Recurrent Thyroid Cancer Research Articles

Detection of Serum Deoxyribonucleic Acid Methylation Markers: A Novel Diagnostic Tool for Thyroid Cancer

Serum DNA methylation markers may potentially be useful in diagnosing thyroid cancer and monitoring its recurrence. The objective of the study was to assess the utility of serum DNA methylation as a diagnostic test for patients with thyroid nodules and a monitoring test to detect thyroid cancer recurrence in previously treated patients. Using real-time quantitative methylation-specific PCR, we analyzed the methylation status of five genes (CALCA, CDH1, TIMP3, DAPK, and RARbeta2) on 96 bisulfite-treated serum DNA samples isolated preoperatively from either solid thyroid nodule patients or patients in follow-up for history of treated thyroid cancer. Diagnostic sensitivity, specificity, and accuracy of serum DNA methylation marker for thyroid cancer were measured. For the patients with thyroid nodules, when a positive result was defined by a serum methylation level above the appropriately chosen cutoff value for any one of the five genes, the preoperative diagnostic sensitivity for thyroid cancer was 68% (26 of 38), the specificity was 95% (18 of 19), and the overall preoperative diagnostic accuracy was 77%, with positive and negative predictive values of 96 and 60%, respectively. In a subset of patients with cytologically indeterminate thyroid nodules, serum DNA methylation testing could correctly diagnose eight of 11 (73%) cancers and four of four (100%) benign tumors, with a diagnostic accuracy of 80%. We also analyzed these serum DNA methylation markers in 39 previously treated thyroid cancer patients. Among the 10 patients proved to have recurrent disease by conventional measures, seven (70%) were positive on methylation testing. Among the 29 patients who had no corroboration of residual or recurrent disease by conventional studies, six (21%) were positive for serum DNA methylation markers. We have demonstrated the potential usefulness of serum DNA methylation markers as a novel tool for differential diagnosis of solid thyroid nodules and thyroid cancer recurrence monitoring.

Increased Expression of Valosin-Containing Protein (p97) Is Correlated With Disease Recurrence in Follicular Thyroid Cancer

Valosin-containing protein (VCP) is involved in the ubiquitin/proteasome-degradation pathway, which works in proliferation and antiapoptosis in human cancer cells. Our previous study showed that VCP expression levels correlated with the recurrence and prognosis of several human cancers, such as hepatocellular carcinoma, gastric carcinoma, and colorectal carcinoma. In this study, the correlation of VCP expression with the prognosis of differentiated thyroid carcinoma was examined. VCP expression in 332 patients who underwent operation for differentiated thyroid carcinoma--257 with papillary thyroid carcinoma and 75 with follicular thyroid carcinoma (FTC)--was analyzed by immunohistochemistry. The staining intensity in tumor cells was categorized as weaker than (low expression), equal to (intermediate expression), or stronger than (high expression) that in endothelial cells in noncancerous tissue. One hundred ten (33.5%) cases showed low VCP expression, 117 (28.0%) showed intermediate expression, and 101 (30.8%) showed high expression. VCP expression significantly correlated with histological subtype (P < .05) and lymph node metastasis (P < .01). However, it correlated with neither any clinicopathologic factor nor prognosis in papillary thyroid carcinoma. VCP expression correlated with extrathyroidal extension (P < .05), pT classification (P < .05), and lymph node metastasis (P < .01) in FTC. Patients with low VCP expressing FTC showed better disease-free and overall survival rates than those with intermediate or high expression (P < .01 and P < .05, respectively). Multivariate analysis revealed VCP expression and extracapsular extension to be independent prognostic factors for disease-free survival in cases of FTC. The prognostic utility of VCP expression in FTC was demonstrated.

