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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. Copyright © 2014 by Lippincott Williams & Wilkins.

Background: There is no consensus as to which surgical approach to the treatment of giant cell tumor of bone is most appropriate or which patients are at a higher risk for recurrence or metastasis.Questions/purposes: Therefore, we asked: (1) Are there subsets of patients who are associated with a more recalcitrant disease course? And (2) are surgeons appropriately stratifying patients by identifying risk factors for increased local recurrence and pulmonary metastases?Methods: We retrospectively reviewed the records of 230 patients with giant cell tumor of bone treated from 1980 to 2010, stratifying them by primary versus recurrent disease and by surgical treatment. From the records, we determined local recurrence, metastatic disease, and complications of treatment. The median follow up was 47 months (range, 0.1-312 months).Results: Overall incidence of local recurrence was 10% and pulmonary metastasis was 2%. When stratified by surgical treatment, the incidence of local recurrence among patients undergoing intralesional curettage (12%) was greater than in those undergoing resection (2%). The incidence of local recurrence among primary tumors, independent of treatment, was 9%, whereas the incidence of local recurrence after treatment of recurrent lesions was 16%. The incidence of pulmonary metastases was similar, regardless of treatment or whether primary or recurrent.Conclusions: Our observations suggest there are subsets of patients with giant cell tumor of bone who are at higher risk of recurrence and should be clinically followed more closely. This should allow surgeons to provide patients with more informed expectations.Level Of Evidence: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Introduction: Utilization of health services is not only associated with the kind of illness one has, but also with patient characteristics like age, sex or psychological variables. Psoriasis (PS) is a chronic inflammatory skin condition, in which psychological interventions were shown to be beneficial regarding not only psychological variables, but also regarding the skin status. The present study investigated with regard to which patient characteristics PS-patients with interest in participation in a short psychological intervention differ from PS-patients without interest., Methods: This cross-sectional questionnaire study was conducted at a German rehabilitation clinic. At the beginning of their stay at the clinic, 127 PS-patients filled in questionnaires to assess the severity of their PS, stress, illness perceptions, mindfulness, anxiety, and depression. Interest in taking part in a short psychological intervention was assessed using a dichotomous item. The statistical analysis comprised group comparisons using t -tests of patients with and without interest to take part in a short psychological intervention., Results: Sixty-four of the participants were male (50.4%). Participants were 50.7 ± 10 years on average (range: 25-65). 50.4% of them had a mild, 37.0% a moderate, and 12.6% a severe PS. Results indicated that patients with interest in a short psychological intervention were younger, reported to have more skin symptoms due to their PS (higher skin-related illness identity), were more anxious and depressed, but less stressed and less mindful than patients without interest., Conclusion: This study shows that in PS-patients with certain characteristics, it might help to raise awareness on the relationship between psychological factors and symptoms of the skin disease in order to motivate this group of patients to take part in psychological interventions to improve their skin condition. Further studies are needed to investigate whether patients who show interest in a psychological intervention also actually take part in the intervention and profit from it. Clinical Trial Registration: DRKS00017426., Competing Interests: CS has received speakers honoraria by Novartis in 2020 and is a consultant for Mahana Therapeutics, United States. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Stadtmüller, Eckardt, Zick, Kupfer and Schut.)

Background: Subjective, varying criteria identify "low-grade" dedifferentiation in well-differentiated/dedifferentiated liposarcoma (WD/DDLPS). The value of mitotic rate (MR) in defining DDLPS is not confirmed. We studied all patients with the resection of their primary or first recurrence retroperitoneal WD/DDLPS at our institution to determine the value of MR in diagnosing DDLPS and if MR associates with patient survival., Design: Ninety-eight patients with retroperitoneal WD/DDLPS operated at our institution from January 1, 1989 to December 31, 2013 were included. Cases were defined as acellular (AC) WDLPS, LS0-4 (tumors with non-lipogenic areas and MR 0-4/10HPFs) or LS5+(non-lipogenic areas, MR≥5/10 HPFs) and graded using the French system. Kaplan-Meier survival estimates with log-rank test and multivariate Cox (mCox) analyses were performed., Results: Follow-up was available on all patients (median 9.3 y, range 0.02-23.16 y). Kaplan-Meier demonstrated a significant ( P =0.004) difference in disease-specific survival (DSS) among the 3 groups. mCox demonstrated no difference in DSS between the AC and LS0-4 groups (HR 1.51; 95% CI 0.57-3.99, P =0.412) but significantly lower DSS in the LS5+group compared with the AC group (HR 2.68; 95% CI 1.07-6.71, P =0.035). The difference in DSS was not significant between grade 2 and 3 tumors ( P =0.094). DSS between MR 5-19/10 HPFs and MR20+/10 HPFs subgroups was significant ( P =0.007) but by mCox did not reach significance (HR 2.47; 95% CI 0.96-6.35, P =0.060)., Conclusion: This study confirms that MR distinguishes DDLPS from WDLPS with non-lipogenic areas, also known as cellular WDLPS. For consistency in diagnosis and research, only WD/DDLPS with≥5 mitoses/10 HPFs should be considered DDLPS., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Surveillance imaging of patients with retroperitoneal liposarcoma (RP-LPS) after surgical resection is based on a projected risk of locoregional and distant recurrence. The duration of surveillance is not well defined because the natural history of RP-LPS after treatment is poorly understood. This study evaluated the long-term risk of recurrence and disease-specific survival (DSS) for a cohort of patients with at least 10 years of progression-free survival (10yr-PFS) from their primary resection., Methods: The prospective University of California, Los Angeles (UCLA) Sarcoma Database identified RP-LPS patients with 10yr-PFS after initial resection. The patients in the 10yr-PFS cohort were subsequently evaluated for recurrence and DSS. The time intervals start at date of initial surgical resection. Cox proportional hazards models were used to determine factors associated with recurrence and DSS., Results: From 1972 to 2010, 76 patients with RP-LPS had at least 10 years of follow-up evaluation. Of these 76 patients, 39 (51%) demonstrated 10yr-PFS. The median follow-up period was 15 years (range 10-33 years). Among the 10yr-PFS patients, 49% (19/39) experienced a recurrence at least 10 years after surgery. Of those who experienced recurrence, 42% (8/19) died of disease. Neither long-term recurrence nor DSS were significantly associated with age, sex, tumor size, LPS subtype, surgical margin, or perioperative treatment with radiation or chemotherapy., Conclusion: Patients who have primary RP-LPS treated with surgical resection ± multimodality therapy face a long-term risk of recurrence and disease-specific death unacknowledged by current surveillance imaging guidelines. Among the patients with 10yr-PFS, 49% experienced a recurrence, and 42% of those died of disease. These findings suggest a need for lifelong surveillance imaging for patients with RP-LPS., (© 2022. Society of Surgical Oncology.)

