Bone loss after discontinuation of denosumab: the devil is in the details.

A 47-year-old postmenopausal woman with osteoporosis was treated with denosumab, which was discontinued due to side effects. She was therefore transitioned to a yearly intravenous infusion of zoledronic acid. An increase in bone turnover markers together with bone loss at the lumbar spine was observed before the second infusion, suggesting an overshooting of bone resorption due to denosumab discontinuation. On physical examination, the patient was restless and reported having lost about 10 kg since the last visit. A solitary left inferior thyroid nodule was noted on neck palpation. Circulating thyroid hormone levels were elevated, with suppressed thyroid-stimulating hormone. A thyroid scan showed increased uptake in the left inferior nodule with suppression of the remainder of the thyroid gland. A diagnosis of hyperthyroidism due to toxic adenoma was made. The patient was treated with radioactive iodine ablation, with consequent complete normalization of thyroid function. She continued yearly treatment with zoledronic acid. She remained clinically well with no further fractures. Bone turnover markers were appropriately suppressed and bone mineral density increased in the spine and hip. This case illustrates how the overshooting phenomenon following denosumab discontinuation may be compounded by the development of secondary conditions, which can result in suboptimal response to antiresorptive osteoporosis medications.

Dihydrotanshinone I exhibits antitumor effects via ß-catenin downregulation in papillary thyroid cancer cell lines.

Thyroid cancer is the most common endocrine carcinoma and, among its different subtypes, the papillary subtype (PTC) is the most frequent. Generally, PTCs are well differentiated, but a minor percentage of PTCs are characterized by a worse prognosis and more aggressive behavior. Phytochemicals, naturally found in plant products, represent a heterogeneous group of bioactive compounds that can interfere with cell proliferation and the regulation of the cell cycle, taking part in multiple signaling pathways that are often disrupted in tumor initiation, proliferation, and progression. In this work, we focused on 15,16-dihydrotanshinone I (DHT), a tanshinone isolated from Salvia miltiorrhiza Bunge (Danshen). We first evaluated DHT biological effect on PTC cells regarding cell viability, colony formation ability, and migration capacity. All of these parameters were downregulated by DHT treatment. We then investigated gene expression changes after DHT treatment by performing RNA-seq. The analysis revealed that DHT significantly reduced the Wnt signaling pathway, which plays a role in various diseases, including cancer. Finally, we demonstrate that DHT treatment decreases protein levels of ß-catenin, a final effector of canonical Wnt signaling pathway. Overall, our data suggest a possible use of this nutraceutical as an adjuvant in the treatment of aggressive papillary thyroid carcinoma.

GRADE-ADOLOPMENT of hyperthyroidism treatment guidelines for a Pakistani context.

INTRODUCTION: The prevalence of hyperthyroidism in Pakistan is 2.9%, which is two times higher than in the United States. Most high-quality hyperthyroidism clinical practice guidelines (CPGs) used internationally originate from high-income countries in the West. Local CPGs in Pakistan are not backed by transparent methodologies. We aimed to produce comprehensive, high-quality CPGs for the management of hyperthyroidism in Pakistan. METHODS: We employed the GRADE-ADOLOPMENT approach utilizing the 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis as the source CPG. Recommendations from the source guideline were either adopted as is, excluded, or adapted according to our local context. RESULTS: The source guideline included a total of 124 recommendations, out of which 71 were adopted and 49 were excluded. 4 recommendations were carried forward for adaptation via the ETD process, with modifications being made to 2 of these. The first addressed the need for liver function tests (LFTs) amongst patients experiencing symptoms of hepatotoxicity while being treated with anti-thyroid drugs (ATDs). The second pertained to thyroid status testing post-treatment by radioactive iodine (RAI) therapy for Graves' Disease (GD). Both adaptations centered around the judicious use of laboratory investigations to reduce costs of hyperthyroidism management. CONCLUSION: Our newly developed hyperthyroidism CPGs for Pakistan contain two context-specific modifications that prioritize patients' finances during the course of hyperthyroidism management and to limit the overuse of laboratory testing in a resource-constrained setting. Future research must investigate the cost-effectiveness and risk-benefit ratio of these modified recommendations.

