Tumorigenic transformation and neoplastic progression of human uroepithelial cells after exposure in vitro to 4-aminobiphenyl or its metabolites.

A multistep in vitro/in vivo transformation system was used to test the transforming effect(s) of the human bladder procarcinogen 4-amino-biphenyl (ABP) and two putative proximate carcinogenic metabolites, N-hydroxy-4-aminobiphenyl (N-OH-ABP) and N-hydroxy-4-acetylamino-biphenyl (N-OH-AABP), on a clonally derived nontumorigenic SV40-immortalized human uroepithelial cell line, SV-HUC. SV-HUC were exposed in vitro to concentrations of ABP, N-OH-ABP, or N-OH-AABP that caused a range of cytotoxicity from 5 to 76%. Tumorigenic transformation of SV-HUC, as assessed by the ability of the exposed cells to form carcinomas when inoculated s.c. into athymic nude mice, was achieved after a single exposure to ABP, N-OH-ABP, or N-OH-AABP. In the tumorigenic transformation experiments, 28 of 45 mice representing all 15 carcinogen-exposed observation groups formed carcinomas, whereas none of 9 mice from control groups formed carcinomas (P = 0.001). Neoplastic progression of a low grade regressive squamous cell carcinoma, MC-T11, was also achieved in this system after in vitro exposure to ABP, N-OH-ABP, or N-OH-AABP. In these progression experiments, 11 of 33 mice representing 7 of 12 carcinogen-exposed observation groups formed persistent, high grade nongressing tumors, while only 1 of 19 untreated MC-T11 controls spontaneously progressed on reinoculation (P = 0.022). Forty independent carcinomas generated in athymic nude mice recapitulated diverse cancer phenotypes (including different growth kinetics and histopathological subtypes and grades) represented in clinical bladder cancers. These results demonstrate for the first time the transforming effects of the potent human carcinogen ABP and two of its proximate N-hydroxy metabolites on a prime human target cell type, HUC.

Neoplastic progression by EJ/ras at different steps of transformation in vitro of human uroepithelial cells.

The biological effects of expression of mutant ras at different stages of human uroepithelial cell (HUC) tumorigenesis were tested after transfection of EJ/ras into nonestablished HUC and three isogeneic cell lines representing different steps in HUC transformation in vitro. Transfection with EJ/ras failed to immortalize diploid HUC and also failed to cause tumorigenic conversion of a near-diploid SV40-immortalized HUC line (SV-HUC) except at one of six nude mouse inoculation sites. In contrast, EJ/ras-transfected aneuploid low-grade squamous cell carcinoma cells formed undifferentiated, invasive carcinomas at four of six inoculation sites. Furthermore, EJ/ras accelerated tumor growth in MC-ppT11-HA2, an aneuploid high-grade transitional cell carcinoma line, as determined by decreased tumor latent periods and doubling times. These results suggest that EJ/ras contributes to progression, possibly by accelerating tumor growth, but does not in itself cause tumorigenic transformation of uroepithelial cells. To test whether chromosome losses accompanied EJ/ras transformation of SV-HUC, the karyotype of the one SV-HUC tumorigenic transformant obtained (above) was examined. This tumor cell line showed losses of chromosome arms 3p, 10p, 11p, and 18, all of which have been hypothesized to contain genes that suppress cancer development. Therefore, these results also provide new evidence suggesting that genetic losses may be required for mutant ras to contribute to HUC tumorigenic progression.

Nonrandom chromosome losses in stepwise neoplastic transformation in vitro of human uroepithelial cells.

An in vitro/in vivo transformation system was used to study chromosome region losses in stepwise neoplastic transformation and progression of human uroepithelial cells. Complete cytogenetic analyses were done on 17 independent carcinomas derived using this system and showed that losses of chromosome regions on 3p (P = 0.0003), 6q (P = 0.01), and 18q (P = 0.0003) were nonrandom. The smallest common losses [i.e., 3(p13----pter), 6(q21----q23), and 18(q21.1----qter)] were in putative cancer suppressor gene regions. In addition, cumulative losses from a group of 10 chromosome arms (i.e., 1p, 1q, 3p, 5q, 6q, 9q, 11p, 13q, 17p, and 18q) frequently deleted in clinical carcinomas were very significant (P = 0.0005) compared to losses from all other arms. Loss of 3p and 18q both correlated with transformation to high grade carcinomas (P = 0.001 and P = 0.004, respectively). These data provide new evidence supporting hypotheses that chromosome regions 3(p13----pter) and 6(q21----q23) contain genes that suppress cancer development. These results also provide new data confirming the hypothesis that genetic loss(es) in the 18(q21.1----qter) region are associated with the development of high grade malignancies.

