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Background/Aim: In 2020, the percentages were removed from the World Health Organization’s criteria for mixed carcinoma. The aim was to examine the clinical significance of an area of serous carcinoma (SC)

The Integran microfibrillar collagen hemostatic matrix is one form of microfibrillar collagen hemostat. This form has a sheet-type structure and has explicitly been used in Japan. In gynecology, this sheet-type matrix has helped effect uterine surface hemostasis, especially in myomectomy and cervical conization. However, cytotechnologists and pathologists have overlooked the foreign materials used for conization in postoperative cervical cytology. We report two cases describing the characteristic cervical cytology findings when Integran was used in conization. The first case was a 67-year-old woman who underwent conization because of cervical intraepithelial neoplasia (CIN) 3. Thirty-six days after the surgery, many cylindrical fragments of glossy acellular materials appeared in the cervical cytology. Fortunately, the content did not impede the diagnosis of NILM. The patient then underwent hysterectomy two months after conization. Surgical specimen revealed a high degree of inflammation and granulation without malignancy. Following surgery, the cylindrical fragments disappeared from microscopic findings. The second case was a 45-year-old woman who underwent conization because of CIN3. Thirty-four days after the surgery, many tubular pieces of glossy acellular materials appeared in cervical cytology, as seen in the first case. The cytological diagnosis was NILM. One hundred days after surgery, cervical cytology revealed many clue cells but no cylindrical fragments. These clusters of cylindrical fragments of glossy acellular materials in cervical cytology after conization might induce a delay in diagnosing the persistence and recurrence of cervical cancer. This article is the first report describing cervical cytology findings associated with Integran use.

ObjectiveTo examine clinico-pathological factors associated with surgical complications and postoperative therapy for clinical stage IB-IIB cervical cancer.MethodsThis nationwide multicenter retrospective study examined women with clinical stage IB-IIB cervical cancer who underwent radical hysterectomy plus pelvic and/or para-aortic lymphadenectomy between 2008-2009 at 87 institutions of the Japanese Gynecologic Oncology Group (n = 693). Multivariate models were used to identify independent predictors of perioperative grade 3-4 complications and bladder dysfunction.ResultsThe overall intraoperative and postoperative complication rates were 3.3% and 9.8%, respectively. Clinical stage was not associated with perioperative complications (P = 0.15). Radiotherapy-based adjuvant therapy was significantly associated with an increased risk of postoperative complications (radiotherapy alone: adjusted-odds ratio [OR] 3.19, 95% confidence interval [CI] 1.46-6.99, P = 0.004; radiotherapy plus chemotherapy: adjusted-OR 3.26, 95%CI 1.66-6.41, P = 0.001), whereas chemotherapy was not (P = 0.45). Nerve-sparing surgery significantly reduced the risk of postoperative bladder dysfunction (adjusted-OR 0.57, 95%CI 0.37-0.90, P = 0.02) whereas adjuvant chemotherapy increased the risk of bladder dysfunction (adjusted-OR 2.06, 95%CI 1.16-3.67, P = 0.01). Among women receiving adjuvant chemotherapy, nerve-sparing radical hysterectomy significantly reduced the risk of bladder dysfunction (15.0% versus 32.9%, OR 0.31, 95%CI 0.14-0.68, P = 0.004). After propensity score matching, survival outcomes were similar with both types of adjuvant therapy (radiotherapy-based versus chemotherapy, P>0.05).ConclusionOur study highlighted two distinct complication profiles of adjuvant therapy after radical hysterectomy for clinical stage IB-IIB cervical cancer, with radiotherapy increasing grade 3-4 adverse events and chemotherapy increasing bladder dysfunction. In this setting, nerve-sparing surgery may be useful if chemotherapy is being considered for adjuvant therapy.

Aim This study aimed to assess adequate conditions for omitting parametrectomy for stage IB1–IIA2 cervical cancer with the aim of reducing postoperative complications during Type III radical hysterectomy (RH). Methods We investigated factors associated with parametrial invasion (PMI) in patients who underwent Type III RH for stage IB1, IB2, IIA1, IIA2 and IIB cervical cancer at two tertiary institutions from November 2006 to February 2018. Both clinicopathological and preoperatively estimated factors were assessed. Results One hundred fifty‐six patients were preoperatively diagnosed with stage IB1 to IIB disease. Thirty‐four patients (21.8%) showed PMI on histological analyses. In the multivariate analysis, an age older than 50 years, tumor size larger than 40 mm, common iliac lymph node metastasis and lymphovascular space invasion were identified as significant risk factors for PMI (P‐values = 0.008, 0.003, 0.004 and 0.004, respectively). The preoperatively estimated risk factors for PMI were an older age, larger tumor size, and common iliac lymph node metastasis (P‐values = 0.007, 0.002 and 0.001, respectively). A combination of these three factors was sufficient to estimate PMI with a high specificity (100%) and positive predictive value (100%) in patients with stage IB1 to IIA2 disease. Conclusion During RH, resecting the posterior layer of the vesicouterine ligament and the paracolpium without removing the cardinal ligament (avoiding parametrectomy) might be feasible for stage IB1–IIA2 cervical cancer in patients younger than 50 years presenting with smaller tumors (

Adenocarcinoma with a stromal micropapillary pattern (SMP) has been described in various organs, but not in the uterus. We encountered a case of uterine cervical carcinoma with SMP. A54-year-old Japanese woman was referred to the hospital with abnormal vaginal bleeding. The cervical cytodiagnosis was adenocarcinoma with features resembling serous adenocarcinoma. Cervical cytology showed many small clusters of tumor cells, present in up to two or three layers, composed of atypical cells with markedly increased nucleus: cytoplasm ratios. A radical hysterectomy with bilateral adnexectomy and retroperitoneal lymph node dissection was performed. Microscopically, the tumor was composed predominantly of adenocarcinoma with SMP. The outer surface of the SMP cell clusters showed membranous expression of mucin-1 (MUC-1). Many lymph node metastases were detected. The tumor was diagnosed as a cervical adenocarcinoma with SMP and coexistent squamous cell carcinoma in situ. The pathology was classified as T1b1N1M1, stage IVB. The patient underwent postoperative adjuvant chemotherapy and is without local recurrence or distant metastasis 48 months after the operation. To the best of our knowledge, this is the first reported case of cervical adenocarcinoma with SMP.

