Inhibition of the integrin/FAK signaling axis and c-Myc synergistically disrupts ovarian cancer malignancy.

Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor. From this screening, JQ1, a potent inhibitor of Myc oncogenic network, emerged as the most robust collaborator. Treatment with a combination of VS-6063 and JQ1 synergistically caused an arrest of tumor cells at the G2/M phase and a decrease in the XIAP-linked cell survival. Our subsequent mechanistic analyses indicate that this functional cooperation was strongly associated with the concomitant disruption of activation or expression of FAK and c-Myc as well as their downstream signaling through the PI3K/Akt pathway. In line with these observations, we detected a strong co-amplification or upregulation at genomic or protein level for FAK and c-Myc in a large portion of primary tumors in the TCGA or a local HGSOC patient cohort. Taken together, our results suggest that the integrin-FAK signaling axis and c-Myc synergistically drive cell proliferation, survival and oncogenic potential in HGSOC. As such, our study provides key genetic, functional and signaling bases for the small-molecule-based co-targeting of these two distinct oncogenic drivers as a new line of targeted therapy against human ovarian cancer.

Survival Advantage Associated with Decrease in Stage at Detection from Stage IIIC to Stage IIIA Epithelial Ovarian Cancer.

Objective. The aim of this study was to document the survival advantage of lowering stage at detection from Stage IIIC to Stage IIIA epithelial ovarian cancer. Methods. Treatment outcomes and survival were evaluated in patients with Stage IIIA and Stage IIIC epithelial ovarian cancer treated from 2000 to 2009 at the University of Kentucky Markey Cancer Center (UKMCC) and SEER institutions. Results. Cytoreduction to no visible disease (P < 0.0001) and complete response to platinum-based chemotherapy (P < 0.025) occurred more frequently in Stage IIIA than in Stage IIIC cases. Time to progression was shorter in patients with Stage IIIC ovarian cancer (17 ± 1 months) than in those with Stage II1A disease (36 ± 8 months). Five-year overall survival (OS) improved from 41% in Stage IIIC patients to 60% in Stage IIIA patients treated at UKMCC and from 37% to 56% in patients treated at SEER institutions for a survival advantage of 19% in both data sets. 53% of Stage IIIA and 14% of Stage IIIC patients had NED at last followup. Conclusions. Decreasing stage at detection from Stage IIIC to stage IIIA epithelial ovarian cancer is associated with a 5-year survival advantage of nearly 20% in patients treated by surgical tumor cytoreduction and platinum-based chemotherapy.

Primary appendiceal cancer: gynecologic manifestations and treatment options.

OBJECTIVE: To determine the presenting symptoms, gynecologic manifestations, and optimal intraoperative management of women with primary appendiceal cancer. METHODS: A multi-institutional investigation was performed to identify female patients with primary appendiceal cancer who were treated from 1990 to present. RESULTS: Forty-eight women with primary appendiceal cancer were identified from the tumor registries of participating institutions. The most common symptoms were abdominal pain (40%) and bloating (23%), but only 8% experienced rectal bleeding. Serum CEA was elevated (>2.5 U/ml) in 67% of patients, and serum Ca-125 was elevated (>35 U/ml) in 50% of patients. Thirty-one patients (65%) presented with a right adnexal or right lower quadrant mass and were operated on initially by a gynecologic oncologist. Ovarian involvement by metastatic appendiceal cancer was documented in 18 patients (38%). All of these patients underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and staging, but only 8 had a right hemicolectomy at the time of initial surgery. Forty-one patients (85%) presented with advanced stage appendiceal cancer (Stage III or IV) and 19 patients (46%) received postoperative chemotherapy, most commonly with a combination of 5-FU/Leukovorin. Following surgery, 22 patients (46%) experienced disease progression or recurrence, and 14 have died of disease. The most common sites of recurrence were abdominal or pelvic peritoneum (18), colon (2), and ovary (2). Patient survival was 70% at 2 years, and 60% at 5 years. CONCLUSION: Women with primary appendiceal cancer frequently present with ovarian metastases, and initial surgical intervention is often performed by a gynecologic oncologist. All patients with mucinous epithelial ovarian cancer should undergo appendectomy at the time of surgical staging. The appendix should be examined intraoperatively, and if appendiceal carcinoma is identified, a right hemicolectomy and appropriate surgical staging should be considered.

