Time-to-Event Analysis of Polatuzumab Vedotin-Induced Peripheral Neuropathy to Assist in the Comparison of Clinical Dosing Regimens.

Polatuzumab vedotin, an antibody-drug conjugate containing monomethyl auristatin E, was associated with an incidence of grade ≥2 peripheral neuropathy (PN) of 55-72% in patients with indolent non-Hodgkin lymphoma in a phase II study, when dosed 1.8-2.4 mg/kg every 3 weeks until progression or for a maximum of 17 cycles. To quantify the correlation of conjugate exposure and treatment duration with PN risk, a time-to-event model was developed using data from phase I and II studies. The model suggested that PN risk increased with conjugate exposure and treatment cycles, and a trend for increased risk with body weight and albumin concentration. When capping the treatment duration to six to eight cycles, the risk ratio of a dose of 2.4 mg/kg vs. 1.8 mg/kg was ≥1.29; the predicted incidence of grade ≥2 PN at 1.8-2.4 mg/kg dose levels was 17.8-37.2%, which is comparable with other antimicrotubule agents for lymphoma treatment.

Integrated Two-Analyte Population Pharmacokinetic Model for Antibody-Drug Conjugates in Patients: Implications for Reducing Pharmacokinetic Sampling.

An integrated pharmacokinetics (PK) model that simultaneously describes concentrations of total antibody (Tab) and antibody-conjugated monomethyl auristatin E (acMMAE) following administration of monomethyl auristatin E (MMAE)-containing antibody-drug conjugates (ADCs) was developed based on phase I PK data with extensive sampling for two ADCs. Two linear two-compartment models that shared all parameters were used to describe the PK of Tab and acMMAE, except that the deconjugation rate was an additional clearance pathway included in the acMMAE PK model compared to Tab. Further, the model demonstrated its ability to predict Tab concentrations and PK parameters based on observed acMMAE PK and various reduced or eliminated Tab PK sampling schemes of phase II data. Thus, this integrated model allows for the reduction of Tab PK sampling in late-phase clinical development without compromising Tab PK characterization.

High-temperature-required protein A2 as a predictive marker for response to chemotherapy and prognosis in patients with high-grade serous ovarian cancers.

BACKGROUND: High-temperature-required protein A2 (HtrA2), a protein relating with apoptosis in a caspases-dependent and non-dependent manner, has been reported to be associated with chemosensitivity in several human cancers. METHODS: Tissue microarrays made from 142 patients with high-grade serous ovarian adenocarcinoma were evaluated to assess whether HtrA2 expression was related with several clinical parameters. RESULTS: Negative HtrA2 expression was observed in 36 cases (25%) of the patients, and related with significantly lower response rates of primary chemotherapy than those with positive HtrA2 expression (56% vs 83%, P<0.01). In addition, negative HtrA2 expression was identified as an independent worse prognostic factor for progression-free survival and overall survival by multivariate analyses. Furthermore, HtrA2 downregulation modulated sensitivity to platinum in serous ovarian cancer cells in vitro. CONCLUSIONS: HtrA2 expression was a predictor for sensitivity to chemotherapy, and could be a candidate of molecular target in the treatment of high-grade serous ovarian cancers.

UGT1A1 genotype-specific phase I and pharmacokinetic study for combination chemotherapy with irinotecan and cisplatin: a Saitama Tumor Board study.

INTRODUCTION: Genotyping of UGTI1Al could be useful for prediction of severe toxicities for patients treated with irinotecan; however, genotype-based recommended dose (RD) has not been established. The aim of the present study was to determine the RD of irinotecan in combination with cisplatin (CPT-P) for individuals with or without UGT1A1 polymorphisms. MATERIALS AND METHODS: According to polymorphisms of UGTIAl*28, *6, and *27, RDs were determined by three-case cohort methods for patients with wild-type and heterotype, and by inter-patient dose escalation for homotype patients. Pharmacokinetic studies were also evaluated. During May 2009 and July 2011, 18 Japanese patients were enrolled; 16 patients with ovarian carcinoma, and two cases with cervical cancer. The RD of irinotecan was determined as 50 mg/m2 for the patients with wild-type, 40 mg/m2 for those with heterotype, and 30 mg/m2 for homotype UGT IAl genotype. RESULTS: Patients with homotype UGTIAl1 alleles had a significantly lower glucuronidation ratio in comparison with UGTIAI wild-type and heterotype cases. CONCLUSION: UGT1A1 genotype-based RDs of irinotecan in CPT-P therapy were determined. Further studies to investigate efficacy of the RD including response evaluation are needed to confirm the present results.

Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort treated predominantly in community practices.

BACKGROUND: Because follicular lymphoma (FL) patients have heterogeneous outcomes, the FL international prognostic index (FLIPI) was developed to risk-stratify patients and to predict survival. However, limited data exist regarding the role of FLIPI in the era of routine first-line rituximab (R) and R-chemotherapy regimens and in the setting of community oncology practices. PATIENTS AND METHODS: We evaluated the outcome data from the National LymphoCare Study (NLCS), a prospective, observational cohort study, which collects data on patients with FL in the United States (US) community practices. RESULTS: Among 1068 male and 1124 female patients with FLIPI data, most were treated in US community practices (79%); 35% were FLIPI good risk, 30% intermediate risk, and 35% poor risk. FLIPI risk groups were significant predictors of overall survival (OS) and progression-free survival (PFS) for patients who undergo watchful waiting (WW), and those who receive non-R-containing regimens, R-alone, and R-chemotherapy combinations. CONCLUSIONS: In the setting of contemporary practice with routine R use, stratifying patients into good, intermediate, and poor FLIPI risk groups predicts distinct outcomes in terms of OS and PFS. FLIPI remains an important prognostic index in the R era and should be used in clinical practices to support discussions about prognosis.

Prognosis of high-grade endometrial cancer: a comparison of serous-type and clear cell type to grade 3 endometrioid-type.

OBJECTIVE: To evaluate prognosis of high-grade endometrial cancers, comparing serous (SC) and clear cell (CCC) types to grade 3 endometrioid carcinoma (ECG3). METHODS: Among patients with endometrial cancer treated in two decades, medical records of patients with high-grade endometrial cancer were retrospectively investigated. RESULTS: Of 447 endometrial cancers, 107 (24%) high-grade endometrial cancers were identified, with the increasing incidence in the last decade (28% vs 19%; p = 0.026). There were 24 SC, 14 CCC and 69 ECG3. Median age was 62, 68, and 61 years, respectively, with the CCC type showing an elder age than the ECG3 type (p = 0.012). The rates of patients with Stage IIIc-IV, lymph node assessment or complete resection at primary surgery, and post-operative chemotherapy were not significantly different; however, response rate to first-line chemotherapy in patients with measurable disease was lower in SC than ECG3 (3 / 11, 27% vs 14 / 19, 74%; p = 0.037), regardless of regimens. Five-year overall survival (OS) was 40%, 71%, and 71% respectively, and five-year progression-free survival (PFS) was 25%, 71%, and 61%, respectively, showing SC with worse prognosis than ECG3 on both OS (p = 0.026) and PFS (p = 0.0028). According to the multivariate analysis, age > or = 70, Stage IIIc-IV and incomplete resection were independent prognostic factors on poor OS, whereas SC, Stage IIIc-IV and incomplete resection were on poor PFS. CONCLUSIONS: The increasing trend of high-grade endometrial cancer and different outcomes according to histological subtypes, especially poor PFS and chemotherapeutic response in SC, were suggested.

Electromyographic and haemodynamic activities in lumbar muscles during bicycle ergometer exercise and walking.

