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Purpose: Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC).Experimental Design: Fifty-nine patients with unresectable progressive MTC per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 within the prior 12 months received lenvatinib (24-mg daily, 28-day cycles) until disease progression, unmanageable toxicity, withdrawal, or death. Prior anti-VEGFR therapy was permitted. The primary endpoint was objective response rate (ORR) by RECIST v1.0 and independent imaging review.Results: Lenvatinib ORR was 36% [95% confidence interval (CI), 24%–49%]; all partial responses. ORR was comparable between patients with (35%) or without (36%) prior anti-VEGFR therapy. Disease control rate (DCR) was 80% (95% CI, 67%–89%); 44% had stable disease. Among responders, median time to response (TTR) was 3.5 months (95% CI, 1.9–3.7). Median progression-free survival (PFS) was 9.0 months (95% CI, 7.0–not evaluable). Common toxicity criteria grade 3/4 treatment-emergent adverse events included diarrhea (14%), hypertension (7%), decreased appetite (7%), fatigue, dysphagia, and increased alanine aminotransferase levels (5% each). Ret proto-oncogene status did not correlate with outcomes. Low baseline levels of angiopoietin-2, hepatocyte growth factor, and IL8 were associated with tumor reduction and prolonged PFS. High baseline levels of VEGF, soluble VEGFR3, and platelet-derived growth factor BB, and low baseline levels of soluble Tie-2, were associated with tumor reduction.Conclusions: Lenvatinib had a high ORR, high DCR, and a short TTR in patients with documented progressive MTC. Toxicities were managed with dose modifications and medications. Clin Cancer Res; 22(1); 44–53. ©2015 AACR.

Tumor response

OBJECTIVE: Smoking has been associated with a reduced risk of thyroid cancer, but whether the association varies between higher- and lower-risk cancers remains unclear. We aimed to assess the association between smoking and risk of thyroid cancer overall as well as by tumour BRAF mutational status as a marker of potentially higher-risk cancer. DESIGN AND PATIENTS: We recruited 1013 people diagnosed with thyroid cancer and 1057 population controls frequency-matched on age and sex. METHODS: Multivariable logistic regression was used to assess the association overall and in analyses stratified by tumour characteristics. We used sensitivity analysis to assess the potential for selection bias. RESULTS: We found little evidence of an association with current smoking (odds ratio [OR] = 0.93; 95% confidence interval [CI]: 0.69-1.26; current vs. never smoking), but a higher number of pack-years of smoking was associated with a lower risk of thyroid cancer (OR = 0.75; 95% CI: 0.57-0.99; ≥20 pack-years vs. never). However, after correcting for potential selection bias, we observed a statistically significant inverse association between current smoking and risk of thyroid cancer (bias-corrected OR = 0.65; 95% CI: 0.51-0.83). Those with BRAF-positive cancers were less likely to be current smokers than those with BRAF-negative cancers (prevalence ratio: 0.79; 95% CI: 0.62-0.99). CONCLUSION: We found smoking was inversely related to thyroid cancer risk and, in particular, current smoking was associated with a reduced risk of potentially more aggressive BRAF-positive than the likely more indolent BRAF-negative papillary thyroid cancers.

Background: Thyroid cancer incidence has increased in many parts of the world since the 1980s, as has the prevalence of obesity. Evidence suggests that people with greater body size have higher thy...

