Anti-tumor activity of histone deacetylase inhibitors and the effect on ATP-binding cassette in ovarian carcinoma cells.

INTRODUCTION: Ovarian cancer is of worldwide importance, and has a significantly high mortality rate due to therapy failure. Drug resistance might be one of most importance factors. Histone deacetylase inhibitors (HDACi) have been reported to be a new class of promising anti-tumor agents, thus this study aimed to investigate the effect of HDAC on the chemo-resistance genes of human ovarian carcinoma cell lines. METHODS: The expressions of ATP binding cassette (ABC) transporter genes, multidrug-resistant protein (MDR1) and multidrug resistance-associated proteins (MRP1 and 2) of ovarian cancer cell lines OC-109 and SK-OV-3 after HDACi treatment were determined. RESULTS: HDACi, including sodium butyrate (NaB), suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) reduced ovarian cancer cell viability from 4.4% to 68.8%, in both dose- and time-dependent manners. The effect of HDACi on MDR1, MRP1, and MRP2 showed induced expression of MDR1 mRNA, but reduced mRNA expression of MRP1 and MRP2. CONCLUSIONS: The effect of HDACi on the reduced viability of ovarian cancer cell lines, concomitant with the induced expression of MDR1 and reduced expression of MRP1 and 2, might provide additional benefits in the management of ovarian cancers in the future.

Whole-body positron emission tomography with 18F-fluorodeoxyglucose is an effective method to detect extra-pelvic recurrence in uterine sarcomas.

PURPOSE OF INVESTIGATION: To assess the clinical use of F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in the post-therapy surveillance of uterine sarcoma. METHODS: Eight whole-body FDG-PET studies were performed in seven women with previously treated uterine sarcoma. Conventional image studies (computed tomography) and physical examinations were performed for follow-up. All FDG-PET studies were indicated to localize suspected recurrences noted by conventional methods. RESULTS: The per case sensitivity of the FDG-PET studies and CT scans was 85.7% (6/7) and 100% (7/7), respectively (p = 0.174). FDG-PET was able to detect seven extrapelvic metastastic sites below the diaphragm (7/7, sensitivity: 100%), including the liver, spleen, paraaortic lymph node, spine and paracolic gutter, as well as pulmonary lesions in five patients, while the CT scan detected only three lesions (3/7, sensitivity: 42.9%; p = 0.070). FDG-PET detected only four recurrent pelvic lesions (4/6) and CT scan detected six (6/6) recurrent pelvic lesions (66.7% vs 100%, p = 0.455). CONCLUSIONS: The FDG-PET showed a better detection rate than the abdominal CT scan for extrapelvic metastatic lesions and a similar detection rate as well as abdominal CT scan. FDG-PET can serve as a useful detection tool for patients with uterine sarcomas because nearly 80% of recurrence involve an extrapelvic site.

Potential role of preoperative serum CA125 for the differential diagnosis between uterine leiomyoma and uterine leiomyosarcoma.

PURPOSE: Most comparisons between uterine leiomyoma and uterine leiomyosarcoma have been based on postoperative pathological or molecular analyses. Very few reports have investigated preoperative differentiation between uterine leiomyoma and uterine leiomyosarcoma. METHODS: Between January 1990 and December 2003, 42 consecutive patients with uterine leiomyosarcoma treated at index hospitals were analyzed. Meanwhile, 84 patients with uterine leiomyomas were used as controls. The diagnostic performance of preoperative serum CA125 for the differential diagnosis between uterine leiomyoma and uterine leiomyosarcoma using receiver operating characteristic (ROC) curves was evaluated. Data presentations were categorized into premenopausal and postmenopausal groups. Diagnostic efficiency was calculated as the sensitivity multiplied by the specificity. RESULTS: Values of preoperative serum CA125 were significantly higher in the uterine leiomyosarcoma group than those in the uterine leiomyoma group. There was significant overlapping of preoperative serum CA125 between the uterine leiomyoma group and early-stage uterine leiomyosarcoma. For both the premenopausal and postmenopausal group, there was a significant difference in the distribution of preoperative serum CA125 in early-stage and advanced-stage uterine leiomyosarcoma. The optimal cutoff values of serum CA125 for the premenopausal group and postmenopausal group was 162 U/mL and 75 U/mL, respectively. CONCLUSION: These findings demonstrated that preoperative serum CA125 had a potential role in the differential diagnosis between early-stage and advanced-stage uterine leiomyosarcoma. Further investigation with a larger sample size at adequate power is necessary to verify the current study.

