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A 43-year-old man with a growing mass in the right groin, concerned for liposarcoma, underwent MRI and 68Ga–fibroblast activation protein inhibitor (FAPI)-46 PET/CT before surgery. Fibroblast activation protein inhibitor PET/CT demonstrated increased uptake (SUVmax, 3.2) predominantly in the solid portion, where MRI showed gadolinium enhancement. The patient subsequently underwent surgery and was diagnosed with hibernoma. The immunohistochemistry of the tumor revealed the fibroblast activation protein expression in the fibrovascular network and myofibroblastic cells of the tumor. This case suggests that the FAPI uptake can be affected by the vascular cells, and thus, a careful interpretation of the FAPI PET signal may be needed.

Sarcomas are rare malignancies with over 100 distinct histological subtypes. Their rarity and heterogeneity pose significant challenges to identifying effective therapies, and approved regimens show varied responses. Novel, personalized approaches to therapy are needed to improve patient outcomes. Patient-derived tumor organoids (PDTOs) model tumor behavior across an array of malignancies. We leverage PDTOs to characterize the landscape of drug resistance and sensitivity in sarcoma, collecting 194 specimens from 126 patients spanning 24 distinct sarcoma subtypes. Our high-throughput organoid screening pipeline tested single agents and combinations, with results available within a week from surgery. Drug sensitivity correlated with clinical features such as tumor subtype, treatment history, and disease trajectory. PDTO screening can facilitate optimal drug selection and mirror patient outcomes in sarcoma. We could identify at least one FDA-approved or NCCN-recommended effective regimen for 59% of the specimens, demonstrating the potential of our pipeline to provide actionable treatment information.

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ABSTRACTIn the present study, a patient-derived orthotopic xenograft (PDOX) model of recurrent cisplatinum (CDDP)-resistant metastatic osteosarcoma was treated with Salmonella typhimuriumA1-R (S. typhimuriumA1-R), which decoys chemoresistant quiescent cancer cells to cycle, and recombinant methioninase (rMETase), which selectively traps cancer cells in late S/G2, and chemotherapy. The PDOX models were randomized into the following groups 14 days after implantation: G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks). G4, S. typhimuriumA1-R (5 × 107CFU/100 μl, i.v., weekly, for 2 weeks); G5, S. typhimuriumA1-R (5 × 107CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G6, S. typhimuriumA1-R (5 × 107CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks) and CDDP (6 mg/kg, i.p. injection, weekly, for 2 weeks). On day 14 after initiation, all treatments except CDDP alone, significantly inhibited tumor growth compared to untreated control: (CDDP: p = 0.586; rMETase: p = 0.002; S. typhimuriumA1-R: p = 0.002; S. typhimuriumA1-R combined with rMETase: p = 0.0004; rMETase combined with both S. typhimuriumA1-R and CDDP: p = 0.0001). The decoy, trap and kill combination of S. typhimuriumA1-R, rMETase and CDDP was the most effective of all therapies and was able to eradicate the metastatic osteosarcoma PDOX.

ABSTRACTGastrointestinal stromal tumor (GIST) with a mutation in exons 11 and 17 of c-kit is a rare type of sarcoma. The aim of this study was to determine drug sensitivity for a regionally-recurrent case of GIST using a patient-derived orthotopic xenograft (PDOX) model. The PDOX model was established in the anterior wall of the stomach. GIST PDOX models were randomized into 5 groups of 6 mice each when the tumor volume reached 60 mm3: G1, control group; G2, imatinib group (oral administration (p.o.), daily, for 3 weeks); G3, sunitinib group (p.o., daily, for 3 weeks); G4, regorafenib (p.o., daily, for 3 weeks); G5, pazopanib (p.o., daily, for 3 weeks). All mice were sacrificed on day 22. Tumor volume was evaluated on day 0 and day 22 by laparotomy. Body weight were measured 2 times per week. Though regorafenib is third-line therapy for GIST, it was the most effective drug and regressed the tumor significantly (p < 0.001). Sunitinib suppressed tumor growth compared to the control group (p = 0.002). Imatinib, first-line therapy for GIST, and pazopanib did not have significant efficacy compared to the control group (p = 0.886, p = 0.766). The implications of this result is discussed for GIST patients.

