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Department of Oncology, Ryhov County Hospital, Jönköping, Sweden
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University of Bergen, Deptartment of Clinical Medicine, Bergen, Norway
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Department of Surgery, Ryhov County Hospital, Jönköping, Sweden
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Small intestinal neuroendocrine tumours (Si-NET) are often studied as a uniform group. Proliferation index Ki-67 influences prognosis and determines tumour grade. We hypothesized that Si-NET grade 2 (G2) tumours, which have a higher Ki-67 than G1 tumours, might benefit less from established treatments for metastatic disease. We conducted a retrospective cohort study of 212 patients with metastatic Si-NET G2 treated in two Swedish hospitals during 20 years (2000–2019). Median cancer-specific survival on first-line somatostatin analogues (SSA) was 77 months. Median progression-free survival (PFS) was 12.4 months when SSA was given as monotherapy and 19 months for all patients receiving first-line SSA. PFS after SSA dose escalation was 6 months in patients with radiological progression. Treatment efficacies of SSA and peptide receptor radionuclide treatment (PRRT) were studied separately in patients with Ki-67 of 3–5%, 5–10% and 10–20%. For SSA, PFS was significantly shorter at higher Ki-67 levels (31, 18 and 10 months, respectively), while there was only a minor difference in PFS for PRRT (29, 25 and 25 months). Median PFS for sequential treatment with interferon-alpha (IFNα), everolimus and chemotherapy was 6, 5 and 9 months. IFNα seemed to be effective in tumours with low somatostatin–receptor expression. In conclusion, established treatments appeared effective in Si-NET G2, despite their higher proliferation index compared to G1 tumours. However, efficacy of SSA but not PRRT was reduced at higher Ki-67 levels. SSA dose escalation provided limited disease stabilization.
Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden
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Endocrine Oncology Site, Princess Margaret Cancer Centre, Toronto, ON, Canada
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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The fifth edition of the Classification of Endocrine and Neuroendocrine Tumors has been released by the World Health Organization. This timely publication integrates several changes to the nomenclature of non-neoplastic and neoplastic thyroid diseases, as well as novel concepts that are essential for patient management. The heterogeneous group of non-neoplastic and benign neoplastic lesions are now collectively termed as ‘thyroid follicular nodular disease’ to better reflect the clonal and non-clonal proliferations that clinically present as multinodular goiter. Thyroid neoplasms originating from follicular cells are distinctly divided into benign, low-risk and malignant neoplasms. The new classification scheme stresses that papillary thyroid carcinoma (PTC) should be subtyped based on histomorphologic features irrespective of tumor size to avoid treating all sub-centimeter/small lesions as low-risk disease. Formerly known as the cribriform-morular variant of PTC is redefined as cribriform-morular thyroid carcinoma since this tumor is now considered a distinct malignant thyroid neoplasm of uncertain histogenesis. The ‘differentiated high-grade thyroid carcinoma’ is a new diagnostic category including PTCs, follicular thyroid carcinomas and oncocytic carcinomas with high-grade features associated with poorer prognosis similar to the traditionally defined poorly differentiated thyroid carcinoma as per Turin criteria. In addition, squamous cell carcinoma of the thyroid is now considered a morphologic pattern/subtype of anaplastic thyroid carcinoma. In this review, we will highlight the key changes in the newly devised fifth edition of the WHO classification scheme of thyroid tumors with reflections on its applicability in patient management and future directions in this field.
