Safety and efficacy of the anti-PD1 immunotherapy with nivolumab in trichoblastic carcinomas.

Trichoblastic carcinoma is a rare malignant cutaneous adnexal tumor with a risk of local invasion and distant metastasis. As of today, there is no consensus for the treatment of locally advanced or metastatic trichoblastic carcinoma. "AcSé Nivolumab" is a multi-center Phase II basket clinical trial (NCT03012581) evaluating the safety and efficacy of nivolumab in several cohorts of rare, advanced cancers. Here we report the results of nivolumab in patients with trichoblastic carcinoma. Of the eleven patients enrolled in the study, five patients had been previously treated by sonic hedgehog inhibitors. The primary endpoint 12-week objective response rate was 9.1% (N = 1/11) with 1 partial response. Six patients who progressed under previous lines of treatment showed stable disease at 12 weeks, reflecting a good control of the disease with nivolumab. Furthermore, 54.5% of the patients (N = 6/11) had their disease under control at 6 months. The 1-year overall survival was 80%, and the median progression-free survival was 8.4 months (95%CI, 5.7 to NA). With 2 responders (2 complete responses), the best response rate to nivolumab at any time was 18.2% (95%CI, 2.3-51.8%). No new safety signals were identified, and adverse events observed herein were previously described and well known with nivolumab monotherapy. These results are promising, suggesting that nivolumab might be an option for patients with advanced trichoblastic carcinomas. Further studies on larger cohorts are necessary to confirm these results and define the role of nivolumab in the treatment of trichoblastic carcinomas.

Gastrostomy and internal cerebrospinal fluid shunt in adults. A systematic review and meta-analysis of the risk of infection.

BACKGROUND: Hydrocephalus is a frequent neurological condition, commonly treated by ventriculoperitoneal shunting (VPS), a neurosurgical procedure with significant risk of infection. Some severely brain-injured hydrocephalic patients with swallowing dysfunction may require percutaneous endoscopic gastrostomy (PEG). There are few data on the safety of PEG in patients with VPS, with contradictory results reported. OBJECTIVE: The aim of this systematic review and meta-analysis was to determine the rate of VPS infection in the setting of PEG. METHODS: Six databases were searched for the period January 1990 to June 2022. Only original articles reporting the rate of shunt infection in the setting of PEG in adults were included. Random-effects meta-analysis was used to assess the rate of infection. RESULTS: Fifteen of the 1,703 identified articles were selected, reporting 701 internal cerebrospinal fluid shunts, with 63 infections. The pooled rate of infection in patients with both PEG and VPS was 7.41% (95% CI [3.67-14.38]). There was a significantly higher risk of VPS infection in the PEG group vs. the control group with VPS without PEG: relative risk (RR)=2.33 (95% CI [1.11-4.89]). On the other hand, the risk of infection was the same whether the PEG was placed before or after the VPS surgery: RR=1.05 (95% CI [0.57-1.92]). CONCLUSION: Gastrostomy tube placement is a significant risk factor for VPS infection. However, onset of infection was not related to the sequence of or interval between VPS and PEG. TRIAL REGISTRATION: This meta-analysis is registered in https://www.crd.york.ac.uk/PROSPERO/, PROSPERO ID: CRDCRD42022326774.

The appropriate and sequential value of standard radiograph, computed tomography and magnetic resonance imaging to characterize a bone tumor.

Radiographs (XR), computed tomography (CT) or magnetic resonance imaging (MRI) are regularly analyzed to determine whether a bone lesion is benign or malignant. An online quiz was created providing 15 cases with a clinical summary, MRI, CT, and XR. After each image, participants were asked to rate the probability (0-100%) the bone tumor was malignant. Order and difficulty of the images were randomly determined. Probability statements regarding the diagnosis were actualized along the sequence of exam, to quantify how the degree of belief changed to account for evidence from those exams. 64 physicians participated and provided 154 assessments from 1 (n = 18) to 3 (n = 44) different cases. After the first image, participants favored the correct malignancy status at 70%; 80% after the second and 80% after the third one. Participants were more likely to favor the correct malignancy status when the lesion was malignant and when first confronted with XR or CT, rather than MRI, though the most predictive factor of correct diagnosis was the difficulty of the case. In conclusion, the additional information provided by successive imaging studies was moderate. XR or CT seemed more appropriate than MRI as first imaging study. Bypassing XR should be discouraged.

