George R. Prout

Superficial Bladder Cancer: Progression and Recurrence

The tumors in 249 patients presenting initially with stages Ta and T1 bladder cancer were analyzed for tumor progression and recurrence. Only transurethral resection and/or fulguration was used before the first recurrence. Patients who received intravesical chemotherapy after the first tumor recurrence were excluded from an analysis of progression. Progression according to stages Ta and T1, and grades I, II and III was 4, 30, 2, 11 and 45 per cent, respectively. All differences were statistically significant. Progression also correlated with nontumor dysplasia and size. High tumor grade, lamina propria invasion, atypia elsewhere in the bladder, positive urinary cytology, tumor multiplicity and large tumors were associated with shorter intervals free of disease.

Age and comorbidity impact surgical therapy in older bladder carcinoma patients: a population-based study.

Bladder carcinoma often occurs in older patients who also may have other comorbid conditions that could influence the administration of surgical therapy. The current study was conducted to describe the distribution of comorbid conditions in patients with bladder carcinoma and ascertain whether these conditions, as grouped by the American Society of Anesthesiologists physical status classification, affected the choice of surgical therapy.

Transitional cell carcinoma of renal pelvis

Sixty-eight patients with transitional cell carcinoma of the renal pelvis were studied with respect to clinical presentation, tumor grade, stage and location, subsequent development of other urothelial tumors, and patient survival. Of the 66 patients with adjacent mucosa available for evaluation, 63 (95 per cent) had abnormal findings with severe dysplasia and CIS common in the high-grade, high-stage tumors. Twenty-eight patients (41 per cent) had transitional cell carcinoma previously, concomitantly, and/or subsequently, and in 14 patients (21 per cent) subsequent bladder tumors developed. Because of the relatively high tumor recurrence rate in the ureter (16 per cent) in patients who underwent subtotal ureterectomies, nephrectomy and complete ureterectomy including a bladder cuff should be the operation of choice in patients with carcinoma of the renal pelvis.

Intratumor Injection as a More Effective Means of Porphyrin Administration for Photodynamic Therapy

Photodynamic therapy (PDT) with hematoporphyrin derivative (HpD) as the photosensitizer is a promising new cancer treatment. The major drawback of this procedure is the resulting skin photosensitivity. Patients must remain in subdued light for four to six weeks to avoid cutaneous phototoxicity. In this study, we examine the possibility of reducing the skin photosensitization while maintaining the tumor phototoxic effect by administering the drug directly into the tumor. A subcutaneously implanted mouse bladder tumor (MBT-2) was used. HpD was administered either intraperitoneally (I.P.; 20 mg./kg. b.w.) or by intratumor injection (I.T.; 0.4 mg./cc tumor). The concentrations of HpD in tumor and various tissues (skin, muscle, liver, spleen, kidney, bladder and whole blood) were analyzed at various times after the injection, by 3H-HpD method and by a fluorometric method. Results indicated that at three to 96 hours after the administration, porphyrin levels in tumor were about three to 15 times higher by I.T. than by I.P. injection, while the concentrations in skin and other tissues were 1.3 to 10 times lower. Consequently, at 24 hours after injection ratios between tumor to skin porphyrin were 14 to 92 times higher for I.T. than I.P. injection. Higher porphyrin levels in tumor and lower in normal tissues would indicate lower skin photosensitivity, systemic cytotoxicity and possible greater tumor photosensitivity. This method of porphyrin administration may be useful for the PDT of certain single lesions that are accessible for direct injection.

Malignant Teratoma of the Testis with an Isochromosome No. 12, i(12p), as the Sole Structural Cytogenetic Abnormality

Cytogenetic analysis of a malignant teratoma of the testis revealed a hypotriploid karyotype with the presence of an isochromosome of the short arm of chromosome 12, i(12p), as the only structural abnormality. Most cells contained 3 copies of chromosome 12 and 2 copies of the i(12p) isochromosome. Thus, the genetic material located on the short arm of chromosome 12 was multiplied in the teratoma cells, being represented by 7 copies compared to 2 to 3 copies of other chromosomes. This finding confirms the reports that the i(12p) isochromosome is a specific chromosomal abnormality in cases of malignant testicular tumors.

Total Bone Uptake in Management of Metastatic Carcinoma of the Prostate

The status of patients with skeletal metastases from prostatic carcinoma was determined from a quantitative uptake and retention measurement of the bone scanning radiopharmaceutical 99mtechnetium-methylene diphosphonate. Whole body counts were performed 5 minutes and 24 hours after intravenous administration of 99mtechnetium-methylene diphosphonate, and were expressed as the percentage uptake by the skeleton at 24 hours. Skeletal uptake determinations were done in 29 patients with prostatic cancer (17 with osseous metastases) who were evaluated at 3 to 6-month intervals. Group 1 consisted of patients who responded to therapy and achieved remission, group 2 included patients with relapse or progressive disease, group 3 consisted of those with metastases who were in remission for longer than 6 months and group 4 included those without evidence of any bony metastases. The baseline mean +/- standard deviation 24-hour skeletal uptake values were 46.1 +/- 12.0 per cent in group 1, 34.3 +/- 13.9 per cent in group 2, 27.0 +/- 5.9 per cent in group 3 and 28.9 +/- 5.5 per cent in group 4. At 3 to 6 months the values in group 1 (responders) decreased by 18 per cent, while those in group 2 (relapse or progression) increased by 19 per cent and those in group 3 (remission) increased by 1.5 per cent. The quantitative 24-hour skeletal uptake test was performed easily, reproducible and at least as useful as concurrent chemical blood tests and subjective bone scan interpretations.

