Endocrine-related cancer最新文献

Adrenocortical carcinoma (ACC) is a devastating disease with few effective treatments. The underlying molecular pathways remain largely unknown. To identify potential pathways and drivers relevant to ACC pathogenesis, we utilized histologically normal adrenals from heterozygous multiple endocrine neoplasia type 1 (Men1) mice to study early adrenocortical tumorigenesis. Employing mass spectrometry based proteomic profiling, we identified 681 proteins of which 52 displayed significant differential regulation in the adrenal tissues of heterozygous Men1 mice in comparison to their wild-type counterparts. Among these were fatty acid synthase (FASN) and ATP-citrate lyase (ACLY), two enzymes previously shown to be upregulated in several other types of tumors. To assess the functional impact of ACLY and FASN in ACC, we used H295R cells as the primary model. Cells were treated with SB-204990 (ACLY inhibitor) or C75 (FASN inhibitor), which both showed a dose-dependent antiproliferative effect. Lipidomic analysis revealed a significant reduction of palmitic acid and palmitoleic acid in treated cells compared to controls, supporting a mechanistic link between ACLY/FASN activity and lipid biosynthesis. Finally, data from the Cancer Genome Atlas showed significantly diminished survival outcomes among ACC patients exhibiting high ACLY or FASN expression. These findings underscore the potential importance of exploring the inhibition of lipid synthesis as a promising avenue for further research in the context of human ACC.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine neoplasms characterized by heterogeneous clinical and genetic profiles. Evidence regarding the efficacy of systemic therapies in this population remains limited. We retrospectively reviewed 157 PPGL patients treated at our center between 2021 and 2024. Clinical, pathological, genetic, and treatment data were collected. Outcomes of targeted therapy, chemotherapy, and somatostatin analogs (SSAs) were analyzed, including progression-free survival (PFS). We found that among the 113 patients who underwent next-generation sequencing, 47.8% harbored pathogenic variant, with SDHB being the most frequent. In the overall cohort, median PFS for targeted therapy, chemotherapy, and SSAs was 8.02, 5.06, and 16.03 months, respectively. For the most frequently used agents in each category - surufatinib, temozolomide-based chemotherapy, and lanreotide - median PFS was 13.08, 10.05, and 19.02 months, respectively (P = 0.46). In the first-line setting, targeted therapy and SSAs demonstrated superior efficacy compared with chemotherapy (median PFS 20.01 and 15.05 vs 4.07 months; P < 0.05), with no significant difference observed between surufatinib and lanreotide. In patients with SDHx pathogenic variant versus SDHx normal patient, the mPFS with lanreotide was 15.05 vs 22.05 months and, with temozolomide chemotherapy, was 11.01 vs 7.04 months; neither comparison showed a statistically significant difference. In the first-line setting, targeted therapy and SSAs were associated with longer PFS than chemotherapy, with surufatinib and lanreotide showing favorable disease control. SDHx pathogenic variant status did not show a clear association with response to TKIs or temozolomide, underscoring the need for validation in larger cohorts.

Multigene panel testing (MGPT) has increased the detection of SDHA pathogenic/likely pathogenic (P/LP) variants in cancer patients, but their clinical interpretation remains challenging due to low penetrance and lack of gene-specific variant interpretation guidelines. This study aimed to evaluate the prevalence and clinical relevance of germline and somatic SDHA P/LP variants in cancer patients. A total of 1,699 consecutively referred cancer patients underwent MGPT between 2021 and 2023. Population controls were obtained from the gnomAD database. When available, tumour samples were analysed for RNA-level characterization and SDHA loss-of-heterozygosity (LOH). Additionally, SDHA copy number variations (CNVs) were assessed in 10,463 pan-cancer and 8,037 breast tumour samples in silico. Germline SDHA variants were rare: 19 heterozygous variants (8 P/LP, 11 variants of unknown significance-VUS) were identified. No association between SDHA variants and tumour types was observed, and LOH was absent in non-SDHA-associated tumours. AI-based functional predictions suggested potential pathogenicity for a subset of VUSs, but their role remained uncertain. Somatic SDHA deletions were detected in 2.5% of pan-cancer and 5.4% of breast tumour samples. In breast cancer, SDHA CNV loss was associated with significantly worse overall and relapse-free survival (HR=1.55 and 1.48, respectively; p<0.05). However, CNVs extended across a 375 kb region around the SDHA locus, suggesting that this association may be related to 5p chromosomal deletions rather than the SDHA loss alone. In conclusion, germline SDHA variants are rare and likely incidental in most cancers, but somatic 5p chromosomal deletions including SDHA in breast cancer may have prognostic value.

