Myeloablative therapy against high risk Ewing's sarcoma: A single institution experience and literature review

Background

Attempts to improve survival outcomes of patients with high risk Ewing''s sarcoma (ES) have focused on chemotherapy dose intensification strategies.

Aim

The objective of this study is to retrospectively evaluate clinical characteristics and outcome of pediatric patients with high risk ES treated at a single institution.

Materials and methods

From 1995 to 2008, seventeen patients (male:female, 14:3) were treated with dose-intensive therapy in our institution. Median age at diagnosis was 10 years (range: 2–15). Seven patients had metastases at diagnosis (lung in 6 cases and bone in one case). Eleven patients presented with unresectable disease. Fifteen (88.2%) received the Spanish Society of Pediatric Oncology protocol which includes six cycles of vincristine, doxorubicin, ifosfamide and etoposide. Two out of the six cases that were resectable received postoperative radiation. In addition, eleven patients received definitive radiation therapy. Finally, twelve (70.5%) out of 17 patients received myeloablative therapy with melphalan/etoposide. The rest of patients (N = 5) received busulfan/melphalan.

Results

Median follow-up was 78 months (range: 15–155 months). Initial responses were complete in all patients, but 9 of them developed progression disease. Seven patients became long-term event-free survivors. No patient died of toxicity after transplantation. The 2- and 5-year overall survival rates for all patients were 93% and 73%, respectively. Event-free survival rates were 74% and 54% at 2 and 5 years, respectively.

Conclusion

This single-institution experience suggests that myeloablative therapy against high risk ES is effective and safe.     

A Phase II Clinical Trial of Concurrent Helical Tomotherapy plus Cetuximab Followed by Adjuvant Chemotherapy with Cisplatin and Docetaxel for Locally Advanced Nasopharyngeal Carcinoma

Purpose: The present clinical trial was designed to evaluate the efficacy and safety of concurrent helical tomotherapy (HT) with cetuximab followed by adjuvant chemotherapy with docetaxel and cisplatin (TP) in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma.Materials and Methods: This phase II clinical trial included 43 patients with Stage III/IV LANC (33 Stage III and 10 Stage IV). The treatment consisted of concurrent HT with cetuximab (400 mg/m² loading dose and weekly 250mg/m²), followed by four cycles of chemotherapy [docetaxel (70 mg/m² on Day 1) and cisplatin (40 mg/m² on Days 1 and 2 every 3 weeks). Side effects were evaluated with CTCAE criteria (Common Terminology Criteria for Adverse Events 3.0).Results: The median follow-up duration was 48.0 months [95% confidence interval (CI) 41.7-58.0 months], the 2-year locoregional failure-free rate (LFFR), progression-free survival (PFS), distant failure-free rate (DFFR) and overall survival (OS) were 95.2%, 79.1%, 88.1% and 93.0% respectively; the 3-year LFFR, DFFR, PFS and OS were 92.7%, 85.6%, 72.0% and 85.7% respectively. The most common grade 3 toxicities were oropharyngeal mucositis (81.4%) and RT-related dermatitis (7.0%). No patients had more than grade 3 radiation related toxicities and no patients required nasogastric feeding. One patient experienced grade 3 osteonecrosis at 18 months after treatment.Conclusions: Concurrent HT with cetuximab followed by adjuvant chemotherapy with TP is an effective strategy for the treatment of LANC with encouraging survival rates and minimal side effects.     

131I]metaiodobenzylguanidine and high-dose chemotherapy with bone marrow rescue in advanced neuroblastoma.

High-dose chemotherapy (HDT) and autologous bone marrow rescue (ABMR) is routinely used as consolidation treatment in advanced neuroblastoma. This study is presently examining the efficacy and toxicity of combined [131I]metaiodobenzylguanidine (131I-MIBG) therapy with HDT and ABMR. Five children (4 male, 1 female), median age of 8 years (range 4-11 years) were treated, 3 at relapse and 2 after initial chemotherapy. A single infusion of 131I-MIBG (median activity 11.1 GBq, range 7.4-11.2 GBq) was followed by HDT and ABMR 14-32 days later. High-dose chemotherapy consisted of carboplatin and melphalan in 4 patients, and vincristine, etoposide, carboplatin and melphalan in 1. One patient developed a septicaemia and died, and another failed to engraft; both had extensive bone marrow infiltration at the time of 131I-MIBG therapy. The combined therapy was well tolerated by the three other patients. Two children have relapsed and died (including one who failed to engraft), and 2 are alive 17 and 41 months after ABMR. In the absence of extensive bone marrow metastases, combined therapy offers potential as a means of consolidating treatment in advanced neuroblastoma.     

