Rivaroxaban Used in the Treatment Patients With Gynecologic Cancer and Venous Thromboembolism: The Experience of Instituto Nacional de Câncer-Rio de Janeiro, Brazil.

INTRODUCTION: Venous thromboembolism (VTE) is a major complication of malignant diseases and is a frequent cause of death in patients with cancer. Managing anticoagulation in these patients is challenging because of the high risk of recurrent VTE and bleeding events. Rivaroxaban is an oral anticoagulant that provides rapid onset of anticoagulation. OBJECTIVE: The aim of this study was to describe the complications of rivaroxaban and potentially associated factors in patients with gynecologic cancer and VTE. METHODS: This was an observational study in women with gynecological cancer who developed VTE and were treated with 15 and 20 mg rivaroxaban at Instituto Nacional de Câncer from July 2014 to July 2015. RESULTS: Forty-one patients were treated with rivaroxaban. Most patients were younger than 60 years and presented cervical cancer; 58.5% of women did not have complications, thus remaining at a dose of 20 mg/d. Because of complications, 12.2% had the dose reduced to 15 mg/d, 12.2% had the drug suspended, 7.3% had progressive worsening of the disease with suspension of anticoagulation, and 9.8% progressed to death because of progression of the disease. CONCLUSIONS: Rivaroxaban has been documented as a low-cost, easily controlled option compared with standard therapy. Most participants in this study had no complications. However, it was not possible to assess associations with statistical significance. Further analytical studies with larger samples are required to evaluate the safety and efficacy of this treatment in patients with gynecologic cancer.

Prevention of blood transfusion with intravenous iron in gynecologic cancer patients receiving platinum-based chemotherapy.

OBJECTIVES: To compare the efficacy of intravenous iron and oral iron for prevention of blood transfusions in gynecologic cancer patients receiving platinum-based chemotherapy. MATERIALS AND METHODS: Sixty-four non anemic gynecologic cancer patients receiving adjuvant platinum-based chemotherapy were stratified and randomized according to baseline hemoglobin levels and chemotherapy regimen. The study group received 200mg of intravenous iron sucrose immediately after each chemotherapy infusion. The control group received oral ferrous fumarate at a dose of 200mg three times a day. Complete blood count was monitored before each chemotherapy infusion. Blood transfusions were given if hemoglobin level was below 10mg/dl. RESULTS: There were 32 patients in each group. No significant differences in baseline hemoglobin levels and baseline characteristics were demonstrated between both groups. Nine patients (28.1%) in the study group and 18 patients (56.3%) in the control group required blood transfusion through 6 cycles of chemotherapy (p=0.02). Fewer median number of total packed red cell units were required in the study group compared to the control group (0 and 0.5 unit, respectively, p=0.04). Serious adverse events and hypersensitivity reactions were not reported. However, constipation was significantly higher in the control group (3.1% and 40.6%, p=<0.001). CONCLUSIONS: Intravenous iron is an effective, well-tolerated treatment for primary prevention of blood transfusions in gynecologic cancer patients receiving platinum-based chemotherapy, associated with less constipation than the oral formulation.

The effects of selenium supplementation on the spontaneously occurring fibroid tumors of oviduct, 8-hydroxy-2'-deoxyguanosine levels, and heat shock protein 70 response in Japanese quail.

Oxidative stress is known to be an important contributing factor in many chronic diseases. Spontaneously occurring benign oviduct leiomyomas are common tumors of the Japanese quail (Coturnix coturnix japonica), which makes it a good animal model for screening potential agents for testing in the prevention and treatment of human myoma uteri. Since dietary intake of selenium has been associated with a reduced risk of a variety of human cancers, we investigated the effects of selenium supplementation on the development of leiomyomas in the Japanese quail. Potential mechanisms of action of selenium include its antioxidant properties and modulation of heat shock protein 70 (Hsp70); therefore, we measured levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-isoprostane levels, and Hsp70 expression in tissue specimens obtained from the quails. One hundred and eighty quails (8 mo old) were assigned to 3 treatment groups consisting of 60 birds in each group. Birds were fed either a basal diet containing 0.048 mg Se per kg or the basal diet supplemented with 0.2 mg or 0.4 mg of selenium (Selenomax, yeast-bound l-selenomethionine, 60%) per kg of diet. The animals were sacrificed after 250 days, and the tumors were identified. Selenium supplementation did not affect the number of leiomyomas as compared to control subjects (P > 0.05). However, the tumors in selenium fed birds were smaller than those found in control birds (P = 0.01). Serum Se increased (P = 0.01), whereas MDA and 8-isoprostane, 8-OHdG concentrations decreased (P = 0.01) with selenium supplementation (P = 0.01). Selenium supplementation decreased Hsp70 in the tissue of birds. The results indicate that dietary supplementation with selenium reduces the size of spontaneously occurring leiomyoma of the oviduct in the Japanese quail.

