Late effects following central nervous system radiation in a pediatric population.

Between 1970 and 1986, 120 children with central nervous system malignancy were treated with radiation therapy. These included 44 low-grade astrocytomas, 11 high grade astrocytomas, 32 medulloblastomas, 15 ependymomas/ependymoblastomas, 3 primitive neuroectodermal tumors and 8 pineal tumors. Seven children were treated without biopsy. Fifty-one treated children were evaluated for the effects of therapy on growth, endocrine function, IQ and hair regrowth. Mean height was 1.5 standard deviations below the mean height for the patient's age at study (range 0-5.7). Height was significantly less in patients receiving radiation to the pituitary and those with somatomedin-C deficiency. Height was also decreased with whole CNS radiation and spine dose > 20 Gy but not to a significant degree. Pituitary radiation in any dose increased the chance of endocrine deficiency (p = 0.004) and 21 of 51 patients had somatomedin-C deficiency. Mean IQ was 92.7 (+/- 18.8), with a slight trend toward decreased IQ with increasing whole brain dose of radiation. Hair regrowth was complete in 20 of 46 evaluated patients, diminished regrowth occurring with increasing volume and dose of radiation. No difference in the measured late effects could be detected with respect to age at treatment, sex, histology or location of tumor.

Phase II trial of combination chemotherapy and irradiation in non-small-cell lung cancer, Radiation Therapy Oncology Group 88-04.

Encouraging results of several clinical trials utilizing combination chemotherapy and irradiation in unresectable non-small-cell lung cancer have been reported. A recent report from a cooperative group study suggested that preirradiation vinblastine and cisplatin improved survival over irradiation alone. In an attempt to enhance the possible effectiveness of combination chemotherapy and irradiation, the Radiation Therapy Oncology Group embarked on a Phase II trial utilizing preirradiation vinblastine (5 mg/m2 weekly x 5) and cisplatin (100 mg/m2) on days 1 and 29 prior to irradiation and on days 50, 71, and 92 during irradiation. The irradiation began on day 50 and consisted of 6300 cGy in 7 weeks. Between May 20, 1988 and May 1, 1989, 30 patients were entered on study. Seventy-two percent of patients had Karnofsky status greater than 90, and 76% had weight loss less than 5%. Forty-eight percent of the patients were younger than 60 years of age. Forty-five percent of the patients had Stage IIIA disease. Eighty-three percent of the patients received at least four courses of vinblastine, and 59% received at least four courses of cisplatin. Seventy-eight percent of the patients received at least 95% of the prescribed irradiation. The major toxicity was hematologic, and there were two fatal complications in the study group. The preliminary survival figures are encouraging. This combination of chemotherapy and irradiation appears to be tolerable and may merit further investigation.

Non-Hodgkin's lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315.

Between 1983 and 1987 the Radiation Therapy Oncology Group conducted a prospective phase II study to evaluate survival in primary non-Hodgkin's lymphoma of the brain treated with whole brain irradiation to 40 Gy and a 20 Gy boost to tumor plus a 2 cm margin. Forty-one patients are reported. Full follow-up is available on 35/41 who have died. Six are alive at 8.8-67.2 months from start of radiation therapy with a median followup of 53.9 months. Overall median survival was 11.6 months from start of radiation therapy and 12.2 months from diagnosis, with 48% surviving 1 year and 28% surviving 2 years. Karnofsky Performance Status and age were significant prognostic factors. Patients with a Karnofsky Performance Status of 70-100 had a median survival of 21.1 months compared to 5.6 months for patients with a status of 40-60 (p less than .001). Fourteen patients less than 60 years of age had a median survival of 23.1 months, while 27 patients greater than or equal to 60 years of age had a median survival of 7.6 months (log-rank p = .001). Disease recurred in the brain in 25/41 (61%) of the patients, (21/41 in the brain only and 4/41 in the brain plus distant metastases). Despite high dose and large volume irradiation, primary Central Nervous System lymphoma still exhibits excessive mortality, especially in older patients. This paradox of the relative radioresistance of primary Central Nervous System lymphoma remains unresolved.

Development of a lyophilized formulation of interleukin-2.

Native human interleukin-2 (IL-2) comprises a group of glycoproteins of MW 13,000-17,500. Recombinant human IL-2 (rhIL-2) (Cetus) is derived from E. coli and is not glycosylated. We have evaluated several processes for manufacturing rhIL-2, based on different chaotropic agents for solubilization of insoluble protein pastes. Formulation work carried out with material purified by one of these processes is reported here. Our studies have indicated that the presence of a stabilizer in the form of an amorphous excipient, such as amino acids, a non-ionic surfactant (polysorbate 80), hydroxypropyl-beta-cyclodextrin or human serum albumin was essential for preservation of rhIL-2 during lyophilization. Each of these formulations exhibited its own unique problems. We have overcome these problems through a systematic formulation development program and have been successful in developing several lyophilized formulations of rhIL-2 with optimum properties and performance.

