Positron emission tomography analysis of [11C]KW-6002 binding to human and rat adenosine A2A receptors in the brain.

Adenosine A(2A) receptors are found on striatal neurones projecting to the external pallidum. KW-6002 (istradefylline) is a potent and selective antagonist for the adenosine A(2A) receptors in the CNS and acts to inhibit the excessive activity of this pathway in the MPTP marmoset model of PD, thus relieving parkinsonism. The objectives of this study were to investigate the regional binding of the novel positron emission tomography tracer [(11)C]KW-6002 in the healthy human brain and the rat brain, along with receptor occupancy by cold KW-6002 at varying doses in human. The highest [(11)C]KW-6002 uptake in the rat brain was seen in striatum and lower levels in cortex and cerebellum. Brain [(11)C]KW-6002 uptake was well characterized in humans by a two-tissue compartmental model with a blood volume term, and the ED(50) of cold KW-6002 was 0.5 mg in the striatum. Over 90% receptor occupancy was achieved with daily oral doses of greater than 5 mg. In humans, blockable binding was present in all gray matter structures including the cerebellum, which has not been reported to express A(2A) receptors. MRS 1745, an A(2B) receptor selective antagonist, had no effect on the cerebellar binding of [(11)C]KW-6002 in rats, suggesting that this blockable signal is unlikely to result from an affinity for adenosine A(2B) receptors.

Symptoms of gastroesophageal reflux in diabetes patients.

We used a simple questionnaire to determine the presence or absence of symptoms of gastroesophageal reflux disease (GERD) among control (n=531) and diabetic patients (n=629). Of 531 controls, 24.3% reported having symptoms, while 24.9% of 629 diabetic patients had symptoms. Symptomatic diabetic patients (n=157) were then asked to complete a supplemental questionnaire (QUEST) to determine the frequency, severity, and duration of GERD symptoms; a total diagnostic score > or =4 was considered to be positive for GERD. Diabetic patients whose QUEST score was > or =4 had a significantly higher BMI (26.9+/-0.4* vs. 24.4+/-0.4), higher HbA1c (7.5+/-0.2* vs. 7.2+/-0.1), longer duration of diabetes (113.5+/-8.7* vs. 94.0+/-10.6 months), and a higher prevalence of diabetic complications (retinopathy, 24.8%* vs. 21.3%; nephropathy, 32.6%* vs. 19.4%; neuropathy, 30.4%* vs. 23.6%) than diabetic patients whose QUEST score was <4 (*p<0.05). In diabetic patients with GERD, therapy should include not only proton pump inhibitor therapy and other specific measures for GERD, but also appropriate therapy for the diabetes, particularly blood glucose control and weight reduction.

Placental site trophoblastic tumor presenting as subaponeurotic metastasis.

Cases of metastatic placental site trophoblastic tumor (PSTT) have a very poor prognosis because these tumors tend to be less sensitive to chemotherapy than other types of gestational trophoblastic disease. We describe the case of a 25-year-old woman who presented with occipital tumor and abnormal vaginal bleeding. Hysterectomy, bilateral salpingo-oophorectomy, and occipital tumor removal revealed a primary PSTT in the uterus, with ovarian and occipital subaponeurotic metastases. She received etoposide, methotrexate, actinomycin-D/cyclophosphamide, vincristine chemotherapy and had a complete clinical remission. Fifteen months later, she had a recurrent subaponeurotic occipital tumor invading the cranium and underwent tumor removal along with cranial bone followed by local irradiation. She was then treated with etoposide, cis-platinum/etoposide, methotrexate, actinomycin-D chemotherapy and again had a remission for 5 months. The patient, however, had a left parietal subaponeurotic tumor, invading the dura mater, and received local irradiation. Soon after, she developed left orbital bone metastasis, treated by local irradiation. These bone metastases responded to the radiation completely. However, multiple organ metastases were found, and she died of the disease. This represents the first case of PSTT with initial subaponeurotic metastasis in a living patient. New modalities of treatment for high-risk or metastatic PSTT need to be developed.

Adenosine A(2A) receptor-mediated modulation of GABA and glutamate release in the output regions of the basal ganglia in a rodent model of Parkinson's disease.

