Adaptation to simulated microgravity in Streptococcus mutans.

Long-term space missions have shown an increased incidence of oral disease in astronauts' and as a result, are one of the top conditions predicted to impact future missions. Here we set out to evaluate the adaptive response of Streptococcus mutans (etiological agent of dental caries) to simulated microgravity. This organism has been well studied on earth and treatment strategies are more predictable. Despite this, we are unsure how the bacterium will respond to the environmental stressors in space. We used experimental evolution for 100-days in high aspect ratio vessels followed by whole genome resequencing to evaluate this adaptive response. Our data shows that planktonic S. mutans did evolve variants in three genes (pknB, SMU_399 and SMU_1307c) that can be uniquely attributed to simulated microgravity populations. In addition, collection of data at multiple time points showed mutations in three additional genes (SMU_399, ptsH and rex) that were detected earlier in simulated microgravity populations than in the normal gravity controls, many of which are consistent with other studies. Comparison of virulence-related phenotypes between biological replicates from simulated microgravity and control orientation cultures generally showed few changes in antibiotic susceptibility, while acid tolerance and adhesion varied significantly between biological replicates and decreased as compared to the ancestral populations. Most importantly, our data shows the importance of a parallel normal gravity control, sequencing at multiple time points and the use of biological replicates for appropriate analysis of adaptation in simulated microgravity.

The Mars 2020 Perseverance Rover Mast Camera Zoom (Mastcam-Z) Multispectral, Stereoscopic Imaging Investigation.

Mastcam-Z is a multispectral, stereoscopic imaging investigation on the Mars 2020 mission's Perseverance rover. Mastcam-Z consists of a pair of focusable, 4:1 zoomable cameras that provide broadband red/green/blue and narrowband 400-1000 nm color imaging with fields of view from 25.6° × 19.2° (26 mm focal length at 283 µrad/pixel) to 6.2° × 4.6° (110 mm focal length at 67.4 µrad/pixel). The cameras can resolve (≥ 5 pixels) ∼0.7 mm features at 2 m and ∼3.3 cm features at 100 m distance. Mastcam-Z shares significant heritage with the Mastcam instruments on the Mars Science Laboratory Curiosity rover. Each Mastcam-Z camera consists of zoom, focus, and filter wheel mechanisms and a 1648 × 1214 pixel charge-coupled device detector and electronics. The two Mastcam-Z cameras are mounted with a 24.4 cm stereo baseline and 2.3° total toe-in on a camera plate ∼2 m above the surface on the rover's Remote Sensing Mast, which provides azimuth and elevation actuation. A separate digital electronics assembly inside the rover provides power, data processing and storage, and the interface to the rover computer. Primary and secondary Mastcam-Z calibration targets mounted on the rover top deck enable tactical reflectance calibration. Mastcam-Z multispectral, stereo, and panoramic images will be used to provide detailed morphology, topography, and geologic context along the rover's traverse; constrain mineralogic, photometric, and physical properties of surface materials; monitor and characterize atmospheric and astronomical phenomena; and document the rover's sample extraction and caching locations. Mastcam-Z images will also provide key engineering information to support sample selection and other rover driving and tool/instrument operations decisions.

MAP2 is differentially phosphorylated in schizophrenia, altering its function.

Schizophrenia (Sz) is a highly polygenic disorder, with common, rare, and structural variants each contributing only a small fraction of overall disease risk. Thus, there is a need to identify downstream points of convergence that can be targeted with therapeutics. Reduction of microtubule-associated protein 2 (MAP2) immunoreactivity (MAP2-IR) is present in individuals with Sz, despite no change in MAP2 protein levels. MAP2 is phosphorylated downstream of multiple receptors and kinases identified as Sz risk genes, altering its immunoreactivity and function. Using an unbiased phosphoproteomics approach, we quantified 18 MAP2 phosphopeptides, 9 of which were significantly altered in Sz subjects. Network analysis grouped MAP2 phosphopeptides into three modules, each with a distinct relationship to dendritic spine loss, synaptic protein levels, and clinical function in Sz subjects. We then investigated the most hyperphosphorylated site in Sz, phosphoserine1782 (pS1782). Computational modeling predicted phosphorylation of S1782 reduces binding of MAP2 to microtubules, which was confirmed experimentally. We generated a transgenic mouse containing a phosphomimetic mutation at S1782 (S1782E) and found reductions in basilar dendritic length and complexity along with reduced spine density. Because only a limited number of MAP2 interacting proteins have been previously identified, we combined co-immunoprecipitation with mass spectrometry to characterize the MAP2 interactome in mouse brain. The MAP2 interactome was enriched for proteins involved in protein translation. These associations were shown to be functional as overexpression of wild type and phosphomimetic MAP2 reduced protein synthesis in vitro. Finally, we found that Sz subjects with low MAP2-IR had reductions in the levels of synaptic proteins relative to nonpsychiatric control (NPC) subjects and to Sz subjects with normal and MAP2-IR, and this same pattern was recapitulated in S1782E mice. These findings suggest a new conceptual framework for Sz-that a large proportion of individuals have a "MAP2opathy"-in which MAP function is altered by phosphorylation, leading to impairments of neuronal structure, synaptic protein synthesis, and function.