Rhabdomyosarcoma: cytogenetics of five cases using fine-needle aspiration samples and review of the literature

Cytogenetic analyses of fine-needle aspiration samples were performed on five cases of which three were alveolar rhabdomyosarcomas (RMS), one was embryonal RMS and one was RMS of mixed alveolar and embryonal histology. Three cases of alveolar RMS and one case of embryonal RMS showed t(2;13). A del(1)(p11) in a mixed alveolar and embryonal RMS was observed without the presence of t(2;13). add(17)(q25) was present in one of the alveolar RMS along with a t(2;13). Modal number of chromosome in the five cases ranged from hyperdiploid to hypertetraploid. Clinical, cytological, histopathological and cytogenetic findings are correlated. The role of additional abnormalities is discussed with a review of appropriate literature.     

Continued Tumor Reduction of Metastatic Pheochromocytoma/Paraganglioma Harboring Succinate Dehydrogenase Subunit B Mutations with Cyclical Chemotherapy

Patients harboring germline mutations in the succinate dehydrogenase complex subunit B (SDHB) gene present with pheochromocytomas and paragangliomas (PPGL) that are more likely malignant and clinically aggressive. The combination chemotherapy cyclophosphamide, vincristine, and dacarbazine (CVD) was retrospectively evaluated in patients with SDHB-associated metastatic PPGL.Query Twelve metastatic PPGL patients harboring SDHB mutations/polymorphisms with undetectable SDHB immunostaining were treated with CVD. CVD therapy consisted of 750 mg/m² cyclophosphamide with 1.4 mg/m² vincristine on day 1 and 600 mg/m² dacarbazine on days 1 and 2, every 21–28 days. Treatment outcome was determined by RECIST criteria as well as determination of response duration and progression-free and overall survivals. A median of 20.5 cycles (range 4–41) was administered. All patients had tumor reduction (12–100% by RECIST). Complete response was seen in two patients, while partial response was observed in 8. The median number of cycles to response was 5.5. Median duration of response was 478 days, with progression-free and overall survivals of 930 and 1190 days, respectively. Serial [¹⁸F]-fluorodeoxyglucose positron emission tomography and computed tomography imaging demonstrated continued incremental reduction in maximal standardized uptake values (SUV_max) values in 26/30 lesions. During treatment administration, the median SUV decreased from?> 25 to?< 6, indicating the efficacy of chemotherapy over a prolonged period of time. Prolonged therapy results in continued incremental tumor reduction, and is consistent with persistent drug sensitivity. CVD chemotherapy is recommended to be considered part of the initial management in patients with metastatic SDHB-related PPGL.     

Chimiothérapie des tumeurs germinales du testicule

Germ cell tumours of the testis represent a model of curable disease, even in advanced stages. Cisplatinbased combination chemotherapy followed by surgical removal of residual metastatic disease has dramatically improved the prognosis of these patients, as about 90% of them are currently cured. The standard cytotoxic drugs used in first-line treatment are bleomycin, etoposide and cisplatin (the so-called BEP regimen). Treatment strategy is based on assessment of risk factors. Three cycles are generally used in patients with advanced pure seminoma or good-risk metastatic non-seminomatous tumours. Four cycles are required in patients with intermediate-or poor-risk metastatic non-seminomatous tumours, while two cycles of BEP constitute a safe and effective treatment option in early-stage tumours but with a high-risk of metastatic spread defined by a high percentage of embryonal carcinoma and/or the presence of vascular invasion. Cure rates as high as 90% are achieved provided risk factor strategies are accurately applied and standard treatment modalities are respected. All protocol violations can decrease the expected efficacy or induce unnecessary toxicity.     

