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Biomedical subjects

Zvi Fuks

Publications and source records attributed to Zvi Fuks.

At least 19 recordsLinked to original sources
PubMed2006

From IMRT to IGRT: frontierland or neverland?

The recent enthusiasm for real-time image guidance in radiotherapy (IGRT) is in part due to the commercial availability of advanced on-line imaging technologies. Perhaps more important than its potential to improve conventional radiotherapy, IGRT may lead to a paradigm shift in facilitating hypo-fractionated or single-dose treatment. However, there are uncertainty regarding features and approaches of competing IGRT systems and as to whether a sub-set of the features of an ideal IGRT system would suffice for specific disease sites and clinical applications. Clinical studies are necessary for the quantification of benefit needed for evidence-based medicine.

Dose Fractionation, Radiation↗
PubMed2006

Image-fusion of MR spectroscopic images for treatment planning of gliomas.

1H magnetic resonance spectroscopic imaging (MRSI) can improve the accuracy of target delineation for gliomas, but it lacks the anatomic resolution needed for image fusion. This paper presents a simple protocol for fusing simulation computer tomography (CT) and MRSI images for glioma intensity-modulated radiotherapy (IMRT), including a retrospective study of 12 patients. Each patient first underwent whole-brain axial fluid-attenuated-inversion-recovery (FLAIR) MRI (3 mm slice thickness, no spacing), followed by three-dimensional (3D) MRSI measurements (TE/TR: 144/1000 ms) of a user-specified volume encompassing the extent of the tumor. The nominal voxel size of MRSI ranged from 8 x 8 x 10 mm3 to 12 x 12 x 10 mm3. A system was developed to grade the tumor using the choline-to-creatine (Cho/Cr) ratios from each MRSI voxel. The merged MRSI images were then generated by replacing the Cho/Cr value of each MRSI voxel with intensities according to the Cho/Cr grades, and resampling the poorer-resolution Cho/Cr map into the higher-resolution FLAIR image space. The FUNCTOOL processing software was also used to create the screen-dumped MRSI images in which these data were overlaid with each FLAIR MRI image. The screen-dumped MRSI images were manually translated and fused with the FLAIR MRI images. Since the merged MRSI images were intrinsically fused with the FLAIR MRI images, they were also registered with the screen-dumped MRSI images. The position of the MRSI volume on the merged MRSI images was compared with that of the screen-dumped MRSI images and was shifted until agreement was within a predetermined tolerance. Three clinical target volumes (CTVs) were then contoured on the FLAIR MRI images corresponding to the Cho/Cr grades. Finally, the FLAIR MRI images were fused with the simulation CT images using a mutual-information algorithm, yielding an IMRT plan that simultaneously delivers three different dose levels to the three CTVs. The image-fusion protocol was tested on 12 (six high-grade and six low-grade) glioma patients. The average agreement of the MRSI volume position on the screen-dumped MRSI images and the merged MRSI images was 0.29 mm with a standard deviation of 0.07 mm. Of all the voxels with Cho/Cr grade one or above, the distribution of Cho/Cr grade was found to correlate with the glioma grade from pathologic finding and is consistent with literature results indicating Cho/Cr elevation as a marker for malignancy. In conclusion, an image-fusion protocol was developed that successfully incorporates MRSI information into the IMRT treatment plan for glioma.

Brain Neoplasms↗
PubMed2005

Whole pelvic radiotherapy for prostate cancer using 3D conformal and intensity-modulated radiotherapy.

