Sorafenib in the treatment of thyroid cancer

Sorafenib has been evaluated in several Phase II and III studies in patients with locally advanced/metastatic radioactive iodine–refractory differentiated thyroid carcinomas (DTCs), reporting partial responses, stabilization of the disease and improvement of progression-free survival. Best responses were observed in lung metastases and minimal responses in bone lesions. On the basis of these studies, sorafenib was approved for the treatment of metastatic DTC in November 2013. Few studies suggested that reduction of thyroglobulin levels, or of average standardized uptake value at the fluorodeoxyglucose-PET, could be helpful for the identification of responding patients; but further studies are needed to confirm these results. Tumor genetic marker levels did not have any prognostic or predictive role in DTC patients.The most common adverse events observed included skin toxicity and gastrointestinal and constitutional symptoms. Encouraging results have also been observed in patients with medullary thyroid cancer. Many studies are ongoing to evaluate the long-term efficacy and tolerability of sorafenib in DTC patients.     

New developments in the diagnosis and treatment of thyroid cancer

Answer questions and earn CME/CNE Thyroid cancer exists in several forms. Differentiated thyroid cancers include those with papillary and follicular histologies. These tumors exist along a spectrum of differentiation, and their incidence continues to climb. A number of advances in the diagnosis and treatment of differentiated thyroid cancers now exist. These include molecular diagnostics and more advanced strategies for risk stratification. Medullary cancer arises from the parafollicular cells and not the follicular cells. Therefore, diagnosis and treatment differs from those of differentiated thyroid tumors. Genetic testing and newer adjuvant therapies have changed the diagnosis and treatment of medullary thyroid cancer. This review will focus on the epidemiology, diagnosis, workup, and treatment of both differentiated and medullary thyroid cancers, focusing specifically on newer developments in the field. CA Cancer J Clin 2013;63:373‐394. ^©2013 American Cancer Society, Inc.     

Molecular basis and targeted therapies for radioiodine refractory thyroid cancer

Patients diagnosed with radioiodine refractory thyroid cancer (RAIR-TC) are not amenable to novel ¹³¹I therapy due to the reduced expression of sodium iodide symporter (Na+/I- symporter, NIS) and/or the impairment of NIS trafficking to the plasma membrane. RAIR-TC patients have a relatively poor prognosis with a mean life expectancy of 3–5 years, contributing to the majority of TC-associated mortality. Identifying RAIR-TC patients and selecting proper treatment strategies remain challenging for clinicians. In this review, we demonstrate the updated clinical scenarios or the so-called “definitions” of RAIR-TC suggested by several associations based on ¹³¹I uptake ability and tumor response post-¹³¹I therapy. We also discuss current knowledge of the molecular alterations involved in membrane-localized NIS loss, which provides a preclinical basis for the development of targeted therapies, in particular, tyrosine kinase inhibitors (TKIs), redifferentiation approaches, and immune checkpoint inhibitors.     

Temozolomide combined with ipilimumab plus nivolumab enhances T cell killing of MGMT-expressing,MSS colorectal cancer cells

Colorectal cancer (CRC) is the third most frequently diagnosed cancer and third-deadliest cancer globally. Over 95% of patients with metastatic CRC have tumors that are microsatellite stable (MSS) and do not respond to immune checkpoint inhibitors (ICI). Results from the 2022 MAYA clinical trial suggest that the DNA-damaging agent temozolomide (TMZ), which is usually used to treat glioblastoma (GBM), sensitizes patients with MSS, MGMT-silenced CRC to ipilimumab + nivolumab ICI. The benefit of adding ipilimumab + nivolumab to TMZ and the impact of MGMT silencing remain unclear. Here, we aimed to determine in a controlled in vitro system if adding ICI to TMZ enhances T cell killing of MSS CRC cells. We also aimed to determine the contribution of MGMT to this response. Western blot analysis indicated that CRC cells (n = 4) had significantly elevated MGMT expression as compared to GBM cells (n = 4) likely due to MGMT promoter methylation in GBM cells. In line with this, CRC cells were slightly more resistant to TMZ compared to GBM cells after five days of treatment. TMZ + ICI sensitized MGMT-expressing, MSS CRC cells to T cell killing. TMZ alone did not enhance T cell killing of MSS or MSI CRC cells but did slightly enhance T cell killing of T98G GBM cells. Our results indicate that TMZ sensitizes MSS, MGMT-expressing CRC cells to ipilimumab + nivolumab ICI. Importantly, this suggests that TMZ-mediated sensitization to ipilimumab + nivolumab appears independent of MGMT status and the patient cohort that may benefit from TMZ + ipilimumab + nivolumab may be expanded to CRC patients with MGMT-expressing, MSS tumors.     

