Chemotherapy-induced thrombocytopenia and clinical bleeding in patients with gynecologic malignancy.

OBJECTIVES: Chemotherapy-induced thrombocytopenia seems to be a relevant problem and the risk or clinical bleeding in patients wim gynecologic malignancy is reported to be higher than other malignancy. In this study, the authors investigated chemotherapy-induced thrombocytopenia recently performed in all patients with gynecologic malignancy. MATERIALS AND METHODS: Between January 2009 and December 2011, the authors examined reported chemotherapy-induced thrombocytopenia using the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. They analyzed the incidence and clinical features of chemotherapy-induced thrombocytopenia in patients with gynecologic malignancy. RESULTS: During this period they administered over 1,614 infusions (29 regimens) to 291 patients. Chemotherapy-induced thrombocytopenia occurred in 43 (14.8%) patients over 56 (3.5%) chemotherapy cycles. Bleeding occurred in 13 (4.5%) patients over 14 (0.9%) cycles. Platelet transfusions were administered for eight (2.7%) patients over eight (0.5%) cycles. Median platelet count at platelet transfusions was 17,000 /µl. Chemotherapy-induced thrombocytopenia was associated with more than five previous chemotherapy cycles, previous radiotherapy, disseminated disease, distant metastatic disease, poor performance status, and taxane-including regimens. Clinical bleeding was associated with previous radiotherapy, distant metastatic disease, poor performance status, and taxane-including regimens. CONCLUSIONS: Estimating bleeding risk factor such as previous radiotherapy, distant metastatic disease, poor performance status, and taxane-including regimens seem to be important for safe management of chemotherapy-induced thrombocytopenia.

Late recurrence of malignant melanoma mimicking primary peritoneal cancer.

BACKGROUND: Malignant melanoma is an extremely malignant tumor with an unpredictable metastatic profile with variable periods of remission. CASE: A 41-year-old woman presented with recurrent malignant melanoma which had clinical features of an acute state mimicking primary peritoneal cancer. The case was an unusual recurrence of malignant melanoma occurring seven years after diagnosis and treatment of malignant melanoma in the patient's arm. The diagnosis was established postoperatively by immunohistochemistry. CONCLUSION: A variety of imaging methods and pathological methods, including an exploratory laparotomy, may be necessary in cases of patients suspecting primary peritoneal cancer with a previous history of melanoma with possible metastatic dissemination. Urgent diagnosis and treatment of these patients seems to be critical.

Chemotherapy-related hypersensitivity reaction in Japanese patients with gynecologic malignancy.

PURPOSE OF INVESTIGATION: Chemotherapy-related hypersensitivity reaction seems to be problematic in the safe management of chemotherapy. In this study we investigated chemotherapy-related hypersensitivity reaction in patients with gynecologic malignancy. METHODS: Between January 2009 and December 2010, we examined hypersensitivity reaction (> or = grade2) using the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. We analyzed the incidence, clinical features, management, and outcome. RESULTS: We administered over 1,057 infusions (24 regimens) to 205 patients. We found a total of four hypersensitivity reactions (> or = grade 2) cases (carboplatin: 2; nedaplatin: 1; docetaxel: 1). Signs and symptoms were varied. In two cases, the same regimen was rechallenged by using anti-allergic drugs. The docetaxel case was successful. The carboplatin case was not successful. CONCLUSION: Chemotherapy-related hypersensitivity reaction (> or = grade2) does not occur frequently. In the case of platinum, especially, carboplatin, re-administering after hypersensitivity reaction should be done carefully though platinum is a key drug in patients with gynecologic malignancies.

Pharmacokinetics of paclitaxel and carboplatin in a hemodialysis patient with advanced ovarian cancer.

Paclitaxel and carboplatin combination chemotherapy (TC) is increasingly performed in ovarian cancer patients undergoing hemodialysis. However, appropriate dosage and time interval between the end of carboplatin administration and the initiation of hemodialysis remain unclear. We performed TC in a hemodialysis patient with ovarian cancer. Paclitaxel was administered at 150 mg/m2 for 3 h, followed by administration of 125 mg of carboplatin within 30 min to achieve a target area under the concentration/time curve (AUC) of 5.0 mg/ml x min by Calvert's formula. At 1 h after completing carboplatin administration, hemodialysis was performed for 4 h. Pharmacokinetic analysis showed we had achieved the desired serum concentration of paclitaxel. However, AUC of free platinum was very low (AUC = 0.98 mg/ml x min). Although the appropriate time interval between the end of carboplatin administration and the initiation of hemodialysis remains a controversial issue, our findings suggest that an interval of at least 1 h is required.

