To assess the prevalence of KRAS, BRAF, and TP53 mutations in cases of low-grade and high-grade serous carcinomas and to evaluate the clinical outcomes of these morphologically distinct carcinomas.
Materials and Methods
Patients with primary invasive serous carcinomas were classified according to the universal grading system. Grade 2 serous tumors were excluded. A total of 100 patients were included for clinical evaluation. Thirty-seven patients, including 20 with low-grade and 17 with high-grade carcinomas, were selected for mutational analysis.
The low-grade carcinoma group was characterized by young age and premenopausal period compared with the high-grade carcinoma group, but there were no statistically significant differences in stage, metastasis of lymph node and residual disease. There were no statistically significant differences in survival rates, however, the low-grade carcinoma group showed a trend for improved progression-free survival compared with the high-grade carcinoma group of early stage (p = 0.064). Mutations in KRAS and BRAF were found in 6 (30%) and 2 (10%) patients in the low-grade carcinoma group, respectively, however, they were not found in the high-grade carcinoma group. KRAS and BRAF mutations were mutually exclusive, and both mutations were observed in 40% (8/20). The frequency of TP53 mutations in low-grade and high-grade carcinoma groups were found in 20% (4/20) and 70.6% (12/17), respectively (p = 0.009).
Low-grade serous carcinoma shows mutation pattern different from that with high-grade carcinoma. As there were no significant differences in stage distribution and survival, especially in advanced stage, we suggest that more studies are needed to segregate these patients into distinct disease entities.
Ovary; serous carcinoma; grade; mutation
Cervical cancer is an important cause of cancer-related deaths in women in developing countries. In Korea, cervical cancer is the third leading cancer among females and is fifth highest in mortality. The persistent oncogenic human papillomavirus (HPV) infections are the greatest risk of developing cervical intraepithelial neoplasia and invasive cancer. The overall prevalence of HPV was 10.4% in Korea and strong risk factors for HPV infection included a young age at sexual debut. The National Cancer Screening Program, which includes cervical cancer screening, has the following principles: the main screening tool is the Papanicolaou test conducted by gynecologists, which targets all women age 30 and over, and which is done every 2 years. HPV DNA tests have not yet been permitted as a screening test for cervical cancer in Korea; however, these are conducted along with a Pap test for screening cervical cancer in the clinic. The use of prophylactic HPV vaccine has been accepted in Korea; The Korean Society of Gynecologic Oncology and Colposcopy's recommendation for routine vaccination is for females aged 15-17 years with a catch-up vaccination recommended for females aged 18-26 years who have not been previously vaccinated. However, many people in Korea are not familiar with the HPV vaccine. Therefore, it is necessary to improve awareness for the disease and HPV vaccination and to establish the effective strategies to obtain funding for HPV vaccination. In the future, cervical cancer is expected to disappear throughout the world, including the Asia Pacific region, through a combination of vaccination and qualified screening programs for cervical cancer.
Cervical cancer; Human papillomavirus vaccines
To compare survival outcomes and treatment-related morbidities between radical hysterectomy (RH) and primary chemoradiation therapy (CRT) in patients with bulky early-stage cervical cancer.
We selected 215 patients with stage IB2 and IIA2 cervical cancer (tumor diameter > 4 cm on magnetic resonance imaging) who underwent RH followed by tailored adjuvant therapy (n=147) or primary CRT (n=68) at two tertiary referral centers between 2001 and 2010.
About twenty nine percent of patients were cured by RH alone and these patients experienced the best survival outcomes with the lowest morbidity rates. After the median follow-up times of 40 months, 27 RH (18.4%) and 20 CRT (29.4%) patients had recurrence (p=0.068) and 23 (15.6%) and 17 (25%) patients died of disease (p=0.101). The 5-year progression-free survival were 77% and 66% (p=0.047), and the 5-year overall survival were 78% and 67% (p=0.048) after RH and primary CRT, respectively. In multivariate analysis, patients who received primary CRT was at higher risk for tumor recurrence (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.24 to 4.14; p=0.008) and death (OR, 3.02; 95% CI, 1.53 to 5.98; p=0.001) than those who received RH. Grade 3-4, early (17% vs. 30.9%, p=0.021) and late (1.4% vs. 8.8%, p=0.007) complications were significantly less frequent after RH than primary CRT.
Thirty percent of patients were cured by RH alone. A treatment outcome was better in this retrospective study in terms of morbidity and survival. Randomized trials are needed to confirm this result.
