Interrelationship of proliferation and hypoxia in carcinoma of the cervix.

PURPOSE: In human cervix cancer treated with radiotherapy, we have previously shown from separate groups of patients that tumor hypoxia and proliferation rate as measured by bromodeoxyuridine (BrdU) labeling index (LI) are important determinants of clinical outcome. We now examine the relationship of these two pre-treatment predictive assays in 43 patients studied prospectively from 1994-98 where both tests were performed for each patient. MATERIAL AND METHODS: Newly diagnosed patients with carcinoma of the cervix were examined under anesthesia for staging purposes. Patients were given BrdU (200 mg) by intravenous route prior to the procedure. Tumor oxygenation was measured with the Eppendorf pO2 histograph. Biopsy of tumor was then performed and the BrdU LI was obtained by flow cytometry. The degree of tumor hypoxia for each tumor was expressed as median pO2 values, and as the percentage of pO2 readings <5 mm Hg (HP5). RESULTS: The median age was 53 years (range 23-79 years). There were 32 squamous, and 11 non-squamous carcinomas. FIGO stages were: IB and IIA, 8; IIB, 17; IIIB, 18; with a median tumor size of 6 cm (range 2-10 cm). The patients received uniform treatment with radical radiation therapy. There were 22 diploid and 21 aneuploid tumors. The median LI, pO2, and HP5 were 8.0%, 5.4 mm Hg, and 46.8%, respectively. Tests for linear associations showed no significant correlation between median pO2 vs. LI (r = 0.078, p = 0.62), and HP5 vs. LI (r = -0.14, p = 0.38). CONCLUSIONS: The clinical outcome in this group of patients is immature, but these results suggest that tumor hypoxia and proliferation measurements are independent and potentially complementary predictive assays in cervix carcinoma. Further investigations are required to examine the distribution of proliferating tumor cells and its relationship with hypoxic tumor cells in tissue sections with the use of immunohistological techniques and image analysis systems.

Tumour proliferation and apoptosis in human uterine cervix carcinoma II: correlations with clinical outcome.

PURPOSE: The prognostic value of tumour proliferation and apoptosis measurements were studied prospectively in patients with carcinoma of the uterine cervix, relative to other established clinical factors. MATERIALS AND METHODS: The labelling index (LI) for bromodeoxyuridine was determined by flow cytometry (fc) and also by immunohistochemistry. Apoptosis was assessed histologically using morphological criteria. Patients were treated with radical radiation therapy (RT). RESULTS: The median/mean LI-fc were 6.7%/7.9% (range 1.52-3.9%). The median/mean apoptosis index (AI) were 1.0%/1.6% (range 0-6.8%). To date, 27 patients have died of disease, and the median follow-up for alive patients is 3.2 years (range 0.4-6.0 years). Among 64 patients who completely responded to treatment, 25 patients have relapsed (six pelvic, 17 distant and two pelvic and distant). In univariate analysis, the most significant factors for disease-free survival (DFS) were large tumour size (P=0.0001), low haemoglobin (P=0.01 ), LI-fc (DFS 67% for LI < 7%, 33% for LI > or = 7%, P=0.03), and T(pot) (DFS 66% for T(pot) > 5 days, 35% for T(pot) < or = 5 days, P=0.04) Stage, overall treatment time (OTT), S-phase fraction, ploidy, T(s), LI by histology, mitotic index, and AI were not significant. Multivariate analysis (Cox's model) showed that the only significant prognostic factors for DFS were tumour size and OTT. However, for small tumours (diameter < 6 cm), either a high LI-fc ( > or = 7%) or a high AI ( > 1%) was associated with poorer DFS, whereas patients with larger tumours (diameter > or = 6 cm) fared poorly regardless of LI-fc and AI. CONCLUSIONS: Tumour size was the most important prognostic factor in cervix carcinoma. Although none of the biologic parameters have independent prognostic significance when the effect of initial tumour size was taken into account, our data suggests that LI and AI may be useful in discriminating outcome for patients with smaller tumours when managed by radical RT. These findings support the hypothesis that rapidly proliferating tumours are less likely to be controlled with a conventional course of RT.

