Analysis of PD-1, PD-L1, and T-cell infiltration in angiosarcoma pathogenetic subgroups.

Angiosarcoma (AS) is a rare malignancy with a poor prognosis. It can develop spontaneously or due to previous radiotherapy (RT), ultraviolet (UV) radiation, or lymphoedema (Stewart Treves AS). Novel therapeutic approaches are needed, but progress is hindered because of the heterogeneity and rarity of AS. In order to explore the potential of immune checkpoint inhibition (ICI), we investigated the protein expression of programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and CD8 + T cells in 165 AS cases in relation to AS subgroups based on clinical classification and in relation to whole-genome methylation profiling based clusters (A1, A2, B1, B2). High PD-L1 and PD-1 expression were predominantly shown in UV-associated, visceral, and soft tissue AS. RT-associated AS showed predominantly high PD-1 expression. CD8 + T cell infiltration was present in the majority of AS samples. Within the UV-associated AS, two different clusters can be distinguished by DNA methylation profiling. Cases in cluster A1 showed higher PD-1 (p = 0.015), PD-L1 (p = 0.015), and CD8 + T cells (p = 0.008) compared to those in cluster B2, suggesting that these UV-AS tumors are more immunogenic than B2 tumors showing a difference even within one subgroup. In soft tissue AS, combined PD-1 and PD-L1 expression showed a trend toward poor survival (p = 0.051), whereas in UV-associated AS, PD-1 expression correlated with better survival (p = 0.035). In conclusion, we show the presence of PD-1, PD-L1, and CD8 + T cells in the majority of AS but reveal differences between and within AS subgroups, providing prognostic information and indicating to be predictive for ICI.

Targeting angiosarcomas of the soft tissues: A challenging effort in a heterogeneous and rare disease.

Angiosarcomas are rare malignant tumors with a heterogeneous clinical presentation and generally poor prognosis. It has been difficult to establish consistent molecular characteristics and driver events in angiosarcoma development. Oncogenic and angiogenesis-related pathways have been investigated pre-clinically and clinically with varying results. A few promising responses to checkpoint inhibitors have been described, but immunological features require further elucidation. With this review we present an overview of the critical biological pathways and processes affected in angiosarcoma, and their potential role in novel, non-cytotoxic, systemic treatments.

Clinicopathological characteristics and outcome of 31 patients with ETV6-NTRK3 fusion gene confirmed (mammary analogue) secretory carcinoma of salivary glands.

OBJECTIVES: In 2010, a new subtype of salivary gland cancer (SGC), (mammary analogue) secretory carcinoma (SC), was defined, characterized by the ETV6-NTRK3 fusion gene. As clinical behavior and outcome data of this histological subtype tumor are still sparse, we aimed to describe the clinicopathological course and outcome of a series of translocation positive SC patients. PATIENT AND METHODS: We re-evaluated the pathological diagnosis of a subset of SGCs, diagnosed in 4 of 8 Dutch head and neck centers. Subsequently, tumors with a morphological resemblance to SC were tested for the ETV6-NTRK3 fusion gene using RT-PCR. Furthermore, patients prospectively diagnosed with SC were included. The clinical characteristics and outcomes were retrieved from the patient files. RESULTS: Thirty-one patients with ETV6-NTRK3 fusion gene positive SC were included. The median age was 49 years, 17 patients (55%) were male. Eighteen tumors (58%) arose in the parotid gland. One patient presented with lymph node metastasis. All patients underwent tumor resection and 4 patients had a neck dissection. Four patients had re-resection and 15 patients (48%) received postoperative radiotherapy. One patient developed a local recurrence, no regional recurrences or distant metastases were observed. After a median follow-up of 49 months the 5- and 10-year overall survival were 95%, the 5- and 10-year disease free survival were 89%. CONCLUSION: The clinical course of SC is favorable with a low rate of locoregional recurrence and excellent survival. Given the low incidence of nodal metastases, elective neck treatment, i.e. surgery and/or radiotherapy, does not seem to be indicated.

Transanal endoscopic microsurgery following treatment with imatinib : a case report of a patient with a rectal gastrointestinal stromal tumor.

BACKGROUND: Gastrointestinal stromal tumors (GIST) of the rectum are a challenge for the colorectal surgeon. In case of a locally advanced rectal GIST, an extended or multivisceral resection with significant morbidity and -mortality is often necessary. Literature is lacking on the combined modality of transanal endoscopisc microsurgery (TEM) following imatinib for these patients. METHODS: We describe a combined approach for a locally advanced GIST of the rectum with preoperative imatinib -treatment and subsequent local excision using the TEM procedure. RESULTS: After six months of treatment with imatinib the TEM procedure was successfully performed with a radical -resection of the remnant tumor. Twenty-four months after surgery this patient has no evidence of disease. CONCLUSIONS: A TEM procedure following treatment with imatinib may safely be performed in selected patients with a locally advanced GIST.

Prognostic and therapeutic relevance of the IGF pathway in Ewing's sarcoma patients.

The optimal target and timing of drugs interfering with the insulin-like growth factor (IGF) signaling system in Ewing's sarcoma (ES) remain undetermined. We examined the expression of IGF signaling proteins in ES samples taken before and after chemotherapy, and speculate about the optimal way of treating ES patients in the future. Tumor material (36 initial biopsies and 24 resection specimens after neoadjuvant chemotherapy) and follow-up data of 41 patients treated for ES at the Radboud University Nijmegen Medical Centre were analyzed. Immunohistochemical staining was done for IGF1, IGF2, IGFBP3, IGF-1R, phosphorylated AKT (pAKT), phosphorylated mTOR (pmTOR), and phosphorylated ERK (pERK), and staining intensity was scored semiquantitatively. Change of protein expression during treatment, correlations of effector cascade signaling, and influence on progression-free (PFS) and overall survival (OS) were tested. All potential targets were widely expressed at both time points. After chemotherapy, pmTOR expression decreased significantly (p = 0.021) while IGFBP3 increased (p = 0.005). Correlations exist between IGF-1R and pERK (ρ = 0.286, p = 0.031), IGF-1R and pAKT (ρ = 0.269, p = 0.045), pAKT and pERK (ρ = 0.460, p = 0.000), and pERK and pmTOR (ρ = 0.273, p = 0.038). In therapy-naive samples, combined expression of pAKT, pmTOR, and pERK predicted worse PFS (median, 11 vs. 32 months; p = 0.039) and OS (median, 18 vs. 83 months; p = 0.023). We identify an unfavorable prognostic group of ES patients with widely activated IGF-effector cascades, demonstrate cooperation between the different downstream pathways, and show how expression of IGF-related proteins may change after exposure to chemotherapy. These findings should be taken into account when designing future trials with IGF-targeting agents. We suggest the prospective exploration of chemotherapy and multi-target tyrosine kinase inhibitors in the first-line setting.