Real-world effectiveness of ixazomib combined with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: the REMIX study.

Ixazomib (IXA) is an oral proteasome inhibitor (PI) used in combination with lenalidomide and dexamethasone (IXA-Rd) for patients with relapsed and/or refractory multiple myeloma (RRMM). The REMIX study is one of the largest prospective, real-world analysis of the effectiveness of IXA-Rd in the setting of RRMM. Conducted in France between August 2017 and October 2019, the REMIX study, a non-interventional prospective study, included 376 patients receiving IXA-Rd in second line or later and followed for at least 24 months. Primary endpoint was the median progression-free survival (mPFS). Median age was 71 years (Q1-Q3 65.0 - 77.5) with 18.4% of participants older than 80 years. IXA-Rd was initiated in L2, L3 and L4 + for 60.4%, 18.1% and 21.5%, respectively. mPFS was 19.1 months (95% CI [15.9, 21.5]) and overall response rate (ORR) was 73.1%. mPFS was 21.5, 21.9 and 5.8 months in patients receiving IXA-Rd as L2, L3, L4 + respectively. Among patients receiving IXA-Rd in L2 and L3, mPFS was similar for patients previously exposed to lenalidomide (19.5 months) than for those lenalidomide naive (not exposed, 22.6 months, p = 0.29). mPFS was 19.1 months in patients younger than 80 years and 17.4 months in those 80 years or older (p = 0.06) with similar ORR (72.4% and 76.8%) in both subgroups. Adverse events (AEs) were reported in 78.2% of patients including 40.7% of treatment-related AE. IXA discontinuation was due to toxicity in 21% of patients. To conclude, the results of the REMIX study are consistent with the results of Tourmaline-MM1 and confirm the benefit of IXA-Rd combination in real life. It shows the interest of IXA-Rd in an older and frailer population, with an acceptable effectiveness and tolerance.

OpenMATB: A Multi-Attribute Task Battery promoting task customization, software extensibility and experiment replicability.

OpenMATB is an open-source variant of the Multi-Attribute Task Battery (MATB) and is available under a free software license. MATB consists of a set of tasks representative of those performed in aircraft piloting. It is used, in particular, to study the effect of automation on decision-making, mental workload, and vigilance. Since the publication of MATB 20 years ago, the subject of automation has grown considerably in importance. After introducing the task battery, this article highlights three main requirements for an up-to-date implementation of MATB. First, there is a need for task customization, to make it possible to change the values, appearance or integrated components (such as rating scales) of the tasks. Second, researchers need software extensibility to enable them to integrate specific features, such as synchronization with psychophysiological devices. Third, to achieve experiment replicability, it is necessary that the source code and the scenario files are easily available and auditable. In the present paper, we explain how these aspects are implemented in OpenMATB by presenting the software architecture and features, while placing special emphasis on the crucial role of the plugin system and the simplicity of the format used in the script files. Finally, we present a number of general trends for the future study of automation in human factors research and ergonomics.

Immunoreactive gastrin-releasing peptide in medullary thyroid carcinoma.

We have previously shown that immunoassayable concentration of somatostatin (SRIH) was elevated in 70% of 34 consecutive medullary thyroid carcinoma (MTC) tissue samples. In the present study gastrin releasing peptide (GRP)-like immunoreactivity was measured in tissue extracts from these 34 MTC (25 inherited, 7 sporadic, 2 unclassified) and in 7 normal thyroid tissue. Plasma SRIH, calcitonin (CT) and carcinoembryonic antigen were assayed in all patients. Normal thyroid tissue contained less than 61 pmol GRP per g wet weight; in contrast GRP concentration was elevated (62-7800 pmol/g) in 32/34 tumor extracts. The distribution of tissue GRP values were similar in sporadic as well as in familial MTC. We found no significant correlation between tumor GRP concentration and plasma SRIH (r = -0.05), plasma CT (r = -0.24), or plasma carcinoembryonic antigen levels (r = -0.21). Tumor concentrations of immunoreactive GRP and SRIH were positively correlated when logarithmic transformation was used (P less than 0.01). Thus GRP, as well as SRIH, is a major product of tumoral C cells in human MTC when systematically evaluated in a large number of cases.

