Intraperitoneal chemotherapy following neoadjuvant chemotherapy and optimal interval tumor reductive surgery for advanced ovarian cancer.

OBJECTIVES: Intraperitoneal (IP) chemotherapy following neoadjuvant chemotherapy (NACT) and interval tumor reductive surgery (TRS) for advanced ovarian cancer is feasible, however, the impact on disease outcomes remains unclear. We compare outcomes of patients treated with IP chemotherapy versus intravenous (IV) chemotherapy following NACT and interval TRS. METHODS: In this retrospective review, patients with advanced ovarian cancer were included if they received NACT followed by optimal interval TRS between 1/2004 and 4/2017. Patients were excluded if they had an ECOG PS >1, received >6 cycles of NACT or postoperative chemotherapy, and/or received bevacizumab during primary therapy. Primary outcomes were progression free survival (PFS) and overall survival (OS). RESULTS: There were 134 patients included in this study, 37 (28%) received IP and 97 (72%) received IV chemotherapy postoperatively. Patients in the IV group were older (median 66.3 vs 59.7 years, p = 0.0039) though there were no differences in BMI, race, BRCA status, stage, or histology. Median PFS was 3 months longer in the IP group (14.5 versus 11.5 months, p = 0.028) however there was no significant difference in OS. On univariate analysis, increasing number of NACT cycles (HR 1.914, 95% CI 1.024-3.497) and residual disease at completion of TRS (HR 1.541, 95% CI 1.042-2.248) were associated with decreased PFS; IP chemotherapy was associated with increased PFS (HR 0.633, 95% CI 0.414-0.944). These associations remained on multivariate analysis. Toxicity was comparable between the groups. CONCLUSIONS: IP after NACT and optimal interval TRS was associated with in improved PFS compared to IV chemotherapy without significant differences in toxicity.

A phase 2, randomized, double-blind, placebo- controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer: a Gynecologic Oncology Group partners study.

BACKGROUND: A phase 2, randomized, placebo-controlled trial was conducted in women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and safety of motolimod-a Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses-combined with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death. PATIENTS AND METHODS: Women with ovarian, fallopian tube, or primary peritoneal carcinoma were randomized 1 : 1 to receive PLD in combination with blinded motolimod or placebo. Randomization was stratified by platinum-free interval (≤6 versus >6-12 months) and Gynecologic Oncology Group (GOG) performance status (0 versus 1). Treatment cycles were repeated every 28 days until disease progression. RESULTS: The addition of motolimod to PLD did not significantly improve overall survival (OS; log rank one-sided P = 0.923, HR = 1.22) or progression-free survival (PFS; log rank one-sided P = 0.943, HR = 1.21). The combination was well tolerated, with no synergistic or unexpected serious toxicity. Most patients experienced adverse events of fatigue, anemia, nausea, decreased white blood cells, and constipation. In pre-specified subgroup analyses, motolimod-treated patients who experienced injection site reactions (ISR) had a lower risk of death compared with those who did not experience ISR. Additionally, pre-treatment in vitro responses of immune biomarkers to TLR8 stimulation predicted OS outcomes in patients receiving motolimod on study. Immune score (tumor infiltrating lymphocytes; TIL), TLR8 single-nucleotide polymorphisms, mutational status in BRCA and other DNA repair genes, and autoantibody biomarkers did not correlate with OS or PFS. CONCLUSIONS: The addition of motolimod to PLD did not improve clinical outcomes compared with placebo. However, subset analyses identified statistically significant differences in the OS of motolimod-treated patients on the basis of ISR and in vitro immune responses. Collectively, these data may provide important clues for identifying patients for treatment with immunomodulatory agents in novel combinations and/or delivery approaches. TRIAL REGISTRATION: Clinicaltrials.gov, NCT 01666444.

Outcomes following percutaneous upper gastrointestinal decompressive tube placement for malignant bowel obstruction in ovarian cancer.

