Atypical bilateral ventilation/perfusion mismatches in an asymptomatic patient suffering from metastatic thyroid cancer

Background Pulmonary embolism is indicated by ventilation/perfusion (V/P) mismatches in ventilation/perfusion scintigraphy. However, other pathologies may also evoke segmental or lobar mismatches. Thus, diagnosis can be difficult in asymptomatic patients with equivocal clinical presentation. Case presentation We present a case of multiple bilateral pulmonary ventilation/perfusion mismatches in a poorly differentiated thyroid cancer patient. Exact diagnosis was difficult, as the patient was asymptomatic and pulmonary embolism is commonly unilateral in tumour patients and not typical for thyroid cancer. External pulmonary artery compression by aortic aneurysm, multiple metastases or additional bronchopulmonary malignancies were considered as differential diagnosis. After unilateral pulmonary and hilar metastasectomy, perfusion normalised on the operated side. Pulmonary perfusion defects due to pulmonary artery compression by hilar metastases were finally diagnosed. Pulmonary embolism was deemed unlikely due to the left-sided post-operative normalisation, persistence of right-sided V/P mismatches, and the lack of clinical symptoms. Conclusion Pulmonary artery compression may mimic pulmonary artery embolism in lung perfusion scintigraphy and should be considered in bronchopulmonary tumour patients with hilar metastases and unilateral ventilation/perfusion mismatches affecting a complete lobe or even lung. Following the presented case, also bilateral segmental and subsegmental mismatches in patients with hilar metastases from non-bronchopulmonary cancer entities should be carefully evaluated.

RAC1 Alterations Induce Acquired Dabrafenib Resistance in Association with Anaplastic Transformation in a Papillary Thyroid Cancer Patient

BRAF-activating mutations are the most frequent driver mutations in papillary thyroid cancer (PTC). Targeted inhibitors such as dabrafenib have been used in advanced BRAF-mutated PTC; however, acquired resistance to the drug is common and little is known about other effectors that may play integral roles in this resistance. In addition, the induction of PTC dedifferentiation into highly aggressive KRAS-driven anaplastic thyroid cancer (ATC) has been reported. We detected a novel RAC1 (P34R) mutation acquired during dabrafenib treatment in a progressive metastatic lesion with ATC phenotype. To identify a potential functional link between this novel mutation and tumor dedifferentiation, we developed a cell line derived from the metastatic lesion and compared its behavior to isogenic cell lines and primary tumor samples. Our data demonstrated that RAC1 mutations induce changes in cell morphology, reorganization of F-actin almost exclusively at the cell cortex, and changes in cell adhesion properties. We also established that RAC1 amplification, with or without mutation, is sufficient to drive cell proliferation and resistance to BRAF inhibition. Further, we identified polyploidy of chromosome 7, which harbors RAC1, in both the metastatic lesion and its derived cell line. Copy number amplification and overexpression of other genes located on this chromosome, such as TWIST1, EGFR, and MET were also detected, which might also lead to dabrafenib resistance. Our study suggests that polyploidy leading to increased expression of specific genes, particularly those located on chromosome 7, should be considered when analyzing aggressive thyroid tumor samples and in further treatments.

False-Positive Radioiodine Uptake in Simple Ovarian Cyst in a DTC Patient: A Case Report

Abnormal radioildine uptake can be caused by various pelvic lesions in differentiated thyroid cancer patient. Here we presented an abnormal uptake in the left side of the pelvic cavity on postablative I-131 scintigraphy in a 51-year-old woman with history of stage T1aN1M0 papillary thyroid cancer. The SPECT/CT fused imaging revealed the lesion in the left ovary. Laparoscopic bilateral adnexectomy showed a left ovarian mass (5 cm) and pathologic finding showed a simple ovarian cyst. The nonstimulated Tg immediately decreased to 143 ng/ml after bilateral adnexectomy 3 days later and to 0.109 ng/ml after 4-month follow-up. Timely intervention measures are very necessary for patients with ovarian cyst with abnormally elevated Tg level.

Challenges in lung cancer multidisciplinary collaboration experienced by specialists in four countries.

