Biomedical subjects
Publications and source records attributed to W H Lakey.
A case of histologically and ultrastructurally confirmed carcinoid tumor of the renal pelvis is reported. The patient's urine sediment showed a few groups and sheets of polygonal malignant cells with scant cytoplasm and oval nuclei displaying chromatin clumping and micronucleoli.
BACKGROUND: The case of a benign oncocytoma arising in a patient from retroperitoneal heterotopic adrenocortical tissue is reported; this tumor was found in a 44-year-old man. METHODS: The tumor consisted of polygonal cells with granular eosinophilic cytoplasm packed with swollen mitochondria. RESULTS: Scattered tumor cells showed abundant smooth endoplasmic reticulum suggesting that the tumor was of adrenocortical origin.
There were 32 high risk patients with stages T2 to T4 bladder cancer treated with neodymium:YAG laser irradiation to the tumor base after cautery resection between July 1981 and October 1986. All 12 patients with stage T2 disease followed for 6 to 78 months had no recurrence locally although 4 had stage T1 recurrences elsewhere in the bladder. Of 14 stage T3 cancer patients 8 demonstrated tumor persistence locally but 3 were well 4 to 24 months later without local recurrence (all stage T3a) and 3 were alive 14 to 24 months later with stage T1 recurrences. Of 6 stage T4 cancer patients 4 obtained reasonable hemorrhagic control with laser irradiation used for palliation purposes. A 90-year-old man with stage T3b disease died 5 days postoperatively of a myocardial infarct but no bladder or bowel perforation was documented. We believe that neodymium:YAG laser irradiation is a safe alternative for the treatment of bladder cancer in selected patients.
To avoid the center effect and the possible hidden interactions of multicenter studies, the validity of the Cox Proportional Hazards Model for the analysis of a single-center kidney transplant program was tested, considering 287 renal transplants performed in a 10-year period. The inclusion of type of donor and main immunosuppressive drug as covariates in the model did not violate the proportionality assumption of the Cox model. According to this method, the following covariates were significant in predicting graft survival: cyclosporine, type of donor, good human leukocyte antigen (HLA)-A and HLA-B match (DR data were not considered), highest percentage of reactive antibodies against panel cells, and nephroangiosclerosis as a primary renal disease. Cyclosporine did not significantly improve graft survival in living related donor transplants. Pretransplant blood transfusions, cold ischemia time, and donor ABO blood group were initially significant but dropped out in the step-down procedure. Recipient's age at transplant, cyclosporine, HLA-A and HLA-B match, and nephroangiosclerosis were significant in predicting patient survival. It was concluded that using long-term data of cadaveric and living related renal transplants either on azathioprine or cyclosporine is a valid way to perform multivariate analysis of single-center transplant programs that do not have large samples.
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It has been proposed that concentrations of nuclear androgen receptor may be predictive of tumor hormone dependence in cases of advanced human prostatic cancer. We have investigated the ability of this receptor population to reflect patient prognosis during endocrine therapy in 12 cases of stage D disease. KCl-extractable, nuclear matrix-bound and total nuclear androgen receptor concentrations showed a significant positive correlation with duration of patient survival (p less than 0.05) while cytosolic and total cellular androgen receptor concentrations were not significantly correlated with survival. However, use of selected threshold concentrations of receptors revealed that only cytosolic, nuclear KCl-extractable and total cellular receptors could significantly differentiate long-term and short-term survivors. Even given the small number of patients studied, the potential use of this androgen receptor assay as an index of both tumor hormone-dependence and patient prognosis was evident. Therefore, in order to make these androgen receptor assays more applicable, we attempted to simplify the methods for use on readily available tissues. Similar amounts of nuclear androgen binding were observed in crude and purified nuclear pellets, in nuclei treated with DNase and KCl in differing orders or in nuclei from tissue homogenized using glass or Polytron homogenization procedures. More importantly, nuclear androgen receptor concentrations in specimens of prostatic cancer or benign hyperplasia taken by needle biopsy or transurethral resection involving electrocautery did not differ from those of parallel specimens taken by Thompson cold punch. Simplified nuclear androgen receptor assays of needle biopsy or electrocautery specimens are accurate and should prove clinically applicable.
Fischer X Copenhagen rats bearing Dunning R3327-AT tumors were treated with hematoporphyrin derivative and red light (630 nm from an argon-driven dye laser) alone or in combination with the hypoxic cell radiosensitizer, misonidazole (MISO). In vitro studies had suggested that hypoxia might significantly decrease the cytotoxicity of photodynamic therapy (PDT) and labeling with [14C]MISO had revealed a significant fraction of viable hypoxic cells in this tumor. PDT alone resulted in a growth delay of 8.8 days but no tumor cures were observed. The administration of MISO (i.p. at 0.5 mg/g) 33 min prior to PDT resulted in an average growth delay of 15.2 days and tumor cures (local control at 33 days) in 20% of animals treated. If MISO at a similar dosage was administered 30 min after PDT an average growth delay of 16.3 days was measured and tumor cure was observed in 70% of the animals treated. These results suggest that the hypoxic cell fraction in R3327-AT tumors might be a limitation to their curability by PDT. The addition of MISO and/or other hypoxic cell cytotoxic agents to PDT procedures may provide an effective means of treating PDT-resistant hypoxic cells in solid tumors.
