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The purpose of this study was to evaluate the effects of salvage chemotherapy on recurrent or persistent ovarian clear cell carcinoma (CCC) with the goal of identifying a more rational treatment regimen for this lethal disease.The medical records of patients with CCC were retrospectively reviewed to select patients that were subsequently treated for recurrent or persistent disease.Of the 164 women with recurrent or persistent CCC, 485 chemotherapy courses with 1766 cycles were administered. Overall, the clinical benefit rate (CBR) was 39.4%, and the mean progression-free survival (PFS) was 4.5 months. Grade 3/4 toxicities occurred in 94 courses (19.4%). The CBR for TC was 45.1%, with a PFS of 3.7 months. Compared to that of TC, the CBRs for PC and CC were significantly lower (P = 0.020 and 0.021, respectively). The CBRs and PFS for PAF-C were slightly higher (P = 0.518 and 0.077, respectively), but showed a significantly higher adverse event rate (AER, P = 0.039). The CBR for bevacizumab was 50% with an extraordinarily long PFS (49.8 months). Gemcitabine and oxaliplatin had similar values for CBRs (44.4% and 44.1%) and PFS (2.5 and 3.4 months), respectively. Docetaxel (weekly) exhibited a notably low AER of 2.7%, and topotecan was associated with a relatively long PFS (7.7 months).For cis/carboplatin-pretreated patients, the existing active agents, such as oxaliplatin, gemcitabine, topotecan, and especially bevacizumab, are promising. Docetaxel (weekly) is well tolerated and might offer a particularly viable option for heavily pretreated patients. However, additional research to identify for a continued search for the optimal combination of chemotherapeutics or novel agents is still warranted.

Struma ovarii is a rare variant of teratoma characterized by the presence of thyroid tissue in more than 50%. Malignant transformation is rare (less than 5%) and the criteria to classify this condition have changed over time. Nowadays it must fulfill the histological categories of differentiated thyroid carcinoma. Its treatment is controversial and there is no unanimous management. We present three cases of women with malignant struma ovarii, diagnosed by the surgical specimen.

Purpose: The combination of low-dose radiotherapy with PARP inhibition has been shown to enhance antitumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with escalating doses of veliparib (ABT-888), a small-molecule PARP inhibitor, in patients with peritoneal carcinomatosis from advanced solid tumor malignancies., Experimental Design: Patients were treated with veliparib (80-320 mg daily) for a total of 3 cycles. LDFWAR consisted of 21.6 Gy in 36 fractions, 0.6 Gy twice daily on days 1 and 5 for weeks 1-3 of each cycle. Circulating tumor cells (CTC) were collected and evaluated for γ-H2AX. Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire., Results: Twenty-two patients were treated. Treatment-related grade 3 and 4 toxicities included lymphopenia (68%), anemia (9%), thrombocytopenia (14%), neutropenia (4%), leukopenia (9%), ascites (4%), vomiting (4%), and dyspnea (4%). No objective responses were observed. Disease stabilization (≥24 weeks) was observed in 7 patients (33%). Median progression-free survival (mPFS) was 4.47 months and median overall survival (mOS) was 13.04 months. In the subset of 8 ovarian and fallopian cancers, mPFS was 6.77 months and mOS was 17.54 months compared with mPFS 2.71 months and mOS 13.01 months in others. Patients with ovarian and fallopian cancers had better QoL over time than those with other cancers. An increased percentage of γ-H2AX-positive CTCs was observed in a subset of patients (3/6 with >2 CTCs at baseline)., Conclusions: Combined veliparib and LDFWAR is a well-tolerated regimen that resulted in prolonged disease stability for some patients with advanced solid tumors and carcinomatosis, particularly in the ovarian and fallopian cancer subpopulation., (©2014 American Association for Cancer Research.)

Background and Purpose: Long-term survivors of cancer can develop adverse effects of the treatment. 60% of cancer patients survive for at least 5 years after diagnosis. Pelvic irradiation can cause bone damage in these long-term survivors, with increased risk of fracture and degeneration of the hip., Patients and Methods: Analyses were based on linkage between the Cancer Registry of Norway (CRN) and the Norwegian Arthroplasty Register (NAR). All women who had been exposed to radiation for curative radiotherapy of gynecological cancer (40-60 Gy for at least 28 days) were identified in the CRN. Radiotherapy had been given between 1998 and 2006 and only patients who were irradiated within 6 months of diagnosis were included. The control group contained women with breast cancer who had also undergone radiotherapy, but not to the pelvic area. Fine and Gray competing-risk analysis was used to calculate subhazard-rate ratios (subHRRs) and cumulative incidence functions (CIFs) for the risk of having a prosthesis accounting for differences in mortality., Results: Of 962 eligible patients with gynecological cancer, 26 (3%) had received a total hip replacement. In the control group without exposure, 253 (3%) of 7,545 patients with breast cancer had undergone total hip replacement. The 8-year CIF for receiving a total hip replacement was 2.7% (95% CI: 2.6-2.8) for gynecological cancer patients and 3.0% (95% CI: 2.95-3.03) for breast cancer patients; subHRR was 0.80 (95% CI: 0.53-1.22; p=0.3). In both groups, the most common reason for hip replacement was idiopathic osteoarthritis., Interpretation: We did not find any statistically significantly higher risk of undergoing total hip replacement in patients with gynecological cancer who had had pelvic radiotherapy than in women with breast cancer who had not had pelvic radiotherapy.

Intensity-modulated radiotherapy (IMRT) plays an important role in cancer radiotherapy. For some patients being treated with IMRT, the extremely low tolerances of critical organs (such as lens, ovaries, and testicles) cannot be met during treatment planning. The aim of this article is to introduce a new planning method to overcome that problem. In current planning practice, jaw positions are automatically set to cover all target volumes by the planning system (e.g., Pinnacle(3) system). Because of such settings, critical organs may be fully blocked by the multileaf collimator (MLC), but they still sit in the field that is shaped by collimator jaws. These critical organs receive doses from the transmission and leakage of MLC leaves. We manually fixed jaw positions to block them to further reduce such doses. This method has been used for different treatment sites in our clinic, and it was thoroughly evaluated in patients with radical hysterectomy plus ovarian transposition after surgery. For each patient, 2 treatment plans were designed with the same optimization parameters: the original plan with automatically chosen jaw positions (called O-plan) and the plan with fixed-jaw positions (named F-plan). In the F-plan, the jaws were manually fixed to block the ovaries. For target coverage, the mean conformity index (CI) of the F-plan (1.28 ± 0.02) was remarkably lower than that of the O-plan (1.53 ± 0.09) (p < 0.05). The F-plan and the O-plan performed similarly in target dose homogeneity. Meanwhile, for the critical organ sparing, the mean dose of both ovaries were much lower in the F-plan than that in the O-plan (p < 0.05). The V20, V30, and V40 of bladder were also lower in the F-plan (93.57 ± 1.98, 73.99 ± 5.76, and 42.33 ± 3.7, respectively) than those in the O-plan (97.98 ± 1.11, 85.07 ± 4.04, and 49.71 ± 3.63, respectively) (p < 0.05). The maximum dose to the spinal cord planning organ at risk (OAR) volume (PRV) in the O-plan (3940.24 ± 102.8) was higher than that in the F-plan (3628.18 ± 131.45) with significant differences (p < 0.01). For other OARs, there were no significant differences in doses between these 2 plans except that the high-dose regions of the rectum were higher for V40 in the O-plan than that in the F-plan (p < 0.01). But the monitor units (MUs) in the F-plan were 1.4 times as much as that in the O-plan. Thus the treatment time could be longer by using the F-plan. As it results in more MUs in spite of better plan quality, it is recommended to be used only in situations in which clinical requirements to critical organs cannot be met with the regular method., (Copyright © 2014 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

Purpose: The L1 cell adhesion molecule (L1CAM) is considered a valuable target for therapeutic intervention in different types of cancer. Recent studies have shown that anti-L1CAM radioimmunotherapy (RIT) with (67)Cu- and (177)Lu-labelled internalising monoclonal antibody (mAb) chCE7 was effective in the treatment of human ovarian cancer xenografts. In this study, we directly compared the therapeutic efficacy of anti-L1CAM RIT against human ovarian cancer under equitoxic conditions with the radiolanthanide (177)Lu and the potential alternative (161)Tb in an ovarian cancer therapy model., Methods: Tb was produced by neutron bombardment of enriched (160)Gd targets. (161)Tb and (177)Lu were used for radiolabelling of DOTA-conjugated antibodies. The in vivo behaviour of the radioimmunoconjugates (RICs) was assessed in IGROV1 tumour-bearing nude mice using biodistribution experiments and SPECT/CT imaging. After ascertaining the maximal tolerated doses (MTD) the therapeutic impact of 50 % MTD of (177)Lu- and (161)Tb-DOTA-chCE7 was evaluated in groups of ten mice by monitoring the tumour size of subcutaneous IGROV1 tumours., Results: The average number of DOTA ligands per antibody was 2.5 and maximum specific activities of 600 MBq/mg were achieved under identical radiolabelling conditions. RICs were stable in human plasma for at least 48 h. (177)Lu- and (161)Tb-DOTA-chCE7 showed high tumour uptake (37.8-39.0 %IA/g, 144 h p.i.) with low levels in off-target organs. SPECT/CT images confirmed the biodistribution data. (161)Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the (177)Lu-labelled counterpart (MTD: 12 MBq). In a comparative therapy study with equitoxic doses, tumour growth inhibition was better by 82.6 % for the (161)Tb-DOTA-chCE7 than the (177)Lu-DOTA-chCE7 RIT., Conclusions: Our study is the first to show that anti-L1CAM (161)Tb RIT is more effective compared to (177)Lu RIT in ovarian cancer xenografts. These results suggest that (161)Tb is a promising candidate for future clinical applications in combination with internalising antibodies.