NA cohort study of thyroid cancer and other thyroid diseases after the Chernobyl accident

BACKGROUND:

The Ukrainian American Cohort Study was established to evaluate the risk of thyroid disorders in a group exposed as children and adolescents to ¹³¹I by the Chernobyl accident (arithmetic mean thyroid dose, 0.79 grays). Individuals are screened by palpation and ultrasound and are referred to surgery according to fine‐needle aspiration biopsy (FNA). However, the accuracy of FNA cytology for detecting histopathologically confirmed malignancy after this level of internal exposure to radioiodines is unknown.

METHODS:

During the first screening cycle (1998‐2000), 13,243 individuals were examined, 356 individuals with thyroid nodules were referred for FNA, 288 individuals completed the procedure, 85 individuals were referred to surgery, 82 individuals underwent surgery, and preoperative cytology was available for review in 78 individuals. Cytologic interpretation for the nodule that resulted in surgical referral was correlated with final pathomorphology; discrepancies were reviewed retrospectively; and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FNA cytology were calculated.

RESULTS:

All 24 cytologic interpretations that were definite for papillary thyroid cancer (PTC) were confirmed histopathologically (PPV, 100%); and, of 11 cytologic interpretations that were suspicious for PTC, 10 were confirmed (PPV, 90.9%). Ten of 41 FNAs that were interpreted as either definite or suspect for follicular neoplasm were confirmed as malignant (PPV, 24.4%), including 2 follicular thyroid cancers and 8 PTCs (all but 1 of the follicular or mixed subtypes). Depending on whether a cytologic interpretation of follicular neoplasm was considered “positive” or “negative,” the sensitivity was 100% and 77.3%, respectively; similarly, the respective specificity was 17.6% and 97.1%, the respective PPV was 61.1% and 97.1%, and the respective NPV was 100% and 76.7%.

CONCLUSIONS:

Among children and adolescents who were exposed to ¹³¹I after the Chernobyl accident and were evaluated 12 to 14 years later, thyroid cytology had a sensitivity and a predictive value similar to those reported in unexposed populations. Cancer (Cancer Cytopathol) 2009. Published 2009 by the American Cancer Society.     

Exploring the potential of immuno-oncology-based treatment for patients with non-small cell lung cancer

Immune evasion is recognized as a key strategy for cancer survival and progression. With increased understanding of immune escape mechanisms, the development of immunotherapies to restore anti-tumor immune responses has flourished. Immuno-oncology (I-O) agents targeting checkpoints in the immune regulation cascade currently form the mainstay of approaches of cancer immunotherapy. Since initial success in melanoma, evidence for the notable effects of the I-O modality has been expanding, with numerous clinical studies underway or completed in a variety of solid tumors, including non-small cell lung cancer. This review highlights the rationale and potential role of immunotherapy in non-small cell lung cancer management, with a focus on immune checkpoint inhibitors. We also discuss the potential for I-O-based combination therapy.     

Risks of papillary and follicular thyroid cancer among immigrants to Sweden

Previous studies have indicated that ionizing radiation, particularly during childhood, is the main established risk factor for thyroid cancer. History of benign nodules/adenoma, goiter, iodine deficiency or high-iodine intake might be other associated factors. We wanted to define the histology-specific thyroid cancer risk in the first-generation immigrants to Sweden. We used the 2010 update of the nation-wide Swedish Family-Cancer Database (>12 million individuals; 1.8 million immigrants; histology code in force since 1958) to calculate standardized incidence ratios (SIRs) for histology-specific thyroid cancer among immigrants compared to the native Swedes. The patient series covered 2,604 male and 6,406 female Swedes, and 247 and 863 immigrants. The median age at immigration was 29 years, and the median age at thyroid cancer diagnosis was 46 years. Increased risks for female papillary carcinoma were observed for Finns (SIR = 1.63), former Yugoslavians (2.36), Russians (2.34), other East Europeans (2.14), Turks (3.16), Iranians (2.68), Iraqis (2.77), East and Southeast Asians (2.92), other Asians (1.69) and South Americans (2.23). Male Iranians (2.85), East and Southeast Asians (3.57) and other Asians (2.26) had an increased risk for papillary carcinoma. Only male East and Southeast Asians (2.93) had an increased risk for follicular carcinoma. The data might suggest that immigrant populations in Sweden from areas of low or high-iodine intake are at risk of papillary carcinoma, implicating iodine imbalance as a contributing factor to our findings. The increased risk of thyroid cancer among Asian immigrants may confirm the role of childhood-ionizing radiation on thyroid cancer risk.     

