Sarcoma in patients with Lynch syndrome and response to immunotherapy.

BACKGROUND: Lynch syndrome (LS) is an autosomal dominant genetic predisposition to multiple malignancies and is characterized by deficient DNA mismatch repair. Increased incidence of sarcomas is not formally ascribed to LS; however, increasing evidence suggests a preponderance of these malignancies in affected families. Sarcomas typically possess a low tumor mutational burden and incite a poor immune infiltrate, thereby rendering them poorly responsive to immunotherapy. METHODS: We searched the University of California, Los Angeles (UCLA) sarcoma program database for patients with a diagnosis of sarcoma and LS from 2016 to 2023. Three such patients were identified and all three were treated with PD1 blockade. RESULTS: We present three cases of LS-associated sarcomas (two soft tissue sarcoma and one osteosarcoma) with increased tumor mutational burdens. These patients were each treated with an anti-PD1 antibody and experienced a response far superior to that reported for non-LS-associated sarcomas. CONCLUSIONS: Increased mutational burden and immune infiltrate are observed for sarcomas associated with LS. Although unselected patients with sarcoma have demonstrated poor response rates to immunotherapy, our findings suggest that patients with Lynch-associated sarcomas are more likely to respond to treatment with anti-PD1. These patients should be given consideration for immunotherapy.

Lifelong Imaging Surveillance is Indicated for Patients with Primary Retroperitoneal Liposarcoma.

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.

Behaviors and Advocacy Related to COVID-19 among Cancer Patients: The Health Belief Model and Opportunities for Messaging and Education.

Cancer patients have an increased risk of severe COVID-19 outcomes and were recommended to be vaccinated, wear a mask, practice social distancing, and increase hand hygiene. We used the Health Belief Model (HBM) to identify constructs that were associated with the likelihood of adhering to and advocating for CDC COVID-19 prevention recommendations. We surveyed adult cancer patients who had an onsite appointment at the Penn State Cancer Institute or at the Hematology and Oncology Associates of Northeastern Pennsylvania. Survey measures included adherence to and informing others of COVID-19 recommendations as well as HBM constructs. Relationships between HBM constructs and outcomes were assessed with Spearman's correlation and multivariable ordinal logistic regression. Of the 106 participants who completed the survey for our objectives of interest, 76% always wore a mask, 29% always practiced social distancing, and 24% washed their hands at least 10 times a day. Limited advocacy behaviors were captured for the COVID-19 vaccine (30%), social distancing (36%), and wearing masks (27%). Perceived benefits, perceived barriers, and cues-to-action were positively associated with the likelihood of adherence or advocacy of COVID-19 recommendations among cancer patients, whereas perceived susceptibility and self-efficacy were negatively associated with the likelihood of adherence or advocacy of COVID-19 recommendations among cancer patients. Perceived benefits may be the strongest predictor for adherence and advocacy for specific COVID-19 guidelines. Future messaging and educational campaigns focused on improving adherence to or advocacy of specific health behaviors should be informed by the HBM and originate from multiple outlets.

Severe organising pneumonia following COVID-19.

Various forms of diffuse parenchymal lung disease have been proposed as potential consequences of severe COVID­19. We describe the clinical, radiological and histological findings of patients with COVID­19-associated acute respiratory distress syndrome who later developed severe organising pneumonia including longitudinal follow-up. Our findings may have important implications for the therapeutic modalities in the late-phase of severe COVID­19 and might partially explain why a subgroup of COVID­19 patients benefits from systemic corticosteroids.

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

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

Low Rates of Chemotherapy Use for Primary, High-Grade Soft Tissue Sarcoma: A National Cancer Database Analysis.

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.

Galectin-3, GDF-15, and sST2 for the assessment of disease severity and therapy response in patients suffering from inoperable chronic thromboembolic pulmonary hypertension.

PURPOSE: This study examined sST2, GDF-15, and galectin-3 as indicators of disease severity and therapy response in chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: This study included 57 inoperable CTEPH patients who underwent balloon pulmonary angioplasty and 25 controls without cardiovascular disease. Biomarker levels were examined in relation to advanced hemodynamic impairment [tertile with worst right atrial pressure (RAP) and cardiac index], hemodynamic therapy response [normalized hemodynamics (meanPAP ≤25 mmHg, PVR ≤3 WU and RAP ≤6 mmHg) or a reduction of meanPAP ≥25%; PVR ≥ 35%, RAP ≥25%]. RESULTS: GDF-15 [820 (556-1315) pg/ml vs. 370 (314-516) pg/ml; p < 0.001] and sST2 [53.7 (45.3-74.1) ng/ml vs. 48.7 (35.5-57.0) ng/ml; p = 0.02] were higher in CTEPH patients than in controls. At baseline, a GDF-15 level ≥1443 pg/ml (AUC 0.88; OR 31.4) and a sST2 level ≥65 ng/ml (AUC 0.80; OR 10.9) were associated with advanced hemodynamic impairment. At follow-up GDF-15 ≤ 958 pg/ml (AUC = 0.74, OR 18) identified patients with optimal hemodynamic therapy response and ≤760 pg/ml (AUC = 0.79, OR 14). CONCLUSION: GDF-15 and sST2 levels are higher in CTEPH and identified patients with advanced hemodynamic impairment. Further, decreased GDF-15 levels at follow-up were associated with hemodynamic therapy response. The diagnostic strength was not superior to NT-proBNP.

