EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer.

BACKGROUND: Although EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some EGFR mutant tumors do respond to these therapies; however, there is a lack of understanding of the characteristics of EGFR mutant lung tumors responsive to immune checkpoint blockade. PATIENTS AND METHODS: We retrospectively analyzed de-identified clinical and molecular data on 171 cases of EGFR mutant lung tumors treated with immune checkpoint inhibitors from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, University of California Los Angeles, and Dana Farber Cancer Institute. A separate cohort of 383 EGFR mutant lung cancer cases with sequencing data available from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, and The Cancer Genome Atlas was compiled to assess the relationship between tumor mutation burden and specific EGFR alterations. RESULTS: Compared with 212 EGFR wild-type lung cancers, outcomes with programmed cell death 1 or programmed death-ligand 1 (PD-(L)1) blockade were worse in patients with lung tumors harboring alterations in exon 19 of EGFR (EGFRΔ19) but similar for EGFRL858R lung tumors. EGFRT790M status and PD-L1 expression did not impact response or survival outcomes to immune checkpoint blockade. PD-L1 expression was similar across EGFR alleles. Lung tumors with EGFRΔ19 alterations harbored a lower tumor mutation burden compared with EGFRL858R lung tumors despite similar smoking history. CONCLUSIONS: EGFR mutant tumors have generally low response to immune checkpoint inhibitors, but outcomes vary by allele. Understanding the heterogeneity of EGFR mutant tumors may be informative for establishing the benefits and uses of PD-(L)1 therapies for patients with this disease.

[Characterization of poisoning by the coconut crab, Birgus latro, in New Caledonia: aspects of clinical and toxicological features and treatment in 23 cases]. / Caractérisation des intoxications par le crabe de cocotier Birgus latro L. en Nouvelle-Calédonie : données cliniques, toxinologiques et thérapeutiques, à partir de vingt-trois cas.

We report 23 cases of poisoning, 4 fatal, due to ingestion of coconut crab, Birgus latro, in New Caledonia. Clinical and biological features of this poisoning are characterized, and the toxin complex is described. We suggest a treatment strategy based on digoxin-specific antibody fragments for patients in a life-threatening condition.

Prospective and serial study of primary amyloidosis with serum amyloid P component scintigraphy: from diagnosis to prognosis.

OBJECTIVE: The purpose of this study was to assess the value of the serum amyloid P (SAP) component scintigraphy in patients with primary amyloidosis (AL). MATERIAL AND METHODS: Pure human SAP labeled with iodine-123 (123I-SAP) was given intravenously to 24 patients with biopsy-proven systemic amyloidosis (15 without multiple myeloma = group 1, and 9 with multiple myeloma = group 2) and to 6 patients with multiple myeloma without any clinical or biological signs of amyloidosis (group 3). Whole-body images as well as regional views and tissue retention levels were obtained after 24 hours. Our study was approved by the institutional review committee and all individuals gave informed consent and were prospectively studied (median 13 months, range 1 to 47 from the date of the scintigraphy to May 1995). RESULTS: Organ localization of 123I-SAP, indicating the presence of substantial visceral amyloid deposits, was observed in all patients in group 1 and 2. The organ uptake of 123I-SAP included the spleen (1 patient was splenectomized) in 20 of 23 cases (87%), the liver in 15 of 24 (60%), and the kidneys in 6 of 24 (25%). Myocardial 123I-SAP was never seen although 13 out of the 24 patients had clinical or echographic data for amyloidosis. Twenty-four hour tissue retention was significantly elevated in all patients (group 1 and group 2): 55.66% +/- 19.16% in group 1 and 34.37% +/- 24.92% in group 2, as compared with normal levels < 24%. The sensitivity of the technique was 79% when only organ uptake was considered but reached 100% when tissue retention was also considered. The 24-hour tissue retention might be correlated with the severity of the amyloidosis: mean survival in patients with tissue retention greater than 50% was 11.3 months versus 24.5 months in patients with levels less or equal to 50%. Five of the 6 patients with multiple myeloma without evidence of amyloidosis had abnormal 123I-SAP imaging and 24-hour tissue retention levels. In 2 of them, amyloidosis was secondly detected. In the 9 patients who had two scintigraphies, variations in 24-hour tissue retention values were in accordance with the clinical evaluation. CONCLUSIONS: Spleen and liver distribution of amyloidosis is mostly revealed by 123I-SAP scintigraphy in patients with AL amyloidosis. The uptake of 123I-SAP appeared in proportion to the quantity of amyloidosis present in different tissues, and the relative quantity of amyloid deposits in the myocardium, carpal tunnel, digestive tract, and kidneys was often small and seldom visualized by 123I-SAP scintigraphy. In contrast 24-hour tissue retention levels were abnormal in all cases of known AL amyloidosis. This may be a positive argument for the diagnosis of amyloidosis when histopathological tests are normal. Tissue retention levels appear important as they may be correlated with survival.