Tumor necrosis is a prognostic predictor for early recurrence and death in lymph node-positive breast cancer: a 10-year follow-up study of 728 Eastern Cooperative Oncology Group patients.

PURPOSE: The Eastern Cooperative Oncology Group (ECOG) entered 766 patients onto two prospectively randomized surgical adjuvant clinical trials for lymph node-positive breast cancer (T1-3N1M0). Ninety-five percent (n = 728) of eligible patients have complete information on the prognostic covariables under study (tumor necrosis [TN], tumor size, number of positive lymph nodes, age) and a median follow-up duration of 10.3 years. METHODS: TN was defined as confluent cell death in invasive areas of primary cancers, visible at 4 x objective lens magnification. Cox proportional hazards models were used to estimate presence versus absence of TN effects on clinical outcomes over full cross-stratification of variables, including delivery of chemotherapy versus observation only. Time-varying effects were modeled using spline functions of time, and by fixing proportional hazards models separately in the time periods 0 to 2 and 2+ years. RESULTS: Presence of TN was an independent predictor for time to recurrence (TTR) (P = .007) and for survival (P = .0003) in the overall 10-year follow-up period. Presence of TN was also an independent predictor for TTR and for survival (each P < .0001) in the period 0 to 2 years after diagnosis. Spline function time-modeling calculations showed different hazard ratios in the TN-present (TN+) versus TN-absent (TN-) groups for both TTR and survival (each P < .0001). This difference is changing over time (P = .0001 for TTR, P = .0005 for survival). Once a patient has been disease-free beyond 2 years after diagnosis, presence or absence of TN is irrelevant to future prognosis. CONCLUSION: Confluent TN of any dimension in invasive areas of lymph node-positive breast cancer is an independent predictor for early recurrence and death from the disease.

HER-2/neu in node-negative breast cancer: prognostic significance of overexpression influenced by the presence of in situ carcinoma.

PURPOSE: Amplification and/or overexpression of the HER-2/neu oncogene have been shown to correlate with poor clinical outcome in patients with axillary node-positive breast cancer. In contrast, the prognostic significance of HER-2/neu in node-negative disease is controversial. This study was undertaken to evaluate further the relationship between HER-2/neu and clinical outcome in node-negative disease. PATIENTS AND METHODS: Overexpression of HER-2/neu was evaluated by permanent-section immunohistochemistry in tumors from 613 patients with long-term clinical follow-up enrolled in the Intergroup Study 0011. Patients were stratified into low-risk (n = 307) and high-risk (n = 306) groups on the basis of tumor size and estrogen-receptor (ER) status. Low-risk patients were defined as having small (less than 3 cm), ER-positive tumors and were observed without additional treatment after initial surgery. High-risk patients had either ER-negative or large (greater than or equal to 3 cm), ER-positive tumors and were randomized to be observed (n = 146) or to receive adjuvant chemotherapy (n = 160) after surgery. RESULTS: The rate of HER-2/neu overexpression was 14.3% in all tumors combined and was higher in invasive carcinomas with (21.5%) than without (11.2%) a significant noninvasive or in situ histologic component (P less than .0001). There was no relationship between overexpression and clinical outcome in the natural history setting of combined low-risk and high-risk patients not receiving adjuvant therapy (n = 453). Based on the reasoning that the influence of HER-2/neu may have been obscured by high-risk features and/or the presence of noninvasive carcinoma, we also analyzed the subset of patients with low-risk lesions not containing a significant in situ component (n = 179). Patients of this group with HER-2/neu-positive tumors showed only 40% disease-free survival (DFS) at 5 years, compared with over 80% in patients with HER-2/neu-negative tumors (P less than .0001). A similar inverse correlation was observed between overexpression and overall survival in the same group of patients (P = .0001). In a separate analysis involving patients receiving adjuvant chemotherapy, those with HER-2/neu-negative tumors showed significantly improved DFS in response to therapy compared with patients with HER-2/neu-positive tumors. CONCLUSION: Overexpression of HER-2/neu is associated with poor clinical outcome in a subset of node-negative patients with small, ER-positive, predominantly invasive tumors and may play a role in resistance to adjuvant chemotherapy.