How is quality of life after total hip replacement related to the reconstructed anatomy? A study with low-dose stereoradiography.

PURPOSE: The purpose of this study was to evaluate the relationships between the three-dimensional anatomy of operated hip in standing position using low-dose stereo-radiography imaging system and postoperative hip disability and osteoarthritis outcome score (HOOS) after total hip arthroplasty (THA). MATERIAL AND METHODS: A total of 123 patients who underwent THA during a one-year period were included. There were 50 men and 73 women with a mean age of 67.3±13.6 (SD) years (range: 19-89 years). All patients underwent pre- and postoperative low-dose stereo-radiography examination and completed a HOOS form (score from 0 to 100, 100 for full satisfaction). We recorded 16 anatomical parameters before THA, and 15 after THA. After binary transformation of HOOS score using 70 as threshold value, outcome was assessed using logistic or generalised linear models. RESULTS: A total of 103 patients (103/123; 83.7%) had a HOOS score≥70 and were considered as the satisfied group. A significant difference in pelvic incidence (the angle between a line perpendicular to the sacral plate at its midpoint and a line connecting the same point to the centre of the bicoxofemoral axis) was found between the satisfied 56.4±10.4 (SD)° (range: 31-85°) and the unsatisfied group 48.7±8.9 (SD)° (range: 40-65) (P=0.006). The relative variation of offset (distance from the centre of rotation of the femoral head to a line bisecting the long axis of the femur) compared to the contralateral hip was -7% in the satisfied group and 7.2% in the unsatisfied group (P=0.01). CONCLUSION: Pelvic incidence, a parameter independent of the reconstructed anatomy, probably influences the quality of life of patients with THA, via pelvic compensatory capabilities. A loss of femoral offset negatively influences the satisfaction of patients.

Determination of the ED95 of intrathecal hyperbaric prilocaine with sufentanil for scheduled cesarean delivery: a dose-finding study based on the continual reassessment method.

BACKGROUND: Scheduled cesarean section is routinely performed under spinal anesthesia using hyperbaric bupivacaine. The current study was undertaken to determine the clinically relevant 95% effective dose of intrathecal 2% hyperbaric prilocaine co-administered with sufentanil for scheduled cesarean section, using continual reassessment method. METHODS: We conducted a dose-response, prospective, double-blinded study to determine the ED95 values of intrathecal hyperbaric prilocaine used with 2,5 mcg of sufentanil and 100 mcg of morphine for cesarean delivery. Each parturient enrolled in the study received an intrathecal dose of hyperbaric prilocaine determined by the CRM and the success or failure of the block was assessed as being the primary endpoint. RESULTS: The doses given for each cohort varied from 35 to 50 mg of HP, according to the CRM, with a final ED95 lying between 45 and 50 mg of Prilocaine after completion of the 10 cohorts. Few side effects were reported and patients were globally satisfied. CONCLUSIONS: The ED95 of intrathecal hyperbaric prilocaine with sufentanil 2.5 µg and morphine 100 µg for elective cesarean delivery was found to be between 45 and 50 mg. It may be an interesting alternative to other long-lasting local anesthetics in this context. TRIAL REGISTRATION: The study was registered on January 30, 2017 - retrospectively registered - and results posted at the public database clinicaltrials.gov ( NCT03036384 ).

Investigating covariate-by-centre interaction in survival data.

