Grégoire Berthod

Introduction Selective internal radiation therapy (SIRT) and sorafenib are used for patients with liver metastases from uveal melanoma. We conducted a phase I study to determine the optimal timing of administration of sorafenib in combination with radioembolisation. Methods Patients received radioembolisation plus sorafenib initiated 14, 11, or 3 days after or 7 days before radioembolisation. The primary endpoint was safety. Secondary endpoints included efficacy and evaluation of circulating angiogenic factors. Sorafenib plasma levels were quantified retrospectively. Results Ten patients received radioembolisation plus sorafenib. The most common grade 2–4 adverse events included rash, abdominal pain, fatigue and lymphocytopenia. Best response was partial response (30%) and stable disease (70%). Median progression-free and overall survival were 6.2 (4.8–not reached) and 11.7 months (9.4–not reached), respectively. Circulating angiogenic factors showed transient elevation at Day 10 post-SIRT when sorafenib was started 11–14 days after SIRT, but not when sorafenib was started before or just after SIRT. Most steady-state sorafenib plasma concentrations were in the upper percentiles relative to reference curves for single-agent sorafenib. Conclusions SIRT plus sorafenib was feasible, but appeared more toxic than sorafenib alone, presumably due to altered pharmacokinetics. Sorafenib may hinder the angiogenic response when initiated before or shortly after SIRT. Clinical trial registration Registry: ClinicalTrials.gov, NCT01893099.

Background/Objectives: Germ cell tumors are the most common neoplasia in males < 50 y. In two case series, thromboembolic events (TEs) were reported in 8% and 13% of patients undergoing chemotherapy, whereas arterial thromboembolic events (ATEs) in other types of cancer treated with cisplatin had a frequency of 2% in a retrospective series and 0.67% in a meta-analysis. Recent data found a frequency of 2.4% for ATE in a large cohort of testicular cancer patients. Risk factors are not clearly identified, and given the severity of these events, further exploration is needed to determine appropriate preventive measures. Methods: We performed a retrospective cohort study of 171 patients undergoing chemotherapy for germ cell tumors in two centers in Switzerland and recorded the occurrence of ATE or venous thromboembolic events (VTEs) during chemotherapy or in the 3 months after its completion. Results: of 171 patients, 33.3% underwent adjuvant chemotherapy for stage I disease. Overall, 32 patients had a TE (18.7%, 95% CI 13.3–25.5%), 26 (15.2%, 95% CI 10.3–21.7%) had VTEs, and 11 (6.4%, 95% CI 3.4–11.5%) had ATEs. Five patients had both a VTE and ATE. VTEs were associated with disease stage (II, III, or relapse, with OR 15.6, p = 0.0002), retroperitoneal lymph nodes ≥ 3.5 cm (OR 3.2, p = 0.012), LDH > 500 UI/L (OR 5.3, p = 0.0025), and age > 35 y (OR 3.4, p = 0.005). The Khorana Score (KS) varied between 1 and 2 in 96% of the patients. ATEs were associated with active smoking (OR 6.5 p = 0.010), KS of ≥2 (OR 6.4 p = 0.004), and age > 35 y (OR 6.3, p = 0.01). Conclusions: Our findings show that ATEs are more frequent in our cohort than previous reports. We found a strong association between smoking and ATEs, which should be further assessed. Platinum-induced endothelial damage may be amplified by smoking in young patients in the absence of other risk factors and preventive medication.

Adoptive cell therapy (ACT) using ex vivo–expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell–intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8 ⁺ TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor–reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network–based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

WHO first recognised extranodal NK/T-cell lymphoma (ENKTCL) in 2001, thanks to technical advances in anatomopathology and immunohistochemistry. It is divided into nasal and extranasal subgroups depending on the primary site. Primary isolated NK/T-cell lymphoma of the testis is rare. Typical recurrence sites of primary testicular NK/T-cell lymphoma are the gastrointestinal tract, lymph nodes, skin, spleen and central nervous system. Nasal relapses of a primary NK/T-cell lymphoma of the testis are very rare and according to our knowledge, no other case has been reported yet in the literature. The authors report the case of a 35-year-old Caucasian man relapsing twice in the nasal cavity 1 year after initial diagnosis and treatment of a primary isolated, stage IE, ENKTCL of the testis. We report the clinical and radiological presentation of the nasal relapses and the different modalities of treatment that were applied. Sinonasal relapses of an isolated primary NK/T-cell lymphoma of the testis are very rare. ENKTCL is a very aggressive entity, even at an early stage, therefore, requiring a multimodal treatment approach including chemotherapy and radiotherapy. New strategies to treat this disease are needed.