Objective: The aim of this study was to evaluate the effectiveness and safety of percutaneous interstitial implantation with (125)I seed under computed tomographic (CT) guidance for recurrent ovarian cancer (ROC)., Materials and Methods: A retrospective review was performed on 17 patients with ROC who were treated with (125)I seed brachytherapy. Treatment planning system was used preoperatively to determine the estimated seeds number and distribution; (125)I seeds were implanted into recurrent lesions under CT guidance. Therapeutic effectiveness and complications were noted during follow-up time., Results: Months are counted from the time of (125)I seed brachytherapy, and the median duration of follow-up was 10.5 months (3-23 months). The objective response rates after 1, 3, 6, 12, and 18 months were 76.5%, 75.0%, 61.5%, 42.9%, and 40%, respectively. The pain relief rate was 61.5%, and the general living quality was improved dramatically. The median progression-free survival time was 5.4 months, the median overall survival time was 11.3 months, and the 1-year survival rate was 41.2%. Complications in this study were very mild; severe adverse events such as massive bleeding, intestinal fistula, and treatment-related deaths did not occur., Conclusions: Our initial experience showed that CT-guided (125)I seed interstitial implantation is safe and feasible in the treatment of patients with ROCs after multiple therapies.

Purpose of Review: Epithelial ovarian cancer is the most frequent cause of gynecologic cancer-related mortality in women, and prognosis for patients with recurrent or metastatic disease is extremely poor. Therefore, there is an enormous unmet need for the development of novel therapies in this indication. Although surgery and chemotherapy can improve survival rates, it is necessary to integrate alternative strategies, such as immunotherapy to improve the outcomes for patients with advanced ovarian cancer., Recent Findings: We will discuss the rationale of immunotherapy and some of the mechanisms of immunogenicity in ovarian cancer. We will highlight current results with cancer vaccines, adoptive T-cell therapy and immunomodulatory agents and will summarize the immune effects of selected chemotherapeutic agents, radiotherapy and recent results with combinatorial approaches in this disease setting. We will also discuss recent and potential future therapeutic interventions that might circumvent tumor-mediated immunosuppression., Summary: Dramatic increase in the number of immunotherapy clinical trials was seen in the past decade with promising results in enhancing antitumor immune response and cancer vaccine efficacy. The future challenge for immunotherapy against ovarian cancer is to use a combinatorial approach to test rational, potentially synergistic immunotherapy combinations that can induce efficient antitumor immunity and prolong patients' survival.

Despite major advances in the treatment of ovarian cancer over the past two decades, it is still an incurable disease and requires the development of better treatment strategies. In recent years, we have developed a greater understanding of tumor immunology and the interactions between tumors and the immune system. This has led to the emergence of cancer immunotherapy as the fourth treatment modality in cancer. In this article, we address the principles of immunotherapy and different approaches that have been investigated over the past decade and discuss the future of immune therapy in ovarian cancer.

Our aim was to design and validate a model of CT findings that predict suboptimal cytoreduction in primary surgery (PS) for Stage III-IV epithelial ovarian cancer (EOC). We performed a retrospective review of preoperative CT scans of patients undergoing PS for EOC in a cancer centre in London, UK, between November 1995 and October 2003 (n = 91). Radiological features predictive of suboptimal cytoreduction were identified and the model tested in a second cohort undergoing PS in Manchester, June 2005 - March 2007 (n = 35). In the London cohort, liver surface disease and infrarenal para-aortic lymph node involvement predicted suboptimal cytoreduction with 80% accuracy. Accuracy of these predictors dropped to 63% when applied to the Manchester cohort. We concluded that CT prediction of suboptimal cytoreduction is unreliable and may not be reproducible. In the absence of favourable data from larger, prospective trials, it should not be used to guide management.

Recent studies have focused on the role of endothelial cells during tumor radiotherapy, and the majority of studies have found that the rate of endothelial cell apoptosis determines the response of the tumor to ionizing radiation treatment. However, gene expression changes in human ovarian cancer-derived endothelial cells in response to X-ray radiation remains poorly understood. The present study was conducted to investigate the radiation-induced gene alterations in human ovarian cancer-derived endothelial cells and to provide novel potential targets for combined anti-angiogenesis and radiation therapy for the treatment of human ovarian cancer. Ovarian cancer-derived endothelial cells, which were harvested from six human ovarian epithelial carcinomas prior to and 4 h after 400 cGy X-ray irradiation, were analyzed using cDNA microarray technology. Significant genes were selected to corroborate the microarray experiments using a quantitative polymerase chain reaction (qPCR). A total of 28 genes common to all the cDNA microarray results were identified, of which 22 genes were found to be consistently upregulated or downregulated. Thirteen genes were upregulated persistently and nine genes downregulated persistently following irradiation with 400 cGy X-ray in comparison with the matched group. The majority of the significantly altered genes (≥2-fold change in expression) were found to have a role in vasculogenesis, cell cycle regulation, inflammation and the immune response, cell growth and apoptosis, nicotinamide metabolism, cell signaling, chemokines and cell adhesion. Eight randomly selected genes were corroborated using qPCR technology. Radiation-induced gene alterations in ovarian cancer-derived endothelial cells and gene-related pathways were associated with vasculogenesis and the radiosensitivity of human ovarian cancer, and may provide promising biomarkers for radiation and anti-angiogenesis treatments against ovarian carcinoma.

RIT has become an attractive strategy in cancer treatment, but still faces important drawbacks due to poor tumor penetration and undesirable pharmacokinetics of the targeting vehicles. Smaller radiolabeled antibody fragments and peptides feature highly specific target accumulation, resulting in low accumulation in healthy tissue, except for the kidneys. Nanobodies are the smallest (MW<15 kDa) functional antigen-binding fragments that are derived from heavy chain-only camelid antibodies. Here, we show that the extend of kidney retention of nanobodies is predominantly dictated by the number of polar residues in the C-terminal amino acid tag. Three nanobodies were produced with different C-terminal amino-acid tag sequences (Myc-His-tagged, His-tagged, and untagged). Dynamic planar imaging of Wistar rats with 111In-DTPA-nanobodies revealed that untagged nanobodies showed a 70% drop in kidney accumulation compared to Myc-His-tagged nanobodies at 50 min p.i.. In addition, coinfusion of untagged nanobodies with the plasma expander Gelofusin led to a final reduction of 90%. Similar findings were obtained with different 177Lu-DTPA-2Rs15d nanobody constructs in HER2pos tumor xenografted mice at 1 h p.i.. Kidney accumulation decreased 88% when comparing Myc-His-tagged to untagged 2Rs15d nanobody, and 95% with a coinfusion of Gelofusin, without affecting the tumor targeting capacity. Consequently, we identified a generic method to reduce kidney retention of radiolabeled nanobodies. Dosimetry calculations of Gelofusin-coinfused, untagged 177Lu-DTPA-2Rs15d revealed a dose of 0.90 Gy/MBq that was delivered to both tumor and kidneys and extremely low doses to healthy tissues. In a comparative study, 177Lu-DTPA-Trastuzumab supplied 6 times more radiation to the tumor than untagged 177Lu-DTPA-2Rs15d, but concomitantly also a 155, 34, 80, 26 and 4180 fold higher radioactivity burden to lung, liver, spleen, bone and blood. Most importantly, nanobody-based targeted radionuclide therapy in mice bearing small estiblashed HER2pos tumors led to an almost complete blockade of tumor growth and a significant difference in event-free survival between the treated and the control groups (P<0.0001). Based on histology analyses, no evidence of renal inflammation, apoptosis or necrosis was obtained. In conclusion, these data highlight the importance of the amino acid composition of the nanobody's C-terminus, as it has a predominant effect on kidney retention. Moreover, we show successful nanobody-based targeted radionuclide therapy in a xenograft model and highlight the potential of radiolabeled nanobodies as a valuable adjuvant therapy candidate for treatment of minimal residual and metastatic disease.

