A patient-derived orthotopic xenograft (PDOX) mouse model of a cisplatinum-resistant osteosarcoma lung metastasis that was sensitive to temozolomide and trabectedin: implications for precision oncology.

In the present study, we evaluated the efficacy of trabectedin (TRAB) and temozolomide (TEM) compared to cisplatinum (CDDP) on a patient-derived orthotopic xenogrraft (PDOX) of a lung-metastasis from an osteosarcoma of a patient who failed CDDP therapy. Osteosarcoma resected from the patient was implanted orthotopically in the distal femur of mice to establish PDOX models which were randomized into the following groups when tumor volume reached approximately 100 mm3: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal injection, weekly, for 2 weeks); G3, TRAB (0.15 mg/kg, intravenous injection, weekly, for 2 weeks); G4, TEM (25 mg/kg, oral, daily, for 14 days). Tumor sizes and body weight were measured with calipers and a digital balance twice a week. On day 14 after initiation of treatment, TEM and TRAB, but not CDDP, significantly inhibited tumor volume compared to untreated control: control (G1): 814.5±258.8 mm3; CDDP (G2): 608.6±126.9 mm3, TRAB (G3): 286.6±133.0 mm3; TEM (G4): 182.9±69.1 mm3. CDDP vs. control, p=0.07; TRAB vs. control, p=0.0004; TEM vs. control p =0.0002; TRAB vs. CDDP, p =0.0002; TEM vs. CDDP, p =0.00003. The results of the present study show that a PDOX model of an osteosarcoma lung-metastasis that recurred after adjuvant CDDP-treatment has identified potentially, highly-effective drugs for this recalcitrant disease, while precisely maintaining the CDDP resistance of the tumor in the patient, thereby demonstrating the potential of the osteosarcoma PDOX model for precision oncology

Tumor-targeting Salmonella typhimurium A1-R regresses an osteosarcoma in a patient-derived xenograft model resistant to a molecular-targeting drug.

Osteosarcoma occurs mostly in children and young adults, who are treated with multiple agents in combination with limb-salvage surgery. However, the overall 5-year survival rate for patients with recurrent or metastatic osteosarcoma is 20-30% which has not improved significantly over 30 years. Refractory patients would benefit from precise individualized therapy. We report here that a patient-derived osteosarcoma growing in a subcutaneous nude-mouse model was regressed by tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R, p<0.001 compared to untreated control). The osteosarcoma was only partially sensitive to the molecular-targeting drug sorafenib, which did not arrest its growth. S. typhimurium A1-R was significantly more effective than sorafenib (P <0.001). S. typhimurium grew in the treated tumors and caused extensive necrosis of the tumor tissue. These data show that S. typhimurium A1-R is powerful therapy for an osteosarcoma patient-derived xenograft model

Aortoesophageal fistula involving the central aortic arch salvaged with emergent percutaneous TEVAR, great vessel coverage and in vivo graft fenestration

Immediate intervention is needed for aortoesophageal fistulas (AEF), a rare but highly lethal cause of massive gastrointestinal hemorrhage. Emergent thoracic endovascular aortic repair (TEVAR) is considered first-line treatment for massive bleeding from AEFs. We describe an unusual and challenging case of TEVAR coverage of an AEF involving the central aortic arch immediately followed by in vivo endograft fenestration to regain arch vessel perfusion. In vivo fenestration, currently a procedure for emergency or investigational purposes only, was shown to be life saving in our case. The main complications associated with the procedure included stroke and infection, requiring esophagectomy and cervical diversion as well as ongoing antibiotic treatment

An Observational Cohort Study of the Kynurenine to Tryptophan Ratio in Sepsis: Association with Impaired Immune and Microvascular Function

Both endothelial and immune dysfunction contribute to the high mortality rate in human sepsis, but the underlying mechanisms are unclear. In response to infection, interferon-γ activates indoleamine 2,3-dioxygenase (IDO) which metabolizes the essential amino acid tryptophan to the toxic metabolite kynurenine. IDO can be expressed in endothelial cells, hepatocytes and mononuclear leukocytes, all of which contribute to sepsis pathophysiology. Increased IDO activity (measured by the kynurenine to tryptophan [KT] ratio in plasma) causes T-cell apoptosis, vasodilation and nitric oxide synthase inhibition. We hypothesized that IDO activity in sepsis would be related to plasma interferon-γ, interleukin-10, T cell lymphopenia and impairment of microvascular reactivity, a measure of endothelial nitric oxide bioavailability. In an observational cohort study of 80 sepsis patients (50 severe and 30 non-severe) and 40 hospital controls, we determined the relationship between IDO activity (plasma KT ratio) and selected plasma cytokines, sepsis severity, nitric oxide-dependent microvascular reactivity and lymphocyte subsets in sepsis. Plasma amino acids were measured by high performance liquid chromatography and microvascular reactivity by peripheral arterial tonometry. The plasma KT ratio was increased in sepsis (median 141 [IQR 64–235]) compared to controls (36 [28–52]); p<0.0001), and correlated with plasma interferon-γ and interleukin-10, and inversely with total lymphocyte count, CD8+ and CD4+ T-lymphocytes, systolic blood pressure and microvascular reactivity. In response to treatment of severe sepsis, the median KT ratio decreased from 162 [IQR 100–286] on day 0 to 89 [65–139] by day 7; p = 0.0006) and this decrease in KT ratio correlated with a decrease in the Sequential Organ Failure Assessment score (p<0.0001). IDO-mediated tryptophan catabolism is associated with dysregulated immune responses and impaired microvascular reactivity in sepsis and may link these two fundamental processes in sepsis pathophysiology

