Does Rapid Drug Desensitization to Chemotherapy Affect Survival Outcomes?

BACKGROUND AND OBJECTIVE: Hypersensitivity reactions to oxaliplatin may affect prognosis by jeopardizing the timely completion of scheduled treatment sessions or by forcing reactive patients into unexpected changes in therapy. Rapid drug desensitization (RDD) enables these patients to receive their first-choice treatments safely. However, the possible effects of RDD on the efficacy of oxaliplatin have never been studied. Objective: The objective of this study was to evaluate the effect of RDD on survival rates in oxaliplatin-hypersensitive patients. METHODS: We performed a 7-year retrospective study to compare survival between oxaliplatin-hypersensitive cases (patients receiving oxaliplatin by RDD) and nonallergic controls (patients receiving standard oxaliplatin infusions). The primary endpoint of this study was overall survival (OS) in cases and controls (Kaplan-Meier method with log-rank test comparisons). RESULTS: OS was 23.7 months (95%CI, 15.3-30.9) for the 67 cases who underwent 337 RDDs, while for controls (n=143), OS was 34.5 months (95%CI, 21.7-55.5). There were no significant differences between the groups (HR, 1.42; 95%CI, 0.93-2.17; P =.104). CONCLUSIONS: Survival outcomes of oxaliplatin-hypersensitive patients who received oxaliplatin via RDD did not differ significantly from those of control patients who received oxaliplatin via standard administration. Receiving oxaliplatin by means of RDD might be an effective therapeutic alternative for oxaliplatin-hypersensitive patients.

Delving into cornerstones of hypersensitivity to antineoplastic and biological agents: value of diagnostic tools prior to desensitization.

BACKGROUND: Evidence regarding drug provocation test (DPT) with antineoplastic and biological agents is scarce. Our aim was to assess the usefulness of including DPT as a paramount gold standard diagnostic tool (prior to desensitization). METHODS: Prospective, observational, longitudinal study with patients who, during a 3-year period, were referred to the Desensitization Program at Ramon y Cajal University Hospital. Patients underwent a structured diagnostic protocol by means of anamnesis, skin tests (ST), risk assessment, and DPT. Oxaliplatin-specific IgE was determined in oxaliplatin-reactive patients (who underwent DPT regardless of oxaliplatin-specific IgE results). Univariate analysis and multivariate analysis were used to identify predictors of the final diagnosis among several variables. RESULTS: A total of 186 patients were assessed. A total of 104 (56%) patients underwent DPT. Sixty-four percent of all DPTs were negative (i.e., hypersensitivity was excluded). Sensitivity for oxaliplatin-specific IgE (0.35 UI/l cutoff point) was 34%, specificity 90.3%, negative predictive value 45.9%, positive predictive value 85%, negative likelihood ratio 0.7, and positive likelihood ratio 3.5. CONCLUSIONS: These are the first reported data based on more than 100 DPTs with antineoplastic and biological agents (paclitaxel, oxaliplatin, rituximab, infliximab, irinotecan, and other drugs). Implementation of DPT in diagnostic protocols helps exclude hypersensitivity (in 36% of all referred patients), and avoids unnecessary desensitizations in nonhypersensitive patients (30-56% of patients, depending on culprit-drug). Drug provocation test is vital to validate diagnostic tools; consequently, quality data are shown on oxaliplatin-specific IgE and oxaliplatin-ST in the largest series of oxaliplatin-reactive patients reported to date (74 oxaliplatin-reactive patients). Identifying phenotypes and predictors of a diagnosis of hypersensitivity may be helpful for tailored plans.

Hypersensitivity and desensitization to antineoplastic agents: outcomes of 189 procedures with a new short protocol and novel diagnostic tools assessment.