Advances in targeted therapy and biomarker research in thyroid cancer.

Driven by the intricacy of the illness and the need for individualized treatments, targeted therapy and biomarker research in thyroid cancer represent an important frontier in oncology. The variety of genetic changes associated with thyroid cancer demand more investigation to elucidate molecular details. This research is clinically significant since it can be used to develop customized treatment plans. A more focused approach is provided by targeted therapies, which target certain molecular targets such as mutant BRAF or RET proteins. This strategy minimizes collateral harm to healthy tissues and may also reduce adverse effects. Simultaneously, patient categorization based on molecular profiles is made possible by biomarker exploration, which allows for customized therapy regimens and maximizes therapeutic results. The benefits of targeted therapy and biomarker research go beyond their immediate clinical impact to encompass the whole cancer landscape. Comprehending the genetic underpinnings of thyroid cancer facilitates the creation of novel treatments that specifically target aberrant molecules. This advances the treatment of thyroid cancer and advances precision medicine, paving the way for the treatment of other cancers. Taken simply, more study on thyroid cancer is promising for better patient care. The concepts discovered during this investigation have the potential to completely transform the way that care is provided, bringing in a new era of personalized, precision medicine. This paradigm shift could improve the prognosis and quality of life for individuals with thyroid cancer and act as an inspiration for advances in other cancer types.

The Accomplishments and Legacy of Saul Hertz, MD.

The early history of the use of radioactive iodine (RAI) is complicated and interesting, and also difficult to discover, especially since several histories have presented inaccurate content. This article is a comprehensive review of the accomplishments of Saul Hertz. Extensive use of primary-source verification has clarified several issues, including the question of whether Hertz alone conceived and asked the pivotal question: "Could iodine be made radioactive artificially?"; on what date RAI was first used to treat hyperthyroidism; and why 2 articles on the first use of RAI for treatment of hyperthyroidism, from 2 different sets of authors from the same department of the same institution, appeared adjacent to each other in the same issue of the Journal of the American Medical Association in 1946. Our review also chronicles several major challenges that Hertz overcame to produce his pivotal work. Hertz was clearly the originator and a visionary of RAI therapy in benign and malignant thyroid disease. We believe he can be considered one of the fathers of nuclear medicine. Hertz's paradigm-changing work was a pivotal medical discovery of the 20th century. The legacy of Hertz continues while the application of RAI therapy continues to evolve. RAI therapy remains the preferred treatment in most situations for autonomous nodules and toxic multinodular goiter and remains a safe and effective treatment for Graves disease after more than 80 y of global clinical use. RAI treatment of differentiated thyroid cancer remains a first-line treatment for most patients after surgery, especially for those with intermediate- or high-risk disease.

Clinical responses to vemurafenib in postoperative recurrence of papillary thyroid carcinoma with esophageal fistula: A case report.

BACKGROUND: While papillary thyroid carcinoma (PTC) generally exhibits a favorable prognosis post-surgery, the poorly differentiated subtype presents elevated rates of postoperative recurrence. Certain aggressive cases demonstrate invasive behavior, compromising adjacent structures and leading to a poor prognosis. This study delineates a unique case of postoperative PTC recurrence, complicated by esophageal fistula, that showed favorable outcomes following brief Vemurafenib treatment. PATIENT DESCRIPTION: A 64-year-old female patient underwent surgical resection for PTC, subsequently experiencing rapid tumor recurrence and development of an esophageal fistula. DIAGNOSIS: The patient was confirmed to have locally advanced PTC through intraoperative cytopathology. The cancer recurred postoperatively, culminating in the formation of an esophageal fistula. METHODS: The patient was administered Vemurafenib at a dosage of 960 mg twice daily following tumor recurrence. RESULTS: A 12-month regimen of targeted Vemurafenib therapy led to a substantial reduction in tumor size. Concurrently, the esophageal fistula underwent complete healing, facilitating successful removal of the gastrostomy tube. The tumor response was classified as stable disease. CONCLUSION SUBSECTIONS: Vemurafenib demonstrates potential as a targeted therapeutic strategy for recurrent PTC harboring the BRAFV600E mutation. This approach may effectively mitigate tumor dimensions and the associated risk of esophageal and tracheal fistulas.

