Surgical, Radiation, and Systemic Treatments of Patients With Thymic Epithelial Tumors: A Clinical Practice Guideline.

INTRODUCTION: The aim of this guideline was to provide recommendations for the most effective therapy for patients with thymic epithelial tumors, including thymoma, thymic carcinoma, and thymic neuroendocrine tumors (NETs). This guideline is intended to be used by all health care professionals managing patients with thymic epithelial tumors. METHODS: The guideline was developed by Ontario Health (Cancer Care Ontario)'s Program in Evidence-Based Care and by the Lung Cancer Disease Site Group through a systematic review of the evidence, expert consensus, and formal internal and external reviews. RESULTS: Evidence-based recommendations were developed to improve the management of patients with thymic epithelial tumors. The guideline includes recommendations for surgical, radiation, and systemic treatments for patients with thymoma, thymic carcinoma, and thymic NETs separated by stage of disease using the TNM staging system. Recommendations for patients with thymic NETs were endorsed from the 2021 National Comprehensive Cancer Network Neuroendocrine and Adrenal Tumors Guideline. CONCLUSIONS: This guideline reflects the new staging system for patients with thymoma and thymic carcinoma and includes supporting evidence from the best available studies.

Cytotoxic Effects of Betel Quid and Areca Nut Aqueous Extracts on Mouse Fibroblast, Human Mouth-Ordinary-Epithelium 1 and Human Oral Squamous Cell Carcinoma Cell Lines.

BACKGROUND: Betel quid chewing is more common among the older generation in rural areas of Malaysia. Oral cancer in Asia has been associated with the habit of chewing betel quid and areca nut. OBJECTIVE:   This study aims to investigate the cytotoxic effects of betel quid and areca nut extracts on the fibroblast (L929), mouth-ordinary-epithelium 1 (MOE1) and oral squamous cell carcinoma (HSC-2) cell lines. METHODS: L929, MOE1 and HSC-2 cells were treated with 0.1, 0.2 and 0.4 g/ml of betel quid and areca nut extracts for 24, 48 and 72 h. MTT assay was performed to assess the cell viability. RESULTS: Both extracts, regardless of concentration, significantly reduced the cell viability of L929 compared with the control (P<0.05). Cell viability of MOE1 was significantly enhanced by all betel quid concentrations compared with the control (P<0.05). By contrast, 0.4 g/ml of areca nut extract significantly reduced the cell viability of MOE1 at 48 and 72 h of incubation. Cell viability of HSC-2 was significantly lowered by all areca nut extracts, but 0.4 g/ml of betel quid significantly increased the cell viability of HSC-2 (P<0.05). CONCLUSION: Areca nut extract is cytotoxic to L929 and HSC-2, whereas the lower concentrations of areca nut extract significantly increased the cell viability of MOE1 compared to the higher concentration and control group. Although betel quid extract is cytotoxic to L929, the same effect is not observed in MOE1 and HSC-2 cell lines. Further investigations are needed to clarify the mechanism of action.
.

Verification of the diagnostic strategy for anterior mediastinal tumors.

BACKGROUND: For thymic epithelial tumors (TETs), the National Comprehensive Cancer Network guideline has suggested that complete excision of the tumor should be performed without a preoperative biopsy when resectable. However, little evidence has been provided to support this strategy. The purpose of this study was to review our diagnostic process and to evaluate the validity of radical resection of anterior mediastinal masses (AMMs) without pathological confirmation. METHODS: A total of 254 patients underwent surgical resection for AMMs between 2004 and 2015. This study included 181 patients with likely TETs according to clinical features, serum levels of tumor markers and autoimmune-antibodies, and radiological findings. In addition, AMMs likely TETs were classified into resectable or unresectable tumors. We retrospectively reviewed the diagnostic process of those patients and validated surgical resection of AMMs without a definitive diagnosis. RESULTS: Among 254 patients, 181 were suspected of having a TET based on the serum levels of tumor markers and autoimmune-antibodies and the radiological findings. Of them, 157 patients were deemed resectable and underwent surgical resection without histological confirmation, and 144 (92%) were diagnosed with TETs in the final pathological examinations. In 13 patients with non-TETs, the tumors were difficult to differentiate from TETs by imaging and clinical findings alone. CONCLUSIONS: A total of 92% of patients suspected of having a TET and who underwent complete resection without pathological confirmation were accurately diagnosed and properly treated. Surgical resection without a definitive diagnosis was feasible in patients suspected of having a TET when they were considered resectable.