Although bicycle ergometer exercise and walking are recommended as aerobic exercise for patients with lumbago, little research has been done to examine the muscular activities and circulatory dynamics during these exercises. In this study, we aimed at obtaining basic information on aerobic exercises effective for patients with lumbago by investigating the activities and circulatory dynamics of their lumbar muscles during bicycle ergometer exercise and walking. As subjects, we selected 10 healthy adults (23.7 +/- 3.4 years old) with no anamnestic history of lumbago. The measurement conditions were 4 types of exercise: walking (4.0 km/h); 25W, 50W and 75W bicycle ergometer exercises. The activities of the lumbar muscles during the exercises were measured by a surface electromyograph, and percent of MVC was calculated from the maximal voluntary contraction (MVC). With regard to the circulatory dynamics of the lumbar muscles, we measured oxygenated hemoglobin (Oxy-Hb) and deoxygenated hemoglobin (Deoxy-Hb) before and after the exercises with near infrared spectroscopy (NIRS). The change rates during the exercises were calculated based on the values before the exercises. Paired t test was employed to analyse the comparison of the circulatory dynamics of the lumbar muscles between, before and during the exercises. With respect to the comparison of the change rates of the muscular activities and circulatory dynamics among each of the exercises, we employed the one-way analysis of variance (ANOVA) (p < .05). The lumbar muscular activities during the walking were significantly higher than those during the bicycle ergometer exercise were at each load level. The Oxy-Hb increased significantly during the 25W and 50W bicycle ergometer exercises, as opposed to before the exercises. It showed a tendency to decrease during the 75W bicycle ergometer exercise and walking, but not significant. The change rate of the Oxy-Hb during the 25W bicycle ergometer exercise indicated a higher value than that of the other exercises. The Deoxy-Hb, on the other hand, declined significantly in every exercise compared with those before the exercises, with no significant differences in the change rates between each of the exercises. Bicycle ergometer exercise has been suggested as an aerobic exercise permitting as much oxygen uptake as walking does, with fewer loads on lumbar muscles and less likelihood of inducing a hypoxic state on lumbar muscles.

The involvement of FOXO1 in cytotoxic stress and drug-resistance induced by paclitaxel in ovarian cancers.

The role of transcriptional factor FOXO1 in the mechanism of drug-resistance in ovarian cancer has not been elucidated. In ovarian cancer cell lines, FOXO1 expression and its correlation with paclitaxel treatment was investigated by cytotoxic assay and silencing experiment. Clinical ovarian cancer samples were also examined for FOXO1 expression by immunohistochemistry. FOXO1 expression was distinctively upregulated in paclitaxel-resistant cell line, and enhanced by exposure to paclitaxel. FOXO1 overexpression was frequently observed in tissue samples from chemoresistant patients compared to chemosensitive patients. FOXO1 silencing in paclitaxel-resistant cell line decreased its resistance. Modification of oxidative stress by co-treatment with pharmacologic modulators of reactive oxygen species attenuated cytotoxicity of paclitaxel. Downstream targets of FOXO1 involving oxidative stress were also attenuated in silencing experiment, suggesting its involvement in altered sensitivity to paclitaxel. These results indicate that FOXO1 links to cytotoxic stress induced by paclitaxel and contributes to the drug-resistance in ovarian cancers.

Effect of high pressure gaseous carbon dioxide on the germination of bacterial spores.

Effect of high pressure gaseous carbon dioxide treatment (HGCT) at 6.5 MPa, 35 degrees C on the germination of bacterial spores was investigated. Germination of bacterial spores was estimated by the decrease of heat tolerance. Approximately, 40% of Bacillus coagulans and 70% of Bacillus licheniformis were germinated by HGCT for 120 min at 35 degrees C, respectively. Germination was confirmed by phase contrast microscopy. The effect of hydrostatic pressure treatment (HPT) at 6.5 MPa, 35 degrees C on the germination of B. coagulans and B. licheniformis spores were also investigated. Spores did not germinate by HPT alone at 6.5 MPa for 120 min.

Atrioventricular septal defects: possible etiologic differences between complete and partial defects.

