ABSTRACT
The efficacy of immune checkpoint inhibitors is limited in refractory solid tumors. T-cell receptor gene-modified T (TCR-T)-cell therapy has attracted attention as a new immunotherapy for refractory cold tumors. We first investigated the preclinical efficacy and mode of action of TCR-T cells combined with the pullulan nanogel:long peptide antigen (LPA) vaccine in a mouse sarcoma model that is resistant to immune checkpoint inhibition. Without lymphodepletion, the pullulan nanogel:LPA vaccine markedly increased the number of TCR-T cells in the draining lymph node and tumor tissue. This change was associated with enhanced CXCR3 expression in TCR-T cells in the draining lymph node. In the phase 1 trial, autologous New York esophageal squamous cell carcinoma 1 (NY-ESO-1)-specific TCR-T cells were infused twice into HLA-matched patients with NY-ESO-1+ soft tissue sarcoma (STS). The pullulan nanogel:LPA vaccine contains an epitope recognized by TCR-T cells, and it was subcutaneously injected 1 day before and 7 days after the infusion of TCR-T cells. Lymphodepletion was not performed. Three patients with refractory synovial sarcoma (SS) were treated. Two out of the three patients developed cytokine release syndrome (CRS) with low-to-moderate cytokine level elevation. We found obvious tumor shrinkage lasting for more than 2 years by tumor imaging and long-term persistence of TCR-T cells in one patient. In conclusion, NY-ESO-1-specific TCR-T-cell therapy plus vaccination with the pullulan nanogel carrying an LPA containing the NY-ESO-1 epitope without lymphodepletion is feasible and can induce promising long-lasting therapeutic effects in refractory SS (Registration ID: JMA-IIA00346).
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Sarcoma, Synovial , Soft Tissue Neoplasms , Vaccines , Animals , Mice , Nanogels , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Antigens, Neoplasm , Sarcoma, Synovial/therapy , Epitopes , Cell- and Tissue-Based TherapyABSTRACT
BACKGROUND: Symptom-based therapeutic management is required for neuropathic pain (NeP) to achieve higher treatment efficacy. In spinal disorders, which have a high prevalence of NeP, neurological symptoms are classified into myelopathy, radiculopathy, and cauda equina syndrome. The characteristics of pain and the treatment efficacy for each of these symptoms require clarification. METHODS: A retrospective patient-based outcome study was conducted in 265 outpatients with chronic NeP (≥3 months) related to spinal disorders. The patients were classified into three groups according to their neurological symptoms: spinal cord-related pain, radicular pain, and cauda equina syndrome. Data were obtained from patient-based questionnaires using the Neuropathic Pain Symptom Inventory (NPSI) and the Brief Scale for Psychiatric Problems in Orthopaedic Patients (BS-POP), and from clinical information. RESULTS: Most of the patients with NeP had a NPSI score >10 (moderate to severe pain) and 40% had psychiatric problems. The common subtype of NeP was spontaneous pain and paresthesia/dysesthesia in patients with radicular pain and cauda equina syndrome, whereas more severe paresthesia/dysesthesia was particularly prominent in patients with spinal cord-related pain. The pain reduction rate was significantly lower in these latter patients, especially in association with residual paresthesia/dysesthesia. CONCLUSIONS: The characteristics and treatment efficacy of NeP in patients with spinal disorders varied according to neurological symptoms. Effective treatment was difficult, especially for paresthesia/dysesthesia in patients with spinal cord-related pain. These findings enhance the understanding of the underlying mechanisms of pain and could help in design of symptom-based therapeutic management.
Subject(s)
Cauda Equina Syndrome , Neuralgia , Spinal Diseases , Humans , Paresthesia , Pain Measurement , Retrospective Studies , Neuralgia/diagnosis , Neuralgia/etiology , Neuralgia/therapy , Treatment OutcomeABSTRACT
ABSTRACT: Matsuo, H, Kubota, M, Shimada, S, Kitade, I, Matsumura, M, Nonoyama, T, Koie, Y, Naruse, H, Takahashi, A, Oki, H, Kokubo, Y, and Matsumine, A. The effect of static stretching duration on muscle blood volume and oxygenation. J Strength Cond Res 36(2): 379-385, 2022-Muscle blood volume increases due to stretching; however, the minimum duration of stretching to sustainably increase the muscle blood volume after stretching has not yet been elucidated. This study examined whether the duration of static stretching influenced the muscle blood volume and oxygenation. Ten healthy male subjects participated in this controlled laboratory study. Static stretching of the gastrocnemius muscle was performed for 5 durations (20 seconds, and 1, 2, 5, and 10 minutes). Changes in both the total-Hb (ΔtHb), as an index of blood volume, and tissue oxygenation index (ΔTOI) from baseline were determined using near-infrared spectroscopy. Both the ΔtHb and ΔTOI decreased during stretching and increased after stretching. The minimum value of ΔtHb during stretching did not differ in each of the 5 durations, but minimum ΔTOI progressively decreased with longer durations of stretching. The peak value of ΔtHb after stretching increased with longer durations of stretching. The value of ΔtHb at 5 minutes after the end of stretching increased with more than 2 minutes of stretching compared with 20 seconds of stretching, although the value of ΔtHb did not significantly differ between the 2, 5, and 10 minutes' durations. These findings suggest that a longer duration of stretching elicits a decrease in muscle oxygenation during stretching, and an increase in both the muscle blood volume and oxygenation after stretching. The results indicated that the minimum duration of stretching to sustain an increase in the muscle blood volume after stretching is 2 minutes.