Modern Approaches to Age-Old Questions About Thyroid Tumors

There is a compelling need for improvement in the diagnosis of thyroid nodules, in predicting thyroid cancer prognosis and, in the treatment of recurrent well-differentiated and anaplastic thyroid cancer. In this review we discuss the impact of genomic technologies such as microarrays, SAGE, and proteomics on the diagnosis, prognosis and treatment of thyroid cancer. Gene expression profiling using these technologies has shown promising results in the molecular classification of different types of cancer, including thyroid. Furthermore, microarrays have been successfully used to identify prognostic markers in other cancer-types, offering the possibility to better tailor thyroid cancer treatment schemes. Lastly, novel therapeutic targeting against tyrosine kinases have shown promising results in the treatment of several cancers and might prove to be beneficial for patients with recurrent or undifferentiated thyroid cancer.

Risk factors of recurrent medullary thyroid cancer and factors that influence on prognosis

5594 Background: Medullary thyroid cancer, which is quite a rare disease that occupies 5 - 10% of total thyroid cancers. Residual or recurrent MTC, manifested by elevated calcitonin levels, occurs commonly following a primary treatment of MTC. Methods: The study group consisted of 37 patients of MTC at Kyungpook National University Hospital between 1985 and July 2003. We analyzed the medical records of MTC operation cases in retrospective ways to find out treatment results and utilized the Kaplan-Meier and chi- square test to figure out the correlation of prognosis and recurrence. Results: The average age of patients was 39.4 years and 7 cases among them had a family history and accompanying disease. No one had metastasis at the time of diagnosis. 24 cases (64.9%) showed unilateral locations. 21.6% of them were diagnosed to be MTC in tests taken before operation and cold thyroid nodules were shown in 32 cases. Calcitonine was measured in 11 cases before operation took place, showing 2438 pg/ml on average and decreased in 10 cases after the operation. 48.6% of them showed lymph node metastasis at the time of operation and invasion of surrounding organs was shown in 13.5% of them. Total thyroidectomy and central neck dissection was carried out in all cases. Modified radical neck dissection was carried out at first in 17 cases. 13 cases out of 37 experienced a recurrence, and most was the neck recurrence. Treatment for neck recurrence was a modified neck dissection. 5 of them died and it was mostly due to lung metastasis. We analyzed the factors that affected recurrence and it was shown that lymph node metastasis and the TNM stage had a statistically significant relationship. No factor showed relevance to prognosis with multivariate analysis. The survival rates were 93.6% for 5 years, 86.1% for 10 years, and 76.5% for 15 years. Conclusions: We could not find any statistical significance in the factor relevant to prognosis in the patients in multivariate analysis. However, as the survival rate was 76.5% for 15 years, if surgical treatment (total thyroidectomy and central neck dissection) and constant follow-up are followed after operation, then future improvement can be expected from treatment for medullary thyroid cancer. No significant financial relationships to disclose.

Altered Expression of Cyclins and Cell Cycle Inhibitors in Papillary Thyroid Cancer: Prognostic Implications

Currently we lack biochemical or molecular markers that predict recurrence and metastases in thyroid cancer. Recent studies in a number of other human malignancies indicate that expression and/or subcellular localization of certain cell cycle regulators has prognostic utility. We have investigated the expression of cyclins D1 and E and of cyclin-dependent kinase inhibitor's p21 and p27 in papillary thyroid cancer (PTC) and correlated this with clinical/histological stage at diagnosis and with clinical outcome. PTCs were compared to normal thyroid, adenomas, and undifferentiated thyroid cancers (UTCs). Our studies indicate that PTCs and UTCs demonstrate low nuclear expression of cyclin E and p27, allowing a clear distinction between adenomas and these carcinomas (p < 0.004). A pattern of low nuclear expression of all four markers was observed in stage IV PTCs and UTCs, while stage I PTCs had low D1 and E accompanied by high p21 or p27. Expression of cytoplasmic cyclin D1 was significantly lower in stage IV PTCs and UTCs than in stage I-III PTC's (p </= 0.020), and appeared to correlate inversely with poor outcome in PTCs (p = 0.010). These studies suggest that evaluation of a panel of these markers and attention to their subcellular localization may be a useful adjunct in differentiating benign from malignant thyroid neoplasms and in predicting tumor behavior.