Euxanthone inhibits glycolysis and triggers mitochondria-mediated apoptosis by targeting hexokinase 2 in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is one of the most prevalent gynaecological cancers. Euxanthone, an active ingredient of the medicinal plant Polygala caudata, exhibits a selective cytotoxic effect in tumour cells. The present study was aimed to determine whether euxanthone could suppress ovarian tumour growth, and to study the relevant mechanism. Two EOC cell lines, SKOV3 and A2780, were used as the in vitro model and treated with euxanthone. Cell viability and apoptosis were assayed using Cell Counting Kit-8 (CCK-8) and Annexin-V FITC/PI staining, respectively. Commercially available kits were used to measure the glucose consumption, lactate production, and intracellular ATP levels. Western blots assay was conducted to examine the level of apoptotic markers. To examine the roles of HK2 and STAT3 in the anti-tumour effect of euxanthone, cells were transfected with vectors overexpressing HK2 or STAT3, and assayed as above. Finally, SKOV3 cells were injected to mice models to appreciate the anti-neoplastic effect of euxanthone in vivo. We found that euxanthone impaired the cell viability and induced apoptosis via the intrinsic pathway in a concentration-dependent fashion in both SKOV3 and A2780 cells. Euxanthone also caused inhibition of glycolysis. Apoptosis and glycolysis inhibition was mediated by the downregulation of HK2, which in turn was a result of STAT3 inactivation. In vivo experiments also supported that euxanthone could exert anti-cancer activities without general toxicity. In conclusion, euxanthone triggered mitochondrial apoptosis and inhibited glycolysis in EOC cells. SIGNIFICANCE OF THE STUDY: Euxanthone triggered mitochondrial apoptosis and inhibited glycolysis in EOC cells. Our findings provide preliminary experimental data that support further studies on the potential therapeutic role of euxanthone in ovarian cancer.

Do differences in medical comorbidities and treatment impact racial disparities in epithelial ovarian cancer?

BACKGROUND: Population-based studies of women with epithelial ovarian cancer suggest that black women have worse survival compared to white women. The primary objective of this study was to determine if, at a National Cancer Institute (NCI)-Designated Comprehensive Cancer Center (CCC) serving a diverse racial and socioeconomic population, race is independently associated with differences in survival. METHODS: A retrospective review of women with EOC diagnosed between 2004-2009 undergoing treatment with follow-up at our institution was performed. Records were reviewed for demographics, comorbidities (as defined by the Charlson Comorbidity Index (CCI)), tumor characteristics, treatment, progression-free (PFS), and overall survival (OS). Survival was calculated using the Kaplan-Meier method and compared with the log-rank test. Multivariate survival analysis was performed with Cox (proportional hazards) model. RESULTS: 367 patients met inclusion criteria. 54 (15%) were black and 308 (84%) were white. Compared to white women, black women had higher BMI, lower rates of optimal surgical cytoreduction, lower rates of intraperitoneal chemotherapy, and higher CCI scores. The median PFS for black and white women were 9.7 and 14.6months, respectively (p=0.033). The median overall survival was 21.7months for black women and 42.6months for white women (p<0.001). On multivariate analysis, black race independently correlated with a worse overall survival (HR 1.61, 95% CI 1.06-2.43). CONCLUSION: In this cohort, racial disparities may be due to higher medical comorbidities and lower rates of optimal surgical cytoreduction. After accounting for these differences, race remained an independent predictor of worse overall survival.

Corilagin sensitizes epithelial ovarian cancer to chemotherapy by inhibiting Snail­glycolysis pathways.