BACKGROUND: Recent advances in clinical, pathological, and genetic aspects of atrioventricular septal defects (AVSD) have set the stage for epidemiologic investigations into possible risk factors. Previous analyses of the total case group of AVSD included complete and partial subtypes without analysis of the subsets. METHODS: To address the question of possible morphogenetic heterogeneity of AVSD, the Baltimore-Washington Infant Study data on live-born cases and controls (1981-1989) was reanalyzed for potential environmental and genetic risk-factor associations in complete AVSD (n = 213), with separate comparisons to the atrial (n = 75) and the ventricular (n = 32) forms of partial AVSD. RESULTS: Complete and ventricular forms of AVSD had a similar proportion of isolated cases (12.2% and 15.6%, respectively, without associated extracardiac anomalies) and high rates of Down syndrome, whereas the atrial form of partial AVSD included 55% isolated cases. Trisomy 18 occurred in 22% of infants with the ventricular form, compared with <2% in the other AVSD groups. Analysis of potential risk factors revealed further distinctions. Complete AVSD as an isolated cardiac defect was strongly associated with maternal diabetes (odds ratio [OR] = 20.6; 95% confidence interval [CI] =5.6-76.4) and also with antitussive use (OR = 8.8; CI = 1.2-48.2); there were no strong associations other than maternal age among Down syndrome infants with this type of heart defect. Isolated cases with the atrial type of partial AVSD were associated with a family history of heart defects (OR = 6.2; CI = 1.4-24.4) and with paternal occupational exposures to ionizing radiation (OR = 5.1; CI = 1.4-27.4), but no risk factors were associated with Down syndrome. There were no significant associations of any risk factors in the numerically small subsets of isolated and Down syndrome cases with the ventricular form of partial AVSD. CONCLUSIONS: These results indicate a similar risk profile of complete AVSD and the ventricular type of partial AVSD, with a possible subset of the latter due to trisomy 18. Maternal diabetes constituted a potentially preventable risk factor for the most severe, complete form of AVSD.

Stromal keratitis and anterior uveitis due to herpes simplex virus-2 in a young child.

BACKGROUND: An uncommon case of stromal keratitis and anterior uveitis due to herpes simplex virus type 2 (HSV-2) is reported. CASE: The patient was a 3-year-old boy admitted for conjunctival injection of the right eye of unknown cause, accompanied by corneal opacity and anterior uveitis. OBSERVATIONS: High titers of antibodies against HSV and Epstein-Barr virus (EBV) were found in blood samples. Polymerase chain reaction (PCR) for the detection of HSV-1, -2, and EBV genome fragments was carried out using an anterior chamber sample as a template. An HSV-2 genome fragment was amplified by PCR. Administration of acyclovir and betamethasone was started, with the consequent elimination of corneal opacity, inflammatory cells, and keratic precipitates. CONCLUSION: PCR clearly showed that HSV-2 was the causative pathogen of the stromal keratitis and anterior uveitis in this young patient. Systemic EVB infection may induce systemic immunocompromised conditions that can lead to reactivation of HSV-2 followed by ocular disorders.

Diagnosis of symptomatic postmenopausal women by traditional Chinese medicine practitioners.

OBJECTIVE: To learn more about the way that practitioners of traditional Chinese medicine (TCM) diagnose women who have menopausal symptoms. DESIGN: We assembled a cohort of 23 postmenopausal women who had hot flushes and were otherwise healthy. Each woman was examined independently by nine practitioners of TCM on the same day. Examination consisted of medical history and physical examination. Diagnoses were recorded and counted. RESULTS: The most frequent diagnosis made by the practitioners of TCM was kidney yin deficiency, which was the diagnosis made after 168 of 207 visits (81%); 23 women seen by nine TCM practitioners. Practitioners showed good agreement regarding presence of kidney yin deficiency: in 12 women (52%), this diagnosis was made by eight of nine practitioners; in 16 women (70%), seven of nine practitioners made this diagnosis; and in all 23 women (100%), at least five of nine practitioners made this diagnosis. CONCLUSIONS: Practitioners of TCM who diagnose postmenopausal women with vasomotor symptoms are likely to make a diagnosis that includes kidney yin deficiency.

Exploratory study of effective chemotherapy to clear cell carcinoma of the ovary.

