Adaptive designs in dermatology clinical trials: Current status and future perspectives.

Current drug development strategies present many challenges that can impede drug approval by regulatory agencies. Alternative study models, such as adaptive trial designs, have recently sparked interest, as they provide a flexible and more efficient approach in conducting clinical trials. Adaptive trial designs offer several potential benefits over traditional randomized controlled trials, which include decrease in costs, reduced clinical development time and limiting exposure of patients to potentially ineffective treatments allowing completion of studies with fewer patients. This article explores the current use of adaptive trial designs in non-oncologic skin diseases and highlights the most common types of adaptive designs used in the field. We also review the operational challenges and statistical considerations associated with such designs and propose clinical development strategies to successfully implement adaptive designs. The article also proposes instances where adaptive trial designs are particularly beneficial, and other situations where they may not be very useful.

Estimands for atopic dermatitis clinical trials: Expert opinion on the importance of intercurrent events.

Despite the emergence of novel targeted treatments for atopic dermatitis (AD), there is a lack of guidelines on standardizing analysis of clinical trial data. To define and estimate meaningful treatment comparisons, several factors, including intercurrent events, must be taken into account. Intercurrent events are defined as events occurring after treatment initiation that affect either the interpretation or existence of the measurements associated with clinical questions of interest. Due to the relapsing, unpredictable nature of AD, intercurrent events frequently occur in AD trials, such as use of rescue therapy for intense itch and sleep deprivation. Despite the impact of intercurrent events in AD, they are often handled in an inconsistent manner across trials, which limits results interpretation. The estimand framework is increasingly used to estimate treatment effects while accounting for intercurrent events. This review explores how guidance from the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) on the use of estimands can be applied to support AD clinical trial design and analysis. We propose that estimands are used in AD trials and defined early during trial design. The use of estimands can provide clinicians with interventional trial results that are more reflective of clinical practice, help facilitate comparisons across clinical trials, and are more informative to enable improved treatment selection for patients.

Human cytomegalovirus (HCMV) long-term shedding and HCMV-specific immune response in pregnant women with primary HCMV infection.

Human cytomegalovirus (HCMV) shedding has been extensively investigated in newborns and in young children, however, much less is known about it in immunocompetent adults. Shedding of HCMV was investigated in saliva, vaginal secretions and urine of pregnant women experiencing primary infection along with the development of the HCMV-specific immune response. Thirty-three pregnant women shed HCMV DNA in peripheral biological fluids at least until one year after onset of infection, while in blood HCMV DNA was cleared earlier. Significantly higher levels of viral load were found in vaginal secretions compared to saliva and urine. All subjects examined two years after the onset of infection showed a high avidity index, with IgM persisting in 36% of women. Viral load in blood was directly correlated with levels of HCMV-specific IgM and inversely correlated with levels of IgG specific for the pentameric complex gH/gL/pUL128L; in addition, viral load in blood was inversely correlated with percentage of HCMV-specific CD4+ and CD8+ expressing IL-7R (long-term memory, LTM) while viral load in biological fluids was inversely correlated with percentage of HCMV-specific CD4+ and CD8+ effector memory RA+(TEMRA). In conclusion, viral shedding during primary infection in pregnancy persists in peripheral biological fluids for at least one year and the development of both antibodies (including those directed toward the pentameric complex) and memory T cells are associated with viral clearance.

Malignant ovarian germ cell tumors in pediatric patients: The AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) study.

