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Julien Hadoux, Thomas Walter, Christina Kanaan, Ségolène Hescot, Vincent Hautefeuille, Marine Perrier, Igor Tauveron, Sandrine Laboureau, Christine Do Cao, Caroline Petorin, Odile Blanchet, Matthieu Faron, Emmanuelle Leteurtre, Marie-Christine Rousselet, Juliette Joubert Zakeyh, Aude Marchal, Denis Chatelain, Clément Beaulaton, Valérie Hervieu, Catherine Lombard-Bohas, Michel Ducreux, Jean-Yves Scoazec, Eric Baudin, , and

Neuroendocrine carcinomas (NEC) are aggressive malignant diseases. Etoposide-based rechallenge (EBR) and the prognostic role of RB transcriptional corepressor 1 (RB1) status in second-line chemotherapy (2L) have not been studied. The objectives of this study were to report the results of 2L including EBR as well as prognostic factors in a national retrospective multicentre study. NEC patients treated with 2L and further, with tissue samples available, were included. RB1 status and morphological classification were reviewed centrally. Among the 121 NEC patients (40% female, median age 61 years) included, there were 73 small-cell NEC (60%), 34 large-cell NEC (28%) and 14 NEC (not otherwise specified, 12%). Primary sites were lung (39%), gastroenteropancreatic (36%), other (13%) and unknown (12%). Median Ki-67 index was 80%. Median progression-free survival (PFS) and overall survival (OS) under 2L were 2.1 and 6.2 months, respectively. No difference was observed between patients who received an ‘adenocarcinoma-like’ or a ‘neuroendocrine-like’ 2L or according to the RB1 status. Thoracic NEC primary was the only adverse prognostic factor for OS. EBR, administered to 31 patients, resulted in a 62% disease control rate with a median PFS and OS of 3.2 and 11.7 months, respectively. In the 94 patients with a relapse-free interval of ≥3 months after first-line platinum–etoposide chemotherapy, the median OS was 12 months in patients who received EBR as compared to 5.9 months in patients who did not (P = 0.043). EBR could be the best 2L option for patient with initial response to first-line platinum–etoposide lasting at least 3 months. RB1 status does not provide prognostic information in this setting.

Open access

Paul Benjamin Loughrey, Federico Roncaroli, Estelle Healy, Philip Weir, Madhu Basetti, Ruth T Casey, Steven J Hunter, and Márta Korbonits

Pituitary neuroendocrine tumours (PitNETs) associated with paragangliomas or phaeochromocytomas are rare. SDHx variants are estimated to be associated with 0.3–1.8% of PitNETs. Only a few case reports have documented the association with MAX variants. Prolactinomas are the most common PitNETs occurring in patients with SDHx variants, followed by somatotrophinomas, clinically non-functioning tumours and corticotrophinomas. One pituitary carcinoma has been described. SDHC, SDHB and SDHA mutations are inherited in an autosomal dominant fashion and tumorigenesis seems to adhere to Knudson’s two-hit hypothesis. SDHD and SDHAF2 mutations most commonly have paternal inheritance. Immunohistochemistry for SDHB or MAX and loss of heterozygosity analysis can support the assessment of pathogenicity of the variants. Metabolomics is promising in the diagnosis of SDHx-related disease. Future research should aim to further clarify the role of SDHx and MAX variants or other genes in the molecular pathogenesis of PitNETs, including pseudohypoxic and kinase signalling pathways along with elucidating epigenetic mechanisms to predict tumour behaviour.

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David Grahame Hardie

Otto Warburg published the first papers describing what became known as the Warburg effect in 1923. All that was known about glucose metabolism at that time was that it occurred in two stages: (i) fermentation or glycolysis, in which glucose was converted to lactate, which did not require oxygen, and (ii) oxidative metabolism, in which the carbon atoms derived from glycolysis were fully oxidized to carbon dioxide, which did require oxygen. Warburg discovered that most tumour tissues produced a large amount of lactate that was reduced but not eliminated in the presence of oxygen, while most normal tissues produced a much smaller amount of lactate that was eliminated by provision of oxygen. These findings were clearly well ahead of their time because it was another 80 years before they were to have any major impact, and even today the mechanisms underlying the Warburg effect are not completely understood.

