E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma.

The retinoblastoma (pRB) family proteins regulate the E2F transcription factors; their complexes regulate critical transitions through the cell cycle. The function of these pRB family/E2F complexes, which includes p130/E2F4, in response to genotoxic agents, is not well understood. We investigated the role of E2F4 in the genotoxic stress response. Following radiation treatment, E2F4 colocalized with p130 in the nucleus during a radiation-induced stable G(2)-phase arrest. Arrested cells had significantly decreased expression of Cyclins A2 and B1 and decreased phosphorylation of mitotic protein monoclonal-2 (MPM-2) mitotic proteins. Small interference RNA (siRNA)-mediated knockdown of E2F4 sensitized cells to subsequent irradiation, resulting in enhanced cellular DNA damage and cell death, as determined by caspase activation and decreased clonogenic cell survival. Downstream E2F4 targets potentially involved in the progression from G(2) into M phase were identified by oligonucleotide microarray expression profiling. Chromatin immunoprecipitation localized E2F4 at promoter regions of the Bub3 and Pttg1 mitotic genes following irradiation, which were among the downregulated genes identified by the microarray. These data suggest that in response to radiation, E2F4 becomes active in the nucleus, enforces a stable G(2) arrest by target gene repression, and thus provides increased cell survival ability by minimizing propagation of cells that have irreparable DNA damage.

The late increase in intracellular free radical oxygen species during apoptosis is associated with cytochrome c release, caspase activation, and mitochondrial dysfunction.

Mitochondria play central roles in cellular metabolism and apoptosis and are a major source of reactive oxygen species (ROS). We investigated the role of ROS and mitochondria in radiation-induced apoptosis in multiple myeloma cells. Two distinct levels of ROS were generated following irradiation: a small increase observed early, and a pronounced late increase, associated with depletion of reduced glutathione (GSH) and collapse of mitochondrial membrane potential (deltapsi(m)). Exogenous ROS and caspase-3 induced deltapsi(m) drop and cytochrome c release from mitochondria, which could be prevented by molecular (dominant-negative caspase-9) and pharmacologic (zVAD-fmk) caspase inhibitors and overexpression of Bcl-2. Exogenous ROS also induced mitochondrial permeability transition (PT) pore opening and cytochrome c release in isolated mitochondria, which could be blocked by inhibition of PT with cyclosporin A. These results indicate that the late ROS production is associated with increased PT pore opening and decreased deltapsi(m), and GSH, events associated with caspase activation and cytochrome c release.

Infectious complications within the first year after nonmyeloablative allogeneic peripheral blood stem cell transplantation.

Nonmyeloablative peripheral blood stem cell transplantation (PBSCT) is a novel therapeutic strategy for patients with malignant and non-malignant hematologic diseases. Infectious complications of this procedure have not been previously well described. Data on 12 patients transplanted at a tertiary care center were collected prospectively and verified retrospectively. Neutropenia developed in a third of patients, lasting for a median of 5 days. All patients developed some degree of graft-versus-host disease, as intended. Most patients achieved full chimerism by week 5. Bacterial infections occurred in two patients (17%). Cytomegalovirus (CMV) viremia occurred in five patients (42%) at a median of 80 days; none had received CMV prophylaxis. Viremia was associated with fever and fatigue in three patients, possible gastrointestinal involvement in one patient and was asymptomatic in one patient. All viremic patients responded to intravenous ganciclovir therapy. No fungal infections were documented. No patients died as a result of infection. The incidence of CMV viremia in our patients was high, but the incidence of invasive disease due to CMV was low. The best strategy to prevent CMV in patients undergoing nonmyeloablative PBSCT remains to be determined, but strategies employed in traditional allogeneic bone marrow transplantation should be considered in these patients.

Fluoroscopic study of tumor motion due to breathing: facilitating precise radiation therapy for lung cancer patients.