OBJECTIVE: Malignant ovarian germ cell tumors (MOGCT) carry an excellent prognosis, and the treatment aims to achieve results with the least possible treatment-related morbidity. The aim of this study was to assess the outcomes of pediatric patients with MOGCT. METHODS: Patients were treated according to their stage: surgery and surveillance for stage I; a modified bleomycin-etoposide-cisplatin (BEP) regimen for stages II (three cycles), III, and IV (three cycles) with surgery on residual disease. RESULTS: Seventy-seven patients were enrolled (median age 11.8 years), 26 with dysgerminoma (Dysg), 13 with immature teratoma and elevated serum alpha-fetoprotein levels (IT + AFP), and 38 with nondysgeminoma (Non-Dysg) staged as follows: 27 stage I, 13 stage II, 32 stage III, 5 stage IV. Among evaluable patients in stage I (5-year event-free survival [EFS] 72.1% [95% CI: 56.4-92.1%]; 5-year overall survival [OS] 100%), seven relapsed (three patients with Dysg and four patients with Non-Dysg) and were rescued with chemotherapy (plus surgery in three patients). Among the evaluable patients with stages II-IV, 48 (98%) achieved complete remission after chemotherapy ± surgery, one (IT + AFP, stage IV) had progressive disease. In the whole series (median follow-up 80 months), the 5-year OS and EFS were 98.5% (95% CI: 95.6-100%) and 84.5% (95% CI: 76.5-93.5%). CONCLUSIONS: We confirm the excellent outcome for MOGCT. Robust data are lacking on surgical staging, surveillance for Non-Dysg with stage I, the management of IT + AFP, and the most appropriate BEP regimen. As pediatric oncologists, we support the role of surveillance after proper surgical staging providing cases are managed by experts at specialized pediatric centers.

Humoral primary immunodeficiency diseases: clinical overview and chest high-resolution computed tomography (HRCT) features in the adult population.

Humoral primary immunodeficiency diseases (hPIDs) are a heterogeneous group of hereditary disorders resulting in abnormal susceptibility to infections of the sinopulmonary tract. Some of these conditions (e.g., common variable immunodeficiency disorders [CVID]) imply a number of non-infectious thoracic complications such as non-infectious airway disorders, diffuse lung parenchymal diseases, and neoplasms. Chest high-resolution computed tomography (HRCT) is a key imaging tool to characterise and quantify the extent of underlying thoracic involvement, as well as to direct and monitor treatment. The aims of this review are to provide a brief clinical overview of hPIDs and describe the related chest HRCT imaging features in the adult population, with a special focus on CVID and its complications.

Multiscale morphology of organic semiconductor thin films controls the adhesion and viability of human neural cells.

We investigate how multiscale morphology of functional thin films affects the in vitro behavior of human neural astrocytoma 1321N1 cells. Pentacene thin film morphology is precisely controlled by means of the film thickness, Theta (here expressed in monolayers (ML)). Fluorescence and atomic force microscopy allow us to correlate the shape, adhesion, and proliferation of cells to the morphological properties of pentacene films controlled by saturated roughness, sigma, correlation length, xi, and fractal dimension, d(f). At early incubation times, cell adhesion exhibits a transition from higher to lower values at Theta approximately 10 ML. This is explained using a model of conformal adhesion of the cell membrane onto the growing pentacene islands. From the model fitting of the data, we show that the cell explores the surface with a deformation of the membrane whose minimum curvature radius is 90 (+/- 45) nm. The transition in the adhesion at approximately 10 ML arises from the saturation of xi accompanied by the monotonic increase of sigma, which leads to a progressive decrease of the pentacene local radius of curvature and hence to the surface area accessible to the cell. Cell proliferation is also enhanced for Theta < 10 ML, and the optimum morphology parameter ranges for cell deployment and growth are sigma 500 nm, and d(f) > 2.45. The characteristic time of cell proliferation is tau approximately 10 +/- 2 h.

Lithiation Mechanism in High-Entropy Oxides as Anode Materials for Li-Ion Batteries: An Operando XAS Study.