Smoking has been associated with a reduced risk of thyroid cancer, but whether the association varies between higher- and lower-risk cancers remains unclear. We aimed to assess the association between smoking and risk of thyroid cancer overall as well as by tumour BRAF mutational status as a marker of potentially higher-risk cancer.We recruited 1013 people diagnosed with thyroid cancer and 1057 population controls frequency-matched on age and sex.Multivariable logistic regression was used to assess the association overall and in analyses stratified by tumour characteristics. We used sensitivity analysis to assess the potential for selection bias.We found little evidence of an association with current smoking (odds ratio [OR] = 0.93; 95% confidence interval [CI]: 0.69-1.26; current vs. never smoking), but a higher number of pack-years of smoking was associated with a lower risk of thyroid cancer (OR = 0.75; 95% CI: 0.57-0.99; ≥20 pack-years vs. never). However, after correcting for potential selection bias, we observed a statistically significant inverse association between current smoking and risk of thyroid cancer (bias-corrected OR = 0.65; 95% CI: 0.51-0.83). Those with BRAF-positive cancers were less likely to be current smokers than those with BRAF-negative cancers (prevalence ratio: 0.79; 95% CI: 0.62-0.99).We found smoking was inversely related to thyroid cancer risk and, in particular, current smoking was associated with a reduced risk of potentially more aggressive BRAF-positive than the likely more indolent BRAF-negative papillary thyroid cancers.

Background Hysterectomy has been associated with increased thyroid cancer risk but whether this reflects a biological link or increased diagnosis of indolent cancers due to greater medical contact remains unclear. Methods We recruited 730 women diagnosed with thyroid cancer and 785 age-matched population controls. Multivariable logistic regression was used to assess the association overall, and by tumour BRAF mutational status as a marker of potentially higher-risk cancers. We used causal mediation analysis to investigate potential mediation of the association by healthcare service use. Results Having had a hysterectomy was associated with an increased risk of thyroid cancer (odds ratio [OR] = 1.45, 95 % confidence interval [CI] 1.07–1.96). When stratified by indication for hysterectomy, the risk appeared stronger for those who had a hysterectomy for menstrual disorders (OR = 1.67, 95 % CI 1.17–2.37) but did not differ by tumour BRAF status. Approximately 20 % of the association between hysterectomy and thyroid cancer may be mediated by more frequent use of healthcare services. Conclusions The observed increased risk of thyroid cancer among those with hysterectomy may be driven, at least partly, by an altered sex steroid hormone milieu. More frequent healthcare service use by women with hysterectomy accounts for only a small proportion of the association.

Purpose: Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC). Experimental Design: Fifty-nine patients with unresectable progressive MTC per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 within the prior 12 months received lenvatinib (24-mg daily, 28-day cycles) until disease progression, unmanageable toxicity, withdrawal, or death. Prior anti-VEGFR therapy was permitted. The primary endpoint was objective response rate (ORR) by RECIST v1.0 and independent imaging review. Results: Lenvatinib ORR was 36% [95% confidence interval (CI), 24%–49%]; all partial responses. ORR was comparable between patients with (35%) or without (36%) prior anti-VEGFR therapy. Disease control rate (DCR) was 80% (95% CI, 67%–89%); 44% had stable disease. Among responders, median time to response (TTR) was 3.5 months (95% CI, 1.9–3.7). Median progression-free survival (PFS) was 9.0 months (95% CI, 7.0–not evaluable). Common toxicity criteria grade 3/4 treatment-emergent adverse events included diarrhea (14%), hypertension (7%), decreased appetite (7%), fatigue, dysphagia, and increased alanine aminotransferase levels (5% each). Ret proto-oncogene status did not correlate with outcomes. Low baseline levels of angiopoietin-2, hepatocyte growth factor, and IL8 were associated with tumor reduction and prolonged PFS. High baseline levels of VEGF, soluble VEGFR3, and platelet-derived growth factor BB, and low baseline levels of soluble Tie-2, were associated with tumor reduction. Conclusions: Lenvatinib had a high ORR, high DCR, and a short TTR in patients with documented progressive MTC. Toxicities were managed with dose modifications and medications. Clin Cancer Res; 22(1); 44–53. ©2015 AACR.