Fat and fish intake and asthma in Japanese women: baseline data from the Osaka Maternal and Child Health Study.

OBJECTIVE: It remains controversial whether the intake of n-3 polyunsaturated fatty acids and fish is preventive against asthma. This cross-sectional study investigated the relationship between fat and fish intake and the prevalence of asthma using baseline data from a prospective study. DESIGN: The subjects were 1002 pregnant Japanese females. A diet history questionnaire was used to assess dietary habits. Current asthma and asthma after age 18 were defined as present if subjects had been treated with medications at some time in the previous 12 months and after reaching the age of 18, respectively. RESULTS: Fish consumption was independently associated with a decreased prevalence of asthma after age 18 and current asthma. A significant inverse relationship was observed between the ratio of n-3 to n-6 polyunsaturated fatty acid intake and the prevalence of current asthma, but not asthma after age 18. Intake of total fat, saturated, monounsaturated, n-3 polyunsaturated and n-6 polyunsaturated fatty acids, cholesterol, meat, eggs or dairy products was not evidently related to either outcome for asthma. CONCLUSION: Our results suggest that fish consumption and the high ratio of n-3 to n-6 polyunsaturated fatty acid intake may be associated with a reduced prevalence of asthma in young female Japanese adults.

Anemia-inducing substance from plasma of patients with advanced malignant neoplasms.

Patients with advanced malignant neoplasms develop anemia and immunosuppression. During an attempt to identify the causes, we have found that plasma from such patients makes RBCs more fragile in hypotonic buffer, according to results obtained with a coil planet centrifuge. Plasma from these patients suppresses mitogen-stimulated lymphocyte proliferation. In this study, we identified the substance with these effects as a protein. During two-dimensional gel electrophoresis, two isomers with M(r) 50,000 and slightly different isoelectric points near 6.0 were found. Cell fractionation showed that these proteins were in both the cytosol and the nuclear fraction of cells in neoplasms. Another protein with the same antigenicity and a M(r) 100,000 found in the nuclear fraction of cells in neoplasms.

Elimination of anemia-inducing substance by cyclic plasma perfusion of tumor-bearing rabbits.

We carried out a fundamental study to search for a therapeutic modality that would remove the anemia-inducing substance (AIS) from the plasma of cancer patients because it is thought to be one of the substances responsible for anemia and immunodeficiency in advanced cancer patients. Using AIS isolated from the plasma of patients with advanced ovarian carcinoma, we confirmed that adsorption of AIS to noncoated charcoal was nonspecific and high. Moreover, it was verified that VX2 carcinoma-bearing rabbits are an optimal experimental model for plasma perfusion. The data obtained on day 40 after transplantation (hemoglobin, 9.1+/-2.1 g/dl; osmotic pressure inducing RBC lysis, 137+/-11 mosmol/kg; lymphocyte stimulation index, 8.8+/-8.6; and RBC fragility-inducing activity, 40+/-9 mosmol/kg) proved similar to the hematological findings in patients with cancer cachexia. A 1-h plasma perfusion (3 ml/min) through noncoated charcoal was performed in tumor-bearing rabbits, and it resulted in the restoration of RBC fragility-inducing activity and suppression of lymphocyte blast formation to pretransplantation values. When plasma perfusion was performed every 3 days, RBC fragility-inducing activity, which increased again 3 days after perfusion, was diminished, and RBC osmotic resistance was within the normal range from the fourth perfusion onward. These results showed that cyclic plasma perfusion is effective in sustained removal of RBC fragility-inducing factor from plasma, suggesting that it might have the potential for clinical application.

Expression of apoptosis regulatory proteins in advanced cancer of the uterine cervix after cyclic balloon-occluded arterial infusion chemotherapy.