High-entropy oxides based on transition metals, such as Mg0.2Co0.2Ni0.2Cu0.2Zn0.2O (TM-HEO), have recently drawn special attention as potential anodes in lithium-ion batteries due to high specific capacity and cycling reversibility. However, the lithiation/delithiation mechanism of such systems is still controversial and not clearly addressed. Here, we report on an operando XAS investigation into TM-HEO-based anodes for lithium-ion cells during the first lithiation/delithiation cycle. This material showed a high specific capacity exceeding 600 mAh g-1 at 0.1 C and Coulombic efficiency very close to unity. The combination of functional and advanced spectroscopic studies revealed complex charging mechanisms, developing through the reduction of transition-metal (TM) cations, which triggers the conversion reaction below 1.0 V. The conversion is irreversible and incomplete, leading to the final collapse of the HEO rock-salt structure. Other redox processes are therefore discussed and called to account for the observed cycling behavior of the TM-HEO-based anode. Despite the irreversible phenomena, the HEO cubic structure remains intact for ∼60% of lithiation capacity, so proving the beneficial role of the configuration entropy in enhancing the stability of the HEO rock-salt structure during the redox phenomena.

Electrical bistability in conductive hybrid composites of doped polyaniline nanofibers-gold nanoparticles capped with dodecane thiol.

A novel electrical bistable hybrid nanocomposite based on doped Polyaniline nanofibers with 1-Dodecanethiol-protected Gold nanoparticle (PAni.AuDT), 3-4 nm in size, as the conductive component and polystyrene as polymer matrix was prepared. The structural morphology of the composite and the dispersion of nanoparticles inside it were evaluated using Transmission Electron Microscopy (TEM). The thermal stability and the ratio Polyaniline/Gold nanoparticles in the composite were determined by using thermogravimetric analysis. The electrical bistability of the PAni.AuDT-PS composite, the influence of the dispersion of the PAni.AuDT conductive network and the basic operation mechanism, have been assessed by measuring the electrical response of planar device architectures, also as a function of the environmental temperature (in the range 200 K < T < 360 K). The basic operation mechanism of the hybrid compound has been then correlated to the combined action of the thermally-induced scattering of charge carriers and the thermal contraction of the hosting polymeric matrix. Moreover, the right compromise between these two effects in terms of the most efficient bistability has been studied, founding the concentration of the conductive component which optimizes the device on-off ratio (I(on)/ I(off)).

Metastatic neuroblastoma in infants: are survival rates excellent only within the stringent framework of clinical trials?

INTRODUCTION: SIOPEN INES protocol yielded excellent 5-year survival rates for MYCN-non-amplified metastatic neuroblastoma. Patients deemed ineligible due to lack or delay of MYCN status or late registration were treated, but not included in the study. Our goal was to analyse survival at 10 years among the whole population. MATERIALS AND METHODS: Italian and Spanish metastatic INES patients' data are reported. SPSS 20.0 was used for statistical analysis. RESULTS: Among 98 infants, 27 had events and 19 died, while 79 were disease free. Five- and 10-year event-free survival (EFS) were 73 and 70 %, and overall survival (OS) was 81 and 74 %, respectively. MYCN status was significant for EFS, but not for OS in multivariate analysis. CONCLUSIONS: The survival rates of patients who complied with all the inclusion criteria for INES trials are higher compared to those that included also not registered patients. Five-year EFS and OS for INES 99.2 were 87.8 and 95.7 %, while our stage 4s population obtained 78 and 87 %. Concerning 99.3, 5-year EFS and OS were 86.7 and 95.6 %, while for stage 4 we registered 61 and 68 %. MYCN amplification had a strong impact on prognosis and therefore we consider it unacceptable that many patients were not studied for MYCN and probably inadequately treated. Ten-year survival rates were shown to decrease: EFS from 73 to 70 % and OS from 81 to 74 %, indicating a risk of late events, particularly in stage 4s. Population-based registries like European ENCCA WP 11-task 11 will possibly clarify these data.

A hybrid living/organic electrochemical transistor based on the Physarum polycephalum cell endowed with both sensing and memristive properties.