2592 Background: Cancer cachexia occurs in more than half of cancer patients and can be the primary cause of death for at least 20% of all patients. Cancer cachexia also lowers quality of life in cancer survivors due to a severe loss of skeletal muscle mass. Although a multitude of cytokines have been implicated in facilitating a cachectic state, the correlation of serum IL-6 and cancer-induced muscle wasting in gynecologic cancer patients has not been elucidated. Methods: The correlation between serum level of IL-6 and skeletal muscle volume in the patients with gynecologic cancers that received multiple lines of therapy was retrospectively evaluated. We used the psoas muscle index [PMI (cm2/m2)], the psoas major muscle area at the fifth lumber level divided by the height squared, measured using digital axial CT images, for the value of skeletal muscle volume. The level of IL-6 cut-off for elevation was defined as more than 12.0 pg/mL. The comparison of the survival distributions from the day of IL-6 measuaments was made using a log-rank test. Results: A total of 74 cases were assessed for the serum IL-6 and PMI: 32 cases with Mullerian cancers, 24 cases with endometrial cancers, 13 cases with cervical cancers, and 5 patients with others. The group with elevated IL-6 were associated with the lower PMI (t-test, p = 0.0154). The patients with IL-6 elevation had significantly worse survival compared with those with normal IL-6 (1y-OS; 31% vs. 80%, p < 0.0001). In 28 patients with more than two-point measurements of IL-6, the patients with the decrease to the level of IL-6 cut-off had favorable survival compared with those without the decrease (6m-OS; 100% vs. 52%, p = 0.0069). Conclusions: Serum level of IL-6 could be a sentinel biomarker for cancer-induced sarcopenia in the patients with gynecologic cancers. Additionally, IL-6 could be a biomarker to determine further continuation of aggressive chemotherapy for the patients that had received multiple lines of chemotherapy.

e17124 Background: The immunotherapy drug, nivolumab, is now approved for several metastatic cancers, and has resulted in responses previously not seen with these cancers. Molecular targeting agents, such as mammalian target of rapamycin (mTOR) inhibitor, have also recently been shown to have modest activity for endometrial cancers, however, the efficacy was limited. The present retrospective analysis is to evaluate the efficacy of Nivolumab alone or combination with molecular targeting agents for recurrent and refractory endometrial cancers. Methods: A retrospective evaluation for medical charts of the patients were conducted: (a) the cases with histologically confirmed endometrial cancers, (b) those that had recurrent diseases, (c) diagnosed as refractory for the previous chemotherapy, (d) those that were treated with combination therapy using tri-weekly Nivolumab (100mg/body, every 3 weeks) alone, or combination with molecular targeting agents. The association with serum markers and response was also investigated. Results: A total of 16 patients were identified: 5 cases with endometrioid G1/2, 4 cases with endometrioid G3, and the 6 cases with serous, and one case with mucinous histology. Median age was 61 years old (range:43-76), and median number of the previous chemotherapy was 4 regimens (range:1-5). Combined drugs included everolimus (n = 9), temozolomide (n = 1), trametinib (n = 1), and nintedanib (n = 1). Among 12 cases with evaluable disease, a complete response over 20 months was observed in one case: a case with endometrial carcinoma G2 treated with Nivolumab and evelorimus (5mg/day, continuously). Stable disease more than three months was achieved in 8 cases (67%), and clinical benefit rate (CR+SD > 3months) was achieved in 75% of the cases. Median progression-free survival was 5 months (range: 3-20+). Non-hematological adverse events included general fatigue, mucositis, dysgeusia, skin rash, edema, and liver dysfunction, but the toxicity greater than grade2 was observed and in a case with liver dysfunction (G3). There was no significant relationship between response and serum levels of VEGF, p53, and IL-6, however, clinical benefit was observed in higher abundance of endometrioid histology compared with serous subtype (86% vs. 50%). Conclusions: Combination therapy using Nivolumab with evelolimus could be a candidate for recurrent and refractory endometrial cancers. Biomarker analyses for the responders are mandatory for further investigation for larger clinical studies.

5529 Background: Although resection of more than 20 lymph-nodes is considered to be adequate in pelvic lymphadenectomy for cervical cancer patients, prognostic significance of the number of resected lymph-nodes (PLN-num) is clinically still unknown. Methods: This nationwide multicenter retrospective study (JGOG 1070S) examined consecutive 693 patients with clinical stage IB-IIB cervical cancer who underwent radical hysterectomy including pelvic and/or para-aortic lymphadenectomy between 2008-2009 at 87 institutions of the Japanese Gynecologic Oncology Group. Maximum number of enrollments from one institution was limited 10 or less to minimize the inter-institutional bias. Correlation between PLN-num and prognosis was analyzed using Cox hazard model with considering histological subtypes. Results: Of 473 eligible cases in this study, the average PLN-num per a case in each institution was positively correlated with the number of total cases treated in each institution per year. (R = 0.42, P = 0.012). Patients with high PLN-num showed favorable progression free survival (PFS) (P = 0.12). Focusing on adeno and adeno-squamous carcinomas, significantly improved PFS was shown in high PLN-num cases (P = 0.012), although no significance was found in squamous cell carcinoma (P = 0.754). Multivariate analysis in adeno and adeno-squamous cases showed PLN-num as an independent prognostic factor (HR; 0.46, 95%CI; 0.24–0.84, P = 0.026) along with disease stage and adjuvant therapeutics. Subset analysis of adeno and adeno-squamous cases without adjuvant therapeutics showed significant improvement of survival in high PLN-num group (P = 0.019). Conclusions: In our study, PLN-num in lymphadenectomy for patients with cervical adeno or adeno-squamous carcinoma was clarified to be a significant prognostic factor. Systematic total lymphadenectomy is recommended for these patients to obtain a favorable prognosis.

Aim Few studies have examined the effect of combined low-risk human papillomavirus (LR-HPV) and high-risk human papillomavirus (HR-HPV) infection on the progression of cervical intraepithelial neoplasia (CIN)2 to CIN3. This multi-institutional prospective cohort study investigated the risk of progression of CIN2 with various combinations of HR-HPV and LR-HPV infection. Methods Between January 2007 and May 2008, 122 women with CIN2 (aged 20–50 years) from 24 hospitals throughout Japan were enrolled in the study. Ninety-three women were analyzed after a 2-year follow-up with cytology, colposcopy, HR-HPV testing and HPV genotyping. Colposcopy-directed biopsy was performed at entry and the end of this study, or when disease progression was suspected. Results Among 93 women with CIN2, 87 (93.5%) had HR-HPV infection. Among these 87 cases, 24 (27.6%) progressed to CIN3 and 49 (56.3%) regressed. None of the six women with CIN2 without HR-HPV infection progressed. The progression rate was significantly lower in women with combined HR-HPV and LR-HPV infection (3/28, 10.7%) than in those with HR-HPV infection only (21/59, 35.6%; P = 0.016). Multivariate analyses showed that CIN2 progression in women with HR-HPV infection was negatively associated with LR-HPV co-infection (hazard ratio = 0.152; 95% confidence interval [CI] = 0.042–0.553). CIN2 regression was positively associated with LR-HPV co-infection (odds ratio = 4.553; 95% CI = 1.378–15.039). Conclusion The risk of CIN2 progression is low in women with combined infection of HR-HPV and LR-HPV. The finding may be useful for management of women diagnosed with CIN2.

