Mohamed Amine Bayar

Phase I trial evaluating the antiviral agent Cidofovir in combination with chemoradiation in cervical cancer patients

Purpose This phase I trial aimed to assess the safety and determine the recommended Phase II dose (RP2D) of Cidofovir combined with chemoradiotherapy in patients with stage IB2-IVA cervical cancer. Experimental design Incremental doses (1, 2.5, 5 and 6.5 mg/kg) of IV Cidofovir were administered weekly for two weeks, and then every 2 weeks from the start of chemoradiotherapy to the initiation of utero-vaginal brachytherapy. Biological expression of HPV was analyzed during treatment and tumor response was assessed according to RECIST v1.0 criteria. Results A total of 15 patients were treated with Cidofovir. Dose-limiting toxicities occurred in 2/6 patients at the 6.5 mg/kg dose level (G3 proteinuria, and G3 acute pyelonephritis with G3 febrile neutropenia). No toxicity occurred at the 5 mg/kg dose level, but only 3 patients received this dose due to trial interruption because of low accrual. The most frequent G3-4 adverse effects observed during the trial were: abdominal pain (n=3), infection (n=2), leuckoneutropenia (n=2), and others (n=6). No toxic death or major renal side effect occurred. The best response was that 8/9 evaluable patients achieved a complete response (89%). In the intention to treat population, the 2-year overall and progression-free survival rates were 93% and 76%, respectively. Biological monitoring of HPV-related markers (decreased p16 expression, and increased p53 and pRb levels) was possible on sequential tumor biopsy samples. The genomic alterations identified were PIK3CA (n=5; one also had a KRAS mutation), and HRAS (n=1) mutations. Conclusion Cidofovir at a dose of 5mg/kg combined with chemoradiotherapy appeared tolerable and yielded tumor regressions. Due to early trial interruption, the RP2D was not confirmed.

New insights into the evaluation of randomized controlled trials for rare diseases over a long-term research horizon: a simulation study.

Large sample sizes are required in randomized clinical trials designed to meet typical one-sided 2.5% α-level and 80% power. This may not be achievable when the disease is rare. We simulated a series of two-arm superiority trials over a 15-year period. The design parameters examined were the α-level and the number of trials conducted over the 15-year period (thus, trial sample size). Different disease severities and accrual rates were considered. The future treatment effect was characterized by its associated hazard rate; different hypotheses of how treatments improve over time were considered. We defined the total survival benefit as the relative difference of the hazard rates at year 15 versus year 0. The optimal design was defined by maximizing the expected total survival benefit, provided that the risk of selecting at year 15 a treatment inferior to the initial control treatment remains below 1%. Compared with two larger trials with typical one-sided 2.5% α-level, performing a series of small trials with relaxed α-levels leads on average to larger survival benefits over a 15-year research horizon, but also to higher risk of selecting a worse treatment at the end of the research period. Under reasonably optimistic assumptions regarding the future treatment effects, optimal designs outperform traditional ones when the disease is severe (baseline median survival ≤ 1 year) and the accrual is ≥100 patients per year, whereas no major improvement is observed in diseases with better prognosis. Trial designs aiming to maximize survival gain over a long research horizon across a series of trials are worth discussing in the context of rare diseases. Copyright

New insights into the evaluation of randomized controlled trials for rare diseases over a long-term research horizon

Large sample sizes are required in randomized clinical trials designed to meet typical one-sided 2.5% α-level and 80% power. This may not be achievable when the disease is rare. We simulated a series of two-arm superiority trials over a 15-year period. The design parameters examined were the α-level and the number of trials conducted over the 15-year period (thus, trial sample size). Different disease severities and accrual rates were considered. The future treatment effect was characterized by its associated hazard rate; different hypotheses of how treatments improve over time were considered. We defined the total survival benefit as the relative difference of the hazard rates at year 15 versus year 0. The optimal design was defined by maximizing the expected total survival benefit, provided that the risk of selecting at year 15 a treatment inferior to the initial control treatment remains below 1%. Compared with two larger trials with typical one-sided 2.5% α-level, performing a series of small trials with relaxed α-levels leads on average to larger survival benefits over a 15-year research horizon, but also to higher risk of selecting a worse treatment at the end of the research period. Under reasonably optimistic assumptions regarding the future treatment effects, optimal designs outperform traditional ones when the disease is severe (baseline median survival ≤ 1 year) and the accrual is ≥100 patients per year, whereas no major improvement is observed in diseases with better prognosis. Trial designs aiming to maximize survival gain over a long research horizon across a series of trials are worth discussing in the context of rare diseases. Copyright

Prevention of Epidural Fibrosis Using Ranibizumab in a Postlaminectomy Rat Model.

AIM One of the most significant reasons for persistent low back pain experienced after spinal surgery is epidural fibrosis seen after laminectomy procedures. This study shows the effects of Ranibizumab on spinal epidural fibrosis in the laminectomy area by blocking the effect of vascular endothelial growth factor. MATERIAL AND METHODS Twenty Wistar rats were used in this study. Rats were divided into two groups; a control group and a ranibizumab group. Only laminectomy was performed to the control group. In the ranibizumab group, 0.6 mg/kg ranibizumab diluted in 0.9% NaCl with the ratio of 1:10 was applied topically. Three weeks later, the vertebral columns were resected en bloc including the whole laminectomy area in both groups and evaluated histopathologically. Results were compared using statistical tools. RESULTS Based on the statistical analysis, our data show that less epidural fibrosis was seen in the ranibizumab group compared to the control group (P < 0.05). CONCLUSION Topically applied Ranibizumab is significantly effective in preventing epidural fibrosis in rats occurred after laminectomy.

