Wichai Termrungruanglert

Human papillomavirus DNA in plasma of patients with cervical cancer

BackgroundHuman papillomavirus (HPV) is a crucial etiological factor for cervical cancer (CC) development. From a diagnostic view-point, the consistent presence of HPV in CC allows the viral DNA to be used as a genetic marker. The aims of this study were to evaluate the presence, physical status and clinical significant of HPV DNA in circulation of CC patients.ResultsWhereas 6 out of 50 (12%) HPV positive CC patients revealed plasma HPV DNA, it was detected in none of 20 normal controls or 13 HPV negative CC cases. The plasma DNA exhibited an HPV type identical to the HPV in the primary tumors and the DNA from both sources was integrated into host genome. Interestingly, several findings suggested an association between plasma HPV DNA and metastasis. First, three of the HPV DNA positive cases were CC patients with clinical stage IVB or recurrence with distance metastases (P = 0.001, RR = 15.67). Second, the amount of plasma HPV DNA from metastatic patients to be three times more than three other patients without metastases. Finally, the later cases had tendency to develop recurrence distant metastases within one year after complete treatment when compared with other HPV associated CC patients with the same stage but without the present of plasma HPV DNA.ConclusionsThe plasma HPV DNA originated from the CC, was associated with metastasis and could be used as a marker representing the circulating free CC DNA.

Cyclin A1 promoter hypermethylation in human papillomavirus-associated cervical cancer

BackgroundThe aim of this study was to evaluate epigenetic status of cyclin A1 in human papillomavirus-associated cervical cancer. Y. Tokumaru et al., Cancer Res64, 5982-7 (Sep 1, 2004)demonstrated in head and neck squamous-cell cancer an inverse correlation between cyclin A1 promoter hypermethylation and TP53 mutation. Human papillomavirus-associated cervical cancer, however, is deprived of TP53 function by a different mechanism. Therefore, it was of interest to investigate the epigenetic alterations during multistep cervical cancer development.MethodsIn this study, we performed duplex methylation-specific PCR and reverse transcriptase PCR on several cervical cancer cell lines and microdissected cervical cancers. Furthermore, the incidence of cyclin A1 methylation was studied in 43 samples of white blood cells, 25 normal cervices, and 24, 5 and 30 human papillomavirus-associated premalignant, microinvasive and invasive cervical lesions, respectively.ResultsWe demonstrated cyclin A1 methylation to be commonly found in cervical cancer, both in vitro and in vivo, with its physiological role being to decrease gene expression. More important, this study demonstrated that not only is cyclin A1 promoter hypermethylation strikingly common in cervical cancer, but is also specific to the invasive phenotype in comparison with other histopathological stages during multistep carcinogenesis. None of the normal cells and low-grade squamous intraepithelial lesions exhibited methylation. In contrast, 36.6%, 60% and 93.3% of high-grade squamous intraepithelial lesions, microinvasive and invasive cancers, respectively, showed methylation.ConclusionThis methylation study indicated that cyclin A1 is a potential tumor marker for early diagnosis of invasive cervical cancer.

Cost and effectiveness evaluation of prophylactic HPV vaccine in developing countries.

BACKGROUND Approximately 80% of cervical cancer cases occur in developing countries. In Thailand, cervical cancer has been the leading cancer in females, with an incidence of 24.7 cases per 100,000 individuals per year. OBJECTIVES We constructed a decision model to simulate the lifetime economic impact for women in the context of human papillomavirus (HPV) infection prevention. HPV-related diseases were of interest: cervical cancer, cervical intraepithelial neoplasia, and genital warts. The two strategies used were 1) current practice and 2) prophylactic quadrivalent vaccine against HPV types 6, 11, 16, and 18. METHODS We developed a Markov simulation model to evaluate the incremental cost-effectiveness ratio of prophylactic HPV vaccine. Women transition through a model either healthy or developing HPV or its related diseases, or die from cervical cancer or from other causes according to transitional probabilities under the Thai health-care context. Costs from a provider perspective were obtained from King Chulalongkorn Memorial Hospital. Costs and benefits were discounted at 3% annually. RESULTS Compared with no prophylactic HPV vaccine, the incremental cost-effectiveness ratio was 160,649.50 baht per quality-adjusted life-year. The mortality rate was reduced by 54.8%. The incidence of cervical cancer, cervical intraepithelial neoplasia grade 1, cervical intraepithelial neoplasia grade 2/3, and genital warts was reduced by up to 55.1%. CONCLUSION Compared with commonly accepted standard thresholds recommended by the World Health Organization Commission on Macroeconomics and Health, the nationwide coverage of HPV vaccination in girls is likely to be cost-effective in Thailand.

Remission of refractory gestational trophoblastic disease with high-dose paclitaxel.

