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Open access

Nassim Ghaffari-Tabrizi-Wizsy, Christina Angelika Passegger, Laura Nebel, Fabian Krismer, Gudrun Herzer-Schneidhofer, Gert Schwach, and Roswitha Pfragner

Preclinical trials of medullary thyroid cancer (MTC) therapeutics require both in vitro and in vivo analyses. Human tumour xenografted rodent models, which are considered the ‘gold standard’ to study and validate the efficacy and toxicity of lead compounds before translation to clinical trials, are very expensive, subject to organismal variability and ethical controversies. The avian chorioallantoic membrane (CAM) assay provides an alternative versatile, cost-effective and ethically less objectionable short-term, in vivo model for reliable screening of drugs. In this work, we grafted two MTC cell lines and patient-derived MTC tumour samples onto the avian CAM and characterised the resulted tumours histologically and immunohistochemically. Our findings provide the evidence that the CAM assay is a suitable model for studying the pathophysiology of MTC and can even be used as in vivo system for drug testing.

Open access

Irasema Mendieta, Rosa Elvira Nuñez-Anita, Gilberto Pérez-Sánchez, Lenin Pavón, Alfredo Rodríguez-Cruz, Guadalupe García-Alcocer, and Laura Cristina Berumen

The present study was designed to determine the effects of factors secreted by the lung adenocarcinoma cell line with the neuroendocrine phenotype, A549NED, on cytotoxic T lymphocytes (CTLs) activity in vitro. A perspective that integrates the nervous, endocrine and immune system in cancer research is essential to understand the complexity of dynamic interactions in tumours. Extensive clinical research suggests that neuroendocrine differentiation (NED) is correlated with worse patient outcomes; however, little is known regarding the effects of neuroendocrine factors on the communication between the immune system and neoplastic cells. The human lung cancer cell line A549 was induced to NED (A549NED) using cAMP-elevating agents. The A549NED cells showed changes in cell morphology, an inhibition of proliferation, an overexpression of chromogranin and a differential pattern of biogenic amine production (decreased dopamine and increased serotonin [5-HT] levels). Using co-cultures to determine the cytolytic CTLs activity on target cells, we showed that the acquisition of NED inhibits the decrease in the viability of the target cells and release of fluorescence. Additionally, the conditioned medium of A549NED and 5-HT considerably decreased the viability and proliferation of the Jurkat cells after 24 h. Thus, our study successfully generated a neuroendocrine phenotype from the A549 cell line. In co-cultures with CTLs, the pattern of secretion by A549NED impaired the proliferation and cytotoxic activity of CTLs, which might be partly explained by the increased release of 5-HT.

Open access

Natalie Rogowski-Lehmann, Aikaterini Geroula, Aleksander Prejbisz, Henri J L M Timmers, Felix Megerle, Mercedes Robledo, Martin Fassnacht, Stephanie M J Fliedner, Martin Reincke, Anthony Stell, Andrzej Januszewicz, Jacques W M Lenders, Graeme Eisenhofer, and Felix Beuschlein

Background

Pheochromocytomas and paragangliomas (PPGLs) are rare but potentially harmful tumors that can vary in their clinical presentation. Tumors may be found due to signs and symptoms, as part of a hereditary syndrome or following an imaging procedure.

Objective

To investigate potential differences in clinical presentation between PPGLs discovered by imaging (iPPGLs), symptomatic cases (sPPGLs) and those diagnosed during follow-up because of earlier disease/known hereditary mutations (fPPGL).

Design

Prospective study protocol, which has enrolled patients from six European centers with confirmed PPGLs. Data were analyzed from 235 patients (37 iPPGLs, 36 sPPGLs, 27% fPPGLs) and compared for tumor volume, biochemical profile, mutation status, presence of metastases and self-reported symptoms. iPPGL patients were diagnosed at a significantly higher age than fPPGLs (P < 0.001), found to have larger tumors (P = 0.003) and higher metanephrine and normetanephrine levels at diagnosis (P = 0.021). Significantly lower than in sPPGL, there was a relevant number of self-reported symptoms in iPPGL (2.9 vs 4.3 symptoms, P < 0.001). In 16.2% of iPPGL, mutations in susceptibility genes were detected, although this proportion was lower than that in fPPGL (60.9%) and sPPGL (21.5%). Patients with PPGLs detected by imaging were older, have higher tumor volume and more excessive hormonal secretion in comparison to those found as part of a surveillance program. Presence of typical symptoms indicates that in a relevant proportion of those patients, the PPGL diagnosis had been delayed.

