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S Makhija,
A Sit,
R Edwards,
K Aufman,
H Weiss,
A Kanbour-Shakir,
W Gooding,
G D'Angelo,
R Ferrell,
S Raja,
T E Godfrey
[show abstract]
[hide abstract]
ABSTRACT: After the completion of primary chemotherapy, the majority of advanced ovarian cancer patients have persistent, chemoresistant disease. Comparative genomic hybridization (CGH) has been used to study genetic alterations that may be responsible for chemoresistance in ovarian cancer. CGH is a useful, genomewide screen but resolution is limited to 5-10 Mb. Recently, quantitative microsatellite analysis (QuMA), a TaqMan-based quantitative PCR technology, has been used for higher resolution of DNA copy number abnormalities. Our goal is to identify specific chromosomal aberrations correlated with platinum resistance.
Snap-frozen ovarian tissue samples taken from 22 patients with ovarian cancer between 1994 and 1998 were analyzed. Patients whose ovarian cancer actually demonstrated growth during platinum-combination treatment or no objective evidence of regression following four to six cycles of therapy were considered to have clinically defined platinum-resistant disease. QuMA was carried out at the following loci using the ABI Prism 7700 (TaqMan) instrument with a microsatellite repeat probe: D3S1553, D3S1617, D5S464, D5S630, D6S1581, D6S446, D8S557, D19S208, D20S196, DXS1068. Fisher's exact test, exact logistic regression, and the Cochran-Armitage trend test were used. Because of multiple hypothesis testing, the P values were adjusted with the Bonferroni procedure to limit the familywise error rate to at most 5%.
Of the 22 patients, 12 (54.5%) were platinum-sensitive and 10 (45.5%) were platinum-resistant. When comparing sensitive and resistant patients, no statistically significant difference was noted among stage, grade, histology, and age (P = 0.1292, P = 1.0000, P = 1.0000, P = 1.0000, respectively). In the QuMA analysis, 10 of the 14 (71.4%) patients who had a low copy number of D6S1581 were platinum-resistant, while none of the patients with a normal or high copy number of D6S1581 were platinum-resistant. This was statistically significant when the marker data were treated as either a continuous or a categorical variable (P = 0.0410 and P = 0.0170, respectively). No other loci correlated significantly with platinum resistance.
D6S1581 was the only genetic marker, of those examined, significantly related to chemoresistance. Patients with a loss of D6S1581 are more likely to be platinum-resistant. Identification of genetic alterations associated with platinum resistance detected by QuMA may contribute to a better understanding of clinical behavior and chemotherapy treatment options for patients.
Gynecologic Oncology 08/2003; 90(1):3-9. · 3.89 Impact Factor
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ABSTRACT: Imaging modalities to evaluate ovarian/fallopian tube cancer patients for recurrence are limited. Positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound lack the sensitivity to consistently detect recurrence or measurable disease in these patients. A new technique combines PET and CT (PET/CT) images to identify increased metabolic activity and to locate that signal with improved anatomic specificity. The objective of this study is to compare PET/CT, CT, and histologic findings in patients with recurrent ovarian/fallopian tube cancers.
Retrospective chart review of eight patients with primary ovarian (n = 6) or fallopian tube (n = 2) cancer was performed. All eight patients underwent initial cytoreductive surgery. Five patients initially received chemotherapy, one received radioactive phosphorus ((32)P), one received tamoxifen, and one received no therapy. Seven of eight patients had a suspected recurrence based on clinical examination, elevated CA-125 level, and/or abnormal CT findings; one patient requested a PET/CT. Histologic findings from surgery were correlated with PET/CT and CT findings.
All eight patients had positive histology, and of these, seven patients had a negative CT and five patients had lesions that were correctly identified by PET/CT.
Five of the eight (62%) patients had recurrent disease based on correlative histology with a positive PET/CT and a negative CT. These preliminary findings suggest that combined PET/CT may be an effective means of identifying patients with recurrent ovarian/fallopian tube cancer. Such patients could potentially proceed to salvage treatment and avoid the morbidity and expense of surgical assessment. Pilot studies comparing CT, PET, PET/CT, and histologic findings are underway.
Gynecologic Oncology 05/2002; 85(1):53-8. · 3.89 Impact Factor
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ABSTRACT: The goal of this work was to determine the complication rate and any predisposing risk factors associated with subcutaneous intraperitoneal (ip) catheters used in the treatment of patients with advanced ovarian cancer.
We retrospectively reviewed the charts of 301 patients who had a subcutaneous Bardport catheter placed for administration of ip chemotherapy at Memorial Sloan--Kettering Cancer Center (MSKCC) from December 1989 to May 1997.