Iodine-123-Tyr-3-octreotide uptake in pancreatic endocrine tumors and in carcinoids in relation to hormonal inhibition by octreotide.

UNLABELLED: Uptake of 123I-Tyr-3-octreotide (TOCT) by hormone-secreting abdominal tumors was studied to compare scintigraphic observations with the reduction in hormone levels brought about by a brief therapeutic test. METHODS: A prospective study was conducted on 17 patients, totalizing 46 proven lesions, with endocrine tumors of the pancreas (10 patients, 20 lesions) and/or carcinoid metastases (8 patients, 26 lesions). Tumor hormonal hypersecretion was inhibited by octreotide. RESULTS: There was good agreement between the results of these examinations. CONCLUSIONS: The detection of abdominal tumors using this radiotracer is strongly related to its functional characteristics. Variations in the scintigraphic and test results according to different tumor types were in agreement with published data on the density of somatostatin receptors measured by in vitro studies or scintigraphy and by the therapeutic effects of octreotide.

Scintiscans and carcinoid tumors.

BACKGROUND: The presence of somatostatin receptors on carcinoid tumors mediates imaging of tumor extent and inhibition of tumor growth and marker secretion. This prospective study aimed to evaluate radiolabeled somatostatin analog scans in the therapeutic workup of carcinoids. METHODS: Twenty-one patients with carcinoids underwent 26 scans with iodine octreotide or indium pentetreotide. The results for tumor and metastases imaging were analyzed and compared with those of a short inhibition test of marker secretion and with those of metaiodobenzylguanidine scan. RESULTS: The sensitivity for obtaining images of the overall 43 tumor sites was 72%. We had no false-positive results. Unknown tumor sites were discovered in three patients. The results were slightly better with indium pentetreotide and metastases imaging. A positive scan did not always preclude responsiveness to the functional effect of octreotide. Results of somatostatin analog scans were better than those with metaidobenzylguanidine. The two techniques were complementary in one patient. CONCLUSIONS: The choice of treatment for patients with carcinoid tumors should benefit from functional inhibition test with octreotide and from indium pentetreotide and metaidobenzylguanidine scans.

'Localized amyloidosis': 123I-labelled SAP component scintigraphy and labial salivary gland biopsy.

In apparently localized amyloidosis, there is no appropriate test to determine whether systemic deposits exist. We studied the value of serum amyloid P component (SAP) scintigraphy and labial salivary gland (LSG) biopsy on patients with apparently localized amyloidosis in 12 patients who had neither clinical nor biological evidence of systemic amyloidosis. All patients had an LSG biopsy and echocardiography. Iodine-123-labelled serum amyloid P component (123I-SAP) scintigraphy was performed in all patients. Whole-body scintigraphy was done, and tissue retention was evaluated at 24 h and 48 h. Of these 12 patients, three had amyloidosis in their LSG and had abnormal 123I-SAP scintigraphy; these three had a secondary clinical history of systemic amyloidosis. Three other patients had abnormal 123I-SAP scintigraphy without detectable systemic amyloid deposits, but one had a previous history of bilateral carpal tunnel syndrome treated with infiltration. 123I-SAP scintigraphy in association with LSG biopsy may be helpful in determining the localized or systemic character of amyloid disease.

