C. William Helm

Current Status and Future Directions of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in the Treatment of Ovarian Cancer

Epithelial ovarian cancer is a peritoneal surface malignancy that most often presents with spread of disease within the peritoneal cavity. Overall 5-year survival is around 50% and progress in improving outcomes is slow. Among other areas of research, hyperthermic intraperitoneal chemotherapy (HIPEC) provides a promising option. This article reviews the current status of treatment of epithelial ovarian cancer, experience with HIPEC to date, and future directions.

Sodium arsenite and hyperthermia modulate cisplatin-DNA damage responses and enhance platinum accumulation in murine metastatic ovarian cancer xenograft after hyperthermic intraperitoneal chemotherapy (HIPEC)

BackgroundEpithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the USA. Recurrence rates are high after front-line therapy and most patients eventually die from platinum (Pt) - resistant disease. Cisplatin resistance is associated with increased nucleotide excision repair (NER), decreased mismatch repair (MMR) and decreased platinum uptake. The objective of this study is to investigate how a novel combination of sodium arsenite (NaAsO2) and hyperthermia (43°C) affect mechanisms of cisplatin resistance in ovarian cancer.MethodsWe established a murine model of metastatic EOC by intraperitoneal injection of A2780/CP70 human ovarian cancer cells into nude mice. We developed a murine hyperthermic intraperitoneal chemotherapy model to treat the mice. Mice with peritoneal metastasis were perfused for 1 h with 3 mg/kg cisplatin ± 26 mg/kg NaAsO2 at 37 or 43°C. Tumors and tissues were collected at 0 and 24 h after treatment.ResultsWestern blot analysis of p53 and key NER proteins (ERCC1, XPC and XPA) and MMR protein (MSH2) suggested that cisplatin induced p53, XPC and XPA and suppressed MSH2 consistent with resistant phenotype. Hyperthermia suppressed cisplatin-induced XPC and prevented the induction of XPA by cisplatin, but it had no effect on Pt uptake or retention in tumors. NaAsO2 prevented XPC induction by cisplatin; it maintained higher levels of MSH2 in tumors and enhanced initial accumulation of Pt in tumors. Combined NaAsO2 and hyperthermia decreased cisplatin-induced XPC 24 h after perfusion, maintained higher levels of MSH2 in tumors and significantly increased initial accumulation of Pt in tumors. ERCC1 levels were generally low except for NaAsO2 co-treatment with cisplatin. Systemic Pt and arsenic accumulation for all treatment conditions were in the order: kidney > liver = spleen > heart > brain and liver > kidney = spleen > heart > brain respectively. Metal levels generally decreased in systemic tissues within 24 h after treatment.ConclusionNaAsO2 and/or hyperthermia have the potential to sensitize tumors to cisplatin by inhibiting NER, maintaining functional MMR and enhancing tumor platinum uptake.

Sodium arsenite ± hyperthermia sensitizes p53 expressing human ovarian cancer cells to cisplatin by modulating platinum DNA damage responses

Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death in the United States. Cisplatin is a DNA damaging agent initially effective against EOC but limited by resistance. P53 plays a critical role in cellular response to DNA damage and has been implicated in EOC response to platinum chemotherapy. In this study, we examined the role of p53 status in EOC response to a novel combination of cisplatin, sodium arsenite, and hyperthermia. Human EOC cells were treated with cisplatin ± 20μM sodium arsenite at 37°C or 39°C for 1 h. Sodium arsenite ± hyperthermia sensitized wild-type p53-expressing (A2780, A2780/CP70, OVCA 420, OVCA 429, and OVCA 433) EOC cells to cisplatin. Hyperthermia sensitized p53-null SKOV-3 and p53-mutant (OVCA 432 and OVCAR-3) cells to cisplatin. P53 small interfering RNA (siRNA) transfection abrogated sodium arsenite sensitization effect. XPC, a critical DNA damage recognition protein in global genome repair pathway, was induced by cisplatin only in wild-type p53-expressing cells. Cotreatment with sodium arsenite ± hyperthermia attenuated cisplatin-induced XPC in wild-type p53-expressing cells. XPC siRNA transfection sensitized wild-type p53-expressing cells to cisplatin, suggesting that sodium arsenite ± hyperthermia attenuation of XPC is a mechanism by which wild-type p53-expressing cells are sensitized to cisplatin. Hyperthermia ± sodium arsenite enhanced cellular and DNA accumulation of platinum in wild-type p53-expressing cells. Only hyperthermia enhanced platinum accumulation in p53-null cells. In conclusion, sodium arsenite ± hyperthermia sensitizes wild-type p53-expressing EOC cells to cisplatin by suppressing DNA repair protein XPC and increasing cellular and DNA platinum accumulation.