The Effect of Verapamil on a Multi-Drug ResistantBladder Carcinoma Cell Line and Its Potential as anIntravesical Chemotherapeutic Agent

A human bladder transitional cell carcinoma cell line, MGH-U1R, exhibits reproducible resistance to doxorubicin. We examined the effects on survival of this cell line caused by verapamil, which has been shown to reverse multi-drug resistance in vitro in other neoplastic cell lines. Both MGH-U1R and MGH-U1, the non-resistant parent cell line, were treated with varying concentrations of doxorubicin alone, verapamil alone, or both drugs simultaneously, all for one hour. Cells were then grown in drug-free medium for 10 days, stained, and counted. Standard survival curves were calculated. Verapamil alone had no significant cytotoxicity. Verapamil at concentrations of 16 micrograms./ml. and 32 micrograms./ml. decreased the IC50 of doxorubicin for MGH-U1R by a factor of 2.5. Using H3-verapamil, we also examined the systemic and local absorption of this drug resulting from intravesical verapamil administration in rabbits. All animals were treated for one hour, and multiple serum samples were drawn during treatment. Verapamil was found in high concentrations in the mucosa, less in the adventitia, and was absent in venous blood. Verapamil effectively reverses resistance to doxorubicin of MGH-U1R in vitro. The intravesical use of verapamil appears to be safe, and may prove to be a useful adjunct in the intravesical therapy of some bladder tumors.

Establishment and Characterization of a Doxorubicin-Resistant Human Bladder Cancer Cell Line (MGH-U1R)

A doxorubicin-resistant bladder cancer cell line has been established. This was accomplished by exposing an established human bladder tumor cell line, MGH-U1, to progressively higher concentrations of doxorubicin over a period of 12 months. The resistant cells, MGH-U1R, are nine times more resistant to doxorubicin and 30 times more resistant to daunorubicin than the parent cells. The MGH-U1R and the MGH-U1 cells have identical isozyme phenotypes. Compared to the parent cells, the resistant cells have a slower growth rate, lower confluent density, are more heterogeneous morphologically, and exhibit more chromosomal aberrations and rearrangements. The resistant cells may now be used as an experimental system for the search of means to overcome drug resistance in human bladder cancer.

Cystoscopic Fluorescence Detector for Photodetection of Bladder Carcinoma with Hematoporphyrin Derivative

Hematoporphyrin derivative, a fluorogenic substance, tends to accumulate at higher levels in most tumor tissues after intravenous injection. These properties provide a potential application for the detection of malignant tumors. We report the development and in vitro evaluation of an instrument designed to excite and detect low levels of hematoporphyrin derivative fluorescence emitted by tumor cells in the bladder after hematoporphyrin derivative administration. The light source of the instrument for specific hematoporphyrin derivative excitation is at a wavelength of 405 nanometers. Optical fibers for both the excitation and detection of fluorescence were bundled in a single 7 French ureteral catheter which can be inserted into a standard cystoscope. The fluorescence is initially detected as an electrical signal which is amplified and then converted into an audio signal. The interference of the cystoscope illuminating white light to the fluorescence signal is eliminated by a phase-sensitive electronic circuit. The instrument thus allows simultaneous viewing of the bladder and detection of hematoporphyrin derivative fluorescence produced from tumor tissues. In vitro testings using hematoporphyrin derivative solutions on filter paper indicated that the instrument detects as little as 30 nanograms per milliliter of hematoporphyrin derivative and has relatively low noise levels from normal tissues. The utility of this instrument for hematoporphyrin derivative photodetection of small tumors and carcinoma in situ in bladder is currently under clinical evaluation.

Correlation of vascular invasion and metastasis in germ cell tumors of testis--a preliminary report.

A preliminary study was conducted to correlate vascular invasion with metastasis in testicular tumors. A lectin-immunoperoxidase procedure was used to identify the vessels. Together with standard hematoxylin and eosin staining, the presence of tumor cells in vessels was detected. Primary tumor specimens from 37 cases and retroperitoneal lymph nodes from 10 cases of germ cell tumors were studied. The results showed good correlations between vascular invasion in primary tumors and metastasis to lymph nodes in nonseminomatous germ cell tumors, and between vascular invasion in retroperitoneal lymph nodes and the presence of other metastases. Eight of the 9 nonseminomatous germ cell tumor patients with vascular invasion had metastases, and all 4 patients that had vascular invasion in the lymph nodes had other metastases. However, there seemed to be no correlation between vascular invasion and clinical staging in cases with seminoma in which retroperitoneal lymph node dissection was not performed. These observations, although based on a limited number of cases, warrant more extensive investigations.