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The present study evaluated low-level laser therapy (LLLT) effects on some physiological pathways that may lead to muscle damage or regeneration capacity in dystrophin-deficient muscle cells of mdx mice, the experimental model of Duchenne muscular dystrophy (DMD). Primary cultures of mdx skeletal muscle cells were irradiated only one time with laser and analyzed after 24 and 48 hours. The LLLT parameter used was 830 nm wavelengths at 5 J/cm² fluence. The following groups were set up: Ctrl (untreated C57BL/10 primary muscle cells), mdx (untreated mdx primary muscle cells), mdx LA 24 (mdx primary muscle cells - LLLT irradiated and analyzed after 24 h), and mdx LA 48 (mdx primary muscle cells - LLLT irradiated and analyzed after 48 h). The mdx LA 24 and mdx LA 48 groups showed significant increase in cell proliferation, higher diameter in muscle cells and decreased MyoD levels compared to the mdx group. The mdx LA 48 group showed significant increase in Myosin Heavy Chain levels compared to the untreated mdx and mdx LA 24 groups. The mdx LA 24 and mdx LA 48 groups showed significant increase in [Ca2+]i. The mdx group showed significant increase in H2O2 production and 4-HNE levels compared to the Ctrl group and LLLT treatment reduced this increase. GSH levels and GPx, GR and SOD activities increased in the mdx group. Laser treatment reduced the GSH levels and GR and SOD activities in dystrophic muscle cells. The mdx group showed significant increase in the TNF-α and NF-κB levels, which in turn was reduced by the LLLT treatment. Together, these results suggest that the laser treatment improved regenerative capacity and decreased inflammatory response and oxidative stress in dystrophic muscle cells, indicating that LLLT could be a helpful alternative therapy to be associated with other treatment for dystrophinopathies.

Objectives: Oxidative stress and inflammatory process play an important role in the pathogenesis of Duchenne muscular dystrophy (DMD). We investigated whether deferoxamine (DFX) improves the antioxidant effects of N-acetylcysteine (NAC) on primary cultures of dystrophic muscle cells from mdx mice, the experimental model of DMD., Methods: Primary cultures of skeletal muscle cells from mdx mice were treated with either NAC (10 mM), DFX (5 mM), or NAC plus DFX for 24 hours. The muscle cells of C57BL/10 mice were used as controls., Results: Production of hydrogen peroxide (H2O2) and levels of 4-hydroxynonenal (4-HNE), tumor necrosis factor alpha (TNF-α), and nuclear factor kappa-B (NF-κB) were significantly higher in mdx muscle cells than in C57BL/10 muscle cells. Treatment with NAC, DFX, or NAC plus DFX significantly decreased H2O2 production (24, 58, and 72%, respectively), and levels of 4-HNE-protein adducts (62, 33, and 71%, respectively), TNF-α (32, 29, and 31%, respectively), and NF-κB (34, 38, and 52%, respectively) on dystrophic muscle cells., Discussion: This study demonstrates that mdx muscle cells are able to produce key oxidative stress and inflammatory markers, without the interference of inflammatory cells, and shows that NAC plus DFX reduced the inflammatory and oxidative stress indicators, mainly H2O2 production and NF-κB levels by dystrophic fibers.

Objective: To evaluate whether plasma cell-free DNA (cfDNA) was related to clinical outcome in inoperable stage I non-small cell lung cancer (NSCLC) patients undergoing stereotactic body radiotherapy (SBRT)., Materials and Methods: Plasma cfDNA was assessed at baseline, before the last day and 45 days after the end of SBRT, in 22 NSCLC patients. Twenty-two healthy controls were also evaluated., Results: Plasma cfDNA was higher in patients than in controls. An association with unfavourable disease-free survival was found for continuous baseline cfDNA increments (HR = 5.9, 95%CI: 1.7-19.8, p = 0.04)., Conclusion: Plasma cfDNA may be a promising prognostic biomarker in high-risk NSCLC patients.

Introduction: The purpose of this study was to better understand the beneficial effects of doxycycline on the dystrophic muscles of the mdx mouse., Methods: Doxycycline (DOX) was administered for 36 days, starting on postnatal day 0, via drinking water. Untreated mdx mice received plain water for the same period and served as a control group., Results: DOX decreased the levels of metalloproteinase-9 and tumor necrosis factor-alpha in the biceps brachii and diaphragm of the mdx mice. It also reduced the total amount of calcium in the muscles studied, concomitant with an increase in the levels of calsequestrin 1., Conclusions: The results show that DOX can affect factors that are important in dystrophic pathogenesis and highlight its potential as a readily accessible therapy in clinical trials for treatment of Duchenne muscular dystrophy., (© 2014 Wiley Periodicals, Inc.)

Purpose: To retrospectively assess toxicity and outcome of re-irradiation with stereotactic body radiation therapy (SBRT) in patients with recurrent or persistent non-small cell lung cancer (NSCLC), who were previously treated with radical radiation therapy (50-60 Gy). The secondary endpoint was to investigate whether there are dosimetric parameter predictors of severe radiation toxicity., Methods and Materials: The analysis was conducted in 17 patients with "in-field" recurrent/persistent centrally located NSCLC, who underwent re-irradiation with SBRT. SBRT consisted of 30 Gy in 5 to 6 fractions; these prescriptions would be equivalent for the tumor to 37.5 to 40 Gy, bringing the total 2-Gy-per-fraction cumulative dose to 87 to 100 Gy, considering the primary radiation therapy treatment. Actuarial analyses and survival were calculated by the Kaplan-Meier method, and P values were estimated by the log-rank test, starting from the date of completion of SBRT. Dosimetric parameters from the subgroups with and without grade ≥3 pulmonary toxicity were compared using a 2-tailed Student t test., Results: The median follow-up was 18 months (range, 4-57 months). Only 2 patients had local failure, corresponding to a local control rate of 86% at 1 year. The Kaplan-Meier estimates of overall survival (OS) rates at 1 and 2 years were 59% and 29%, respectively; the median OS was 19 months. Four patients (23%) experienced grade 3 radiation pneumonitis, and 1 patient developed fatal pneumonitis. One patient died of fatal hemoptysis 2 months after the completion of SBRT. Unexpectedly, heart maximum dose, D5 (minimum dose to at least 5% of the heart volume), and D10 were correlated with risk of radiation pneumonitis (P<.05)., Conclusions: Re-irradiation with SBRT for recurrent/persistent centrally located NSCLC achieves excellent results in terms of local control. However, the high rate of severe toxicity reported in our study is of concern., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Pyoderma gangrenosum is a rare neutrophilic dermatosis, often associated with underlying systemic diseases. Treatment usually consists of topics and sometimes systemic immunosuppression. We present the case of a 32-year-old female patient undergoing radiation therapy for extensive recalcitrant pyoderma gangrenosum in which immunosuppressive measures were ineffective to control the disease. Treatment outcome was favourable with only mild side effects in the irradiated areas. Localized radiation therapy hence is a potential effective palliation for refractory cases of pyoderma gangrenosum, or patients unfit to undergo aggressive systemic immunosuppression.