The effects of Aurora Kinase inhibition on thyroid cancer growth and sensitivity to MAPK-directed therapies.

Thyroid cancer is one of the deadliest endocrine cancers, and its incidence has been increasing. While mutations in BRAF are common in thyroid cancer, advanced PTC patients currently lack therapeutic options targeting the MAPK pathway, and despite the approved combination of BRAF and MEK1/2 inhibition for BRAF-mutant ATC, resistance often occurs. Here, we assess growth and signaling responses to combined BRAF and MEK1/2 inhibition in a panel of BRAF-mutant thyroid cancer cell lines. We first showed that combined BRAF and MEK1/2 inhibition synergistically inhibits cell growth in four out of six of the -BRAF-mutant thyroid cancer cell lines tested. Western blotting showed that the MAPK pathway was robustly inhibited in all cell lines. Therefore, to identify potential mechanisms of resistance, we performed RNA-sequencing in cells sensitive or resistant to MEK1/2 inhibition. In response to MEK1/2 inhibition, we identified a downregulation of Aurora Kinase B (AURKB) in sensitive but not resistant cells. We further demonstrated that combined MEK1/2 and AURKB inhibition slowed cell growth, which was phenocopied by inhibiting AURKB and ERK1/2. Finally, we show that combined AURKB and ERK1/2 inhibition induces apoptosis in BRAF-mutant thyroid cancer cell lines, together suggesting a potential combination therapy for BRAF-mutant thyroid cancer patients.

Tyrosine kinase inhibitors in patients with advanced anaplastic thyroid cancer: an effective analysis based on real-world retrospective studies.

Background: Tyrosine kinase inhibitors (TKIs) contribute to the treatment of patients with anaplastic thyroid cancer (ATC). Although prospective clinical studies of TKIs exhibit limited efficacy, whether ATC patients benefit from TKI treatment in real-world clinical practice may enlighten future explorations. Therefore, we conducted this effective analysis based on real-world retrospective studies to illustrate the efficacy of TKI treatment in ATC patients. Methods: We systematically searched the online databases on September 03, 2023. Survival curves were collected and reconstructed to summarize the pooled curves. Responses were analyzed by using the "meta" package. The primary endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Results: 12 studies involving 227 patients were enrolled in the study. Therapeutic strategies included: anlotinib, lenvatinib, dabrafenib plus trametinib, vemurafenib, pembrolizumab plus dabrafenib and trametinib, pembrolizumab plus lenvatinib, pembrolizumab plus trametinib, and sorafenib. The pooled median OS and PFS were 6.37 months (95% CI 4.19-10.33) and 5.50 months (95% CI 2.17-12.03). The integrated ORR and DCR were 32% (95% CI 23%-41%) and 40% (95% CI 12%-74%). Conclusion: In real-world clinical practice, ATC patients could benefit from TKI therapy. In future studies, more basic experiments and clinical explorations are needed to enhance the effects of TKIs in the treatment of patients with ATC.

Protective effects of Panax Ginseng against 131I-induced genotoxicity in patients with differentiated thyroid cancer.

BACKGROUND: Radioiodine (131I) therapy (RAIT) is associated with oxidative stress (OS)-induced DNA damage in patients with differentiated thyroid cancer (DTC). The goal of this study was to evaluate the possible ameliorating effects of Panax Ginseng (PG) on RAIT-induced genotoxicity in patients with DTC. MATERIALS AND METHODS: Forty DTC patients who had received 131I (100 to 175 mCi) were enrolled in this study. The patients were randomly classified (n = 10) into control, placebo, PG1 groups (receiving 500 mg/day of PG for 2 days before RAIT), and PG2 group (receiving 500 mg/day of PG for 2 days before to 1 day after RAIT). Blood samples were collected before and 2 days after RAIT. Lymphocyte micronuclei (MN) frequency was measured using the MN assay. Serum total antioxidant capacity (TAC) and ischemia-modified albumin (IMA) were measured using colorimetric assays. Serum albumin, blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured using commercial kits. RESULTS: The mean of baseline MN frequency was the same in the four groups. RAIT increased the MN frequencies to at least three times the baseline values in the control (39 ± 5) and placebo groups (38 ± 6) (P < 0.001). PG caused a significant decrease in the MN frequencies in the treated groups compared to the control and placebo groups (P < 0.001). RAIT and PG administration had no significant effects on the serum IMA, TAC, and markers of liver and kidney toxicity. CONCLUSION: PG could be considered a useful remedy for the protection against RAIT-induced chromosomal damage in DCT patients.

