Platelets are not hyperreactive in patients with ovarian cancer

Paraneoplastic thrombocytosis has been reported in different types of solid tumors, including ovarian epithelial cancer, and found to be associated with a worse outcome. Although the effect of cancer on increasing platelet counts is well documented, the effect of cancer on platelet functions is not well known. We compared in vitro aggregation response of platelets isolated from 34 patients with ovarian cancer to those of platelets from 19 patients with benign ovarian tumors. Aggregation studies were conducted in a light transmission aggregometer, using both a high and a low dose of ADP and collagen. We evaluated platelet preactivation by measuring the plasma concentration of β-thromboglobulin (β-TG) and platelet factor-4 (PF-4) as markers of platelet α granule secretion, using ELISA. We found that ovarian cancer is not associated with an enhanced aggregation response of platelets to ADP or collagen, and plasma concentration of β-TG and PF-4 is not higher in patients with ovarian cancer compared to those in patients with benign ovarian tumors.     

Pseudo-Meigs syndrome: particular management of ovarian metastases in colorectal cancer

Ascites and/or pleural effusion with ovarian metastases in colorectal cancer are usually related to peritoneal carcinomatosis. Pseudo-Meigs syndrome is a characterized by non-malignant ascites and/or pleural effusion caused by pelvic tumors other than solid benign ovarian tumors. We treated two patients who developed this syndrome in a context of colorectal cancer. After ovarian metastasis resection, ascites and pleural diffusion disappeared. In the presence of acellular ascites with ovarian metastases from colorectal cancer, diagnosis of pseudo-Meigs syndrome may allow surgical treatment with curative intent.     

Distribution and rearrangements of alleles of c-Ha-ras-1 protooncogene and their correlation with the development of lung, ovarian and thyroid cancers

The protooncogene c-Ha-ras-1 locus in 84 cancer patients was examined for allelic restriction fragment length polymorphism. The distribution of four common c-Ha-ras-1 alleles (a1, a2, a3 and a4) in lung, ovarian and thyroid cancer patients was analyzed. In approximately half (8 out of 15) of lung and ovarian carcinomas possessing the a4 allele, alterations of the c-Ha-ras-1 locus (deletion of allele with the shorter fragment length, amplification of a4 allele, change of allele fragment length) were detected as compared to 2 cases of rearrangement out of 40 tumors lacking the a4 allele. An increased a4 allele frequency was found in individuals with lung and ovarian tumors as compared to controls presented in literary data and thyroid cancer patients. On the other hand, homozygosity for the a2 locus resulting from the deletion of another allele, and increased a2 allele frequency in thyroid cancer patients were observed. Thus the a4 and a2 alleles of c-Ha-ras-1 may perhaps be viewed as genetic markers of predisposition to lung, ovarian and thyroid cancer, respectively, in combination with other clinical parameters.     

卵巢癌患者血清SMRP和HE4的表达及其临床意义

目的 探讨血清可溶性间皮素相关蛋白(SMRP)和人附睾蛋白-4(HE4)在卵巢癌早期诊断及病情监测中的临床意义.方法 血清标本取自44例卵巢癌、56例良性肿瘤及40例健康志愿者.ELISA试剂盒测定血清HE4和SMRP,化学发光法测定CA125.结果 卵巢癌组血清CA125、HE4和SMRP高于其他两组.经过理想肿瘤减灭术的卵巢癌术后1 w血清CA125、HE4和SMRP水平明显减低.在诊断效能上,单独检测HE4特异度为100.00%,灵敏度86.36%;SMRP灵敏度77.27%,特异度97.92%;二者与CA125联合检测均可提高灵敏度或特异度.结论 HE4和SMRP补充完善了CA125用于卵巢癌的早期诊断和病情监测,具有较高的临床应用价值.     