We have already reported satisfactory therapeutic results of cisplatin-based cyclic balloon-occluded arterial infusion chemotherapy (BOAI) because it enabled advanced cervical cancer of the uterus (cervical cancer) to be treated by simple total hysterectomy (STH). In the present study, we investigated the expression of apoptosis regulatory proteins in advanced cervical cancer treated by cyclic BOAI. The results showed that the proportion of Bax-positive cells was 75.2 +/- 5.6% after the first BOAI in the cases in which STH became possible (group C), and significantly lower, 11.6 +/- 11.7% (p=0.0001), in the cases in which STH remained impossible (group I). The proportion of Bax-positive cells was significantly higher in group C than in group I throughout the treatment period, but there was no significant difference in Bcl-2 expression between the two groups. The survival rate by the Kaplan-Meier method was significantly higher in group C than in group I. These results suggest that the antitumor effect of cyclic BOAI is closely associated with apoptotic cell death, which may in part be influenced by the expression of Bax.

Survivin, bcl-2 and matrix metalloproteinase-2 enhance progression of clear cell- and serous-type ovarian carcinomas.

Clear cell adenocarcinomas (CA), unlike serous adenocarcinomas (SA) of the ovary, are often at stage I, are resistant to platinum-based drugs and have a poor prognosis. The causes of these differences are unclear. In this study, the differences in progression between CA and SA were examined in terms of apoptosis-related and tumor invasion-related factors. The 16 cases of CA and the 16 cases of SA were reviewed. Excised tissues were classified into primary or metastatic loci, and the expressions of survivin, Bcl-2 and matrix metalloproteinase-2 (MMP-2) in each locus immunohistochemically assayed. Whether the expression of each protein was correlated to prognosis was investigated and additionally the invasion ability of cell strains established from CA and SA were examined using in vitro invasion assay. CA at stage I showed significantly higher survivin expression than SA (p<0.05). In CA, survivin tended to be expressed higher in primary locus than in metastatic locus (p=0.068), however, Bcl-2 was expressed relatively higher in the latter (p=0.087). SA did not have these tendencies. While MMP-2 was expressed significantly higher in SA than in CA (p<0.05), and more so in metastatic locus than in primary locus of SA (p<0.05). Invasion assay showed that the invasion of cells derived from SA was significantly inhibited by tissue inhibitors of metalloproteinase-2, an MMP inhibitor. The disease-free interval was significantly shorter when survivin expression was observed in the nucleus. These results suggest that the expression of apoptosis inhibiting factors and enhanced invasion ability affect progression of CA and SA, respectively.

Angiogenesis in the adipose tissue of tumor-bearing rabbits treated by cyclic plasma perfusion.

The mechanisms of cancer cachexia have not been elucidated. We previously reported that cyclic plasma perfusion using non-coated charcoal was effective in cancer cachexia. In the present study we investigated the angiogenic effect of cyclic plasma perfusion on adipose tissue. Twenty rabbits were divided into two groups, i.e., tumor-bearing rabbits subjected to cyclic plasma perfusion (n=10, PP group), and tumor-bearing rabbits subjected to sham-perfusion (n=10, SP group). The changes in body weight, total body fat, and expression of angiogenic factors were investigated. Loss of body weight and total body fat was significantly suppressed in the PP group. Apoptosis of adipocytes was seen in both groups only in the early stage of tumor bearing. Lipolytic activity in the PP group showed a lower ratio than that in the SP group. In the PP group, increased microvessel density and expression of vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) were seen at 40 days after transplantation. Similar findings were not seen in the SP group. These results suggest that cyclic plasma perfusion not only decreased lipolytic activity but induced angiogenesis in the adipose tissue.

Effect of cyclic plasma perfusion on apoptosis regulatory proteins in primary tumors of VX2-carcinoma-bearing rabbits.

Although the mechanism of cancer cachexia is unknown, in previous studies we reported that cyclic plasma perfusion through non-coated charcoal was effective in preventing cancer cachexia. In the present study we investigated the effect of cyclic plasma perfusion on VX2 carcinoma. Sixteen tumor-bearing rabbits were divided into two groups: i) a group subjected to cyclic plasma perfusion (n=8, group PP) and ii) a group subjected to sham-perfusion (n=8, group SP), and changes in body weight, tumor size, and morphological findings were investigated. Body weight loss and tumor growth were significantly suppressed in group PP. The tumor cells in group PP showed apoptosis and a high Bax/Bcl-2 ratio, and the survival rate was significantly higher than in group SP. These results suggest that cyclic plasma perfusion is effective not only in preventing cancer cachexia but in suppressing tumor growth and improving outcome.

Association of the shrinkage of uterine leiomyoma treated with GnRH agonist and deletion of long arm of chromosome 7.