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Tae Hwan Kim, Mi Yeon Lee, Sung Min Jin, and Sang Hyuk Lee

The impact of serum thyroid hormone levels on thyroid cancer risk is unclear. Some studies reported elevated TSH (thyroid stimulating hormone) is associated with higher risk for incidence of thyroid cancer, but other studies reported no relationship. We conducted a large cohort study in 164,596 South Korea men and women who were free of thyroid cancer at baseline and underwent health examination with hormone levels of thyroid function. A parametric proportional hazard model was used to evaluate the adjusted hazard ratio (HR) and 95% confidence interval (CI). During 2,277,749.78 person-years of follow-up, 1280 incident thyroid cancers were identified (men=593, women=687). Among men, the multivariable-adjusted HR (95% CI) for thyroid cancer comparing low levels of TSH with normal levels of TSH was 2.95 (1.67-5.23) whereases the corresponding HR (95% CI) in women was 1.5 (0.88-2.55). High levels of free T4 and free T3 were also associated with incident thyroid cancer in both men and women. In clinical implication, over hyperthyroidism is associated with thyroid cancer both in men and women. Within the euthyroid range, the highest tertile of TSH was associated with a lower risk of thyroid cancer than lowest TSH tertile and highest FT4 tertile was associated with a higher risk of thyroid cancer than the lowest FT4 tertile both in men and women. Our finding indicates that low levels of TSH and high levels of FT4, even with in the normal range, were associated with an increased risk of incident thyroid cancer.

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Jacob A Quaytman, Yuri E Nikiforov, Marina N Nikiforova, and Elena Morariu

The incidence of cancer in thyroid nodules carrying germline or somatic phosphatase and tensin homolog (PTEN) mutations is not well-defined. This study characterizes the clinical and histopathologic features of thyroid nodules with preoperatively detected PTEN mutations and their impact on management. Thyroid nodules with PTEN mutations on molecular testing of fine-needle aspiration (FNA) specimens from November 2017 to July 2020 at our institution were included. Demographic and clinicopathologic data were obtained through retrospective chart review. We identified 49 PTEN mutation-positive nodules from 48 patients. Surveillance was pursued for 28 patients and surgery for 20 patients. There were 14 follicular adenomas (FA), 4 oncocytic adenomas, 1 oncocytic hyperplastic nodule, and 1 encapsulated follicular variant papillary thyroid carcinoma (EFVPTC). The EFVPTC had two somatic PTEN mutations, an NRAS mutation, and was a low-risk tumor with capsular but no angiolymphatic invasion. Four patients, all with multiple nodules, had PTEN hamartoma syndrome (PHTS) with germline mutations or a clinical diagnosis of Cowden syndrome (CS); two had surgery finding FAs, and one previously had follicular carcinoma removed. Among surveillance patients, 1/20 had a significant increase in the size of the thyroid nodule and underwent repeat FNA, and no thyroid malignancy was found with a mean of 1.77 years of follow-up (range 1.00–2.78). Thyroid nodules with isolated somatic PTEN mutations are primarily benign and unlikely to grow at a high rate, at least on short-term follow-up. About 8% of patients with PTEN mutations may have PHTS or CS, which should be suspected in younger patients with multiple thyroid nodules.

Free access

Manuel D Gahete, Natalia Herman-Sanchez, Antonio C Fuentes-Fayos, Juan L Lopez-Canovas, and Raúl M Luque

The dysregulation of the splicing process has emerged as a novel hallmark of metabolic and tumor pathologies. In breast cancer (BCa), which represents the most diagnosed cancer type among women worldwide, the generation and/or dysregulation of several oncogenic splicing variants have been described. This is the case of the splicing variants of HER2, ER, BRCA1, or the recently identified by our group, In1-ghrelin and SST5TMD4, which exhibit oncogenic roles, increasing the malignancy, poor prognosis, and resistance to treatment of BCa. This altered expression of oncogenic splicing variants has been closely linked with the dysregulation of the elements belonging to the macromolecular machinery that controls the splicing process (spliceosome components and the associated splicing factors). In this review, we compile the current knowledge demonstrating the altered expression of splicing variants and spliceosomal components in BCa, showing the existence of a growing body of evidence supporting the close implication of the alteration in the splicing process in mammary tumorigenesis.

