Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule.

The protein-protein interaction between leukocyte functional antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) is critical to lymphocyte and immune system function. Here, we report on the transfer of the contiguous, nonlinear epitope of ICAM-1, responsible for its association with LFA-1, to a small-molecule framework. These LFA-1 antagonists bound LFA-1, blocked binding of ICAM-1, and inhibited a mixed lymphocyte reaction (MLR) with potency significantly greater than that of cyclosporine A. Furthermore, in comparison to an antibody to LFA-1, they exhibited significant anti-inflammatory effects in vivo. These results demonstrate the utility of small-molecule mimics of nonlinear protein epitopes and the protein epitopes themselves as leads in the identification of novel pharmaceutical agents.

An analysis of the late effects of radiotherapy in pediatric central nervous system tumors.

PURPOSE: The purpose of this study is to assess the long term results of all pediatric patients diagnosed with central nervous system (CNS) tumors treated with external beam radiotherapy either primarily or postoperatively. MATERIALS: Forty-seven pediatric patients with CNS tumors were treated between 1978 and 1989 with external beam radiotherapy to customized fields using cobalt 60, 4, 6, or 18 MV photons. Daily doses ranged from 1.5 to 2.0 Gray; total doses from 35 to 66 Gray. Ages ranged from one month to 18 years of age, with an average age of 8.2 years. Thirty-nine patients survived more than 12 months (range 36 to 178 months; median 62 months) and were included for analysis. Ten of 39 (25.6%) patients experienced Grade I to II complications and six patients had (15.7%) Grade III to IV complications for an overall incidence of 41%. The influence of field size, radiation dose, chemotherapy, age, and extent of surgical resection upon long-term complications were studied. CONCLUSION: Radiation therapy for pediatric CNS malignancies is associated with long-term complications. Significant long-term complications can be limited to an acceptable level of approximately 15%.

Retrospective analysis of patients with primary fallopian tube carcinoma treated at the University of Louisville.

Medical records of patients diagnosed with primary fallopian tube carcinoma between 1979 and 1989 were reviewed. Twenty-six patients were eligible; 8 patients were excluded after pathologic review, leaving 18 patients included in the study for this analysis. The median and mean age were 61 and 59 years, respectively, with a range of 39-80 years. There were three Stage I, five Stage II, seven Stage III, and three Stage IV patients. The most common presenting symptoms were abdominal/pelvic pain, abdominal distension, and vaginal discharge/bleeding. The primary site of the lesion was determined to be the right tube in 44% of the cases, the left tube in 39% of the patients, bilateral lesions in 11% of the patients, and indeterminate in 6%. Histologic grade was poorly differentiated (Grade III) in 13 patients, moderately differentiated (Grade II) in 4 patients, and well differentiated (Grade I) in one. No patient was correctly diagnosed preoperatively. Survival at 5 years of the entire group was 35% with a 3 year minimum followup. Corresponding disease free survival was 30%. Mean and median survival times were 74 and 37 months, respectively. The range of survival times was from 1 to 120 months. All Stage I patients, 80% (4/5) of Stage II, and 29% (2/7) of Stage III patients are alive without disease. None (0/3) of the Stage IV patients are alive. Treatment regimens consisted of intraperitoneal P-32, external beam radiotherapy, and/or chemotherapy. Radiotherapy was associated with a low incidence of treatment-related complications, the majority being gastrointestinal related. There was one chemotherapy-related death. These patients and their treatment outcomes add to the data base of numerous previous reports on fallopian tube carcinoma. Stage I and II patients fared excellently with primary surgical and adjuvant therapy. While the prognosis of Stage III and IV patients is much worse, significant levels of long term survival can be achieved with aggressive treatment.

Overexpression of p53 protein and outcome of patients treated with chemoradiation for carcinoma of the anal canal: a report of randomized trial RTOG 87-04. Radiation Therapy Oncology Group.