Statistical approaches for evaluating body composition markers in clinical cancer research

ABSTRACT Introduction: The term ‘morphomics’ stands for the markers of body composition in muscle and adipose tissues. in recent years, as part of clinical cancer research, several associations between morphomics and outcome or toxicity were found in different treatment settings leading to a growing interest. we aim to review statistical approaches used to evaluate these markers and suggest practical statistical recommendations. Area covered: We identified statistical methods used recently to take into account properties of morphomics measurements. We also reviewed adjustment methods on major confounding factors such as gender and approaches to model morphomic data, especially mixed models for repeated measures. Finally, we focused on methods for determining a cut-off for a morphomic marker that could be used in clinical practice and how to assess its robustness. Expert commentary: From our review, we proposed 13 key points to strengthen analyses and reporting of clinical research assessing associations between morphomics and outcome or toxicity.

A gene signature to predict high tumor-infiltrating lymphocytes after neoadjuvant chemotherapy and outcome in patients with triple-negative breast cancer

Background In patients with triple-negative breast cancer (TNBC), the extent of tumor-infiltrating lymphocytes (TILs) in the residual disease after neoadjuvant chemotherapy (NACT) is associated with better prognosis. Our objective was to develop a gene signature from pretreatment samples to predict the extent of TILs after NACT and then to test its prognostic value on survival. Patients and methods Using 99 pretreatment samples, we generated a four-gene signature associated with high post-NACT TILs. Prognostic value of the signature on distant relapse-free survival (DRFS) was first assessed on the training set (n = 99) and then on an independent validation set (n = 115). Results A four-gene signature combining the expression levels of HLF, CXCL13, SULT1E1, and GBP1 was developed in baseline samples to predict the extent of lymphocytic infiltration after NACT. In a multivariate analysis performed on the training set, this signature was associated with DRFS [hazard ratio (HR): 0.28, for a one-unit increase in the value of the four-gene signature, 95% confidence interval (CI): 0.13-0.63)]. In a multivariate analysis performed on an independent validation set, the four-gene signature was significantly associated with DRFS (HR: 0.17, 95% CI: 0.06-0.43). The four-gene signature added significant prognostic information when compared with the clinicopathologic pretreatment model (likelihood ratio test in the training set P = 0.004 and in the validation set P = 0.002). Conclusions A four-gene signature predicts high levels of TILs after anthracycline-containing NACT and outcome in patients with TNBC and adds prognostic information to a clinicopathological model at diagnosis.

Integrating Tenascin-C protein expression and 1q25 copy number status in pediatric intracranial ependymoma prognostication: A new model for risk stratification.

Purpose Despite multimodal therapy, prognosis of pediatric intracranial ependymomas remains poor with a 5-year survival rate below 70% and frequent late deaths. Experimental design This multicentric European study evaluated putative prognostic biomarkers. Tenascin-C (TNC) immunohistochemical expression and copy number status of 1q25 were retained for a pooled analysis of 5 independent cohorts. The prognostic value of TNC and 1q25 on the overall survival (OS) was assessed using a Cox model adjusted to age at diagnosis, tumor location, WHO grade, extent of resection, radiotherapy and stratified by cohort. Stratification on a predictor that did not satisfy the proportional hazards assumption was considered. Model performance was evaluated and an internal-external cross validation was performed. Results Among complete cases with 5-year median follow-up (n = 470; 131 deaths), TNC and 1q25 gain were significantly associated with age at diagnosis and posterior fossa tumor location. 1q25 status added independent prognostic value for death beyond the classical variables with a hazard ratio (HR) = 2.19 95%CI = [1.29; 3.76] (p = 0.004), while TNC prognostic relation was tumor location-dependent with HR = 2.19 95%CI = [1.29; 3.76] (p = 0.004) in posterior fossa and HR = 0.64 [0.28; 1.48] (p = 0.295) in supratentorial (interaction p value = 0.015). The derived prognostic score identified 3 different robust risk groups. The omission of upfront RT was not associated with OS for good and intermediate prognostic groups while the absence of upfront RT was negatively associated with OS in the poor risk group. Conclusion Integrated TNC expression and 1q25 status are useful to better stratify patients and to eventually adapt treatment regimens in pediatric intracranial ependymoma.

The role of pegaptanib sodium in the suppression of epidural fibrosis in a postlaminectomy rat model

OBJECTIVE Spinal epidural fibrosis is a clinical condition that develops after laminectomy and can compress the spine. Many agents have been tried for the treatment, but none has entered clinical use at present. Pegaptanib sodium is an antiangiogenetic drug that prevents the development of new vessels and thus adhesion by inhibiting the effect of VEGF. MATERIAL AND METHOD 20 Wistar rats were used in this study. The rats were divided into 2 different groups as the control and pegaptanib sodium group. Three levels of laminectomy were performed. Only laminectomy was performed in the control group. A cotton ball soaked with 3 mg/kg Pegaptanib sodium diluted 1: 10 with 0.9 % NaCl was topically applied to the dura in the surgical field for 5 minutes in the pegaptanib sodium group. The rats were sacrificed 3 weeks later and histopathologically examined. The epidural fibrosis was graded. RESULTS The epidural fibrosis grade in the pegaptanib sodium was significantly lower than in the control group c2 = 11,65; (p = 0.004)CONCLUSION: Pegaptanib sodium blocked the VEGF through its anti-VEGF effect and decreased spinal epidural fibrosis in rats that had undergone laminectomy (Tab. 2, Fig. 3, Ref. 53).