Objective: To evaluate the usefulness of intraoperative ultrasonography (IU) for para-aortic nodes to identify women who do not require pelvic and paraaortic lymphadenectomy in ovarian carcinoma. Methods: Computed tomography (CT) was used for assessing both pelvic and para-aortic lymph nodes, and IU only for para-aortic nodes in 87 women with ovarian carcinoma. All women underwent surgery with routine systematic pelvic and para-aortic lymphadenectomy. We assumed that no lymphadenectomy had been performed when no enlarged node was detected by either CT or IU or when the woman was in T1 stage. Under these assumptions, the numbers of women who would have had missed metastases and who could have avoided lymphadenectomy were counted. These figures were recounted on the combination of T stage and IU. Results: A total of 22 women had pathological node metastases. The numbers of women with missed metastases on the basis of CT, IU, and T stage were 12, 2, 5, and these who could have avoided lymphadenectomy were 72, 39, and 49, respectively. There were more women avoiding lymphadenectomy by CT than IU and T stage; however, more women with missed node metastases. Both numbers were not significantly different between IU and T stage. On the combination of T stage and IU, 29 of 49 women in T1 stage could have avoided lymphadenectomy without missed metastases. Conclusions: IU for the para-aortic node is a useful method for identifying women who do not require lymphadenectomy for T1 stage ovarian carcinoma.

The efficacy and adverse events of neoadjuvant chemotherapy with irinotecan hydrochloride and nedaplatin were evaluated in patients with bulky stage Ib2 to IIb cervical squamous cell carcinoma. Eligibility included patients who received irinotecan (60 mg/m2) on days 1 and 8 and nedaplatin (80 mg/m2) on day 1 of a 21-day cycle. After 1-3 courses of chemotherapy, radical hysterectomy was performed. Sixty-eight patients were enrolled. Sixty-six were included in the full analysis set. Their median age was 47 years (range 22-71), the FIGO stage was Ib2 in 18 patients, IIa in 10, and IIb in 38. Radical hysterectomy was performed after NAC in 63 patients (95.5%). The number of administered courses of NAC was 1 in 13 patients, 2 in 43, and 3 in 10. The response rate, the primary endpoint of this study, was 75.8% (CR in 2 patients, PR in 48, SD in 12, PD in 0, and NE in 4). The mean number of treatment courses required for a response was 1.42 (1 course in 30 patients, 2 courses in 19, and 3 courses in 1). The incidences of grade 3 or 4 hematological toxicities were: neutropenia 72.2%, leukopenia 16.7%, anemia 13.6%, thrombocytopenia 7.6%, febrile neutropenia 1.5%, and elevations of alanine aminotransferase and aspartate aminotransferase 1.5%. Grade 3 or 4 non-hematologic toxicities were as follows: diarrhea 6.1%, nausea 3%, anorexia 1.5%, vomiting 1.5%, fever 1.5%, allergic reactions 1.5%, ileus 1.5% and vesicovaginal fistula 1.5%. Neoadjuvant chemotherapy with irinotecan and nedaplatin was an effective and well-tolerated treatment for patients with bulky stage Ib2 to IIb squamous cell carcinoma of the uterine cervix.

Objectives Currently, pegylated liposomal doxorubicin (PLD) is regarded as one of the standard treatment options in recurrent ovarian cancers (ROC). Bevacizumab has shown significant antitumor activity for ROC in single-agent or in combination with cytotoxic agents. We have conducted a preliminary study to investigate effects of combination of bevacizumab and PLD for heavily pretreated patients with ROC. Methods Thirty patients with ROC were treated with combination therapy with weekly bevacizumab and PLD, 2 mg/kg of continuous weekly bevacizumab and 10 mg/m2 of PLD (3 weeks on, 1 week off). The treatment was continued until development of disease progression, or unmanageable adverse effects. Response evaluation was based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and Gynecologic Cancer Intergroup (GCIG) CA125 response criteria. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Results Overall response rate was 33%, and clinical benefit rate (CR + PD + SD) was 73%. Median progression-free survival was 6 months (range: 2–20 months), and a 6-months progression-free survival was 47%. Any hematological toxicities more than grade 3 were not observed. Two cases developed non-hematologic toxicities more than grade 2; a case with grade 3 hand-foot syndrome, another with grade 3 gastrointestinal perforation (GIP). The case with GIP was conservatively treated and recovered after 2 months, and there was no case with treatment-related death. Conclusion The present investigation suggested that combination therapy with bevacizumab and PLD was active and well tolerated for patients with ROC. We recommend the regimen be evaluated in further clinical studies.

Objectives In recent years, cancer stem cells (CSCs) have been reported to be correlated with chemoresistance and may also be enriched in side populations (SPs). In this study, the relationship between resistance to paclitaxel (PTX) and cisplatin (CDDP) and side populations was examined in three parental PTX- and CDDP-sensitive ovarian cancer cell lines (2008, KF28, and TU-OM-1) and several other cell lines derived from these as well as the additional effects of interferon-alpha (INF-α). Methods SP of three different parental cell lines and PTX- and/or CDDP-resistant cell lines derived from these was analyzed with flow cytometry. The expression of ABCB1 and ABCG2 in KF28 and its derived cell lines was examined. Additional cell-death effect of INF-α with PTX was also examined. Results In the three parental cell lines and the PTX-sensitive cell lines derived from these lines, SP was very low. Conversely, in PTX-resistant cell lines, regardless of CDDP resistance, SP increased. ABCB1 was strongly expressed in the PTX-resistant cells, but not in their parental lines, which are sensitive to PTX. While INF-α showed only slight enhancement of the cell-death effect of PTX in PTX-sensitive cells, INF-α itself strongly induced apoptosis in PTX-resistant cells regardless of PTX concentration. Conclusions The SP could be correlated with resistance to PTX. SP could be a target of INF-α, and resistance to PTX might be overcome by INF-α.

Aim: To determine whether concurrent chemoradiotherapy (CCRT) can improve the survival rate of high-risk uterine cervical cancer. Material & Methods: We analyzed 16 cases of uterine cervical cancer that had undergone radical hysterectomy and pelvic lymphadenectomy from 2003 to 2008. The patients were eligible if they had histologically confirmed positive parametrial involvement, positive pelvic lymph nodes or non-squamous cell carcinoma. They received 50 Gy of external beam radiotherapy (RT) for the pelvis which was combined with chemotherapy. Cisplatin was administered intravenously every 3 weeks at a dose of 70 mg/m2 during the RT. For renal function complication case, carboplatin was administered weekly. For control purposes, there were 14 cases treated in our hospital from 1995 to 2003 who had received only RT. Results: We did not find any statistically significant difference in the disease-free survival rate between the CCRT group and the RT group. However, the overall survival rate was significantly higher for patients in the CCRT group compared with the RT group in positive lymph node cases and non-squamous cell carcinoma cases. Adverse effects were more frequent in the CCRT group. Over grade 3 toxicities were manifested as leukopenia, diarrhea and anemia. There was no local recurrence in CCRT group patients. Conclusion: CCRT seems to be beneficial for improving the survival rate of either positive lymph node or non-squamous cell carcinoma cases in high-risk uterine cervical cancer patients.

