Medullary Cancer Research Articles

Role of thyroid scintigraphy vs. fine needle aspiration cytology in the clinical evaluation of solitary thyroid nodule a clinicoradiopathologic study

To asses the value of qualitative and quantitative analysis of the radioisotopes 99m Tc tetrofosmin (Myoview) and 99m Tc (V) DMSA in the evaluation of malignant solitary thyroid cold nodule pre-operatively and to verify their exact value in diagnosis of differentiated thyroid carcinoma. In general there is a 5%-10% chance of malignancy in all thyroid nodules for the total population with higher incidence in single cold nodule than in multinodular goiter. The main role of 99m Tc (V) DMSA as a tumor imaging agent is in the diagnosis and follow-up of patients with medullary cancer thyroid. This work included 103 patients, 88 females and 15 males with a mean age of (37.86±13.59 years). All studied were subjected to history taking, proper clinical examination, thyroid function test profile, thyroid radioisotope imaging ( 99m Tc pertechnetate, 99m Tc tetrofosmin and 99m Tc (V) DMSA thyroid scans) and cytologic assessment of thyroid nodule proved to be cold on conventional thyroid scan. The current study combined both 99m Tc tetrofosmin and 99m Tc (V) DMSA to evaluate thyroid cold nodules and to verify possibility to differentiate between benign and malignant lesions preoperatively and as confirmed on cytology of lesions obtained by fine needle aspiration cytology (FNAC) modality. Our results showed that 99m Tc pertechnetate scan alone is not a reliable diagnostic tool to differentiate between benign and malignant thyroid nodules and that high early myoview uptake in the cold nodule is not specific for malignancy, it is also concluded that both 99m Tc tetrofosmin and 99m Tc (V) DMSA thyroid scans are valuable diagnostic tools when combined together.

Therapeutic approach guided by genetic alteration: Use of MTOR inhibitor in renal medullary carcinoma with loss of PTEN expression

Renal Medullary Cancer (RMC) is a rare and aggressive type of renal cell cancer that presents predominantly in patients with sickle cell hemoglobinopathies, and is typically metastatic at the time of presentation. Although platinum based chemotherapeutic regimens have recently emerged as the best option for producing a clinically significant response as reported in various case series, the response is far from satisfactory, as most RMC patients still succumb to their disease within a year of diagnosis. There is currently no standard of care for treatment of this disease. We report, to our knowledge, the first case of RMC where in molecular characterization of the tumor was used to guide therapy. In our patient, molecular analysis identified a decreased expression of Ribonucleotide Reductase M1(RRM1) and phosphatase and tensin homolog (PTEN). Based on these results of PTEN deficiency, we started our patient on everolimus (an MTOR inhibitor) maintenance after treating him with an induction chemotherapy regimen of Paclitaxel-Cisplatin-Gemcitabine (PCG). His tumor responded to induction therapy and he went into complete remission and remained in remission for 7 months. He is now alive about 14 months from his diagnosis and is asymptomatic with minimal disease. The rarity of RMC makes it very difficult to do any meaningful clinical trials in this group of patients. The overall prognosis for RMC remains very poor and knowledge about driver mutations may help in guiding therapy to improve survival in this select group of patients, where there is dearth of available therapies.

