环磷酰胺联合羟基喜树碱二线治疗进展期尤文肉瘤的临床观察

目的探讨环磷酰胺(CTX)联合羟基喜树碱(HCPT)二线治疗进展期尤文肉瘤的疗效和不良反应。方法收集一线化疗失败的进展期尤文肉瘤患者27例,给予CTX联合HCPT治疗,具体为:CTX 0.6g/m2静推,d1;HCPT 6mg/m2静滴,d1～d5,21天为1周期。观察患者的疗效和不良反应。结果 27例患者均可评价疗效及不良反应。全组患者获CR 2例(7.4%),PR 6例(22.2%),SD 14例(51.9%),PD 5例(18.5%),有效率为29.6%(8/27),疾病控制率为81.5%(22/27)。主要不良反应为骨髓抑制、胃肠道反应和脱发。所有患者随访5～24个月,无进展生存期(PFS)为3～10个月,中位PFS为7个月;总生存期(OS)为5～18个月,中位OS为11个月;1年生存率为48.1%。至2010年11月死亡9例,无化疗相关性死亡,无瘤生存2例,带瘤生存16例。结论进展期尤文肉瘤患者一线化疗失败后用CTX联合HCPT二线治疗能够有效控制肿瘤进展,不良反应可以耐受,值得进一步深入研究。     

Combination therapy of a solid murine tumor with cyclophosphamide and radiation: The effects of time,dose and assay method

The combined effects of Cyclophosphamide (CY) and radiation on the EMT6/SF tumor growing subcutaneously in mice were studied using both the growth delay assay and an in vitro assay. When drug was given between 48 hr before and 48 hr after radiation, cyclic variations in response were seen with the in vitro assay, e.g. the response was always greater when drug was given 1 or 8 hr compared with 4 hr after irradiation, Combined CY and radiation using doses which reduced survival to approx. 10% when each agent was given alone (120 mg/kg CY and 800 rad) produced slight potentiation at some time intervals. With the growth delay assay at these doses apparent potentiation was seen but which was probably due to the slower regrowth rate of tumors after combined treatment. No potentiation was seen with either assay when a lower drug dose (50 mg/kg) was used. Potentiation was seen with the growth delay assay, however, when larger doses were used (150 mg/kg CY, 1500 or 2000 rad X-rays), indicating a marked dose dependence for potentiation.     

Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients

BACKGROUND

A long‐term follow‐up was conducted of 18 patients with a diagnosis of pheochromocytoma/paraganglioma treated with a combination of cyclophosphamide, vincristine, and dacarbazine (CVD).

METHODS

The study design was a nonrandomized, single‐arm trial conducted at a government medical referral center. Eighteen patients with metastatic malignant pheochromocytoma/paraganglioma were studied. After controlling symptoms of catecholamine excess, patients were treated with cyclophosphamide at 750 mg/m², vincristine at 1.4 mg/m², and dacarbazine at 600 mg/m² on Day 1 and dacarbazine at 600 mg/m² on Day 2, every 21 to 28 days.

RESULTS

Combination chemotherapy with CVD produced a complete response rate of 11% and a partial response rate of 44%. Median survival from a landmark was 3.8 years for patients whose tumors responded to therapy and 1.8 years for patients whose tumors did not respond (P = .65). All patients with tumors scored as responding reported improvement in their symptoms related to excessive catecholamine release and had objective improvements in blood pressure. CVD was well tolerated with only grade I/II toxicities.

CONCLUSIONS

Combination chemotherapy with CVD produced objective tumor responses in patients with advanced malignant pheochromocytoma/paraganglioma. In this 22‐year follow‐up there was no difference in overall survival between patients whose tumors objectively shrank and those with stable or progressive disease. However, patients reported improvement in symptoms, had objective improvements in blood pressure, and had tumor shrinkage that made surgical resection possible. The authors conclude that CVD therapy is not indicated in every patient with metastatic pheochromocytoma/paraganglioma, but should be considered in the management of patients with symptoms and where tumor shrinkage might be beneficial. Cancer 2008. © 2008 American Cancer Society.     

