ABSTRACT
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.
Subject(s)
Liposarcoma , Retroperitoneal Neoplasms , Humans , Prospective Studies , Lipopolysaccharides , Retrospective Studies , Retroperitoneal Neoplasms/diagnostic imaging , Retroperitoneal Neoplasms/surgery , Liposarcoma/diagnostic imaging , Liposarcoma/surgery , Liposarcoma/pathology , Neoplasm Recurrence, Local/pathologyABSTRACT
Sclerosing epithelioid fibrosarcoma (SEF) is a rare sarcoma subtype characterized by monomorphic epithelioid cells embedded in a densely sclerotic collagenous matrix. The overwhelming majority of tumors arise in soft tissues; however, rare cases have been documented to occur primarily in bone. The hallmarks of soft tissue SEF include MUC4 immunoreactivity and the presence of an EWSR1-CREB3L1 fusion. Rare cases with alternative fusions have also been reported such as EWSR1-CREB3L2 and FUS-CREB3L2 transcripts. The molecular alterations of skeletal SEF have not been well-defined, with only rare cases analyzed to date. In this study we investigated the clinicopathologic and molecular features of seven patients presenting with primary osseous SEF. There were 3 males and 4 females, with a mean age at diagnosis of 38 years. All cases had microscopic features within the histologic spectrum of SEF and showed strong and diffuse MUC4 positivity, while lacking SATB2 expression. However, due to its unusual presentation within bone, four cases were initially misinterpreted as either osteosarcoma, Ewing sarcoma or chondroblastoma. Half of the patients with follow-up data developed metastasis. The cases were tested by targeted RNA sequencing, MSK-IMPACT, and/or fluorescence in situ hybridization, showing EWSR1-CREB3L1 in six cases and EWSR1-CREB3L2 in one case. The fusion transcripts were composed of EWSR1 exon 11 to either exon 6 of CREB3L1 or CREB3L2. In summary, due to their rarity in the bone, skeletal SEF are often misdiagnosed, resulting in inadequate treatment modalities. Similar to their soft tissue counterpart, bone SEF follow an aggressive clinical behavior and show similar EWSR1-CREB3L1/CREB3L2 fusions.
Subject(s)
Bone Neoplasms/diagnosis , Bone Neoplasms/etiology , Fibrosarcoma/diagnosis , Fibrosarcoma/etiology , Adolescent , Adult , Biomarkers, Tumor , Biopsy , Child , Diagnostic Imaging , Disease Management , Disease Susceptibility , Female , Gene Rearrangement , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Oncogene Proteins, Fusion , Young AdultABSTRACT
The incidence of syphilis is increasing. Syphilitic proctitis involving the rectal mucosa often presents with pain on defecation, rectal bleeding, or ulceration. We present a case of asymptomatic syphilitic proctitis diagnosed upon a routine screening colonoscopy.
Subject(s)
Asymptomatic Infections , Proctitis/diagnosis , Syphilis/diagnosis , Anti-Bacterial Agents/therapeutic use , Colonoscopy , HIV Infections/complications , HIV Infections/drug therapy , Humans , Male , Middle Aged , Proctitis/drug therapy , Proctitis/microbiology , Proctitis/pathology , Rectum/diagnostic imaging , Rectum/microbiology , Rectum/pathology , Syphilis/drug therapy , Syphilis/microbiology , Syphilis/pathologyABSTRACT
PURPOSE: Medication-related osteonecrosis of the jaw (MRONJ) is a rare but severe side effect of antiresorptive medications. Most animal models use tooth extraction as an instigating local factor to induce MRONJ, with varied results. However, these teeth are healthy and absent of dental disease, a rare finding that does not reflect clinical practices. The authors hypothesized that extraction of teeth with periapical inflammation would lead to MRONJ in rats treated with high-dose bisphosphonates. MATERIALS AND METHODS: Rats were pretreated with zoledronic acid (ZA) for 1 week. Pulp exposure (PE) was established by exposing the pulpal chamber of the first and second molars. Experimental periapical disease (EPD) was induced by PE and bacterial inoculation into pulp chambers of the first and second mandibular molars. The mandibular molars were extracted 4 weeks after PE or EPD, and animals were euthanized 4 weeks after tooth extraction. Extraction sockets were assessed clinically, radiographically, and histologically. RESULTS: Clinically, radiographically, and histologically, socket healing was observed in all vehicle-treated animals and in ZA-treated animals after extraction of healthy teeth or teeth with PE. In contrast, bone exposure, lack of socket healing, and osteonecrosis were present in most ZA-treated animals after extraction of teeth with EPD. Bacterial presence was noted in areas of osteonecrotic alveolar bone. CONCLUSION: These data support a synergistic contribution of severe dental disease and tooth extraction to MRONJ pathogenesis. Importantly, this model is amenable to manipulation of methodologic conditions for the dissection of parameters involved in MRONJ pathogenesis.