MEDULLARY CARCINOMA OF THE BREAST: ROENTGENOLOGIC AND ULTRASOUND SEMIOTICS

Breast cancer (BC) is the most common female cancer type and the leading cause of female cancer mortality in Russia and in majority countries of the world. Along with the most common type of BC – ductal carcinoma, there are a lot of histological types, distinguished by structure features, which lead to a variable clinical and instrumental semiotics. Thes e histological types of BC in the group marked out special types of BC, including medullary carcinoma. The concept of medullary cancer includes typical medullary BC, atypical medullary BC and invasive ductal BC with evidence of medullary morphology. Base d on the current literature data, the authors discuss the main epidemiological, clinical and morphological diagnostic features of medullary BC. The authors pay special influence pathological picture, forming the characteristic diagnostic features of medullary cancer detected using X-ray mammography and ultrasound of the breast – the basic techniques of BC and other breast diseases detection. I n 2003–2013 diagnosed 19 medullary BC cases in women aged 18–56 years, with 18 of them were recorded in patients aged 34–56 years. The authors describe in detail the features of clinical, mammographic and ultrasound semiotics of medullary BC. Article is focused on the main X-ray and ultrasound characteristics, such as mass shape and margin features, as well as its internal structure, and also the results of power Doppler. One of the main features of this article is description of ultrasound elastography pattern of medullary BC, which could be find in only a small number of scientific articles. T ypica l medullary BC, atypical medullary cancer and ductal carcinoma with medullary signs have different prognosis. This problem leads to necessity find reliable distinguishing features in mammograpic and ultrasound semiotics. It is seems important to reveal sites with indistinct margin. We have found the indistinct margin detection is not statistically significant for the differential diagnosis of typical forms of medullary BC from atypical forms and invasive ductal BC with evidence of medullary structure. Th e authors conclude that the mammographic and ultrasound semiotics of medullary BC makes accurate differential diagnosis with benign breast pathology by X-ray mammography as well as breast ultrasound impossible. There are no statistically significant differences in the results of the mammography and breast ultrasound in different histological types of medullary BC. So these diagnostic features are not reliable for the differential diagnosis. However, the application of a comprehensive usage of mammography and breast ultrasound using modern technology of ultrasound diagnosis allows to suspect BC.

Thyroid nodules in children - rules of management

In children, thyroid lesions both palpable (nodules) and non-palpable, but visible during ultrasound (incidentaloma), require a full diagnostic procedure in accordance with the nodular goiter management algorithm. It is especially important because in children the risk of neoplastic process in thyroid nodule is 4-5 times higher than in adult patients, and reaches between 9 and 50% (on average 25%). The pathogenesis of a goiter is not entirely known. Among the causative factors for thyroid nodules or focal lesions the literature mentions: environmental factors i.e. iodine excess or insufficiency, exposure to radiation, natural goitrogens, chemical substances (lithium carbonate), pollution (phenols, phthalates, pyridines and aromatic carbohydrates), hormonal factors (TSH, IGF-I, EGF, FGF), neuropeptides, cytokines (TGF- β), immunoglobulins (TGI) and genetic factors – TSH receptor mutation, RAS oncogene mutation (mainly responsible for follicular adenoma), mutations and polymorphisms of several genes including thyroid peroxidase gene, thymoglobulin gene, sodium-iodide symporter gene, BRAF gene, as well as mutation of genes encoding microRNA. The DICER 1 mutation and germinal mutation of KEAP 1 have recently been discovered. It is also worth mentioning that during adolescence, when the requirement for thyroid hormones is increased, the thyroid gland is particularly susceptible to enlargement. Hyperglobulinemia resulting from augmented estrogen secretion in girls is another factor. It causes an increase in the pool of globulin-bound hormones and therefore relative free thyroxin (FT4) deficiency. That, in turn, leads to increased TSH levels, which is the most important factor stimulating thyroid growth. Thyroid nodules are present in 0.2-5% of children, more frequently in girls. Morbidity increases with age. The rate of malignancy in thyroid nodules is greater in children before the age of 10 and in boys. Similarly, as in adults, papillary carcinoma is the most common thyroid malignancy. Thyroid nodules in children demonstrate particular characteristics. Most neoplastic and non-neoplastic lesions tend to form singular nodules. Children present clinical signs such as dyspnea, dysphagia or hoarseness more rarely than adults. Patients are usually asymptomatic. Thyroid nodules in children comprise neoplastic and non-neoplastic masses, among the latter the nodular type of Hashimoto disease is the most frequent. However it is important to remember about the possibility of thyroid congenital disorders. The main goal of thyroid nodule diagnostic process is to detect patients with malignancy risk factors. Primarily, the medical history should be obtained to gain information about the occurrence of thyroid diseases, including cancers, in patient’s family. Especially, the family history in first-degree relatives should be carefully determined for MEN (multiple endocrine neoplasm) type 1 and 2, familiar medullary thyroid cancer and familial non-medullary thyroid cancer. Medical history should also include information about exposition to therapeutic or environmental radiation, about symptoms which may indicate hyper- or hypothyroidism, the history of nodule growth (rapid growth), neck pain or any symptoms of compression. Palpation allows estimation of the size and consistency of the thyroid gland, nodules and local lymph nodes. Among complementary diagnostic methods, the main role is reserved for ultrasound-guided fine needle aspiration (FNA). Moreover, thyroid function tests should always be performed, including measuring concentrations of TSH, thyroid hormones, and anti-thyroid autoantibodies. Thyroid scintigraphy is recommended in some cases, such as preparation for radioiodine therapy of hyperthyroidism, examination of ectopic thyroid gland or diagnosis of congenital hypothyroidism. It is important to evaluate calcitonin level in the following cases: clinical suspicion of medullary cancer or confirmed RET mutation, non-diagnostic FNA with no further plans for surgery, FNA indicating follicular neoplasm, coexistence of thyroid nodules and adrenal gland lesions, and – finally – before each thyroid surgery, as the knowledge of calcitonin level enhances pre- and intraoperative diagnosis of medullary cancer and helps to determine the extent of the surgery. In benign thyroid nodules that do not enlarge, it is acceptable to follow a “watch and wait” approach. Pharmacotherapy with levothyroxine (L-T4) is recommended in small, benign nodules presenting in children inhabiting iodide-deficient regions. The aim is to suppress TSH secretion. The dose of L-T4 is regulated based on TSH level, which should remain in lower limit of normal range. If the environmental iodide supply is adequate, this kind of therapy ought to be considered when anti-thyroid autoantibodies are detected. Nevertheless, thyroidectomy (subtotal or – less frequently – lobectomy) remains the most efficient therapeutic measure in thyroid nodules in children.