Bulky early-stage cervical cancer; Chemoradiation therapy; Radical hysterectomy; Stage IB2; Stage IIA2
The study assessed the immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Korean women aged 15-25 years.
Phase IIIB, double-blind, randomised (2:1), multi-centre trial was conducted in Korea from June 2007 to March 2008. The study enrolled 225 women in the HPV (N=149) and placebo (N=76) groups who received three doses of HPV-16/18 AS04-adjuvanted vaccine or placebo (aluminium hydroxide) administered intramuscularly at 0, 1, and 6 months and were followed until one month post-dose 3. Serum samples were collected pre-vaccination and one month post-dose 3. Safety and reactogenicity data were collected throughout.
In this trial, 208 women completed the study (141 in HPV group; 67 in placebo group). At month 7, all initially seronegative women had seroconverted for HPV-16 and HPV-18 antibodies with anti-HPV-16 and anti-HPV-18 geometric mean titres of 9,351.4 El.U/mL (95% CI, 8,145.5 to 10,735.8) and 4204.1 El.U/mL (95% CI, 3,626.5 to 4,873.6), respectively. Initially seropositive women showed similar increase in geometric mean titre levels. Compliance to the three dose vaccination course was 95.3% in HPV and 89.5% in placebo group. Solicited local (pain) and general (fatigue, myalgia or headache) symptoms were commonly reported in both groups. Three serious adverse events were reported (two in HPV group; one in placebo group), all unrelated to vaccination by the investigator; all recovered.
The HPV-16/18 AS04-adjuvanted vaccine was highly immunogenic with a clinically acceptable safety profile in Korean women. This study was in line with previous global studies in Europe, North America, and Brazil. (ClinicalTrials.gov number, NCT 00485732.)
AS04-adjuvanted; Cervical cancer; Geometric mean titres; Human papillomavirus-16/18; Immunogenicity; Seroconversion
Regulatory T lymphocytes evoke the immune tolerance by suppressing and inactivating cytotoxic T lymphocytes. The objective of this study was to compare the proportion of regulatory T lymphocytes, precisely defined as CD4+CD25high+Foxp3+ T lymphocytes, in primary and recurrent ovarian carcinoma before and after ex vivo expansion of ascites with interleukin-2 (IL-2).
Ascitic fluid samples were obtained from 26 patients with ovarian carcinoma. Lymphocytes were isolated from ascites and cell markers were analyzed by flow cytometry using anti-CD3/CD4/CD8/CD16/CD56/CD25 and anti-Foxp3 antibodies. Lymphocytes were incubated for 2 to 3 weeks and expanded ex vivo by IL-2 stimulation and their phenotypes were analyzed by flow cytometry.
Following ex vivo expansion, ascitic fluid lymphocytes increased by a greater extent in the recurrent group than in the primary group. The proportion of ex vivo-expanded lymphocytes changed as follows; CD4+ T lymphocytes increased, CD8+ T lymphocytes decreased, and the proportion of CD3-CD16+56+ NK cells was unchanged. The proportion of CD4+CD25high+Foxp3+ regulatory T lymphocytes in CD4+ T lymphocytes increased after ex vivo expansion in both groups, but to a greater degree in the recurrent group.
This study showed that regulatory T lymphocytes, neither cytotoxic T lymphocytes nor NK cells, were extensively increased after ex vivo expansion, especially in recurrent ovarian carcinoma. These results may provide information that helps to guide the future development of adoptive immunotherapy against ovarian carcinoma.
Regulatory T lymphocyte; Foxp3; Ex vivo expansion; Ovarian carcinoma; Ascites
The aim of this study was to assess the efficacy of consolidation therapy with hexamethylmelamine (HMM) in patients with advanced epithelial ovarian cancer (EOC). Patients treated at our hospital between January 1997 and November 2006 and in documented clinical complete response from advanced ovarian cancer following front-line platinum-based therapy were retrospectively analyzed. The patients treated with HMM were compared to the patients of matched counterpart without consolidation therapy. Of 102 patients enrolled, 49 were treated with HMM and 53 received no consolidation treatment. For patients with HMM and observed patients, the mean age were 54.6 and 55.6 yr; the distribution of stage was similar (P=0.977); the optimal surgery was performed in 36 (73.5%) and 44 (83%) (P=0.336); the recurrence rate were 27 (55.1%) and 33 (62.3%) (P=0.463); and the median progression-free survival were 38 months and 21 months for patients with HMM and observed patients (P=0.235). No treatment-related adverse events were reported during the follow-up period. Although this study failed to show the significant survival benefit of consolidation therapy with HMM in patients with advanced EOC, we consider that our study can contribute data to investigate the effectiveness of consolidation therapy in epithelial ovarian cancer.