Randomized trial of epirubicin and cisplatin chemotherapy followed by pelvic radiation in locally advanced cervical cancer. Cervical Cancer Study Group of the Asian Oceanian Clinical Oncology Association.

PURPOSE: Pelvic radiation is standard treatment for women with stage IIb to IVa cervical cancer, but treatment results are disappointing, particularly for women with bulky tumors. We investigated the role of primary chemotherapy followed by pelvic radiotherapy in a randomized trial. PATIENTS AND METHODS: Two hundred sixty patients with stage IIb and IVa cervical cancer received either standard pelvic radiotherapy or primary chemotherapy with cisplatin 60 mg/m2 and epirubicin 110 mg/m2 administered at 3-week intervals for three cycles, followed by pelvic radiotherapy. RESULTS: Ninety-nine patients have relapsed with a median follow-up duration of 1.3 years; in 62 patients, the first site of progressive disease was the pelvis. Patients who received primary chemotherapy had a significantly higher pelvic failure rate than those who received radiotherapy alone (P < .003). Seventy-six patients have died, and those who received primary chemotherapy had significantly inferior survival compared with those who received radiotherapy alone (P = .02). Tumor response following chemotherapy was observed in 63%. After radiotherapy, tumor response occurred in 72% of those who received combined modality treatment, compared with 92% of those who received radiotherapy alone. CONCLUSION: Primary chemotherapy with epirubicin and cisplatin, although resulting in tumor response in a significant proportion of patients, is accompanied by an inferior local control rate and survival compared with standard pelvic radiotherapy alone.

Radical hysterectomy: past, present, and future.

After an analysis of 3,441 radical hysterectomies performed in our department, we found, after modification of the operative technique in 1983, the more lateral the excision the less the recurrence rate. The recurrence rate for Stage 1b-2a and Stage 2b patients comparing the years before 1983 to the years after decreased to 12.4% from 15.7% (158/1,006 vs 268/2,163; p = 0.009) in Stage 1b-2a and 24.6% from 55.8% (38/68 vs 47/191; p = 0.0007) in Stage 2b, respectively. With the modern trend of aspiring for an easier lifestyle, most physicians practice earlier. Therefore only very few physicians study radical hysterectomy. As the skill of surgery needs a longer period of education and training, it may only interest physicians who work with medical professionals as part of a team at a medical center. In the future, we should provide gynecological residents not only with a training program using the classic textbooks, but also with different points of view on changes and developments in radical hysterectomy. We hope to promote an attitude of offering patients access to different choices and opportunities of therapy. Radical hysterectomy is in fact a treatment option for patients with bulky cervical lesions and Stage 2b in particular.

Ovarian metastasis from cervical carcinoma.

OBJECTIVE: To study the prognosis and metastatic route of cervical carcinoma with ovarian metastasis. METHOD: From 1980 to 1993, 10 of the 1507 patients with cervical carcinoma operated and who had ovarian metastasis were analyzed. RESULTS: Six patients had squamous cell carcinomas and 4 patients had adenocarcinomas. Their mean age was 45 years. Six of 9 patients undergoing pelvic lymphadenectomy had nodal metastasis. One patient did not have nodal dissection in the treatment course. Five of 10 patients had involvement of corpus: 3 were accompanied with nodal metastasis, 1 was not and 1 other was unknown. None of our cases survived more than 5 years. Their mean survival time was 20.8 months for squamous cell carcinomas and 29 months for adenocarcinomas. CONCLUSIONS: (1) Ovarian metastasis is histologically one of the ominous signs of cervical carcinomas regardless of stage. The prognosis of patients with ovarian metastasis from cervical squamous cell carcinoma from our data is not different from those from cervical adenocarcinoma. (2) Lymphatic spread and transtubal implantation are possible pathways of cervical cancer metastasizing to ovary, and involvement of the corpus may potentiate this mechanism.