多西紫杉醇联合适形放疗治疗老年贲门癌患者的疗效观察

目的:探讨周剂量多西紫杉醇联合三维适形放疗(3DCRT)治疗进展期贲门癌患者的疗效。方法:2007年10月到2009年5月38例不能手术的贲门癌患者行3DCRT,处方剂量62Gy,1.8Gy/次,5次/周;同时联合多西紫杉醇75mg/m2,每周1次,连续6周。用Kaplan-Meier法分析患者的中位无进展生存时间。结果:完全缓解12例,部分缓解18例,30名患者缓解(78.9%),中位无进展生存时间16.4个月。治疗过程中的毒副作用轻,患者可以耐受。结论:周剂量多西紫杉醇化疗联合适形放疗对进展期贲门癌患者是安全、有效的。     

Erythropoietic protein supportive treatment in small cell lung cancer

Anemia is common among patients with malignant tumors, due to the disease and chemotherapy. Anemia decreases patient's quality of life, and worsens the dose intensity of chemotherapy. The aim of this retrospective data-analysis was to determine the rate of transfusions and the maintenance of chemotherapeutic dose intensity in 9 small cell lung cancer patients receiving beta-erythropoietin, due to anemia observed after the first cycle of chemotherapy. The mean pre-treatment hemoglobin concentration of the patients was 116.67+/-8.17 g/L (mean+/-SD). The mean pre-erythropoietin hemoglobin concentration at baseline was 103.11+/-7.52 g/L. Six cycles of platinum compounds and etoposide were used. The post-treatment hemoglobin concentration of patients was 110.11+/-5.37 g/L (p = 0,028 vs. baseline). During these 54 chemotherapeutic cycles, only 2 patients needed transfusion, each of them once. According to our experience, the use of beta-erythropoietin in 9 anemic small cell lung cancer patients resulted in a low rate of transfusions and maintenance of cytotoxic treatment dose intensity. The adequate use of beta-erythropoietin is of great help to the physician in the management of small cell lung cancer patients.     

Comparison of efficacy of different route of administration of chemotherapy on unresectable, advanced gastric cancer

ABSTRACT: BACKGROUND: The aim of this study was to compare the efficacy of two neoadjuvant chemotherapies (FLEEOX and XELOX) with different routes of administration for unresectable gastric cancer. METHODS: A total of 85 patients with unresectable gastric cancer hospitalized from January 2007 to December 2009 received neoadjuvant chemotherapy. The FLEEOX group (48 patients) received the FLEEOX regimen(fluorouracil, leucovorin, epirubicin, epotoside, and oxaliplatin), which combined arterial with venous administration for one or two cycles, while the XELOX group (37 patients) received XELOX (capecitabine plus oxaliplatin) via venous administration for two to four cycles. The clinical response and overall survival of the two groups were compared. RESULTS: In the FLEEOX group, the clinical response rate (RR) of chemotherapy was 85.4% (41 of 48 patients) and the median survival time was 25 months. The 1-year and 2-year disease-free survival (DFS) rates were 85.4% and 45.8%, respectively. In the XELOX group, the clinical RR was 59.5% and the median survival time was 9 months, while the 1-year and 2-year survival rates were 35.2% and 8.3%, respectively. The clinical RR, the R0 resection rate, the median survival time, and the 1-year and 2-year DFS rates were significantly better (P <0.05) in the FLEEOX group than in the XELOX group. In addition, there were no significant differences in the rates of toxic and adverse reactions or post-operative complications between the two groups. CONCLUSIONS: For patients with a preoperative diagnosis of unresectable gastric cancer, the efficacy of the FLEEOX regimen, which combines arterial with venous administration, was better than that of the XELOX regimen, using venous administration only. This combination of arterial and venous administration could be useful for improving the efficacy of neoadjuvant chemotherapy for gastric cancer.     

