First-line selpercatinib for a patient with RET fusion-positive pulmonary large cell neuroendocrine carcinoma.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is an uncommon variant of non-small cell lung cancer (NSCLC), known for its aggressive behavior. This includes rapid progression, widespread metastases, and resistance to conventional chemotherapy, all of which contribute to a dismal prognosis. Consequently, managing pulmonary LCNEC remains a significant challenge. In this case report, we describe the successful use of selpercatinib, RET (rearranged during transfection) kinase inhibitor, as a first-line treatment in a patient with advanced pulmonary LCNEC harboring a RET fusion gene. Although RET fusion genes are exceedingly rare in pulmonary LCNEC, this case underscores the importance of early genetic testing in patients with pulmonary LCNEC to tailor targeted therapies effectively.

Pralsetinib as neoadjuvant therapy for RET-Altered differentiated thyroid cancer: Two case reports.

BACKGROUND: 5-10% of thyroid cancers are at locally advanced stage. Neoadjuvant targeted therapy will likely create surgical opportunities for these patients with unresectable or borderline resectable tumors. Pralsetinib, a RET inhibitor, has been approved for advanced or metastatic RET-altered thyroid cancer. However, there is no evidence on the efficacy of pralsetinib as neoadjuvant therapy in locally advanced RET-altered thyroid cancer. CASE REPORT: Two patients with locally advanced pappilary thyroid carcinoma (PTC) were treated with pralsetinib (400 mg daily) to reduce tumor size and increase the chance of R0 resection. Both PTCs, characterized by RET-fusion, underwent successful R0 resection without major surgical complications after 4-months neoadjuvant pralsetinib. CONCLUSION: There is a potential for pralsetinib as a neoadjuvant treatment in PTC with RET-fusion.

Correlation between gene mutations and clinical characteristics in papillary thyroid cancer: a retrospective analysis of BRAF mutations and RET rearrangements.

INTRODUCTION: Activation of the MAPK pathway by genetic mutations (such as BRAF and RET) initiates and accelerates the growth of papillary thyroid carcinoma (PTC). However, the correlation between genetic mutations and clinical features remains to be established. Therefore, this study aimed to retrospectively analyze major genetic mutations, specifically BRAF mutations and RET rearrangements, and develop a treatment algorithm by comparing background and clinical characteristics. METHOD: One hundred thirteen patients with primary PTC were included in this study. BRAF mutations were detected via Sanger sequencing and RET rearrangements were detected via fluorescence in situ hybridization (FISH) analysis, and reverse transcription polymerase chain reaction (RT-PCR). The patients were categorized into two groups based on the presence of BRAF mutations and RET rearrangements and their clinical characteristics (age, sex, TNM, stage, extratumoral extension, tumor size, unifocal/multifocal lesions, vascular invasion, differentiation, chronic thyroiditis, preoperative serum thyroglobulin level, and 18F-fluorodeoxyglucose (FDG) uptake) were compared subsequently. RESULT: After excluding unanalyzable specimens, 80 PTC patients (22 males and 58 females, mean age: 57.2 years) were included in the study. RET rearrangements were positive in 8 cases (10%), and BRAF mutation was positive in 63 (78.6%). The RET rearrangement group was significantly associated with younger age (p = 0.024), multifocal lesion (p = 0.048), distant metastasis (p = 0.025) and decreased 18F-fluorodeoxyglucose uptake (p < 0.001). The BRAF mutation group was significantly associated with unifocal lesions (p = 0.02) and increased 18F-FDG uptake (p = 0.004). CONCLUSION: In this study, an increase in M classification cases was found in the RET rearrangements group. However, genetic mutations were not associated with the clinical stage, and no factors that could be incorporated into the treatment algorithm were identified.

Diagnosis, Treatment Patterns, and Outcomes in Real-World Patients with RET Fusion-Positive Non-small Cell Lung Cancer in China.