Expression of sodium iodide symporter in metastatic and follicular human thyroid tissues

Active iodide uptake across the basal membrane mediated by human sodiumiodide symporter (hNIS) has been shown to be a process coupled with the flowof sodium. There is still controversy as to the amount of hNIS expressionpresent in different kinds of human thyroid cancer tissues. In this study, wepresent a 58-year-old women with follicular thyroid carcinoma with vertebraand skull metastases. ²⁰¹Tl and 5 mCi ¹³¹I scans clearlydemonstrated the metastatic lesions in the brain of this patient. Thyroid andmetastatic tissues were then obtained for this study, which is aimed atcomparing the iodide trapping ability in vivo and in vitro of hNIS, and then comparing their expression in both thyroid tissue andmetastatic tissues. Polyclonal antibodies to hNIS and competitive RT–PCRwere used to analyze the symporter protein and mRNA expressed in follicularhuman thyroid and metastatic tissues. Positive staining of the symporterprotein was performed in the follicular thyroid carcinomas, otherwise, themetastatic tissues could not have demonstrated the protein in the staining.Follicular thyroid carcinoma tissues from thyroid were revealed around 5 pghNIS expressed in follicular thyroid carcinoma tissues from the thyroid.Otherwise, there was almost an absence of hNIS expression in the metastatictissue. These discrepancies of the expression in hNIS in vivo and in vitrostudies need further investigation.     

甲状腺髓样癌的放射治疗新进展

甲状腺髓样癌（MTC）是一种源自甲状腺滤泡旁C细胞的神经内分泌肿瘤。 甲状腺髓样癌的初始治疗通常是手术。临床分期较晚的患者,尽管进行了积极的手术治疗,但局部复发风险仍很高。随着辐射技术的改进,足够的放疗剂量可以有效地照射到高危区域,同时最小化周围关键组织结构的受照剂量。因此放射治疗应该是局部晚期甲状腺髓样癌的治疗选择,以提高局部区域控制。     

Cytotoxic activity of the histone deacetylase inhibitor panobinostat (LBH589) in anaplastic thyroid cancer in vitro and in vivo

Anaplastic thyroid carcinoma (ATC) has a rapidly fatal clinical course, being resistant to multimodal treatments. Microtubules, α/β tubulin heterodimers, are crucial in cell signaling, division and mitosis and are among the most successful targets for anticancer therapy. Panobinostat (LBH589) is a potent deacetylase inhibitor acting both on histones and nonhistonic proteins, including α-tubulin. In vitro LBH589, evaluated in three ATC cell lines (BHT-101, CAL-62 and 8305C), resulted in impairment of cell viability, inhibition of colony formation, cell cycle arrest and apoptosis induction. Mechanistically, we showed that LBH589 not only affected the expression of p21 and cyclin D1, but markedly determined microtubule stabilization as evidenced by tubulin acetylation and increased tubulin polymerization. In a SCID xenograft model implanted with CAL-62 cells, the cytotoxic properties of LBH589 were confirmed. The drug at the dose of 20 mg/kg significantly impaired tumor growth (final tumor volume 2.5-fold smaller than in untreated animals); at this dose, no relevant side effects were observed. In tumors of treated animals, a significant reduction of Ki67, which was negatively correlated with tubulin acetylation, was observed. Moreover, acetyl-tubulin levels negatively correlated with tumor volume at sacrifice, reinforcing the opinion that tubulin acetylation has a role in the inhibition of tumor growth. In conclusion, LBH589, acting on both histones and nonhistonic proteins in anaplastic thyroid cancer, appears to be a promising therapeutic agent for the treatment of this kind of cancer which is known not to respond to conventional therapy.     

Differential miRNA expression profiles in variants of papillary thyroid carcinoma and encapsulated follicular thyroid tumours

Background:

Recent studies showed a significant upregulation of distinct microRNAs (miRNAs) in papillary thyroid carcinoma (PTC). The objective of this study was to explore whether this upregulation could also be assigned to distinct histomorphological variants of PTC, especially the follicular variant and other encapsulated follicular thyroid tumours.