OBJECTIVE: The objective of this study was to evaluate peri-operative and survival outcomes of ovarian cancer patients undergoing percutaneous upper gastrointestinal decompression for malignant bowel obstruction (MBO). METHODS: Retrospective chart review was used to identify patients with ovarian, peritoneal, or fallopian tube cancer who underwent palliative decompressive treatment for MBO from 1/2002 to 12/2010. Kaplan-Meier methods were used to estimate the median survival (MS) and multivariate analysis used to determine if any variables were associated with the hazard of death. RESULTS: Fifty-three patients met inclusion criteria. Median length of diagnosis prior to intervention was 21 months. Fifteen (28.3%) patients experienced complications and 9 required revision. Forty-nine (92.5%) experienced relief of symptoms after placement, and 91% tolerated some form of oral intake. Following placement, 19 (36%) patients received additional chemotherapy and 21(41%) patients received total parental nutrition (TPN). Thirty-five patients were discharged home/outpatient facility, 16 to hospice care, and 2 died prior to discharge. MS for all patients was 46 days. Patients who received chemotherapy had a MS of 169 days compared to 33 days (p<0.001). We failed to find an association between survival and TPN or performance status. CONCLUSIONS: Malignant bowel obstruction is a common complication of ovarian cancer. Management is palliative; risks and benefits of any therapy must be considered. Percutaneous decompressive therapy provides relief from associated symptoms, and allows patients to be discharged home. Median survival in this group is limited, and decisions regarding aggressive therapy should be individualized.

Effect of chemotherapy delays and dose reductions on progression free and overall survival in the treatment of epithelial ovarian cancer.

INTRODUCTION: Hematologic, gastrointestinal, and neurologic complications are common side effects of the platinum and taxane-based chemotherapy used in the primary treatment of epithelial ovarian cancer (EOC). These side effects and the impact of the resultant chemotherapy dose modification on disease free interval have not been extensively studied. The goal of this study was to determine the effect of chemotherapy delays and dose reductions on progression free survival (PFS) and overall survival (OS). METHODS: A review of patients with primary epithelial ovarian, peritoneal, and fallopian tube carcinoma treated between 1/2000 and 12/2007 was performed. Inclusion criteria were advanced stage disease and first line chemotherapy with a platinum and taxane regimen. Cox proportional hazard models were used to determine the effect of chemotherapy reductions and delays on PFS and OS. RESULTS: One hundred and fifty seven patients met the inclusion criteria. Patients were divided into four groups: no delays or reductions (48%), delay only (27%), reduction only (8%), and both delay and reduction (18%). The mean number of delays/reductions per patient was 1.1 (range=0-5) and therapy was delayed a mean of 8 days. The most common reasons for delays/reductions were neutropenia (n=51), thrombocytopenia (n=45), and neuropathy (n=18). There were no differences detected in PFS or OS between groups. CONCLUSIONS: There were no differences detected in survival between patients who required dose adjustments and treatment delays and those who did not. The lack of association between survival and chemotherapy alterations suggests that in specific circumstances patients with advanced ovarian cancer should have individualized treatment plans.

Which factors predict bowel complications in patients with recurrent epithelial ovarian cancer being treated with bevacizumab?

BACKGROUND: Increased rates of bowel perforation in patients with recurrent epithelial ovarian cancer (EOC) treated with bevacizumab have been reported, but the risk factors for this association are uncertain. We sought to identify factors associated with bowel perforation and fistula formation in recurrent EOC patients treated with bevacizumab. METHODS: A chart review of all patients treated with bevacizumab for recurrent EOC at a single institution was performed. Pertinent patient characteristics and treatment information were collected. Univariate logistic regression was performed to analyze multiple variables. RESULTS: One hundred twelve patients who were treated with 160 different bevacizumab regimens were identified. The median age was 60 years (range, 29-78 years). Patients had received a median of 4 prior chemotherapy regimens (range, 1-10). The median number of cycles was 4 (range, 0.5-31). Ten patients (9%) were diagnosed with bowel perforations, and another 2 patients (1.8%) were diagnosed with fistulas. The 30-day mortality following perforation was 50%, with 30% of patients dying within 1 week. Patients with rectovaginal nodularity were more likely to develop a bowel perforation or fistula than those who did not have this finding, OR=3.64 (95% CI=1.1 to 12.1, p=0.04). None of the other variables were significantly associated with bowel perforations or fistula formation. CONCLUSIONS: Rectovaginal nodularity is associated with an increased risk of bowel perforation or fistula formation for patients with recurrent EOC treated with bevacizumab. Careful consideration should be given prior to initiating bevacizumab treatment in EOC patients with rectovaginal nodularity since the mortality rate with bevacizumab associated bowel perforations is 50%.

