Pembrolizumab for anaplastic thyroid cancer: a case study.

Blockade of the PD-1/PD-L1 pathway with targeted monoclonal antibodies has demonstrated encouraging anti-tumour activity in multiple cancer types. We present the case of a patient with BRAF-negative stage IVC anaplastic thyroid cancer (ATC) treated with the anti-PD-1 monoclonal antibody, pembrolizumab, following radiographic progression on chemoradiation. Blood samples were collected prior to and at four time points during treatment with pembrolizumab. Mass cytometry was used to determine expression of relevant biomarkers by peripheral blood mononuclear cells. Faecal samples were collected at baseline and 4 weeks following treatment initiation; taxonomic profiling using 16S ribosomal RNA (rRNA) gene sequencing was performed. Following treatment, a marked expansion in CD20+ B cell, CD16+ CD56lo NK cell and CD45RO+ CCR7+ central memory CD4+ T-cell populations was observed in the peripheral blood. Proportions of cells expressing the co-receptors TIGIT, OX40 and CD86 also increased during treatment. A high abundance of bacteria of the order Bacteroidales, specifically from the Bacteroidaceae and Rikenellaceae families, was identified in the faecal microbiota. Moreover, the patient's microbiome was enriched in Clostridiales order members Ruminococcaceae, Veillonellaceae and Lachnospiraceae. Alpha diversity of the gut microbiome was significantly higher following initiation of checkpoint therapy as assessed by the Shannon and Simpson index. Our results suggest that treatment with pembrolizumab promotes expansion of T-, B- and NK cell populations in the peripheral blood at the time of tumour regression and have the potential to be implemented as predictive biomarkers in the context of checkpoint blockade therapy. Larger studies to confirm these findings are warranted.

The diagnostic utility of routine clot analysis after endovascular thrombectomy in a patient with systemic lupus erythematosus and antiphospholipid syndrome.

We present a case demonstrating histopathological clot findings after endovascular thrombectomy for acute ischaemic stroke in a 38 year-old male with systemic lupus erythematosus and antiphospholipid syndrome (APS). The differential diagnosis was embolism of a suspected Libman-Sacks vegetation or less likely an in-situ thrombosis. Clot analysis provided guidance with patient management and anticoagulation was commenced. The utility of clot analysis in this case provides support for routine clot analysis, which has been standard practice at our institution, and is likely to evolve as endovascular thrombectomy becomes more widely accessible.

Clot Histopathology in Ischemic Stroke with Infective Endocarditis.

BACKGROUND: Endovascular thrombectomy (EVT) has shown efficacy in acute ischemic stroke (AIS) patients with infective endocarditis (IE). The possibility to undertake advanced histopathological clot analysis following EVT offers a new avenue to establish the etiological basis of the stroke - which is often labelled "cryptogenic." In this paper, we present our findings from four consecutive patients with IE who underwent EVT following an AIS at our tertiary referral comprehensive stroke centre. METHODS: Comprehensive histopathological analysis of clot retrieved after EVT, including morphology, was undertaken. RESULTS: The consistent observation was the presence of dense paucicellular fibrinoid material mixed/interspersed with clusters of bacterial cocci. This clot morphology may be specific to septic embolus due to IE unlike incidental bacteraemia and could possibly explain the refractoriness of such clots to systemic thrombolysis. CONCLUSION: Detailed morphological and histopathological analysis of EVT-retrieved clots including Gram staining can assist in etiological classification of the clot. Understanding the composition of the clot may be of clinical value in early diagnostics and mapping treatment planning in IE.

Promoter hypermethylation of the O(6)-methylguanine DNA methyltransferase gene and microsatellite instability in metastatic melanoma.

Tumor spread to distant organs is the most serious consequence of melanoma, as only 10-20% of stage IV patients respond to current chemotherapies. Tumor sensitivity to alkylating agents is affected by the activity of cellular DNA repair proteins, such as O(6)-methylguanine DNA methyltransferase (MGMT) and the DNA mismatch repair proteins. Chemosensitivity may be enhanced by reduced MGMT activity, but the frequency of MGMT promoter silencing through hypermethylation is unknown in distant melanoma metastases. The frequency and significance of microsatellite instability (MSI) in metastatic melanoma is also unclear, and it has been suggested that MSI frequency increases during the metastatic process. We undertook an analysis of 84 melanoma metastases from 47 patients. MGMT methylation was detected using methylation-specific PCR in 26 of the 84 metastases (31%), but there was discordance between individual metastases from the same patient. Therefore, as a result of this variation, MGMT methylation may have only limited value as a predictor of chemosensitivity. High MSI involving mononucleotide repeat markers was not found. Low MSI was detected in five of 50 metastases (10%) and only one of the five metastases also had MGMT methylation. These results demonstrate that in contrast to some previous reports, these tumors have a low frequency of MSI.