In vitro chemosensitivity testing in the treatment of ovarian carcinoma

Summary In vitro chemosensitivity to cisplatinum, adriamycin, cyclophosphamide, and 5-fluorouracil was investigated in 58 cases of ovarian carcinoma using Volm's short-term test. These in vitro results were retrospectively correlated with the relapse-free interval. Operative treatment in all patients (FIGO stage I (5), III (43), IV (10)) comprised maximum debulking procedure including hysterectomy, adnexectomy, omentectomy, pelvic and in most cases additionally paraaortic lymphadenectomy. Subsequently, all patients were treated with the cisplatinum-epirubicin-cyclophosphamide regimen. 33/58 tumors (66%) were sensitive in vitro (inhibition of nucleic acid precursor incorporation of more than 45% as compared to untreated controls). The median relapse-free interval of patients with sensitive tumors was significantly longer than that of those with resistant carcinomas (30.3 versus 22.6 months, respectively;P<0.05). Histopathological evaluation showed the majority of serous cystadenocarcinomas to be sensitive (26/33=79%,P<0.05).     

卵巢上皮性癌脑转移四例临床分析

目的 探讨卵巢上皮性癌脑转移的发生率,相关因素,诊断和治疗方法。方法 分析１９８９年至１９９７年,卵巢上皮性癌１３２例,其中４例发生脑转移。结果 脑转移发生率为３％,脑争生与晚期癌和肿瘤分化程度有关,与肿瘤病理类型无关。晚期患者接受肿瘤细胞减灭术和系统化疗后生存时间延长;出现腹腔外转移者,脑转移发生率增高。     

卵巢癌拓扑异构酶Ⅱα表达与化疗敏感性的关系

目的 :研究卵巢癌拓扑异构酶Ⅱα表达与化疗敏感性的关系。方法 :采用免疫组化Envision法检测 81例上皮性卵巢癌TopoⅡα的表达 ,并予以 3～ 8个疗程以铂类为主的联合化疗。结果 :低分化卵巢癌TopoⅡα的表达明显高于中、高分化者 (P =0 .0 4 7) ,术前行化疗的卵巢癌TopoⅡα表达明显低于术前未化疗者 (P =0 .0 0 2 ) ,而复发性卵巢癌TopoⅡα表达再次升高 ;不考虑MDR1因素时 ,TopoⅡα与化疗敏感性间未见明显的相关性 (P =0 .0 73) ,而在排除MDR1影响后 ,TopoⅡα表达与化疗疗效间具有明显相关性 (P=0 .0 2 6 ) ,阳性表达时化疗效果好 ,未发现TopoⅡα的表达强度与化疗疗效间有相关性(P =0 .98)。结论 :TopoⅡα表达与卵巢癌分化程度有关 ,化疗影响TopoⅡα的表达 ,复发病例TopoⅡα表达重新增强 ,MDR1阴性时 ,TopoⅡα表达与化疗敏感性间具有明显相关性。因此 ,可以根据卵巢癌TopoⅡα表达情况 ,制定合理的化疗方案     

