Long-term toxicity and neuropathology associated with the sequencing of cranial irradiation and enhanced chemotherapy delivery.

OBJECTIVE: The goal was to evaluate, at 1 year, 75 Long-Evans rats for survival rates and toxicity associated with the sequencing of cranial irradiation and enhanced chemotherapy delivery. METHODS: Seventy-five Long-Evans rats were randomized into four groups and evaluated at 1 year for survival rates and toxicity associated with the sequencing of cranial irradiation and enhanced chemotherapy delivery. Radiation (2,000 cGy) was administered as a single fraction, by using parallel opposed portals, 30 days before chemotherapy (Group 1), 24 hours before chemotherapy (Group 2), 30 days after chemotherapy (Group 3), or without chemotherapy or without radiation (control group, Group 4). Five subgroups within each treatment group included rats receiving intra-arterially administered methotrexate (1 g/m2) or intravenously administered etoposide (200 mg/m2) combined with intra-arterially administered carboplatin (200 mg/m2), administered with or without osmotic blood-rain barrier disruption, and a group receiving normal saline solution after blood-brain barrier disruption. RESULTS: There was a significant increase in total toxic effects when the three experimental groups were compared with the control group (P = 0.001, 0.006, and 0.013 for Groups 1, 2, and 3, respectively). All groups receiving radiation and chemotherapy (particularly carboplatin and etoposide) had an increased incidence of hind limb paralysis, resembling experimental allergic neuritis (P = 0.053). Statistical analysis showed a trend toward increased mortality rates in Group 1 (antecedent radiation), compared with the control group (P = 0.082), and an increased incidence of intracerebral calcification (P = 0.019). No differences in mortality rates were observed for Group 2 or 3, compared with the control group. CONCLUSION: Radiation before chemotherapy was a more toxic sequence and, surprisingly, carboplatin/etoposide administered in combination with radiotherapy was more detrimental than methotrexate. Additional studies are in progress to evaluate the toxicity and efficacy of sequences of cranial irradiation and enhanced chemotherapy in tumor-bearing rats.

Squamous cell carcinoma of the pharyngeal walls treated with radiotherapy.

PURPOSE: To assess the impact of fractionation schedule, chemotherapy, and tumor location on local control and survival in patients treated with definitive irradiation for carcinoma of the pharyngeal walls. METHODS AND MATERIALS: Between May 1971 and December 1991, 74 patients with previously untreated squamous cell carcinoma of the pharyngeal walls (excluding nasopharynx, tonsil, and pyriform sinus) were treated with radical megavoltage irradiation with or without chemotherapy at Oregon Health Sciences University. RESULTS: Two-year local control rates by stage were: T1: 100%, T2: 55%, T3: 31%, and T4: 29% . Twice-a-day irradiation improved local control rates as compared with once-a-day irradiation for patients with Stage T3 lesions, with 5 out of 7 (71.4%) vs. 4 out of 19 (21%) patients controlled at 2 years (p = 0.015). No improvement was seen in 2-year local control of all stages when chemotherapy was used in conjunction with once-a-day fractionation; however, six of eight patients (75%) treated with twice-a-day irradiation combined with either induction or concurrent chemotherapy had local control. The 2-year local control rate of 100% (6 out of 6) for the group of patients treated with concurrent chemotherapy and b.i.d. irradiation (all with Stage T3 and T4 tumors) is a dramatic improvement over the 2-year local control rate of 30% (10 out of 33) for our entire group of patients with Stage T3 and T4 tumors. Local control rates did not differ by tumor location on the pharyngeal walls. Adjusted disease-specific survival rates by stage were: 1: 100%, II: 85%, III: 58%, IV: 40%. Overall survival rates by stage were: I: 75%, II: 67%, III: 33%, IV: 30%. CONCLUSION: We advocate radical irradiation as the primary therapy for pharyngeal wall carcinomas with the use of twice-a-day fractionation for Stages T2-T4. Our preliminary results with concurrent chemotherapy and b.i.d. irradiation for advanced T3 and T4 tumors appear to be comparable to reported results with hyperfractionated radiation alone. The relative contribution of chemotherapy to b.i.d. irradiation cannot be determined from this small retrospective series; however, in view of the relatively poor results for patients with advanced stage disease, we feel this treatment combination deserves further investigation.

Decreased delivery and acute toxicity of cranial irradiation and chemotherapy given with osmotic blood-brain barrier disruption in a rodent model: the issue of sequence.

