Comparison of Clinical Features and Outcomes in Epithelial Ovarian Cancer according to Tumorigenicity in Patient-Derived Xenograft Models / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Although the use of xenograft models is increasing, few studies have compared the clinical features or outcomes of epithelial ovarian cancer (EOC) patients according to the tumorigenicity of engrafted specimens. The purpose of this study was to evaluate whether tumorigenicity was associated with the clinical features and outcomes of EOC patients. MATERIALS AND METHODS: Eighty-eight EOC patients who underwent primary or interval debulking surgery from June 2014 to December 2015 were included. Fresh tumor specimens were implanted subcutaneously on each flank of immunodeficient mice. Patient characteristics, progression-free survival (PFS), and germline mutation spectra were compared according to tumorigenicity. RESULTS: Xenografts were established successfully from 49 of 88 specimens. Tumorigenicity was associated with lymphovascular invasion and there was a propensity to engraft successfully with high-grade tumors. Tumors from patientswho underwent non-optimal (residual disease ≥ 1 cm) primary orinterval debulking surgery had a significantly greater propensity to achieve tumorigenicity than those who received optimal surgery. In addition, patients whose tumors became engrafted seemed to have a shorter PFS and more frequent germline mutations than patients whose tumors failed to engraft. Tumorigenicity was a significant factor for predicting PFS with advanced International Federation of Gynecology and Obstetrics stage and high-grade cancers. CONCLUSION: sTumorigenicity in a xenograft model was a strong prognostic factor and was associated with more aggressive tumors in EOC patients. Xenograft models can be useful as a preclinical tool to predict prognosis and could be applied to further pharmacologic and genomic studies on personalized treatments.

Practice guidelines for management of uterine corpus cancer in Korea: a Korean Society of Gynecologic Oncology Consensus Statement / 부인종양

Clinical practice guidelines for gynecologic cancers have been developed by many organizations. Although these guidelines have much in common in terms of the practice of standard of care for uterine corpus cancer, practice guidelines that reflect the characteristics of patients and healthcare and insurance systems are needed for each country. The Korean Society of Gynecologic Oncology (KSGO) published the first edition of practice guidelines for gynecologic cancer treatment in late 2006; the second edition was released in July 2010 as an evidence-based recommendation. The Guidelines Revision Committee was established in 2015 and decided to produce the third edition of the guidelines as an advanced form based on evidence-based medicine, considering up-to-date clinical trials and abundant qualified Korean data. These guidelines cover screening, surgery, adjuvant treatment, and advanced and recurrent disease with respect to endometrial carcinoma and uterine sarcoma. The committee members and many gynecologic oncologists derived key questions from the discussion, and a number of relevant scientific literatures were reviewed in advance. Recommendations for each specific question were developed by the consensus conference, and they are summarized here, together with other details. The objective of these practice guidelines is to establish standard policies on issues in clinical areas related to the management of uterine corpus cancer based on the findings in published papers to date and the consensus of experts as a KSGO Consensus Statement.

API5 induces cisplatin resistance through FGFR signaling in human cancer cells

Most tumors frequently undergo initial treatment with a chemotherapeutic agent but ultimately develop resistance, which limits the success of chemotherapies. As cisplatin exerts a high therapeutic effect in a variety of cancer types, it is often used in diverse strategies, such as neoadjuvant, adjuvant and combination chemotherapies. However, cisplatin resistance has often manifested regardless of cancer type, and it represents an unmet clinical need. Since we found that API5 expression was positively correlated with chemotherapy resistance in several specimens from patients with cervical cancer, we decided to investigate whether API5 is involved in the development of resistance after chemotherapy and to explore whether targeting API5 or its downstream effectors can reverse chemo-resistance. For this purpose, cisplatin-resistant cells (CaSki P3 CR) were established using three rounds of in vivo selection with cisplatin in a xenografted mouse. In the CaSki P3 CR cells, we observed that API5 acted as a chemo-resistant factor by rendering cancer cells resistant to cisplatin-induced apoptosis. Mechanistic investigations revealed that API5 mediated chemo-resistance by activating FGFR1 signaling, which led to Bim degradation. Importantly, FGFR1 inhibition using either an siRNA or a specific inhibitor disrupted cisplatin resistance in various types of API5(high) cancer cells in an in vitro cell culture system as well as in an in vivo xenograft model. Thus, our results demonstrated that API5 promotes chemo-resistance and that targeting either API5 or its downstream FGFR1 effectors can sensitize chemo-refractory cancers.

