High-dose chemotherapy and autologous peripheral blood stem cell transplantation in adult patients with high-risk or advanced Ewing and soft tissue sarcoma

Purpose Despite the availability of combined-modality treatment for Ewing sarcoma (ES) and soft tissue sarcomas (STS), results from independent groups still indicate a poor prognosis for high-risk and metastasized patients. The benefit of high-dose chemotherapy (HDCT) with autologous peripheral blood stem cell transplantation (ASCT) as compared to standard treatment is not defined.Methods Here, we report of HDCT in 35 consecutive adult patients with poor-risk ES or rhabdomyosarcoma (n = 11) and STS (n = 24) undergoing ASCT between July 1992 and March 2003. At a median follow-up of 100.6 months after ASCT, 11 patients are alive, with nine in sustained complete remission (CR) and each one in partial remission (PR) and stable disease. Median overall survival (OS) from ASCT was 17.1 months. Response to pretreatment, Karnofsky index > 80%, R ₀ resection and first-line ASCT were associated with long-term OS (p < 0.05).Conclusion These data indicate that (1) patients achieving a CR or PR following induction, with preserved performance status and R ₀ resection may benefit from ASCT and (2) that this can be an useful therapeutic modality in a subset of patients, in some achieving remarkable responses.     

Synergistic antitumor effect of melatonin with several chemotherapeutic drugs on human Ewing sarcoma cancer cells: potentiation of the extrinsic apoptotic pathway

Abstract:  Ewing sarcoma, the second most frequent bone cancer type, affects mainly adolescents, who have a survival of 50% 5 yr after diagnosis. Current treatments include a combination of surgery, radiotherapy and chemotherapy, which present potential serious side effects. Melatonin, a natural molecule without relevant side effects, has been previously shown to induce cytotoxicity in SK-N-MC cells, a Ewing sarcoma cell line. Here, we found that there is a synergy in the antitumor effect when melatonin (50 μ m –1 m m ) is combined with vincristine at the concentration of 5–10 n m or with ifosfamide at the range of 100 μ m –1 m m . This synergism is due to the potentiation of cell death, particularly to the potentiation of apoptosis, i.e., mainly the extrinsic apoptotic pathway. There is a significant increase in the activation of caspase-3, -8, -9 and Bid when melatonin is combined with vincristine or ifosfamide compared to the individual treatments. Finally, there is also a potentiation of the early free radical production, likely dependent on the extrinsic apoptosis pathway activation, when the drugs are combined with melatonin. Other proteins which are related to this pathway including mitogen-activated protein kinase or protein kinase B/Akt are not involved in apoptosis induced by these agents separately or when combined. The results shown here together with the facts that: (i) no relevant side effects have been reported for melatonin and (ii) melatonin has a cytoprotective effect on noncancer cells, opens the door for a new approach in the treatment of the Ewing sarcoma family of tumors.     

Thymic hyperplasia in adults following chemotherapy for malignancy

Background: The accuracy of the assessment of patients with malignant disease and of their response to chemotherapy has been significantly improved with the routine availability of computerized tomography (CT) scanning. CT abnormalities, however, may be non-specific, especially after chemotherapy. Rebound enlargement of the thymus gland after chemotherapy induced atrophy is one cause of an abnormal thoracic CT scan on re-staging.
Aims: This phenomenon has previously been reported mainly in relation to the treatment of lymphoma and germ cell cancers. This paper highlights the occurrence of thymic hyperplasia after chemotherapy in these and other tumour types.
Methods: We discuss five cases including three patients with malignancies other than lymphoma in whom thymus enlargement occurred during or after intensive chemotherapy.
Results: Clear identification of the nature of CT abnormalities after chemotherapy, particularly in the mediastinum, is required prior to embarking on further anti-cancer treatments. (Aust NZ J Med 1993; 23: 264–267.)     

