Drug-induced inactivation or gene silencing of class I histone deacetylases suppresses ovarian cancer cell growth: implications for therapy

There is an urgent need to develop new strategies to treat ovarian cancer, the most deadly gynecologic malignancy. Histone deacetylase (HDAC) inhibitors are emerging as novel therapeutic drugs in the treatment of a variety of cancers, including those resistant to standard chemotherapy. Since there are multiple HDAC isoforms, determining the precise role of individual HDAC isoenzymes in the growth and progression of ovarian cancer has the potential to influence the use of selective HDAC inhibitors as strategic therapeutic agents that elicit fewer undesirable side effects. Unfortunately, there is limited information about the expression of HDAC isoforms in human ovarian tissues. This report provides evidence for the first time that Class I HDACs are expressed at significantly higher levels in ovarian cancers in comparison to normal ovarian tissues, with no significant difference in Class II HDAC expression between the two groups. Furthermore, ovarian cancer cells are far more sensitive than normal ovarian cells to the potent HDAC inhibitor romidepsin (FK228), a drug that displays greater inhibitory selectivity for Class I HDACs over Class II isoforms. Using small interfering RNA (siRNA) methodology, we demonstrate that knocking down the gene expression of HDAC3 and other members of the Class I HDAC family suppresses ovarian cancer cell growth. Taken together, the present studies offer several novel findings that have direct relevance for the strategic use of inhibitors that target Class I HDACs, particularly HDAC3, in the treatment of ovarian cancer.     

Coordinate patterns of estrogen receptor,progesterone receptor,and Wilms tumor 1 expression in the histopathologic distinction of ovarian from endometrial serous adenocarcinomas

The purpose of this study is to assess whether composite or coordinate immunoexpression patterns of estrogen receptor (ER), progesterone receptor (PR), and Wilms tumor 1 (WT1) gene can significantly distinguish between endometrial serous carcinoma (ESC) and ovarian serous carcinoma (OSC). Immunohistochemical analyses were performed on whole tissue sections from 22 uterus-confined ESCs and on a tissue microarray of 140 high-grade, pan-stage OSCs, using antibodies to ER, PR, and WT-1. Estrogen receptor, PR, and WT1 expressions were present in 37%, 49%, and 81% of OSC, respectively, but these markers were also present in 18%, 27%, and 36% of ESC. The ER+/PR+/WT1+ coordinate profile was identified in 33.6% of OSC but in none of ESC (P = .0006), resulting in a calculated sensitivity and specificity of this profile for OSC of 33.6% and 100%, respectively. By contrast, the ER?/PR?/WT1? coordinate profile was identified in 41% of ESC but in only 6.4% of OSC (P = .0001), resulting in a calculated sensitivity and specificity of this profile for ESC of 50% and 94%. In summary, in the differential diagnosis between OSC and ESC, positivity for all 3 markers favors an extrauterine origin, whereas negativity for all 3 markers is supportive of an endometrial origin. The use of single markers for this purpose is not recommended, as each lacks optimal discriminatory power. Coordinate profiles, in general, have a high specificity but low sensitivity in this differential diagnosis.     

Evaluation of generic medical information accessed via mobile phones at the point of care in resource-limited settings

Objective

Many mobile phone resources have been developed to increase access to health education in the developing world, yet few studies have compared these resources or quantified their performance in a resource-limited setting. This study aims to compare the performance of resident physicians in answering clinical scenarios using PubMed abstracts accessed via the PubMed for Handhelds (PubMed4Hh) website versus medical/drug reference applications (Medical Apps) accessed via software on the mobile phone.

Methods

A two-arm comparative study with crossover design was conducted. Subjects, who were resident physicians at the University of Botswana, completed eight scenarios, each with multi-part questions. The primary outcome was a grade for each question. The primary independent variable was the intervention arm and other independent variables included residency and question.

Results

Within each question type there were significant differences in ‘percentage correct’ between Medical Apps and PubMed4Hh for three of the six types of questions: drug-related, diagnosis/definitions, and treatment/management. Within each of these question types, Medical Apps had a higher percentage of fully correct responses than PubMed4Hh (63% vs 13%, 33% vs 12%, and 41% vs 13%, respectively). PubMed4Hh performed better for epidemiologic questions.