ABSTRACTDoxorubicin (DOX) is often first-line treatment of undifferentiated/unclassified soft tissue sarcoma (USTS). However, the DOX response rate for USTS patients is low. Individualized precision-medicine technology that could identify DOX responders as well as non-responders would be of high value to cancer patients. In the present study, we established 5 patient-derived orthotopic xenograft (PDOX) nude mouse models from 5 USTS patients and evaluated the efficacy of DOX in each PDOX model. USTS's were grown orthotopically in the right thigh of nude mice to establish the PDOX models. Two weeks after implantation, the mouse models were randomized into two groups of 8 mice each: untreated control; and DOX (3 mg/kg, i.p., once a week for 2 weeks). DOX showed significant growth inhibition in only 2 USTS PDOX models out of 5 (p= 0.0054, p= 0.0055, respectively) on day 14 after initiation. DOX was ineffective in the other 3 PDOX models. However, even in the DOX-sensitive cases, DOX could not regress the PDOX tumors responding to treatment. The present study has important implications since this is the first in vivostudy to compare the DOX sensitivity for USTS on multiple patient tumors. We showed that only two of five USTS were responsive to DOX, despite DOX being first line chemotherapy for USTS. The 3 resistant cases should not be treated with DOX clinically, in order to spare the patients' unnecessary toxicity. This PDOX model is useful for precise individualized drug sensitivity testing, especially for rare heterogeneous recalcitrant sarcomas such as USTS.

ABSTRACTThe elevated methionine (MET) use by cancer cells is termed MET dependence and may be the only known general metabolic defect in cancer. Targeting MET by recombinant methioninase (rMETase) can arrest the growth of cancer cells in vitro and in vivo. We previously reported that rMETase, administrated by intra-peritoneal injection (ip-rMETase), could inhibit tumor growth in a patient-derived orthotopic xenograft (PDOX) model of a BRAF-V600E mutant melanoma. In the present study, we compared ip-rMETase and oral rMETase (o-rMETase) for efficacy on the melanoma PDOX. Melanoma PDOX nude mice were randomized into four groups of 5 mice each: untreated control; ip-rMETase (100 units, i.p., 14 consecutive days); o-rMETase (100 units, p.o., 14 consecutive days); o-rMETase+ip-rMETase (100 units, p.o.+100 units, i.p., 14 consecutive days). All treatments inhibited tumor growth on day 14 after treatment initiation, compared to untreated control (ip-rMETase, p<0.0001; o-rMETase, p<0.0001; o-rMETase+ip-rMETase, p<0.0001). o-rMETase was significantly more effective than ip-rMETase (p= 0.0086). o-rMETase+ip-rMETase was significantly more effective than either mono-therapy: ip-rMETase, p= 0.0005; or o-rMETase, p= 0.0367. The present study is the first demonstrating that o-rMETase is effective as an anticancer agent. The results of the present study indicate the potential of clinical development of o-rMETase as an agent for chronic cancer therapy and for cancer prevention and possibly for life extension since dietary MET reduction extends life span in many animal models.