卵巢上皮性癌组织中β-catenin、E-cadherin表达变化及意义

目的观察卵巢上皮性癌（卵巢癌）组织中-βcatenin、E-cadherin的表达变化,并探讨其意义。方法采用免疫组化SABC法检测49例上皮性卵巢癌、10例交界性囊腺瘤及16例良性卵巢肿瘤患者肿瘤组织中的β-catenin、E-cadherin。结果卵巢癌组织中-βcatenin、E-cadherin的异常表达率分别为79.59%（39/49）、67.35%（33/49）,明显高于良性卵巢肿瘤组织的25%（4/16）、0和交界性卵巢囊腺瘤组织的30.00%（3/10）、20.00%（2/10）,P均〈0.01。良性卵巢肿瘤与卵巢交界性囊腺瘤组织中β-catenin、E-cadherin的异常表达率相比P均〉0.05。β-catenin与卵巢癌病理类型、病理分级和腹腔转移有关（P均〈0.05）。E-cadherin与卵巢癌病理类型、临床分期、腹腔转移和术后有无残余瘤有关（P均〈0.05）。卵巢癌组织中的β-catenin、E-cadherin的异常表达呈正相关（r=0.525 8,P〈0.05）。结论卵巢癌组织中-βcatenin、E-cadherin表达下调。二者在卵巢肿瘤发生、发展过程中起重要作用。     

Identification of biomarkers for ovarian cancer using strong anion-exchange ProteinChips: potential use in diagnosis and prognosis

One hundred eighty-four serum samples from patients with ovarian cancer (n = 109), patients with benign tumors (n = 19), and healthy donors (n = 56) were analyzed on strong anion-exchange surfaces using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry technology. Univariate and multivariate statistical analyses applied to protein-profiling data obtained from 140 training serum samples identified three biomarker protein panels. The first panel of five candidate protein biomarkers, termed the screening biomarker panel, effectively diagnosed benign and malignant ovarian neoplasia [95.7% sensitivity, 82.6% specificity, 89.2% accuracy, and receiver operating characteristic (ROC) area under the curve of 0.94]. The other two panels, consisting of five and four candidate protein biomarkers each, effectively distinguished between benign and malignant ovarian neoplasia and were therefore referred to as validation biomarker panel I (81.5% sensitivity, 94.9% specificity, 88.2% accuracy, and ROC = 0.94) and validation biomarker panel II (72.8% sensitivity, 94.9% specificity, 83.9% accuracy, and ROC = 0.90). The three ovarian cancer biomarker protein panels correctly diagnosed 41 of the 44 blinded test samples: 21 of 22 malignant ovarian neoplasias [10 of 11 early-stage ovarian cancer (I/II) and 11 of 11 advanced-stage ovarian cancer (III/IV)], 6 of 6 low malignant potential, 5 of the 6 benign tumors, and 9 of 10 normal patient samples. In conclusion, we have discovered three ovarian cancer biomarker protein panels that, when used together, effectively distinguished serum samples from healthy controls and patients with either benign or malignant ovarian neoplasia.     

Endocrine factors in common epithelial ovarian cancer.

Ovarian cancer is responsible for 4% of all cancers in females and 6% of all their cancer deaths. Its mortality rate is greater than that of cervical and endometrial cancer together. The concentration of estrogen receptors (ER) rises and progesterone receptors (PR) falls in malignant ovarian tumors. In fact, ER and PR at present in 61% and 49% of malignant ovarian tumors respectively. 36% of these tumors contain both ER and PR. Further 69-90% of such tumors contain androgen receptors (AR). After (anti)hormonal agent therapy fails, physicians use progestins in combination with the synthetic antiestrogen tamoxifen in progressive or recurrent advanced ovarian cancer. The response rate for this treatment of ovarian cancer is only around 15%. Patients with malignant ovarian tumors with PR levels =or+ 50 fmol/mg tend to have a better prognosis than those with PR levels 50 fmol/mg. Neither age, stage of disease, nor tumor histology affect the prognostic value of PR. In vitro studies demonstrate that pure antiandrogens significantly inhibit about 60% of ovarian tumors. Another study also demonstrates that antiandrogen therapy alone may an effective endocrine therapy. As a result, the Gynecologic Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer if conducting a clinical trial on the effect of the antiandrogen flutamide on advanced or recurrent ovarian cancer. Researchers plan to investigate the effect of combining endocrine therapy with current standard chemotherapy. In fact, they intend to learn if combined chemo-endocrine therapy should be used as 1st line treatment for ovarian cancer.     