Abstract #900: Use of Multiple Imaging Modalities for Detection of Recurrent and Metastatic Thyroid Cancer

Abstract #900: Use of Multiple Imaging Modalities for Detection of Recurrent and Metastatic Thyroid Cancer

Intraoperative parathyroid hormone levels in thyroid surgery are predictive of postoperative hypoparathyroidism and need for vitamin D supplementation

Background Intraoperative parathyroid hormone (ioPTH) levels are not monitored routinely in thyroid surgery, although they are used widely during parathyroidectomy as an indicator of parathyroid gland function. This prospective study evaluated the occurrence of hypoparathyroidism after thyroid surgery and the use of ioPTH levels to predict the need for postoperative vitamin D supplementation. Methods Seventy-two patients underwent thyroidectomy or neck dissection by 1 surgeon. Forty-five patients had a total thyroidectomy, 16 patients had a hemithyroidectomy, 9 patients had a completion thyroidectomy, and 2 patients had a neck dissection alone for recurrent thyroid cancer. ioPTH and serum calcium (SCa) levels were obtained during the course of surgery and 1 month after surgery. Levels from these time points were compared, and correlated with the need for vitamin D supplementation at the 1-month follow-up evaluation using the Fisher exact test. Results Of the 72 patients, 14 had an ioPTH level less than 10 pg/mL at closure. At the 1-month evaluation, 11 of these 14 patients required vitamin D supplementation because of persistent hypoparathyroidism or hypocalcemia ( P <.001). The remaining 3 of the 14 patients with ioPTH levels less than 10 pg/mL at closure did not require vitamin D supplementation at the 1-month evaluation because they were asymptomatic and their PTH and SCa levels had normalized. None of the 58 patients with an ioPTH level greater than 10 pg/mL at closure needed vitamin D supplementation at the 1-month follow-up evaluation. Conclusions An ioPTH level less than 10 pg/mL at closure is a strong predictor of hypoparathyroidism after thyroid surgery. Patients with ioPTH levels less than 10 pg/mL at closure should be placed on vitamin D supplementation after surgery to anticipate decreased parathyroid gland function and to avoid symptomatic hypocalcemia.

The Role of Positron Emission Tomography/Computed Tomography in the Management of Recurrent Papillary Thyroid Carcinoma

The aim of the study was to evaluate the role of combined positron emission tomography/computed tomography (PET/CT) fusion imaging in the detection and management of recurrent papillary thyroid cancer. A retrospective analysis of 33 patients with suspected recurrent papillary thyroid carcinoma who had undergone PET/CT was performed. PET/CT was compared with standard imaging techniques in each patient to determine whether PET/CT contributed to the therapeutic management plan. Histopathological findings were correlated to PET/CT in patients who underwent surgery. The senior author reviewed the charts of 33 patients with recurrent papillary thyroid carcinoma to determine the impact PET/CT had on management. PET/CT was compared with conventional imaging results. In surgical patients, PET/CT was compared with histopathological findings to determine its sensitivity, specificity, accuracy, positive predictive value, and negative predictive value. In 67% of the cases (22 of 33), PET/CT supplied additional information that altered or confirmed the management plan. Twenty of 33 patients underwent surgery with 36 sites assessed by histopathological analysis. PET/CT correlated with histopathological findings in 25 of 36 distinct anatomical sites, with an accuracy of 70%. The sensitivity of PET/CT in identifying recurrence was found to be 66%, with a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 27%. Combined PET/CT fusion scanning was most useful in the detection and management of recurrent papillary thyroid cancer in patients who had average thyroglobulin levels greater than 10 ng/mL and when the tumor no longer concentrated radioactive iodine. In 100% of the cases in which PET/CT localized a region suspicious for malignancy, histopathological analysis confirmed the results. When PET/CT is positive, it is a powerful tool for predicting exact locations of recurrent papillary thyroid cancer, thus making it a reliable guide for surgical planning. PET/CT is a supplement to conventional imaging and fine-needle aspiration in the workup of recurrent papillary thyroid cancer. A negative finding on PET/CT is not sufficiently reliable to preclude further investigation and treatment.

