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Table of microinjected drugs

Microinjection of olaratumab does not inhibit PDGFRα, ERK, or S6 phosphorylation.

All adverse events reported on the study

Supplementary Legend

Distinct drug induced phenotypes and apoptotic responses specific to drug mechanism of action are seen at sites of CIVO microinjection.

Purpose:A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed Comparative In Vivo Oncology (CIVO), which enables in situ investigation of multiple microdosed drugs simultaneously in a patient's tumor. This study was designed to test CIVO's safety and feasibility in patients with soft tissue sarcoma (STS).Patients and Methods:We conducted a single arm, prospective, 13-patient pilot study. Patients scheduled for incisional biopsy or tumor resection were CIVO-injected 1 to 3 days prior to surgery. Saline or microdoses of anticancer agents were percutaneously injected into the tumor in a columnar fashion through each of eight needles. Following excision, drug responses were evaluated in the injected tissue.Results:The primary objective was met, establishing CIVO's feasibility and safety. Device-related adverse events were limited to transient grade 1 nonserious events. In addition, biomarker evaluation of localized tumor response to CIVO microinjected drugs by IHC or with NanoString GeoMx Digital Spatial Profiler demonstrated consistency with known mechanisms of action of each drug, impact on the tumor microenvironment, and historic clinical activity.Conclusions:These results are an advance toward use of CIVO as a translational research tool for early evaluation of investigational agents and drug combinations in a novel approach to phase 0 trials.See related commentary by Sleijfer and Lolkema, p. 3897

Representative images of tumors from patients who received radiation treatment.

Device performance

Clinical Trial Design

Increased phosphorylation of PDGFR� and downstream effectors in an undifferentiated pleomorphic sarcoma displaying a lack of apoptotic response to microdosed doxorubicin.

Purpose: A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed Comparative In Vivo Oncology (CIVO), which enables in situ investigation of multiple microdosed drugs simultaneously in a patient's tumor. This study was designed to test CIVO's safety and feasibility in patients with soft tissue sarcoma (STS). Patients and Methods: We conducted a single arm, prospective, 13-patient pilot study. Patients scheduled for incisional biopsy or tumor resection were CIVO-injected 1 to 3 days prior to surgery. Saline or microdoses of anticancer agents were percutaneously injected into the tumor in a columnar fashion through each of eight needles. Following excision, drug responses were evaluated in the injected tissue. Results: The primary objective was met, establishing CIVO's feasibility and safety. Device-related adverse events were limited to transient grade 1 nonserious events. In addition, biomarker evaluation of localized tumor response to CIVO microinjected drugs by IHC or with NanoString GeoMx Digital Spatial Profiler demonstrated consistency with known mechanisms of action of each drug, impact on the tumor microenvironment, and historic clinical activity. Conclusions: These results are an advance toward use of CIVO as a translational research tool for early evaluation of investigational agents and drug combinations in a novel approach to phase 0 trials. See related commentary by Sleijfer and Lolkema, p. 3897

A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed ComparativeWe conducted a single arm, prospective, 13-patient pilot study. Patients scheduled for incisional biopsy or tumor resection were CIVO-injected 1 to 3 days prior to surgery. Saline or microdoses of anticancer agents were percutaneously injected into the tumor in a columnar fashion through each of eight needles. Following excision, drug responses were evaluated in the injected tissue.The primary objective was met, establishing CIVO's feasibility and safety. Device-related adverse events were limited to transient grade 1 nonserious events. In addition, biomarker evaluation of localized tumor response to CIVO microinjected drugs by IHC or with NanoString GeoMx Digital Spatial Profiler demonstrated consistency with known mechanisms of action of each drug, impact on the tumor microenvironment, and historic clinical activity.These results are an advance toward use of CIVO as a translational research tool for early evaluation of investigational agents and drug combinations in a novel approach to phase 0 trials.

We describe a case of a 44-year-old woman with locally advanced aggressive angiomyxoma with a novel translocation high-mobility group AT-hook 2–yes-associated protein 1 (HMGA2-YAP1) fusion, implying a t(11;12)(q22.1;q14.3) translocation. She was started on gonadotropin-releasing hormone agonist injection and an aromatase inhibitor for persistent disease, which responded to treatment; she was subsequently treated with radiation before a more definitive operation was conducted. This case report indicates that HGMA2-YAP1–translocated aggressive angiomyxoma is responsive to oestrogen antagonism and hopefully will allow for the development of diagnostics useful for this rare but often morbid neoplasm. This case also highlights the importance of appropriate workup of a soft tissue mass.

e23574 Background: FDCS and HS are rare tumors arising from sustentacular cells of the lymph node, rather than lymphocytes. Surgical resection is often employed in case of localized disease, but for unresectable disease, anthracycline-based therapy is commonly used. PD-L1 staining is reportedly positive in 50-80% of FDCS. As a result, we treated 3 patients (pts) with ICI ipilimumab and nivolumab (Ipi/Nivo), and demonstrated the activity of these agents in these rare cancers. Methods: Two FDCS pts and one HS pt, all with B symptoms at the start of treatment, received Ipi/Nivo in the approved dose/schedule (Table). The HS patient was HIV(+) with undetectable viral load on treatment. One FDCS patient received radiation therapy to an active site of disease during immunotherapy. We reimaged patients every 2 months for the first 6 months, then less frequently. PDL-1 IHC and mutation data were available in all cases. Results: Mutation burden varied from low to intermediate; mutations in kinase genes were also observed. Case 1 (FDCS) demonstrated RECIST 1.1 complete response, but also received radiation, and Case 2 (FDCS) had RECIST partial response. Both continue on treatment 9 months after initiation. Case 3 (HS) demonstrated a minor response to treatment, then disease worsened after 4 months, and he subsequently received radiation to the residual site of disease. All patients showed resolution of B symptoms on ICI. Conclusions: We treated these pts with ICI based on their role as antigen presenting cells, as well as their high PD-L1 expression. We speculate that FDCS and related tumors such as HS represent extreme examples of cancers that have evidence of tertiary lymphoid structures, increasingly recognized as important in ICI responsiveness. Prospective clinical trials of ICI in these diagnoses will help us understand the basis of immune responses to ICI in other cancers. [Table: see text]