Subject(s)
Muscle Stretching Exercises , Blood Volume , Humans , Male , Muscle, Skeletal , Respiratory Physiological Phenomena , Spectroscopy, Near-InfraredABSTRACT
PURPOSE: To determine the beneficial effects of knee extension exercise applied from 4 h after TKA. METHODS: Patients undergoing TKA for osteoarthritis were assigned to early rehabilitation (n = 41) and control rehabilitation (n = 39) groups. Rehabilitation of knee extension exercise was started within 4 h postoperative in the early group and 2 days after surgery in the control group. Joint range of motion and pain were assessed before surgery and at 3 days to 12 months after surgery. Muscle strength and gait parameters were assessed before and 3 weeks after surgery. RESULTS: Extension range of motion was significantly increased in the early group than the control at 3 days, 3 weeks and 6 months after surgery. In gait parameters, peak knee flexion and extension angles during stance phase were significantly improved in the early group than the control group at 3 weeks after surgery. Flexion range of motion was increased in the early group than the control at 12 months after surgery. CONCLUSION: Starting knee extension exercise within 4 h after TKA reduced the early loss of extension range of motion and improved gait pattern and seemed to contribute to be better functional outcome one year after surgery.
Subject(s)
Arthroplasty, Replacement, Knee , Osteoarthritis, Knee , Arthroplasty, Replacement, Knee/rehabilitation , Exercise Therapy , Gait/physiology , Humans , Knee Joint , Osteoarthritis, Knee/surgery , Range of Motion, Articular/physiology , Treatment OutcomeABSTRACT
PURPOSE: Symptomatic thoracic disc herniation (TDH) is relatively rare, but patients with progressive myelopathy require surgical treatment without delay in diagnosis. The aim of this study was to review clinical and radiological features in patients with TDH presenting with myelopathy. METHODS: A total of 28 consecutive patients with thoracic myelopathy (Frankel grade C or worse) due to TDH who underwent surgery were divided into 3 groups based on the time for development of myelopathy (acute (< 72 h), subacute (within a few weeks), and chronic [gradually over > 1 month)] and their data were analyzed. RESULTS: The patients in the acute group were significantly younger and had a higher body mass index (BMI) compared to those in the subacute and chronic groups. Most cases of acute myelopathy were affected in the upper thoracic level, whereas all patients with subacute and chronic myelopathy had lesions in the lower thoracic level below T8-9. Interestingly, the affected thoracic level in patients with acute myelopathy matched the upper line of the sternum. The rate of acquired walking ability without assistance was only 50.0% in the acute group. CONCLUSIONS: This study suggests that TDH presenting with acute myelopathy may have different clinical and radiological features compared to those of TDH with subacute and chronic myelopathy. Upper TDH should be suspected in cases of acute myelopathy that develops with sudden-onset back pain after certain triggers in younger and higher BMI people. These affected thoracic level matched with the upper line of the sternum in each case.