The purpose of this study was to evaluate 18 F-FLT PET/CT as an early prognostic imaging biomarker of long-term overall survival and disease-specific survival (DSS) in soft-tissue sarcoma (STS) patients treated with neoadjuvant therapy (NAT) and surgical resection. Methods: This was a 10-y follow-up of a previous single-center, single-arm prospective clinical trial. Patients underwent 18 F-FLT PET/CT before treatment (PET1) and after NAT (PET2). Posttreatment pathology specimens were assessed for tumor necrosis or fibrosis and for Ki-67 and thymidine kinase 1 expression. Maximally selected cutoffs for PET and histopathologic factors were applied. Survival was calculated from the date of subject consent to the date of death or last follow-up. Results: The study population consisted of 26 patients who underwent PET1; 16 of the 26 with primary STS underwent PET2. Thirteen deaths occurred during a median follow-up of 104 mo. In the overall cohort, overall survival was longer in patients with a low than a high PET1 tumor SUV max (dichotomized by an SUV max of ≥8.5 vs. <8.5: not yet reached vs. 49.7 mo; P = 0.0064). DSS showed a trend toward significance ( P = 0.096). In a subanalysis of primary STS, DSS was significantly longer in patients with a low PET1 tumor SUV max (dichotomized by an SUV max of ≥8 vs. <8; P = 0.034). There were no significant 18 F-FLT PET response thresholds corresponding to DSS or overall survival after NAT at PET2. Conclusion: 18 F-FLT PET may serve as a prognostic baseline imaging biomarker for DSS in patients with primary STS., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

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., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

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.

The use of upfront chemotherapy for primary localized soft tissue sarcoma (STS) of the extremity and trunk is debated. It remains unclear if chemotherapy adds clinical benefit, which patients are likely to benefit, and whether the timing of therapy affects outcomes. We used the National Cancer Database (NCDB) to examine the association between overall survival (OS) and chemotherapy in 5436 patients with the five most common subtypes of STS with primary disease localized to the extremity or trunk, mirroring the patient population of a modern phase 3 clinical trial of neoadjuvant chemotherapy. We then examined associations between timing of multi-agent chemotherapy (neoadjuvant or adjuvant) and OS. We used a Cox proportional hazards model and propensity score matching (PSM) to account for covariates including demographic, patient, clinical, treatment, and facility factors. In the overall cohort, we observed no association between multi-agent chemotherapy or its timing and improved OS. Multi-agent chemotherapy was associated with improved OS in several subgroups, including patients with larger tumors (>5 cm), those treated at high-volume centers, or those who received radiation. We also identified an OS benefit to multi-agent chemotherapy among the elderly (>70 years) and African American patients. Multi-agent chemotherapy was associated with improved survival for patients with tumors >5 cm, who receive radiation, or who receive care at high-volume centers. Neither younger age nor chemotherapy timing was associated with better outcomes. These 'real-world' findings align with recent randomized trial data supporting the use of multi-agent chemotherapy in high-risk patients with localized STS.

Background: There is conflicting evidence regarding the role of chemotherapy for high-grade soft tissue sarcoma (STS) in adults. We sought to characterize patterns of chemotherapy use, including multiagent and neoadjuvant chemotherapy, in the United States., Patients and Methods: Using the National Cancer Database, we identified 19,969 adult patients who underwent surgical resection for primary high-grade STS from 2004 to 2016. Using logistic regression, we examined factors associated with overall, multiagent, and neoadjuvant chemotherapy use., Results: Chemotherapy was administered to 22% (n=4,377) of the study population. Among patients treated using chemotherapy, 85% received multiagent treatment and 47% received neoadjuvant treatment. On multivariate analysis, factors associated with chemotherapy use included tumor size, depth, histology, and primary site; receipt of radiation treatment; younger age; higher patient income; and academic treatment facility. Factors associated with multiagent chemotherapy use included tumor histology, tumor primary site, and younger age. Factors associated with neoadjuvant chemotherapy use included tumor size, depth, margin status, and primary site; receipt of radiation treatment; higher patient income; academic treatment facility type; and distance to treatment facility. Treatment at a high-volume facility was the only factor associated with overall, multiagent, and neoadjuvant chemotherapy use. No significant temporal trend was seen in overall, multiagent, or neoadjuvant chemotherapy use., Conclusions: Overall chemotherapy use was low (22%). The variability in chemotherapy use was driven by clinical, patient, demographic, and facility factors. Among patients treated with chemotherapy, the use of multiagent chemotherapy was high (85%), and nearly half received neoadjuvant therapy. There was a discrepancy in the use of chemotherapy-including neoadjuvant and multiagent chemotherapy-between high- and low-volume treatment centers.