Objective: To detect protein dynamic changes of cellular localization and the DNA damage response of epithelial ovarian cancer cells to chemo-radiotherapy., Methods: 28 specimens of epithelial ovarian cancer were collected, with 6 cases diagnosed as borderline serous cystadenoma, 5 as highly differentiated, 6 as medium differentiated and 11 as poorly differentiated cystadenocarcinoma. Collagenase A was used for digesting tissues before primary culture. We compared the characteristics of cells cultured in different mediums (MCDB/M199 medium, primary culture medium, and DMEM medium) supplemented with multiple growth-promoting factors. The characteristics of cells were examined in terms of the maintenance of normal cell morphology, proliferation potential, and cell fibrosis proteins (53BP1 and gamma-H2AX) responsive to DNA damage [those in the ATM checkpoint pathway determined by indirect immunofluorescent staining after treatment with camptothecin (CPT) and X-ray]., Results: Normal morphology was maintained relatively well in the cells cultured in MCDB/M199 medium and its cell fibrosis was slow compared with the cells cultured in other media. Gradually increased endogenous damage was demonstrated by the expression of 53BP1 and gamma-H2AX foci (P < 0.05) in all of the ovarian primary cells. After treatment with CPT and ionizing radiation, increased levels of DNA double-strand breaks were observed indicating a classic DNA damage response., Conclusion: We have successfully established a protocol for the primary culture of epithelial ovarian cancer cells, which provides an important platform for characterizing DNA damage responses of the cells. With the progression of epithelial ovarian cancers, the ATM checkpoint pathway is activated by endogenous DNA lesions. This signaling pathway can be further activated by CPT or X-ray irradiation, hampering the growth of tumor cells and further progression of cancers.

Purpose: Study distribution, pharmacokinetics, and safety of intraperitoneal (IP) 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy., Experimental Design: IP 212Pb-TCMC-trastuzumab was delivered, after 4 mg/kg intravenous (IV) trastuzumab, to 3 patients with HER-2-expressing cancer who had failed standard therapies. Patients were monitored for toxicity and pharmacokinetics/dosimetry parameters., Results: Imaging studies after 0.2 mCi/m2 (7.4 MBq/m2) show little redistribution out of the peritoneal cavity and no significant uptake in major organs. Peak blood level of the radiolabeled antibody, determined by decay corrected counts, was <23% injected dose at 63 hours; maximum blood radioactivity concentration was 6.3nCi/mL at 18 hours. Cumulative urinary excretion was ≤6% in 2.3 half-lives. The maximum external exposure rate immediately post-infusion at skin contact over the abdomen averaged 7.67 mR/h and dropped to 0.67 mR/h by 24 hours. The exposure rates at the other positions monitored (axilla, chest, and femur) decreased as a function of distance from the abdomen. The data points correlate closely with 212Pb physical decay (T1/2=10.6 hours). Follow-up >6 months showed no evidence of agent-related toxicity., Conclusions: Pharmacokinetics and imaging after 0.2 mCi/m2 IP 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy showed minimal distribution outside the peritoneal cavity, ≤6% urinary excretion, and good tolerance.

Purpose: To determine the incidence of duodenal toxicity in patients receiving intensity modulated radiation therapy (IMRT) for treatment of para-aortic nodes and to identify dosimetric parameters predictive of late duodenal toxicity., Methods and Materials: We identified 105 eligible patients with gynecologic malignancies who were treated with IMRT for gross metastatic disease in the para-aortic nodes from January 1, 2005, through December 31, 2009. Patients were treated to a nodal clinical target volume to 45 to 50.4 Gy with a boost to 60 to 66 Gy. The duodenum was contoured, and dosimetric data were exported for analysis. Duodenal toxicity was scored according to Radiation Therapy Oncology Group criteria. Univariate Cox proportional hazards analysis and recursive partitioning analysis were used to determine associations between dosimetric variables and time to toxicity and to identify the optimal threshold that separated patients according to risk of toxicity., Results: Nine of the 105 patients experienced grade 2 to grade 5 duodenal toxicity, confirmed by endoscopy in all cases. The 3-year actuarial rate of any duodenal toxicity was 11.7%. A larger volume of the duodenum receiving 55 Gy (V55) was associated with higher rates of duodenal toxicity. The 3-year actuarial rates of duodenal toxicity with V55 above and below 15 cm(3) were 48.6% and 7.4%, respectively (P<.01). In Cox univariate analysis of dosimetric variables, V55 was associated with duodenal toxicity (P=.029). In recursive partitioning analysis, V55 less than 13.94% segregated all patients with duodenal toxicity., Conclusions: Dose-escalated IMRT can safely and effectively treat para-aortic nodal disease in gynecologic malignancies, provided that care is taken to limit the dose to the duodenum to reduce the risk of late duodenal toxicity. Limiting V55 to below 15 cm(3) may reduce the risk of duodenal complications. In cases where the treatment cannot be delivered within these constraints, consideration should be given to other treatment approaches such as resection or initial chemotherapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aggressive epithelial ovarian cancers (EOCs) frequently progress and become fatal, even when cytoreduction surgery plus platinum-based chemotherapy are performed. Thus, the early detection of high-risk subgroups is important in order to provide opportunities for better treatment outcomes, using alternative therapeutic strategies. This study aimed to explore the expression of circulating IGF system components and their relationship with treatment outcome in EOC. We included 228 patients with a median follow-up time of 44 months at two tertiary centers. There were 68 cancer deaths and 108 cases of cancer progression in the cohort. Preoperative serum levels of total IGF1, IGF2, IGF-binding protein 2 (IGFBP2), and IGFBP3 were analyzed using an ELISA and were then converted into an IGF1:IGFBP3 molar ratio. The risks of mortality and progression were estimated using Cox regression models in univariate and multivariate analyses. Our results showed that high IGF1, IGF2, and IGFBP3 levels were significantly associated with an early cancer stage, non-serous histology, and optimal cytoreduction. High IGFBP2 levels were associated with an advanced stage and serous histology. Overall and progression-free survival durations were significantly better among patients with high IGF1 (P=0.003 and P=0.001), IGF2 (P=0.003 and P=0.02), or IGFBP3 levels (P=0.02 and P=0.008). In multivariate analysis, serum IGFBP2 levels were significantly associated with increased risk of mortality (hazard ratio=1.84, 95% CI: 1.07-3.18, P=0.03), indicating that IGFBP2 could be used as an early predictor of EOC-related mortality. The combination of elevated IGFBP2 and reduced IGF1 levels at diagnosis could further facilitate the identification of a patient subgroup with the worst prognosis.

Radiation therapy in ovarian cancers has been considered an outdated concept for many years, mainly due to toxicity and failure to show benefit in terms of survival. Chemotherapy has been extensively used after surgery for these cancers and it has almost replaced radiation therapy as an adjuvant treatment. Nevertheless, failures in ovarian cancers continue to occur even with the use of newer and effective chemotherapy regimens. About 70% patients demonstrate recurrence in the abdomen or pelvis after first line chemotherapy in ovarian cancers. With advances in technology and sophistication of radiation techniques, along with the molecular and biological knowledge of distinct histological subtypes, there is a need to redefine the role of radiation therapy. This review article focuses on the literature on use of radiation in ovarian cancers and its rationale and indications in the present day. For this, a literature pub med/medline search was performed from January 1975 to March 2014 to redefine the role of radiotherapy in ovarian cancers.

This paper aimed to investigate the treatment efficiency of 188Re labeled folate targeting albumin nanoparticles with cis-Diamminedichloroplatinum Cisplatin (188Re-folate-CDDP/HAS MNP) on human ovarian cancer. SKOV3 cells or tumor-bearing mice were divided into different groups and treated as follow: (A) negative control; (B) chemotherapy; (C) radiotherapy; (D) hyperthermia; (E) chemotherapy and radiotherapy; (F) chemotherapy and hyperthermia; (G) radiotherapy and hyperthermia; (H) chemotherapy, radiotherapy and hyperthermia. Treatment of B to H inhibited proliferation of SKOV3 cells, with the greatest inhibition being observed in group H (P<0.05). Obvious apoptotic hypodiploid peak appeared beside G1 phase in groups of B to H. The apoptotic rates of SKOV3 cells in groups of A to H were 0.08%, 7.56%, 8.64%, 17.14%, 21.64%, 23.77%, 33.94% and 57.16%, respectively. Our findings in vivo study showed that the mass of tumor in each group of B to H was significantly lower than that in the negative control (p <0.05). In addition, compared with each group of B to G, group H showed highest inhibition of tumor growth (p<0.05). In conclusion, the combination of magnetic induced hyperthermia, chemotherapy and targeted radionuclide of radiation exposure can effectively inhibit the growth of ovarian cancer, which indicates a potential applications in ovarian cancer treatment.