PURPOSE: To investigate the correlations between observed clinical morbidity and dosimetric parameters for whole pelvic radiotherapy (WPRT) for prostate cancer using either three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Between December 1996 and January 2002, 27 patients with prostate adenocarcinoma were treated with conformal WPRT as part of their definitive treatment. WPRT was delivered with 3D-CRT in 14 patients and with IMRT in 13 patients. For each of the patients treated with IMRT, optimized conventional two-dimensional (2D) and 3D-CRT plans were retrospectively generated for the whole pelvic phase of the treatment. Dose-volume histograms for the bowel, bladder, and rectum were compared for the three techniques. Acute toxicities were evaluated for all 27 patients, and late toxicities were evaluated for 25 patients with sufficient follow-up. Toxicities were scored according to the Radiation Therapy Oncology Group morbidity grading scales. Median follow-up was 30 months. RESULTS: Three-dimensional-CRT resulted in a 40% relative reduction (p < 0.001) in the volume of bowel receiving 45 Gy compared with 2D, and IMRT provided a further 60% reduction relative to 3D-CRT (p < 0.001). Compared with either 2D or 3D-CRT, IMRT reduced the volume of rectum receiving 45 Gy by 90% (p < 0.001). Overall, 9 patients (33%) experienced acute Grade 2 gastrointestinal (GI) toxicity, and only 1 of these patients was treated with IMRT. Antidiarrhea medication was required for 6 patients (22%). However, 5 of these 6 patients also received chemotherapy, and none were treated with IMRT. No Grade 3 or higher acute or late GI toxicities were observed. No cases of late radiation enteritis were observed. Acute and late genitourinary toxicity did not appear significantly increased by the addition of conformal WPRT. CONCLUSIONS: Compared to conventional 2D planning, conformal planning for WPRT resulted in significant reductions in the doses delivered to the bowel, rectum, and bladder. IMRT was superior to 3D-CRT in limiting the volume of bowel and rectum within high-dose regions. These dosimetric findings correlated with low rates of acute and late GI morbidity.

Adult↗
PubMed2005

ATM regulates target switching to escalating doses of radiation in the intestines.

Although stem cells succumbing to reproductive death are assumed to be the single relevant targets in radiation tissue damage, recent studies showed intestinal stem cell damage is conditionally linked to crypt endothelial apoptosis, defining a two-target model. Here we report that when mouse intestines were protected against microvascular apoptosis, radiation switched as the dose escalated to a previously unrecognized crypt stem cell target, activating ceramide synthase-mediated apoptosis to initiate intestinal damage. Whereas ataxia telangiectasia-mutated (ATM) kinase normally represses ceramide synthase, its derepression in Atm(-/-) mice increased crypt stem cell radiosensitivity 3.7-fold without sensitizing the microvascular response. Discovery of this intestinal radiosensitivity mechanism allowed design of an antisense Atm oligonucleotide treatment which phenocopied the Atm(-/-) mouse, reordering ceramide synthase-mediated stem cell death to become the first-line gastrointestinal response of wild-type littermates. These experiments indicate that tissues operate multiple potential targets activated consecutively according to their inherent radiosensitivities that may be reordered therapeutically to control radiation tissue responses.

Animals↗
PubMed2005

Caspase-dependent and -independent activation of acid sphingomyelinase signaling.

Recent evidence suggests clustering of plasma membrane rafts into ceramide-enriched platforms serves as a transmembrane signaling mechanism for a subset of cell surface receptors and environmental stresses (Grassme, H., Jekle, A., Riehle, A., Schwarz, H., Berger, J., Sandhoff, K., Kolesnick, R., and Gulbins, E. (2001) J. Biol. Chem. 276, 20589-20596; Cremesti, A., Paris, F., Grassme, H., Holler, N., Tschopp, J., Fuks, Z., Gulbins, E., and Kolesnick, R. (2001) J. Biol. Chem. 276, 23954-23961). Translocation of the secretory form of acid sphingomyelinase (ASMase) into microscopic rafts generates therein the ceramide that drives raft coalescence. This process serves to feed forward Fas activation, with approximately 2% of full caspase 8 activation sufficient for maximal ASMase translocation, leading to death-inducing signaling complex formation within ceramide-rich platforms, and apoptosis. Here we report that treatment of Jurkat T cells with UV-C also induces ASMase translocation into rafts within 1 min, catalyzing sphingomyelin hydrolysis to ceramide and raft clustering. In contrast to Fas, UV-induced ASMase translocation and activation were caspase-independent. Nonetheless, ceramide-rich platforms promoted UV-C-induced death signaling, because ASMase inhibition or raft disruption inhibited apoptosis, improving clonogenic cell survival. These studies thus define two distinct mechanisms for biologically relevant ASMase activation within rafts; a Fas-mediated mechanism dependent upon caspase 8 and FADD, and a UV-induced mechanism independent of caspase activation. Consistent with this notion, genetic depletion or pharmacologic inhibition of caspase 8 or FADD, which render Jurkat cells incapable of sphingolipid signaling and apoptosis upon Fas ligation, did not impair these events upon UV-C stimulation.