Use of a leucocyte filter to remove tumour cells from intra-operative cell salvage blood.

SUMMARY: The intra-operative blood loss of 50 consecutive gynae-oncology patients undergoing surgery for endometrial, cervical or ovarian cancer was cell salvaged and filtered. In each case blood samples were taken from the effluent tumour vein, a central venous line, the cell saver reservoir, the cell salvage re-transfusion bag after processing but before filtration and from the cell salvage re-transfusion bag after processing and filtration. Samples were examined using immunohistochemical monoclonal antibody markers for epithelial cell lines. Viable, nucleated malignant cells were detected in 2/50 central venous samples, 34/50 reservoir samples and 31/50 unfiltered cell salvaged samples. After passage through a Pall RS leucocyte depletion filter no remaining viable, nucleated malignant cells were detected in any sample. The clinical risks of cell salvage in these circumstances should be reviewed in the light of the risks of allogeneic blood transfusion.

Dietary tomato powder supplementation in the prevention of leiomyoma of the oviduct in the Japanese quail.

Spontaneous leiomyomas of the oviduct are common tumors of the Japanese Quail (Coturnix coturnix japonica), which makes it a good animal model for screening potential agents for testing in the prevention and treatment of human myoma uteri. We have previously reported a decreased incidence of leiomyomas in the oviduct of Japanese quail with lycopene supplementation. Although the major carotenoid in tomatoes is lycopene, tomatoes also contain other compounds, which may contribute to their health benefit. Therefore, in this study, we investigated the effects of tomato powder supplementation on the development of leiomyomas in the oviduct of Japanese quail. We also measured serum levels of malondialdehyde (MDA), carotenoids, and vitamins C, E, and A. A total of 150 quails (3 mo old) were assigned to 3 treatment groups consisting of 5 replicates of 10 birds in each group. Birds were fed either a basal diet (control group) or the basal diet supplemented with 25 g (Treatment I) or 50 g (Treatment II) of tomato powder (0.8 mg lycopene per g of tomato powder) per kg of diet. The animals were sacrificed after 365 days, and the tumors were identified. Tomato powder supplementation significantly decreased the number of leiomyomas as compared to control birds (P < 0.01). The tumors in tomato powder fed birds were smaller than those found in control birds (P < 0.01). Serum lycopene, lutein, zeaxantin, and vitamins C, E, and A increased (P = 0.01), whereas MDA concentrations decreased (P = 0.01) with tomato powder supplementation. No measurable lycopene could be detected in the serum of control birds, whereas a dose-dependent increase was observed in the serum of birds supplemented with tomato powder. The results indicate that dietary supplementation with tomato powder reduces the incidence and size of spontaneously occurring leiomyoma of the oviduct in the Japanese quail. Clinical trials should be conducted to investigate the efficacy of tomato powder supplementation in the prevention and treatment of uterine leiomyoma in humans.

The antioxidative role of selenium in pathogenesis of cancer of the female reproductive system.