Objectives: Peripheral nerve sheath tumors (PNSTs) are clinically heterogenous, comprising benign (BPNST) and malignant (MPNST) variants. BPNSTs can be managed with nerve-sparing excision or observation. MPNSTs require radical resection and multidisciplinary oncologic management (1, 15). Image-guided core-needle biopsy (IGCNBx) is the well-established standard to obtain preoperative tissue diagnosis of soft tissue tumors. However, there has been resistance to performing IGCNBx of PNSTs because of the presumed risk of nerve injury and unknown accuracy in determining malignancy. We sought to define the accuracy and safety of IGCNBx in PNSTs., Materials and Methods: All patients that underwent both IGCNBx and surgical resection of a PNST at our institution between 2002 and 2016 were analyzed. The accuracy of IGCNBx in determining malignancy was calculated, including subgroup analyses by histologic subtype and neurofibromatosis 1 status. Complication data were collected and analyzed., Results: Among the 78 PNSTs with IGCNBx and postresection surgical pathology, 76% (n=59) had BPNST and 24% (n=19) had MPNST on postresection surgical pathology. IGCNBx accurately determined malignancy in 94% of cases. IGCNBx demonstrating schwannoma or MPNST were 100% accurate in determining malignancy. IGCNBx demonstrating neurofibroma or indeterminate results were 33% and 57% malignant on postresection surgical pathology, respectively. There were no long-term complications, including sensory or motor deficits, from IGCNBx., Conclusions: Percutaneous IGCNBx demonstrates 94% accuracy in differentiating benign from malignant PNSTs. IGCNBx demonstrating neurofibroma or indeterminate pathology should be interpreted with caution because of risk of malignant reclassification on surgical pathology. Our results reaffirm the safety of IGCNBx, as no patients experienced long-term complications.

Background: Malignant peripheral nerve sheath tumors (MPNSTs) comprise a rare, aggressive subtype of soft tissue sarcoma. While surgery is the mainstay of therapy for this disease, the role of neoadjuvant therapy remains undefined., Methods: This study reviewed patients 16 years of age and older who underwent surgical treatment for MPNST between 1974 and 2012 at the authors' institution. Univariate and multivariate analyses were performed of clinicopathologic and treatment variables predictive of disease-specific survival (DSS) and disease-free survival., Results: Eighty-eight patients with primary localized MPNST underwent surgical treatment between 1974 and 2012 at our institution. Of these, 38 (43%) underwent neoadjuvant chemotherapy and had tissue available for analysis. Neoadjuvant radiation was given to 25 patients (68%). The median follow-up time for survivors was 12.5 years (range, 4 to 27 y). Nine patients (23%) had underlying MPNST. With a cutoff of ≥90% pathologic necrosis and/or fibrosis defining response, we identified 14 responders (36%). On univariate analysis, patient age, tumor size, and pathologic response were significantly associated with DSS (P=0.015, 0.011, and 0.030, respectively)., Conclusions: Although the impact of neoadjuvant chemotherapy on the outcome of primary localized MPNST patients continues to be debated, this study shows that a pathologic response to therapy is associated with a significant improvement in DSS. The challenge moving forward is to determine upfront which patients will be "responders" to standard systemic therapy and which patients should be considered for newer investigational agents as part of a clinical trial.

Liposarcoma is the most common type of soft tissue sarcoma. Among the subtypes of liposarcoma, dedifferentiated liposarcoma (DDLPS) is recalcitrant and has the lowest survival rate. The aim of the present study is to determine the efficacy of metabolic targeting with recombinant methioninase (rMETase) combined with palbociclib (PAL) against a doxorubicin (DOX)-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) model. A resected tumor from a patient with recurrent high-grade DDLPS in the right retroperitoneum was grown orthotopically in the right retroperitoneum of nude mice to establish a PDOX model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm 3 : G1, control without treatment; G2, DOX; G3, PAL; G4, recombinant methioninase (rMETase); G5, PAL combined with rMETase. Tumor length and width were measured both pre- and post-treatment. On day 14 after initiation, all treatments significantly inhibited tumor growth compared to the untreated control except DOX. PAL combined with rMETase was significantly more effective than both DOX, rMETase alone, and PAL alone. Combining PAL and rMETase significantly regressed tumor volume on day 14 after initiation of treatment and was the only treatment to do so. The relative body weight on day 14 compared with day 0 did not significantly differ between each treatment group. The results of the present study indicate the powerful combination of rMETase and PAL should be tested clinically against DDLPS in the near future., (Published by Elsevier Inc.)

Myxofibrosarcoma (MFS) is the most common sarcomas in elderly patients and is either chemo-resistant or recurs with metastasis after chemotherapy. This recalcitrant cancer in need of improved treatment. We have established a patient-derived orthotopic xenograft (PDOX) of MFS. The MFS PDOX model was established in the biceps femoris of nude mice and randomized into 7 groups of 7 mice each: control; doxorubicin (DOX); pazopanib (PAZ); temozolomide (TEM); Irinotecan (IRN); IRN combined with TEM; IRN combined with cisplatinum (CDDP) and Salmonella typhimurium A1-R (S. typhimurium A1-R). Treatment was evaluated by relative tumor volume and relative body weight. The MFS PDOX models were DOX, PAZ, and TEM resistant. IRN combined with TEM and IRN combined with CDDP were most effective on the MFS PDOX. S. typhimurium A1-R arrested the MFS PDOX tumor. There was no significant body weight loss in any group. The present study suggests that the combination of IRN with either TEM or CDDP, and S. typhimurium have clinical potential for MFS., (Published by Elsevier Inc.)