The efficacy of adjuvant platinum-based chemotherapy in Stage I uterine papillary serous carcinoma (UPSC).

OBJECTIVE: To determine the efficacy of adjuvant platinum-based chemotherapy in Stage I uterine papillary serous carcinoma (UPSC). METHODS: A retrospective multi-institutional investigation was performed to identify surgically staged patients with Stage I UPSC who were (1) treated after surgery with 3-6 courses of platinum-based chemotherapy without radiation from 1990-2003, and (2) followed for a minimum of 12 months, or until recurrence. RESULTS: Six patients (IA-2, IB-3, IC-1) were treated with carboplatin (AUC 6) or cisplatin (50 mg/m2) alone. One patient recurred to the vagina, was treated with chemo-radiation, and is alive and well at 122 months. One patient recurred to the lung, liver, and brain, and died of disease at 24 months. The remaining 4 patients are alive with no evidence of disease 15-124 months (mean 62 months) after treatment. Two patients (IB-1, IC-1) were treated with cisplatin (50 mg/m2) and cyclophosphamide (1000 mg/m2), and both are alive and well with no evidence of disease 75 and 168 months after treatment. Twenty-one patients (IA-5, IB-13, IC-3) were treated with a combination of carboplatin (AUC 6) and paclitaxel (135 mg/m2-175 mg/m2). One patient recurred to the vagina after 3 cycles of carboplatin/paclitaxel, and was treated with chemo-radiation. She is now without evidence of disease 10 months after treatment. At present, all 21 patients with Stage I UPSC treated following surgical staging with carboplatin/paclitaxel chemotherapy are alive and well with no evidence of disease 10-138 months (mean 41 months) after treatment. CONCLUSION: Combination carboplatin/paclitaxel chemotherapy following surgery is effective in the treatment of Stage I UPSC.

The accuracy of examination under anesthesia and transvaginal sonography in evaluating ovarian size.

OBJECTIVE: To compare pelvic examination under anesthesia to transvaginal sonography (TVS) as a method for ovarian detection and measurement. METHODS: Two hundred and eighty-nine ovaries from 151 women were evaluated. After induction of anesthesia, a complete pelvic examination and TVS were performed, and the ovaries were removed surgically. Ovarian dimensions generated sonographically and estimated on clinical examination were compared to those obtained from the measured surgical specimen. RESULTS: Forty-four percent of ovaries were palpable clinically whereas 85% were visualized sonographically (P < 0.001). Right ovaries were palpable more frequently than left ovaries (P < 0.01). Ovaries were detected clinically in 30% of women > or = 55 years of age versus 51% of women <55 years of age (P < 0.05), in 9% of women weighing > or = 200 lb versus 55% of women weighing <200 lb (P < 0.001), and in 12% of women with a uterine weight > or = 200 g versus 51% of women with a uterine weight <200 g (P < 0.001). TVS was significantly more accurate than clinical examination in detecting ovaries in women with these high risk characteristics. CONCLUSIONS: TVS is significantly more accurate than clinical examination in detecting ovaries and in defining their dimensions. Ovaries frequently are not palpable in women > or = 55 years of age, women who weigh > or = 200 lb, or women with an enlarged uterus (> 200 g). The addition of TVS to annual pelvic examination may be beneficial in women > or = 55 years of age who are overweight and therefore at high risk to develop ovarian cancer.

Preoperative differentiation of malignant from benign ovarian tumors: the efficacy of morphology indexing and Doppler flow sonography.