INTRODUCTION: Epidemiological studies on non-small cell lung cancer (NSCLC) have noted RET fusions as an oncogenic driver. However, real-world data on RET biomarker testing and treatment patterns in China remain limited. This study aimed to examine demographics, clinical and molecular features, and RET testing and treatment patterns and outcomes in patients with RET fusion-positive NSCLC. METHODS: Utilizing real-world data from the Chinese Multi-center Lung Cancer Precision Medicine Registry, this retrospective cohort study focused on Chinese patients diagnosed with RET fusion-positive NSCLC between January 1, 2016, and November 30, 2021. The cohort was divided into early-stage and advanced-stage subgroups. Demographics, clinical and molecular profiles, treatment received, and outcomes including real-world event free survival (rwEFS), real-world progression free survival (rwPFS), and overall survival (OS) were assessed. RESULTS: The study included 121 patients with RET fusion-positive NSCLC, comprising 80 early-stage and 58 advanced-stage patients. High biomarker testing rates were observed at diagnosis (75% for early-stage, 78% for advanced-stage). RET testing was often conducted via tissue samples (95.9%) and next-generation sequencing (89.3%). KIF5B (57.0%) and CCDC6 (20.7%) were the most common gene fusion partners. The most frequent oncogenic mutations were TP53 (15.7%) and EGFR (6.6%). Platinum-based chemotherapy was the most common first-line treatment among advanced-stage patients. Median rwPFS was 9.22 months for advanced-stage patients on first-line chemotherapy, and median OS was 30.7 months for all advanced-stage patients. The 2-year rwEFS rate for early-stage patients was 86.0%, with a median OS of 91.9 months. CONCLUSIONS: The study observed high biomarker testing rates at initial diagnosis for early- and advanced-stage RET fusion-positive NSCLC patients in China. The heterogeneous treatment pattern of advanced patients suggests the need for more precise, evidence-based treatment to guide clinical decisions. Given the existing therapeutic regimens fall short of adequately addressing treatment needs, targeted therapies are essential to improve outcomes.

Discovery of 7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridine derivatives as potent inhibitors of rearranged during transfection (RET) and RET solvent-front mutants for overcoming selpercatinib resistance.

Rearranged during transfection kinase (RET) inhibition has been considered a promising therapeutic approach for treatment of a variety of cancers. However, the clinical therapeutic benefits of the second-generation RET inhibitor selpercatinib are greatly compromised by acquired resistance mediated by solvent-front mutations (e.g., RETG810 R/S/C). Herein, we report a class of 7-(1-methyl-1H-pyrazol-4-yl)-1,6-naphthyridine derivatives as potent RET and RET solvent-front mutant inhibitors for overcoming selpercatinib resistance. The representative compound 20p exhibited excellent in vitro inhibitory activities against solvent-front mutations (RETG810R, RETG810S, and RETG810C) with low nanomolar range (IC50 of 5.7-8.3 nM), which was 15-29-fold more potent than selpercatinib (IC50 of 95.3-244.1 nM). Additionally, 20p exhibited acceptable pharmacokinetic properties with oral bioavailability of 30.4 %. Importantly, 20p exhibited highly impressive antitumor potency in both a Ba/F3-KIF5B-RETWT-derived xenograft mouse model and a selpercatinib-resistant Ba/F3-KIF5B-RETG810R-positive mutant xenograft mouse model. Overall, 20p represents a novel and promising drug lead for overcoming RET solvent-front mutation-based resistance to selpercatinib.

Assessing the Effectiveness of Selective RET Inhibitors in RET-Positive Cancers through Fluorodeoxyglucose Uptake Analysis.

Selective RET inhibitors, such as selpercatinib and pralsetinib, have revolutionized the treatment of cancers with RET gene alterations. These inhibitors have shown remarkable clinical efficacy, particularly in RET-driven lung cancer, medullary thyroid cancer, and other solid tumors driven by RET gene fusions. The assessment of treatment response in oncology has been greatly enhanced by Fluorodeoxyglucose Positron Emission Tomography (FDG-PET), a valuable tool that measures tumor metabolism and provides early indicators of treatment effectiveness. This work explores the effectiveness of selective RET inhibitors in targeting RET-positive cancers and investigates the utility of FDG-PET in assessing treatment response. The paper includes insightful case studies that highlight the successful application of RET inhibitors in the treatment of RET-positive cancers. The findings suggest that FDG-PET has the potential to serve as a non-invasive biomarker for monitoring treatment response in patients with RET-positive cancers. However, further research is required to establish standardized criteria for interpreting FDG-PET scans in the context of selective RET inhibitors and to uncover the broader applications of FDG-PET in precision oncology.