Subject(s)
Bisphosphonate-Associated Osteonecrosis of the Jaw , Periapical Diseases , Animals , Bone Density Conservation Agents , Diphosphonates , Male , Rats , Rats, Wistar , Tooth ExtractionABSTRACT
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.
Subject(s)
Doxorubicin/administration & dosage , Drug Resistance, Neoplasm/drug effects , Furans/administration & dosage , Ketones/administration & dosage , Sarcoma, Ewing/drug therapy , Administration, Intravenous , Animals , Body Weight/drug effects , Doxorubicin/pharmacology , Drug Administration Schedule , Furans/pharmacology , Humans , Injections, Intraperitoneal , Ketones/pharmacology , Mice , Mice, Nude , Random Allocation , Sarcoma, Ewing/pathology , Treatment Outcome , Tumor Burden/drug effects , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
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.
Subject(s)
Doxorubicin/pharmacology , Precision Medicine , Sarcoma/drug therapy , Temozolomide/pharmacology , Xenograft Model Antitumor Assays , Animals , Humans , Male , Mice , Mice, Nude , Middle Aged , Sarcoma/metabolism , Sarcoma/pathologyABSTRACT
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.
Subject(s)
Doxorubicin/administration & dosage , Liposarcoma/drug therapy , Receptor, Platelet-Derived Growth Factor alpha/genetics , Salmonella typhimurium/physiology , Sarcoma/drug therapy , Aged , Animals , Body Weight , Combined Modality Therapy , Doxorubicin/pharmacology , Drug Resistance, Neoplasm/drug effects , Gene Amplification , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Humans , Liposarcoma/genetics , Male , Mice , Random Allocation , Salmonella typhimurium/genetics , Sarcoma/genetics , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
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.
Subject(s)
Carbon-Sulfur Lyases/therapeutic use , Doxorubicin/therapeutic use , Melanoma/drug therapy , Sarcoma, Ewing/drug therapy , Animals , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Disease Models, Animal , Docetaxel , Female , Indazoles , Mice , Mice, Nude , Pyrimidines/therapeutic use , Sulfonamides/therapeutic use , Taxoids/therapeutic use , Xenograft Model Antitumor Assays , GemcitabineABSTRACT
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.
Subject(s)
Neoplasms/microbiology , Salmonella typhimurium , Sarcoma/therapy , Aged , Animals , CD8-Positive T-Lymphocytes , Doxorubicin/therapeutic use , Female , Green Fluorescent Proteins/metabolism , Heterografts , Humans , Male , Mice , Mice, Nude , Middle Aged , Neoplasms/diagnostic imaging , Salmonella Infections , Salmonella typhimurium/pathogenicity , Sarcoma/microbiologyABSTRACT
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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Fibrosarcoma/drug therapy , Salmonella Infections/drug therapy , Xenograft Model Antitumor Assays , Animals , Cisplatin/administration & dosage , Doxorubicin/administration & dosage , Fibrosarcoma/microbiology , Humans , Indazoles , Irinotecan/administration & dosage , Male , Mice, Nude , Pyrimidines/administration & dosage , Random Allocation , Salmonella Infections/microbiology , Salmonella typhimurium/physiology , Sulfonamides/administration & dosage , Temozolomide/administration & dosage , Tumor Burden/drug effectsABSTRACT
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 100â¯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.
