Evaluation of discordance measures in oncology studies with blinded independent central review of progression-free survival using an observational error model.

To confirm results obtained from local evaluation at investigational centers, many oncology studies utilize blinded independent central review (BICR) to make assessments of the primary endpoint, progression-free survival (PFS). The comparison of data often leads to large discordances between these observations, casting doubt on the reliability of the estimated treatment effects from these trials. Here we propose new statistics to measure discordance and evaluate their utility to detect bias in the local evaluation of progression relative to the standard measures of discordance. A new observational error model is proposed that can be used to describe the discordance in patient assessments between multiple readers.

Blinded independent central review of progression in cancer clinical trials: results from a meta-analysis.

PURPOSE: Progression free survival (PFS) is increasingly used as a primary end-point in oncology clinical trials. This paper provides observations and recommendations on the use of a blinded independent central review (BICR) for progression. PATIENTS AND METHODS: The findings and recommendations are based on extensive simulations and a meta-analysis based on 27 previously conducted randomised phase III trials with BICR performed by the Pharmaceutical Research and Manufacturers Association (PhRMA) sponsored PFS Independent Review Working Group. RESULTS: Results of the meta-analysis demonstrate a strong correlation between LE and BICR estimates of treatment effect (R=0.947). Further, differences between treatment groups in discordance rates predict the differences between LE and BICR estimates of treatment effect supporting the use of a sample-based BICR on a subgroup of patients. CONCLUSION: The meta-analysis demonstrates that local evaluation (LE) provides a reliable estimate of the treatment effect with little evidence for systematic evaluation bias. Therefore, when a trial is blinded or a large effect on PFS is observed a BICR may not be warranted. When a BICR is warranted, a sample-based BICR may provide a reduction in operational complexity without compromising the credibility of trial results. While for large trials that are not adequately blinded a sample-based BICR may be recommended. A full BICR should be considered in the case of smaller trials or in situations in which there is a particular need to increase the confidence in the LE results.

The influence of ipratropium bromide in the recovery phase of methacholine induced-bronchospasm.

BACKGROUND: The protective effect of Ipratropium Bromide (IB) in the methacholine-induced bronchospasm is well known from some time. The objective of the present study was to assess whether a pretreatment with IB may influence the subsequent phase of methacholine-induced bronchospasm relief. METHODS: Sixteen patients with bronchial hyper-reactivity (PD20 FEV1 < 200 microg) were randomly assigned to three methacholine challenge tests at a 48 to 72 hours interval apart. In the first test IB was inhaled before the challenge (pre-IB), in the second IB was administered soon after the PD20 FEV1 (post-IB), and in the third no treatment was given (control). RESULTS: The pre-IB PD20 FEV1 (695 +/- 587.6 microg) was significantly greater (p < 0.0001) than that of post-IB (82.2 +/- 49.18 microg) and of control (73.9 +/- 41.8 microg). The dose response slope (DRS) (decline percentage of FEV1/cumulative methacholine dose), in pre-IB was greatly lower (p < 0.0001) than that in post-IB and in control. During the bronchospasm relief phase, the increase of FEV1 measured after 5, 10, 15, 30 and 60 minutes from the PD20 FEV1 was significantly greater in post-IB (p < 0.05) compared with the other two conditions. Conversely, the recovery slope (RS) (increase percentage of FEV1 at 60 minutes after PD20 FEV1 x cumulative methacholine dose) was significantly more efficient (p < 0.001) in pre-IB than in post-IB and in control. CONCLUSION: In conclusion, ipratropium bromide confirmed to have a good protective activity against methacholine-induced bronchospasm; the pre-administration of ipratropium bromide showed also a positive effect on the recovery phase.

Changes in monocyte phagocyting activity after multi-agent chemotherapy in non-small cell lung cancer.

