Roger M. Macklis

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 patients 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.

Long-term responses in patients with recurring or refractory B-cell non-Hodgkin lymphoma treated with yttrium 90 ibritumomab tiuxetan†

Radioimmunotherapy with radiolabeled monoclonal antibodies to CD20 produces a high response rate in patients with recurring non‐Hodgkin lymphoma (NHL), but the durability of those remissions is not well defined.

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

AbstractMitochondria 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 (Δψm). Exogenous ROS and caspase-3 induced Δψm 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 Δψm, and GSH, events associated with caspase activation and cytochrome c release.

Cellular Kinetics, Dosimetry, and Radiobiology of α-Particle Radioimmunotherapy: Induction of Apoptosis

Though clinical results for radioimmunoconjugate therapy of most common epithelial tumors have been disappointing, dramatic responses have been observed repeatedly in the treatment of high- and low-grade malignant lymphomas. This high clinical responsiveness after radioimmunoconjugate therapy sometimes appears to be out of proportion to the calculated radiation dose absorbed by the lymphoma tissue. Here we describe some key aspects of the kinetics, dosimetry, and cellular radiobiology of murine lymphoma cells exposed to 212Bi-radiolabeled alpha-particle-emitting immunoconjugates specific for the differentiation antigen Thy 1.2. Approximately 25 cell-bound alpha-particle-emitting immunoconjugates per target cell were required to reduce clonogenic survival by 90% (the radiobiological D10). Serial kinetic analyses of the antibody and radioisotope components of the immunoconjugates revealed significant levels of dechelation and up to 7.5% cellular internalization of the isotope. Cellular radiation dosimetry performed by Monte Carlo computer simulation of alpha-particle energy deposition patterns based on the observed radiopharmacokinetics showed that the D10 resulted from approximately four alpha-particle traversals through the nucleus, corresponding to an absorbed radiation dose of approximately 0.95 Gy to the cell nucleus. Electron micrographs and DNA gel studies of murine lymphoma cells undergoing radioimmunoconjugate therapy in vivo and in vitro demonstrated bizarre blebbing patterns, condensation of chromosomal material, and internucleosomal DNA fragmentation patterns characteristic of programmed cell death (apoptosis). We conjecture that the efficacy of radioimmunoconjugates against responsive cell types may be the result of passive DNA damage by ionizing radiation and the initiation of apoptosis in response to radioimmunotherapy.

Effective targeting of magnetic radioactive90Y-microspheres to tumor cells by an externally applied magnetic field. Preliminary in vitro and in vivo results

Magnetic biodegradable poly(lactic acid) microspheres that incorporate both magnetite and the beta-emitter 90Y were prepared. By applying a directional external magnetic field gradient in excess of 0.02 Tesla/cm across a 96-well plate containing neuroblastoma cells incubated with the 90Y magnetite loaded microspheres, the radiation dose to the cells could be enhanced or reduced relative to the dose from a uniform loading of the well with 90Y-DTPA. Using the MTT assay, cell survival was measured for the magnetic field directed from above (cell sparing) and from below (cell targeting) the well plate, resulting in 65 +/- 8% or 18 +/- 5% survival respectively. This method was then applied to an in vivo murine tumor model. The biodistribution of intraperitoneally injected magnetic radioactive microspheres, after 24 h in mice, showed that 73 +/- 32% of the radioactivity was found on the subcutaneous tumor that had a rare earth magnet fixed above it. In contrast, the tumor radioactivity with no attached magnet was 6 +/- 4%. Magnetically targeted radiopolymers such as 90Y-microspheres show great promise for regional or intracavitary radiotherapy.

Family history of prostate cancer in patients with localized prostate cancer: an independent predictor of treatment outcome.

PURPOSE To determine if familial prostate cancer patients have a less favorable prognosis than patients with sporadic prostate cancer after treatment for localized disease with either radiotherapy (RT) or radical prostatectomy (RP). PATIENTS AND METHODS One thousand thirty-eight patients treated with either RT (n = 583) or RP (n = 455) were included in this analysis. These patients were noted as having a positive family history if they confirmed the diagnosis of prostate cancer in a first-degree relative. The outcome of interest was biochemical relapse-free survival (bRFS). We used proportional hazards to analyze the effect of the presence of family history and other potential confounding variables (ie, age, treatment modality, stage, biopsy Gleason sum [GS], and initial prostate-specific antigen [iPSA] levels) on treatment outcome. RESULTS Eleven percent of all patients had a positive family history. The 5-year bRFS rates for patients with negative and positive family histories were 52% and 29%, respectively (P < .001). The potential confounders with bRFS rates were iPSA levels, biopsy GS, and clinical tumor stage; treatment modality and age did not appear to be associated with outcome. After adjusting for potential confounders, family history of prostate cancer remained strongly associated with biochemical failure. CONCLUSION This is the first study to demonstrate that the presence of a family history of prostate cancer correlates with treatment outcome in a large unselected series of patients. Our findings suggest that familial prostate cancer may have a more aggressive course than nonfamilial prostate cancer, and that clinical and/or pathologic parameters may not adequately predict this course.