Reduction of cyclophosphamide bioactivation by thioTEPA: critical sequence-dependency in high-dose chemotherapy regimens

Purpose: Cyclophosphamide and thioTEPA are frequently used simultaneously in high-dose chemotherapy regimens. During a pharmacokinetic study of 31 courses in 20 patients of cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide given in the combination cyclophosphamide–thioTEPA–carboplatin, a sharp decrease in 4-hydroxycyclophosphamide concentration was observed immediately after the start of the thioTEPA infusion. A drug-drug interaction was suspected. This putative interaction was investigated in this study. Methods: Possible sequence dependency, due to inhibition of the formation of 4-hydroxycyclophosphamide by thioTEPA, was investigated by altering the sequence of infusion in three patients (four courses) receiving high-dose chemotherapy with cyclophosphamide (1000 or 1500 mg/m² per day), thioTEPA (80 or 120 mg/m² per day) and carboplatin (265 or 400 mg/m² per day) in short infusions for four consecutive days. The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide were established. Possible inhibition of the metabolism of cyclophosphamide and thioTEPA was investigated in human microsomes. Results: A striking sequence dependency of the pharmacokinetics of 4-hydroxycyclophosphamide was observed. Administration of thioTEPA 1 h prior to cyclophosphamide resulted in decreased C_max (−62%) and AUC (−26%) values of 4-hydroxycyclophosphamide compared to those of thioTEPA administered 1 h after cyclophosphamide. In human microsomes an inhibition of the conversion of cyclophosphamide to 4-hydroxycyclophosphamide by thioTEPA was observed at clinically relevant concentrations with an IC₅₀ of 23 μM. No inhibition of the formation of TEPA by cyclophosphamide was observed. Conclusions: ThioTEPA strongly inhibits the bioactivation of cyclophosphamide and this may decrease both efficacy and toxicity. Our results seriously question the practice of the simultaneous continuous infusion of cyclophosphamide and thioTEPA and suggest that the sequencing and scheduling of these two agents in high-dose chemotherapy regimens may be of critical importance. Received: 31 January 2000 / Accepted: 10 April 2000     

Periosteal osteosarcoma--a European review of outcome

Periosteal osteosarcoma is a rare primary malignant bone tumour. Treatment is by surgical excision, but controversy remains about the value of chemotherapy. The members of the European Musculo Skeletal Oncology Society (EMSOS) collaborated to produce a dataset of 119 patients. The predominant site for the tumour was the femur, followed by the tibia. All but 2 patients underwent surgery, with 9 requiring amputation and the others having limb salvage. A total of 81 patients had chemotherapy, of whom 50 had neoadjuvant chemotherapy. There was no standard chemotherapy regime, but all patients receiving chemotherapy were given doxorubicin combined with at least one other agent. The overall survival was 89% at 5 years and 83% at 10 years. Eight patients developed local recurrence, of whom 5 died. Survival was related to appearance of local recurrence (P < 0.0001) but no other single factor. The use of chemotherapy was not shown to be a prognostic factor, but was used in two-thirds of the patients in this study.     

Lung cancer treatment with high cyclophosphamide doses versus high cyclophosphamide doses plus radiotherapy.

Sixty-six evaluable male patients with a histologically proved inoperable lung cancer, with a Karnofsky's score ≥30, were considered for study. The mean age was 57.2 (range 20–74) years. Tumor cell types were of epidermoid carcinoma 50, adenocarcinoma 6, undifferentiated small cell carcinoma 5, and undifferentiated large cell carcinoma 5. Fifty patients had limited disease and 15 had extensive disease. They were treated with combined modality therapy Cyclophosphamide (CY) 50 mg/kg body weight, administered into the tubing of a freely running intravenous infusion of 5% dextrose every 10–12 days, followed by radiation therapy with ⁶⁰Co, 6000 rad and then, with CY 17 mg/kg body weight every 15 days until progression (ChRCh group). The control group (Ch) of 31 patients was treated with CY 50 mg/kg body every 10/12 days. Complete response was achieved in $\text{3}\text{35}$ patients and partial response in $\text{15}\text{35}$ patients of the ChRCh group. In the control group, $\text{12}\text{31}$ patients achieved partial response. Total dose of CY was higher in responders achieving a significantly longer survival (median 12+ months) in comparison to non-responders (median 7 months) and the control group (median 6 months). Less toxic reactions were seen in patients responding to ChRCh regimen.Bone marrow depletion did not affect the patient's survival, but cystitis and alopecia, it appeared, decreased life expectancy. It is concluded that combined modality therapy is better than chemotherapy alone, with less cytotoxicity in responders.     