Thyroid Malignancy and Cutaneous Lichen Amyloidosis: Key Points Amid RET Pathogenic Variants in Medullary Thyroid Cancer/Multiple Endocrine Neoplasia Type 2 (MEN2).

We aimed to provide an updated narrative review with respect to the RET pathogenic variants and their implications at the clinical and molecular level in the diagnosis of medullary thyroid cancer (MTC)/multiple endocrine neoplasia (MEN) type 2, particularly with respect to the presence of cutaneous lichen amyloidosis (CLA). We searched English-language, in extenso original articles with no timeline nor study design restriction that were published on PubMed. A traditional interplay stands for CLA and MTC in MEN2 (not MEN3) confirmation. While the connection has been reported for more than three decades, there is still a large gap in understanding and addressing it. The majority of patients with MEN2A-CLA have RET pathogenic variants at codon 634; hence, it suggests an involvement of this specific cysteine residue in both disorders (most data agree that one-third of C634-positive subjects have CLA, but the ranges are between 9% and 50%). Females seem more prone to MEN2-CLA than males. Non-C634 germline RET pathogenic variants included (at a low level of statistical evidence) the following: RET V804M mutation in exon 14 for MTC-CLA (CLA at upper back); RET S891A mutation in exon 15 binding OSMR variant G513D (familial MTC and CLA comprising the lower legs to thighs, upper back, shoulders, arms, and forearms); and C611Y (CLA at interscapular region), respectively. Typically, CLA is detected at an early age (from childhood until young adulthood) before the actual MTC identification unless RET screening protocols are already applied. The time frame between CLA diagnosis and the identification of RET pathogenic variants was between 5 and 60 years according to one study. The same RET mutation in one family is not necessarily associated with the same CLA presentation. In MTC/MEN2 subjects, the most affected CLA area was the scapular region of the upper back. Alternatively, another hypothesis highlighted the fact that CLA is secondary to long-term prurit/notalgia paresthetica (NP) in MTC/MEN2. OSMR p. G513D may play a role in modifying the evolutionary processes of CLA in subjects co-harboring RET mutations (further studies are necessary to sustain this aspect). Awareness in CLA-positive patients is essential, including the decision of RET testing in selected cases.

Molecular genetics, therapeutics and RET inhibitor resistance for medullary thyroid carcinoma and future perspectives.

Medullary thyroid carcinoma (MTC) is a rare type of thyroid malignancy that accounts for approximately 1-2% of all thyroid cancers (TCs). MTC include hereditary and sporadic cases, the former derived from a germline mutation of rearrangement during transfection (RET) proto-oncogene, whereas somatic RET mutations are frequently present in the latter. Surgery is the standard treatment for early stage MTC, and the 10-year survival rate of early MTC is over 80%. While for metastatic MTC, chemotherapy showing low response rate, and there was a lack of effective systemic therapies in the past. Due to the high risk (ca. 15-20%) of distant metastasis and limited systemic therapies, the 10-year survival rate of patients with advanced MTC was only 10-40% from the time of first metastasis. Over the past decade, targeted therapy for RET has developed rapidly, bringing hopes to patients with advanced and progressive MTC. Two multi-kinase inhibitors (MKIs) including Cabozantinib and Vandetanib have been shown to increase progression-free survival (PFS) for patients with metastatic MTC and have been approved as choices of first-line treatment. However, these MKIs have not prolonged overall survival (OS) and their utility is limited due to high rates of off-target toxicities. Recently, new generation TKIs, including Selpercatinib and Pralsetinib, have demonstrated highly selective efficacy against RET and more favorable side effect profiles, and gained approval as second-line treatment options. Despite the ongoing development of RET inhibitors, the management of advanced and progressive MTC remains challenging, drug resistance remains the main reason for treatment failure, and the mechanisms are still unclear. Besides, new promising therapeutic approaches, such as novel drug combinations and next generation RET inhibitors are under development. Herein, we overview the pathogenesis, molecular genetics and current management approaches of MTC, and focus on the recent advances of RET inhibitors, summarize the current situation and unmet needs of these RET inhibitors in MTC, and provide an overview of novel strategies for optimizing therapeutic effects.