Subject(s)
Intervertebral Disc Displacement , Spinal Cord Diseases , Humans , Intervertebral Disc Displacement/diagnostic imaging , Radiography , Thoracic Vertebrae , Treatment OutcomeABSTRACT
Pazopanib, a targeted molecular drug, has been proposed as an effective treatment for soft tissue tumour and as a novel adjuvant therapy. There has been a paradoxical concern that wound healing could be inhibited by its anti-angiogenic properties, especially in reconstructive surgery. This paper reports on a 28-year-old woman who underwent flap surgery due to a skin and soft tissue injury after an effective treatment with pazopanib for refractory epithelioid sarcoma. The flap survived without any complication in off-periods of pazopanib for four weeks before and after the surgery, although it is only recommended that the washout periods of pazopanib commence at least seven days before scheduled surgery.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Myocutaneous Flap , Pyrimidines/therapeutic use , Quadriceps Muscle , Sarcoma/therapy , Sulfonamides/therapeutic use , Adult , Angiogenesis Inhibitors/administration & dosage , Buttocks , Combined Modality Therapy , Female , Humans , Indazoles , Magnetic Resonance Imaging , Pyrimidines/administration & dosage , Sarcoma/diagnostic imaging , Sulfonamides/administration & dosage , Treatment Outcome , Wound HealingABSTRACT
BACKGROUND: Previous basic research and clinical studies examined the effects of mesenchymal stem cells (MSCs) on regeneration and maintenance of articular cartilage. However, our pilot study suggested that MSCs are more effective at suppressing inflammation and pain rather than promoting cartilage regeneration in osteoarthritis. Adipose tissue is considered a useful source of MSCs; it can be harvested easily in larger quantities compared with the bone marrow. The present study was designed to evaluate the anti-inflammatory, analgesic, and regenerative effects of intra-articularly injected processed lipoaspirate (PLA) cells (containing adipose-derived MSCs) on degenerative cartilage in a rat osteoarthritis model. METHODS: PLA cells were isolated from subcutaneous adipose tissue of 12-week-old female Sprague-Dawley rats. Osteoarthritis was induced by injection of monoiodoacetate (MIA). Each rat received 1 × 106 MSCs into the joint at day 7 (early injection group) and day 14 (late injection group) post-MIA injection. At 7, 14, 21 days after MIA administration, pain was assessed by immunostaining and western blotting of dorsal root ganglion (DRG). Cartilage quality was assessed macroscopically and by safranin-O and H&E staining, and joint inflammation was assessed by western blotting of the synovium. RESULTS: The early injection group showed less cartilage degradation, whereas the late injection group showed cartilage damage similar to untreated OA group. The relative expression level of CGRP protein in DRG neurons was significantly lower in the two treatment groups, compared with the untreated group. CONCLUSIONS: Intra-articular injection of PLA cells prevented degenerative changes in the early injection group, but had little effect in promoting cartilage repair in the late injection group. Interestingly, intra-articular injection of PLA cells resulted in suppression of inflammation and pain in both OA groups. Further studies are needed to determine the long-term effects of intra-articular injection of PLA cells in osteoarthritis.
Subject(s)
Arthralgia/therapy , Arthritis, Experimental/therapy , Cartilage, Articular/pathology , Mesenchymal Stem Cell Transplantation/methods , Osteoarthritis/therapy , Adipose Tissue/cytology , Animals , Arthralgia/diagnosis , Arthralgia/etiology , Arthritis, Experimental/chemically induced , Biomarkers/analysis , Female , Ganglia, Spinal/pathology , Humans , Injections, Intra-Articular , Iodoacetic Acid/toxicity , Knee Joint/innervation , Knee Joint/pathology , Osteoarthritis/chemically induced , Osteoarthritis/pathology , Pain Measurement/methods , Rats , Rats, Sprague-Dawley , Treatment OutcomeABSTRACT
BACKGROUND: A tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue. Diffuse TGCT (D-TGCT) most commonly develops in the knee, followed by the hip, ankle, elbow, and shoulder. Surgical removal is the only effective treatment option for the patients. However, a local recurrence rate as high as 47% has been reported. Recently, we revealed that zaltoprofen, a nonsteroidal anti-inflammatory drug possessing the ability to activate peroxisome proliferator-activated receptor gamma (PPARγ), can inhibit the proliferation of TGCT stromal cells via PPARγ. PPARγ is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. It plays an important role in the differentiation of adipocytes from precursor cells and exhibits antitumorigenic effects on certain malignancies. Therefore, we are conducting this investigator-initiated clinical trial to evaluate whether zaltoprofen is safe and effective for patients with D-TGCT or unresectable localized TGCT (L-TGCT). METHODS: This study is a randomized, placebo-controlled, double-blind, multicenter trial to evaluate the safety and efficacy of zaltoprofen for patients with D-TGCT or L-TGCT. For the treatment group, zaltoprofen 480 mg/day will be administered for 48 weeks; the placebo group will receive similar dosages without zaltoprofen. Twenty participants in each group are needed in this trial (40 participants total). The primary outcome is the progression-free rate at 48 weeks after treatment administration. "Progression" is defined as any serious events (1. Repetitive joint swelling due to hemorrhage, 2. Joint range of motion limitation, 3. Invasion of adjacent cartilage or bone, 4. Severe joint space narrowing, 5. Increase in tumor size) requiring surgical interventions. We hypothesize that the zaltoprofen group will have a higher progression-free rate compared to that of the placebo group at 48 weeks. DISCUSSION: This is the first study to evaluate the efficacy of zaltoprofen in patients with D-TGCT or unresectable L-TGCT. We believe that the results of this trial will validate a novel treatment option, zaltoprofen, to stabilize disease progression for TGCT patients. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( UMIN000025901 ) registered on 4/01/2017.