Thyroid Cancers Express CD-40 and CD-40 Ligand: Cancers That Express CD-40 Ligand May Have a Greater Risk of Recurrence in Young Patients

The immune response might suppress thyroid cancer recurrence. Although the factors that control this are unknown, CD-40 and CD-40 ligand might be important. To test this, we stained 36 papillary (PTC) and four follicular (FTC) thyroid carcinomas for CD-40 (n = 37) and CD-40 ligand (n = 36) and graded staining from absent (grade 0) to intense (grade 3). Follicular cells of the majority of thyroid tumors expressed CD-40 (30/37, 81%) and CD-40 ligand (15/24, 69%). Cancers from young patients (< or =21 years of age) that expressed CD-40 contained more numerous lymphocytes/high-power field (36 +/- 11) than cancers that failed to express CD-40 (4 +/- 3, p = 0.01), but there was no correlation with clinical outcome. Among young patients, CD-40 ligand expression was more intense in multifocal (1.1 +/- 0.2 vs. 0.45 +/- 0.2, p = 0.037), aggressive (1.14 +/- 0.14 vs. 0.65 +/- 0.2, p = 0.05) and recurrent tumors (1.2 +/- 0.2 vs. 0.65 +/- 0.2, p = 0.05) and associated with reduced disease-free survival (p = 0.03). We conclude that the majority of thyroid cancers express CD-40 and CD-40 ligand. In patients < or =21 years of age, tumors with intense expression of CD-40 ligand are more often multifocal, aggressive, and recurrent.

Minimally Invasive Radio-Guided Surgery for Recurrent Thyroid Cancer Using Iodine-123

Minimally invasive radio-guided surgery is widely used in the setting of sentinel node biopsy for breast, melanoma, and other malignancies, as well as in minimally invasive parathyroid surgery. A 20-year-old woman with recurrent papillary carcinoma of the thyroid underwent minimally invasive radio-guided surgery after localization of recurrent disease using 1-123.

Using recombinant human thyroid‐stimulating hormone for the diagnosis of recurrent thyroid cancer

Recombinant human thyroid-stimulating hormone (rhTSH) has been suggested as a diagnostic agent in the diagnosis of recurrent thyroid cancer, instead of the current practice of thyroid hormone (THT) withdrawal. An evidenced-based literature review was used as the basis for a cost-utility, decision-analytic model. Outcome measures were safety, efficacy (diagnostic performance and quality of life) and cost effectiveness of rhTSH. The literature search identified six comparative studies of rhTSH versus THT withdrawal. The most common adverse events associated with the use of rhTSH were headache (3.5-11.1%) and nausea (7.7-17%). When used as a diagnostic agent, the unadjusted sensitivity and specificity for rhTSH were 87% and 95%, respectively. Thus the use of rhTSH instead of THT withdrawal would result in a reduction in diagnostic accuracy, with 11% of patients' disease status being misclassified. Use of rhTSH resulted in a higher quality of life in the period prior to diagnostic testing than THT withdrawal (P < 0.001). When the impact of diagnostic performance, patient compliance to follow-up and modified quality of life were modelled over a 5 year time-frame, the incremental cost per QALY of rhTSH relative to THT withdrawal was $51 344.42. The use of rhTSH as a diagnostic agent appears to be safe but less diagnostically accurate and less cost-effective (on whole of healthcare cost basis) when used in the follow-up of patients with thyroid cancer who have had a previous negative radioiodine scan after thyroid hormone withdrawal.