Cytoreductive surgery for patients with recurrent epithelial ovarian carcinoma

OBJECTIVE: This study aims to identify favorable preoperative characteristics and examine the impact of secondary cytoreductive surgery on survival for patients with recurrent epithelial ovarian carcinoma. METHODS: Patients who underwent cytoreductive surgery for recurrent epithelial ovarian cancer were identified in our surgical database for the period 1988-2004. Patient charts were reviewed and data collected regarding patient demographics, surgical management, preoperative evaluation, perioperative complications, and oncologic outcome. RESULTS: Eighty-five patients met eligibility criteria. Preoperative factors that correlated with improved survival were disease-free interval of greater than 12 months (p<0.01) and residual disease after primary surgery of <2 cm (p<0.02). Other preoperative factors evaluated but not found significant included radiographic findings, physical findings, previous histology, stage, grade, previous chemotherapy, prior recurrence, and serum CA-125 level. Optimal resection to <1 cm residual disease was achieved in 86% of patients who had secondary cytoreduction. Small bowel and colon resection for cytoreduction occurred in 7% and 51% of patients, respectively. Operative complications occurred in 14% and postoperative complications occurred in 21% of patients. The median survival of patients who were optimally cytoreduced to <1 cm was 30 months compared to 17 months for patients with residual disease>or=1 cm (p<0.05). Operative factors that were evaluated and did not significantly effect survival were location of recurrence, presence of ascites, and extent of recurrence. Recurrent or progressive disease occurred in 75% of patients during follow-up. CONCLUSION: When selecting patients for secondary cytoreduction, the most significant preoperative factors are disease-free interval and success of a prior cytoreductive effort. Once secondary cytoreductive surgery is attempted, the most important factor for improved survival is optimal cytoreduction. Of equal importance is counseling regarding the significant risk for bowel surgery, colostomy, and complications.     

Lymph node sampling in patients with epithelial ovarian carcinoma.

Lymph node sampling is part of the FIGO staging of patients with ovarian carcinoma and is usually part of a meticulous second look operation. We analyzed the primary lymph node status of patients and compared this to the lymph node status at second look operation. From 3/86-3/91, 97 patients with epithelial ovarian tumors were treated at this institution. Seventy-one of the 97 patients (73.2%) had lymph node sampling at primary surgery. Thirty of the 71 patients had positive lymph nodes (42.2%) and 41 patients were lymph node negative (57.8%). Of the initial 97 patients, 58 were eligible for second look operation (59.8%), and 48 of these patients had lymph nodes sampled at second look operation. Nine of the 48 patients had positive lymph nodes (18.7%) and 39 had negative lymph nodes at second look operation (81.3%). Of the patients with negative lymph nodes at primary surgery, 25 patients had second look operation and 24 of these patients had lymph node sampling at second look operation. All patients with negative lymph nodes at primary surgery had negative lymph nodes at second look operation. Of the 30 patients with positive lymph nodes at primary surgery, 12 underwent second look operation. Four patients had persistent positive lymph nodes and 8 patients had negative lymph nodes. Our data suggest that patients with negative lymph nodes at primary surgery are unlikely to have positive lymph nodes at second look operation. Therefore, we believe that lymph node sampling under these circumstances is unnecessary.     

DCC基因对卵巢上皮性癌细胞生长及其化疗敏感性的影响

目的研究DCC基因对卵巢上皮性癌（卵巢癌）细胞生长及其化疗敏感性的影响。方法采用脂质体转染法将含有DCC基因的真核表达载体pcDNA3．1（＋）-DCC质粒导人卵巢癌细胞系HO8910细胞中（HO8910-DCC组）,以转染空载体pcDNA3．1（＋）质粒（HO8910-Neo组）和脂质体（空白对照组）为对照。转染24h后,经氨基糖甙类抗生素G418筛选,RT-PCR技术以及免疫组化法检测3组细胞DCC mRNA及蛋白表达情况;四甲基偶氮唑蓝（MTT）比色法测定3组细胞转染后1～7d的细胞生长情况及经梯度浓度[0．1、0．2、1．0、5．0、10．0血浆峰浓度（PPC）]化疗药物顺铂和紫杉醇处理后48h的细胞存活率,并绘制细胞生长曲线。结果转染DCC基因后,DCC基因可在HO8910细胞中稳定表达。转染后1～7d,HO8910-DCC组细胞生长速度较其他两组细胞明显减慢,除转染后第1天外,分别比较,差异均有统计学意义（P〈0．01）;空白对照组和HO8910-Neo组细胞生长速度比较,差异则无统计学意义（P〉0．05）。HO8910-DCC组细胞经0．1～5．0PPC的顺铂和紫杉醇处理后,细胞存活率显著低于空白对照组和HO8910-Neo组（P〈0．01）;经10．0PPC的顺铂处理后细胞存活率也明显低于空白对照组和HO8910-Neo组（P〈0．05）;但经10．0PPC的紫杉醇处理后细胞存活率与空白对照组和HO8910-Neo组相比,差异则无统计学意义（P〉0．05）。空白对照组和HO8910-Neo组细胞经各梯度浓度药物处理后的细胞存活率间比较,差异均无统计学意义（P〉0．05）。结论DCC基因可明显抑制卵巢癌细胞的生长,并增强卵巢癌细胞对化疗药物的敏感性。     