Subject(s)
Antineoplastic Agents/therapeutic use , Benzopyrans/therapeutic use , Giant Cell Tumor of Tendon Sheath/drug therapy , Propionates/therapeutic use , Adult , Aged , Antineoplastic Agents/adverse effects , Benzopyrans/adverse effects , Clinical Trials, Phase II as Topic , Disease Progression , Double-Blind Method , Female , Giant Cell Tumor of Tendon Sheath/diagnostic imaging , Giant Cell Tumor of Tendon Sheath/metabolism , Giant Cell Tumor of Tendon Sheath/pathology , Humans , Japan , Male , Middle Aged , Multicenter Studies as Topic , PPAR gamma/agonists , PPAR gamma/metabolism , Progression-Free Survival , Propionates/adverse effects , Randomized Controlled Trials as Topic , Time Factors , Young AdultABSTRACT
BACKGROUND: Even though the number of patients with cervical spinal cord injury (CSCI) without major bone injury is increased, the treatment with either surgery or conservative measures remains controversial. The aim of this study was to assess its prognostic value in the prediction of useful motor recovery and to clarify whether the patients should be treated surgically are present. METHODS: We reviewed 63 patients (conservative, n = 36; surgery, n = 27) with CSCI without major bone injury (Frankel A-C). Neurological examination using modified Frankel grade at admission and 6 months after injury and International Stoke Mandeville Games (ISMG) classification at subacute phase after injury, MRI findings including rate of spinal cord compression, extent of cord damage and type of signal intensity change were assessed. RESULTS: Thirty-five of 63 patients were improved to walk at 6 months after injury. In multivariate analysis, rate of spinal cord compression, extent of cord damage and improvement of ISMG grade were associated with useful motor recovery. There was no difference in the neurological improvement between conservative and surgical groups. However, patients with spinal cord compression of ≥33.2% showed better motor recovery at 6 months post-injury after surgery than those treated conservatively. There was a positive correlation between the improvement of ISMG grade at subacute phase and Frankel grade at 6 months post-injury. It is difficult to obtain satisfactory surgical outcome for patients with Frankel A or B1 on admission and/or extensive spinal cord damage on T2-weighted image. CONCLUSIONS: Conservative treatment is recommended for patients with CSCI without major bone injury. However, we also recommend surgical treatment to acquire walking ability for patients with spinal cord compression of ≥33.2% and low ISMG grade at subacute phase. Among such patients, careful consideration should be given to patients with Frankel A or B1 and/or extensive spinal cord damage on MRI.
Subject(s)
Conservative Treatment/methods , Decompression, Surgical/methods , Fractures, Bone/diagnostic imaging , Magnetic Resonance Imaging/methods , Spinal Cord Injuries/surgery , Walking/physiology , Adult , Aged , Cervical Vertebrae/injuries , Cohort Studies , Female , Fractures, Bone/therapy , Humans , Injury Severity Score , Logistic Models , Male , Middle Aged , Multivariate Analysis , Neurologic Examination/methods , Prognosis , ROC Curve , Retrospective Studies , Risk Assessment , Spinal Cord Compression/diagnostic imaging , Spinal Cord Compression/therapy , Spinal Cord Injuries/diagnostic imaging , Spinal Cord Injuries/therapy , Statistics, Nonparametric , Time Factors , Treatment OutcomeABSTRACT
Benign fibrous histiocytoma (BFH) is a rare benign primary bone lesion that occurs most frequently in the nonmetaphysis region of the long bones and the pelvic bones. The talus is a rare location for a BFH, which has not been reported previously in the literature. We report the case of a 19-year-old male patient with BFH of the talus, who was treated with curettage, followed by filling of the bone defect with calcium phosphate cement. The patient was free of pain and without local recurrence 5 years after the surgery. We describe the detailed radiographic findings of this rare lesion and discuss the differential diagnosis of such talar lesions.