Target motion due to breathing is one of the major obstacles in dose escalation of radiation therapy to some tumors in the thoracoabdominal region. The development of beam gating or target motion tracking techniques provides a possibility to reduce normal tissue volume in a treatment field. Tumor motion monitoring in those techniques plays a crucial role, but has not yet been adequately explored. This paper reports our preliminary investigation on breath introduced tumor motion. Tumor locations and motion properties were determined from digitized fluoroscopic videos acquired during patient simulation. Image distortion due to irregularities in the imaging chain, such as the pincushion distortion, was corrected with a polynomial unwarping method. Temporal Fourier transformation of the fluoroscopic video was introduced to convert the motion information over time to a static view of a motion field, in which regions with different motion ranges can be directly measured. Patient breathing patterns vary from patient to patient and so does the kinematic behavior of individual tumors. In order to evaluate the feasibility for tracking internal target motion with nonionizing-radiation techniques, motion patterns between internal targets and external radio opaque markers placed on patient's chest during fluoroscopic video acquisition were compared. For some patients, significant motion phase discrepancies between an internal target and an external marker have been observed. Quantitative measurements are reported. These results will be useful in the design of a motion tracking or gated radiotherapy system.

Promoting patient safety: is technology the solution?

BACKGROUND: On April 30, 2001, the Cleveland Clinic Foundation and Cleveland Clinic Health System Quality Institute sponsored a 1-day conference focused on technology in patient safety. PATIENT SAFETY-A CALL TO ACTION: Kenneth W. Kizer focused on ten high-priority patient safety strategies identified by the National Quality Forum-including implementing recognized "safe practices", recognizing and dealing with professional misconduct, and supporting efforts to create a nonpunitive environment for health care error reporting. CULTURAL IMPLICATIONS OF INTRODUCING NEW TECHNOLOGY: Randolph A. Miller described a computerized clinician order-entry system used to provide decision support, reduce excess test ordering, introduce cost savings, and meet regulations for inpatient radiology and cardiology tests. USING BAR CODES TO ELIMINATE MEDICATION ERRORS: Jeff Ramirez reported on the Veterans Health Administration's use of bar coding technology for point-of-care validation of medication administration, which has resulted in improvements in response time; the efficiency of the dispensing, delivery, and administration process; and patient care. HOW TO MAKE COMPUTERS TEAM PLAYERS: The knowledge base exists to design computers as team players that expand human expertise and help health care practitioners better create safety. Yet David D. Woods challenged the audience to anticipate the changing shape of iatrogenic risk as a result of increasing dependence on automation in health care. TECHNOLOGY AND MEDICATION SYSTEMS: Mark Neuenschwander spoke about automating various steps within the medication use system, through computerized prescriber order entry and bedside scanning. FUTURE TECHNOLOGICAL POSSIBILITIES: Charles Denham suggested how technology may aid health care professionals in their care of patients, such as in using predictive modeling to identify the risks of therapeutic intervention.

Contralateral breast cancer risk.

The use of breast-conserving treatment approaches for breast cancer has now become a standard option for early stage disease. Numerous randomized studies have shown medical equivalence when mastectomy is compared to lumpectomy followed by radiotherapy for the local management of this common problem. With an increased emphasis on patient involvement in the therapeutic decision making process, it is important to identify and quantify any unforeseen risks of the conservation approach. One concern that has been raised is the question of radiation- related contralateral breast cancer after breast radiotherapy. Although most studies do not show statistically significant evidence that patients treated with breast radiotherapy are at increased risk of developing contralateral breast cancer when compared to control groups treated with mastectomy alone, there are clear data showing the amount of scattered radiation absorbed by the contralateral breast during a routine course of breast radiotherapy is considerable (several Gy) and is therefore within the range where one might be concerned about radiogenic contralateral tumors. While radiation related risks of contralateral breast cancer appear to be small enough to be statistically insignificant for the majority of patients, there may exist a smaller subset which, for genetic or environmental reasons, is at special risk for scatter related second tumors. If such a group could be predicted, it would seem appropriate to offer either special counseling or special prevention procedures aimed at mitigating this second tumor risk. The use of genetic testing, detailed analysis of breast cancer family history, and the identification of patients who acquired their first breast cancer at a very early age may all be candidate screening procedures useful in identifying such at- risk groups. Since some risk mitigation strategies are convenient and easy to utilize, it makes sense to follow the classic 'ALARA' (as low as reasonably achievable) principles and to minimize scattered radiation for these special risk groups and perhaps for all patients undergoing breast radiotherapy. This paper reviews the literature on the risk of radiation- related second contralateral breast cancers.