In survival analysis, assessing the existence of potential centre effects on the baseline hazard or on the effect of fixed covariates on the baseline hazard, such as treatment-by-centre interaction, is a frequent clinical concern in multicentre studies. Survival models with random effects on the baseline hazard and/or on the effect of the covariates of interest have been largely applied, for instance, to investigate potential centre effects. We aimed to develop a procedure to routinely test for multiple random effects in survival analyses. We propose a statistic and a permutation approach to test whether all or a subset of components of the variance-covariance matrix of random effects are non-zero in a mixed-effects Cox model framework. Performances of the proposed permutation tests are examined under different null hypotheses corresponding to the different components of the variance-covariance matrix, i.e ., to the different random effects considered on the baseline hazard and/or on the covariates effects. Several alternative hypotheses are evaluated using simulations. The results indicate that the permutation tests have valid type I error rates under the null and achieve satisfactory power under all alternatives. The procedure is applied to two European cohorts of haematological stem cell transplants in acute leukaemia to investigate the heterogeneity across centres in leukaemia-free survival and the potential heterogeneity in prognostic factors effects across centres.

Clinical impact of NK-cell reconstitution after reduced intensity conditioned unrelated cord blood transplantation in patients with acute myeloid leukemia: analysis of a prospective phase II multicenter trial on behalf of the Société Française de Greffe de Moelle Osseuse et Thérapie Cellulaire and Eurocord.

Unrelated cord blood transplantation (UCBT) after a reduced intensity conditioning regimen (RIC) has extended the use of UCB in elderly patients and those with co-morbidities without an HLA-identical donor, although post-transplant relapse remains a concern in high-risk acute myeloid leukemia (AML) patients. HLA incompatibilities between donor and recipient might enhance the alloreactivity of natural killer (NK) cells after allogeneic hematopoietic stem-cell transplantation (HSCT). We studied the reconstitution of NK cells and KIR-L mismatch in 54 patients who underwent a RIC-UCBT for AML in CR in a prospective phase II clinical trial. After RIC-UCBT, NK cells displayed phenotypic features of both activation and immaturity. Restoration of their polyfunctional capacities depended on the timing of their acquisition of phenotypic markers of maturity. The incidence of treatment-related mortality (TRM) was correlated with low CD16 expression (P=0.043) and high HLA-DR expression (P=0.0008), whereas overall survival was associated with increased frequency of NK-cell degranulation (P=0.001). These features reflect a general impairment of the NK licensing process in HLA-mismatched HSCT and may aid the development of future strategies for selecting optimal UCB units and enhancing immune recovery.

Monitoring antimicrobial resistance (AMR) using CUSUM control charts.

We evaluated the use of the Cumulative Summation (CUSUM) control chart methodology for detection of an excessive increase in antimicrobial-resistant (AMR) bacteria acquisition. We used administrative, clinical and bacteriological data from all 157,570 patients hospitalized for at least 48 h from January 1, 2010 to December 31, 2015 in a 654-bed university teaching hospital in Paris, France. Monthly computed CUSUM were evaluated for the detection of out-of-control situations, defined as incidence rates of acquired AMR bacterial colonization exceeding acceptable thresholds at the hospital and ward levels (based on six selected wards) for AMR bacteria overall and Extended-spectrum beta-lactamases Enterobacteriaceae (ESBL-E) and Methicillin-resistant Staphylococcus aureus (MRSA), specifically. During the study period, 1,403 samples of acquired AMR bacteria were identified including 1,129 ESBL-E and 151 MRSA. The incidence rate of acquired AMR bacteria was stable at the hospital and the wards level. When based on AMR bacteria overall, CUSUM alarms were triggered at the hospital level and at the ward level in four units. For ESBL-E, CUSUM tests generated alarms at the hospital level and for the same four wards, and for MRSA, CUSUM tests detected out-of-control situations in all the wards. The CUSUM approach appears complementary with hospital infection control strategies currently in practice and appears of interest in common practice as a simple tool for AMR surveillance.

