During the past years, targeted therapies for cancer have been developed using drugs that have significant metabolic consequences. Among them, the mammalian target of rapamycin (mTOR) inhibitors and, to a much lesser extent, the tyrosine kinase inhibitors (TKIs) are involved. mTOR plays a key role in the regulation of cell growth as well as lipid and glucose metabolism. Treatment with mTOR inhibitors is associated with a significant increase in plasma triglycerides and LDL cholesterol. mTOR inhibitors seem to increase plasma triglycerides by reducing the activity of the lipoprotein lipase which is in charge of the catabolism of triglyceride-rich lipoproteins. The increase in LDL cholesterol observed with mTOR inhibitors seems to be due to a decrease in LDL catabolism secondary to a reduction of LDL receptor expression. In addition, treatment with mTOR inhibitors is associated with a high incidence of hyperglycemia, ranging from 13 to 50% in the clinical trials. The mechanisms responsible for hyperglycemia with new onset diabetes are not clear, but are likely due to the combination of impaired insulin secretion and insulin resistance. TKIs do not induce hyperlipidemia but alter glucose homeostasis. Treatment with TKIs may be associated either with hyperglycemia or hypoglycemia. The molecular mechanism by which TKIs control glucose homeostasis remains unknown. Owing to the metabolic consequences of these agents used as targeted anti-cancer therapies, a specific and personalized follow-up of blood glucose and lipids is recommended when using mTOR inhibitors and of blood glucose when using TKIs.
Bruno Vergès, Thomas Walter, and Bertrand Cariou
Ralf Paschke, Norbert Brückner, Thomas Eck, Ludwig Schaaf, Walter Back, and Klaus Henning Usadel
The significance of intrathyroidal lymphocytic infiltration is not known. However, several indirect lines of evidence suggest that interstitial or intraepithelial lymphocytes are the effector or thyroid autoantibodyproducing lymphocytes in Graves' disease. This has not been investigated in vivo. Changes of nuclear volume of endocrine cells have previously been shown to be a reliable parameter of functional stimulation of endocrine glands. Therefore we investigated this parameter near and off lymphocytic aggregates, loosely distributed plasma cells and memory T cells in paraffine sections of Graves' disease thyroid glands. In 21 Graves' disease thyroid glands we found significant increases of thyroid epithelial cell nuclear volume near plasma cells (198.4 μm3) as well as near lymphocytic aggregates (219.1 μm3) compared with thyroid epithelial cell nuclear volume one microscopic field away (160.1 and 137.7 μm3 respectively). Similar nuclear volume differences were observed after propanolol and thiourelene antithyroid drug treatment. These nuclear volume differences could not be observed in 10 control thyroid glands and around CD45R0-positive memory T cells in Graves' disease thyroid glands. These direct in vivo investigations of regional functional stimulation of thyroid epithelial cells in Graves' disease show local stimulation near lymphocytic aggregates and diffusely distributed plasma cells. Therefore our in vivo data do not permit to identify stimulatory lymphocytes only interstitially or intraepithelially as previously suggested.
Louis de Mestier, Thomas Walter, Hedia Brixi, Catherine Lombard-Bohas, and Guillaume Cadiot
VIPomas are rare-functioning neuroendocrine tumors (NETs). Overproduction of vasointestinal peptide (VIP) leads to the Verner–Morrison syndrome, whose management is challenging when refractory to somatostatin analogs. Two patients with progressive metastatic pancreatic NETs and refractory VIPoma symptoms were treated with sunitinib. This led to fast and sustained total relief of VIPoma symptoms, enabling earlier discharge from hospital and improvement in their quality of life. In both cases, sunitinib discontinuation led to the quick recurrence of watery diarrhea, which resolved within a few days after reintroducing sunitinib. The anti-secretory effect of sunitinib on VIPoma syndrome was probably not related to any anti-tumor effect. These observations agree with the rare reported cases of anti-secretory effects with targeted therapies. The sunitinib-driven inhibition of multiple-tyrosine kinase receptors might act on secretory pathways and describe sunitinib's ability to improve VIPoma symptoms. Sunitinib could be a therapeutic option to control refractory VIPoma symptoms in patients with NETs.
Thomas Walter, Laurence Chardon, Valérie Hervieu, Richard Cohen, Jean-Alain Chayvialle, Jean-Yves Scoazec, and Catherine Lombard-Bohas
We aimed to gain insight into the functional consequences of ghrelin overproduction in patients with neuroendocrine tumors and its relations with disease characteristics and evolution.
We retrospectively analyzed three cases of neuroendocrine carcinomas associated with very high levels of circulating ghrelin.
Between February and October 2007, serum ghrelin levels were determined in all patients with well-differentiated endocrine carcinoma referred to our center (n=72). Three patients were found to have circulating ghrelin levels >10-fold the upper limit of normal. The clinical, biochemical, and pathological characteristics of these three patients were reviewed. The ratio between circulating acyl and total ghrelin was determined, and tumor tissue expression of ghrelin was assayed by immunohistochemistry.
The three patients had massive hyperghrelinemia (respectively 49 028, 63 711, and 101 996 pg/ml), with <10% of acyl ghrelin. The corresponding primary tumors were located in the pancreas, rectum, and gallbladder; all were metastatic. There was no acromegaly; there was a decrease in appetite; and body mass index was low. Serum GH levels were only slightly increased and serum IGF1 levels were normal. Immunoreactive ghrelin was detected in the tumor tissue in the two cases in which tissue material was available. All three patients died before 12 months after the diagnosis of hyperghrelinemia.
Well-differentiated neuroendocrine carcinomas of various origins may produce markedly high levels of circulating ghrelin, without evidence of clinical or functional consequences.
