Spectrin αII and ßII tetramers contribute to platinum anticancer drug resistance in ovarian serous adenocarcinoma.

To overcome drug resistance in ovarian carcinoma, novel resistance mechanisms must be elucidated for clinical application. We purified 2 proteins in the 300 kDa range from cisplatin-resistant cells (NOS2CR2) by affinity chromatography with cisplatin-exposed Glutathione Sepharose 4B. The purified proteins were identified as spectrin αII and ßII by peptide mass mapping analysis. Western blot analysis detected greater expression of spectrin αII and ßII in NOS2CR2 than in wild-type cells (NOS2). The same result was obtained for spectrin ßII expression by immunohistochemical staining. To determine whether spectrin αII and ßII contribute to resistance, a drug sensitivity test was performed on SKOV3 ovarian cancer cells transfected with small interfering RNA. Sensitivity to platinum drugs was increased in the expression reduced cells. In a clinical study of five ovarian serous adenocarcinoma cases, tumor specimens taken after treatment with carboplatin stained more strongly for spectrin ßII expression than untreated specimens. Fifty-two tumor specimens from 46 patients with ovarian serous adenocarcinoma were immunohistochemically stained for spectrin ßII and scored. Tumors previously treated by chemotherapy scored higher than those not treated. Of 27 cases with detectable residual tumors at the time of surgery, cases scoring 4-6 had shorter progression-free survival periods after platinum-based chemotherapy than cases scoring 0-3 (p = 0.012). The cytoskeleton proteins Spectrin αII and ßII contributed to drug resistance by anchoring the GS-Pt complex to the cell membrane, arresting cisplatin activity. Thus spectrin ßII may be a useful predictor of platinum sensitivity in ovarian serous adenocarcinoma.

Long-term clinical outcome of patients with recurrent epithelial ovarian carcinoma: is it the same for each histological type?

OBJECTIVE: This study was conducted to estimate the long-term clinical outcome of patients with recurrent ovarian carcinoma (ROC). METHODS: Six hundred three patients with ROC were analyzed in this study. The pathological slides were evaluated under central pathological review. The prognostic significances of clinicopathologic factors were evaluated using both univariate and multivariate analysis. RESULTS: The 5-year overall survival (OS) and postrecurrence survival (PRS) rates were 31.1 and 16.9%, respectively. On stratifying to treatment periods, the PRS has been prolonged over the last decade (year ≥2000) compared with before this period (year ≤1999) (P = 0.0002). In contrast, on stratifying to histological types and treatment periods, in both OS and PRS, the prognosis of patients with the nonmucinous/clear-cell histology, including serous, endometrioid, and other histological types, was significantly improved after 2000 compared with before (year ≤1999) (OS, P = 0.0009; PRS, P < 0.0001). In contrast, that of patients with the mucinous/clear-cell histology did not significantly differ regardless of the treatment period (≥2000 vs ≤1999: OS, P = 0.3887; PRS, P = 0.7617). In multivariate analysis, the stage, period of starting initial treatment, histological type, and the treatment-free interval were independent prognostic factors of a poor OS and PRS (OS/PRS: histological type: mucinous/clear-cell vs nonmucinous/clear-cell: hazard ratio, 1.300/1.498; 95% confidence interval [CI], 1.039-1.626/1.197-1.874). CONCLUSIONS: Despite the continuous administration of treatment for ROC, survival is poor, and the extent of therapeutic progress differs according to the histological type.

Postrecurrent oncologic outcome of patients with ovarian clear cell carcinoma.

OBJECTIVES: To estimate the long-term clinical outcome of patients with recurrent clear cell carcinoma (RCCC) of the ovary in comparison with those with recurrent serous adenocarcinoma (RSAC). PATIENTS AND METHODS: In this study, 113 patients with RCCC and 365 patients with RSAC were analyzed. The pathological slides were evaluated under central pathological review. End points were the overall survival (OS), postrecurrence survival (PRS), and timing of death of mortality cases. RESULTS: The 5-year OS and PRS rates of patients with RCCC were 22.5 and 13.2%, respectively. In both OS and PRS, the prognosis of patients with RCCC was significantly poorer than that of the patients with RSAC (OS: P = 0.0007; PRS: P < 0.0001). Moreover, regardless of the status of the residual tumor (RT) at the initial surgery, the OS and PRS of the patients with RCCC were markedly shorter than those with RSAC (RT [-]: OS, P = 0.0005: PRS, P = 0.0002: RT [+]: OS, P < 0.0001: PRS, P < 0.0001). In multivariable analysis, the histological type was a significantly poorer prognostic indicator for OS and PRS (OS [RCCC vs RSAC]: hazard ratio, 2.302: 95% confidence interval, 1.723-3.076; P < 0.0001: PRS [RCCC vs RSAC]; hazard ratio, 2.353: 95% confidence interval, 1.756-3.155; P < 0.0001). Even in the deceased patients (n = 350), the rate of patients with RCCC dying within 12 months of recurrence was higher than that of RSAC (RCCC, 67.8%; RSAC, 40.7%; [P < 0.0001]). CONCLUSIONS: The long-term clinical outcome of patients with RCCC was extremely poor. We confirmed that RCCC should be investigated as a different malignancy compared with RSAC.