Gefitinib is highly active in patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring activating mutation of the epidermal growth factor receptor (EGFR) gene. The feasibility and the degree of response to treatment with gefitinib in patients with chronic renal failure (CRF) undergoing hemodialysis has not yet been fully described in literature. We describe the case of a 70-year-old man with CRF undergoing hemodialysis three times-a-week who developed vertebral and rib bone metastasis three years after lobectomy. The bone biopsy confirmed the pulmonary origin and pyrosequencing analysis revealed deletion in E746-E750 of exon 19. We started daily administration of 250 mg gefitinib with no changes in the hemodialysis schedule. Gefitinib was well-tolerated without any adverse event. After three months, the (18)F-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG PET/CT) showed complete metabolic remission of bone lesions. The patient is still under treatment and maintains response (30 months to date). To our knowledge, this is the first description of complete metabolic remission in this type of patient. In conclusion, gefitinib has been safely administered to a patient with NSCLC with EGFR-activating mutation undergoing chronic hemodialysis and its use has achieved an excellent and prolonged response on bone metastases.

Purpose: We have previously shown the feasibility of delivering high doses of radiotherapy in malignant pleural mesothelioma (MPM) patients who underwent radical pleurectomy/decortication (P/D) or surgical biopsy. In this report, we present the long-term results of MPM patients treated with radical P/D followed by high doses of radiotherapy., Methods and Materials: Twenty consecutive MPM patients were enrolled in this prospective study and underwent radical P/D followed by high dose radiotherapy. The clinical target volume was defined as the entire hemithorax excluding the intact lung. The dose prescribed was 50 Gy in 25 fractions. Any FDG-avid areas or regions of particular concern for residual disease were given a simultaneous boost to 60 Gy. Nineteen patients received cisplatin/pemetrexed chemotherapy. Kaplan-Meier analysis was used to calculate rates of overall survival (OS), progression-free survival (PFS), and loco-regional control (LRC)., Results: The median follow-up was of 27 months. The median OS and PFS were 33 and 29 months, respectively. The median LRC was not reached. The Kaplan-Meier estimates of OS at 2 and 3 years were 70% and 49%, respectively. The estimates of PFS at 2 and 3 years were 65% and 46%, respectively. The estimates of LRC at 2 and 3 years were 68% and 59%, respectively. The predominant pattern of failure was distant: 7 patients developed distant metastases as the first site of relapse, whereas only 3 patients experienced an isolated loco-regional recurrence. No fatal toxicity was reported. Five Grades 2-3 pneumonitis were documented., Conclusions: High dose radiation therapy following radical P/D led to excellent loco-regional control and survival results in MPM patients. A median OS of 33 months and a 3-year OS rate of 49% are among the best observed in recent studies, supporting the idea that this approach represents a concrete therapeutic option for malignant pleural mesothelioma., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Concurrent chemo-radiotherapy is demonstrately superior to sequential chemo-radiotherapy in the treatment of advanced Non-Small-Cell Lung Cancer not suitable for surgery. Docetaxel is considered to enhance the cytotoxic effect of radiotherapy on the tumour cells. Tomotherapy (HT) is a novel radiotherapeutic technique, which allows the delivery of Image Guided-IMRT (IG-IMRT), with a highly conformal radiation dose distribution.The goal of the study was to estimate tolerability of Docetaxel concurrent with IMRT and to find the maximum tolerated dose of weekly Docetaxel concurrent with IMRT delivered with HT Tomotherapy after induction chemotherapy with Cisplatin and Docetaxel in patients affected with stage III Non-Small Cell Lung Cancer., Methods: We designed a phase I, dose-finding study to determine the dose of weekly Docetaxel concurrent with Tomotherapy after induction chemotherapy, in patients affected by Non-Small Cell Lung Cancer with Stage III disease, not suitable for surgery., Results: Concurrent weekly Docetaxel and Tomotherapy are feasible; we did not reach a maximum tolerated dose, because no life-threatening toxicity was observed, stopping the accrual at a level of weekly docetaxel 38 mg/m2, a greater dose than in previous assessments, from both phase-I studies with weekly docetaxel alone and with Docetaxel concomitant with standard radiotherapy., Conclusions: Concurrent weekly Docetaxel and Tomotherapy are feasible, and even with Docetaxel at 38 mg/m2/week we did not observe any limiting toxicity. For those patients who completed the combined chemo-radio treatment, median progression-free survival (PFS) was 20 months and median overall survival (OS) was 24 months.