Altretamine; Consolidation Therapy; Advanced Epithelial Ovarian Cancer
Basaloid squamous cell carcinoma of the uterine cervix is an extremely rare malignancy of the female genital tract with a poorer clinical outcome than squamous cell carcinoma of the uterine cervix. We report a case of pure basaloid squamous cell carcinoma of the uterine cervix. A 70-yr-old woman with vaginal bleeding was referred to our institute. A basaloid squamous cell carcinoma of the uterine cervix, of International Federation of Gynecology and Obstetrics (FIGO) stage Ib1, was diagnosed by a loop electrosurgical excision procedure cone biopsy. A radical hysterectomy was performed, along with bilateral salpingo-oophorectomy, pelvic lymph node dissection, and para-aortic lymph node sampling. Pathologic findings were consistent with a basaloid squamous cell carcinoma confined to the cervix without an extracervical tumor. No further treatment was administered and there was no clinical evidence of recurrence during the 12 months of follow-up. Follow-up for the patient is ongoing. Although basaloid squamous cell carcinoma of the uterine cervix is thought to behave aggressively, accumulation of data on these rare tumors is necessary to determine whether their behavior differs significantly from that of conventional cervical squamous cell carcinoma of similar clinical stage. These data would be useful for defining the best diagnosis and treatment for these rare tumors.
Basaloid; Carcinoma, Squamous Cell; Cervix Uteri
To evaluate the efficacy of taxane and platinum-based chemotherapy guided by extreme drug resistance assay (EDRA) in patients with epithelial ovarian cancer.
Thirty-nine patients were enrolled, who were diagnosed as epithelial ovarian cancer, tubal cancer or primary peritoneal carcinoma and received both debulking surgery and EDRA in Asan Medical Center between August 2004 and August 2006. Another thirty-nine patients were enrolled, who did not receive EDRA as control. Paclitaxel 175 mg/m2 and carboplatin AUC 5 were administered as primary combination chemotherapy to both EDRA group and the control group. In the EDRA group, paclitaxel was replaced by docetaxel 75 mg/m2 if a patient showed extreme drug resistance (EDR) to paclitaxel and not to docetaxel. Carboplatin was replaced by cisplatin 75 mg/m2 if a patient showed EDR to carboplatin and not to cisplatin. If only one drug showed low drug resistance (LDR), it was allowed to add another drug which showed LDR such as gemcitabine 1,000 mg/m2. CT scan was performed every three cycles and CA-125 was checked at each cycle.
There was no significant difference in overall response rate between EDRA group and the control group (84.5% vs. 71.8%, p=0.107). However, 93.8% of patients in EDRA group did not show EDR to at least one drug and its response rate was significantly higher than that of the control group (93.3% vs. 71.8%, p=0.023).
we could choose a combination of taxane and platinum which did not show EDR and could obtain a good response in the patients with ovarian cancer.
Ovarian neoplasms; Antineoplastic combined chemotherapy protocol; Drug resistance; neoplasm; Biologic assay
Postoperative acute renal failure (PO-ARF) is an important cause of mortality among surgical patients. Although there have been many reports on PO-ARF after cardiac surgery and liver transplantation, less is known about the risk of PO-ARF after gynecologic operations. We aimed to investigate the risk of PO-ARF on gynecologic malignancy operations.
1,155 patients' medical charts were reviewed who underwent therapeutic surgery for gynecologic malignancies from January 1, 2005 to December 31, 2007, at the Asan Medical Center, Seoul, Korea.
Of these, 10 patients, comprising 0.89% of those who underwent radical hysterectomies and 0.86% of those who underwent debulking operations, were diagnosed with PO-ARF. Their mean age was 61.9±10.1 years. Five patients had preoperative risk factors. Mean operating time was 360.8±96.2 minutes. Five patients experienced intra-operative hypotension and all patients were given blood transfusions during surgery. Eight patients underwent hemodialysis, with two continuing on dialysis to date. Only two patients fully recovered.
Patients undergoing surgery for gynecologic malignancies may be at high risk for PO-ARF, because of old age, long operation times, and profuse bleeding. It is necessary to monitor these patients for postoperative renal function and urine output. If a postoperative oliguric state is detected, aggressive volume expansion should be started immediately, followed by hemodialysis.