OBJECTIVE: The goal of this study was to determine the efficacy of morphology indexing and Doppler flow sonography as methods to predict risk of malignancy in sonographically confirmed ovarian tumors. METHODS: Risk of malignancy was assessed preoperatively in 442 ovarian tumors using a new morphology index (MI) based on tumor volume and wall structure. Each tumor was assigned a score of 0 to 10 based on increasing volume and morphologic complexity. Doppler flow studies were performed on 371 of these tumors. Following morphologic evaluation, all ovarian tumors were removed surgically. RESULTS: Of 315 tumors with a MI < 5 there was only 1 malignancy (a stage IA granulosa cell tumor <2 cm in diameter) whereas there were 52 malignancies in 127 tumors with a MI > or = 5. Stage of disease was as follows: stage I, 33; stage II, 6; stage III, 14. Risk of malignancy was related directly to MI score, varying from 0.3% in tumors with a MI < 5 to 84% in tumors with a MI > or = 8. A MI value of > or = 5 as indicative of malignancy was associated with the following statistical parameters: sensitivity 0.981, specificity 0.808, PPV 0.409, NPV 0.997. A pulsatility index (PI) < 1.0 as indicative of malignancy was associated with: sensitivity 0.528, specificity 0.776, PPV 0.288, NPV 0.906. A resistive index (RI) < 0.4 as indicative of malignancy was associated with: sensitivity 0.222, specificity 0.867, PPV 0.222, and NPV 0.867. The addition of Doppler flow indices to MI did not improve the accuracy of predicting malignancy. Likewise, the absence or presence of ovarian tumor blood flow was not reliable as a means to differentiate benign from malignant ovarian tumors. CONCLUSIONS: Morphology indexing is an accurate and inexpensive method of differentiating benign from malignant ovarian tumors, and can be a valuable adjunct in treatment planning. The addition of Doppler flow studies did not improve diagnostic accuracy of MI.

Risk of malignancy in unilocular ovarian cystic tumors less than 10 centimeters in diameter.

OBJECTIVE: To determine the natural history and to estimate the risk of malignancy of unilocular ovarian cystic tumors less than 10 cm in diameter followed conservatively by transvaginal ultrasound. METHODS: From 1987 to 2002, 15,106 asymptomatic women at least 50 years old entered the University of Kentucky's Ovarian Cancer Screening Program and underwent initial transvaginal ultrasonography. If the screen revealed nothing abnormal, women were asked to repeat transvaginal ultrasonography yearly. If the screen revealed abnormalities, transvaginal ultrasonography was repeated in 4 to 6 weeks, along with Doppler flow ultrasonography and CA 125 testing. RESULTS: Of the 15,106 women at least 50 years old, 2763 women (18%) were diagnosed with 3259 unilocular ovarian cysts. A total of 2261 (69.4%) of these cysts resolved spontaneously, 537 (16.5%) developed a septum, 189 (5.8%) developed a solid area, and 220 (6.8%) persisted as a unilocular lesion. During this time, 27 women received a diagnosis of ovarian cancer, and ten had been previously diagnosed with simple ovarian cysts. All ten of these women, however, developed another morphologic abnormality, experienced resolution of the cyst before developing cancer, or developed cancer in the contralateral ovary. No woman with an isolated unilocular cystic ovarian tumor has developed ovarian cancer in this population. CONCLUSION: The risk of malignancy in unilocular ovarian cystic tumors less than 10 cm in diameter in women 50 years old or older is extremely low. The majority will resolve spontaneously and can be followed conservatively with serial transvaginal ultrasonography.

Continuing participation supports ultrasound screening for ovarian cancer.

The effect of ovarian cancer screening on survival is enabled by women who continue to actively participate in screening. In this report, factors that affect participation are examined. Participants included 13,963 Kentucky women who received 56,392 screens accounting for a 46,113 screening year experience. Background, health history and reasons for participating in transvaginal sonographic screening were collected via a self-reported questionnaire. Screening participants were characterized as > 50 years old, mostly married, well educated, medically insured, health conscious women, living in the vicinity of the screening centre or 51-150 miles away. Approximately 70% of the participants can be considered active in the study based upon a screening visit during the 1997-1998 2-year period. The probabilities of a return screen at 1, 2, 5 and 7.5 years were 77.8%, 72.0%, 58.7% and 50.6%, respectively. A total of 96% of return visits occurred within 2 years, with 33.7% having intervals of < 1 year. Perceived family history was not observed to affect continuation. However, abnormal findings were associated with a shortened participation. These high levels of continuation in ultrasound screening indicate that women take this disease seriously and demonstrate that this disease is of consequence to them.

The efficacy of transvaginal sonographic screening in asymptomatic women at risk for ovarian cancer.