High-risk metastatic gestational trophoblastic disease (GTD) in patients who have failed primary chemotherapy has a very poor prognosis. About 25% of women with high-risk metastatic disease become refractory to EMA-CO (etoposide, methotrexate, actinomycin-D, cyclophosphamide and vincristine) and fall to achieve a complete remission. Currently, there is no standard salvage chemotherapeutic regime for EMA-CO failure. Paclitaxel, a taxane analog extracted from the bark of the western yew (Taxus brevlfolla), has shown antitumor activity in a variety of cancer cell lines. High in vivo efficacy was confirmed in phase II trials, especially for breast and epithelial ovarian cancer patients. Recently, two in vitro studies have shown that paclitaxel is a highly effective antineoplastic agent in choriocarcinoma cell lines. We present the first clinical report of a serologic remission with high-dose paclitaxel (250 mg/m2 i.v. infusion over 24 h every 3 weeks) of a highly refractory GTD in a patient who developed brain metastasis after multiple combined chemotherapeutic regimens. The patient tolerated paclitaxel with granulocyte colony stimulating factor support very well. The remission with paclitaxel in this patient confirms its preclinical activity in high-risk, refractory GTD.

Salvage chemotherapy in recurrent platinum-resistant or refractory epithelial ovarian cancer with Carboplatin and distearoylphosphatidylcholine pegylated liposomal Doxorubicin (lipo-dox®).

BACKGROUND To evaluate the efficacy and safety of distearoylphosphatidylcholine pegylated liposomal doxorubicin (DPLD) combined with carboplatin for the treatment of platinum resistant or refractory epithelial ovarian cancer (EOC) or fallopian tube cancer. MATERIALS AND METHODS A retrospective analysis of women who received DPLD with carboplatin for recurrent EOC or fallopian tube cancer in King Chulalongkorn Memorial Hospital Thailand from January 2006 to August 2011 was conducted. Patients were identified from the medical records and data on demographic factors, stage, histology, surgical findings, cytoreduction status, and prior chemotherapies were abstracted. The efficacy and toxicity of DPLD/carboplatin were evaluated. Progression-free (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. RESULTS A total of 65 patients, 64 with platinum resistant or refractory epithelial ovarian cancer and 1 with fallopian tube cancer, were enrolled. DPLD and carboplatin were given for an average of 4.46 cycles per patient with a total of 273 cycles. Among the 65 evaluable patients, 0% achieved CR, 7.69% PR, 15.4% SD and 76.% PD. The overall response rate was 23.1%. With a median follow-up of 27.4 months, the median progression-free and median overall survival in the 36 patients was 4.46 months and 8.76 months respectively. In the aspect of side effects, palmar-plantar erythrodysesthesia (PPE) occurred in 33.3% (Grade I 22.2%, Grade II 11.1%) and mucositis in 41.7% (Grade I 27.8%, Grade II 13.9%) of all treatment cycles, all Grade 1 or 2. Anemia, leukopenia and thrombocytopenia occurred in 58.3% (Grade I 41.7%, Grade II 16.7%), 66.7% (Grade I 47.2%, Grade II 19.4%), and 22.2% (Grade I 16.6%, Grade II 5.56%) of cycle respectively, and were mostly Grade 1 or 2. CONCLUSIONS DPLD, the second-generation PLD drug combined with carboplatin every 4 weeks, is effective and has low toxicity for treatment of patients with recurrent platinum-resistant or refractory epithelial ovarian cancer.

Is complete surgical staging necessary in clinically early-stage endometrial carcinoma?

The purpose of this study was to evaluate the incidence of pelvic/para-aortic node metastases and the other pathological characteristics from medical records of patients with endometrial carcinoma treated at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between1996 and 2005. The records of 213 patients with endometrial carcinoma who had complete surgical staging were reviewed. A particular focus was on clinically early-stage disease. Clinical staging could be determined in 206 patients. Of the 206 patients, 182 (88.3%) presented with clinical stage I disease. However, only 142 (78%) of these patients were confirmed as surgical stage I and 22% were upstaged. Preoperative histologic grade was diagnosed inaccurately in 15.9% of patients and 7.7% were upgraded. Of patients with preoperative histologic grade 1, 33% had deep myometrial invasion, 8.2% had pelvic node metastasis, and 3.3% had para-aortic node metastasis. Even in clinical stage IaG1, pelvic node metastasis occurred in 5.6% and para-aortic node metastasis in 1.3%. It has been suggested that complete surgical staging may not be necessary in patients with low-risk endometrial carcinoma who have disease limited to the uterus without grade 3 or deep myometrial invasion. However, proper selection of such low-risk patients remains problematic. In situations where there is limited preoperative and intraoperative assessment of high-risk factors, particularly radiographic imaging and frozen section assessment, the role of complete surgical staging is beneficial.