Combination of the tumor angiogenesis inhibitor bevacizumab and intratumoral oncolytic herpes virus injections as a treatment strategy for human gastric cancers.

BACKGROUND/AIMS: Advanced gastric cancer is difficult to treat due to the frequency of liver metastases and peritoneal dissemination. A combination of two new strategies, including the anti-angiogenesis inhibitor bevacizumab and an oncolytic herpes virus is a promising treatment for advanced cancer. METHODOLOGY: The effects of bevacizumab on oncolytic herpes virus replication and viral cytotoxicity were examined at varying bevacizumab concentrations and viral titers. In addition, the ability of these two new promising anticancer agents to inhibit tumor growth was studied. Histological examinations of CD31 and LacZ were used to assess angiogenesis and virus distribution within the tumor, respectively. RESULTS: Bevacizumab did not affect viral replication or viral cytotoxicity in vitro. The combination of bevacizumab and the oncolytic herpes virus hrR3 significantly reduced tumor growth in vivo in an experimental gastric cancer model. Bevacizumab inhibited angiogenesis caused by local injection of hrR3 and induced virus spread. Bevacizumab increased the distribution of the intratumorally injected oncolytic herpes virus within the tumor. CONCLUSIONS: Combination therapy consisting of bevacizumab and an oncolytic herpes virus is a promising new treatment strategy for gastric cancer.

Organic anion transporting polypeptide 2-mediated uptake of paclitaxel and 2'-ethylcarbonate-linked paclitaxel in freshly isolated rat hepatocytes.

OBJECTIVES: The P-glycoprotein (P-gp) efflux pump plays an important role in paclitaxel detoxification. However, hepatic uptake of paclitaxel mediated by a solute-linked carrier transporter family is still poorly understood in animals and humans. Freshly isolated hepatocyte suspensions are a well established in-vitro model for studying drug transport and xenobiotic metabolism. Therefore, the hepatic uptake of paclitaxel and its P-gp-insensitive prodrug, 2'-ethylcarbonate-linked paclitaxel (TAX-2'-Et), has been characterized using freshly isolated and pregnenolone-16-alpha-carbonitrile (PCN)-treated hepatocytes in rats. METHODS: Paclitaxel and TAX-2'-Et were incubated with rat hepatocyte suspensions in the presence or absence of inhibitors. KEY FINDINGS: Paclitaxel and TAX-2'-Et showed concentration-dependent uptake in rat hepatocytes. The intrinsic transport capacity was two-fold higher for paclitaxel uptake than for TAX-2'-Et uptake. Rifampicin (a potent inhibitor of organic anion transporting polypeptide (Oatp) 2), but not indometacin (a representative inhibitor of organic anion transporter (Oat) 2 and Oatp1) treatment, significantly inhibited the uptake of paclitaxel and TAX-2'-Et. We characterized the rifampicin-sensitive uptake of paclitaxel and TAX-2'-Et using rat hepatocytes treated with PCN, which dramatically enhances hepatic Oatp2 protein levels. PCN-treated hepatocytes displayed a 1.6-fold greater uptake of paclitaxel and TAX-2'-Et than the vehicle-treated hepatocytes. The uptake of the two compounds was significantly reduced by rifampicin but not by indometacin treatment. These findings demonstrated that the rat Oatp2, but not Oatp1 or Oat2, was a candidate transporter for the hepatic uptake of paclitaxel and TAX-2'-Et. CONCLUSIONS: The findings have provided an important step towards identifying a key transporter in hepatic detoxification of paclitaxel and TAX-2'-Et in small animals.

Spontaneous regression of gestational trophoblastic neoplasia.

•We present two cases of postmolar gestational trophoblastic neoplasia (GTN).•Both cases presented with lung metastases after hydatidiform mole.•Both cases showed spontaneous regression without treatment.•The mechanism behind this phenomenon remains unclear.•Patients with postmolar GTN and declining hCG values may not need chemotherapy.

Expression of Twist enhances risk of poor oncologic outcome in patients with stage Ib to II cervical carcinoma with lymphovascular space involvement.