Amino Acid Chloromethyl Ketones↗
PubMed2005

Down-regulation of ATM protein sensitizes human prostate cancer cells to radiation-induced apoptosis.

Treatment with the protein kinase C activator 12-O-tetradecanoylphorbol 12-acetate (TPA) enables radiation-resistant LNCaP human prostate cancer cells to undergo radiation-induced apoptosis, mediated via activation of the enzyme ceramide synthase (CS) and de novo synthesis of the sphingolipid ceramide (Garzotto, M., Haimovitz-Friedman, A., Liao, W. C., White-Jones, M., Huryk, R., Heston, D. W. W., Cardon-Cardo, C., Kolesnick, R., and Fuks, Z. (1999) Cancer Res. 59, 5194-5201). Here, we show that TPA functions to decrease the cellular level of the ATM (ataxia telangiectasia mutated) protein, known to repress CS activation (Liao, W.-C., Haimovitz-Friedman, A., Persaud, R., McLoughlin, M., Ehleiter, D., Zhang, N., Gatei, M., Lavin, M., Kolesnick, R., and Fuks, Z. (1999) J. Biol. Chem. 274, 17908-17917). Gel shift analysis in LNCaP and CWR22-Rv1 cells demonstrated a significant reduction in DNA binding of the Sp1 transcription factor to the ATM promoter, and quantitative reverse transcription-PCR showed a 50% reduction of ATM mRNA between 8 and 16 h of TPA treatment, indicating that TPA inhibits ATM transcription. Furthermore, treatment of LNCaP, CWR22-Rv1, PC-3, and DU-145 human prostate cells with antisense-ATM oligonucleotides, which markedly reduced cellular ATM levels, significantly enhanced radiation-induced CS activation and apoptosis, leading to apoptosis at doses as a low as 1 gray. These data suggest that the CS pathway initiates a generic mode of radiation-induced apoptosis in human prostate cancer cells, regulated by a suppressive function of ATM, and that ATM might represent a potential target for pharmacologic inactivation with potential clinical applications in human prostate cancer.

Apoptosis↗
PubMed2005

Engaging the vascular component of the tumor response.

Recent research has shed new light on the critical role of tissue microvasculature in regulating the tumor response to radiation and drugs. In this issue of Cancer Cell, Moeller et al.(2005) demonstrate that HIF-1 activation during the course of fractionated radiotherapy initiates pleiotropic adaptive responses in both tumor cells and the microvascular network, radiosensitizing tumor cells but concomitantly conferring tumor radioresistance due to protection of the microvascular endothelium. HIF-1 thus serves as a legitimate target for differential modulation of tissue response to radiation.

Capillaries↗
PubMed2005

Accurate setup of paraspinal patients using a noninvasive patient immobilization cradle and portal imaging.