Melanoma is a recalcitrant cancer. To improve and individualize treatment for this disease, we previously developed a patient-derived orthotopic xenograft (PDOX) model for melanoma. We previously reported the individual efficacy of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) and recombinant methioninase (rMETase) for melanoma in the PDOX models of this disease. In the present study, we evaluated the efficacy of the combination of S. typhimurium A1-R with orally-administered rMETase (o-rMETase) for BRAF-V600E-negative melanoma in a PDOX model. Three weeks after implantation, 60 PDOX mouse models were randomized into six groups of 10 mice each: untreated control, temozolomide (TEM); o-rMETase; S. typhimurium A1-R; TEM + rMETase, S. typhimurium A1-R + rMETase. All treatments inhibited tumor growth compared to untreated control (TEM: p < 0.0001, rMETase: p < 0.0001, S. typhimurium A1-R: p < 0.0001, TEM + rMETase: p < 0.0001, S. typhimurium A1-R + rMETase: p < 0.0001). The most effective was the combination of S. typhimurium A1-R + o-rMETase which regressed this melanoma PDOX, thereby indicating a new paradigm for treatment of metastatic melanoma., (Published by Elsevier Inc.)

Pleomorphic liposarcoma (PLPS) is a recalcitrant soft-tissue sarcoma (STS) subtype in need of transformative therapy. We have previously established a patient-derived orthotopic xenograft (PDOX) model, of PLPS with PDGFRA amplification, using surgical orthotopic implantation. In the current study, the PLPS PDOX model was randomized into 3 groups of 7 mice each: untreated control; doxorubicin (DOX)-treated; and treated with Salmonella typhimurium A1-R (S. typhimurium A1-R) expressing green fluorescent protein (GFP). Tumor volume and body weight were monitored during the treatment period. The PLPS PDOX was resistant to DOX. In contrast, the PLPS PDOX was highly sensitive to S. typhimurium A1-R. There was no significant body-weight loss among these 3 groups. Fluorescence imaging demonstrated that S. typhimurium A1-R-GFP was very effective to target the PLPS PDOX tumor. The current study demonstrates that a PLPS PDOX, resistant to first-line therapy DOX, was highly sensitive to tumor targeting S. typhimurium A1-R., (© 2018 Wiley Periodicals, Inc.)

Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant cancer, resistant to conventional chemotherapy. A patient with high-grade USCS from a striated muscle was implanted orthotopically in the right biceps femoris muscle of mice to establish a patient-derived orthotopic xenograft (PDOX) model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm 3 : G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks); G3, temozolomide (TEM) (25 mg/kg, p.o., daily, for 14 days). Tumor size and body weight were measured with calipers and a digital balance twice a week. TEM significantly inhibited tumor volume growth compared to the untreated control and the DOX-treated group on day 14 after treatment initiation: control (G1): 343 ± 78 mm 3 ; DOX (G2): 308 ± 31 mm 3 , P = 0.272; TEM (G3): 85 ± 21 mm 3 , P < 0.0001. TEM significantly regressed the tumor volume compared to day 0 (P = 0.019). There were no animal deaths in any group. The body weight of treated mice was not significantly different in any group. Tumors treated with DOX were comprised of spindle-shaped viable cells without apparent necrosis or inflammatory changes. In contrast, tumors treated with TEM showed extensive tumor necrosis. The present study demonstrates the potential power of matching the patient with an effective drug and saving the patient needless toxicity from ineffective drugs., (© 2018 Wiley Periodicals, Inc.)

Synovial sarcoma (SS) is a recalcitrant subgroup of soft tissue sarcoma (STS). A tumor from a patient with high grade SS from a lower extremity was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) mouse model. The PDOX mice were randomized into the following groups when tumor volume reached approximately 100 mm 3 : G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks; G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G4 DOX (3mg/kg), i.p. weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks). On day 14 after treatment initiation, all therapies significantly inhibited tumor growth compared to untreated control, except DOX: (DOX: p = 0.48; rMETase: p < 0.005; DOX combined with rMETase < 0.0001). DOX combined with rMETase was significantly more effective than both DOX alone ( p < 0.001) and rMETase alone ( p < 0.05). The relative body weight on day 14 compared with day 0 did not significantly differ between any treatment group or untreated control. The results indicate that r-METase can overcome DOX-resistance in this recalcitrant disease., Competing Interests: CONFLICTS OF INTEREST None.

Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant -cancer in need of individualized therapy. A high-grade USCS from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In a previous study, we evaluated the efficacy of standard first-line chemotherapy of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. In the present study, mice-bearing the USCS PDOX tumors were randomized into the following groups when tumor volume reached 100 mm 3 : G1, untreated control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, L-methionine α-deamino-γ-mercaptomethane lyase (recombinant methioninase [rMETase]) (100 U/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. The methionine level of supernatants derived from sonicated tumors was also measured. rMETase inhibited tumor growth, measured by tumor volume, compared to untreated controls and the DOX-treated group on day 14 after initiation of treatment: control (G1): 347.6 ± 88 mm 3 ; DOX (G2): 329.5 ± 79 mm 3 , P = 0.670; rMETase (G3): 162.6 ± 51 mm 3 , P = 0.0003. The mouse body weight of the treated mice was not significantly different from the untreated controls. Tumor L-methionine levels were reduced after the rMETase-treatment compared to untreated control and pre-rMETase treatment. We previously reported efficacy of rMETase against Ewing's sarcoma and melanoma in a PDOX models. These studies suggest clinical development of rMETase, especially in recalcitrant cancers such as sarcoma., (© 2017 Wiley Periodicals, Inc.)