Postoperative acute renal failure; Gynecologic malignancy
To compare the efficacy of neoadjuvant chemotherapy with paclitaxel plus platinum followed by radical hysterectomy with radical surgery alone in patients with stage IB2-IIA bulky cervical cancer.
From November 1999 to September 2007, stage IB2-IIA cervical cancers with tumor diameter >4 cm, as measured by MRI, were managed with two cycles of preoperative paclitaxel and platinum. As a control group, we selected 35 patients treated with radical surgery alone.
There were no significant between group differences in age, tumor size, FIGO stage, level of SCC Ag, histopathologic type and grade. Operating time, estimated blood loss, the number of lymph nodes yielded and the rate of complications were similar in the two groups. In surgical specimens, lymph-vascular space invasion (LVSI), nodal metastasis and parametrial involvement did not differ significantly between the two groups. In the neoadjuvant group, pathologic tumor size was significantly smaller and fewer patients had deep cervical invasion. Radiotherapy, alone and in the form of concurrent chemoradiation, was administered to more patients treated with radical surgery alone (82.9% vs. 52.9%, p=0.006). No recurrence was observed in patients who could avoid adjuvant radiotherapy owing to improved risk factors after neoadjuvant chemotherapy. There were no significant differences in 5-year disease free and overall survival.
As neoadjuvant chemotherapy would improve pathologic prognostic factors, adjuvant radiotherapy can be avoided, without worsening the prognosis, in patients with locally advanced bulky cervical cancer. Neoadjuvant chemotherapy would be improving the quality of life after radical hysterectomy in patients with bulky cervical cancer.
Locally advanced cervical cancer; Neoadjuvant chemotherapy; Radical hysterectomy
To verify whether it can be justified to classify patients to stage IIIC epithelial ovarian cancer based on nodal involvement only.
This study included all consecutive patients with stage IIIC epithelial ovarian cancer who underwent upfront cytoreductive surgery according to the FIGO guideline followed by platinum based chemotherapy from September 1989 to September 2006 at Asan Medical Center.
During the study period, a total of 272 patients met the inclusion criteria. Optimal cytoreduction was achieved in 213 patients, and complete cytoreduction was achieved in 85 patients. Median follow-up time was 37 months (range, 6-181 months). The 5-year disease free survival (DFS) and overall survival (OS) rate of all patients were 23% and 57%, respectively. Forty-one patients were allocated to stage IIIC by positive nodes only. Patients with stage IIIC disease due to positive nodes only had significantly longer DFS and OS compared to other stage IIIC patients (p<0.001 and p<0.001). The DFS and OS of these patients was significantly better than those of other stage IIIC patients who achieved complete or optimal cytoreduction (p<0.001 and p<0.001). The outcome was even better than that of stage IIIA and IIIB patients (p<0.05 and p<0.05).
Patients with stage IIIC epithelial ovarian cancer due to positive nodes only had a more favorable prognosis compared to other stage IIIC patients. Therefore, reevaluation of the current FIGO staging system for stage IIIC epithelial ovarian cancer is required.
Epithelial ovarian cancer; Stage IIIC; Lymph node metastasis; Prognosis
Transjugular intrahepatic portosystemic shunt (TIPSS) is a promising method of treatment for gastric or esophageal variceal bleeding. This study was performed to determine the prognostic factors contributing to the survival of patients after TIPSS for gastric or esophageal variceal bleeding. One hundred and fifty-five patients who underwent TIPSS between September 1991 and March 2001 were followed up by clinical examination, upper gastrointestinal endoscopy, and Duplex sonography. The mean portohepatic pressure gradient prior to TIPSS was 20.5+/-9.93 mmHg and dropped to 10.7+/-6.62 mmHg after TIPSS (p<0.001). The cumulative survival rate was 75.1% at 6 months, 66.6% at 1 yr, 58.4% at 2 yr, and 38.1% at 5 yr. Survival after TIPSS was inversely related to the Child-Pugh classification (p<0.05). The rebleeding rate was 18.3% at 6 months, 21.0% at 1 yr, 32.8% at 2 yr, and 53.1% at 5 yr. The causes of deaths were hepatic failure (53.5%), recurrent variceal bleeding (11.6%), pneumonia (4.6%), sepsis (3.5%), hepatic encephalopathy (2.3%), and unknown (17.4%). Multivariate analysis (Cox proportional hazard model) revealed that the Child-Pugh classification and age were statistically significant independent prognostic factors. In conclusion, TIPSS is an effective method of treatment for variceal bleeding in cases where other treatment modalities including endoscopic therapy are unsuccessful and the most important prognostic factors are preprocedural hepatic reserve (Child-Pugh class) and age.