Enhancement of accelerated carbonation of alkaline waste residues by ultrasound.

The continuous growth of anthropogenic CO2 emissions into the atmosphere and the disposal of hazardous wastes into landfills present serious economic and environmental issues. Reaction of CO2 with alkaline residues or cementitius materials, known as accelerated carbonation, occurs rapidly under ambient temperature and pressure and is a proven and effective process of sequestering the gas. Moreover, further improvement of the reaction efficiency would increase the amount of CO2 that could be permanently sequestered into solid products. This paper examines the potential of enhancing the accelerated carbonation of air pollution control residues, cement bypass dust and ladle slag by applying ultrasound at various water-to-solid (w/s) ratios. Experimental results showed that application of ultrasound increased the CO2 uptake by up to four times at high w/s ratios, whereas the reactivity at low water content showed little change compared with controls. Upon sonication, the particle size of the waste residues decreased and the amount of calcite precipitates increased. Finally, the sonicated particles exhibited a rounded morphology when observed by scanning electron microscopy.

[Hypothetical link between endometriosis and xenobiotics-associated genetically modified food]. / Lien hypothétique entre l'endométriose et l'accumulation de xénobiotiques associés aux aliments génétiquement modifiés.

Endometriosis is an oestrogen-dependent inflammatory disease affecting 10 % of reproductive-aged women. Often accompanied by chronic pelvic pain and infertility, endometriosis rigorously interferes with women's quality of life. Although the pathophysiology of endometriosis remains unclear, a growing body of evidence points to the implication of environmental toxicants. Over the last decade, an increase in the incidence of endometriosis has been reported and coincides with the introduction of genetically modified foods in our diet. Even though assessments of genetically modified food risk have not indicated any hazard on human health, xenobiotics-associated genetically modified food, such as pesticides residues and xenoproteins, could be harmful in the long-term. The "low-dose hypothesis", accumulation and biotransformation of pesticides-associated genetically modified food and the multiplied toxicity of pesticides-formulation adjuvants support this hypothesis. This review summarizes toxic effects (in vitro and on animal models) of some xenobiotics-associated genetically modified food, such as glyphosate and Cry1Ab protein, and extrapolates on their potential role in the pathophysiology of endometriosis. Their roles as immune toxicants, pro-oxidants, endocrine disruptors and epigenetic modulators are discussed.

Identifying health disparities across the tobacco continuum.

AIMS: Few frameworks have addressed work-force diversity, inequities and inequalities as part of a comprehensive approach to eliminating tobacco-related health disparities. This paper summarizes the literature and describes the known disparities that exist along the tobacco disease continuum for minority racial and ethnic groups, those living in poverty, those with low education and blue-collar and service workers. The paper also discusses how work-force diversity, inequities in research practice and knowledge allocation and inequalities in access to and quality of health care are fundamental to addressing disparities in health. METHODS: We examined the available scientific literature and existing public health reports to identify disparities across the tobacco disease continuum by minority racial/ethnic group, poverty status, education level and occupation. FINDINGS: Results indicate that differences in risk indicators along the tobacco disease continuum do not explain fully tobacco-related cancer consequences among some minority racial/ethnic groups, particularly among the aggregate groups, blacks/African Americans and American Indians/Alaska Natives. The lack of within-race/ethnic group data and its interactions with socio-economic factors across the life-span contribute to the inconsistency we observe in the disease causal paradigm. CONCLUSIONS: More comprehensive models are needed to understand the relationships among disparities, social context, diversity, inequalities and inequities. A systematic approach will also help researchers, practitioners, advocates and policy makers determine critical points for interventions, the types of studies and programs needed and integrative approaches needed to eliminate tobacco-related disparities.

Postmastectomy chest wall radiation with electron-beam therapy: outcomes and complications at the University of Louisville.