Background & Aims: In Duchenne muscular dystrophy (DMD) and in the mdx mouse model of DMD, the lack of dystrophin leads to muscle degeneration and inflammation contributes to progression of the disease. In this study, we evaluated the effects of commercially available fish oil containing EPA and docosahexaenoic acid (DHA) on mdx., Methods: Mdx mice (14 days old) were treated with fish oil (FDC Vitamins; 0.002 g EPA and 0.001 g DHA) for 16 days by gavage. Control mdx mice received mineral oil (Nujol). Grip strength measurement was used for functional evaluation. The sternomastoid, diaphragm and biceps brachii muscles were removed and processed for histopathology and Western blot analysis., Results: Fish oil decreased creatine kinase and myonecrosis. In all muscles studied, the inflammatory area was significantly reduced after treatment (18.0 ± 3.0% inflammatory area in untreated mdx mice versus 4.0 ± 1% in treated mdx mice). Fish oil protected against the loss of muscle strength. Fish oil significantly reduced the levels of TNF-α and the levels of 4-HNE-protein adducts (30-34% reduction for both) in all muscles studied., Conclusions: Commercially available fish oil may be potentially useful to ameliorate dystrophic progression of skeletal muscles, deserving further clinical trials in DMD patients., (Copyright © 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background & Aims: Duchenne muscular dystrophy (DMD) is a genetic muscle disease caused by the absence of dystrophin. An established animal model of DMD is the mdx mouse, which is unable to express dystrophin. Inflammation, particularly the proinflammatory cytokine tumor necrosis factor alpha (TNF-α), strongly contributes to necrosis in the dystrophin-deficient fibers of the mdx mice and in DMD. In this study we investigated whether the antioxidant N-acetylcysteine (NAC) decreases TNF-α levels and protects the diaphragm muscle of mdx mice against necrosis., Methods: Mdx mice (14 days old) received daily intraperitoneal injections of NAC for 14 days, followed by removal of the diaphragm muscle. Control mdx mice were injected with saline., Results: NAC reduced TNF-α and 4-HNE-protein adducts levels, inflammation, creatine kinase levels, and myonecrosis in diaphragm muscle., Conclusions: NAC may be used as a complementary treatment for dystrophinopathies. However, clinical trials are needed to determine the appropriate dose for patients with Duchenne muscular dystrophy., (Copyright © 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objective: Oxidative stress contributes to myonecrosis in the dystrophin-deficient fibers of mdx mice and in Duchenne's muscular dystrophy. We examined the effects of ascorbic acid (AA), an antioxidant and free radical scavenger, on the dystrophic diaphragm muscle., Methods: Mdx mice (14 d old) received AA for 14 d. Control mdx mice received saline. The muscle damage was visualized by the penetration of Evans blue dye into myofibers and the extent of inflammation was assessed by histologic analysis. Creatine kinase levels were measured for the biochemical evaluation of muscle fiber degeneration. The levels of tumor necrosis factor-α (a proinflammatory cytokine) and 4-hydroxynonenal (a marker of lipid peroxidation) were analyzed by immunoblotting., Results: Ascorbic acid decreased creatine kinase levels, myonecrosis, inflammation, and the levels of tumor necrosis factor-α and 4-hydroxynonenal., Conclusion: The present results suggest that AA plays a protective role in dystrophic muscle degeneration, possibly by decreasing reactive oxygen species, and support further investigations of AA as a potential therapy for dystrophinopathies., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Helical Tomotherapy (HT) is a highly conformal image-guided radiation technique, introduced into clinical routine in 2006 at the Centro di Riferimento Oncologico Aviano (Italy). With this new technology, intensity-modulated radiotherapy (IMRT) is delivered using a helicoidal method. Here we present our dosimetric experiences using HT in 100 children, adolescents and young adults treated from May 2006 to February 2011. The median age of the patients was 13 years (range 1-24). The most common treated site was the central nervous system (50; of these, 24 were craniospinal irradiations), followed by thorax (22), head and neck (10), abdomen and pelvis (11), and limbs (7). The use of HT was calculated in accordance to the target dose conformation, the target size and shape, the dose to critical organs adjacent to the target, simultaneous treatment of multiple targets, and re-irradiation. HT has demonstrated to improve target volume dose homogeneity and the sparing of critical structures, when compared to 3D Linac-based radiotherapy (RT). In standard cases this technique represented a comparable alternative to IMRT delivered with conventional linear accelerator. In certain cases (e.g., craniospinal and pleural treatments) only HT generated adequate treatment plans with good target volume coverage. However, the gain in target conformality should be balanced with the spread of low-doses to distant areas. This remains an open issue for the potential risk of secondary malignancies (SMNs) and longer follow-up is mandatory.

Aims and Background: The present study evaluated toxicity, local control, and survival in patients with relapsed high-grade glioma after surgery and external beam radiation therapy and treated with re-operation and GliaSite brachytherapy., Methods: Between 2006 and 2008, 15 patients with recurrent high-grade glioma underwent re-operation and GliaSite brachytherapy. Ten patients were males and 5 females. Median age was 40 years (range, 20-71). Karnofsky performance status was ≥70. All patients but one received GliaSite irradiation of the surgical cavity wall at the dose of 4500 cGy at a depth of 1 cm., Results: No severe acute side effects were observed during GliaSite brachytherapy. Pathologically documented, symptomatic late radiation necrosis was observed in 3 patients (20%); 2 subsequently died of further complications. Two patients were alive at a median follow-up 13 months (range, 1-30). Median overall survival after GliaSite brachytherapy was 13 months., Conclusions: Patients with recurrent high-grade glioma can be treated with additional surgery and GliaSite brachytherapy, delivering 4500 cGy at 1 cm depth without significant acute side effects but with a significant rate (20%) of late radiation necrosis, resulting in 13% of treatment-related deaths. Compared with the literature, survival results in our study appear to be satisfactory, but they may be related to patient selection criteria. Re-intervention followed by GliaSite brachytherapy should not be offered as a standard treatment for recurrent high-grade glioma, because of the high rate of late complications, treatment-related deaths, and high treatment costs.

The muscle fiber phenotype is mainly determined by motoneuron innervation and changes in neuromuscular interaction alter the muscle fiber type. In dystrophin-deficient mdx mice, changes in the molecular assembly of the neuromuscular junction and in nerve terminal sprouting occur in the sternomastoid (STN) muscle during early stages of the disease. In this study, we were interested to see whether early changes in neuromuscular assembly are correlated with alterations in fiber type in dystrophic STN at 2 months of age. A predominance of hybrid fast myofibers (about 52% type IIDB) was observed in control (C57Bl/10) STN. In mdx muscle, the lack of dystrophin did not change this profile (about 54% hybrid type IIDB). Pure fast type IID fibers predominated in normal and dystrophic diaphragm (DIA; about 39% in control and 30% in mdx muscle) and a population of slow Type I fibers was also present (about 10% in control and 13% in mdx muscle). In conclusion, early changes in neuromuscular assembly do not affect the fiber type composition of dystrophic STN. In contrast to the pure fast fibers of the more affected DIA, the hybrid phenotype of the STN may permit dynamic adaptations during progression of the disease., (Copyright © 2010 Wiley-Liss, Inc.)

