Daria Handkiewicz-Junak

Background: To enhance sodium-iodide symporter expression and, thereby, radiopharmaceutical uptake/retention in differentiated thyroid carcinoma (DTC) metastases, radioiodine therapy (RAIT) can be stimulated by recombinant human TSH (rhTSH) or thyroid hormone withdrawal (THW). We investigated the association of thyrotropin (TSH) stimulation methodology with treatment outcomes in patients with radioiodine-avid distantly metastatic DTC. Methods: Single-center retrospective cohort study involving 189 consecutive eligible patients initiating RAIT from 2005 to 2015, a period allowing sufficient follow-up to adequately assess long-term outcomes. Patients were dichotomized into “rhTSH only” or “mixed stimulation” subgroups (respectively, all RAIT activities prepared by rhTSH or ≥1 activity prepared using THW; n = 81, n = 108). Patients given only THW ( n = 5) were excluded due to low numbers for statistical analysis. Endpoints comprised radiological/biochemical response and time-to-progression (TTP) and overall survival (OS) estimated via the Kaplan–Meier method. Unadjusted inter-subgroup differences underwent log-rank testing; multivariable Cox modeling assessed independent associations with TTP and OS of disease/treatment characteristics, including stimulation methodology. Propensity score matching was performed to reduce baseline differences between the stimulation groups. Results: Median (minimum–maximum) follow-up was 123 (3–182) months. The best radiologic response consisted predominantly of stable disease (49%), with complete and partial responses observed in 23% and 18% of patients, respectively, and progressive disease in 10%, without significant differences between the TSH stimulation subgroups. Unadjusted analyses favored the mixed subgroup regarding TTP (141 vs. 42 months; p < 0.05) and OS (116 vs. 68 months; p < 0.01). However, after adjustment, TSH stimulation method was not independently associated with these outcomes; metastatic burden (macrometastasis) and age at DTC diagnosis were the strongest independent predictors. Consistent results were observed in the propensity score-matched cohort, with no significant differences in TTP or OS between stimulation groups. Conclusions: In radioiodine-avid metastatic DTC, rhTSH or mixed rhTSH/THW preparation is associated with comparable adjusted outcomes. Prognosis appears to be chiefly driven by metastatic burden and age. Clinical Implications: In patients with radioiodine-avid metastatic DTC, the choice between rhTSH and THW should be individualized based on comorbidities, logistics, and patient preference rather than an assumed difference in oncologic efficacy.

Pancreatic neuroendocrine neoplasms (pNENs) are the second most common type of pancreatic cancer after pancreatic ductal adenocarcinoma. Germline mutations in DNA repair genes drive several hereditary and sporadic cancers; however, their role in pNENs remains poorly defined. This pilot study aimed to assess the frequency and clinical relevance of germline DNA repair gene mutations in patients with pNENs, both with and without a family history of cancer. Germline DNA from 57 Polish patients with pNENs was analyzed using targeted next-generation sequencing to identify variants in a panel of DNA repair genes. Variant classification followed the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. Germline mutations were identified in 14 patients (24.6%), both with and without a family history of malignancy. Two patients carried pathogenic variants in BRCA2 and CHEK2, while seven carried variants of uncertain significance (VUS). The identified variants have been implicated in various cancer types, including breast, ovarian, prostate, gastric, colorectal, and pancreatic cancers. These findings indicate that germline mutations in DNA repair genes may contribute to the pathogenesis of pNENs, even in patients without a family history. Broader germline testing and population-specific studies are needed to clarify the genetic landscape and clinical implications of these alterations.

Purpose NETTER-P, an open-label Phase II study, evaluated the safety and dosimetry of [¹⁷⁷Lu]Lu-DOTA-TATE (hereafter ¹⁷⁷Lu-DOTATATE) in adolescents with advanced, somatostatin receptor-positive, well-differentiated, Grade 1/2 gastroenteropancreatic neuroendocrine tumours (GEP-NET) or pheochromocytoma and paragangliomas (PPGL). Methods Patients (12–17 years old) received four cycles of ¹⁷⁷Lu-DOTATATE (7.4 GBq every 8 ± 1 weeks; cumulative administered activity: 29.6 GBq). Primary endpoints were absorbed dose (kidneys and bone marrow) and safety after first administration. Safety during treatment and comparative assessments of dosimetry and pharmacokinetics between adolescents and historical adult patients were evaluated. Results Eleven patients (4 GEP-NET, 7 PPGL; median age 15 [range, 13–17] years) were enrolled and received ≥ 1 administration of ¹⁷⁷Lu-DOTATATE. Median (range) cumulative administered activity was 28.2 (7.3–29.9) GBq. Lymphopenia/lymphocyte count decreased and headache were the most common adverse events (AEs) during Cycle 1 (each 4/11 [36%]). Cycle 1 Grade ≥ 3 AEs occurred in 4/11 patients (36%). During the treatment period, the most common AE was lymphopenia/lymphocyte count decreased (7/11 [64%]; Grade ≥ 3, 5/11 [45%]). No clinically meaningful impacts on safety biomarkers nor any treatment-related nephrotoxicities were observed. Projected median (range) cumulative absorbed doses (four administrations) were 21 (14–40) Gy in kidneys and 0.76 (0.55-1.0) Gy in bone marrow (using blood data). Dosimetry values were predicted to be within safety thresholds for adolescents and adults; pharmacokinetics were comparable in both populations. Conclusion No new safety signals attributable to ¹⁷⁷Lu-DOTATATE were identified in adolescents with GEP-NET or PPGL versus adults with GEP-NET. Long-term follow-up is ongoing. Trial registration ClinicalTrials.gov, NCT04711135. Registered 15 January 2021.

