, VF test duration and filtration surgery on IOP fluctuations.
There was no significant change in IOP after VF testing, with IOP's 15.14 ± 4.00 mmHg before and 14.98 ± 3.33 mmHg after the VF (P = 0.4). The average change in IOP was 0.15 ± 1.82 mmHg. Using multivariate analysis, no effect of the VF test on IOP was found (global model fit R
= 0.12), whether based on duration of the VF test (P = 0.18) or the MD (P = 0.7) after adjustment for age, gender, CCT and history of glaucoma surgery. Similarly, there was no significant difference within different types of glaucoma, including open-angle glaucoma (P = 0.36), chronic angle closure glaucoma (P = 0.85) and OHT (P = 0.42). The subgroup of patients with an IOP elevation ≥2 mmHg had a significantly higher VF test duration (P = 0.002).
VF testing does not influence IOP as measured with a non-contact tonometer.
Background: Ewing sarcoma (ES) is a rare and aggressive pediatric cancer. Numerous studies have attempted to identify new prognostic biomarkers. The predictive value of serum LDH and CRP has not been ...clearly described, to date. Methods: The objective of our retrospective study was to investigate the prognostic value of LDH and CRP levels and their association with overall survival in a series of ES patients. Results: Between 2004 and 2019, 89 ES patients were included. In a univariable analysis, high levels of LDH and CRP were associated with the worst prognosis. In a multivariable analysis, only higher LDH values remained associated with a lower survival. The high-LDH-level group experienced all 21 deaths registered in our population (24%) and about 90% of disease progressions. The 5-year overall survival was 66.4% in the high-LDH-level group, while no deaths were observed in the low-LDH-level group. The 5-year progression-free survival was 57.9% in the high-LDH-level group versus 80.4% in the low-LDH-level group. Conclusions: In our study, LDH levels at diagnosis were strongly correlated with the prognosis, and they might be considered a prognostic factor in Ewing sarcoma. The LDH value, along with its very low cost and its reproducibility in almost all centers, make it suitable as a potential prognostic biomarker in clinical practice.
The occurrence of cancer in newborns within the first 28 days of life is uncommon, with different clinical presentation from other age groups. Prenatal diagnosis is reported in about half of ...patients, while a genetic predisposition condition is supposed. The management of a newborn with cancer can be challenging and needs to be tailored according to the histology and the primary tumor site; surgery represents the main strategy, while chemotherapy should be considered with caution because of the higher toxicity and mortality due to different pharmacokinetics in neonates compared to older children. We describe the first Italian series over a 15-year period of patients affected by both benign and malignant neoplastic diseases diagnosed within the first 28 days of life; 74 newborns were diagnosed with neonatal tumors, representing 1.5% of the cancer population in the same period, and a prevalence of germ cell tumors (55%) and neuroblastoma (16%) was observed. Surgery was performed on 80% of patients, while chemotherapy was necessary for about 20% of patients. The 5-year overall survival (OS) exceeded 90%; treatment-related deaths are a major concern, representing 80% of overall deaths. A genetic/syndromic condition was detected in 16% of the population; additionally, a cancer predisposition syndrome (CPS) was identified in about 10% of patients. According to our experience, all newborns affected by cancer should warrant genetic counselling and a screening test for CPS.
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