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.

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 ).

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.

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.

Severe infections requiring intensive care unit admission in kidney transplant recipients: impact on graft outcome.

BACKGROUND: Kidney transplant recipients are at risk for life-threatening infections, which may affect the long-term prognosis. METHODS: We retrospectively included all kidney transplant recipients admitted for sepsis, severe sepsis, or septic shock to the medical intensive care unit (ICU) of the Saint-Louis Hospital, Paris, France, between 2000 and 2010. The main objective was to identify factors associated with survival without graft impairment 90 days after ICU discharge. RESULTS: Data were available for 83 of 100 eligible patients. The main sites of infection were the lungs (54%), urinary tract (24%), and bloodstream (22%). Among documented infections (55/83), 80% were bacterial. Fungal infections were more common among patients transplanted after 2005 (5% vs. 23%, P = 0.02). Mechanical ventilation was used in 46 (56%) patients, vasopressors in 39 (47%), and renal replacement therapy (RRT) in 34 (41%). In-hospital and day-90 mortality rates were 20% and 22%, respectively. On day 90, among the 65 survivors, 39 (47%) had recovered their previous graft function and 26 (31%) had impaired graft function, including 16 (19%) who were dependent on RRT. Factors independently associated with day-90 survival and graft function recovery were baseline serum creatinine (odds ratio [OR] for a 10 µmol/L increase 0.94, 95% confidence interval [CI] 0.88-1.00) and cyclosporine therapy (OR 0.30, 95% CI 0.11-0.79). CONCLUSION: Sepsis was chiefly related to bacterial pneumonia or urinary tract infection. Pneumocystis jirovecii was the leading opportunistic agent, with a trend toward an increase over time. Infections often induced severe graft function impairment. Baseline creatinine and cyclosporine therapy independently predicted the outcome.

Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: correlations with clinical phenotype and polymorphism of the neonatal Fc receptor.

Treatment of common variable immunodeficiency disorders (CVID) is based on replacement therapy using intravenous (i.v.) or subcutaneous (s.c.) immunoglobulin (Ig)G. Interindividual variation of IgG dose is common. A total of 380 CVID patients on stable IgG replacement from two prospective cohorts were analysed. An 'efficiency' index was defined as the ratio of serum IgG trough level minus IgG residual to the average weekly dose of IgG infusion. A reduced efficiency of IgG was associated independently with the i.v. route (P < 0·001) and with the presence of at least one CVID disease-related phenotype (lymphoproliferation, autoimmune cytopenia or enteropathy) (P < 0·001). High IgG efficiency was noted in patients homozygotes for the variable number tandem repeat (VNTR) 3/3 polymorphism of the neonatal Fc receptor gene [IgG Fc fragment receptor transporter alpha chain (FCGRT)] promoter, and this was particularly significant in patients treated with IVIG (P < 0.01). In a multivariate analysis, FCGRT VNTR 3/3 genotype (P = 0·008) and high serum albumin (P < 0·001) were associated independently with increased efficiency of i.v. Ig.

What is the ED95 of prilocaine for femoral nerve block using ultrasound?

BACKGROUND: Our aim was to estimate the ED95 of prilocaine 1% w/v for femoral nerve block. METHODS: This two-stage dose-finding sequential clinical trial followed an adaptive design based on the continual reassessment method (CRM). Adult patients undergoing Vastus medialis muscle biopsy under ultrasound-guided femoral nerve block were recruited. Data from previously published studies and our own previous experience were used to set the dose levels and their guesstimate probabilities of response. RESULTS: Forty patients were recruited in the trial (n=26 in the first stage and n=14 in the second stage). Using the CRM, the estimated response probabilities with 13 and 17 ml prilocaine 1% w/v were 90.4% (95% credibility interval: 68-98%) and 99.1% (95% credibility interval: 89-100%), respectively. CONCLUSION: Our study demonstrates that the dose closest to the ED(95) of prilocaine 1% w/v for ultrasound-guided femoral nerve block is 17 ml. The study also illustrates the value of CRM in dose-finding experiments.

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.

Inclusion of patients with acute leukemia in clinical trials: a prospective multicenter survey of 1066 cases.