Quality of life and Q-TWiST were not adversely affected in Ewing sarcoma patients treated with combined anlotinib,irinotecan, and vincristine: (Peking University People's Hospital Ewing sarcoma trial-02, PKUPH-EWS-02)

Background:Combined treatment with anlotinib, irinotecan, as well as vincristine for advanced Ewing sarcoma (EWS) has been verified been effective in the prospective trial of Peking University People''s Hospital EWS trial-02. We aimed to assess the dynamic changes in health-related quality of life (QoL) and the benefit-risk in quality-adjusted survival in current study.Methods:Twelve “pediatric” patients and 23 “adult” patients were enrolled. QoL was assessed with the EORTC QLQ-C30 for adults and PedsQL 3.0 Cancer Module for children and adolescents. The quality-adjusted time without symptoms of disease progression or toxicity of treatment (Q-TWiST) analysis was used to describe treatment results.Results:Progression-free survival was not accompanied by diminished QoL. Differences in scores on the QoL global health status and specific functioning before, during, and after treatment were not significantly different with time (P = .14 for adults and .91 for children). During treatment, there was a statistically insignificant trend towards improved QoL with reduced tumor burden (P = .14 for adults and .10 for children), but QoL significantly declined with progression of disease (P = .05 for adults and .04 for children). The most common adverse events were neutropenia (12.1%), leukopenia (16.6%), anemia (12.7%), and diarrhea (4.93%). Results across the trial analyses showed that the median time of Q-TWiST was 0.73 (interquartile range, 0–1.57) months, whereas the median time with toxicity before disease progression was 3.9 (interquartile range, 2.3, 6.1).Conclusion:QoL exhibited a trend towards improvement in accordance with high objective response in this trial with the receipt of combination therapy of anlotinib, vinsristine, and irinotecan for advanced EWS. The toxicity profile did not translate into significantly worse overall scores during treatment.     

Successful limb salvage in progressive proximal tibia osteosarcoma following denosumab chemotherapy: A case report

Rationale:Osteosarcoma (OS) is a primary malignant bone tumor that originates in the mesenchymal tissue. It is the most common type of pleomorphic tumor occurring in children and adolescents. Currently, there is no established systematic treatment for OS that progresses during standard preoperative chemotherapy.Patient concerns and diagnoses:We describe a 14-year-old male patient with a 4-month history of pain in the upper right leg. Based on the results of percutaneous biopsy, a diagnosis of OS was made. After admission, the patient was treated with first-line chemotherapy agents. After a single course of treatment, the tumor progressed locally and no limb salvage was feasible.Interventions and outcomes:Intervention with denosumab combined with chemotherapy led to a significant reduction in tumor volume and ossification of soft tissue, which successfully resulted in limb salvage rather than amputation. The patient showed no evidence of recurrent or distant metastasis at 6-month follow-up.Lessons:Treatment with receptor activator of nuclear factor-ĸB ligand inhibitor denosumab combined with standard chemotherapy is effective for advanced OS progressing after chemotherapy. We recommend denosumab therapy for successful limb salvage in patients with high-grade OS associated with osteolytic bone destruction and refractory to preoperative neoadjuvant chemotherapy.     

Philadelphia chromosome-positive acute lymphoblastic leukemia secondary to chemoradiotherapy for Ewing sarcoma. Report of two cases and concise review of the literature

Survivors of childhood solid tumors including Ewing sarcoma (ES) have an increased risk of secondary malignant neoplasms (SMNs) as a consequence of exposure to chemotherapy and/or radiation (see: Bhatia S, Sklar C. Nat Rev Cancer 2002;2:124-132). The most common hematologic SMNs are myelodysplasia (MDS) and acute myelogenous leukemia (AML). Acute lymphoblastic leukemia (ALL) is uncommon in this patient population, and Philadelphia chromosome positive (Ph+) ALL in particular, is rare. We report herein two cases of young adult patients who were both diagnosed with Ph+ ALL 19 years after successful treatment for ES with combined modality therapy. A review of the relevant literature follows the case reports.     

Simultaneous inhibition of mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways augment the sensitivity to actinomycin D in Ewing sarcoma

Purpose  Ewing sarcoma cells, of which over 85% retain chimeric fusion gene EWS/Fli-1, are by and large more resistant to chemotherapeutics compared to nonneoplastic cells. The purpose of this study is to determine the role of EWS/Fli-1 fusion and its downstream targets regarding the cells’ resistance against actinomycin D (ActD), which is one of the most commonly used antitumor agents in combination chemotherapy of Ewing sarcomas. Methods  Cytotoxicity was measured by WST-8 assay. Caspase-dependent and -independent cell death was examined by fluorescence microscope. Protein expression was analyzed by western blotting. Caspase activity was determined by Caspase-Glo assay. Results  ActD-induced caspase-dependent apoptotic cell death to Ewing sarcoma TC-135 cells in a dose- and time- dependent manner. Knockdown of EWS/Fli-1 fusion by siRNA resulted in enhancement of ActD-induced apoptosis. ActD treatment activated both mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways although in a distinctive manner. Combined administration of U0126 (MEK inhibitor) and LY294002 (PI3K inhibitor) significantly enhanced ActD-induced apoptosis in vitro and suppressed xenograft tumor growth in vivo. Conclusions  The present study demonstrated for the first time that combination of U0126 and LY294002 can augment the cytotoxicity of ActD against Ewing sarcoma cells in vitro and in vivo. Our results indicate that further study on combination of conventional chemotherapies with MEK and PI3K inhibitors may be considered for innovative treatments of Ewing sarcoma patients.     