Subject(s)
Bone Neoplasms/diagnostic imaging , Foot Diseases/diagnostic imaging , Histiocytoma, Benign Fibrous/diagnostic imaging , Talus/diagnostic imaging , Adolescent , Athletes , Bone Neoplasms/pathology , Bone Neoplasms/surgery , Diagnosis, Differential , Foot Diseases/pathology , Foot Diseases/surgery , Histiocytoma, Benign Fibrous/pathology , Histiocytoma, Benign Fibrous/surgery , Humans , Magnetic Resonance Imaging , Male , Radiography , Talus/pathology , Talus/surgeryABSTRACT
BACKGROUND: Chordomas are very rare primary malignant bone tumors that arise commonly from the sacrum (50-60%) and clivus (25-35%). Chordomas have a high rate of recurrence. The authors confirmed a unique histologic infiltration pattern of chordomas that resembles a skip-metastatic lesion in normal tissue around tumor, which they named "micro-skip metastasis." This study aimed to examine the correlations between the clinicopathologic features of chordomas, including micro-skip metastasis, and the clinical outcomes, including overall survival, local recurrence-free survival, and distant metastasis-free survival. METHODS: The study analyzed histopathologic and clinical data from patients with sacral chordomas who underwent en bloc resection from July 1991 through July 2014. Cases with a minimum follow-up period shorter than 20 months after resection were excluded. Kaplan-Meier survival analyses with log-rank tests were performed for overall survival, metastasis-free survival, and recurrence-free survival. RESULTS: The study retrospectively reviewed 40 patients. The mean follow-up period was 98.2 months (range 22-297 months). The local recurrence rate was 41.3%. Micro-skip metastases, observed in 17 patients (42.5%), were associated with a significantly increased risk of local recurrence (p = 0.023) but not with overall survival or distant metastasis-free survival. Poorer overall survival was associated with histologic vascular invasion (p = 0.030) and a greater maximum tumor diameter (p = 0.050). CONCLUSIONS: The presence of micro-skip metastasis was associated with a higher rate of local recurrence. The maximum tumor diameter and the presence of histologic vascular invasion were associated with poorer overall survival.
Subject(s)
Chordoma/mortality , Neoplasm Recurrence, Local/mortality , Postoperative Complications/mortality , Sacrum/surgery , Chordoma/pathology , Chordoma/surgery , Female , Follow-Up Studies , Humans , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/surgery , Prognosis , Retrospective Studies , Sacrum/pathology , Survival RateABSTRACT
BACKGROUND: We conducted a nationwide survey of prosthetic reconstruction using a constrained-type hip tumor prosthesis (C-THA) following resection of periacetabular tumors. METHODS: Eighty patients with periacetabular tumors underwent wide resection and prosthetic reconstruction using C-THA at JMOG-affiliated institutions (39 males and 41 females; mean age, 46.7 years; mean follow-up period, 65 months). Primary bone or soft tissue sarcoma accounted for 75% of the cases. Adjuvant radiotherapy and chemotherapy were performed for 12 and 37 patients, respectively. RESULTS: There were 21 local recurrences (26%), necessitating amputation in 2 patients. Other postoperative complications included deep infection in 31 patients (39%), delayed wound healing in 25 (31%), and prosthesis-related complications requiring surgery in 7 (9%). Removal of the prosthesis was required in 23 patients (29%) (deep infection (n = 20), local recurrence resulting in amputation (n = 2), and outer cup displacement (n = 1). Patients whose abductor muscle was conserved or who underwent functional abductor muscle reconstruction showed significantly longer prosthesis survival. No postoperative wound complications occurred in three recent patients undergoing wound management with a RAM flap. The mean MSTS score was 43%. CONCLUSIONS: We analyzed the outcome of 80 patients with periacetabular tumors undergoing C-THA reconstruction. The rates of postoperative complication were still high, but comparable to those in previous studies. Our results suggest wound management using a RAM flap is useful for reducing wound complications.