Précis

Pheochromocytoma/paraganglioma discovered by imaging are often symptomatic and carry a significant proportion of germline mutations in susceptibility genes.

Open access

Jean-Benoît Corcuff, Laurence Chardon, Ines El Hajji Ridah, and Julie Brossaud

Context

Biogenic amines such as 5-hydroxy-indole acetic acid (5HIAA) the main metabolite of serotonin or metanephrines (catecholamines metabolites) are used as biomarkers of neuroendocrine tumours.

Objective

To re-evaluate the recommendations for urinary sampling (preservatives, diet, drugs, etc.) as many of the reported analytical interferences supporting these recommendations are related to obsolete assays.

Methods

Bibliographic analysis of old and modern assays concerning preservation, extraction, assay and interferences.

Results

5HIAA may degrade as soon as urine is excreted. Thus, acids as preservatives (hydrochloric or acetic acid) have to be immediately added. Care should be taken not to decrease the pH under 2. Urine preservative for metanephrine assays is not mandatory. Diets including serotonin-, tryptophan- and dopamine-rich foods have to be avoided depending on the biomarkers investigated (bananas, plantain, nuts, etc.). Tryptophan-rich over-the-counter formulas have to be prohibited when 5HIAA has to be assayed. Acetaminophen may interfere with electrochemical detection depending on high-pressure liquid chromatography (HPLC) parameters. No interference is known with mass spectrometric assays but with the one described for metanephrines determination. Some drugs interfere however with serotonin and catecholamines secretion and/or metabolism (monoamine oxidase inhibitors, serotonin or dopamine recapture inhibitors, etc.).

Conclusion

Revisited recommendations are provided for the diet, the drugs and the preservatives before HPLC coupled with electrochemical and mass spectrometry assays.

Open access

Anne M Drewes, Maria E Møller, Rasmus Hertzum-Larsen, Gerda Engholm, and Hans H Storm

Introduction

Cancer registry data in the USA indicated that women diagnosed with breast cancer before the age of 40 were at increased risk of a new primary tumour within the brain and women aged 50 years or above were at lower risk than expected. Our aim was to investigate if similar results could be found in Danish population-based data, considering an explanatory role of hormonal status.

Methods

Our study cohort included all women diagnosed with breast cancer below the age of 60 between 1978 and 2013 in Denmark. A total of 47,920 women were followed up in the Danish Cancer Registry for primary brain cancer. Standardized incidence ratios (observed/expected cases (O/E)) were used to estimate the risk of getting a primary brain tumour in the breast cancer cohort.

Results

Data indicated an increased tendency of brain cancer following breast cancer at ages below 60 years (O/E = 1.24). For premenopausal women (age <49 at the diagnosis of breast cancer) the O/E was 1.25. Stratifying by time of breast cancer diagnosis, we observed an increased risk of being diagnosed with a brain tumour among women aged 49 years or younger at breast cancer diagnosis between 2004 and 2013.

Conclusion

The results indicate an increased tendency of developing a primary brain tumour in women with previous breast cancer history. Whereas the finding in premenopausal women is in line with the SEER data, the finding among postmenopausal is not. Primary brain tumours in breast cancer patients call for research in genetics and hormones to establish common risk factors.

Open access

Liza Das, Kim Vaiphei, Ashutosh Rai, Chirag Kamal Ahuja, Paramjeet Singh, Ishani Mohapatra, Rajesh Chhabra, Anil Bhansali, Bishan Dass Radotra, Ashley B Grossman, Márta Korbonits, and Pinaki Dutta

Objective

Posterior pituitary tumours (PPTs) are rare neoplasms with the four recognised subtypes unified by thyroid transcription factor -1 (TTF-1) expression, according to the 2017 WHO classification. Though traditionally defined as low-grade neoplasms, a substantial proportion of them show recurrence/persistence following surgery.