Entire genome characterization of human papillomavirus type 16 from infected Thai women with different cytological findings

Global prevalence of human papillomavirus type 16 (HPV16) exceeds that of other types. This project has been aimed at attaining basic molecular knowledge of HPV16 by sequencing the whole genome of HPV16 isolated from Thai women at various clinical stages of disease progression. Our group analyzed seven samples of HPV16 in infected women ranging from normal to cervical cancer and discovered two critical non-synonymous changes within the coding region converting the E2-219P prototype to E2-219T in cervical cancer and the L2-269S prototype to L2-269D in CIN III, respectively. Phylogenetic analysis based on the whole genome with special emphasis on the genes E2, E6, L1, and L2 showed the Thai samples to be more closely related to the European than the non-European strains. The vaccine strain’s L1 polypeptides showed close relationship to our samples. The results provide basic data for future research on cervical cancer pathogenesis and representative data of HPV16 genome in Southeast Asia.

Comparison of Perioperative and Oncologic Outcomes with Laparotomy, and Laparoscopic or Robotic Surgery for Women with Endometrial Cancer

PURPOSE To compare perioperative outcomes and oncologic outcomes in endometrial cancer patients treated with laparotomy, and laparoscopic or robotic surgery. MATERIALS AND METHODS Endometrial cancer patients who underwent primary surgery from January 2011 to December 2014 were retrospectively reviewed. Perioperative outcomes, including estimated blood loss (EBL), operation time, number of lymph nodes retrieved, and intra and postoperative complications, were reviewed. Recovery time, disease free survival (DFS) and overall survival (OS) were compared. RESULTS Of the total of 218 patients, 143 underwent laparotomy, 47 laparoscopy, and 28 robotic surgery. The laparotomy group had the highest EBL (300, 200, 200 ml, p<0.05) while the robotic group had the longest operative time (302 min) as compared with laparoscopy (180 min) and laparotomy (125 min) (p<0.05). Intra and postoperative complications were not different with any of the surgical approaches. No significant difference in number of lymph nodes retrieved was identified. The longest hospital stay was reported in the laparotomy group (four days) but there was no difference between the laparoscopy (three days) and robotic (three days) groups. Recovery was significantly faster in robotic group than laparotomy group (14 and 28 days, p=0.003). No significant difference in DFS and OS at 21 months of median follow up time was observed among the three groups. CONCLUSIONS Minimally invasive surgery has more favorable outcomes, including lower blood loss, shorter hospital stay, and faster recovery time than laparotomy. It also has equivalent perioperative complications and short term oncologic outcomes. MIS is feasible as an alternative option to surgery of endometrial cancer.

Acceptability of self-sampling HPV testing among Thai women for cervical cancer screening.

BACKGROUND Acceptability of self-sampling HPV testing is confirmed worldwide. However, some cultural differences may affect this question. Therefore, this study was conducted to evaluate the acceptability of self- sampling HPV testing in Thai women. MATERIALS AND METHODS One hundred women aged 30-65 years with an intact cervix were included in this study. The participants were asked to do the Pap test by physicians and then brush type self-sampling instruments were assigned for self-collection and finally completed a questionnaire for acceptability evaluation. The questionnaire contains 2 parts. Part one covered general information of the participants and part two is the acceptability questions. RESULTS Mean age was 40.6 years. The incidence of high risk HPV detection in this study was 16%. The most common reason for doing Pap smear was for annual checkup. On the topic of ease of use, 85 % of the subjects agreed. Most of the participants (82%) reported that they felt less pain. However, reliability of the result was not satisfactory because 37% of the participants hesitated to rely on the results of the test. According to the price, if the price is less than 1,000 Baht (32.59 Baht = 1USD), 82% of the subjects would use it for their next screening. CONCLUSIONS The acceptability of self-sampling device in this study is quite good but the reliability of the test was questioned by some of the participants. Moreover, the price of the test in Thailand may also influence the acceptability of the test.

Whole-genome sequence analysis of human papillomavirus type 18 from infected Thai women.

Objective: The aim of this study was to attain molecular knowledge of human papillomavirus type 18 (HPV18) by sequencing the whole genome of HPV18 isolated from Thai women at various clinical stages of disease progression. Method: Our group analyzed 9 samples of whole-genome HPV18 in infected women ranging from normal to cervical cancer by PCR, a sequencing method and bioinformatics programs. Results: Phylogenetic analysis based on the whole genome showed that HPV18 samples were more closely related to the European and Asian-American type than the African type. The vaccine strain’s L1 nucleotide (US patent 5820870) showed a close relationship to the African type. However, our data cannot indicate the correlation between cytological data and nucleotide or amino acid variation. Conclusion: Our group cannot draw any inference between the clinical stage of disease progression and amino acid alterations as there were only 1 or 2 samples available for each clinical trial. However, we hope that these new data on the HPV genome, which are representative of the entire genome of HPV in Southeast Asia, can serve as basis data for future research on the pathogenesis of cervical cancer. Additionally, the second-generation HPV18 vaccines should be tested on both HPV18-L1 and HPV18-L2 for increasing potential protection.