We identified that corilagin is a major component extracted from a well-known hepatoprotective and antiviral medicinal herb, Phyllanthus niruri L with antitumor activity. Our previous study found that corilagin inhibited the growth of ovarian cancer cells via the TGF-ß/AKT/ERK signaling pathways. Recently, we demonstrated that corilagin enhanced the sensitivity of ovarian cancer cells to chemotherapy. Ovarian cancer cell lines, SKOv3ip, Hey and HO-8910PM-Snail, were treated with different concentrations of corilagin in combination with paclitaxel and carboplatin. Corilagin distinctly enhanced the inhibitory effects of paclitaxel and carboplatin. To understand the mechanisms involved in the chemo-sensitization by corilagin, we performed reverse phase protein array analysis to determine the signaling networks induced by corilagin. We observed that both paclitaxel and carboplatin upregulated the expression levels of several apoptotic and death-related proteins, such as caspase 3, caspase 7 and PDCD4, which were further enhanced when combined with corilagin. Meanwhile, corilagin induced distinct pathways to paclitaxel and carboplatin treatment. We also performed isobaric tags for relative and absolute quantitation proteomics analysis in corilagen-treated ovarian cancer cells. This analysis indicated that corilagin is mainly involved in the glycolysis pathway. Seahorse XF96 extracellular acidification rate analysis confirmed that corilagin inhibited glycolysis by downregulation of CD44 and STAT3. In summary, our observations indicate that corilagin sensitized epithelial ovarian cancer cells to paclitaxel and carboplatin treatment by primarily inhibiting Snail-glycolysis pathways. Corilagin is a herbal medicine with low toxic effects to normal cells, particularly hepatoprotective, and may be an ideal complimentary medicine when combined with highly toxic chemotherapeutic agents.

Bevacizumab-Based Chemotherapy Combined with Regional Deep Capacitive Hyperthermia in Metastatic Cancer Patients: A Pilot Study.

As an angiogenesis inhibitor, bevacizumab has been investigated in combination with different chemotherapeutic agents, achieving an established role for metastatic cancer treatment. However, potential synergic anti-angiogenic effects of hyperthermia have not tested to date in literature. The aim of our study was to analyze efficacy, safety, and survival of anti-angiogenic-based chemotherapy associated to regional deep capacitive hyperthermia (HT) in metastatic cancer patients. Twenty-three patients with metastatic colorectal (n = 16), ovarian (n = 5), and breast (n = 2) cancer were treated with HT in addition to a standard bevacizumab-based chemotherapy regimen. Treatment response assessment was performed, according to the modified Response Evaluation Criteria for Solid Tumors (mRECIST), at 80 days (timepoint-1) and at 160 days (timepoint-2) after therapy. Disease Response Rate (DRR), considered as the proportion of patients who had the best response rating (complete response (CR), partial response (PR), or stable disease (SD)), was assessed at timepoint-1 and timepoint-2. Chi-squared for linear trend test was performed to evaluated the association between response groups (R/NR) and the number of previous treatment (none, 1, 2, 3), number of chemotherapy cycles (<6, 6, 12, >12), number of hyperthermia sessions (<12, 12, 24, >24), and lines of chemotherapy (I, II). Survival curves were estimated by Kaplan-Meier method. DRR was 85.7% and 72.2% at timepoint-1 and timepoint-2, respectively. HT was well tolerated without additional adverse effects on chemotherapy-related toxicity. Chi-squared for linear trend test demonstrated that the percentage of responders grew in relation to the number of chemotherapy cycles (p = 0.015) and to number of HT sessions (p < 0.001) performed. Both overall survival (OS) and time to progression (TTP) were influenced by the number of chemotherapy cycles (p < 0.001) and HT sessions (p < 0.001) performed. Our preliminary data, that need to be confirmed in larger studies, suggest that the combined treatment of bevacizumab-based chemotherapy with HT has a favorable tumor response, is feasible and well tolerated, and offers a potentially promising option for metastatic cancer patients.

Statin treatment is associated with survival in a nationally representative population of elderly women with epithelial ovarian cancer.

