Limited clinical activity has been seen in osteosarcoma (OS) patients treated with immune checkpoint inhibitors (ICI). To gain insights into the immunogenic potential of these tumors, we conducted whole genome, RNA, and T-cell receptor sequencing, immunohistochemistry and reverse phase protein array profiling (RPPA) on OS specimens from 48 pediatric and adult patients with primary, relapsed, and metastatic OS. Median immune infiltrate level was lower than in other tumor types where ICI are effective, with concomitant low T-cell receptor clonalities. Neoantigen expression in OS was lacking and significantly associated with high levels of nonsense-mediated decay (NMD). Samples with low immune infiltrate had higher number of deleted genes while those with high immune infiltrate expressed higher levels of adaptive resistance pathways. PARP2 expression levels were significantly negatively associated with the immune infiltrate. Together, these data reveal multiple immunosuppressive features of OS and suggest immunotherapeutic opportunities in OS patients.

BACKGROUND The authors have recently shown that a majority of patients with myelodysplastic syndrome (MDS) classified by the International Prognostic Scoring System as lower risk die without transformation to acute myelogenous leukemia (AML). The cause of death (COD) of these patients is not well understood. Identifying the COD could help to guide early therapy decisions. METHODS The authors retrospectively analyzed the COD in a cohort of 273 deceased patients with lower-risk MDS according to the International Prognostic Scoring System at presentation to The University of Texas M. D. Anderson Cancer Center from 1980 to 2004. MDS-related death was defined as infection, bleeding, transformation to AML, or disease progression. Remaining CODs were classified as non–MDS-related. RESULTS Median age at presentation was 66 years (range, 19-88 years). Overall median survival was 59 weeks (range, 1-831 weeks). All French-American-British leukemia classification subgroups were represented. The percentage of International Prognostic Scoring System low and intermediate-1 groups were 21% and 79%, respectively. The most common cytogenetic abnormality (9%) was del(5q). Patients received supportive care only. The COD was identified as MDS-related in 230 of 273 (84%) patients. The most common disease-related CODs were infection (38%), transformation to AML (15%), and hemorrhage (13%). The most frequent non–disease-related COD was cardiovascular events (19 of 43 patients). CONCLUSIONS The majority of patients with low- or intermediate-1 risk MDS will die because of causes related to their underlying disease. Although these results need to be validated in different populations, early therapeutic intervention could be considered in the management of these patients to improve survival.

BackgroundImmunotherapies, specifically those based on immune checkpoint inhibitors, have shown promising activity in multiple tumor types. Other than mifamurtide (MEPACT®) for osteosarcoma approved by European Medicines Agency, there are no approved immunotherapies for sarcomas.MethodsWe analyzed medical records of patients with advanced sarcoma who were referred to Phase 1 clinic at MD Anderson and received an immunotherapy (checkpoint inhibitors, vaccines, or cytokine based therapies). Clinical parameters including demographics, clinical history, toxicity, and response were abstracted.ResultsAmong 50 patients enrolled in immunotherapy trials (Bone 10; Soft-tissue 40) we found 14 different subtypes of sarcomas. Royal Marsden Hospital (RMH) prognostic score was <2 (86%). Performance status (PS) was 0–1 in 48 patients (96%); median number of prior therapies was 3 (0–12). Immunotherapy consisted of checkpoint inhibitors (82%: PD1 = 7, PD-L1 = 11, CTLA4 = 22, other = 1) of which 42% were combinations, as well as vaccines (14%), and cytokines (4%). Median overall survival (OS) was 13.4 months (11.2 months: not reached). Median progression free survival (PFS) was 2.4 months (95% CI = 1.9–3.2 months). Best response was partial response (PR) in 2 patients with alveolar soft part sarcoma (ASPS) and stable disease (SD) in 11 patients (3 GIST, 3 liposarcomas (2 DDLS, 1 WDLS), 2 ASPS, 2 leiomyo, 1 osteo). PFS was 34% (23%, at 50%) at 3 months, 16% (8%, 30%) at 6 months, and 6% (2%, 20%) at 1 year. Pseudo-progression followed by stable disease was observed in 2 patients (4%). Grade 3/4 adverse events included rash (10%), fever (6%), fatigue (6%), and nausea/vomiting (6%).ConclusionImmunotherapies were well tolerated in advanced sarcoma patients enrolled in trials. All four ASPS patients had clinical benefit with checkpoint inhibitors and this was the only subtype experiencing partial response. Further evaluation of checkpoint inhibitors in ASPS is warranted.