Performance of a block detector PET scanner in imaging non-pure positron emitters—modelling and experimental validation with 124I

The key performance measures of resolution, count rate, sensitivity and scatter fraction are predicted for a dedicated BGO block detector patient PET scanner (GE Advance) in 2D mode for imaging with the non-pure positron-emitting radionuclides 124I, 55Co, 61Cu, 62Cu, 64Cu and 76Br. Model calculations including parameters of the scanner, decay characteristics of the radionuclides and measured parameters in imaging the pure positron-emitter 18F are used to predict performance according to the National Electrical Manufacturers Association (NEMA) NU 2-1994 criteria. Predictions are tested with measurements made using 124I and show that, in comparison with 18F, resolution degrades by 1.2 mm radially and tangentially throughout the field-of-view (prediction: 1.2 mm), count-rate performance reduces considerably and in close accordance with calculations, sensitivity decreases to 23.4% of that with 18F (prediction: 22.9%) and measured scatter fraction increases from 10.0% to 14.5% (prediction: 14.7%). Model predictions are expected to be equally accurate for other radionuclides and may be extended to similar scanners. Although performance is worse with 124I than 18F, imaging is not precluded in 2D mode. The viability of 124I imaging and performance in a clinical context compared with 18F is illustrated with images of a patient with recurrent thyroid cancer acquired using both [124I]-sodium iodide and [18F]-2-fluoro-2-deoxyglucose.

18F]Fluorodeoxyglucose Uptake in Recurrent Thyroid Cancer Is Related to Hexokinase I Expression in the Primary Tumor

Patients suspected of recurrent differentiated thyroid cancer (DTC) may require "blind" (131)I therapy, with the disadvantage of unpredictable efficacy and toxicity. Alternatively, positron emission tomography (PET) with [(18)F]fluorodeoxyglucose ((18)FDG) can document the recurrence, thereby rationalizing therapeutic options. This study compared (18)FDG uptake in vivo with biomarkers expected to be involved in the underlying biological mechanisms. Additionally, we investigated whether such features were present in the primary tumors. Preoperatively, 19 patients with recurrent DTC underwent PET. (18)FDG uptake was compared with histological and immunohistochemical features in surgical specimens of recurrent and primary tumor. Thirteen of 19 recurrences were positive at PET, and (18)FDG uptake was associated with the expression of hexokinase type I (HK I; P = 0.011). All lesions with HK I overexpression were positive on (18)FDG PET. HK I expression in the original primary tumor and the metastases was similar in 82% (rho = 0.648; P = 0.005). In suspected recurrent thyroid cancer, stratification for (18)FDG PET may benefit from pretest immunohistochemical analysis of HK I of the primary tumor, as HK I negativity indicates a low likelihood of PET positivity.

Morbidity Following Central Compartment Reoperation for Recurrent or Persistent Thyroid Cancer

To determine the incidence of recurrent laryngeal nerve injury and hypoparathyroidism, we reviewed our experience with central compartment reoperation. Patients underwent preoperative ultrasonography and magnetic resonance imaging of the neck. Ultrasound-guided fine-needle aspiration biopsy was performed and demonstrated evidence of tumor in 15 patients. At the time of surgery, hook wire electrodes were placed endoscopically into 1 or both vocal cords to monitor the integrity of the recurrent laryngeal nerve. The study population comprised 20 patients who had undergone reoperative central compartment dissections between the years 1997 and 2001. There were 15 women and 5 men whose mean age was 49.4 years. All of the patients had prior total or subtotal thyroidectomy, and 4 patients had prior neck dissections. A primary thyroid cancer recurrence in the thyroid bed was present in 7 patients, and the remainder of the patients had cytological evidence of paratracheal or mediastinal metastases. A single patient had evidence of distant metastases involving the lung. Short- and long-term postoperative morbidity. Of the 20 patients, 18 had histologic evidence of metastases to the paratracheal lymph nodes, whereas 8 patients had metastases involving the anterior mediastinal lymph nodes. The mean number of lymph nodes removed was 6.5, and the mean number of positive lymph nodes was 4.7. None of the patients with normal preoperative laryngeal function had postoperative recurrent laryngeal nerve paresis or paralysis. There were 18 patients with normal preoperative parathyroid function. Four patients developed transient postoperative hypocalcemia. All 4 patients with transient postoperative hypocalcemia are currently eucalcemic. A single patient continues to receive calcium and calcitriol supplementation 1 month following her third central compartment dissection for recurrent thyroid cancer. Reoperation for recurrent or persistent thyroid cancer presents a significant challenge. However, intraoperative recurrent laryngeal nerve monitoring and preservation of the vascular pedicle of the parathyroid glands has reduced the morbidity of reoperative central compartment dissections to acceptable levels. Revision surgery in the central compartment of the neck is compatible with successful eradication of recurrent thyroid cancers and acceptable morbidity.