Parametrial tumor spreading patterns in cervix cancer patients treated by radical hysterectomy.

OBJECTIVES: To evaluate tumor-spreading patterns in the parametrium. METHODS: We conducted a prospective clinical trial between January 1998 and December 2000 to define a new method for parametrium evaluation. The parametrium was divided into three areas, paracorpus, paracervix, and paravagina. A total of 284 consecutive patients with FIGO stage IB to IIA cervical cancer who had undergone radical hysterectomy were considered for the study. RESULTS: Of the 262 patients who were found eligible for evaluation, 135 had histopathologic analysis performed according to the new method and 127 with the traditional method. The detection of rate of parametrial invasion was 36 (26.7%) with the new and 13 (10.2%) with the traditional method (P=0.0014). The frequency of pelvic lymph node metastasis was 66.7% in patients who had tested positive for invasion of the paracorpus, 57.7% in those who had tested positive for invasion of the paracervix, and 71.4% in those who had tested positive for invasion of the paravagina. The frequency of pelvic lymph node metastasis in patients who had tested negative for invasion of the paracorpus, paracervix, or paravagina was 4.0%. Tumor cells tend to spread laterally and inferiorly in the parametrium. CONCLUSIONS: Using our classification of three parametrium areas for histologic examination can increase the detection rates of parametrial tumor invasion and help prevent failure of local treatment by allowing to implement appropriate adjuvant therapy.

Modified pelvic anterior exenteration.

During a 20-year time period, 117 patients with various histologic types of cancer underwent pelvic exentereation. Six of the 107 patients who needed anterior exenteration with urinary diversion received partial excision of the urinary bladder and modification surgery, of which three had uretero-cystostomy, two had mobilization of bladder and uretero-cystostomy and one had uretero-uterostomy. These six patients, except for two, died of disease in 1 year. Two patients are alive and happy, with quality of life because they can urinate normally. We suggest that anterior exenteration should be modified whenever possible to preserve the bladder and not to do an urinary diversion.

Prognosis-predicting system based on factors related to survival of cervical carcinoma.

OBJECTIVE: To establish a different category system based on grouping of the risk factors in patients with cervical smear. METHODS: Univariate and multivariate analyses of factors associated with survival time were performed in 443 patients with stage Ib-IIa squamous cell carcinoma (SCC) from 1985 to 1989. RESULTS: Univariate analysis showed that parametrial extension, bulky tumor size (> or = 4 cm), uterine body involvement, poor differentiation and pelvic lymph node (LN) metastasis were prognostically significant. However, by multiple regression method, only LN metastasis, deep stromal invasion (DSI), and poor differentiation (PD) were significantly related to the patient's survival time with risk ratios of 2.78, 2.61 and 1.52, respectively. A prognosis-predicting system was established on the basis of these simplified factors: groups of high, intermediate, low and very low-risks, obtained survival rates of 93-96%, 77%, 51% and 25-37%, respectively. CONCLUSIONS: Using this simple model, cervical carcinomas can be classified prognostically for predicting 5-year-survival rates, and for risk-guided therapy in the future.

Intraperitoneal cisplatin-based chemotherapy vs. intravenous cisplatin-based chemotherapy for stage III optimally cytoreduced epithelial ovarian cancer.