Separation of new antidepressants and their metabolites by micellar electrokinetic capillary chromatography.

Selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenergic reuptake inhibitors (SNaRIs) and noradrenergic and specific serotoninergic antidepressant (NaSSA) are widely used in the treatment of depression. An increase in antidepressant intoxications led to the development of reliable analytical methods for their analysis. A new determination procedure for these compounds (milnacipran, venlafaxine, desmethylvenlafaxine, mirtazapine, desmethylmirtazapine, citalopram, desmethylcitalopram, fluvoxamine, paroxetine, sertraline and fluoxetine) was developed by micellar electrokinetic capillary chromatography (MEKC) with diode array detection (DAD). Separation and determination were optimised on an uncoated fused-silica capillary (600 mm, 75 microm I.D.). The migration buffer consisted of 20 mM sodium borate, pH 8.55, with 20 mM SDS and 15% isopropanol, at an operating voltage of 25 kV. The column temperature was maintained at 40 degrees C. Injection in the capillary was performed in the hydrodynamic mode (0.5 p.s.i., 15 s). In these conditions, the migration time of the antidepressants was less than 11 min. In most cases, calibration curves were established for 30 - 2000 ng/ml (r > 0.995). The limit of detection and the limit of quantification were ranged between 10 and 20 and between 20 and 30 ng/ml, respectively, for all the molecules. This method allowed the determination of some of these compounds in biological fluids (blood, urine) in post-mortem cases. Samples (1 ml) were extracted with diethyl ether (5 ml) at pH 9.6 and reconstituted in diluted migration buffer. Similar results were obtained by a HPLC-DAD determination, performed as a reference method. These results suggest that this MEKC method can be useful for the determination of new antidepressants in post-mortem cases.

A fatal case of buflomedil self-poisoning: toxicological data and literature review.

A fatal case of buflomedil (Fonzylane) self-poisoning is presented. Drug identification and quantification in postmortem blood, urine and gastric contents was achieved by means of high pressure liquid chromatography with diode-array detection (HPLC/DAD). Blood concentration was 275 micrograms/ml, > 70 times the usual therapeutic values. Toxicological results are discussed in the light of the existing literature.

Immunoassay of digoxin in hair.

Digoxin analysis in blood is an essential tool for therapeutic drug monitoring in cardiology because compliance with the treatment is a critical issue for the patient. Unfortunately, in postmortem cases blood digoxin concentration is of poor quality because there is a possible drug redistribution in the corpse and because of digoxin-like factors present in some people's blood. On the other hand, no biological fluid can be obtained at the autopsy. The aim of the present study was to evaluate the ability of an immunological method to determine digoxin in hair, in order to confirm that hair analysis can provide information on digoxin use before death. We studied 35 elderly patients who had been taking digoxin (60-250 micrograms/day) for 1-5 years. Two decontamination procedures were tested: washing by dichloromethane or by water and methanol. Three extraction procedures were compared: crushing in a ball mill and chloroform/acetone: crushing and methanol; enzymatic digestion. Immunoassays were performed by a microparticulate enzyme immunoassay. Serum digoxin levels were also assayed when sampling hair. The best results were obtained after decontamination with water and methanol followed by enzymatic digestion. Hair digoxin concentrations range from 3.6 to 11.4 pg/mg. Those very low concentrations are probably due to low and narrow range serum digoxin levels (0.3-1.4 ng/ml). No correlation was found between hair and blood digoxin. A forensic case is presented with 5 pg/mg digoxin in hair.

The hair analysis proficiency testing program of the French Society of Analytical Toxicology.