OBJECTIVE: The purpose of this study was to determine the efficacy of annual transvaginal sonography (TVS) as a screening method for ovarian cancer. METHODS: Annual TVS screening was performed on 14, 469 asymptomatic women from 1987 to 1999. Eligibility criteria included (1) all women >/= 50 years of age and (2) women >/= 25 years of age with a family history of ovarian cancer. Ovarian volume was calculated using the prolate ellipsoid (length x height x width x 0.523). An abnormal sonogram was defined by (1) an ovarian volume >10 cm(3) in postmenopausal women or >20 cm(3) in premenopausal women or (2) a papillary or complex tissue projection into a cystic ovarian tumor. All women with abnormal TVS had a repeat sonogram in 4-6 weeks. Patients with a persistently abnormal second screen had a serum CA-125 determination, tumor morphology indexing, and Doppler flow sonography, and were advised to have surgical tumor removal. RESULTS: One hundred eighty patients with persisting TVS abnormalities underwent exploratory laparoscopy or laparotomy. Seventeen ovarian cancers were detected: 11 Stage I, 3 Stage II, and 3 Stage III. Only three patients with Stage I cancers had a palpable ovarian mass on clinical examination. All patients with Stage I and II ovarian cancer are alive without recurrence 1.8-9.8 years (median, 4.5 years) after diagnosis. Two of the three Stage III patients have died of disease: one at 4.3 years and one at 7.7 years after detection. Four patients developed ovarian cancer within 12 months of a negative scan (FN): 2 Stage II, 2 Stage III. Three of these patients are alive with no evidence of disease 0.4, 1.9, and 5.5 years after diagnosis, and 1 patient has died of disease 0.7 years after diagnosis. Four patients developed ovarian cancer more than 12 months following a normal screen. All 4 presented clinically with Stage III disease. Two of these patients have died of disease and two patients are alive 1.5 and 2.1 years after diagnosis. TVS screening was associated with the following statistical variables: sensitivity, 81%; specificity, 98.9%; positive predictive value (PPV), 9.4%; and negative predictive value (NPV), 99.97%. After 46, 113 screening years, there have been 3 ovarian cancer deaths in the annually screened population and 2 ovarian cancer deaths in women receiving less than annual screening. The survival of ovarian cancer patients in the annually screened population was 95.0 +/- 4.9% at 2 years and 88.2 +/- 8.0% at 5 years. Excluding all cases of nonepithelial or borderline epithelial malignancies, the survival of patients with ovarian cancer in the annually screened population was 92.9 +/- 6.9% at 2 years and 83.6 +/- 10.8% at 5 years. CONCLUSIONS: (1) TVS screening, when performed annually, is associated with a decrease in stage at detection and a decrease in case-specific ovarian cancer mortality. (2) TVS screening does not appear to be effective in detecting ovarian cancer in which ovarian volume is normal.

Ovarian volume related to age.

OBJECTIVE: The goal of this study was to determine the relationship of ovarian volume to age, height, and weight in women undergoing transvaginal sonography. METHODS: Thirteen thousand nine hundred sixty-three women 25-91 years of age undergoing annual transvaginal sonography as part of the University of Kentucky Ovarian Cancer Screening Program were the subjects for this investigation. Each ovary was measured in three dimensions, and ovarian volume was calculated using the prolate ellipsoid formula (L x H x W x 0.523). Mean ovarian volume according to age was calculated for each decade of life. RESULTS: Data were obtained from 58,673 observations of ovarian volume. Mean ovarian volume was 6.6 +/- 0.19 cm(3) in women less than 30 years of age; 6.1 +/- 0.06 cm(3) in women 30-39; 4.8 +/- 0.03 cm(3) in women 40-49; 2.6 +/- 0.01 cm(3) in women 50-59; 2. 1 +/- 0.01 cm(3) in women 60-69; and 1.8 +/- 0.08 cm(3) in women >/=70. Mean ovarian volume was 4.9 +/- 0.03 cm(3) in premenopausal women and 2.2 +/- 0.01 cm(3) in postmenopausal women (P < 0.001). The use of exogenous estrogens was associated with a significant reduction in ovarian volume in women 40-59 years of age, but not in women >/= 60. Ovarian volume was unrelated to patient weight but was greater in tall women (>68 in.) than in short women (<58 in.). CONCLUSION: There is a statistically significant decrease in ovarian volume with each decade of life from age 30 to age 70. Mean ovarian volume in premenopausal women is significantly greater than that in postmenopausal women. The upper limit of normal for ovarian volume is 20 cm(3) in premenopausal women and 10 cm(3) in postmenopausal women.

Ovarian steroid cell tumors, not otherwise specified: a case report and literature review.