Interstitial fluid pressure in cervical carcinoma: within tumor heterogeneity, and relation to oxygen tension.

BACKGROUND: Interstitial fluid pressure (IFP) is elevated in many animal and human tumors. The authors assessed tumor IFP and its relation to tumor oxygenation in a prospective clinical study of patients with cervical carcinoma. METHODS: Measurements were made in 77 patients with cervical carcinoma prior to treatment. IFP was measured in normal paravaginal submucosal tissue and at one to five positions in the visible tumor with the patients anesthetized and in the lithotomy position. Tumor oxygen tension was measured immediately prior to IFP using a polarographic needle electrode. Patients were treated with radiotherapy only. Response was evaluated 3 months after the completion of radiotherapy. RESULTS: There was substantial variation in IFP from region to region in some tumors. The mean IFP in individual tumors ranged from 3 to 48 millimeters of mercury (mmHg). The overall mean and median values for the entire patient group were 19 mmHg and 17 mmHg, respectively. IFP was significantly higher in tumor tissue than in normal tissue (P < 0.0001). Tumors with high IFP were more likely to be hypoxic (P < 0.007) and less likely to regress completely with radiotherapy (P < 0.04). CONCLUSIONS: IFP in cervical carcinoma is elevated above normal tissue values. Multiple measurements are needed to evaluate IFP in these tumors. High IFP is associated with hypoxia and may provide information about the mechanism of hypoxia on which treatment can be based.

Squamous cell carcinoma of the breast.

OBJECTIVE: To review the mammographic and ultrasonographic features of primary breast cancer containing squamous cell carcinoma. PATIENTS AND METHODS: From medical records for breast cancer patients seen over a 37-year period the authors identified 19 patients with squamous cell carcinoma, for 5 of whom histologic sections and imaging studies were available. The tumours were classified on the basis of histologic findings as pure (in two patients) or predominantly (in three patients) squamous cell carcinoma. Mammograms were available for four of the patients, and the mammographic report only was available for analysis for the fifth. Ultrasonography had been performed for four of the patients; the images were available for two of the patients and the reports only for two. RESULTS: The median age of the patients was 55 years. The mean size of the tumours, all of which were palpable, was 5.0 cm. None of the tumours was connected to the skin, arose in the nipple-areolar complex or was metastatic. On mammography, the margins of all five masses, which were oval in shape, were indistinct and partly well-circumscribed; in three cases, the tumour margin was also partly spiculated. No malignant microcalcifications were seen. The two "pure" squamous cell carcinoma tumours appeared on ultrasonography as solid hypoechoic masses, and two of the predominantly squamous cell carcinoma tumours had both cystic and solid components. At gross pathological examination, four of the tumours (two "pure" and two predominantly squamous cell carcinoma) were cystic, which reflected areas of necrosis and cyst formation. CONCLUSION: Although "pure" or predominantly squamous cell carcinoma is a rare histologic variant of breast cancer that lacks any typical mammographic features, this tumour can be added to the differential diagnosis of cystic breast masses seen on ultrasonography.

Proliferation measurements with flow cytometry Tpot in cancer of the uterine cervix: correlation between two laboratories and preliminary clinical results.