PURPOSE: Postmastectomy chest wall radiation therapy using electron-beam therapy has been reported to increase lung radiation dose and the potential for pneumonitis. These reports describe treatment with varying energy electron beams prescribed to the breast/chest wall junction. Because the tissue at risk includes dermal lymphatics and subcutaneous tissues, low-energy electron beams may reduce lung radiation dose and the incidence of pneumonitis yet preserve good local control. At the University of Louisville, patients who have undergone mastectomy are treated with 6-MeV electron beam and bolus. PATIENTS AND METHODS: From 1985 through 1998, 273 patients underwent postmastectomy radiation therapy at the University of Louisville. The chest wall was treated using 6-MeV electron beam with 5-mm bolus prescribed to the 90% isodose-line, ensuring adequate dermal lymphatic dose. Internal mammary nodes were treated with electron-beam energy sufficient to treat to depth (approximately 15 MeV). Supraclavicular nodes were treated using 6-MV photon beam. Patients' charts were reviewed with respect to complications and outcome. RESULTS: Radiation pneumonitis was confirmed in one case (0.4%). The pneumonitis resolved with prednisone treatment. Twenty patients experienced locoregional failure (7.3%), 14 of whom failed in the chest wall (5.1%). DISCUSSION: Local control in our study is excellent and comparable to results expected for postmastectomy radiation therapy as reported in the literature. We conclude that postmastectomy patients can be treated with low-energy electron beam radiation therapy, protecting underlying lung without sacrificing local disease control.

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.

Prognostic and predictive significance of ErbB-2 breast tumor levels measured by enzyme immunoassay.

PURPOSE: A retrospective analysis to assess the prognostic and predictive clinical value of breast tumor ErbB-2 receptor expression quantified by enzyme immunoassay (EIA), to compare levels measured by EIA with ErbB-2 status determined by immunohistochemistry (IHC), and to correlate receptor content with levels of phosphorylated (Y1248-P) ErbB-2, a measure of functional tyrosine kinase activity. MATERIALS AND METHODS: EIA quantification of ErbB-2 was performed on membrane extracts from 3,208 well-characterized primary breast cancers. Overall, relapse-free, distant disease-free, and local/regional-free patient survival data were available on 1,123 of these tumors. IHC scoring for ErbB-2 status (HercepTest; DAKO, Glostrup, Denmark) was performed on adjacent sections of 151 cases, and receptor functionality was measured in 230 tumors by an antibody specific for phosphorylated (Y1248-P) ErbB-2. RESULTS: Unlike nonmalignant breast tissues, breast tumors showed increased ErbB-2 levels in a bimodal distribution, with 12% constituting a distinct set of ErbB-2-overexpressing tumors. The intermodal threshold value for ErbB-2 overexpression distinguished tumors with reduced estrogen and progesterone receptor content, high IHC score for ErbB-2, and significantly increased levels of phosphorylated (Y1248-P) ErbB-2 receptor. By multivariate analysis, EIA-determined ErbB-2 overexpression predicted significantly reduced patient survival that was unaffected by tamoxifen or cyclophosphamide, methotrexate, and fluorouracil adjuvant therapy. CONCLUSION: Determination of ErbB-2 receptor expression by EIA offers a clinically valuable alternative to semiquantitative IHC assessment of breast tumor ErbB-2 overexpression and affords the opportunity to evaluate ErbB-2 phosphorylation, which may represent an important predictive parameter of receptor functionality.

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%.

Recurrent chondrosarcoma of the cranial base: a durable response to ifosfamide-doxorubicin chemotherapy.

The case of a 46-year old woman with recurrent chondrosarcoma of the cranial base, refractory to neurosurgical intervention and external radiotherapy is reported. She received five cycles of systemic chemotherapy utilizing ifosfamide and doxorubicin which resulted in a durable clinical and radiographic response lasting 52+ months. A review of the management options for recurrent chondrosarcoma of the cranial base is also presented.

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.

Rhabdomyosarcoma in children--a ten year review.

PURPOSE: The purpose of this study is to retrospectively analyze all pediatric patients with Rhabdomyosarcoma (RMS) of various anatomic sites, treated in our department over a 10-year period, for treatment results. Anatomical site, group, and gender are individually analyzed as prognostic indicators of overall survival. MATERIALS AND METHODS: Sixteen rhabdomyosarcoma patients diagnosed by biopsy or surgical resection were reviewed. All patients were treated according to assigned IRS protocols except one. Age ranged from 1 to 19 years with a median age of 4 years. Ten patients were male and 6 were female, 14 were white and 2 black. Anatomic sites included six from the head and neck region, seven in the trunk and three in the extremities. Embryonal RMS was present in all but one which was classified as undifferentiated. All patients had surgery (biopsy-5, partial-1 or complete resection-10) and chemotherapy (VA, VAC, VAC plus Adriamycin, or VAC plus Adriamycin, CIS Platinum and VP-16). Ten patients received irradiation consisting of 3060 cGy to 5850 cGy using shrinking fields with 1.8 to 2.0 Gy/day/5 day/wk. RESULTS: Patients tolerated the treatment well and there were no late complications. Only one patient had a recurrence in the primary site with a median follow-up of 61 months (range 5-118 months) for the whole group. The 5-year disease free survival and actuarial survival for all patients treated were 73% and 87% respectively, with four patients developing metastasis and three of those dead of disease. CONCLUSION: This study represents a heterogeneous group of patients with RMS treated over a 10-year-period. The results correlate with those found in the most recent published IRS data for embryonal histology. From experience gained from earlier studies, newer IRS protocols have tailored treatment protocols to specific site with more intense therapy used for difficult treatment sites.