OBJECTIVE: Observational studies suggest that statin therapy for cardio-protection is associated with improved survival in cancer patients. We sought to evaluate the impact of statin treatment on ovarian cancer survival in a nationally representative elderly population. METHODS: The linked Surveillance, Epidemiology, and End Results (SEER) registries and Medicare claims data on patients diagnosed with epithelial ovarian cancer in 2007-2009 were used to extract data on statin prescription fills, population characteristics, primary treatment, comorbidity and survival. Cox regression models were used to examine the association between statin treatment and overall survival. RESULTS: Among the 1431 ovarian cancer patients who underwent surgical resection, 609 (42.6%) filled prescriptions for statin. The majority of statin-users (89%) were prescribed a lipophilic formulation. Mean overall survival among statin-users was 32.3months compared to 28.8months for non-users (p<0.0001). A 34% reduction in death was associated with statin therapy, independent of age, race, neighborhood median household income, stage, platinum therapy and comorbid conditions (HR=0.66, 95% CI 0.55-0.81). Improved overall survival with statin use was observed for both serous (HR=0.69, 95% CI 0.54-0.87) and non-serous (HR=0.63, 95% CI 0.44-0.90) histologies. When statin treatment was categorized by lipophilicity and intensity, a significant survival benefit was limited to lipophilic statin users and those who took statins of moderate intensity. CONCLUSIONS: This SEER-Medicare analysis demonstrates improvement in overall survival with lipophilic statin use after surgery in elderly patients with epithelial ovarian cancer. A clinical trial to evaluate the impact of statin treatment in ovarian cancer survival is warranted.

Evaluation of the efficacy and toxicity profile associated with intraperitoneal chemotherapy use in older women.

OBJECTIVE: Intraperitoneal (IP) chemotherapy (CT) for treatment of epithelial ovarian cancer (EOC) has been shown to provide a substantial OS advantage. This study aims to compare the toxicity and benefits of IP CT in patients ≥70 with those <70. METHODS: We performed a single institution retrospective review of patients diagnosed with Stage IIA-IIIC EOC from 2000 to 2013 who received IP CT. Clinicopathologic characteristics were extracted, and survival was calculated. RESULTS: 133 patients were included with 100 pts. <70years old and 33 pts. ≥70years old. Clinical trial enrollment was similar despite age. In trial enrolled patients, older patients received statistically fewer cycles of therapy (6.4 vs 5.8, p=0.002) but had similar dose delays (0.9 vs 0.7, p=0.72), and modifications (0.9 vs 0.36, p=0.11). Median PFS (27 vs 31months) and OS (71 and 62months) were not statistically different. Grade 3/4 neutropenia was significantly worse in the older patients (82% vs 100%, p=0.04). Neuropathy grade ≥2 and other non-hematologic toxicities were not different between age groups. CONCLUSIONS: Despite completing fewer cycles of IP CT, older EOC patients had comparable survival to younger patients. The population of older patients receiving IP CT in this study were on clinical trial and likely to be heartier than the general older population. IP CT appears well tolerated and effective among select older patients and is likely under-utilized outside of clinical trials.

Factors Predicting Use of Neoadjuvant Chemotherapy Compared With Primary Debulking Surgery in Advanced Stage Ovarian Cancer-A National Cancer Database Study.