A hybrid bio-organic electrochemical transistor was developed by interfacing an organic semiconductor, poly(3,4-ethylenedioxythiophene) doped with poly(styrene sulfonate), with the Physarum polycephalum cell. The system shows unprecedented performances since it could be operated both as a transistor, in a three-terminal configuration, and as a memristive device in a two terminal configuration mode. This is quite a remarkable achievement since, in the transistor mode, it can be used as a very sensitive bio-sensor directly monitoring biochemical processes occurring in the cell, while, as a memristive device, it represents one of the very first examples of a bio-hybrid system demonstrating such a property. Our system combines memory and sensing in the same system, possibly interfacing unconventional computing. The system was studied by a full electrical characterization using a series of different gate electrodes, namely made of Ag, Au and Pt, which typically show different operation modes in organic electrochemical transistors. Our experiment demonstrates that a remarkable sensing capability could potentially be implemented. We envisage that this system could be classified as a Bio-Organic Sensing/Memristive Device (BOSMD), where the dual functionality allows merging of the sensing and memory properties, paving the way to new and unexplored opportunities in bioelectronics.

High-dose cytosine arabinoside and fractionated total body irradiation as a preparative regimen for the treatment of children with acute lymphoblastic leukemia and Down syndrome by allogeneic bone marrow transplantation.

The early toxicity, incidence of graft-versus-host disease (GVHD) and long-term follow-up were evaluated in two children with Down syndrome (DS) treated for acute lymphoblastic leukemia (ALL) in second complete remission by HLA-matched sibling allogeneic bone marrow transplantation (BMT). Preparative conditioning therapy consisted of cytosine arabinoside (Ara-C) and fractionated total body irradiation (F-TBI) and GVHD prophylaxis of cyclosporin A. The conditioning regimen was well tolerated, the only acute complication being mild mucositis. Engraftment (polymorphonuclear cells >500/microliter) was documented by day +17 in both patients. One child remains in continuous complete remission, without medical problems, 60 months after BMT. The second patient died from complications associated with chronic GVHD 21 months following BMT. Ara-C and F-TBI is a well-tolerated preparative regimen for children with DS undergoing allogeneic BMT.

Central venous catheter-related complications after bone marrow transplantation in children with hematological malignancies.

We studied infectious and mechanical complications occurring with 55 central venous catheters (CVCs) managed in hospital and at home, in 53 children with hematological malignancies who underwent bone marrow transplantation (BMT). The total catheter life span was 6906 days (median 111), 2359 days (median 40) in hospital and 4547 days (median 78.5) at home. Duration of neutropenia was 1241 days (median 20), mostly in hospital. We observed 21 CVC-related infections from 17/55 CVCs (31%): 0.30 episodes/100 days of CVC use with 0.55/100 days in hospital vs 0.17/100 days at home. Antibiotic treatment resolved 72% of infections without CVC removal, which was required in six instances. There were 14 mechanical complications (0.20 episodes/100 days of CVC use) in 6/55 CVCs (11%), with three removals. Interventions to resolve mechanical problems included catheter declotting by urokinase, repair and replacement. We conclude that CVC is an essential component of care of children with cancer undergoing BMT and that it has a relatively low complication rate. Most complications can be resolved by an appropriate CVC handling and by a multidisciplinary intervention in the critical post-BMT phase.

Acute Intravascular Haemolysis Associated with High Dose Immunoglobulin after Bone Marrow Transplantation for Acute Myelogenous Leukemia.

A 12-year-old boy developed persistent thrombocytopenia after undergoing bone marrow transplantation for acute myelogenous leukemia. High doses of intravenous immunoglobulins were used to treat overt hemorrhage and a sudden intravascular hemolysis occurred. The serologic findings point to an acute hemolysis secondary to the presence of isohemoagglutinins in the intravenous immunoglobulin preparations.

Stereotactic excisional breast biopsies utilizing the advanced breast biopsy instrumentation system.