In an effort to improve laboratories performing hair analysis in forensic cases, the French Society of Analytical Toxicology (S.F.T.A.) has implemented a proficiency testing program since 1992. Actually about 10 laboratories are participating. Each survey is dedicated to one analyte or one pharmacological class: opiates (6-monoacetylmorphine, morphine and codeine), cocaine and benzoylecgonine, tetrahydrocannabinol, buprenorphine and norbuprenorphine, beta-blockers (metoprolol, atenolol), beta 2-agonists (salbutamol, clenbuterol). Animal hair was tested for clenbuterol. Prior to sending, hair samples were reduced to a powdered form, well mixed to ensure homogeneity, and then tested by GC/MS or HPLC/MS. Results confirm those obtained in a preliminary study on opiates and cocaine analysis in hair: a common analytical procedure has to be used by all the participants, including hydrolysis of hair. It is essential to work on authentic drug-positive hair samples and not on spiked samples. Participation at this program is free of charge and considered as an educational tool. Comparison of the results with those of other laboratories in Europe and USA shows that the analytical methods used during this program are in accordance with all the other procedures.

A case of fatal salt water intoxication following an exorcism session.

In response to a recent article published in this review, we present in this paper, an unusual case of fatal salt water intoxication. In this case, we point out three special features, the type of water ingested, the physiopathologic consequences of the ingestion and the very strange context of occurrence. This complex case allows us to point out complications due to salt poisoning and others caused by water intoxication.

Morphine extraction in necrophagous insects remains for determining ante-mortem opiate intoxication.

To study the potential use of insects remains as toxicological indicators, we measured morphine in desiccated entomological materials using a radioimmunoassay method (Coat-A-Count Serum Morphine, Dade Behring, France) following enzymatic hydrolysis.First, enzymatic cuticle extraction of morphine (pronase digestion preceded by a 2h incubation with a dithiothreitol solution) was performed on various substrates (Calliphoridae puparial cases and desiccated adults, and desiccated pupae of Dermestidae) which were then tested to identify possible interferences with the radioimmunoassay procedure. This same procedure was performed on puparial cases and desiccated adults of Lucilia sericata (Diptera, Calliphoridae) previously reared on minced meat containing various morphine concentrations. Morphine was detected only in cuticle powder from insects reared on meats containing 100 and 1000mg/kg. Higher concentrations were measured in puparial cases. Rearings on psoas from eight heroin overdose victims confirmed previous experimental results. Remains of necrophagous insects, particularly puparial cases, are often preserved for a long time, and consequently can serve as late alternative specimens for toxicological analysis when suitable tissues are not available.

Morphine perfused rabbits: a tool for experiments in forensic entomotoxicology.

In order to establish an animal model for entomotoxicological studies, the kinetics of morphine elimination from blood after a single intravenous injection of morphine and the concentration of morphine in tissues following a continuous perfusion were studied. The aim of these experiments was to obtain controlled morphine tissue concentrations similar to those encountered in fatal human heroin overdoses. These tissues can be used as a food source for developing fly larvae in entomotoxicological studies. In the single injection experiment, seven rabbits were administered 1 or 2 mg/kg body weight of morphine chlorhydrate via the main ear artery. Blood samples of 200 microL were removed regularly via a catheter. Morphine concentration was determined using RIA techniques. Morphine was found to be first rapidly distributed and then slowly eliminated, following a two-exponential equation. Elimination of morphine from blood can be described as a two-compartment model. Constants of the equation were determined using the Kaleidagraph program. Using those constants, the main pharmacokinetics parameters were calculated. Results of these parameters showed the following: clearance from 13.3 to 16.2 L.h.1, half-life of the distribution phase from 0.6 to 0.9 min, and half-life of the elimination phase from 21 to 26 min. These results were used to calculate the rate of perfusion of morphine for rabbits to obtain desired, controlled, and constant concentrations of morphine in tissues. In the second experiment, three rabbits received a perfusion of morphine intravascularly at a rate of 2 mg/kg/h for a period of 3 h. These rabbits were sacrificed and analyses performed on several abdominal and thoracic organs. Results showed that the concentrations of morphine differed according to the organ analyzed, but were reproducible for organs between animals. These concentrations were similar to those normally encountered in cases of human death due to heroin overdoses.