Treatment of Wilms tumor relapsing after initial treatment with vincristine, actinomycin D, and doxorubicin. A report from the national Wilms tumor study group

We evaluated the use of alternating cycles of cyclophosphamide/etoposide and carboplatin/etoposide in children entered on National Wilms Tumor Study (NWTS)‐5 who were diagnosed between August 1, 1995 and May 31, 2002 and who relapsed after chemotherapy with vincristine, actinomycin D, and doxorubicin (VAD) and radiation therapy (DD‐4A).

Modulation of Radiation-Induced Apoptosis and G2/M Block in Murine T-Lymphoma Cells

Radiation-induced apoptosis in lymphocyte-derived cell lines is characterized by endonucleolytic cleavage of cellular DNA within hours after radiation exposure. We have studied this phenomenon qualitatively (DNA gel electrophoresis) and quantitatively (diphenylamine reagent assay) in murine EL4 T-lymphoma cells exposed to 137Cs gamma irradiation. Fragmentation was discernible within 18-24 h after exposure. It increased with time and dose and reached a plateau after 8 Gy of gamma radiation. We studied the effect of several pharmacological agents on the radiation-induced G2/M block and DNA fragmentation. The agents which reduced the radiation-induced G2/M-phase arrest (caffeine, theobromine, theophylline and 2-aminopurine) enhanced the degree of DNA fragmentation at 24 h. In contrast, the agents which sustained the radiation-induced G2/M-phase arrest (TPA, DBcAMP, IBMX and 3-aminobenzamide) inhibited the DNA fragmentation at 24 h. These studies on EL4 lymphoma cells are consistent with the hypothesis that cells with radiation-induced genetic damage are eliminated by apoptosis subsequent to a G2/M block. Furthermore, it may be possible to modulate the process of radiation-induced apoptosis in lymphoma cells with pharmacological agents that modify the radiation-induced G2/M block, and to use this effect in the treatment of patients with malignant disease.

Error rates in clinical radiotherapy.

PURPOSE Error rates in clinical oncology are undergoing increasing scrutiny. The purpose of this study was to understand error frequency, error patterns, underlying causal links, consequences, and possible prevention strategies in clinical radiotherapy. PATIENTS AND METHODS Treatment information, self-reported error documentation, and retrospective analyses of electronic treatment verification transcripts for 1,925 consecutive patients treated with a total of 93,332 individual radiotherapy fields were reviewed and analyzed. RESULTS A total of 59 separate errors that affected 168 individual treatment fields were detected, which yielded a crude radiation delivery error rate of 0.18%. All 59 errors were judged to be level I (negligible chance of adverse medical outcome) with the most common error category being a minor treatment field block misplacement. A comprehensive quality assurance program and an electronic record-and-verify linear accelerator interlock system seem to have prevented the occurrence of many additional errors. However, nine of the 59 errors were directly related to the use of this system and generally involved the transposition of similar numbers within series of treatment coordinate data-sets. Overall, radiotherapy error rates favorably compare with reported error rates for pharmaceutical administration in large tertiary care hospitals. CONCLUSION When modern automated error-minimization methods are used along with nonpunitive error reporting systems, clinical radiotherapy seems to be highly safe. Formal error analysis studies may allow the rational design of prevention strategies that are attuned to the frequency, seriousness, and antecedent causes of many classes of potential radiotherapy errors.

Treatment of Wilms tumor relapsing after initial treatment with vincristine and actinomycin D: A report from the National Wilms Tumor Study Group

NWTS‐5 was a multi‐institutional clinical trial for patients less than 16 years of age at diagnosis with specific renal neoplasms who were diagnosed between August 1, 1995 and May 31, 2002. A uniform approach to the treatment of patients with relapse was employed.