BACKGROUND: Desensitization to antineoplastic agents is becoming a standard of care. Efforts to establish and improve these techniques are being made at many institutions. Our aims are to evaluate a new rapid desensitization protocol designed to be shorter (approximately 4 h) and safer (reducing hazardous drugs exposure risks) and to assess the oxaliplatin-specific immunoglobulin E (IgE) as a novel diagnostic tool. METHODS: Prospective, observational, longitudinal study with patients who, for a 1-year period, suffered reactions to antineoplastic agents and were referred to the Desensitization Program at Ramon y Cajal University Hospital (RCUH). Patients were included or excluded as desensitization candidates after anamnesis, skin testing, risk assessment, and graded challenge. Specific IgE was determined in oxaliplatin-reactive patients. Candidate patients were desensitized using the new RCUH rapid desensitization protocol. RESULTS: Of 189 intravenous rapid desensitizations, 188 were successfully accomplished in the 23 patients who met inclusion criteria for desensitization (of 58 referred patients). No breakthrough reactions occurred in 94% of desensitizations, and most breakthrough reactions were mild. In 10 oxaliplatin-reactive patients, 38 desensitizations were successfully accomplished. Sensitivity for oxaliplatin-specific IgE was 38% (0.35UI/l cutoff point) and 54% (0.10UI/l cutoff point); specificity was 100% for both cutoff points. CONCLUSIONS: In the hands of a Desensitization Program, managed by drug desensitization experts, this new protocol has proven an effective therapeutic tool for hypersensitivity to several antineoplastic agents (oxaliplatin, carboplatin, paclitaxel, docetaxel, cyclophosphamide, and rituximab); moreover, it improves safety handling of hazardous drugs. We report the first large series of oxaliplatin desensitizations. Oxaliplatin-specific IgE determination could be helpful.

European Academy of Allergy and Clinical Immunology task force report on 'dose-response relationship in allergen-specific immunotherapy'.

BACKGROUND: For a century, allergen-specific immunotherapy (SIT) has proven to be an effective treatment for allergic rhinitis, asthma, and insect sting allergy. However, as allergen doses are frequently adapted to the individual patient, there are few data on dose-response relationship in SIT. Allergen products for SIT are being increasingly required to conform to regulatory requirements for human medicines, which include the need to demonstrate dose-dependent effects. METHODS: This report, produced by a Task Force of the EAACI Immunotherapy Interest Group, evaluates the currently available data on dose-response relationships in SIT and aims to provide recommendations for the design of future studies. RESULTS: Fifteen dose-ranging studies fulfilled the inclusion criteria and twelve reported a dose-response relationship for clinical efficacy. Several studies also reported a dose-response relationship for immunological and safety endpoints. Due to the use of different reference materials and methodologies for the determination of allergen content, variations in study design, and choice of endpoints, no comparisons could be made between studies and, as a consequence, no general dosing recommendations can be made. CONCLUSION: Despite recently introduced guidelines on the standardization of allergen preparations and study design, the Task Force identified a need for universally accepted standards for the measurement of allergen content in SIT preparations, dosing protocols, and selection of clinical endpoints to enable dose-response effects to be compared across studies.

Microscopic magnetic resonance imaging of the thoracic venous system in rats with congenital diaphragmatic hernia.

BACKGROUND/AIM: Infants and rats with congenital diaphragmatic hernia (CDH) have malformations of the heart and the great arteries caused by neural crest (NC) dysregulation during embryogenesis. Abnormally narrow jugular veins have been found in babies during cannulation for ECMO. However, the venous system has not been examined in depth so far. We hypothesized that abnormal patterning and/or size of the thoracic veins could occur in rats with CDH. This hypothesis was tested by microscopic magnetic resonance imaging (MMRI), a high-resolution tool able to detect subtle changes of vessels in small animals. MATERIAL/METHODS: Fetuses from pregnant rats fed either 100 mg i.g. nitrofen or vehicle on E9.5 were recovered near term. A 7 T MMRI system with a coronal multislice fast spin echo sequence allowed diagnosis of CDH (n = 19), and T2 SE high-resolution sequences made assessment of the pattern and width of cervico-thoracic veins possible. Values were corrected for body size by dividing them by the length of thoracic vertebrae T3-T5. The results in nitrofen and control (n = 11) groups were compared by non-parametric tests (*p < 0.05). RESULTS: Congenital diaphragmatic hernia fetuses were smaller than controls (4.5 ± 0.26 vs. 5.3 ± 0.2 g*). The widths (corrected for body size) of left external, both innominate, right superior vena cava and azygos veins were significantly smaller in CDH rats than in controls. CONCLUSIONS: The cervico-thoracic veins are normally patterned but abnormally narrow (except the internal jugulars) in rats with CDH. The same embryonic NC dysregulation that accounts for cardiovascular malformations could also explain these venous anomalies in CDH.