A Phase 2 Study of Encorafenib in Combination with Binimetinib in Patients with Metastatic BRAF-Mutated Thyroid Cancer in Japan.

Background: Driver mutations at BRAF V600 are frequently identified in papillary thyroid cancer and anaplastic thyroid cancer (ATC), in which BRAF inhibitors have shown clinical effectiveness. This Japanese phase 2 study evaluated the efficacy and safety of a BRAF inhibitor, encorafenib, combined with an MEK inhibitor, binimetinib, in patients with BRAF V600-mutated thyroid cancer. Methods: This phase 2, open-label, uncontrolled study was conducted at 10 institutions targeted patients with BRAF V600-mutated locally advanced or distant metastatic thyroid cancer not amenable to curative treatment who became refractory/intolerant to ≥1 previous vascular endothelial growth factor receptor-targeted regimen(s) or were considered ineligible for those. The primary endpoint was centrally assessed objective response rate (ORR). The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: We enrolled 22 patients with BRAFV600E-mutated thyroid cancer: 17 had differentiated thyroid cancer (DTC), and 5 had ATC. At data cutoff (October 26, 2022), the median follow-up was 11.5 (range = 3.4-19.0) months. The primary endpoint of centrally assessed ORR was 54.5% (95% confidence interval [CI] 32.2-75.6; partial response in 12 patients and stable disease in 10). The ORRs in patients with DTC and ATC were 47.1% (8 of 17) and 80.0% (4 of 5), respectively. The medians for DOR and PFS by central assessment and for OS were not reached in the overall population, the DTC subgroup, or the ATC subgroup. At 12 months, the rate of ongoing response was 90.9%, and the PFS and OS rates were 78.8% and 81.8%, respectively. All patients developed ≥1 adverse events (AEs): grade 3 AEs in 6 patients (27.3%). No patients developed grade 4-5 AEs. The most common grade 3 AE was lipase increased (4 patients [18.2%]). Those toxicities were mostly manageable with appropriate monitoring and dose adjustment. Conclusions: Treatment with encorafenib plus binimetinib met the primary endpoint criteria and demonstrated clinical benefit in patients with BRAFV600E-mutated thyroid cancer regardless of its histological type, such as DTC or ATC, with no new safety concerns identified. Encorafenib plus binimetinib could thus be a new treatment option for BRAF V600-mutated thyroid cancer. Clinical Trial Registration number: Japan Registry of Clinical Trials: jRCT2011200018.

Glucagon-Like Peptide-1 Receptor Agonists and Thyroid Cancer: A Narrative Review.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are highly effective medications for the treatment of type 2 diabetes and obesity. Pharmacological studies in rodents support an association between the use of GLP-1 RAs and the development of medullary thyroid cancer (MTC) resulting in a black box warning for these agents in patients at risk for this condition. Yet, the association between GLP-1 RAs and non-MTC remains controversial. Excessive worry about unproven thyroid cancer risk might lead to underutilizing GLP-1 RAs in patients who could otherwise experience substantial benefits. Unwarranted concerns about thyroid cancer could lead to unnecessary thyroid cancer screening and harms from overdiagnosis. Summary: The body of evidence assessing the association between GLP-1 RA use and thyroid cancer spans a wide range of methodologies, including basic and translational research investigating biological plausibility; randomized trials assessing clinical efficacy and providing the strongest evidence for causality; observational studies providing real-life outcome evaluation in larger populations but with limited evaluation of covariates or dependable outcome definitions; and pharmacovigilance studies that provide postmarketing assessments of a safety signal but do not address causality. There is biological plausibility supporting an association between GLP-1 RA and MTC in rodents, which is less clear for non-MTC in humans. Clinical evidence from randomized trials and associated meta-analysis suggest thyroid cancer as a rare event making effect estimates imprecise but without conclusive and consistent evidence of increase risk in those receiving GLP-1 RA. Observational studies at higher risk of bias also show low event rates for thyroid cancer, with effect estimates that are inconsistent among different studies. Pharmacovigilance studies consistently show a signal of increased reporting of thyroid cancer in patients treated with GLP-1 RA. Conclusions: Evidence from randomized controlled trials indicates occurrence of thyroid cancer is infrequent in individuals exposed to GLP-1 RA. Observational studies at higher risk of bias yield inconsistent results. Overall there is no conclusive evidence of elevated thyroid cancer risk. These findings can help clinicians when addressing patient's concerns about a potential yet unproven link between GLP-1 RA therapy and thyroid cancer.