颈静脉鼓室副神经节瘤6例及相关文献复习

目的:探讨颈静脉鼓室副神经节瘤的临床病理特点、诊断及鉴别诊断等。方法:搜集6例颈静脉鼓室副神经节瘤的临床病理资料,光镜下观察HE切片并进行免疫组织化学染色。结果:6例患者均为女性,年龄14～53岁,平均年龄44.7岁。主要临床表现为耳鸣、耳痛、听力下降。大体为红色肿物,部分见包膜;镜下瘤细胞呈巢团状、条索状排列,胞质丰富,核深染。免疫组化:Syn阳性,其他S100、CgA等均有不同程度表达,CKp、CD34、CD31、SMA阴性,Ki-67增殖指数较低,约<10%。结论:颈静脉鼓室副神经节瘤为罕见的头颈部肿瘤,确诊主要依据病理学形态及免疫表型特征。     

环磷酰胺与顺铂联合治疗肿瘤患者剂量优化试验研究

目的 探讨环磷酰胺与顺铂联合化疗最佳给药剂量.方法 对120例卵巢癌和恶性淋巴瘤患者按完全随机分组法分为6组,分别按照环磷酰胺（CTX）500 mg/m2＋顺铂（DDP） 40 mg/m2、CTX 500 mg/m2＋ DDP 50 mg/ m2、CTX 500 mg/m2＋ DDP 60 mg/m2、CTX 600 mg/m2＋ DDP 40 mg/m2、CTX 600 mg/ m2＋ DDP 50 mg/m2、CTX 600 mg/m2＋ DDP 60 mg/m2静脉给药,每周1次,连用2周,比较各组疗效、不良反应.结果 各组间疗效差异无统计学意义（P＞0.05）.高剂量化疗组（CTX 500 mg/m2＋DDP 60 mg/m2、CTX 600 mg/m2＋ DDP 60 mg/m2）白细胞抑制率较高,分别为72.6％、79.3％,淋巴细胞损伤最大,血肌酐、血尿素氮、丙氨酸氨基转移酶、天冬氨酸氨基转移酶水平显著下降,而最低剂量化疗组（CTX 500 mg/m2＋DDP 40 mg/ m2）血象在正常范围,肾功能、肝功能损伤发生率低.结论 CTX与DDP联合化疗最佳给药剂量分别为500、40 mg/m2.     

Imaging of pheochromocytoma and paraganglioma

Paragangliomas are tumours that arise within the sympathetic nervous system originating from the neural crest. These tumours can be found anywhere from the neck to the pelvis in locations of sympathetic ganglions. Although in the majority of paragangliomas the diagnosis is based on measuring catecholamines and metabolites in plasma or urine, imaging plays an important preoperative role. Today, there are several morphological and radionuclide imaging methods available that predict tumour localisation and tumour extent and give anatomic information to the surgeon. MRI is the morphological imaging modality of choice in localising pheochromocytomas and extra-adrenal paragangliomas. It provides excellent anatomic detail and has the advantage of lacking ionising radiation. The overall accuracy of computed tomography (CT) in detecting primary adrenal pheochromocytomas is very high, but CT lacks in specificity as difficulties may occur in distinguishing between paragangliomas and other tumour entities. The major advantages of radionuclide imaging are very high specificity and routinely performed whole-body scanning. Furthermore, metabolic imaging is not influenced by artifacts like scar tissue or metallic clips in post-surgical follow-up. Currently, a reported specificity of 99% and a cumulative sensitivity of about 90% in paragangliomas make ¹²³I-MIBG the most important nuclear imaging method. However, ¹⁸F-DOPA-PET seems to be a very promising procedure which offers higher accuracy. The higher spatial resolution of PET-scanners enables the detection of small lesions not visualised with ¹²³I-MIBG. Both use of radiolabelled somatostatin analogue like ¹¹¹In-pentetreotide and ¹⁸F-FDG is limited due to low specificity of the tracers and should be restricted to MIBG- and F-DOPA-negative cases.     