Methylation of the BRCA1 promoter in peripheral blood DNA is associated with triple-negative and medullary breast cancer.

It has been proposed that methylation signatures in blood-derived DNA may correlate with cancer risk. In this study, we evaluated whether methylation of the promoter region of the BRCA1 gene detectable in DNA from peripheral blood cells is a risk factor for breast cancer, in particular for tumors with pathologic features characteristic for cancers with BRCA1 gene mutations. We conducted a case-control study of 66 breast cancer cases and 36 unaffected controls. Cases were triple-negative or of medullary histology, or both; 30 carried a constitutional BRCA1 mutation and 36 did not carry a mutation. Blood for DNA methylation analysis was taken within three months of diagnosis. Methylation of the promoter of the BRCA1 gene was measured in cases and controls using methylation-sensitive high-resolution melting (MS-HRM). A sample with any detectable level of methylation was considered to be positive. Methylation of the BRCA1 promoter was detected in 15 of 66 cases and in 2of 36 controls (OR 5.0, p=0.03). Methylation was present in 15 of 36 women with breast cancer and without germline BRCA1 mutation, but in none of 30 women with breast cancer and a germline mutation (p<0.01). The association between methylation and breast cancer was restricted to women with no constitutional BRCA1 mutation (OR 12.1, p=0.0006). Methylation of the promoter of the BRCA1 gene detectable in peripheral blood DNA may be a marker of increased susceptibility to triple-negative or medullary breast cancer.

Thyroid Diseases

The thyroid plays a key role in normal metabolic and homeostatic processes, including thermomodulation, protein synthesis, carbohydrate and lipid metabolism, and modulation of adrenergic regulation. Surgical consultations are most often requested for control of hyperthyroidism or for treatment of euthyroid nodular disease. This review describes the approach to the patient with hyperthyroidism and with euthyroid nodular disease, including papillary, follicular, anaplastic, medullary, and primary thyroid cancer, and oncocytic (Hürthle cell) carcinoma. Operative techniques of thyroidectomy are described and include positioning, incisions-making, and troubleshooting. Postoperative care, including thyroid hormone management, is described. Complications and outcome evaluation are discussed. Tables list the etiologies of hyperthyroidism, benign and malignant etiologies of euthyroid nodular disease, familial syndromes of thyroid disease, the Bethesda classification of fine needle aspiration cytology and associated malignancy risk, the elements of common prognostic schemes for well-differentiated thyroid cancer, and the staging of differentiated, medullary, and anaplastic thyroid cancer. Figures show the six levels of cervical lymph nodes, the initial incision in a thyroidectomy, a midline incision, the superior pole vessels, the upper and lower parathyroid glands, the recurrent laryngeal nerve, and Delphian lymph nodes. An algorithm shows the approach to the patient with thyroid disease This review contains 7 figures, 8 tables, and 64 references.