Adjuvant therapy with a doxorubicin regimen and long-term tamoxifen in premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial.

PURPOSE: A randomized trial was performed in premenopausal postoperative women with ipsilateral axillary node-positive (N+) breast carcinoma and known estrogen receptor (ER) status to assess the efficacy of an Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH)-based induction regimen and 5 or more years of tamoxifen (Tam). PATIENTS AND METHODS: Patients received 12 28-day cycles of cyclophosphamide 100 mg/m2 orally days 1 to 14, methotrexate 40 mg/m2 intravenously (IV) days 1 and 8, fluorouracil 600 mg/m2 IV days 1 and 8, prednisone 40 mg/m2 orally days 1 to 14, and Tam 10 mg orally twice daily (CMFPT), or the same regimen plus halotestin 10 mg orally twice daily (CMFPTH) alternating monthly with 22-day cycles of vinblastine 4.5 mg/m2 IV day 1, Adriamycin 45 mg/m2 IV day 1, thiotepa 12 mg/m2 IV day 1, halotestin, and Tam (ALTER). Prednisone in the ALTER regimen was stopped after the second CMFPTH cycle. After 12 cycles, patients were again randomized to stop or continue Tam. After 5 years, patients on Tam were again randomized to continue or stop Tam; the results from this randomization are still coded. Among 533 analyzed induction cases, 263 received CMFPT and 270 ALTER. Among 396 analyzed maintenance cases, 201 continued Tam and 195 were observed. Pretreatment characteristics were balanced among treatments. The median follow-up times are 5.1 years for induction and 4.1 years for maintenance. RESULTS: The time to relapse (TTR) was superior for the ALTER regimen (P = .04) and for the maintenance Tam (P = .05). Overall survival comparisons between the regimens are not statistically different. A longer TTR was associated with decreasing nodal involvement, ER+ status, and increasing age. The favorable effects of decreasing nodal involvement and ER+ status carried over to survival; a progesterone receptor-positive (PgR+) status and decreasing tumor size were also associated with longer survival. Development of amenorrhea was associated with improved TTR and survival. Toxicity was similar for the two induction regimens and for the two maintenance regimens. Overall relapse patterns were similar among the induction regimens, but continuing Tam led to fewer locoregional relapses. CONCLUSION: The results suggest significant overall TTR therapeutic benefits of an Adriamycin-containing alternating induction regimen and of continuing maintenance Tam therapy for at least 5 years.

Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189.

PURPOSE: The identification of a subset of patients with axillary lymph node-positive breast cancer with an improved prognosis would be clinically useful. We report the prognostic importance of histologic grading and proliferative activity in a cohort of patients with axillary lymph node-positive breast cancer and compare these parameters with other established prognostic factors. PATIENTS AND METHODS: This Eastern Cooperative Oncology Group laboratory companion study (E4189) centered on 560 axillary lymph node-positive patients registered onto one of six eligible clinical protocols. Flow cytometric (ploidy and S-phase fraction [SPF]) and histopathologic analyses (Nottingham Combined Histologic Grade and mitotic index) were performed on paraffin-embedded tissue from 368 patients. RESULTS: Disease recurred in 208 patients; in 161 (77%), within the first 5 years. Mitotic index and grade were associated with both ploidy and SPF (P

Prognostic significance of S-phase fraction in good-risk, node-negative breast cancer patients.