A target neuron of adenosine A(2A) receptor antagonists to exert anti-parkinsonian activities has been currently identified to be, at least in part, striatopallidal medium spiny neurons (MSNs). In the present study, we determine whether A(2A) receptor-mediated modulation is associated with changes in the release of GABA and glutamate in the substantia nigra pars reticulata (SNr), an output structure of the whole basal ganglia network, using in vivo microdialysis in a rat Parkinson's disease (PD) model. In 6-hydroxydopamine (OHDA)-lesioned rats compared with normal rats, basal extracellular GABA levels in the SNr show no change, whereas basal glutamate levels are significantly increased. Oral administration of the A(2A) receptor-selective antagonist (E-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1-H-purine-2,6-dion (KW-6002) to 6-OHDA-lesioned rats at 1 mg/kg caused a marked and sustained increase of GABA and glutamate levels in the SNr. The increase of nigral glutamate by KW-6002 was abolished by a kainic acid-induced lesion of the globus pallidus (GP) or subthalamic nucleus (STN) in 6-OHDA-lesioned rats, whereas the increase of nigral GABA was completely blocked by the GP-lesion but only partially blocked by the STN-lesion. These results indicate that changes in neurotransmitter release in the SNr brought about by KW-6002 are largely attributable to blockade of A(2A) receptor-mediated modulation of striatopallidal MSNs. Thus, these actions of KW-6002 on striatopallidal MSNs may be the main mechanism for ameliorating PD by A(2A) antagonists.

Low risk endometrial cancer: a study of pelvic lymph node metastasis.

The aim of our study was to find preoperative or intraoperative pathologic indicators that would discriminate a subgroup of early corpus cancers that would not require lymphadenectomy. A retrospective review of the medical records of 107 patients with endometrioid adenocarcinoma, FIGO grade 1 or 2 tumor, myometrial invasion

Docetaxel in combination with carboplatin for chemo-naive patients with epithelial ovarian cancer.

We conducted a study of docetaxel-carboplatin combination therapy to confirm the efficacy and toxicity in chemotherapy-naive patients with ovarian cancer. Docetaxel 70 mg/m2 and carboplatin (area under the concentration-vs.-time curve of 5) were administered consecutively on day 1 of a 21-day cycle for five planned cycles in chemo-naive patients with the International Federation of Gynecology and Obstetrics stage IC to IV ovarian cancer with or without successful cytoreductive surgery at staging laparotomy. Twenty-six patients (median age, 53 years; range, 34-76 years) were enrolled into this trial at Niigata University Hospital. The major toxicity with this regimen was neutropenia. The incidence of grade 3 and 4 neutropenia were 27% (7/26) and 69% (18/26), respectively. However, the neutropenia was brief and reversible with G-CSF support. Nausea/emesis, fatigue, arthralgia/myalgias, and alopecia were the most common nonhematologic toxicities, in which no grade 3 or 4 toxicity was observed. Neurotoxicity was infrequently observed. Nine of 11 assessable patients responded to the regimen. We conclude that the combination of carboplatin and docetaxel seems to be highly active in ovarian cancer with the major toxicity of neutropenia, and the extremely low incidence of clinically significant neurotoxicity. Randomized controlled clinical trials should be conducted to define a role for this regimen in ovarian cancer.

Evaluation of [4-O-methyl-(11)C]KW-6002 as a potential PET ligand for mapping central adenosine A(2A) receptors in rats.

KW-6002, a xanthine-based adenosine A(2A) antagonist, was labelled with the positron emitter carbon-11 by O-methylation of its precursor, KF23325, using [(11)C]iodomethane and was evaluated in rats as a putative in vivo radioligand for positron emission tomography (PET). Following intravenous injection of [(11)C]KW-6002, radioactivity was measured in blood, plasma, peripheral tissues, and in discrete brain tissues over a 2-h time period commensurate with PET scanning. In brain, [(11)C]KW-6002 showed highest retention in striata, with evidence of saturable binding, and lowest retention in frontal cortex (a tissue low in adenosine A(2A) receptors). PET scanning with [(11)C]KW-6002 demonstrated a specific signal in the striata which could be described using compartmental modelling. Specific binding was, however, also detected in extrastriatal regions, including brain areas reported to have low adenosine A(2A) receptor density. Blocking studies with the A(1) selective antagonist KF15372 and the non xanthine-type A(2A) antagonist ZM 241385 failed to elucidate the nature of this binding. Thus, although [(11)C]KW-6002 shows some potential for development as a PET ligand for quantifying striatal adenosine A(2A) receptor function, its in vivo selectivity requires further investigation.

