Sarah Zohar

Autologous bone marrow transplantation in the treatment of refractory systemic sclerosis: early results from a French multicentre phase I-II study.

Summary. Haematopoietic stem cell transplantation (HSCT) has been proposed for refractory autoimmune diseases, including systemic sclerosis (SSc). A sequential Bayesian phase I–II clinical trial was conducted in SSc patients to assess the feasibility, the tolerance and the efficacy of autologous HSCT. Peripheral blood stem cells (PBSC) were collected using cyclophosphamide (4 g/m2) and recombinant human granulocyte colony‐stimulating factor (5 µg/kg/d) and reinfused after positive CD34+ selection. Conditioning used cyclophosphamide (200 mg/kg) or melphalan (140 mg/m2) according to cardiac function. The main end‐point was the failure of the procedure, defined by failure of either PBSC mobilization, CD34+ selection or intensification procedure, or by procedure‐related death. Among the 12 enrolled patients, three failures occurred: one PBSC mobilization, one CD34+ selection and one CD34+ intensification. Probability of graft failure was estimated at 0·286 (95% confidence interval: 0·095–0·54). Autologous PBSC (n = 10) or bone marrow (n = 1) transplantation was actually performed in 11 patients with one procedure‐related death. Median time to neutrophil (> 0·5 × 109/l) and platelet (> 25 × 109/l) haematopoietic reconstitution was 12 and 10 d respectively. After 18 months (range 1–26), eight out of 11 patients have shown major or partial response. Non‐myeloablative conditioning, followed by a T cell‐depleted autologous PBSC or bone marrow transplantation, appears feasible with low toxicity in severe SSc with short‐term clinical benefits.

Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial

BACKGROUND Preclinical data suggest that the loop-diuretic bumetanide might be an effective treatment for neonatal seizures. We aimed to assess dose and feasibility of intravenous bumetanide as an add-on to phenobarbital for treatment of neonatal seizures. METHODS In this open-label, dose finding, and feasibility phase 1/2 trial, we recruited full-term infants younger than 48 h who had hypoxic ischaemic encephalopathy and electrographic seizures not responding to a loading-dose of phenobarbital from eight neonatal intensive care units across Europe. Newborn babies were allocated to receive an additional dose of phenobarbital and one of four bumetanide dose levels by use of a bivariate Bayesian sequential dose-escalation design to assess safety and efficacy. We assessed adverse events, pharmacokinetics, and seizure burden during 48 h continuous electroencephalogram (EEG) monitoring. The primary efficacy endpoint was a reduction in electrographic seizure burden of more than 80% without the need for rescue antiepileptic drugs in more than 50% of infants. The trial is registered with ClinicalTrials.gov, number NCT01434225. FINDINGS Between Sept 1, 2011, and Sept 28, 2013, we screened 30 infants who had electrographic seizures due to hypoxic ischaemic encephalopathy. 14 of these infants (10 boys) were included in the study (dose allocation: 0·05 mg/kg, n=4; 0·1 mg/kg, n=3; 0·2 mg/kg, n=6; 0·3 mg/kg, n=1). All babies received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (one on 0·05 mg/kg, one on 0·1 mg/kg and three on 0·2 mg/kg), and only two did not need rescue antiepileptic drugs (ie, met rescue criteria; one on 0·05 mg/kg and one on 0·3 mg/kg). We recorded no short-term dose-limiting toxic effects, but three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common non-serious adverse reactions were moderate dehydration in one, mild hypotension in seven, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction. INTERPRETATION Our findings suggest that bumetanide as an add-on to phenobarbital does not improve seizure control in newborn infants who have hypoxic ischaemic encephalopathy and might increase the risk of hearing loss, highlighting the risks associated with the off-label use of drugs in newborn infants before safety assessment in controlled trials. FUNDING European Communitys Seventh Framework Programme.

Late morbidity after colon interposition for corrosive esophageal injury: risk factors, management, and outcome. A 20-years experience.