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Thomas Yang Sun, Lan Zhao, Paul Van Hummelen, Brock Martin, Kathleen Hornbacker, HoJoon Lee, Li C. Xia, Sukhmani K. Padda, Hanlee P. Ji, and Pamela Kunz

High grade (grade 3) neuroendocrine neoplasms (G3 NENs) have poor survival outcomes. From a clinical standpoint, G3 NENs are usually grouped regardless of primary site and treated similarly. Little is known regarding the underlying genomics of these rare tumors, especially when compared across different primary sites. We performed whole transcriptome (n = 46), whole exome (n = 40) and gene copy number (n = 43) sequencing on G3 NEN FFPE samples from diverse organs (in total 17 were lung, 16 were gastroenteropancreatic, 13 other). G3 NENs despite arising from diverse primary sites did not have gene expression profiles that were easily segregated by organ of origin. Across all G3 NENs, TP53, APC, RB1 and CDKN2A were significantly mutated. The CDK4/6 cell cycling pathway was mutated in 95% of cases, with upregulation of oncogenes within this pathway. G3 NENs had high tumor mutation burden (mean 7.09 mutations/MB), with 20% having >10 mutations/MB. Two somatic copy number alterations were significantly associated with worse prognosis across tissue types: focal deletion 22q13.31 (HR, 7.82; p = 0.034) and arm amplification 19q (HR, 4.82; p = 0.032). This study is among the most diverse genomic study of high-grade neuroendocrine neoplasms. We uncovered genomic features previously unrecognized for this rapidly fatal and rare cancer type that could have potential prognostic and therapeutic implications.

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Marta Araujo-Castro, César Mínguez Ojeda, Rogelio Garcia Centeno, María-Carmen López-García, Cristina Lamas, Felicia Alexandra Hanzu, Mireia Mora, María del Castillo Tous, Pablo Rodríguez de Vera Gómez, Paola Parra Ramírez, Cristina Alvarez-Escola, Concepción Blanco Carrera, Rebeca Barahona San Millán, Monica Recasens, Nuria Valdés, Paola Gracia Gimeno, Paz de Miguel Novoa, Almudena Vicente, Laura Manjón, Iñigo García Sanz, Theodora Michalopoulou, and María Calatayud

The objective of our study was to determine de prevalence of glycemic disorders (diabetes mellitus and prediabetes) in patients with pheochromocytomas and sympathetic paragangliomas (PPGLs) and identify risk factors for their development and the likelihood of their resolution after surgery. A multicentric retrospective study of patients with PPGLs submitted to surgery between 2000-2021 in seventeen Spanish hospitals was performed. Diabetes-specific data were collected at diagnosis, in the immediate and long-term postsurgical follow-up. A total of 229 patients with PPGLs were included (218 with pheochromocytomas and 11 with sympathetic paragangliomas). Before surgery, glycemic disorders were diagnosed in 35.4% of the patients (n=81): 54 with diabetes and 27 with prediabetes. The variables independently associated with a higher risk of glycemic disorders were sporadic PPGL (OR=3.26 [1.14-9.36]) and hypertension (OR=3.14 [1.09-9.01]). A significant decrease in fasting plasma glucose and HbA1c levels was observed after surgery, in the short-term and long-term follow up (P<0.001). After a median follow-up of 48.5 months [range 3.3 to 168.9], after surgery, 52% of diabetic and 68% of prediabetic patients experienced a complete resolution. Lower BMI (P=0.001), lower glucose levels (P=0.047) and shorter duration of diabetes prior to surgery (P=0.021) were associated with a higher probability of diabetes resolution. In conclusion, glycemic disorders in patients with PPGLs are present in more than a third of them at diagnosis. Sporadic PPGL and hypertension are risk factors for their development. More than 50% of the cases experienced a complete resolution of the glycemic disorder after the resection of the PPGL.