Weekly topotecan in heavily pretreated patients with recurrent epithelial ovarian carcinoma

OBJECTIVE: To investigate weekly topotecan in heavily pretreated patients with recurrent ovarian cancer. METHODS: The records of patients with recurrent epithelial ovarian cancer who were treated with weekly topotecan after failure of > or =1 prior regimen were reviewed. Patients received topotecan (median starting dose approximately 2.5 mg/m(2)) on days 1, 8, and 15 of a 28-day cycle. Antitumor response was assessed after 2 cycles by serial CA-125 levels. RESULTS: Thirty-five heavily pretreated patients received a mean of 5 cycles of topotecan (range, 1-13 cycles). Thirty-two patients had definable platinum sensitivity (16 sensitive, 8 resistant, 8 refractory). Median age was 56 years. A total of 177 cycles (534 weeks) of topotecan was administered. Hematologic toxicity was generally mild, and no grade 4 toxicities were observed. Grade 3 hematologic toxicity, including leukopenia, neutropenia, thrombocytopenia, and anemia, was observed in 2, 2, 1, and 0 patients, respectively. No patients experienced grade 3 or 4 nonhematologic toxicity. Based on serial CA-125 measurements, there were 1 (3%) complete and 5 (15%) partial responses, with 1 of the partial responses in a patient with platinum-refractory disease. Stable disease was reported in 13 (38%) patients, including 5 patients with platinum-resistant/refractory disease. CONCLUSION: Weekly topotecan demonstrates activity and is well tolerated compared with historical data with the standard 5-day schedule. Higher doses may be warranted because of the high tolerability shown for weekly topotecan. Weekly topotecan may be an appropriate treatment option for patients with recurrent ovarian cancer, especially heavily pretreated patients who might require dosing schedules with improved tolerability.     

卵巢上皮性癌血清肿瘤标志物谱变化的临床意义

目的 探讨卵巢上皮性癌(卵巢癌)患者化疗后肿瘤标志物谱的变化及其潜在的临床意义.方法 选择1999年1月至2007年7月期间经肿瘤细胞减灭术及规范化疗的卵巢癌患者102例,对其术前、术后、每次化疗前、随访期间和复发前后的血清肿瘤标志物CA125、CA19-9和CP2的水平进行检测、分析,其中48例患者的肿瘤标志物记录完整而纳入分析,复发患者为28例,初治化疗患者20例(均为耐药病例).根据肿瘤标志物谱变化与否,分别将复发和初治化疗患者分为肿瘤标志物谱变化组与未变化组.平均随访时间为25个月.结果 (1)肿瘤标志物谱的主要变化表现为标志物的数最变化和(或)标志物的种类改变.28例复发患者中肿瘤标志物谱发生变化者占46%(13/28),20例初治化疗患者中标志物谱发生变化者占45%(9/20).(2)肿瘤标志物谱变化的复发患者中,病理类型以浆液性癌所占比例最高,为77%(10/13),而初治化疗患者中,以黏液性癌所占比例最高,为4/9.(3)复发患者肿瘤标志物谱变化组的无疾病进展期和中位总生存时间分别为22.2、60.0个月,较未变化组(分别为17.4、46.0个月)明显延长(P均<0.05);初治化疗患者肿瘤标志物谱变化组的中位总生存时间较未变化组(分别为15.9、25.0个月)明显缩短(P<0.05).结论 卵巢癌化疗期间和复发后肿瘤标志物谱可发生变化,化疗及随访期间应对肿瘤标志物进行联合检测.     