Changes in monocyte functions have been described in several human malignancies. The monocyte/macrophage system is known to play a crucial role in the rejection of tumor cells and phagocytosis represents an important defense mechanism used by these cells. This paper reports the adherence power and phagocyting ability (latex beads) of circulating monocytes in 20 patients with unresectable non-small cell lung cancer (NSCLC), stage IIIB or stage IV, before and after multiagent chemotherapy (carboplatin + etoposide + ifosfamide or cisplatinum + etoposide). We demonstrated that both monocyte adherence and phagocytosis were not affected in lung cancer patients before chemotherapy in comparison with healthy controls. After chemotherapy, a statistically significant decrease in monocyte count on day 4 (p < 0.05) and in their phagocyting ability on day 4 and 15 (p < 0.001 and p < 0.05 respectively) was showed. In addition, a statistically reduced monocyte adherence was found on day 4 (p < 0.05). The described impairment was prolonged but reversible. These changes in monocyte functions after chemotherapy could be due to a direct effect of the chemotherapy on these cells or to functionally immature cells circulating after myelodepression. The in vitro assessment of monocyte functions may be useful to better clarify mechanisms by which anti-neoplastic agents may act on immune functions and prevent adverse side effects.

[Significant increase of incidence of cypress pollen allergy in the city of Rome]. / Aumento significativo dell'incidenza dell'allergia alle cupressaceae nella città di Roma.

In the second semester of 1999, 246 patients, living in a Roman urban area, were subjected to a prick-test screening. 194 (78.9%) of the patients showed a positive answer toward almost one of the tested allergens, whereas the other 51 persons (21.1%) turned out to be negative. Of the patients with a positive cutireaction, 59 (24% of total survey and 30.4% of allergic subjects), with an average age of 29.6 (SD = 12.78) showed sensitization toward cypressus. The results were compared with a case-study of 900 atopic subjects, recruited by the same Center between 1994-96 and living in the same Roman area. In this last group we only found 84 pts (9.3%) with a positive prick-test toward Cypressus, with an average age of 35.2 (DS = 13.48). This analysis wants to stress the increasing incidence of allergy toward cypressus among atopic subjects, switching from 9.3% to 30.4%, in the same urban area, during these last three years.

Dopamine receptors in human platelets.

The expression of dopamine receptors by human platelets was investigated by Western blot analysis and immunocytochemical techniques using antibodies raised against dopamine D1-D5 receptor protein. The influence of dopamine D1-like and D2-like receptor agonists on adrenaline-induced platelet aggregation was also investigated. Western blot analysis revealed that platelet membranes bind anti-dopamine D3 or D5 receptor protein antibodies, but not anti-D1, D2 or D4 receptor protein antibodies. Cytospin centrifuged human platelets exposed to anti-dopamine D3 or D5 receptor protein antibodies developed a specific immune staining, whereas no positive staining was noticeable in platelets exposed to other antibodies tested. Both the D1-like receptor agonist 1-phenyl2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF 38393) and the D2-like receptor agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) dose-dependently inhibited adrenaline-induced platelet aggregation. These effects were decreased respectively by the D-like and D2-like receptor antagonists R(+)-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hydrochloride (SCH 23390) and (-)sulpiride. The above findings indicate that human platelets express dopamine D3 and D5 receptors probably involved in the regulation of platelet function.

Partial caudal duplication in a newborn associated with meningomyelocele and complex heart anomaly.

BACKGROUND: Caudal duplication is a spectrum of rare congenital anomalies with a possible heterogeneous pathogenesis including incomplete separation of monovular twins. METHODS: We report an autopsy case of a full-term infant with incomplete caudal duplication syndrome associated with multiple anomalies. RESULTS: These anomalies included a duplicated penis; double urinary bladder with an attenuated tunica muscularis; duplication of lower bowel with two ilia, appendices and colons; colonic hypogangliosis and left imperforated anus associated with rectourethral fistula. Other anomalies consisted of sacral meningomyelocele, sacral duplication with hypoplastic left sacrum and pelvic bones, muscle atrophy and hypoplasia of the left lower extremity, abnormal lobation of liver with stomach entrapment, omphalocele, and right atrial isomerism syndrome. The complex pattern of anomalies suggests the possibility that partial caudal duplication might be part of the spectrum of conjoined twinning.