Subject(s)
Acetabulum/surgery , Bone Neoplasms/surgery , Hip Prosthesis/adverse effects , Neoplasm Recurrence, Local/diagnosis , Plastic Surgery Procedures/adverse effects , Postoperative Complications , Surgical Wound Infection/etiology , Acetabulum/pathology , Adolescent , Adult , Aged , Bone Neoplasms/pathology , Child , Female , Follow-Up Studies , Humans , Japan/epidemiology , Limb Salvage , Male , Middle Aged , Neoplasm Recurrence, Local/epidemiology , Prosthesis Design , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Trabectedin is reported as effective, especially against translocation-related sarcomas (TRSs) after failure of or intolerance to standard chemotherapy. We conducted two phase II studies of TRS, confirming high efficacy of 1.2 mg/m2 trabectedin. The updated data of 66 patients in these studies was integrated to evaluate the efficacy of trabectedin against each histological subtype, and analyze final overall survival (OS). METHODS: Trabectedin was administered on day one of a 21-day cycle. Efficacy was assessed using progression-free survival (PFS), OS, and best overall response. An analysis of OS and PFS was performed for subgroups divided by baseline lymphocyte count (<1,000/µL, ≥1,000/µL) or number of previous chemotherapy regimens (0, 1, 2, ≥3 regimens), and a Weibull parametric model was used to estimate the numerical relationship between lymphocyte count and PFS and OS. RESULTS: Median PFS and OS in overall patients were 5.6 (95% confidence interval [CI]: 4.1-7.3) and 17.5 months (95% CI: 12.6-23.6), respectively. PFS in the myxoid and round-cell liposarcoma (MRCL) group (7.4 months [95% CI: 5.6-11.1]) was longer than in the other subtypes. The response rate was also highest in the MRCL group. Median OS was longer in patients with baseline lymphocyte counts ≥1,000/µL than in those with counts of <1,000/µL, but median PFS was not different between the two subgroups. CONCLUSION: Our updated and pooled data showed that trabectedin exerted prolonged disease control and antitumor effects in patients with advanced TRS, especially in MRCL. We consider that the subgroup analyses also provide important information for trabectedin treatment in patients with TRS. IMPLICATIONS FOR PRACTICE: The progression-free survival (PFS) for the integrated data of 66 patients with translocation-related sarcomas (TRSs) in two phase II studies of trabectedin 1.2 mg/m2 was 5.6 months (95% confidence interval: 4.1-7.3). PFS and response rate in myxoid/round-cell liposarcoma was longer than that of other subtypes. The overall survival (OS) in all TRS subtypes was similar to previous data of TRS patients. In subgroup analysis, the patients with baseline lymphocyte count ≥1,000/µL exhibited better OS, although PFS was not different by baseline lymphocyte count. Our data are considered important information for trabectedin treatment in TRS patients.
Subject(s)
Antineoplastic Agents, Alkylating/administration & dosage , Dioxoles/administration & dosage , Liposarcoma, Myxoid/drug therapy , Sarcoma/drug therapy , Tetrahydroisoquinolines/administration & dosage , Adult , Aged , Antineoplastic Agents, Alkylating/adverse effects , Dioxoles/adverse effects , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Liposarcoma, Myxoid/epidemiology , Liposarcoma, Myxoid/pathology , Male , Middle Aged , Neoplasm Staging , Sarcoma/epidemiology , Sarcoma/pathology , Tetrahydroisoquinolines/adverse effects , Trabectedin , Treatment OutcomeABSTRACT
Objective: Eribulin, a microtubule dynamics inhibitor, is approved for the treatment of patients with breast cancer and soft tissue sarcoma. We investigated the efficacy and safety of eribulin in Japanese patients with soft tissue sarcoma. Methods: This open-label, multicenter, nonrandomized, Phase 2 study enrolled Japanese patients with measurable, advanced/metastatic soft tissue sarcoma of high/intermediate grade and ≥1 prior chemotherapy for advanced disease. Patients received eribulin mesilate 1.4 mg/m2 intravenously over 25 minutes on Days 1 and 8 of a 21-day cycle. The primary endpoint was progression-free rate at 12 weeks. Secondary endpoints included overall survival, progression-free survival and safety. Efficacy analyses were stratified by histology (liposarcoma or leiomyosarcoma, and other subtypes). Results: Overall, 52 patients were enrolled and 51 patients were treated. Patients with liposarcoma/leiomyosarcoma (n = 35) had similar characteristics to those with other subtypes (n = 16), except for a higher proportion of women (63% vs 38%, respectively) and patients with Eastern Cooperative Oncology Group performance status 0 (57% vs 44%). Progression-free rate at 12 weeks was 60% in liposarcoma/leiomyosarcoma patients, 31% in other subtypes and 51% overall. Median progression-free survival was 5.5 months in liposarcoma/leiomyosarcoma patients, 2.0 months in other subtypes and 4.1 months overall. Median overall survival was 17.0 months in liposarcoma/leiomyosarcoma patients, 7.6 months in other subtypes and 13.2 months overall. The most common Grade 34 adverse events were neutropenia (86%), leukopenia (75%), lymphopenia (33%), anemia (14%) and febrile neutropenia (8%). Conclusion: Eribulin showed clinical activity with a manageable safety profile in previously treated Japanese patients with advanced/metastatic soft tissue sarcoma.
