Gavin C.E. Stuart

A phase I/II evaluation of tirapazamine administered intravenously concurrent with cisplatin and radiotherapy in women with locally advanced cervical cancer

PURPOSE This is a Phase I/II dose escalation study to determine the tolerable dose of tirapazamine (TPZ), and the toxicity of a regimen using TPZ with cisplatin, and radiotherapy in women with locally advanced cervical cancer. METHODS AND MATERIALS Eligible women for this study were those with a diagnosis of locally advanced cervix cancer, who were less than 75 years of age, having provided informed consent, and who had undergone the necessary prestudy investigations. External-beam radiotherapy (RT) was given to a minimum dose of 4500 cGy in 25 fractions (Day 1-35), and brachytherapy then delivered to bring the total dose at point A to 8500 cGy. The first dose level of the study used TPZ 190 mg/m(2) and cisplatin 75 mg/m(2) on Days 1, 15, and 29 of RT. TPZ 160 mg/m(2) alone was used on Days 8, 10, 12 and 22, 24, 26 of RT. A conventional dose-escalation step method was then used to determine the maximum tolerated dose (MTD) of TPZ. RESULTS Four patients were treated at Level 1, 6 at Level 2, and 5 at Level 3. Only 1 patient experienced a dose-limiting toxicity (DLT) at Level 2, but 2 of the 5 patients at Level 3 incurred DLTs. Level 2 was declared the MDT (TPZ 290 mg/m(2) on Days 1, 15, 29 and 220 mg/m(2) on Days 8, 10, 12 and 22, 24, 26). At 6 months, 13 of 15 patients had complete pelvic control of disease. CONCLUSION Level 2 of this regime was identified as the MDT. The use of TPZ with concurrent cisplatin and pelvic radiotherapy has acceptable toxicity and should be considered for further Phase 2 testing in view of the promising responses noted.

The human papillomavirus status of invasive cervical adenocarcinoma: A clinicopathological and outcome analysis

Accumulating evidence highlights the human papillomavirus (HPV) as a risk factor for cervical adenocarcinoma. However, the part played by the HPV in predicting tumor outcome or the increasing frequency of cervical adenocarcinoma is incompletely studied. In a retrospective study the association between HPV status and the clinicopathological characteristics of 77 cases of cervical adenocarcinoma was investigated. The data were then analyzed for temporal differences in HPV status and to identify outcome predictors. Human papillomavirus status was determined by dot blot hybridization using probes for HPV 6, 11, 16, 18, 31, 33, and 35, followed by polymerase chain reaction amplification of the dot blot negative cases. Seven type-specific and consensus HPV primers were used. Human papillomavirus type 16, 18, or 33 was present in 53 (70%) cases. Human papillomavirus status did not correlate with disease outcome or any clinicopathological variable, except that tumors presenting in and after 1981 were more frequently HPV positive than those presenting before 1981 (P = .014). In a multivariate analysis only clinical stage at presentation was predictive of disease outcome. Because temporal differences in clinicopathological characteristics were not identified, the increasing frequency of cervical adenocarcinoma may relate to a more important oncogenic role for the HPV in tumors presenting after 1980.

Endometrial carcinoma occurring in patients under the age of 45 years.

Endometrial adenocarcinoma is frequently unsuspected in women under the age of 45 years by the gynecologist or the pathologist, but it does occur. Twenty-seven cases of endometrial adenocarcinoma in this age group, from 1980 to 1985, were reviewed clinically and pathologically. Five cases were excluded by histologic examination. Obesity and abnormal vaginal bleeding were shown to be risk factors. Endometrial screening is to be encouraged. This cancer may arise de novo rather than from a premalignant precursor. Implications of this neoplasm for the premenopausal woman are considered.

The human papillomavirus status of 114 endocervical adenocarcinoma cases by dot blot hybridization

The reported rate of human papillomavirus (HPV) positivity in cases of endocervical adenocarcinoma averages 38% (range, 0% to 100%) and, in contrast to cervical squamous cell carcinoma, HPV type 18 rather than type 16 is the predominant type. The HPV positivity rate and distribution of types (status) in 114 endocervical adenocarcinoma cases (37 in situ and 77 invasive) were determined by dot blot hybridization using biotinylated probes to HPV types 6, 11, 16, 18, 31, 33, and 35. Human papillomavirus DNA was present in 27% of in situ and in 44% of invasive adenocarcinomas, and in nearly all histologic subtypes of invasive adenocarcinoma. Human papillomavirus status was not predictive of tumor grade, volume, depth of invasion, lymph-vascular space involvement, age at presentation, or year of diagnosis. Type of HPV might influence the histologic subtype of invasive adenocarcinoma, as HPV type 16 predominated in the adenosquamous carcinomas while HPV type 18 was more frequently found in all other subtypes. Since only types 16, 18, and 33 were identified, an oncogenic role for HPV in endocervical carcinogenesis was supported.

Ependymoma of the uterosacral ligament

Extraspinal ependymomas have been described in the subcutaneous sacrococcygeal and presacral areas. Since 1984, eight pelvic ependymomas have been reported that have originated in the ovary, broad ligament, mesovarium, and omentum. This report documents an additional case arising from the right uterosacral ligament in a 48‐year‐old woman. The diagnosis of ependymoma was supported by a histologic pattern of true rosettes and pseudo‐rosettes, glial fibrillary acidic protein (GFAP) positivity, and electron microscopic findings of cilia, blepharoplasts, and intermediate filaments. The tumor was positive for cytokeratin and vimentin. Ultrastructurally, neurosecretory granules were present within the cytoplasm. These features have not been described previously in pelvic ependymomas. These tumors, although easily confused with serous papillary carcinoma, should be distinguished from serous papillary carcinoma because of their apparently better prognosis and tendency for late recurrence. Cancer 64:2565–2571, 1989.