ABSTRACTA metastatic melanoma obtained from the right chest wall of a patient was previously established orthotopically in the right chest wall of nude mice as a patient-derived orthotopic xenograft (PDOX) model. We previously showed that the combination of tumor-targeting Salmonella typhimuriumA1-R (S. typhimuriumA1-R) and chemotherapy was highly effective against the melanoma PDOX. In the present study, we investigated the mechanism of the high efficacy of this combination. Two weeks after implantation, 40 PDOX mouse models were randomized into 4 groups of 10 mice each: untreated control (n = 10); treated with S. typhimuriumA1-R (5 × 107CFU/100 μl, i.v., once a week for 2 weeks, n = 10); treated with temozolomide (TEM) (25 mg/kg, p.o. for 14 consecutive days) combined with S. typhimuriumA1-R (5 × 107CFU/100 μl, i.v., once a week for 2 weeks, n = 10); treated with vemurafenib (VEM) (30 mg/kg, p.o., for 14 consecutive days) combined with S. typhimuriumA1-R (5 × 107CFU/100 μl, i.v., once a week for 2 weeks) (n = 10). On day 14 from initiation, all treatments significantly inhibited tumor growth compared with untreated control (S. typhimuriumA1-R: p< 0.01; TEM combined with S. typhimuriumA1-R: p< 0.01; VEM combined with S. typhimuriumA1-R: p< 0.01). Combination therapy with S. typhimuriumA1-R was significantly more effective on tumor growth than S. typhimuriumA1-R alone (with TEM: p< 0.01; with VEM: p< 0.01). Combination therapy significantly increased S. typhimuriumA1-R tumor targeting alone (S. typhimuriumA1-R + TEM: p< 0.01, S. typhimuriumA1-R + VEM: p< 0.01), relative to S. typhimuriumA1-R alone, respectively. In conclusion, chemotherapy drugs promoted targeting of S. typhimuriumA1-R of melanoma, thereby enhancing efficacy against the melanoma PDOX.

ABSTRACTPreviously, a patient-derived orthotopic xenograft (PDOX) model was established with a lung metastasis from an osteosarcoma patient which developed after adjuvant cisplatinum (CDDP) treatment. In this model, we previously demonstrated the efficacy of trabectedin (TRAB) and temozolomide (TEM) compared with CDDP. In the present report, osteosarcoma tissue was implanted orthotopically in the distal femur of mice which were randomized into the following groups when tumor volume reached approximately 100 mm3; On day 14 after initiation of treatment, all but CDDP significantly inhibited tumor volume growth compared with untreated controls. Control (G1): 793.7 ± 215.0 mm3; CDDP (G2): 588.1 ± 176.9 mm3; Salmonella typhimuriumA1-R (S. typhimuriumA1-R) intravenous (i.v.) (G3): 269.7 ± 72.7 mm3; S. typhimuriumA1-R intra-arterial (i.a.) (G4): 70.2 ± 18.9 mm3(CDDP: p = 0.056; S. typhimuriumA1-R i.v.: p = 0.0001; S. typhimuriumA1-R i.a.: p = 0.00003, all vs. untreated controls). i.a. administration of S. typhimuriumA1-R was significantly more effective than either CDDP (p = 0.00007), or i.v. administration of S. typhimuriumA1-R (p = 0.00007) and significantly regressed the tumor volume compared with day 0 (p = 0.001). The new model of i.a. administration of S. typhimuriumA1-R has great promise for the treatment of recalcitrant osteosarcoma.