Methylation profile in benign,borderline and malignant ovarian tumors

Purpose Promoter hypermethylation is a common phenomenon in neoplasm. The aims of this study were (a) to compare the methylation profiles in different types of ovarian tumors and (b) to determine the possible relationship between the methylation status and different clinicopathologic characteristics. Methods We examined the promoter methylation status of 9 tumor suppressor genes (RARβ2, TMS1, RIZ1, P15, P16, PTEN, MINT31, APC and HIC1) in 89 ovarian cancers, 16 borderline ovarian tumors, 19 benign ovarian tumors, 16 normal ovarian tissue and 5 ovarian cancer cell lines. The methylation status was examined with respect to clinicopathologic characteristics of the ovarian cancer patients. Results Methylation indices for ovarian cancer, borderline ovarian tumor, benign ovarian tumor, normal ovarian tissue and ovarian cancer cell lines were 28.8, 20.1, 10.5, 11.8 and 42.2%, respectively. It was significantly higher in ovarian cancer, borderline ovarian tumor and ovarian cancer cell lines (X ² test, P < 0.001, P = 0.01 and P < 0.001, respectively) than benign or normal ovarian tissues. In ovarian cancer, concurrent methylation of at least two genes (CM2) was associated with early stage disease (X ² test, P = 0.035) and less recurrence (X ² test, P = 0.020). When the methylation statuses of the nine genes as well as CM2 were included in multivariate Cox Regression analysis, CM2 was the only independent predictor for survival (P = 0.013). Conclusion CM2 was an independent predictor for survival in ovarian cancer.     

Determination of N-acetylneuraminic acid for the differential diagnosis of cystic ovarian tumors

The concentrations of N-acetylneuraminic acid (NANA) were determined in the fluid of cystic ovarian tumors and in the blood serum from a total of 95 patients. The estimation of NANA was based on the method of Svennerholm. It was found that the mean content of NANA in the cystic fluid is more than 3.0 mmol/l in serous and more than 5.5 mmol/l in mucinous malignant ovarian tumors. The mean value of NANA in the serum of patients is mostly more than 3.5 mmol/l if there is an ovarian cancer. The estimation of NANA is useful for the preoperative diagnosis of cystic ovarian tumors.     

Ovarian cancer: a solid tumor with evidence of normal cellular immune function but abnormal B cell function.

Immunologic assays of B and T lymphocyte function were performed on 21 patients with epithelial ovarian cancer prior to either chemotherapy or radiotherapy. The results were compared to similar studies on 12 age-matched normal women. The total peripheral blood lymphocyte counts, proportion of E rosette positive cells, stimulation of T cells by phytohemagglutinin and concanavalin A, recall skin tests, and the ability to have a primary delayed hypersensitivity response to keyhold limpet hemocyanin did not differ between patients and controls. However, patients with ovarian cancer had statistically significant reduction in surface immunoglobulin positive cells, proliferative response to pokeweed mitogen and primary antibody response to keyhole limpet hemocyanin. In contrast to results in patients with other solid tumors, these data indicate that untreated patients with ovarian cancer have evidence of normal cellular immune function but abnormal B cell function.     

Modified administration schedule of adriamycin in solid tumors.

Eighty one patients (59 females, 22 males) with advanced solid tumors were treated with Adriamycin in doses of 40 mg/m2 body surgace daily, in two days cycles, with resting periods of 3 weeks. Overall response rate was 46% (37/81). In breast cancer response rate was 56% (13/23) and in ovarian cancer 48% (13/27). In various other tumors remission was observed in soft tissue sarcomas (3/8), thyroid cancer (1/7), osteogenic sarcoma (1/4), oesophageal cancer (2/4), lung cancer (2/4), bladder cancer (1/2) and hepatoma (1/2). In breast cancer patients, 2-7 month remission duration was observed (M equal to 4.5 month) and in ovarian cancer 1.5-5 month (M equal to 3.2 month). Adriamycin was also applied intrapleurally in 31 patients with malignant pleural effusions with a low response rate (26%). This modified schedule of Adriamycin administration showed a high antitumor activity in breast and ovarian cancer and in soft tissue sarcomas. Squamous cell carcinoma of the esophagus was also sensitive to Adriamycin therapy. The very low rate of myelosuppression and oral ulceration showed the decreased toxicity of this Adriamycin administration schedule.     