Objectives:The purpose of this study was to evaluate the association of ABCF2 (adenosine triphosphate-binding cassette superfamily F2) protein expression with response to chemotherapy and prognosis in patients with clear cell adenocarcinoma (CCC) of the ovary.Methods:One hundred sixty-five patients with CCC were studied, and cytoplasmic ABCF2 expression was detected by immunohistochemical staining. All patients underwent platinum-based primary chemotherapy followed by primary surgery.Results:Adenosine triphosphate-binding cassette superfamily F2 expression was detected in 118 (71.5%) of 165 patients and was not related to age or clinical stage. The response rate to chemotherapy in 38 patients with measurable disease was 47.3% (18/38). The response rate tended to be higher in patients without ABCF2 expression than in those with ABCF2 expression; however, this difference was not significant (66.7% vs 34.8%, P = 0.096). There was no significant difference in overall survival between ABCF2-positive and ABCF2-negative cases (median survival time, 1175 vs 1257 days; P = 0.24).Conclusions:Adenosine triphosphate-binding cassette superfamily F2 protein was highly expressed in CCC of the ovary, but expression was not related to age, clinical stage, chemoresponse, or prognosis.

e17544Background: Cancer cachexia occurs in approximately 80% of cancer patients, and is the primary cause of death for 22–30% of all cancer patients. Cancer cachexia also diminishes quality of lif...

Background: To investigate the effects of UDP-glucuronosyltransferase 1A1 (UGT1A1) *28, *6 and *27 in patients with gynecologic cancer who received chemotherapy with irinotecan and cisplatin. Methods: Patients eligible for this study had cervical or ovarian cancer treated with chemotherapy; a course of the regimen consisted of 60 mg/m2 of irinotecan on days 1, 8 and 15, and 60 mg/m2 of cisplatin on day 1 every 4 weeks. UGT1A1 polymorphisms and toxicities were analyzed. Results: From March 2007 to December 2007, 30 Japanese patients were enrolled; 24 ovarian carcinoma patients and 6 cervical cancer patients. The following genotypes of UGT1A1 were found: wild type in 17 patients (57%), *28 in 4 patients (13%), *6 in 8 patients (27%), *28*6 in 1 case (3%) and no case of *27 (0%). Grade 3/4 neutropenia, thrombocytopenia and diarrhea were significantly more frequent in *6 patients compared with wild-type patients. Also, in *6 patients irinotecan administration on days 8 or 15 was significantly more often omitted due to toxicities. In patients with *28 or *28*6, side effects were similar to those in patients with *6. Conclusion: In addition to UGT1A1*28, UGT1A1*6 might also be a key candidate to determine the dose of combination chemotherapy with irinotecan and cisplatin.

Clear cell carcinoma (CCC) of the ovary has been recognized to show resistance to anticancer agents in the first-line chemotherapy. Our aim was to evaluate the effect of second-line chemotherapy in a retrospective study. A total of 75 patients diagnosed with CCC and treated between 1992 and 2002 in collaborating hospitals were reviewed. Criteria for the patients' enrollment were 1) diagnosis of pure-type CCC at the initial operation, 2) treatment after one systemic postoperative chemotherapy, 3) measurable recurrent or refractory tumor, 4) at least two cycles of second-line chemotherapy and assessable for the response, and 5) adequate clinical information. Regimens of first-line chemotherapy were conventional platinum-based therapy in 33 cases, paclitaxel plus platinum in 24 cases, irinotecan plus platinum in 9 cases, and irinotecan plus mitomycin C in 7 cases. Treatment-free periods were more than 6 months in 24 cases (group A) and less than 6 months in 51 cases (group B). In group A, response was observed in two cases (8%): one with conventional platinum therapy and another with irinotecan plus platinum. In group B, three cases (6%) responded: two with platinum plus etoposide and one case with irinotecan plus platinum. Median overall survival was 16 months in group A and 7 months in group B (P= 0.04). These findings suggest recurrent or resistant CCC is extremely chemoresistant, and there is only small benefit of long treatment-free period in CCC patients. Another strategy including molecular-targeting therapy is warranted for the treatment of recurrent or refractory CCC.

Recently, oncogenic potential of the WT1 gene has been proposed in some human solid tumors and leukemias. Although previous studies have shown the frequent expression of the WT1 protein in ovarian serous adenocarcinomas (OSAs), its clinicopathologic significance is still unclear. We immunohistochemically examined the expression status of WT1 in 119 OSAs and analyzed the correlation of the intensity of WT1 immunoreactivity with the level of WT1 mRNA expression by quantitative real-time polymerase chain reaction, clinicopathologic variables, expression of p53, Bcl-2, and Ki-67 labeling index (LI). Of 119 OSAs, nuclear WT1 immunoreactivity was positive in 99 (83%), of which 44 (44%) and 55 (56%) exhibited high and low WT1 immunoreactivities, respectively. The quantitative WT1 mRNA levels were significantly correlated with the intensity of WT1 immunoreactivity (P < 0.05). In comparison with WT1-negative OSAs, the WT1-positive OSAs showed a higher grade (P = 0.007), advanced stage (P = 0.018), and higher Ki-67 LI (P < 0.001). Additionally, high WT1 immunoreactivity was correlated with a higher grade (P = 0.003), Ki-67 LI (P = 0.012), Bcl-2 expression (P = 0.003), and poorer patient outcome (5-year survival, 36.5 vs 63.8%, P = 0.008 by log-rank test). The WT1 protein may be an accelerator of the progression of OSA.

The transporter protein genes and lipids in human ovarian carcinoma-derived KF28 cells with anticancer-drug-sensitive properties were compared with those in resistant cells, taxol-resistant KF28TX, cisplatin-resistant KFr13, and taxol- and cisplatin-resistant KFr13TX, to identify the molecules required for anticancer-drug resistance. In accordance with previous reports, taxol and cisplatin resistance was closely correlated with expression of the multidrug resistance 1 and bile acid export pump, and multidrug resistance-associated protein 2 genes, respectively. In addition, we found a distinct difference in glycosphingolipids between the sensitive and resistant cells. Although GlcCer was the major glycolipid (83.0%) in sensitive cells, GalCer, LacCer and, particularly, Gb3Cer were characteristically increased in all resistant cells, irrespective of whether the resistance was to taxol or cisplatin, and comprised 65–84% of total glycosphingolipids. GM3, which was present at 0.04 µg/mg dry weight in the sensitive cells, showed a twofold increase in the taxol-resistant cells, but was absent in the cisplatin-resistant cells. The altered glycolipid composition was proven to be due to enhanced or suppressed expression of the respective sugar transferase genes. In addition, the ceramide moiety of ceramide monohexoside in the sensitive cells constituted 83% of non-hydroxy fatty acids, but that in the resistant cells comprised 67–74% of α-hydroxy fatty acids. Thus, cells containing Gb3Cer with α-hydroxy fatty acids were found to survive selectively in the presence of taxol and cisplatin, and modification of the glycolipid structure was revealed to occur in association with anticancer-drug resistance. (Cancer Sci 2006; 97: 1321–1326)

Bisphosphonates are now well established as successful agents for the prevention and treatment of postmenopausal osteoporosis and corticosteroid-induced bone loss. Bisphosphonates have also recently become important in the management of cancer-induced bone disease, and they now have a widely recognized role for patients with multiple myeloma and bone metastases secondary to breast cancer and prostate cancer. Recent studies suggest that, besides the strong antiosteoclastic activity, the efficacy of such compounds in the oncological setting could also be due to direct anti-tumor effect. However, the effect of bisphosphonates to ovarian and endometrial cancers has not been elucidated. Thus, we examined the direct effect of bisphosphonates on the various ovarian cancer cell lines. Except for etidronate, all of bisphosphonates examined had the direct inhibitory effects on proliferation of all ovarian cancer cell lines used. Especially, pamidronate had the most marked inhibitory effect and inhibited dose-dependently the proliferation of ovarian cancer cell lines. KFr 13 cells among ovarian cancer cell lines used was the most sensitive to pamidronate and the caspase 3 activity was markedly stimulated by treatment with pamidronate, suggesting induction of apoptosis.