Selenium, as a component of few antioxidant enzymes, participates indirectly in elimination of reactive oxygen species and in antioxidative defense of the organism. There is a correlation between the concentration of selenium, activity of glutathione peroxidases (GSH-Px), and other parameters of antioxidative defense in blood components. The above mentioned factors were suggested to play an important role in etiopathogenesis of neoplastic diseases. Therefore, the aim of our present study was to compare the selenium status and GSH-Px activity in the plasma of 22 healthy women, 50 individuals suffering from cancer of uterine cervix, uterine corpus or ovary, and 49 women diagnosed with benign neoplasia of the uterine corpus or ovary. In addition, the selenium concentration was measured in postoperative cancer tissues, benign tumors, and histopatologically healthy surgical margins of the aforementioned patients. An average selenium concentration and GSH-Px activity in blood plasma of cancer patients and benign neoplasia patients was significantly lower than in the plasma of healthy women. It suggests that lower overall selenium status and lower selenium-dependent antioxidative capacity of the organism might partly contribute to development of neoplastic diseases of reproductive system. Postoperative tissues of patients revealed significantly higher selenium concentrations in cancer tissues of uterine cervix and corpus, and benign tumors of uterine corpus, as compared to corresponding healthy tissue margins. Higher accumulation of selenium in these neoplastic tissues might reflect a compensatory up-regulation of antioxidant defense systems in tumors that often undergo a persistent oxidative stress.

A novel method of preoperative autologous blood donation with a large volume of plasma for surgery in gynecologic malignancies.

The objective of this study was to establish a novel method of preoperative autologous blood donation (PAD) for surgery of gynecologic malignancies, which requires considerable amounts of plasma relative to the red blood cell component. To collect a double volume of plasma over the amount obtained from whole blood without using an aphaeresis system, we first collected 500 ml of whole blood (2.5 units), and centrifuged it. We gave back the resultant red cell component alone, and retained the plasma component. We further collected an additional 500 ml of whole blood, and centrifuged it. The red cell component (2.5 units) was stored in the refrigerator (as a concentrated red cell, CRC). The resultant plasma together with the plasma collected first (5 units) was frozen and stored in the freezer (fresh frozen plasma, FFP), We repeated this procedure at most three times at intervals of 1 week. Erythropoietin was injected once a week and iron tablets were prescribed. Ninety-nine patients undergoing surgery for a gynecological malignancy were subjected to this method and 86 patients without PAD served as a control. We conducted the procedure for PAD without any noticeable side effects. The amount of actual use of allogeneic CRC and FFP were significantly reduced in the PAD group compared with the control group. In particular, 93.6% of the PAD cases who gave 10 or less units of FFP could go without allogeneic FFP. Postoperative serum albumin levels were higher in the PAD group compared with the control. We have established a novel PAD method which can yield a greater volume of FFP relative to CRC, thus meeting requirements for surgery for gynecological malignancies.

[Reactive oxygen species as an inducing factor of neoplasms of female reproductive organs ]. / Reaktywne formy tlenu jako jeden z czynników rozwoju nowotworów narzadów plciowych kobiet.

AIM: In our study we measured selenium concentration in the blood of women with diagnosed cancer and benign tumors. The results were compared with healthy women. Some other parameters of the antioxidant system in all studied groups were also investigated, namely, activity of glutatione peroxidase, superoxide dismutase, as well as the levels of glutathione and malondialdehyde. MATERIAL AND METHODS: All parameters were determined in peripheral blood of (a) 47 women with diagnosed cancer (b) 46 women with diagnosed benign tumors, and (c) 20 healthy women (control group). Statistical analysis of the results was performed using "Statistica" software. RESULTS: Our results showed lower selenium concentration in the whole blood and plasma of cancer and benign tumor patients as compared to healthy women. An activity of glutathione peroxidase in erythrocytes and plasma were also lower in both patients' groups than in the control group. Statistical analysis of data revealed a positive correlation between selenium concentration and glutathione peroxidase activity in plasma. Lower activity of superoxide dismutase and increased concentration of malondialdehyde was noted in plasma of cancer patients as compared to healthy women. CONCLUSIONS: 1. A status of antioxidant systems plays an important role in carcinogenesis. 2. The antioxidant system of the women suffering from cancer is deficient. 3. A capacity of that system depends greatly on the concentration of antioxidants and activity of antioxidant enzymes, among them glutathione peroxidase.

Viability of gynecological malignant cultured cells after 4 degrees C storage in citrate-phosphate-dextrose solution.