The sequence of chemotherapy administered prior to cranial irradiation rather than the more traditional order of radiation followed by chemotherapy is currently being evaluated. This rodent study was designed to assess the sequencing of radiation therapy and chemotherapy administered with osmotic blood-brain barrier disruption (BBBD). Drug delivery and acute toxicity were evaluated. Two clinically relevant chemotherapy regimens were given with BBBD: intraarterial methotrexate (MTX, 1 g/m2), or a combination of intraarterial carboplatin (200 mg/m2) and i.v. etoposide (200 mg/m2). In a randomized protocol, the standard rodent model of 2000 cGy as a single fraction using parallel opposed portals was administered 30 days prior to, concurrent with (24 h prior), or 30 days after these two chemotherapeutic regimens. A total of 72 animals was evaluated in this study. The administration of external beam radiation therapy either prior to or concurrent with the administration of a high molecular weight marker 14C-labeled dextran 70 (Mr 70,000), or a low molecular weight marker 3H-labeled MTX (Mr 456) resulted in a statistically significant (P < 0.01) decrease in drug delivery when compared to animals not receiving cranial irradiation. Seizures were observed in 26% of the animals that received radiation prior to the administration of intraarterial MTX after BBBD. It did not matter whether the radiotherapy was administered 30 days prior to or concurrent with MTX. Seizures were not seen in any other group. The mortality in animals receiving radiotherapy 30 days prior to chemotherapy was significantly (P = 0.03) higher than the mortality in control animals receiving chemotherapy after osmotic BBBD, but no radiation. Drug delivery was significantly decreased when the animals received prior radiotherapy; the administration of radiation prior to MTX with BBBD resulted in an increased incidence of seizures, and there was a significant increase in mortality when cranial irradiation was given 30 days prior to chemotherapy administered with BBBD. With regard to delivery and toxicity, chemotherapy with BBBD administered prior to radiotherapy may have advantages over the other sequences utilizing chemotherapy and cranial irradiation.

Small cell carcinoma of urinary bladder.

A fifty-seven-year-old woman with urinary bladder carcinoma with extensive areas resembling oat cell carcinoma of the lung in whom distant metastases developed, died seven months after diagnosis. Argyrophil cells could not be demonstrated, but electron microscopy demonstrated dense-core, membrane-bound intracytoplasmic granules. We reviewed 12 cases of epithelial neoplasms of the bladder from the literature in which there was ultrastructural evidence of neuroendocrine differentiation. Cases with malignant histologic features, like their pulmonary counterparts, have the potential for widespread dissemination and rapid growth. We support the previous suggestion that these neoplasms may be of considerable incidence and their recognition is important to determine prognosis and selection of therapy.

Treatment of obliterated membranous and bulbous urethras by direct vision internal urethrotomy.

Acute placement of a suprapubic bladder tube followed months later by open urethroplasty has been the traditional manner for managing traumatic disruption of the proximal urethra. The latter procedure has generally been performed via the transpubic or perineal approach. These procedures have been complicated by excessive blood loss, impotence, incontinence, strictures, and extended hospitalizations. Since 1979, 12 patients with obliterated urethras (ten membranous, two bulbous) have been treated by direct vision urethrotomy using a second cystoscope or sound passed through the previously placed suprapubic tract as a guide. Mean blood loss, hospital stay, and followup were 70 ml, 6 days, and 22 months, respectively. Six patients required at least one additional internal urethrotomy. With the exception of one patient who still requires intermittent self-catheterization, all have stable strictures. Ten are continent (one was incontinent secondary to previous radical prostatectomy before urethrotomy and one became incontinent after a TURP performed 3 years after urethrotomy). Five are potent and none lost potency as a result of urethrotomy. Flow rates range from 15-25 ml/second in the continent patients. This is a reasonable first procedure for restoring continuity of traumatically obliterated membranous and bulbous urethras.

Early morphological and chemical changes induced by cisplatin in the guinea pig organ of Corti.

Guinea pigs were treated with a single dose of Cisplatin (5 mg IP). After 2-4 days the cochleas were prepared for morphological analysis by scanning electron microscopy and chemical analysis by X-ray dispersive microanalysis. Following Cisplatin, the bundles of stereocilia on the hair cells were found to be rough, disarrayed, fused, and finally absorbed. Significant increases were found in the levels of calcium, sulphur, and phosphorus in the abnormal hair cells. It is suggested that the high calcium levels might be due to the inhibition of enzymes which normally keep cytoplasmic calcium low, and that some of the changes in the stereocilia might be secondary to this.

Intraoperative consultation for the ureter.

Being called to the operating room to repair a surgically damaged ureter is an opportunity and challenge that requires on-the-spot decisions based on our training and experience and can result in restoring urinary tract continuity and avoiding secondary operations. A variety of functional reparative techniques are available; however, after consideration of each case in the context in which it arises, the best solution can usually be selected.

Percutaneous vaso-occlusion for nonmalignant renal lesions.

Transarterial renal embolization has been used in the management of renal cancer. We report on 9 patients who underwent selective and superselective renal arterial embolization for nonmalignant renal lesions. Embolization was done in 5 patients for hemorrhage owing to renal angiomas, renal artery, pseudoaneurysm, percutaneous renal biopsy and adult polycystic kidney disease, and in 2 patients with end stage renal disease because of massive proteinuria. Another chronic renal failure patient with severe hypertension was treated successfully with bilateral renal embolization. A postoperative renal arteriovenous fistula was treated successfully by catheter vaso-occlusion. Renal embolization may be a suitable alternative to surgery in poor operative risk patients and for technically difficult benign lesions. Renal infection is a contraindication to embolization.