Objective:The aim of this study was to report our experience in the management of late morbidity after colonic interposition for caustic injury and to assess the influence of coloplasty dysfunction on patient outcome. Summary Background Data:Reports on coloplasty dysfunction after colon interposition for corrosive esophageal injuries are scarce in the literature. Dysfunction of the colonic substitute might jeopardize an already fragile functional result, and appropriate management can improve outcome. Methods:Long-term follow-up (>6 months) was conducted in 223 patients (125 men; median age, 35 years) who underwent colonic interposition for caustic injuries between 1987 and 2006. Statistical tests were performed on this cohort to identify risk factors for late morbidity and functional outcome. During the same period, 28 patients who underwent colon interposition for caustic injury in another center were referred for treatment of coloplasty dysfunction. Data from these patients were used together with those of our patients to describe specific coloplasty-related complications and their management. Results:With a median follow-up of 5 years (range: 6 months–20 years), late complications were recorded in 125 (55%) of our patients (stenosis 36%, reflux 11%, redundancy 5%). A delay in reconstruction <6 months (P = 0.03) and absence of thoracic inlet enlargement (P = 0.002) were independent predictive factors for cervical anastomotic stenosis. Functional failure was recorded in 52 patients (23%) and was associated with a delay in reconstruction <6 months (P = 0.009) and emergency tracheotomy (P = 0.002). Coloplasty dysfunction was responsible for half of the recorded failures. Revision surgery for coloplasty dysfunction was performed in 96 patients (68 local, 28 referred) with an overall 70% success rate. Conclusions:Late complications occurred in half of the patients after colonic interposition for corrosive injuries and accounted for half of the functional failures. Prolonged surgical follow-up and appropriate management of coloplasty dysfunction are key factors for long-term success after esophageal reconstruction for caustic injuries.

Recent Developments in Adaptive Designs for Phase I/II Dose-Finding Studies

Cancer dose-finding trials aim at assessing the maximum tolerated dose (MTD) of a new treatment or combination. Owing to ethical constraint, they are based on adaptive designs, sequentially allocating patients to increased doses on the basis of previous responses. More recently, the concept of MTD has been extended to the largest concept of most successful or most desirable dose, based on efficacy criterion under toxicity restrictions. The aim of this paper is to present three main approaches proposed to estimate such a dose, in the setting of Phase I/II trials. Two case-studies allow to illustrate these new approaches.

Colopharyngoplasty for the treatment of severe pharyngoesophageal caustic injuries: an audit of 58 patients.

Objective:The aim of this study was to describe the technique of colopharyngoplasty for the reconstruction of concomitant esophageal and pharyngeal caustic injuries and to evaluate the postoperative course and late functional outcomes. Summary Background Data:Surgical treatment of esophageal and pharyngeal strictures is a difficult challenge because reconstruction at this level interferes with the mechanisms of deglutition and respiration. Several techniques have been described for the treatment of this condition but none is accepted as the gold standard. Methods:Fifty-eight patients (34 men, median age 37 years) underwent colopharyngoplasty for caustic injuries between 1993 and 2005. Forty patients (69%) had a previous psychiatric history of depression (n = 30) or schizophrenia (n = 10). After removal of all scar tissues, the pharyngeal reconstruction was performed with the cervical end of the colic transplant employed for esophageal replacement. Laryngeal resection was associated in half of the patients. Success of the procedure was defined as recovery of nutritional autonomy and airway patency. Results:Operative mortality was 2%. Postoperative complications required reoperation in 16 patients (28%). The functional outcome was evaluated in 46 patients with a follow-up of more than 6 months. The tracheostomy was withdrawn in 42 (91%) patients after a median of 42 days (range, 20–1020). The jejunostomy was removed in 32 patients (70%) after a median of 12 months (range, 2–54). Finally, the procedure was successful in 31 patients (67%). Logistic regression analysis showed that advanced age, a previous history of psychiatric disease, and early reoperation had an adverse impact on fuctional outcome. Seven patients (12%) repeated the suicide attempt. Conclusions:Colopharyngoplasty is a simple and reliable procedure that can be successfully employed to restore the digestive continuity in patients with concomitant esophageal and pharyngeal caustic injuries. Control of the underlying psychiatric disease before reconstruction is a key factor for success.