OBJECTIVE: To compare the survival between intraperitoneal cisplatin-based chemotherapy (IPCT) and intravenous cisplatin-based chemotherapy (IVCT) in stage III epithelial ovarian cancer with minimal residual disease (<1 cm) after primary debulking surgery. METHOD: One hundred and thirty-two patients with stage III epithelial ovarian cancer after optimal primary debulking surgery with minimal residual disease between April 1990 and March 1995 were entered into a randomized clinical trial in which IPCT or IVCT was administered at 3-week intervals. Patients in the IPCT arm received cisplatin-based (100 mg/m(2)) intraperitoneal chemotherapy. Patients in the IVCT arm received cisplatin-based (50 mg/m(2)) intravenous chemotherapy. The tumor response was assessed every 3 months. The hematological toxicity using the South West Oncology Group (SWOG) toxicity criteria was assessed. Catheter complications associated with intraperitoneal chemotherapy were also analyzed. RESULT: The estimated median survival in the IPCT group was 43 months (95% confidence interval, 34-54) and IVCT group was 48 months (95% confidence interval, 37-59). The hazard ratio of death was not statistically significant between IPCT and IVCT (hazard ratio, 1.13; 95% CI, 0.69-1.86; P=0.317). The frequencies of hematological toxic effects were significantly lower in the IPCT group than in the IVCT group. CONCLUSION: Intravenous and intraperitoneal chemotherapy are associated with equivalent survival in patients with minimal residual stage III epithelial ovarian cancer after optimal cytoreductive surgery.

Squamous cell carcinoma of the cervix after laparoscopic surgery. A case report.

BACKGROUND: Although more than 50 cases of recurrence at the sites of cannula insertion after laparoscopy for malignant tumors have been reported in the literature, the majority were adenocarcinoma. We report a case of intraperitoneal carcinomatosis and abdominal wall metastases of the trocar site after laparoscopically assisted radical vaginal hysterectomy for the treatment of squamous cell carcinoma of the cervix. CASE: A 47-year-old woman underwent curative, laparoscopically assisted radical vaginal hysterectomy and pelvic lymphadenectomy for treating squamous cell carcinoma of the cervix, stage IB. The postoperative course was uneventful until two months later when abdominal recurrences at the trocar site and diffuse peritoneal carcinomatosis were noted. Pathology proved recurrent intraperitoneal squamous cell carcinoma with invasion of the abdominal port site. CONCLUSION: This case further alerts gynecologic oncologists of the potential risks of laparoscopic surgery for potentially curable gynecologic malignancies.

Detection of HPV infection by analyzing the changes in structure of peripheral blood lymphocytes specifically induced by HPV E7 antigen.

PURPOSE: Detection of human papilloma virus (HPV) infection in clinical practice was examined based on the observation that peripheral blood lymphocytes exposed in vitro to antigenic or mitogenic stimulation change their intracellular structures as measured by polarization of fluorescent light emitted by labeled cells. MATERIALS AND METHODS: A total of 47 women were enrolled in this study. They were classified into four groups based on the results of HPV-DNA detection in cervical tissues by the Hybrid Capture II kit (Digene, Gaithersburg, MD, USA) and pathological examination. Ten women with no HPV-DNA detection were used as a normal control group. Fifteen women without pathological diagnosis in the cervical tissues had HPV-DNA detection. Ten women with CIN lesions had 80% HPV-DNA detection. Twelve women with invasive squamous cell carcinoma had 100% HPV detection. Peripheral blood lymphocytes derived from all women were collected and then exposed to HPV-E7 antigen and PHA mitogen. RESULTS: The positive response rate of HPV-E7 antigen was ten percent (1/10) in the normal control group, 73.3% (11/15) in the HPV infectious women, 50% (5/10) in the CIN women, and 91.7% (11/12) in the cervical cancer patients. The overall sensitivity rate of blood tests was 77.1% and the specificity rate was 57.8% when the Hybrid Capture II HPV Test kit was used as the standard detection method for cervical tissue. CONCLUSIONS: The results showed that peripheral blood lymphocytes derived from patients with cervical lesions might be another choice to be used as a screening method to detect HPV infection compared with conventional methods.