We have previously established a patient-derived orthotopic xenograft (PDOX) model of undifferentiated spindle cell sarcoma (USCS). Recombinant methioninase (rMETase) has previously demonstrated efficacy in PDOX mouse models of human cancers. In the present study, we determined if rMETase in combination with doxorubicin (DOX) can overcome first-line DOX resistance in a PDOX models of USCS. The USCS PDOX mouse models were randomized into the following groups when tumor volume reached 100 mm 3 : G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks); G3, rMETase (100 units/mouse, i.p., daily, for 2 weeks); G4, DOX (3 mg/kg, i.p., weekly, for 2 weeks) combined with rMETase (100 units/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured twice a week. On day 14 after initiation, the USCS PDOX tumor sizes were (G1): 360 ± 85 mm 3 ; DOX (G2): 355 ± 111 mm 3 , p = .927; rMETase (G3): 182 ± 57 mm 3 , p = .0003; DOX + rMETase (G4): 134 ± 29 mm 3 , p = .00001. These results indicate that rMETase can overcome USCS resistance to DOX, which is first line therapy for this disease. The body weight of treated mice was not significantly different in any group. The present results demonstrate the power of the PDOX model to identify effective therapy for recalcitrant cancer and the potential of rMETase to overcome DOX resistance., (Published by Elsevier B.V.)

Undifferentiated soft tissue sarcoma (USTS) is a recalcitrant and heterogeneous subgroup of soft tissue sarcoma with high risk of metastasis and recurrence. Due to heterogeneity of USTS, there is no reliably effective first-line therapy. We have generated tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R), which previously showed strong efficacy on single patient-derived orthotopic xenograft (PDOX) models of Ewing's sarcoma and follicular dendritic cell sarcoma. In the present study, tumor resected from 4 patients with a biopsy-proven USTS (2 undifferentiated pleomorphic sarcoma [UPS], 1 undifferentiated sarcoma not otherwise specified [NOS] and 1 undifferentiated spindle cell sarcoma [USS]) were grown orthotopically in the biceps femoris muscle of mice to establish PDOX models. One USS model and one UPS model were doxorubicin (DOX) resistant. One UPS and the NOS model were partially sensitive to DOX. DOX is first-line therapy for these diseases. S. typhimurium A1-R arrested tumor growth all 4 models. In addition to arresting tumor growth in each case, S. typhimurium A1-R was significantly more efficacious than DOX in each case, thereby surpassing first-line therapy. These results suggest that S. typhimurium A1-R can be a general therapeutic for USTS and possibly sarcoma in general., (Published by Elsevier Inc.)

Study Design: Retrospective study., Objective: Evaluate the effect of age on the efficacy of allograft/demineralized bone matrix (DBM) enriched with concentrated bone marrow aspirate (BMA) in posterolateral lumbar fusions (PLFs)., Summary of Background Data: Cell-based therapies such as concentrated BMA have been developed as a potential alternative to iliac crest bone graft (ICBG). BMA contains mesenchymal stem cells (MSCs) and growth factors that can confer osteogenic and osteoinductive potential to osteoconductive scaffolds such as DBM/allograft. To date, no studies have examined the role of age on fusion outcomes when BMA is utilized despite the well-established deleterious effects of advanced age on bone marrow and MSC potential., Materials and Methods: Fifty-one patients that underwent PLF were divided into 3 groups. Group A (n=14) composed of patients age 65 years and older who received BMA with DBM. Group B (n=17) consisted of patients younger than 65 years of age who received BMA with DBM. Group C (n=20) composed of patients age 65 years and older who received ICBG. Fusion rates and clinical outcomes were assessed., Results: Fusion was significantly lower in group A (35.7%) compared with both groups B (76.4%) and C (80%) (A vs. B, P=0.03; A vs. C, P=0.01). There were no differences in clinical outcomes among all groups except for pseudarthrosis which occurred in 28.6% of patients in group A compared with none and 5% of patients in groups B and C, respectively (A vs. B, P=0.03; A vs. C, P=0.13)., Conclusions: Elderly patients undergoing PLF using DBM enriched with BMA achieved lower radiographic fusion success compared with their nonelderly counterparts and compared with elderly patients that had fusion with ICBG. This may be partly due to the effect of advanced age on MSC potential.

An excessive requirement for methionine (MET) for growth, termed MET dependence, appears to be a general metabolic defect in cancer. We have previously shown that cancer-cell growth can be selectively arrested by MET restriction such as with recombinant methioninase (rMETase). In the present study, we utilized patient-derived orthotopic xenograft (PDOX) nude mouse models with pancreatic cancer or melanoma to determine the relationship between intra-tumor MET level and tumor size. After the tumors grew to 100 mm 3 , the PDOX nude mice were divided into two groups: untreated control and treated with rMETase (100 units, i.p., 14 consecutive days). On day 14 from initiation of treatment, intra-tumor MET levels were measured and found to highly correlate with tumor volume, both in the pancreatic cancer PDOX ( p <0.0001, R 2 =0.89016) and melanoma PDOX ( p <0.0001, R 2 =0.88114). Tumors with low concentration of MET were smaller. The present results demonstrates that patient tumors are highly dependent on MET for growth and that rMETase effectively lowers tumor MET., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Ewing's sarcoma is a recalcitrant tumor greatly in need of more effective therapy. The aim of this study was to determine the efficacy of eribulin on a doxorubicin (DOX)-resistant Ewing's sarcoma patient derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma PDOX model was previously established in the right chest wall of nude mice from tumor resected form the patient's right chest wall. In the previous study, the Ewing's sarcoma PDOX was resistant to doxorubicin (DOX) and sensitive to palbociclib and linsitinib. In the present study, the PDOX models were randomized into three groups when the tumor volume reached 60 mm 3 : G1, untreated control (n = 6); G2, DOX treated (n = 6), intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, Eribulin treated (n = 6, intravenous (i.v.) injection, weekly for 2 weeks). All mice were sacrificed on day 15. Changes in body weight and tumor volume were assessed two times per week. Tumor weight was measured after sacrifice. DOX did not suppress tumor growth compared to the control group (P = 0.589), consistent with the previous results in the patient and PDOX. Eribulin regressed tumor size significantly compared to G1 and G2 (P = 0.006, P = 0.017) respectively. No significant difference was observed in body weight among any group. Our results demonstrate that eribulin is a promising novel therapeutic agent for Ewing's sarcoma., (© 2017 Wiley Periodicals, Inc.)