Targeting Nrf2 to treat thyroid cancer.

Oxidative stress (OS) is recognized as a contributing factor in the development and progression of thyroid cancer. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal transcription factor involved in against OS generated by excessive reactive oxygen species (ROS). It governs the expression of a wide array of genes implicated in detoxification and antioxidant pathways. However, studies have demonstrated that the sustained activation of Nrf2 can contribute to tumor progression and drug resistance in cancers. The expression of Nrf2 was notably elevated in papillary thyroid cancer tissues compared to normal tissues, indicating that Nrf2 may play an oncogenic role in the development of papillary thyroid cancer. Nrf2 and its downstream targets are involved in the progression of thyroid cancer by impacting the prognosis and ferroptosis. Furthermore, the inhibition of Nrf2 can increase the sensitivity of target therapy in thyroid cancer. Therefore, Nrf2 appears to be a potential therapeutic target for the treatment of thyroid cancer. This review summarized current data on Nrf2 expression in thyroid cancer, discussed the function of Nrf2 in thyroid cancer, and analyzed various strategies to inhibit Nrf2.

Ruxolitinib induces apoptosis and pyroptosis of anaplastic thyroid cancer via the transcriptional inhibition of DRP1-mediated mitochondrial fission.

Anaplastic thyroid carcinoma (ATC) has a 100% disease-specific mortality rate. The JAK1/2-STAT3 pathway presents a promising target for treating hematologic and solid tumors. However, it is unknown whether the JAK1/2-STAT3 pathway is activated in ATC, and the anti-cancer effects and the mechanism of action of its inhibitor, ruxolitinib (Ruxo, a clinical JAK1/2 inhibitor), remain elusive. Our data indicated that the JAK1/2-STAT3 signaling pathway is significantly upregulated in ATC tumor tissues than in normal thyroid and papillary thyroid cancer tissues. Apoptosis and GSDME-pyroptosis were observed in ATC cells following the in vitro and in vivo administration of Ruxo. Mechanistically, Ruxo suppresses the phosphorylation of STAT3, resulting in the repression of DRP1 transactivation and causing mitochondrial fission deficiency. This deficiency is essential for activating caspase 9/3-dependent apoptosis and GSDME-mediated pyroptosis within ATC cells. In conclusion, our findings indicate DRP1 is directly regulated and transactivated by STAT3; this exhibits a novel and crucial aspect of JAK1/2-STAT3 on the regulation of mitochondrial dynamics. In ATC, the transcriptional inhibition of DRP1 by Ruxo hampered mitochondrial division and triggered apoptosis and GSDME-pyroptosis through caspase 9/3-dependent mechanisms. These results provide compelling evidence for the potential therapeutic effectiveness of Ruxo in treating ATC.

Deep response to a combination of mTOR inhibitor temsirolimus and dual immunotherapy of nivolumab/ipilimumab in poorly differentiated thyroid carcinoma with PTEN mutation: a case report and literature review.