OBJECTIVES: We performed a patterns-of-care study to characterize the types of patients with epithelial ovarian cancer (EOC) who received neoadjuvant chemotherapy (NACT) versus primary debulking surgery (PDS) using the National Cancer Database (NCDB). METHODS: We identified patients with stages IIIC and IV EOC in the NCDB diagnosed from 2003 to 2011. Patients who received chemotherapy (CT) prior to surgery were classified as receiving NACT; if surgery preceded CT, then it was classified as PDS. Data collected from the NCDB included demographics, medical comorbidity index, cancer characteristics and treatment, and hospital characteristics. Univariate and multivariable analyses were performed using χ test, logistic regression, log-rank test, and Cox proportional hazards modeling as indicated. Statistical significance was set at P < 0.05. RESULTS: A total of 62,727 patients with stages IIIC and IV EOC were identified. The sequence of surgery and CT was identified, of which 6922 (11%) had NACT and 31,280 (50%) had PDS. Neoadjuvant CT was more frequently done in stage IV than stage IIIC (13% vs 9%), and its use markedly increased over time. Variables associated with increased likelihood of NACT use were as follows: age older than 50 years and those with higher comorbidities, stage IV, and higher-grade EOC. Neoadjuvant CT use was also associated with hospitals that were adherent to the National Comprehensive Cancer Network guidelines, high-volume facilities, those in the Midwest and West, and academic centers. CONCLUSIONS: Evidence suggests that patients with greater adverse risk factors are more likely to receive NACT instead of PDS. Use of NACT has significantly increased over the study period, especially in patients with stage IV ovarian cancer.

Aqueous-phase synthesis of iron oxide nanoparticles and composites for cancer diagnosis and therapy.

The design and development of multifunctional nanoplatforms for biomedical applications still remains to be challenging. This review reports the recent advances in aqueous-phase synthesis of iron oxide nanoparticles (Fe3O4 NPs) and their composites for magnetic resonance (MR) imaging and photothermal therapy of cancer. Water dispersible and colloidally stable Fe3O4 NPs synthesized via controlled coprecipitation route, hydrothermal route and mild reduction route are introduced. Some of key strategies to improve the r2 relaxivity of Fe3O4 NPs and to enhance their uptake by cancer cells are discussed in detail. These aqueous-phase synthetic methods can also be applied to prepare Fe3O4 NP-based composites for dual-mode molecular imaging applications. More interestingly, aqueous-phase synthesized Fe3O4 NPs are able to be fabricated as multifunctional theranostic agents for multi-mode imaging and photothermal therapy of cancer. This review will provide some meaningful information for the design and development of various Fe3O4 NP-based multifunctional nanoplatforms for cancer diagnosis and therapy.

Patient-Derived Xenograft Models of Epithelial Ovarian Cancer for Preclinical Studies.

PURPOSE: Patient-derived tumor xenografts (PDXs) can provide more reliable information about tumor biology than cell line models. We developed PDXs for epithelial ovarian cancer (EOC) that have histopathologic and genetic similarities to the primary patient tissues and evaluated their potential for use as a platform for translational EOC research. MATERIALS AND METHODS: We successfully established PDXs by subrenal capsule implantation of primary EOC tissues into female BALB/C-nude mice. The rate of successful PDX engraftment was 48.8% (22/45 cases). Hematoxylin and eosin staining and short tandem repeat analysis showed histopathological and genetic similarity between the PDX and primary patient tissues. RESULTS: Patients whose tumors were successfully engrafted in mice had significantly inferior overall survival when compared with those whose tumors failed to engraft (p=0.040). In preclinical tests of this model, we found that paclitaxel-carboplatin combination chemotherapy significantly deceased tumor weight in PDXs compared with the control treatment (p=0.013). Moreover, erlotinib treatment significantly decreased tumor weight in epidermal growth factor receptor-overexpressing PDX with clear cell histology (p=0.023). CONCLUSION: PDXs for EOC with histopathological and genetic stability can be efficiently developed by subrenal capsule implantation and have the potential to provide a promising platform for future translational research and precision medicine for EOC.

Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) with primary or secondary cytoreductive surgery in the treatment of advanced epithelial ovarian cancer.