Clinical characteristics and outcomes of 1,331 patients with COVID-19: HM Spanish Cohort.

OBJECTIVE: Spain is one of the European countries most affected by the COVID-19 pandemic. Epidemiologic studies are warranted to improve the disease understanding, evaluate the care procedure and prepare for futures waves. The aim of the study was to describe epidemiologic characteristics associated with hospitalized patients with COVID-19. METHODS: This real-world, observational, multicenter and retrospective study screened all consecutive patients admitted to 8 Spanish private hospitals. Inclusion criteria: hospitalized adults (age≥18 years old) with clinically and radiologically findings compatible with COVID-19 disease from March 1st to April 5th, 2020. Exclusion criteria: patients presenting negative PCR for SARS-CoV-2 during the first 7 days from hospital admission, transfer to a hospital not belonging to the HM consortium, lack of data and discharge against medical advice in emergency departments. RESULTS: One thousand and three hundred thirty-one COVID-19 patients (medium age 66.9 years old; males n= 841, medium length of hospital stayed 8 days, non-survivors n=233) were analyzed. One hundred and fifteen were admitted to intensive care unit (medium length of stay 16 days, invasive mechanical ventilation n= 95, septic shock n= 37 and renal replacement therapy n= 17). Age, male gender, leukocytes, platelets, oxygen saturation, chronic therapy with steroids and treatment with hydroxychloroquine/azithromycin were independent factors associated with mortality. The proportion of patients that survive and received tocilizumab and steroids were lesser and higher respectively than those that die, but their association was not significant. CONCLUSIONS: Overall crude mortality rate was 17.5%, rising up to 36.5% in the subgroup of patients that were admitted to the intensive care unit. Seven factors impact in hospital mortality. No immunomodulatory intervention were associated with in-hospital mortality.

Role of computed tomography and magnetic resonance imaging in aortobronchial fistula diagnosis following aortic coarctation reparative surgery. Report of two cases.

Aortobronchial fistula (ABF) is an uncommon complication of aortic coarctation repair which may occur years after successful coarctation correction. It is invariably fatal if not diagnosed and treated. ABF diagnosis poses a challenge for clinicians and radiologists because of the difficulty in detecting the fistula and the risks associated with some of the diagnostic procedures. Two cases of ABF occurring 1 and 20 years after reparative surgery of aortic coarctation are reported. The advantages and disadvantages of different imaging procedures for the evaluation of patients with suspected ABF are reviewed and the role of computed tomography angiography and magnetic resonance imaging is underlined.

Calibration of a low background gas-flow proportional counter to estimate 234Th activity in coastal waters.

This paper relates the calibration of a low background gas-flow proportional counter. This calibration has been used to determine low activity of 234Th in coastal water samples. Two methods were used to prepare calibration samples: Evaporation and Electrodeposition. First method was rejected due to the lack of reproducibility because the different geometry adopted by the drops of tracer once dried on the disk. On the contrary, through the second method, similar efficiencies were obtained in all detectors with an average of 0.401±0.004. In this paper, the whole procedure to obtain 234Th activity in dissolution as well as in particulate matter has been detailed, and all the algorithms needed to calculate activities and efficiencies are shown. Finally, two experiments have been designed in order to validate the calibration of the beta counter and the method to determine 234Th in coastal waters with high concentration of particulate matter.

[Guidelines for the clinical management of neuropathic pain (II)]. / Guías de práctica clínica del dolor neuropático (II).