Subject(s)
Furans/therapeutic use , Ketones/therapeutic use , Sarcoma/drug therapy , Adult , Aged , Disease-Free Survival , Female , Humans , Middle Aged , Neoplasm Metastasis , Sarcoma/pathology , Treatment OutcomeABSTRACT
Although prognosis in patients with localized osteosarcoma has been dramatically improved by the introduction of multiple chemotherapy agents known as combination chemotherapy, there is growing concern about the development of secondary malignant neoplasms. We report the case of a 13-year-old girl in whom the diagnosis of Ewing sarcoma of bone localized on the shaft of left femur was made 2 years after successful treatment without radiotherapy for osteosarcoma of right proximal femur. EWS-FLI1 fusion gene was detected by reverse transcriptase-polymerase chain reaction. To our knowledge, this is the first case with Ewing sarcoma of the bone as a secondary malignant neoplasm developed in osteosarcoma survivor. We collected 15 cases, included this case, with secondary Ewing sarcoma family of tumor by utilizing the PubMed search and might consider the causes of this secondary cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Femoral Neoplasms/drug therapy , Femoral Neoplasms/genetics , Neoplasms, Second Primary/genetics , Oncogene Proteins, Fusion/genetics , Osteosarcoma/drug therapy , Proto-Oncogene Protein c-fli-1/genetics , RNA-Binding Protein EWS/genetics , Sarcoma, Ewing/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/administration & dosage , Carboplatin/adverse effects , Child , Cisplatin/administration & dosage , Cisplatin/adverse effects , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Doxorubicin/analogs & derivatives , Etoposide/administration & dosage , Etoposide/adverse effects , Female , Femoral Neoplasms/surgery , Humans , Ifosfamide/administration & dosage , Ifosfamide/adverse effects , Limb Salvage , Methotrexate/administration & dosage , Methotrexate/adverse effects , Neoplasms, Second Primary/drug therapy , Neoplasms, Second Primary/surgery , Osteosarcoma/surgery , Remission Induction , Sarcoma, Ewing/drug therapy , Sarcoma, Ewing/surgery , Vincristine/administration & dosageABSTRACT
Surgical excision is the most reliable treatment for the localized soft tissue sarcoma, and chemotherapy and/or radiation therapy may be recommended as adjuvant therapy, depending on the histologic type, grading, tumor size and location. For the unresectable tumors, radiation therapy including particle beam radiation therapy may be taken into consideration. For the recurrent or metastatic disease, the combination therapy with chemotherapy, radiation therapy and surgical excision may be indicated to improve the patient's prognosis and QOL.
Subject(s)
Sarcoma/therapy , Combined Modality Therapy , Disease Progression , Humans , Neoplasm Metastasis , Prognosis , Sarcoma/diagnosis , Sarcoma/epidemiologyABSTRACT
BACKGROUND: Because the efficacy and safety of pazopanib in Japanese patients with soft tissue sarcoma (STS) had not been evaluated previously in a large-scale cohort, the authors investigated the efficacy and safety of pazopanib in 156 Japanese patients with relapsed STS. This was a retrospective study based on the collection of real-life, postmarketing surveillance data. METHODS: Patients received pazopanib with the objective of treating local recurrence (n = 20), metastasis (n = 104), and both (n = 32). The patient median age was 53.8 years. The primary objective of this study was to clarify the efficacy of pazopanib for patients with STS. RESULTS: The median treatment duration was 28.7 weeks, and the average dose intensity of pazopanib was 609 mg. Adverse events occurred in 127 patients (81.4%). In addition to the main common toxicities, such as hypertension and liver disorder, pneumothorax (n = 11) and thrombocytopenia (n = 16) also were observed. The median progression-free survival for all patients was 15.4 weeks. The median progression-free survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 18.6 weeks, 16.4 weeks, 15.3 weeks, and 8 weeks, respectively. The median survival for all patients was 11.2 months. The median survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 20.1 months, 10.6 months, 9.5 months, and 7.3 months, respectively. CONCLUSIONS: There were apparent differences in the efficacy of pazopanib treatment among histologic types of STS. Pazopanib treatment is a new treatment option; however, adverse events like pneumothorax and thrombocytopenia, which did not occur frequently in the PALETTE study (pazopanib for metastatic soft-tissue sarcoma), should be taken into consideration. Cancer 2016;122:1408-16. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Pyrimidines/administration & dosage , Sarcoma/drug therapy , Sulfonamides/administration & dosage , Adolescent , Adult , Aged , Aged, 80 and over , Angiogenesis Inhibitors/adverse effects , Chemical and Drug Induced Liver Injury/etiology , Disease-Free Survival , Female , Fibrosarcoma/drug therapy , Fibrosarcoma/mortality , Humans , Hypertension/chemically induced , Indazoles , Japan/epidemiology , Leiomyosarcoma/drug therapy , Leiomyosarcoma/mortality , Liposarcoma/drug therapy , Liposarcoma/mortality , Male , Middle Aged , Neoplasm Recurrence, Local/mortality , Neurilemmoma/drug therapy , Neurilemmoma/mortality , Pneumothorax/chemically induced , Product Surveillance, Postmarketing , Pyrimidines/adverse effects , Retrospective Studies , Sarcoma/mortality , Sarcoma/secondary , Sarcoma, Synovial/drug therapy , Sarcoma, Synovial/mortality , Sulfonamides/adverse effects , Survival Analysis , Thrombocytopenia/chemically inducedABSTRACT