PD1-4 - Molecular Targeting Therapy for Thyroid Cancer: Problems in Clinical Practice

Several molecular targeting drugs, especially RAF-, RET- and/or VEGFR-targeting drugs have been developed for thyroid cancer. Sorafenib for differentiated cancer and vandetanib for medullary cancer are approved in US and will be approved in Japan in near future. Those drugs have some unique adverse events (AEs) and should be properly managed for effective therapy.Sorafenib is a multi-tyrosine kinase inhibitor (TKI) and inhibits RAF, VEGFR-2,3, PDGFR, c-kit, Flt-3, and already approved for renal cell carcinoma and hepatic cell carcinoma in Japan. Major AEs caused by sorafenib are hypertension, hand foot syndrome (HFS), eruption, diarrhea, and fatigue, and considered to be mainly caused by VEGFR inhibition.Hypertension usually develops early (within 6 weeks), and mostly controlled by antihypertensive drugs such as Ca antagonists or angiotensin receptor blockers. HFS can have a significant impact on QOL of patients, and seems more frequent in thyroid cancer patients and Japanese. It often develops early (within 1-2 weeks) at regions with mechanical stress. Preventive measures such as keeping skin clean, removal of hyperkeratotic areas, and usage of cushioning are recommended. If symptoms reach grade 2 or more, the mainstay of management is dose modification, but supportive treatment, topical corticosteroid and analgesics should be used. Eruptions are usually mild, but Japanese patients occasionally cause erythema multiforme or Stevens-Johnson syndrome. Diarrhea is frequent especially in patients treated for long time, but severe cases are rare. Severe fatigue is also infrequent.Endocrine surgeons who mainly treat thyroid cancer are not familiar with AEs of TKIs, so cooperation with medical oncologist and team-oriented therapy with nurses, pharmacists, or others are very important for effective therapy with molecular targeting agents.

Approach to thyroid nodules in children and adolescents

Thyroid nodule prevalence is about 1.8% in healthy children; however, malignancy frequency is higher than in adults. Approximately 26.4% of thyroid nodules generate thyroid cancer in childhood. Coexisting thyroid disease, history of irradiation of the neck, post-pubertal age, female sex, and thyroid malignancy in the family are risk factors for developing nodules. After evaluation of the medical history and detailed physical examination, the second step is assessment of thyroid function and measurement of calcitonin level. Thyroid stimulating hormone (TSH) value in the upper range seems to be correlated with cancer. Calcitonin levels must be evaluated, especially if medullary cancer is suspected. Ultrasonography (USG) is the first-line imaging tool in the diagnosis of thyroid nodules. It gives information about the nodule size, echogenicity and location. Hypoechogenicity, microcalcifications, undefined margins, high internodular vascular flow, and subcapsular localization are clues of malignant lesions. Scintigraphy is only recommended in a solid nodule with the presence of suppressed TSH. Fine-needle aspiration biopsy (FNAB) has 90% accuracy and is very useful in the selection of patients for surgery. It must be applied to all nodules &amp;#x2265;1 cm and nodules &amp;#x2264;1 cm suspicious for malignancy. The other diagnostic tools are elastography, immunocytochemical markers and genetic evaluation. In the management of thyroid nodules, surgery is advised, especially if there is difficulty in distinguishing benign lesions from carcinoma.

Use of transoral sonography with an endocavitary transducer in diagnosis, fine-needle aspiration biopsy, and intraoperative localization of retropharyngeal masses.

The purpose of this article is to describe the use of transoral sonography in the diagnosis, fine-needle aspiration (FNA) biopsy, and intraoperative localization of retropharyngeal masses. We reviewed images and data for eight patients with a retropharyngeal mass identified on CT, MRI, or PET/CT as being suspicious for a metastatic Rouviere node. Transoral ultrasound was performed using a commercially available endorectal or endovaginal transducer. Transoral ultrasound-guided FNA biopsy was performed using a needle guide attached to the transducer shaft. Color and power Doppler imaging were used to identify the internal carotid artery and jugular vein and to plan the safest path to the targeted mass. The mass was intraoperatively localized by marking the mucosa with a permanent marker or by injecting methylene blue. There were six patients with a history of thyroid cancer (five papillary cancers and one medullary cancer), one patient with a history of esthesioneuroblastoma, and one patient with no history of cancer. Transoral ultrasound imaging was successful in all eight patients. Transoral ultrasound-guided FNA biopsy was performed in four patients, and a satisfactory cytologic diagnosis was obtained in all cases, although in one of those four cases, an additional core biopsy with an 18-gauge needle was performed to completely rule out lymphoma. Six patients underwent a transoral resection of the lesion. In three of them, the lesion was localized intraoperatively by making a mark on the mucosa and in one case by adding transoral ultrasound-guided injection of methylene blue. Transoral ultrasound can be used to visualize, sample, and localize abnormal masses in the retropharyngeal space, such as metastatic Rouviere nodes in patients with a history of head and neck cancer.

