Water-fat MRI for assessing changes in bone marrow composition due to radiation and chemotherapy in gynecologic cancer patients.

PURPOSE: To assess the feasibility of using fat-fraction imaging for measuring marrow composition changes over large regions in patients undergoing cancer therapy. MATERIALS AND METHODS: Thirteen women with gynecologic malignancies who were to receive radiation and/or chemotherapy were recruited for this study. Subjects were imaged on a 3T magnetic resonance (MR) scanner at baseline (after surgery but before radiation or chemotherapy), 6 months, and 12 months after treatment. Water-fat imaging was used to generate high-resolution, 3D signal fat fraction (sFF) maps extending from mid-femur to L3. Treatment changes were assessed by measuring marrow sFF in the L4 vertebra, femoral necks, and control tissues. RESULTS: Pretreatment and 6-month scans were compared in nine women. sFF increased significantly in both the L4 vertebral marrow (P = 0.04) and the femoral necks (P = 0.03), while no significant change was observed in control regions. Qualitatively, chemotherapy changes were more uniform in space, whereas the radiation-induced changes were largest in marrow regions inside and close to the target radiation field. CONCLUSION: Water-fat MRI is sensitive to changes in red/yellow marrow composition, and can be used for quantitative and qualitative assessment of treatment-induced marrow damage.

Predicting response to the anti-estrogen fulvestrant in recurrent ovarian cancer.

BACKGROUND: Anti-estrogen therapy appears to have efficacy in a subset of ovarian cancers, as demonstrated in multiple phase II studies. Identifying sensitive patients early in treatment may allow for targeted, low-toxicity primary therapy or prevention of recurrence. We have previously demonstrated that the likelihood of response to letrozole could be improved by patient selection based on estrogen-pathway marker expression. We sought to identify ovarian cancer biomarkers that might indicate sensitivity to fulvestrant, an estrogen receptor antagonist. METHODS: Tissue samples from the primary tumors of patients enrolled in a phase II study of fulvestrant for the treatment of multiply-recurrent ovarian cancer were embedded randomly in a tissue microarray (TMA). Estrogen receptor alpha (ERα) expression was assessed by both conventional immunohistochemistry (IHC) and quantitative immunofluorescence (IF) (AQUA) while expression of 14 other estrogen-regulated markers was assessed by quantitative IF and correlated with clinical outcomes. RESULTS: Almost half of patients experienced clinical benefit (CR+PR+SD) at 90 days despite a median of 5 previous treatment regimens. 24 of 26 patient samples were available and included in the TMA. ERα expression, measured either by conventional IHC or by AQUA analysis, was associated with clinical benefit, while TFF1 and vimentin expression (measured by IF AQUA score) was predictive of progression-free survival. CONCLUSIONS: These results confirm our previous observation that clinical ovarian cancer includes a subset of tumors with sensitivity to estrogen pathway blockade. Expression profile of sensitive tumors appears to be detectably different from insensitive tumors, suggesting that further improvements in treatment efficacy can be obtained through appropriate patient selection.

Hyperthermic intraperitoneal chemotherapy with carboplatin for optimally-cytoreduced, recurrent, platinum-sensitive ovarian carcinoma: a pilot study.

OBJECTIVE: We aimed to evaluate the feasibility and tolerability of hyperthermic intraperitoneal carboplatin (HIPEC-carboplatin) following secondary cytoreduction for recurrent, platinum-sensitive ovarian cancer. METHODS: In a single institution prospective, pilot study, ten patients underwent secondary cytoreductive surgery followed by HIPEC-carboplatin at 1000 mg/m(2). Consolidation (6 cycles) was with platinum-based regimens. Adverse and quality of life were measured throughout treatment. RESULTS: Twelve patients were enrolled of which 2 were excluded (one each for extra-abdominal disease indentified before surgery and suboptimal cytoreduction). All 10 remaining patients received prescribed HIPEC-carboplatin. There were no intra-operative complications or AEs attributable to HIPEC-therapy. Grade 1/2 nausea was the most common post-operative toxicity (6/10 patients). Two patients had grade 4 post-operative neutropenia and thrombocytopenia but only one experienced transient treatment delay. The median hospital stay was 5.5 days. 69/70 (98%) of planned chemotherapy doses were ultimately delivered with 1 patient electively forgoing her final treatment. At a median (range) follow-up of 16 (6-23) months, three patients have recurred at 8, 14, and 16 months from surgery. The median disease-free and overall survivals have not been reached. Fact-O scores were significantly lower following surgery (126 vs. 108, p<.01), but improved by completion of therapy (108 vs. 113, p=0.27). CONCLUSIONS: HIPEC-carboplatin at 1000 mg/m(2) following optimal cytoreduction for ovarian cancer is feasible. Surgical complications were not observed, and post-operative AEs were largely within expected ranges. Consolidation using standard platinum-based regimens was feasible following HIPEC-carboplatin, and preliminary survival data suggests efficacy. Further investigation of HIPEC-carboplatin in the setting of debulkable cancer recurrence is warranted.