Background. The present study was conducted to determine the frequency and clinicopathological features of ovarian metastasis in a large population of patients with stage Ib–IIb cervical cancer. Methods. The study population consisted of 3471 patients with stage Ib to IIb cervical cancer who underwent radical hysterectomy, including pelvic lymphadenectomy and bilateral salpingo-oophorectomy, at our six institutions between 1981 and 2000. To our knowledge, this study is the largest review of patients with ovarian metastasis from cervical cancer. We reviewed the patients' medical records to determine clinicopathological features. Results. Fifty-two patients (1.50%) had ovarian metastases: 6 in stage Ib1, 12 in stage Ib2, 5 in stage IIa, and 29 in stage IIb. The mean age of patients with ovarian metastasis was 49.9 years (range: 29–73 years). The incidence of ovarian metastasis in patients with cervical cancer was 0.22% for stage Ib, 0.75% for stage IIa, and 2.17% for stage IIb with squamous cell carcinoma, and 3.72%, 5.26%, and 9.85%, respectively, in adenocarcinoma. Ovarian metastasis occurred more frequently among patients with adenocarcinoma than among those with squamous cell carcinoma (5.31% vs. 0.79%). Outcome for patients with ovarian metastasis was very poor and not related to FIGO stage and histological type. The presence of ovarian metastasis did not correlate with lymph node involvement or parametrial invasion. Conclusion. Study results indicate that ovaries can be preserved in patients with stage Ib–IIa squamous cell carcinoma but removed in all patients with adenocarcinoma.

Antiangiogenic scheduling of cancer chemotherapeutics has been increasingly recognized to be a potential application of the paclitaxel in cancer therapy. The purpose of this study is to confirm antiangiogenic effects of weekly low-dose paclitaxel in recurrent ovarian carcinoma. Measurements of serum vascular endothelial cell growth factor (VEGF) and interleukin (IL)-8 were performed using enzyme-linked immunosorbent assay (ELISA) kits. Serum was collected with written informed consents. Serum levels of VEGF and IL-8 were measured in patients with benign ovarian tumors, low malignant potential ovarian tumors (LMP), and ovarian carcinomas. Among 20 patients with pretreated recurrent ovarian carcinoma, 10 patients receiving treatment with paclitaxel (180 mg/m2) given once every 3 weeks (triweekly paclitaxel) and the other 10 patients receiving treatment with weekly paclitaxel (80 mg/m2) were randomly allocated. Sera from these patients were collected before treatment and 3 weeks after initiation of treatment to determine changes of VEGF and IL-8 levels. Although VEGF levels were highest in patients with ovarian carcinoma, there was no significant difference among benign, LMP, and carcinoma. Among patients with detectable levels of IL-8, ovarian carcinoma showed significantly higher IL-8 levels than benign tumors followed by LMP. VEGF levels in patients with treatment by triweekly paclitaxel did not show any significant change before and after treatment, while those in patients with treatment by weekly paclitaxel decreased significantly after treatment. Similarly, in patients with detectable IL-8 levels, weekly paclitaxel resulted in a significant decrease of IL-8 levels after treatment, while triweekly paclitaxel did not result in any significant change of IL-8 levels. The present study demonstrated that weekly but not triweekly paclitaxel had significant antiangiogenic effects.

Accurate preoperative diagnosis for gastrointestinal stromal tumor (GIST) was obtained using the endoscopic approach in about 50% of the cases. Preoperative assessment is quite important in reproductive women for the treatment of pelvic tumor. We report the first case of GIST of the rectum that was accurately diagnosed with preoperative needle biopsy from the vaginal wall. The case was a 38-year-old woman who presented with a history of genital bleeding. Internal examination revealed a round and elastic mass (7 x 7 cm) in the left pelvic cavity. The biopsy specimen from the left sidewall of the vagina using a manually manipulated biopsy needle showed strong reaction for CD34 and CD117 (c-KIT). The patient underwent low anterior resection of the rectum, tumor resection, and partial resection of the posterior vagina. Preoperative biopsy with vaginal approach might be helpful to make a diagnosis for pelvic tumor of unknown origin and unknown malignant potential.

The aim of this study was to describe the clinicopathologic features and prognosis of endometrial cancer patients diagnosed during or after tamoxifen treatment for breast cancer.Fifty-six tamoxifen-related endometrial cancers were identified from 10 hospitals in Japan. Past users were defined as endometrial cancer patients diagnosed more than 12 months after the cessation of tamoxifen treatment for breast cancer. All other users were classified as recent users.Age at diagnosis of the endometrial cancer ranged from 29 to 81 years. Sixteen (29%) and 19 (34%) patients were nulliparous and overweight, respectively. When the patients were divided into two groups: 30 recent and 26 past users, the distribution of various clinical characteristics, except for age at the time of diagnosis for endometrial cancer and the interval between the diagnoses of two cancers, was similar for two groups. The daily dose, duration and cumulative dose also showed no significant difference between the two groups. Past users had histopathologically more invasive tumors showing prognostically more unfavorable subtypes than recent users. The background lesions including endometrial polyps and diffuse cystic changes were similar for the two groups. The cumulative 3-year survival was significantly worse for past users than for recent users (74.8% and 96.4%, respectively, P0.04). In multivariate analysis including recentness of tamoxifen use and age at diagnosis of endometrial cancer, the significance of past user disappeared.Past users had a worse prognosis of endometrial cancer with more invasive histologic features than recent users, probably because they included more elderly patients.

Objectives . We have reported that single weekly paclitaxel has moderate activity in heavily pretreated ovarian cancer patients and is associated with a favorable toxicity profile. The purpose of this study was to reconfirm the effect of weekly paclitaxel in more number of cases. Methods . Although 39 patients were enrolled, 37 patients with recurrent or persistent ovarian cancer previously treated with between one and three chemotherapeutic regimens containing platinum were eligible. Patients had measurable or assessable disease defined by clinical exam, radiographic studies, or serum CA 125. One cycle of treatment consisted of paclitaxel 80 mg/m 2 /week in 1-h infusion, 3 weeks on, 1 week off, and repeated at least twice. Two patients were withdrawn because of refusal of further treatment for neuropathy after the first cycle. Clinical responses were defined by established criteria. Results . Thirty-seven patients were included in this intent-to-treat study. The overall clinical response rate was 45.9% (5 complete responses, 12 partial responses). The clinical response rate in patients with measurable tumor was 25.0% (2 complete responses, 1 partial response), while that in patients without measurable tumor and with assessable CA 125 levels was 56.0% (3 complete responses, 11 partial responses). Clinical response rate in patients with chemotherapy-free interval more than 6 months had about twice higher than that in patients with chemotherapy-free interval less than 6 months. The clinical response rate by number of prior regimens revealed that as number of prior regimens increases, the response rate decreases. Conclusion . Weekly paclitaxel has significant antitumor activity in heavily pretreated patients with recurrent or persistent ovarian carcinoma and warrants as second or third line chemotherapy in such setting.