Clinical Significance of CA125 Level after the First Cycle of Chemotherapy on Survival of Patients with Advanced Ovarian Cancer

PURPOSE: To determine the most powerful cancer antigen 125 (CA125)-related prognostic factor for advanced epithelial ovarian cancer (EOC) and to identify cut-off values that distinguish patients with a poor prognosis from those with a good prognosis. MATERIALS AND METHODS: We included 223 patients who received staging laparotomy and were diagnosed with stage IIC-IV serous EOC. Cox regression analysis was used to determine the most significant prognostic factor among the following variables: serum CA125 before surgery and after the first, second, and sixth cycles of chemotherapy; the nadir CA125 value; the relative percentage change in CA125 levels after the first and second cycles of chemotherapy compared to baseline CA125; CA125 half-life; time to nadir; and time to normalization of the CA125 level. RESULTS: The CA125 level after the first chemotherapy cycle was the most significant independent prognostic factor for overall survival (OS). Time to normalization (p=0.028) and relative percentage change between CA125 levels at baseline and after the first chemotherapy cycle (p=0.021) were additional independent prognostic factors in terms of OS. The CA125 level after the first chemotherapy cycle (p=0.001) and time to normalization (p<0.001) were identified as independent prognostic factors for progression free survival (PFS). CONCLUSION: Among well-established CA125-related prognostic factors, serum CA125 levels after the first cycle of chemotherapy and time to normalization were the most significant prognostic factors for both OS and PFS.

ATP-Based Chemotherapy Response Assay in Primary or Recurrent Ovarian and Peritoneal Cancer

PURPOSE: To investigate chemosensitivity with an adenosine triphosphate-based chemotherapy response assay in patients with epithelial ovarian or peritoneal cancer according to tumor histology, grade, and disease status. MATERIALS AND METHODS: One hundred specimens were collected during primary or secondary debulking from 67 patients with primary ovarian cancer, 24 patients with recurrent ovarian cancer, 5 patients with primary peritoneal cancer, and 4 patients with recurrent peritoneal cancer; samples were collected between August 2006 and June 2009. Tumor cells were isolated and cultured for 48 hours in media containing chemotherapy. The chemosensitivity index (CI) was calculated as 300 minus the sum of the cell death rate at 0.2x, 1x, and 5x drug concentrations, and the CI values were compared. RESULTS: CI values were obtained from 93 of 100 patients. The most active agents against primary disease were ifosfamide and paclitaxel. For primary serous adenocarcinoma, paclitaxel and irinotecan were the most active, followed by ifosfamide. For clear cell carcinoma, ifosfamide was the most active, followed by paclitaxel and irinotecan. Although not statistically significant, the CIs of cisplatin, carboplatin, paclitaxel, and docetaxel decreased as tumor grade increased. In 14 cases of recurrent disease, paclitaxel was the most active, followed by ifosfamide and cisplatin. CONCLUSION: Ifosfamide and paclitaxel were the most active drugs for primary and recurrent disease. Therefore, we recommend further clinical studies to confirm the efficacy of paclitaxel, ifosfamide, and cisplatin combination chemotherapy for recurrent and primary ovarian cancer.