Value of image cytometry in the subclassification of rhabdomyosarcoma

OBJECTIVE: To test the discriminatory capability of nuclear features in the subclassification of rhabdomyosarcoma (RMS) and especially to differentiate embryonal from alveolar RMS. STUDY DESIGN: The study included 42 patients with RMS. We performed the analysis on Feulgen-stained filtrates of cell suspensions prepared from deparaffinized tissue sections. Image analysis was performed by an automated, high-resolution image cytometer on at least 200 nuclear images. Photometric, morphometric and nuclear texture features were analyzed. Probability density distributions were calculated for each nuclear feature of individual RMS subgroups and compared in order to detect possible differences. RESULTS: There were significant differences between embryonal and alveolar RMS in five nuclear features: DNA index, sphericity, elongation, low_DNA_area and fractall_area. We were able to differentiate between the two main RMS subgroups in 82% of cases on the basis of either sphericity or elongation alone, while the power of differentiation for texture features was 72-79%. CONCLUSION: Differentiation between embryonal and alveolar RMS using one nuclear feature is not an important adjunct to light microscopy. However, the possibility of using a combination of nuclear features would probably increase the discriminatory ability.     

Disseminated Cryptococcosis in a Non-Hodgkin’s Lymphoma Patient with Late-Onset Neutropenia Following Rituximab-CHOP Chemotherapy: A Case Report and Literature Review

Rituximab-related late-onset neutropenia (R-LON) is an adverse event associated with rituximab. A 65-year-old woman presented with diffuse large B-cell lymphoma of the kidney without bone marrow involvement. She was treated with 4 cycles of CHOP chemotherapy consisting of doxorubicin, cyclophosphamide, vincristine, and prednisolone at 4-week intervals. Rituximab was also administrated of the second, third, fourth CHOP cycles. She developed a high fever of 38°C, nausea, and severe neutropenia following the four cycles of R-CHOP chemotherapy. Her leukocyte count was 160/μl without neutrophils. Initially, a blood and pleural fluid and cerebrospinal fluid cultures were positive for Cryptococcus neoformans. Once she became asymptomatic following treatment with fluconazole and neutropenia was recovered with lenograstim, she had neck stiffness and admitted soon. Cerebro-spinal fluid (CSF) culture was positive for Cryptococcus neoformans. Treatment with amphotericin B(AMPH-B) and flucytosine(5-FC) was initiated as diagnosis of cryptococcus meningitis. Lenograstim was administrated for 9 months, and amount of dose was 9,750 μg. Cryptococcosis with malignant lymphoma is rare disease, and previously 17 cases were reported. Of note, mortality of disseminated cryptococcosis with malignant lymphoma is 54%. The more and more rituximab is widely used; the cases of severe infection in R-LON may increase.     

Differential expression of Snail1 transcription factor and Snail1-related genes in alveolar and embryonal rhabdomyosarcoma subtypes

Rhabdomyosarcoma (RMS) represents the most common sarcoma of soft tissue among children. Two main RMS subtypes are alveolar (ARMS) and embryonal (ERMS). The major goal of this study was to find differentially expressed genes between RMS subtypes that could explain higher metastatic potential in ARMS and would be useful for the differential diagnosis. Using RQ-PCR analysis we compared expression of Snail1 and Snail-related genes among 7 ARMS and 8 ERMS patients' samples obtained from the primary tumors and among 2 alveolar and 2 embryonal cell lines. Our results show that Snail1 is highly expressed both in ARMS patients' samples and the alveolar cell lines. We also found that the expression of E-Cadherin was downregulated and the expression of Matrix Metalloproteinases 2 and 9 (MMP-2 and MMP-9) was upregulated in ARMS. We assume that, as in many tumors, also in RMS Snail1 acts as a regulator for pathways known for their role in cells' metastasis and that Snail1 activity results in increased MMPs and decreased E-Cadherin expression. Our findings may explain higher ARMS aggressiveness. Moreover, we suggest that further studies should be performed to verify if Snail1 can be considered as a potential target for ARMS therapy.     

Amplification of CDK4, MDM2, SAS and GLI genes in leiomyosarcoma, alveolar and embryonal rhabdomyosarcoma