Objectives: While radiation therapy is administered as a palliative treatment for recurrent ovarian cancer, it remains unclear whether it improves the prognosis., Methods: The effects and adverse events of radiation therapy for patients with recurrent epithelial ovarian cancer were investigated using medical records., Results: Herein, 46 subjects comprising 33 patients whose recurrent lesions were contained within the irradiation field (therapeutic radiation group; TRG) and 13 patients with some recurrent lesions outside the irradiation field (palliative radiation group; PRG) were included. The TRG achieved a response rate (RR) of 66%, a disease control rate (DCR) of 100%, a progression-free survival (PFS) of 10 months, and an overall survival (OS) of 20 months. The PFS after radiation therapy was significantly longer than that following chemotherapy received just before radiation therapy. The PFS of patients with recurrent intrapelvic lesions was longer than that of patients with some extrapelvic recurrence. There was no significant association between PFS after radiation therapy and the duration from the previous chemotherapy or histological type. The RR, DCR, PFS, and OS of the PRG were 30 and 90% and 2 and 6 months, respectively. Serious adverse events were rare., Conclusions: Radiation therapy is a potential option for chemotherapy-resistant, localized recurrent ovarian cancer. © 2014 S. Karger AG, Basel.

Purpose: We aimed to detect the expression of HIF-1α, VEGF, HPSE-1 and CD31 in SKOV3 xenografts in nude mice treated with different doses of ionizing radiation, trying to explore the possible mechanism of hypoxia and radioresistance., Methods: Nude mice bearing SKOV3 xenografts were randomly divided into 4 groups: Group A (control group, no ionizing radiation), Group B (treated with low dose of ionizing radiation: 50cGy), Group C (treated with high dose of ionizing radiation: 300cGy), Group D ( combined ionizing radiation, treated with ionizing radiation from low dose to high dose : 50cGy first and 300cGy after 6h interval). The mRNA levels of HIF-1 and VEGF in each group were detected by real time polymerase chain reaction, while HPSE-1 expression was measured by ELISA. The microvessel density (MVD) and hypoxic cells were determined through immunohistochemical (IHC) staining of CD31 and HIF-1a., Results: Significant differences of HIF-1α mRNA level could be found among the 4 groups (F=74.164, P<0.001): Group C>Group A>Group D> Group B. The mRNA level of VEGF in Group C was significantly higher than in the other three groups (t=-5.267, P=0.000), while no significant difference was observed among Group A, B and D (t=1.528, 1.588; P=0.205, 0.222). In addition, the MVD was shown to be the highest in Group C (t=6.253, P=0.000), whereas the HPSE-1 level in Group A was lower than in Group B (t=14.066, P=0.000) and higher than in Group C (t=-21.919, P=0.000), and similar with Group D (t=-2.066, P=0.058). Through IHC staining of HIF-1a, the expression of hypoxic cells in Group A was (++), Group B was (+), Group C was (+++) and Group D was (+)., Conclusion: Ionizing radiation with lower- doses might improve tumor hypoxia through inhibiting the expression of HIF-1 and HPSE-1, whereas higher- doses worsen tumor hypoxic conditions by up-regulating HIF-1α, HPSE-1, VEGF and CD31 levels. A protocol of low-dose ionizing radiation followed by a high-dose irradiation might at least partly improve tumor hypoxia and enhance radiosensitivity.

Angiosarcoma is a rare form of sarcoma which may be either a primary tumor or it may result from previous irradiation because of another tumor. In this paper, we present a case of a female patient diagnosed as having peritoneal disseminated angiosarcoma 20 years after ovarian cancer treatment (surgery, chemotherapy and radiotherapy). The case was very atypical because of an extremely rare peritoneal location and disseminated nature of the changes. Based on the initial histological picture, poorly differentiated cancer metastasis was diagnosed, suggesting a recurrence of the ovarian cancer that had been diagnosed earlier. The time elapsed from the ovarian cancer diagnosis, history of the previous irradiation and concentration of tumor markers were the only additional clinical data provided to the pathologists, which ultimately contributed to a correct diagnosis. The case we present herein shows and emphasizes the importance of proper communication between a clinician and a pathologist, which is a prerequisite for a correct diagnosis and, consequently, for proper treatment of patients. It also confirms the high specificity of the HE4 (human epididymis protein 4) marker in the monitoring of ovarian cancer, which was within normal limits in spite of peritoneal tumor dissemination.

Objectives: Adipose tissue contains a population of multipotent adipose stem cells (ASCs) that form tumor stroma and can promote tumor progression. Given the high rate of ovarian cancer metastasis to the omental adipose, we hypothesized that omental-derived ASC may contribute to ovarian cancer growth and dissemination., Materials and Methods: We isolated ASCs from the omentum of three patients with ovarian cancer, with (O-ASC4, O-ASC5) and without (O-ASC1) omental metastasis. BM-MSCs, SQ-ASCs, O-ASCs were characterized with gene expression arrays and metabolic analysis. Stromal cells effects on ovarian cancer cells proliferation, chemoresistance and radiation resistance was evaluated using co-culture assays with luciferase-labeled human ovarian cancer cell lines. Transwell migration assays were performed with conditioned media from O-ASCs and control cell lines. SKOV3 cells were intraperitionally injected with or without O-ASC1 to track in-vivo engraftment., Results: O-ASCs significantly promoted in vitro proliferation, migration chemotherapy and radiation response of ovarian cancer cell lines. O-ASC4 had more marked effects on migration and chemotherapy response on OVCA 429 and OVCA 433 cells than O-ASC1. Analysis of microarray data revealed that O-ASC4 and O-ASC5 have similar gene expression profiles, in contrast to O-ASC1, which was more similar to BM-MSCs and subcutaneous ASCs in hierarchical clustering. Human O-ASCs were detected in the stroma of human ovarian cancer murine xenografts but not uninvolved ovaries., Conclusions: ASCs derived from the human omentum can promote ovarian cancer proliferation, migration, chemoresistance and radiation resistance in-vitro. Furthermore, clinical O-ASCs isolates demonstrate heterogenous effects on ovarian cancer in-vitro.

Purpose: The purpose of this study was to investigate the effect of α-particle-emitting (227)Th-trastuzumab radioimmunotherapy on tumor vasculature to increase the knowledge about the mechanisms of action of (227)Th-trastuzumab., Methods and Materials: Human HER2-expressing SKOV-3 ovarian cancer xenografts were grown bilaterally in athymic nude mice. Mice with tumor volumes 253 ± 36 mm(3) (mean ± SEM) were treated with a single injection of either (227)Th-trastuzumab at a dose of 1000 kBq/kg body weight (treated group, n=14 tumors) or 0.9% NaCl (control group, n=10 tumors). Dynamic T1-weighted contrast-enhanced magnetic resonance imaging (DCEMRI) was used to study the effect of (227)Th-trastuzumab on tumor vasculature. DCEMRI was performed before treatment and 1, 2, and 3 weeks after therapy. Tumor contrast-enhancement curves were extracted voxel by voxel and fitted to the Brix pharmacokinetic model. Pharmacokinetic parameters for the tumors that underwent radioimmunotherapy were compared with the corresponding parameters of control tumors., Results: Significant increases of kep, the rate constant of diffusion from the extravascular extracellular space to the plasma (P<.05), and kel, the rate of clearance of contrast agent from the plasma (P<.01), were seen in the radioimmunotherapy group 2 and 3 weeks after injection, compared with the control group. The product of kep and the amplitude parameter A, associated with increased vessel permeability and perfusion, was also significantly increased in the radioimmunotherapy group 2 and 3 weeks after injection (P<.01)., Conclusions: Pharmacokinetic modeling of MRI contrast-enhancement curves evidenced significant alterations in parameters associated with increased tumor vessel permeability and tumor perfusion after (227)Th-trastuzumab treatment of HER2-expressing ovarian cancer xenografts., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: To analyse the diagnostic accuracy and to establish a predictive score based on diffusion-weighted magnetic resonance imaging (DWMRI) compared to exploratory laparotomy (EL) for predicting suboptimal cytoreductive surgery for different intra-abdominal sites of implants in patients with ovarian cancer., Methods: Thirty-four patients with advanced ovarian carcinoma were studied. Preoperative DWMRI of the abdomen and pelvis was performed. DWMRI findings were compared with EL. Ten anatomical sites were selected for inclusion in the score. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy for suboptimal cytoreduction were calculated for both DWMRI and EL. Receiver operating characteristic (ROC) curve analysis was used to assess the ability to predict suboptimal cytoreduction., Results: Using predictive score, ROC curves were generated with an area under the curve of 0.938 for DWMRI and 0.947 for EL (P < 0.0001). For DWMRI, a score ≥6 had the highest overall accuracy at 91.1 % and identified patients with unnecessary EL with a sensitivity of 75 %. For EL, a score ≥4 had the highest overall accuracy at 88.2 % and was able to identify patients with unnecessary EL with a sensitivity of 87.5 %., Conclusions: DWMRI is an emerging technique that may be useful to predict suboptimal cytoreduction in ovarian cancer., Key Points: • DWMRI is increasingly used in ovarian cancer. • DWMRI is an accurate technique for depicting intra-abdominal sites of implants • DWMRI is useful for predicting optimal cytoreductive surgical outcome. • We report a high predictive value similar to exploratory laparotomy.