OBJECTIVE: To compare the stereotactic excisional breast biopsy ABBI (Advanced Breast Biopsy Instrumentation) system with "open" excisional breast biopsy with needle localization. METHODS: Twenty-three women underwent excisional breast biopsy using the ABBI system, 23 women concomitantly underwent needle localization and excisional breast biopsy. All women had mammograms displaying microcalcifications or nonpalpable noncystic nodular densities suspicious for cancer. RESULTS: Biopsies with ABBI were undertaken with local anesthesia whereas needle localization biopsies were undertaken using general anesthesia. The ABBI system allowed completion mammography. Although preoperative mammograms were comparable, biopsy specimen diameter, volume, and weight were less with ABBI, and patient acceptance was higher. Efficacy, procedural duration, and blood loss were not different between the techniques. CONCLUSIONS: The ABBI system is a minimally invasive yet efficacious excisional breast biopsy technique. It is utilized with local anesthesia in an environment more relaxed and less expensive than the operating room. It allows for smaller biopsy specimens and higher patient acceptance and is as efficacious as needle localization biopsy techniques. The ABBI system belongs in the surgical armamentarium against indeterminant nonpalpable mammographic breast lesions.

Maze performance: a direct comparison of food vs. water mazes.

The purpose of these experiments was to evaluate the utility of a water maze for testing performance in nonfood-restricted rats. Water maze performance was compared to performance in a food-rewarded (food) maze. Separate groups of rats were given single daily trials of 34 days in one of two mazes. The path through each maze was identical; in fact, the same maze was used with the exception that the maze was filled with water during water maze testing and left dry during the food maze testing. In the food maze, a chocolate peanut butter chip was placed at the finish. In the water maze an out-of-the-water platform was placed at the finish. The time to reach the finish was measured for each trial. Both free-feeding and food-restricted rats were tested in each maze. Free-feeding rats learned the food maze with great difficulty, requiring more than 30 trials. Food-restricted rats learned the food maze more quickly than did free-feeding rats. Free-feeding rats learned to solve the water maze more quickly than the food maze. Food-restricted rats also learned the water maze more quickly than the food maze and learned both mazes faster than free-feeding rats. Plasma levels of corticosterone, ACTH and prolactin were measured in all rats immediately following completion of the last maze trial. Plasma corticosterone levels were elevated and plasma prolactin levels were decreased in both food-restricted groups as compared to free-feeding rats, demonstrating that food restriction was chronically stressful.(ABSTRACT TRUNCATED AT 250 WORDS)

[Syndrome X and surgical stress. A clinical case]. / Sindrome X e stress chirurgico. Caso clinico.

The syndrome X is a clinical disease characterised by anginous pain with the absence of significant and angiographically visible stenosis of the coronary tree. D. P. M., a 61-year-old woman suffering from biliary lithiasis, underwent cholecystectomy. During the immediate postoperative period, the patient showed difficulty in regaining consciousness and there were electrocardiographic signs of extensive anterior ischemia; prior to the operation only a 1st degree atrio-ventricular block and a positive history of occasional precordial pain had been reported. On the 2nd postoperative day the patient complained of violent retrosternal pain irradiated to the left shoulder. Given that the signs of ischemia had regressed, various instrumental tests were performed: echocardiogram, cycloergometric test, dipyridamole test, cold pressure test, Holter's dynamic ECG, all of which were within the normal; moreover, selective coronarography did not reveal significant stenosis of the coronary tree. The patient was therefore diagnosed as suffering from syndrome X. In the light of the present case, the authors conclusion may be summarised as follows: the diagnosis of syndrome X, which is by definition not easy, may sometimes become critical, as in the present case, since rapid intervention would have enabled prophylactic therapy to be performed to combat surgical stress.

[Control of postoperative pain with intrapleural analgesia]. / Controllo del dolore postoperatorio con analgesia intrapleurica.