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The objective of this study is to present the complete biomarker response dataset from a pivotal trial evaluating the efficacy and safety of high-specific-activity I-131 meta-iodobenzylguanidine in patients with advanced pheochromocytoma or paraganglioma. Biomarker status was assessed and post-treatment responses were analyzed for catecholamines, metanephrines, and serum chromogranin A. Complete biomarker response (normalization) or partial response, defined as at least 50% reduction from baseline if above the normal range, was evaluated at specified time points over a 12-month period. These results were correlated with two other study objectives: blood pressure control and objective tumor response as per RECIST 1.0. In this open-label, single-arm study, 68 patients received at least one therapeutic dose (~18.5 GBq (~500 mCi)) of high-specific-activity I-131 meta-iodobenzylguanidine. Of the patients, 79% and 72% had tumors associated with elevated total plasma free metanephrines and serum chromogranin A levels, respectively. Best overall biomarker responses (complete or partial response) for total plasma free metanephrines and chromogranin A were observed in 69% (37/54) and 80% (39/49) of patients, respectively. The best response for individual biomarkers was observed 6–12 months following the first administration of high-specific-activity I-131 meta-iodobenzylguanidine. Biochemical tumor marker response was significantly associated with both reduction in antihypertensive medication use (correlation coefficient 0.35; P = 0.006) as well as objective tumor response (correlation coefficient 0.36; P = 0.007). Treatment with high-specific-activity I-131 meta-iodobenzylguanidine resulted in long-lasting biomarker responses in patients with advanced pheochromocytoma or paraganglioma that correlated with blood pressure control and objective response rate. ClinicalTrials.gov number: NCT00874614.
Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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In a previous systematic review and meta-analysis of studies reporting associations between hyper-/hypothyroidism and breast cancer incidence published through 29 January 2019, we identified a higher risk with diagnosed hyperthyroidism compared to euthyroidism, but no association with diagnosed hypothyroidism. This 2-year updated meta-analysis aims to investigate the role of menopause in this association and the dose–response relationship with blood levels of thyroid-stimulating hormone (TSH) and thyroid hormones. After the exclusion of studies with only mortality follow-up, with thyroid dysfunction evaluated as a cancer biomarker or after prior breast cancer diagnosis, we reviewed 25 studies that were published up to 01 December 2021 and identified in MEDLINE, the COCHRANE library, Embase, or Web of Science; of these, 9 were included in the previous meta-analysis. Risk estimates from 22 of the 25 studies were included in the meta-analysis and pooled using random-effects models. Compared to euthyroidism, hyperthyroidism and hypothyroidism diagnoses were associated with higher (pooled risk ratio (RR): 1.12, 95% CI: 1.06–1.18, 3829 exposed cases) and lower risks (RR = 0.93, 95% CI: 0.86–1.00, 5632 exposed cases) of breast cancer, respectively. The increased risk after hyperthyroidism was greater among postmenopausal women (RR = 1.19, 95% CI 1.09–1.30) and the decreased risk after hypothyroidism was more pronounced among premenopausal women (RR = 0.69, 95% CI 0.53–0.89). Among women with no prior history of thyroid disease, every 1 mIU/L increase in TSH level was associated with a 0.8% (95% CI > 0–1.5%) lower risk of breast cancer. In conclusion, this meta-analysis supports an association between thyroid hormone levels and breast cancer risk, which could be modified by menopausal status.
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It has long been recognised that cancer cells critically depend on reprogrammed patterns of metabolism that can enable robust and abnormally high levels of cell proliferation. As mitochondria form hubs of cellular metabolic activity, it is reasonable to propose that pathways within these organelles can form targets that can be manipulated to compromise the ability of cancer cells to cause disease. However, mitochondria are highly multi-functional, and the full range of mechanistic inter-connections are still being unravelled to enable the full potential of targeting mitochondria in cancer therapeutics. Here, we aim to highlight the potential of modulating mitochondrial dynamics to target key metabolic or apoptotic pathways in cancer cells. Distinct roles have been demonstrated for mitochondrial fission and fusion in different cancer contexts. Targeting of factors mediating mitochondrial dynamics may be directly related to impairment of oxidative phosphorylation, which is essential to sustain cancer cell growth and can also alter sensitivity to chemotherapeutic compounds. This area is still lacking a unified model, although further investigation will more comprehensively map the underlying molecular mechanisms to enable better rational therapeutic strategies based on these pathways.