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Michaela Kuhlen, Pascal Mier, Marina Kunstreich, Lienhard Lessel, Dominik Schneider, Ines Brecht, Denis M Schewe, Michael C Frühwald, Peter Vorwerk, and Antje Redlich

Adjuvant treatment with mitotane and chemotherapy is recommended for paediatric advanced and metastatic adrenocortical carcinoma (ACC). Yet, questions on the indication, dosage, and length of therapy are unanswered. Data from the German Paediatric Oncology Haematology-Malignant Endocrine Tumour studies were analysed retrospectively for patients receiving mitotane during first- and/or second-line therapy. Forty-three patients were identified (median age: 7.5 years (range: 0.2–17.8); 29 female) with median follow-up of 2.2 years (range: 0.04–12.71). Three-year overall (OS) and progression-free survival (PFS) were 44.9% and 28.5%, respectively. Eleven of 43 patients received mitotane as neoadjuvant treatment, and 4/11 tumours reached partial remission (PR). Twenty-seven of 43 patients received mitotane combined with chemotherapy in an adjuvant setting resulting in PR of measurable target lesions in 5/13 patients. Metastatic disease (hazard ratio (HR): 3.2; 95% CI: 1.2–18.6; P = 0.018), duration of mitotane treatment <9 months (HR: 5.6; 95% CI: 1.9–16.9; P = 0.002), and not achieving drug target range (TR) (HR: 28.5; 95% CI: 5.4–150.3; P < 0.001) significantly impacted as negative prognostic factors upon PFS and OS (metastatic disease: HR: 4.9; 95% CI: 1.6–15.5; P = 0.006; duration of mitotane treatment: HR: 7.0: 95% CI 1.9–26.0; P = 0.004; TR not reached: HR: 13.5; 95% CI 3.6–50.3; P < 0.001). Cox regression determined the risk of event decreasing by 10.4% for each month of mitotane treatment (P = 0.015). Re-treatment with mitotane after first-line treatment proved ineffective. The duration of mitotane treatment and reaching mitotane TR significantly impacted survival. Improving the efficacy of mitotane, including appropriate indications, needs to be evaluated in prospective randomized trials.

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Luming Wu, Jing Xie, Yan Qi, Tingwei Su, Lei Jiang, Weiwei Zhou, Yiran Jiang, Cui Zhang, Xu Zhong, Yanan Cao, and Weiqing Wang

Adrenal incidentalomas are the most frequent human neoplasms. Recent genomic investigations on functional adrenocortical tumors have demonstrated that somatic mutations in PRKACA and KCNJ5 responsible for the development of adrenocortical adenomas (ACAs) are associated with hypercortisolism and aldosteronism, respectively. Several studies have identified CTNNB1 mutations in ACAs and have been mostly involved in the tumorigenesis of non-functional ACA (NFACA). However, integrated genomic characterization of NFACAs is lacking. In the current study, we utilized pan-genomic methods to comprehensively analyze 60 NFACA samples. A total of 1264 somatic mutations in coding regions among the 60 samples were identified, with a median of 15 non-silent mutations per tumor. Twenty-two NFACAs (36.67%) had genetic alterations in CTNNB1. We also identified several somatic mutations in genes of the cAMP/PKA pathway and KCNJ5. Histone modification genes (KMT2A, KMT2C, and KMT2D) were altered in 10% of cases. Germline mutations of MEN1 and RET were also found. Finally, by comparison of our transcriptome data with those available in the TCGA, we illustrated the molecular characterization of NFACA. We revealed the genetic profiling and molecular landscape of NFACA. Wnt/β-catenin pathway activation as shown ssby nuclear and/or cytoplasmic β-catenin accumulation is frequent, occurring in about one–third of ACA cases. cytochrome P450 enzymes could be markers to reveal the functional status of adrenocortical tumors. These observations strongly suggest the involvement of the Wnt/β-catenin pathway in benign adrenal tumorigenesis and possibly in the regulation of steroid secretion.