Surgery for Caustic Injuries of the Upper Gastrointestinal Tract

Background:Surgery is the criterion standard for the treatment of severe burns and of late sequels after ingestion of corrosive agents, but long-term outcome is unknown. Methods:Patients who underwent surgery between 1987 and 2006, for the treatment of severe caustic burns (group I, n = 268) or of late sequels (group II, n = 79) were included in the study. Survival and functional outcomes were analyzed. Functional success was defined as nutritional autonomy after removal of the jejunostomy and tracheotomy tubes. To compare the observed mortality with the expected mortality in the general population, a standardized mortality ratio (SMR) was used. Results:Overall Kaplan-Meyer survival at 1, 5, 10, and 20 years of patients in group I was 76.4%, 63.6%, 53.9%, and 44.1%, respectively. On multivariate analysis, advanced age (P = 0.0021), extended resection (P = 0.0009), emergency esophagectomy (P = 0.013), and tracheobronchial injuries (P = 0.0011) were independent negative predictors of survival. The SMR of patients in group I was increased to 21.5 when compared to the general French population. Functional success was recorded in 147 (56%) patients in group I. Advanced age (P = 0.012), extended resection (P = 0.012), and emergency tracheotomy (P = 0.02) were independent predictors for failure. After esophageal reconstruction, patients in group II fared better than patients in group I in terms of survival (P = 0.0006) and functional success (P < 0.0001). Still, the SMR of patients in group II increased to 3.67. Conclusions:The need to perform surgery for caustic injuries has a persistent long-term negative impact on survival and functional outcome.

Anal carcinoma in HIV-infected patients in the era of antiretroviral therapy: a comparative study.

BACKGROUND: Before the introduction of highly active antiretroviral therapy, prognosis of anal squamous-cell carcinoma was worse when patients were infected with HIV. Since then, contradictory results have been reported. OBJECTIVE: To compare the results of chemoradiotherapy in HIV-infected and uninfected patients with anal carcinoma. DESIGN: Retrospective analysis of medical records. SETTING: Tertiary care center in France. PATIENTS: Patients with invasive anal carcinoma treated from 2001 through 2006. INTERVENTIONS: Chemoradiotherapy included 60 Gy pelvic irradiation and cisplatin-based chemotherapy. Surgery was performed for local failures or complications. MAIN OUTCOME MEASURES: Tolerance for chemoradiotherapy, tumor control, and survival were evaluated. RESULTS: A total of 46 patients (20 HIV-infected and 26 uninfected) were treated for nonmetastatic anal carcinoma. Median follow-up was 32.5 (range, 7–84) months. HIV-infected patients were more likely to be men (95% vs 23%, P < .001) and were younger (median age, 46 vs 62 years, P < .001) than uninfected patients. The viral load was less than 200 copies/mL in 15 (75%) of the HIV-infected patients. The duration of chemoradiotherapy was longer in HIV-infected than in uninfected patients (median, 103 vs 84 days, P = .027). Chemoradiotherapy failed to achieve local control in 10 (50%) HIV-infected and in 6 (23%) uninfected patients (P = .057). In HIV-infected patients, failure rates were higher in patients who required prolonged chemoradiotherapy than in those who received treatment as scheduled (7/11, 64% vs 1/7, 14%; P = .039). During follow-up, 7 (35%) of the HIV-infected and 3 (12%) of the uninfected patients died, all from anal carcinoma. The 5-year overall survival rate was 39% for HIV-infected and 84% for uninfected patients (P = .026); 5-year disease-free survival was 37% in HIV-infected and 75% in uninfected patients (P = .06). LIMITATIONS: Retrospective design, lack of data regarding precise toxicity grading, and use of cisplatin-based chemoradiotherapy. CONCLUSIONS: Even in the era of highly active antiretroviral therapy, HIV-infected patients with anal squamous-cell carcinoma show impaired tolerance to chemoradiotherapy, have a lower survival rate, and may have a higher rate of local failure compared with uninfected patients.