Diagnosis of medullary carcinoma of the thyroid (MCT) by calcitonin assay using monoclonal antibodies: criteria for the pentagastrin stimulation test in hereditary MCT.

A new calcitonin (CT) immunoradiometric assay, using anti-11-7 and anti-24-32 CT fragment monoclonal antibodies was evaluated and compared to classical RIA. The sensitivity was 2.5 ng/L, the normal basal level (n = 83) was lower than 10 ng/L, the response to pentagastrin stimulation in control subjects was absent in nine and between 10-30 ng/L in nine others. (mean, 15.4). In patients with renal failure the basal level was increased between 10-52 ng/L. In patients with medullary thyroid carcinoma (MTC; n = 28), the basal level was between 189-28,900 ng/L. A pentagastrin test was performed as screening for familial MTC in eight patients with confirmed MTC at subsequent surgery; the calcitonin peak was equal or greater than 38 ng/L. Large differences exist between CT levels measured by RIA and immunoradiometric assay. The latter method provides a greater sensitivity to pentagastrin test and allows a better identification of microcarcinoma in hereditary cases of MTC.

Pentagastrin stimulation test and early diagnosis of medullary thyroid carcinoma using an immunoradiometric assay of calcitonin: comparison with genetic screening in hereditary medullary thyroid carcinoma.

A pentagastrin stimulation test using a calcitonin (CT) immunoradiometric assay was performed in 38 healthy subjects and in the following 50 patients: 25 subjects from families with at least 2 known cases of medullary thyroid carcinoma (MTC), 11 subjects from families with apparently sporadic MTC, 2 pheochromocytoma carriers, 1 primary hyperparathyroidism, 8 patients with thyroid nodules, and 3 others with various diseases. In healthy volunteers, basal CT values were always less than 10 ng/L; the response to pentagastrin was below 30 ng/L for 36, and for the remaining 2, the peaks reached 30 for 1 subject and 48 ng/L for the other. The pentagastrin-stimulated CT peak was above 30 ng/L in each of the patients presented here, and all were thyroidectomized. In screening the 25 relatives of patients with familial MTC, a CT peak level over 30 ng/L was constantly associated with C-cell disease (23 cases of MTC and 2 of C-cell hyperplasia). A response to pentagastrin above 100 ng/L was observed in 15 patients among the 23 with MTC. In 8 of the 10 patients with a peak CT level between 30-100 ng/L, pathological examination showed a MTC; the other 2 had C-cell hyperplasia and a negative linkage study analysis. In the 25 other patients in the study without familial MTC, the pentagastrin-stimulated CT level was over 100 ng/L in 11 of the 14 subjects with MTC. The abnormal CT response to pentagastrin, which has been used as a criterion for surgical treatment, is currently determined by an immunoradiometric assay. Our study confirms that subjects with a peak CT level above 100 ng/L should undergo surgery whatever the reason for the test. In the context of inherited MTC, our results suggest that for patients with a CT peak level between 30-100 ng/L, surgery may actually be postponed when their probability of being gene carriers is low. Recent progress with the characterization of specific mutations in affected individuals will make familial screening much easier in the next few months.

PCR amplification of CGRP II mRNA. Variable expression in tumoral and non-tumoral human thyroid.

Two genes code for calcitonin gene-related peptides (CGRPs). One expresses by tissue-specific alternate splicing calcitonin and CGRP I mRNAs, the other CGRP II mRNA. Calcitonin is the marker of sporadic or hereditary human medullary thyroid carcinoma (MTC). CGRP II expression is not well established in normal or tumoral thyroid. After amplification by polymerase chain reaction, CGRP I and II mRNAs were detected in six cases of MTC associated with other endocrine neoplasia (MEN IIa) and in two cases of isolated MTC. CGRP I was detected in all non-C cell tumoral thyroids (6 samples), CGRP II was barely detectable in three out of six cases. CGRP II could be a specific tumoral marker of MTC.

Heterogeneity of circulating calcitonin levels: relations with calcitonin biosynthesis in medullary thyroid carcinomas.