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Clinical Genomics Linköping, Linköping University, Linköping, Sweden
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Department of Surgery, Linköping University, Linköping, Sweden
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Mitochondrial DNA (mtDNA) alterations have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is little information about its involvement in pheochromocytomas and paragangliomas (PCCs/PGLs) formation. PCCs and PGLs are rare endocrine tumors of the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia that can synthesize and secrete catecholamines. Over the last 3 decades, the genetic background of about 60% of PCCs/PGLs involving nuclear DNA alterations has been determined. Recently, a study showed that mitochondrial alterations can be found in around 17% of the remaining PCCs/PGLs. In this review, we summarize recent knowledge regarding both nuclear and mitochondrial alterations and their involvement in PCCs/PGLs. We also provide brief insights into the genetics and the molecular pathways associated with PCCs/PGLs and potential therapeutical targets.
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Otto Warburg published the first paper 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 (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 the 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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Foundation for the Finnish Cancer Institute, Helsinki, Finland
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Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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Fimlab Laboratories Ltd, Tampere, Finland
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Prostate cancer research suffers from the lack of suitable models to study the role of normal cells in prostate carcinogenesis. To address this challenge, we developed a cell line model mimicking luminal prostate epithelial cells by modifying the immortalized prostate epithelial cell line RWPE-1 to constitutively express the androgen receptor (AR). RWPE-1-AR cells express known AR target genes, and exhibit coexpression of luminal and basal markers characteristic of transient amplifying cells, and an RNA signature resembling prostate luminal progenitor cells. Under unstimulated conditions, constitutive AR expression does not have a biologically significant effect on the proliferation of RWPE-1 cells, but when stimulated by androgens, growth is retarded. The transcriptional response of RWPE-1-AR cells to androgen stimulation involves suppression of the growth-related KRAS pathway and is thus markedly different from that of the prostate cancer cell line LNCaP and its derivative AR-overexpressing LNCaP-ARhi cells, in which growth- and cancer-related pathways are upregulated. Hence, the nonmalignant AR-positive RWPE-1-AR cell line model could be used to study the transformation of the prostate epithelium.
Ipatimup – Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
ICBAS – Instituto de Ciências Biomédicas Abel Salazar da Universidade do Porto, Porto, Portugal
FMUP – Faculdade de Medicina da Universidade do Porto, Porto, Portugal
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Ipatimup – Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
FMUP – Faculdade de Medicina da Universidade do Porto, Porto, Portugal
Department of Pathology, Centro Hospitalar e Universitário de São João, Porto, Portugal
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Ipatimup – Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
FMUP – Faculdade de Medicina da Universidade do Porto, Porto, Portugal
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Ipatimup – Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
FMUP – Faculdade de Medicina da Universidade do Porto, Porto, Portugal
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Pancreatic neuroendocrine neoplasms (PanNENs) are rare and clinically challenging entities. At the molecular level, PanNENs’ genetic profile is well characterized, but there is limited knowledge regarding the contribution of the newly identified genes to tumor initiation and progression. Genetically engineered mouse models (GEMMs) are the most versatile tool for studying the plethora of genetic variations influencing PanNENs’ etiopathogenesis and behavior over time. In this review, we present the state of the art of the most relevant PanNEN GEMMs available and correlate their findings with the human neoplasms’ counterparts. We discuss the historic GEMMs as the most used and with higher translational utility models. GEMMs with Men1 and glucagon receptor gene germline alterations stand out as the most faithful models in recapitulating human disease; RIP-Tag models are unique models of early-onset, highly vascularized, invasive carcinomas. We also include a section of the most recent GEMMs that evaluate pathways related to cell cycle and apoptosis, Pi3k/Akt/mTOR, and Atrx/Daxx. For the latter, their tumorigenic effect is heterogeneous. In particular, for Atrx/Daxx, we will require more in-depth studies to evaluate their contribution; even though they are prevalent genetic events in PanNENs, they have low/inexistent tumorigenic capacity per se in GEMMs. Researchers planning to use GEMMs can find a road map of the main clinical features in this review, presented as a guide that summarizes the chief milestones achieved. We identify pitfalls to overcome, concerning the novel designs and standardization of results, so that future models can replicate human disease more closely.