INTRODUCTION: Up to 5% of the population suffers from neuropathic pain (NP). A bibliographical search in several databases revealed that, to date, there are no protocols to guide physicians who are not specialists in pain that enable them to treat NP and thus improve patients' quality of life. AIMS: The aim of this study is to provide Spanish-speaking physicians who are not specialists in pain with a set of guidelines for the treatment of NP. A bibliographical search was performed in order to base the results and conclusions on the evidence-based medicine methodology. DEVELOPMENT: First, we review the most effective clinical and paraclinical methods for diagnosing NP, and the LANSS pain scale is reported as the most appropriate method of clinically evaluating NP. The anatomical paths and the physiology of pain are then described and we review the molecular variables involved. Finally, we point out the current therapeutic options and propose an algorithm for the treatment of NP. CONCLUSIONS: There is no specific set of guidelines for the treatment of NP. At the present time, the keystone of NP treatment consists in the use of antidepressant and anticonvulsive drugs. There is a need for further clinical trials to prove the effectiveness of using combined medication.

[Guidelines for the clinical management of neuropathic pain (I). Protocol]. / Guías de práctica clínica del dolor neuropático (I). Protocolo.

AIMS: The aim of this study is to develop a set of guidelines for the clinical management of neuropathic pain (NP), a disorder suffered by up to 5% of the population, specifically for use by the Spanish-speaking community, in order to improve the quality of medical care and to standardise the treatments offered in medical centres. DEVELOPMENT: The paper describes the methodology used to search for guidelines concerning the clinical management of NP in databases, written communications and other resources, and the results of this search are presented. The research group is split into three groups: anatomical-physiological, diagnosis and therapeutic approach, each of which defines the nature of the papers that used to design the protocol.

Synthesis and transport applications of 3-aminobicyclo[3.2.1] octane-3-carboxylic acids.

The isomeric 3-aminobicyclo[3.2.1]octane-3-carboxylic acids were synthesized and compared with the widely used (1R,2S,4S)-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid as to specificity to the Na+-independent membrane transport system L of the Ehrlich ascites tumor cell and of the rat hepatoma cell line HTC. The presence of an additional methylene group in the ring system leads to an optically symmetrical amino acid, with the advantages that the product is devoid of isomeric contamination. Hence, optical resolution is not necessary to secure a homogeneous test substrate for discrimination of amino acid transport systems. Through its inhibitory action on the cellular uptake of known system-specific amino acids, the bicyclo[3.2.1]octane amino acid proved more reactive than the bicycloheptane analogue with the Na+-independent amino acid transport system of the test cells and not perceptibly reactive with the accompanying Na+-dependent systems. Recent evidence of the presence of a second component of Na+-independent amino acid transport, beyond system L, increases the importance of securing a variety of possibly discriminatory model substrates.

Percutaneous vertebroplasty: a special syringe for cement injection.

Percutaneous vertebroplasty is an effective treatment for many focal vertebral lesions. Methyl methacrylate is too viscous to be handled without difficulty in the conventional way because injection time is short. The operator is left with little time and must fumble with multiple syringes. We describe a special screw-system syringe that decreases the effort needed to inject the cement. In addition, it can standardize the injection pressures and control the injected volume because the threaded plunger affords greater control of injection pressure and volume delivered than does the conventional method.

Preoperative carbohydrate antigen 195 (CA195) and CEA serum levels as prognostic factors in patients with colorectal cancer.

We evaluated in 214 patients with primary colorectal cancer the prognostic value of the preoperative serum levels of CEA and CA195. For CEA these levels were above the cutoff of 6 ng/ml in 31.3% of patients, whereas for CA195 they were higher than 12 U/ml in 35.9% of patients. The simultaneous use of both antigens increased the sensitivity to 49%, which was significantly higher than that of CEA (p < 0.001) and CA195 (p < 0.01) taken singly. The mean preoperative CEA levels were significantly (p < 0.001) correlated with Dukes' stage only, while there was a significant correlation between preoperative serum levels of CA195 and Dukes' stage (p < 0.001), grade of differentiation (p < 0.01) and tumor location (p < 0.05). The results indicated that high preoperative serum levels of CEA and CA195 were associated with a shorter overall survival (p < 0.0001). In addition, separate Cox multivariate analysis showed that preoperative CA195 was, after Dukes' stage, the strongest factor to predict overall survival (p < 0.0001).