Induction and recovery phases of methacholine-induced bronchoconstriction using FEV1 according to the degree of bronchial hyperresponsiveness.

Forty-eight patients suffering from intermittent bronchial asthma underwent methacholine challenge test. Response was stronger in 29 patients and less pronounced in 19. The two groups had the same characteristics except for the cumulative methacholine dose which was lower in severe hyperresponsiveness. The patients were studied both in the phase of induced bronchospasm and in the subsequent phase of spontaneous recovery. Dose-response curves to methacholine were analyzed as FEV1% decline/methacholine dose for the induction phase of bronchoconstriction and as FEV1% increase*methacholine dose/time after PD20FEV1 for the recovery phase. The phase of induced bronchospasm as well as spontaneous recovery had a linear pattern in severe hyperresponsiveness; in patients with moderate response, induced bronchoconstriction had a curvilinear pattern whereas spontaneous recovery had a linear pattern. This latter group had to break down an amount of methacholine that was fivefold greater than the former, therefore the mechanism of local homeostasis recovery may be more efficient in moderate hyperresponsiveness. However, in both groups recovery after the bronchospasm was not complete after 60 min (p < 0.01 versus baseline). Furthermore, recovery was faster in the first 15 min than in the remaining time. In conclusion the behavior of methacholine-induced bronchospasm and its spontaneous recovery in both severe and moderate hyperresponsiveness seem to be different although several and not well-established mechanisms may be responsible for this phenomenon.

Three-dimensional ultrasonographic imaging of the neonatal brain in high-risk neonates: preliminary study.

The aim of this investigation was to compare the utility of three-dimensional ultrasonography versus two-dimensional ultrasonography in imaging the neonatal brain. Thirty patients in the neonatal intensive care unit underwent two-dimensional and three-dimensional ultrasonography. The resultant two- and three-dimensional images recorded on film and three-dimensional volumes (reviewed on a workstation) were evaluated independently. Comparable numbers of normal and abnormal studies were diagnosed by each modality. Axial images were considered useful in approximately 50% of three-dimensional cases. Image quality, overall and in the far-field, was rated higher on two-dimensional images. Three-dimensional sonographic acquisition time in the neonatal intensive care unit (1.7 min+/-0.7 standard deviation) was significantly shorter than that for two-dimensional sonography (9.0+/-4.5 min). The total time for evaluation on the three-dimensional workstation (4.4+/-1.1 min) was significantly less than that for two-dimensional images on film (10.6+/-4.7 min). In conclusion, three-dimensional ultrasonography is a promising, diagnostically accurate, and efficient imaging tool for evaluation of the neonatal brain; however, visualization must improve before it can replace two-dimensional ultrasonography.

Immune response to blood transfusion invery-low-birthweight infants.

BACKGROUND: Allogeneic blood transfusion is common in the treatment of neonatal anemia of prematurity or anemia due to multiple phlebotomies. The immune response of neonates to passenger leukocytes from allogeneic red cells was investigated. STUDY DESIGN AND METHODS: Fourteen infants (4 male, 10 female) prospectively were randomly assigned to receive either white cell-reduced (Group 1) or non-white-cell reduced (Group 2) irradiated blood. Blood samples were taken before and at various time intervals after transfusion (Days 1, 5-7,and 10-14). Cord blood from 11 healthy term infants was used for comparison. The following surface markers were used to assess immune modulation by flow cytometry: CD45RA/CD45RO, CD4/CD8, CD25/CD28, CD3/DR, CD14/B7, and CD3/CD56+CD16. Donor cell microchimerism was studied using semi-quantitative polymerase chain reaction Y-chromosome detection in female infants who received male donor blood. Donor and recipient HLA class II typing was performed with polymerase chain reaction with sequence specific primers. RESULTS: The lymphocyte counts in both groups were significantly increased after transfusion, and there was a significant increase in lymphocytes expressing CD45RA, CD3-/CD16+CD56, CD80, and CD3-/DR on Day 14. The premature infants' pretransfusion natural killer cell population (CD3-/CD16+CD56) was significantly lower than that of term infants, but it reached a similar level by Days 10-14. CD8 subpopulations were increased but not CD4+ cells. Two female infants (of 6) had circulating Y chromosomes 1 day after transfusion, and most of the infants effectively cleared the donor cells within 24 hours of transfusion. Two Group 2 infants who by chance received presumably HLA-haploidentical donor blood developed necrotizing enterocolitis. CONCLUSION: Blood transfusion alters immune cell antigen expression in premature neonates and may initially be immunostimulatory and later immunosuppressive.