The prognostic factors of Ewing sarcoma/peripheral primitive neuroectodermal tumor: A retrospective analysis of 67 patients at a single center

To investigate the characteristics and factors that impact the prognosis of Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/pPNET) patients. We retrospectively analyzed ES/pPNET patients diagnosed at our hospital from January 2011 to December 2020. We used 1-way analysis of variance to investigate whether the age differences between different subgroups were statistically significant and used the Kaplan–Meier method and Cox regression model for the survival analysis. Of the 67 included patients, 13 had central nervous system PNET, and 54 had ES/pPNET. The median survival time of the 54 ES/pPNET patients was 18 months; the 1-year, 3-year and 5-year progression-free survival rates were 37.0% and 9.3% and 1.9%, respectively; and the 1-year, 3-year and 5-year overall survival (OS) rates were 66.7%, 27.8%, and 7.4%, respectively. The 1-way analysis of variance results showed no statistically significant age difference between the different subgroups (P = .127 between the central nervous system PNET and ES/pPNET groups, P = .764 between different subgroups within the ES/pPNET group). The univariate survival analysis showed that metastasis at diagnosis and the treatment method were independent factors affecting the OS rate of ES/pPNET patient (P = .003 and 0.000, respectively). The multivariate survival analysis also showed that the treatment method and metastasis at diagnosis were related factors affecting OS (P = .025 and 0.001, respectively). The prognosis of patients with primitive neuroectodermal tumors is poor. The treatment method and metastasis at the time of diagnosis influences ES/pPNET patient survival time, but there is no significant tumor site-dependent correlation with patient age or sex.     

Pediatric Ewing sarcoma of the rib: role of neoadjuvant chemotherapy in tumoral shrinking and sterilization. A case report

Ewing sarcoma is a rare tumor, which represents, nevertheless, the most common primary chest wall tumor in children. The management and prognosis of these tumors have markedly improved with the use of multimodal therapy including adjuvant chemotherapy, surgery and/or irradiation. A good response to chemotherapy often avoids the need for extensive local treatment without sacrificing local control or long-term survival. Here, we report a new case of a bulky rib Ewing sarcoma, well managed by neoadjuvant chemotherapy resulting in significantly tumor shrinking that allowed complete resection. At the histological examination of the specimen, there was only inflammatory and fibrosis tissues without viable tumoral tissue.     

Spontaneous pneumothorax after chemotherapy for sarcoma with lung metastases: Case report and consideration of pathogenesis

Spontaneous pneumothorax is a rare complication of chemotherapy for lung neoplasm. Herein, we report a case of right spontaneous pneumothorax occurring in a patient in whom lung metastases from synovial cell sarcoma were treated with combination chemotherapy. Chest tube alone was unable to attempt the resolution of air leaks. Thus, it was connected to gentle suction set at minus 15 cm of water which achieved complete re-expansion of the lung with reduction of air leaks. In closure, chemical pleurodesis was attempted using 5 gram of talc diluted in 50 ml normal saline solution instilled into the right pleural cavity via chest tube. The connecting tube was suspended at 30 cm above the level of the patient's chest for one hour and the patient's position was changed at 15 minutes intervals to ensure uniform distribution. At three months of follow-up, the patient had no-recurrence of pneumothorax.     