INTRODUCTION: Personal experience in the treatment of postoperative pain using intrapleural analgesia applied on 50 patients chosen at random in a group of 90 after thoracotomy is reported. METHODS: At the end of operation a peridural catheter for continuative infusion was applied in the paravertebral socket by direct transfixion of chest wall. A local anaesthetic has been given (75 mg of bupivacaine 0.50%) through the catheter at 8 hours interval for three times at the most. The degree of analgesia has been valued immediately before and after medicine administration and during the 8 hours interval by recording the cardiocirculatory and haemogasanalytical parameters. The measurement of pain intensity has been achieved by visual analogous just an hour after operation and subsequently every 4 hours during the first post operative day and every 8 hours during the following days. RESULTS: Most of the examined patients (90%), reported a remarkable attenuation of pain, valued by achromatic grey test after 4 hours since the first giving. The catheter has always been removed during the 8th postoperative day and it did not cause intrapleural complications. The method used warrants a good level of analgesia, improving the respiratory per-formance and giving a rapid mobilization, essential items in the reduction of immediate post operative complications. CONCLUSIONS: The results confirm the validity of this treatment in the pain control of thoracothomized patients with a positive answer in 45 out of 50 examined patients without remarkable complications.

[Chest drainage combined with intracavitary therapy in neoplastic pleural effusion: comparison of three different protocols]. / Il drenaggio toracico associato alla terapia endocavitaria nei versamenti pleurici neoplastici: confronto di tre diverse metodiche.

Twenty-eight patients with malignant pleural effusion observed in a two year period were treated with intrapleural instillation of different substances: Tetracycline, Corynebacterium parvum and Beta-Interferon. Different results were observed: complete responsiveness (no recurrence of pleural effusion within three months); partial responsiveness (recurrence of moderate pleural effusion within one month after drainage removal); insufficient responsiveness (recurrence of massive effusion within one month). Among patients treated with Tetracycline seven complete, five partial and one insufficient responses were observed. Instillation of Corynebacterium parvum allowed two complete, two partial and three insufficient responses. Finally, in the group treated with Beta-Interferon complete responsiveness was obtained in just one patient, partial responsiveness in three, while the treatment was insufficient in the last two. These results suggest pleural drainage is the best treatment in patients with malignant pleural effusion, however, the association of Tetracycline instillation allows better results.

Development of micro-electrode array based tests for neurotoxicity: assessment of interlaboratory reproducibility with neuroactive chemicals.

Neuronal assemblies within the nervous system produce electrical activity that can be recorded in terms of action potential patterns. Such patterns provide a sensitive endpoint to detect effects of a variety of chemical and physical perturbations. They are a function of synaptic changes and do not necessarily involve structural alterations. In vitro neuronal networks (NNs) grown on micro-electrode arrays (MEAs) respond to neuroactive substances as well as the in vivo brain. As such, they constitute a valuable tool for investigating changes in the electrophysiological activity of the neurons in response to chemical exposures. However, the reproducibility of NN responses to chemical exposure has not been systematically documented. To this purpose six independent laboratories (in Europe and in USA) evaluated the response to the same pharmacological compounds (Fluoxetine, Muscimol, and Verapamil) in primary neuronal cultures. Common standardization principles and acceptance criteria for the quality of the cultures have been established to compare the obtained results. These studies involved more than 100 experiments before the final conclusions have been drawn that MEA technology has a potential for standard in vitro neurotoxicity/neuropharmacology evaluation. The obtained results show good intra- and inter-laboratory reproducibility of the responses. The consistent inhibitory effects of the compounds were observed in all the laboratories with the 50% Inhibiting Concentrations (IC(50)s) ranging from: (mean ± SEM, in µM) 1.53 ± 0.17 to 5.4 ± 0.7 (n = 35) for Fluoxetine, 0.16 ± 0.03 to 0.38 ± 0.16 µM (n = 35) for Muscimol, and 2.68 ± 0.32 to 5.23 ± 1.7 (n = 32) for Verapamil. The outcome of this study indicates that the MEA approach is a robust tool leading to reproducible results. The future direction will be to extend the set of testing compounds and to propose the MEA approach as a standard screen for identification and prioritization of chemicals with neurotoxicity potential.