Rapid and long-lasting response to selpercatinib of paraneoplastic Cushing's syndrome in medullary thyroid carcinoma.

The endocrine secretions of carcinomas can be life-threatening. Medullary thyroid carcinoma (MTC) is a rare cancer that is often associated with cortisol secretion, leading to paraneoplastic Cushing's syndrome. Mutations of the proto-oncogene RET are driver molecular events in 70% of MTC cases. Here, we report a case of a woman, born in 1956, who was diagnosed with sporadic MTC in 2005, with subsequent relapses treated with focal treatments. In April 2019, she presented with severe and rapidly progressive paraneoplastic Cushing's syndrome associated with lymph node, lung, liver and bone metastases. A supraclavicular lymph node biopsy revealed a somatic p.M918T (c.2753T>C) mutation in exon 16 of the RET proto-oncogene. The patient began treatment with selpercatinib in September 2019. Clinical efficacy was immediate. Chronic diarrhea disappeared within a few days. Clinical hypercorticism quickly disappeared, with quick improvements in muscle and skin conditions and fatigue. Two months after treatment initiation, urinary free cortisol normalized to 42 µg/24 h. Levels of the tumor markers carcinoembryonic antigen (CEA) and calcitonin also greatly decreased from baseline. After 34 months of treatment, selpercatinib elicits sustained clinical, biological and morphological responses. In summary, this case report illustrates the rapid and long-lasting antisecretory effect of selpercatinib associated with tumor control. As Cushing's syndrome associated with medullary thyroid cancer is associated with poor prognosis, this case report is very encouraging. In addition, this suggests the potential benefit of molecular testing in all cases of medullary thyroid cancer.

hTERT promotes imatinib resistance in chronic myeloid leukemia cells: therapeutic implications.

Imatinib mesylate has shown remarkable efficacy in the treatment of patients in the chronic phase of chronic myeloid leukemia. However, despite an overall significant hematological and cytogenetic response, imatinib therapy may favor the emergence of drug-resistant clones, ultimately leading to relapse. Some imatinib resistance mechanisms had not been fully elucidated yet. In this study we used sensitive and resistant sublines from a Bcr-Abl positive cell line to investigate the putative involvement of telomerase in the promotion of imatinib resistance. We showed that sensitivity to imatinib can be partly restored in imatinib-resistant cells by targeting telomerase expression, either by the introduction of a dominant-negative form of the catalytic protein subunit of the telomerase (hTERT) or by the treatment with all-trans-retinoic acid, a clinically used drug. Furthermore, we showed that hTERT overexpression favors the development of imatinib resistance through both its antiapoptotic and telomere maintenance functions. Therefore, combining antitelomerase strategies to imatinib treatment at the beginning of the treatment should be promoted to reduce the risk of imatinib resistance development and increase the probability of eradicating the disease.

Telomerase regulation in hematological cancers: a matter of stemness?

Human telomerase is a nuclear ribonucleoprotein enzyme complex that catalyzes the synthesis and extension of telomeric DNA. This enzyme is highly expressed and active in most malignant tumors while it is usually not or transiently detectable in normal somatic cells, suggesting that it plays an important role in cellular immortalization and tumorigenesis. As most leukemic cells are generally telomerase-positive and have often shortened telomeres, our understanding of how telomerase is deregulated in these diseases could help to define novel therapies targeting the telomere/telomerase complex. Nonetheless, considering that normal hematopoietic stem cells and some of their progeny do express a functional telomerase, it is tempting to consider such an activity in leukemias as a sustained stemness feature and important to understand how telomere length and telomerase activity are regulated in the various forms of leukemias.

The impact of pre- and post-transplantation positron emission tomography using 18-fluorodeoxyglucose on poor-prognosis lymphoma patients undergoing autologous stem cell transplantation.