Twist, a basic helix-loop-helix transcription factor, promotes cancer cell epithelial-mesenchymal transition and metastasis. Here, we aimed to examine the association between Twist expression and lymphovascular space involvement for early-stage cervical carcinoma. Paraffin sections from 90 patients with stage Ib to IIb cervical carcinoma were immunostained with Twist antibody, and the staining intensities were semiquantitatively evaluated. Of the 90 cervical carcinoma specimens examined in this study, 51 (56.7%) were negative for Twist and 39 (43.3%) were positive for Twist immunoreactivity. The 5-year overall survival rates of patients in the Twist-negative and Twist-positive groups were 98.0% and 75.8%, respectively. Univariate and multivariate analyses demonstrated that Twist expression was an independent prognostic factor for overall survival and recurrence-free survival (univariate: P = .0069 [overall survival], P = .0092 [recurrence-free survival]: multivariate: P = .0118 [overall survival], P = .0118 [recurrence-free survival]). On stratifying based on the negative lymphovascular space involvement status, the overall survival and recurrence-free survival of patients in the Twist-negative group was the same as that of those in the Twist-positive group (log-rank: P = .262 [recurrence-free survival], P = .899 [overall survival]). In contrast, with lymphovascular space involvement, a significantly poorer recurrence-free survival was predicted for patients in the Twist-positive group compared with that in the Twist-negative group (P = .0021). Twelve (75.0%) of 16 patients showing recurrence belonged to the Twist-positive group, and 83.3% (10/12) of them experienced recurrence in distant organs or the peritoneal cavity. This study suggested that the assessment of the Twist immunoreactivity and lymphovascular space involvement may distinguish high- from low-risk patients with locally invasive cervical carcinoma.

Expression of CXCR4 indicates poor prognosis in patients with clear cell carcinoma of the ovary.

Recent reports have shown that CXCR4 is expressed in various solid tumors and is involved in tumor development and metastasis. We examined the distribution and expression of this molecule in clear cell carcinoma of the ovary to elucidate its clinical significance. Paraffin sections from clear cell carcinoma of the ovary tissues (n = 42) were immunostained with CXCR4 antibody, and the staining intensities were evaluated. The clinicopathologic factors examined were age, FIGO (International Federation of Gynecology and Obstetrics) staging, preoperative value of cancer antigen 125 test, and residual tumor after cytoreductive surgery. Overall survival and progression-free survival were evaluated using the Kaplan-Meier method, and multivariate analysis was completed using Cox proportional hazards analysis. Of the 42 carcinomas, lower level CXCR4 immunoexpression was observed in 21 cases (50.0%) (CXCR4(low) group); and higher level immunoexpression, in 21 cases (50.0%) (CXCR4(high) group). Five-year overall survival was significantly poorer in the CXCR4(high) group than in the CXCR4(low) group (overall survival, CXCR4(low) group [90.2%], CXCR4(high) group [50.3%]; P = .0002). In addition, CXCR4(high) immunoexpression significantly predicted a poorer progression-free survival when compared with lower expression (5-year progression-free survival, CXCR4(low) group [90.5%], CXCR4(high) group [36.2%]; P < .0001). Furthermore, multivariate analyses including the age, preoperative cancer antigen 125 test value, FIGO stage, and CXCR4 expressions revealed that CXCR4(high) expression was an independent prognostic factor for poorer overall survival and progression-free survival of patients with clear cell carcinoma of the ovary (overall survival, P = .0011; progression-free survival, P = .0008, respectively). Our current study suggested that the assessment of CXCR4 immunoreactivity may be a useful prognostic indicator and that CXCR4 may play a critical role in the progression of clear cell carcinoma of the ovary.

Thyroid transcription factor 1 expression in ovarian carcinomas is an independent prognostic factor.

Tthyroid transcription factor 1 is a marker of lung and thyroid carcinomas, but thyroid transcription factor 1 immunoreactivity is seen in other malignancies. We examined the incidence of thyroid transcription factor 1 expression in gynecologic tumors in Japanese patients, and we further evaluated the presence of epidermal growth factor receptor mutations in thyroid transcription factor 1-positive gynecologic malignancies. A total of 186 patient samples collected at our hospitals between 1991 and 2006 were analyzed, and these specimens consisted of 83 ovarian carcinomas, 55 endometrioid endometrial adenocarcinomas of the uterus, 28 cervical adenocarcinomas of the uterus, and 20 leiomyosarcomas of the uterus. Thyroid transcription factor 1 expression was assessed by immunohistochemistry. The presence of epidermal growth factor receptor mutations was investigated by polymerase chain reaction analyses. Thyroid transcription factor 1 was detected in the nuclei of 11 ovarian carcinomas (13%) and 5 endometrioid adenocarcinomas (10%) of the uterus. In patients with ovarian carcinoma, thyroid transcription factor 1 staining was associated with significantly improved progression-free (P = .017) and overall survival (P = .017) using univariate analysis. Multivariate analysis identified thyroid transcription factor 1 expression as an independent prognostic factor for ovarian cancer (P = .0467). No epidermal growth factor receptor mutations were found in our study. Thyroid transcription factor 1 is expressed with relatively low frequencies in gynecologic malignancies, but thyroid transcription factor 1 expression confers a better prognosis in patients with ovarian cancer. No epidermal growth factor receptor mutations were found in the thyroid transcription factor 1-positive gynecologic malignancies, and we were unable to establish a relationship between epidermal growth factor receptor mutations and thyroid transcription factor 1 immunopositivity, as was previously shown for lung cancer.