A 36-year old Korean woman consulted a clinic for a regular gynecological examination, and a mass was noticed in her pelvis. She was referred to the Asan Medical Center, Seoul where transvaginal ultrasonography confirmed a pelvic mass exceeding 10 cm in diameter. She received total abdominal hysterectomy and bilateral salpingoophorectomy, and a borderline serous neoplasm with micropapillary features involving the left ovary and right ovarian serosa was histopathologically confirmed. In addition, a section of a nematode with numerous eggs was found in the parenchyma of the left ovary. The worm had degenerated but the eggs were well-preserved and were identified as those of Enterobius vermicularis. She is an incidentally recognized case of ovarian enterobiasis.
Enterobius vermicularis; ovary; ectopic parasitism
Regarding vulvar cancer, a nomogram has been suggested for the prediction of relapse-free survival (RFS). While the nomogram has been developed and validated in a Western study, there was no validation in Korean population. Thus, we have undertaken the study to assess the applicability of nomogram for predicting RFS in Korean patients with vulvar cancer.
A total of 204 cases newly diagnosed as vulvar cancer between 1982 and 2006 were identified. Among them 70 cases were not eligible due to inappropriate cell type (40 cases) and radiation as primary therapy (30 cases). Forty-four cases were not evaluable due to inadequate data and persistent disease. Finally a total of 90 patients primarily treated by surgery were included for analysis. Variables including age and the characteristics of primary tumor, nodal status, and surgical margin were collected for predicting RFS based on nomogram, which was compared with actual RFS. A calibration plot was drawn showing the actual versus predicted probability for 6 groups of patients segregated according to their predicted probabilities. In addition, discrimination of the nomogram was quantified with the concordance index.
Patients' mean age was 58 years and mean follow-up period was 47.9 months. Observed 2y- and 5y-RFS rates were 81% and 68%, respectively, corresponding to 79% and 72% in the original cohort. The trend line in calibration plot showed comparable concordance with an ideal line, having a slope of 1.04 for 2y-RFS (R2=.35) and 0.98 for 5y-RFS (R2=.80), respectively. The concordance index was 0.79 in the KGOG data set, which was improved to 0.82 with the data set limited to squamous cell carcinoma.
The nomogram provides the predictive capacity for relapse-free survival in Korean patients with vulvar cancer.
Vulvar cancer; Nomogram; External validation; Prediction
To determine the superior chemotherapeutic regimen between monthly 5-FU plus cisplatin (FP) and weekly cisplatin alone in concurrent chemoradiotherapy for locally advanced cervical cancer, the compliance of treatment, response, survival and toxicities were analyzed between the two arms.
Materials and Methods
Between March 1998 and December 2001, 61 patients with locally advanced cervical cancer (stage IIB through IVA) and negative para-aortic lymph nodes were randomly assigned to either 'monthly FP' (arm I, n=34) or 'weekly cisplatin' (arm II, n=27) with concurrent radiotherapy. The patients of arm I received FP (5-FU 1,000 mg/m2/day + cisplatin 20 mg/m2/day, for 5 days, for 3 cycles at 4 week intervals) and those of arm II received cisplatin (30 mg/m2/day, for 6 cycles at 1 week intervals) with concurrent radiotherapy. The radiotherapy consisted of 41.4~50.4 Gy external beam irradiation in 23~28 fractions to the whole pelvis, with high dose rate brachytherapy delivering a dose of 30~35 Gy in 6~7 fractions to point A. During the brachytherapy, a parametrial boost was delivered. The median follow-up period for survivors was 44 months.
The compliance of treatment in monthly FP weekly cisplatin arms were 62 and 81%, respectively. The complete response rates at 3 months were 96 and 88% in arms I and II, respectively. The 4-year overall survival and disease free survival rates were 64 and 54% in the arm I and 77 and 66% in the arm II, respectively. The incidence of hematologic toxicity more than grade 2 was 29% in the arm I and 15% in the arm II. Only one patient in arm I experienced grade 3 gastrointestinal toxicity. No severe genitourinary toxicity was observed.
No significant difference was observed in the compliance, responses, survival rates and acute toxicities between the two treatment arms. More patients and further follow up will be required.
Randomized trials; Cervical neoplasm; Concurrent chemoradiotherapy