Stage III endometrial cancer: analysis of prognostic factors and failure patterns after adjuvant chemotherapy.

OBJECTIVE: This study was performed to assess the prognostic factors and patterns of recurrence in stage III endometrial carcinoma treated with surgery and adjuvant chemotherapy. METHODS: A retrospective review of 61 stage III endometrial carcinoma patients treated between 1988 and 1998 at Niigata University Hospital was performed. All patients underwent surgery, followed by adjuvant chemotherapy consisting of intravenous cisplatin, doxorubicin, and cyclophosphamide. Multivariate analysis was performed for the prognostic factors and actuarial techniques were used for the survival and recurrence rates. RESULTS: The 5-year disease-free survival was 78.6%. Multivariate analysis revealed deep myometrial invasion and lymph-vascular space involvement correlated significantly with disease-free survival. Based on these two factors, the patients could be divided into low-risk and high-risk groups. The 5-year disease-free survival for the low-risk group was 100%, which was significantly better than the 59.1% for the high-risk group. Disease recurrence occurred in 13 of 30 high-risk patients, and there was no recurrence in the 31 low-risk patients. Looking at the patterns of recurrence for the high-risk group by lymph node metastasis, 5 recurrences were locoregional, 1 was locoregional/distant, and 1 was distant in 16 node-positive high-risk patients. In 14 node-negative patients, 5 had distant and 1 had locoregional/distant recurrences. CONCLUSIONS: The locoregional failure in the node-positive high-risk group deserves further attention. For improvement of locoregional control, it may be worthwhile to consider new strategies. The role of new adjuvant chemotherapy should be investigated to control distant failure in node-negative high-risk patients.

Neoadjuvant chemotherapy for patients younger than 50 years with high-risk squamous cell carcinoma of the cervix.

OBJECTIVE: To evaluate the response rate and toxicity and to improve survival, neoadjuvant chemotherapy (NAC) was utilized in patients younger than 50 years with locally advanced cervical squamous cell carcinoma. METHODS: Twenty-one patients were treated with preoperative NAC. Eligibility included patients with previously untreated stage IB or IIA with deep stromal invasion assessed by magnetic resonance imaging or bulky tumor or IIB squamous cell carcinoma who were younger than 50 years. The NAC consisted of cisplatin (60 mg/m(2)) on day 1, vinblastine (4 mg/m(2)/day) on days 1 and 2, and peplomycin (10 mg/day) on days 1, 8, and 15 (PVP). Treatment was repeated every 3 weeks for a total of two cycles. All 21 patients underwent radical hysterectomy following NAC. Postoperative radiotherapy was given to 18 patients. We used 21 patients who underwent radical hysterectomy and postoperative radiation therapy as a nonrandomized control group. RESULTS: The response rate for NAC was 86% (18/21). Two patients required discontinuation of PVP treatment after one administration because of grade 4 neutropenia and thrombocytopenia, and decreased carbon monoxide diffusion capacity, respectively. In the NAC group, stromal invasion was significantly reduced (P = 0.0103), and the incidence of lymph node metastasis was decreased. No patients had positive parametrial and vaginal margins. The overall 5-year survival rate was 84.0% in the NAC group, which was significantly better than that in the control group (58.9%) (P = 0.0434). CONCLUSIONS: NAC for younger patients with locally advanced cervical carcinoma is thought to be safe, well tolerated, effective, and useful for increasing operability, decreasing pathological risk factors, and improving survival.

Prognostic factors and failure pattern in lymph node-negative stage IB and II cervical carcinoma treated with radical hysterectomy and postoperative irradiation.