Thirty (10%) patients were identified as having catheter-related complications, with 19 (6.3%) experiencing inflow obstruction and 11 (3.6%) experiencing infection. Only 21 of 301 (7%) required cessation of chemotherapy prior to its expected completion, with 14 (4.6%) occurring in the malfunction group and 7 (2.3%) in the infection group. Three hundred thirteen patients received an ip catheter; however, 12 patients who received their ip chemotherapy elsewhere were excluded when determining the complication rate. Overall, 218 of 313 (69.6%) catheters were placed at the time of laparotomy, 61 of 313 (19.5%) catheters were placed at the time of laparoscopy, and 34 of 313 (10.9%) were placed as a separate procedure. In the malfunction group, 18 of 19 (94.7%) patients had their catheters placed at the time of laparotomy, none were placed at the time of laparoscopy, and 1 of 19 (5.3%) was placed as a separate procedure. In the infection group, 8 of 11 (72.7%) catheters were placed at laparotomy, 2 of 11 (18.3%) were placed at the time of laparoscopy, and 1 of 11 (9.0%) was placed as a separate procedure. Complications occurred in 3 of 54 (5.5%) patients who received platinum alone, 11 of 134 (8.2%) who received platinum in combination, 2 of 43 (4.7%) who received paclitaxel alone, 13 of 61 (21.3%) who received mitoxantrone alone or in combination, and 1 of 9 (11.1%) who received other regimens.
Subcutaneous ip catheters are associated with a lower rate of catheter-related complications than previously reported, perhaps due in part to both avoiding insertion of ip catheters at the time of bowel surgery and placing ip catheters at the time of laparoscopy.
Gynecologic Oncology 05/2001; 81(1):77-81. · 3.89 Impact Factor
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ABSTRACT: The aim of this study was to review the role and safety of intraperitoneal (IP) cisplatin and intravenous (IV) paclitaxel in platinum-sensitive epithelial ovarian cancer patients who were found to have small-volume disease (<1 cm) at the time of their second-look procedure.
In a retrospective review, 32 patients with small-volume disease had an IP Bardport catheter placed at the time of second look at Memorial Sloan-Kettering Cancer Center (1995-1998). Patients received IP cisplatin (75 mg/m(2)) every 3 weeks and either IV paclitaxel (135 mg/ m(2)) every 3 weeks or IV paclitaxel (80 mg/m(2)) weekly for a maximum of five cycles.
Twenty-four (75%) of 32 patients received IP cisplatin/IV paclitaxel every 3 weeks and 8 (25%) received IP cisplatin every 3 weeks with weekly IV paclitaxel. Seven (21.9%) of 32 patients required interruption of treatment secondary to neuropathy. Of these, 4 (15.6%) were changed to another IV chemotherapeutic agent, and 3 (9.3%) required discontinuation of IV paclitaxel only. Two (6%) patients required IP port removal secondary to malfunction and were changed to IV therapy and 1 (3%) requested discontinuation of IP therapy secondary to abdominal pain. Median follow-up was 19 months (mean, 20.1 months; range, 6-36 months). Progression of disease after completion of IP therapy was documented by clinical exam, abnormal CT, and/or rising CA-125 levels. The median progression-free interval was 13 months (mean, 15.1 months; range, 2-33 months). Median overall survival was 27 months (mean, 34.2 months; range, 10-42 months). At the time of review, 13 (40.6%) of the 32 patients were alive with disease, 7 (21.9%) were without evidence of disease, and 12 (37.5%) were dead of disease.
IP cisplatin in combination with IV paclitaxel appears to be no more effective than other reported regimens as second-line therapy for patients with persistent small-volume disease. Neurotoxicity is dose limiting, and the combination cannot be recommended for the routine care of persistent peritoneal cancers.
Gynecologic Oncology 11/2000; 79(1):28-32. · 3.89 Impact Factor
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ABSTRACT: Expression of Bcl-2, Bax, p53 and induction of apoptosis were studied in cisplatin or Taxol treated monolayer and spheroid cultures of ovarian cancer cell lines (SKOV-3, UL-1, UL-3C). While cisplatin (15-75 microg/ml) induced apoptosis in monolayer and spheroid cultures, Taxol (100-800 nM) induced fragmentation in monolayers only. Cisplatin induced up to 5-fold DNA fragmentation in monolayers, while 3-fold (UL-3C, SKOV-3), and 1.5-fold (UL-1) in spheroids. Taxol treatment of monolayers resulted in the characteristic phosphorylation of Bcl-2, which was not demonstrated in spheroid cultures. Bax expression was reduced in spheroids following cisplatin or Taxol treatment, while p53 levels remained unchanged.