BACKGROUND: Peritoneal dissemination is the most common route of spread of epithelial ovarian cancer (EOC). Cytoreductive surgery (CRS) followed by platinum-based systemic chemotherapy is the current standard treatment in advanced stages, with suboptimal results. The aim of this study is to analyze the outcome of advanced EOC treated with CRS plus hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) combined with systemic chemotherapy. METHODS: We analyze a cohort of women treated with CRS plus HIPEC for peritoneal carcinomatosis secondary to EOC from May 2007 to December 2014. We included both patients with peritoneal disease at first diagnosis of EOC and peritoneal recurrences after initial treatment. RESULTS: We performed 61 CRS with HIPEC procedures, 31 cases as primary treatment (4 as upfront therapy and 27 after neoadjuvant chemotherapy) and 30 as secondary treatment (recurrences). Median Peritoneal Carcinomatosis Index (PCI) was 9; the cytoreduction was optimal in 92% of the procedures. Severe morbidity (Grade III-IV of Clavien-Dindo classification) was 29.5%, without mortality. Median follow-up was 23 months and median disease-free survival (DFS) was 14 months (14 in primary surgery group and 17 in recurrence group, P=0.51). Median overall survival (OS) was 57 months; in primary surgery group, OS was 96.8% at 1 year, and 55% at 5 years, and median OS was not reached; OS in recurrence group was 89.3% at 1 year and 47.1% at 5 years, and median OS was 57 months. CONCLUSIONS: CRS with HIPEC is a treatment option for EOC with good results in terms of morbidity and survival, in experienced centers.

Three dimensional tumor models for cancer studies.

It is well recognized that one of the major drawbacks of using traditional two dimensional cultures to model the living systems is inaccurately reflecting the physiological manner in which modulators, nutrients, oxygen, and metabolites are applied and removed. Moreover, the two dimensional culture system poorly reflects how different cell types interact with each other in the same microenvironment. Since the first global development of three dimensional (3D) cell culture techniques in the late 1960s, this last decade has seen an explosion of studies to promote 3D models in the fields of regenerative medicine and cancer. The recent surge of interest in 3D cell culture in cancer research is attributable to the interest in developing closer to real life models. The ability to include various cell types and extracellular components reflect more the physiological conditions of tumor microenvironment. In this short review, we will discuss different approaches of 3D culture system models and techniques with a focus on the 3D interactions of cancer cells with stromal cells in the goal to reevaluate old and develop new therapeutics.

Precise Diagnosis and Treatment of Thymic Epithelial Tumors Based on Molecular Biomarkers.

Thymic epithelial tumors (TETs), including thymoma and thymic carcinoma, are rare malignant tumors. The mainstay of treatment patients with TET is surgical resection, and chemotherapy is necessary for patients with tumor invasion or metastasis who are unable to undergo complete radical excision. However, for those patients who are resistant to chemotherapy, targeted therapy has become the most popular tumor treatment program, as well as for thymic tumors. Many genes implicated in tumorigenesis and metastasis have also been reported to be therapeutic targets in thymic malignancies. A significant advance in TET treatment may derive from the identification of novel molecular biomarkers that can improve the diagnosis, prognosis, and treatment of tumors. We review a number of case reports and small clinical trials reporting that a few inhibitors, such as sorafenib and sunitinib, are effective in the treatment of thymoma. In this review, we describe the current potential drug targets and their roles in the development of thymic malignancy.

Re-purposing of curcumin as an anti-metastatic agent for the treatment of epithelial ovarian cancer: in vitro model using cancer stem cell enriched ovarian cancer spheroids.

Malignant epithelial ovarian cancer (EOC) spheroids high frequently are detected in the malignant ascites of the patients with the extensive peritoneal metastasis of ovarian cancer, which represent a significant obstacle to efficacious treatment. Clinical data also suggested that EOC spheroids play a putative role in the development of chemoresistance. Since standard surgery and conventional chemotherapy is the only available treatment, there is an urgent need to identify a more effective therapeutic strategy. Recent studies demonstrated that curcumin exerts an anticancer effect in a variety of human cancers including ovarian cancer. This study evaluates anti-peritoneal metastasis and chemoresistance of curcumin related to the EOC spheroids. In this study, we confirm that the high invasive EOC cells forming the spheroids express a high level of a cancer stem cell (CSC) marker, aldehyde dehydrogenase 1 family member A1 (ALDH1A1), which was significantly down-regulated by curcumin treatment. Curcumin treatment markedly enhances the sensitivity of EOC spheroids to cisplatin in a dose-dependent manner. Our experiments provided evidence that curcumin could abolish the sphere-forming capacity of EOC cells in a dose-dependent manner. Moreover, curcumin substantially suppressed the growth of the pre-existed EOC spheroids, inhibited the adhesion of EOC spheroids to ECM as well as the invasion of EOC spheroids to the mesothelial monolayers. We propose to re-purpose curcumin as anti-metastatic and chemoresistant agent for EOC management in combination with conventional regimen. Further preclinical studies are necessary to validate the anti-cancer effect of curcumin in patients with EOC.