Objective: To evaluate the effectiveness of definitive involved-field radiation therapy (IFRT) for selected patients with locoregionally-recurrent ovarian cancer., Methods: We retrospectively reviewed records of 102 epithelial ovarian cancer patients treated with definitive IFRT (≥45Gy). IFRT was directed to localized nodal (49%) and extranodal (51%) recurrences., Results: The median time from diagnosis to IFRT was 36 months (range, 1-311), and the median follow-up after IFRT was 37 months (range, 1-123). Patients received a median of three chemotherapy courses before IFRT (range, 0-9). Five-year overall (OS) and progression-free survival (PFS) rates after IFRT were 40% and 24% respectively; the 5-year in-field disease control rate was 71%. Thirty-five patients (35%) had no evidence of disease at a median of 38 months after IFRT (range, 7-122), including 25 continuously without disease for a median of 61 months (range, 17-122) and 10 with salvage treatment following disease recurrence, disease-free for a median of 39 months after salvage treatment (range, 7-92). Eight clear cell carcinoma patients had higher 5-year OS (88% versus 37%; p=0.05) and PFS (75% versus 20%; p=0.01) rates than other patients. Patients sensitive to initial platinum chemotherapy had a higher 5-year OS rate than platinum-resistant patients (43% versus 27%, p=0.03). Patients who required chemotherapy for recurrence after IFRT often benefitted from longer chemotherapy-free intervals after than before IFRT., Conclusions: Definitive IFRT can yield excellent local control, protracted disease-free intervals, and even cures in carefully selected patients. RT should be considered a tool in the curative management of locoregionally-recurrent ovarian cancer., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Epithelial ovarian cancer accounts for about 90% of all cases of ovarian cancer. Debulking surgery and six courses of platinum-based chemotherapy results in complete clinical remission (CCR) in up to 75% of cases. However, 75% of the responders will relapse within a median time of 18 to 28 months and only 20% to 40% of women will survive beyond five years. It has been suggested that maintenance chemotherapy could assist in prolonging remission. To date, there has not been a systematic review on the impact of maintenance chemotherapy for epithelial ovarian cancer., Objectives: To assess the effectiveness and toxicity of maintenance chemotherapy for epithelial ovarian cancer and to evaluate the impact on quality of life (QoL)., Search Methods: In the original review we searched the Cochrane Gynaecological Cancer Review Group Specialised Register, The Cochrane Central Register of Controlled Trails (CENTRAL, The Cochrane Library 2009, Issue 1), MEDLINE, EMBASE, PubMed, CBMdisc, CNKI and VIP (to May 2009). We collected information from ongoing trials, checked reference lists of published articles and consulted experts in the field. For this update, the searches were extended to October 2012., Selection Criteria: Randomised controlled trials (RCTs) comparing maintenance chemotherapy with no further intervention, maintenance radiotherapy or other maintenance therapy., Data Collection and Analysis: Two review authors independently assessed trials for eligibility and quality and extracted data. We analysed overall survival (OS) and progression-free survival (PFS) rates as dichotomous variables. Toxicity and QoL data were extracted where present. All analyses were based on intention-to-treat (ITT) on the endpoint of survival. We also analysed data by subgroups of drugs., Main Results: We included eight trials (1644 women). When all chemotherapy regimens were combined, meta-analysis indicated no significant difference in three-, five- and 10-year OS or PFS. For five-year OS, the combined risk ratio (RR) was 1.03 (95% confidence interval (CI) 0.96 to 1.10) and for the five-year PFS, the combined RR was 1.06 (95% CI 0.97 to 1.17). Results were very similar when trials of different regimens were analysed. Comparing chemotherapy with radiotherapy, only the RR for 10-year PFS in pathological complete remission (PCR) was in favour of whole abdominal radiotherapy 0.51 (95% CI 0.27 to 1.00), while three- and five-year OS rates have no significant difference between the two groups., Authors' Conclusions: There is no evidence to suggest that the use of platinum agents, doxorubicin or paclitaxel used as maintenance chemotherapy is more effective than observation alone. Further investigations regarding the effect of paclitaxel used as maintenance chemotherapy are required.

Unlabelled: The aim of the current study was to investigate the therapeutic effect of 227Th-radioimmunotherapy on intraperitoneally growing human bioluminescent HER2 positive ovarian cancer cells., Methods: In vitro toxicity of 227Th-trastuzumab in bioluminescent SKOV3-luc-D3 ovarian cancer cells was assessed in a growth assay. The biodistribution of intraperitoneally administrated 227Th-trastuzumab in athymic nude mice without tumor cells was determined. For in vivo therapy, seventy female athymic nude mice were intraperitoneally inoculated with tumor cells 17 days prior to injection of single 227Th-trastuzumab doses of 1000 kBq/kg, 600 kBq/kg or 400 kBq/kg, or three injections with 400 kBq/kg 227Th-trastuzumab separated by 4 weeks. Two control groups were given either 20 µg unlabeled trastuzumab or 0.9% NaCl. In vivo bioluminescence imaging was performed weekly before and after onset of therapy. Tumor growth, survival and toxicity were compared., Results: There was a statistically significant therapeutic effect of the 227Th-trastuzumab treatment both with respect to survival and tumor growth. The maximum tolerated dosage was 600 kBq/kg 227Th-trastuzumab. In the in vitro study, two hours incubation with 20 kBq/ml of 227Th-trastuzumab, followed by washing, and subsequent culture of the cells resulted in an average absorbed radiation dose of 6 Gy after 11 days and complete growth inhibition., Conclusion: Targeted alpha therapy with 227Th-trastuzumab of human SKOV3-luc-D3 cells growing intraperitoneally in nude mice was clearly superior to unlabeled trastuzumab therapy. The results warrant further studies of 227Th-radioimmunotherapy used as adjuvant treatment and for metastatic cancer.

Unlabelled: Because of their better penetration, smaller targeting proteins may be superior to antibodies for radioimmunotherapy of solid tumors. Therefore, Affibody molecules (6.5 kDa) have a potential for being suitable as targeted moiety for radiolabeled therapeutic proteins. Previous studies have demonstrated that a fusion of an Affibody molecule with an albumin-binding domain (ABD) provides a strong noncovalent binding to albumin in vivo. This strong noncovalent binding can be used for reduction of the renal uptake of the Affibody molecule while maintaining a size smaller than that of an antibody, which is important when using residualizing radionuclide labels conjugated to Affibody molecules. The goal of this study was to design and evaluate a new targeting Affibody-ABD fusion protein with improved biodistribution properties for radionuclide therapy., Methods: A novel Affibody-based construct, ZHER2:2891-ABD035-DOTA (ABY-027), was created by fusion of the reengineered HER2-binding Affibody molecule ZHER2:2891 to the N terminus of the high-affinity ABD035, and a maleimido-derivative of DOTA was conjugated at the C terminus of the construct. Binding and processing of (177)Lu-ABY-027 by HER2-expressing cells were evaluated in vitro. Targeting of HER2-expressing SKOV-3 xenografts was evaluated in BALB/C nu/nu mice and compared with targeting of previously reported ABD-(ZHER2:342)2., Results: The binding affinity (dissociation constant) of ABY-027 to HER2 (74 pM) was the same as for the parental ZHER2:2891 (76 pM). ABY-027 was stably labeled with (177)Lu and (111)In with preserved specific binding to HER2-expressing cells in vitro. In vivo receptor saturation experiments demonstrated that targeting of SKOV-3 xenografts in BALB/C nu/nu mice was HER2-specific. (177)Lu-ABY-027 demonstrated substantially (2- to 3-fold) lower renal and hepatic uptake than previously assessed HER2-specific Affibody-based albumin-binding agents. Tumor uptake of radiolabeled ABY-027 at 48 h after injection was 2-fold higher than that for previously reported ABD-(ZHER2:342)2., Conclusion: An optimized molecular design of an ABD fusion protein resulted in an Affibody molecule construct with better properties for therapy. Fully preserved in vivo targeting of the fusion protein was shown in xenografted mice. Site-specific coupling of DOTA provides a uniform conjugate and creates the potential for labeling with a broad range of therapeutic radionuclides. The biodistribution of (177)Lu-ABY-027 in a murine model suggests it is more suitable for therapy than alternative approaches.