Central compartment dissection (of levels VI and VII) for carcinoma of the larynx, hypopharynx, cervical esophagus, and thyroid

Lymphatic spread to the paratracheal and upper mediastinal nodes most often arises from tumors of the hypopharynx, larynx, cervical esophagus, and thyroid. The paratracheal and upper mediastinal lymph nodes are within the described lymphatic drainage pathways for tumors arising in these sites. Failure to address these lymphatics can lead to central compartment recurrence after thyroidectomy in cases of differentiated thyroid cancer or stomal recurrence after total laryngectomy in cases of squamous carcinoma of the larynx, hypopharynx, and cervical esophagus. We briefly review the lymphatic drainage to the central compartment (levels VI and VII), and we describe the operative techniques for appropriate lymphadenectomy. Rouviere’s 1,2 classic description of the lymphatic drainage of the larynx was expanded by the more contemporary work of Welsh et al, 3 who used injection of radioactive tracers to define lymphatic pathways. Interestingly, these injection studies demonstrated that supraglottic laryngeal lymphatics drain primarily to the ipsilateral upper and midjugular lymph nodes. However, small areas of uptake also were found in the contralateral side of the neck, and the tracer was demonstrated in the ipsilateral thyroid lobe and the paratracheal lymph nodes. Subglottic injections drained to the paratracheal and upper mediastinal lymph nodes. The cervical esophagus is richly supplied with lymphatics, and primary tumors at this site drain to the paratracheal, upper mediastinal, and retropharyngeal lymph nodes. The efferent hypopharyngeal lymphatics drain into the anterior pathway that pierces the thyrohyoid membrane, terminating in the superior and midjugular lymph nodes, whereas the posterior pathway drains the inferior hypopharynx and proceeds to the paratracheal, retroesophageal, and internal jugular lymph nodes. 4 Lymphatic drainage from the thyroid gland follows multiple routes and is routinely bilateral. The primary echelon of nodal drainage from the thyroid is to the cricothyroid (“Delphian”) lymph node, the paratracheal nodes, and the upper mediastinal lymph nodes.

Clinical review 170: A systematic review and metaanalysis of the effectiveness of radioactive iodine remnant ablation for well-differentiated thyroid cancer.