Correlation between patient weight and defects in DNA mismatch repair: is this the link between an increased risk of previous cancer in thinner women with endometrial cancer?

The objective is to determine the relationship between obesity and defects in DNA mismatch repair (MMR) in women with endometrial cancer and to establish whether our previous finding of a higher rate of previous malignancy in thinner women with endometrial cancer is related to these factors. Specimens from 109 patients with primary uterine cancer were used to create a tissue microarray, which was stained with antibodies against MMR genes MLH1, MSH2, MSH6, and PMS2. Genotyping of normal and tumor tissues for microsatellite instability (MSI) was performed. Patients were stratified by body mass index (BMI) and correlated with a history of previous malignancy and defects in MMR. The average BMI of the overall population was 33 kg/m(2). Defective MMR was seen in 22% of tumors. The mean BMI in patients with tumors with MSI was 30.5, compared with 33.8 in microsatellite stable (MSS) tumors (P= 0.06); MSS tumors were more commonly seen in patients with a BMI more than 40 (25% vs 5% in patients with tumors with MSI, P= 0.07). Prior to their diagnosis of endometrial cancer, 16/109 (15%) patients reported having a prior malignancy, 11 (69%) had breast cancer, and 1 had colorectal cancer. Patients with tumors with MSI had previous cancer in 17% of cases, compared with 14% of patients with MSS tumors (P= 0.75). Our previous finding of an increased rate of prior malignancy in thinner patients with endometrial cancer does not appear to be due to alterations in MMR, and hereditary nonpolyposis colorectal cancer-associated cancers are rarely the prior malignancy.

Phase I study of paclitaxel, carboplatin, and increasing days of prolonged oral etoposide in ovarian, peritoneal, and tubal carcinoma: a gynecologic oncology group study.

PURPOSE: Given the activity of prolonged oral etoposide in platinum and paclitaxel-resistant ovarian carcinoma, a phase I trial was conducted that combined increasing days of oral etoposide therapy with paclitaxel and carboplatin in chemotherapy-naive patients with ovarian peritoneal and tubal carcinoma to establish a maximum-tolerated dose (MTD) of this combination. PATIENTS AND METHODS: Paclitaxel at 175 mg/m(2) given over 3 hours and carboplatin at an area under the curve of 5 were administered on day 1 followed by oral etoposide 50 mg/m(2)/d beginning on day 2. The number of days of etoposide therapy was escalated on the basis of toxicity. Toxicity end points included neutropenic sepsis, grade 4 thrombocytopenia, or grade 3 neutropenia or thrombocytopenia during etoposide administration. Cycles were repeated every 21 days for a maximum of six courses. Due to hematologic toxicity, the duration of the paclitaxel infusion was decreased to 1 hour for a second stage of accrual. RESULTS: Of 52 patients studied, 29 were in the first stage of accrual. Dose-limiting toxicity occurred with 8 days of oral etoposide, making the MTD six days of therapy. Twenty-three patients were entered into the second stage of accrual. Dose-limiting toxicity occurred at 12 days of oral etoposide, making the MTD 10 days of therapy. Three patients developed acute myeloid leukemia 16, 27, and 35 months after receiving a cumulative dose of 200 mg/m(2), 1,200 mg/m(2), and 2,400 mg/m(2), respectively. CONCLUSION: One-hour paclitaxel, carboplatin, and oral etoposide at 50 mg/m(2)/d for 10 days is tolerable without supportive therapy. The leukemogenic potential is cause for concern and precludes its use in chemotherapy-naive ovarian carcinoma.

Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group.