The rapid progress made in recent years in thyroid cancer research has necessitated the systematic updating of current clinical recommendations. This update presents the evidence-based management of differentiated thyroid carcinoma (DTC) and medullary thyroid carcinoma in children, including preoperative diagnostics, surgical management, radioiodine therapy in DTC treatment with L-thyroxine, disease monitoring, treatment of advanced disease, and finally, consequences of thyroid cancer treatment. Each recommendation is evaluated regarding its strength (Strength of Recommendation; SoR) and the quality of supporting data (QoE — Quality of Evidence). Keywords: differentiated thyroid cancer papillary thyroid cancer medullary thyroid cancer total thyroidectomy thyroid lobectomy radioiodine L-thyroxine therapy guidelines recommendations

Advances in the diagnosis and treatment of adrenocortical carcinoma (ACC), along with the development of new therapeutic and diagnostic methods, have prompted a team of experts to formulate the first Polish guidelines for managing ACC. This article presents the diagnostic and therapeutic recommendations resulting from the discussion of specialists from various medical specialities, who participated in a series of online meetings aimed at developing consistent and effective recommendations under the National Oncology Strategy. These guidelines aim to optimise ACC treatment in Poland through coordinated efforts of multidisciplinary specialist teams, ensuring an effective and modern approach.

Insulinoma is the most common functional neuroendocrine tumor of the pancreas, with the main clinical symptom being hypoglycemia. The standard treatment is surgery, but some patients are not eligible for surgery, while in those operated on, the risk of perioperative complications is up to 30%. Diazoxide treatment to prevent hypoglycemia is effective only in 50% of patients. To prevent tumor growth and hormonal excess, stereotactic radiotherapy may be an alternative to surgical treatment. In our paper, we present two cases of patients with insulinoma treated successfully with stereotactic body radiation therapy (SBRT).

Purpose Peptide receptor radionuclide therapy (PRRT) and somatostatin analogues (SSAs) are commonly combined as primary treatment for neuroendocrine neoplasms (NEN), and SSAs given as maintenance. We sought to evaluate whether sequential therapy with PRRT followed by SSAs has progression or survival benefits in patients with NEN after disease control by PRRT. Methods This prospective, randomised, single-centre study had as principal eligibility criteria: unresectable, locally advanced, or metastatic, histologically confirmed well-differentiated NEN; no symptoms/biochemical diagnosis of carcinoid syndrome; no SSAs or ≤ 3 months of SSAs before PRRT; and stable disease or partial or complete response after PRRT. Altogether, 115 patients were randomised 2:1 to an SSA group (n = 74) given octreotide acetate LAR every 4 weeks, or a control group (n = 41) receiving only best supportive care. Octreotide treatment was to stop upon intolerable toxicity or patient refusal, or, at physician/patient discretion, upon NEN progression. The primary endpoint was progression-free survival (PFS), the secondary endpoint, and overall survival (OS). Results Median (25th–75th percentile) follow-up from the first PRRT activity to death or latest observation was 6.6 (3.18–10.22) years. During that time, 71/115 patients (62%) progressed, 52/74 (70%) in the SSA group, and 19/41 (46%) in the control group (p = 0.01). Eighty-eight/115 patients (76%) died, 58/74 (78%) in the SSA group, and 30/41 (73%) in the control group (p = 0.52). Median (95% CI) PFS was 4.7 (2.8–7.7) years in the SSA group, and 6.4 (4.1–not reached) years in controls. Overall, median OS was 6.6 years. Neither PFS nor OS differed between groups (p = 0.129, p = 0.985, respectively). Conclusions In patients with disease control after PRRT, subsequent SSA treatment appeared not to be associated with better PFS or OS. Whether to continue SSA administration upon progression after PRRT requires evaluation in a prospective, randomised, controlled multicentre study with a relatively homogeneous sample.