Clinical therapeutic effects of combined methotrexate and other chemotherapeutic agents in treating children and young patients with osteosarcoma: A protocol for systematic review and meta-analysis

Background:Osteosarcoma is one of the most common primary bone tumour in children and young patients, and the third most common among adults. Its main treatment option is currently based on neoadjuvant or adjuvant chemoradiotherapy along with the lesion''s surgical resection. The current study''s primary aim is to examine the clinical therapeutic impacts of combined methotrexate, along with other chemotherapeutic agents to treat children and young adults suffering from osteosarcoma.Methods:We will perform a comprehensive literature search in English database (PubMed, EMBASE, Cochran Library CINAHL, and PsycINFO) and Chinese database (Chinese National Knowledge Infrastructure, VIP information database, Chinese Biomedical Database, and WanFang Database) with no language restriction from their inception to the search date. Additionally, two independent authors will screen the works of literature obtained from these databases, obtain information, and examine the risks of data included for the studies’ bias. Furthermore, we intend to employ the Q statistics as well as I² statistics to calculate heterogeneity among each study''s analysis. Accordingly, we will utilize the funnel plots and Egger test to assess the possibility of publication bias where relevant.Results:The current study aims to provide significant information regarding the clinical therapeutic impacts of combines methotrexate along with other chemotherapeutic agents to treat children and young adults suffering from osteosarcoma.Conclusions:The present study will generate compelling evidence of combined methotrexate as well as other chemotherapeutic agents for osteosarcoma among children and young adults. Also, it will provide clinical practice suggestions.Ethics and dissemination:The study is founded upon published data. Therefore, there is no requirement for ethics approval.OSF registration number:March 26, 2021.osf.io/a23rc. (https://osf.io/a23rc/)     

Persistent mediastinal mass is not indicative of recurrence after chemotherapy only in paediatric Hodgkin's disease

Most patients with Hodgkin's disease are treated with chemotherapy in conjunction with radiotherapy, but at the end of treatment a residual mass is often present. After combined therapy, it has been assumed that no additional treatment is needed. However, for children treated without radiotherapy, no data exist on the relevance of a residual mediastinal mass to risk of relapse. We report on the findings of follow-up thorax radiographs of a group of 27 children with initial mediastinal involvement, who were treated with chemotherapy only. We conclude that the regression rate of the mediastinal mass was not related to a later recurrence. Regression after chemotherapy without radiotherapy is probably slower than after combined therapy. We consider chest radiograph examinations to be appropriate for the follow-up of tumour regression. When the data were compared with a group of children with Hodgkin's disease without mediastinal involvement, we found that survival was not related to initial mediastinal involvement.     

Thrombotic thrombocytopenic purpura associated with HIV and visceral Kaposi's sarcoma treated with plasmapheresis and chemotherapy

We present a case of a patient who is HIV positive and developed both thrombotic thrombocytopenia purpura and visceral Kaposi's sarcoma (KS) with hemorrhage. This case presents a difficult management problem in that the patient's bleeding originated from KS lesions and did not quickly abate with plasmapheresis therapy despite both clinical and laboratory improvement after 2–4 days. Chemotherapy was initiated on day 13 and the patient's condition improved markedly afterward. We believe the addition of chemotherapy to plasmapheresis hastened the improvement of our patient's thrombotic thrombocytopenic purpura (TTP) and KS-related bleeding. Therefore, under similar conditions, we recommend combining plasmapheresis and chemotherapy at the onset of therapy. Am. J. Hematol. 58:148–149, 1998. Published 1998 Wiley-Liss, Inc.

1 This article is a U.S. Government work and, as such, is in the public domain in the United States of America.

     

An unusual cutaneous lymphoma with B and T cell characteristics showing gallium-67 positive benign thymic hyperplasia following intensive chemotherapy

Abstract This case illustrates two interesting features. Firstly it describes an unusual cutaneous lymphoma in an adolescent girl. This lymphoma showed features of B and T cell lineages with rearrangements of both immunoglobulin heavy chain and T cell /3 chain genes. Secondly it describes the development of gallium-67 citrate (⁶⁷Ga) scan positive benign thymic hyperplasia, 15 months after diagnosis and three months after cessation of intensive chemotherapy. (Aust NZ J Med 1991; 21: 447–450)     

Effect assessment of methotrexate in combination with other chemotherapeutic agents for osteosarcoma in children: A protocol for systematic review and meta-analysis