PURPOSE: To compare the progression-free and overall survival in small-volume residual ovarian cancer after treatment with intravenous (IV) cisplatin and paclitaxel or an experimental regimen of IV carboplatin followed by IV paclitaxel and intraperitoneal cisplatin. PATIENTS AND METHODS: Patients were randomized to receive either IV paclitaxel 135 mg/m(2) over 24 hours followed by IV cisplatin 75 mg/m(2) every 3 weeks for six courses or IV carboplatin (area under curve 9) every 28 days for two courses, then IV paclitaxel 135 mg/m(2) over 24 hours followed by intraperitoneal (IP) cisplatin 100 mg/m(2) every 3 weeks for six courses. RESULTS: Of the 523 patients who entered this trial, 462 were determined to be assessable, with prognostic factors well balanced between the treatments. Neutropenia, thrombocytopenia, and gastrointestinal and metabolic toxicities were greater in the experimental arm. As a result, 18% of the patients received < or = two courses of IP therapy. Progression-free survival was superior for patients randomized to the experimental treatment arm (median, 28 v 22 months; relative risk, 0.78; log-rank P =.01, one-tail). There was a borderline improvement in overall survival associated with this regimen (median, 63 v 52 months; relative risk, 0.81; P =.05, one-tail). CONCLUSION: An experimental regimen including moderately high-dose IV carboplatin followed by IP paclitaxel and IV cisplatin yielded a significant improvement in progression-free survival when compared with a standard regimen of IV cisplatin and paclitaxel. Because the improvement in overall survival was of borderline statistical significance and toxicity was greater, the experimental arm is not recommended for routine use. However, the results provide direction for further clinical investigation in small-volume ovarian cancer.

Phase I trial of escalating doses of paclitaxel combined with fixed doses of cisplatin and doxorubicin in advanced endometrial cancer and other gynecologic malignancies: a Gynecologic Oncology Group study.

PURPOSE: The primary objective of this phase I trial was to determine the feasibility of administering a combination of paclitaxel, cisplatin, and doxorubicin with or without granulocyte colony-stimulating factor (G-CSF) in patients with advanced endometrial and other gynecologic cancers. PATIENTS AND METHODS: Patients were chemotherapy-naive. Doxorubicin was administered as a brief infusion, paclitaxel for 3 hours, and cisplatin for 60 minutes. Treatments were repeated every 3 weeks. For most dose levels, the cisplatin and doxorubicin were fixed at 60 mg/m(2) and 45 mg/m(2), whereas the paclitaxel was escalated in successive cohorts from 90 to 250 mg/m(2). Patients who had received previous radiotherapy to the whole pelvis were escalated separately from those who had not. RESULTS: Eighty patients received 320 cycles of therapy. When G-CSF was not used, myelosuppression prevented escalation beyond the starting dose for patients with or without previous pelvic radiotherapy. When G-CSF was added, neurotoxicity became dose-limiting for both groups. Ten patients were removed from the study for asymptomatic declines in ejection fraction, but no symptomatic congestive heart failure was observed. Major antitumor responses occurred in 46% of patients (six of 13) with measurable endometrial carcinoma and 50% of patients (eight of 16) with measurable cervical carcinoma. CONCLUSION: The combination of paclitaxel, doxorubicin, and cisplatin at relevant single-agent doses is active and feasible with the addition of G-CSF. A regimen of cisplatin 60 mg/m(2), doxorubicin 45 mg/m(2), and paclitaxel 160 mg/m(2) with G-CSF support is recommended for further testing.

Erythropoietin increases hemoglobin during radiation therapy for cervical cancer.