Endoscopic Detection of Small Bowel Dysplasia and Adenocarcinoma in Crohn's Disease: A Prospective Cohort-Study in High-Risk Patients.

BACKGROUND AND AIMS: Crohn's disease [CD] is associated with an increased risk of small bowel adenocarcinoma [SBA]. There are no recommendations on endoscopic screening of SBA in CD patients. The aim of this study was to evaluate the feasibility and value of endoscopic screening for SBA in CD patients at high-risk of SBA. METHODS: We performed an exploratory multi-centre study in a prospective cohort of CD patients at high-risk of SBA defined as long-term small bowel disease without bowel resection for the past 10 years. Depending on the location of the disease, baseline upper and/or lower enteroscopies were performed. Random and targeted biopsies using chromoendoscopy were taken. Patients were followed-up for at least 1 year after inclusion. RESULTS: In total, 101 patients [62 men; median age: 48 years; median duration of disease: 19 years] were recruited in ten centres. The endoscopic procedure was incomplete in 47 cases because of impassable strictures and dilation was performed in four patients. Indeterminate small bowel dysplasia was identified in two patients at endoscopic screening; SBA was confirmed in one after surgical resection. With an at least 1-year follow-up duration, two additional cases of SBA were identified in patients who underwent surgery for obstruction, resulting in a 33% sensitivity rate for SBA endoscopic screening. CONCLUSION: In a cohort of high-risk patients, the prevalence of dysplasia and SBA on CD was 4%. Because of its low sensitivity, endoscopic screening cannot be recommended for surveillance in CD patients at high-risk of SBA.

Rituximab and risk of second primary malignancies in patients with non-Hodgkin lymphoma: a systematic review and meta-analysis.

BACKGROUND: Addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy improves response rates and survival in patients with B-cell non-Hodgkin lymphoma (NHL). However, rituximab induces a transient B-cell depletion and a dose-dependent T-cell inactivation that could impair T-cell immunosurveillance. The impact of rituximab on second primary malignancy (SPM) risk remains unclear so far. We thus carried out a systematic review to compare SPM risk among patients treated or not with rituximab. PATIENTS AND METHODS: We retrieved trials from MEDLINE and EMBASE and updated data presented at American Society of Hematology and American Society of Clinical Oncology meetings from 1998 to 2013. We selected randomized, controlled trials addressing newly or relapsed/progressive B-cell NHL in which randomization arms differed only from rituximab administration. Two authors extracted data and assessed the study quality. RESULTS: We analyzed nine trials involving 4621 patients. At a median follow-up of 73 months, a total of 169 SPMs were observed in patients randomized to rituximab compared with 165 SPMs in patients not randomized to rituximab (OR = 0.88; 95% CI 0.66-1.19). The proportion of females, histology subtypes, use of rituximab in first line or in maintenance did not influence SPM risk (P = 0.94, P = 0.80, P = 0.87, P = 0.87, respectively). Cumulative exposure through prolonged administration in trials with rituximab maintenance did not contribute to an increased risk of SPM (P = 0.86). CONCLUSION: Our meta-analysis suggests no SPM predisposition among NHL survivors exposed to rituximab at a median follow-up of 6 years.

A Bayesian Hybrid Adaptive Randomisation Design for Clinical Trials with Survival Outcomes.