Background:Osteosarcoma is a primary form of malignant bone tumor. It is commonly prevalent among children. Treating osteosarcoma with chemotherapy has had limited clinical outcomes due to side effects and the formation of drug resistance. Presently, a mixture of doxorubicin, cisplatin, ifosfamide, epirubicin methrotrexate, and other supplementary medications are used in osteosarcoma chemotherapy. Therefore, this study aims to investigate the clinical therapeutic effects of combining methotrexate with other chemotherapeutic agents to treat osteosarcoma in children.Methods:The search of several electronic databases will lead to source related published studies. The electronic databases include both English (PubMed, EMBASE, Web of Science, and the Cochrane Library) and Chinese (China National Knowledge Infrastructure, WanFang, and China Biomedical Database) databases. All studies published from inception to November 19, 2020 are searched. Study selection, extraction of data, and evaluation of the bias risk in included studies are carried out by two authors independently. The software, RevMan 5.3, is used to analyze the data.Results:This study provides evidence of substantial quality for the clinical therapeutic effects of methotrexate combined with other chemotherapeutic agents for treating osteosarcoma in children.Conclusion:The results of this study provide conclusive evidence with regards to the clinical application of methotrexate combined with other chemotherapeutic agents for treating osteosarcoma in children.Ethics and dissemination:Since this study will use published data, ethical approval is not required.Systematic review registration number:This protocol has been registered on INPLASY202110024.     

Cytotoxic chemotherapy following tandem autotransplants in multiple myeloma patients

High-dose treatment (HDT) with autologous stem cell transplant (ASCT) is superior to conventional chemotherapy in multiple myeloma. However, relapses eventually occur, especially in the presence of unfavourable cytogenetic abnormalities, high beta-2 microglobulin levels prior to transplant and extensive prior treatment. Cytotoxic consolidation chemotherapy, following tandem transplants (TT), was given to 75 myeloma patients with at least one poor prognostic factor. When their outcome was compared with that of 75 matched controls who received dexamethasone +/- interferon post TT, no event-free or overall survival advantage was observed. Other approaches may be required to improve survival in multiple myeloma.     

High-dose methotrexate treatment and liver function in patients with osteosarcoma

Abstract. Objectives. To study the effects of short-term high-dose methotrexate therapy on liver function in patients with osteosarcoma. Design. Open prospective study. Setting. Department of Internal Medicine and Oncology. Istituto Ortopedico Rizzoli, Bologna, Italy. Subjects. Fourteen patients with osteosarcoma, with no evidence of previous or actual liver disease at the time of diagnosis. Interventions. All patients received a cumulative dose of 30–57 gm^?2 of methotrexate within 6 months as neo-adjuvant chemotherapy (pre- and post-surgery). Each course of chemotherapy included methotrexate at a dose of 8–12 g m^?2 and, in addition, adriamycin and cisplatinum. Main outcome measures. Galactose elimination capacity and antipyrine clearance were measured at baseline, after the first course of chemotherapy, at the end of the pre-operative period and at the end of chemotherapy. In each case they were carried out after transaminase levels had returned to normal. Results. Galactose elimination capacity decreased from 2.45 (±0.48) mM min^?1 to 2.04 (±0.60) mM min^?1 after the five planned courses of chemotherapy (P = 0.013, Wilcoxon signed-rank test), without any change in routine liver function tests. No differences in antipyrine clearance and half-life were demonstrated (n = 8). Conclusions. The data are consistent with a decreased reserve capacity of the liver after short-term, high-dose methotrexate. Long-term survivors deserve monitoring of liver function for safer methotrexate use, in the light of progressive dosage increments to improve prognosis in neoplastic diseases.     

Characteristics,management, and outcomes of patients with follicular dendritic cell sarcoma

Dendritic cell sarcomas are rare tumours of antigen presenting cells. Data regarding their biology, management and outcomes are sparse. We analysed 66 patients with follicular dendritic cell sarcoma (FDCS). Six patients also had Castleman disease, 9 had another malignancy and 13 had an autoimmune disease. Fifty‐four per cent of patients presented with localized disease and 46% with systemic involvement. The median progression‐free (PFS) and overall survival (OS) following frontline therapy was 21 and 50 months, respectively. Survival outcomes were significantly inferior in patients with extranodal, bulky or intra‐abdominal disease at presentation. Stage was not associated with survival. Management approaches were heterogeneous. Patients who underwent an upfront gross total resection (GTR) experienced better PFS and OS (both P < 0·0001). In patients who underwent a GTR, consolidative radiotherapy was associated with improved local control (P = 0·03), PFS (P = 0·04) and OS (P = 0·05). In patients with measureable disease, gemcitabine with a taxane yielded an overall response rate of 80%. The pattern of relapse was predominantly locoregional. Salvage rates after recurrence were poor. Studies are underway at our institution to define the genomic profile in FDCS and identify potential novel therapeutic targets.