Treating advanced thyroid cancer presents challenges due to its resistance to various treatment modalities, thereby limiting therapeutic options. To our knowledge, this study is the first to report the efficacy of temsirolimus in conjunction with dual immunotherapy of nivolumab/ipilimumab to treat heavily treated advanced PDTC. A 50-year-old female initially presented with a rapidly enlarging mass on her right neck. Subsequent diagnosis revealed poorly differentiated thyroid carcinoma, leading to a total thyroidectomy followed by post-operative radioablation therapy. After four years, an examination for persistent cough revealed a recurrence of the disease within multiple mediastinal nodes. Genetic analysis of blood samples uncovered somatic mutations in the tumor, specifically involving PTEN and TP53. The disease progressed despite palliative radiation, lenvatinib, and nivolumab/ipilimumab therapy. Consequently, temsirolimus, functioning as an mTOR inhibitor, was introduced as an adjunct to the nivolumab/ipilimumab regimen. This combination approach yielded remarkable clinical improvement and disease control for a duration of approximately six months. Temsirolimus likely suppressed the aberrantly activated PI3K/AKT/mTOR signaling pathway, facilitated by the PTEN genetic alteration, thus engendering an effective treatment response. This synergy between targeted agents and immunotherapy presents a promising therapeutic strategy for advanced PDTC patients with limited treatment alternatives. In previous clinical trials, mTOR inhibitors have demonstrated the ability to maintain stable disease (SD) in 65% to 74% for advanced thyroid cancer patients, including those with PDTC. When combined with other targeted therapies, the observed SD or partial response rates range from 80% to 97%. Many of these trials primarily involved differentiated thyroid carcinoma, with diverse genetic mutations. Thyroid cancer patients with alterations in the PI3K/mTOR/Akt appeared to benefit most from mTOR inhibitors. However, no clear association between the efficacy of mTOR inhibitors and specific histologies or genetic mutations has been established. Future studies are warranted to elucidate these associations.

Effects of postoperative antioxidants on the salivary glands in patients with thyroid cancer undergoing radioactive iodine-131 treatment.

OBJECTIVE: This study aimed to evaluate the effects of three antioxidants, selenium yeast capsule, vitamin E and vitamin C, alone or in combination, on the salivary glands of patients with differentiated thyroid cancer (DTC) treated with iodine-131 ( 131 I). METHODS: A total of 69 postoperative DTC patients were randomly divided into three groups: vitamin E combined with vitamin C group (21 cases); selenium yeast group (23 cases); and selenium yeast combined with vitamin C group (25 cases). Salivary gland functional changes were assessed by salivary gland dynamic imaging functional parameters in the enrolled patients before and 1 month after 131 I treatment. RESULTS: Comparison of salivary gland function parameters before and after 131 I treatment in the three groups were evaluated. In the vitamin E combined with the vitamin C group, the left parotid gland excretion fraction (EF) value was significantly higher than that before treatment. In the selenium yeast group, the left parotid gland excretion part, bilateral parotid gland excretion ratio (ER), left submandibular gland maximum uptake ratio within 20 min (UR20), and the right submandibular gland ER values were significantly higher than that before treatment, while in the selenium yeast combined with vitamin C group, the bilateral parotid gland EF, bilateral submandibular gland UR20, EF, and left submandibular gland ER values were significantly higher than that before treatment (all P < 0.05). CONCLUSION: During high-dose 131 I treatment, vitamin E combined with vitamin C improved the excretory function of parotid glands in DTC patients; selenium supplementation had a protective effect on salivary glands; and the combination of selenium and vitamin C had a better effect.

Significance of Continuous Low-Dose Lenvatinib for the Treating of the Patients with Unresectable Thyroid Carcinoma.

The tyrosine kinase inhibitor lenvatinib has been confirmed as an effective treatment option for patients with unresectable thyroid carcinoma. We conducted a retrospective analysis of the significance of the effect of continued lenvatinib treatment for the longest duration possible at a reasonable daily dose and with a minimum discontinuation period in 42 patients with unresectable thyroid carcinoma treated with lenvatinib between 2015 and 2020. A Cox proportional hazard model-based analysis revealed that the overall survival of the patients treated with a <8 mg/day mean dose of lenvatinib was significantly better than that of the patients treated with 8-24 mg/day (hazard ratio [HR] 0.38 for 1.14-4.54 mg/day, and HR 0.01 for 4.56-7.97 mg/day) adjusted for various factors (e.g., sex, age, drug interruption period). The cumulative dose of lenvatinib administered tended to be higher in the patients treated with low doses (< 8 mg/day) than in the patients treated with relatively high doses (8-24 mg/day). Considering its adverse events, the continuation of lenvatinib treatment with an adequate daily dose and drug interruption may help prolong the survival of patients with unresectable thyroid carcinoma.