Purpose Peptide receptor radionuclide therapy (PRRT) and somatostatin analogues (SSAs) are commonly combined as primary treatment for neuroendocrine neoplasm (NEN), and SSAs given as maintenance treatment. We sought to evaluate whether sequential therapy with PRRT followed by SSAs has progression or survival benefits in patients with NEN.Methods This prospective, randomised, single-centre study had as principal eligibility criteria: unresectable, locally-advanced, or metastatic, histologically-confirmed well-differentiated NEN; no symptoms of carcinoid syndrome; no SSAs or ≤3 months of SSAs before PRRT; and stable disease or partial/complete response after PRRT. Altogether 115 patients were randomised 2:1 to an SSA group (n=74) given octreotide acetate LAR every 4 weeks, or to a control group (n=41) receiving best supportive care. Octreotide treatment was to stop upon intolerable toxicity or patient refusal, or, at physician/patient discretion, upon progression. Primary study endpoint was progression-free survival (PFS).Results Overall, median (25^th-75^th percentile) follow-up from the first PRRT activity to death or latest observation was 6.6 (3.18-10.22) years. During that time, 71/115 patients (62%) progressed, 52/74 (70%) in the SSA group, 19/41 (46%) in the control group (p = 0.01). Eighty-eight /115 (76%) patients died, 58/74 (78%) in the SSA group, 30/41 (73%) in the control group (p = 0.52). Median (95% CI) PFS was respectively, 4.7 (2.8-7.7) in the SSA group, and 6.4 (4.1-not reached) years in controls. Median OS was 6,6 years in whole group of patients. Neither PFS nor OS differed between groups (p = 0.129, p = 0.985, respectively).Conclusions In patients with disease control after PRRT, subsequent SSA treatment appeared not to be associated with better PFS or OS. Whether to continue or stop SSA administration upon progression after PRRT requires evaluation in a prospective, randomised, controlled multicenter study with a relatively homogeneous sample.

Molecular mechanisms of distant metastases (M1) in papillary thyroid cancer (PTC) are poorly understood. We attempted to analyze the gene expression profile in PTC primary tumors to seek the genes associated with M1 status and characterize their molecular function. One hundred and twenty-three patients, including 36 M1 cases, were subjected to transcriptome oligonucleotide microarray analyses: (set A—U133, set B—HG 1.0 ST) at transcript and gene group level (limma, gene set enrichment analysis (GSEA)). An additional independent set of 63 PTCs, including 9 M1 cases, was used to validate results by qPCR. The analysis on dataset A detected eleven transcripts showing significant differences in expression between metastatic and non-metastatic PTC. These genes were validated on microarray dataset B. The differential expression was positively confirmed for only two genes: IGFBP3, (most significant) and ECM1. However, when analyzed on an independent dataset by qPCR, the IGFBP3 gene showed no differences in expression. Gene group analysis showed differences mainly among immune-related transcripts, indicating the potential influence of tumor immune infiltration or signal within the primary tumor. The differences in gene expression profile between metastatic and non-metastatic PTC, if they exist, are subtle and potentially detectable only in large datasets.

Background: Telomerase reverse transcriptase promoter (TERTp) mutations are related to a worse prognosis in various malignancies, including papillary thyroid carcinoma (PTC). Since mechanisms responsible for the poorer outcome of TERTp(+) patients are still unknown, searching for molecular consequences of TERTp mutations in PTC was the aim of our study. Methods: The studied cohort consisted of 54 PTCs, among them 24 cases with distant metastases. BRAF V600E, RAS, and TERTp mutational status was evaluated in all cases. Differences in gene expression profile between TERTp(+) and TERTp(−) PTCs were examined using microarrays. The evaluation of signaling pathways and gene ontology was based on the Gene Set Enrichment Analysis. Results: Fifty-nine percent (32/54) of analyzed PTCs were positive for at least one mutation: 27 were BRAF(+), among them eight were TERTp(+), and 1 NRAS(+), whereas five other samples harbored RAS mutations. Expression of four genes significantly differed in BRAF(+)TERTp(+) and BRAF(+)TERTp(−) PTCs. Deregulation of pathways involved in key cell processes was observed. Conclusions: TERTp mutations are related to higher PTC aggressiveness. CRABP2 gene was validated as associated with TERTp mutations. However, its potential use in diagnostics or risk stratification in PTC patients needs further studies.