Objective: To characterize the clinicopathological features and evaluate the treatment outcomes for cases of primary extramammary Paget's disease of the vulva (EMPDV)., Methods: The medical records and pathology slides were reviewed and analyzed for 43 patients with primary EMPDV., Results: The mean age of the patients was 68.6 years (range, 52-85). Intraepithelial EMPDV, invasive EMPDV and EMPDV with adnexal adenocarcinoma were observed in 33 (76.7%), 7 (16.3%) and 3 (7.0%) cases, respectively. Varied surgical procedures were initially performed in 35 (81.4%) cases. A positive incision margin was observed in 16 cases (47.0%). Definitive radiotherapy at a median dose of 60 Gy was performed in 8 (18.6%) patients. Six patients received postoperative radiotherapy due to a positive margin or lymph node metastasis after surgical excision. During a follow-up period of 6-169 months (median, 54), recurrence was observed in 12 (34.3%) patients. Nine (75.0%) patients underwent repeated surgery and 3 (25.0%) patients received radiotherapy. Long-term overall survival was observed in patients with intraepithelial EMPDV. The median overall survival was 124.5 months in intraepithelial cases, 70.8 months in invasive cases and 21.3 months in cases with adnexal adenocarcinoma (log rank, P=0.032)., Conclusions: Intraepithelial EMPDV accounted for the majority of primary cases and had a better prognosis. Surgical excision was the standard curative treatment for EMPDV. Radiotherapy was an alternative choice for patients with medical contradiction or surgical difficulties. Postoperative radiotherapy could be considered in cases with positive surgical margin or lymph node metastasis. Recurrence was common and repeated excision was often necessary., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Unlabelled: Abstract Purpose: Pretargeted radioimmunotherapy (PRIT) against intraperitoneal (i.p.) ovarian microtumors using avidin-conjugated monoclonal antibody MX35 (avidin-MX35) and (211)At-labeled, biotinylated, succinylated poly-l-lysine ((211)At-B-PLsuc) was compared with conventional radioimmunotherapy (RIT) using (211)At-labeled MX35 in a nude mouse model., Methods: Mice were inoculated i.p. with 1×10(7) NIH:OVCAR-3 cells. After 3 weeks, they received PRIT (1.0 or 1.5 MBq), RIT (0.9 MBq), or no treatment. Concurrently, 10 additional animals were sacrificed and examined to determine disease progression at the start of therapy. Treated animals were analyzed with regard to presence of tumors and ascites (tumor-free fraction; TFF), 8 weeks after therapy., Results: Tumor status at baseline was advanced: 70% of sacrificed animals exhibited ascites. The TFFs were 0.35 (PRIT 1.0 MBq), 0.45 (PRIT 1.5 MBq), and 0.45 (RIT). The 1.5-MBq PRIT group exhibited lower incidence of ascites and fewer tumors >1 mm than RIT-treated animals., Conclusions: PRIT was as effective as RIT with regard to TFF; however, the size distribution of tumors and presence of ascites indicated that 1.5-MBq PRIT was more efficient. Despite advanced disease in many animals at the time of treatment, PRIT demonstrated good potential to treat disseminated ovarian cancer.

The purpose of this study was to assess the efficacy and toxicity of definitive radiotherapy (RT) for the recurrence of epithelial ovarian cancer, which is limited to one or two gross regions, after complete remission had been achieved with aggressive front-line therapy. Twenty-seven patients were treated with definitive RT and were retrospectively analyzed. Their median tumor size was 3.0 cm. Twenty-six (96%) patients received external irradiation at a median total dose of 60 Gy, and a median daily dose of 2 Gy. Only two patients received intracavitary brachytherapy. Twenty (74%) of the 27 patients received systemic chemotherapy for the treatment of a limited recurrent tumor followed by definitive RT. Six (22%) of the patients received concurrent chemotherapy and seven (26%) of the patients also underwent regional hyperthermia during definitive RT. Twenty-two (82%) patients had an objective response (CR: 11, PR: 11). The 2-year overall survival, progression-free survival and local (in-field) control rates after RT were 53%, 39% and 96%, respectively. The toxicities were mild, no Grade 3 or higher toxicity was observed in any of the patients. The tumor size( < 3 cm), period between front-line therapy and RT (≥2 year) and objective tumor response (CR) were significant prognostic factors of the overall survival rate. In conclusion, definitive RT for limited recurrence of epithelial ovarian cancer achieves a better local control rate without severe toxicity, and it may therefore be a potentially effective modality for inducing long-term survival in selected patients.

Background: Ovarian carcinosarcoma, also known as malignant mixed Mullerian tumour, is a rare malignant gynaecological tumour constituting about 1% or less of all ovarian cancers. In over 80% of cases, there is extra-ovarian intra-abdominal spread at diagnosis. The primary treatment has traditionally been surgical cytoreduction followed by radiotherapy and chemotherapy or chemotherapy alone. Regimes have included cisplatin alone; a combination of doxorubicin, ifosfamide, dacarbazine, cyclophosphamide, taxol; and various other combinations. The effectiveness of these various regimens appears to be mixed. Therefore, there is a need to clarify if there is an optimum neoadjuvant or adjuvant therapy after surgical cytoreduction for this rare tumour. Also, it is important to address quality of life (QoL) issues related to treatment, particularly toxicity, as the overall prognosis appears to be poor., Objectives: To assess the effectiveness and safety of various adjuvant and neoadjuvant chemotherapy and radiotherapy options or chemotherapy alone in combination with surgery in the management of ovarian carcinosarcoma., Search Methods: We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE up to February 2012. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of review articles and contacted experts in the field., Selection Criteria: We searched for randomised controlled trials (RCTs) that compared neoadjuvant or adjuvant chemotherapy and radiotherapy, or chemotherapy alone, in women with ovarian carcinosarcoma (malignant mixed Mullerian sarcoma of the ovary). We also reviewed non-randomised studies (NRS) for discussion in the absence of RCTs., Data Collection and Analysis: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. No trials were found and therefore no data were analysed., Main Results: The search strategy identified 297 unique references of which all were excluded., Authors' Conclusions: We found no evidence to inform decisions about neoadjuvant and adjuvant chemotherapy and radiotherapy regimens, or chemotherapy alone, for women with ovarian carcinosarcoma. Ideally, an RCT that is multicentre or multinational, or well designed non-randomised studies that use multivariate analysis to adjust for baseline imbalances, are needed to compare treatment modalities and improve current knowledge. Further research in genetic and molecular signalling pathways might improve understanding of this tumour subtype.

Background: Brain metastases (BM) and leptomeningeal disease (LMD) are uncommon in epithelial ovarian cancer (EOC). We investigate the outcomes of modern radiation therapy (RT) as a primary treatment modality in patients with EOC BM and LMD., Methods: We evaluated 60 patients with EOC treated at our institution from 1996 to 2010 who developed BM. All information was obtained from chart review., Results: At EOC diagnosis, median age was 56.1 years and 88% of patients were stage III-IV. At time of BM diagnosis, 46.7% of patients had 1 BM, 16.7% had two to three, 26.7% had four or more, and 10% had LMD. Median follow-up after BM was 9.3 months (range, 0.3-82.3). All patients received RT, and 37% had surgical resection. LMD occurred in the primary or recurrent setting in 12 patients (20%), 9 of whom received RT. Median overall survival (OS) after BM was 9.7 months for all patients (95% CI 5.9-13.5), and 16.1 months (95% CI 3.8-28.3) in patients with one BM. On multivariate analysis, Karnofsky performance status less than 70 (hazard ratio [HR] 2.86, p = 0.018), four or more BM (HR 3.18, p = 0.05), LMD (HR 8.22, p = 0.013), and uncontrolled primary tumor (HR 2.84, p = 0.008) were significantly associated with inferior OS. Use of surgery was not significant (p = 0.31). Median central nervous system freedom from progression (CNS-FFP) in 47 patients with follow-up was 18.5 months (95% CI, 9.3-27.9). Only four or more BM (HR 2.56, p = 0.04) was significantly associated with poorer CNS-FFP., Conclusions: Based on our results, RT appears to be an effective treatment modality for brain metastases from EOC and should be routinely offered. Karnofsky performance status less than 70, four or more BM, LMD, and uncontrolled primary tumor predict for worse survival after RT for EOC BM. Whether RT is superior to surgery or chemotherapy for EOC BM remains to be seen in a larger cohort.