Abstract: The purpose of this study is to assess the feasibility, efficacy and safety of cone-beam computed tomography (CBCT)-guided cryoablation of bone metastases in thyroid and adrenocortical cancers. Adult patients with bone metastases and at least 1 skeletal-related event (pain, risk of fracture, spinal cord compression or hypercalcemia) at baseline were enrolled in a prospective, single-arm, single-center IRB-approved study (ClinicalTrials: NCT03986593). Brief Pain Inventory - Short Form (BPI-SF) and morphine-equivalent daily dose (M-EDD) were recorded at baseline and weekly during the first 8 weeks and 3, 6, 12 and 24 months post-cryoablation. Adverse events (AEs) and pre- and post-treatment cross-sectional (CT or MR) and functional imaging with PET/CT were analyzed. Seventeen patients (mean age of 58.3 ± 16.2 years old; 11 women) with either differentiated (n = 8; 47.1%) or medullary thyroid cancer (n = 6; 35.6%), or adrenocortical cancer (n = 3; 17.3%) were enrolled. CBCT-guided cryoablation of 24 bone metastases reached 100% technical success rate. An overall drop of 4.8 points (P < 0.05) in the worst pain in the last 24 h and M-EDD overall intake decrease (P < 0.05) were observed. In addition to pain improvement, no patients required surgery. Three patients (17.6%) required radiotherapy due to refractory or recurrent pain over a follow-up of 14.9 ± 14.0 (median ± IQR) months. No grade 4 or 5 AE was reported. One grade 3 AE (5.9%) and two grade 2 AEs (11.8%) occurred. PET/CT imaging showed a 52% reduction in FDG uptake immediately after cryoablation. Cryoablation of bone metastases in thyroid and adrenocortical cancers was safe and effective, providing rapid and long-lasting pain relief and improving quality of life. ClinicalTrials.gov: NCT03986593.

Clinical relevance statements: Cryoablation led to a sustained reduction in pain with a mean improvement of 7.2 points on a 1-10 scale of the Brief Pain Inventory - Short Form (BPI-SF) after 54 weeks. Pain relief and quality-of-life improvement (assessed by the BPI-SF) were observed in 81.3% of bone metastases just one week after cryoablation with an overall pain score reduction of 4.8 points. Cryoablation of bone metastases from endocrine cancers was safe and effective, providing long-lasting pain relief.

The aim of this study was to quantify the cancer-specific death (CSD) benefit of radioactive iodine therapy (RAIT) in older patients with N1b differentiated thyroid carcinoma, a population designated by the ATA-2025 guideline as a 'consider RAIT' zone despite unproven mortality benefit, and to translate this recommendation into clinically actionable subgroups using a competing-risks framework. We used data from the Surveillance, Epidemiology, and End Results (SEER) programme (2004-2015) and analysed papillary thyroid carcinoma (PTC) cases aged ≥55 years with N1b, M0. After 1:1 propensity score matching, cumulative incidence function and Fine-Gray models evaluated associations between RAIT and CSD. Stratifications included tumour size, positive lymph node burden (PLN > 5), and ETE. A nomogram was developed for 1-, 3-, and 5-year CSD prediction, and absolute risk reduction (ARR) and number needed to treat (NNT) were estimated. Among 1,142 patients, 648 were matched (n = 324/group; median follow-up = 69 months). Five-year CSD was 14.1% without RAIT versus 5.1% with RAIT (P = 0.001), yielding ARR ≈ 9% and NNT ≈ 11. RAIT was independently protective (SHR 0.33, 95% CI: 0.14-0.76). Benefit concentrated in tumours 2-4 cm, PLN > 5, and ETE-positive strata. The nomogram showed strong discrimination and calibration. In patients aged ≥55 years with N1b PTC, RAIT confers measurable mortality benefit, most evident in 2-4 cm, PLN > 5, or ETE-positive disease. Integrating ARR, NNT, and a validated nomogram, this study converts the conceptual 'consider RAIT' into clinically actionable 'RAIT-favoured' and 'RAIT-optional' pathways.