Ovarian cancer patients with paclitaxel-resistance have been reported to respond to a weekly schedule of the same drug. In this report, two cases with long progression free interval by weekly paclitaxel (T) are presented. Case 1. A 41-year-old Japanese woman, gravida 2, para 0, was referred to our hospital in September 16, 1998, because of abdominal mass accompanying large amount of ascites with elevated CA125 (8400 U / ml) and CA19-9 (770 U / ml). Exploratory laparotomy (tumor biopsy plus partial omentectomy) was performed September 21, 1998. After the surgery, the tumor was diagnosed as serous cystadenocarcinoma of the ovary (stage IV) and 6 cycles of treatment consisting of cyclophosphamide, adriamycin and cisplatin (CAP) were performed. The CA 125 level (8400 U / ml) rapidly declined to 150 U / ml by this CAP therapy. After second cytoreductive surgery (SRS) (total hysterectomy and bilateral salpingo-oophorectomy), residual tumor was less than 2 cm. Although 7 cycles of CAP was added, ascites and elevation of CA 125 (5100 U / ml) were observed. Therefore, treatment with single weekly T was performed and CA 125 levels remained between 70-90 U / ml during 13 cycles of this therapy (progression free interval; more than 1 year). Thereafter, she is alive with disease and followed-up. Case 2. A 48-year-old Japanese woman, gravida 3, para 2, was referred to our hospital in July 22, 1998, because of abdominal swelling and pain. Computing tomography (CT) and magnetic resonance imaging (MRI) revealed large amount of ascite and pelvic mass (9 x 7 x 7 cm), and low density area (3 x 3 cm) suggesting metastasis in right lobe of liver. Serum CA 125 level elevated to 5100 U / ml. Bilateral salpingo-oophorectomy and infracolic omentectomy were performed on August 5, 1998. The tumor was diagnosed as endometrioid adenocarcinoma of the ovary, stage IV and chemotherapy with CAP was initiated on September 5, 1998. After 6 cycles of CAP, SRS was performed. After SRS, 3 cycles of CAP were added and changed to weekly T because of damage of renal function. The CA 125 level returned within normal range during weekly T. Total 13 cycles of weekly T were performed and progression free interval was about 18 months. Thereafter, she received treatments with gamma knife and CAP for brain metastasis. She is alive without disease and followed-up. Side effects by weekly T were mild and tolerable despite of long term treatment. In addition, weekly T can be safely used in outpatient setting and even in patients with poor performance status (PS), and warrant long time to progression.

Expressed sequence tags and genome sequencing have virtually uncovered all the genes and transcripts in the human genome. Functional genomic analysis of these genes will undoubtedly reveal their physiological roles in cells in the near future. Coupled with the advent of DNA microarray, cellular response to perturbation can now be examined at genome-wide levels in a single analysis, yielding clues to the network of pathways and interacting pathways that underlie a comprehensive systems response to exposure to small molecule perturbants. This post-genomic information will be the foundation for knowledge-based in silico systems biology. It is envisioned that querying such relational databases will generate testable hypotheses as well as revealing information on networks of regulatory genes and pathways that could further fuel and shape molecular and drug target discovery, and ushering in a new era in genomic medicine. In this review, we will first discuss examples of laboratory results generated from high-throughput microarray analyses that illuminated previously unrecognized networks of regulatory genes and pathways that point to the mechanisms of action for the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate, and the green tea polyphenol, epi-gallocatechin gallate. We will then focus on the application of gene expression profiles in genomic medicine for predicting treatment response in cancer, using clinical specimens obtained from patients. These studies and others point to an increasing trend in modern biology in which high-throughput genome scale comprehensive biological information is incorporated into databases for constructing and reconstructing pathways and networks of interacting pathways that constitute a physiological response to environmental perturbation at the organism or systems levels. Drug Dev. Res. 62:124–133, 2004. © 2004 Wiley-Liss, Inc.

The aim of this study is to evaluate clinical usefulness of Korean red ginseng (RG) on various postmenopausal syndromes. Total plasminogen inhibitor-1 (tPAI-1) in peripheral blood from 9 postmenopausal women with climacteric syndromes (CS) was measured before and 3 months after treatment with daily oral administrat i on of 6g RG and that from 8 postmenopausal women without any CS was also measured as healthy controls. Blood samples were collected in the early morning on the bed-rest. Psychological conditions of postmenopausal women with CS were measured before and 3 months after treatment with RG using simplified menopausal index (SMI). In addition, OKETSU (blood stagnation) syndrome scores and KI deficiency (generalized energy stagnation) scores proposed by Terasawa et al., were recorded before and 3months after treatment with RG in postmenopausal women with CS and in healthy postmenopausal women. OKETSU syndrome scores and tPAI-1 levels in postmenopausal patients with CS were significantly (P P

Mechanisms of cAMP signal transduction have been thoroughly investigated for more than 40 years. From the binding of hormonal ligands to their receptors on the outer surface of the plasma membrane to the cytoplasmic activation of effectors, the ensuing cAMP signaling cascades and the nuclear gene regulatory functions, coupled with the structural elucidation of the cAMP-dependent protein kinase (PKA) and in vivo functional characterizations of each of the components of PKA by homologous recombination gene targeting, our understanding of cAMP-mediated signal transduction has reached its pinnacle. Despite this trove of knowledge, some recent findings have emerged that suggest hitherto novel and alternative mechanisms of cAMP action that could increase the signaling bandwidth of cAMP and PKA in cell growth and transcriptional regulation. This article attempts to review some of these novel and unconventional mechanisms of cAMP and PKA signaling, and to generate further enthusiasm in investigating and validating these new frontiers of the cAMP signal transduction pathway.

11056 Background: Uterine leiomyosarcomas (ULMs) tend to recur regardless of their stage, and there is no satisfactory report for relapsed ULMs. Temozolomide (T) is derivatives of dacarbazin and these agents have been used for treatment of ULMs. ULMs has a plenty of vessels compared to uterine myoma so that bevacizumab (B) was used in ULMs. In the present study, we evaluated the effect of TB in heavily pretreated relapsed ULMs. Methods: From 2009 to 2016, total 19 patients (pts) with heavily pretreated ULMs were enrolled. Patients were treated with T (80mg/body/day) and B (2mg/kg; days 1, 8 and 15, q4 weeks). Treatment was continued until disease progression and/or unmanageable toxicities. Response was evaluated with the response evaluation criteria in solid tumors (RECIST) v1.1, and adverse effect (AE) was assessed by common terminology criteria for adverse events (CTCAE) v4.0. Results: Seventeen of 19 pts were subjected to response evaluation. Median age of pts was 56.3 years (range: 31-69). Three pts (18%) had complete response (CR), 2 (12%) had partial response, and 7 (41%) had stable disease (SD). The response rate (RR: CR+PR) and clinical benefit rate (CBR: CR+PR+SD) were 29% and 71%. The median progression-free survival was 14.2 months (range: 0-89). Median administration cycle was 9.5 (range: 2-48). AE with grade 3 and more over were observed in 6 pts. There was one dead case from perforation, but toxicity was almost manageable. Conclusions: We experienced 3 cases of CR, and two of them had CR for more than two years. Intriguingly, TB could be substantially effective even in relapsed patients with heavily pretreated ULMs. These results warrant further prospective and randomized studies.