Follicular dendritic cell sarcoma (FDCS) is a rare and unusual cancer that arises from sustentacular cells of the lymph node that present antigen to B cells, rather than lymphocytes themselves. While surgery for primary disease is still paramount in primary management, for unresectable, recurrent and metastatic tumours, FDCS is frequently treated with anthracycline-based lymphoma chemotherapy regimens. In recent years, it is clear that Programmed Cell Death 1 (PD1)-directed immune checkpoint inhibitors (ICIs) are active in Hodgkin lymphoma, but significantly less active in non-Hodgkin’s lymphoma. These data raised the question of whether FDCS respond to ICI therapy. We present two patients with FDCS who were treated with nivolumab and ipilimumab with evidence of tumour response. These cases also highlight the difficulty in arriving at a proper diagnosis, emphasising the need for expert review of pathology to optimise treatment for these and other patients with sarcoma.

Single crystals of a new family of layered lanthanide oxychlorides, Ba

We describe a case of a 44-year-old woman with locally advanced aggressive angiomyxoma with a novel translocation high-mobility group AT-hook 2–yes-associated protein 1 (HMGA2-YAP1) fusion, implying a t(11;12)(q22.1;q14.3) translocation. She was started on gonadotropin-releasing hormone agonist injection and an aromatase inhibitor for persistent disease, which responded to treatment; she was subsequently treated with radiation before a more definitive operation was conducted. This case report indicates that HGMA2-YAP1–translocated aggressive angiomyxoma is responsive to oestrogen antagonism and hopefully will allow for the development of diagnostics useful for this rare but often morbid neoplasm. This case also highlights the importance of appropriate workup of a soft tissue mass.

A 72-year-old female presented with dyspepsia for 2 years and an incidental mass in the head of the pancreas on abdominal computed tomography (CT) scan. Patient had multiple negative endoscopic ultrasound guided biopsies. She was followed up for 3 years with serial imaging until an abdominal CT scan showed an increase in size of the pancreatic mass. Physical examination was unremarkable. Laboratory tests including tumor markers were normal. Given the enlarging size of the mass and its impingement on the portal vein, the consensus was to proceed with surgery. Histology revealed a 3.5 cm mass showing a spindle cell neoplasm with mild atypia. The lesion was well defined and nerve tissue was noted at the periphery. On immuno-stains, the spindle cells were positive for S-100 protein and negative for pan-cytokeratin, CD-34, CD- 117, smooth muscle actin and Melan A, consistent with the diagnosis of a pancreatic schwannoma.

Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment., This Consensus Statement highlights the importance of cancer-associated fibroblasts in cancer biology and progression, and issues a call to action for all cancer researchers to standardize assays and report metadata in studies of cancer-associated fibroblasts to advance our understanding of this important cell type in the tumour microenvironment.

e22514 Background: Aggressive angiomyxoma (AA) is a rare neoplasm typically found in the perineum or pelvis, often with a gelatinous consistency and a highly vascular nature that leads to surgical complications and a high recurrence rate following what otherwise are attempts at curative surgery. For patients with recurrent disease in whom surgery is not indicated or potentially mutilating, estrogen antagonism has been successfully employed. HMGA2 on chromosome 12 has been known to be translocated in this tumor for over a decade, but no partners have been identified for HMGA2 in this tumor type. Methods: A 44-year-old woman with a perineal mass underwent attempted resection, but this was halted due to extensive blood loss after removal of a portion of what proved to be an AA. She was referred for systemic treatment to the sarcoma clinic. A Foundation Medicine Heme test was conducted on the patient's tumor. Results: The patient was treated with leuprolide and anastrozole with a RECIST 1.1 partial response and loss of vascularity consistent with a radiological response. She underwent preoperative radiation therapy and a follow up operation with negative margins. The resection specimen showed evidence of a very good result from systemic therapy and radiation. Molecular testing demonstrated a HMGA2-YAP1 fusion, implying a t(11;12)(q22.1;q14.3) translocation. Conclusions: This is the first demonstration of a partner for the HMGA2 gene in AA. A variety of other translocations have been found in AA, some of which involve chromosome 12. Thus, as with benign lesions such as lipomas, myolipomas, osteochondrolipomas, leiomyomas, pleomorphic adenomas, as well as a smaller number of overt malignancies, there appears to be promiscuity in HMGA2 (or other translocation) fusion products that lead to development of AA. Not all patients with AA respond to estrogen antagonism, or will show evidence of benefit before getting worse, as shown in case series and reports of AA patients. Assessing HMGA2 partners and their outcomes may better stratify future patients with AA with respect to possible benefit of estrogen antagonism.