Adenosarcomas are rare malignancies of the female genital tract, accounting for approximately 5 % of uterine sarcomas. Occasionally, adenosarcoma occurs in the ovaries or in extra-uterine tissue, which may be related to endometriosis. These tumors are characterized by benign epithelial elements and a malignant mesenchymal component. Pathologic diagnosis is dependent on the identification of the characteristic morphologic features. The most common immunohistochemical markers for adenosarcoma are CD10 and WT1, but these are not specific. The most frequent presenting symptom is abnormal uterine bleeding. The majority of patients present with stage I disease, with a 5-year overall survival of 60 to 80 %. Survival is influenced by the presence of myometrial invasion, sarcomatous overgrowth, lymphovascular invasion, necrosis, and the presence of heterologous elements including rhabdomyoblastic differentiation. Patients with sarcomatous overgrowth have significantly increased risk of recurrence 23 versus 77 % and decreased 5-year overall survival 50 to 60 %. Standard of care treatment is total hysterectomy with bilateral salpingo-oophorectomy without lymphadenectomy, as the incidence of lymph node metastasis is rare. Retrospective data does not support the use of adjuvant pelvic radiotherapy in uterine adenosarcomas as no survival benefit is seen. Insufficient data exists to recommend routinely neoadjuvant or adjuvant chemotherapy for uterine adenosarcomas. Limited evidence exists for the role of hormonal therapy in uterine adenosarcomas. The PIK3/AKT/PTEN pathway is mutated in ∼70 % of adenosarcomas, and this may represent a possible therapeutic target. This article reviews the current state of knowledge concerning uterine adenosarcoma and discusses the management of this rare tumor.

Solitary fibrous tumor (SFT) is a mesenchymal neoplasm of fibrous origin. The 2013 WHO classification of soft tissue tumors defines malignant forms as hypercellular, mitotically active (>4 mitosis/10 high-power fields), with cytological atypia, tumor necrosis, and/or infiltrative margins. With an IRB-approved protocol, we investigated patient records and clinicopathologic data from our Sarcoma Database to describe the clinical characteristics of both benign and malignant SFT. All pathology specimens were reviewed by two pathologists. Descriptive statistics and univariate/multivariate survival analysis were performed. Patient records and Social Security Death Index were used to evaluate vital status. Of 82 patients, 47 (57%) were women and 73 (89%) were Caucasian. Median age was 62 years (range, 20 to 89). Thirty-two (39%) patients succumbed to the disease. Primary tumor site was lung/pleura in 28 (34%), abdomen/pelvis in 23 (28%), extremity in 13 (16%), and head/neck in 9 (11%) patients. Pathology was described as benign in 42 (51%) and malignant in 40 (49%) patients. Compared to benign SFT, malignant histology is associated with larger tumor size, higher mitotic counts, metastatic disease at diagnosis, and greater use of chemotherapy and radiation therapy. Gender, age, and tumor site were not significantly different between benign and malignant subtypes. By univariate analysis, only benign vs. malignant variant and complete resection positively impacted overall survival (P = 0.02 and P<0.0001, respectively). In the multivariable analysis of overall survival, receiving chemotherapy or not receiving surgery were two variables significantly associated with higher failure rate in overall survival: patients with chemotherapy vs. no chemotherapy (P = 0.003, HR = 4.55, with 95% CI: 1.68–12.34) and patients without surgery vs. with surgery (P = 0.005, HR = 25.49, with 95% CI: 2.62–247.57). Clear survival differences exist between benign and malignant SFT. While surgery appears to be the best treatment option for benign and malignant SFT, better systemic therapies are needed to improve outcomes of patients with metastatic, malignant SFT.