ABSTRACTGastric leiomyosarcoma is a recalcitrant cancer and the chemotherapy strategy is controversial. The present study used a patient-derived orthotopic xenograft (PDOX) nude mouse model of gastric leiomyosarcoma to identify an effective therapeutic regimen to develop individualized precision medicine for this disease. The gastric leiomyosarcoma obtained from a patient was first grown in transgenic nude mice ubiquitously expressing red fluorescent protein (RFP) to stably label the tumor stroma. The RFP-expressing tumor was then passaged orthotopically in the gastric wall of non-transgenic nude mice to establish an imageable PDOX (iPDOX) model. The bright fluorescent tumor was readily imaged over time to determine drug efficacy. Four weeks after implantation, 70 PDOX nude mice were divided into 7 groups: control without treatment (n = 10); doxorubicin (DOX) (2.4 mg/kg, intraperitoneally (i.p.), once a week for 2 weeks, n = 10); gemcitabine (GEM)/ docetaxel (DOC) (GEM: 100 mg/kg, DOC: 20 mg/kg, i.p., once a week for 2 weeks, n = 10); cyclophosphamide (CPA) (140 mg/kg, i.p., once a week for 2 weeks, n = 10); temozolomide (TEM) (25 mg/kg, orally, daily for 14 consecutive days, n = 10); yondelis (YON) (0.15 mg/kg, i.v., once a week for 2 weeks, n = 10); pazopanib (PAZ) (100 mg/kg, orally, daily for 14 consecutive days, n = 10). On day 14 from initiation of treatment, all treatments except PAZ significantly inhibited tumor growth compared with untreated control (DOX: p< 0.01, GEM/DOC: p< 0.01, CPA: p< 0.01, TEM: p< 0.01, YON: p< 0.01) on day 14 after initiation. In addition, only GEM/DOC was more significantly effective than DOX (p< 0.05). GEM/DOC could regress the leimyosarcoma in the PDOX model and has important clinical potential for precision individual treatment of leiomyosarcoma patients.

ABSTRACTWilliam B. Coley developed bacterial therapy of cancer more than 100 years ago and had clinical success. James Ewing, a very famous cancer pathologist for whom the Ewing sarcoma is named, was Coley's boss at Memorial Hospital in New York and terminated Coley's bacterial therapy of cancer. A tumor from a patient with soft-tissue Ewing's sarcoma, who failed doxorubicin (DOX) therapy, was previously implanted in nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the Ewing's sarcoma PDOX was treated with tumor-targeting S. typhimuriumA1-R expressing green fluorescent (GFP), alone and in combination with DOX. S. typhimuriumA1-R-GFP was detected in the tumors after intratumor (i.t.) or intravenous (i.v.) injection. The combination of S. typhimuriumA1-R and DOX significantly reduced tumor weight (37.8 ± 15.6 mg) compared to the untreated control (73.8 ± 10.1 mg, P< 0.01). S. typhimuriumA1-R monotherapy-treated tumors tended to be smaller (50.9 ± 17.8 mg, P= 0.051). DOX monotherapy did not show efficacy (66.3 ± 26.4 mg, P= 0.82), as was the case with the patient. The PDOX model faithfully replicated the DOX resistance the Ewing's sarcoma had in the patient. S. typhimuriumA1-R converted the Ewing's sarcoma from DOX resistant to sensitive. One can only wonder how bacterial therapy and immunotherapy of cancer would have developed over the past 80 years if Ewing did not stop Coley.

ABSTRACTRhabdomyosarcoma (RMS) is a rare mesenchymal tumor. The aim of the present study was to develop a patient-derived orthotopic xenograft (PDOX) mouse model of RMS and compare the PDOX model to a subcutaneous (s.c.)-transplant model. A patient RMS from a striated muscle was grown orthotopically in the right biceps femoris muscle and right quadriceps muscle of nude mice to establish a PDOX model, as well as under the skin to establish an s.c. model. PDOX tumors grew at a statistically-significant faster rate compared to the s.c. tumors. Recurrence after surgical resection occurred only in PDOX tumors, not in the s.c. model. Histologically, only the PDOX model was shown to be invasive. In conclusion, these results indicate that the PDOX model of adult RMS is malignant and the subcutaneous model is benign. These results emphasize that a proper tumor microenvironment is necessary for patient-like behavior of a tumor in a mouse model.

Malignant peripheral nerve sheath tumor (MPNST) is the sixth most common type of soft tissue sarcoma. Most MPNSTs arise in association with a peripheral nerve or preexisting neurofibroma. Neurofibromatosis type is the most important risk factor for MPNST. Tumor size and fludeoxyglucose F 18 avidity are among the most helpful parameters to distinguish MPNST from a benign peripheral nerve sheath tumor. The histopathologic diagnosis is predominantly a diagnosis of light microscopy. Immunohistochemical stains are most helpful to distinguish high-grade MPNST from its histologic mimics. Current surgical management of high-grade MPNST is similar to that of other high-grade soft tissue sarcomas.