Dunning R3327-H and R3327-AT tumors growing subcutaneously in the flanks of Fischer X Copenhagen rats were irradiated with 137Cs gamma-rays at volumes of approximately 300 mm. The effects of various doses of radiation were estimated by measurements of subsequent tumor growth as well as by histological evaluation. The well-differentiated, hormonally-responsive R3327-H tumor was more radiosensitive than the anaplastic R3327-AT tumor. The reasons for this increased radiation sensitivity of the R3327-H tumor include a greater "apparent" radiation sensitivity of tumor cells and the absence of tumor hypoxia. The presence of hypoxic tumor stem cells was inferred from significant radiosensitization of tumor growth delay by 0.5 mg./gm. misonidazole and by a technique which utilizes radioactively-labelled misonidazole as a marker for hypoxic cells. The persistence of a mass of R3327-H tumor tissue after aggressive radiotherapy was not indicative of tumor cells. Furthermore, the rapid increase in volume of R3327-AT cells after aggressive radiotherapy was attributed to limited proliferation of tumor cells which were destined to ultimately die. Possible implications of these findings for the management of human prostatic adenocarcinoma are discussed.
Two prostate tumour models (Dunning R3327H and AT) were tested in rats to see if they were sensitive to hematoporphyrin-photoradiation therapy (HPD-PRT). The R3327H tumours were irradiated by implantation of a single fiber optic and the R3327 AT tumours were treated with implantation of four fiber optics simultaneously. Thermal measurements made at the tip of the fiber and up to 1 cm from the tip indicated temperature rises from 1.5 degree C to 20 degrees C at the tip and 0 degree to 8 degrees C distal to the tip, with power densities ranging from 100 mW to 500 mW. The R3327H tumour was controlled up to 8 weeks post-HPD-PRT, when the initial tumour size was 400-500 mm3. The R3327 AT tumours also respond to the HPD-PRT but a significant laser-induced thermal rise in the tumour is suspected.
To further characterize human prostatic androgen receptor, nuclei were isolated from normal prostate (no. = 3) and benign prostatic hyperplasia specimens (no. = 10). High ionic strength (0.6 M KCl) treatment of nuclei released nuclear extractable androgen receptor and DNase I digestion then yielded nuclear matrices. Androgen receptor was quantified in the nuclear extract and nuclear matrix preparations by Scatchard analysis of specific R1881 binding. Only 1 of the 3 normal tissues had extractable androgen receptor (113 fmol. per gm. of tissue) while the mean concentration of extractable androgen receptor for BPH was 189 fmol. per gm. of tissue. The mean concentrations of matrix-bound androgen receptor were 325 fmol. per gm. of tissue and 548 fmol. per gm. of tissue for normal and hyperplastic prostate, respectively. The androgen binding sites on nuclear matrix may represent the functional intranuclear androgen receptor and a characterization of these sites may provide an understanding of the etiology of BPH.
The relationship between androgen receptor concentrations and clinical response to endocrine therapy for prostatic adenocarcinoma was investigated for 13 stage D patients. Both cytoplasmic and nuclear-androgen receptors were quantified. For nuclear androgen receptor, nuclei were isolated and treated with high ionic strength buffer (0.6 M KCl) to yield a KCl-extractable fraction; the nuclei were then treated with DNase I to yield nuclear matrices. Electron microscopy confirmed the relative nuclear purity and revealed matrix morphology. An hydroxylapatite binding assay and methyltrienolone (R1881) were used to quantify androgen receptor in cytosol, the KCl-extract and matrix preparations. Following 6 months of hormonal therapy, the clinical status of patients was re-evaluated and the patients were grouped according to disease response. The androgen receptor data obtained prior to therapy were compared for the disease response groups. The mean concentrations of cytoplasmic androgen receptor, KCl-extractable nuclear androgen receptor and nuclear matrix-bound androgen receptor, respectively, in those patients with disease progression or death (no. = 6), were 671 +/- 232, 45 +/- 17 and 119 +/- 34 fmol. per gm. of tissue +/- S.E.M., and for those with disease regression or stabilization (no. = 7), 1427 +/- 435, 193 +/- 53 and 611 +/- 92 fmol. per gm. of tissue +/- S.E.M. While cytoplasmic androgen receptor concentrations were not related to clinical status, both extractable and matrix-bound nuclear androgen receptor concentrations were significantly higher in the group which responded to hormonal therapy. These results suggest that nuclear-extractable and nonextractable androgen receptor concentrations are useful indices for the prediction of hormone-dependence of prostatic cancer.