MIG6 loss increased RET inhibitor tolerant persister cells in RET-rearranged non-small cell lung cancer.

Recently approved RET tyrosine kinase inhibitors (TKIs) have shown promising therapeutic effects against RET-rearranged non-small cell lung cancer (NSCLC) or RET-mutated thyroid cancer. However, resistance develops, limiting long-term efficacy. Although many RET-TKI resistance mechanisms, such as secondary mutations in RET or activation of bypass pathways, are known, some primary or acquired resistance mechanisms are unclear. Here, human genome-wide CRISPR/Cas9 screening was performed to identify genes related to drug-tolerant persister cells. Patient-derived cells with RET-fusion were introduced genome-wide sgRNA library and treated with RET-TKI for 9 days, resulting in the discovery of several candidate genes. Knockout of MED12 or MIG6 significantly increased residual drug-tolerant persister cells under RET-TKI treatment. MIG6 loss induced significant EGFR activation even with low concentrations of EGFR ligands and led to resistance to RET-TKIs. EGFR inhibition with afatinib or cetuximab in combination with RET TKIs was effective in addressing drug persistence. By contrast, a KIF5B-RET positive cells established from a RET-rearranged NSCLC patient, showed significant resistance to RET-TKIs and high dependence on EGFR bypass signaling. Consistently, knocking out EGFR or RET led to high sensitivity to RET or EGFR inhibitor respectively. Here, we have provided a comprehensive analysis of adaptive and acquired resistance against RET-rearranged NSCLC.

Efficacy and safety of pralsetinib in patients with RET fusion positive non-small cell lung cancer: An observational real world study.

BACKGROUND: Pralsetinib, a selective RET targeted tyrosine kinase inhibitor (TKI), has been approved for treating locally advanced or metastatic RET fusion-positive NSCLC in adults who have previously received platinum-based chemotherapy in China. METHODS: In this retrospective analysis conducted at Hunan Cancer Hospital in China, we examined 36 patients with advanced NSCLC with RET fusion, who were treated with pralsetinib between January 2021 and December 2023. The study focused on assessing the efficacy (Progression-free survival (PFS) and overall survival (OS)) and safety profile of pralsetinib in these patients. Statistical analyses were conducted using SPSS version 20.0, with a significance level set at p < 0.05. RESULTS: The results revealed that pralsetinib exhibited significant activity in this patient cohort. Kaplan-Meier survival analysis indicated a median PFS of 10.7 months and a median OS of 21.2 months. The overall response rate(ORR) and disease control rate (DCR) was 55.6 % and 72.2 %, respectively. Pralsetinib was generally well tolerated, with most adverse events being mild to moderate (grades 1-2). The most common serious adverse events (≥grade 3) observed were lymphopenia (13.9 %), hypertension (11.1 %), leukopenia (8.3 %), neutropenia (8.3 %), and creatine kinase elevation (8.3 %). CONCLUSION: Pralsetinib demonstrated promising activity in patients with advanced NSCLC harboring RET fusion with a favorable safety profile.

Erratum: Extensive patient-to-patient single nucleus transcriptome heterogeneity in pheochromocytomas and paragangliomas.

[This corrects the article DOI: 10.3389/fonc.2022.965168.].

Fluctuating obliterative bronchiolitis in RET-mutant medullary thyroid cancer patient treated with selpercatinib.

Highly selective RET inhibitor selpercatinib has demonstrated notable efficacy in advanced/progressive RET-mutant medullary thyroid cancer (MTC) patients. However, despite a more tolerable toxicity profile than multikinase inhibitors, peculiar adverse events (AEs) have been described. Obliterative bronchiolitis (OB) is a respiratory disease characterized by inflammation and fibrosis in small conducting airways. We evaluated a 70-year-old man with advanced RET-mutant MTC who developed OB during treatment with selpercatinib. Radiological features of OB occurred early and persisted during selpercatinib treatment, with a waxing and waning pattern. Notably, a partial response of MTC was achieved during the treatment, and selpercatinib was never reduced or interrupted. The almost complete absence of symptoms and the fluctuating trend, without specific treatment for OB, suggested that it is necessary to carefully evaluate the risks mediated by this AE with the risks of modifying or discontinuing the anti-cancer therapy.