Although clear cell carcinoma of the ovary is considered to be a tumor with poor prognosis, the clinical characteristics has not been defined. The aim of this study was to evaluate the response of clear cell carcinoma of the ovary to first and second-line chemotherapy and explore effective chemotherapy. Fifty-three patients with clear cell carcinoma of the ovary were enrolled between 1988 and 1997 at our department. Since taxol was not available in Japan at that time, cisplatin-based combination chemotherapy has been exclusively used as a standard first-line chemotherapy. Retrospective analyses of clinical characteristics and the response to first or second-line chemotherapy were performed. Median age was 52 years (range 27-71 years). Tumors were 34% (18/53) stage I, 19% (5/53) stage II, 38% (20/53) stage III, and 9% (5/53) stage IV. All patients with I or II stage disease had optimal cytoreduction. Out of 25 patients with III or IV stage disease 20% (5/25) had negative residual tumor, 36% (9/25) had <2 cm residual tumor, and 44% (11/25) had >/=2 cm residual tumor. All patients received postoperative platinum-based chemotherapy. Of 23 patients with measurable residual tumor 8.7% (2/23) completely and 13% (3/23) partially responded to first-line chemotherapy consisting of cisplatin, adriamycin and cyclophosphamide (CAP) or cisplatin and cyclophosphamide (CP) by CT scan or second look laparotomy. Presence of endometriosis was 55% (29/53) but was not a prognostic factor. Although overall response rate of ovarian clear cell carcinoma to first-line chemotherapy by CAP or CP was about 22%, EP or EJ consisting of etoposide and cisplatin or carboplatin used as a second-line chemotherapy showed 29% response rate, while CPT-P consisting of CPT-11 and cisplatin showed 40% response rate. Clear cell carcinomas were frequently present at early stage, with association of endometriosis and with poor overall prognosis. Although patients with advanced ovarian clear cell carcinoma seemed to have better response to CPT-P than conventional platinum-based chemotherapy, further studies are required with larger number of patients to draw firm conclusions.

Treatment with paclitaxel alone rather than combination with paclitaxel and cisplatin may be selective for cisplatin-resistant ovarian carcinoma.

BACKGROUND: We have previously reported that paclitaxel (taxol) results in cisplatin sensitization to human ovarian cancer cells with cisplatin resistance in vitro. This study was designed to determine effects of taxol and its combination with cisplatin on growth of cisplatin-sensitive cell line (KF28) and the cisplatin-resistant counterpart (KFr13) in nude mice. METHODS: From 14 days after tumor inoculation treatment was initiated. Taxol (3 mg/kg) and cisplatin (2 mg/kg) were administered i.p. once a week for 5 weeks. RESULTS: In nude mice bearing cisplatin-sensitive cells (KF28), taxol followed by cisplatin and cisplatin plus taxol inhibited significantly (P < 0.05) the tumor growth rate compared with that in nude mice treated with cisplatin alone or taxol alone and cisplatin followed by taxol. On the other hand, in nude mice bearing cisplatin-resistant KFr13 cells, treatment with taxol alone inhibited completely the tumor growth rate, whereas no schedule-dependent interaction of taxol with cisplatin was observed. CONCLUSION: These results suggest that treatment with taxol alone may be superior to combination of taxol with cisplatin in patients with cisplatin-resistant ovarian carcinoma.

[Post aortic left innominate vein in a patient with a surgically corrected double outlet right ventricle].

We report the presence of a post aortic left innominate vein (PALIV) in a patient with a surgically corrected double outlet right ventricle. A 30-year-old male was admitted to our hospital with exertional dyspnea. The patient had undergone right ventricular outflow tract reconstruction and closure of ventricular septal defect at the age of 14. Echocardiography and cardiac catheterization showed severe pulmonary regurgitation and a residual ventricular septal shunt. After resternotomy, right ventricular outflow tract reconstruction and residual shunt closure were performed. During the operation, the left innominate vein was not found in front of the aorta. Postoperative cardiac catheterization and computed tomography showed that the left innominate vein was positioned behind the ascending aorta draining to the superior caval vein.