Because of the proximity of the spinal cord, effective radiotherapy of paraspinal tumors to high doses requires highly conformal dose distributions, accurate patient setup, setup verification, and patient immobilization. An immobilization cradle has been designed to facilitate the rapid setup and radiation treatment of patients with paraspinal disease. For all treatments, patients were set up to within 2.5 mm of the design using an amorphous silicon portal imager. Setup reproducibility of the target using the cradle and associated clinical procedures was assessed by measuring the setup error prior to any correction. From 350 anterior/posterior images, and 303 lateral images, the standard deviations, as determined by the imaging procedure, were 1.3 m, 1.6 m, and 2.1 in the ant/post, right/left, and superior/inferior directions. Immobilization was assessed by measuring patient shifts between localization images taken before and after treatment. From 67 ant/post image pairs and 49 lateral image pairs, the standard deviations were found to be less than 1 mm in all directions. Careful patient positioning and immobilization has enabled us to develop a successful clinical program of high dose, conformal radiotherapy of paraspinal disease using a conventional Linac equipped with dynamic multileaf collimation and an amorphous silicon portal imager.

Equipment Design↗
PubMed2004

Host acid sphingomyelinase regulates microvascular function not tumor immunity.

Previous studies provided evidence that MCA/129 fibrosarcomas and B16 melanomas grow 2- to 4-fold faster in acid sphingomyelinase (asmase)-deficient mice than in asmase(+/+) littermates and are resistant to single-dose irradiation due to inability to mount an apoptotic response in tumor microvascular endothelium. However, others postulated the differences might be associated with a host antitumor immune response in asmase(+/+) mice that is not expressed in asmase(-/-) mice due to phenotypic deficiency in antitumor immunity. The present studies demonstrate that none of the tumor-host combinations displayed the classic criteria of an immunogenic tumor because they lacked endotumoral or peritumoral infiltrates almost entirely. Furthermore, neither MCA/129 fibrosarcoma nor B16 melanoma tumors showed differences in growth or radioresponsiveness when implanted into mutant mouse models (Rag(-/-) and MEF(-/-)) lacking functional immune cell [natural killer (NK), NK-T, T, and B cells] populations. Additionally, development and function of B-, T-, and NK-cell populations in asmase(-/-) mice were normal, indistinguishable from their wild-type littermates. These data provide definitive evidence that MCA/129 fibrosarcomas and B16F1 melanomas do not elicit a host immune response in wild-type mice and that the asmase(-/-) phenotype is not deficient in antitumor immunity, supporting the notion that the patterns of tumors growth and radiation response are conditionally linked to the ability of the tumor endothelium to undergo ASMase-mediated apoptosis.

Animals↗
PubMed2004

Caenorhabditis elegans ABL-1 antagonizes p53-mediated germline apoptosis after ionizing irradiation.

c-Abl, a conserved nonreceptor tyrosine kinase, integrates genotoxic stress responses, acting as a transducer of both pro- and antiapoptotic effector pathways. Nuclear c-Abl seems to interact with the p53 homolog p73 to elicit apoptosis. Although several observations suggest that cytoplasmic localization of c-Abl is required for antiapoptotic function, the signals that mediate its antiapoptotic effect are largely unknown. Here we show that worms carrying an abl-1 deletion allele, abl-1(ok171), are specifically hypersensitive to radiation-induced apoptosis in the Caenorhabditis elegans germ line. Our findings delineate an apoptotic pathway antagonized by ABL-1, which requires sequentially the cell cycle checkpoint genes clk-2, hus-1 and mrt-2; the C. elegans p53 homolog, cep-1; and the genes encoding the components of the conserved apoptotic machinery, ced-3, ced-9 and egl-1. ABL-1 does not antagonize germline apoptosis induced by the DNA-alkylating agent ethylnitrosourea. Furthermore, worms treated with the c-Abl inhibitor STI-571 (Gleevec; used in human cancer therapy), two newly synthesized STI-571 variants or PD166326 had a phenotype similar to that generated by abl-1(ok171). These studies indicate that ABL-1 distinguishes proapoptotic signals triggered by two different DNA-damaging agents and suggest that C. elegans might provide tissue models for development of anticancer drugs.

Amino Acid Sequence↗
PubMed2003

Pretreatment nomogram that predicts 5-year probability of metastasis following three-dimensional conformal radiation therapy for localized prostate cancer.