[Dermatofibrosarcoma protuberans: authors' experience]. / Dermatofibrosarcoma protuberans: nostra esperienza.

Dermatofibrosarcoma protuberans is an uncommon slow-growing cutaneous neoplasm. Surgical excision is an effective therapeutic approach although a significant number of local recurrences has been documented in the literature. In the present paper the Authors report 3 cases of dermatofibrosarcoma protuberans. All cases have been surgically treated with a wide local excision extended up to 3 cm from the tumor borders. No local recurrence has been reported. The Authors conclude that the surgical technique employed could reduce the local recurrence rate of dermatofibrosarcoma protuberans.

Radioligand binding assay of M1-M5 muscarinic cholinergic receptor subtypes in human peripheral blood lymphocytes.

Analysis of lymphocyte muscarinic cholinergic receptors using quantitative techniques such as radioligand binding assay is made difficult due to the low density of these sites and the lack of subtype-specific selectivity of most available muscarinic ligands. In this study, a combined kinetic and equilibrium labeling technique recently developed for brain tissue was used for labeling the five muscarinic cholinergic receptor subtypes in intact human peripheral blood lymphocytes. No specific muscarinic M1 receptor binding was detectable in human peripheral blood lymphocytes using [3H]-pirenzepine as a ligand. Labeling of M2-M5 muscarinic receptors using [3H]N-methyl-scopolamine (NMS) by occluding various receptor subtypes with muscarinic antagonist and mamba venom resulted in the labeling of M2-M5 receptors in brain as well as in human peripheral blood lymphocytes. The relative density of different receptor subtypes was M3 > M5 > M4 > M2. The development of a reproducible technique for assaying muscarinic cholinergic receptor subtypes expressed by human peripheral blood lymphocytes may contribute to clarify their role in lymphocyte function.

Aerosol characterization of three corticosteroid metered dose inhalers with volumatic holding chambers and metered dose inhalers alone at two inspiratory flow rates.

Inhaled corticosteroids are first-choice drugs in the treatment of chronic asthma. A metered dose inhaler (MDI) equipped with a spacer device is easier to use for patients with a poor inhalatory technique; it favors a reduction in the size of the particles delivered to the patient and thus a reduction in the incidence of local and systemic side effects of these drugs. The aim of this study was to determine the particle characteristics of fluticasone propionate (FP), flunisolide (FLUN), and beclomethasone dipropionate (BDP), each administered at a rate of 250 micrograms per puff and at inspiratory flow rates of 30 and 60 L/min in vitro, to estimate the particle characteristics of these drugs aspirated via an MDI alone and via a large-volume holding chamber (Volumatic). Compared with the MDI alone, at 30 L/min, the Volumatic (Glaxo Wellcome, Ware, UK) significantly reduced the mass median aerodynamic diameter (MMAD) and increased the fine particles (< 5 microns and < 2 microns) generated by all three drugs. At 60 L/min, the MMAD increased and the generation of fine particles decreased with both devices. These data suggest that the inspiratory flow applied by means of the devices may be a determinant for the deposition of the drug in the lower airways in that by increasing the inspiratory flow, the MMAD increases and the percentage of fine particles decreases, probably because of the reaggregation favored by the higher flows.

[The immediate reconstruction of the breast after a mastectomy for carcinoma. Our experience]. / Ricostruzione immediata della mammella dopo mastectomia per carcinoma. Nostra esperienza.