We evaluated amplification and overrepresentation of CDK4, MDM2, GLI and SAS genes of the 12q13-15 region, in a group of soft tissue sarcomas including leiomyosarcomas (LMS), alveolar rhabdomyosarcomas (ARMS) and embryonal (anaplastic and classic variants) rhabdomyosarcomas (ERMS), to ascertain genomic alterations and possible differences within histologic subtypes of rhabdomyosarcoma (RMS). Quantitative real-time PCR was performed on DNA samples from 29 LMS, 9 ARMS, 7 anaplastic ERMS and 6 classic ERMS. Alteration of one or more of the 12q13-15 genes was revealed in 13/29 LMS (45%) and 12/22 RMS (54%) including 5/9 ARMS (56%), 5/7 anaplastic ERMS (71%) and 2/6 classic ERMS (33%). The potential importance of overproduction of protein products in neoplastic development, led us also to study a possible high expression of cdk4, mdm2 and gli proteins in immunohistochemical staining experiments on paraffin-embedded tissue samples of the same cases. Among LMS and RMS most cases with CDK4, MDM2 and GLI gene alterations also showed a simultaneous high expression of the relative protein. In summary, these results indicate that amplification or overerepresentation of genes at 12q13-15 region involve both LMS and RMS. Moreover these genes alterations reveal predominantly in the alveolar and in the anaplastic variant of the embryonal subtype. These two seem to have a more similar behavior than anaplastic and classic embryonal that are classified in the same subtype.     

A novel predictive model for idiopathic multicentric Castleman disease: the internatiman disease consortium study

Castleman disease (CD) is a rare and heterogeneous disease whose treatment options and prognosis vary with clinical types. Multicentric Castleman disease (MCD) is characterized by poor prognosis, and effective treatment options are still being explored. This study aimed to determine whether the E-COD (E: etoposide 50 mg/m²/d, d1–3; C: phosphoramide 750 mg/m², d1, d3; O: vincristine 2 mg, d1; D: dexamethasone 10 mg/d, d1–5) regimen is effective in treating human herpesvirus-8 (HHV-8)-negative MCD. A group of patients diagnosed with MCD at Shengjing Hospital of China Medical University were treated with E-COD regimen. The effectiveness evaluation was conducted after four treatment cycles and follow-up for survival. A total of 101 patients were included in this study from January 2003 to December 2021, of whom 29 patients had HHV-8 negative MCD subtype. Seven HHV-8 negative MCD patients received four courses of E-COD chemotherapy. The complete response, partial response, and stable disease were 14.3%, 71.4%, and 14.3%, respectively. The follow-up ended on June 1, 2021. Two patients died, and five patients survived, with a survival period ranging from 2 to 11 years. This study suggests that the E-COD regimen is a safe, efficient, and affordable therapy option for HHV-8 negative MCD patients.     

Combined Use of Anticancer Drugs and an Inhibitor of Multiple Drug Resistance-Associated Protein-1 Increases Sensitivity and Decreases Survival of Glioblastoma Multiforme Cells In Vitro

Glioblastoma multiforme (GBM) is a brain tumour characterised by a remarkably high chemoresistance and infiltrating capability. To date, chemotherapy with temozolomide has contributed only poorly to improved survival rates in patients. One of the most important mechanisms of chemoresistance comes about through the activity of certain proteins from the ATP-binding cassette superfamily that extrudes antitumour drugs, or their metabolites, from cells. We identify an increased expression of the multiple drug resistance-associated protein 1 (Mrp1) in glioblastoma multiforme biopsies and in T98G and G44 cell lines. The activity of this transporter was also confirmed by measuring the extrusion of the fluorescent substrate CFDA. The sensitivity of GBM cells was low upon exposure to temozolomide, vincristine and etoposide, with decreases in cell viability of below 20% seen at therapeutic concentrations of these drugs. However, combined exposure to vincristine or etoposide with an inhibitor of Mrp1 efficiently decreased cell viability by up to 80%. We conclude that chemosensitization of cells with inhibitors of Mrp1 activity might be an efficient tool for the treatment of human GBM.     

Effect of combination of renin inhibitor and Mas-receptor agonist in DOCA–salt-induced hypertension in rats

To investigate the combined effect of aliskiren, a renin inhibitor, and AVE 0991, a Mas-receptor agonist, in experimental hypertension (HT) in rats. HT was produced by administration of deoxycorticosterone acetate (DOCA) and mean arterial blood pressure (MABP) was assessed by tail-cuff method. Treatments were started from 4th week onwards and were continued for 9 days. A significant increase in MABP was noted after 1 week in DOCA control rats, as compared with the base line value. A stable HT developed after 4 weeks of DOCA administration. Treatments with aliskiren and AVE 0991 alone, dose-dependently decreased MABP in DOCA-treated rats. Further, combination of low doses of aliskiren and AVE 0991 significantly reduced MABP, as compared with DOCA control rats and with either drug alone in low doses. It may be concluded that treatment with aliskiren produced down-regulation of both harmful Ang II–AT1-receptor and survival Ang(1–7)/Mas-receptor axis of RAAS. Treatment with combination of low doses of aliskiren and AVE 0991, for the first time, has been shown to produce synergistic blood pressure lowering effect. Therefore, combination of renin inhibitor with Mas-receptor agonist may prove beneficial for the treatment of hypertensive patients.     