The predictive role of thrombocytosis in benign,borderline and malignant ovarian tumors

Abstract

Ovarian cancer is a lethal gynecological malignancy. Although CA-125 is commonly measured in women with adnexal mass, it is estimated that it only has a positive predictive value (PPV) of 69% and a negative predictive value (NPV) of 88% for the detection of ovarian cancer. The aim of this study was to investigate the diagnostic significance and predictive impact of thrombocytosis in women with suspected or confirmed ovarian cancer. This was a retrospective study of women who had surgery for adnexal mass over a 48-month period between September 2014 and September 2018 at Swansea Gynecological Oncology Center in Wales, UK. A total of 294 women who underwent surgery for high-risk pelvic mass or biopsy-confirmed ovarian cancer were identified. 206 women (70%) had final histology confirming ovarian cancer, 54 women (18%) had benign tumors while 34 women (12%) had borderline tumors. 90/206 women (43.7%) with ovarian cancer had thrombocytosis prior to primary surgery or neoadjuvant chemotherapy compared to 8/54 (14.8%) for benign tumors and 4/34 (11.8%) for borderline tumors. Thrombocytosis was observed in 23.2%, 40%, 45.1%, and 65.1% of Stages I, II, III, and IV ovarian cancer, respectively. Thrombocytosis was a stronger predictor of ovarian malignancy in younger women of less than 60 years (p = .041). Overall, the positive likelihood ratio of platelet count in the detection of ovarian cancer was 2.61 while the negative likelihood ratio was 0.72, with a diagnostic odds ratio of 3.625. Thrombocytosis was strongly associated with advanced stage ovarian cancer (Stage III/IV) (p = .002). Interestingly, 4/8 (50%) women with thrombocytosis in the benign ovarian tumor group were diagnosed with ovarian fibroma/fibrothecoma, which often mimics advanced ovarian cancer at presentation. Predictive markers for borderline tumors continue to remain a challenge. We believe that there is a role for platelet count in primary care algorithm for women with suspected ovarian cancer. We suspect that platelets play a role in the metastasis of ovarian cancer.     

Genetic alterations in gynecological malignancies

The aim of the study was to estimate genetic alterations detected in ovarian and cervical cancer cells, in correlation with other available parameters of a histopathological and clinical character and to find the important associations and differences of both these tumor sites with diverse impacts on the cancer's prognosis. Sixty patients presenting with ovarian cancer and twenty patients manifesting cervical cancer were included in the study. The histological type and grade, MIB-1 and p53 were estimated. For genetic testing, both conventional and molecular methods were applied. The results were subjected to statistical evaluation, using analysis of variances and I2 test. Ovarian cancer patients with extensive chromosomal rearrangements were assessed to be significantly younger. The typical findings, different in ovarian and cervical cancer cells have been found, including some less frequent findings (deletion of 22q in 36% of all ovarian cancer samples, as well as amplifications of chromosome 2 and deletions of chromosome 10, 11p and 21q in cervical cancer cells). The expression of proliferation marker MIB-1 was observed to be significantly higher in women with a high p53 HSCORE. The significant importance of genetic alterations and the activity of proliferative markers, including common correlations with an unfavorable outcome with respect to ovarian tumors in younger women were found. Key words: chromosomal rearrangements, genetic alterations, ovarian cancer, cervical cancer, prognostic significance.     