The aim was to determine the prognostic factors and recurrence pattern in stages IB and II cervical carcinoma patients with negative pelvic lymph nodes. 224 patients with stages IB and II cervical carcinoma underwent radical hysterectomy (RH) from 1982 through 1995. Of 161 patients with negative lymph nodes, 65 patients received postoperative irradiation (RT) and 96 patients were given no further therapy according to surgical pathological findings. The overall 5-year disease-free survival was 94.1%. Two of 96 RH patients (2%) and 10 of 65 RH + RT patients (15%) had recurrence in pelvic and distant sites almost equally. Multivariate analysis revealed deep cervical invasion as the only independent prognostic factor. The 5-year disease-free survival was 98.8% for patients with shallow invasion and 85.8% for patients with deep invasion (p < 0.0001). It is worthwhile to develop new strategies for the lymph node-negative patients with deep stromal invasion.

MR imaging underestimates stromal invasion in patients with adenocarcinoma of the uterine cervix.

PURPOSE OF INVESTIGATION: To evaluate magnetic resonance (MR) imaging in assessing the depth of stromal invasion in patients with adenocarcinoma of the uterine cervix. METHODS: Twenty-three women with adenocarcinoma of the cervix underwent T2-weighted and dynamic MR imaging before surgical evaluation. The images were evaluated for the depth of stromal invasion and compared with histological results. RESULTS: Twelve of 23 patients (52%) were correctly diagnosed in agreement with the histological findings. However, the depth of stromal invasion was underestimated in ten patients (44%). In four of nine patients who exhibited scattered type lesions, no lesions were detected by MR imaging, although deep stromal invasion (more than 1/3) was recognized histologically. In contrast, all 11 patients showed cancer lesions in solid type adenocarcinomas with deep stromal invasion. CONCLUSION: MR imaging detected less stromal invasive lesions in adenocarcinoma of the cervix than surgical specimens, and some scattered type adenocarcinomas could not be visualized.

New aspects of physiological and pathophysiological functions of adenosine A2A receptor in basal ganglia.

There is now growing interest in the functional role of adenosine A2A receptors. Their distribution within the brain is restricted in the basal ganglia, particularly abundant in the striatum, which are thought to play a crucial role in the control of motor behavior. Indeed, newly developed A2A receptor selective antagonists have a profound influence on motor functions, with anti-Parkinsonian activities in several animal models. Striatal spiny neurons serve as a major anatomical locus for the relay of cortical information flow through the basal ganglia. The GABA releasing projection neurons represent the A2A receptor-mediated main target of adenosine. The GABAergic synaptic neurotransmission is regulated by adenosine via A2A receptors on the presynaptic terminals. Blockade of this modulatory function by A2A antagonists could repair striatopallidal abnormal neuronal activities provoked by striatal dopamine depletion in the Parkinsonian state. A2A receptor antagonists provide a novel therapeutic potential for the treatment of Parkinson's disease.

Adenosine A(2A) receptor enhances GABA(A)-mediated IPSCs in the rat globus pallidus.

1. The actions of adenosine A(2A) receptor agonists were examined on GABAergic synaptic transmission in the globus pallidus (GP) in rat brain slices using whole-cell patch-clamp recording. GP neurones were characterized into two major groups, type I and type II, according to the degree of time-dependent hyperpolarization-activated inward rectification and the size of input resistance. 2. The A(2A) receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido- adenosine (CGS21680; 0.3-3 microM) enhanced IPSCs evoked by stimulation within the GP. The actions of CGS21680 were blocked by the A(2A) antagonists (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF17837) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385). 3. The CGS21680-induced increase in IPSCs was associated with a reduction in paired-pulse facilitation. CGS21680 (0.3 microM) increased the frequency of miniature IPSCs (mIPSCs) without affecting mIPSC amplitude. These observations demonstrated that the enhancement of IPSCs in the GP was attributable to presynaptic, but not postsynaptic, A(2A) receptors. 4. The results suggest that A(2A) receptors in the GP serve to inhibit GP neuronal activity, thereby disinhibiting subthalamic nucleus neurone activity. Thus, the A(2A) receptor-mediated presynaptic regulation in the GP, together with the A(2A) receptor-mediated intrastriatal presynaptic control of GABAergic neurotransmission described previously, may play a crucial role in controlling the neuronal functions of basal ganglia. This A(2A) receptor-mediated presynaptic dual control in the striatopallidal pathway could also afford the mode of action of A(2A) antagonists for ameliorating the symptoms of Parkinson's disease in an animal model.