BACKGROUND: Despite encouraging results with chemoradiation as the primary means of managing carcinoma of the anal canal, approximately 20% of patients will develop a local recurrence. This study examined the prognostic significance of p53 nuclear protein overexpression in the pretreatment biopsies of patients treated with chemoradiation for epidermoid carcinoma of the anal canal. METHODS: All patients were treated in a prospective, randomized Radiation Therapy Oncology Group trial (RTOG 87-04) in which radiotherapy to the pelvis was compared with concurrent 5-fluorouracil (5-FU) or 5-FU and mitomycin-C. Formalin fixed, paraffin embedded blocks or unstained slides from the pretreatment biopsies of 64 patients were obtained from referring institutions and evaluated immunohistochemically with the polyclonal p53 antibody CM-1. A multivariate analysis was conducted to analyze overexpression of p53 in terms of locoregional control, no evidence of disease (NED), and overall survival. RESULTS: p53 protein was overexpressed in 48.4% of the cases. Although not statistically significant, there was a trend for patients whose tumors overexpressed p53 to have inferior locoregional control (52% vs. 72%, P = 0.13), NED survival (52% vs. 68%, P = 0.27), and absolute survival (58% vs. 78%, P = 0.14). Of all the pretreatment factors analyzed, only International Union Against Cancer stage was predictive of outcome in multivariate analysis. Among those patients whose tumors overexpressed p53, there was a trend toward improved outcome in the arm that received 5-FU and mitomycin-C compared with the arm that received 5-FU only. CONCLUSIONS: Overexpression of the p53 protein may be associated with inferior outcome for patients managed with definitive chemoradiation for epidermoid carcinoma of the anal canal.

Brachytherapy in early prostate cancer--early experience.

Use of brachytherapy with radioactive seeds in the management of early prostate cancer is commonly used in the United States. The early experience has been reported from the prostate treatment centers in Seattle for the last 10 years. In this manuscript we are reporting our early experience of 150 radioactive seed implantations in early stage prostate cancer using either Iodine 125 or Palladium 103 seeds. The average age of the patient is 66 years and the median Gleason score is 5.4 with a median PSA of 6. A brief description of the evolution of the treatment of prostate cancer as well as the preparation for the seed implantation using the volume study with ultrasound of the prostate, pubic arch study using CT scan of the pelvis and the complete planning using the treatment planning computers are discussed. We also have described the current technique which is used in our experience based on the Seattle guidelines. We plan a follow-up report with the results of the studies with longer follow-up.

Wilms' tumor in an adult: a case report and review of the literature.

Wilms' tumor in an adult is extremely rare, with less than 250 cases reported in the world literature. Treatment guidelines for pediatric Wilms' tumor are well established; those for adults are not. This article presents the case of a 19-year-old male diagnosed with Wilms' tumor after complaints of hematuria. He was categorized as Stage IV after nephrectomy and received post-operative radiotherapy and chemotherapy consisting of Vincristine, Adriamycin, and Actinomycin-D. Two years later he was found to have metastases to brain and lungs. He was treated with radiotherapy and bone marrow transplantation, and died of septic shock. The literature regarding Wilms' tumor in adults is reviewed, and current therapy is discussed.

Suppository administration of chemotherapeutic drugs with concomitant radiation for rectal cancer.

PURPOSE: Preoperative radiation with combined chemotherapy is effective in shrinking advanced rectal cancer locally and facilitating subsequent surgery. Suppository delivery of 5-fluorouracil is associated with less toxicity and higher rectal tissue concentrations than intravenous administration. This prompted us to evaluate suppository and intravenous administration of 5-fluorouracil and mitomycin C with concomitant radiation to determine associated toxicity. METHODS: Rectal, liver, lymph node, and lung tissue and systemic and portal blood were collected serially from male Sprague Dawley rats to determine drug concentrations following suppository or intravenous delivery of 5-fluorouracil or mitomycin C. Thirty-six animals were randomly assigned to treatment groups and received 5-fluorouracil suppositories, mitomycin C suppositories, or an equivalent intravenous dose of 5-fluorouracil or mitomycin C 30 minutes before radiation therapy. Before and 3, 6, 10, and 15 days following this treatment, blood was collected, colonoscopy was performed, and rectal tissue was harvested for histologic examination. RESULTS: Mitomycin C suppository was significantly less toxic compared with intravenous delivery, and higher rectal tissue concentrations were observed from 10 to 30 minutes (P < 0.05). Compared with intravenous 5-fluorouracil administration and radiation, 5-fluorouracil suppository and radiation resulted in additive myelosuppression at day 6 (P < 0.05) with rapid recovery. CONCLUSIONS: 5-Fluorouracil and mitomycin C suppository delivery combined with radiation causes less systemic toxicity and is more effective than intravenous administration.

Radiation therapy for pituitary adenomas. A retrospective study of the University of Louisville experience.