PURPOSE: Anemia during radiation therapy independently predicts poor outcome in patients with cervical cancer. Despite a randomized trial demonstrating red cell transfusions improve local control and survival, many patients are not transfused due to toxicity concerns. This study evaluates the efficacy of recombinant human erythropoietin (r-HuEPO) in reversing anemia in patients undergoing radiation therapy. METHODS AND MATERIALS: Twenty patients with criteria of anemia (Hgb < 12.5 g/dL) and surgically staged cervical cancer FIGO stages IB (n = 7), IIA (n = 1), IIB (n = 9), and IIIB (n = 3), ranging in ages from 23-75 years (median 43), were included in this Phase I/II study. Fifteen were treated with r-HuEPO (200 U/kg/day) and ferrous sulfate 5-10 days prior to initiation of external beam radiation therapy, continuing until Hgb was < or = 14 g/dL or completion of radiation therapy. Five patients were treated with ferrous sulfate alone. An additional 61 historical controls meeting eligibility criteria were analyzed. All received external beam radiation therapy and two intracavitary cesium applications. Cisplatinum chemotherapy (20 mg/m2/week) was given as a radiosensitizer in 14 r-HuEPO patients, 4 concurrent controls, and 17 historical controls. RESULTS: A marked reticulocytosis was seen in the r-HuEPO group, but not the study controls. In the r-HuEPO group, the mean +/- SD serum Hgb rose + 30% over the course of radiation therapy from a baseline of 10.3 +/- 1.04 g/dL to 13.2 +/- 1.7 g/dL. Average increase in Hgb was 0.5 g/dL per week. Average Hgb during RT was 13.4 g/dL. In study and historical controls, mean initial Hgb levels were 10.7 +/- 1.04 g/dL and 11.1 +/- 1.3g/dL, respectively, remaining unchanged over the course of radiation therapy. Average Hgb levels during radiation therapy were 11.1 g/dL in study controls and 11.4 g/dL in historical controls, significantly lower than r-HuEPO patients (p = 0.0001). Erythropoietin was well tolerated. There were no significant differences in white blood counts (p = 0.6) or platelet counts (p = 0.4) between r-HuEPO patients and both control groups. No patients had blood pressure changes during r-HuEPO therapy. The only possible side effect was deep venous thrombosis, occurring in two patients who were withdrawn from r-HuEPO therapy. Two additional patients developed deep venous thrombosis 9 and 10 days after radiation therapy and r-HuEPO were completed. CONCLUSION: Erythropoietin appears to be both safe and effective at raising Hgb levels in anemic cervical cancer patients receiving radiation therapy and chemotherapy.

Radical vulvectomy with postoperative irradiation for vulvar cancer: therapeutic implications of a central block.

PURPOSE/OBJECTIVE: To report the long-term results of vulvectomy, node dissection, and postoperative nodal irradiation using a midline vulvar block in patients with node positive vulvar cancer. METHODS AND MATERIALS: From 1971 through 1992, 27 patients with carcinoma of the vulva and histologically involved inguinal lymph nodes were treated postoperatively with radiation therapy after radical vulvectomy and bilateral lymphadenectomy (n = 25), radical vulvectomy and unilateral lymphadenectomy (n = 1), or hemivulvectomy and bilateral lymphadenectomy (n = 1). Federation Internationale de Gynecologic et d'Obstetrique stages were III (n = 14), IVA (n = 8), and IVB (n = 5) squamous cell carcinoma. Inguinal lymph nodes were involved with tumor in all patients (average number positive = 4, range 1-15). Postoperative irradiation was directed at the bilateral groin and pelvic nodes (n = 19), unilateral groin and pelvic nodes (n = 6), or unilateral groin only (n = 1). These 26 patients had the midline blocked. In addition, one patient received irradiation to the entire pelvis and perineum. Doses ranged from 10.8 to 50.7 Gy (median 45.5) with all patients except 1 receiving > or = 42.0 Gy. RESULTS: Actuarial 5-year overall survival and disease-free survival estimates were 40% and 35%, respectively. Recurrences developed in 63% (17/27) of the patients at a median of 9 months from surgery (range 3 months to 6 years) and 15 of these have died; two patients with recurrences are surviving at 24 and 96 months after further surgery and radiation therapy. Central recurrences (under the midline block) were present in 13 of these 17 patients (76%), either as central only (n = 8), central and regional (n = 4), or central and distant (n = 1). Additionally, three patients developed regional recurrences and one patient developed a concurrent regional and distant relapse. One patient developed a squamous cell cancer of the anus under the midline block 54 months after the initial vulvar cancer and an additional patient developed transitional cell carcinoma of the ureter (outside the radiation field) 12 months after diagnosis. Factors associated with a decreased relapse-free survival included increasing Federation Internationale de Gynecologic et d'Obstetrique stage (p = 0.01) and invasion of the tumor into the subcutaneous (SC) fat or deep soft tissue (p = 0.05). Chronic lower extremity edema developed in four patients, but there have been no other complications. CONCLUSIONS: Radical vulvectomy has often been considered sufficient central treatment for vulvar carcinoma, with postoperative irradiation directed only to the nodes. Although designed to protect the radiosensitive vulva, use of a midline block in this series resulted in a 48% (13/27) central recurrence rate, much higher than the 8.5% rate previously reported with this technique. Routine use of the midline block should be abandoned and, instead, postoperative irradiation volumes should be tailored to the individual patient.