The authors surgically treated 281 consecutive women with breast cancer by breast conservation techniques (45.2%) or by mastectomy (38.8%), during a four-year period. Forty-five of these 281 patients (16%) were treated in the same period of time by mastectomy and immediate reconstruction (IR) of the breast. IR of the breast was performed by inserting a submuscular tissue expander at the same time of mastectomy (first stage of reconstruction). A second operation allowed the replacement of the expander with a prosthesis (second stage of reconstruction) and the simultaneous symmetrization of the contralateral breast (not always performed, however). In some cases nipple-areola complex was eventually reconstructed with a delayed surgical procedure (third stage of reconstruction). In the present paper the authors analyze the results and outline the advantages of IR. This easy and safe technique slightly increased the average operative time of a mastectomy, did not interfere with routine oncological follow-up, did definitely reduce patient's psychological trauma following mastectomy. The authors conclude that IR of the breast undoubtedly plays a major role in the so called "onco-plastic"" surgical management of breast cancer.

Plasma thyroid hormones in premature infants: effect of gestational age and antenatal thyrotropin-releasing hormone treatment. TRH Collaborative Trial Participants.

Thyroid hormones are important for both perinatal adaptation and long-term psychomotor development; however, there is limited information on the effects of extreme prematurity and antenatal TSH-releasing hormone (TRH) treatment on pituitary-thyroid function. In this study we assayed plasma triiodothyronine (T3) and TSH in infants who were part of a collaborative trial of antenatal maternal TRH therapy. Within the control population (n = 166), infants of 24-28-wk and 28-32-wk gestational age had comparable levels of T3 (0.94 and 1.06 nmol/L, respectively) and TSH (5.7 and 7.2 mU/L) at birth, but the increases at 2 h and subsequent T3 levels were less in the 24-28 wk versus 28-32-wk gestation infants. In the TRH-treated group (n = 131), T3 was lower in the first day for infants delivered 7-72 h after antenatal TRH compared with control infants. TSH at birth was approximately 3.5-fold greater for infants delivered at 0-6 h after the last TRH dose compared with the control group and was suppressed in infants delivering at 7-36 h. T3 and TSH levels were not different between control and TRH-treated groups at 3-28 d of age. In TRH stimulation tests on d 28, control and TRH-treated groups had similar peak levels of TSH and incidence of exaggerated response (TSH > or = 35 mU/L). We conclude that extremely premature infants have a reduced postnatal surge in TSH and T3 and maintain lower T3 concentrations, probably reflecting tertiary hypothyroidism. The stimulatory and suppressive effects of antenatal TRH treatment observed at birth are transient and do not affect pituitary-thyroid responsiveness at 28 d of age.

Peripheral blood lymphocyte muscarinic cholinergic receptors in airway hyperresponsiveness: a marker of cholinergic dysfunction?

1. Muscarinic cholinergic receptors were assayed in human peripheral blood lymphocytes of healthy control and airway hyperresponsive subjects using a radioligand binding assay technique and the muscarinic cholinergic receptor antagonist [3H]-quinuclidinyl benzilate (QNB) as a radioligand. Subjects investigated were divided in four different groups based on threshold responses to methacholine inhaled as challenge test. 2. [3H]-QNB was bound to human peripheral blood lymphocytes in a manner consistent with the labelling of muscarinic cholinergic receptors. Dissociation constant (Kd) values of [3H]-QNB binding were similar in the different groups examined, whereas maximum density of binding sites (Bmax) was increased in airway hyperresponsive subjects in comparison with healthy controls. 3. The above findings indicate that the density of muscarinic cholinergic receptors is increased in peripheral blood lymphocytes of airway hyperresponsive subjects. 4. This suggests that airway hyperresponsiveness is associated with cholinergic hyperreactivity and is probably a systemic cholinergic dysfunction since it is accompanied by changes in the density of muscarinic cholinergic receptors expressed by peripheral blood lymphocytes.

[Tobramycin aerosol: could the delivery system influence the particle size and deposition in the lower airways?]. / Aerosol di tobramicina: può il sistema di erogazione influenzare le caratteristiche granulometriche e la deposizione nelle vie aeree inferiori?