PURPOSE: Formalin-fixed, paraffin-embedded tissues from axillary node-negative breast cancer patients were analyzed by flow cytometry to determine the prognostic significance of DNA ploidy and S-phase fraction (SPF). PATIENTS AND METHODS: All patients were registered on a good-risk control arm of an intergroup clinical trial. They had small- to intermediate-sized (less than 3 cm), estrogen receptor (ER)-positive tumors and received no adjuvant therapy after modified radical mastectomy or total mastectomy with low axillary-node sampling. The median follow-up was 4.8 years. RESULTS: Assessable ploidy results were obtained from 92% of the 298 specimens studied (51% diploid, 49% aneuploid), and SPFs were assessable for 83% of the tumors. SPFs for diploid tumors ranged from 0.7% to 11.9% (median, 3.6%), compared with a range of 1.2% to 26.7% (median, 7.6%) for aneuploid tumors (P less than .0001). No significant differences in disease-free or overall survival were observed between patients with diploid and aneuploid tumors. Using different SPF cutoffs by ploidy status (4.4% for diploid, 7.0% for aneuploid), patients with low SPFs had significantly longer disease-free survival rates than patients with high SPFs (P = .0008). The actuarial 5-year relapse rates were 15% and 32% for patients with low (n = 142) and high SPFs (n = 105), respectively. Similar relationships between SPF and clinical outcome were observed for patients with diploid tumors (P = .053) and for patients with aneuploid tumors (P = .0012). CONCLUSION: S-phase fraction provides additional prognostic information for predicting disease-free survival for axillary node-negative breast cancer patients with small, ER-positive tumors.

Six-year results of the Eastern Cooperative Oncology Group trial of observation versus CMFP versus CMFPT in postmenopausal patients with node-positive breast cancer.

The Eastern Cooperative Oncology Group (ECOG) trial of adjuvant cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen (CMFPT) for 1 year compared with observation alone in 265 postmenopausal patients with node-positive breast cancer is reported with 74 months median follow-up. Overall relapse-free survival tended to favor CMFPT (P = .08), but no survival differences existed between any treatment group. The addition of tamoxifen to CMFP led to slightly (but not significantly) better relapse-free status in all subgroups analyzed. Subgroup analysis based on stratification variables showed significant benefit from CMFP (+/- T) only in estrogen receptor (ER)-negative patients with respect to disease-free status (P = .0003), but not survival (P = .54). Relapse-free status was actually worse for CMFP-treated patients with ER-positive tumors, but not significantly so (P = .15). By multivariate analysis other significant risk factors for relapse-free status were primary tumor size, number of nodes pathologically involved, and the number of nodes examined. ER status was prognostic only for the observation group with the benefit from chemotherapy on ER-negative patients obliterating this difference in treated patients. Survival was affected by the number of involved nodes, tumor size, presence of tumor necrosis, and patient obesity. Analysis of toxicity showed elevation of liver enzymes during the first year to be more common in the observation group compared with those patients receiving adjuvant treatment and to be associated with early recurrence. Toxicity from adjuvant treatment persisted beyond termination of therapy in 53% of patients, but was usually mild and self-limited. We conclude CMFPT offers relapse-free survival benefit in ER-negative patients, but the value of chemotherapy in ER-positive postmenopausal, node-positive patients must be questioned.

Chemotherapy versus observation in high-risk node-negative breast cancer patients.

Postoperative women with breast cancer but without histopathological evidence of metastases to the axillary lymph nodes or clinical evidence of metastases were studied. Six hundred fifty-five "good-risk" patients who were estrogen receptor positive (ER+) with primary tumors less than 3 cm were registered for observation. Twenty-four of these patients were treated with chemotherapy. Five hundred thirty-six "poor-risk" patients who were either ER+ with primary tumors greater than or equal to 3 cm or estrogen receptor negative (ER-) with any primary tumor size were randomly assigned between chemotherapy and observation. Randomization was stratified by type of surgical procedure, number of lymph nodes examined, menopausal status, tumor size, and ER status. The chemotherapy (CMFP) consisted of six 4-week cycles of cyclophosphamide, 100 mg/m2 orally days 1-14; methotrexate, 40 mg/m2 intravenously (IV) days 1 and 8; fluorouracil, 600 mg/m2 IV days 1 and 8; and prednisone, 40 mg/m2 orally days 1-14. Treatment arms in the randomly assigned patients were balanced with respect to pretreatment characteristics. This analysis includes 445 eligible patients entered in the registration arm and 425 eligible patients entered into the randomized treatments. The median follow-up is 4.5 years in the randomly assigned cohort and 4.8 years in the registered cohort. The overall 5-year disease-free survival (DFS) among the randomly assigned patients was 83% with CMFP and 61% with observation (P less than .0001). A DFS treatment benefit was observed in premenopausal and postmenopausal patients as well as in patients with ER+ or ER- tumors. There were fewer local-regional and distant relapses among the CMFP-treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic potential of DNA flow cytometry measurements in node-negative breast cancer patients: preliminary analysis of an intergroup study (INT 0076).