HOXB13 promotes ovarian cancer progression

Deregulated expression of HOXB13 in a subset of estrogen receptor-positive breast cancer patients treated with tamoxifen monotherapy is associated with an aggressive clinical course and poor outcome. Because the ovary is another hormone-responsive organ, we investigated whether HOXB13 plays a role in ovarian cancer progression. We show that HOXB13 is expressed in multiple human ovarian cancer cell lines and tumors and that knockdown of endogenous HOXB13 by RNA interference in human ovarian cancer cell lines is associated with reduced cell proliferation. Ectopic expression of HOXB13 is capable of transforming p53(-/-) mouse embryonic fibroblasts and promotes cell proliferation and anchorage-independent growth in mouse ovarian cancer cell lines that contain genetic alterations in p53, myc, and ras. In this genetically defined cell line model of ovarian cancer, we demonstrate that HOXB13 collaborates with activated ras to markedly promote tumor growth in vivo and that HOXB13 confers resistance to tamoxifen-mediated apoptosis. Taken together, our results support a pro-proliferative and pro-survival role for HOXB13 in ovarian cancer.     

Hormone therapy in epithelial ovarian cancer

Although epidemiologic studies, animal experiments and receptor studies have shown that not only normal ovaries but also many malignant ovarian tumors can be considered as endocrine related and hormone dependent, the place of hormonal therapy in the management of patients with ovarian cancer remains unsettled. Most trials of hormonal treatment in ovarian cancer have been retrospective, involved only limited numbers of patients, and lacked important patient-related data and information pertaining to tumor characteristics. In addition, a variety of hormonal preparations with different degrees of potency and in different dosages were included in these studies. A literature review shows that response to hormonal therapy even in a preterminal setting, is modest, with about 8% objective response but almost no side effects. In a similar patient setting, more toxic therapeutic agents do not yield a better response. The place of hormonal therapy in the management of patients with epithelial ovarian cancer needs more thorough evaluation in well-designed randomized trials.     

Models of ovarian cancer--are we there yet?

Ovarian cancer is the most lethal of all gynecological cancers and arises most commonly from the surface epithelium. Successful clinical management of patients with epithelial ovarian cancer is limited by the lack of a reliable and specific method for early detection, and the frequent recurrence of chemoresistant disease. Experimental models are of crucial importance not only to understand the biological and genetic factors that influence the phenotypic characteristics of the disease but also to utilize as a basis for developing rational intervention strategies. Ovarian cancer cell lines derived from ascites or primary ovarian tumors have been used extensively and can be very effective for studying the processes controlling growth regulation and chemosensitivity or evaluating novel therapeutics, both in vitro and in xenograft models. While our limited knowledge of the initiating events of ovarian cancer has restricted the development of models in which the early pathogenic events can be studied, recent advances in the ability to manipulate gene expression in ovarian surface epithelial cells in vitro and in vivo have begun to provide insights into the molecular changes that may contribute to the development of ovarian cancer. This review highlights the strengths and weaknesses of some of the current models of ovarian cancer, with special consideration of the recent progress in modeling ovarian cancer using genetically engineered mice.     

Changes of lymphocyte subsets in peripheral blood before and after operation of patients with advanced ovarian carcinoma

Summary Comparison was made between lymphocyte subsets in peripheral blood from patients with benign ovarian tumor and those with advanced ovarian carcinoma. In addition, changes of lymphocyte subsets of patients with ovarian carcinoma before and after operation were also examined. The percentage and absolute number of CD3^–/HLA-DR⁺ (B cells) in peripheral blood from patients with advanced ovarian carcinoma were significantly lower than values from patients with benign ovarian tumor, whereas both percentage and absolute number of CD3^–/HLA-DR^– (null cells) cells in patients with advanced ovarian carcinoma were significantly higher. Although there was no significant difference in natural killer (NK) cell subsets (CD57⁺CD16^– and CD57⁺ CD16⁺ cells) between patients with benign ovarian tumor and ovarian carcinoma, the percentage and absolute number of CD57^–/CD16⁺ (highly differentiated NK cells) cells in patients with ovarian carcinoma were significantly higher than those in patients with benign ovarian tumor. Both the absolute number and percentage of CD3⁺/HLA-DR⁺ (activated T cells) cells in ovarian cancer patients with minimal residual tumors after operation were significantly increased, compared to the levels before operation, while the values in the patients with large residual tumors were significantly decreased. In addition, the percentage and absolute number of CD3^–/HLA-DR^– (null cells) cells in the patients with minimal residual tumors were significantly decreased after operation, while values in the patients with large residual tumors remained unchanged before and after operation. The patients with minimal residual tumors after operation were characterized by a significant increase in the percentage of CD57^–CD16⁺ (highly differentiated NK cells) cells. On the other hand, in the patients with large residual tumors no change of the NK cell subsets was observed before and after operation.Abbreviation NK natural killer - FITC fluorescein isothiocyamate - PE phycoerythrin     