Effect of Korean red ginseng on psychological functions in patients with severe climacteric syndromes.

OBJECTIVE: To evaluate the degree of psychological dysfunction and levels of stress hormones in postmenopausal women with climacteric syndromes and effect of Korean red ginseng (RG) on them. METHODS: ACTH, cortisol and DHEA-S in peripheral blood from 12 postmenopausal women with climacteric syndromes or 8 postmenopausal women without any climacteric syndrome were measured before and 30 days after treatment with daily oral administration of 6 g RG. Blood samples were collected in the early morning on the bed-rest. In postmenopausal women with climacteric syndromes such as fatigue, insomnia and depression, psychological tests using the Cornell Medical Index (CMI) and the State-Trait Anxiety Inventory (STAI) were performed before and 30 days after treatment with RG. RESULTS: CMI score as well as anxiety (A)-state in STAI score in postmenopausal women with climacteric syndromes was significantly higher than that without climacteric syndrome, while DHEA-S levels in postmenopausal women with climacteric syndromes were about a half of those without climacteric syndrome. Consequently, cortisol/DHEA-S (C/D) ratio was significantly higher in postmenopausal women with climacteric syndromes than in those without climacteric syndrome. When postmenopausal women with climacteric syndromes were treated with daily oral administration of 6 g RG for 30 days, CMI and STAI A-state scores decreased within normal range. Although the decreased DHEA-S levels were not restored to the levels in postmenopausal women without climacteric syndrome, the C/D ratio decreased significantly after treatment with RG. CONCLUSIONS: Improvement of CMI and STAI scores in postmenopausal women suffering climacteric syndromes, particularly fatigue, insomnia and depression, by RG seemed to be brought about in part by effects of RG on stress-related hormones as shown by a decrease in C/D ratio.

Bcl-2 as a predictor of chemosensitivity and prognosis in primary epithelial ovarian cancer.

This retrospective study of ovarian cancer aimed to elucidate whether expression of apoptosis-related proteins, bcl-2, p53 or MDM-2, is associated with resistance to chemotherapy, especially cisplatin (CDDP) based chemotherapy. Expression of bcl-2, p53 and MDM-2 was assessed by immunohistochemical staining of tumour tissues collected at initial surgery prior to treatment with CDDP-based chemotherapy. Among 66 patients with advanced ovarian cancer with measurable tumour following surgery and evaluable for response to chemotherapy, 42, 45 and 56% were positive for bcl-2, p53 and MDM-2, respectively. Significantly fewer tumours of patients who had a complete response to chemotherapy (CR) showed positivity for bcl-2 (2/20) than for p53 (6/20) and MDM-2 (8/20, P < 0.001). There was an inverse correlation between bcl-2 staining and initial response to chemotherapy, especially in serous and endometrial adenocarcinomas. In patients with stage III-IV, serous or endometrioid adenocarcinomas, significantly poorer survival was seen for those with bcl-2 positive tumours than those with negative bcl-2 staining (P = 0.0064). p53 and MDM-2 were not correlated with initial response to chemotherapy. Multivariate analysis revealed that bcl-2, residual tumour size and histology were significant independent prognostic factors. These results suggest that bcl-2 can be a possible predictor of response to chemotherapy and prognosis in patients with advanced ovarian carcinoma.

Preoperative determination of several serum tumor markers in patients with primary epithelial ovarian carcinoma.