Calcitonin (CT), a hypocalcemic and hypophosphatemic hormone, is produced by the C-cells of the thyroid gland. It is the main tumoral marker of medullary thyroid carcinoma (MTC). Hypersecretion of CT is also associated with other types of tumors. Thus, heterogeneity of circulating CT can play an important role in the accurate determination of hormone levels in blood samples obtained from MTC patients. Further studies will be necessary to establish the predictive value of the several peptides coded by the calcitonin gene family. All of them specifically reflect the ways and the pattern of alternative splicing of the primary transcript of the Calc I gene. Such relations implicate further investigations concerning the relationship between calcitonin circulating levels, biosynthetic activity of C-cells and the expression of gene encoding for this hormone, in normal and neoplastic conditions.

On the presence of autoantibodies in the plasma of patients suffering from medullary carcinoma of the thyroid.

Thyroiditis is associated with certain cases of medullary carcinoma of the thyroid (MCT). In order to determine if this was due to the presence of autoantibodies, we have investigated whether plasma from patients suffering from the disease contain autoantibodies. The specificity of the reaction was established using specific antibodies to antigens such as: calcitonin (CT), carcinoembryonic antigen (CEA) and thyroglobulin (Tg); no antibodies against CT, CEA or Tg were detected in the plasma from the patients investigated. The presence of autoantibodies to a constituent of the tumor was established in each case studied. The detection of autoantibodies to a "specific" constituent of MCT could be of potential interest in the early screening for the disease.

[Analysis of circulating calcitonin for the detection of familial and sporadic medullary cancer]. / Dosage de la calcitonine circulante pour la détection du cancer médullaire familial et sporadique.

Medullary carcinoma of the thyroid is always linked to a high basal level of calcitonin or to an abnormal increase of the hormone after stimulation: this is generally the case in incipient tumoral metastases and in sub-clinical familial cases. Moreover, a normal stimulation test does not allow to eliminate the probability of a tumoral heredity and it is often difficult to discriminate between sporadic and familial cases or normal and high risk subjects during familial screening. So, in the absence of established rules of follow-up, repetitive stimulation tests will be often necessary as well as an extensive investigation of members of the families.

[Medullary cancer of the thyroid]. / Cancer médullaire de la thyroïde.

Medullary thyroid cancer (MTC) is either of the sporadic or familial type, whether it be isolated or constitute part of a type II multiple endocrine neoplasia. Progress in the knowledge of the disease has recently been obtained in the following ways: the IRMA assay of mature calcitonin, the disease marker, has permitted earlier diagnosis of familial cases and recurrence; the locus assignment of the gene on chromosome 10 now enables a valid discrimination in certain families of gene carriers; collaborative clinical, biological, pathological, therapeutic and epidemiological research on a nation-wide scale has had a beneficial effect on patients, with improvement in diagnosis of the familial forms, in disease prognosis, in cancer detection at an infraclinical stage, and in the regrouping and distribution of families in France.

[Calcitonin cancers: definition, history, various forms]. / Les cancers à calcitonine: définition, historique, différentes formes.

Calcitonin secreting tumors, as their name indicates, share a common denominator; yet, their clinical, morphological and biochemical features are polymorphous. Medullary thyroid carcinoma is a well-known disease, with sporadic and familial forms, associated or not with type II multiendocrinopathy; not only calcitonin and carcinoembryonic antigen, its reliable markers, but also multiple other hormones may be secreted. Atypical forms, more or less undifferentiated, even heterogenous may also exist: the presence of the hormone in tumoral cells allows their recognition. Moreover, ectopic calcitonin secretion may be related to quite different tumors with regard to their clinic, pathologic, embryologic aspects. Thus, strict criteria are necessary for their diagnosis. Molecular biology will certainly help the understanding of the functional and genetic aspects of these tumors.

An uncommon apudoma: a functional chemodectoma of the larynx. Report of a case and review of the literature.

The authors report a case of laryngeal chemodectoma in a 53-year-old man who died from general dissemination and lymphatic and subcutaneous metastases. This functional neoplasm secreted calcitonin revealed by fluorescence and biochemical tests and perhaps adrenaline-like substances. Its cells looked like the light chief cells of the human carotid body; they contained secretory granules and lysosomal formations. Thirty similar cases had been previously reported. The superior laryngeal glomi and more occasionally the inferior ones were the seat of these tumours which occurred with an equal frequency in both sexes. A hoarseness was often the unique symptom noticed during the several months or years preceding the first examination of this slow growing neoplasm. Nevertheless among the chemodectomas of the head and the neck region those arising in the larynx had the highest incidence of malignant evolution. Five of the patients presented a general dissemination, two had lymphatic metastases and one a local recurrence. The ultra-structural features and sometimes the rarely detected functional activity of these chemodectomas are those of apudomas whose cells might originate from the cephalic portion of the neural crests.