PURPOSE: To assess the prognostic value of the pretreatment potential doubling time (Tpot) in carcinoma of the uterine cervix, relative to other established clinical factors. METHODS AND MATERIALS: Fifty-two patients with cervical cancer were studied prospectively from March 1991 to October 1993. Pretreatment evaluation included examination under anesthesia and tumor biopsy 6 h following the intravenous administration of bromodeoxyuridine (200 mg). Tpot was determined by deriving the labeling index (LI) and S-phase synthesis time (Ts) using flow cytometry. Six patients were not evaluable and excluded. The remaining 46 patients (average age 55 years) were treated uniformly with radical radiation therapy. There were 39 squamous carcinomas and 7 adenocarcinomas. Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stages were: Ib and IIa, 12 patients; IIb, 18 patients; III and IV, 16 patients. The median external beam dose was 50 Gy (range, 45-52.8 Gy) delivered in 25 fractions. The median intracavitary dose was 40 Gy (range. 25.5-40 Gy) delivered with a single line source to a point 2 cm lateral of the midline, with a mean dose rate of 0.71 Gy/h. The median overall treatment time was 45 days (range, 34-73 days). As of July 31, 1994, 12 patients had died of disease, and the average follow-up for alive patients was 1.4 years (range, 0.5-3.3 years). RESULTS: There were 27 tumors with diploid deoxyribonucleic acid (DNA) content and 19 tumors were aneuploid. The median and mean Tpot for the 46 patients were 5.5 and 6.6 days, respectively [range, 2.0-25.6 days; coefficient of variation (CV), 74%]. For 25 patients where Tpot measurements were performed at two separate laboratories, there was a fair correlation (r = 0.74), but systematic differences were detected suggesting that the lack of agreement was not simply due to intratumoral variation. To date, 30 patients remained disease free, while 8 patients had pelvic failure and 9 patients developed distant metastases as the first failure site (1 patient developed both at the same time). In univariate analysis, the only significant prognostic factor for disease-free survival was tumor size (p = 0.004). A short Tpot (or high LI) and long overall treatment time (OTT) were weakly associated with poorer disease-free survival, although not statistically significant (1/Tpot, p = 0.14; LI, p = 0.23; OTT, p = 0.04). Age, FIGO stage, hemoglobin level, S-phase fraction, DNA ploidy, and Ts were not associated with disease-free survival. Multiple regression analysis was not performed because of the relatively small number of patients and short follow-up. CONCLUSIONS: Tpot values determined with current techniques by different laboratories cannot be used interchangeably for the purpose of therapy decisions. Vigorous quality assurance and standardization of the laboratory procedures and analysis methods are important to reduce interlaboratory variation. In this uniformly treated group of patients with cancer of the uterine cervix, traditional clinical prognostic factors remain the most important. Preliminary data suggest that the flow cytometry-determined Tpot and labeling index predict for disease-free survival, although a larger number of patients with longer follow-up is required to assess the true prognostic significance of these assays and to determine if their effect is independent of other clinical factors.

Prognostic factors in patients with cervix cancer treated by radiation therapy: results of a multiple regression analysis.

A retrospective analysis of 965 patients with invasive cervix cancer treated by radiation therapy between 1976 and 1981 was performed in order to evaluate prognostic factors for disease-free survival (DFS) and pelvic control. FIGO stage was the most powerful prognostic factor followed by radiation dose and treatment duration (P values = 0.0001). If the analysis was limited to patients treated with radical doses of 75 Gy or more, dose was no longer significant. Young age at diagnosis, non-squamous histology and transfusion during treatment were also adverse prognostic factors for survival and control. Para-aortic nodal involvement on lymphogram was associated with a reduction in DFS (P = 0.0027), whereas pelvic lymph node involvement alone was not. In patients with Stage I and IIA disease, tumour size was the most powerful prognostic factor for survival (P = 0.0001) and the extent of pelvic sidewall involvement was significant in patients with Stage III tumours (P = 0.007). Histological grade appeared to be a predictive factor but was only recorded in 712 patients. These features should be considered in the staging of patients and in the design of clinical trials.

Analysis of complications in patients treated with abdomino-pelvic radiation therapy for ovarian carcinoma.