Thyroid nodules are extremely common with a prevalence of up to 70% in the general population (1). While the majority of these are benign, 5-10% harbor a malignancy. Fine-needle aspiration (FNA) has been widely implemented to stratify the cancer risk of thyroid nodules. Standardized diagnoses using the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) (2) has aided in the triaging of nodules. While many cases are categorized with a definite diagnosis of benign (Bethesda II) or malignant (Bethesda VI) results, approximately 25% of cases are diagnosed as atypia of undetermined significance (AUS) (Bethesda III) or follicular neoplasm (FN) (Bethesda IV). These cytological categories imply an intermediate risk of malignancy ranging from 16-48% (3). These nodules, collectively defined as indeterminate thyroid nodules (ITN), pose diagnostic and management challenges. In recent years, several commercial molecular tests (MT) have become available to improve risk stratification, successfully helping to reduce unnecessary surgeries. In this review, we provide an overview of MT, present practical guidance on interpreting test results, and conclude with a discussion on future directions in the field.

Abstract: Well-differentiated grade 3 neuroendocrine tumors (NETs) have recently been described as a distinct category, and randomized data regarding efficacy of therapy for these patients are scarce. In the phase 3 CABINET trial, cabozantinib improved PFS compared with placebo in patients with advanced, previously treated, progressive extra-pancreatic NETs (epNETs) and pancreatic NETs (pNETs) of all grades. Here, we evaluate if these results remain consistent in a subgroup of patients with well-differentiated G3 NETs. Patients with locally advanced or metastatic epNETs or pNETs were randomized 2:1 in independent cohorts to receive cabozantinib 60 mg daily vs placebo. We analyzed outcomes of the subset of patients with G3 NETs (Ki-67 > 20%), combining patients in the pNET and epNET cohorts due to small sample sizes. Twenty-four patients had G3 NETs, 16 randomized to cabozantinib and 8 to placebo. Primary sites included pancreas (n = 12), GI tract (n = 7), unknown primary sites (n = 3), and lung/thymus (n = 2). Median PFS for patients with G3 NETs treated with cabozantinib was 7.9 vs 3 months with placebo (HR = 0.15, 95% CI: 0.04-0.57, 1-sided log-rank P = 0.0034). The confirmed overall radiographic response rate was 25% (4/16) with cabozantinib vs 0% (0/8) with placebo. Safety outcomes were consistent with published data for the trial as a whole. Subset analysis of the CABINET trial showed improved PFS associated with cabozantinib vs placebo for G3 NETs of pancreatic and extra-pancreatic origin. Despite limited numbers, these results suggest that cabozantinib can be an effective option for patients with advanced G3 NETs. ClinicalTrials.gov Identifier: NCT03375320.