Efficacy of second-look laparotomy for patients with epithelial ovarian carcinoma

Second-look laparotomies (SLL) were performed on 42 patients with ovarian carcinoma. Ten (24%) had residual disease. Serum CA 125 values before SLL predicted the presence of residual tumors, but its relatively high false negative rate made it unable to take place of SLL. Positive peritoneal cytology at initial surgery significantly influenced SLL results in patients with early disease. Residual pelvic lesions at initial surgery seemed to resist subsequent chemotherapy. Salvage therapy with external pelvic irradiation was effective on lesions confined to the pelvis without serious toxicity. Patients with advanced disease, undergoing SLL achieved better survival than without SLL. This study shows SLL is still the most accurate procedure in assessing the efficacy of treatment, and useful in selecting second-line therapy.     

The value of second-look operation in patients with advanced epithelial ovarian carcinoma

Summary A second-look operation was performed on 151 patients with stage III and IV epithelial ovarian carcinoma who had responded to primary surgery and chemotherapy. 19% of the 79 patients who appeared clinically to be free of disease had microscopic recurrences and 23% had macroscopic residual disease at a second-look operation. The 5-year survival rate for patients with no histological and for those with microscopic secondaries at second-look operation were 55% and 35% respectively (P=0.45). Only patients with well or moderately well differentiated tumors and a small residual tumor mass at first operation had a good prognosis after a second-look operation even without further chemotherapy. Median survival after secondary debulking was 15 to 17 months and was independent in the radicality of the second-look procedure. Outside of clinical trials second-look laparotomy should therefore only be performed as a diagnostic procedured as a diagnostic procedure in patients with well or moderately well differentiated tumors who are left with a small residual tumor mass at the time of the first operation. Because this is a group of patients in whom chemotherapy can be discontinued after a negative second-look operation.     

Predictive value of the ATP chemosensitivity assay in epithelial ovarian cancer

OBJECTIVE: The aims of this study were to define the specific parameters of the ATP chemosensitivity assay which most accurately predict a patient's clinical response to chemotherapeutic agents in epithelial ovarian cancer and to assess the clinical utility of the ATP assay. METHODS: In our laboratory from 1992 to 1994, fresh tumor specimens from patients with epithelial ovarian carcinomas were assayed with the ATP chemosensitivity assay (ATP-CSA) for their in vitro responses to several chemotherapeutic agents including cisplatin, paclitaxel, and cyclophosphamide. Clinical data on 161 of those patients including all follow-up assessments were then collected, and an investigator blinded to the in vitro assay results determined the patients' responses to chemotherapy. In order to determine which parameter of the assay was the best predictor of clinical response for each drug, receiver-operator characteristic (ROC) curves were constructed for several parameters, including the amount of cell kill at particular dosage levels of drug, the slope of the dose-response curve, and the IC50, or the average concentration of drug at which 50% of the cells were nonviable. RESULTS: The specific parameter of the ATP-CSA which was most predictive of clinical response differed for each drug tested. The resulting positive predictive values for cisplatin, cyclophosphamide, and paclitaxel ranged from 70.0 to 78.3% and negative predictive values from 46.2 to 60.9%, with overall ATP-CSA positive and negative predictive values of 83.0 and 56.5%. Overall, patients whose tumors tested sensitive to an agent in vitro were almost twice as likely (83% versus 43%) to show a clinical response (RR 1.91, 95% CI 1.34-2.71). CONCLUSION: Analysis of the ROC curves in this study shows that different parameters of the ATP-CSA need to be utilized for each drug tested in order to give the best prediction of clinical chemosensitivity. Although the ATP-CSA shows predictive ability, routine use of the ATP-CSA for clinical selection of drug therapy in patients with epithelial ovarian cancer would not be warranted without a prospective study comparing chemotherapy treatment based on assay results versus clinician selection of drug.     