Measurement of tumour size with mammography, sonography and magnetic resonance imaging as compared to histological tumour size in primary breast cancer

BackgroundTumour size in breast cancer influences therapeutic decisions. The purpose of this study was to evaluate sizing of primary breast cancer using mammography, sonography and magnetic resonance imaging (MRI) and thereby establish which imaging method most accurately corresponds with the size of the histological result.MethodsData from 121 patients with primary breast cancer were analysed in a retrospective study. The results were divided into the groups “ductal carcinoma in situ (DCIS)”, invasive ductal carcinoma (IDC) + ductal carcinoma in situ (DCIS)”, “invasive ductal carcinoma (IDC)”, “invasive lobular carcinoma (ILC)” and “other tumours” (tubular, medullary, mucinous and papillary breast cancer). The largest tumour diameter was chosen as the sizing reference in each case. Bland-Altman analysis was used to determine to what extent the imaging tumour size correlated with the histopathological tumour sizes.ResultsTumour size was found to be significantly underestimated with sonography, especially for the tumour groups IDC + DCIS, IDC and ILC. The greatest difference between sonographic sizing and actual histological tumour size was found with invasive lobular breast cancer. There was no significant difference between mammographic and histological sizing. MRI overestimated non-significantly the tumour size and is superior to the other imaging techniques in sizing of IDC + DCIS and ILC.ConclusionsThe histological subtype should be included in imaging interpretation for planning surgery in order to estimate the histological tumour size as accurately as possible.

Saving the bones in breast cancer: aromatase inhibitor-induced osteoporosis

The prognosis in breast cancer is worse in younger patients, invasive papillary, classic lobular and medullary cancers, tumors more than 1 cm in diameter, four or more positive axillary node and es...

P-201EXTENDED TRANSCERVIVAL APPROACH WITH ELEVATION OF THE STERNUM FOR RESECTION OF THE THYROID CANCER METASTATIC NODES AFTER PREVIOUS THYROIDECTOMY: ANALYSIS OF THE LARGEST REPORTED SERIES

Objectives: Analysis of the operative technique and the results of the minimally invasive transcervical approach for resection of the mediastinal metastatic lymph nodes of the thyroid cancer. Methods: Clinical diagnosis of the metastatic spread to the mediastinal nodes was based on the elevated thyreoglobulin (Tg) level for papillary and follicular cancer, elevated calcitonin (Ct) level for medullary cancer and on visualization of the suspicious nodules on the imaging studies (CT, PET/CT, scintigraphy). The patients with retrosternal goiter and ectopic mediastinal goiter were excluded. Operative technique included elevation of the sternum with a hook connected to special frame (Rochard bar, Aesculap-Chifa, Nowy Tomysl, Poland) which widened the access to the mediastinum. The mediastinal nodes were resected en-bloc with the surrounding fatty tissue. The dissection was guided by the previous imaging studies. Results: Overall, there were 94 patients operated on in the period from 1 July 2007 to 31 December 2012. In 5 patients (5.3%) concomitant thyroidectomy was performed. Re-resection of the recurrent metastases was performed in 7 patients. In 43 patients there was single mediastinal nodal station involved and in 51 patients there were multiple (2-5) nodal stations involved. Resection was incomplete in 5 patients (5.3%). Conversion to sternotomy/thoracotomy was necessary in 3 patients (3.2%). In 5 patients (5.3%) concomitant partial sternectomy was performed for sternal metastasis. There was no mortality and 8.9% morbidity. Conclusions: Analysis of this largest reported series of the mediastinal metastases of the thyroid cancer showed that transcervical approach with elevation of the sternum enabled minimally invasive, safe and effective resection with sternotomy or thoracotomy avoided in almost all patients. Detailed imaging studies of chest should be a standard of preoperative evaluation of patients with thyroid cancer. Disclosure: All authors have declared no conflicts of interest. Interactive CardioVascular and Thoracic Surgery

New developments in the diagnosis and treatment of thyroid cancer

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.