Extramammary Paget's disease found by abnormal vulvar brush sampling.

INTRODUCTION: Doctors are usually reluctant to perform a vulvar biopsy on a patient with non-specific chronic vulvitis--especially because of the rarity of vulvar malignancy in young women--until the lesion is suspected of being malignant. Therefore, most cases of extramammary Paget's disease (EMPD) were originally misdiagnosed as chronic and recurrent vulvar lesions. Late diagnosis of invasive lesions occurring in elderly females have resulted in cases of death. CASE: A 37-year-old patient showed an extended lesion on the vulva and perineum. In addition, abnormal cells were found from a vulvar scrape smear, and a following punch biopsy was used to diagnose and determine the extension of the disease. CONCLUSION: Diagnosis and demarcation of EMPD remain difficult due to the multifocal lesions and subtle nature of the disease. Brush sampling taken from suspicious areas can be a guide for multiple biopsies to demarcate the lesion before major surgery. A brush biopsy is presented as a first-step method to detect vulvar malignancy.

Intraperitoneal cancer spread after laparoscopic cystectomy for mature teratoma with malignant transformation.

Laparoscopic surgery for ovarian dermoid cysts has been accepted. However, its potential limitations should be considered, including technique difficulty, intraoperative tumor spillage and malignant transformation. We report a case of ovarian dermoid cysts with malignant transformation that was initially treated using laparoscopic cystectomy, but was complicated by intraperitoneal tumor dissemination.

Primary epithelial ovarian carcinoma in Taiwanese women.

PURPOSE OF INVESTIGATION: Primary epithelial ovarian carcinoma is common in industrial countries but rare in the Orient. In fact, it is still a rare disease in Taiwan. In this article, we report the general data of Taiwanese patients with primary epithelial ovarian carcinoma. METHODS: In this retrospective study we used univariate and multivariate analysis models to analyze the prognosis of patients with surgically confirmed primary epithelial ovarian carcinoma. One hundred and ninety-four patients from 1990 to 1996 were identified and enrolled in this study. RESULTS: The mean follow-up time was 44.7 months with an interval between 15.1 months and 105.9 months. Univariate analysis showed postmenopausal status, advanced stage, presence of lymph node metastasis, poor differentiation, and suboptimal surgery as risk factors for disease recurrence and subsequent deaths. Multivariate analysis demonstrated stage as the most important factor correlated with recurrent disease (risk ratio: 7.303 and 5.409, respectively), followed by optimal surgery (RR: 2.447), and cellular differentiation (RR: 1.677). CONCLUSIONS: Our data on the Taiwan population were consistent with other reports of different races. Early detection for primary epithelial ovarian cancer is of great importance because stage is still the most important predictor in disease-free survival and disease-related deaths. Application of the most reliable and acceptable methods of screening is our goal in the next century after weighing benefits over costs.

Identifying local tumor variables for operable node-negative, margin-free patients with bulky cervical carcinoma of FIGO stage IB, IIA and IIB without adjuvant therapies.

PURPOSE: To identify local risk factors for FIGO IB, IIA and IIB bulky cervical squamous cell carcinoma (tumor size > or = 4 cm) patients with node-negative, margin-free tumors treated by radical hysterectomy, pelvic lymph node and para-aortic lymph node dissections without adjuvant therapies. MATERIALS AND METHODS: Thirty-four patients were recruited between 1976 and 1989 because they all declined any postoperative adjuvant therapy. The pathology reports showed that all the specimen margins were free from cancer cells with no para-aortic or pelvic lymph node metastases. The survival interval was calculated starting from the time of surgical intervention to the time of death or the end of this study in the year 2000. RESULT: Tumor variables including cell differentiation, depth of stromal invasion, parametrial invasion, vaginal invasion, uterine body invasion, age, and FIGO stage were analyzed. Only vaginal invasion showed statistical significance for decreasing patient disease-free survival in both univariate and multivariate analyses with p values of 0.003 and 0.002, respectively. CONCLUSION: For node-negative and margin-free patients with bulky cervical squamous cell carcinoma with operable stage IB and IIB, surgical intervention alone could suffice when no vaginal invasion is noted plus an 85% survival rate could be achieved. A prospective pilot study should be initiated although this study showed an excellent survival rate which is perhaps due to the limited number of cases.