氟西汀联合同步放化疗治疗局部晚期非小细胞肺癌的临床观察

目的：观察氟西汀联合同步放化疗治疗局部晚期非小细胞肺癌（none small cells lung carcinoma,NSCLC）的临床疗效及其安全性。方法：选择2010年10月～2011年4月我院收治的III期不能手术的NSCLC患者47例,根据患者的入院顺序,随机分为两组,同步放化疗组（对照组）22例,接受三维适形或调强放疗：肿瘤处方剂量60~66Gy,常规分割：1．8～2．0Gy／次;放疗期间同步两周期“紫杉醇＋顺铂”方案化疗,放疗后再原方案巩固化疗2--3个周期;氟西汀联合治疗组（实验组）25例,从同步放化疗开始起同时服用氟西汀（20-40mg／day）,持续服药半年。随访至1年,观察和评价两组的疗效以及不良反应的发生情况。结果：对照组与实验组的客观有效率分别为77-3％（17／22）和80％（20／25）（P〉0．05）;1年生存率分别为68．2％（15／22）和80％（20／25）（P〉0．05）;1年局控率分别为45．5％（10／22）和76％（19／25）,差异有统计学意义（P〈0．05）。治疗后,实验组患者CD＋／CD8＋比率由1．34±0．23升至1．58±0．22（P〈0．05）,而汉密尔顿抑郁量表（HAMD）总分由13．4±4．8降至9．6±3（P〈0．05）;全组患者主要不良反应为骨髓抑制、消化道反应、放射性食管炎和放射性肺炎,来发生4级不良反应,两组3级不良反应发生率无明显差异（P〉0．05）。结论：对于不能手术的局部晚期NSCLC患者,在同步放化疗的基础上联合氟西汀治疗可以提高肿瘤的1年局控率,促进抗肿瘤免疫,并缓解患者的抑郁情绪,且不加重不良反应。     

Daunomycin, cytosin-arabinoside and VP-16 (DAV) for myeloid blast crisis of CML

Nine patients with myeloid blast crisis of Philadelphia chromosome-positive chronic myelocytic leukemia received 1-3 courses of intensive induction chemotherapy with DAT (daunomycin, cytosin-arabinoside and 6-thioguanin) or DAV (daunomycin, cytosin-arabinoside and VP-16). Eight patients responded with clearing of blasts from peripheral blood giving a response rate of 89%. However, bone marrow aplasia with less than 5% blasts was seen in only 2 patients. These 2 patients subsequently received an allogeneic bone marrow transplant and achieved complete remissions of 3 and 6 month duration. All patients died due to progression of blast crisis. Median survival of the group was 164 days. These results were compared to a historical control group of 31 patients with myeloid blast crisis treated with vincristine and prednisone. Despite a significantly better response rate with DAV or DAT (8 of 9 versus 9 of 31, p = 0.01) survival was not significantly different than that of the control group.     

Defective myogenic differentiation of human rhabdomyosarcoma cells is characterized by sialidase Neu2 loss of expression

Sialidase Neu2 is a glycohydrolytic enzyme whose tissue distribution has been detected principally in differentiated skeletal muscle. In this study we show that Neu2 expression is absent in different embryonal and alveolar human tumor rhabdomyosarcoma (RMS) cells, which are genetically committed myoblasts characterized by delayed differentiation. Forced myogenic differentiation of an embryonal RMS cell line, as obtained via pharmacological and genetic p38 activation or via follistatin overexpression, was characterized by Neu2 loss of expression despite the significant rise of different muscle-specific markers, suggesting therefore that the defective myogenic program of RMS cells is accompanied by Neu2 suppression.