For the surgery of gynecological malignant tumors, a predeposit type of autologous blood transfusion has been widely used. However, using molecular biologic techniques, malignant cells have been found in the peripheral blood of cancer patients. Therefore, to evaluate the utility of presurgical blood deposits, we studied the survival of gynecological malignant cultured cells after 4 degrees C storage in citrate-phosphate-dextrose solution. Ten cultured cell lines derived from gynecological malignant tumors were used. Mixtures of 1 x 105 cells, culture medium, and citrate-phosphate-dextrose (CPD) solution were stored at 4 degrees C. After 0, 1, 4, 8, 15, or 22 days of storage, cells were placed in 96-well microtiter plates in culture medium with 1 x 104 cells/100 micro l/well. After 24 h culture in the incubator, the survival rate was calculated from the optical density by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay. More than 10% of surviving cells were seen in nine cell lines after 4 days of storage, in seven cell lines after 8 days, in three cell lines after 15 days, and in two cell lines after 22 days. Cancer cells in presurgical blood deposits may survive a 3-week storage period at 4 degrees C in CPD solution.

Haptoglobin-alpha subunit as potential serum biomarker in ovarian cancer: identification and characterization using proteomic profiling and mass spectrometry.

PURPOSE: The objective of this study was to identify and characterize new serum biomarkers in ovarian cancer patients using mass spectrometric protein profiling and specific immunological assays. EXPERIMENTAL DESIGN: Serum samples from 80 cancer patients and 91 healthy women were analyzed by surface enhanced laser desorption and ionization-mass spectrometry (MS) profiling. A candidate biomarker was purified by affinity chromatography, and its sequence was determined by liquid chromatography-tandem MS. An antibody was generated from the synthesized peptide for quantitative validation in the cases and controls. CA125 was determined and compared with the same set of specimens. RESULTS: Using surface enhanced laser desorption and ionization, we found a serum biomarker at approximately 11700 Da, which had peak intensity significantly higher in cases (1.366) compared with controls (0.208, P = 0.002), and subsequently identified this as the alpha chain of haptoglobin. ELISA indicated that Hp-alpha was

The utility of a growth factor: r-HuEPO as a treatment for preoperative autologous blood donation in gynecological tumor surgery.

The use of r-HuEPO and sodium ferrous gluconate has been shown to be a safe and effective treatment which can be used by transfusional centers and surgeons to avoid allogeneic blood transfusions and to schedule short-term selective surgery. In this study the authors submitted 20 patients scheduled to undergo surgery for gynecological tumors to a program of pre-operative autologous blood donation. All the patients received both r-HuEPO and sodium ferrous gluconate in the pre- and post-donation period. r-HuEPO was administered subcutaneously in a dose of 200 IU/kg thrice weekly during the week before and after autologous blood donation (400 ml). Sodium ferrous gluconate was administered intravenously shortly before the first and fourth administration of 125 mg of r-HuEPO. Surgery was scheduled to be performed 10-15 days after the last r-HuEPo administration, i.e. within 15-20 days from blood donation. All the patients were tested for the following blood chemistry parameters: hematocrit, hemoglobin, sideremia and ferritin at treatment start, prior to donation, at treatment end, prior to autologous blood infusion and on the third and seventh day after surgery. No patient receiving r-HuEPO required allogeneic blood transfusion as both the hematocrit and hemoglobin values remained normal. r-HuEPO was observed to be a safe and effective treatment to be used in autologous blood donation programs in all patients scheduled to undergo surgery. It limits the decrease of hematocrit values following autologous blood donation thus enabling all the patients who for a variety of reasons to refuse allogeneic blood infusion to predeposit autologus blood shortly before the date scheduled for surgery.

[Blood transfusion in surgical gynecology. Strategies for preventing homologous blood transfusion]. / Blutbedarf in der operativen Gynäkologie. Strategien zur Vermeidung von Fremdblut.

A statistical evaluation of homologous blood transfusions is imperative in any gynecological surgical department, to be able to define the transfusion-associated risk of the individual interventions. On the basis of our own statistical data and reports in the literature, strategies for limiting the use of homologous blood are discussed. So far, experience with autologous blood transfusion in surgical gynecology is limited, and clinical studies are needed to better define its role. In special cases, the use of erythropoietin and gonadotropin-releasing hormone (GnRH) analogues extends the possibilities for reducing homologous blood transfusion.

Evaluation of two functional assays for protein C inhibitor/plasminogen activator inhibitor-3 activity.