Specific chromosomal abnormalities, such as del(7q), t(12;14), 12 trisomy, or the rearrangement of 6p, are seen in approximately 30% of uterine leiomyomas despite their benign status. We investigated the association between the shrinkage of uterine leiomyomas treated with a GnRH agonist and the interstitial deletion of chromosome 7q, which is one of the most common chromosomal abnormalities in uterine leiomyomas. This study covered 29 women with uterine leiomyomas who were treated with a GnRH agonist before surgery. The volume of the largest myoma nodule was measured by means of MRI before and at 12 weeks after the beginning of GnRH agonist treatment, and the percentage of the reduction in volume was calculated. Genomic DNA was extracted from leiomyoma tissue and peripheral blood, and amplified by PCR using fluorescently-tagged oligonucleotide primers of twelve microsatellite loci on chromosome 7. The PCR products were analyzed for loss of heterozygosity (LOH) using an automated fluorescent DNA sequencer. Of the 29 informative tumors, five (17%) showed LOH with deletion of the common region, D7S491. The mean percentages of the reduction in volume of the largest myomas with LOH or without LOH were 32+/-13 and 18+/-58%, respectively (not significant). One tumor showing interstitial deletion of both alleles (homo-deletion) reduced in volume by 19%. Another tumor showing an extraband increased in volume by 13%. Although tumor specific chromosomal deletion suggested the existence of tumor suppressor genes in this region, there was no significant association between the shrinkage of uterine leiomyomas treated with a GnRH agonist and the interstitial deletion of chromosome 7q.

Combined analysis of p53 and RB pathways in epithelial ovarian cancer.

Disruptions of the p16-CDK4/cyclin D1-pRb pathway (RB pathway) and the p14ARF-MDM2-p53 pathway (p53 pathway) are important mechanisms in the development of human malignancies. In this study, we investigated RB and p53 pathways in 46 epithelial ovarian cancers (EOCs). In the RB pathway, 16 (34.8%) of 46 cases had p16 gene alterations or loss of expression. The deletion of the p16 gene was a rare event. In 7 cases, we observed methylation in the 5'CpG island in the promoter region of the p16 gene. Abnormal expressions of pRb and CDK4/cyclin D1 were 10.9% and 30.4%, respectively. In the p53 pathway, 10 (21.7%) of 46 cases had p14ARF gene alterations or abnormal expression. In 4 cases, methylation in the 5'CpG island in the promoter region of the p14ARF gene was present. MDM2 overexpression was a rare event. Thirty-six (78.3%) of 46 patients had p53 gene alterations or expression. In our studied cases, p14ARF abnormalities were independent of p16 abnormalities. Abnormal RB and p53 pathways were present in 60.9% and 80.4% of cases, respectively. In conclusion, disruptions of p53 and RB pathways are frequent events and the inverse correlations were present between the abnormality of p16 and p14ARF in EOCs.

A simplified method for measuring fetal hemoglobin.

Despite confirmation of the placental location by ultrasound examination, bloody tap during diagnostic and therapeutic amniocentesis may occur. If the blood originates from the fetus, such unfavorable complications as fetomaternal transfusion or maternal sensitization may result. Thus, it is necessary to determine immediatley the origin of the blood by the presence of fetal hemoglobin (HbF) in the specimen. To meet an urgent demand for a simpler and faster method for measuring HbF within a few minutes at bedside without requiring complicated procedures or instrumentation, a method has been developed which uses the alkali denaturation technic.

Ultrastructural comparison of uterine leiomyoma cells from the same myoma nodule before and after gonadotropin-releasing hormone agonist treatment.

OBJECTIVE: To compare ultrastructural features of leiomyoma cells from the same uterine myoma nodule before and after GnRH agonist (GnRH-a) treatment and to examine the relation between these ultrastructural changes and the extent of myoma volume reduction with GnRH-a treatment. DESIGN: Prospective clinical study. SETTING: University teaching hospital. PATIENT(S): Twenty women with uterine leiomyomas who were scheduled for surgery. INTERVENTION(S): Transcervical needle biopsy of uterine myoma, s.c. leuprolide acetate injection (3.75 mg) at least three times every 4 weeks before surgery, and hysterectomy or myomectomy. MAIN OUTCOME MEASURE(S): The changes in ultrastructural features of uterine leiomyoma cells and the percentage decrease in the volume of the largest myoma at 12 weeks of GnRH-a treatment measured by magnetic resonance imaging. RESULT(S): A decrease in myofilaments, mitochondrial swelling, and emergence of the lysosomal body were observed in relation to GnRH-a treatment. Furthermore, a positive correlation was observed between the decrease in myofilaments and myoma shrinkage. CONCLUSION(S): Cellular atrophy due to a decrease in myofilaments plays a major role in the reversible myoma shrinkage resulting from GnRH-a treatment.