International Journal of Oncology 04/1999; 14(3):515-21. · 2.40 Impact Factor
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ABSTRACT: The intraperitoneal delivery of chemotherapeutic agents is presently being investigated as a part of salvage treatment for epithelial ovarian cancer. There are several promising new agents that appear to demonstrate a benefit in selected patients.
Current Opinion in Obstetrics and Gynecology 03/1999; 11(1):23-7. · 2.38 Impact Factor
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Journal of Clinical Oncology 09/1998; 16(8):2577-8. · 18.37 Impact Factor
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ABSTRACT: Trends in CA-125 levels after completion of therapy in ovarian cancer patients who received intraperitoneal radioactive chromic phosphate therapy (32P) after primary surgical resection or second-look surgery were evaluated. Ninety patients who underwent surgical exploration and 32P were reviewed. Twenty-nine patients were excluded due to insufficient number of CA-125 levels or recurrence within 12 months, with 61 patients with serial CA-125 levels and no evidence of disease for 12 months available for analysis. 32P followed initial resection in 24 patients (16 Stage I, 3 Stage II, 5 Stage III). 32P followed chemotherapy and second-look procedures in 37 patients (4 Stage I, 3 Stage II, 27 Stage III, 3 Stage IV). Elevated CA-125 levels were present in 25 (41%) patients within 12 months of 32P (46% after primary exploration, 38% after second-look). The degree of CA-125 elevation (U/ml) was 30-100 (23%), 100-200 (11%), and >200 (7%). Of the 25 patients with an elevated CA-125, the elevation persisted more than 4 months in 11 (44%). All but two patients had normal CA-125 levels by 12 months. An abnormal elevation in CA-125 was seen in 33% of patients 4 months after receiving 32P and abdominal surgery, with values ranging as high as 500 U/ml. Although elevations in CA-125 are reported following surgery alone, the duration of elevation appears to be longer with 32P. Therefore, persistent elevations of CA-125 following 32P between 4 and 12 months should be judged with caution as they may not reflect recurrent disease.
Gynecologic Oncology 10/1996; 63(1):85-8. · 3.89 Impact Factor
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International Journal of Gynecological Cancer 15(1):1-3. · 1.65 Impact Factor
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S Makhija,
A Sit,
R Edwards,
K Aufman,
H Weiss,
A Kanbour-Shakir,
W Gooding,
G D’Angelo,
R Ferrell,
S Raja,
T.E Godfrey
[show abstract]
[hide abstract]
ABSTRACT: ObjectiveAfter the completion of primary chemotherapy, the majority of advanced ovarian cancer patients have persistent, chemoresistant disease. Comparative genomic hybridization (CGH) has been used to study genetic alterations that may be responsible for chemoresistance in ovarian cancer. CGH is a useful, genomewide screen but resolution is limited to 5–10 Mb. Recently, quantitative microsatellite analysis (QuMA), a TaqMan-based quantitative PCR technology, has been used for higher resolution of DNA copy number abnormalities. Our goal is to identify specific chromosomal aberrations correlated with platinum resistance.MethodsSnap-frozen ovarian tissue samples taken from 22 patients with ovarian cancer between 1994 and 1998 were analyzed. Patients whose ovarian cancer actually demonstrated growth during platinum-combination treatment or no objective evidence of regression following four to six cycles of therapy were considered to have clinically defined platinum-resistant disease. QuMA was carried out at the following loci using the ABI Prism 7700 (TaqMan) instrument with a microsatellite repeat probe: D3S1553, D3S1617, D5S464, D5S630, D6S1581, D6S446, D8S557, D19S208, D20S196, DXS1068. Fisher’s exact test, exact logistic regression, and the Cochran–Armitage trend test were used. Because of multiple hypothesis testing, the P values were adjusted with the Bonferroni procedure to limit the familywise error rate to at most 5%.ResultsOf the 22 patients, 12 (54.5%) were platinum-sensitive and 10 (45.5%) were platinum-resistant. When comparing sensitive and resistant patients, no statistically significant difference was noted among stage, grade, histology, and age (P = 0.1292, P = 1.0000, P = 1.0000, P = 1.0000, respectively). In the QuMA analysis, 10 of the 14 (71.4%) patients who had a low copy number of D6S1581 were platinum-resistant, while none of the patients with a normal or high copy number of D6S1581 were platinum-resistant. This was statistically significant when the marker data were treated as either a continuous or a categorical variable (P = 0.0410 and P = 0.0170, respectively). No other loci correlated significantly with platinum resistance.ConclusionsD6S1581 was the only genetic marker, of those examined, significantly related to chemoresistance. Patients with a loss of D6S1581 are more likely to be platinum-resistant. Identification of genetic alterations associated with platinum resistance detected by QuMA may contribute to a better understanding of clinical behavior and chemotherapy treatment options for patients.
Gynecologic Oncology.