Background and Purpose: Advanced epithelial ovarian cancer is associated with high relapse rates. Various consolidative therapies, including whole abdominal radiation therapy (WAR), have been tried in the past with limited success. We report here a feasibility study and clinical outcome of WAR with helical tomotherapy (HT)., Materials and Methods: Eight patients with relapsed carcinoma ovary after standard treatment and deemed not suitable for further chemotherapy were treated with WAR using HT. All patients underwent intensity-modulated radiotherapy (IMRT) planning process and a dose of 25 Gy/25#, at 1 Gy/# to the whole of the abdomen [abdominal planning treatment volume (PTV)] with a simultaneous boost of 45 Gy/25#, at 1.8 Gy/# to the pelvic PTV was prescribed., Results: There was an excellent coverage in both abdominal and pelvic PTVs.The V 95% (volume covered by the 95% isodose) and V 107% (volume receiving 107% dose) was 95.6 (± 2.7)% and 2.6 (± 0.5)% for abdominal PTV and 95.7 (± 2.4)% and 0% for pelvic PTV, respectively. With a median follow-up of 15 months (10-24 months, mean: 14 months), 3 patients developed disease recurrence. All 3 recurred in the peritoneum, one progressed to intestinal obstruction and fatal septicemia., Conclusion: WAR in recurrent/relapsed epithelial ovarian cancer is feasible with acceptable toxicities.

Unlabelled: Mesoporous silica nanoparticles (MSNs) were explored as a carrier material for the stable isotope (165)Ho and, after neutron capture, its subsequent therapeutic radionuclide, (166)Ho (half-life, 26.8 h), for use in radionuclide therapy of ovarian cancer metastasis., Methods: (165)Ho-MSNs were prepared using (165)Ho-acetylacetonate and MCM-41 silica particles, and stability was determined after irradiation in a nuclear reactor (reactor power, 1 MW; thermal neutron flux of approximately 5.5 × 10(12) neutrons/cm(2)s). SPECT/CT and tissue biodistribution studies were performed after intraperitoneal administration of (166)Ho-MSNs to SKOV-3 ovarian tumor-bearing mice. Radiotherapeutic efficacy was studied by using PET/CT with (18)F-FDG to determine tumor volume and by monitoring survival., Results: The holmium-MSNs were able to withstand long irradiation times in a nuclear reactor and did not release (166)Ho after significant dilution. SPECT/CT images and tissue distribution results revealed that (166)Ho-MSNs accumulated predominantly in tumors (32.8% ± 8.1% injected dose/g after 24 h; 81% ± 7.5% injected dose/g after 1 wk) after intraperitoneal administration. PET/CT images showed reduced (18)F-FDG uptake in tumors, which correlated with a marked increase in survival after treatment with approximately 4 MBq of (166)Ho-MSNs., Conclusion: The retention of holmium in nanoparticles during irradiation and in vivo after intraperitoneal administration as well as their efficacy in extending survival in tumor-bearing mice underscores their potential as a radiotherapeutic agent for ovarian cancer metastasis.

The antiproliferative response to anticancer treatment is the result of concurrent responses in all cell cycle phases, extending over several cell generations, whose complexity is not captured by current methods. In the proposed experimental/computational approach, the contemporary use of time-lapse live cell microscopy and flow cytometric data supported the computer rendering of the proliferative process through the cell cycle and subsequent generations during/after treatment. The effects of treatments were modelled with modules describing the functional activity of the main pathways causing arrest, repair and cell death in each phase. A framework modelling environment was created, enabling us to apply different types of modules in each phase and test models at the complexity level justified by the available data. We challenged the method with time-course measures taken in parallel with flow cytometry and time-lapse live cell microscopy in X-ray-treated human ovarian cancer cells, spanning a wide range of doses. The most suitable model of the treatment, including the dose-response of each effect, was progressively built, combining modules with a rational strategy and fitting simultaneously all data of different doses and platforms. The final model gave for the first time the complete rendering in silico of the cycling process following X-ray exposure, providing separate and quantitative measures of the dose-dependence of G1, S and G2M checkpoint activities in subsequent generations, reconciling known effects of ionizing radiations and new insights in a unique scenario.

Except for its palliative use, radiation has been largely abandoned in the management of ovarian cancers because of the recognized efficacy of chemotherapy agents. Whole abdominal irradiation (WAR), however, has been shown to be of adjuvant and curative value in ovarian cancer with microscopic or minimal residual disease in the pelvis, the so-called "intermediate risk group." Recent hypothesis generating data from the use of adjuvant radiation following adjuvant chemotherapy in ovarian cancer has shown an incremental survival benefit for the rarer non-serous ovarian subtypes including clear cell, endometrioid, and mucinous. No incremental benefit was observed for the more common serous subtype. A retrospective examination of early trials using WAR as the sole postoperative treatment in ovarian cancer has determined that the majority of patients in these studies and cured by radiation actually had the non-serous subtypes. The recognition that the non-serous subtypes differ from the serous cancers in their stage of presentation, their molecular characteristics, their response to classic chemotherapy, and their outcomes suggest the non-serous subtypes should be treated as rare and different cancers. In addition to specific targeting therapies that may be developed, radiation should be reconsidered as part of the treatment armamentarium for these diseases.

The new technology of combined treatment for patients with ovarian carcinoma of III-IV stages and its relapse is presented. The essentially new component is systemic radiotherapy in nontumoricidal doses. It is used with both traditional surgical and chemotherapeutic components. Systemic radiotherapy is carried out in a form of subtotal body irradiation in two dose-time options with total dose of 1 Gy and 9 Gy. The choice of radiation option is carried out taking into account the initial somatic resource of patients estimated by the condition of lymphopoiesis. The use of systemic radiotherapy in combined treatment of advanced ovarian carcinoma allowed to achieve the significant increase of 3-, 5-year survival in patients as compared to traditional chemo-surgical method. Indirect mechanism of nontumoricidal systemic radiotherapy is to be considered as a vital way for tumor control.

Aim: The present study was designed to explore the radiation-resistance mechanism by interfering in checkpoints kinase 1 (CHK1) and DNA-activated protein kinase (DNA-PK) genes with short hairpin RNA (shRNA) transfection into Skov3 cells derived from ovarian cancer and HeLa cells derived from cervical cancer., Materials and Methods: The cultured Skov3 and HeLa cells were transfected with plasmid vectors containing CHK1 shRNA and DNA-PK shRNA, respectively, through Lipofectimine™ 2000 mediation, and cultured for 20 hours before exposure to 2 Gy X-radiation. The cells were harvested 4 and 28 after X-irradiation respectively then washed 3 times with PBS. These cells were stained with Annexin V/PI and applied by flow cytometer to analyze alteration of apoptosis with software CellQuest., Results: The apoptotic response in Skov3 cells to X-radiation was significantly lower than that in HeLa cells at 4 hour (t = 15.22, P < 0.001) and 28 hours (t = 15.78, P < 0.001) of post-irradiation. The shRNA might not affect the apoptosis of Skov3 and HeLa cells, while shRNA-transfection significantly enhanced the apoptotic response in Skov3 cells to X-radiation as compared with that in HeLa cells., Conclusions: The present work suggests that the CHK1 and DNA-PK genes are very likely to play a role in developing a radiation resistance in ovarian cancer.

Objective: Radiotherapy is a common mode of treatment for many types of cancer, particularly cancers that are not detected until late stages, as is common with ovarian cancer. Although radiotherapy is effective in preferentially killing tumor cells, DNA damage induced by ionizing radiation can also have toxic effects on non-tumor cells. The aim of this study was to investigate the extent of toxicity on non-tumor cells following radiotherapy for ovarian cancer., Materials and Methods: The authors used the comet assay to assess DNA damage in peripheral blood lymphocytes of 60 ovarian cancer patients undergoing radiotherapy. Venous blood samples were collected from patients before radiotherapy and after accumulated doses of 10, 20, 30, 40, and 50 Gy of radiotherapy., Results: Comet frequencies, reflecting the proportion of damaged cells, were significantly higher after radiotherapy than before radiotherapy (f = 69.66, p < 0.05) and demonstrated a linear relationship with accumulated dose (y = 9.87 + 0.2987x, r = 0.9497, p < 0.05). Additionally, the comet tail length, reflecting the relationship between undamaged and damaged DNA, was significantly longer after radiotherapy (f = 175.13, p < 0.05)., Conclusions: These results demonstrate that radiotherapy induces DNA damage in lymphocytes of ovarian cancer patients and suggest that radiotherapy doses should be limited during clinical treatment to reduce toxic side-effects.