The present prospective study seeks to evaluate overall and disease free survival, response and organ preservation rate, and toxicity of an intensive chemotherapy regimen (CT) followed by unconventional radiotherapy (RT) in patients with locally advanced operable head and neck cancer. Between January 1998 and December 2006 (June 2005), 115 patients with locally advanced, operable head and neck cancer were evaluated. A total of 333 cycles of neoadjuvant CT (cisplatin-5FU, days 1, 14, 28) followed by hyperfractionated/accelerated radiotherapy were given to 108 patients. A total of 108 patients were evaluable and received the planned CT-RT treatment. Two months after the end of RT, 97.2% of patients had a clinical complete remission of the primary and 67.5% of the neck node site. The overall survival was 55% and cause-specific survival was 73% at 5 years. Of the 33 relapsed patients, 12 recurred only at the primary site and 10 patients had distant metastases. The overall organ preservation rate was 73.5%. The chemotherapy regimen reported an overall cardiotoxicity from 5FU in 14% of patients, with severe toxicity in 3%. The radiotherapy schedule developed 84% of Grade 3-4 mucositis in the observed patients. The accelerated CT-RT regimen is able to achieve a high rate of larynx preservation, a good tolerability, and a satisfactory cause-specific overall survival.

In dystrophin-deficient fibers of mdx mice and in Duchenne dystrophy, the lack of dystrophin leads to sarcolemma breakdown and muscle degeneration. We verified that cromolyn, a mast-cell stabilizer agent, stabilized dystrophic muscle fibers using Evans blue dye as a marker of sarcolemma leakiness. Mdx mice (n=8; 14 days of age) received daily intraperitoneal injections of cromolyn (50 mg/kg body weight) for 15 days. Untreated mdx mice (n=8) were injected with saline. Cryostat cross-sections of the sternomastoid, tibialis anterior, and diaphragm muscles were stained with hematoxylin and eosin. Cromolyn dramatically reduced Evans blue dye-positive fibers in all muscles (P<0.05; Student's t-test) and led to a significant increase in the percentage of fibers with peripheral nuclei. This study supports the protective effects of cromolyn in dystrophic muscles and further indicates its action against muscle fiber leakiness in muscles that are differently affected by the lack of dystrophin.

Intrinsic laryngeal muscles share many anatomical and physiological properties with extraocular muscles, which are unaffected in both Duchenne muscular dystrophy and mdx mice. We hypothesized that intrinsic laryngeal muscles are spared from myonecrosis in mdx mice and may serve as an additional tool to understand the mechanisms of muscle sparing in dystrophinopathy. Intrinsic laryngeal muscles and tibialis anterior (TA) muscle of adult and aged mdx and control C57Bl/10 mice were investigated. The percentage of central nucleated fibers, as a sign of muscle fibers that had undergone injury and regeneration, and myofiber labeling with Evans blue dye, as a marker of myofiber damage, were studied. Except for the cricothyroid muscle, none of the intrinsic laryngeal muscles from adult and old mdx mice showed signs of myofiber damage or Evans blue dye labeling, and all appeared to be normal. Central nucleation was readily visible in the TA of the same mdx mice. A significant increase in the percentage of central nucleated fibers was observed in adult cricothyroid muscle compared to the other intrinsic laryngeal muscles, which worsened with age. Thus, we have shown that the intrinsic laryngeal muscles are spared from the lack of dystrophin and may serve as a useful model to study the mechanisms of muscle sparing in dystrophinopathy.

Changes in the distribution of acetylcholine receptors have been reported to occur at the neuromuscular junction of mdx mice and may be a consequence of muscle fiber regeneration rather than the absence of dystrophin. In the present study, we examined whether the nerve terminal determines the fate of acetylcholine receptor distribution in the dystrophic muscle fibers of mdx mice. The left sternomastoid muscle of young (1-month-old) and adult (6-month-old) mdx mice was injected with 60 microl lidocaine hydrochloride to induce muscle degeneration-regeneration. Some mice had their sternomastoid muscle denervated at the time of lidocaine injection. After 10 days of muscle denervation, nerve terminals and acetylcholine receptors were labeled with 4-Di-2-ASP and rhodamine-alpha-bungarotoxin, respectively, for confocal microscopy. In young mdx mice, 75% (n = 137 endplates) of the receptors were distributed in islands. The same was observed in 100% (n = 114 endplates) of the adult junctions. In denervated-regenerated fibers of young mice, the receptors were distributed as branches in 89% of the endplates (n = 90). In denervated-regenerated fibers of adult mice, the receptors were distributed in islands in 100% of the endplates (n = 100). These findings show that nerve-dependent mechanisms are also involved in the changes in receptor distribution in young dystrophic muscles. In older dystrophic muscles, other factors may play a role in receptor distribution.

Dystrophic muscles show alterations in the dystrophin-glycoprotein complex and a lack of neuronal nitric oxide (NO) synthase. In mdx mice, presynaptic expression of neuronal NO synthase is decreased, suggesting that presynaptic signaling may be altered in dystrophic muscle. In this study, we examined the nerve-terminal and Schwann-cell responses after a crush lesion in control and NO-deficient mice. Seven days after nerve crush, 24% of control neuromuscular junctions (n = 200) showed ultraterminal sprouts, whereas in NO-deficient mice this frequency was 28.5% (n = 217; P > 0.05 compared to controls; chi-square test). Schwann-cell response did not change in the absence of NO, after a nerve lesion of 7-day duration. Fourteen days after the lesion, nerve terminals sprouted and Schwann cells showed an extensive network of processes away from the synaptic site in controls. In the absence of NO, there was a dramatic decrease in nerve-terminal sprouting and Schwann-cell processes failed to extend away from the endplate. These results show that NO is involved in the nerve-terminal and Schwann-cell response to nerve injury. They also suggest that presynaptic molecular signaling may be impaired in dystrophic muscles, and this could influence the innervation and survival of newly formed myofibers generated by cell-mediated therapies.

The primary objective of the current study was to determine the maximum tolerated dose of paclitaxel (PTX) that could be added daily to radiation therapy (RT) in patients with non-small cell lung cancer (NSCLC). The secondary objective was to achieve a plasma concentration of PTX estimated to exert a radiosensitizing effect. Eighteen patients with locally advanced NSCLC were treated. 60 Gy of RT were given in 2 Gy fractions, 5 days per week. A daily dose of PTX was delivered by 4-h i.v. infusion before RT. The initial dose level of PTX was 9 mg/m2/day, escalated by 1 mg at each additional patient triplet. Two out of 6 patients experienced acute dose limiting toxicity (DLT) at the 12 mg/m2/day PTX dose level. PTX continuously greater than 10 nM, the estimated radiosensitizing condition, was achieved at the PTX dose level of 12 mg/m2/day. PTX at doses up to 11 mg/m2/day may be safely added to a conventional conformal RT course. Both DLT and the estimated radiosensitizing plasma exposure to PTX were encountered at the 12 mg/m(2)/day dose level.