An ancillary study (INT 0076) to the Intergroup clinical trial of node-negative breast cancer patients (INT 0011) was performed to retrospectively evaluate DNA flow cytometry measurements of ploidy (DNA content) and proliferative capacity (S-phase fraction) for their ability to predict time to recurrence. Of the 915 patients eligible for the clinical trial, 788 were registered for the ancillary flow cytometry study (INT 0076). Four hundred and three of these patients [estrogen receptor (ER)-positive, tumor size less than 3 cm] had been registered to the observation arm of the clinical trial and 385 (ER-negative and/or tumor size greater than or equal to 3 cm) had been randomly assigned to adjuvant chemotherapy (cyclophosphamide, methotrexate, fluorouracil, and prednisone for six cycles) or to observation. Paraffin blocks from 95% (748 of 788) of these patients were obtained, 712 of which had sufficient cancer tissue to be evaluable for the flow cytometric assay. DNA ploidy status (DNA diploid vs DNA aneuploid) was evaluable for 565 (79%) specimens, 64% of which were aneuploid. Proliferative capacity was estimated by the percentage of cells having an S-phase DNA content, using a trapezoidal modeling algorithm(s) as previously described. The median S-phase value for the entire group (both registered and randomly assigned patients) was 6.97%, which defined the cutoff for interpretation of high or low S-phase values. With a median follow-up time of 4.55 years, S-phase fraction, but not ploidy status, is a significant predictor for time to recurrence in both the randomly assigned and the untreated population (observed registered group and observed randomly assigned group).(ABSTRACT TRUNCATED AT 250 WORDS)

A proposal for the reporting of cancer by hospital pathologists.

A proposal is presented that pathologists submit diagnostic information in each newly diagnosed case of cancer. An existing regional cancer incidence reporting system would be the recipient of these confidential data. The information could be used for monitoring the total cancer population within a geopolitical region. Problems that can be anticipated in planning for implementation of this proposal are addressed in general terms.

Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer.

Using permanent-section immunohistochemistry, we investigated the role of HER-2/neu in the development and progression of human breast cancer by measuring its overexpression in a series of hyperplastic (n = 30), dysplastic (n = 15), and malignant neoplastic (n = 708) lesions of ductal epithelium and by evaluating the relationships between overexpression and clinicopathologic features known to have prognostic significance in these lesions. The neoplasms included pure ductal carcinoma in situ (DCIS; n = 59) and infiltrating ductal carcinoma (IDC; n = 649). The latter were all node negative and stratified into IDC combined (n = 237) or not combined (n = 412) with a "significant amount" of DCIS (defined as DCIS greater than or equal to 10% of total tumor cellularity). Overexpression of HER-2/neu was not observed in any of the hyperplastic or dysplastic lesions. In contrast, it was present in 56% of pure DCIS and in 77% of the comedo subtype of this group. Only 15% of IDC overexpressed HER-2/neu. However, the rate of overexpression was significantly higher in the subset of IDC combined with DCIS compared with the subset of IDC not combined with DCIS (22% v 11%, respectively; P less than .0001). These results are consistent with the hypothesis that HER-2/neu plays a more important role in initiation than in progression of ductal carcinomas. They also suggest that overexpression decreases within individual tumors as they evolve from in situ to increasingly invasive lesions or, alternatively, that many invasive carcinomas arise de novo (ie, without progressing through a significant in situ stage) by mechanisms not involving HER-2/neu. In addition, overexpression of HER-2/neu was associated with several poor prognostic features (younger patient age, premenopause, negative estrogen receptor status, negative progesterone receptor status, and high nuclear grade) in the subset of IDC combined with DCIS. With one exception (negative estrogen receptor status) these associations were lost in IDC not combined with DCIS, also suggesting that the role of HER-2/neu changes during the progression of human breast cancer.

Interobserver variation in the identification of breast carcinoma in intramammary lymphatics.