BACKGROUND: Response-adaptive randomisation designs have been proposed to improve the efficiency of phase III randomised clinical trials and improve the outcomes of the clinical trial population. In the setting of failure time outcomes, Zhang and Rosenberger (2007) developed a response-adaptive randomisation approach that targets an optimal allocation, based on a fixed sample size. OBJECTIVES: The aim of this research is to propose a response-adaptive randomisation procedure for survival trials with an interim monitoring plan, based on the following optimal criterion: for fixed variance of the estimated log hazard ratio, what allocation minimizes the expected hazard of failure? We demonstrate the utility of the design by redesigning a clinical trial on multiple myeloma. METHODS: To handle continuous monitoring of data, we propose a Bayesian response-adaptive randomisation procedure, where the log hazard ratio is the effect measure of interest. Combining the prior with the normal likelihood, the mean posterior estimate of the log hazard ratio allows derivation of the optimal target allocation. We perform a simulation study to assess and compare the performance of this proposed Bayesian hybrid adaptive design to those of fixed, sequential or adaptive - either frequentist or fully Bayesian - designs. Non informative normal priors of the log hazard ratio were used, as well as mixture of enthusiastic and skeptical priors. Stopping rules based on the posterior distribution of the log hazard ratio were computed. The method is then illustrated by redesigning a phase III randomised clinical trial of chemotherapy in patients with multiple myeloma, with mixture of normal priors elicited from experts. RESULTS: As expected, there was a reduction in the proportion of observed deaths in the adaptive vs. non-adaptive designs; this reduction was maximized using a Bayes mixture prior, with no clear-cut improvement by using a fully Bayesian procedure. The use of stopping rules allows a slight decrease in the observed proportion of deaths under the alternate hypothesis compared with the adaptive designs with no stopping rules. CONCLUSIONS: Such Bayesian hybrid adaptive survival trials may be promising alternatives to traditional designs, reducing the duration of survival trials, as well as optimizing the ethical concerns for patients enrolled in the trial.

Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion.

After failure of erythropoiesis-stimulating agents (ESAs), lenalidomide (LEN) yields red blood cell (RBC) transfusion independence (TI) in 20-30% of lower-risk non-del5q myelodysplastic syndrome (MDS). Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after four treatment cycles (primary end point) was 23.1% (95% CI 13.5-35.2) in the L arm and 39.4% (95% CI 27.6-52.2) in the LE arm (P=0.044), while RBC-TI was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the two arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-del5q MDS patients with anemia resistant to ESA.

Fistula Plug in Fistulising Ano-Perineal Crohn's Disease: a Randomised Controlled Trial.

BACKGROUND AND AIMS: Anal fistula plug [AFP] is a bioabsorbable bioprosthesis used in ano-perineal fistula treatment. We aimed to assess efficacy and safety of AFP in fistulising ano-perineal Crohn's disease [FAP-CD]. METHODS: In a multicentre, open-label, randomised controlled trial we compared seton removal alone [control group] with AFP insertion [AFP group] in 106 Crohn's disease patients with non- or mildly active disease having at least one ano-perineal fistula tract drained for more than 1 month. Patients with abscess [collection ≥ 3mm on magnetic resonance imaging or recto-vaginal fistulas were excluded. Randomisation was stratified in simple or complex fistulas according to AGA classification. Primary end point was fistula closure at Week 12. RESULTS: In all, 54 patients were randomised to AFP group [control group 52]. Median fistula duration was 23 [10-53] months. Median Crohn's Disease Activity Index at baseline was 81 [45-135]. Fistula closure at Week 12 was achieved in 31.5% patients in the AFP group and in 23.1 % in the control group (relative risk [RR] stratified on AGA classification: 1.31; 95% confidence interval: 0.59-4.02; p = 0.19). No interaction in treatment effect with complexity stratum was found; 33.3% of patients with complex fistula and 30.8% of patients with simple fistula closed the tracts after AFP, as compared with 15.4% and 25.6% in controls, respectively [RR of success = 2.17 in complex fistula vs RR = 1.20 in simple fistula; p = 0.45]. Concerning safety, at Week 12, 17 patients developed at least one adverse event in the AFP group vs 8 in the controls [p = 0.07]. CONCLUSION: AFP is not more effective than seton removal alone to achieve FAP-CD closure.

Propensity score estimators for the average treatment effect and the average treatment effect on the treated may yield very different estimates.