Two functional assays for protein C inhibitor (PCI) were evaluated in parallel for the same plasma samples. One assay is specific for active PCI and measures its ability to form complexes with activated protein C (APC) in the presence of heparin (España et al, Thromb Res 64, 309, 1991) (Method A). After incubation of samples with heparin and an excess of APC, the amount of APC:PCI formed is measured by an ELISA. The second functional PCI assay is based on the determination of the residual amidolytic activity of the APC added to the sample. In all cases a good correlation was obtained with both methods. For 20 healthy subjects and 20 patients before surgery, there were no significant between-assay differences in the levels of functional PCI activity. On the other hand, there were significant between-assays differences in the levels of functional PCI of the 20 patients measured 1 and 3 days after surgery. In this case, method B gave higher values than method A (38% +/- 13% versus 29% +/- 11% at day 1 and 59% +/- 16% versus 43% +/- 12% at day 3) (mean +/- SD). The level of alpha 1-antitrypsin (alpha 1 AT), the second major plasma APC inhibitor, was significantly increased in patients at day 1 and day 3 (133% +/- 30% and 190% +/- 57%, respectively). Furthermore, there was a positive correlation between the level of alpha 1AT and the normalized difference between the level of functional PCI measured by method B and that measured by method A. Additionally, when normal plasma was supplemented with increasing amounts of purified alpha 1AT, the level of PCI activity measured by method B increased parallel to the increase in alpha 1AT added, but that measured by method A did not. Determination of APC:inhibitor complexes in aliquots of the final mixtures utilized in the PCI assays revealed that the level of APC:alpha 1AT complex increased parallel to the increase in the amount of alpha 1AT added, whereas the APC:PCI complex level remained unchanged. We conclude that current functional PCI assays based on the determination of APC residual activity in plasma are not specific for PCI, are influenced by the level of plasma alpha 1AT and are not reliable for the determination of functional PCI levels in patients with altered levels of alpha 1AT.(ABSTRACT TRUNCATED AT 400 WORDS)

[Concentration of selenium and vitamin E in the serum of women with malignant genital neoplasms and their family members]. / Stezenie selenu i witaminy E w surowicy krwi kobiet z nowotworami zlosliwymi narzadów plciowych oraz u czlonków ich rodzin.

Lower concentrations of selenium and vitamin E were found in the serum of 50 women with malignant neoplasms of the genitals as compared with the concentrations in 55 healthy women family members of the patients living with them in common households. The degree of concentration decrease of these substances in the serum depended on the location of the tumour, and in cases of cervical neoplasms was 28% for selenium and 12% for vitamin E of the values in controls while in cases of ovarian neoplasms it was 34% and 37% respectively and in endometrial tumours it was 40% and 23% respectively. The third studied group comprised 36 healthy subjects not belonging to the families of the patients. The highest concentrations of selenium and vitamin E were found in the serum in the third group of women. The results suggest that various family factors not analysed in this study affect the concentrations of selenium and vitamin E in the serum of women with malignant neoplasms of genitals and in their family members.

Serum vitamin E level and risk of female cancers.

A sample of 15,093 women, aged 15-99 and initially free from cancer, participated in the Finnish Social Insurance Institution's Mobile Clinic Health Survey in 1968-71. A record linkage to the Cancer Registry revealed that during a mean follow-up of eight years cancer was diagnosed in 313 women. Serum alpha-tocopherol levels were measured from stored samples (at -20 C) of the cancer patients and of 578 controls, matched for municipality and age. An inverse relation was observed between alpha-tocopherol level and risk of cancer, even if the cancers in the first two years of follow-up were excluded. Women in the lowest quintile for alpha-tocopherol levels compared to those with higher values had a 1.6-fold (95% confidence interval: 1.1-2.5) risk of cancer as adjusted for possible confounding effects of several other factors. A low level of alpha-tocopherol in general strongly predicted epithelial cancers while it carried an only slightly elevated risk of cancers in reproductive organs exposed to oestrogens. The results suggest that a low vitamin E intake is a risk factor for cancer in many, but not all, organs. The expression of its protective effect may depend on the primary causes, which vary between different cancers.

Serum selenium and thromboxane in patients with gynaecological cancer.