BACKGROUND: Thyroid cancer incidence has been increasing worldwide. Some suggest greater ascertainment of indolent tumours is the only driver, but others suggest there has been a true increase. Increases in Australia appear to have been among the largest in the world, so we investigated incidence trends in the Australian state of Queensland to help understand reasons for the rise. METHODS: Thyroid cancers diagnoses in Queensland 1982-2008 were ascertained from the Queensland Cancer Registry. We calculated age-standardized incidence rates (ASR) and used Poisson regression to estimate annual percentage change (APC) in thyroid cancer incidence by socio-demographic and tumour-related factors. RESULTS: Thyroid cancer ASR in Queensland increased from 2.2 to 10.6/100 000 between 1982 and 2008 equating to an APC of 5.5% [95% confidence interval (CI) 4.7-6.4] in men and 6.1% (95% CI 5.5-6.6) in women. The rise was evident, and did not significantly differ, across socio-economic and remoteness-of-residence categories. The largest increase seen was in the papillary subtype in women (APC 7.9%, 95% CI 7.3-8.5). Incidence of localized and more advanced-stage cancers rose over time although the increase was greater for early-stage cancers. CONCLUSION: There has been a marked increase in thyroid cancer incidence in Queensland. The increase is evident in men and women across all adult age groups, socio-economic strata and remoteness-of-residence categories as well as in localized and more advanced-stage cancers. Our results suggest 'overdiagnosis' may not entirely explain rising incidence. Contemporary aetiological data and individual-level information about diagnostic circumstances are required to further understand reasons for rising thyroid cancer incidence.

Purpose To estimate the α/β ratio of prostate cancer treated with external beam radiation only by use of a model of long-term prostate-specific antigen (PSA) dynamics. Methods and Materials Repeated measures of PSA from 5,093 patients from 6 institutions treated for localized prostate cancer by external beam radiation therapy (EBRT) without planned androgen deprivation were analyzed. A biphasic linear mixed model described the post-treatment evolution of PSA, rather than a conventional model of time to biochemical recurrence. The model was adjusted for standard prognostic factors (T stage, initial PSA level, and Gleason score) and cohort-specific effects. The radiation dose fractionation effect was estimated from the long-term rate of rise of PSA level. Results Adjusted for other factors, total dose of EBRT and sum of squared doses per fraction were associated with long-term rate of change of PSA level ( p = 0.0017 and p = 0.0003, respectively), an increase of each being associated with a lower rate of rise. The α/β ratio was estimated at 1.55 Gy (95% confidence band, 0.46–4.52 Gy). This estimate was robust to adjustment of the linear mixed model. Conclusions By analysis of a large EBRT-only cohort along with a method that uses all the repeated measures of PSA after the end of treatment, a low and precise α/β was estimated. These data support the use of hypofractionation at fractional doses up to 2.8 Gy but cannot presently be assumed to accurately represent higher doses per fraction.

Bilateral uveal metastases from papillary thyroid carcinoma are extremely rare. A 36-year-old woman with a 12-month history of papillary thyroid carcinoma presented with sudden loss of visual acuity and fields in the left eye. An examination and B-scan revealed a large, solid choroidal lesion in the left eye causing exudative retinal detachment. A small solid mass was also observed in the right eye fundus. Following left eye enucleation, immunohistopathology confirmed metastatic papillary thyroid carcinoma. The authors report the third known case of bilateral choroidal metastases.

Targeted treatment education for cancer patients has the potential to promote adjustment through assisting patients to participate in treatment decision making, comply with treatment regimens and cope more effectively with treatment side effects. A quasi-experimental longitudinal pre-test post-test and follow-up design was used to assess the effect of a patient education video about radiation therapy on patients' psychological distress, knowledge about radiation therapy, self-efficacy about coping with treatment and physical symptoms. Patients with head and neck (n=26) and breast cancer (n=66) were recruited into the study and allocated into control and intervention groups. No significant differences were found between the control and intervention groups on any of the outcome variables. However, patients in the intervention group reported high levels of satisfaction with the video and all reported that they would recommend the video to other patients preparing for radiation therapy. As well, 90% of patients in the intervention group reported that some or all of the information in the video was new to them. Education materials that have excellent face validity and that are well received by patients may fail to produce significant change using standard controlled study designs. Future research in this area may need to consider alternative paradigms for evaluating the helpfulness of such materials.