The ON-Q pain management system in elective gynecology oncologic surgery: Management of postoperative surgical site pain compared to intravenous patient-controlled analgesia

OBJECTIVE: The goal of this study was to compare postoperative surgical site pain in gynecologic cancer patients who underwent elective extended lower midline laparotomy and managed their pain with either the ON-Q pain management system (surgical incision site pain relief system, ON-Q pump) or an intravenous patient-controlled analgesia pump (IV PCA). METHODS: Twenty gynecologic cancer patients who underwent elective extended lower midline laparotomy were divided into two groups. One group received a 72-hour continuous wound perfusion of the local anesthetic ropivacaine (0.5%, study group) into the supraperitoneal layer of the abdominal incision through the ON-Q pump. The other group received intravenous infusion pump of patient-controlled analgesia (fentanyl citrate 20 mg/mL . kg+ondansetron hydrochloride 16 mg/8 mL+normal saline). Postoperative pain was assessed immediately and at 6, 24, 48, 72, and 96 hours after surgery using the visual analogue scale. RESULTS: Postoperative surgical site pain scores at 24, 48, and 72 hours after surgery were lower in the ON-Q group than the IV PCA group. Pain scores at 24 hours and 48 hours after surgery were significantly different between the two groups (P=0.023, P<0.001). Overall painkiller administration was higher in the ON-Q group but this difference was not statistically significant (5.1 vs. 4.3, P=0.481). CONCLUSION: This study revealed that the ON-Q pain management system is a more effective approach than IV PCA for acute postoperative surgical site pain relief after extended lower midline laparotomy in gynecologic cancer patients.

Treatment of the patients with abnormal cervical cytology: a "see-and-treat" versus three-step strategy / 부인종양

OBJECTIVE: To examine the correlation between cervical cytology and final histological results in patients who have undergone loop electrosurgical excision procedure (LEEP) with or without colposcopy-directed biopsy. METHODS: A retrospective review was performed of 829 patients who underwent LEEP for abnormal cervical cytology at Gangnam Severance Hospital between January 2004 and December 2008. Patients were classified to three groups according to cervical cytology and also divided into two groups based on the treatment they received: see-and-treat group and the standard three-step group. Final histological results were compared for the each study group. RESULTS: There were no differences in the final histological results between see-and-treat and three-step group in patients with high-grade squamous intraepithelial lesions (HSIL) cytology (N=523) (p=0.71). However, in patients with low-grade squamous intraepithelial lesions (LSIL)/atypical squamous cells of undetermined significance (ASCUS) (N=257) or normal cytology (N=49), the final histological results were significantly different between see-and-treat and three-step group (p<0.001) and the rate of overtreatment was significantly higher in the see-and-treat group (p<0.001). CONCLUSION: A see-and-treat protocol may be a viable alternative only in patients with HSIL cytology if colposcopic impression is suggestive of cervical intraepithelial neoplasia (CIN) 2 or 3 lesions.

Detection of Cancer with PET and PET/CT in Asymptomatic Volunteers / 핵의학분자영상

PURPOSE: We retrospectively investigated the diagnostic performance of (18)F-fluorodeoxyglucose positron emission tomography (PET) and PET/CT for cancer detection in asymptomatic health-check examinees. MATERIALS AND METHODS: This study consisted of 5091 PET or PET/CT conducted as part of annual health examination at one hospital from March 1998 to February 2008. To find the incidence of cancers, medical records of the subjects were thoroughly reviewed for a follow-up period of one year. The patterns of formal readings of PET and PET/CT were analyzed to assess the sensitivity and specificity for cancer detection. The histopathology and stage of the cancers were evaluated in relation to the results of PET. RESULTS: Eighty-six cancers (1.7%) were diagnosed within one year after PET or PET/CT. When PET and PET/CT results were combined, the sensitivity was 48.8% and specificity was 81.1% for cancer detection. PET only had a sensitivity of 46.2% and a specificity of 81.4%, and PET/CT only had a sensitivity of 75.0% and a specificity of 78.5% respectively. There were no significant differences in cancer site, stage and histopathology between PET positive and PET negative cancers. In 19.3% of formal readings of PET and PET/CT, further evaluation to exclude malignancy or significant disease was recommended. Head and neck area and upper gastrointestinal tract were commonly recommended sites for further evaluation. CONCLUSIONS: PET and PET/CT showed moderate performance for detecting cancers in asymptomatic adults in this study. More experience and further investigation are needed to overcome limitations of PET and PET/CT for cancer screening.