[A case of stage IV gastric cancer responding to combined chemotherapy by intravenous, intraarterial and intraperitoneal injection].

We treated a case of unresectable gastric cancer in which peritoneal lavage cytology and the primary tumor responded to combined chemotherapy by intravenous, intraarterial and intraperitoneal injection. The patient was a 61-year-old male with loss of appetite. He underwent laparotomy for gastric cancer in November, 1997. An intraperitoneal catheter was set without gastrectomy because of the unresectability due to extensive peritoneal dissemination and local invasion to pancreas. The patient was given combined chemotherapy using 5-FU 6,000 mg i.v., CDDP 360 mg i.p. and 5-FU 10,500 mg ia by the catheters in the supra vena cava, right gastroepiploic artery and peritoneal cavity. One month after laparotomy, peritoneal lavage cytology had changed to class I from class V, and the primary tumor had been reduced to 10 mm in size from a diffusely infiltrating tumor. His quality of life in appetite and activity was improved for 13 months.

Systemic administration of adenosine A(2A) receptor antagonist reverses increased GABA release in the globus pallidus of unilateral 6-hydroxydopamine-lesioned rats: a microdialysis study.

The ability of adenosine A(2A) receptor antagonists to exhibit antiparkinsonian activity has recently been reported, but the mechanisms of action are still unknown. Since A(2A) receptors have been localized to GABAergic striatopallidal neurons, it is probable that these antagonists affect the activity of these neurons. In the present study, extracellular GABA basal levels were increased in the ipsilateral striatum and globus pallidus following a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. The A(2A) receptor-selective antagonist KW-6002 (3mg/kg, p.o.) caused a marked and sustained decrease of extracellular GABA levels in the globus pallidus of the 6-hydroxydopamine-lesioned rats, whereas no changes in GABA levels were observed in the globus pallidus of the non-lesioned rats. Microinjection of the A(2A) receptor agonist CGS21680 (0.005-0.5 microg) into the striatum of non-lesioned animals increased GABA concentrations in the globus pallidus, which was abolished by the voltage-dependent Na(+) channel blocker tetrodotoxin (1 micromol/l) delivered locally to the globus pallidus via the dialysis membrane. Furthermore, intrapallidal infusion of CGS21680 (10 micromol/l) also increased GABA levels in the globus pallidus. These data indicate that GABA release from striatopallidal neurons is regulated through A(2A) receptors in both the striatum and globus pallidus. The reversal of the 6-hydroxydopamine-induced increase in pallidal GABA levels by KW-6002 suggests that the antiparkinsonian effects of A(2A) receptor antagonists occur on the striatopallidal neurons.

Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist.

In Parkinson's disease a degeneration of dopaminergic neurons of the nigrostriatal pathway is observed. Loss of dopaminergic regulation of striatal neuron activity results in altered motor functions. Adenosine A2A (A2AR) and dopamine D2 (D2R) receptors are colocalized in striatal medium spiny neurons. It has been proposed that adenosine binding to A2AR lowers the affinity of dopamine for D2R, thus modulating the function of this receptor. Absence of D2R in knockout mice (D2R-/-) results in impaired locomotion and coordinated movements. This indicates that absence of dopamine in Parkinson's disease might principally affect D2R-mediated effects with regard to locomotor functions. A2AR-selective antagonists have been demonstrated to have anti- parkinsonian activities in various models of Parkinson's disease in rodents and nonhuman primates. In this article, D2R-/- mice were used to explore the possibility that an A2AR antagonist might reestablish their motor impairment. Interestingly, blockade of A2AR rescues the behavioral parameters altered in D2R-/- mice. In addition, the level of expression of enkephalin and substance P, which were altered in D2R-/-, were also reestablished to normal levels after A2AR antagonist treatment. These results show that A2AR and D2R have antagonistic and independent activities in controlling neuronal and motor functions in the basal ganglia. They also provide evidence that selective A2AR antagonists can exhibit their anti-parkinsonian activities through a nondopaminergic mechanism.

Synthesis of tricyclic compounds as steroid 5alpha-reductase inhibitors.