Steroid cell tumors, not otherwise specified, are rare ovarian sex cord-stromal tumors with malignant potential. The majority of these tumors produce steroids with testosterone being the most common. A case of a 46-year-old woman who presented with sudden onset of virilization and a pelvic mass is reported. Various aspects of the presentation, diagnosis, and treatment of these tumors are discussed.

Ultrasound evaluation of pelvic masses: predictors of malignancy for the general gynecologist.

Recent data indicate that assessment of sonographically determined tumor volume and morphology is the most accurate means to differentiate benign from malignant ovarian tumors. Doppler flow studies generally have shown a lower impedance to flow in vessels supplying ovarian malignancies than in those associated with benign tumors. However, the overlap in pulsatility index and resistive index values of benign and malignant ovarian tumors, and the cost of this procedure, make its routine use impractical. In a postmenopausal woman with a sonographically confirmed ovarian tumor, a progressively rising serum Ca-125 is highly suspicious for malignancy.

Neuroendocrine signet ring cell adenocarcinoma of the endocervix.

Signet ring cell morphology in mixed carcinoma of the uterine cervix is not uncommon. It is rare for such morphology to predominate, however, and there are no reported cases of a signet ring cell adenocarcinoma (SRCA) of the endocervix with neuroendocrine differentiation. A 53-year-old woman presented with abnormal perimenopausal bleeding, and uterine curettings revealed a signet ring cell carcinoma. After clinical evaluation to eliminate a metastasis from an extra-uterine primary, the patient underwent surgical therapy and staging, and was treated with postoperative adjuvant chemoradiation. Pathologic evaluation found the tumor to arise from the endocervix and to be of predominant signet ring cell morphology. Immunohistochemical staining revealed that the tumor exhibited neuroendocrine differentiation and helped confirm its endocervical origin. The patient remains without evidence of disease 6 months after primary therapy. This is the first case report of endocervical SRCA with neuroendocrine differentiation (SRCA with features of carcinoid tumor). Discussion of this entity is provided.

The malignant potential of small cystic ovarian tumors in women over 50 years of age.

OBJECTIVE: The aim of this study was to determine the risk of malignancy in cystic ovarian tumors < 10 cm in diameter in asymptomatic postmenopausal women or women >or =50 years of age. METHODS: All cystic ovarian tumors detected by transvaginal sonography screening in asymptomatic postmenopausal women or women > or =50 years of age were evaluated with respect to size and morphology. Histology was recorded on all tumors removed surgically. Follow-up data were available both on patients undergoing surgery and on those who elected to be followed without operative intervention. RESULTS: Unilocular cystic tumors were detected in 256 of 7705 patients (3.3%). All tumors were < 10 cm in diameter and 90% were < 5 cm in diameter. One hundred twenty-five of these cysts (49%) resolved spontaneously within 60 days and 131 (51%) persisted. Forty-five patients with persisting ovarian cysts underwent operative removal of these tumors. Thirty-two patients had ovarian serous cystadenomas, and the remainder had a variety of benign lesions. There were no cases of ovarian carcinoma in this group. Eighty-six patients with unilocular cystic ovarian tumors were followed at 3- to 6-month intervals without surgery, and none have developed ovarian cancer. Complex cystic ovarian tumors were detected in 250 patients (3.2%). All tumors were < 10 cm in diameter and 89% were < 5 cm in diameter. One hundred thirty-five (55%) resolved spontaneously within 60 days, and 115 (45%) persisted. One hundred fourteen of these patients underwent operative tumor removal. Seven patients had ovarian carcinoma, 1 had primary peritoneal cancer, and 1 had metastatic breast cancer to the ovary. CONCLUSION: Unilocular ovarian cysts < 10 cm in diameter in asymptomatic postmenopausal women or women > or =50 years of age are associated with minimal risk for ovarian cancer. In contrast, complex ovarian cysts with wall abnormalities or solid areas are associated with a significant risk for malignancy. These data are important in determining optimal strategies for operative intervention in these patients.

Transvaginal sonography as a screening method for the detection of early ovarian cancer.