Methods:

We used total RNA of 113 formalin-fixed paraffin-embedded tissues of 50 PTCs ((10 conventional type (PTC-CT), 10 tall cell variants (PTC-TCVs), 30 follicular variants (PTC-FVs)), 10 follicular adenomas (FAs), 10 multinodular goitres (MNGs), 21 follicular thyroid carcinomas and 22 well-differentiated tumours of unknown malignant potential (WDT-UMP) to analyse the miRNA expression pattern of five selected miRNAs (146b, 181b, 21, 221 and 222) using RT–PCR TaqMan miRNA assay to explore the diagnostic utility of this method.

Results:

The mean values of the expression pattern of all miRNAS in PTCs show a statistically significant difference from those in MNG and FA with fold changes up to 90 for miRNA 146b, P<0.001. No differences in expression pattern could be showed between MNG and FA. The PTC-FVs differ significantly from FA in all five miRNAS, from MNG in three and from WDT-UMP in one miRNA with fold changes between 1.7 and 21.2, but failed to be of diagnostic value regarding individual cases with substantial overlaps.

Conclusion:

We conclude that analysis of a set of five selected miRNAS distinguish common variants of PTC from FA/MNG but failed to be a useful diagnostic method in individual and doubtful cases, especially in the differential diagnosis of encapsulated follicular thyroid tumours.     

Ultrasound‐guided fine‐needle aspiration biopsy of thyroid bed lesions from patients with thyroidectomy for thyroid carcinomas

BACKGROUND:

To evaluate the efficacy and the limitation of fine‐needle aspiration (FNA) biopsy in thyroid bed lesions, a retrospective review was performed of the medical records of thyroid cancer patients who underwent ultrasound‐guided FNA biopsy of the thyroid bed at The University of Texas MD Anderson Cancer Center over a 5‐year period.

METHODS:

Data were reviewed on 220 FNA biopsies taken from thyroid bed lesions in 195 patients who had undergone thyroidectomy for thyroid carcinoma. Thyroid bed FNA results were compared with clinical follow‐up, including neck dissection results.

RESULTS:

Recurrent carcinoma was diagnosed by FNA biopsy in 139 of 220 (63%) cases. Neck dissections were performed for 112 sites identified by FNA biopsies, and recurrent carcinoma was confirmed in 110 sites. The concordance between positive and/or suspicious FNA diagnosis and positive neck dissection results was 98% (118 of 120 cases). A false‐positive FNA occurred in one patient with follicular thyroid carcinoma. The other discrepancy was attributed to failure to remove the lesion by neck dissection. The diagnostic accuracy of thyroid bed FNA was 100% in papillary and medullary thyroid carcinoma and 93% in follicular thyroid carcinoma. Suspicious and rare false‐negative FNA results were attributed to low cellularity and lack of characteristic cytomorphologic features of thyroid carcinoma.

CONCLUSIONS:

Ultrasound‐guided thyroid bed FNA biopsy is accurate and efficient in triaging patients who require post‐thyroidectomy follow‐up for recurrent thyroid carcinoma. Caution should be taken in the interpretation of FNA specimens that have low cellularity and lack characteristic cytologic features of thyroid carcinoma. Cancer (Cancer Cytopathol) 2013. © 2012 American Cancer Society.     

Papillary thyroid cancer in identical twins

The cases of a set of 19-year old monozygotic twins are presented--the first report of thyroid cancer of follicular origin occurring in identical twins. This report includes a brief review of reports of cancer of various sites in twins. Several studies and reports emphasize genetic factors influencing the concurrence of cancer. Other reports downgrade the likelihood of genetic influence in cancer.     

Medical management of metastatic medullary thyroid cancer

Medullary thyroid cancer (MTC) is an aggressive form of thyroid cancer that occurs in both heritable and sporadic forms. Discovery that mutations in the rearranged during transfection (RET) proto‐oncogene predispose to familial cases of this disease has allowed for presymptomatic identification of gene carriers and prophylactic surgery to improve the prognosis of these patients. A significant number of patients with the sporadic type of MTC and even those with familial disease still present with lymph node or distant metastases, making surgical cure difficult. Over the past several decades, many different types of therapy for metastatic disease have been attempted with limited success. Improved understanding of the molecular defects and pathways involved in both familial and sporadic MTC has resulted in new hope for these patients with the development of drugs targeting the specific alterations responsible. This new era of targeted therapy with kinase inhibitors represents a significant step forward from previous trials of chemotherapy, radiotherapy, and hormone therapy. Although much progress has been made, additional agents and strategies are needed to achieve durable, long‐term responses in patients with metastatic MTC. This article reviews the history and results of medical management for metastatic MTC from the early 1970s up until the present day. Cancer 2014;120:3287–3301. © 2014 American Cancer Society.