BACKGROUND Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1‐VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1‐FGFR4), platelet‐derived growth factor receptor α (PDGFRα), ret proto‐oncogene (RET), and v‐kit Hardy‐Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine‐refractory, differentiated thyroid cancer (RR‐DTC). METHODS Fifty‐eight patients with RR‐DTC who had disease progression during the previous 12 months received lenvatinib 24 mg once daily in 28‐day cycles until disease progression, unmanageable toxicity, withdrawal, or death. Previous VEGFR‐targeted therapy was permitted. The primary endpoint was the objective response rate (ORR) based on independent imaging review. Secondary endpoints included progression‐free survival (PFS) and safety. Serum levels of 51 circulating cytokines and angiogenic factors also were assessed. RESULTS After ≥14 months of follow‐up, patients had an ORR of 50% (95% confidence interval [CI], 37%‐63%) with only partial responses reported. The median time to response was 3.6 months, the median response duration was 12.7 months, and the median PFS was 12.6 months (95% CI, 9.9‐16.1 months). The ORR for patients who had received previous VEGF therapy (n = 17) was 59% (95% CI, 33%‐82%). Lower baseline levels of angiopoietin‐2 were suggestive of tumor response and longer PFS. Grade 3 and 4 treatment‐emergent adverse events, regardless of their relation to treatment, occurred in 72% of patients and most frequently included weight loss (12%), hypertension (10%), proteinuria (10%), and diarrhea (10%). CONCLUSIONS In patients with and without prior exposure to VEGF therapy, the encouraging response rates, median time to response, and PFS for lenvatinib have prompted further investigation in a phase 3 trial. Cancer 2015;121:2749‐2756. © 2015 American Cancer Society, This phase 2 study demonstrates that lenvatinib produces encouraging objective response and progression‐free survival rates in patients with radioiodine‐refractory, differentiated thyroid cancer and also has a well defined safety profile. Lenvatinib also exhibits activity in patients who previously received vascular endothelial growth factor/vascular endothelial growth factor receptor‐targeted therapies.

Purpose: Primary radiation therapy following breast-conserving surgery has been an accepted alternative to mastectomy in Europe and North America for many years. In Australia, however, the history of breast conservation for early invasive breast cancer is much shorter. The purpose of this study was to evaluate the results of breast conservation in a state-wide Australian radiotherapy service. Methods and Materials: Between January 1982 and December 1989, 512 patients were treated with primary radiation therapy after breast conserving surgery. This analysis is based on a review of these patients, all of whom had Stage I or II breast cancer. Results: With a median follow-up of 50 months, the 5-year actuarial rate of overall survival was 84% and disease-free survival was 80%. There have been 22 isolated local recurrences in the breast. The time to an isolated breast recurrence ranged from 12 to 83 months (median, 26 months). The 5-year actuarial rate of an isolated breast recurrence was 4%. The recurrence rate was higher for patients with involved margins (15% vs. 2%, p

Purpose To validate the interval to biochemical failure (IBF) as a prognostic factor at the time of biochemical failure for prostate cancer mortality (PCM) following radiotherapy (RT). Patients and Methods From a collaborative data set of men with clinically localized prostate cancer treated with RT from four institutions in three countries, we identified 1,722 men with biochemical failure (BF; prostate-specific antigen nadir + 2 ng/mL). The IBF was defined as the time interval from completion of treatment to the date of BF. The primary outcome measure was discriminatory power in the form of the concordance index (c-index). Results Seventeen percent of men had an IBF ≤ 18 months. Median potential follow-up beyond the time of BF was 67 months. There were 290 deaths from prostate cancer. The IBF was the most discriminating individual prognostic factor overall, with a sensitivity of IBF ≤ 18 months to predict PCM within 10 years of 48.4% (95% CI, 43.3% to 54.1%); the specificity was 86.1% (95% CI, 84.5% to 87.7%), equating to a c-index of 0.611 (95% CI, 0.578 to 0.647). The 5-year cumulative incidence of PCM for IBF more than 18 months versus IBF ≤ 18 months was 9.4% (95% CI, 7.7% to 11.5%) versus 26.3% (95% CI, 21.2% to 31.8%); corresponding 10-year estimates were 26.2% (95% CI, 21.5% to 30.8%) versus 55.9% (95% CI, 48.9% to 63.0%), respectively (P < .001 for both). IBF exhibited minimal change in performance across various follow-up durations. Conclusion IBF is the single most robust prognostic factor for PCM following RT without androgen deprivation therapy. This external validation demonstrates that patients and clinicians can use this information to make decisions about subsequent treatments.