First effectiveness data of lenvatinib and pembrolizumab as first-line therapy in advanced anaplastic thyroid cancer: a retrospective cohort study.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare and aggressive neoplasm. We still lack effective treatment options, so survival rates remain very low. Here, we aimed to evaluate the activity of the combination of lenvatinib and pembrolizumab as systemic first-line therapy in ATC. METHODS: In a retrospective analysis, we investigated the activity and tolerability of combined lenvatinib (starting dose 14 to 24 mg daily) and pembrolizumab (200 mg every three weeks) as first-line therapy in an institutional cohort of ATC patients. RESULTS: Five patients with metastatic ATC received lenvatinib and pembrolizumab as systemic first-line therapy. The median progression-free survival was 4.7 (range 0.8-5.9) months, and the median overall survival was 6.3 (range 0.8-not reached) months. At the first follow-up, one patient had partial response, three patients had stable disease, and one patient was formally not evaluable due to interference of assessment by concomitant acute infectious thyroiditis. This patient was then stable for more than one year and was still on therapy at the data cutoff without disease progression. Further analyses revealed deficient DNA mismatch repair, high CD8+ lymphocyte infiltration, and low macrophage infiltration in this patient. Of the other patients, two had progressive disease after adverse drug reactions and therapy de-escalation, and two died after the first staging. For all patients, the PD-L1 combined positive score ranged from 12 to 100%. CONCLUSIONS: The combination of lenvatinib and pembrolizumab was effective and moderately tolerated in treatment-naïve ATC patients with occasional long-lasting response. However, we could not confirm the exceptional responses for this combination therapy reported before in pretreated patients.

Anti-papillary thyroid carcinoma effects of dioscorea bulbifera L. through ferroptosis and the PI3K/AKT pathway based on network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Papillary thyroid carcinoma (PTC) is the predominant form of thyroid cancer with a rising global incidence. Despite favorable prognoses, a significant recurrence rate persists. Dioscorea bulbifera L. (DBL), a traditional Chinese medicine, has been historically used for thyroid-related disorders. However, its therapeutic effects and mechanisms of action on PTC remain unclear. AIM OF THE STUDY: To explore the potential therapeutic effects, principal active components, and molecular mechanisms of DBL in the treatment of PTC through network pharmacology and molecular docking, with experimental validation conducted to corroborate these findings. MATERIALS AND METHODS: The Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) was utilized as a systematic tool for collecting and screening the phytochemical components of DBL, and for establishing associations between these components and molecular targets. Based on this, network data was visually processed using Cytoscape software (version 3.8.0). Concurrently, precise molecular docking studies of the principal active components of DBL and their corresponding targets were conducted using Autodock software. Additionally, PTC-related genes were selected through the GeneCards and GEO databases. We further employed the DAVID bioinformatics resources to conduct comprehensive Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses on the intersecting genes between DBL and PTC. These analyses aid in predicting the potential therapeutic actions of DBL on PTC and its mechanisms of action. To validate these findings, corresponding in vitro experimental studies were also conducted. RESULTS: In this investigation, 14 bioactive compounds of DBL and 195 corresponding molecular targets were identified, with 127 common targets shared between DBL and PTC. Molecular docking revealed strong binding affinities between major bioactive compounds and target proteins. GO enrichment analysis unveiled key processes involved in DBL's action. KEGG analysis highlighted DBL's modulation of the PI3K/AKT signaling pathway. Experimental outcomes demonstrated DBL's potential in inhibiting PTC cell proliferation and migration, suppressing PI3K/AKT pathway activation, and promoting ferroptosis. CONCLUSION: In conclusion, DBL offers a multifaceted therapeutic approach for PTC, targeting multiple molecular entities and influencing diverse biological pathways. Network pharmacology and molecular docking shed light on DBL's potential utility in PTC treatment, substantiated by experimental validation. This study contributes valuable insights into using DBL as a promising therapeutic agent for PTC management.

Checkpoint Inhibition in Addition to Dabrafenib/Trametinib for BRAFV600E-Mutated Anaplastic Thyroid Carcinoma.