Determination of drug levels in larvae of Lucilia sericata (Diptera: Calliphoridae) reared on rabbit carcasses containing morphine.

This study concerns the determination of morphine concentrations in fly larvae reared on rabbits administered different concentrations of morphine and a correlation between concentrations of the drug in larvae and tissues. Three rabbits (R1, R2 and R3) were given dosages of 12.5, 25.0 and 50.0 mg/h of morphine over a 3 h period via continuous ear artery perfusion. These dosages and time of perfusion were calculated to create tissue concentrations of morphine similar to those encountered in human death due to overdose. Morphine blood level plateau was attained after 1 h of perfusion. A fourth rabbit was used as a control. To evaluate drug concentrations, tissues were sampled using a coelioscopic technique. Approximately 400 eggs of Lucilia sericata, all of the same age category, were placed in eyes, nostrils and mouth of each rabbit carcass. Larvae and puparia were regularly collected from each rabbit for toxicological analysis. The concentrations of the drug in the tissues sampled were determined to be similar to those normally encountered in human overdoses and were correlated with the dosage of morphine that had been administered. Morphine was detected in all larvae and pupae fed on tissues from carcasses administered morphine, except for puparia from the colony fed on the R1 animal which received 12.5 mg/h dosage of morphine. All samples from the control rabbit were negative for morphine. Concentrations of morphine in larvae reared on rabbit carcasses containing morphine were 30 to 100 times lower than the concentrations found in the tissues. A correlation between the tissue concentrations and larval concentrations was found in only 3rd instar larvae (80 to 140 h following hatching). No correlations were found between administered dosages, tissue concentrations and younger larvae, prepuparial larvae or puparia.

Effects of morphine in decomposing bodies on the development of Lucilia sericata (Diptera: Calliphoridae).

This study concerns the effects of morphine in tissues on the rate of development of Lucilia sericata (Diptera: Calliphoridae) using those tissues as a food source. Lucilia sericata is a species of fly commonly found on human corpses in Europe during the early stages of decomposition and thus of forensic interest. Three rabbits were administered 12.5, 25.0 and 50.0 mg/h of morphine chlorhydrate via ear perfusion over a period of 3 h. These dosages and duration of perfusion were calculated to give tissue concentrations of morphine similar to those encountered in fatal human overdoses. A fourth rabbit was used as a control. Following administration of the drug, rabbits were sacrificed and 400 eggs of Lucilia sericata, all of the same age, were placed in the eyes, nostrils and mouth of each rabbit. Developing larvae were sampled daily to determine growth rate and weight. Puparia and emerging adult flies were also sampled. Data were analyzed using analysis of variance (ANOVA) and Student's T-test. Results of this study show that an underestimation of the postmortem interval of 24 h is possible if the presence of morphine in tissues is not considered. This study demonstrates again the necessity of considering the possible effects of drugs in tissues on insect growth rates when estimating the postmortem interval using entomological techniques.

Determination of drug levels in larvae of Protophormia terraenovae and Calliphora vicina (Diptera: Calliphoridae) reared on rabbit carcasses containing morphine.

Two species of blow flies (Diptera: Calliphoridae) were reared on tissues from rabbits administered different dosages of morphine. These species, Protophormia terraenovae and Calliphora vicina are among the first wave of insects colonizing a dead body. Two series of 3 rabbits were given dosages of 10, 20, and 40 mg/h of morphine over a 3 h period via ear artery perfusion. A morphine blood level plateau was attained after 1 h of perfusion. Two other rabbits were used as controls. Samples of tissues collected from rabbits using a coelioscopic technique were determined to have morphine concentrations similar to those encountered in human overdoses and were correlated with dosages of morphine administered. All samples from control rabbits were negative for morphine. Larvae and puparia of both species were regularly collected from each rabbit for toxicological analysis. Concentrations of morphine in larvae reared on rabbit carcasses containing morphine were significantly lower than concentrations found in the tissues. There was a decrease in concentration in morphine observed in transition from feeding 3rd instar larva to puparium. A correlation between larval concentration and tissue concentration was found only in feeding 3rd instar larvae.