PURPOSE: There are several nomograms for the patient considering radiation therapy for clinically localized prostate cancer. Because of the questionable clinical implications of prostate-specific antigen (PSA) recurrence, its use as an end point has been criticized in several of these nomograms. The goal of this study was to create and to externally validate a nomogram for predicting the probability that a patient will develop metastasis within 5 years after three-dimensional conformal radiation therapy (CRT). PATIENTS AND METHODS: We conducted a retrospective, nonrandomized analysis of 1,677 patients treated with three-dimensional CRT at Memorial Sloan-Kettering Cancer Center (MSKCC) from 1988 to 2000. Clinical parameters examined were pretreatment PSA level, clinical stage, and biopsy Gleason sum. Patients were followed until their deaths, and the time at which they developed metastasis was noted. A nomogram for predicting the 5-year probability of developing metastasis was constructed from the MSKCC cohort and validated using the Cleveland Clinic series of 1,626 patients. RESULTS: After three-dimensional CRT, 159 patients developed metastasis. At 5 years, 11% of patients experienced metastasis by cumulative incidence analysis (95% CI, 9% to 13%). A nomogram constructed from the data gathered from these men showed an excellent ability to discriminate among patients in an external validation data set, as shown by a concordance index of 0.81. CONCLUSION: A nomogram with reasonable accuracy and discrimination has been constructed and validated using an external data set to predict the probability that a patient will experience metastasis within 5 years after three-dimensional CRT.

Adenocarcinoma↗
PubMed2003

Pharmacologic inactivation of kinase suppressor of ras-1 abrogates Ras-mediated pancreatic cancer.

Inhibition of the kinase suppressor of ras-1 (KSR1) gene by continuous infusion of phosphorothioate antisense oligonucleotides (ODNs) prevented growth of K-Ras-dependent human PANC-1 pancreatic and A549 non-small-cell lung carcinoma xenografts in nude mice, effected regression of established PANC-1 tumors and inhibited A549 lung metastases, all without apparent toxicity. These studies suggest KSR1 antisense ODNs as a treatment for Ras-dependent human malignancies, in particular pancreatic cancer, which lacks effective curative therapy.

Animals↗
PubMed2003

Radiation and ceramide-induced apoptosis.

Ceramide is a sphingolipid that acts as a second messenger in ubiquitous, evolutionarily conserved, signaling systems. Emerging data suggest that radiation acts directly on the plasma membrane of several cell types, activating acid sphingomyelinase, which generates ceramide by enzymatic hydrolysis of sphingomyelin. Ceramide then acts as a second messenger in initiating an apoptotic response via the mitochondrial system. Radiation-induced DNA damage can also initiate ceramide generation by activation of mitochondrial ceramide synthase and de novo synthesis of ceramide. In some cells and tissues, BAX is activated downstream of ceramide, regulating commitment to the apoptotic process via release of mitochondrial cytochrome c. Genetic and pharmacologic studies in vivo showed that radiation targets the acid sphingomyelinase apoptotic system of microvascular endothelial cells in the lungs, intestines and brain, as well as in oocytes, to initiate the pathogenesis of tissue damage. Regulated ceramide metabolism may produce metabolites, such as sphingosine 1-phosphate, shown to signal antiapoptosis, thus controlling the intensity of the apoptotic response and constituting a mechanism for radiation sensitivity or resistance. An improved understanding of this signaling system may offer new opportunities for the modulation of radiation effects in the treatment of cancer.

Animals↗
PubMed2003

Microvascular function regulates intestinal crypt response to radiation.

Recent evidence suggests that microvascular endothelial apoptosis represents the primary lesion in radiation damage to the gastrointestinal (GI) tract. Rescue of endothelium by depletion of acid sphingomyelinase or i.v. treatment with basic fibroblast growth factor (FGF) prevented the lethal GI syndrome in C(57)Bl/6 mice. Here we show that basic FGF increased crypt survival after irradiation by 2-3 fold, with a dose modification factor at D(10) of 1.15 (P < 0.01). Basic FGF inhibited initial crypt damage, assessed by crypt shrinkage at 18-24 h, but did not significantly affect the regeneration of surviving crypts at 3.5 days after irradiation. These data suggest that microvascular function regulates expression of radiation-induced crypt stem cell clonogen damage in the evolution of radiation injury to the GI mucosa.