A retrospective analysis of treatment outcome was performed on patients treated with radiation for pituitary adenomas at the University of Louisville from January 1988 to December 1992. The study population included 27 patients. Twenty received radiation as a component of their initial treatment while seven received radiation as part of their treatment for recurrent disease. Nineteen patients were treated with post-operative radiation, and eight were treated with radiation alone. Follow-up interval ranged from 1 month to 109 months, with a median of 28 months. All three patients with stage I disease were controlled with radiation alone (1/3) or combined surgery and postoperative radiation (2/3), whereas six of eight stage II patients had disease control following surgery and postoperative radiation. Both patients with stage III adenomas treated with radiation alone had local control, whereas local control was achieved in six of seven with post-operative radiation. Three of five patients with recurrent disease had local control with radiation alone, whereas both patients undergoing surgery and postoperative radiation had local control. This retrospective analysis supports previous findings that radiation therapy alone or combined with transphenoidal resection is effective in long-term control of pituitary adenomas. It further suggests that immediate radiation therapy may be superior to radiation for surgical or medical failures.

Results of irradiation in patients with high-grade gliomas evaluated by magnetic resonance imaging.

Evidence shows that most high-grade gliomas are a diffuse process. Prior studies reported a median survival with surgery and postoperative radiotherapy of 8.6 months for glioblastoma multiforme (GBM) and 36.2 months for anaplastic astrocytoma (AA). Since MRI delineated the glioma better than CT scan, using MRI-based radiotherapy treatment planning allows for more precise treatment volumes. We retrospectively reviewed the records of the first 36 patients with malignant glioma, who had a presurgery MRI-based radiotherapy treatment planning. These patients were diagnosed between January 1986 and February 1991. Minimum follow up was 14 months and median survival was 15.4 months for GBM (7-42 months) and 27.4 months for AA (7-53 months). We feel that the trend for increased median survival in GBM (15.4 vs 8.6 months) is partly due to better definition of the tumor volume by using MRI. Larger studies are needed to confirm this finding.

Radiation therapy for pancreatic cancer: a retrospective study of the University of Louisville experience.

Although multiple regimens and approaches have been used in attempts to treat pancreatic cancer, the 5-year disease-free survival is dismal. With an increase in incidence of pancreatic cancer over the past 35 years, researchers continue their efforts to find an effective treatment for this aggressive disease. Between January 1983 and January 1993, we treated 77 patients with radiotherapy for pancreatic cancer. Only 35 of these patients had localized adenocarcinoma and were treated for cure. In this group of 35 patients, 5 received < 4,000 cGy (mean survival of 5.6 months) and 30 received > or = 4,000 cGy (mean survival of 14.7 months). Twenty-four of these 30 received > or = 5,000 cGy, resulting in a mean survival of 15.4 months, and 17 of these 24 received > or = 6,000 cGy, with a mean survival of 15.7 months. Some palliation of symptoms was achieved in 57% of all patients. These results at the University of Louisville Brown Cancer Center are comparable to other published results, but the prognosis for patients with pancreatic cancer remains bleak.

Phase I-II study of multiple daily fractions for palliation of advanced head and neck malignancies.

PURPOSE: To assess palliation of advance head and neck malignancies with the use of rapid hyper fractionation studies similar to the RTOG 85-02. MATERIALS AND METHODS: 37 patients with 39 lesions were entered into the non-randomized Phase I-II protocol, between 1984 and 1991. Previously untreated malignancies were present in 24 lesions, primary recurrent diseases in six patients, metastasis to the head and neck in five patients and skin primaries in the remaining two cases. At presentation 15 of 37 patients (or 17 of 39 lesions) were in operable due to poor medical status, eight patients were considered technically in operable due to extent of disease, 10 patients had distant metastasis and four patients refused surgery. The protocol uses twice a day fraction (370 cGy per fraction) for 2 consecutive days totalling 1,480 cGy per course. Three courses were given at 3-week intervals for a final tumor dose of 4,440 cGy in twelve fraction over 8-9 weeks. RESULTS: Eleven of 39 lesions had complete response; 19 lesions had partial response; 4 lesions had no response; 3 lesions progressed under treatment. Response could not be assessed in two patients. The average survival after completion of therapy was 4.5 months ranging from 2 weeks to 31 months. Palliation was achieved in 33 of 39 lesions. The acute reactions were minimal and no late or long term complications were noted. CONCLUSION: The absence of significant complications with reasonable response in the high rate of palliation suggests that this rapid hyper fractionation palliation study should be studied for further evaluation.

