Combinatorial Hypofractionated Radiotherapy and Pembrolizumab in Anaplastic Thyroid Cancer.

Objectives Anaplastic thyroid cancer (ATC) is an aggressive disease associated with poor outcomes and resistance to therapies. Our study aim was to evaluate the activity of a combinatorial regimen of sandwich sequencing of pembrolizumab immunotherapy and hypofractionated radiotherapy (RT). Methods In this case series, patients with ATC received hypofractionated RT (QUAD-shot) and intravenous pembrolizumab 200mg every 3-4 weeks. Pembrolizumab was continued until disease progression or up till 24 months. Concurrent Lenvatinib treatment was allowed. Primary endpoint was best overall response (BOR) and progression-free survival (PFS). Additionally, we performed immune profiling of circulating T cells in a responder to investigate the immune response to our combinatorial treatment. Results At median follow-up of 32.6 months (IQR: 26.4-38.8), of a cohort of 5 patients, BOR was 80%; with 2 complete responses (CR) and 2 partial responses (PR). Patients who achieved CR remained disease-free at last follow-up. Median PFS was 7.6 months (IQR: 6.2-NR), and 1-year PFS and overall survival rate was 40% (95% CI: 13.7-100) for both. Treatment was well-tolerated, with mostly grade 1-2 adverse events. Immune profiling of one partial responder revealed an increase in activated CD4 and CD8 T cells post-QUAD-shot RT, which was further enhanced during the maintenance phase of pembrolizumab. Conclusions Herein, we reported a case series of 5 patients with ATC, with 2 long-term survivors who were treated with surgical debulking followed by QUAD-shot RT and pembrolizumab, possibly due to synergy of local and systemic treatments in activating anti-tumour immunogenic cytotoxicity. This regimen warrants further investigation in a larger cohort of patients.

Boosted abscopal effect from radiotherapy and pembrolizumab in anaplastic thyroid cancer: a mini-review and case report.

BACKGROUND: The abscopal effect, in which radiation induces a systemic anti-tumour immune response, has been demonstrated with radiotherapy. Immunotherapy boosts the abscopal effect by facilitating the immune response to radiation. Radiotherapy and programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) blockade has resulted in the boosted abscopal effect in solid cancers, but its role in anaplastic thyroid cancer (ATC) is unknown. In this mini-review, we describe the abscopal effect and summarise its proposed underlying mechanisms. We then present a potential case of boosted abscopal effect in ATC. CASE DESCRIPTION: In our case presentation, we describe a 51-year-old female who presented with 3 weeks of rapidly enlarging thyroid mass. Examination revealed a 3-cm thyroid nodule which was Bethesda V on fine needle aspiration cytology (FNAC). Intraoperatively, there was a gross extrathyroidal extension into the cricoid cartilage. After total thyroidectomy, post-operative histopathology showed widely invasive follicular thyroid cancer with anaplastic transformation (>50%). Immunohistochemistry showed high PD-L1 expression [combined positive score (CPS) >70%]. Due to residual cricoid cartilage disease and several peri-hilar and lung metastases on positron emission tomography-computed tomography (PET-CT) scan, she underwent post-operative palliative radiotherapy and pembrolizumab. After two cycles of pembrolizumab, repeat PET-CT scan showed complete response (CR) of local and distant disease. She remained well for 32 months, before recent discovery of a right mandible bony metastasis planned for radiotherapy. CONCLUSIONS: This case demonstrates exceptional response to radiotherapy and anti-PD-1 immunotherapy in ATC, potentially illustrating the first known abscopal effect in ATC with this treatment.

Rapidly progressing necrotic hand ulcer in a patient with angioimmunoblastic T-cell lymphoma.

Mucormycosis is a fungal infection caused by opportunistic fungi of the phylum Glomeromycota, subphylum Mucormycotina. In developed countries, it affects patients with haematological malignancies undergoing chemotherapy and those who have received allogenic stem cell transplants, while in developing countries it is seen in those with uncontrolled diabetes mellitus. Herein, we report a case of cutaneous mucormycosis in a 67yo Chinese gentleman with background of angioimmunoblastic T cell lymphoma (AITL) on chemotherapy. We also share the clinicopathological findings of this and correlate these findings with those present in the current literature. Finally, we outline treatment options and prognosis of cutaneous mucormycosis.

A single tertiary institution review of the international system for serous fluid cytopathology and the impact of cell block and ancillary studies on its performance.

INTRODUCTION: We sought to assess the utility of the International System for Serous Fluid Cytopathology (TIS) in the context of our department's routine practice. MATERIALS AND METHODS: We examined 1028 archived effusion cytology (pleural, peritoneal, and pericardial) cases from 2018 to 2019, and re-classified them along the international system into the following diagnostic categories: nondiagnostic (ND), negative for malignancy (NFM), atypia cells of undetermined significance (AUS), suspicious for malignancy (SFM), and malignant (MAL). RESULTS: The full distribution of the cases examined was as follows: ND 2.0%; NFM 66.1%; AUS 6.0%; SFM 4.7%; MAL 21.2%. Overall risk of malignancy for each category was calculated as: ND 30.0%; NFM 18.0%; AUS 61.9%; SFM 100%; MAL 94.4%. The overall performance attributes of TIS were as follows: sensitivity 57.1%; specificity 98.3%; positive predictive value 94.4%; negative predictive value 82.0%; diagnostic accuracy 84.5%. CONCLUSIONS: The new classification was simple and intuitive to use and our results appear to fall within the expected ranges of the new guidelines, with risk of malignancy and accuracy comparable to similar studies. The availability of a cell block allowed for refinement of the diagnosis in a majority of cases with equivocal cytology, though this was dependent on the cell yield.