The 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.

In the present study, a patient-derived orthotopic xenograft (PDOX) model of recurrent cisplatinum (CDDP)-resistant metastatic osteosarcoma was treated with Salmonella typhimurium A1-R (S. typhimurium A1-R), which decoys chemoresistant quiescent cancer cells to cycle, and recombinant methioninase (rMETase), which selectively traps cancer cells in late S/G 2 , 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. typhimurium A1-R (5 × 10 7 CFU/100 μl, i.v., weekly, for 2 weeks); G5, S. typhimurium A1-R (5 × 10 7 CFU/100 μl, i.v., weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G6, S. typhimurium A1-R (5 × 10 7 CFU/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. typhimurium A1-R: p = 0.002; S. typhimurium A1-R combined with rMETase: p = 0.0004; rMETase combined with both S. typhimurium A1-R and CDDP: p = 0.0001). The decoy, trap and kill combination of S. typhimurium A1-R, rMETase and CDDP was the most effective of all therapies and was able to eradicate the metastatic osteosarcoma PDOX.

Relapsed osteosarcoma is a recalcitrant tumor. A patient's cisplatinum (CDDP)-resistant relapsed osteosarcoma lung metastasis was previously established orthotopically in the distal femur of mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the PDOX models were randomized into the following groups when tumor volume reached 100 mm 3 : G1, control without treatment; G2, CDDP (6 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); gemcitabine (GEM) (100 mg/kg, i.p., weekly, for 2 weeks) combined with docetaxel (DOC) (20 mg/kg, i.p., once); temozolomide (TEM) (25 mg/kg, p.o., daily, for 2 weeks) combined with irinotecan (IRN) (4 mg/kg i.p., daily for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. After 2 weeks, all treatments significantly inhibited tumor growth except CDDP compared to the untreated control: CDDP: p = 0.093; GEM+DOC: p = 0.0002, TEM+IRN: p < 0.0001. TEM combined with IRN was significantly more effective than either CDDP ( p = 0.0001) or GEM combined with DOC ( p = 0.0003) and significantly regressed the tumor volume compared to day 0 ( p = 0.003). Thus the PDOX model precisely identified the combination of TEM-IRN that could regress the CDDP-resistant relapsed metastatic osteosarcoma PDOX., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

The aim of the present study was to determine the usefulness of a patient-derived orthotopic xenograft (PDOX) nude-mouse model of a doxorubicin-resistant metastatic Ewing's sarcoma, with a unique combination of a FUS-ERG fusion and CDKN2A deletion, to identify effective drugs for third-line chemotherapy of the patient. Our previous study showed that cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors were effective on the Ewing's sarcoma PDOX, but not doxorubicin, similar to the patient's resistance to doxorubicin. The results of the previous PDOX study were successfully used for second-line therapy of the patiend. In the present study, the PDOX mice established with the Ewing's sarcoma in the right chest wall were randomized into 5 groups when the tumor volume reached 60 mm 3 : untreated control; gemcitabine combined with docetaxel (intraperitoneal [i.p.] injection, weekly, for 2 weeks); irinotecan combined with temozolomide (irinotecan: i.p. injection; temozolomide: oral administration, daily, for 2 weeks); pazopanib (oral administration, daily, for 2 weeks); yondelis (intravenous injection, weekly, for 2 weeks). All mice were sacrificed on day 15. Body weight and tumor volume were assessed 2 times per week. Tumor weight was measured after sacrifice. Irinotecan combined with temozolomide was the most effective regimen compared to the untreated control group (p=0.022). Gemcitabine combined with docetaxel was also effective (p=0.026). Pazopanib and yondelis did not have significant efficacy compared to the untreated control (p=0.130, p=0.818). These results could be obtained within two months after the physician's request and were used for third-line therapy of the patient., Competing Interests: CONFLICTS OF INTEREST K.M., T.M., T.K., K.I., K.K. M.M., and R.M.H. are unsalaried associates of AntiCancer Inc. There are no other competing financial interests.