Management of pediatric and adolescent breast masses.

Breast masses in children and adolescents are uncommon and most often benign. Occasionally, however, they require surgical intervention for lifestyle limiting symptoms or malignant potential. These masses are best evaluated with physical exam and ultrasound. Breast masses likely to be encountered by the surgeon in the pediatric and adolescent population include intraductal papillomas, phyllodes tumors, primary breast cancer, and metastatic lesions. Unlike adults, pediatric and adolescent breast cancer tends to be of the secretory variety and typically have less metastatic potential. However, cases of inflammatory and medullary breast cancers have also been reported in girls and appear more aggressive. Radiation exposure during breast development is a risk factor to subsequent development of breast cancer. Surgical objective for a concerning pediatric and adolescent breast mass is complete resection while preserving normal breast development, when appropriate. The need for routine axillary dissection for malignant cases in children appears unnecessary from the limited data available, and the authors favor sentinel lymph node sampling and reserve axillary dissection for positive lymph nodes.

Risk stratification in medullary thyroid cancer: Moving beyond static anatomic staging

Much progress has been made over the last 10 years with regard to risk estimation in non-medullary differentiated thyroid cancer with risk of recurrence systems and response to therapy re-evaluation approaches being used to augment initial risk estimates obtained using standard anatomic staging systems. Furthermore, risk stratification is being increasingly viewed as an active, evolving, dynamic process that requires re-evaluation during follow-up rather than a single static risk estimate predicted by initial staging. As with differentiated thyroid cancer, multiple clinico-pathologic factors have been demonstrated to correlate with the risk of disease specific mortality, risk of death, likelihood of disease progression, likelihood of cure with initial therapy, and likelihood of cure with additional therapy in medullary thyroid cancer. In this review, we re-examine the clinically important initial risk factors in medullary thyroid cancer and then re-evaluate how some of these risk factors can be used to alter risk estimates over time as they reflect the response to therapy and the clinical course of the disease. We demonstrate that the same response to therapy nomenclature that we have proposed and validated in differentiated thyroid cancer (excellent response, biochemical incomplete response, structural incomplete response, indeterminant response) can be easily applied to medullary cancer and used to guide on-going clinical management.

Abstract 4096: FAK inhibition with small molecule inhibitor Y15 decreases viability in thyroid cancer cell lines.

Abstract Introduction: Thyroid cancer is the most common endocrine malignancy and papillary the most common subtype. While low stage papillary carcinomas are treatable, for nonresectable tumors that do not respond to iodine, a treatment is still needed. In comparison, for advanced medullary cancer, a tyrosine kinase inhibitor, Vandetanib, is currently being used. Focal Adhesion Kinase (FAK) is a tyrosine kinase involved in many protein-protein interactions that control important cellular functions. FAK is upregulated in many cancer cell lines, including thyroid. It contains an autophosphorylation site Y397, which is blocked by 1,2,4,5-Benzenetetraamine tetrahydrochloride (Y15), a small molecule FAK inhibitor. We propose that this inhibitor, Y15, will decrease viability of thyroid cancer cell lines. Methods: Four human thyroid cancer cell lines were cultured in vitro. K1, BCPAP, and TPC1 were derived from papillary thyroid carcinomas, and TT was derived from a medullary thyroid carcinoma. Western blots were used to detect expression of FAK and pY397 FAK in each untreated line. These were repeated with differing concentrations of Y15 plus the Novartis FAK inhibitor TAE226 as a positive control. MTS assays of each cell line were used to measure cell viability with increasing doses of Y15. Untreated medium, DMSO, and TAE226 were used as negative and positive controls. Results: All untreated thyroid cancer cell lines expressed FAK and phosphorylated Y397 FAK on Western blotting. Increasing doses of Y15 in Western blotting decreased the expression of pY397 FAK in all cell lines. This was also associated with increased cell detachment. In MTS assays, viability was also decreased with Y15 in a dose-dependent manner across all cell lines. Significant inhibition was reached at relatively low doses: there was a 90% decrease in viability with 10μM Y15 in TPC1 cells and 5μM Y15 in TT cells. The effects were seen across all lines, but most profound in TPC1 and TT. Conclusions: Papillary thyroid cancer cell lines and medullary carcinoma cells express FAK and pY397. The FAK inhibitor Y15 causes a dose-dependent decrease of phosphorylated FAK, and this disruption decreases cell viability. Our data suggests Y15 may be an effective potential treatment for advanced papillary thyroid cancer. Citation Format: Shalana B. O'Brien, Vita M. Golubovskaya, William G. Cance. FAK inhibition with small molecule inhibitor Y15 decreases viability in thyroid cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4096. doi:10.1158/1538-7445.AM2013-4096