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.

Model peptide studies demonstrate that amphipathic secondary structures can be recognized by the chaperonin GroEL (cpn60).

The molecular chaperone cpn60 binds many unfolded proteins and facilitates their proper folding. Synthetic peptides have been used to probe the question of how cpn60 might recognize such a diverse set of unfolded proteins. Three hybrid peptides were synthesized encompassing portions of the bee venom peptide, apamin, and the sequence KWLAESVRAGK from an amphipathic helix in the NH2-terminal region of bovine rhodanese. Two disulfides connecting cysteine residues hold the peptides in stable helical conformations with unobstructed faces oriented away from the disulfides. Peptides were designed to present either a hydrophobic or hydrophilic face of the amphipathic helix that is similar to the one near the amino terminus of rhodanese. Aggregation of these peptides was detected by measuring 1,1'-bis(4-anilino)napthalene-5,5'-disulfonic acid (bisANS) fluorescence at increasing peptide concentrations, and aggregation was not apparent below 2 microM. Thus, all experiments with the peptides were performed at a concentration of 1 microM. Reducing agents cause these helical peptides to form random coils. Fluorescence anisotropy measurements of fluorescein-labeled peptide with the exposed hydrophobic face yielded a Kd = approximately 106 microM for binding to cpn60, whereas there was no detectable binding of the reduced form. The peptide with the exposed hydrophilic face did not bind to cpn60 in either the oxidized or reduced states. Fluorescence experiments utilizing bisANS as a probe showed that binding of the helical hydrophobic peptide could induce the exposure of hydrophobic surfaces on cpn60, whereas the same peptide in its random coil form had no effect. Thus, binding to cpn60 is favored by a secondary structure that organizes and exposes a hydrophobic surface, a feature found in amphipathic helices. Further, the binding of a hydrophobic surface to cpn60 can induce further exposure of complementary surfaces on cpn60 complexes, thus amplifying interactions available for target proteins.

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.

Dose escalation in chemoradiation for anal cancer: preliminary results of RTOG 92-08.

PURPOSE: Radiation Therapy Oncology Group experience with chemoradiation for anal cancer has shown a local failure rate of 20% to 30% with radiotherapy doses of 45 to 50 cGy. This study was undertaken to assess the effect of higher radiotherapy doses on toxicity, local control, and survival in this disease. MATERIALS AND METHODS: Forty-seven patients with anal cancers measuring > or = 2 cm were treated with a concurrent combination of two cycles of 5-fluorouracil infusion (1000 mg/m2 over 24 hrs for 4 days) and mitomycin C (10 mg/m2 bolus) plus 59.6 Gy of pelvic and perineal radiotherapy administered over 8.5 weeks, including a 2-week rest period. Patients were followed for toxicity, disease status, and colostomy-free survival. Twenty-three (49%) patients had advanced (T3-4) primary tumors; 42 (92%) patients had NO disease, and 36 (77%) patients had squamous histology. For perspective, a comparative analysis was made with 147 patients treated on the previous RTOG protocol for anal cancers (RTOG 87-04) with identical chemotherapy but radiotherapy doses of 40 to 50.4 Gy. RESULTS: Transient hematologic and skin toxicity predominated during treatment or in early follow-up. One patient developed septicemia and died of multiple gastrointestinal toxicities. Twelve (26%) patients had greater than grade 3 complications and, of these, 9 (20%) had hematologic side effects alone. A comparative analysis with 147 patients treated on RTOG protocol 87-04 showed no significant differences in pretreatment characteristics of disease extent, performance status, or histology. A mandatory 2-week split in the current chemoradiation protocol contrasted with 12% of patients having a 2-week or greater treatment break in RTOG 87-04. Patients treated on the current protocol (RTOG 92-08) had a markedly lower incidence of > or = grade 3 dermal toxicity (34% vs. 55%) but a higher colostomy rate at 1 year (23% vs. 6%) and at 2 years (30% vs. 7%) compared with RTOG 87-04. CONCLUSIONS: Numerical increases in radiotherapy dose over those used in conventional chemotherapy regimens for anal cancers do not appear to increase local control when given in split-course fashion. For higher radiotherapy doses (> 50 Gy) to increase local control, radiation may have to be given in continuous fashion, which almost certainly means that our threshold of acceptable acute toxicity, particularly dermal toxicity, may have to be raised.

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.