Conclusions

While mobile access to primary literature remains important and serves an information niche, mobile applications with condensed content may be more appropriate for point-of-care information needs. Further research is required to examine the specific information needs of clinicians in resource-limited settings and to evaluate the appropriateness of current resources in bridging location- and context-specific information gaps.     

Patterns of failure after the multimodality treatment of uterine papillary serous carcinoma

PURPOSE: Uterine papillary serous carcinoma (UPSC) is an aggressive variant of endometrial carcinoma. The majority of patients with clinical Stage I UPSC are found to have extrauterine disease at the time of surgery. Most authors report survival rates of 35-50% for Stage I-II and 0-15% for Stage III and IV UPSC. Surgical treatment as the sole therapy for patients with Stage I-IV UPSC is unacceptable because of high recurrence rates. Chemotherapy, radiotherapy, or both have been added after surgery in an attempt to improve survival. However, the survival benefit to patients from such multimodality therapy remains uncertain. This study analyzes the patterns of failure in patients with FIGO Stages I-IV UPSC treated by multimodality therapy. METHODS AND MATERIALS: Forty-two women with FIGO Stages I-IV UPSC who were treated by multimodality therapy were analyzed retrospectively between 1988 and 1998. Data were obtained from tumor registry, hospital, and radiotherapy chart reviews, operative notes, pathology, and chemotherapy flow sheets. All the patients underwent staging laparotomy, peritoneal cytology, total abdominal hysterectomy and salpingo oophorectomy, pelvic and para-aortic lymph node sampling, omentectomy, and cytoreductive surgery, when indicated followed by radiotherapy and/or chemotherapy. Therapy consisted of external beam radiation therapy in 11 patients (26%), systemic chemotherapy in 20 (48%), and both radiotherapy and chemotherapy in 11 (26%). The treatments were not assigned in a randomized fashion. The dose of external beam radiation therapy ranged from 45-50.40 Gy (median 45). Of the 31 patients (74%) who received chemotherapy, 18 received single-agent (58%), whereas 13 received multiagent chemotherapy (42%). RESULTS: Median follow-up for all patients was 19 months (range 4-72). Median follow-up for the surviving patients was 36 months (range 21-72). Their median age was 65 years. Six patients (14%) had Stage I, 8 patients (19%) had Stage II, 10 (24%) had Stage III, and 18 (43%) had Stage IV disease. Twenty-nine patients (69%) had suffered recurrence at the time of last follow-up. The actuarial failure rate at 2 and 5 years was 58% and 67%, respectively. The majority of the patients (19/29) recurred in the abdomen, vagina, or pelvis (66%). Metastases outside the abdomen were much less common as the first site of failure (17%). Twenty-five patients (60%) had died at the time of reporting; the observed survival rate at 2 years and 5 years was 52% and 43%, respectively. CONCLUSIONS: Our data suggest that, after multimodality therapy of FIGO Stage I-IV UPSC, most patients developed abdominopelvic (locoregional) failure, and the great majority of the failures occurred in the abdomen, vagina, and pelvis (66%). Abdominopelvic failure as a component of distant failure occurred in an additional 5 patients (17%). Distant failure alone occurred in 17% of the patients.We propose that future studies should combine whole abdominal radiotherapy (WART) with pelvic and vaginal boosts, in addition to chemotherapy for FIGO Stage I-IV UPSC, especially in patients with minimal residual disease, to attempt to improve the dismal prognosis of patients with UPSC.     

Sensitivity of Raman spectroscopy to normal patient variability

Many groups have used Raman spectroscopy for diagnosing cervical dysplasia; however, there have been few studies looking at the effect of normal physiological variations on Raman spectra. We assess four patient variables that may affect normal Raman spectra: Race/ethnicity, body mass index (BMI), parity, and socioeconomic status. Raman spectra were acquired from a diverse population of 75 patients undergoing routine screening for cervical dysplasia. Classification of Raman spectra from patients with a normal cervix is performed using sparse multinomial logistic regression (SMLR) to determine if any of these variables has a significant effect. Results suggest that BMI and parity have the greatest impact, whereas race/ethnicity and socioeconomic status have a limited effect. Incorporating BMI and obstetric history into classification algorithms may increase sensitivity and specificity rates of disease classification using Raman spectroscopy. Studies are underway to assess the effect of these variables on disease.     