Angiogenesis in ovarian clear cell carcinoma and its relation to endometriosis.

Twenty-five patients with ovarian clear cell carcinoma (CC-Ca) were enrolled in this study, and tumor cell expression of vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) was investigated, and correlated with the microvessel count (MVC) and the impact of complication endometriosis. Expression of VEGF was strongly positive in 16 cases, weakly positive in 6 cases, and negative in 3 cases. Expression of PD-ECGF was strongly positive in 11 cases, weakly positive in 6 cases, and negative in 8 cases. VEGF expression and the MVC were significantly correlated (p<0.01), and there were no correlations among complication by endometriosis, expression of VEGF, expression of PD-ECGF, and MVC.

Retrospective study of the prognostic factors of remission induction for single-agent chemotherapy with cisplatin in advanced epithelial ovarian cancer.

A retrospective study to explore the prognostic factor was conducted in 39 patients with advanced epithelial ovarian cancer, FIGO stage III-IV, who underwent single-agent adjuvant chemotherapy with cisplatin following primary debulking surgery. The survival rate following the adjuvant chemotherapy was 50.9% after 3 years and 44. 7% after 5 years, with a median survival time of 40.4 months. The actual dose intensity of the cisplatin ranged from 14.38 to 46.30 mg/m2/week, and the total dose/m2 was 143.79 to 645.83 mg/m2. Under these therapeutic conditions, the actual dose intensity was found to correlate with survival time (p<0.05), but there was no correlation between the total dose/m2 and survival time.

Bleomycin, actinomycin-D, and cisplatin treatment of ovarian germ-cell malignancies contributes to reducing adverse drug reactions.

Sixteen ovarian germ-cell malignancy (OGCM) patients between 1983 and 1999 were randomly divided into the BEP group (n=6; bleomycin, etoposide and cisplatin) and the BAP group (n=10; bleomycin, actinomycin-D and cisplatin). The patients were evaluated for adverse drug reactions (ADRs) based on severity-grading of the National Cancer Institute Common Toxicity Criteria. The ADRs in the BAP group were milder than in the BEP group, as seen in regard to alopecia (p=0.0126), low hemoglobin (p=0.0147), and decreased neutrophil count (p=0.0197). The five-year survival rate was 87.5% in the BAP group and 83.3% in the BEP group, and the difference was not significant (p=0.5954). BAP therapy is likely to be more beneficial for OGCM patients than BEP therapy, because ADRs are reduced with no difference in outcome.

An intranodal morcellation technique employing loop electrosurgical excision procedure for large prolapsed pedunculated myomas.

For minimally invasive resection of large prolapsed pedunculated submucous myomas, improved techniques need to be established. An intranodal loop electrosurgical excision procedure (LEEP) was specifically developed for the morcellation of myoma tissue during vaginal myomectomy. Vaginal myomectomy was performed on a 28-year old woman with a large myoma occupying the small pelvis. A prolapsed pedunculated leiomyoma of the uterus 13 cm in maximal diameter was resected by intranodal morcellation of the myoma tissue employing LEEP. Intranodal morcellation technique utilizing LEEP is an effective method for the minimally invasive resection of large prolapsed pedunculated myomas.

Kinetics of plasma platinum in a hemodialysis patient receiving repeated doses of cisplatin.

The pharmacokinetics of cisplatin were studied in a 46-year-old hemodialysis patient treated for uterine cancer with weekly cisplatin. Hemodialysis was performed immediately before, one-hour after, and two-hours after cisplatin administration for two consecutive cycles each. The concentrations of total and free platinum were measured. The decay curve of both total platinum and free platinum showed a biphasic pattern characterized by an alpha-phase and a beta-phase, the same as in non-hemodialysis patients. There were no differences between the individual cycles in the peak platinum concentration or the decay pattern. The plasma platinum concentration decreased to below detection limit 3 months after the final dose.