Anti-influenza A activity of some N-substituted bicyclo[3.2.1]octane-3-spiro-3'-pyrrolidine hydrochlorides: synthesis and structure.

Some N-substituted bicyclo[3.2.1]octane-3-spiro-3'-pyrrolidine hydrochlorides (IX-XII) prepared from bicyclo[3.2.1]octan-3-one (I), were assayed in vitro against influenza A viruses. All materials showed activity similar to 1-adamantanamine hydrochloride. A 1H-NMR study revealed only one isomer at the spiro carbon atom.

Synthesis and biological activity of new 1,8-diaza-2,9,10-anthracenetrione derivatives.

Diels-Alder heterocycloaddition reactions of 2,5,8-quinolinetriones and 1-azadienes afford 1,8-diaza-2,9,10-anthracenetriones, which are simple analogues of the antitumoral antibiotic diazaquinomicin A. Cytotoxicity in this series and antitumor activity of the lead compound, 6-methyl-1,8-diaza-2,9,10-anthracenetrione, are reported.

Development of a time-cycled volume-controlled pressure-limited respirator and lung mechanics system for total liquid ventilation.

Total liquid ventilation can support gas exchange in animal models of lung injury. Clinical application awaits further technical improvements and performance verification. Our aim was to develop a liquid ventilator, able to deliver accurate tidal volumes, and a computerized system for measuring lung mechanics. The computer-assisted, piston-driven respirator controlled ventilatory parameters that were displayed and modified on a real-time basis. Pressure and temperature transducers along with a lineal displacement controller provided the necessary signals to calculate lung mechanics. Ten newborn lambs (<6 days old) with respiratory failure induced by lung lavage, were monitored using the system. Electromechanical, hydraulic, and data acquisition/analysis components of the ventilator were developed and tested in animals with respiratory failure. All pulmonary signals were collected synchronized in time, displayed in real-time, and archived on digital media. The total mean error (due to transducers, analog-to-digital conversion, amplifiers, etc.) was less than 5% compared with calibrated signals. Components (tubing, pistons, etc.) in contact with exchange fluids were developed so that they could be readily switched, a feature that will be important in clinical settings. Improvements in gas exchange and lung mechanics were observed during liquid ventilation, without impairment of cardiovascular profiles. The total liquid ventilator maintained accurate control of tidal volumes and the sequencing of inspiration/expiration. The computerized system demonstrated its ability to monitor in vivo lung mechanics, providing valuable data for early decision making.

The cardiovascular effects of partial liquid ventilation in newborn lambs after experimental meconium aspiration.

OBJECTIVE: To study the effects of partial liquid ventilation with perfluorocarbon on cardiovascular function, pulmonary gas exchange, and lung mechanics in term newborn lambs with pulmonary hypertension induced by tracheal instillation of human meconium. DESIGN: Prospective, randomized study. SETTING: Research Unit at a university-affiliated hospital. SUBJECTS: Twelve term newborn lambs (<6 days old). INTERVENTIONS: Lambs were studied in two groups (n = 6): meconium aspiration (3-5 ml/kg 20% meconium solution) managed on pressure-limited conventional mechanical ventilation with or without partial liquid ventilation with perfluorocarbon. MEASUREMENTS AND MAIN RESULTS: Heart rate, systemic and pulmonary arterial pressures, arterial pH and blood gases, cardiac output, and pulmonary mechanics were measured. Partial liquid ventilation in term newborn lambs with experimental meconium aspiration did not alter cardiovascular profile: heart rate, systemic arterial pressure, and cardiac output maintained initial values throughout the experiment. There was a significant improvement in gas exchange (oxygenation increased from values of <100 torr to 338 torr, and ventilation reached normal values in 15 mins). Dynamic compliance increased in 30 mins, reaching basal values (1.1 +/- 0.3 ml/cm H(2)O per kg). Despite the good response (blood gases and cardiovascular profile) to partial liquid ventilation in meconium aspiration syndrome, pulmonary hypertension did not decrease. CONCLUSIONS: Partial liquid ventilation with perfluorocarbon could be a good noninvasive alternative technique that improves gas exchange and pulmonary mechanics in meconium aspiration syndrome without impairing cardiovascular function.