5550 Background: Eribulin is a candidate for paclitaxel-refractory breast cancers, and Bevacizumab (B) is known to enhance efficacy of anti-cancer agents in ovarian cancers. A phase II study to evaluate weekly administration of B with eribulin and oxaliplatin (EriOX) in patients with platinum-resistant and refractory ovarian carcinomas (PR-ROC) was performed. Methods: Eligible patients were as follows: (a) ECOG PS = 0~2 (b) histologically confirmed epithelial ovarian cancer (c) diagnosed as platinum-resistant ovarian cancer (d) written informed consent. Patients were treated with weekly-B-EriOX consisting of B (2mg/kg), eribulin (1mg/m2) and oxaliplatin (30mg/m2), three weeks on and on week off, q4weeks. The study was conducted using two-stage design of Simon (type I error = 0.05, power = 0.9, true response rate = 25%). Biomarker analyses including serum VEGF, BNP, p53, IL-6, and Her-2 were also conducted. Results: A total of 34 patients were enrolled in the present study: 13 cases in the first-stage, and additional 21 cases in the second-stage. There were 3 responders (≧2) in the first-stage, and the protocol was proceeded to the second-stage. Median age of the patient was 58.5 years (range: 35-76), and median number of previous regimen was 4 (range: 2-9). Overall, two patients (6%) had a complete response (CR), 8 patients (24%) had a partial remission (PR) and 16 patients (47%) had a stable disease (SD). The response rate and clinical benefit rate (CR+PR+SD) were 29% and 76%, respectively. Median progression-free survival was 4 months (range: 1-27+). Hematological adverse effects (AE) with grade 3/4 were observed in 4 patients (11%). Non-hematological AE greater than grade2 was observed in one case: hypo albuminemia and edema, which were manageable and tolerable. As there were 10 responders (≧6), the protocol was considered for additional investigation. The Patients with elevated serum mutated p53 / IL-6 showed lower response and worse prognoses. Conclusions: Weekly B and EriOX administration was considered for additional investigation for patients with PR-ROC. Serum mutated p53 protein and/or IL-6 could be biomarkers in PR-ROC patients treated with weekly B and EriOX.

We collected blood samples from 70 HIV-1-infected pregnant women and 76 babies born to HIV-1-infected women in Japan, from 1989 to 1999. To analyze the genetic diversity of HIV-1 among mothers and children, we sequenced the C2-V3 regions of HIV-1 gp120. Phylogenetic tree analysis of these regions revealed that multiple HIV-1 subtypes, A, B, D, E, and G, were circulating among mothers and children in Japan. Thus, the genetic heterogeneity of HIV-1 among mothers and children in Japan is steadily increasing, although the number of cases remains small. Perhaps the longest term survivor, an 11-year-old child with a vertical HIV-1 subtype G infection in Japan, is one of our subjects.

13,14-Dihydro-15-deoxy-Delta7-prostaglandin A1 methyl ester (TEI-9826), an antitumor prostaglandin analog, is a candidate for clinical trial. In the present study, we examined its biological stability in vitro, antitumor activity in vitro and in vivo, and pharmacokinetics. Although TEI-9826 was rapidly hydrolyzed to the carboxylic acid form (TOK-4528), TOK-4528 as well as Delta12-prostaglandin J2 (PGJ2) were found to be stable in rat, mouse and human serum in vitro. TEI-9826 exhibited nearly identical or greater potential antitumor activity compared to Delta12-PGJ2 and Delta7-PGA1 in vitro against Colon26 tumor cells. Further evaluation of TEI-9826 using the 38 human cancer cell lines panel and COMPARE analysis suggested that its mode of action is quite different from other anticancer agents that are currently used. TEI-9826 was integrated into lipid microspheres (Lipo TEI-9826) for dosing. Growth inhibition by Lipo TEI-9826 against Colon26 tumor inoculated s.c. in mice depended on administration route, i.e. at 80 mg/kg, no growth suppressive effect was observed for daily bolus i.v., but significant growth suppressive effect was observed for daily i.p., daily s.c. every other day s.c. and 4 times a day continuous (5 min) i.v. These tumor growth-suppressive effects were cytostatic and the tumor started to regrow at the end or a few days after the end of administration. The pharmacokinetic study suggested that maintaining the blood level of TEI-9826 and/or TOK-4528 was essential for their antitumor effects. These results show that continuous i.v. infusion might be the most suitable administration method of Lipo TEI-9826 for clinical trial.

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.

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.

A collaborative group for studying vertical transmission of human immunodeficiency virus (HIV)-1 in pregnant women and their babies was established in Japan in 1989. Forty-two infants, including 13 HIV-1-infected, 25 uninfected and four of undetermined status and 15 control children born to HIV-1 negative mothers were diagnosed and followed from birth to 1.5 years. All strains from HIV-positive infants were either clade E (eight infants, 61.5%) or B (five infants, 38.5%) according to DNA sequencing specific for the HIV-1 C2-V3 region. The 42 mothers with HIV-1 were women with sexual-risk behavior from all regions, but were concentrated in the Kanto District. In this group of HIV-infected children, there was no significant difference between the transmissibility of their mother's clade E and B viruses. Eight (61.5%) of the 13 virus-infected babies were Japanese and five (62.5%) of the eight were positive for HIV-1 clade E. The V3 loop region of the clade E virus of the babies was conserved but approximately 60% of the sequences which showed a substitution of aspartic acid by asparagine at position 29. The results suggest that HIV-1 clade E may be predominant in vertical transmissions and are phenotypically different from HIV-1 in persons with various other risk behaviors in Japan.

Adenocarcinoma with a stromal micropapillary pattern (SMP) has been described in various organs, but not in the uterus. We encountered a case of uterine cervical carcinoma with SMP. A54-year-old Japanese woman was referred to the hospital with abnormal vaginal bleeding. The cervical cytodiagnosis was adenocarcinoma with features resembling serous adenocarcinoma. Cervical cytology showed many small clusters of tumor cells, present in up to two or three layers, composed of atypical cells with markedly increased nucleus: cytoplasm ratios. A radical hysterectomy with bilateral adnexectomy and retroperitoneal lymph node dissection was performed. Microscopically, the tumor was composed predominantly of adenocarcinoma with SMP. The outer surface of the SMP cell clusters showed membranous expression of mucin-1 (MUC-1). Many lymph node metastases were detected. The tumor was diagnosed as a cervical adenocarcinoma with SMP and coexistent squamous cell carcinoma in situ. The pathology was classified as T1b1N1M1, stage IVB. The patient underwent postoperative adjuvant chemotherapy and is without local recurrence or distant metastasis 48 months after the operation. To the best of our knowledge, this is the first reported case of cervical adenocarcinoma with SMP.