BACKGROUND: to estimate the prevalence of adults and children with acute leukemia (AL) included in clinical trials and to determine factors associated with noninclusion. PATIENTS AND METHODS: all patients with AL admitted to the 17 departments managing AL in Paris area from 2005 to 2007 were prospectively included. Clinical data, therapeutic decisions, and enrollment in trials were recorded. Reasons that prevented accrual were identified. RESULTS: a total of 1066 admissions with AL (85% of adults) were recorded, and 34 trials were open. In adults, the rate of inclusion in a trial was 25% [95% confidence interval (CI) 21% to 28%] for acute myeloid leukemia (AML) and 23% (95% CI 17% to 29%) for acute lymphoid leukemia (ALL). In children, the rate of inclusion was 58% (95% CI 41% to 73%) for AML and 64% (95% CI 55% to 72%) for ALL. The rate of inclusion varied across centers, with a significant increase when they were involved in clinical research. Patients included in trials differed significantly from those not included according to age, primary/secondary AL, leukemia type, results of cytogenetic analyses, and stage of disease. CONCLUSIONS: the rate of inclusion is higher than in oncology. This difference may be explained by management in specialized centers often involved in clinical research.

Procedure volume is one determinant of centre effect in mechanically ventilated patients.

Survival rates vary significantly between intensive care units, most notably in patients requiring mechanical ventilation (MV). The present study sought to estimate the effect of hospital MV volume on hospital mortality. We included 179,197 consecutive patients who received mechanical ventilation in 294 hospitals. Multivariate logistic regression models with random intercepts were used to estimate the effect of annual MV volume in each hospital, adjusting for differences in severity of illness and case mix. Median annual MV volume was 162 patients (interquartile range 99-282). Hospital mortality in MV patients was 31.4% overall, 40.8% in the lowest annual volume quartile and 28.2% in the highest quartile. After adjustment for severity of illness, age, diagnosis and organ failure, higher MV volume was associated with significantly lower hospital mortality among MV patients (OR 0.9985 per 10 additional patients, 95% CI 0.9978-0.9992; p = 0.0001). A significant centre effect on hospital mortality persisted after adjustment for volume effect (p < 0.0001). Our study demonstrated higher hospital MV volume to be independently associated with increased survival among MV patients. Significant differences in outcomes persisted between centres after adjustment for hospital MV volume, supporting a role for other significant determinants of the centre effect.

Dose-finding design driven by efficacy in onco-hematology phase I/II trials.

We present an adaptive model-based procedure for dose finding in phase I/II clinical trials when both efficacy and toxicity responses are available. In this setting, previous designs aimed at identifying the maximum tolerated dose as a surrogate for efficacy or the most successful dose, defined as the dose with the highest probability of efficacy without toxicity. Rather than using this definition of success, we propose considering all responses conditionally on the probability that dose-limiting toxicity is under a pre-specified threshold. The presented approach uses a joint model for the probability of an efficacy response and toxicity, and is evaluated through simulations. A retrospective application to a Phase I trial conducted in chronic lymphocytic leukemia is presented.

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.

The impact of preexisting or acquired Kaposi sarcoma herpesvirus infection in kidney transplant recipients on morbidity and survival.

The impact of preexisting or acquired Kaposi sarcoma herpesvirus (KSHV) infection in kidney transplant recipients was evaluated in a prospective study. Serum collected from kidney donors and recipients before transplantation were tested for antibodies against KSHV latent nuclear antigen. Three groups of recipients were defined: group A (KSHV+), group B (KSHV-, KSHV+ donor) and group C (donor and recipient KSHV-). Blood was collected from recipients, every 3 months for 3 years, for KSHV viremia (groups A and B), quantitative (group A) and qualitative serology (group B). Data of group C recipients were extracted from a French database. The prevalence of KSHV antibodies was 1.1% in donors and 3.2% in recipients. There were respectively 161, 64 and 4744 recipients in groups A, B and C. In group A, 13% developed Kaposi's sarcoma (KS). Age >53.5 years (p = 0.025) and black skin (p = 0.0054) were associated with KS development. In group B, three recipients developed clinical manifestations related to KSHV infection. There was no difference in terms of survival and graft loss between the three groups. In conclusion, although kidney recipients should be aware of the additional risk of KSHV morbidity, KSHV+ recipients should not be systematically excluded from kidney transplantation.

Asymmetrical transmission of human herpesvirus 8 among spouses of patients with Kaposi sarcoma.

BACKGROUND: Among heterosexuals, the sexual transmission of human herpesvirus 8 (HHV8) has not been established. OBJECTIVES: To assess HHV8 seroprevalence in spouses of patients with classic and endemic Kaposi sarcoma (KS) and to suggest possible routes of transmission. METHODS: A case-control study was carried out in a teaching hospital among spouses of human immunodeficiency virus-negative patients with KS (cases - exposed subjects) and controls who did not have KS nor were related to patients with KS (nonexposed subjects). HHV8 seroprevalence in spouses of patients with KS was compared with HHV8 seroprevalence in controls matched for age, gender and place of birth. Other serology tests were compared between cases and controls. Among heterosexual couples, HHV8-seropositive and HHV8-seronegative spouses were compared for possible risk factors for virus transmission. RESULTS: HHV8 seroprevalence was significantly higher among spouses of patients with KS (13 of 22; 59%) than among matched controls (19 of 58; 33%; P = 0.043). Among heterosexual couples, five of five (100%) male spouses were HHV8 positive vs. six of 15 (40%) female spouses (P = 0.04). There was no significant difference between HHV8-seropositive and HHV8-seronegative spouses for all other factors screened for among heterosexual couples. CONCLUSIONS: Being a spouse of a patient with KS is a risk factor for HHV8 seropositivity. Our results suggest that female-to-male HHV8 transmission could be more efficient than male-to-female transmission among couples including a patient with KS. Transmission could involve distinctive behaviours, or currently unknown biological properties of HHV8.