Natural history of the minimally abnormal Papanicolaou smear.

OBJECTIVE: We sought to determine the natural history of the cytologic and colposcopic changes in patients with minimal abnormalities on their Papanicolaou smears (atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion [SIL]). METHODS: Between November 1988 and November 1990, 632 women with abnormal Papanicolaou smears as listed above were evaluated at Los Angeles County-Olive View Medical Center. Each had review of cytology, repeat Papanicolaou smear, and colposcopy of the lower genital tract. We excluded those who were pregnant or had findings demonstrative of moderate dysplasia or worse, or had a cervical biopsy for any other indication. Women with symptomatic vaginal discharge were treated and remained in the study. Subjects were followed every 3 months with repeat Papanicolaou smear and colposcopy for a minimum of 9 months. If at any time the Papanicolaou smear or colposcopy was consistent with moderate dysplasia or worse, directed biopsies and endocervical curettage were performed, and treatment was given accordingly. Two hundred ninety-four patients fulfilled all inclusion criteria and had adequate follow-up data. RESULTS: Nine months after enrollment, 42 of 91 women (46.2%) with atypical squamous cells had persistent changes, none had progression, and 49 (53.8%) had regression to normal. In those with low-grade SIL, 37 of 203 cases (18.2%) persisted, seven (3.4%) progressed, and 159 (78.3%) regressed by 9 months. Patients in the first group were more likely to have persistence of the cytologic abnormalities than were those in the second (P less than .01). Only the latter group progressed to high-grade dysplasia during the 9-month study interval. CONCLUSION: The majority of women with confirmed minimal cytologic changes on Papanicolaou smear will have complete colposcopic and cytologic regression over a short interval.

Effect of CO2 laser conization of the uterine cervix on pathologic interpretation of cervical intraepithelial neoplasia.

The CO2 laser has become a valuable tool for the treatment of lower genital tract neoplasia. The records of 52 women who underwent CO2 laser cervical conization were analyzed retrospectively to evaluate the effect of tissue thermal damage on histopathologic interpretation. Lesion evaluability, defined by the ability to diagnose neoplasia accurately in the specimen, was satisfactory in only 26 cases; in the other 26, thermal damage was severe enough to preclude accurate diagnosis. A postoperative diagnosis of cervical intraepithelial neoplasia III was made in 17 instances, and microinvasion was suspected but unverifiable in two of these. Two patients had frankly invasive cancer, but vascular space involvement in one could not be evaluated accurately because of thermal damage. Tissue thermal damage sufficient to interfere with accurate histologic evaluation was noted in the majority of laser conization specimens. The value of a conization is both diagnostic and therapeutic. The potential impact of a diagnosis compromised by thermal damage is serious.

Quality assurance of second opinion pathology in gynecologic oncology.

