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.

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.

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.

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.

Fibroma of the left ventricle in a patient with Sotos syndrome.

Primary tumors of the heart are rare, with an incidence between 0.001% and 0.33% in autopsy findings, and with fibromas representing about 4% of benign cardiac tumors. We report the case of a cardiac fibroma in a 5-year-old child affected by Sotos syndrome. The mean sign was a ventricular tachycardia.

Transfusional hemochromatosis: quantitative relation of MR imaging pituitary signal intensity reduction to hypogonadotropic hypogonadism.

PURPOSE: To assess the relationship between magnetic resonance (MR) imaging pituitary signal intensity reduction in patients with transfusional hemochromatosis and the clinical manifestation of hypogonadotropic hypogonadism. MATERIALS AND METHODS: Pituitary MR imaging at 0.5 T was performed in 38 consecutive patients affected by secondary hemochromatosis and in 20 healthy volunteers. Serum ferritin levels were estimated in the affected population. Twenty (53%) of the 38 patients had hypogonadotropic hypogonadism diagnosed. Pituitary-to-fat signal intensity ratios were calculated from coronal gradient-echo (GRE) T2*-weighted MR images. The relationship between the quantitative reduction of the pituitary-to-fat signal intensity ratio and the clinical manifestation of pituitary dysfunction was assessed in the affected population. Signal intensity reduction in the anterior lobe of the pituitary gland was also correlated with the serum ferritin level. RESULTS: The degree of reduction of the pituitary-to-fat signal intensity ratio correlated with the presence of hypogonadotropic hypogonadism, with a sensitivity of 90%, a specificity of 89%, and an overall accuracy of 89%. In addition, the reduction of pituitary signal intensity was greater in patients with higher ferritin levels (r = -0.55, r(2) = -0.30, P <.001). CONCLUSION: The degree of signal intensity reduction, measured as the pituitary-to-fat signal intensity ratio for GRE T2*-weighted images, in patients with secondary hemochromatosis correlates with the severity of pituitary dysfunction.

One hundred consecutive advanced breast biopsy instrumentation procedures: complications, costs, and outcome.

BACKGROUND: Needle localization and excision have been the preferred techniques for treating nonpalpable mammographic abnormalities. Recently, a less invasive approach, using the Advanced Breast Biopsy Instrumentation (ABBI) system, was introduced. This study was undertaken to determine the feasibility, utility, and cost of this new alternative approach. METHODS: Between April 1996 and May 1997, 100 consecutive women underwent excisional breast biopsies using the ABBI system. Demographic information, mammographic findings, pathological findings, hospital/professional fees, complications, and subsequent interventions were documented. RESULTS: Excisional biopsies using the ABBI system were successful for 99 women (average age, 62 years; range, 34-87 years). Of the 99 lesions removed with the ABBI system, 27 were microcalcifications, 60 were suspicious solid nodules, and 12 were nodules with microcalcifications. The ABBI system was used in an outpatient surgical setting, with only one patient requiring sedation (because of anxiety). Cancer was seen in the biopsy specimens for 18 patients, seven of whom (35%) exhibited no residual tumor at the time of definitive treatment. Postoperative hematomas occurred in two patients; one hematoma required surgical drainage. One missed cancer was detected in follow-up mammograms 6 months after biopsy. The total average procedural cost was $3406.44 +/- 486.63. CONCLUSIONS: Excisional breast biopsy using the ABBI system is an effective diagnostic method. It has a low complication rate, and its cost is comparable to that of classical needle localization.

The breakpoints of a constitutional inversion of chromosome 9 associated with haemophagocytic lymphohistiocytosis are not linked to the disease gene.

Haemophagocytic lymphohistiocytosis (HLH) is a severe disorder of early infancy consistent with an autosomal recessive inheritance. Neither the genetic locus nor the biochemical defect is known for the disease. A constitutional pericentric inversion of chromosome 9, with breakpoints in bands 9p23 and 9q31, has been reported in a case of HLH, suggesting a possible relationship between this chromosome abnormality and the disease. We investigated such an association, performing a genetic linkage analysis in a set of five consanguineous HLH families. 27 polymorphic markers on chromosome 9 were studied, excluding most of chromosome 9 as a putative site for the HLH gene.

Effect of intraocular acetylcholine and carbachol on the corneal endothelium. In vivo comparative study.

The purpose of this study is to evaluate differences in corneal endothelial cell loss after intraocular use of two different miotics in subjects who have undergone extracapsular cataract extraction with posterior chamber intraocular lens implantation. The patients were divided into two groups: the first received 1 ml of 1% acetylcholine chloride and the second 0.5 ml of 0.01% carbachol as intraocular miotics. The endothelial count was done preoperatively and then 1 month after cataract extraction. There were no statistically significant differences in the mean cell loss between both groups. The authors believe that both miotics could be used in cataract surgery.