The use of image-guided percutaneous core needle biopsy (PCNB) to obtain tissue diagnosis of musculoskeletal lesions has become the standard of care in adult patients with a success rate of over 80. Previous reports indicate a similar success rate in diagnosing pediatric solid tumors. In this large study, we analyzed >10 years of data in which PCNB was used for tissue diagnosis of musculoskeletal lesions in children; we evaluated the histopathologic accuracy, anesthetic requirements, and complications of these procedures. In 122 children, tissue diagnosis was successfully obtained in 82 of cases, and there were 0 complications associated with the procedure. There was a significantly higher PCNB diagnostic success rate in malignant lesions (93). These data suggest that the use of PCNB is a safe and effective means of diagnosing musculoskeletal lesions in children.

Liposarcoma is a type of soft tissue sarcoma that exhibits poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, which emphasizes the need for better understanding of this disease. Because very few in vivoand in vitromodels can reproducibly recapitulate the human disease, we generated several xenograft models from surgically resected human dedifferentiated liposarcoma. All xenografts recapitulated morphological and gene expression characteristics of the patient tumors after continuous in vivopassages. Importantly, xenograftability was directly correlated with disease-specific survival of liposarcoma patients. Thus, the ability for the tumor of a patient to engraft may help identify those patients who will benefit from more aggressive treatment regimens. Gene expression analyses highlighted the association between xenograftability and a unique gene expression signature, including down-regulated PTENtumor-suppressor gene expression and a progenitor-like phenotype. When treated with the PI3K/AKT/mTOR pathway inhibitor rapamycin alone or in combination with the multikinase inhibitor sorafenib, all xenografts responded with increased lipid content and a more differentiated gene expression profile. These human xenograft models may facilitate liposarcoma research and accelerate the generation of readily translatable preclinical data that could ultimately influence patient care.

18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is being used with increased frequency in the care of patients with sarcoma. In this review, the recent literature covering all aspects of PET imaging in the management of patients with soft tissue and bone sarcomas will be discussed.

On the basis of a prospectively followed cohort of adult patients with primary soft tissue sarcoma (STS) who were treated at Memorial Sloan‐Kettering Cancer Center (MSKCC; New York, NY), a nomogram for predicting sarcoma‐specific mortality was developed. Although this nomogram was found to be accurate by internal validation tests, it had not been validated in an external patient cohort, and thus its universal applicability remained unproven.Between 1975 and 2002, 1167 adult patients (age ≥ 16 years) underwent treatment for primary STS at the University of California–Los Angeles (UCLA; Los Angeles, CA). All patients treated with an ifosfamide‐based chemotherapy protocol (n = 238) were excluded from the current analysis. The remaining 929 patients constituted the population on which the validation study was performed. The nomogram validation process comprised two activities. First, the extent of discrimination was quantified using the concordance index. Second, the level of calibration was assessed by grouping patients with respect to their nomogram‐predicted mortality probabilities and then comparing group means with observed Kaplan–Meier estimates of disease‐specific survival.With median follow‐up intervals of 48 months for all patients and 60 months for surviving patients, the 5‐year and 10‐year disease‐specific survival rates were 77% (95% confidence interval [CI], 74–80%) and 71% (95% CI, 67–75%), respectively. Application of the nomogram to the UCLA data set yielded a concordance index of 0.76, and the observed correspondence between predicted and actual outcomes suggested a high level of calibration.In the current study, the MSKCC Sarcoma Nomogram was found to provide accurate survival predictions when it was applied to an external cohort of patients who were treated at UCLA. Cancer 2004. © 2004 American Cancer Society.