Breast irradiation following silicone gel implants.

Little information is found in the literature regarding breast irradiation in patients with reconstructed or augmented breasts. From November 1970 to October 1984, we treated ten patients with silicone gel prostheses with external radiation for recurrent disease, or as primary therapy. All patients were treated with megavoltage equipment. Technique and doses varied with the clinical situation, but generally, patients received 5000 rad in five weeks to the breast or mound with opposed tangential fields. The majority of patients had excellent cosmetic results with minimal late skin changes and no fibrosis or contracture. We conclude that, with proper surgical and radiotherapeutic techniques, good cosmetic results can be obtained in these patients, without compromising their therapy.

Mortality and morbidity after anterior lesser curve seromyotomy with posterior truncal vagotomy for duodenal ulcer.

A survey has been performed of the mortality and morbidity of anterior lesser curve seromyotomy with posterior truncal vagotomy in the elective treatment of chronic duodenal ulcer. There was one death in a series of 605 patients due to a myocardial infarction, an operative mortality of 0.16 per cent. There was no case of ischaemic necrosis of the lesser curvature or fundus of the stomach. Eleven patients had symptoms of delayed gastric emptying (1.7 per cent) and seven of these underwent a drainage procedure (1.3 per cent). Postoperative dumping did not occur, significant diarrhoea was present in two patients (0.33 per cent). This operation is relatively simple, quick and extremely safe to perform. It is suggested that the more widespread use of this type of elective surgery for duodenal ulcer might reduce the mortality from the condition.

Magnetic-induction hyperthermia. Results of a 5-year multi-institutional national cooperative trial in advanced cancer patients.

Nine US institutions performed 14,807 Phase I-II treatments of magnetic-induction (Magnetrode [Henry Medical Electronics, Inc., Los Angeles, CA]) hyperthermia in 1170 adults. All had advanced tumors: 20% had untreated inoperable cancer or disease progression despite surgery (10%), radiation therapy (XRT) (3%), chemotherapy (27%), or combinations (40%); 67% had pain; and 79% had reduced activity. Eighteen percent were advanced primaries, 26% were recurrent, and 56% metastatic tumors in the head and neck (7%), body wall (7%), extremity (4%), abdominal cavity (17%), pelvis (17%), lung (15%), or liver (30%); 36% were less than 5 cm and 64% greater than or equal to 5 cm. Treatments were to safe tolerance for 30 to 60 minutes for five or more treatments. Results in 960 evaluable patients were complete response 9% (1-34 months; median, 7 months), partial response 18% (1-39 months; median, 4 months), minimal response 10% (1-15 months; median, 3 months), and no change 33% (1-32 months; median, 3 months), with decreased pain in 30% and improved activity in 21%, independent of histologic type or site. Regression was dependent on treatment type and minimum temperature: heat only, 23%; heat + XRT, 60%; heat + less-than-standard XRT because of prior XRT failure, 39%, heat + intravenous (IV) chemotherapy, 28%; heat + same previously failed IV chemotherapy, 20%; heat + intraarterial (IA) chemotherapy, 28%; heat + same previously failed IA chemotherapy, 15%; heat + standard XRT + chemotherapy, 58%; heat + less-than-standard XRT + chemotherapy, 47%; less than 40 degrees C, 31%; 40 to 40.9 degrees C, 45%; 41 to 41.9 degrees C, 54%; 42 to 42.9 degrees C, 47%; 43 to 43.9 degrees C, 40%; 44 to 44.9 degrees C, 33%; 45 to 45.9 degrees C, 55%; 46 to 46.9 degrees C, 63%; greater than 47 degrees C, 100%. There were 49 (0.33%) skin burns and 2 systemic injuries (stomach ulcer at 1 month; lung fibrosis at 9 months). This trial indicates that localized hyperthermia has a significant role in palliation of human advanced solid cancer.

A comparison of deep regional hyperthermia from an annular array and a concentric coil in the same patients.