Detection of human papillomavirus DNA and genotyping in patients with epithelial ovarian carcinoma

AIM: The purpose of this study was to investigate the possible role of human papillomavirus (HPV) in Turkish patients with epithelial ovarian cancer by using the highly sensitive technique of polymerase chain reaction (PCR) to identify all the subtypes of this unique oncogenic virus. METHODS: All patients were subjected to initial surgery, and subsequently recruited for postoperative chemotherapy depending on the extent of the disease and their condition. HPV PCR screening was done from paraffin embedded samples. PCR amplifications were done using the MY09/11 primer set after digestion and phenol-chloroform extraction of the DNA. HPV PCR-positive samples were analyzed and genotyped using an OpenGene automated DNA sequencing system. RESULTS: Overall, 94 patients were included in this study. The mean age was 52.7 years (range, 21-76 years). As a histopathologic diagnosis, the majority of the patients had serous papillary tumors (81%). HPV was found to be positive in eight patients (8.5%). All of the positive patients had serous papillary tumors (8/76, 10.5%) and advanced stage disease. Six patients had HPV type 16, and the remaining two patients had HPV type 33. None of the patients had more than one type of HPV. CONCLUSION: HPV may have a role in the carcinogenesis of ovarian cancer. It is worth investigating this possible relation both in large case-control studies and in vitro models by using more sensitive techniques.     

卵巢上皮性癌序贯化疗41例临床分析

目的探讨卵巢上皮性癌不同化疗方案的序贯化疗效果。方法回顾性分析1998年1月-2007年11月肿瘤细胞减灭术后规范化疗的卵巢上皮性癌患者41例,其中序贯化疗组11例,应用化疗方案为TP和／或CAP和／或IAP;常规化疗组30例,应用化疗方案为TP或CAP,比较化疗毒性反应、反应率、无疾病进展期和总生存时间。结果①两组在年龄、病理类型、临床分期、组织分化程度和术后残留病灶方面差异无统计学意义（P〉0．05）;②序贯化疗组的完全缓解率（CR）、部分缓解率（PR）和总缓解率（CR＋PR）分别为57．1％、23．8X和81．oH,常规化疗组的CR、PR和CR＋PR分别为55．3％、23．4％和78．7％,组间比较,差异无统计学意义（P〉0．05）;③序贯化疗组中位无疾病进展和中位总生存时间分别为41个月和60个月,常规化疗组分别为30个月和59个月,较常规化疗组延长,但差异无统计学意义（P〉O．05）;④序贯化疗组发生3～4级白细胞减少症4例,占36．36％,常规化疗组发生10例,占33．33％,组间比较,差异无统计学意义（P〉0．05）;非血液系统化疗毒性反应主要为神经系统毒性反应,序贯化疗组发生3～4级神经系统毒性反应1例（9．09％）,常规化疗组6例（20％）。结论序贯化疗可延长卵巢癌患者的无疾病生存期,且毒性反应减少,有待今后进一步研究后用于卵巢癌一线化疗。     

小儿造血干细胞移植后出血性膀胱炎的临床特征与危险因素分析

目的 分析小儿造血干细胞移植(HSCT)后出血性膀胱炎(HC)的临床特点，探讨其发病危险因素。 方法 对1998年10月至2004年6月中山大学附属二院儿科完成的52例小儿HSCT后11例HC的临床资料进行回顾分析。 结果 11例HC中轻度(Ⅰ~Ⅱ度)6例，重度(Ⅲ~Ⅳ度)5例；早发性4例，迟发性7例；发病时间为术后+2d至+25d(中位数为+15d)，病程3~60d(中位数为17d)。临床表现均有血尿，其中典型尿频、尿急、尿痛及肉眼血尿7例。HC患儿组中性粒细胞植入时间和血小板植入时间与非HC患儿组比较差异无显著性(P>0.05)。受者移植年龄≥6岁、aGVHD阳性、CMV感染组的HC发生率分别高于年龄<6岁(321%和83%，P<0.05)、GVHD阴性(34.6%和7.7%，P<0.05)、CMV未感染组(62.5%和13.6%，P<0.05)。 结论 小儿HSCT后HC有其自身的临床特征；受者移植年龄≥6岁、aGVHD阳性、CMV感染为其发生的危险因素。     