Nine surgical pathologists participated in a microscopic review of 35 cases of pT1-2 N0 M0 breast carcinoma. The pathologists outlined strict criteria for the identification of intramammary lymphatics and blood vessels and for the identification of cancerous emboli in these vascular channels. Each mastectomy case was studied by three different pathologists. All three concurred on the presence or absence of intralymphatic cancer in 12 of the 35 cases. Observers agreed on the absence of blood vessel invasion in 30 of the 35 cases. There was no consistent bias on the part of a single reviewer, either alone or with another pathologist, in identifying the emboli. We conclude that the identification of intralymphatic cancerous emboli in mastectomy specimens is not a reliably reproducible prognostic finding on which recommendation of systemic chemotherapy in stage I breast carcinoma patients can be based.

In vitro radiation-induced neoplastic progression of low-grade uroepithelial tumors.

Recent interest has focused on the identification of molecular genetic mechanisms in multistep neoplastic transformation. In vitro exposure of simian virus 40 (SV40)-immortalized human uroepithelial cells (SV-HUC) that are environmentally relevant to bladder carcinogens has been shown to produce tumorigenic transformation, as assessed by the ability of cells exposed to a carcinogen to form xenograph tumors with heterogeneous cancer phenotypes ranging from very aggressive, invasive high-grade carcinomas to superficial low-grade indolent tumors. In addition, exposure of a low-grade indolent tumor generated in the SV-HUC system, MC-T11, to the same carcinogens results in neoplastic progression as assessed by the production of high-grade aggressive cancers. In the present study, we show neoplastic progression of MC-T11 after in vitro exposure to a single dose of 6 Gy X rays. In addition, we show that the chromosome deletions, including losses of 4q, 11p, 13q and 18, observed in these radiation-induced tumors are similar to those observed in carcinogen-induced tumors, thus supporting the hypothesis that the experimental cell system, not the transforming agent, dictates the genetic losses required for tumorigenic transformation and progression.

Value of colonoscopy after ureterosigmoidostomy.

Ureterosigmoidostomy (US) is an acceptable procedure for urinary diversion. Despite problems with ascending pyelonephritis, anal incontinence, and recently a reported 100- to 500-fold increase in the incidence of colonic carcinoma, the popularity of US is predicted to increase. The records of 110 patients who have undergone US at our institution have been reviewed. Invasive colon cancer developed at the site of ureter implantation in three of these patients. All patients had rectal bleeding and obstipation as initial symptoms. We have located 17 of our US patients and all consented to colonoscopy and urologic follow-up. At colonoscopy 41% of these patients had one to three polyps (0.5 to 6 cm) involving or near the site of the US. No polyps were seen proximal to the US sites. Polyps were histologically defined as tubovillous adenomas or mixed tubovillous-transitional cell adenomas. A single patient with three 4 to 6 cm polyps had superficial adenocarcinoma found in two of the polyps. Recurrent polyps or dysplasia has not been found on follow-up examination. Despite the disadvantages of US, the likely increased popularity of this procedure mandates that all patients be followed regularly for polyps and cancer. Our data support the following recommendations: (1) surveillance colonoscopy should be started soon after US, and (2) conversion to an alternative diversion should be made if recurrent polyps, cancer, or dysplasia is found. Yearly colonoscopy and screening for occult blood must be part of the comprehensive follow-up on all patients after US.

Eastern Cooperative Oncology Group study 1879: mitotane and adriamycin in patients with advanced adrenocortical carcinoma.

From November 1979 to July 1986, 52 patients (27 women and 25 men; median age 52 years) with advanced adrenocortical carcinoma entered a prospective, nonrandomized study evaluating moderate-dose mitotane and doxorubicin hydrochloride (Adriamycin). Thirty-two tumors (62%) were well differentiated and evidence of hormone production was present in 24 patients (46%). Patients with well-differentiated or functional tumors received mitotane, 6 gm daily; patients for whom mitotane failed or those with poorly differentiated, non-hormone-producing tumors received Adriamycin, 60 mg/m2 every 3 weeks. Initially, 36 patients were treated with mitotane and 16 patients with Adriamycin. Eight patients (22%) responded to mitotane and three (19%) responded to Adriamycin. No response was noted in the 15 patients for whom mitotane failed and who then received Adriamycin. Severe toxicity occurred in 36% of patients who received mitotane and in 26% who received Adriamycin. Overall median survival after onset of treatment was 14 months. We conclude that mitotane or Adriamycin used initially can induce tumor regression in about 22% and 19% of selected patients, respectively. However, Adriamycin is ineffective as second-line chemotherapy for patients with well-differentiated or functioning tumors for whom mitotane is ineffective.