[Hemothorax disclosing hemorrhagic necrosis of a pheochromocytoma: circumstance for detection of multiple endocrine neoplasia type IIa. Detection of 5 familial cases]. / Hémothorax révélateur d'une nécrose hémorragique d'un phéochromocytome: circonstance de découverte d'une néoplasie endocrine multiple de type II a. Dépistage de cinq cas familiaux.

Whilst investigating 26 members of the same family, we discovered 5 cases of multiple endocrine neoplasia type II a. The present report demonstrates the diagnostic value of basal plasma thyrocalcitonin (TCT) assays, before and after stimulation with pentagastrin, and of plasma carcinoembryonic antigen (CEA) assays. Some of the clinical features encountered were novel--e.g. in one patient the phaeochromocytoma was revealed by a haemothorax with cardiovascular collapse--and others were peculiar; thus, in 4 cases the medullary thyroid carcinoma (MTC) was less than 2 cm in diameter and without lymph node or visceral metastases, even in patients aged 87, 59 and 56. More classically, MTC, always multifocal, was clinically silent, as were the two cases of phaeochromocytoma and hyperparathyroidism. Phaeochromocytomas were difficult to diagnose. Ultrasonic tomography did not prove very helpful and the disease was transmitted as an autosomal dominant trait. Finally, MTC secreted a variety of substances (TCT, CEA, beta-endorphin, somatostatin), and HLA A2-B15 antigens were found in 3 patients.

[Medullary cancer of the thyroid. Apropos of 20 years' experience in France]. / Cancer médullaire de la thyroïde. A propos d'une expérience de 20 ans en France.

The majority (1013) of cases of medullary carcinoma of the thyroid observed in France in the last twenty years have been registered in a national file. Once overcome the difficulty of diagnosing the index case, all first degree parents at least should undergo a pentagastrin stimulation test and calcitonin estimation. Though such a policy involves difficulties of several types, it has resulted in the detection of 203 cases belonging to 61 families. 29 families suffered only from isolated MCT; in the 32 other families this cancer was a part of polyendocrinopathies of type 2a (28 cases) or type 2b (4 cases). The tumour was apparently of the sporadic type in 208 subjects. In 602 other cases the data were insufficient for a correct classification. An epidemiological enquiry of the disease is in progress since 1986. Though the number of complete files analysed is still insufficient, this study will be essential in understanding the natural history of the disease, the causes of its heterogeneity and in deducing eventually preventive measures even if in meantime a genetic marker is available.

[Familial surveys in screening for thyroid cancers with amyloid stroma. Report of a personal survey carried out on 80 members of the same family]. / Les enquêtes familiales pour dépistage du cancer de la thyroïde à stroma amyloïde. Présentation d'une enquête personnelle portant sur 80 membres d'une même famille.

We have recently studied a large family of 80 persons in which 47 were examined. The evaluation included history, blood pressure determination, palpation of the thyroid gland and determination of serum carcino-embryonic antigen (C.E.A.) and calcitonin (C.T.). Two members of the kindred had a proven M.C.T. without pheochromocytoma, hyperparathyroidism or Cushing's disease and two others a probable M.C.T. Four members suffered from intestinal occlusion and death occurred in three of them. Our conclusions are: 1) In this family traced through 4 generations: it appears that M.C.T. is transmitted as an autosomal dominant trait with a high degree of penetrance; 2) Our cases associated with those reported in the literature in the past few years point to the existence of a rare but distinct syndrome characterised by the association of M.C.T. and congenital megacolon with hyperplasia of the myenteric plexus; 3) As far as we know, this is the first indication of C.E.A. coupled with elevated calcitonin among several individuals of the same family. We confirm here the conclusions of previous studies: "C.E.A. is a valuable tumour marker which can be used for the detection of M.C.T., particularly if no calcitonin radio-immuno assay is available.