Our laboratory pioneered patient-derived orthotopic xenograft (PDOX) mouse models using surgical orthotopic implantation (SOI). PDOX models are patient-like, in contrast to the ectopic subcutaneous-transplant cancer models. In the present study, we demonstrate that an undifferentiated pleomorphic soft-tissue sarcoma (UPS-STS) PDOX model acquired bright RFP-expressing stroma through one passage in red fluorescent protein (RFP) transgenic mice, which upon passage to non-colored nude mice was non-invasively imageable. A PDOX nude mouse model of UPS-STS was established in the biceps femoris of nude mice. After the tumors grew to a diameter of 10 mm, the tumors were subsequently passaged to RFP transgenic mice, and after tumor growth were then passaged to non-transgenic nude mice. Tumors were divided into small fragments and transplanted in the biceps femoris at each passage. The OV100 Small Animal Fluorescence Imaging System and FV1000 laser scanning confocal microscope were used to image RFP fluorescence in the UPS-STS PDOX models. UPS-STS PDOX tumors, previously grown in RFP transgenic nude mice for only one passage, had very bright fluorescence and after passage to non-transgenic nude mice maintained the bright fluorescence and were non-invasively imageable. FV1000 confocal imaging revealed diffusely distributed bright RFP stromal cells in the PDOX tumor, both in RFP transgenic mice and after passage to non-transgenic mice. These results demonstrate a powerful method to make the PDOX UPS-STS model brightly fluorescent for non-invasive imaging, as well as for confocal microscopy of individual stromal cells associated with the tumor. The RFP-labeled UPS PDOX has the potential to rapidly screen for novel effective agents for individual patients, including stroma-targeting drugs, whereby the stromal cells are a visual target. J. Cell. Biochem. 118: 361-365, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Purpose: Given the diverse and aggressive nature of soft tissue sarcomas (STSs), a need exists for more-precise therapy. Patient-derived orthotopic xenografts (PDOXs) provide a unique platform for personalized treatment. Thus, identification of patient and treatment factors that predict PDOX establishment is important. This study assessed the feasibility of incorporating PDOXs into the clinical setting and identifying factors associated with PDOX establishment., Patients and Methods: From May 2015 to May 2016, 107 patients with biopsy-proven or potential STS were enrolled. Tumor samples were obtained intraoperatively and orthotopically implanted into nude mice in the corresponding anatomic location. PDOXs were considered established after engraftment and serial passage. Factors associated with establishment were analyzed by logistic regression and time to establishment by time-to-event analysis., Results: Only high-grade tumors established (32 of 72 [44.4%]). The establishment rate (ER) varied by neoadjuvant therapy and treatment response, with the highest ER among untreated high-grade tumors (26 of 42 [61.9%]). Tumors exposed to radiation preoperatively did not establish (zero of 11 [0%]), and tumors exposed to neoadjuvant chemotherapy had a lower ER(31.9%) than untreated tumors. Only STSs with minimal pathologic response to neoadjuvant treatment (≤ 30%) established a PDOX (six of 18 [33.3%]). Median establishment time was 54 days, which varied by neoadjuvant therapy but was not statistically significant ( P = .180)., Conclusion: To our knowledge, in the largest STS PDOX study to date, we demonstrate a 62% ER among untreated high-grade tumors with a median establishment time of 54 days. Neoadjuvant therapy, particularly radiation, and pathologic response to treatment were associated with a reduced rate of PDOX establishment., Competing Interests: AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or po.ascopubs.org/site/ifc. Tara A. Russell No relationship to disclose Mark A. Eckardt No relationship to disclose Takashi Murakami No relationship to disclose Irmina A. Elliott No relationship to disclose Kei Kawaguchi No relationship to disclose Tasuku Kiyuna No relationship to disclose Kentaro Igarashi No relationship to disclose Yungfeng Li No relationship to disclose Joseph G. Crompton No relationship to disclose Danielle S. Graham Stock and Other Ownership Interests: DaVita (I) Sarah M. Dry No relationship to disclose Nicholas Bernthal Honoraria: Daiichi Sankyo Consulting or Advisory Role: Onkos Surgical, Bonesupport Research Funding: Onkos Surgical Jane Yanagawa No relationship to disclose Anusha Kalbasi No relationship to disclose Noah Federman Stock and Other Ownership Interests: Genmab, Kite Pharma Consulting or Advisory Role: Zelda Therapeutics Bartosz Chmielowski Consulting or Advisory Role: Amgen, Bristol-Myers Squibb, Merck, Genentech, Roche, Eisai, Immunocore Speakers’ Bureau: Genentech, Roche, Janssen Pharmaceuticals Travel, Accommodations, Expenses: Genentech, Roche, Bristol-Myers Squibb, Janssen Pharmaceuticals, Merck Arun S. Singh Consulting or Advisory Role: Eli Lilly, Daiichi Sankyo Speakers’ Bureau: Eli Lilly, Eisai Travel, Accommodations, Expenses: Eli Lilly, Daiichi Sankyo, Eisai Stock and Other Ownership Interests: AntiCancer-PDOX Robert M. Hoffman Stock and Other Ownership Interests: AntiCancer-PDOX Fritz C. Eilber Stock and Other Ownership Interests: AntiCancer-PDOX

Background: Multiple studies have demonstrated that a significant amount of variability exists in various demineralized bone matrix (DBM) formulations, which casts doubts on its reliability in consistently promoting fusion. Bone marrow aspirate (BMA) is a cellular based graft that contains mesenchymal stem cells (MSCs) and growth factors can confer osteogenic and osteoinductive potential to DBM. The goal of this study was to describe the outcome of DBM enriched with concentrated BMA in patients undergoing combined lumbar interbody and posterolateral fusion., Methods: Eighty patients with a minimum of 12 months of follow-up were evaluated. Fusion and rates of complication were evaluated. Functional outcomes were assessed based on the modified Odom's criteria. Multiple logistic regression analysis was used to examine the effects of independent variables on fusion outcome., Results: The overall rate of solid fusion (i.e patients with both solid posterolateral and interbody fusion) was 81.3% (65/80). Specifically, the radiographic evidence of solid posterolateral and interbody fusions were 81.3% (65/80) and 92.5% (74/80), respectively. Seven (8.75%) patients developed hardware-related complications, 2 (2.5%) patients developed a postoperative infection and 2 (2.5%) patients developed clinical pseudarthrosis. Charlson comorbidity index (CCI) scores of 3 and 4 were associated with non-solid unions (CCI-3, p = 0.048; CCI-4, p = 0.03). Excellent or good outcomes were achieved in 58 (72.5%) patients., Conclusions: Patients undergoing lumbar fusion using an enriched bone graft containing concentrated BMA added to DBM can achieve successful fusion with relatively low complications and good functional outcomes. Despite these findings, more studies with higher level of evidence are needed to better understand the efficacy of this promising graft option.