Hyperthermic intraperitoneal chemotherapy in ovarian cancer: rationale and clinical data

The outcome of ovarian cancer remains poor with conventional therapy. Intraperitoneal chemotherapy has some advantages over systemic chemotherapy, including favorable pharmacokinetics and optimal treatment timing. Intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) provides improved exposure of the entire seroperitoneal surface to the agent and utilizes the direct cytoxic and drug-enhancing effect of hyperthermia. While standard normothermic, nonintraoperative, intraperitoneal chemotherapy has been demonstrated to be beneficial in randomized trials and meta-analyses, there are no data from randomized HIPEC trials available yet. Cautious extrapolation of data from standard normothermic, nonintraoperative, intraperitoneal chemotherapy and data from Phase II and nonrandomized comparative studies suggest that HIPEC delivered at the time of surgery for ovarian cancer has definite potential. Data from ongoing randomized HIPEC trials to adequately answer the question of whether the addition of HIPEC actually prolongs survival in patients with peritoneal dissemination of primary and recurrent ovarian cancer are awaited in the near future.

Cisplatin Plus Sodium Arsenite and Hyperthermia Induces Pseudo-G1 Associated Apoptotic Cell Death in Ovarian Cancer Cells

Cisplatin is effective against solid tumors including ovarian cancer. However, inherent or acquired cisplatin resistance limits clinical success. We recently demonstrated that a combination of sodium arsenite (NaAsO2) and hyperthermia sensitizes p53-expressing ovarian cancer cells to cisplatin by modulating DNA repair pathway and enhancing platinum accumulation. However, it is not understood how this combination therapy modulates cell cycle following platinum-DNA damage. The goal of the present study was to determine if NaAsO2 and hyperthermia alter cisplatin-induced G2 arrest and cause mitotic arrest and mitotic catastrophe. Human epithelial ovarian cancer cells (A2780 and A2780/CP70) were treated with cisplatin ± 20 μM NaAsO2 at 37 or 39°C for 1 h. Cisplatin ± NaAsO2 at 37 or 39°C caused cells to accumulate in G2/M compartment at 36 h after treatment. Western blot analysis of cyclin A and cyclin B suggested that combined NaAsO2, hyperthermia, and cisplatin induced mitotic arrest. However, we observed < 3% mitotic index and phosphorylation of histone H3 on serine 10 was undetectable. These results did not confirm mitotic arrest. BUBR1 (BUB1B) also was not phosphorylated, suggesting disrupted mitotic checkpoint. Postmitotic cells accumulated in pseudo-G1 as demonstrated by cyclin E stabilization, CDKN1A induction, and hypophosphorylation of retinoblastoma protein. These cells also were positive for Annexin V binding indicating they were apoptotic. In summary, cisplatin plus NaAsO2 and hyperthermia induced pseudo-G1 associated apoptosis in ovarian cancer cells.

Laparoscopic surgery for endometrial cancer: increasing body mass index does not impact postoperative complications

Objective To determine the effect of body mass index on postoperative complications and the performance of lymph node dissection in women undergoing laparoscopy or laparotomy for endometrial cancer. Methods Retrospective chart review of all patients undergoing surgery for endometrial cancer between 8/2004 and 12/2008. Complications graded and analyzed using Common Toxicity Criteria for Adverse Events ver. 4.03 classification. Results 168 women underwent surgery: laparoscopy n=65, laparotomy n=103. Overall median body mass index 36.2 (range, 18.1 to 72.7) with similar distributions for age, body mass index and performance of lymph node dissection between groups. Following laparoscopy vs. laparotomy the percent rate of overall complications 53.8:73.8 (p=0.01), grade ≥3 complications 9.2:34.0 (p<0.01), ≥3 wound complications 3.1:22.3 (p<0.01) and ≥3 wound infection 3.1:20.4 (p=0.01) were significantly lower after laparoscopy. In a logistic model there was no effect of body mass index (≥36 and<36) on complications after laparoscopy in contrast to laparotomy. Para-aortic lymph node dissection was performed by laparoscopy 19/65 (29%): by laparotomy 34/103 (33%) p=0.61 and pelvic lymph node dissection by laparoscopy 21/65 (32.3%): by laparotomy 46/103 (44.7%) p=0.11. Logistic regression analysis revealed that for patients undergoing laparoscopy for stage I disease there was an inverse relationship between the performance of both para-aortic lymph node dissection and pelvic lymph node dissection and increasing body mass index (p=0.03 and p<0.01 respectively) in contrast to the laparotomy group where there was a trend only (p=0.09 and 0.05). Conclusion For patients undergoing laparoscopy, increasing body mass index did not impact postoperative complications but did influence the decision to perform lymph node dissection.