A series of 4-phenoxybutyric acid derivatives attached to a tricyclic skeleton were prepared and evaluated as 5alpha-reductase inhibitors. Structure activity relationships for these compounds in terms of rat epididymis (type 2) 5alpha-reductase inhibitory activities reveal that 1) the substitution pattern at the 11-position of dibenz[b,e]oxepin influenced potency, 2) higher lipophilicity of the tricyclic skeleton improved potency, whereas the existence of a basic nitrogen atom in this skeleton was detrimental to potency, and 3) isobutyl substitution at the 8 positon of the azepine skeleton was tolerated. Among the tricyclic compounds studied, 4-[3-[5-benzyl-8-(2-methyl)propyl-10,11-dihydrodibenz[b,f]azepine- 2-carboxamido]phenoxy]butyric acid (26) was the most potent inhibitor of rat type 2 5alpha-reductase at 0.1 microM.

Combined use of the adenosine A(2A) antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys.

The novel selective adenosine A(2A) receptor antagonist KW-6002 improves motor disability in MPTP-treated parkinsonian marmosets without provoking dyskinesia. In this study we have investigated whether KW-6002 in combination with l-DOPA or selective D1 or D2 dopamine receptor agonists enhances antiparkinsonian activity in MPTP-treated common marmosets. Combination of KW-6002 with the selective dopamine D2 receptor agonist quinpirole or the D1 receptor agonist SKF80723 produced an additive improvement in motor disability. Coadministration of KW-6002 with a low dose of L-DOPA also produced an additive improvement in motor disability, and increased locomotor activity. The ability of KW-6002 to enhance antiparkinsonian activity was more marked with L-DOPA and quinpirole than with the D1 agonist. However, despite producing an enhanced antiparkinsonian response KW-6002 did not exacerbate L-DOPA-induced dyskinesia in MPTP-treated common marmosets previously primed to exhibit dyskinesia by prior exposure to L-DOPA. Selective adenosine A(2A) receptor antagonists, such as KW-6002, may be one means of reducing the dosage of L-DOPA used in treating Parkinson's disease and are potentially a novel approach to treating the illness both as monotherapy and in combination with dopaminergic drugs.

Palmar fasciitis and polyarthritis associated with squamous cell carcinoma of the cervix.

Palmar fasciitis and polyarthritis (PFPA) is an uncommon syndrome characterized by progressive and extensive rheumatic disease. We present the first example of PFPA in association with squamous cell carcinoma of the uterine cervix and peritoneal carcinoma. A 54-year-old woman developed pain in both shoulders and flexion deformities of all fingers in both hands due to an increasing swelling of both palms. She underwent surgery and histologic examination of the removed uterus revealed squamous cell carcinoma, nonkeratinizing type with a small portion of undifferentiated carcinoma. Chemotherapy resulted in an excellent response, during which the arthritic symptoms improved gradually. PFPA can occur in a wide range of cancers and warrants extensive investigation for a malignant tumor.

Ovarian metastasis in stage IB and II cervical adenocarcinoma.

We performed the present study to identify those patients with adenocarcinoma of the cervix in whom ovarian preservation might be acceptable. Between January 1971 and December 1996, 82 patients with International Federation of Gynecology and Obstetrics stage IB and II cervical adenocarcinoma and adenosquamous carcinoma, treated by radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic node dissection, were identified. The mean age of the patients was 44.6 years (range 27-72). The incidence of ovarian metastasis was more frequent in stage II (19.0%) than in stage IB disease (2.5%), in which only 1 patient with apparent extrauterine disease at laparotomy had an ovarian metastasis. No patients with up to inner two-thirds of stromal invasion had ovarian metastasis; however, 5 of 24 patients with outer one-third stromal invasion (20.8%) and 4 of 20 with parametrial invasion (20.0%) had ovarian metastasis. A significantly higher incidence of ovarian metastasis was also observed in 5 of 20 cases with lymph node metastasis (25.0%) than in 4 of 62 patients without lymph node metastasis (6.5%). Multivariate analysis, however, found only deep stromal invasion to be an independent risk factor for ovarian metastasis. Although it would be reasonable to conserve normal-appearing ovaries in young women undergoing radical hysterectomy for treatment of stage IB cervical adenocarcinoma and adenosquamous carcinoma, gross intraoperative inspection of the radical hysterectomy specimen may identify deep cervical invasion or extrauterine spread in those who are at increased risk of ovarian metastases.