Ewing's sarcoma is a rare and aggressive malignancy. In the present study, tumor from a patient with a Ewing's sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present study was to determine efficacy of cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors on the Ewing's sarcoma PDOX. The PDOX models were randomized into the following groups when tumor volume reached 50 mm3: G1, untreated control; G2, doxorubicin (DOX) (intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, CDK4/6 inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, IGF-1R inhibitor (linsitinib, OSI-906, p.o., daily, for 14 days). Tumor growth was significantly suppressed both in G3 (palbociclib) and in G4 (linsitinib) compared to G1 (untreated control) at all measured time points. In contrast, DOX did not inhibit tumor growth at any time point, which is consistent with the failure of DOX to control tumor growth in the patient. The results of the present study demonstrate the power of the PDOX model to identify effective targeted molecular therapy of a recalcitrant DOX-resistant Ewing's sarcoma with specific genetic alterations. The results of this study suggest the potential of PDOX models for individually-tailored, effective targeted therapy for recalcitrant cancer., Competing Interests: Y.Z. is an employee of AntiCancer Inc. T.M., T.K., K.I., K.K. and R.M.H. are unsalaried associates of AntiCancer Inc. R.M.H. is an unsalaried associate of PDOX Inc. There are no other competing financial interests.

Purpose: Cell-based therapies such as concentrated bone marrow aspirate (BMA) with allograft and demineralized bone matrix (DBM) have been developed as a potential alternative to iliac crest bone graft (ICBG) in spinal fusion. BMA contains mesenchymal stem cells (MSCs) and growth factors that confer osteogenic and osteoinductive potential to osteoconductive scaffolds like allograft and DBM. It is well established that there is an age-related decline in bone marrow MSC population and efficacy. This might be problematic in spine arthrodesis when utilizing BMA derived from elderly patients as a fusion aide. The goal of this study was to describe the outcomes of concentrated BMA with allograft and DBM in elderly patients undergoing posterolateral and interbody lumbar fusion., Methods: Thirty-one patients, age 65 and older, with a minimum of 12 months follow-up underwent combined primary posterolateral and transforaminal lumbar interbody fusion. Radiographic fusion, complications, reoperation rates and clinical outcomes were assessed. Multiple logistic regression analysis was used to examine the effects of variables such as patient age, gender, smoking, osteoporosis, Charlson co-morbidity index score, single versus multilevel fusion, length of hospital stay, and length of follow-up time on fusion outcome., Results: The overall rate of a solid fusion (i.e. the concomitant presence of solid posterolateral and interbody fusion in a patient) was 83.9 % (26/31). Specifically, radiographic evidence of a successful posterolateral fusion was 83.9 % (26/31) while the radiographic evidence of a successful interbody fusion was 96.8 % (30/31). Using logistic regression analysis, none of the variables of interest had an association with non-solid unions. One (3.2 %) patient developed a seroma and one (3.2 %) patient developed clinical pseudarthrosis. None of the patients developed hardware-related complications or graft donor site morbidities. Five (16.1 %) patients required reoperation. Excellent or good results were achieved in 83.9 % of patients., Conclusions: Despite the concerns of reduced fusion potential in elderly patients, autologous concentrated BMA mixed with allograft and DBM in posterolateral and interbody fusions can achieve successful fusion rates with good clinical outcomes and low complication rates.

Aurora kinases play important roles in cell division and are frequently overexpressed in human cancer. AMG 900 is a novel pan-Aurora kinase inhibitor currently being tested in Phase I clinical trials. We aimed to evaluate the in vitro activity of AMG 900 in a panel of 44 human breast cancer and immortalized cell lines and identify predictors of response. AMG 900 inhibited proliferation at low nanomolar concentrations in all cell lines tested. Response was further classified based on the induction of lethality. 25 cell lines were classified as highly sensitive (lethality at 10 nM of AMG 900 >10 %), 19 cell lines as less sensitive to AMG 900 (lethality at 10 nM of AMG 900 <10 %). Traditional molecular subtypes of breast cancer did not predict for this differential response. There was a weak association between AURKA amplification and response to AMG 900 (response ratio = 2.53, p = 0.09). mRNA expression levels of AURKA, AURKB, and AURKC and baseline protein levels of Aurora kinases A and B did not significantly associate with response. Cell lines with TP53 loss of function mutations (RR = 1.86, p = 0.004) and low baseline p21 protein levels (RR = 2.28, p = 0.0004) were far more likely to be classified as highly sensitive to AMG 900. AMG 900 induced p53 and p21 protein expression in cell lines with wt TP53. AMG 900 caused the accumulation of cells with >4 N DNA content in a majority of cell lines independently of sensitivity and p53 status. AMG 900 induced more pronounced apoptosis in highly sensitive p53-dysfunctional cell lines. We have found that AMG 900 is highly active in breast cancer cell lines and that TP53 loss of function mutations as well as low baseline expression of p21 protein predict strongly for increased sensitivity to this compound in vitro.

Chemotherapeutic induction of radiation recall (RR) is a rare event in which a chemotherapeutic agent given days to years after radiation therapy causes an inflammation reaction of the tissues within the irradiated area-"recalling" increased radiation effects to that area. In this unique case, a 14-year-old girl with a synovial sarcoma of the forearm was treated with neoadjuvant chemotherapy and radiation therapy. Gemcitabine was administered in an adjuvant setting inducing a RR reaction. The severity of the inflammation resulted in a forearm myositis secondarily causing a compartment syndrome that was treated with several prolonged courses of corticosteroids. The symptoms of RR and compartment syndrome have resolved 1 year postonset, although magnetic resonance imaging continues to show myositis and soft-tissue edema. This case highlights the need to maintain a heightened awareness to recognizing the signs and symptoms of RR and the potential severity of RR in pediatric cancer patients in conjunction with chemotherapeutic agents used more frequently in adults.

Chronic myelogenous leukemia (CML) constitutes less than 5% of childhood leukemias. The authors describe a rare case of a 14-year-old boy who presented with CML in blast crisis. Unique to this patient was the evidence of both breakpoint cluster region-c-abl oncogene 1 (BCR-ABL1) fusions as well as an additional unbalanced t(1;19) translocation. This combination has not previously been reported in the same patient. Initial treatment with dasatinib achieved a complete cytogenetic response within 2 months of therapy. This case highlights the heterogeneous presentation of CML in children and rationale for use of dasatinib as a first-line agent for patients with blast crisis.