Between 1971 and 1985, 598 patients with ovarian carcinoma were treated with abdomino-pelvic radiation therapy. Acute complications included nausea and vomiting in 364 patients (61%) which were severe in 36, and diarrhea in 407 patients (68%), severe in 35. Leukopenia (less than 2.0 x 10(9) cells/liter) and thrombocytopenia (less than 100 x 10(9) cells/liter) occurred in 64 patients (11%) each. Treatment interruptions occurred in 136 patients (23%), and 62 patients (10%) did not complete treatment. In both situations the most common cause was myelosuppression. Late complications included chronic diarrhea in 85 patients (14%), transient hepatic enzyme elevation in 224 (44%), and symptomatic basal pneumonitis in 23 (4%). Serious late bowel complications were infrequent: 25 patients (4.2%) developed bowel obstruction and 16 required operation. Multivariate analysis was unable to determine any significant prognostic factors for bowel obstruction; however, the moving-strip technique of radiation therapy was associated with a significantly greater risk of developing chronic diarrhea, pneumonitis, and hepatic enzyme elevation than was the open beam technique. We conclude that abdomino-pelvic radiation therapy as used in these patients is associated with modest acute complications and a low risk of serious late toxicity.

Borderline epithelial ovarian tumors: a review of 81 cases with an assessment of the impact of treatment.

Optimal management of borderline epithelial ovarian tumors remains controversial because of the lack of clear, universally accepted pathologic criteria for diagnosis, the lack of complete understanding of the significance of intraperitoneal implants, and the desire to employ more limited surgery in young women. We reviewed the experience with borderline epithelial ovarian tumors at Princess Margaret Hospital in order to assess the natural history of the disease, to determine prognostic factors that would aid in management decisions, and to determine if adjuvant therapy influenced outcome. Eighty-one patients were analyzed. The mean age was 48 years. Seventy-two percent of tumors were of the serous histologic sub-type and 28% were mucinous. Seventy-eight percent were Stage I, 11% Stage II, and 11% Stage III. Peritoneal washings contained malignant cells in 14 of 32 patients (not recorded or obtained in 49), cyst rupture occurred in 25%, surface excrescences in 40%, and adhesions in 46%. None of these factors had a significant effect on recurrence rate or survival. Eleven patients received adjuvant radiation therapy (10 abdomino-pelvic and 1 pelvic alone), four adjuvant chemotherapy, and one both radiation therapy and chemotherapy. The rest (65) received no adjuvant therapy. Due to the small numbers and infrequent events, it was not possible to analyze and thus draw valid conclusions regarding the effect of adjuvant therapy on survival or recurrence. The overall survival (OS) and cause specific survival (CSS) were 85% and 96% at 10 years, respectively. No Stage I patient died of tumor. OS for Stage I patients was 90% at 10 years, the majority of whom (61 of 63) received no adjuvant therapy, and is thus unnecessary in Stage I disease. The adequacy of unilateral oophorectomy or ovarian cystectomy could not be confirmed because of small numbers. The 10 year OS and disease-free survival in Stage II and III were 75% and 50%, respectively, despite the use of adjuvant radiation therapy, chemotherapy, or both. It is necessary to create a multi-center tumor registry in order to acquire a prospective data base from which to develop sound therapeutic decisions.

The frequency of malignant neoplasms in patients with polymyositis-dermatomyositis. A controlled study.

Seventy-one patients with polymyositis-dermatomyositis (PM/DM) admitted to the Wellesley Hospital Rheumatic Disease Unit (RDU) in Toronto between 1965 and 1980 were followed up to 1981. The frequencies of malignant neoplasms occurring prior to or concurrent with initial RDU admission were compared, using case-control methods, with age- and sex-matched control groups with a diagnosis of any non-PM/DM rheumatic disease (rheumatic disease controls) or osteoarthritis, fibrositis, or fracture (noninflammatory musculoskeletal controls). In a cohort analysis, the incidence of malignant neoplasm subsequent to initial RDU admission in patients with PM/DM was compared with the expected incidence in the Canadian population. Fifteen of 71 patients with PM/DM had an antecedent or concurrent cancer compared with four of 71 rheumatic disease controls and one of 71 noninflammatory musculoskeletal controls. Cohort analysis showed no increase in the number of subsequent malignant neoplasms in patients with PM/DM compared with the age- and sex-matched Canadian population.