The reliability of telephone interviews compared with in-person interviews using memory aids.

PURPOSE Information obtained by telephone interviews and in-person interviews is generally considered comparable, but it is unclear if extensive memory aids can be used effectively with telephone interviews. We compared a telephone interview to an in-person interview using the same questionnaire and memory aids in both. METHODS A convenience sample of 103 women, aged 25 to 69 years, completed a telephone interview and at least four weeks later, completed an in-person interview. Memory aids included a life events calendar, cue lists, and worksheets. RESULTS Agreement values, measured by kappa/weighted kappa, were as follows: parity (1.00), age at menarche (0.76), menopausal status (0.95), a history of reproductive organ surgery (0.98) or tubal ligation (0.91), self-reported infertility (0.76), and a first degree family history of breast/ovarian cancer (0.90). Agreement values for duration variables, measured by the intraclass correlation, were as follows: lactation (0.96), oral contraceptive use (0.98), any hormone replacement therapy (0.98), exclusive estrogen and progesterone therapy (0.83), and exclusive estrogen therapy (0.99). CONCLUSIONS The good to excellent level of agreement found in this study indicates that telephone administration of our questionnaire with extensive memory aids is a reliable method of obtaining detailed exposure information relative to in-person interviews.

Laser vaporization of vaginal intraepithelial neoplasia

Laser vaporization was used to treat 27 women diagnosed at the Tom Baker Cancer Centre, Calgary, Alberta, Canada, as having vaginal intraepithelial neoplasia. The diagnosis was established after review of vaginal cytologic examination and a histologic biopsy. Treatment was performed with a carbon dioxide laser unit attached to an operating microscope. All but three patients had general anesthesia for the purpose of treatment. Tissue destruction was accomplished to a depth of 2 to 3 mm. Patients were followed up for an average of 14.4 months with regular colposcopy, cytologic evaluation, and biopsy when persistent or recurrent disease was suspected. Failure of therapy was defined as evidence of intraepithelial neoplasia in any one of these three parameters. Four patients required a second treatment. After one or two treatments the success rate of therapy was 78%. In our institution, laser vaporization with the patient under general anesthesia on an outpatient basis is the treatment of choice for vaginal intraepithelial neoplasia.

The effect of estrous cycle and buthionine sulfoximine on glutathione release from the in vitro perfused rat ovary

There is little known regarding the intracellular mechanisms of modification of damage in the ovary. Ovarian perfusion of en block dissections of the rat right ovary with aorta and vena cava were done to determine (a) if glutathione (GSH) is released by the ovary, (b) if the release is cycle dependent, and (c) if GSH released is the product of de novo ovarian synthesis. All perfused ovaries released GSH and the release was maximal at estrus and least at metestrus. Perfusion with buthionine sulfoximine, a specific inhibitor of gamma-glutamylcysteine synthetase, resulted in a dose-dependent reduction in GSH released, indicating inhibition of de novo synthesis during perfusion.

Invasive squamous cell carcinoma of the cervix in women less than 35 years old: Recurrent versus nonrecurrent disease

Invasive cervical squamous cell carcinoma was diagnosed in 45 patients <35 years old from 1980 to 1985. Thirty-two cases were Stage IB; 10, Stage IIB; and three, Stage IIIB. Twenty-two patients developed persistent or recurrent disease. Only one of these is now alive with no evidence of tumor. The mean interval from diagnosis to recurrence was 8.7 months (median of 7.0) and from diagnosis to death was 14.7 months (median of 12.0). Eleven of 32 patients with Stage IB disease developed a recurrence; the intervals to recurrence in Stage IB disease were similar to those for more advanced stages. Factors predicting recurrence included advanced stage of the disease and tumor bulk (maximum size, depth of invasion, and number of involved quadrants) as well as an exophytic or ulcerative tumor and a symptomatic presentation. These factors may identify the patient at high risk for recurrence who would benefit from adjuvant therapy.

Evidence of a role for the INK4 family of cyclin-dependent kinase inhibitors in ovarian granulosa cell tumors

Granulosa cell tumors (GCTs) of the ovary are relatively rare and account for <5% of all ovarian cancers. The molecular pathogenesis of these tumors is not well understood. We tested the hypothesis that cyclin‐dependent kinase inhibitors, specifically the inhibitors of the cyclin‐dependent kinase 4 (INK4) family, are targets for altered gene expression in GCTs. The status of RB1, INK4A, INK4B, INK4C, INK4D, and ARF in 13 adult and 2 juvenile ovarian GCTs was determined by reverse transcription–polymerase chain reaction of total RNA and exon‐specific sequencing of genomic DNA. Tumors showing loss of INK4A expression were assayed further by exon‐deletion analysis and methylation‐specific PCR. None of the juvenile tumors demonstrated altered expression, but 7/12 (58%) adult GCTs lacked expression of INK4A, INK4B, or both. In one of these cases, we noted a homozygous deletion of the INK4A locus, and in the remaining tumors we found hypermethylation of the promoter region, a mechanism that can lead to gene inactivation. These data support a role for the INK4 family of CDK inhibitors in the biology of GCTs.