OBJECTIVE: To determine the effect of routine second review of pathologic material that was sent to Ohio State University before initiation of therapy. METHODS: All the gynecologic-oncologic histopathology review diagnoses made during a 1-year period were compared with original pathologic diagnoses. When there was a discrepant diagnosis with the second interpretation, the case was reviewed by at least two pathologists. Discrepancies were coded as no diagnostic disagreement, no diagnostic disagreement but pertinent information not included, diagnostic disagreement without clinical consequences, diagnostic disagreement with minor clinical significance, or diagnostic disagreement with major clinical significance. Proportions and confidence intervals were calculated. RESULTS: Pathology reports from 295 referred patients were reviewed. Two hundred forty-five (83.1%) showed no discrepancy. Discrepancies were found in 50 cases (16.9%). There was significant information missing in four cases (1.4%), diagnostic disagreement with no clinical significance in 22 cases (7.5%), and diagnostic disagreement with minor clinical significance in 10 cases (3.4%). In 14 cases (4.7%, 95% confidence interval 2.28, 7.12) the changes in diagnoses had major therapeutic or prognostic implications that included changes from malignant or low malignant potential to benign (seven cases), malignant to low malignant potential (three cases), change in tumor type (two cases), and assessment of invasion (two cases). The cost of reviewing 295 specimens was approximately $39,235. The cost of identifying each major discrepancy was about $2802. CONCLUSION: Routine pathology review of gynecologic-oncologic cases before definite treatment revealed notable discrepancies in diagnoses. In 4.7% of cases, the change in diagnosis had a major effect on proper treatment planning or a significant prognostic implication.

Experimental Trypanosoma cruzi infection in rhesus monkeys 111. Electrocardiographic and histopathological findings.

In five rhesus monkeys surviving 'Peru strain' or 'strain 7' Trypanosoma cruzi infection for six to eight years, positive xenodiagnosis results and high indirect fluorescent antibody titres (4096 - 65536) persisted until the animals were killed. Abnormal electrocardiograph patterns in two monkeys (H and K) were possibly compatible with myocardial damage. Histopathological changes attributable to T. cruzi infection were minor in four monkeys but severe in one (R). In this animal, infected with what was judged previously to be the less virulent of the two T. cruzi stocks used ('strain 7'), there was severe myocarditis, with myofibre degeneration, and lesions of the oesophagus. Elevated serum levels of five enzymes were not detected in any of the chronically infected monkeys.

Concurrent interstitial radiotherapy and infusional chemotherapy for recurrent gynecologic malignancies.

Patients with unresectable locally recurrent gynecologic malignancies pose a difficult therapeutic challenge. Conventional therapies are frequently unsuccessful and offer only marginal palliation. In this study, interstitial 192iridium-needle implants and concomitant infusional 5-fluorouracil (5FU) and cisplatin (CDDP) or carboplatin (CBDCA) chemotherapy were used to treat 14 women with recurrent pelvic tumors. Malignancies of the cervix, endometrium ovary, tube and vulva are represented; all patients were heavily pretreated. Twenty interstitial implants were performed in these 14 patients. Needle distributions and doses were individualized to accommodate the recurrent tumor volumes. Tumor responses were seen in 12 patients (six complete and six partial responses). Four women remain clinically free of disease and four are alive with disease at 18-34 months of follow-up. There were no severe acute toxicities, however, four patients have subsequently developed fistulae associated with tumor progression. Although longer follow-up is required, the high response rate, wide applicability and acceptable toxicity observed in this heavily pretreated patient population warrant further study of combined interstitial radiation and chemotherapy.

Peritoneal adenocarcinoma (serous) of Müllerian type: a subgroup of women presenting with peritoneal carcinomatosis.

Peritoneal adenocarcinoma (serous or other subtype) of Müllerian type (PAMT) is frequently misclassified as another primary tumor. Peritoneal carcinomatosis in women without evidence of a primary site may occur secondary to a number of processes. Confusion regarding the nomenclature has made it difficult to determine the incidence and natural history of this unique malignancy. Other terms used for this tumor include mesothelioma, peritoneal papillary serous carcinoma, extra-ovarian serous carcinoma, and normal-sized ovarian carcinoma syndrome. Thirty-four patients (33 serous and one endometrioid) were identified with PAMT during 1976 through 1988. One hundred and thirty-seven patients underwent primary cytoreductive surgery for a preoperative diagnosis consistent with ovarian cancer. Twenty-nine (21.2%) were classified as PAMT (5 of the 34 had their initial surgery at other institutions). The mean age was 61.4 years. The primary symptoms and signs were abdominal pain (68%) and ascites (52%). Twenty-five (73%) had a preoperative diagnosis of ovarian cancer while the postoperative diagnosis was unknown (44%), PAMT (29%), and ovarian cancer (27%). Univariate and multivariate survival analysis were performed. Survival was independent of age, residual disease, grade, ascites, type of chemotherapy, and second-look results. In patients with residual disease < 1.5 cm, extended survival was found in (hose with ascites < 1000 ml, residual disease in pelvis only, and small residual volume but statistical significance was not obtained. Twenty-eight patients received >/=4 courses of chemotherapy after primary surgery. Twelve of 21 patients (57%) who received cisplatin (CDDP) survived between 23 and 92 months, while no patient receiving other chemotherapeutic regimens survived more than 25 months. The 2 and 3 year survival rate for CDDP was 47% and 33% vs. 14% and 0% for other regimens. Optimal cytoreductive surgery was not an independent prognostic factor as found in ovarian cancer, probably secondary to unresectable peritoneal carcinomatosis. PAMT is sensitive to chemotherapy but only the use of CDDP was associated with long term survival. Based on these results, women with peritoneal carcinomatosis consistent with PAMT should receive a CDDP-based regimen after primary surgery.