High success rate of first proficiency testing for RET fusions and RET mutations in lung and thyroid cancer samples by various methods.

This study describes the external quality assessment (EQA) scheme for molecular testing of RET alterations in non-small cell lung cancer (NSCLC), medullary thyroid carcinomas (MTC), and non-MTC. The lead panel institute and Quality Assurance Initiative in Pathology (Qualitätssicherungs-Initiative Pathologie [QuIP] GmbH) selected formalin-fixed paraffin-embedded (FFPE) tissue from MTC for RET mutation testing by next-generation sequencing (NGS) methods and FFPE tissue from NSCLC and non-MTC for RET gene fusion testing using either in situ hybridisation (ISH) or NGS methods, forming 3 sub-schemes of the EQA scheme. Tissue material underwent an internal validation phase followed by an external testing phase. The internal validation phase served as a cross-validation step conducted by panel institutes. In the external testing phase, the number of participating institutes in the RET point mutation sub-scheme, RET fusion (ISH) sub-scheme, and RET fusion (NGS) sub-scheme was 32, 24, and 38, respectively. The reported success rates for external testing were 96.0%, 89.5%, and 93.5% for the RET point mutation, the ISH RET fusion, and the NGS RET fusion EQA sub-schemes, respectively. These findings confirm the reliability of the NGS method in detecting RET alterations and align with current screening recommendations. Overall, 31 institutes were certified for RET point mutation testing by NGS methods, 22 institutes were certified for RET fusion testing by ISH, and 36 institutes were certified for RET fusion testing by NGS methods. Results can be employed to inform real-world diagnostic decisions in Germany, Austria, and Switzerland.

Clinicopathological Features of CCDC6-RET and NCOA4-RET Fusions in Thyroid Cancer: A Single-Center Retrospective Cohort Study in a Chinese Population.

Background: The rearranged during transfection (RET) proto-oncogene fusion is common in papillary thyroid cancer (PTC), varying across ethnic groups. However, comprehensive comparisons of RET fusion types are limited. This study aims to identify predominant RET fusions and analyze their clinicopathological characteristics in a cohort of Chinese thyroid cancer cases. Methods: This single-center retrospective cohort study analyzed thyroid cancer data, utilizing next-generation sequencing on formalin-fixed, paraffin-embedded tissue samples. Detailed clinicopathological data of thyroid cancer cases with RET fusions were collected. Results: Among 2300 thyroid cancer cases, RET fusions were exclusively found in PTC or differentiated high-grade thyroid carcinoma (DHGTC) cases (2234 cases), absent in other types (66 cases). Of the 2234 PTC or DHGTC cases, 113 (5.06%) exhibited RET fusions, including 100 primary cases. Coiled-coil domain containing 6 (CCDC6)-RET fusions predominated (78.0%, 78/100), with nuclear receptor coactivator 4 (NCOA4)-RET fusions representing 22.0% (22/100). NCOA4-RET fusions were more prevalent in patients aged 45 years and older (54.5% vs. 28.2%, p = 0.021) and DHGTC cases (p < 0.05) and associated with higher rates of lymph node metastases (90.9% vs. 67.9%, p = 0.032). CCDC6-RET fusion exhibited a higher prevalence of Hashimoto's thyroiditis (HT) (67.9% vs. 22.7%, p < 0.001) and elevated thyroglobulin antibody levels (14.11 [1.86-174.32] IU/mL vs. 2.01 [1.14-15.41] IU/mL, p = 0.018). Moreover, CCDC6-RET fusion predominantly occurred in classical PTC (56.4%, 44/78) and infiltrative follicular PTC (17.9%, 14/78), whereas NCOA4-RET fusion was more frequent in classical PTC (36.4%, 8/22), solid PTC (27.3%, 6/22), and DHGTC (27.3%, 6/22). RET fusions with compound mutations were associated with older age (≥45 years) and bilateral thyroid involvement. Follow-up data showed a higher recurrence rate in the RET fusion group compared with the BRAFV600E mutation group (5.0% vs. 0.0%, p = 0.018). Although the NCOA4-RET group showed a numerically higher recurrence rate compared with CCDC6-RET (9.1% vs. 3.8%), this difference was not statistically significant (p = 0.559). Conclusions: RET fusions are specific to PTC or DHGTC cases among Chinese thyroid cancer cases. CCDC6-RET and NCOA4-RET fusions exhibited distinct clinicopathological features, with NCOA4-RET being more aggressive.