[Thyroid cancer with amyloid stroma. Results of a familial study]. / Cancer de la thyroïde à stroma amyloïde. Résultats d'une enquête familiale.

We have recently studied a kindred in which there have been 2 proven and 2 probable cases of medullary thyroid carcinoma without pheochromocytoma, hyperparathyroidism or Cushing's disease. Four other members suffered from intestinal occlusion and death occurred in three of them. The family has been traced through 4 generations (80 members) and 47 members could be examined; circulating calcitonin and carcinoembryonic antigen levels were measured. This study leads to two conclusions: 1) Medullary thyroid carcinoma is transmitted as an autosomal dominant trait with a high degree of penetrance. 2) Carcinoembryonic antigen is a valuable tumour marker particularly if no calcitonin radioimmunoassay is avialable for the diagnosis of M.C.T.

[Endocrine polyadenomatosis of 2a type (MEN 2a). Clinical and genetic study of a family]. / Polyadénomatose endocrinienne de type 2a (MEN 2a). Etude clinique et génétique d'une famille (GETC).

In a large kindred with multiple endocrine neoplasia type 2a (MEN 2a) (137 members, 5 generations), bilateral thyroid medullary carcinoma was found in all affected members. Pheochromocytoma was present in 59% of the cases, and was responsible at least for 4 out the 5 deaths related to MEN 2a. Hyperparathyroidism was less frequent (41%). Family screening leads to a reduction in age for diagnosis and to an improvement in the prevalence of complete healing after surgery. Linkage between HLA loci and a dominant gene for MEN 2a was investigated in this kindred. Lod scores for recombination fraction were all negative (-0.47 for a recombination fraction of 0.05). These results comfort the lack of linkage between MEN 2a and the HLA complex.

[Plurality of calcitonin-producing thyroid cancers]. / Pluralité des cancers thyroïdiens à calcitonine.

Abnormal levels of calcitonin and carcinoembryonic antigen in plasma, and detectable amounts of these markers in tumours are not restricted to typical forms of medullary cancer of the thyroid but are also characteristic of some other tumours of the gland. The diagnosis of these tumours, therefore, should not rely entirely on histological findings but should include a search for specific biochemical markers in plasma and tissues.

[Multiple endocrine neoplasms type 2. Recent aspects]. / Néoplasies endocriniennes multiples de type 2. Aspects récents.

Multiple endocrine neoplasia type 2 (MEN 2) is transmitted as an autosomal dominant trait, with 3 different forms. MEN 2a consists of medullary thyroid carcinoma, phaeochromocytoma(s) and hyperparathyroidism. In MEN 2b, parathyroid hyperplasia is absent, but a Marfan-like syndrome and neuromas of the mucosae are present. In some families, the only manifestation of MEN 2 is a medullary thyroid carcinoma. These 3 forms seem to related to one or several gene(s) located in the pericentromeric region of chromosome 10. The histological lesions of MEN 2a are multifocal, bilateral and associated with hyperplasia (which affects C-cells in the thyroid gland). Screening for familial medullary thyroid carcinoma is based upon plasma calcitonin levels measured before and after a pentagastrin stimulation test. The demonstration of DNA markers near the gene(s) of the disease in chromosome 10 pericentromeric region makes it possible to identify, with good probability, the subjects at risk for the disease. It is only by determining the responsible gene(s) that subjects carrying the hereditary anomaly will be identified directly, without marker assays.

[Familial medullary thyroid cancer. Contribution of genealogy and genetics to the study of two families]. / Cancer médullaire familial de la thyroïde. Apport de la généalogie et de la génétique à l'étude de deux familles.

A geneological study made it possible to establish a link between two medullary thyroid carcinoma families from Normandy totalling 9 sick subjects, and a probable link with a third family. The study contributed to the diagnosis of multiple endocrine neoplasia type IIa, whereas the condition had been diagnosed for 6 years as familial medullary thyroid carcinoma, without phaechromocytoma. Group in these two families together increased the number of subjects tested, thereby facilitating genetic link analysis and enabling the link with markers of the disease on chromosome 10 to be asserted. The genetic study can now be used to detect individuals at risk, and with regular laboratory tests the diagnosis will be made at the "precancerous" stage. A genealogical study going back to the family-founding couple will increase the population which will benefit from screening in this region north of Rouen.