Methods

We selected patients with PPTs in our cohort of 1760 patients operated for pituitary tumours over the past 10 years (2010–2019). The clinical, radiological, hormonal, histopathological profiles and long-term outcomes of the three cases identified (two pituicytomas and one spindle cell oncocytoma, SCO) were analysed. Following a literature review, data of all published cases with documented TTF-1 positive pituicytomas and SCOs were analysed to determine the predictors of recurrence/persistence in these tumours.

Results

Patients presented with compressive features or hypogonadism. Two had sellar-suprasellar masses. One had a purely suprasellar mass with a pre-operative radiological suspicion of pituicytoma. Two were operated by transsphenoidal surgery and one transcranially guided by neuronavigation. Histopathology confirmed spindle cells in a storiform arrangement and low Ki67 index. Immunohistochemistry showed positive TTF-1, S-100 expression and variable positivity for EMA, vimentin and GFAP. Re-evaluation showed recurrence/persistence in two patients. A literature review of recurrent/persistent pituicytoma (n = 17) and SCO (n = 9) cases revealed clinical clues (headache for pituicytomas, male gender for SCO), baseline tumour size (≥20.5 mm with sensitivity exceeding 80%) and longer follow-up duration as determinants of recurrence/persistence.

Conclusion

PPTs are rare sellar masses with quintessential TTF-1 positivity. Recurrent/persistent disease following surgery is determined by greater tumour size at baseline and duration of follow-up. This warrants intensive and long-term surveillance in these patients.

Open access

Sanjeet Kumar Jaiswal, Vijaya Sarathi, Saba Samad Memon, Robin Garg, Gaurav Malhotra, Priyanka Verma, Ravikumar Shah, Manjeet Kaur Sehemby, Virendra A Patil, Swati Jadhav, Anurag Ranjan Lila, Nalini S Shah, and Tushar R Bandgar

Introduction:

177Lu-DOTATATE-based peptide receptor radionuclide therapy (PRRT) is a promising therapy for metastatic and/or inoperable pheochromocytoma and paraganglioma (PPGL). We aim to evaluate the efficacy and safety of and identify predictors of response to 177Lu-DOTATATE therapy in metastatic and/or inoperable PPGL.

Methods:

This retrospective study involved 15 patients of metastatic or unresectable PPGL, who received 177Lu-DOTATATE PRRT therapy. Clinical, biochemical (plasma-free normetanephrine), and radiological (anatomical and functional) responses were compared before and after the last therapy.

Results:

A total of 15 patients (4 PCC, 4 sPGL, 5 HNPGL, 1 PCC + sPGL, 1 HNPGL + sPGL) were included. The median duration of follow up was 27 (range: 11–62) months from the start of PRRT. Based on the RECIST (1.1) criteria, progressive disease was seen in three (20%), stable disease in eight (53%), partial response in one (7%), and minor response in three (20%) and controlled disease in 12 (80%). On linear regression analysis the presence of PGL (P= 0.044) and baseline SUVmax >21 (P < 0.0001) were significant positive predictors of early response to PRRT. Encouraging safety profiles were noted with no long term nephrotoxicity and hematotoxicity.

Conclusion:

177Lu-DOTATATE therapy is an effective and safe modality of treatment for patients with metastatic/inoperable PPGL. Although it is not prudent to withhold PRRT in metastatic PPGL with baseline SUVmax < 21, baseline SUVmax >21 can be used to predict early response to PRRT.

Open access

Mahmoud Al-Masri, Tawfiq Al-Shobaki, Hani Al-Najjar, Rafal Iskanderian, Enas Younis, Niveen Abdallah, Abdelghani Tbakhi, Hussam Haddad, Mohammad Al-Masri, Zeinab Obeid, and Awad Jarrar

Purpose

This study focuses on the oncologic influence of BRAF V600E mutations in a cohort of Middle Eastern papillary thyroid carcinoma (PTC) patients treated at a single centre. We tested the association of BRAF V600E mutation with papillary thyroid carcinoma at King Hussein Cancer Center.

Methods

Patients with histologically confirmed PTC who underwent surgical treatment between 2006 and 2015 were included in this study. Oncological outcomes, both short- and long-termed, were collected.