To explore the relationships between the antioxidant selenium and pro-aggregatory thromboxane A2 in patients with gynaecological cancer, we measured the serum concentrations of selenium and the production of thromboxane B2 (TxB2, a stable metabolite of thromboxane A2) by the aggregating platelets in patients with endometrial (n = 35), ovarian (n = 30) and cervical cancer (n = 25), and in 32 control women. The selenium concentration in endometrial (1.14 +/- 0.04 mumol/l; mean +/- SE), ovarian (0.96 +/- 0.04 mumol/l) and cervical cancer (0.97 +/- 0.06 mumol/l) was significantly lower than in control subjects (1.26 +/- 0.03 mumol/l). The release of TxB2 into serum during spontaneous clotting of the blood was significantly increased in ovarian cancer (229.2 +/- 15.9 ng/ml), decreased in endometrial cancer (142.6 +/- 12.4 ng/ml) and normal in cervical cancer (185.9 +/- 14.8 ng/ml) as compared with control subjects (185.9 +/- 11.9 ng/ml). The levels of selenium and TxB2 did not correlate with each other in the whole series or in any subgroup. Thus, selenium does not seem to be an important determinant in the biosynthesis of TxB2 in patients with gynaecological malignancy.

Annual variation of serum selenium in patients with gynaecological cancer during 1978-1983 in Finland, a low selenium area.

To explore the relationship between selenium deficiency in cancer and nutritional factors, we measured the serum concentrations of selenium in 1978-1983 in patients with gynaecological cancer (N = 277) and correlated these with the estimated daily intake of selenium, which varies in Finland depending on the proportion of selenium-rich imported grain. The selenium concentration increased significantly from 1978-1979 to 1982 in the series of all cancer patients (p less than 0.001) and separately in cases of cervical (p less than 0.001) and endometrial cancer (p less than 0.02), parallel to the increased daily intake of selenium. The serum level of selenium decreased in 1983, when the import of selenium-rich grain was reduced. Low serum selenium in cancer patients thus seems to be mainly dependent on dietary factors.

Serum selenium and glutathione peroxidase, and plasma lipid peroxides in uterine, ovarian or vulvar cancer, and their responses to antioxidants in patients with ovarian cancer.

The concentrations of serum selenium and plasma lipid peroxides, and the activity of serum glutathione peroxidase (GSH-Px) were measured before any therapy in patients suffering from uterine, ovarian or vulvar cancer, and in association with 1-day combination cytotoxic chemotherapy of ovarian cancer following 1-week supplementation with selenium (96 micrograms/day), vitamin E (300 mg/day), selenium and vitamin E, or placebo. Patients with gynaecological cancer (N = 44) had lower serum concentration of selenium (1.15 +/- 0.04 S.E. mumol/l; P less than 0.05) and serum activity of GSH-Px (404 +/- 13 units/l, P less than 0.01) than the control subjects (N = 56; 1.25 +/- 0.03 mumol/l and 444 +/- 8 units/l, respectively). In association with cytotoxic chemotherapy selenium alone (P less than 0.05), vitamin E alone (P less than 0.05) and both of them together (P less than 0.001) decreased the plasma concentration of lipid peroxides, and the combination of selenium and vitamin E also increased the activity of serum GSH-Px (P less than 0.01). During placebo, cytotoxic chemotherapy did not affect plasma lipid peroxides but it decreased (P less than 0.001) the activity of GSH-Px. Selenium inhibited this effect. Our data suggest that antioxidative mechanisms of patients with gynaecological cancer may be defective and that treatment with selenium and vitamin E results in changes of biochemical factors related to lipid peroxidation.

[Ozone-oxygen therapy for gynecologic carcinomas. The effect of parenteral-ozone oxygen mixture administration on free fatty acids and triglycerides in patients with gynecologic carcinomas]. / Ozon-Sauerstoff-Therapie bei gynäkologischen Karzinomen. Der Einfluss von parenteraler Ozon-Sauerstoff-Gemisch-Applikation auf freie Fettsäuren und Triglyzeride bei Patientinnen mit gynäkologischen Karzinomen.

As some authors suspect that ozone influences the metabolic process of fat, we tried to analyse the influence of an ozone-oxygen gas which was applied parenterally. 40 patients with gynecological cancer received 10 ml ozone-oxygen gas with a content of 450 gamma ozone and venous blood was removed before and 10 minutes after application. The serum was lyophilized and the level of fatty acids and triglycerids was determined by the method of Randerath (1965). a statistically significant decrease of the concentrations was observed after application of ozone. Different theories as to the cause of this action are discussed.