Mdx mice are deficient in dystrophin and show muscle fiber regeneration. Changes in the distribution of acetylcholine receptors have been reported at the neuromuscular junction of mdx mice and may be a consequence of muscle fiber regeneration. In this study, we examined whether the distribution of receptors was still altered in long-term, regenerated muscle fibers from C57Bl/10 mice. The left sternomastoid muscle of adult mice was injected with 60 microl of lidocaine hydrochloride to induce muscle degeneration-regeneration. In some mice, the sternomastoid muscle was denervated at the time of lidocaine injection. After 90 and 150 days, the nicotinic acetylcholine receptors were labeled with rhodamine-alpha-bungarotoxin for confocal microscopy. At both intervals studied, the receptors were distributed in spots. In denervated-regenerated fibers, the receptors were distributed as regular branches similar to denervated muscles without lidocaine treatment. These findings suggested that nerve-dependent mechanisms were involved in the changes in receptor distribution seen in regenerated muscle fibers after lidocaine treatment, and that a similar phenomenon could explain the changes in receptor distribution seen in dystrophic muscle fibers.

Activation of muscle satellite cells, a fundamental step in the success of muscle regeneration is mediated by nitric oxide (NO). In this study, we investigated whether isosorbide dinitrate (ISD), an NO donor, could improve muscle regeneration in dystrophic mdx mice. The right tibialis anterior muscle of mdx and C57Bl/10 mice was injected with bupivacaine (0.3 ml, 33 mg/kg), a myotoxic agent, to induce muscle fiber regeneration. After bupivacaine injection, mice were treated with ISD (30 mg/kg; i.p.), verapamil (a non-NO donor vasodilator, 15 mg/kg, i.p.) or saline solution (vehicle, 0.3 ml, i.p.) for 20 days. Some bupivacaine-injected mice received no pharmacological treatment (control group). Muscle regeneration was evaluated by counting the total number of muscle fibers and measuring myofiber cross-sectional area. ISD significantly improved bupivacaine-induced muscle regeneration in mdx by increasing by 20% the total number of muscle fibers compared to the other groups. Spontaneous muscle regeneration, evaluated in the contralateral non-injected muscle, was not affected. ISD treatment did not affect myofiber cross-sectional area. Verapamil and saline had no effect on muscle regeneration. These results suggested that NO derived from ISD stimulated and/or recruited satellite cells. Pharmacological treatment with ISD could be clinically useful for improving muscle regeneration in Duchenne muscular dystrophy.

In normal skeletal muscle, the protein dystrophin is associated with plasma membrane glycoproteins and may be involved in the stabilization of the sarcolemma. Mutant mdx mice are markedly deficient in dystrophin and show muscle fiber necrosis followed by regeneration. Changes in the distribution of acetylcholine receptors (AChRs) have been reported at the neuromuscular junction of mdx mice possibly as a result of alterations in the release or response to neural trophic factors. One such factor is calcitonin gene-related peptide (CGRP), which has been implicated in AChR synthesis and function. In this study, we used rhodamine-alpha-bungarotoxin and anti-CGRP IgG FITC to study AChR and CGRP distribution at the neuromuscular junction of mdx mice. Using laser scanning fluorescence confocal microscopy, it was possible to see that CGRP-like immunoreactivity had a presynaptic distribution, covering the AChRs. Thirty-four percent of dystrophic junctions were found to be labeled with CGRP compared to 80% of control endplates. Since CGRP-positive and -negative fibers showed similar changes in AChR distribution, it is suggested that CGRP is probably not directly involved in the altered pattern of AChR seen in dystrophin-deficient muscle fibers of mdx mice.

The pattern of innervation of the vertebrate neuromuscular junction is established during early development, when junctions go from multiple to single innervation in the phenomenon of synapse elimination, suggesting that changes at the molecular level in the postsynaptic cell lead to the removal of nerve terminals. The mdx mouse is deficient in dystrophin and associated proteins that are part of the postsynaptic cytoskeleton. We used rhodamine-alpha-bungarotoxin and anti-neurofilament IgG-FITC to stain acetylcholine receptors and nerve terminals of the sternomastoid muscle during postnatal development in mdx and control C57BL/10 mice. Using fluorescence confocal microscopy, we observed that, 7 days after birth, 86.7% of the endplates of mdx mice were monoinnervated (n = 200) compared with 41.4% in control mice (n = 200). By the end of the second postnatal week, all endplates were innervated singly (100% mdx and 94.7% controls, n = 200 per group). These results show that dystrophic fibers achieve single innervation earlier, perhaps because dystrophin or a normal cytoskeletal complex is implicated in this phenomenon.

Background: Radiotherapy (RT) has a remarkable success rate in the treatment of patients with glottic carcinoma. The objectives of the current study were to assess the results in a group of consecutive patients with comparable characteristics who were treated with RT (6-megavolt photon linear accelerator) and to determine the prognostic factors that may influence local control in patients with early-stage glottic carcinoma. The impact on local control of tobacco smoking and second primary malignancies also was investigated., Methods: Four hundred ten patients with T1-T2 squamous cell carcinoma of the glottis who were treated between 1986 and 2001 were analyzed retrospectively with regard to local control and overall survival. Potential prognostic factors for local control were evaluated with univariate and multivariate models. The impact of technologic advances also was evaluated., Results: The 5-year and 10-year overall survival rates were 83% and 63.5%, respectively. The overall 10-year local control rate for patients with T1-T2 glottic carcinoma was 89%. The median time to recurrence was 7 months. Univariate analysis showed that tumor category, tumor size, macroscopic appearance of the lesion, RT fraction size, persistent edema, year of RT treatment, unchanged dysphonia, and surgical option all had a significant influence on local control; whereas multivariate analysis showed that only persistent dysphonia and year of RT treatment were significantly associated with increased local control. A 22.2% rate of second primary malignancies was reported: second primary tumors were the major cause of death in the patients studied. Only 2 patients died of laryngeal carcinoma; 304 patients were alive with their disease in complete remission, 1 patient was alive with recurrent laryngeal carcinoma after undergoing salvage surgery, and 103 patients died of either intercurrent disease or a second primary tumor., Conclusions: The use of a 6-megavolt photon linear accelerator achieved a high rate of local control in patients with T1-T2 glottic carcinoma. Dysphonia and the year of RT treatment were the most important prognostically significant factors for patient outcome. The occurrence of a second primary tumor was the most frequent cause of death, especially among patients who did not stop smoking after a diagnosis of glottic carcinoma., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11575)