Bilateral uveal metastases from papillary thyroid carcinoma are extremely rare. A 36-year-old woman with a 12-month history of papillary thyroid carcinoma presented with sudden loss of visual acuity and fields in the left eye. An examination and B-scan revealed a large, solid choroidal lesion in the left eye causing exudative retinal detachment. A small solid mass was also observed in the right eye fundus. Following left eye enucleation, immunohistopathology confirmed metastatic papillary thyroid carcinoma. The authors report the third known case of bilateral choroidal metastases.

The purpose of this study was to delineate the key emotional concerns of women newly diagnosed with recurrent or metastatic breast cancer. Sixty-six women diagnosed with metastatic breast cancer within the previous 6 months, receiving treatment at the Medical Oncology Departments of two metropolitan teaching hospitals, completed measures of HADS, IES, CARES-SF and Memorial Symptom Assessment Scale, and participated in a semistructured interview. There were high levels of psychological morbidity, 56.7% of women younger than 55 years qualifying as 'cases' on the HADS, compared with 34.5% of women aged over 55 years. The total HADS score was significantly correlated with the Global and Physical Subscales of the MSAS and CARES. Women younger than 55 years had significantly higher levels of intrusive and avoidant symptoms than women over 55 years. Women also reported high numbers of physical symptoms. Key themes which emerged during the interviews were: difficulties in communicating with doctors, perceived delay in diagnosis, the emotional impact, concerns about the family, feelings about why the cancer developed, other life stress and trauma, and use of non-prescribed treatments. Copyright (c) 2004 John Wiley & Sons, Ltd.

Background Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRb. In phase I studies of lenvatinib partial responses (PR) were observed in thyroid as well as melanoma, endometrial, and renal cancers. Methods Patients with unresectable MTC and disease progression demonstrated by RECIST during the prior 12 months were enrolled. They may have received prior VEGFR-targeted therapy and were treated with a starting dose of lenvatinib 24 mg once daily in 28-day cycles until disease progression or development of unmanageable toxic effects. Primary end point was response rate (RR) by RECIST. Tumor genetic analysis and circulating cytokine and angiogenic factors (CAF) analysis were carried out. Results Fifty-nine patients were enrolled (med age: 52; male: 63%) and are evaluable for response. Fifty-four percent of patients required a dose reduction for management of toxicity, and 22% were withdrawn from therapy due to toxicity. The most common treatment-related adverse events were proteinuria 58% (gr 3: 2%), diarrhea 56% (gr 3: 5%), hypertension 48% (gr 3: 7%), fatigue 44% (gr 3: 5%), decreased appetite 41% (gr 3: 5%), nausea 34% (gr 3: 0), and weight decreased 32% (gr 3: 3%). No gr 4 events were reported for these event categories. Confirmed PRs were observed in 21 patients (RR: 36%, 95% CI: 24–49) based on independent imaging review (IIR) and 29 patients (RR: 49%, 95% CI: 36–62) based on investigator assessment. For patients who received prior VEGFR-directed treatment (n = 26) RR = 35% (IIR); with no prior VEGFR-directed treatment (n = 33) RR = 36 % (IIR). Median PFS by IRR is 9.0 months (95% CI: 7.0–) (based on minimum 8 months f/u, 46% events observed). There was no clear difference in the treatment response between RET-mutant (RET-mu) and RET-wild-type (RET-wt) patients. Low baseline levels of ANG2, sTie-2, HGF and IL-8 were associated with greater tumor shrinkage and prolonged PFS, whereas high baseline levels of VEGF and sVEGFR3 were associated with greater tumor shrinkage. Conclusions Lenvatinib administered orally at a dose of 24 mg once daily to patients with MTC is associated with manageable toxicity and an RR of 36%, identifying lenvatinib as a promising new potential therapeutic agent for treating patients affected with this disease.