Background: The dabrafenib plus trametinib combination (DT) has revolutionized the treatment of BRAFV600E-mutated anaplastic thyroid carcinoma (BRAFm-ATC). However, patients eventually develop resistance and progress. Single-agent anti-PD-1 inhibitor spartalizumab has shown a median overall survival (mOS) of 5.9 months. Combination of immunotherapy with BRAF/MEK inhibitors (BRAF/MEKi) seems to improve outcomes compared with BRAF/MEKi alone, although no direct comparison is available. BRAF-targeted therapy before surgery (neoadjuvant approach) has also shown improvement in survival. We studied the efficacy and safety of DT plus pembrolizumab (DTP) compared with current standard-of-care DT alone as an initial treatment, as well as in the neoadjuvant setting. Methods: Retrospective single-center study of patients with BRAFm-ATC treated with first-line BRAF-directed therapy between January 2014 and March 2023. Three groups were evaluated: DT, DTP (pembrolizumab added upfront or at progression), and neoadjuvant (DT before surgery, and pembrolizumab added before or after surgery). The primary endpoint was mOS between DT and DTP. Secondary endpoints included median progression-free survival (mPFS) and response rate with DT versus DTP as initial treatments, and the exploratory endpoint was mOS in the neoadjuvant group. Results: Seventy-one patients were included in the primary analysis: n = 23 in DT and n = 48 in DTP. Baseline demographics were similar between groups, including the presence of metastatic disease at start of treatment (p = 0.427) and prior treatments with surgery (p = 0.864) and radiation (p = 0.678). mOS was significantly longer with DTP (17.0 months [confidence interval CI, 11.9-22.1]) compared with DT alone (9.0 months [CI, 4.5-13.5]), p = 0.037. mPFS was also significantly improved with DTP as the initial treatment (11.0 months [CI, 7.0-15.0]) compared with DT alone (4.0 months [CI, 0.7-7.3]), p = 0.049. Twenty-three patients were in the exploratory neoadjuvant group, where mOS was the longest (63.0 months [CI, 15.5-110.5]). No grade 5 adverse events (AEs) occurred in all three cohorts, and 32.4% had immune-related AEs, most frequently hepatitis and colitis. Conclusions: Our results show that in BRAFm-ATC, addition of pembrolizumab to dabrafenib/trametinib may significantly prolong survival. Surgical resection of the primary tumor after initial BRAF-targeted therapy in selected patients may provide further survival benefit. However, conclusions are limited by the retrospective nature of the study. Additional prospective data are needed to confirm this observation.

Efficacy and safety of pralsetinib in Chinese advanced RET-mutant medullary thyroid cancer patients.

Pralsetinib has demonstrated efficacious activity in various solid tumors, including medullary thyroid cancer (MTC), as observed in the phase 1/2 global ARROW study (BLU-667-1101; NCT03037385). We evaluated the safety and efficacy of pralsetinib in Chinese patients with advanced RET-mutant MTC. In the extension cohort of ARROW, adult patients with advanced MTC, who had not received systemic therapy (except for cytotoxic chemotherapy), were treated with pralsetinib (400 mg once daily, orally). The primary endpoints were blinded independent central-reviewed (BICR) objective response rate (ORR) and safety. Between October 9, 2019, and April 29, 2020, 34 patients were enrolled at 12 centers across China. Among them, 28 patients tested positive for RET mutations in the central laboratory, and 26 of these, with measurable disease at baseline per BICR, were included in the analysis set for tumor response. As of April 12, 2021 (data cutoff), the ORR was 73.1% (95% CI: 52.2-88.4), and the median duration of response was not reached. The most common (≥15%) grade ≥3 treatment-related adverse events (TRAEs) in the 28 patients with RET-mutant MTC were neutrophil count decreased (8/28, 28.6%), blood creatine phosphokinase increased (6/28, 21.4%), and lymphocyte count decreased (5/28, 17.9%). Serious TRAEs were reported by six patients (21.4%), with the most common event being pneumonia (3/28, 10.7%). No patient discontinued treatment or died from pralsetinib-related adverse events. Pralsetinib demonstrated broad, deep, and durable efficacy, as well as a manageable and acceptable safety profile in Chinese patients with advanced RET-mutant MTC.