RASMutations in Thyroid FNA Specimens Are Highly Predictive of Predominantly Low-Risk Follicular-Pattern Cancers

RAS mutations are common in thyroid tumors and confer a high risk of cancer when detected in fine-needle aspiration (FNA) specimens. Specific characteristics of RAS-positive thyroid cancers are not well described. From April 2007 to April 2009, 921 consecutive patients undergoing FNA were evaluated prospectively with a panel of molecular markers. Ultrasonographic, cytological, histological, and surgical outcomes were retrospectively assessed. Sixty-eight aspirates from 66 patients were positive for RAS mutations including 63 cytologically indeterminate (93%), 3 malignant (4%), and 2 benign (3%) specimens. Cancer was histologically confirmed in 52 of 63 aspirates (83%) including the following: 46 papillary thyroid cancers, 4 follicular thyroid cancers, 1 medullary cancer, and 1 anaplastic cancer. All 46 RAS-positive papillary thyroid cancers, including 1 metastatic cancer, had follicular variant histology papillary thyroid cancer; only 11 tumors demonstrated vascular/capsular invasion and 4 had infiltrative growth. Of 48 patients with differentiated thyroid cancer, lymph node metastasis was uncommon and bilateral cancer was present in 48%. Only 33% of malignant nodules were suspicious by preoperative ultrasonography. At a mean follow-up of 22 months, 31 of 35 differentiated thyroid cancer patients (89%) have no evidence of recurrence, 4 patients (9%) have detectable thyroglobulin, 1 patient has bone metastases, and both patients with medullary and anaplastic cancer have died. Most RAS-positive thyroid cancers have indeterminate cytology, lack suspicious ultrasound features, and are histologically low-grade follicular variant histology papillary thyroid cancer. Lymph node and distant metastases are uncommon but bilateral disease is frequent. Total thyroidectomy should be considered for initial surgical management of most patients with RAS-positive FNA results. The role of prophylactic lymphadenectomy remains unclear.

Paediatric thyroid cancer: the Scottish experience

Paediatric thyroid cancer is a rare disease, making diagnosis and treatment particularly challenging. Here we present the Scottish experience of thyroid cancer in the paediatric population and give an overview of how a child or adolescent that presents with a thyroid nodule should be investigated and managed. Data has been obtained from ISD Scotland, giving population-based information on paediatric thyroid cancer. A literature review has been performed on the management and treatment of thyroid cancer in the younger population. Paediatric thyroid cancer in Scotland is a rare disease, although the incidence is increasing each year. In general, differentiated paediatric thyroid cancer carries a good prognosis, while the results are more mixed in the rarer pathologies such as medullary cancer. Due to the small numbers of patients diagnosed each year in Scotland, it is imperative that these patients are discussed at a multidisciplinary thyroid MDT and managed in a tertiary referral centre by consultants and medical/nursing support staff who have experience in treating these patients.