Evaluation of low-dose intraperitoneal interferon-alpha for palliation of ascites in patients with non-ovarian gynecologic malignancies

OBJECTIVE: Intraperitoneal interferon-alpha (IP-IFNalpha) has shown some benefit in the treatment of patients with ovarian cancer. Our goal was to evaluate the use of low-dose IP-IFNalpha for the palliative control of ascites in non-ovarian gynecologic malignancies, including primary peritoneal and uterine papillary serous carcinomas. METHODS: Fifteen patients with non-ovarian gynecologic malignancies received one or two doses of 10 MU (10 x 10(6) U/m(2)) of IP-IFNalpha via single-use drum catheter for the symptomatic control of ascites. The median age for this patient group was 61 years (range 40-84). Histopathologic diagnoses were confirmed on all patients. Eleven of 15 (73%) patients had uterine cancers. Four of 15 (27%) patients had papillary serous primary peritoneal carcinomas. Thirteen of 15 (87%) patients had Stage III disease or more. All patients had been heavily pretreated with chemotherapy and all had progressive disease. RESULTS: Specific parameters used to evaluate IP-IFNalpha were (1) median survival; (2) number of days to recurrent ascites; (3) number of subsequent paracenteses required for symptomatic relief; and (4) symptomatology and side effects. Median overall survival was 3 months (range 0.5-13). Seven of 15 (47%) patients survived >3 months. Twelve of 15 (80%) patients had recurrent ascites within 30 days of treatment. However, 3/15 (20%) patients had a prolonged, >30-day period, without symptomatic ascites. One patient (6%) had a 270-day response with no ascites. Toxicity was minimal from IP-IFNalpha infusion. The most common side effect was fever in 6/15 (40%) patients. CONCLUSION: IP-IFNalpha was well tolerated and may have some benefit in a subset of patients. Although 80% of patients had recurrent ascites within 30 days, 20% had a prolonged, >30-day response. Further study is warranted to determine the role of immune modulators, such as IP-IFNalpha, in the palliative management of patients with non-ovarian gynecologic malignancies that cause ascites.     

Ovarian volume measurements in mice with high-resolution ultrasonography.

OBJECTIVE: The aim of our study was to evaluate the intraobserver and interobserver variability of ovarian volume measurements in mice with high-resolution 2-dimensional ultrasonography (2DUS) and 3-dimensional ultrasonography (3DUS). METHODS: Ovaries of 10 nude mice were visualized with a small-animal ultrasound scanner and a 40-MHz probe. For each ovary, volume was measured 3 times by 2 independent readers using both 2DUS and 3DUS methods. The 2DUS method used a biplane ellipsoid model. The 3DUS method estimated the volume by integrating 10 to 12 parallel image planes of the ovary after semiautomated outlining of the boundaries. For each type of measurement, intraobserver and interobserver standard error of measurement (SEM) values and minimal detectable volume changes were calculated by analysis of variance. RESULTS: Two-dimensional ultrasonography showed much poorer reproducibility, with higher absolute intraobserver and interobserver SEM values (0.50 and 0.61 mm3, respectively) than 3DUS (0.20 and 0.35 mm3; P < .01). Relative intraobserver and interobserver SEM values were also much higher for 2DUS (12.20% and 14.88%) than for 3DUS (5.12% and 8.97%; P < .01). The minimal volume changes that could be detected with a 95% confidence level in successive measurements by the same (or different) observers were 33.90% (41.22%) for 2DUS and 14.10% (24.87%) for 3DUS. CONCLUSIONS: High-resolution 3DUS can provide a reliable tool for noninvasive, longitudinal ovarian volume measurements in mice.