From December 1987 to December 1993, 6470 women underwent screening with transvaginal sonography (TVS) as part of the University of Kentucky Ovarian Cancer Screening Project. Two groups of women were eligible to participate in this investigation: (i) asymptomatic postmenopausal patients or patients >50 years of age, and (ii) asymptomatic women >30 years of age with a family history of ovarian cancer. Ovarian volume was calculated using the prolate ellipsoid formula (length x height x width x 0.523). An abnormal sonogram was defined by (1) an ovarian volume >10 cm3 in postmenopausal women or >20 cm3 in premenopausal women, and (2) a papillary or complex tissue projection into a cystic ovarian tumor. All women with an abnormal TVS had a repeat sonogram in 4-6 weeks. Patients with persistently abnormal scans had a serum CA-125 determination, tumor morphology indexing, and color Doppler sonography. Ninety patients (1.4%) with a persisting abnormality on TVS underwent exploratory laparotomy or laparoscopy for tumor removal. Thirty-seven patients had serous cystadenomas and six had primary ovarian cancers. Five patients had Stage IA ovarian cancer and one patient had Stage IIIB disease. Only one of the ovarian cancer patients had a palpable abnormality on pelvic examination, and none had an elevated (>35 u/ml) serum CA-125. All these patients are presently alive and well 1-5 years after conventional therapy. There was one false negative in this study, a 38-year-old white female who was noted to have a small ovarian cancer at the time of laparoscopic prophylactic oophorectomy 11 months after a normal scan. Over 17,000 screening years have been accrued and there have been no deaths from primary ovarian cancer in the screened population. A cost analysis of TVS screening is presented.

Lymph node metastases and prognosis in patients with stage IA2 cervical cancer.

Ninety-four patients with squamous cell carcinoma invading the cervical stroma to a depth of >3.0-5.0 mm with 7 mm or less in horizontal spread (FIGO Stage IA2) were evaluated. Depth and lateral extent of stromal invasion were verified using an ocular micrometer. Cell type and lymph vascular space invasion (LVSI) were recorded in each case. Patients were treated primarily by radical hysterectomy with pelvic lymphadenectomy, and those with lymph node metastases were offered postoperative radiation. Following treatment, patients were seen at 3-month intervals for 2 years, and every 6 months thereafter. The mean duration of follow-up was 6.9 years (range 0.4-23.5 years). Seven of 94 patients (7.4%) had lymph node metastases. Five patients had 1 positive node, 1 patient had 2 positive nodes, and 1 patient had 3 positive nodes. Five patients developed recurrent cancer and 4 died of disease. LVSI was present in 31 cases (33%). Tumor recurrence was significantly increased in patients with positive LVSI (9.7% vs 3.2%). The 5-year survival rate of patients with LVSI was 89% vs 98% in patients without this finding (P = 0.058). The 5-year survival rate of all Stage IA2 cervical cancer patients was 95%. Patients with Stage IA2 cervical cancer have a significant risk of lymph node metastases and should be treated by radical hysterectomy with pelvic lymphadenectomy. LVSI is an important prognostic variable in these patients and should be recorded in all cases.

Evidence for a unifocal origin in familial ovarian cancer.

OBJECTIVE: The purpose of this investigation was to determine the pattern of loss of heterozygosity in multiple tumor sites from familial ovarian cancer cases. If ovarian cancer arises focally in one ovary and then metastasizes to other sites, a similar pattern should be seen in all tumor sites. However, if ovarian cancer arises multifocally throughout the peritoneal cavity, a different pattern of loss would be expected among the different sites. STUDY DESIGN: The presence or absence of loss of specific alleles for 9 loci on chromosomes 1, 6, 11, 13, 16, and 17 was determined in multiple tumor sites from 12 familial ovarian cancer cases. RESULTS: The frequency of loss of heterozygosity was as follows: chromosome 17 (100%), chromosome 13 (82%), chromosome 6 (80%), chromosome 16 (73%), chromosome 1 (57%), and chromosome 11 (22%). In every case an identical pattern was present for at least one locus. In four cases loss of the same allele was present in tumor from the ovary and all metastatic sites for all informative loci. In the remaining eight cases loss of the same allele for one to five (mean three) loci was detected. CONCLUSIONS: The pattern of loss of heterozygosity in the 12 familial ovarian cancers included in this investigation favors a unifocal origin of disease. A dual primary origin could not be absolutely excluded in 3 cases. High frequencies on chromosomes 17q and 13 suggest that loss of whole or part of these chromosomes is important in ovarian carcinogenesis.