We investigated whether pre-terminal axons and motor terminals retained their ability to sprout in the murine X-linked muscular dystrophy (mdx). Immunofluorescence confocal microscopy observation of nerve terminals and acetylcholine receptors in mdx muscles with crushed and non-crushed nerves showed that most of the junctions had intraterminal sprouting and that the number of junctions with extraterminal sprouting increased after the nerve crush lesion. Since new dystrophin-positive muscle fibers generated by cell-mediated therapies need to be innervated to proceed with their maturation and dystrophin production, these results suggest that the use of inducing factors to increase the sprouting capacity of nerve terminals could be an additional tool in the success of cell-mediated therapies.

Purpose: To compare conventional fractionation radiation therapy (RT), Arm A, vs. split-course accelerated hyperfractionated RT (S-AHF), Arm B, vs. conventional fractionation RT plus concomitant chemotherapy (CT), Arm C, in terms of survival and toxicity for advanced, unresectable epidermoid tumors of oropharynx., Methods and Materials: Between January 1993 and June 1998, 192 previously untreated patients affected with Stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were accrued in a multicenter, randomized Phase III trial (ORO 93-01). For Arms A and C, 66-70 Gy in 33-35 fractions, 5 days a week, were administered in 6.5-7 weeks to tumor and positive nodes. In Arm B, the dose delivered to tumor and involved nodes was 64-67.2 Gy, giving 2 fractions of 1.6 Gy every day with an interfraction interval of at least 4 h and preferably 6 h, 5 days a week. At 38.4 Gy, a 2-week split was planned; after the split, RT was resumed with the same modality. In Arm C, CT regimen consisted of carboplatin and 5-fluorouracil (CBDCA 75 mg/m(2), Days 1-4; 5-FU 1,000 mg/m(2) i.v. over 96 h, Days 1-4, recycling every 28 days (at 1st, 5th, and 9th week)., Results: No statistically significant difference was detected in overall survival (p = 0.129): 40% Arm A vs. 37% Arm B vs. 51% Arm C were alive at 24 months. Similarly, there was no statistically significant difference in terms of event-free survival (p = 0.196): 20% for Arm A, 19% for Arm B, and 37% for Arm C were event free at 24 months. On the contrary, the 2-year disease-free survival was significantly different among the three arms (p = 0.022), with a superiority for Arm C. At 24 months, the proportion of patients without relapse was 42% for Arm C vs. 23% for Arm A and 20% for Arm B. Patients in Arm A less frequently developed G3+ acute mucositis than their counterparts in Arm B or C (14.7% vs. 40.3% vs. 44%). Regarding the CT-related acute toxicity, apart from 1 case of fatal nephrotoxicity, only hematologic G3+ (Grade 3 or higher) acute sequelae were observed (World Health Organization scale), most commonly leukopenia (22.7%). Arm C showed slightly more G3+ skin, s.c. tissue, and mucosal late side effects (RTOG scale), although significant sequelae were relatively uncommon, and mucosal sequelae were most commonly transient. The occurrence of persistent G3 xerostomia was comparable in all three treatment arms., Conclusions: The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone in advanced oropharyngeal squamous-cell carcinomas, by increasing disease-free survival. This improvement, however, did not translate into an overall survival improvement, and was associated with a higher incidence of acute morbidity.

Background: During the last 20 years, survival rates of head and neck carcinoma patients in the United States and Europe have plateaued. To determine the factors that can reduce mortality rates, we examined changes in clinical presentation and survival rates across 24 years of treatment of head and neck carcinoma patients., Methods: A retrospective study of patients with head and neck carcinoma was conducted from January 1, 1975, to December 31, 1998. We identified 2143 eligible patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx. Changes in gender, clinical stage, and therapy were evaluated separately for each site of cancer across five consecutive periods. Probability of dying and overall survival rates were estimated. Odds ratios (ORs) and hazard ratios were calculated., Results: An increase in T1 versus T2 or higher stage carcinoma was more probable for the oral cavity and larynx (OR = 4.1 and 3.0, respectively) in the last versus the earliest period. An increase in radical treatments was more probable for carcinomas of the oral cavity, oropharynx, hypopharynx, and larynx (10.2, 34.8, 12.5, and 2.1-fold, respectively) in the last versus the earliest period. A decreasing trend of probability of dying from the first head and neck carcinoma during the 1970s versus the 1990s was found. The overall survival rates at 5 years was 32% in 1975-1978 versus 51% in 1989-1993., Conclusions: In contrast with survival rates in the United States and Europe, our findings show a significant increase in overall survival rates during the last 20 years. This increase is attributable to changes in diagnostic-therapeutic approaches and to early consultation with a physician for symptoms arising in the head and neck region., (Copyright 2002 American Cancer Society.)

Breast cancer may affect the eye and orbit by metastatic neoplastic infiltration, uvea being the most common site of presentation. Management of these cases with radiotherapy is usually gratifying with reported response rate of approximately 75%. A retrospective evaluation of cases treated in five Institutions participating in a collaborative radiation therapy group of north-Italy is reported. Fifty-four cases of metastases to the eye or orbit were referred for radiation therapy to the Departments participating in the survey in the period 1977-1995. There were 49 female patients aged between 28 and 75 years (median, 44 years) at presentation of orbital metastasis. Thirty-eight lesions (70%) were metastases to the choroid, 9 involved other parts of the eye, and 7 patients had orbital metastases. Five of the 49 patients had bilateral choroidal metastases. Radiotherapy was employed with megavoltage equipment. The median total dose delivered was 40 Gy (range, 16-60 Gy). All the patients were treated 5 times per week with fraction sizes ranging from 1.8 to 3.0 Gy (median, 2.0 Gy). Of the 43 evaluable eyes, 34 (79%) showed a definite improvement after radiotherapy. There was a stabilization of the process in 4 patients. The rest (11 lesions) were lost to detailed follow-up of the response of the eye metastases. Twelve patients experienced acute transient cheratoconjunctivitis and in a case a subconjunctival haemorrhage was observed; as late side effects, two cases of chataract were observed during a period of observation of 37 and 117 months. A median survival time of 17 months was observed. The goal of irradiation was to improve vision or at least prevent blindness and enucleation. The palliative effect of irradiation was confirmed with a response rate consistent with the data of the literature on this subject.