OBJECTIVE: Propensity score matching is typically used to estimate the average treatment effect for the treated while inverse probability of treatment weighting aims at estimating the population average treatment effect. We illustrate how different estimands can result in very different conclusions. STUDY DESIGN: We applied the two propensity score methods to assess the effect of continuous positive airway pressure on mortality in patients hospitalized for acute heart failure. We used Monte Carlo simulations to investigate the important differences in the two estimates. RESULTS: Continuous positive airway pressure application increased hospital mortality overall, but no continuous positive airway pressure effect was found on the treated. Potential reasons were (1) violation of the positivity assumption; (2) treatment effect was not uniform across the distribution of the propensity score. From simulations, we concluded that positivity bias was of limited magnitude and did not explain the large differences in the point estimates. However, when treatment effect varies according to the propensity score (E[Y(1)-Y(0)|g(X)] is not constant, Y being the outcome and g(X) the propensity score), propensity score matching ATT estimate could strongly differ from the inverse probability of treatment weighting-average treatment effect estimate. We show that this empirical result is supported by theory. CONCLUSION: Although both approaches are recommended as valid methods for causal inference, propensity score-matching for ATT and inverse probability of treatment weighting for average treatment effect yield substantially different estimates of treatment effect. The choice of the estimand should drive the choice of the method.

Adenovirus infection and disease in paediatric haematopoietic stem cell transplant patients: clues for antiviral pre-emptive treatment.

Human adenovirus (HAdV) infections constitute a major cause of morbidity in paediatric haematopoietic stem cell transplant (HSCT) patients. New antiviral treatments offer promising perspectives. However, it remains challenging to identify patients at risk for disseminated infection, and who should receive early antiviral intervention. We conducted a longitudinal study of allogeneic HSCT recipients, including weekly HAdV monitoring, to determine the risks factors associated with HAdV infection and dissemination, and to assess whether HAdV loads in stools may be used as surrogate markers for HAdV dissemination. Between September 2010 and December 2011, out of 72 patients, the cumulative incidence rates at day 100 of HAdV digestive infection, systemic infection and related disease were 35.9%, 24.0%, and 18.3%, respectively. In multivariate analysis, the risk factors for HAdV digestive and systemic infection were cord blood and in vitro T-cell depletion. Graft-versus-host disease (GVHD) grade >2 was also associated with systemic infection. In patients with HAdV digestive shedding, GVHD grade >2 and HAdV load in stools were the only risk factors for systemic infection. The median peak levels of HAdV in stool were 7.9 and 4.0 log10 copies/mL, respectively, in patients with HAdV systemic infection and in those without. HAdV monitoring in stools of paediatric HSCT recipients receiving cord blood or in vitro T-cell depleted transplants helps to predict patients at risk for HAdV systemic infection. Our results provide a rationale for randomized controlled trials to evaluate the benefit of anti-HAdV pre-emptive treatments based on HAdV DNA levels in stools.

Changes in intensive care for allogeneic hematopoietic stem cell transplant recipients.

Intensive care unit (ICU) admission is associated with high mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Whether mortality has decreased recently is unknown. The 497 adult allogeneic HSCT recipients admitted to three ICUs between 1997 and 2011 were evaluated retrospectively. Two hundred and nine patients admitted between 1997 and 2003 were compared with the 288 patients admitted from 2004 to 2011. Factors associated with 90-day mortality were identified. The recent cohort was characterized by older age, lower conditioning intensity, and greater use of peripheral blood or unrelated-donor graft. In the recent cohort, ICU was used more often for patients in hematological remission (67% vs 44%; P<0.0001) and without GVHD (73% vs 48%; P<0.0001) or invasive fungal infection (85% vs 73%; P=0.0003) despite a stable admission rate (21.7%). These changes were associated with significantly better 90-day survival (49% vs 31%). Independent predictors of hospital mortality were GVHD, mechanical ventilation (MV) and renal replacement therapy (RRT). Among patients who required MV or RRT, survival was 29% and 18%, respectively, but dropped to 18% and 6% in those with GVHD. The use of ICU admission has changed and translated into improved survival, but advanced life support in patients with GVHD usually provides no benefits.