Diagnostic and Therapeutic Implications of Tumor-Infiltrating Lymphocytes in Breast Cancer

In the age of personalized medicine, the multitude of scientific publications describing new biomarkers has raised a lot of criticism, as many of these results have been rather difficult to validate. As a consequence to this criticism, we are observing a considerable improvement in the design of clinical biomarker studies, which are increasingly based on large sample cohorts from clinical trials. The article by Loi et al that accompanies this editorial exemplifies this. Loi et al report a prognostic role for tumor-associated lymphocytes in triple-negative breast cancer in a large prospective clinical trial, evaluating more than 2,000 tumor samples from patients with nodepositive breast cancer treated within the Breast International Group (BIG) 02-98 trial. The main finding of the study was that in estrogen receptor–negative/human epidermal growth factor receptor 2 (HER2) –negative breast cancer (n 256) an increased lymphocytic infiltrate was linked to a reduced relapse rate and improved survival. This association was independent of the type of chemotherapy and was not observed in hormone receptor–positive tumors (n 1,078). In the subgroup of HER2-positive tumors (n 297) there was a significant interaction with benefit from anthracycline-only chemotherapy. It should be noted, however, that trastuzumab was not part of the adjuvant treatment in BIG 2 to 98, which limits the interpretationof theresults intheHER2-positivesubset inthecontextofcurrent therapeutic approaches. The study by Loi et al shows that tumor-infiltrating lymphocytes can be evaluated as a distinctive histological parameter using the predefined standardized definitions of intratumoral lymphocytes, stromal lymphocytes and lymphocyte-predominant breast cancer (LPBC). We have evaluated the nearly identical parameters in tumor samples from the neoadjuvant GeparTrio study, with a slightly different definition of LPBC. In this study, we have shown that a pretherapeutic immunological infiltrate is a predictive factor for response to neoadjuvant therapy. In the neoadjuvant situation, an increased rate of pathological complete response was observed in different tumor subtypes including hormone receptor–positive tumors. In contrast, the survival effect in the study by Loi et al was present only in the triple-negative subgroup. This difference could be explained by the fact that pathological complete remission is a surrogate end point for survival for triple-negative, but not for hormone receptor–positive breast cancer. The results of this report are consistent with the functional model that is emerging from preclinical studies. Zitvogel et al has evaluated the interaction between tumor cells and the immune system in various cellular and animal models. From their research the concept is emerging that the response to chemotherapy is at least partly dependent on an immunological reaction against those tumor cells that are dying during the chemotherapy. In a recent paper, it has been shown that in particular those cancer cells that are hyperploid become immunogenic due to an increased accumulation of calreticulin on the cell surface. Those results from preclinical models as well as translational studies suggest that the combination of standard chemotherapy with immunomodulatory concepts might be worth an evaluation in clinical trials. It should be noted that a similar prognostic effect of increased lymphocytic infiltrate in triple-negative tumors has been observed in another study by West et al using immunohistochemistry as well as gene expression analysis of inflammatory markers. Molecular immunological parameters, such as immunoglobulin kappa C and IL8 have been reported as prognostic parameters in breast cancer, suggesting that those parameters could form a basis for future molecular diagnostic tests. From a pathologist’s point of view, the concept of a tumor that has a predominant lymphocytic infiltrate is similar to the classical tumor type of medullary breast cancer that has been described by Moore and Foote already in 1949. In classical pathology several definitions for medullary breast cancer have been suggested including parameters such as a predominant lymphocytic infiltrate, a so-called syncytial cell architecture and a well-defined border of the tumor. It has been shown that this tumor type has a particularly good prognosis. However, true medullary carcinoma is extremely rare, a recent evaluation of 12,409 patients from International Breast Cancer Study Group trials has found only 127 medullary carcinomas (1%). In addition to medullary breast cancer, a prominent lymphoplasmacellular infiltrate is observed in certain types of hereditary breast cancer. Evaluation of tumor-associated lymphocytes by standard hematoxylin and eosin staining is extremely inexpensive and can be performed easily in the setting of the routine histopathological evaluation. Considering that medullary breast cancer is an old pathology concept and that tumor-associated lymphocytes are also relevant for BRCA-mutation–associated breast cancer, pathologists should perhaps get used to reporting this parameter as a part of the standard histological description of breast cancer. In addition, the parameters of stromal and intratumoral infiltrate should be added to the standard parameters evaluated in the context of clinical studies. This is already JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 7 MARCH 2013

Общие аспекты диагностики и лечения местно-распространенного рака щитовидной железы

The paper deals with current trends in the diagnosis and treatment of locally advanced, recurrent and metastatic medullary and low-grade thyroid cancer. It highlights problems in the diagnosis and surgical treatment of this pathology on the basis of our clinic’s experience. Data on global trends in medical treatment for low-grade radioactive iodine therapy-refractory thyroid tumors, as well as disseminated and metastatic medullary cancer are given.