Standard treatment regimens for haematological malignancies include myeloablative chemoradiotherapy and subsequent rescue by stem cell transplantation. However, these treatment regimens have significant associated mortality and morbidity, and disease recurrence remains a problem. One alternative approach is the targeted delivery of radiotherapy to the marrow using a bone-seeking agent labelled with an appropriate radioisotope, with the aim of delivering a potentially ablative radiation dose to marrow while minimising non-haematological toxicity. Pharmacokinetics and radiation dosimetry for a commercial preparation of samarium-153 ethylene diamine tetramethylene phosphonate (EDTMP; Quadramet) were evaluated in 43 tracer (average dose 740 MBq) studies of 42 patients with haematological malignancies. Measurements of 24-h retention were also available following infusion of 18-48 GBq in 15 patients. Quadramet cleared rapidly from the tissue, with a median biological half-life of 1.4 h. Activity taken up by the skeleton was firmly bound, with activity decreasing according to physical half-life at 24 h in 29 of the 43 cases. The percentage activity retained in the skeleton at 24 h with tracer doses was high (62%+/-13%), although this decreased to approximately 30% with therapy infusions. Because of this decrease in retention, the maximum feasible therapy activity for this formulation of Quadramet is 35 GBq. Median absorbed marrow radiation dose was 0.78 Gy/GBq in tracer studies: the decreased retention at high activities means that this corresponds to a median dose of 12 Gy for 35 GBq administered activity. It is possible to use 24-h retention as a rough guide to marrow dose in individual patients. In tracer studies, median bladder radiation dose was 0.22 Gy/GBq and radiation dose to the liver was very conservatively estimated at 0.2 Gy/GBq. After therapy infusions of up to 50 GBq in 37 patients, non-haematopoietic toxicity was not seen in any patient. In addition, myelosuppression was achieved without evidence of myelofibrosis. The residual dose rate to marrow fell to a level acceptable for stem cell re-infusion by 2 weeks after administration.

5518 Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In a phase II study of lenvatinib, 58 patients (pts) with DTC were enrolled and a response rate of 50% was observed (Sherman, ASCO 2011). Methods: Pts received lenvatinib at a starting dose of 24 mg oral once daily in 28-day cycles. Serum was collected at baseline (BL), on day 8 and on day 36 and concentrations of 47 CAFs were measured using multiplex bead arrays and enzyme-linked immunosorbent assay (ELISA). 33 genes (443 mutations) were examined in archival tumor tissues (n=25). Association of baseline CAF, changes in CAF levels upon treatment and gene mutation status with treatment outcomes was investigated. Results: Combination of low baseline VEGF and ANG-2 (p=0.02 and HR=0.386) correlated with longer PFS. Both baseline and changes in CAF levels demonstrated an association with gene mutation status. High baseline levels of VEGF were observed in pts with wild type RAS and BRAF (p=0.035) whereas high baseline sTIE-2 levels associated with RAS mutation (p=0.023). Supporting pre-clinical mouse xenograft tumor model developed using ANG2-overexpressing human thyroid cancer cell line FTC-286 demonstrated reduced sensitivity to lenvatinib treatment. Increased levels of IL-10 and FGF-2 8-day post-treatment (8d post-tx) significantly associated with RAS (N- or K-) and BRAF mutation. Combination of gene mutation status with baseline CAF levels provided better prediction of longer PFS compared to gene mutation alone. Hierarchical clustering modeling using changes in CAF levels 8d post-tx with tumor shrinkage identified a set of CAFs that could predict two categories of lenvatinib response: longer PFS and greater tumor shrinkage or longer PFS in the absence of significant tumor shrinkage. Conclusions: CAF profiling identified potential predictive biomarkers of lenvatinib treatment outcomes in DTC. Combination of RAS and BRAF mutation with baseline VEGF and ANG-2 or treatment-associated changes in FGF-2 and IL-10 level correlated with lenvatinib treatment response.