Lazarus Response to Selpercatinib for Bleeding Colic Metastasis in a Patient With RET Fusion-Positive Pulmonary Sarcomatoid Carcinoma: A Case Report.

In recent years, the widespread use of next-generation sequencing (NGS) allowed clinicians to identify and treat non-small cell lung cancer (NSCLC) efficiently with target therapy. RET inhibitors, like selpercatinib and pralsetinib, for RET rearrangements in lung cancer showed high efficacy and clinical benefit. Nevertheless, to date, the use of molecular-targeted agents has not been tested in all lung cancer subtypes. Indeed, pulmonary sarcomatoid carcinoma (PSC) remains a rare form of NSCLC, unresponsive to standard chemotherapy, and associated with extremely poor prognosis. We report the first case of a patient affected by RET fusion-positive PSC with a bleeding colic metastasis and a consequent poor performance status who achieved a dramatic response to selpercatinib and a remarkable clinico-radiological benefit.

Low-dose ionizing radiation-induced RET/PTC1 rearrangement via the non-homologous end joining pathway to drive thyroid cancer.

Thyroid cancer incidence increases worldwide annually, primarily due to factors such as ionizing radiation (IR), iodine intake, and genetics. Papillary carcinoma of the thyroid (PTC) accounts for about 80% of thyroid cancer cases. RET/PTC1 (coiled-coil domain containing 6 [CCDC6]-rearranged during transfection) rearrangement is a distinctive feature in over 70% of thyroid cancers who exposed to low doses of IR in Chernobyl and Hiroshima‒Nagasaki atomic bombings. This study aims to elucidate mechanism between RET/PTC1 rearrangement and IR in PTC. N-thy-ori-3-1 cells were subjected to varying doses of IR (2/1/0.5/0.2/0.1/0.05 Gy) of IR at different days, and result showed low-dose IR-induced RET/PTC1 rearrangement in a dose-dependent manner. RET/PTC1 has been observed to promote PTC both in vivo and in vitro. To delineate the role of different DNA repair pathways, SCR7, RI-1, and Olaparib were employed to inhibit non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ), respectively. Notably, inhibiting NHEJ enhanced HR repair efficiency and reduced IR-induced RET/PTC1 rearrangement. Conversely, inhibiting HR increased NHEJ repair efficiency and subsequent RET/PTC1 rearrangement. The MMEJ did not show a markable role in this progress. Additionally, inhibiting DNA-dependent protein kinase catalytic subunit (DNA-PKcs) decreased the efficiency of NHEJ and thus reduced IR-induced RET/PTC1 rearrangement. To conclude, the data suggest that NHEJ, rather than HR or MMEJ, is the critical cause of IR-induced RET/PTC1 rearrangement. Targeting DNA-PKcs to inhibit the NHEJ has emerged as a promising therapeutic strategy for addressing IR-induced RET/PTC1 rearrangement in PTC.

The role of reticulocyte hemoglobin equivalent on the evaluation of iron deficiency and iron deficiency anemia in pediatric cyanotic heart disease: a diagnostic study in Indonesia.