Intraperitoneal chemotherapy after interval debulking surgery for advanced-stage ovarian cancer: Feasibility and outcomes at a comprehensive cancer center.

OBJECTIVES: Intraperitoneal (IP)-based chemotherapy following primary debulking surgery (PDS), although associated with substantial toxicity, is supported by a strong evidence base. We sought to determine feasibility and outcomes of IP chemotherapy after interval debulking surgery (IDS) among patients deemed ineligible for PDS. METHODS: We identified all patients with high-grade, stage III/IV ovarian cancer treated at our institution with neoadjuvant chemotherapy (NACT) followed by IDS and postoperative chemotherapy from 1/2008-5/2013. IP and intravenous (IV) regimens were defined; demographic and clinical data were analyzed using appropriate statistics. RESULTS: Of 128 evaluable patients, 118 (92%) achieved ≤1cm residual disease at IDS and 74 (58%) achieved a complete gross resection (CGR). An IP port was placed in 54/128 patients (42%), with 89% port utilization. Forty-eight (38%) of 128 patients received IP chemotherapy, 17 (13%) weekly IV paclitaxel/q3week carboplatin, and 63 (49%) q3week IV carboplatin/paclitaxel. Patients completed a median of 3 IP cycles (range, 2-6), with 3 (5.5%) of 54 ports removed due to complications. Overall survival (OS) for patients with a CGR treated with IP and weekly IV chemotherapy was 53.2months (range, 24.7-NE), and 44.2months (range, 30.2-NE) with any visible residual disease (p<0.001). Median OS was 53.2months (range, 44.5-NE) for IP-, not reached for weekly IV-, and 34.2months (range, 27.5-49.8) for q3week IV-treated patients (p=0.1). CONCLUSIONS: Patients administered IP after IDS had a high rate of successful port utilization, with few regimen switches. Oncologic outcomes were optimal in patients with a CGR at IDS, regardless of chemotherapy used.

The American Society of Peritoneal Surface Malignancies Multi-Institution evaluation of 1,051 advanced ovarian cancer patients undergoing cytoreductive surgery and HIPEC: An introduction of the peritoneal surface disease severity score.

BACKGROUND: Standard treatment for ovarian epithelial cancer (OEC) consists of cytoreductive surgery (CRS) and a platinum-taxane chemotherapy combination. There is increasing interest in evaluating hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with stage IIIC/IV disease. The peritoneal surface disease severity score (PSDSS) was introduced as a basis to improve patient selection for this therapy in OEC. METHODS: The charts of 1,051 patients with advanced OEC who underwent CRS/HIPEC were retrospectively evaluated using the following preoperatively obtained criteria: symptoms, peritoneal dissemination, and tumor histology. Overall survival was analyzed according to PSDSS as well as the timings and agents used during CRS/HIPEC. RESULTS: Median survival for all 1,051 patients was 73.4 months. PSDSS information was available for 553 patients. Survival correlated negatively with PSDSS (P < 0.001). Furthermore, combining PSDSS scores into I/II and III/IV described two distinct patient populations with vastly different outcomes, 100 versus 55 months, respectively (P < 0.001). Multivariate analysis failed to describe any differences between timings of HIPEC or chemotherapy agents used. CONCLUSION: PSDSS was capable of identifying a better surviving patient population in advanced-stage OEC. While randomized trials to evaluate the benefit of HIPEC are needed, the PSDSS may be a useful tool for selecting and stratifying OEC patients in clinical trials. J. Surg. Oncol. 2016;114:779-784. © 2016 2016 Wiley Periodicals, Inc.