Current understanding of risk factors for ovarian cancer.

OPINION STATEMENT: Ovarian cancer is the deadliest gynecologic cancer. Unlike many cancers such as breast, cervical and colon cancers, there is no easily clinically identifiable pre-malignant phase of this malignancy making early identification difficult. Similarly, unlike lung, head and neck, and skin cancers, there is not easily identifiable risk factor making prevention short of oophorectomy difficult. Even so, theories as to the causative factors of ovarian cancer continue to evolve making our understanding of the genesis of ovarian cancer more clear. Genetics, parity, environment, hormonal factors, and inflammation all play an important and pivotal role in the development of ovarian cancer. The most current understanding of these elements and their respective contribution to the development of this cancer are presented in this chapter.

Red Snappers and Red Herrings: Pelvic Tuberculosis Causing Elevated CA 125 and Mimicking Advanced Ovarian Cancer. A Case Report and Literature Review.

Female genital tuberculosis (FGTB) is a form of extra-pulmonary tuberculosis that has been primarily described in developing countries, where it is an important cause of infertility, ectopic pregnancy, and miscarriage. FGTB is rare in the United States and because its clinical presentation is non-specific and often insidious, FGTB may be misdiagnosed as a gynecologic malignancy or endometriosis. The tendency of tuberculosis to dramatically increase serum CA 125 levels contributes to the potential for FGTB to be mistaken for ovarian cancer in particular. We describe the case of a young woman who presented with what was initially thought to be advanced ovarian cancer but who had tuberculosis of the peritoneum, uterus, and ovaries discovered at laparotomy. This case emphasizes the importance of considering tuberculosis in the differential of any patient presenting with an abdomino-pelvic mass and an elevated CA 125 level.

Prevalence and management of abnormal pap smear in antenatal care clinic at Thammasat University Hospital.

OBJECTIVE: To investigate the prevalence of abnormal Papanicolaou smear in pregnant patients who attend the Antenatal Care Clinic at Thammasat University Hospital. MATERIAL AND METHOD: Pregnant patients who attended the antenatal care clinic at Thammasat University Hospital from August 2003 to December 2003 were recruited for Papanicolaou test. Patients who had abnormal results of equally or over "abnormal squamous/glandular cells of undetermined significance" were assigned for colposcopy and colposcopic biopsy to confirm the result. RESULTS: From 500 Papanicolaou smear performed, there were only four patients who had abnormal Pap tests, which were: 2 ASC-US and 2 LSIL. The prevalence of abnormal Pap smear in pregnant patients who attended the antenatal clinic at Thammasat University Hospital was 0.8 percent. CONCLUSION: The prevalence of abnormal Papanicolaou smear in pregnant patients attending antenatal care clinic at Thammasat University Hospital was quite low in compares with other literature.

A phase I feasibility study of multi-modality imaging assessing rapid expansion of marrow fat and decreased bone mineral density in cancer patients.

PURPOSE: Cancer survivors are at an increased risk for fractures, but lack of effective and economical biomarkers limits quantitative assessments of marrow fat (MF), bone mineral density (BMD) and their relation in response to cytotoxic cancer treatment. We report dual energy CT (DECT) imaging, commonly used for cancer diagnosis, treatment and surveillance, as a novel biomarker of MF and BMD. METHODS: We validated DECT in pre-clinical and phase I clinical trials and verified with water-fat MRI (WF-MRI), quantitative CT (QCT) and dual-energy X-ray absorptiometry (DXA). Basis material composition framework was validated using water and small-chain alcohols simulating different components of bone marrow. Histologic validation was achieved by measuring percent adipocyte in the cadaver vertebrae and compared with DECT and WF-MRI. For a phase I trial, sixteen patients with gynecologic malignancies (treated with oophorectomy, radiotherapy or chemotherapy) underwent DECT, QCT, WF-MRI and DXA before and 12months after treatment. BMD and MF percent and distribution were quantified in the lumbar vertebrae and the right femoral neck. RESULTS: Measured precision (3mg/cm(3)) was sufficient to distinguish test solutions. Adiposity in cadaver bone histology was highly correlated with MF measured using DECT and WF-MRI (r=0.80 and 0.77, respectively). In the clinical trial, DECT showed high overall correlation (r=0.77, 95% CI: 0.69, 0.83) with WF-MRI. MF increased significantly after treatment (p<0.002). Chemotherapy and radiation caused greater increases in MF than oophorectomy (p<0.032). L4 BMD decreased 14% by DECT, 20% by QCT, but only 5% by DXA (p<0.002 for all). At baseline, we observed a statistically significant inverse association between MF and BMD which was dramatically attenuated after treatment. CONCLUSION: Our study demonstrated that DECT, similar to WF-MRI, can accurately measure marrow adiposity. Both imaging modalities show rapid increase in MF following cancer treatment. Our results suggest that MF and BMD cannot be used interchangeably to monitor skeletal health following cancer therapy.