Ionizing radiation induces CD20 surface expression on human B cells.

The CD20 surface antigen is expressed on the great majority of B-cell lymphoma cases. The expression of this antigen ranges from moderate to bright, and it is neither internalized nor shed. These characteristics make CD20 a common target for antibody directed lymphoma therapy. The development of strategies to significantly increase CD20 expression on lymphoma cells is therefore of great interest as a means of increasing specific targeting and cell kill in antibody therapy and radio-immunotherapy. We present here data demonstrating that relatively low doses of external beam radiotherapy are capable of significant and consistent increases in CD20 surface expression in vitro. The effect is dose related up to approximately 10 Gy and is maximal in the first day after radiotherapy. We believe that these data may suggest a potent way to combine a short pretreatment course of external beam radiotherapy with a subsequent course of immunotherapy using either an unlabeled antibody or a radio-immunotoxin.

Stability of biodegradable radioactive rhenium (Re-186 and Re-188) microspheres after neutron-activation.

Our objective was to determine if microspheres made from the biodegradable polymer poly(lactic acid) that contained rhenium could withstand the conditions of direct neutron activation necessary to produce therapeutic amounts of radioactive rhenium. The radiation damage of the polymer produced by gamma-doses of up to 1.05 MGy from Re-186 and Re-188 was examined by scanning electron microscopy and size exclusion chromatography. At a thermal neutron flux of 1.5 x 10(13)n/cm2/s the microspheres melted after 3 h in the nuclear reactor, but suffered little damage after 1 h of radiation and released less than 5% of the radioactivity during incubation in buffer at 37 degrees C. The radioactive microspheres produced in this manner have a specific activity too low for radioembolization for treatment of liver tumors, but could be injected directly into tumors or applied topically to the wound bed of partially resected tumors.

Radiation therapy in pregnancy: risk calculation and risk minimization.

The benefits of radiation therapy (RT) as part of a treatment regimen for cancer must be weighed against the potential risk of harm to the patient and in the pregnant patient, the risk to the developing fetus. Information necessary for determining the potential effects of RT on the developing fetus include the gestational age, absorbed fetal dose-equivalent, and dose-rate. The risk periods in humans for RT-induced prenatal or neonatal death, congenital anomalies, severe mental retardation (SMR), temporary (TGR) or permanent growth retardation (PGR), carcinogenesis, sterility, and germ cell mutations have been elicited directly from the study of Japanese victims of the atomic bombs and unintentional medical exposures, and indirectly from animal experiments. The wide range of congenital anomalies elicited from animal studies have not occurred in the Japanese atomic bomb victims exposed in utero. The major congenital anomaly observed in the Japanese cohort has been microcephaly. The highest risk period for SMR correlates with the proliferation, differentiation, and, most importantly, migration of neurons from their proliferative zones. PGR was apparent 17 years after ionizing radiation (IR) exposure at Hiroshima in children who were within 1,500 meters of the hypocenter. Children were on average 2.25 cm shorter, 3 kg lighter, and had head diameters 1.1 cm smaller than age-matched children. The projected lifetime risk of cancer mortality in the Japanese cohort is 14% per gray. The risk of a radiation-induced hereditary disorder is reported to be approximately 1% per gray. RT plays a major role in the definitive treatment of cervical and breast carcinomas, Hodgkin's disease, and non-Hodgkin's lymphoma. With appropriate abdominal shielding in place, the estimated fetal dose can be reduced by 50% or greater in most cases. In certain clinical situations, RT may be administered during pregnancy.

Lymphoma and pregnancy.