Hyperthermic intraperitoneal chemotherapy with paclitaxel or cisplatin in patients with stage III-C/IV ovarian cancer. Is there any difference?

OBJETIVE: To compare the results of the administration of HIPEC with Paclitaxel or Cisplatin after cytoreduction in patients with stage IIIC-IV ovarian cancer, especially focused on disease-free survival. PATIENTS: We retrospectively analyzed a consecutive series of patients operated after being diagnosed with stage III-C/IV serous epithelial ovarian carcinoma. Patients included in the study were treated between January 2008 and March 2015. After cytoreduction, Paclitaxel (doses of 60 mg/m(2)O or Cisplatin (doses of 75 mg/m(2)) were used. RESULTS: A total of 111 patients were included. Median age was 61 years. In 60 of them (54%) Paclitaxel was used during HIPEC treatment and 51 patients (46%) were treated with Cisplatin. PCI was similar between groups (PCI = 11 in both cases). Median follow up was 34 months (12-96 months). The median disease free survival in Paclitaxel Group was 27 months and 33 months in Cisplatin Group (p = 0.551). In patients treated with Paclitaxel disease free survival rates at 1, 2, and 3 years were 79%, 60% and 46%. In patients treated with Cisplatin disease free survival at 1, 2, and 3 years were 64%, 50% and 40% respectively. After a multivariate analysis, incomplete cytoreduction (HR: 6.54, 95% CI 2.98-10.17, p < 0.01) and PCI >11 (HR: 2.15, 95% CI 1.42-6.68, p < 0.05) were identified as independent factors associated with a reduced disease-free survival. Cystotatic used was not relevant regarding disease free survival analysis. CONCLUSION: HIPEC with paclitaxel or cisplatin after cytoreduction in patients with ovarian cancer IIIC-IV has not shown different results in disease-free survival outcomes.

Procyanidin-rich extract of natural cocoa powder causes ROS-mediated caspase-3 dependent apoptosis and reduction of pro-MMP-2 in epithelial ovarian carcinoma cell lines.

Over the last four centuries, cocoa and chocolate have been described as having potential medicinal value. As of today, Theobroma cacao L. (Sterculiaceae) and its products are consumed worldwide. They are of great research interest because of the concentration dependent antioxidant as well as pro-oxidant properties of some of their polyphenolic constituents, specially procyanidins and flavan-3-ols such as catechin. This study was aimed at investigating the cellular and molecular changes associated with cytotoxicity, caused due pro-oxidant activity of cocoa catechins and procyanidins, in ovarian cancer cell lines. Extract of non-alkalized cocoa powder enriched with catechins and procyanidins was used to treat human epithelial ovarian cancer cell lines OAW42 and OVCAR3 at various concentrations ≤1000µg/mL. The effect of treatment on intracellular reactive oxygen species (ROS) levels was determined. Apoptotic cell death, post treatment, was evaluated microscopically and using flow cytometry by means of annexin-propidium iodide (PI) dual staining. Levels of active caspase-3 as a pro-apoptotic marker and matrix metalloproteinase 2 (MMP2) as an invasive potential marker were detected using Western blotting and gelatin zymography. Treatment with extract caused an increase in intracellular ROS levels in OAW42 and OVCAR3 cell lines. Bright field and fluorescence microscopy of treated cells revealed apoptotic morphology and DNA damage. Increase in annexin positive cell population and dose dependent upregulation of caspase-3 confirmed apoptotic cell death. pro-MMP2 was found to be downregulated in a dose dependent manner in cells treated with the extract. Treated cells also showed a reduction in MMP2 activity. Our data suggests that cocoa catechins and procyanidins are cytotoxic to epithelial ovarian cancer, inducing apoptotic morphological changes, DNA damage and caspase-3 mediated cell death. Downregulation of pro-MMP2 and reduction in active MMP2 levels imply a decrease in invasive potential of the cells. Apoptosis and MMP2 downregulation appear to be linked to the increase in intracellular ROS levels, caused due to the prooxidant effect of cocoa procyanidin extract.