[Prospective evaluation of the efficacy of the combination of budesonide/formoterol in obstructive airway disease after allogeneic hematopoietic stem cell transplantation]. / Efficacité de l'association budésonide/formotérol dans le trouble ventilatoire obstructif survenant après allogreffe de cellules souches hématopoïétiques.

BACKGROUND: Although it has not been evaluated prospectively, the usual treatment for obstructive airway disease after allogeneic hematopoietic stem cell transplantation, which is related to graft versus host disease, consists of intensification of systemic immunosuppressive therapy. However, this treatment has a limited efficacy and is associated with a significant number of serious adverse effects, particularly infectious. Alternative treatments are therefore required. Recently, clinical and functional improvement in patients with obstructive airway disease following allogenic hematopoietic stem cell transplantation treated with inhaled combined Budesonide/Formoterol has been retrospectively reported. METHODS: The present prospective multi-centered, randomised double-blind trial is designed to evaluate the efficacy of the combination of budesonide/formoterol (400/12 microg 2 inhalations bid) versus placebo in patients with moderate to severe obstructive airway disease, not requiring initiation or intensification of systemic immunosuppressive therapy for extra thoracic graft versus host disease. The primary outcome will be the improvement of FEV1 at 1 month of treatment. The secondary outcomes will be the clinical and functional pulmonary improvements at 6 months. EXPECTED RESULTS: The leading hypothesis is that patients treated with inhaled combined Budesonide/Formoterol will show significant improvement of their clinical symptoms and pulmonary functional testing.

Case volume and mortality in haematological patients with acute respiratory failure.

High case volume is associated with improved survival in medical and surgical conditions. The present study sought to determine whether intensive care unit (ICU) case volume was associated with survival of critically ill patients with haematological malignancies and acute respiratory failure (ARF). A regional database containing data from 1,753 haematological patients with ARF admitted to 28 medical ICUs from 1997 to 2004 was used. Multivariate analysis using mixed models was performed to adjust for severity of illness and other confounding factors, including a propensity score that incorporates differences between ICUs with different case volumes. The three case volume tertiles were: low volume (<12 admissions per year), intermediate volume (12-30 admissions per year), and high volume (>30 admissions per year). In univariate analyses, ICU case volume was not associated with ICU mortality. After adjusting for prognostic factors for ICU mortality and the propensity score, patients in high-volume ICUs had lower mortality than other patients. A case volume increase of one admission per year led to a significant mortality reduction with an odds ratio of 0.98 (95% confidence limits 0.97-0.99). Mortality was independently associated with severity of organ dysfunction. In intensive care units admitting larger numbers of critically ill haematological patients with acute respiratory failure, mortality was lower than in other intensive care units. The mechanisms of the relationship between volume and outcome among haematological patients with acute respiratory deserve additional studies.

High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group.

Pivotal phase II studies in acute myeloblastic leukemia (AML) patients in first relapse have used gemtuzumab ozogamicin (GO) (Mylotarg) at a dose of 9 mg/m(2) on days 1 and 14. These studies showed a 26% response rate (13% complete remission (CR) and 13% CRp (complete remission with incomplete platelet recovery)) but with high degree of hematological and liver toxicities. Based on in vitro studies showing a re-expression of CD33 antigenic sites on the cell surface of blasts cells after exposure to GO, we hypothesized that fractionated doses of GO may be efficient and better tolerated. Fifty-seven patients with AML in first relapse received GO at a dose of 3 mg/m(2) on days 1, 4 and 7 for one course. Fifteen patients (26%) achieved CR and four (7%) CRp. Remission rate correlated strongly with P-glycoprotein and MRP1 activities. The median relapse-free survival was 11 months, similar for CR or CRp patients. Median duration of neutropenia < 500/microl and thrombocytopenia < 50,000/microl were, respectively, 23 and 21 days. No grade 3 or 4 liver toxicity was observed. No veno-occlusive disease occurred after GO or after hematopoietic stem cell transplantation given after GO in seven patients. Mylotarg administered in fractionated doses demonstrated an excellent efficacy/safety profile.