Adjuvant chemotherapy with vinblastine and bleomycin in stage B nonseminomatous germ cell tumors of the testis.

Between 1974 and 1980, 48 lymph node dissections were done for nonseminomatous tumors. Of 23 patients with pathologic stage A disease 1 (4 per cent) suffered recurrence but is free of disease after chemotherapy and pulmonary resection. All 23 patients (100 per cent) are free of disease. Adjuvant chemotherapy with high dose vinblastine and constant infusion of bleomycin was given in 25 patients with stage stage B disease and none had maintenance chemotherapy. Of these 25 patients 2 (8 per cent) had evidence of recurrent disease after adjuvant chemotherapy and both are free of disease after further chemotherapy, which included cis-platinum. One patient died after a second primary embryonal carcinoma developed in the remaining testis 3 years after the initial tumor. Twenty-four of the 25 patients with stage B tumor (96 per cent) are free of disease 15 months to greater than 7 years after therapy.

Uroepithelial carcinoma in association with cyclophosphamide ingestion.

The association of daily oral cyclophosphamide with the development of transitional cell carcinoma or squamous cell carcinoma of the bladder had been documented. We report the first 2 cases of transitional cell carcinoma of the renal pelvis and an additional 4 cases of transitional cell carcinoma of the bladder following cyclophosphamide ingestion. Patients who have been taking daily oral cyclophosphamide for a prolonged period should have excretory urography, cystoscopy and bladder mucosal biopsies performed as part of a cancer surveillance protocol.

Transureteroureterostomy: 25-year experience with 100 patients.

During the last 25 years 100 patients have been subjected to transureteroureterostomy. In 2 cases postoperative death was attributable to other pathologic processes. We treated 94 donor units successfully in this manner. An additional 2 units, normal for several years after transureteroureterostomy, had periureteral fibrosis and stricture owing to the inferior mesenteric artery syndrome and required another definitive surgical procedure. Ninety-seven recipient kidneys remained normal after the procedure.

Radical prostatectomy for carcinoma: 30-year experience and 15-year survivals.

Three strata of medical care are shown in this series of patients undergoing radical prostatectomy for carcinoma: (1) Medical School Hospital patients had an average age 4 years greater than patients in the other 2 groups and the lowest 15-year survival rate of 15 per cent. 2) The Veterans Hospital patients had an average age 4 years younger than patients in the Medical School Hospital group but there was little opportunity for preventive care by early diagnosis and they had a 15-year survival rate of 26 per cent. 3) The Emanuel series of private patients had good preventive private medical care, allowing for earlier diagnosis in a patient population without other serious medical problems, and a 15-year survival rate of 61 per cent. The 15-year survival figures for other modalities of therapy, including various types of radiation, chemotherapy and immunotherapy, are necessary for meaningful evaluation of efficacy.

Specific binding of prolactin by the prostate gland of the rat and man.

Specific binding sites for 125iodine-prolactin are present in membrane particles obtained from the rat ventral prostate, human benign prostatic hyperplasia and prostatic adenocarcinoma. In the ventral prostate glands of young rats (1 to 4 months old) specific binding of 125iodine-prolactin is higher than in older animals (greater than 8 months old). Subcellular distribution studies revealed that specific 125iodine-prolactin binding activity is associated primarily with the 15,000 and 100,000 g particulate membrane fractions of the rat ventral prostate and human prostate glands. In rats between 2 and 4 months old significant increases in the prolactin binding activity in the 100,000 g membrane fraction of the ventral prostate are observed to occur without concomitant increases in prolactin binding activity in the 15,000 g fraction. The level of specific 125iodine-prolactin binding activity present in the human prostate gland is lower than that observed in the rat ventral prostate gland. Localization of specific prolactin binding sites in the rat ventral psotate and the human prostate gland suggests that prolactin could influence the function of these tissues directly.

Renal oncocytoma.

Renal oncocytoma is a rare tumor of probable proximal tubular origin characterized by uniform cells with abundant, granular, brightly eosinophilic cytoplasm containing numerous mitochondria. The tumor is benign clinically and can be distinguished from renal cell carcinoma.

Auditory and vestibular damage in head injuries at work.

A series of 50 unselected patients who reported a head injury to the Workers' Compensation Board of British Columbia were referred to the AudioVestibular Unit of the Vancouver General Hospital for studies of auditory and vestibular function. All patients were interviewed and examined by a neuro-otology team during the course of their investigation. It was found that dizziness was the most common symptom of which they complained (60%), and bleeding from the ear was the least common (4%). Of the 50 patients studied, 32% showed evidence of either auditory and/or vestibular injury. Of the total number studied, 16% had auditory injuries and 26% had vestibular injuries. The most common auditory injury was unilateral partial loss of hearing. Central vestibular dysfunction was the most common vestibular injury. A study of the most effective means of selecting patients from the population with head injuries for referral for audiology and vestibular testing was undertaken. The most effective combination of symptoms for referral is the presence of one or more of the triad: hearing loss, unsteadiness, or loss of consciousness/amnesia.