Tetrapeptide inhibitors of protein farnesyltransferase: amino-terminal substitution in phenylalanine-containing tetrapeptides restores farnesylation.

Protein farnesyltransferase from rat brain transfers farnesyl residues to cysteine residues in tetrapeptides that conform to the sequence CA1A2X, where C is cysteine, A1 and A2 are aliphatic amino acids, and X is methionine or serine. When the A2 residue is aromatic [e.g., phenylalanine as in Cys-Val-Phe-Met (CVFM)], the tetrapeptide continues to bind to the enzyme, but it can no longer accept a farnesyl group, and it becomes a pure inhibitor. The current studies show that this resistance to farnesylation also requires a positive charge on the cysteine amino group. Derivatization of this group with acetyl, octanoyl, or cholic acid residues or extension of the peptide with an additional amino acid restores the ability of phenylalanine-containing peptides to accept a farnesyl residue. The same result was obtained when the amino group of cysteine was deleted (mercaptopropionyl-VFM). These data suggest that the positive change on the cysteine amino group acts in concert with an aromatic residue in the A2 position to render peptides resistant to farnesylation by the rat brain enzyme.

Incidence of complications with mini vaginal culpostats in carcinoma of the uterine cervix.

Between 1980 and 1987, 298 patients with carcinoma of the uterine cervix were treated at the University of Louisville Department of Radiation Oncology. Of these, 197 (66.1%) were treated for cure by radiotherapy alone: 36 by external beam alone and 161 by external beam and tandem and ovoid applications. The F.I.G.O. staging of the 161 patients was 82 (50.1%) Stage IB, 9 (5.6%) Stage IIA, 40 (24.9%) Stage IIB, and 30 (18.6%) Stage III. The usual treatment was whole pelvis irradiation followed by two intracavitary applications using the Fletcher Suit Applicators of tandem and ovoids in 79/161 patients (49%), a 3-M Mini Applicator (Fletcher Suit Delcos Applicator) in 52/161 patients (32.3%), and a 3-M Mini Applicator with Caps in 30/161 patients (18.6%). The incidence of grade 3-4 gastrointestinal or genitourinary complications as defined by the RTOG was 19.3% (31/161). Various treatment parameters were analyzed to define possible contributing factors. Grade 3-4 complications were seen in 7.6% (6/79) of patients treated with the standard ovoid Fletcher system, 26.9% (14/52) treated with the mini-ovoid system, and 36.6% (11/30) treated with the mini-ovoid system with caps (p = .0006). Although trends were noted, neither the vaginal surface dose (VSD) from the ovoids nor the addition of the external beam dose to the VSD (total vaginal surface dose = TVSD) were significant independent variables (p = 0.19 and = 0.133, respectively). The TVSD was significant when comparisons were made between different ovoid systems (p = 0.05 for less than 12,000 cGy and p = 0.004 for greater than 12,000 cGy). In this study, the 3-M mini applicator was associated with a significant increase in grade 3-4 complications as compared to the Standard Fletcher Suit Applicator.

Medulloblastoma: results of treatment.

Fourteen patients with a diagnosis of medulloblastoma were treated in the Department of Radiation Oncology, University of Louisville School of Medicine from 1973 to 1979. The age of these patients ranged from 2 to 47 years with a median of 9 years. Twelve of them were 15 years or younger. All patients received craniospinal radiation after surgery, with a boost to the primary site by reduced field. The median dose to the primary was 4736 rads (range 3600 to 5600 rad). The median follow-up was 29.5 months. Six patients have died, and four of those six patients lived more than two years. Eight patients are alive to the last follow-up with a median survival of 29 months. Eight of 14 patients had local control and one patient developed distant metastasis. A brief review of the literature is done in this paper.

Budd-Chiari syndrome secondary to hepatic vein thrombus from Wilm's tumor. Case report and literature review.

We describe a case of Budd-Chiari Syndrome in a 6-year-old boy secondary to Wilm's tumor. The patient had a right nephrectomy and mediastinotomy with removal of the tumor from the right atrium, inferior vena cava, and hepatic vein. Postoperatively, the patient had chemotherapy consisting of Actinomycin-D to be followed by radiation to the tumor bed to a total dose of 2000 rads in 10 fractions by using AP/PA field on 6 MeV Linear Accelerator. Currently, the child is receiving combination chemotherapy.