Cécile Nozières, Laurence Chardon, Bernard Goichot, Françoise Borson-Chazot, Valérie Hervieu, Karim Chikh, Catherine Lombard-Bohas, and Thomas Walter
Inappropriate calcitonin (CT) release, a major feature of medullary thyroid cancer (MTC), may occur in neuroendocrine tumors (NETs). The aims of this retrospective study were to assess i) the characteristics and prognosis of CT-producing NETs, and ii) the value of CT monitoring during follow-up.
All patients with NETs in whom serum CT was assayed between 2010 and 2012 were included. MTCs were excluded. Clinical, biological, and histological characteristics were studied.
Twenty-one (12%) of 176 patients in whom serum CT was systematically assayed had concentrations >100 ng/l, with tumours predominantly of bronchial or pancreatic origin (P<0.0001), and of high grade (P=0.0006). Poor prognosis was linked to high CT levels, poor differentiation, and grade 3. In a total group of 24 patients with serum CT >100 ng/l, symptoms potentially attributable to CT were recorded in eight, with occasional overlap with the carcinoid syndrome among other secretory syndromes. Immunohistochemistry could be performed in six tumor specimens, CT being detected in five. In 11 patients with five or more successive CT assays, hormone levels were fairly well correlated with clinical courses.
Serum CT levels may be raised in some patients with NETs, especially from foregut origin, and of high grade. The suggested value of CT monitoring during follow-up must be confirmed in further studies.
Vera Tiedje, Saskia Ting, Robert Fred Walter, Thomas Herold, Karl Worm, Julia Badziong, Denise Zwanziger, Kurt Werner Schmid, and Dagmar Führer
Medullary thyroid carcinoma (MTC) occurs sporadically in 75% of patients. Metastatic disease is associated with significantly poorer survival. The aim of this study was to identify prognostic markers for progressive MTC and oncogenic factors associated with response to vandetanib therapy.
Design and methods
Clinical courses of 32 patients with sporadic MTC (n=10 pN0cM0, n=8 pN1cM0, n=14 pN1cM1) were compared with genetic profiles of the patients’ primary tumour tissue. Analysis for RET proto-oncogene mutations was performed by Sanger sequencing and next-generation sequencing (NGS). The mRNA expression (mRNA count) of 33 targets was measured by nCounter NanoString analysis.
Somatic RET mutations occurred in 21/32 patients. The RET918 mutation was found in 8/14 pN1cM1 patients. BRAF (P=0.019), FGFR2 (P=0.007), FGFR3 (P=0.044) and VEGFC (P=0.042) mRNA expression was significantly lower in pN1cM0/pN1cM1 compared with pN0cM0 patients, whereas PDGFRA (P=0.026) mRNA expression was significantly higher in pN1cM0/pN1cM1 when compared with pN0cM0 patients. Among the 10/32 vandetanib-treated patients, 5 showed partial response (PR), all harbouring the RET918 mutation. mRNA expression of FLT1 (P=0.039), FLT4 (P=0.025) and VEGFB (P=0.042) was significantly higher in therapy responders.
In this study, we identified molecular markers in primary tumour tissue of sporadic MTC associated with the development of metastasis (both lymph node and organ metastasis) as well as response to vandetanib therapy.
Cécile Nozières, Thomas Walter, Marie-Odile Joly, Sophie Giraud, Jean-Yves Scoazec, Françoise Borson-Chazot, Chantal Simon, Jean-Paul Riou, and Catherine Lombard-Bohas
Ten percent of paragangliomas are malignant and one-third occurs in a genetic background. We report a case of succinate dehydrogenase subunit B (SDHB)-related malignant paraganglioma with dramatic response to temozolomide and capecitabine regimen (decrease in tumor size of 70% with RECIST criteria). Tumor cells harbored a new mutation in SDHB gene and showed aberrant hypermethylation of O6-methylguanine-DNA-methyltransferase promoter. Our report suggests the importance of molecular predictive factors of response for the selection of chemotherapeutic as well as targeted agents. This observation points to a possible genotype response to treatment relationships, which could help to design tailor-made treatments in the future.
Juliette Maurel, Rosine Guimbaud, Thierry Lecomte, Astrid Lièvre, Vincent Hautefeuille, Philip Robinson, Laurent Francois, Catherine Lombard-Bohas, Julien Forestier, Laurent Milot, Fabien Subtil, and Thomas Walter
Literature on patient-reported outcomes (PRO) of carcinoid syndrome symptoms (CSS) is scarce. We used a patient-reported outcome measure (PROM) to evaluate CSS, the domains of daily life impacted by CSS, the main symptoms that affect daily life, its change according to clinical, biological and morphological evolution, and the risk factors for a poor PRO-CSS score.
Patients completed the PRO-CSS, EORTC-QLQ30, and GI-NET21 questionnaires at the time of their clinical, laboratory, and morphological assessments in a multicentre French cohort study from February 2019 to May 2020.
In total, 147 patients with metastatic ileal (n =126), lung (n =20), or unknown primitive neuroendocrine tumour but high 5-hydroxyindole-3-acetic acid level (n =1) were included; 42 (32%) received an above-label dose of somatostatin analogues. Fifty-one (35%) patients had a poor PRO-CSS score. Travelling and food restriction were the two main domains affected. Diarrhoea (mean: 2.3/5 on Likert scale), imperiousness (mean of 2.5/5), fatigue (2.2/5), abdominal pain (1.7/5), and flushing episodes (1.5/5) were the main symptoms affecting daily life. The PRO-CSS score was not correlated to the clinical assessment performed by physicians at the baseline and during the follow-up. Patients with a poor PRO-CSS score had a higher tumour burden.
PROM-CSS may help physicians make an objective assessment of CSS and its impact in daily practice; this tool could become a key evaluation criterion in clinical trials focusing on CSS.