e23002 Background: The importance and challenges of Multidisciplinary Team (MDT) collaboration in managing lung cancer have been increasingly recognized in an ever more complex therapeutic environment. Data on physicians’ viewpoints regarding MDT collaboration in lung cancer care, collected in a broader study assessing challenges related to lung/thyroid cancer patient management, are presented. Methods: A mixed-methods approach was used to analyze this data, combining qualitative interviews and a quantitative survey. Pulmonologists (PLM), oncologists (ONC) and pathologists (PTH) from Germany (GE), Japan (JP), the United Kingdom (UK) and the United States (US) were recruited. Results: A total of 44 specialists participated in interviews and 377 in a survey. Quantitative data reveal that 53% of pulmonologists in JP and 39% in GE have suboptimal knowledge of the timing of patient referral to an oncologist. Fewer PLM/PTH from JP (43%/47%) report a fully integrated MDT team approach in their clinical setting, compared to those from GE (80%/95%), the UK (96%/82%) and the US (82%/97%). Qualitative data indicate that current MDT team practices are perceived as delaying patient care due to significant inefficiencies (sometimes due to lack of knowledge/skills) and unclear responsibilities within the team. Around half of ONC in each country and 78% of PLM from the UK report a gap in knowledge and relevance of each genetic biomarker test according to clinical presentation. PTH in the UK (70%), the US (50%), and JP (72%) report sub-optimal skills identifying biomarker tests to inform the progression of lung cancer (also a challenge for PLM/ONC). Conclusions: This study indicates a need for multi-level interventions addressing systemic and attitudinal barriers as well as knowledge gaps which affect physicians’ ability to collaborate in lung cancer care.

Targeting Glycogen Metabolism as a Novel Therapeutic Approach in Anaplastic Thyroid Cancer

Effective treatment options for well-differentiated papillary (PTC) and follicular (FTC) thyroid cancers afford positive patient prognoses. The absence of effective interventions for the stem-like, dedifferentiated anaplastic thyroid cancer (ATC) results in poor patient outcomes with a mortality rate higher than all other endocrine cancers combined (1). While receptor tyrosine kinase inhibitors such as sorafenib can extend ATC patient survival, drug resistance and tumor reoccurrence often develop (2). Therefore, there is a critical need for more effective targeted therapies for ATC. Although the cell signaling landscape of ATC tumors is well described, very little is known about tumorigenic adaptations in ATC cellular metabolism. Tumors exhibit an increased consumption of glucose compared to normal tissues to fuel tumor progression. Some cancers meet this high glucose requirement by storing and breaking down glycogen. In our studies here, we show for the first time that normal thyroid, PTC, FTC, and ATC cells express genes necessary for glycogen metabolism. We confirm these observations in patient samples in normal thyroid and thyroid cancer patient samples via immunofluorescence in tissue microarrays. Furthermore, we detect intracellular glycogen stores in cell lines representing normal thyroid, PTC, FTC, and ATC cells. Importantly, we demonstrate that glycogen phosphorylase inhibitors result in accumulation of intracellular glycogen and induce subsequent apoptosis in ATC cells. We further show that glycogen phosphorylase inhibitors synergize with kinase inhibitors such as sorafenib and buparlisib to decrease ATC cell viability. Our work establishes glycogen metabolism as a novel metabolic process in thyroid cells that is associated with thyroid cancer dedifferentiation and provides insight to the effectiveness of inhibiting glycogen metabolism as a therapeutic strategy in ATC. References: 1. Siegel, R.L., Miller, K.D. and Jemal, A. (2017), Cancer statistics, 2017. CA: A Cancer Journal for Clinicians, 67: 7-30. doi:10.3322/caac.21387 2. Saini S, Tulla K, Maker AV, Burman KD, Prabhakar BS. Therapeutic Advances in Anaplastic Thyroid Cancer: A Current Perspective. Mol Cancer. 2018;17(1):154. doi:10.1186/s12943-018-0903-0

Targeting EML4-ALK gene fusion variant 3 in thyroid cancer

Finding targetable gene fusions can expand the limited treatment options in radioactive iodine-refractory (RAI-r) thyroid cancer. To that end, we established a novel cell line ‘JVE404’ derived from an advanced RAI-r papillary thyroid cancer (PTC) patient, harboring an EML4-ALK gene fusion variant 3 (v3). Different EML4-ALK gene fusions can have different clinical repercussions. JVE404 cells were evaluated for cell viability and cell signaling in response to ALK inhibitors crizotinib, ceritinib and lorlatinib, in parallel to the patient’s treatment. He received, after first-line lenvatinib, crizotinib (Drug Rediscovery Protocol (DRUP) trial), and lorlatinib (compassionate use). In vitro treatment with crizotinib or ceritinib decreased viability in JVE404, but most potently and significantly only with lorlatinib. Western blot analysis showed a near total decrease of 99% and 89%, respectively, in pALK and pERK expression levels in JVE404 cells with lorlatinib, in contrast to remaining signal intensities of a half and a third of control, respectively, with crizotinib. The patient had a six-month lasting stable disease on crizotinib, but progressive disease occurred, including the finding of cerebral metastases, at 8 months. With lorlatinib, partial response, including clinical cerebral activity, was already achieved at 11 weeks’ use and ongoing partial response at 7 months. To our best knowledge, this is the first reported case describing a patient-specific targeted treatment with lorlatinib based on an EML-ALK gene fusion v3 in a thyroid cancer patient, and own cancer cell line. Tumor-agnostic targeted therapy may provide valuable treatment options in personalized medicine.