BACKGROUND: In light of prolonged hypoxia, children with cyanotic heart disase (CHD) are at a high risk of developing iron deficiency iron deficiency (ID) and iron deficiency anemia (IDA). Reticulocyte hemoglobin equivalent (Ret-He) is a novel and dependable indicator for assessing iron status. However, there has been no previous study regarding cut-off value in pediatric CHD group. The purpose of this study is to assess the role of Ret-He and to establish cut-off points in the diagnosis of iron deficiency and IDA in pediatric cyanotic heart disease. METHOD: This study was conducted in two tertiary hospitals in Jakarta, Indonesia. 59 children with CHD, aged 3 months to 18 years, were enrolled consecutively. To determine iron status, hematological parameters (hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin) and biochemical parameters for iron status (serum ferritin, transferrin saturation) were analysed and compared to Ret-He levels. The receiver operating characteristic (ROC) analysis was performed for the Ret-He cut-off points for ID and IDA. Sensitivity, specificity, positive and negative predictive value were calculated for each cut-off point. RESULT: Normal iron status was identified in 27 (45.8%) subjects, ID in 8 (13.5%) subjects, and IDA 24 (40.7%) subjects. The ID cut-off value for Ret-He is 28.8 pg (sensitivity 75%, specificity 85.2%, PPV 60%, NPV 92%, and AUC 0.828) and the Ret-He cut-off point for IDA is 28.15 pg (sensitivity 75%, specificity 88.9%, PPV 85.7%, NPV 80%, and AUC 0.824). Hemoglobin should be used in conjunction with Ret-He. ID might be detected in this cohort with Ret-He 28.8 pg and hemoglobin > 16,5 g/dL. While Ret-He 28.15 pg or Ret-He 28.15-28.8 pg with hemoglobin 16.5 g/dL could be used to diagnose IDA. CONCLUSION: The reticulocyte hemolgobin equivalent could be utilised as an iron status parameter in pediatric CHD, with a cut-off value of 28.8 pg for ID and 28.15 pg for IDA.

REThinking the role of the RET oncogene in breast cancer.

The REarranged during Transfection (RET) receptor tyrosine kinase plays a crucial role in the development of various anatomical structures during embryogenesis and it is involved in many physiological cellular processes. This protein is also associated with the initiation of various cancer types, such as thyroid cancer, non-small cell lung cancer, and multiple endocrine neoplasms. In breast cancer, and especially in the estrogen receptor-positive (ER+) subtype, the activity of RET is of notable importance. Indeed, RET seems to be involved in tumor progression, resistance to therapies, and cellular proliferation. Nevertheless, the ways RET alterations could impact the prognosis of breast cancer and its response to treatment remain only partially elucidated. Several inhibitors of RET kinase have been developed thus far, with various degrees of selectivity toward RET inhibition. These molecules showed notable efficacy in the treatment of RET-driven tumors, including some breast cancer cases. Despite these encouraging results, further investigation is needed to fully understand the potential role RET inhibition in breast cancer. This review aims to recapitulate the existing evidence about the role of RET oncogene in breast cancer, from its pathogenic and potentially prognostic role, to the clinical applications of RET inhibitors.

Non-Small-Cell Lung Cancers (NSCLCs) Harboring RET Gene Fusion, from Their Discovery to the Advent of New Selective Potent RET Inhibitors: "Shadows and Fogs".

RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1-2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the 'old' multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events.

Origin and impact of multifocal growth in sporadic vs. hereditary medullary thyroid cancer.

Multifocal growth is characteristic of hereditary medullary thyroid cancer (MTC), whereas origin and impact of multifocal growth is enigmatic for sporadic MTC. To address this, 460 RET-negative patients with sporadic MTC, stratified by 1 (93.3 %), 2 (5.7 %) and 3 (1.1 %) thyroid tumor foci, were compared with 219 RET-positive patients with hereditary MTC, stratified by 1 (38.4 %), 2 (45.7 %), 3 (6.4 %), 4 (6.8 %) and ≥5 (2.7 %) thyroid tumor foci. For sporadic MTC, significant associations were identified with bilateral thyroid lobe involvement, microscopic lymphatic invasion, extrathyroid extension, node and distant metastases, number of node metastases, preoperative basal calcitonin level, and decreasing biochemical cure. For hereditary MTC, significant associations were limited to bilateral thyroid lobe involvement, largest thyroid tumor diameter, and preoperative basal calcitonin level. In sporadic MTC, multifocal growth is due to lymphatic invasion with frequent node metastases, whereas in hereditary MTC, it reflects malignant progression from C-cell hyperplasia to cancer.