This study was designed to evaluate the clinical significance of the use of preoperative serum tumor markers in primary epithelial ovarian cancer. Subjects comprised 111 patients with primary epithelial ovarian cancer. Lactate dehydrogenase (LDH), alpha-hydroxybutyrate dehydrogenase (HBDH), carcinoembryonic antigen (CEA), CA19-9, tissue polypeptide antigen (TPA), CA125 and sialyl TN (STN) serum levels were measured within 7 days before surgery. The tumor marker values were compared with the histopathologic diagnosis. The overall agreement between the test results and the actual outcome was calculated using Student's t test and analysis of variance (ANOVA). Survival curves were constructed according to the Kaplan-Meier method, and differences in survival were assessed with the log-rank test. The prognostic significance of tumor markers for survival was assessed in a multivariate analysis with the Cox proportional hazards model. Of the tumor markers examined in this study, CA125 showed the highest positive rate (77.6%), followed by 63.2% for STN and 55.9% for CA19-9. When the positive rate was compared according to histologic types, serous cystadenocarcinoma, mucinous cystadenocarcinoma, endometrioid adenocarcinoma and clear cell carcinoma showed the highest positive rates for CA125 (94.1%), CA19-9 (76.9%), CA125 (91.7%) and STN (75.0%), respectively. Regarding the distribution of tumor marker levels according to the FIGO stage, LDH, HBDH, TPA and CA125 were correlated with the clinical stage while CEA, CA19-9 and STN did not show any correlation. From analyses of tumor marker levels according to histologic types, all patients with a ratio of CA125 to CEA of >1, 000 had serous cystadenocarcinoma and a ratio of CA125 to CA19-9 of >50 showed serous cystadenocarcinoma or endometrioid adenocarcinoma. On the other hand, all patients with a ratio of LDH or HBDH to CA19-9 of <1.0 had mucinous cystadenocarcinoma or clear cell carcinoma. From univariate analysis, the survival time of patients with elevated CA125, TPA or STN was significantly shorter than that of patients with normal CA125, TPA or STN levels. When the Cox's proportional hazard model was used, we identified age, clinical stage, clear cell carcinoma and serum STN as independent prognostic factors. Serum CA125, TPA or STN may give significant prognostic information in epithelial ovarian carcinoma. It is noteworthy that STN has been identified as an independent prognostic factor and has a high rate of positivity in clear cell carcinoma.

Inhibitory effects of ginsenoside Rh2 on tumor growth in nude mice bearing human ovarian cancer cells.

Ginsenoside Rh2 (Rh2), isolated from an ethanol extract of the processed root of Panax ginseng CA Meyer, inhibits the growth of B16 melanoma cells. This study was designed to evaluate the ability of Rh2 to inhibit growth of human ovarian cancer cells (HRA) in vitro and in nude mouse. Rh2 inhibited proliferations of various established human ovarian cancer cell lines in a dose-dependent manner between 10 and 60 microM in vitro and induced apoptosis at around the IC50 dose. When HRA cells were inoculated s.c. into the right flank of nude mice, all mice formed a palpable tumor within 14 days. Although i.p. administration of Rh2 alone hardly inhibited the tumor growth, when Rh2 was combined with cis-diamminedichloroplatinum(II) (CDDP) the tumor growth was significantly inhibited, compared to treatment with CDDP alone. When mice were treated p.o. with Rh2 daily (but not weekly), the tumor growth was significantly (P<0.01) inhibited, compared to CDDP treatment alone. When Rh2 was combined with CDDP, the degree of tumor growth retardation was not potentiated. The survival time was significantly (P<0.05) longer than that of medium alone-treated controls or the group treated with CDDP alone. Then, we examined whether p.o. administration of Rh2 has a dose-dependent inhibitory effect on the tumor growth. I.p. and weekly administration of CDDP had more potent antitumor activity in the order of 1 mg/kg, 2 mg/kg and 4 mg/kg, whereas p.o. and daily administration of Rh, (0.4 to 1.6 mg/kg) not only had antitumor activity comparable to that of 4 mg/kg CDDP, but also resulted in a significant increase of the survival. Doses of Rh2 used in this study did not result in any adverse side-effects as confirmed by monitoring hematocrit values and body weight, unlike 4 mg/kg CDDP, which had severe side-effects. It is noteworthy that p.o. but not i.p. treatment with Rh2 resulted in induction of apoptotic cells in the tumor in addition to augmentation of the natural killer activity in spleen cells from tumor-hearing nude mice. Thus, particularly in view of the toxicity of CDDP, Rh2 alone would seem to warrant further evaluation for treatment of recurrent or refractory ovarian tumor.