Method for obtaining primary ovarian cancer cells from solid specimens.

Reliable tools for investigating ovarian cancer initiation and progression are urgently needed. While the use of ovarian cancer cell lines remains a valuable tool for understanding ovarian cancer, their use has many limitations. These include the lack of heterogeneity and the plethora of genetic alterations associated with extended in vitro passaging. Here we describe a method that allows for rapid establishment of primary ovarian cancer cells form solid clinical specimens collected at the time of surgery. The method consists of subjecting clinical specimens to enzymatic digestion for 30 min. The isolated cell suspension is allowed to grow and can be used for downstream application including drug screening. The advantage of primary ovarian cancer cell lines over established ovarian cancer cell lines is that they are representative of the original specific clinical specimens they are derived from and can be derived from different sites whether primary or metastatic ovarian cancer.

Establishment, characterization and downstream application of primary ovarian cancer cells derived from solid tumors.

Ovarian cancer is the deadliest of the gynecological diseases and the fifth cause of cancer death among American women. This is mainly due to the lack of prognostic tools capable of detecting early stages of ovarian cancer and to the high rate of resistance to the current chemotherapeutic regimens. In this scenario the overall 5-year survival rate for ovarian cancer patients diagnosed at late stage is less than 25%. Abnormalities associated with the malignant phenotype and the mechanisms of tumor progression are not clearly understood. In vitro studies are necessary, yet have been hampered due to the limitations accompanied with the use of ovarian cancer cell lines and the heterogeneity of the ovarian cancer cell population derived from ascites fluids. In this study we present a simple, rapid and reproducible method for the isolation and characterization of ovarian cancer cells from solid tumor tissue and show that enzymatic digestion for 30 minutes with dispase II results in the most effective recovery of viable epithelial ovarian cancer (EOC) cells. The resulting cancer (EOC) cell preparations demonstrate a significant yield, high levels of viability and are fibroblast-free. They grow for up to six passages and retain the capacity of forming spheroids-like structures in agarose. In addition, they can be genetically manipulated and used for drug screening, thus rendering them highly suitable for downstream applications. Notably, isolation of ovarian cancer cells from solid specimens using this method has the advantage of allowing for isolation of cancer cells from early stages of ovarian cancer as well as obtaining cells from defined either primary and/or metastatic ovarian cancer sites. Thus, these cells are highly suitable for investigations aimed at understanding ovarian cancer.

Solitary fibrous tumors arising from the female pelvis.

BACKGROUND: Solitary fibrous tumor is a rare mesenchymal tumor reported initially in the pleura but that is now reported in widely ranging anatomic sites with a variable clinical course. Solitary fibrous tumor arising from the female genital tract is extremely rare and the management of this condition is controversial. CASES: We report three cases of female genital tract solitary fibrous tumors displaying different clinical behaviors and review literature with regard to diagnosis, possible prognostic factors, and management of this tumor. CONCLUSION: The primary treatment of this disease should be surgical. The rarity and disparate clinical manifestations of this disease preclude a definitive statement on use and optimization of adjuvant therapy. Nevertheless, both pathologic and clinical findings may be useful in gauging risk and assessing the merits of individualized adjuvant therapy.

Stressing the ubiquitin-proteasome system without 20S proteolytic inhibition selectively kills cervical cancer cells.

Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate, and for specific signaling pathways, notably HPV E6-targeted degradation of p53 and PDZ proteins. Natural compounds with antioxidant properties including flavonoids and triterpenoids hold promise as anticancer agents by interfering with ubiquitin-dependent protein degradation. An increasing body of evidence indicates that their α-ß unsaturated carbonyl system is the molecular determinant for inhibition of ubiquitin-mediated protein degradation up-stream of the catalytic sites of the 20S proteasome. Herein we report the identification and characterization of a new class of chalcone-based, potent and cell permeable chemical inhibitors of ubiquitin-dependent protein degradation, and a lead compound RAMB1. RAMB1 inhibits ubiquitin-dependent protein degradation without compromising the catalytic activities of the 20S proteasome, a mechanism distinct from that of Bortezomib. Treatment of cervical cancer cells with RAMB1 triggers unfolded protein responses, including aggresome formation and Hsp90 stabilization, and increases p53 steady state levels. RAMB1 treatment results in activation of lysosomal-dependent degradation pathways as a mechanism to compensate for increasing levels of poly-ubiquitin enriched toxic aggregates. Importantly, RAMB1 synergistically triggers cell death of cervical cancer cells when combined with the lysosome inhibitor Chloroquine.

Lack of prognostic significance of HER-2/neu in early epithelial ovarian cancer.

A total of 74 patients with apparent early stage epithelial ovarian cancer who underwent exploratory laparotomy at King Chulalongkorn Memorial Hospital or other hospitals and were referred for further treatment, were evaluated. Formalin fixed paraffin-embedded ovarian tissue specimens were collected and immuno-stained with HER-2/neu antibodies for comparison with clinicopathologic data after median follow up of 46 months (range 3 - 83 months). The prevalence of HER-2/neu overexpression in these patients was 10.2%. No significant correlation between HER-2/neu overexpression and clinicopathological parameters (stage, ascites, capsular rupture, capsular adherence, histological subtype and histological grade) was found. Disease free survival and overall survival did not statistically differ between those with lesions positive or negative for HER-2/neu overexpression.

Ovarian teratoma with diffused peritoneal reactions mimicking advanced ovarian malignancy.

BACKGROUND: Benign cystic teratomas are one of the most common benign ovarian neoplasms. Although its rupture is rare, once occurred it can cause complications such as granulomatous peritonitis, mimicking metastatic ovarian malignancy. CASE: A 39-year-old woman, Para 0-0-0-0, presented to the hospital with rapid abdominal distention for 3 months. Her physical examination and ultrasonographic findings led to a diagnosis of advanced stage ovarian carcinoma. An exploratory laparotomy was performed and the operative impression was that of stage III ovarian carcinoma. Total hysterectomy with bilateral salpingo-oophorectomy and surgical staging were done. The postoperative pathology revealed a benign cystic teratoma of right ovary with chronic granulomatous peritonitis. She was well at discharge and at her 1-year follow-up. CONCLUSION: Although ruptured a benign cystic teratoma is rare, it can cause granulomatous peritonitis, the clinical findings of which mimic advanced stage ovarian carcinoma. This warrants physicians to be aware of and intraoperative frozen section should be used, its correct management will provide a good outcome with less complication.

Pregnancy in the broad ligament.

Pregnancy in the broad ligament is a rare form of ectopic pregnancy, and one type of abdominal pregnancy. The diagnosis is seldom established before surgery. A 38-year-old, 11-week pregnant woman, gravida 3, para 2, presented with vaginal bleeding. She had undergone two cesarean sections 10 and 6 years earlier. Pregnancy in the right broad ligament was diagnosed from clinical and transvaginal ultrasonographic findings. Emergency laparotomy and excision of a pregnancy in the right broad ligament and right salpingectomy were performed. She was well at discharge and at the 6-week follow up. We suggest the use of clinical and ultrasonographic findings for the suspicion of pregnancy in the broad ligament.

Posterior leukoencephalopathy following cisplatin, bleomycin and vinblastine therapy for germ cell tumor of the ovary.

A 31-year-old female developed multiple episodes of grand mal seizures after combination chemotherapy with cisplatin, vinblastine and bleomycin for germ cell ovarian cancer stage Ic. The clinicoradiologic features in this patient were consistent with posterior leukoencephalopathy, which is a rare complication of chemotherapy. Seizures were controlled by the anticonvulsive agent Dilantin (Pfizer, Khet Klongtoey, Bangkok) and she returned home without any permanent neurologic deficits. Follow-up magnetic resonance imaging 2 weeks later showed complete resolution of the abnormalities. This syndrome has been previously reported following cisplatin-based chemotherapy. Physicians should remain alert to the potential hazards of chemotherapy to the central nervous system. Risks and benefits should be seriously considered before starting treatment.