BACKGROUND: In patients with lymphoma who had a poor prognosis, pretransplantation 18-fluorodeoxyglucose (FDG)-positron-emission tomography (PET) was important for the evaluation of response and outcome. However, little is known about the correlation of FDG-PET with post-transplantation PET. The current study was designed to ascertain whether positive pretransplantation PET images are modified by the conditioning regimen. METHODS: Sixty consecutive patients who had achieved remission and underwent consolidation by autologous stem cell transplantation (ASCT) had PET images obtained before ASCT (after 3 or 4 chemotherapy cycles) and 100 days after ASCT. The correlation was explored between the presence of abnormal 18-FDG uptake (PET positive) or its absence (PET negative) and patient outcomes. RESULTS: Before ASCT, 31 patients achieved complete remission (CR), and 23 patients achieved uncertain CR. Before ASCT, 44 patients (75%) were had negative PET images; and, after ASCT, 48 patients (80%) had negative PET images. One year after ASCT, the estimated event-free survival (EFS) rate was 80% in patients who had negative pre-ASCT PET images compared with 43% in patients who had positive pre-ASCT PET images (P = .0002). The EFS rate was 81% in patients who had negative post-ASCT PET images compared with 25% in patients who had negative post-ASCT PET images (P < .0001). In multivariate analysis, only the results for pre- and post-ASCT PET images retained prognostic value, with relative risks of failure estimated at 4.9 and 11.9, respectively. CONCLUSIONS: A positive pre-ASCT PET image indicated a high risk of ASCT failure, which was increased by a positive post-ASCT PET image. For patients with lymphoma who have positive pre-ASCT PET images, more investigations using new treatment approaches will be required. For patients who have negative pre-ASCT PET images, obtaining post-ASCT PET images does not seem to be mandatory.

Diagnostics, prognostic and therapeutic exploitation of telomeres and telomerase in leukemias.

Telomeres are specialized structures at the end of human chromosomes. Telomere length decreases with each cell division, thus, reflecting the mitotic history of somatic cells. Telomerase, the ribonucleoprotein enzyme which maintains telomeres of eukaryotic chromosomes, is up-regulated in the vast majority of human neoplasia but not in normal somatic tissues. In contrast to other somatic cells, normal primitive human hematopoietic cells and some peripheral blood cells expressed low levels of telomerase activity. This activity is thought to play an important role in self-renewal of hematopoietic stem cells. In malignant disorders, telomere lengths are generally shortened and telomerase expression and activity enhanced with high differences in the levels. Although it is necessary to be cautious in interpreting these data, there are indications that telomere length and telomerase expression and activity can serve as a molecular marker of the clinical progression and prognosis of most leukemias. Approaches that directly target telomerase, telomeres or telomerase regulatory mechanisms have been developed. Some of these anti-telomerase strategies in combination with conventional drugs proved to be promising in some types of leukemias.

KIT overexpression and amplification in gastrointestinal stromal tumors (GISTs).

The tyrosine kinase receptor KIT plays a major role in gastrointestinal stromal tumors (GISTs) oncogenesis. Indeed, 95% of GISTs express KIT protein, and about 70% exhibit activating mutations of the KIT gene. However, little is known about KIT overexpression mechanisms in these tumors, and the correlation with KIT mutations. GISTs with mutations within exon 11 (n=12) or 9 (n=1) of KIT were compared with GISTs without KIT mutations in exons 9, 11, 13, and 17 (n=10), two of them had PDGFRA mutations. KIT amplification was studied by real-time PCR of KIT and beta-ACTIN genes, and by fluorescence in situ hybridization (FISH) using KIT and chromosome 4 centromere specific probes. KIT transcripts and protein expression were quantified by reverse transcription real-time PCR and Western blot respectively. Genomic analysis revealed a single mutated GIST with KIT amplification. KIT protein and RNA levels were highly variable in GISTs but closely correlated (r=0.82, P<1.10(-5)), and were higher in GISTs with KIT mutations (P=0.07 and P=0.03 respectively). In conclusion, contrasting with the regulation of other tyrosine kinase receptors, KIT overexpression in GISTs is rarely related to a gene amplification, which suggests a deregulation of KIT gene transcription.