Subject(s)
Carbon-Sulfur Lyases/therapeutic use , Doxorubicin/therapeutic use , Drug Resistance, Neoplasm , Liposarcoma/drug therapy , Piperazines/therapeutic use , Pyridines/therapeutic use , Recombinant Proteins/therapeutic use , Aged , Animals , Body Weight/drug effects , Carbon-Sulfur Lyases/pharmacology , Cell Proliferation/drug effects , Doxorubicin/pharmacology , Humans , Liposarcoma/pathology , Male , Mice, Nude , Piperazines/pharmacology , Pyridines/pharmacology , Recombinant Proteins/pharmacologyABSTRACT
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.
Subject(s)
Antineoplastic Agents/therapeutic use , Carbon-Sulfur Lyases/therapeutic use , Melanoma/therapy , Pseudomonas putida/enzymology , Salmonella typhimurium , Temozolomide/therapeutic use , Administration, Oral , Animals , Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Agents/administration & dosage , Carbon-Sulfur Lyases/administration & dosage , Disease Models, Animal , Drug Delivery Systems , Humans , Male , Melanoma/genetics , Melanoma/microbiology , Melanoma/pathology , Mice, Nude , Point Mutation , Proto-Oncogene Proteins B-raf/genetics , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use , Salmonella typhimurium/physiology , Temozolomide/administration & dosageABSTRACT
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.
Subject(s)
Dioxoles/administration & dosage , Doxorubicin/administration & dosage , Liposarcoma/drug therapy , Receptor, Platelet-Derived Growth Factor alpha/genetics , Tetrahydroisoquinolines/administration & dosage , Aged , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Doxorubicin/adverse effects , Drug Resistance, Neoplasm/genetics , Humans , Liposarcoma/genetics , Liposarcoma/pathology , Male , Mice , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Trabectedin , Xenograft Model Antitumor AssaysABSTRACT
Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant -cancer. Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). In the present study, we evaluated the efficacy of standard first-line chemistry of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. A high-grade USCS from a striated muscle of the patients was grown orthotopically in the right biceps femoris muscle of nude mice to establish the PDOX model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm3 : G1, control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, GEM (100 mg/kg, i.p., weekly, for 2 weeks) combined with DOC (20 mg/kg, i.p., once); G4, PAZ (100 mg/kg, p.o., daily, for 14 days). All treatments except DOX significantly inhibited tumor growth compared to untreated control on day 14 after treatment initiation. Tumor sizes were as fallows: control (G1): 332.0 ± 58.7 mm3 ; DOX (G2): 316.9 ± 55.9 mm3 , P = 0.605; GEM + DOC (G3): 228.9 ± 39.8 mm3 , P = 0.001; PAZ (G4): 173.8 ± 23.3 mm3 , P < 0.0001. PAZ showed significantly more efficacy compared to other therapies evaluated: DOX (P < 0.0001), GEM + DOC (P = 0.006). There were no animal deaths in any group and body weight of treated mice was not significantly different in each group. The present results demonstrate that the PDOX model of USCS can identify a promising novel agent with significantly greater efficacy than first-line therapy for this recalcitrant disease. J. Cell. Biochem. 118: 2739-2743, 2017. © 2017 Wiley Periodicals, Inc.