In 5-day incubation of an estrogen receptor-negative human ovarian cancer cell line (KF) with N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl (DPPE), the concentration of DPPE required for 50% inhibition of KF cell proliferation (IC50) was 1.7 microM. The IC50 of DPPE for inhibition of protein kinase C (PKC) activity was 3.0 microM, a similar value to those of other antiestrogens such as tamoxifen and clomiphene. DPPE also inhibited phosphorylation of mitogen-activated protein kinase in KF cells. When treatment with DPPE was started 7 days after inoculation of KF cells into nude mice, 50 mg/kg DPPE alone resulted in a significant growth retardation in the early stage of tumor growth. Although 25 mg/kg DPPE showed a similar effect to 2 mg/kg cisplatin (CDDP), the combination had the most marked tumor growth-inhibitory effect. Nude mice treated with combinations of CDDP and DPPE survived significantly longer than not only untreated, but also CDDP-alone-treated mice, while 50 mg/kg but not 25 mg/kg DPPE alone had an effect comparable to that of 2 mg/kg CDDP alone. If treatment with DPPE was begun from the day after tumor inoculation, the inhibitory effect of DPPE was further enhanced, especially when combined with CDDP. If treatment with DPPE was started in nude mice with a lower tumor burden, 25 mg/kg as well as 50 mg/kg DPPE had a similar effect to 2 mg/kg CDDP, in terms of survival. When DPPE was combined with CDDP, the effect was significantly enhanced, compared to that of either alone. These treatments could be done without any adverse side effect. Thus, we conclude that DPPE has an antiestrogen action and its tumor growth-inhibiting activity is enhanced on administration in combination with CDDP.

This study was designed to elucidate the mechanisms of cisplatin (CDDP) resistance using two human ovarian cancer cell lines, KF and TYK, and two CDDP-resistant lines, KFr and TYK/R, derived from the former lines. KFr and TYK/R showed about 3-fold higher resistance to the cytotoxic effects of CDDP than their parental lines. They also showed a significant increase in sensitivity to not only etoposide, but also (+)-(4S)-4, 11-diethyl-4-hydroxy-9-[(4-piperidino -piperidino)carbonyloxy]-1H -pyrano[3',4':6,7]inodolizino[1,2-b]quinoline-3,14(4H, 12H)-dione hydrochloride trihydrate (CPT-11). Cellular CDDP accumulation levels in KFr and TYK/R were decreased from those of the parental cells. By contrast, the cellular glutathione (GSH) content in KFr cells was 1.7-fold higher than that in KF, whereas TYK/R cells had a 40% lower content than TYK cells. Cellular mRNA levels of drug-resistance-related genes, such as DNA topoisomerase (topo) I and topo II, glutathione S-transferase-pi (GST-pi), gamma-glutamylcysteine synthetase (gamma-GCS), and metallothionein (hMT) genes, were compared between drug-sensitive KF or TYK and KFr or TYK/R. KFr cells had 8.5- and 24.7-fold higher mRNA levels of gamma-GCS and topo II genes than KF cells while KFr had only a slight increase in GST-pi mRNA level as compared with KF. By contrast, TYK/R cells had 2.9- and 1.7-fold higher hMT and topo I mRNA levels than TYK cells. Acquisition of CDDP resistance in human ovarian cancer cells thus appeared to be related mainly to expression of gamma-GCS, topo II and hMT genes, and partly to that of topo I and GST-pi genes, in addition to a decrease in CDDP accumulation.

This study was designed to the elucidate sensitising effects of the intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy] ethanamine· HCl (DPPE) on the antitumour activity of cis-diamminedichloroplatinum (II) (CDDP) using human ovarian cancer cell lines with different sensitivities to CDDP (KF, sensitive) KFra (acquired CDDP resistant derived from KF), and KK and MH, intrinsically CDDP resistant. The KF cells were most sensitive to CDDP among cell lines used in this study and followed by MH, KK and KFra showing approximately 3.5, 4.0 and 9.1-fold IC50 values to KF, respectively. The acquired CDDP resistant KFra cells were approximately 6.1-fold more sensitive to DPPE than the parent KF cells, while MH and KK cells were more than 10-fold more resistant to DPPE than the KF cells. With regard to the inhibition of human ovarian cancer cell proliferation, phenyltoloxamine and L-histidinol were 5–2500-fold less cytotoxic than DPPE. Analysis of flow cytometry (FCM) revealed that with concentrations based on the IC50 to KF and KFra cells, DPPE resulted in G2-M accumulation in the KF (but not KFra) cells in a time-dependent manner during the course of 48 h incubation time. In addition, from a median effect analysis, DPPE seemed to have additive and somewhat synergistic effects on the antitumour activity of CDDP in KK and MH cells with intrinsic CDDP resistance, while minor antagonism in KFra cells with acquired CDDP resistance was observed. Although DPPE alone did not significantly inhibit the tumour growth of nude mice bearing KF cells, combinations of DPPE with CDDP resulted in improved survival compared with treatment with only CDDP. Adverse side-effects, as confirmed by monitoring haematocrit and the body weight were not observed during the experimental period. These results suggest that DPPE may be of clinical use for the treatment of intrinsically refractory ovarian carcinoma when combined with CDDP.

Objective Combination therapy using gemcitabine with oxaliplatin (GEMOX) showed moderate activity in recurrent ovarian cancers. However, severe toxicities have been observed in patients who received full-dose therapy of GEMOX. On the other hand, bevacizumab enhances chemotherapeutic efficacy in various cancers. Here, we evaluated the effect of weekly low-dose administration of GEMOX in combination with bevacizumab (B-GEMOX) for patients with recurrent and refractory ovarian cancers (ROCs). Methods A total of 19 patients with ROC were treated with B-GEMOX: 2 mg/kg of bevacizumab, 300 mg/m2 of gemcitabine, and 30 mg/m2 of oxaliplatin, 3 weeks on and 1 week off, q4weeks. The treatment was continued until development of severe toxicities or progressive disease. Tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors and Gynecologic Cancer Intergroup criteria. Results Median number of the B-GEMOX therapy was 5 cycles. Response was observed in 4 (34%) cases by Response Evaluation Criteria in Solid Tumors, and in 2 (29%) cases by Gynecologic Cancer Intergroup criteria, resulting in overall response rate of 32%. Clinical benefit excluding progressive disease was obtained in 79% of the patients. Median progression-free survival was 4.5 months (range, 2–16+ months). Toxicities were mild and mainly consisted of hematologic, gastrointestinal, and neuropathy; however, there were no nonhematologic toxicities more than grade 1. Conclusions Weekly administration of B-GEMOX was active for patients with ROC and showed mild toxicities. These results warrant further prospective studies for patients with ROC.