Radioactive iodine remnant ablation destroys residual thyroid tissue after surgical resection of papillary or follicular thyroid cancer. We systematically reviewed 1543 English references to determine whether remnant ablation decreases the risk of thyroid cancer-related death or recurrence after bilateral thyroidectomy for papillary or follicular thyroid cancer. In 13 cohort studies in which the analysis of thyroid cancer-related outcomes was statistically adjusted to a variable degree for prognostic factors or cointerventions, rates of recurrences of thyroid cancer-related outcomes were significantly decreased in the following: one of seven studies examining thyroid cancer-related mortality, three of six studies examining any tumor recurrence, three of three studies examining locoregional recurrence, and two of three studies examining distant metastases. Thyroid hormone suppressive therapy was not adjusted for in the majority of these analyses. In 18 cohort studies not adjusted for prognostic factors or interventions, the benefit of radioactive iodine ablation in decreasing the thyroid cancer-related mortality and any recurrence at 10 yr was inconsistent among centers. However, pooled analyses were suggestive of a statistically significant treatment effect of ablation for the following 10-yr outcomes: locoregional recurrence (relative risk of 0.31, 95% confidence interval, 0.2, 0.49) and distant metastases (absolute decrease in risk 3%, 95% confidence interval, risk decreases 1-4%). In conclusion, radioactive iodine ablation may be beneficial in decreasing recurrence of well-differentiated thyroid cancer; however, results are inconsistent among centers for some outcomes, and the incremental benefit of remnant ablation in low-risk patients treated with bilateral thyroidectomy and thyroid hormone suppressive therapy is unclear.

Functional imaging of endocrine tumors: role of positron emission tomography.

This article provides an update on functional imaging approaches for diagnostic localization of endocrine tumors, with emphasis on positron emission tomography (PET). [18F]Fluorodeoxyglucose PET scanning is now a widely accepted imaging approach in clinical oncology. Benefits include improved patient outcome facilitated by staging and monitoring of disease and better treatment planning. [18F]Fluorodeoxyglucose PET is also useful in some endocrine tumors, particularly in recurrent or metastatic thyroid cancer where the degree of accumulation of the radionuclide has prognostic value. However, this imaging approach does not take full advantage of the unique characteristics of endocrine tumors. Endocrine tumor cells take up hormone precursors, express receptors and transporters, and synthesize, store, and release hormones. These characteristics offer highly specific targets for PET. Radiopharmaceuticals developed for such approaches include 6-[18F]fluorodopamine, and [11C]hydroxyephedrine for localization of pheochromocytomas, [11C]5-hydroxytryptophan and [11C]L-dihydroxyphenylalanine for carcinoid tumors, and [11C]metomidate for adrenocortical tumors. These functional imaging approaches are not meant to supplant conventional imaging modalities but should be used conjointly to better identify specific characteristics of endocrine tumors. This represents a relatively new and evolving approach to imaging that promises to answer specific questions about the behavior and growth of endocrine tumors, their malignant potential, and responsiveness to different treatment modalities.

Update of cladribine in the treatment of adults with Langerhans-cell histiocytosis (LCH)

6602 Background: LCH is a neoplasm of the monocytic-phagocytic system for which treatment is palliative. We previously reported on the activity of cladribine (2-CdA [2-chlorodeoxyadenosine]; Leustatin, Ortho Biotech, Raritan, NJ) in adults with LCH (Saven, A. et al., Blood; 93, 4125–30, 1999). Herein we update previous results and expand on the original observations. Methods: Cladribine was administered at 0.14 mg/kg/d IV over 2 hours for 5 consecutive days, every 4 wks. for a maximum of 6 cycles. Results: 16 pts. (9 female), median age 44 yrs. (range, 19–72) were treated. Median duration from diagnosis to cladribine was 82 mos. (range, 1–288). 14/16 pts. (88%) had received prior treatment; median number 3 (range, 1–6). At study entry, 11 pts. (69%) had stage I, 4 pts.(25%) had stage II, and 1 pt. (6%) had stage 3 disease. Organ involvement included skin in 10 pts., bone in 6, lung in 6, adenopathy in 5, diabetes insipidus in 4, colon in 2, and thyroid in 1 pt.. Median of 3 cycles of cladribine (range, 1–6) was administered. 16 were evaluable for toxicity, and 15 for response. 1 pt. was removed from the study after an allergic reaction during the first infusion. CR was achieved in 7 (44%) and PR in 3 pts. (19%), ORR of 63%. Median response duration was 36.2 mos. (range, 0.9- 112.5); 5 of the CRs remain in remission at 97.1+ mos. (range, 40.8–114.8+). Leukopenia was the principal toxicity with 8 pts. (50%) experiencing grade 3/4 neutropenia. Febrile neutropenia developed in 2 pts., and 1 pt. developed dermatomal zoster. The following second malignancies were observed in single pts.: recurrent thyroid cancer, nonmelanoma skin cancer, CMMoL (>3 years from cladribine), and refractory anemia (9 years from treatment). With a median follow-up of 105.6 mos. (range, 8.5–149.3), 3 pts. died (2 from progressive LCH and 1 from CMMoL), and 13 remain alive (7 NED, 2 on salvage therapy, and 4 remain alive at last contact). Conclusions: Bolus cladribine is a safe, convenient and effective therapy for adults with LCH, even when heavily pretreated; unmaintained durable remissions can be achieved in a subset of pts.. Long term follow-up of these pts. is necessary since myelodysplasia may complicate cladribine treatment. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ortho Biotech Ortho Biotech