Coincident lymphoma and pregnancy is rare, occurring in only one of 1,000 or fewer deliveries. Patients with Hodgkin's disease usually present with typical manifestations, and most studies suggest that the disease probably has little or no effect on the pregnancy and vise versa. In contrast, patients with non-Hodgkin's lymphoma often have unusual manifestations and their diagnosis is frequently delayed. These patients usually have aggressive, advanced-stage disease and a poor outcome. The optimal management of these women requires special considerations. Treatment during the first trimester is associated with significant risk to the developing fetus and should be avoided. Women requiring treatment at this time should have a therapeutic abortion. Beyond the first trimester, the management options for women with Hodgkin's disease include observation until disease progression or delivery, single-agent vinblastine, modified or standard combination chemotherapy, and radiation therapy (with appropriate shielding). Because of their poor prognosis, women with non-Hodgkin's lymphoma should receive standard chemotherapy (despite the potential risk to the developing fetus).

Radiotherapy for pediatric genitourinary tumors. Its role and long-term consequences.

Radiation therapy has traditionally played a major role in the treatment of pediatric genitourinary malignancies. In particular, Wilms' tumor, rhabdomyosarcoma, and neuroblastoma often include radiotherapy in the local control phase of treatment. Recently, clinical trials have focused on decreasing the toxicity of radiotherapy through dose modifications and conformal field arrangements. Radiotherapy will continue to be a major treatment modality for this patient group if technologic advances in radiation delivery continue to increase efficacy without comorbidities.

Treatment of prognosis of primary breast lymphoma: a review of 13 cases.

Primary non-Hodgkin's lymphoma (NHL) of the breast is a rare entity that does not have a well-defined treatment strategy. At presentation, most patients are clinically thought to have a primary breast carcinoma, and the diagnosis of lymphoma is made at biopsy. Once the diagnosis of lymphoma is made, patients are treated with some combination of chemotherapy, radiation therapy, and surgery. We review The Cleveland Clinic Foundation experience with primary breast lymphoma. Between 1980 and 1996, 17 patients with primary breast lymphoma were seen at The Cleveland Clinic Foundation, and 13 had follow-up information available. All patients underwent a staging workup including computed tomography (CT) scan of the chest, abdomen, and pelvis, as well as bilateral bone marrow biopsies; all patients staged IE (breast involvement only) or IIE (limited to the breast and ipsilateral axilla) were included. We did not include patients with more extensive supradiaphragmatic nodal involvement who were stage IIE. Patients received some combination of surgery, radiation, and chemotherapy. The median follow-up was 34 months, with a range of 7 to 138 months. There was an equal incidence of right- versus left-sided lesions. Five patients survived at least 5 years from the time of diagnosis. Long-term survival in patients with primary NHL of the breast is possible. We recommend treating patients with aggressive NHL of the breast with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, followed by involved field radiation and treating those patients with indolent lymphoma with involved field radiation alone.

Palliative radiotherapy.

Radiotherapy is often used for the palliative treatment of advanced cancer. Although each cancer is unique in its histology and natural history, there are several scenarios that repeatedly challenge physicians. Specifically, skeletal metastases, spinal cord compression, brain metastasis, bronchial obstruction, and vena cava obstruction are regularly encountered. This review will discuss the diagnosis and treatment of these common important situations.

Reducing scatter radiation to the contralateral breast with a mobile, conformal shield during breast cancer radiotherapy.

During a standard course of breast radiotherapy, the contralateral breast generally receives approximately 2.5 to 6.0 Gy of scattered radiation. Although most studies have not found an overall increase in metachronous contralateral breast cancers in patients undergoing radiotherapy, a cohort of younger women may be genetically more susceptible to radiation-induced breast cancers and may thus be adversely affected by the scattered radiation. We are attempting to develop a simple, convenient, effective mechanism for minimizing the scattered radiation to the contralateral breast during the process of clinical breast radiotherapy. We therefore designed a conformal, platform-based breast shield consisting of 2.5 cm of molded lead in a mobile counterweighted polystyrene casing. This shield was intended to serve as a physical barrier to prevent both low and high energy scattered photons from the medial and lateral tangential fields. We conducted a prospective trial of 20 women, each woman serving as her own control. Each woman received breast radiotherapy with and without shield, and an array of thermoluminescent dosimeters was positioned across the contralateral breast to evaluate the in vivo dosimetry and the impact of the breast shield on surface absorption of scattered radiation. We found that the use of the breast shield reduced the median dose of scattered radiation by approximately 60% (p < 0.0001). This represented a median dose reduction of approximately 300 cGy at the nipple. The shield was easily positioned and added < 1 min to daily setup time. We conclude that the use of this sort of surface barrier shielding technique was feasible, effective, and practical for clinical use. The degree of scatter reduction accomplished through the use of this breast shield may be biologically significant, especially for those patients with biologic or epidemiologic risk factors that may predispose them to the development of radiogenic breast cancers.