Background: Since there is increasing evidence that both acute (perfusion-limited) and chronic (diffusion-limited) hypoxia, and tumor repopulation may prejudice the outcome of radiotherapy, the combination of carbogen (95% oxygen-5% carbon dioxide) and nicotinamide with accelerated radiotherapy (ARCON) should reduce the impact of these factors of radioresistance., Aim: This clinical study was aimed at determining the feasibility, as well as the qualitative and quantitative toxic effects of a therapeutic approach based on ARCON, and assessing the tumor response rates that can be achieved with this regime in patients with locally advanced tumors of the head and neck., Methods: A phase I/II study conducted between 1993 and 1996 by the Co-operative Group of Radiotherapy of the EORTC included three consecutive steps: accelerated fractionation (AF) combined with carbogen (11 analyzable patients), AF combined with the daily administration of nicotinamide (n=10), and AF with both carbogen and nicotinamide (n=17). Radiotherapy was based on an accelerated regime (72 Gy in 5.5 weeks). Nicotinamide was delivered 90 min before the first irradiation session, at a daily dose of 6 g. Carbogen breathing started 5 min before irradiation and lasted throughout the entire radiotherapy sessions., Results: No significant difference in loco-regional toxicity was found among the three study steps, when carbogen and nicotinamide, either alone or in combination, were combined with AF. The feasibility of the ARCON protocol, as proposed in the present EORTC study, appears to be significantly impaired when nicotinamide is added, at a daily dose of 6 g, to AF and carbogen, in an unselected group of patients. More than 20% of patients experienced grade 2 or 3 emesis. It also demonstrates, in unselected groups of patients, no significant difference in tumor response and local control when carbogen and nicotinamide, either alone or in combination, are added to accelerated radiotherapy. The percentages of objective response at 2 months were 81, 70 and 87%, respectively., Conclusion: Future ARCON trials should target selected head and neck tumor localizations and stages, and a lower nicotinamide dose is needed to reduce severe upper gastro-intestinal toxicity.

This paper describes the mechanisms of action of ionizing radiations combined with antineoplastic drugs. Some relevant drugs for the combined modality treatments of locally advanced lung cancer are reported. The meta-analyses including randomized trials comparing single agent (radiotherapy or chemotherapy) versus combined chemotherapy and radiotherapy in patients with unresectable non small cell lung cancer and limited small cell lung cancer are then reviewed. The clinical outcome in relation to different schedules of chemoradiotherapy (sequential, alternating and concurrent) is also focussed.

Aims and Background: Radiation has been shown to affect the uptake of micromolecules by the tissues within the radiation fields. We measured tumor drug uptake throughout a course of radiotherapy for stage III non-operable non-small-cell lung cancer (NSCLC)., Patients and Methods: Thirty patients were treated with radiotherapy consisting of 15 fractions of 300 cGy given over 3 weeks. They were divided into groups of 2. At 1.5 hr before a given fraction of radiotherapy, one group was given i.v. a bolus of 6 mg/m2 CDDP (cis-diamminedichloroplatinum). Between 1.5 and 2 hr after radiotherapy, the patients underwent bronchoscopy, during which a biopsy was taken from the tumor mass. A similar procedure was carried out on a different group of 2 patients at each of the 15 radiotherapy fractions. The amount of platinum in the biopsy sample was measured by atomic absorption spectroscopy and expressed as ng platinum/mg tissue. In another 13 patients, a biopsy was taken before beginning the radiotherapy, and they served as controls., Results: The quantity of platinum/g of tissue in the patients was 11 +/- 4.4 ng/mg tissue. During the course of fractionated radiotherapy, the quantity of platinum/g of tumor varied considerably between radiotherapy fractions. Maximum uptake was at fractions 8 and 9 (92 ng platinum/mg tissue) with the minima during the first few fractions and at fractions 10, 11 and 12 (an average 20 ng platinum/mg tissue)., Conclusions: The cyclical variations in the uptake of CDDP by the tumor tissue during the protracted course of fractionated radiotherapy are probably due to the well-known effects of radiation on vascular function and capillary permeability. The results may have implications for future clinical protocols involving chemo- and radiotherapy for the treatment of the disease.

From January 1984 to December 1986, 94 patients with unresectable, locally advanced, non-small cell lung cancer (NSCLC) were treated to assess both the efficacy and the toxicity of a combined modality treatment including radiation therapy (45 Gy/15 fractions/3 weeks) and daily low dose cDDP (6 mg/m2). The overall response rate for the 90 evaluable patients was 54.3% with 16.6% of complete responses. At a minimum follow-up of 4 years, the overall median survival time was 12 months. Provided adequate hydration is ensured, the cDDP regimen chosen as a radiosensitizer can be safely combined with radiation therapy.

From April 1983 through December 1989, 42 consecutive patients with diagnosis of epithelial ovarian carcinoma were initially managed by aggressive surgery and three courses of endoperitoneal cis-platinum-based chemotherapy followed by an alternating combination chemotherapy and second-look laparotomy. Patients with residual tumor less than or equal to 2 cm subsequently received whole abdominal radiation therapy (WAR). Twenty-eight patients (42% with no residual disease, 21% with microscopic disease, and 36% with residual disease less than 2 cm) were eligible for WAR. WAR was delivered using an open-field technique up to 22 Gy in 20 fractions followed by a pelvic boost of 18 Gy in 10 fractions. The kidneys were shielded posteriorly at 1100 cGy; hepatic shields were not added. One patient did not complete WAR for lung metastases after 5 radiotherapy fractions. The complete treatment program lasted 8 months (range, 6.8-11). The median follow-up of the 28 patients entered into the study was 50 months. Eight patients are alive and disease-free at 5 years. The overall and disease-free survival rates at 5 years are 45 and 30%, respectively. All but 2 patients relapsed within the abdominopelvic cavity and 3 developed brain metastases. Toxic effects, during WAR, required treatment interruption in all but 4 patients: 3 developed a small bowel obstruction requiring surgery and 1 died of surgical complications in complete remission. The poor disease-free survival and the severe toxicity encountered have been valid indications that WAR should be discontinued as a treatment modality in advanced ovarian cancer at our department.