Pancreatic neuroendocrine tumors (PanNETs) represent a rare subset of pancreatic cancers, comprising approximately 1-2% of all cases. Non-functioning PanNETs (NF-PanNETs), which account for the majority of PanNETs, can be difficult to treat as they show no hormone-related symptoms and are often not diagnosed until the more advanced stages. Current therapeutic agents have limited efficacy, highlighting the need for novel treatment strategies. Multiple endocrine neoplasia type 1 is a hereditary syndrome strongly associated with PanNETs and pituitary neuroendocrine tumors (PitNETs), caused by germline mutations in the MEN1 gene. Using Men1f/f-RipCre+ mice, which develop both NF-PanNETs and PitNETs, we investigated whether long-term administration of metformin, a first-line anti-diabetic drug, could suppress tumor development and progression. Metformin significantly inhibited the elevation of blood glucose in Men1f/f-RipCre+ mice, and longer-term treatment attenuated PanNETs and restored normal insulin secretion. Metformin suppressed the proliferative pathways including the PI3K/Akt/mTOR signaling pathway. In addition to its effects on PanNETs, metformin also attenuated PitNET development, elevated antiproliferative pathways and suppressed angiogenic pathways. Furthermore, clinical data revealed that NF-PanNET patients with prior metformin use exhibited improved prognosis. These findings demonstrate that blood glucose control through metformin represents a promising preventive and therapeutic strategy for NF-PanNETs and MEN1-associated neuroendocrine tumors.

Introduction: Rectal neuroendocrine tumors (rNETs) are among the most common NETs and account for approximately 12-27% of all gastrointestinal NETs in North America. Significant discrepancies persist in the management of NETS regarding surveillance strategies, staging modalities, high-risk features, and criteria for surgical intervention.

Methods: This guideline updates current practices of rectal NETs stage I-III with the utilization of GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) methodology and consensus DELPHI agreement across leading experts in the North American region.

Results: Several technological advances such as 68-Gallium-or 64 Cu-DOTATATE SRRT PET/CT and broad adoption of pelvic MRI has improved staging of rNETs, along with modified endoscopic mucosal and submucosal resection and full thickness excision techniques that demonstrate efficacy and safety for resection. Pivotal long-term outcome studies provide insight to 1) risk factors for regional lymph node metastasis, 2) the impact of R1 excision (endoscopic), 3) best practices for intermediate sized rNETs (11-20mm), and 4) risk in small rNETs (<10 mm). Recommendations were developed upon evidence-based conclusions from the GRADE review to define the role of baseline staging with MRI, advanced endoscopy and transanal endoscopic surgical methods appropriate for T1 rNETs, the role of salvage therapy in cases of R1 resection, and the consideration of pathologic variables to direct definitive treatment and surveillance.

Conclusions: Advances in screening programs and imaging allow for improved detection and staging of rNETs, while long-term outcome studies can better direct patients towards evidence-based treatment management and rectal organ preservation through less radical resection methods.

Therapy-induced senescence (TIS) is a potential outcome of anti-cancer treatments, characterized by a stable cell cycle arrest. However, it is now widely accepted that this process acts as a double-edged sword: in facts, senescent cells are active drivers of cancer relapse, aggressiveness and metastasis, through the release of pro-inflammatory factors and the ability to resume proliferation. Therefore, selectively targeting TIS cells, a strategy named one-two punch approach, is crucial to avoid their harmful effects. This may become particularly important for those aggressive tumors that currently lack effective therapeutic options, such as dedifferentiated thyroid tumors. To this purpose, identifying targetable characteristics of TIS cells is essential for the development of new senotherapeutics. TIS is often associated with variations of the autophagic flux, therefore, we investigated the interplay between autophagy and therapy-induced senescence in thyroid cancer cells, to explore a new potential target for senotherapy. We demonstrate that TIS thyroid cancer cells do not always exhibit a sufficient enlargement of the lysosomal compartment to maintain autophagy function. The deficiency in lysosomal biogenesis is driven by the inability of TFEB, this process' master regulator, to properly enter and remain inside the nucleus. The disruption of the autophagic flux leads to the accumulation of SQSTM1/p62, which in turn activates the Nrf2 pathway. In contrast to cells with functional autophagy, Nrf2-activated cells display a higher tolerance to oxidative stress, making them resistant to the senolytic activity of lysosomal inhibitors.