Twenty-two patients with advanced pelvic or abdominal malignancy (or both) were treated on successive occasions with hyperthermia produced by an annular array (AA) (60-80 MHz, 500-1800 W forward power) and a concentric coil (CC) (13.56 MHz, 350-1000 W forward power). Both devices were compared with respect to acute toxicity and power limitations. There was no power limiting factor in pelvic heating in 7/14 patients treated with the AA, however 13/14 experienced power limiting sacrococcygeal pain with the CC. The 9 patients who underwent abdominal heating had a variety of power limitations with both devices. Thermal mapping was performed in 23 treatments with the AA and in 19 with the CC. Composite thermal maps of patients with similar thermometry sites show that heating patterns produced by the CC were predictable from theory and static phantom measurements. The AA achieved broader regional heating, particularly at depth, but heating patterns were less predictable. Spatial thermal dose (TD) analysis revealed higher minimum tumor TDs and more favorable mean tumor/normal tissue TD ratios with the AA than with the CC. We conclude that the AA is superior to the CC for pelvic treatment and that both devices have limitations in abdominal treatment.

Jejunal perforation as a result of massive gastrointestinal bleeding from a duodenal ulcer.

A complication of massive upper gastrointestinal bleeding is presented as a case report of a patient who developed a spontaneous perforation of the small intestine as a result of massive bleeding from a duodenal ulcer.

Radiotherapy of bronchogenic carcinoma. Analysis of a treatment schedule designed for use with hyperbaric oxygen.

All cases of bronchogenic carcinoma treated with curative intent over an eight-year period were reviewed. Most were treated with 12 X 400 rad in 32 days using 60Co, a schedule designed to optimize the radiation-sensitizing properties of hyperbaric oxygen. While O2 gave no obvious benefit, overall four-year survival was 10.6% and that of patients with good prognostic indicators was 18%. No radiation myelitis was observed. This protocol delivers an adequate tumor dose and appears to be tolerated well by most patients.

Obstructive uropathy after pan-proctocolectomy for ulcerative colitis.

We report two cases of pan-proctocolectomy for ulcerative colitis who some time postoperatively developed an obstructive uropathy with the clinical and radiological features of retroperitoneal fibrosis. The incidence of this complication appears to be around 10% and the possibility of such a diagnosis should be borne in mind in any patient who has non-specific symptoms after surgery for ulcerative colitis.

The effects of modification with N-bromosuccinimide on the binding of ligands to dihydrofolate reductase.

The binding constants of substrate, inhibitors and coenzymes to native Lactobacillus casei dihydrofolate reductase and to the enzyme modified (at Trp-21) by N-bromosuccinimide have been determined using fluorimetric and spectrophotometric methods. The modification leads to only modest decreases (factors of 2-4) in the binding of substrate or substrate analogues, but the effects of coenzyme binding are much larger. The binding of NADPH is decreased by a factor of 200, but that of NADP+ by only a factor of 4, indicating a clear difference in their mode of interaction with the enzyme. The nature of this difference is discussed in the light of crystallographic and n.m.r. studies of the enzyme.

Proton nuclear magnetic resonance studies of the effects of ligand binding on tryptophan residues of selectively deuterated dihydrofolate reductase from Lactobacillus casei.

We have prepared a selectively deuterated dihydrofolate reductase in which all the aromatic protons except the C(2) protons of tryptophan have been replaced by deuterium and have examined the 1H NMR spectra of its complexes with folate, trimethoprim, methotrexate, NADP+, and NADPH. One of the four Trp C(2)-proton resonance signals (signal P at 3.66 ppm from dioxane) has been assigned to Trp-21 by examining the NMR spectrum of a selectively deuterated N-bromosuccinimide-modified dihydrofolate reductase. This signal is not perturbed by NADPH, indicating that the coenzyme is not binding close to the 2 position of Trp-21. This contrasts markedly with the 19F shift (2.7 ppm) observed for the 19F signal of Trp-21 in the NADPH complex with the 6-fluorotryptophan-labeled enzyme. In fact the crystal structure of the enzyme . methotrexate . NADPH shows that the carboxamide group of the reduced nicotinamide ring is near to the 6 position of Trp-21 but remote from its 2 position. The nonadditivity of the 1H chemical-shift contributions for signals tentatively assigned to Trp-5 and -133 indicates that these residues are influenced by ligand-induced conformational changes.

Laboratory and field control of clinical mastitis in dairy cows around Bulawayo.

The organisms responsible for clinical mastitis in dairly herds around Bulawayo were identified and their antibiotic sensitivity was determined. Streptococci, staphylococci and coliforms were responsible for 37%, 28% and 29,5% of cases respectively. Antibiotic resistance increased over the 3 year period. The high incidence of coliform mastitis is discussed, as is the effect of dry cow therapy on peri-natal mastitis and the nature of the scheme of control. The laboratory is considered an essential adjunct to other control methods.