膀胱无功能性副神经节瘤2例报告及文献复习

目的：探讨膀胱无功能性副神经节瘤的临床病理特点和诊断治疗方法。方法：HE及免疫组化染色观察2例膀胱无功能性副神经节瘤并复习文献。结果：膀胱无功能性瘤不具有内分泌功能引起的相应症状，如头痛，心悸，多汗，排尿后血压一过性升高等。病理见肿瘤细胞排列成片状、巢状结构，部分呈菊形团样，周边血窦围绕形成器官样结构。免疫组化示神经特异性烯醇化酶（NSE），嗜铬粒蛋白（CHGA），突触囊泡蛋白（SYN），S-100蛋白阳性，CK，AE1／3阴性。2例均行膀胱部分切除术，效果满意。结论：膀胱无功能性副神经节瘤是膀胱肿瘤中较少见的一种类型，有其特殊的临床表现与病理特点。诊断需结合临床，病理及免疫组化结果，建议长期随访。     

Malignant retroperitoneal paraganglioma: Case report and review of treatment options

A case of retroperitoneal paraganglioma metastasizing to bone is presented. This is followed by a literature review of treatment options, including external beam radiotherapy, chemotherapy and ¹³¹I‐metaiodobenzylguanidine.     

SDHC mutations in hereditary paraganglioma/pheochromocytoma

Mutations in genes coding for three of the four components of mitochondrial complex II can cause paragangliomas (PGLs)/pheochromocytomas. The three genes include SDHB, -C, and -D. SDHC and SDHD anchor the catalytic subunits SDHA and -B of mitochondrial complex II in the inner mitochondrial membrane. SDHD is maternally imprinted but SDHB and -C are not. While SDHD and – to a lesser degree – SDHB mutations have been found in many cases of hereditary PGL, SDHC mutations are rare. This article reviews the SDHC mutations described to date and discusses possible mechanisms of tumorigenesis.     

Urinary bladder malignant paraganglioma with vertebral metastasis:a case report with literature review

Paraganglioma is a rare neuroendocrine neoplasm observed in patients of all ages, with an estimated incidence of 3/1,000,000 population. It has long been recognized that some cases are familial. The majority of these tumors are benign, and the only absolute criterion for malignancy is the presence of metastases at sites where chromaffin tissue is not usually found. Some tumors show gross local invasion and recurrence, which may indeed kill the patient, but this does not necessarily associate with metastatic potential. Here, we report a case of vertebral metastatic paraganglioma that occurred 19 months after the patient had undergone partial cystectomy for urinary bladder paraganglioma. We believe this to be a rarely reported bone metastasis of paraganglioma arising originally within the urinary bladder. In this report, we also provide a summary of the general characteristics of this disease, together with progress in diagnosis, treatment, and prognosis.     

Altered cyclophosphamide and thiotepa pharmacokinetics in a patient with moderate renal insufficiency

Purpose  We report a patient with renal insufficiency (creatinine clearance, CL_cr = 38 mL/min) who received high-dose chemotherapy with cyclophosphamide (1,500 mg/m² day⁻¹), thiotepa (120 mg/m² day⁻¹) and carboplatin (AUC = 5 mg min/mL day⁻¹) for four consecutive days. Methods  Blood samples were collected on day 1 and 3 and plasma levels of cyclophosphamide, its active metabolite 4-hydroxycyclophosphamide, thiotepa, its main metabolite tepa and carboplatin were determined. Results  Pharmacokinetic analyses indicated that the elimination of cyclophosphamide, thiotepa, carboplatin, but especially tepa was strongly reduced in this patient, resulting in increased exposures to these compounds of 67, 43, 30 and 157%, respectively, compared to a reference population (n = 24) receiving similar doses. Exposure to 4-hydroxycyclophosphamide increased 11%. Conclusion  These results suggest that it may not be necessary to alter the dose of cyclophosphamide in patients with moderate renal impairment. However, because high exposures to thiotepa and tepa have been correlated with increased toxicity, caution should be applied when administering thiotepa to patients with renal insufficiency.     