Prediction of malignancy using transvaginal color flow Doppler in patients with gynecologic tumors.

Eighty-five patients referred to the Women's Cancer Center, University of Minnesota had transvaginal color flow Doppler performed to determine if pelvic malignancy could be predicted by blood flow assessment. Their mean age was 49 years (range 21-86 years). Thirty-five patients were subsequently found to have malignant tumors of the cervix, uterus or ovary. The presence of increased intratumoral blood flow as depicted by color flow Doppler had a sensitivity of 83%, specificity of 100%, positive predictive value (PPV) of 100% and negative predictive value (NPV) of 89% for malignancy. The mean intratumoral Pulsatility Index (PI) of the patients with malignant tumors was 0.81 (SD 0.24; range 0.3-1.2), which was significantly lower than for the benign group (P = 0.001). A PI of

Mixed mesodermal sarcoma of the ovary in a young patient.

Mixed mesodermal tumors (MMT) of the ovary are rare and have a poor prognosis. This ovarian malignancy usually occurs in postmenopausal women. We report an unusual ovarian MMT in a young woman given treatment similar to one used for ovarian germ cell malignancies. We believe this is the youngest patient reported with an homologous MMT of the ovary.

First Report of Daylily Rust in the United States.

In August 2000, rust symptoms were observed on the leaves of daylily plants (Hemerocallis sp. cv. Pardon Me) at a nursery in Dearing, GA. Based on urediniospore characters, the pathogen was tentatively identified as Puccinia hemerocallidis Thuem. Urediniospores were globose to ellipsoid and measured 19 to 30 × 17 to 22 µm (average size of 22 × 19 µm), corresponding to the previously reported description from Japan (1). Teliospores were absent from the sample but were found on daylily plants (cv. Star Struck) with symptoms similar to cv. Pardon Me from the same nursery in Dearing beginning in October 2000. However, the teliospores differed from those in the published description in that many one-celled teliospores (i.e., mesospores), measuring 32 to 43 × 14 to 19 µm (average size of 38 × 16 µm), were produced in addition to two-celled teliospores, which measured 41 to 53 × 16 to 21 µm (average size of 46 × 18 µm). Similar mesospores were present in a slide from an isotype specimen of P. hemerocallidis (US 72719) housed in the U.S. National Fungus Collection (Beltsville, MD). Daylily plants (cv. Pardon Me) were reinoculated with urediniospores by shaking infected plants over uninfected plants and exposing plants to 100% relative humidity for 24 h. Initial symptoms of small, discrete, yellow spots and streaks on the upper surfaces of leaves developed within 3 to 7 days, and uredia with urediniospores were evident at 7 to 14 days after inoculation. Daylily rust is native to Asia and may have been introduced into Georgia on plant materials sent from Central America. The original source of daylily rust is unclear because Central American producers also purchase and import plants from the United States for propagation and then sell divisions back to U.S. growers. Daylily rust is a disease of major concern for both daylily producers and gardeners. References: (1) N. Hiratsuka, et al. The Rust Flora of Japan. Tsukuba Shuppankai, Ibaraki, Japan, 1992.