Combination of stereotactic radiotherapy and targeted therapy: patterns-of-care survey in German-speaking countries.

INTRODUCTION: Stereotactic body radiotherapy (SBRT) is increasingly used in metastasized patients receiving targeted/immunotherapy. Information on safety and effectivity of concurrent SBRT and targeted/immunotherapy remains limited, resulting in a lack of consensus on treatment strategies. This study aimed to investigate how SBRT-experienced centers in German-speaking countries combine both therapies. MATERIALS AND METHODS: Patterns-of-care of combined treatment with SBRT and targeted/immunotherapy were assessed in 27 radiation oncology centers (19 German, 1 Austrian and 7 Swiss centers). A survey was performed to analyze the details of SBRT, SBRT planning and combined modality treatment. Consensus was defined as ≥75% agreement among participants. RESULTS: Most participants (60%) were university centers. SBRT for oligometastases has been performed since the year 2008 (median, range 1997-2016), since then a median of 140 cases (5-1100) of SBRT have been performed. In all, 67% performed concurrent SBRT and targeted agents. BRAF inhibitors and VEGF/EGFR inhibitors (bevacizumab [90%], erlotinib [11%], sorafenib [19%], lapatinib [4%]) were considered a contraindication. Bevacizumab was never given simultaneously with SBRT; other agents were given concurrently in 7-52% of centers. A majority (59%) paused targeted agents 1 week before/after SBRT. Only 1 center reduced SBRT dose when combined with targeted agents. CONCLUSION: Although evidence for safety and efficacy of concurrent SBRT and targeted agents is limited, it is regularly performed outside of clinical trials. The survey showed consensus not to combine SBRT with antiangiogenic agents, especially bevacizumab. Furthermore, SBRT with concurrent BRAF inhibitors should be practiced with caution and BRAF inhibitors should be paused at least 1 week before SBRT.

Development of renal function during staged balloon pulmonary angioplasty for inoperable chronic thromboembolic pulmonary hypertension.

Balloon pulmonary angioplasty (BPA), for chronic thromboembolic pulmonary hypertension, improves pulmonary and systemic hemodynamics. The kidney might benefit from this effect. However, staged BPA therapy comes along with repetitive administration of contrast agent. This study examined the overall effect of BPA therapy on renal function. This study included consecutive patients who underwent BPA treatment and completed a 6-month follow-up between March 2014 and March 2017. Biomarker-based evaluation of renal function was performed at baseline, consecutively prior to and after each BPA and at 6-month follow-up. The 51 patients underwent an average of 5 (±2) BPA sessions. In this course, patients received 133 (±48; 21-300) mL of contrast agent per session and 691 (±24; 240-1410) mL during the whole sequence. Acute kidney injury occurred after 6 (2.3%) procedures. The creatinine [80.1 (IQR 67.8-96.8) µmol/L vs. 77.4 (IQR 66.9-91.5) µmol/L, p = .02] and urea level [13.7 (IQR10.7-16.6) mmol/L vs. 12.5 (IQR 10.0-15.5) mmol/L, p = .02] decreased from baseline to the 6-month follow-up. The estimated glomerular filtration rate (eGFR) [79 (IQR 59-94) mL/min/m2 vs. 79.6 (IQR 67.1-95.0) mL/min/m2, p = .11] did not change. The Chronic kidney disease (CKD) stages at baseline were: G1:15; G2:23; G3a:10; G3b:2; G4:1; G5:0. Among patients with a CKD-stage ≥2, analysis revealed an increase of eGFR, decrease of creatinine and urea from baseline to 6-month follow-up. Among those patients, the baseline-CKD-stage improved in 14 (41.2%) patients. BPA therapy improves pulmonary and systemic hemodynamics, with positive effects on renal function. Repetitive administration of contrast agent seems not to be harmful regarding renal function.

Eribulin regresses a doxorubicin-resistant Ewing's sarcoma with a FUS-ERG fusion and CDKN2A-deletion in a patient-derived orthotopic xenograft (PDOX) nude mouse model.

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 mm3 : 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.