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.

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.

Isolated ocular relapse in childhood acute lymphoblastic leukemia during continuing complete remission.

Leukemic relapse of the eye has sometimes been cured. In this paper we review the cases of leukemic infiltration of the eye tissue with the aim of ascertaining whether an optimal treatment can be suggested. Data from 25 children (16 males, 9 females) with isolated ocular relapse (10 in therapy, 15 off therapy) of acute lymphoblastic leukemia (ALL) in first complete remission are examined. The patients were treated according to different chemotherapy schedules, with (20 pts) or without local radiotherapy (5 pts). Isolated ocular relapse can be successfully treated, especially if it occurs after the withdrawal of therapy; second ocular infiltration was seen only in anterior chamber involvement after low doses of local radiotherapy. While the need for high doses of chemotherapy is not evident, high doses of ocular radiotherapy (> 20 Gy) seem to be mandatory to cure this leukemic relapse.

Prognostic value of nephromegaly at diagnosis of childhood acute lymphoblastic leukemia.

In order to assess the prognostic value of nephromegaly (kidney enlargement > or = 2 SD from mean for age) in children at diagnosis of acute lymphoblastic leukemia (ALL), kidney size was investigated by intravenous pyelogram (IP), according to the method of Ekl of and Ringertz, in 101 children diagnosed with ALL in the period of 1975-1983. In the same period 103 additional patients with ALL were not investigated with IP for logistical reasons. Characteristics at the diagnosis of ALL in the patients of the investigated and non-investigated (with IP) groups were quite similar and event-free-survival (EFS) curves superimposable. Eighty-nine (50 males and 39 females, median age 61 months) out of 101 patients underwent IP before starting any therapy and were evaluated in the study; 27 (30.3%) presented with nephromegaly (bilateral in 13 cases and unilateral in 14). With a median follow-up time of 14.4 years (range 11-19 years), the EFS at 15 years from diagnosis was 18.5% (SE 9.5) in the nephromegalic group and 48.4% (SE 6.4) in the non-nephromegalic group. The association of poorer EFS with nephromegaly was confirmed when the comparison was adjusted by white blood cell count and age at diagnosis in a Cox regression model. Nephromegaly at diagnosis of childhood ALL may have an independent prognostic value in patients treated with 'not intensive' protocols; however, this finding should be confirmed in patients treated uniformly with contemporary intensive protocols.

Leukemic ophthalmopathy: a report of 21 pediatric cases.

A multicentric retrospective study on leukemic ophthalmopathy (LO) is reported. It includes 21 patients, 16 males and 5 females, with acute leukemia (AL) observed in 10 SIOP centers. LO developed in three patients at the time of diagnosis of AL; five patients were in first complete remission (three off therapy); four patients were in second or third remission; and nine were in combined relapse. Most frequent symptoms were blurred vision, photophobia, and ocular pain. Two patients with acute nonlymphoblastic leukemia died before treatment; another underwent bone marrow transplantation; one patient with B-cell acute lymphoblastic leukemia (B-ALL) treated with chemotherapy and radiotherapy died 4 months after LO; the remaining 17 children were treated according to different schedules with (10) or without (7) radiotherapy on the affected eye. Twelve patients achieved ocular remission and four of these had a second ocular relapse. Complete remission after LO treatment lasting for more than 3, 7, 24, 29 months was observed in four patients. The authors conclude that cure is possible in patients who had LO in first complete remission treated with chemotherapy and radiotherapy at high dose on the affected eye.

[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.

Severe osteoporosis and multiple vertebral collapses in a child during treatment for B-ALL.

The incidence of bone lesions at diagnosis of childhood acute lymphoblastic leukemia (ALL) is relatively high. However, no cases of severe osteoporosis with multiple vertebral collapses secondary to treatment in children with ALL have been reported. We report the case of a 9-year-old-boy with B-ALL, with no bone lesions at the diagnosis that, following the 4th block of aggressive chemotherapy (protocol B-ALL BFM 86), presented severe back pain and functional impairment with diffuse osteoporosis and vertebral collapses. He was treated with calcitonin, vitamin D, calcium, physical therapy and orthopedic corset. Osteoporosis progressed slowly during the following 2 months of chemotherapy and the boy developed dorsal kyphosis. After discontinuing antiblastic treatment progressive clinical improvement was observed, with complete resolution of kyphosis in about 6 months. An almost complete bone recovery was seen on X-ray survey at 26-months follow-up.