Resection of tumor from the supragastric lesser sac with peritonectomy

This 48 yr old lady underwent laparotomy for primary appendiceal carcinoma metastatic within the peritoneal cavity including the lesser omentum (LO) and supragastric lesser sac (Fig. 1). The left triangular ligament was divided allowing retraction of the left lobe of the liver. The stomachwasmanually pulled to stretch out the LO and facilitate resection. The left gastric, common hepatic and left hepatic arteries and the vagal nerves of Latarjet running along the lesser curve of the stomachwere avoided. Tumorwasmobilized frombetween the left liver and anterior caudate lobe and from behind the pont hepatique. Care was taken to avoid damage to a branch of the left hepatic artery running in the roof of the lesser sac. The stomach was elevated and the caudate lobe carefully retracted to expose the posterior surface of the supragastric lesser sac formed by a single layer of peritoneum. This was stripped off and then detached from the caudate lobe. Tumor was then stripped or wiped off the anterior surface of the caudate lobe. Residual visible tumor was ablated. At the end of the procedure there was no visible disease. The patientwas then treatedwith hyperthermic intraperitoneal chemotherapy with mitomycin for 90min. The postoperative course was uncomplicated apart from short-term ileus and urinary retention.

Systems approach to identify environmental exposures contributing to organ-specific carcinogenesis.

BACKGROUND The most effective way to reduce cancer burden is Q2 prevention which is dependent on identifying individuals at risk for a particular cancer and counseling them to avoid exposure to causative agents. Other than a few well characterized environmental agents linked to specific cancers, linkage between any particular environmental exposure and a specific type of cancer is mostly unknown. Thus, we propose a systems approach to analyze publicly available large datasets to identify candidate agents that play a role in organ-specific carcinogenesis. METHODS Publicly available datasets for mRNA and miRNA expression in ovarian cancer were queried to define the differentially expressed genes that are also targets of differentially expressed miRNAs. These target genes were then used to query the Comparative Toxicogenomics Database to identify interacting chemicals and also were analyzed by Ingenuity Pathway Analysis to identify pathways. RESULTS The interacting chemicals interact with genes in known pathways in ovarian carcinogenesis and support the hypothesis that these chemicals are likely etiologic agents in ovarian carcinogenesis. CONCLUSION A systems approach may prove useful to identify specific etiologic agents to better develop personalized preventive medicine strategies for those most at risk.

Morison's Pouch peritonectomy in cytoreductive surgery

• Morisons Pouch is a frequent site of metastatic disease from ovarian and appendiceal cancer.

Division of the pont hepatique of the liver in cytoreductive surgery for peritoneal malignancy

The pont hepatique (also called the pons hepatis and hepatic bridge) connects segments 3 and 4B of the liver and forms a tunnel (Fig 1) in which occult metastatic tumor can occur in peritoneal malignancies including ovarian cancer. A thorough knowledge of the anatomy of this area andprocedure for dividing the pont, exposing the tunnel and ⁎ Corresponding author. Fax: +1 314 646 8627. E-mail address: chelm4@slu.edu (C.W. Helm). Fig. 1. The ligamentum teres is retracted anteriorly to allow the infero-posterior surface of the liver to be inspected. The inferior edge of the liver now lies at the top. The pont hepatique connects hepatic segments 3 and 4B. The ligamentum teres enters the inferior end of the tunnel and the left hepatic artery and left portal vein pass to the liver in close proximity to the superior end. 0090-8258/