Subject(s)
Drug Resistance, Neoplasm/drug effects , Neoplasms, Experimental/drug therapy , Pyrimidines/pharmacology , Sarcoma/drug therapy , Sulfonamides/pharmacology , Aged , Animals , Heterografts , Humans , Indazoles , Male , Mice , Mice, Nude , Neoplasm Transplantation , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Sarcoma/metabolism , Sarcoma/pathology , Xenograft Model Antitumor AssaysABSTRACT
Previously, a BRAF-V600E-mutant melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. Trametinib (TRA), an MEK inhibitor, caused tumor regression. In contrast, another MEK inhibitor, cobimetinib (COB) could slow but not arrest growth or cause regression of the melanoma PDOX. First-line therapy temozolomide (TEM) could slow but not arrest tumor growth or cause regression. In addition, vemurafenib (VEM) was not effective even though VEM is supposed to target the BRAF-V600E mutation. We also previously demonstrated that tumor-targeting with S. typhimurium A1-R combined with TEM was significantly more effective than either S. typhimurium A1-R alone or TEM alone on the melanoma PDOX with the BRAF-V600E mutation. The present study used this PDOX model of melanoma to test its sensitivity to VEM combined with S. typhimurium A1-R compared to VEM alone and VEM combined with COB. VEM combined with S. typhimurium A1-R was significantly more effective than VEM alone or VEM combined with COB (P = 0.0216) which is currently first line therapy for advanced melanoma with a BRAF-V600E mutation. J. Cell. Biochem. 118: 2314-2319, 2017. © 2017 Wiley Periodicals, Inc.
Subject(s)
Azetidines/therapeutic use , Indoles/therapeutic use , Melanoma/drug therapy , Piperidines/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Pyridones/therapeutic use , Pyrimidinones/therapeutic use , Salmonella typhimurium/physiology , Sulfonamides/therapeutic use , Aged , Animals , Cell Line, Tumor , Disease Models, Animal , Female , Humans , Melanoma/genetics , Mice , Mice, Nude , Microscopy, Confocal , Microscopy, Electron, Transmission , Mutation/genetics , Salmonella typhimurium/genetics , Vemurafenib , Xenograft Model Antitumor AssaysABSTRACT
NELL-1 (NEL-like Protein 1) is an osteoinductive protein with increasing usage as a bone graft substitute in preclinical animal models. NELL-1 was first identified to have bone-forming properties by its overexpression in fusing cranial sutures. Since this time, addition of recombinant NELL-1 has been used to successfully induce bone formation in the calvarial, axial and appendicular skeleton. With increasing interest in the use of NELL-1 as a bone-graft substitute, we sought to examine the expression of NELL-1 in a wide spectrum of benign and malignant bone-forming skeletal tumors. Immunohistochemical expression was examined in human pathologic specimens. Quantitative RT-PCR evaluated NELL-1 expression among OS cell lines in vitro. Results showed NELL-1 expression in all bone tumors. Likewise, all OS cell lines demonstrated increased NELL-1 expression in comparison to non-lesional human bone marrow stromal cells. Among, benign bone tumors (osteoid osteoma and osteoblastoma), strong and diffuse staining was observed, which spatially correlated with markers of osteogenic differentiation. In contrast, a relative reduction in NELL-1 staining was observed in osteosarcoma, accompanied by increased variation between tumors. Among osteosarcoma specimens, NELL-1 expression did not correlate well with markers of osteogenic differentiation. Surprisingly, among osteosarcoma subtypes, fibroblastic osteosarcoma demonstrated the highest expression of NELL-1. In summary, NELL-1 demonstrates diffuse and reliable expression in benign but not malignant bone-forming skeletal tumors. Future studies will further define the basic biologic, diagnostic and prognostic importance of NELL-1 in bone neoplasms.
Subject(s)
Bone Neoplasms/metabolism , Nerve Tissue Proteins/metabolism , Osteosarcoma/metabolism , Bone Neoplasms/classification , Bone Neoplasms/pathology , Calcium-Binding Proteins , Cell Line, Tumor , Humans , Osteosarcoma/classification , Osteosarcoma/pathology , Polymerase Chain ReactionABSTRACT
A diagnosis of neuroendocrine carcinoma is often morphologically straight-forward; however, the tumor site of origin may remain elusive in a metastatic presentation. Neuroendocrine tumor subtyping has important implications for staging and patient management. In this study, the novel use and performance of a 92-gene molecular cancer classifier for determination of the site of tumor origin are described in a series of 75 neuroendocrine tumors (44 metastatic, 31 primary; gastrointestinal (n=12), pulmonary (n=22), Merkel cell (n=10), pancreatic (n=10), pheochromocytoma (n=10), and medullary thyroid carcinoma (n=11)). Formalin-fixed, paraffin-embedded samples passing multicenter pathologist adjudication were blinded and tested by a 92-gene molecular assay that predicts tumor type/subtype based upon relative quantitative PCR expression measurements for 87 tumor-related and 5 reference genes. The 92-gene assay demonstrated 99% (74/75; 95% confidence interval (CI) 0.93-0.99) accuracy for classification of neuroendocrine carcinomas and correctly subtyped the tumor site of origin in 95% (71/75; 95% CI 0.87-0.98) of cases. Analysis of gene expression subsignatures within the 92-gene assay panel showed 4 genes with promising discriminatory value for tumor typing and 15 genes for tumor subtyping. The 92-gene classifier demonstrated excellent accuracy for classifying and determining the site of origin in tumors with neuroendocrine differentiation. These results show promise for use of this test to aid in classifying neuroendocrine tumors of indeterminate primary site, particularly in the metastatic setting.