Purpose: Autophagy has attracted attentions as a novel mechanism for tumor development. In this study Human ovarian carcinoma cell line SKOV3 and multidrug-resistant phenotype SKVCR cells were used and the roles of autophagy in radiation-induced cell death were analyzed., Methods and Materials: Cell viability was examined by colony formation and cell counting kit-8 (CCK-8) assay, 3MA and ZVAD were used to block autophagy and apoptosis, respectively. Quantitative real-time PCR was used to detect mRNA level and Western blot was used to detect protein expression, monodansylcadaverine (MDC) staining and flow cytometery were used for autophagy, apoptosis and cell cycle dynamics, respectively., Results: (1) The radiosensitivity exhibited differently in SKOV3 and SKVCR cells (SKOV3: D0=3.37, SKVCR: D0= 4.18); compared with SKOV3 the constitutive expression of MAPLC3 in SKVCR was higher, but no change of Caspase-3 and cleaved Caspase-3. (2) The ionizing radiation (IR)- induced apoptosis and autophagy were significant in both cells (P<0.05); inhibition of apoptosis with ZVAD showed no impact on survival of SKOV3 and SKVCR cells after radiation, while inhibition of autophagy significantly decreased viability in SKVCR cells, for SKVO3 cells only low level of radiation (2 Gy and 4 Gy) could decrease the viability(P<0.05). (3) ZVAD inhibited apoptosis and autophagy in both cells, 3MA inhibit apoptosis in SKOV3, and promote apoptosis in SKVCR, together with inhibition of autophagy. (4) G2/M arrest was induced by radiation in both cells; the accumulation of G2/M was more significant in SKOV3, 3MA attenuated the radiation-induced S phase delay in SKVCR., Conclusion: IR-induced autophagy provides a self-protective mechanism against radiotherapy in SKVCR cells, the use of autophagy inhibitor, 3MA, increases the killing effects of radiation by inhibiting autophagy and radiation- induced S phase delay, also by the increase of apoptosis, which suggests a better therapeutic strategy in drug- resistant SKVCR ovarian cancer cells.

Targeted alpha therapy (TAT) a promising treatment for small, residual, and micrometastatic diseases has questionable efficacy against malignant lesions larger than the α-particle range, and likely requires favorable intratumoral activity distribution. Here, we characterized and quantified the activity distribution of an alpha-particle emitter radiolabelled antibody within >100-µm micrometastases in a murine ovarian carcinoma model. Nude mice bearing ovarian micrometastases were injected intra-peritoneally with 211At-MX35 (total injected activity 6 MBq, specific activity 650 MBq/mg). Animals were sacrificed at several time points, and peritoneal samples were excised and prepared for alpha-camera imaging. Spatial and temporal activity distributions within micrometastases were derived and used for small-scale dosimetry. We observed two activity distribution patterns: uniform distribution and high stable uptake (>100% IA/g at all time points) in micrometastases with no visible stromal compartment, and radial distribution (high activity on the edge and poor uptake in the core) in tumor cell lobules surrounded by fibroblasts. Activity distributions over time were characterized by a peak (140% IA/g at 4 h) in the outer tumor layer and a sharp drop beyond a depth of 50 µm. Small-scale dosimetry was performed on a multi-cellular micrometastasis model, using time-integrated activities derived from the experimental data. With injected activity of 400 kBq, tumors exhibiting uniform activity distribution received <25 Gy (EUD=13 Gy), whereas tumors presenting radial activity distribution received mean absorbed doses of <8 Gy (EUD=5 Gy). These results provide new insight into important aspects of TAT, and may explain why micrometastases >100 µm might not be effectively treated by the examined regimen.

The management of neuroendocrine tumours is challenging when curative surgery is ruled out because of distant metastases. We report a case of gastrointestinal carcinoid with bilateral ovarian metastases in a 50-year-old female who received octreotide therapy followed by peptide receptor radionuclide therapy and surgery thereafter. Somatostatin receptor expression on neuroendocrine tumours has implications in diagnosis and therapy. (68)Ga-DOTA-NOC PET is a recent advancement in the field of somatostatin receptor imaging. The lesions which demonstrate tracer uptake on positron emission tomographic studies can be further planned for treatment with octreotide and (177)Lu-DOTA-TATE. The case in discussion responded well to non-invasive treatment options before proceeding to definitive surgical management.

Objective: To explore the feasibility, short-term efficacies and complications of computed tomography (CT)-guided ¹²⁵I interstitial implant therapy for recurrent ovarian cancer., Methods: From October 2009 to November 2010, a total of 25 lesions for 12 patients were diagnosed as recurrent ovarian cancer by positron emission tomography/computed tomography (PET/CT). Among 25 lesions, 21 underwent ¹²⁵I seed implantation. And 4 lesions of liver and spleen in one patient were treated with microwave ablation. Nine patients underwent 2 - 6 cycles of chemotherapy after seeding. There were 11 lesions with diameter > 2 cm and 10 ≤ 2 cm. According to the area of physiologic 18FDG uptake in lesions, the treatment plans were formulated by computerized treatment planning system (TPS) and Memorial Sloan-Ketterin nomograph. The matched peripheral dose (MPD) was 145 Gy in target mass. A median of 20.5 seeds per patient (range: 9 - 45) were implanted. The efficacies were evaluated by CT and 18F-FDG PET/CT findings., Results: One patient died of renal failure while the other patients survived during a median follow-up of 15 mouths (range: 9 - 19). Ten lesions showed complete remission, 6 partial remission and 5 progressive disease. The effective rate was 76.2% (16/21). Compared with those > 2 cm, the lesions ≤ 2 cm in diameter had a better local control rate by Fisher's exact test (P = 0.035). The hepatic and renal lesions treated by microwave ablation showed inactivation on PET/CT. Only one patient suffered from sciatic nerve injury caused by punctuation and numbness and pain of right lower extremity were persistent. There was no onset of the complications of radiation injury, such as intestinal fistula and proctitis., Conclusion: The CT-guided ¹²⁵I interstitial implant therapy for recurrent ovarian cancer yields excellent short-term efficacies with fewer complications. The combined modality of ¹²⁵I interstitial implant and chemotherapy may further improve the patient outcomes.

We report the synthesis and characterization of metal-chelating polymers (MCPs) with a terminal biotin and a polyacrylamide backbone harboring multiple diethylenetriaminepentaacetic acid (DTPA) chelating sites. These polymers are conjugated to a streptavidin (SAv)-modified Fab fragment of trastuzumab (tmFab) and subsequently complexed with (111)In through DTPA. Trastuzumab has specific targeting ability toward human epidermal growth factor receptor-2 (HER2), which is overexpressed on some types of breast cancer cells and ovarian cancer cells. (111)In can generate Auger electrons which cause lethal DNA double strand breaks. The radioimmunoconjugates (RICs) were designed to target HER2 overexpressing cancer cells and carry multiple copies of (111)In to these cells. The mole maximum specific activities of these polymers were investigated by loading the polymers with (111)In at an increasing (111)In to polymer ratio. The polymers show 55-fold to 138-fold higher maximum specific activity than DTPA modified tmFab-SAv. Moreover, the HER2 immunoreactivities of these RICs were evaluated by measuring their specific binding ability toward HER2 overexpressing SKOV-3 ovarian cancer cells. The results demonstrate that although in the presence of polymer there is increased nonspecific binding, HER2 targeting ability was retained, ensuring the radionuclide delivery ability of these RICs.

Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor A and is used for the treatment of several cancers. We labeled this monoclonal antibody with Iodine-131 (¹³¹I) and performed in vitro quality control and tumor cell growth inhibition tests. Bevacizumab was labeled with ¹³¹I using chloramine T. Radiochemical purity and stability in phosphate-buffered saline and human blood serum were determined using thin-layer chromatography and radio-sodium dodecyl sulfate-polyacrylamide gel electrophoresis, respectively, performed at different times. Cell-specific binding, internalization, and toxicity of the radiolabeled antibody were tested using the SKOV-3 ovarian cancer cell line. The biodistribution of ¹³¹I-bevacizumab was investigated using male mice. The radiochemical purity of the complex was 99% ± 0.7%. Its stability in phosphate-buffered saline and human blood serum at 48 hours postpreparation was 78% ± 1.2% and 93% ± 0.6%, respectively. (131)I-bevacizumab was significantly bound to SKOV-3. The internalization of ¹³¹I-bevacizumab was time dependent, and it was cleared from the blood after 24 hours. Significant reductions in SKOV-3 cell viability were achieved with (131)I-bevacizumab at a concentration of 500 nM. A low accumulation of ¹³¹I-bevacizumab was observed in the stomach and salivary glands after 24 hours and 48 hours. These findings indicate that the new radiolabeled antibody should be further evaluated in animals and, possibly, in humans as a new radiopharmaceutical agent for use in radioimmunotherapy for ovarian cancer.