卵巢上皮性癌患者外周血中癌细胞的检测

目的 检测卵巢上皮性癌患者外周血干细胞（ＰＢＳＣ）中有无癌细胞污染及原发晚期卵巢上皮性细胞患者外周循环血中有无癌细胞。方法 应用卵白素－生物素酶－复合物（ＡＢＣ）法,检测２例患者ＰＢＳＣ及８例患者外周血。为了确定ＡＢＣ法检测血中癌细胞的灵敏度,分别用卵巢癌细胞系ＳＫＯＶ３,３ＡＯ以及从浆性乳头状腺癌,未分化腺癌虱腹水中得到的原代癌细胞,制成癌细胞与单核细胞的不同浓度模型,应用单克隆抗体ＣＯＣ１８３     

Genetic testing for epithelial ovarian cancer

As the treatment of epithelial ovarian cancer (OC) moves further into personalised medicine, the importance of determining the presence or absence of inherited mutations in cancer susceptibility genes has grown. It is now becoming routine to test for germline mutations in the BRCA1 and BRCA2 genes, which are responsible for a significant proportion of hereditary epithelial OC and are established predictive biomarkers of potential benefit from poly ADP ribose polymerase (PARP) inhibitors. The identification of patients with hereditary OC allows the patient to benefit from personalised treatment, while allowing family members to undergo cascade testing, where identification of unaffected carriers can allow early detection, risk-reduction or prevention for both breast and OC, and ultimately improve long-term outcomes. Other susceptibility genes, include the Lynch Syndrome (mismatch repair) genes and several other genes involved in the homologous recombination pathway (HRD genes), are implicated in OC genesis, and are also becoming of increasing interest as therapeutic options grow for these patients. This review will highlight the importance of the early detection of a germline gene pathogenic variant, which informs on the clinical course of disease in a particular patient, and therefore, guides therapeutic management including risk reducing and personalised treatment.     

Apoptosis-based evaluation of chemosensitivity in ovarian cancer patients

OBJECTIVE: Induction of apoptosis in target cells is a key mechanism by which chemotherapy induces cell killing. We have established an in vitro system for determining the chemosensitivity of epithelial ovarian cancer cells to carboplatin and paclitaxel (Taxol). Practical assays to predict the likelihood of individual tumor sensitivity are needed to facilitate the choice of adequate treatment. We sought to determine whether epithelial ovarian cancer cells (EOC) collected from the ascites fluid of patients known to be clinically chemosensitive or chemoresistant to carboplatin and paclitaxel would show a similar response to chemotherapeutic drugs after in vitro treatment. METHODS: Thirteen patients with stage III and IV ovarian cancer treated with carboplatin and paclitaxel were studied. Caspase-3 activation was used as a surrogate marker for activation of chemotherapy-induced programmed cell death. We compared the in vitro apoptotic response to the clinical response of the patients from whom the tumor cells were isolated. Clinical sensitivity was defined as no evidence of disease recurrence for 6 months after optimal debulking surgery and completion of chemotherapy. RESULTS: Of seven chemosensitive patients, five cell samples treated in vitro had increased caspase-3 activity in response to both carboplatin and paclitaxel. Five of six chemoresistant cases did not show caspase-3 activity in response to only one or to neither agent. CONCLUSION: Quantifiable markers of apoptosis such as caspase-3 activation have the potential to predict the clinical response to chemotherapy. Application of this assay in clinical laboratories could optimize the potential for efficient treatment and avoid the toxicities of ineffective drugs.