The landscape of drug sensitivity and resistance in sarcoma.

Sarcomas are a family of rare malignancies composed of over 100 distinct histological subtypes. The rarity of sarcoma poses significant challenges in conducting clinical trials to identify effective therapies, to the point that many rarer subtypes of sarcoma do not have standard-of-care treatment. Even for established regimens, there can be substantial heterogeneity in responses. Overall, novel, personalized approaches for identifying effective treatments are needed to improve patient out-comes. Patient-derived tumor organoids (PDTOs) are clinically relevant models representative of the physiological behavior of tumors across an array of malignancies. Here, we use PDTOs as a tool to better understand the biology of individual tumors and characterize the landscape of drug resistance and sensitivity in sarcoma. We collected n=194 specimens from n=126 sarcoma patients, spanning 24 distinct subtypes. We characterized PDTOs established from over 120 biopsy, resection, and metastasectomy samples. We leveraged our organoid high-throughput drug screening pipeline to test the efficacy of chemotherapeutics, targeted agents, and combination therapies, with results available within a week from tissue collection. Sarcoma PDTOs showed patient-specific growth characteristics and subtype-specific histopathology. Organoid sensitivity correlated with diagnostic subtype, patient age at diagnosis, lesion type, prior treatment history, and disease trajectory for a subset of the compounds screened. We found 90 biological pathways that were implicated in response to treatment of bone and soft tissue sarcoma organoids. By comparing functional responses of organoids and genetic features of the tumors, we show how PDTO drug screening can provide an orthogonal set of information to facilitate optimal drug selection, avoid ineffective therapies, and mirror patient outcomes in sarcoma. In aggregate, we were able to identify at least one effective FDA-approved or NCCN-recommended regimen for 59% of the specimens tested, providing an estimate of the proportion of immediately actionable information identified through our pipeline. Highlights: Standardized organoid culture preserve unique sarcoma histopathological featuresDrug screening on patient-derived sarcoma organoids provides sensitivity information that correlates with clinical features and yields actionable information for treatment guidanceHigh-throughput screenings provide orthogonal information to genetic sequencingSarcoma organoid response to treatment correlates with patient response to therapyLarge scale, functional precision medicine programs for rare cancers are feasible within a single institution.

Retrospective analysis of adjuvant treatment for localized, operable uterine leiomyosarcoma.

OBJECTIVE: Currently, there is no standard adjuvant treatment protocol for localized uterine leiomyosarcoma (uLMS) as clinical trials to address this question have been retrospective, underpowered, or undermined by slow accrual rates. The aim of this study is to determine the benefit of adjuvant chemotherapy for uLMS. METHODS: We reviewed the medical records of localized uLMS patients who had underwent adjuvant therapy after upfront surgery between 2000 and 2020. The cases were blinded for review. We evaluated the influence of various clinical characteristics and different types of adjuvant therapies on specific outcomes. RESULTS: Sixty-eight patients (median age: 50 years) were included for analysis. Forty of 68 (58.8%) patients received adjuvant chemotherapy +/- radiation therapy and 25 patients (38.6%) did not receive any adjuvant therapy. At a median follow-up time of 43.3 months, 45 patients (66.1%) had relapsed disease. The median disease-free survival (mDFS) for all patients was 23.1 months. Patients who received any adjuvant treatment (chemotherapy and/or radiation) trended toward a longer mDFS compared with those who did not receive any adjuvant therapy (29.7 vs. 14.1 months, p = 0.26). Patients who received adjuvant chemotherapy alone had a longer, but nonstatistically significant mDFS compared with those who did not receive any adjuvant treatment (22.2 vs. 14.1 months, p = 0.18). Additionally, univariate analysis found that tumor size large than 10 cm, and a mitotic rate >10/10hpf were independent prognostic factors for worse DFS. CONCLUSIONS: Though DFS was more favorable among those who received adjuvant therapy, it was not statistically significant, and thus based on this data adjuvant therapy for resected uLMS is still in question.

Aggressive osteoblastoma with a secondary aneurysmal bone cyst treated with denosumab.

Osteoblastomas and aneurysmal bone cysts (ABC) are rare benign bone tumors that make up about 1%-2% of primary bone malignancies, typically occurring in young patients with a median age of 20 years, most commonly effecting the axial skeleton. ABCs may develop independently as primary lesions, or secondary to other bony lesions including osteoblastomas, chondroblastomas, and giant cell tumors. Treatment of unresectable or extensive osteoblastomas can be challenging. In 2013, the Food and Drug Administration (FDA) approved denosumab for the treatment of giant cell tumors of the bone due to its efficacy in these morbid bony lesions. Various case reports have shown that osteoblastomas can respond to denosumab. Furthermore, numerous ABC case reports have described the efficacy of denosumab in these situations. We herein describe a unique case of a young patient with an aggressive osteoblastoma and secondary ABCs who was successfully treated with denosumab.

Translating Knowledge About the Immune Microenvironment of Gastrointestinal Stromal Tumors into Effective Clinical Strategies.

OPINION STATEMENT: The role of targeted therapy is firmly established for gastrointestinal stromal tumors (GISTs); other modalities for targeting this disease are necessary for recurrent and refractory disease. There are several lines of evidence pointing to an active role of the immune system in GIST. Preclinical and clinical studies revealed that the most common type of immune cell infiltration in GISTs is tumor-associated macrophages (TAMs). The mechanism of how TAMs sculpt the tumor microenvironment in GIST is not clear, but it seems that the presence of immunosuppressive regulatory T cells (Tregs) is correlated with the number of TAMs, thus linking macrophages to immunosuppression. CD3+ T cells and NK infiltrates are found in the GIST microenvironment and carry some prognostic value. In early clinical trials, there is evidence for an active role for immunotherapy in treating GIST patients. Moreover, preclinical evidence has indicated that combining TKIs with checkpoint blockers may be synergistic in murine GIST models. Overall, there is substantial preclinical and clinical evidence to support a role for immunoregulation in GIST and further studies will be important for the development of immunotherapies for GIST.