Esophageal replacement by allogenic aorta in a porcine model.

BACKGROUND Esophageal replacement is a challenging problem requiring complex reconstruction. In response to the recent success of tracheal replacement by fresh allogenic aorta in humans, we assessed in a pig model the feasibility of circumferential segmental esophageal replacement by a fresh aortic allograft. METHODS A 4-cm long aortic allograft was interposed after a circumferential 2-cm long resection of the cervical esophagus in 18 minipigs. Anastomoses were protected temporarily by self-expanding polyester-silicone stents (Polyflex; Boston Scientific, Montigny-le-Bretonneux, France). No immunosuppression was given. When stenosis occurred after stent removal or migration, a new stent was inserted. After clinical and endoscopic evaluation, pigs were killed sequentially at 1, 3, 6 and 12 months for analysis. RESULTS Mortality during the first month was 33%. Four animals died from stent migration during the entire follow-up. Maintenance of a lumen through the graft area by a stent was necessary for 6 months, in order to avoid stenosis occurrence. After the sixth postoperative month, esophageal lumen remained patent until the twelfth month, allowing an apparently normal feeding and weight gain. Gradual contraction of the graft area was observed with time. Sequential histologic analysis showed an inflammatory reaction that decreased with time and a progressive epithelialization of the graft area which became similar to native esophageal epithelium. After 12 months, islets of smooth muscle organized as fascicules or in bundles were visible within the fibrotic tissue. CONCLUSION Short esophageal replacement by fresh aortic allograft, under the cover of a temporary maintenance of the lumen of the graft area by an esophageal stent, allows the restitution of a patent esophageal lumen and nutritional autonomy.

Autologous Hematopoietic Stem Cell Transplant in Systemic Sclerosis: Quantitative High Resolution Computed Tomography of the Chest Scoring

Objective. Using high resolution computed tomography (HRCT), to assess the lung involvement outcome after autologous hematopoietic stem cell transplant (AHSCT) in patients with scleroderma (systemic sclerosis, SSc). Methods. HCRT scans prospectively performed before (n = 9 patients) and after (n = 47) AHSCT were blindly reviewed by 2 independent investigators using the Wells score. Results. After a median 60 months’ followup, the overall disease extent score from HCRT scans decreased from 10 (0–45) to 4 (0–36) (p = 0.04) 6 months after AHSCT, and thereafter increased up to 36 months and stabilized; the modified Rodnan skin score fell (p < 0.05). Conclusion. The extent of SSc lung involvement on HRCT rapidly but transiently regressed after AHSCT.

Software to compute and conduct sequential Bayesian phase I or II dose-ranging clinical trials with stopping rules

The aim of dose-ranging phase I (resp. phase II) clinical trials is to rapidly identify the maximum tolerated dose (MTD) (resp., minimal effective dose (MED)) of a new drug or combination. For the conduct and analysis of such trials, Bayesian approaches such as the Continual Reassessment Method (CRM) have been proposed, based on a sequential design and analysis up to a completed fixed sample size. To optimize sample sizes, Zohar and Chevret have proposed stopping rules (Stat. Med. 20 (2001) 2827), the computation of which is not provided by available softwares. We present in this paper a user-friendly software for the design and analysis of these Bayesian Phase I (resp. phase II) dose-ranging Clinical Trials (BPCT). It allows to carry out the CRM with stopping rules or not, from the planning of the trial, with choice of model parameterization based on its operating characteristics, up to the sequential conduct and analysis of the trial, with estimation at stopping of the MTD (resp. MED) of the new drug or combination.