Gangliocytic paraganglioma: An overview and future perspective

Gangliocytic paraganglioma (GP) is rare neuroendocrine tumor (NET) with a good prognosis that commonly arising from duodenum. Although the tumor is characterized by its unique triphasic cells (epithelioid, spindle, and ganglion-like cells), the proportions of these three tumor cells vary widely from case to case, and occasionally, morphological and immunohistochemical similarities are found between GP and NET G1 (carcinoid tumors). Further, GP accounts for a substantial number of duodenal NETs. Therefore, GP continues to be misdiagnosed, most often as NET G1. However, GP has a better prognosis than NET G1, and it is important to differentiate GP from NET G1. In this article, I wish to provide up-to-date clinicopathological information to help oncologists gain better insight into the diagnosis and clinical management of this tumor.     

Treatment strategies and outcomes of primary Myxofibrosarcomas in a large patients cohort

Backgroundthis study analysed primary myxofibrosarcoma (MFS) to investigate patient outcomes focusing on histopathologic margins and perioperative treatments.Patients and methodsdata from consecutive patients affected by primary and localized MFS of the extremities or trunk wall who underwent surgery (2002–2017) were analysed. Local recurrence (LR), amputation rate, incidence of distant metastasis (DM), and overall survival (OS) were studied.ResultsOf 293 included patients, 52 (17%) patients received perioperative treatments and 54 (18%) had positive microscopic histopathologic margins (R1). Median follow-up was 80 months (IQR, 49–109). 5-yr CCI of LR was 0.12 (SE: 0.02). Status of histopathologic margins (P < 0.001), tumour malignancy grade (P = 0.018) and size (P = 0023) were independent prognostic factor for LR. Nine amputations (amputation rate: 3%) were performed (N = 1 for primary tumour; N = 8 for LR). Larger tumour size (P = 0.015) and higher grade (P = 0.025) were independent prognostic factor for DM. 5-year OS was 0.84 (95%CI 0.79–0.88). Patient age (P = 0.008), tumour size (P = 0.013) and malignancy grade (P = 0.018) were independently associated to OS. In the subgroup of patients who had a re-excision for a primary MFS (N = 116, 40%), the presence of residual disease was not associated with LR, DM, or OS.Conclusionin this study 5-year LR, DM and OS were 12%, 17%, and 84%, respectively. One in six patients had a positive surgical margin, which was a prognostic factor for LR, while DM and OS were predicted by tumour grade and size. Findings from this large patient cohort may set benchmarks for investigating new treatment options for MFS.     

Impact of hepatectomy margin on survival following resection of colorectal metastasis: The role of adjuvant therapy and its effects

Introduction

The optimal width of microscopic margin and the use of adjuvant therapy after a positive margin for hepatic resection for colorectal liver metastasis (CRCLM) has not been conclusively determined. The aim of the current study is to evaluate the influence of width of surgical margin and adjunctive therapy upon disease free and overall survival.

Methods

All patients undergoing hepatectomy for CRCLM from 1997 to 2012 were identified from a prospectively maintained, IRB approved database. Patients were divided into four subgroups based on the parenchymal margin: positive, <0.1 cm, 0.1 cm–1 cm, and >1 cm.

Results

A total of 373 patients were included for analysis with a median follow up of 26 months (range 9–103 months) and a median overall survival of 53 months. The resection margin was positive (26 patients median OS 24 months), <0.1 cm (48 patients median OS 36 mon), 0.1 cm–1 cm (82 patients median OS 44 months), and >1 cm (217 patients median OS 64 months). The most common adjunctive therapy was chemotherapy, hepatic arterial therapy, or local. Patients with positive margins also had the shortest disease free survival (DFS), 16 months. The DFS was similar amongst the other margin groups (<0.1 cm: 21 months, 0.1–1 cm: 22 months, >1 cm 25 months). Hepatectomy margin independently influenced survival (p = 0.017) and disease free survival (p = 0.034). Patients with negative margins has similar overall recurrence rates (p = 0.36) and survival rates (p = 0.89).

Conclusions

A positive surgical margin indicates a worse overall biology of disease for patients undergoing hepatectomy for CRCLM, and appropriate multi-disciplinary therapy should be considered in this high risk patient population. Marginal width if a complete resection has been achieved does not adversely effect overall surgical in patients with CRCLM.