Improved early detection of cervical intraepithelial lesions by combination of conventional Pap smear and speculoscopy.

PURPOSE: To evaluate the efficacy of the addition of speculoscopy to a Pap smear in cervical cancer screening. METHODS: All women were screened using the Pap smear plus speculoscopy (PapSure) and colposcopy in the multicenter trial. The final diagnosis of each patient was based on a histological evaluation of the colposcopic target biopsy. Results were analyzed using a proportional compare test, sensitivity, specificity and predictive value with significant value determined at less than 0.05. RESULTS: Of 1,717 eligible cases, 26 cases had LGSIL and 16 cases had HGSIL. Of the Pap smears, five cases had LSIL and 14 cases had HGSIL. Of the combination of the PapSure, 23 cases had LGSIL and 16 cases had HGSIL. The sensitivity of the Pap smear to that of PapSure was calculated at 45.2% and 92.9%, respectively (p < 0.001). The estimated cost to detect a cervical lesion using PapSure is less than that of the Pap smear. CONCLUSION: The addition of speculoscopy along with a Pap smear screening results in early detection of cervical lesions in comparison to the Pap smear alone. This screening combination is also more cost-effective and requires fewer visits to the clinic in comparison to a Pap smear screening alone.

Persistence of renal nerve and spinal reflex activities and visceral motility after asphyxial anoxia.

Phrenic and renal nerves activities, spinal reflex (knee jerk and the evoked monosynaptic reflex response from the 5th lumbar ventral root), motility of the stomach, duodenum, jejunum and colon, and motility of urinary bladder during and after the lethal asphyxia were studied in cats under intraperitoneal urethane (400 mg/kg) and chloralose (40 mg/kg) anesthesia. Asphyxial anoxia produced one or two peaks of elevation of systemic arterial pressure (SAP) followed by a progressive decrease of SAP and narrowing of pulse pressure and eventual complete cardiovascular arrest. The phrenic nerve activity increased markedly during the final asphyxial SAP elevation; it then decreased along with the decline of SAP and ceased permanently when the SAP reached about 50 mmHg. The renal nerve activity increased along with each phase of pressure elevation. During the terminal stage of progressive SAP fall, the renal nerve activity fluctuated up and down 2-3 times before the SAP dropped to zero, and the activity persisted for an average of 202 sec thereafter. Data suggest that the motoneurons of the phrenic nerve in the cervical spinal cord and medulla oblongata are more vulnerable to asphyxia than the motoneurons responsible for the spinal reflex in the pathway from medulla, the intermediolateral column of the spinal cord and the celiac ganglion. During anoxia, the lumbar spinal reflex showed an initial inhibition then potentiation afterward. Even after the SAP had reached zero, the spinal reflex could still be elicited for one to a few minutes. This suggests that the spinal cord can function sometime after complete cardiac arrest subsequent to asphyxia. The motility of the stomach, duodenum, jejunum, colon and urinary bladder usually decreased during the period of pressure elevation. However, the activity was enhanced during the terminal stage of pressure decline. The enhancement of the colon and bladder motility, spasmodic in nature, was particularly prominent, more so than the others. After complete cardiovascular arrest, the motility of the above viscera became temporary quiescent but about 10 minutes later, it resumed activity again with an enhancement of action in some of the animals. The motility, persisted from few minutes to over six hours. These phenomena indicate that despite a complete deprivation of circulatory and respiratory supports, or death of the animal, the viscera can still contract for a certain period of time.