Animals↗
PubMed2003

Tumor response to radiotherapy regulated by endothelial cell apoptosis.

About 50% of cancer patients receive radiation therapy. Here we investigated the hypothesis that tumor response to radiation is determined not only by tumor cell phenotype but also by microvascular sensitivity. MCA/129 fibrosarcomas and B16F1 melanomas grown in apoptosis-resistant acid sphingomyelinase (asmase)-deficient or Bax-deficient mice displayed markedly reduced baseline microvascular endothelial apoptosis and grew 200 to 400% faster than tumors on wild-type microvasculature. Thus, endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth. Moreover, these tumors exhibited reduced endothelial apoptosis upon irradiation and, unlike tumors in wild-type mice, they were resistant to single-dose radiation up to 20 grays (Gy). These studies indicate that microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range.

Animals↗
PubMed2003

Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer.

PURPOSE: To identify predictors of biochemical outcome following radiotherapy in patients with a rising prostate-specific antigen (PSA) after radical prostatectomy for prostate cancer. PATIENTS AND METHODS: One hundred fifteen patients with a rising PSA after radical prostatectomy received salvage three-dimensional conformal radiotherapy (3D-CRT) alone or with neoadjuvant androgen deprivation. Tumor-related and treatment-related factors were evaluated to identify predictors of subsequent PSA failure. RESULTS: The median follow-up time after 3D-CRT was 42 months. The 4-year actuarial PSA relapse-free survival, distant metastasis-free survival, and overall survival rates were 46%, 83%, and 95%, respectively. Multivariate analysis, which was limited to 70 patients receiving radiation without androgen deprivation therapy, showed that negative/close margins (P =.03), absence of extracapsular extension (P <.01), and presence of seminal vesicle invasion (P <.01) were independent predictors of PSA relapse after radiotherapy. Neoadjuvant androgen deprivation did not improve the 4-year PSA relapse-free survival in patients with positive margins, extracapsular extension, and no seminal vesicle invasion (P =.24). However, neoadjuvant androgen deprivation did improve PSA relapse-free survival when one or more of these variables were absent (P =.03). CONCLUSIONS: Salvage 3D-CRT can provide biochemical control in selected patients with a rising PSA after radical prostatectomy. Among patients with positive margins and no poor prognostic features, 77% achieved PSA control after salvage 3D-CRT. Salvage neoadjuvant androgen deprivation therapy may improve short-term biochemical control, but it requires further study.

Adult↗
PubMed2003

Technological advances in external-beam radiation therapy for the treatment of localized prostate cancer.

The relative inability of conventional radiotherapy to control localized prostate cancer results from resistance of subpopulations of tumor clonogens to dose levels of 65 to 70 Gy, the maximum feasible with traditional two-dimensional (2D) treatment planning and delivery techniques. Several technological advances have enhanced the precision and improved the outcome of external-beam radiotherapy. The three-dimensional conformal radiotherapy (3D-CRT) approach has permitted significant increases in the tumor dose to levels beyond those feasible with conventional techniques. Intensity-modulated radiotherapy (IMRT), an advanced form of conformal radiotherapy, has resulted in reduced rectal toxicity, permitting tumor dose escalation to previously unattainable levels with a concomitant improvement in local tumor control and disease-free survival. The combination of androgen deprivation and conventional-dose radiotherapy, tested mainly in patients with locally advanced disease, has also produced significant outcome improvements. Whether androgen deprivation will preclude the need for dose escalation or whether high-dose radiotherapy will obviate the need for androgen deprivation remains unknown. In some patients, both approaches may be necessary to maximize the probability of cure. In view of the favorable benefit-risk ratio of high-dose IMRT, the design of clinical trials to resolve these critical questions is essential.

Actuarial Analysis↗