BACKGROUND: Trabectedin is reported to be particularly effective against translocation-related sarcoma. Recently, a randomized phase 2 study in patients with translocation-related sarcomas unresponsive or intolerable to standard chemotherapy was conducted, which showed clinical benefit of trabectedin compared with best supportive care (BSC). Extraskeletal myxoid chondrosarcoma (EMCS) and Mesenchymal chondrosarcoma (MCS) are very rare malignant soft tissue sarcomas, and are associated with translocations resulting in fusion genes. In addition, the previous in vivo data showed that trabectedin affect tumor necrosis and reduction in vascularization in a xenograft model of a human high-grade chondrosarcoma. The aim of the present analysis was to clarify the efficacy of trabectedin for EMCS and MCS subjects in the randomized phase 2 study. METHODS: Five subjects with EMCS and MCS received trabectedin treatment in the randomized phase 2 study. Three MCS subjects were allocated to the BSC group. Objective response and progression-free survival (PFS) were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by central radiology imaging review. RESULTS: The median follow-up time of the randomized phase 2 study was 22.7 months, and one subject with MCS was still receiving trabectedin treatment at the final data cutoff. The median PFS was 12.5 months (95 % CI: 7.4-not reached) in the trabectedin group, while 1.0 months (95 % CI: 0.3-1.0 months) in MCS subjects of the BSC group. The six-month progression-free rate was 100 % in the trabectedin group. One subject with MCS showed partial response, and the others in the trabectedin group showed stable disease. Overall survival of EMCS and MCS subjects was 26.4 months (range, 10.4-26.4 months) in the trabectedin group. At the final data cutoff, two of five subjects were still alive. CONCLUSIONS: This sub-analysis shows that trabectedin is effective for patients with EMCS and MCS compared with BSC. The efficacy results were better than previously reported data of TRS. These facts suggest that trabectedin become an important choice of treatment for patients with advanced EMCS or MCS who failed or were intolerable to standard chemotherapy. TRIAL REGISTRATION: The randomized phase 2 study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-121850 (May 31, 2012).
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Bone Neoplasms/drug therapy , Chondrosarcoma, Mesenchymal/drug therapy , Chondrosarcoma/drug therapy , Dioxoles/therapeutic use , Neoplasms, Connective and Soft Tissue/drug therapy , Tetrahydroisoquinolines/therapeutic use , Adult , Aged , Bone Neoplasms/mortality , Chondrosarcoma/mortality , Chondrosarcoma, Mesenchymal/mortality , Disease-Free Survival , Humans , Kaplan-Meier Estimate , Middle Aged , Neoplasms, Connective and Soft Tissue/mortality , Trabectedin , Treatment OutcomeABSTRACT
OBJECTIVE: This analysis of the Japanese subpopulation of the PALETTE Phase III, randomized, placebo-controlled study investigated efficacy and safety of pazopanib in patients with metastatic soft tissue sarcoma after failure of standard chemotherapy. METHODS: Patients were randomly assigned in a 2:1 ratio to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Primary endpoint was progression-free survival. Secondary endpoints included overall survival and overall response rate. Efficacy analysis was by intent-to-treat. Safety was also investigated. RESULTS: Forty-seven patients received either pazopanib (n = 31) or placebo (n = 16). Median progression-free survival was 7.0 weeks (95% confidence interval: 4.0-11.7) for placebo and 24.7 weeks (95% confidence interval: 8.6-28.1) for pazopanib (hazard ratio = 0.41 [95% confidence interval: 0.19-0.90]; P = 0.002). Median overall survival was 14.9 months (95% confidence interval: 6.8-not calculable) for placebo and 15.4 months (95% confidence interval: 7.9-28.8) for pazopanib (hazard ratio = 0.87 [95% confidence interval: 0.41-1.83]; P = 0.687). More patients receiving pazopanib experienced best response of stable disease versus placebo. Adverse events were similar to the global population; those leading to dose reduction were more common and mean daily dose was lower in the Japanese population versus the global population (45 vs. 32% and 624.4 vs. 700.4 mg, respectively). CONCLUSIONS: The efficacy and safety of pazopanib observed in the Japanese subpopulation of PALETTE were similar to those in the global population. Pazopanib is a new treatment option for Japanese patients with metastatic non-adipocytic soft tissue sarcoma after chemotherapy. CLINICAL TRIAL REGISTRATION NUMBER: NCT00753688; GSK study ID: VEG110727; http://www.gsk-clinicalstudyregister.com/study/VEG110727#ps.