The role of radiation therapy in the management of Wilms' tumor.

Since the early decades of this century, radiation therapy has played an important role in the management of Wilms' tumor. Although in prior years the high radiation doses and eccentric field arrangements used in treatment were responsible for significant late toxicity, examination of long-term survivors and the important information obtained from the National Wilms' Tumor Studies (NWTS) and Societe Internationale d'Oncologie Pediatrique studies have now allowed us to tailor radiation fields and doses to provide high levels of local tumor control with minimal late effects. At present, most patients with NWTS stage III and stage IV tumors are offered radiotherapy as an integral component of their cancer management. Attempts to further refine selection criteria defining those patient groups who will benefit from radiation therapy are ongoing.

Successful conversion from a linear accelerator-based program to a Gamma Knife radiosurgery program: the Cleveland Clinic experience.

From August 1989 to January 1997, 307 treatments in 293 patients were performed with a linear accelerator-based (LINAC) stereotactic radiosurgery system. Because of the program s success, the need for a dedicated radiosurgery unit in Ohio and the desire to treat functional disorders, the Cleveland Clinic Health System (CCHS) obtained the first Gamma Knife in the state of Ohio. Based on the previous volume of patients for radiosurgery, it was estimated that 75-100 patients would be treated during the first year of operation. However, during the first calendar year, 214 treatments were performed on 205 patients, which far exceeded expectations. The success of the CCHS Gamma Knife Center can be attributed to an increase in a number of factors. These included marketing efforts, patient awareness, increased use for functional disorders, physician understanding of radiosurgery, use by qualified nonaffiliated radiation oncologists and neurosurgeons, and outpatient delivery (95% with the Gamma Knife vs <5% with the LINAC). With proper planning, education, and awareness, the opening of a Gamma Knife Center can greatly increase the volume of radiosurgery performed when compared with a LINAC-based program.

Brief courses of palliative radiotherapy for metastatic bone pain: a pilot cost-minimization comparison with narcotic analgesics.

The use of radiotherapy to treat metastatic bone pain is being challenged by claims of high cost and by more readily available, noninvasive treatment approaches. The authors assessed the effectiveness of brief courses of radiotherapy in reducing pain and estimated cost data for a pilot comparison between radiotherapy and narcotic analgesics in patients with cancer. A representative group of outpatients undergoing brief courses of radiotherapy with Karnofsky scores above 70 and without serious comorbidities were recruited from 1995 through 1996. Patients indicated their pain at rest and with movement on a scale of from 1 to 10 both before and up to 12 months after radiotherapy. Radiotherapy costs were estimated from Medicare-allowable charges. Narcotic analgesia costs were estimated from published values. In 66 patients with 131 individually treated sites, median at rest pain score decreased by about 4 points after treatment (5.58 [-/+3.28] before treatment vs. 1.55 [-/+1.8] after treatment; p < 0.05). Median with movement pain score was about 5 points lower after treatment (7.32 [-/+2.72] before treatment vs. 1.94 [-/+2.07] after treatment; p < 0.05). No differences were found when stratifying by type of pain, tumor histologic type, or skeletal site. The estimated cost per patient ranged from $1,200 to $2,500 for radiotherapy. This compares with an estimated cost of $9,000 to $36,000 for 9 months of narcotics. In this pilot study, a brief course of radiotherapy significantly reduced pain and appeared to be cost effective when compared with narcotic analgesia. A full economic evaluation is warranted.