Temozolomide regresses a doxorubicin-resistant undifferentiated spindle-cell sarcoma patient-derived orthotopic xenograft (PDOX): precision-oncology nude-mouse model matching the patient with effective therapy.

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 mm3 : 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 mm3 ; DOX (G2): 308 ± 31 mm3 , P = 0.272; TEM (G3): 85 ± 21 mm3 , 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.

Tumor-targeting Salmonella typhimurium A1-R arrests a doxorubicin-resistant PDGFRA-amplified patient-derived orthotopic xenograft mouse model of pleomorphic liposarcoma.

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.

Growth of doxorubicin-resistant undifferentiated spindle-cell sarcoma PDOX is arrested by metabolic targeting with recombinant methioninase.

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 mm3 : 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 mm3 ; DOX (G2): 329.5 ± 79 mm3 , P = 0.670; rMETase (G3): 162.6 ± 51 mm3 , 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.

Tumor-targeting Salmonella typhimurium A1-R is a highly effective general therapeutic for undifferentiated soft tissue sarcoma patient-derived orthotopic xenograft nude-mouse models.

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.

A combination of irinotecan/cisplatinum and irinotecan/temozolomide or tumor-targeting Salmonella typhimurium A1-R arrest doxorubicin- and temozolomide-resistant myxofibrosarcoma in a PDOX mouse model.

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.

Metabolic targeting with recombinant methioninase combined with palbociclib regresses a doxorubicin-resistant dedifferentiated liposarcoma.

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 mm3: 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.

Combination therapy of tumor-targeting Salmonella typhimurium A1-R and oral recombinant methioninase regresses a BRAF-V600E-negative melanoma.

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.

Trabectedin arrests a doxorubicin-resistant PDGFRA-activated liposarcoma patient-derived orthotopic xenograft (PDOX) nude mouse model.

BACKGROUND: Pleomorphic liposarcoma (PLPS) is a rare, heterogeneous and an aggressive variant of liposarcoma. Therefore, individualized therapy is urgently needed. Our recent reports suggest that trabectedin (TRAB) is effective against several patient-derived orthotopic xenograft (PDOX) mouse models. Here, we compared the efficacy of first-line therapy, doxorubicin (DOX), and TRAB in a platelet-derived growth factor receptor-α (PDGFRA)-amplified PLPS. METHODS: We used a fresh sample of PLPS tumor derived from a 68-year-old male patient diagnosed with a recurrent PLPS. Subcutaneous implantation of tumor tissue was performed in a nude mouse. After three weeks of implantation, tumor tissues were isolated and cut into small pieces. To match the patient a PDGFRA-amplified PLPS PDOX was created in the biceps femoris of nude mice. Mice were randomized into three groups: Group 1 (G1), control (untreated); Group 2 (G2), DOX-treated; Group 3 (G3), TRAB-treated. Measurement was done twice a week for tumor width, length, and mouse body weight. RESULTS: The PLPS PDOX showed resistance towards DOX. However, TRAB could arrest the PLPS (p < 0.05 compared to control; p < 0.05 compared to DOX) without any significant changes in body-weight. CONCLUSIONS: The data presented here suggest that for the individual patient the PLPS PDOX model could specifically distinguish both effective and ineffective drugs. This is especially crucial for PLPS because effective first-line therapy is harder to establish if it is not individualized.

Long-term outcomes of cement in cement technique for revision endoprosthesis surgery.

BACKGROUND AND OBJECTIVE: Cemented endoprosthetic reconstruction after resection of primary bone sarcomas has been a standard-of-care option for decades. With increased patient survival, the incidence of failed endoprostheses requiring revision surgery has increased. Revision of cemented endoprotheses by cementing into the existing cement mantle (CiC) is technically demanding. METHODS: This is a retrospective review of our endoprosthesis database of 512 consecutive cemented endoprosthetic reconstructions performed for oncologic diagnoses between 1980 and 2014. A total of 54 implants (mean patient age 32 years, range 13-81) were revised with a CiC technique. Outcomes evaluated were prosthesis survival, revision surgery categorized according to the Henderson Failure Mode Classification, complications, and functional scores. RESULTS: Fifteen-year Kaplan-Meier survival rate was 34% for initial revision and 39% for subsequent revision implants. Mean revised Musculoskeletal Tumor Society (MSTS) Score was 27 at latest follow-up. Infection rate was 2%, 9%, and 13% for primary endoprostheses, initial revisions, and subsequent revisions, respectively. Limb salvage rate was 87%. CONCLUSIONS: At long-term follow up, endoprostheses revised with the CiC technique showed consistent 15-year survival from initial (34%) to subsequent (39%) revision. Despite a relatively high failure rate, these results are encouraging and demonstrate that this is a conservative, repeatable technique.