Quality of patient-reported outcome reporting across cancer randomized controlled trials according to the CONSORT patient-reported outcome extension: A pooled analysis of 557 trials

The main objectives of this study were to identify the number of randomized controlled trials (RCTs) including a patient-reported outcome (PRO) endpoint across a wide range of cancer specialties and to evaluate the completeness of PRO reporting according to the Consolidated Standards of Reporting Trials (CONSORT) PRO extension. RCTs with a PRO endpoint that had been performed across several cancer specialties and published between 2004 and 2013 were considered. Studies were evaluated on the basis of previously defined criteria, including the CONSORT PRO extension and the Cochrane Collaboration's tool for assessing the risk of bias of RCTs. Analyses were also conducted by the type of PRO endpoint (primary vs secondary) and by the cancer disease site. A total of 56,696 potentially eligible records were scrutinized, and 557 RCTs with a PRO evaluation, enrolling 254,677 patients overall, were identified. PROs were most frequently used in RCTs of breast (n = 123), lung (n = 85), and colorectal cancer (n = 66). Overall, PROs were secondary endpoints in 421 RCTs (76%). Four of 6 evaluated CONSORT PRO items were documented in less than 50% of the RCTs. The level of reporting was higher in RCTs with a PRO as a primary endpoint. The presence of a supplementary report was the only statistically significant factor associated with greater completeness of reporting for both RCTs with PROs as primary endpoints (β = .19, P = .001) and RCTs with PROs as secondary endpoints (β = .30, P < .001). Implementation of the CONSORT PRO extension is equally important across all cancer specialties. Its use can also contribute to revealing the robust PRO design of some studies, which might be obscured by poor outcome reportin

Abstract 3914: High-throughput drug screening of personalized chordoma organoids: A case series of six patients

Abstract Chordoma is a rare malignant tumor that arises from embryonic remnants of the notochord (Sahyouni et al, J Neurosurg Spine, 2018). This tumor is highly chemotherapy resistant, and there are no known compounds which have demonstrated clinically significant remissions (Gelderblom et al, Oncologist, 2008). With local therapies (surgery and/or radiation), local recurrence rates are high (∼40%). Repeated surgeries with or without radiation have dismal results (Fuch et al, J Bone Joint Surg, 2005). Systemic therapies are largely ineffective and often highly toxic. Given its rarity, there is limited randomized clinical data regarding effective treatments. Moreover, less than ten validated chordoma cell lines and fewer PDX models are currently available, further hindering drug development and discovery studies (Bosotti et al, Sci Reports, 2017). Here, we take advantage of tumor organoids to establish chordoma models that can be rapidly and effectively screened ex vivo to identify effective therapies. Tumor organoids are capable of reproducing many crucial features of the cancer they are generated from, including heterogeneity, cell organization as well as drug response. We have developed an automated high-throughput screening platform to test the response of patient-derived tumor organoids to hundreds of therapeutic agents, with results available within a week from surgery, a timeline compatible with therapeutic decision-making (Phan et al, Communications Biol, 2019). Here we show how our platform can be effectively used to investigate drug susceptibilities and heterogeneity in chordoma. Fresh tumour tissue from n=6 patients obtained from needle biopsies or surgical resections was processed to single cell suspension prior to establishing organoids according to our unique geometry. We performed a drug screening of up to 230 compounds on seven samples established from n=6 patients and determined organoid viability after a 48h exposure to the drugs. Our data suggest the potential efficacy of particular compounds that target the mTOR and PI3K pathways. We will show validation as well as histopathology of the organoids including staining for S100, Ki-67 and brachyury that was observed also in the pathology of specimens derived from the same patient. Overall, we have successfully established organoids from chordoma patients with a 100% success rate and 7/7 specimens growing and yielding biologically and therapeutically relevant models. Our methodology allows us to perform large drug screenings including for low grade chordomas, which are typically refractory to growth in immunocompromised mice as patient-derived xenografts. Determining the clinical efficacy of any new therapeutic approach is challenging in chordoma due to its natural history and slow growth rates. Our organoid-based functional sensitivity profile may be used to tailor therapy to each patient and to potentially rule out ineffective drugs, thus sparing ineffective therapies and associated toxicities. Citation Format: Ardy Davarifar, Huyen T. Nguyen, Nasrin Tavanaie, Jane Yanagawa, Robert Damoiseaux, Noah Federman, Nicholas Bernthal, Scott Nelson, Francis Hornicek, Alice Soragni. High-throughput drug screening of personalized chordoma organoids: A case series of six patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3914