Abnormal rectal mucosa of the anal transitional zone in ulcerative colitis.

OBJECTIVE: To determine the frequency of atypia and active ulcerative colitis (UC) in rectal mucosa within the anal transitional zone (ATZ). DESIGN: Surgeons identified ATZ tissues from restorative proctocolectomy specimens for determination by surgical pathologists of specific histopathologic features in rectal mucosa of the ATZ. SETTING: Surgical referral center for restorative proctocolectomy. PATIENTS: Ninety-four patients with symptomatic UC underwent restorative proctocolectomy between January 1991 and December 1994. INTERVENTIONS: Specific histopathologic features of active UC in the ATZ were evaluated by a single reviewer who did not know the clinicopathologic details of individual study patients. MAIN OUTCOME MEASUREMENTS: Presence and coexistence of rectal mucosal dysplasia (high or low grade), mucosa classified as indefinite for dysplasia, and acute UC (crypt abscess or cryptitis) in the ATZ. RESULTS: Of 94 ATZ tissue specimens, acute intracryptic inflammation was present in 60 rectal mucosa specimens (64%). In 29 (48%) of these 60 specimens, inflammation was neither widespread nor intense. Rectal mucosal dysplasia (low grade but not high grade) was present in 15 (16%) of 94 ATZs specimens. Inflammation elsewhere in the rectal mucosa accompanied dysplasia in 11 (73%) of 15 ATZ specimens. Rectal mucosa classified as indefinite for dysplasia was present in 24 (26%) of 94 ATZ specimens and coexisted with inflammation in 15 (63%) of these 24. Thus, rectal mucosal atypia was present in 39 (41%) of 94 ATZ specimens, and in 26 (67%) of these 39, abnormal rectal mucosa coexisted with acute inflammation. CONCLUSIONS: Rectal mucosa in the ATZ can exhibit active UC and/or atypia. Long-term monitoring is advisable if the ATZ is preserved during restorative proctocolectomy.

Chromosome losses in tumorigenic revertants of EJ/ras-expressing somatic cell hybrids.

Tumorigenic transformation of SV40-immortalized human uroepithelial cells (SV-HUC) after transfection with EJ/ras was previously reported to be a rare event. To test the hypothesis that ras transformation requires loss of suppressor genes, somatic cell hybrids were generated between a rare tumorigenic transformant and an isogeneic nontumorigenic EJ/ras transfectant obtained in the same experiment. Both parental cell lines, as well as all hybrid progeny, expressed mutant p21 ras protein, but injections of three such independent hybrids into athymic nude mice at passage (P) 4 demonstrated that tumorigenicity was suppressed at 20 of 22 sites. Two tumors developed, after a relatively long 17-week latent period, as compared with a 4-week latent period for the tumorigenic parent. All three hybrids produced tumors at P8, but these showed different latent periods (3-14 weeks). Revertant hybrid tumors were high-grade carcinomas. Cell lines derived from these tumors expressed mutant p21 ras and retained at least 1 EJ/ras integration site. Karyotypic analysis of six independent hybrid tumor revertants showed that each had a unique clonal karyotype. Losses of two or more homologues of 1p, 3p, 4, 8, 10p, 11p, 13q, and 18 were identified in one or more tumorigenic revertants. Losses of all these chromosomes were previously associated with transformation of SV-HUC by EJ/ras, but were also associated with chemical transformation of SV-HUC in tumors that did not express mutant ras. Genetic losses involving most of these chromosomes have also been identified in clinical bladder cancers (i.e., 1p, 3p, 8, 11p, 13 and 18q). These data show that expression of EJ/ras does not negate or significantly alter requirements for multiple genetic losses in HUC tumorigenesis.

Multifocal fibrous pseudotumor of testicular tunics. Possible clinical dilemma.

A morphologic characterization of a tunical multifocal fibrous pseudotumor is presented because of the clinical dilemma this rare entity causes urologists and pathologists. This report demonstrates the necessity for familiarity with testicular pseudotumors in order to avoid an unnecessary orchiectomy. If histopathologic examination of biopsies from every pseudotumor nodule fails to demonstrate malignancy, excision of the entire tunics including the pseudotumors is appropriate therapy.