From March 1985 to July 1989, 22 patients with unresectable pancreatic adenocarcinoma entered the study to receive external beam irradiation with chemotherapy. Radiation therapy consisted of 60 Gy in 3 courses (20 Gy each course) delivered over a period of 2 weeks, with a 2-week rest between the courses. Chemotherapy consisted of 5 fluorouracil, 500 mg/m2, plus cisplatinum, 20 mg/m2, administered on days 1, 2 and 3 of each radiation therapy course. Of the 22 evaluable patients, 10 were males and 12 females; their median age was 63 years (range, 32-77), and their median performance status was 80 (range, 60-90). After treatment, 12 partial remissions and 6 no changes were reported. In 4 cases, abdominal progression of disease during treatment required interruption of the therapy program. At the start of treatment, abdominal pain was the most important symptom in 17 patients; improvement of abdominal pain was observed in 10 cases (76%) after treatment and lasted for a median of 5 months. Median survival time was 7.5 months, and time to progression was 6.2 months. Median follow-up was 7 months (range, 14 days -38). In 2 cases, persistent hematologic toxicity did not permit completion of therapy, and in another 3 cases grade II hematologic toxicity required a 2-week rest period over the normal split-course program. In another 4 cases, grade I hematologic toxicity did not require any delay in the therapy program. Our results are comparable with those achieved in other major studies and are acceptable in terms of survival time, palliation of symptoms and toxicity. In our experience, the combination of radiotherapy plus 5-fluorouracil and cisplatinum does not seem to offer any advantage over the combination of radiation therapy and 5-fluorouracil.

This retrospective study was conducted on 255 consecutive patients with locally advanced squamous-cell carcinoma of the oral cavity, oropharynx, larynx or hypopharynx, treated at the Radiotherapy Department of Pordenone General Hospital between January 1975 and December 1985. All patients underwent radical surgery followed, after an interval ranging from 10 days to 2.9 months, by radiotherapy given either through a 6 MeV linear accelerator or a cobalt-60 unit. Field extension and dose delivered were comparable in relation to stage and involvement of the surgical resection margins. The aims of the study were to evaluate the survival rate and to analyze the clinical parameters which can influence the disease-free survival. The adjusted overall 5-year survival rate was 71%; stage, performance status at diagnosis, and site of the primary tumor were significant factors in determining patient prognosis, whereas infiltration of resection margins was not significant in determining loco-regional control of disease. Seventy-five patients relapsed and 67 died of cancer-related diseases whereas death in 52 patients was not related to the head and neck cancer. The combined modality treatment consisting of surgery followed by radiotherapy was well tolerated and proved to be effective in the treatment of locally advanced head and neck tumors.

Between July 1981 and December 1983, 63 patients, with brain metastases were treated with an accelerated split course regimen; irradiation was given to the whole brain in 3 daily fractions of 160 cGy each (with 4-h interval between the fractions), for 5 days a week. The cycle was repeated after 2 weeks to a total dose of 4800 cGy. Male-female ratio was 3:1 (48 males and 15 females). Median age was 58 years (range 24 to 75). The most frequent site of primary tumor was lung (squamous cell carcinoma in 33 patients and oat cell carcinoma in 8 patients), breast in 6 patients, melanoma in 3 patients, other sites in 8 patients and unknown cancer in 5 patients. Thirty-five patients had multiple brain metastases localizations. In 33 patients (52.3%), metastases were present in other sites outside the central nervous system. Two patients failed to complete the scheduled treatment: one because of early death and the other by refusal of therapy during treatment. We obtained complete remission (CR) in 4 patients and partial remission (PR) in 24 patients. The median survival time was 21 weeks. The overall response rate was 42.5%. Toxicity was not considerable. The treatment results were not influenced by the site of primary tumor or by disease spreading; only the neurologic status before radiotherapy and the response to treatment influenced survival. The results we obtained are similar to those reported by other studies; however, with the accelerated split course regimen the treatment time was reduced and a shorter period of hospitalization was required.

From January 1975 to March 1981, 97 consecutive patients with brain metastases from various tumors were treated with cobalt-radiotherapy. Two successive treatment schedules were employed: the first 52 patients were treated according to a conventional schedule (30 or 40 Gy in 15 or 20 treatments over a 3 or 4 week period), while in the successive 45 patients a concentrated schedule was employed (2 series of 17 Gy in 2 sessions over a 3 day period, separated by an interval of 3 weeks). In the 87 evaluable patients, no significant difference was noted regarding the efficacy of radiotherapeutic treatment (25/47 and 20/40 partial remissions, respectively, with median survival of 4 and 3 months, respectively). Acute toxicity was more relevant with concentrated irradiation (approximately 20% of cases).

Experience with a multiple fractions per day radiation therapy program for inoperable esophageal cancer is reported. The treatment program consisted of 3 daily fractions of 1.6 Gy, with a 4 hr interval between fractions, for 5 consecutive days (24 Gy). After a rest period of 2 weeks, a second course of radiation was given with the same dose and fractionation for a total dose of 48 Gy in an overall treatment time of 4 weeks. Thirty-four patients were treated between February 1981 and July 1983. Acute reactions consisted of mild esophagitis noted in 30% of patients. No treatment related complications were reported. Median survival was 7 months and the 2- and 5-year survival rates were 12 and 9%, respectively. Tumor size and Karnofsky performance status were found to be the most important prognostic indicators for prolonged survival. Prompt palliation of symptoms was noted. Thirty-three per cent of patients had complete resolution and 41% had partial improvement of symptoms after completion of treatment. Four patients (12%) obtained complete tumor regression with negative biopsy at endoscopic examination and 2 of them are free of disease at 58 and 64 months. A partial response was reported in 12 patients (35%) for a median duration of 5 months (3-26). Treatment with multiple fractions per day was feasible in patients with esophageal cancer and could be preferred to more conventional fractionations for promptness of palliation and the shorter treatment time. The expected therapeutic gain is discussed.