IgG4-Related Disease of the Thyroid Gland Requiring Emergent Total Thyroidectomy: A Case Report.

IgG4-related disease of the thyroid gland is a recently recognized subtype of thyroiditis, often with rapid progression requiring surgical treatment. It is considered as a spectrum of disease varying from early IgG4-related Hashimoto's thyroiditis (HT) pattern to late fibrosing HT or Riedel's thyroiditis patterns. Here, we report a 47-year-old Malay woman presenting with progressively painless neck swelling over 3 years and subclinical hypothyroidism. Computed tomography (CT) scan revealed diffuse thyroid enlargement (up to 13 cm) with retrosternal extension and without regional lymphadenopathy. Fine needle aspiration of the thyroid showed a limited number of follicular epithelial cell groups with widespread Hurthle cell change and scanty background colloid, but no evidence of lymphocytosis. The cytologic features fell into the category of 'atypia of undetermined significance'. Subsequently, the patient developed hypercapnic respiratory failure secondary to extrinsic upper airway compression by the thyroid mass and underwent emergent total thyroidectomy. Histology of the thyroid showed diffuse dense lymphoplasmacytic infiltrate and fibrosis. Follicular cells exhibited reactive nuclear features and some Hurthle cell change. IgG4+ plasma cells were over 40/high power field while overall IgG4/IgG ratio was above 50%. The overall features suggest the diagnosis of IgG4-related disease of the thyroid gland in the form of IgG4-related HT. Post-surgery, the patient was found to have markedly elevated serum IgG4 concentration but PET/CT did not show significant increased fludeoxyglucose uptake in other areas. Her recovery was complicated by a ventilator-associated pneumonia with empyema, limiting early use of corticosteroids for treatment of IgG4-related disease.

GNA13 expression promotes drug resistance and tumor-initiating phenotypes in squamous cell cancers.

Treatment failure in solid tumors occurs due to the survival of specific subpopulations of cells that possess tumor-initiating (TIC) phenotypes. Studies have implicated G protein-coupled-receptors (GPCRs) in cancer progression and the acquisition of TIC phenotypes. Many of the implicated GPCRs signal through the G protein GNA13. In this study, we demonstrate that GNA13 is upregulated in many solid tumors and impacts survival and metastases in patients. GNA13 levels modulate drug resistance and TIC-like phenotypes in patient-derived head and neck squamous cell carcinoma (HNSCC) cells in vitro and in vivo. Blockade of GNA13 expression, or of select downstream pathways, using small-molecule inhibitors abrogates GNA13-induced TIC phenotypes, rendering cells vulnerable to standard-of-care cytotoxic therapies. Taken together, these data indicate that GNA13 expression is a potential prognostic biomarker for tumor progression, and that interfering with GNA13-induced signaling provides a novel strategy to block TICs and drug resistance in HNSCCs.

Clinical management of pheochromocytoma and paraganglioma in Singapore: missed opportunities for genetic testing.

BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors of the adrenal glands and paraganglia, occurring sporadically or as a range of hereditary tumor syndromes. About 30% of PPGLs are attributed to germline mutations. Clinical presentation, including localization, malignant potential, and age of onset, varies depending on the genetic background. Genetic testing for PPGLs is not well studied in Southeast Asia. We reviewed clinical management of PPGLs in Singapore, highlighting current gaps in clinical practice. METHODS: Medical records of patients with PPGLs between 2005 and 2016 were reviewed. Diagnosis was confirmed histologically and stratified into sporadic or familial/syndromic (FS). RESULTS: Twenty-seven (21.8%) patients were referred to the Cancer Genetics Service (CGS). FS PPGLs (18.5%) and extra-adrenal PPGLs (58.1%) incidences were higher than previous studies. Referrals were lower for sporadic PPGLs compared to FS PPGLs (3.7% vs. 100%). Referrals were highest at diagnosis age <20 years old (80%) and decreased with increasing age; ≥20-<40 years old (32.1%), ≥40-<60 years old (10.6%). Genetic testing was taken up in 12/27 (44.4%) patients of which 7/12 (58.3%, 3 SDHB, 2 SDHD, 2 VHL) had germline mutations. CONCLUSION: Opportunities for genetic testing are frequently missed due to low referral rates in patients with apparently sporadic PPGLs, particularly between ages 20-60.

Phenotype-driven precision oncology as a guide for clinical decisions one patient at a time.

Genomics-driven cancer therapeutics has gained prominence in personalized cancer treatment. However, its utility in indications lacking biomarker-driven treatment strategies remains limited. Here we present a "phenotype-driven precision-oncology" approach, based on the notion that biological response to perturbations, chemical or genetic, in ex vivo patient-individualized models can serve as predictive biomarkers for therapeutic response in the clinic. We generated a library of "screenable" patient-derived primary cultures (PDCs) for head and neck squamous cell carcinomas that reproducibly predicted treatment response in matched patient-derived-xenograft models. Importantly, PDCs could guide clinical practice and predict tumour progression in two n = 1 co-clinical trials. Comprehensive "-omics" interrogation of PDCs derived from one of these models revealed YAP1 as a putative biomarker for treatment response and survival in ~24% of oral squamous cell carcinoma. We envision that scaling of the proposed PDC approach could uncover biomarkers for therapeutic stratification and guide real-time therapeutic decisions in the future.Treatment response in patient-derived models may serve as a biomarker for response in the clinic. Here, the authors use paired patient-derived mouse xenografts and patient-derived primary culture models from head and neck squamous cell carcinomas, including metastasis, as models for high-throughput screening of anti-cancer drugs.