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Estrogens have been proposed as a major etiological factor in the pathogenesis of benign prostatic hyperplasia in man. The presence of estrogen receptor in benign prostatic hyperplasia would support this concept. Using the receptor stabilizer, sodium molybdate, and a hydroxylapatite assay we assayed human benign prostatic hyperplasia for the presence of cytosolic estrogen receptor. For comparison, we assayed estrogen receptor in cytosols of prostatic cancer and normal tissue, and we also measured androgen receptor and progesterone receptor concentrations in the 3 tissue types. Estrogen receptor was present in 8 of 15 benign prostatic hyperplasia specimens at a mean concentration of 9.2 fmol./mg. protein for the estrogen-receptor-positive samples. Sucrose gradient analysis of the estrogen receptor of benign prostatic hyperplasia revealed that it sedimented in the region of 8S, and steroid specificity studies confirmed that the binding to estrogen receptor was estrogen-specific. Estrogen receptor was also found in normal (3 of 3) and malignant (4 of 6) tissues, and all tissues were positive for androgen receptor. The presence of estrogen receptor in human benign prostatic hyperplasia supports the proposal that circulating estrogens may have a role in the pathogenesis of this disorder.
The Neodymium YAG laser energy source can be readily adapted for cystoscopic use by some simple modifications of existing urologic equipment. Both the fiberoptic resectoscope and a deflecting cystourethroscope have been adapted for this purpose. Fixation of the fiber tip 1 cm. from the target and use of a divergent beam of 36 degrees allows the delivery of standardized dosage to a relatively large bladder tissue volume. Animal experiments involving 35 mongrel dogs established that repetitive overlapping doses of 200 joules ech can successfully treat a large area of bladder resulting in a full thickness bladder wall injury. This technique has been used in 4 high risk patients with infiltrating bladder cancer without adverse sequelae. The ability to reliably produce a full thickness lesion may give this modality a therapeutic advantage over conventional cautery techniques especially for the treatment of residual infiltrative carcinoma.
Dunning R3327H prostatic adenocarcinoma was bilaterally transplanted in the flanks of animals at the Papanicolaou Institute in Miami, and the animals were received at the Cross Cancer Institute (Edmonton, Alberta, Canada) each month. The animal flanks were palpated weekly, and when tumor volumes reached a size of approximately 300 mm3 the animals were randomized into treatment groups for the assessment of various therapies. Tumor volumes were determined each week before and after various treatments, and tumor growth was compared to that in untreated controls. Ionizing radiation at relatively small single doses completely inhibits tumor growth for a period of up to 6 months. Some interesting characteristics of this radiation-induced growth arrest are that tumors do not die and shrink away as with some other tumor models but remain static in size and show histologic evidence of viable tumor cells. The hypoxic cell radiosensitizer misonidazole potentiates radiation response in this tumor model. Cisplatin, vincristine, etoposide, and estramustine phosphate administered in drug doses approaching their toxic limits have a partial effect on tumor growth.
Reports have been made in important advances in the therapy of nonseminomatous germ cell tumors from specialized cancer therapy centers that treat a selected referred patient population. We herein examine the impact of these improvements on the total community of a large geographic area. Using the facilities of a comprehensive cancer registry and standardizing the treatment of nonseminomatous germ cell tumors from 1976 to the present, we have shown that there has been a marked improvement in the over-all survival of patients with these tumors in northern Alberta. During the 4-year interval the survival rates were 100 per cent for patients with stage I, 93 per cent for those with stage II and 83 per cent for those with stage III tumor. The over-all survival rate for patients with nonseminomatous germ cell tumors in this community presently is comparable to that of patients with pure seminomas. We have shown that aggressive, multidisciplinary treatment, developed in specialized centers, can significantly improve the outlook for all patients with nonseminomatous germ call tumors in a defined community.
We describe 2 unusual cases of genitourinary neurofibromas. In 1 case a large solitary neurofibroma developed on the glans penis and in the other case a plexiform neurofibroma of the pelvis was present in young women with von Recklinghausen's disease. Each case represents either end of the spectrum of urologic involvement by this rare tumor. The solitary neurofibroma requires only local excision but the plexiform neurofibroma, causing urinary obstruction, necessitates urinary diversion. Recurrence and malignant degeneration, while virtually unheard of in the former, are relatively common in the latter. The prognosis of each type is discussed.
Hypospadias is a common congenital anomaly with a prevalence estimated to be as high as 1 in 125 live male births. Its etiology is not entirely resolved but is embryologic in origin and has been attributed to fusion defects. Several authors believe it is a manifestation of intersex. Experience to date has produced a general consensus with regard to indications, timing and surgical principles for repair of the hypospadiac meatus. While two-stage procedures have been the mainstay of therapy, successful single-stage procedures have recently been developed. The prevention and management of the complications of persistant chordee, fistula and stricture make hypospadias repair one of the more challenging urologic procedures.