UNLABELLED: Aerosolized tobramycin represents an efficient alternative to the systemic administration, especially in patients with cystic fibrosis and bronchiectasis affected with Pseudomonas aeruginosa infections. Aim of this study was, using a Time Of Flight Aerosol Beam Spectrometer (API Aerosizer Mach2), to compare the granulometric characteristics of tobramycin aerosolized in 1 sec by three nebulizers and, using mathematic models, to value the particles and drug deposition in the lower airways, particularly at: P level, which includes bronchiolar and alveolar tract; TB level, which includes tracheobronchial tract; ET level, which includes the extrathoracic tract; the amount of particles (Dp) and drug (Dd) dispersed. RESULTS: Nebula Nuovo: Mass Median Aerodynamic Diameter (MMAD): 3,722 microns; Geometric Standard Deviation (GSD): 2,382; Particles deposited-P: 42.86%; TB: 4.99%; ET: 8.7%; Dp: 43.45%; Tobramycin deposited-P: 36.84%; TB: 11.52; ET: 26.36%; Dd: 25.28. Pari IS2: MMAD: 3,179 microns; GSD: 1,367; Particles deposited--P: 41.99%; TB: 8.67%; ET: 17.26%; Dp: 32.07%; Tobramycin deposited-P: 33.19%; TB: 14.37%; ET: 34.12%; Dd: 18.3%. Artsana with Sidestream ampulla-MMAD: 3,083 microns; GSD: 2,313; Particles deposited-P: 43.96%; TB: 7.11%; ET: 6.23%; Dp: 42.68%; Tobramycin deposited-P: 43.63%; TB: 8.1%; ET: 15.3%; Dd: 32.97%. CONCLUSIONS: Differences in nebulizers performance influence therapeutic effects and tobramicyn deposition in the lower airways.

Parathyroid hormone-related protein in tracheal aspirates of newborn infants.

PTH-related protein (PTHrP) is found with its receptor in a variety of normal mammalian embryonic tissues where it apparently regulates cellular growth and differentiation. PTHrP stimulates phosphatidylcholine synthesis in rat fetal lung explants, suggesting a role in fetal type II alveolar maturation and surfactant production. We investigated PTHrP levels in tracheal aspirates of newborn infants. We collected tracheal aspirates from 40 intubated newborn infants within the first 24 h of life. PTHrP levels were measured by a RIA using rabbit antisera to PTHrP peptide 38-64. We found significantly lower PTHrP levels in tracheal aspirates from infants born at less than 35 wk of gestation (p = 0.02) and with a birth weight less than 2 kg (p = 0.04). We also found significantly lower PTHrP levels in male preterm (<35 wk of gestation) infants compared with female infants (p = 0.01), and in preterm infants who required multiple doses of surfactant (p = 0.005). Preterm infants exposed to antenatal steroids had significantly higher levels of PTHrP in tracheal aspirates (p = 0.02). PTHrP is associated with various indices of lung maturation and may prove to be a mediator of differentiation and growth.

Thoracoabdominal motion in newborns during ventilation delivered by endotracheal tube or nasal prongs.

Preterm infants have asynchronous thoracoabdominal motion (TAM) secondary to a highly compliant chest wall and different lung mechanics compared to term infants. We compared TAM during continuous positive airway pressure (CPAP) administered through an endotracheal tube (ETT-CPAP) or nasal prongs (nasal-CPAP), and during synchronized intermittent mandatory ventilation administered by nasal prongs (nasal-SIMV) in 14 preterm newborn infants. Asynchrony of TAM was quantified by measuring relative motion of chest wall and abdomen with strain gauges and calculating phase angles (theta). Phase angles were lower during nasal-SIMV compared to nasal-CPAP or ETT-CPAP (P < 0.05), and lower during nasal-CPAP compared to ETT-CPAP (P < 0.05). The reduced TAM asynchrony during nasal-SIMV and nasal-CPAP may be due to elimination of resistance of the ETT and/or effective stabilization of the chest wall. These data suggest that nasal-SIMV may be an effective mode of respiratory support for preterm infants requiring minimal ventilatory support.