Subject(s)
Biomarkers, Tumor/genetics , Gene Expression Profiling/methods , Genetic Testing/methods , Neoplasms, Unknown Primary/genetics , Neoplasms, Unknown Primary/pathology , Neuroendocrine Tumors/genetics , Neuroendocrine Tumors/secondary , Adult , Aged , Aged, 80 and over , Biopsy , Female , Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Neoplasm Grading , Neoplasms, Unknown Primary/classification , Neuroendocrine Tumors/classification , Phenotype , Predictive Value of Tests , Reproducibility of Results , United StatesABSTRACT
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 vivo and in vitro models 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 vivo passages. 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 PTEN tumor-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.
Subject(s)
Down-Regulation/genetics , Liposarcoma/enzymology , Liposarcoma/genetics , PTEN Phosphohydrolase/genetics , Phosphatidylinositol 3-Kinases/metabolism , Signal Transduction , Xenograft Model Antitumor Assays , Adult , Aged , Aged, 80 and over , Animals , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cell Proliferation/drug effects , Down-Regulation/drug effects , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lipid Metabolism/drug effects , Liposarcoma/drug therapy , Liposarcoma/pathology , Male , Mice , Middle Aged , Neoplasm Invasiveness , PTEN Phosphohydrolase/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Signal Transduction/drug effects , Signal Transduction/genetics , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Up-Regulation/drug effects , Up-Regulation/geneticsABSTRACT
BACKGROUND: Gender-based differences in disease onset in murine models of malignant peripheral nerve sheath tumor (MPNST) and in patients with Neurofibromatosis type-1-(NF-1)-associated or spontaneous MPNST has not been well studied. METHODS: Forty-three mGFAP-Cre+;Ptenloxp/+;LSL-K-rasG12D/+ mice were observed for tumor development and evaluated for gender disparity in age of MPNST onset. Patient data from the prospectively collected UCLA sarcoma database (1974-2011, n = 113 MPNST patients) and 39 published studies on MPNST patients (n = 916) were analyzed for age of onset differences between sexes and between NF-1 and spontaneous MPNST patients. RESULTS: Our murine model showed gender-based differences in MPNST onset, with males developing MPNST significantly earlier than females (142 vs. 162 days, p = 0.015). In the UCLA patient population, males also developed MPNST earlier than females (median age 35 vs. 39.5 years, p = 0.048). Patients with NF-1-associated MPNST had significantly earlier age of onset compared to spontaneous MPNST (median age 33 vs. 39 years, p = 0.007). However, expanded analysis of 916 published MPNST cases revealed no significant age difference in MPNST onset between males and females. Similar to the UCLA dataset, patients with NF-1 developed MPNST at a significantly younger age than spontaneous MPNST patients (p < 0.0001, median age 28 vs. 41 years) and this disparity was maintained across North American, European, and Asian populations. CONCLUSIONS: Although our preclinical model and single-institution patient cohort show gender dimorphism in MPNST onset, no significant gender disparity was detected in the larger MPNST patient meta-dataset. NF-1 patients develop MPNST 13 years earlier than patients with spontaneous MPNST, with little geographical variance.