5503 Background: E7080 is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In phase I studies of E7080 partial responses (PR) were observed in thyroid as well as melanoma, endometrial, and renal cancers. Methods: Between Oct 2, 2008 and Feb 5, 2010, patients (pts) with advanced, RAI-refractory DTC (papillary, follicular or Hurthle Cell) and disease progression demonstrated by RECIST during the prior 12 months were enrolled. Pts may have received prior VEGFR targeted therapy. Pts were treated with a starting dose of E7080 24 mg once daily in 28 day cycles until disease progression or development of unmanageable toxicities. Primary end point was Response Rate (RR) by RECIST. Results: 58 pts were enrolled (med age: 62; M:59%, F:41%) and are evaluable for response. 35% of pts required dose reduction for management of toxicity, and 23% were withdrawn from therapy due to toxicity. The most common adverse events were hypertension 64% (Gr 3: 4%), fatigue 55% (Gr3: 7%), diarrhea...

In this thesis the interaction of a normal gas dynamic shock wave with a gas containing a distribution of small solid spherical particles of two distinct radii, σ1 and σ2, is studied (1) to demonstrate that the methods of kinetic theory can be extended to treat solid particle collision phenomena in multidimensional gas-particle flows; (2) to elucidate some of the essential physical characteristics associated with particle-particle collision processes; and (3) to give some indication regarding the importance of particle collisions in particle-laden gas flows. It is assumed that upstream of the shock wave particles σ1 are uniformly distributed while particles σ2 are non-uniformly distributed parallel to the shock face and in much smaller numbers than particles σ1. Under these conditions the gas-particle σ1 flow downstream of the shock wave is very nearly one-dimensional and independent of the presence of particles σ2. The usual shock relaxation zone is established by the interaction of particles σ and the gas downstream of the shock wave. The collisional model pro- posed by Marble3 is then extended and used with a modified form of the mean free path method of kinetic theory to calculate the macroscopic distribution and velocity of particles σ2 as determined by the particle σ1- particle σ2 and particle σ2-gas interactions. Within the condition that the random velocity imparted to a particle σ2 by a collision is damped by its viscous interaction with the gas before it suffers another collision, the kinetic theory method established here may be extended to include more general particle-particle and particle-gas interaction laws than those used by Marble. However, the collisional model employed is particularly important because the criteria for its application are easy to establish and because it admits a wide class of physically interesting situations. Within the restrictions of this collision model, it is possible to analyze the macroscopic motion of particles σ2 in three important limiting cases: (σ2/σ1)2 >> ⊥,(σ2/σ1)2 << ⊥ and (σ2/σ1)2 ~ ⊥. It is found that when (σ2/σ1)2 >> ⊥ there is essentially no redistribution of particles σ2 normal to the gas flow. The only effect of particle σ1 -particle σ2 encounters is a drag force acting to slow down particles σ2. When (σ2/σ1)2 << ⊥ it is found that particles σ2. may have many collisions during their passage through the shock relaxation zone. As a consequence there may be a substantial redistribution of particles σ2 downstream of the shock wave. The physical features of this process are studied in detail together with the range of validity of this diffusion model. The case (σ2/σ1)2 ~ ⊥ is analyzed under the condition particles σ2 have at most one collision during their passage through the shock relaxation zone. It is found that when the gas or particle σ1 density is low, the single collision effects may be important even when σ2/σ1 differs significantly from unity and the particles are not very small. Under most conditions of practical significance, because there is invariably a distribution of particles sizes present in a dusty gas, the calculation of the particle distribution in the shock relaxation zone should account for the effects of particle-particle encounters. It is suggested that an experimental observation of particle size distribution in a shock relaxation zone can yield significant information on particle-particle and particle-gas interaction laws.