Antiproliferative Effects of Src Inhibition on Medullary Thyroid Cancer

There is no effective treatment for recurrent or metastatic medullary thyroid cancer (MTC). Hereditary MTC is associated with mutations in the RET protooncogene, which encodes for a tyrosine kinase. We postulated that Src tyrosine kinases regulate MTC proliferation. Proliferation of the human MTC cell line, TT, was examined in the presence of a Src-specific tyrosine kinase inhibitor, PP2, or genistein. Cell counts were performed with a Coulter counter or by flow cytometry. DNA synthesis was evaluated by bromodeoxyuridine incorporation. A cell death ELISA was used to assess apoptosis. Akt phosphorylation was determined by Western immunoblot. MAPK activity was measured using an immunoprecipitation kinase assay, and MAPK inhibition was achieved with SB202190 (p38 MAPK) and PD098059 (MAPK kinase). Data were analyzed by ANOVA. Compared with controls, PP2 reduced DNA synthesis, abolished Akt phosphorylation, and increased apoptosis. The MAPK kinase inhibitor, PD098059, attenuated DNA synthesis, whereas genistein caused modest declines in cell count and DNA synthesis and minimal changes in apoptosis. We conclude that Src-dependent MTC proliferation occurs via increased DNA synthesis and reduced apoptosis. The latter effect may be mediated by Akt survival signals. Modulation of Src activity is a potential therapeutic target in MTC.

Evaluation of circulating thyroid-specific transcripts as markers of thyroid cancer relapse.

Circulating thyroid-specific transcripts have been suggested as potential molecular markers of residual or recurrent thyroid cancer. We assessed the accuracy of real-time RT-PCR-based detection of a panel of thyroid-specific markers, including TG, TPO, TSHR, NIS and PDS, in comparison with serum TG measurements in a series of 55 patients operated for differentiated thyroid cancer (DTC). Serum TG levels were higher in patients with residual thyroid tissue or metastatic cancer than in disease-free patients during thyroid hormone suppressive therapy (THST) and after stimulation with rhTSH (P < 0.05). Recombinant hTSH increased serum TG values in patients with tumor relapse (P < 0.05), but not in disease-free patients. This assay showed high specificity and good sensitivity in detecting tumor relapse (accuracy under THST = 81.4%; after rhTSH stimulation = 90.9%). TPO and TSHR mRNA, either under THST or after rhTSH, showed a significant correlation with disease status for molecular assays. Qualitative analysis of baseline and stimulated TG, NIS and PDS mRNA showed high sensitivity but low specificity in the prediction of thyroid cancer recurrence or metastases (accuracy under THST = 51%, 43% and 54%, respectively), whereas TPO and TSHR mRNA assays had higher specificity but low sensitivity, with accuracy under THST of 67% and 61%, respectively, that improved when these tests were combined. Our findings indicate that serum TG assay after TSH stimulation is the most accurate test for monitoring DTC. Combined measurements of TPO and TSHR mRNA levels during THST may represent a specific test for early detection of DTC relapse.