[The exact costs of studies in a hospital nuclear medicine department]. / Le coût exact des examens dans un service hospitalier de médecine nucléaire.

Objective data about the costs of nuclear medicine examinations are scarce and rather conflicting. Authors describe a method quantitating the costs of nuclear medicine investigations. These calculations were applied to a medium-sized nuclear medicine center set up in a teaching hospital. Calculations were as a tarification and followed the rules of monographic studies. They rely on exhaustive evaluation of each expense and precise analysis of their repartition. Average cost of the examination was 1,016 FF but the study reveals that costs varied from 664 to 6,746 FF. It appears that, but the more common investigations, exact costs are poorly related with nomenclature codification and that radiopharmaceutical costs have to be separately dealt with. This method allows to simulate costs-effects of any structure modification before being applied. One of the major feature of such a study is that it depicts a given center at a given time. Although it is to be hoped that the method should be spread, it should be hazardous to generalize its results.

Contribution of scintigraphy to verify the reliability of different preparation processes for enteric coated capsules.

The aim of this work was to use radiopharmaceuticals such as technetium (99mTc) and indium (DTPA-Ca111In) to visualize, with a gamma-camera, the disintegration area and time of 3 types of enteric coated hard gelatin capsules (obtained by 3 different preparation processes) and thus, to verify that they are really resistant in gastric fluids and soluble in intestinal zones. Results are well correlated with those previously obtained in vitro (disintegration, dissolution) and in vivo (profiles of plasmatic concentrations versus time).

[Judicial expertise in blood alcohol determination and toxicological analysis]. / Expertises judiciaires en matière d'alcoolémie et de toxicologie.

Blood alcohol determination or toxicological expert evaluation are a part of the judicial inquiry. They are devoted to authorized professionals registrated by the court of appeal and they are obliged to perform themselves the analysis. They bind the civil and penal liability of the professionals who are designated. After a reapparaisal of the French legislation concerning blood alcohol levels, the authors review the totality of problems resulting from the interpretation of results as well as the relationship to judicial authorities: expert nomination procedure, professional criterions, legal points, daily practice. Among usual questions from magistrates and policemen, the expert has to estimate the quantity of alcohol taken by an individual, evaluate the blood ethanol content of a subject when the blood collection is late, calculate blood ethanol from breath alcohol analysis. For forensic toxicology, professional criterions and legal aspects are also touched on.

[Localized or systemic amyloidosis? Value and limitations of Iodine-123 labelled amyloid P component scintigraphy, role of biopsy of minor salivary glands]. / Amylose localisée ou systémique? Intérêt et limites de la scintigraphie au composant amyloïde P marqué à l'iode 123, place de la biopsie de glandes salivaires accessoires.

We evaluated the value of serum amyloid P component scintigraphy (123I-SAP) and labial salivary gland biopsy in four patients with apparently localized amyloidosis. One patient had pharyngeal amyloidosis, the second laryngeal amyloidosis, the third retro-ocular amyloidosis and the fourth had carpal tunnel syndrome. Three patients (no 2, no 3, no 4) have abnormal whole body retention of 123I-SAP and positive labial salivary gland biopsy for amyloidosis. Only the first patient had effectively localized amyloidosis and local treatment was sufficient. Melphalan was given to the patients no 2 and no 3, colchicine was given to the patient no 4. Labial salivary gland biopsy and 123I-SAP scintigraphy may give positive argument for the diagnosis of systemic amyloidosis in patients with apparently localized amyloidosis.