Hereditary ovarian cancer

At least 10% of ovarian tumors are hereditary and associated with highly penetrant, autosomal, dominant genetic predisposition. Three clinical manifestations of hereditary ovarian cancer have been identified: site-specific ovarian cancer, hereditary breast and/or ovarian cancer (HBOC) and hereditary non-polyposis colorectal cancer (HNPCC) syndromes. BRCA germline mutations account for more than 90% of all hereditary epithelial ovarian tumors whereas most of the remaining 10% are caused by MLH1 and MSH2 mutations, which are susceptibility genes of HNPCC. Genetic testing is available for each of the three hereditary syndromes above mentioned. The recommendations for OC surveillance in high-risk women having a strong family history or BRCA mutation carriers include transvaginal pelvic ultrasound with color Doppler and serum CA125 every 6 months. Bilateral salpingo-oophorectomy appears to be effective to reduce the risk of ovarian cancer in BRCA mutation carriers. Hysterosalpingo-oophorectomy should be considered in HNPCC women who undergo surgery for colorectal carcinoma.     

FSH and LH serum/tumor fluid ratios and malignant tumors of the ovary

The aim of this work was to compare mean concentrations of gonadotropins in serum and fluid from malignant and benign ovarian tumors. We enrolled 126 patients diagnosed with malignant epithelial tumors (n=40), borderline epithelial tumors (n=14), benign cystadenomas (n=28) and simple cysts (n=44) of the ovary. Premenopausal and postmenopausal subgroups were formed in each group. The concentration of FSH and LH was measured in serum and tumor fluid and the serum/tumor fluid ratio was calculated. The results in each group were compared and the sensitivity, specificity, positive and negative predictive values were determined. Mean concentrations of both gonadotropins in ovarian cancer fluid were significantly higher than in the remaining groups (P ranged from <0.005 to <0.0001). Mean serum/fluid ratios were lowest in ovarian cancer (FSH=2.91, LH=4.19). Our findings support the hypothesis that gonadotropins are involved in ovarian carcinogenesis and suggest that gonadotropin serum/tumor fluid ratios could be of value in the differential diagnosis of functional and organic cysts of the ovary.     

Modified administration schedule of Adriamycin in solid tumors

Summary Eighty one patients (59 females, 22 males) with advanced solid tumors were treated with Adriamycin in doses of 40 mg/m² body surface daily, in two days cycles, with resting periods of 3 weeks. Overall response rate was 46% (37/81). In breast cancer response rate was 56% (13/23) and in ovarian cancer 48% (13/27). In various other tumors remission was observed in soft tissue sarcomas (3/8), thyroid cancer (1/7), osteogenic sarcoma (1/4), oesophageal cancer (2/4), lung cancer (2/4), bladder cancer (1/2) and hepatoma (1/2).In breast cancer patients, 2–7 month remission duration was observed (M=4.5 month) and in ovarian cancer 1.5–5 month (M=3.2 month).Adriamycin was also applied intrapleurally in 31 patients with malignant pleural effusions with a low response rate (26%).This modified schedule of Adriamycin administration showed a high antitumor activity in breast and ovarian cancer and in soft tissue sarcomas. Squamous cell carcinoma of the esophagus was also sensitive to Adriamycin therapy. The very low rate of myelosuppression and oral ulceration showed the decreased toxicity of this Adriamycin administration schedule.Presented at the II. National Congress of Medical Oncology Trieste, Italy, May, 1976