Results

A total of 128 patients (68% females) were included in this study with a mean age of 38 years (±13.8). The median follow-up period was 50 months. The BRAF V600E mutation was found in 71% of patients. The tumour size for patients with a negative BRAF V600E mutation was significantly larger in comparison to patients who tested positive for the mutation (3.47 cm vs 2.31 cm, respectively, P = 0.009). The two groups showed similar disease-free survival (DFS) rates; positive = 75% (median 43 months (0–168)) compared to 78% for the negative BRAF V600E mutation (median 38 months (3–142)) (P = 0.162, HR = 0.731) Furthermore, both groups showed similar overall survival rates, positive = 94.5% (median 56 months (0–228)) compared to 94.6% for the negative BRAF V600E mutation (median 43 months (3–157)) (P = 0.941, HR = 0.940).

Conclusion

BRAF V600E mutation had no effect on loco-regional recurrence, distant metastasis, overall survival, or DFS. These findings may be attributed to geographic variations or reflect that BRAF V600E may only serve as an indicator of poor prognosis in high-risk group as such.

Open access

Manon Engels, Paul N Span, Rod T Mitchell, Joop J T M Heuvel, Monica A Marijnissen-van Zanten, Antonius E van Herwaarden, Christina A Hulsbergen-van de Kaa, Egbert Oosterwijk, Nike M Stikkelbroeck, Lee B Smith, Fred C G J Sweep, and Hedi L Claahsen-van der Grinten

Testicular adrenal rest tumours (TARTs) are benign adrenal-like testicular tumours that frequently occur in male patients with congenital adrenal hyperplasia. Recently, GATA transcription factors have been linked to the development of TARTs in mice. The aim of our study was to determine GATA expression in human TARTs and other steroidogenic tissues. We determined GATA expression in TARTs (n = 16), Leydig cell tumours (LCTs; n = 7), adrenal (foetal (n = 6) + adult (n = 10)) and testis (foetal (n = 13) + adult (n = 8)). We found testis-like GATA4, and adrenal-like GATA3 and GATA6 gene expressions by qPCR in human TARTs, indicating mixed testicular and adrenal characteristics of TARTs. Currently, no marker is available to discriminate TARTs from LCTs, leading to misdiagnosis and incorrect treatment. GATA3 and GATA6 mRNAs exhibited excellent discriminative power (area under the curve of 0.908 and 0.816, respectively), while immunohistochemistry did not. GATA genes contain several CREB-binding sites and incubation with 0.1 mM dibutyryl cAMP for 4 h stimulated GATA3, GATA4 and GATA6 expressions in a human foetal testis cell line (hs181.tes). Incubation of adrenocortical cells (H295RA) with ACTH, however, did not induce GATA expression in vitro. Although ACTH did not dysregulate GATA expression in the only human ACTH-sensitive in vitro model available, our results do suggest that aberrant expression of GATA transcription factors in human TARTs might be involved in TART formation.

Open access

Xinlei Chen, Liru Hu, Caojie Liu, Guangcheng Ni, and Yuwei Zhang

Objective

The proportion of incidentally discovered pheochromocytomas and paragangliomas (PPGL) has increased over time. However, our knowledge of them is quite limited. The purpose of this retrospective study is to generalize the commonalities in incidentally discovered PPGL, offer evidence for clinical diagnosis and management.

Methods

Five hundred twenty-six patients were included in our study after filtration from the database of West China Hospital of Sichuan University between May, 2007 and December, 2016. Among the patients, 148 of them were incidental findings and 378 of them were suspected findings. All patients’ demography and tumor characteristics were recorded in detail, especially hemodynamic records and hormonal assays. The reasons for taking radiography were also collected. Most patients received preoperative medical preparation. Intraoperative and postoperative courses as well as surgical outcomes were also analyzed to identify differences between incidental findings and suspected findings.

Results

Incidentally discovered PPGL took up 28.1% of the study population. Suspected PPGLs had a higher prevalence of hypertension, lower proportion of non-functioning PPGL, higher prevalence of MEN2 and better post-surgical blood pressure recovery than incidental finding group. However, patients in the incidental finding group showed no significant difference in preoperative blood pressure and hormonal assays with suspected findings in metaphrine and normetaphrine in plasma and urine (P > 0.05).

Conclusions

Due to the development of technology, more PPGLs are discovered incidentally. Considering the tumor characteristics and surgical outcome, surgical decisions should be made more cautiously.