A clinical series and literature review of the management of inguinal nodal metastases in patients with primary extramammary Paget disease of the scrotum

We describe a series of five patients with extramammary Paget disease of the scrotum with inguinal nodal metastases. These patients underwent combined groin dissection. All patients experienced invasion to the dermis. One patient had invasion of the dartos muscle, another had tumor invading into the skeletal muscle and femoral vein. Four patients had positive Cloquet node involvement on frozen section and formal histology, but only one patient had positive pelvic nodal disease. Another patient with pelvic nodal metastases seen on computed tomography scan had no Cloquet node identified intraoperatively but had positive pelvic nodal metastases. The mean disease-free survival and the overall survival were 28.6 months (range: 2–60 months) and 33.4 months (range: 2–60 months), respectively, for all patients. Three patients developed distant metastases and two patients were disease free to date. No locoregional recurrences were observed. Aggressive lymphadenectomy in selected cases can provide a long-term survival benefit. The use of Cloquet node in the prediction of pelvic nodal disease should be considered. Based on the literature review, sentinel lymph node biopsy can potentially diagnose occult metastases in otherwise nonenlarged nodes

Clinicopathologic Features and Whole Genome Sequencing of a Primary Osteosarcoma of the Uterus

Primary osteosarcoma (OS) of the uterus is a distinctly rare and aggressive disease with fewer than 20 cases reported worldwide. We describe a case of primary uterine OS with rapid development of pulmonary and brain metastasis in a 50-year-old woman. Histopathologic examination of the uterine tumor showed atypical spindle cells producing an osteoid matrix with calcification in keeping with OS. Despite initial response to doxorubicin and ifosfamide, the patient succumbed to brain metastases just 8 months from diagnosis. Whole genome sequencing was performed on tumor and blood samples to analyze genetic alterations in this highly aggressive tumor. A pathogenic somatic missense mutation resulting in substitution of glutamate for lysine at position 653 within the protein kinase domain of the platelet-derived growth factor receptor beta (PDGFRB) was found. The PDGF pathway is involved in cell proliferation and angiogenesis, and it has been implicated in malignancy. Crucially, this pathogenic mutation may be amenable to PDGFR tyrosine kinase inhibition, representing a possible treatment approach in this rare sarcoma

Prognostic value of CD8 + PD-1+ immune infiltrates and PDCD1 gene expression in triple negative breast cancer

Abstract The role of programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) in triple negative breast cancer (TNBC) remains to be fully understood. In this study, we investigated the role of PD-1 as a prognostic marker for TNBC in an Asian cohort (n = 269). Samples from patients with TNBC were labeled with antibodies against PD-L1 and PD-1, and subjected to NanoString assays to measure the expression of immune-related genes. Associations between disease-free survival (DFS), overall survival (OS) and biomarker expression were investigated. Multivariate analysis showed that tumors with high PD-1+ immune infiltrates harbored significantly increased DFS, and this increase was significant even after controlling for clinicopathological parameters (HR 0.95; P = 0.030). In addition, the density of cells expressing both CD8 and PD-1, but not the density of CD8−PD-1+ immune infiltrates, was associated with improved DFS. Notably, this prognostic significance was independent of clinicopathological parameters and the densities of total CD8+ cell (HR 0.43, P = 0.011). At the transcriptional level, high expression of PDCD1 within the tumor was significantly associated with improved DFS (HR 0.38; P = 0.027). In line with these findings, high expression of IFNG (HR 0.38; P = 0.001) and IFN signaling genes (HR 0.46; p = 0.027) was also associated with favorable DFS. Inclusion of PD-1 immune infiltrates and PDCD1 gene expression added significant prognostic value for DFS (ΔLRχ2 = 6.35; P = 0.041) and OS (ΔLRχ2 = 9.53; P = 0.008), beyond that provided by classical clinicopathological variables. Thus, PD-1 mRNA and protein expression status represent a promising, independent indicator of prognosis in TNBC

Combinatorial hypofractionated radiotherapy and pembrolizumab in anaplastic thyroid cancer

Objective: 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 200 mg 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 five patients, BOR was 80%; with two complete responses (CR) and two 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. Conclusion: Herein, we report a case series of five patients with ATC, with two 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