Metastatic Melanoma of Uncertain Primary with 5-Year Durable Response after Conventional Therapy: A Case Report with Literature Review.

A 51-year-old Thai woman presented with bilateral leg edema and painful left inguinal mass for 6 months. Physical examination revealed matted bilateral inguinal lymph nodes up to 9 cm in size. Otherwise, physical examinations including skin were unremarkable. The result of the lymph node incisional biopsy is consistent with that of metastatic melanoma. The extensive investigation demonstrated multiple intra-abdominal and inguinal lymph nodes without detectable primary tumor. Palliative radiation and conventional chemotherapy were prescribed. The CT scan between treatments showed that the response was stable disease, but the following CT scan demonstrated a gradual decrease in size from August 2012 to November 2017 including the lesions outside radiation fields. Moreover, she developed vitiligo during a follow-up visit. The previous data reported the median overall survival among the patients who were treated with conventional chemotherapy ranging from 9.1 to 9.3 months and whose 5-year survival was less than 10%. This case represented a metastatic melanoma of unknown primary who achieved a durable response by conventional treatment. The clinical features including nodal-only disease, vitiligo, and abscopal effect of radiation were considered to be the favorable factors.

Compound A attenuates toll-like receptor 4-mediated paclitaxel resistance in breast cancer and melanoma through suppression of IL-8.

BACKGROUND: Paclitaxel (PTX) is a potent anti-cancer drug commonly used for the treatment of advanced breast cancer (BCA) and melanoma. Toll-like receptor 4 (TLR4) promotes the production of pro-inflammatory cytokines associated with cancer chemoresistance. This study aims to explore the effect of TLR4 in PTX resistance in triple-negative BCA and advanced melanoma and the effect of compound A (CpdA) to attenuate this resistance. METHODS: BCA and melanoma cell lines were checked for the response to PTX by cytotoxic assay. The response to PTX of TLR4-transient knockdown cells by siRNA transfection was evaluated compared to the control cells. Levels of pro-inflammatory cytokines, IL-6 and IL-8, and anti-apoptotic protein, XIAP were measured by real-time PCR whereas the secreted IL-8 was quantitated by ELISA in TLR4-transient knockdown cancer cells with or without CpdA treatment. The apoptotic cells after adding PTX alone or in combination with CpdA were detected by caspase-3/7 assay. RESULTS: PTX could markedly induce TLR4 expression in both MDA-MB-231 BCA and MDA-MB-435 melanoma cell lines having a basal level of TLR4 whereas no significant induction in TLR4-transient knockdown cells occurred. The siTLR4-treated BCA cells revealed more dead cells after PTX treatment than that of mock control cells. IL-6, IL-8 and XIAP showed increased expressions in PTX-treated cells and this over-production effect was inhibited in TLR4-transient knockdown cells. Apoptotic cells were detected higher when PTX and CpdA were combined than PTX treatment alone. Isobologram exhibited the synergistic effect of CpdA and PTX. CpdA could significantly decrease expressions of IL-6, XIAP and IL-8, as well as excreted IL-8 levels together with reduced cancer viability after PTX treatment. CONCLUSIONS: The acquired TLR4-mediated PTX resistance in BCA and melanoma is explained partly by the paracrine effect of IL-6 and IL-8 released into the tumor microenvironment and over-production of anti-apoptotic protein, XIAP, in BCA cells and importantly CpdA could reduce this effect and sensitize PTX-induced apoptosis in a synergistic manner. In conclusion, the possible impact of TLR4-dependent signaling pathway in PTX resistance in BCA and melanoma is proposed and using PTX in combination with CpdA may attenuate TLR4-mediated PTX resistance in the treatment of the patients.

Efficacy of ginger for prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving adriamycin-cyclophosphamide regimen: a randomized, double-blind, placebo-controlled, crossover study.

PURPOSE: The purpose of this study is to determine the efficacy of ginger for reducing chemotherapy-induced nausea and vomiting (CINV) in breast cancer patients receiving adriamycin and cyclophosphamide (AC) regimens. METHODS: We enrolled breast cancer patients receiving AC who experienced moderate to severe nausea or vomiting during the first chemotherapy cycle. Subjects were randomized to receive a 500-mg ginger capsule or placebo twice a day for 5 days starting on the first day of the second AC cycle and were switched to the other treatment in the third cycle. All participants also received ondansetron and dexamethasone for CINV prophylaxis. Nausea severity was recorded once a day during the first 5 days of each cycle. The primary outcome was reduction in nausea score. RESULTS: Thirty-four subjects (68 cycles of AC) were enrolled. Mean (range) maximum nausea score in the first AC cycle was 58 (40-90). Thirty-three subjects (97 %) received the same AC doses in the second as in the third cycle. Mean (±standard error) maximum nausea scores in patients receiving ginger and placebo were 35.36 (±4.43) and 32.17 (±3.71), respectively. The difference in mean maximum nausea scores was 3 (95 % confidence interval, -3 to 9; P = 0.3). There were no significant differences between ginger and placebo in terms of vomiting incidence and severity, rescue medication use, chemotherapy compliance, and adverse events. CONCLUSIONS: Ginger (500 mg) twice daily was safe, but conferred no additional benefit in terms of reducing nausea severity in breast cancer patients receiving AC and ondansetron and dexamethasone for CINV prophylaxis.