Clinical and technical challenges of cancer reirradiation: Words of wisdom.

Since the development of new radiotherapy techniques that have improved healthy tissue sparing, reirradiation (reRT) has become possible. The selection of patients eligible for reRT is complex given that it can induce severe or even fatal side effects. The first step should therefore be to assess, in the context of multidisciplinary staff meeting, the patient's physical status, the presence of sequelae resulting from the first irradiation and the best treatment option available. ReRT can be performed either curatively or palliatively to treat a cancer-related symptom that is detrimental to the patient's quality of life. The selected techniques for reRT should provide the best protection of healthy tissue. The construction of target volumes and the evaluation of constraints regarding the doses that can be used in this context have not yet been fully codified. These points raised in the literature suggest that randomized studies should be undertaken to answer pending questions.

Highly hypofractionated schedules for localized prostate cancer: Recommendations of the GETUG radiation oncology group.

Stereotactic body radiotherapy (SBRT) has become treatment option for localized prostate cancer but the evidence base remains incomplete. Several clinical studies, both prospective and retrospective, have been published. However, treatment techniques, target volumes and dose constraints lack consistency between studies. Based on the current available literature, the French Genito-Urinary Group (GETUG) suggests that.

Addressing the dosimetric impact of bone cement and vertebroplasty in stereotactic body radiation therapy.

PURPOSE: Bone cement used for vertebroplasty can affect the accuracy on the dose calculation of the radiation therapy treatment. In addition the CT values of high density objects themselves can be misrepresented in kVCT images. The aim of our study is then to propose a streamlined approach for estimating the real density of cement implants used in stereotactic body radiation therapy. METHODS: Several samples of cement were manufactured and irradiated in order to investigate the impact of their composition on the radiation dose. The validity of the CT conversion method for a range of photon energies was investigated, for the studied samples and on six patients. Calculations and measurements were carried out with various overridden densities and dose prediction algorithms (AXB with dose-to-medium reporting or AAA) in order to find the effective density override. RESULTS: Relative dose differences of several percent were found between the dose measured and calculated downstream of the implant using an ion chamber and TPS or EPID dosimetry. If the correct density is assigned to the implant, calculations can provide clinically acceptable accuracy (gamma criteria of 3%/2 mm). The use of MV imaging significantly favors the attribution of a correct equivalent density to the implants compared to the use of kVCT images. CONCLUSION: The porosity and relative density of the various studied implants vary significantly. Bone cement density estimations can be characterized using MV imaging or planar in vivo dosimetry, which could help determining whether errors in dose calculations are due to incorrect densities.

Sarcoidosis: clinical, hormonal, and magnetic resonance imaging (MRI) manifestations of hypothalamic-pituitary disease in 9 patients and review of the literature.

Hypothalamic-pituitary (HP) sarcoidosis has 2 main endocrine manifestations: diabetes insipidus and hyperprolactinemia. We conducted the current study to investigate pituitary dysfunction and perform imaging of the HP area in patients both immediately following diagnosis and after treatment. The study included 6 men and 3 women, with a mean age of 30 years at the onset of sarcoidosis. All patients had both hormonal and magnetic resonance imaging (MRI) HP disorders. All patients had anterior pituitary dysfunction, 7 of them with associated diabetes insipidus. Nine patients had gonadotropin deficiency and 3 had hyperprolactinemia. MRI revealed infundibulum involvement in 5 patients, pituitary stalk thickness abnormality in 5, and involvement of the pituitary gland in 2, associated with other parenchymal brain or spinal cord lesions in 6 patients. All patients had multiple localizations of sarcoidosis, and 5 had histologically confirmed sinonasal localizations. Mean follow-up of the HP disorder was 7.5 years. All patients received prednisone. There was no correlation between the number of hormonal dysfunctions and the area of the HP axis involved as assessed by MRI. Although corticoid treatment was associated with a reduction of radiologic lesions, only 2 patients had partial recovery of hormonal deficiency. In conclusion, hormonal deficiencies associated with HP sarcoidosis frequently include hypogonadism (all patients) and to a lesser degree diabetes insipidus (7 of 9 patients). MRI abnormalities improved or disappeared in 7 cases under corticosteroid treatment, but most endocrine defects were irreversible despite regression of the granulomatous process. Most cases presented with multivisceral localizations and an abnormally high proportion of sinonasal localizations.

Analysis of antibiotic resistance gene expression in Pseudomonas aeruginosa by quantitative real-time-PCR.

In Pseudomonas aeruginosa many of the clinically relevant resistance mechanisms result from changes in gene expression as exemplified by the Mex drug efflux pumps, the AmpC beta-lactamase and the carbapenem-specific porin OprD. We used quantitative real-time-PCR to analyze the expression of these genes in susceptible and antibiotic-resistant laboratory and clinical strains. In nalB mutants, which overexpress OprM, we observed a four- to eightfold increase in the expression of mexA, mexB, and oprM genes. MexX and mexY genes were induced eight to 12 times in the presence of 2 mg L(-1) tetracycline. The mexC/oprJ and mexE/oprN gene expression levels were increased 30- to 250-fold and 100- to 760-fold in nfxB and nfxC mutants, respectively. We further found that in defined laboratory strains expression levels of ampC and oprD genes paralleled beta-lactamase activity and OprD protein levels, respectively. Our data support the use of quantitative real-time-PCR chain reaction for the analysis of the antimicrobial resistance gene expression in P. aeruginosa.

Transient neurological disorders during a simulated ascent of Mount Everest.

BACKGROUND: Transient neurological disorders are often observed at high altitude but are poorly documented under field conditions. The mechanism usually invoked is a hypocapnic vasoconstriction due to severe hypoxic hyperventilation. During a simulated ascent of Mount Everest in a hypobaric chamber by eight volunteer alpinists (Operation Everest III, Comex '97), three subjects presented neurological symptoms. We report here on the clinical observations and testing to detect mechanisms in addition to hypocapnic vasoconstriction. METHODS: The experiment was designed to investigate factors limiting physiological performance at altitude and the pathophysiology of acute mountain sickness. A retrospective analysis was made comparing the three cases of transient neurological disorder at high altitude (TNDHA) with the five subjects who had no neurological symptoms. RESULTS: Analysis of clinical and blood parameters showed no difference between cases and controls. The cases showed no neurological sequelae following the experiment and were normal on cardiac imaging. However, one case had a history of migraine in his youth, leading us to hypothesize that segmental vasoconstriction was a factor. In another case, gas bubbles were detected in the pulmonary artery by transthoracic echocardiography when he was symptomatic, suggesting that gas emboli may have played a role. All three cases shared a possible triggering factor in that each experienced hyperventilation alternating with straining against a closed glottis shortly before the onset of symptoms. CONCLUSION: Mechanisms other than hypocapnic vasoconstriction in hypoxia may be causal factors of TNDHA. The existence of triggering factors and evidence of a possible embolic mechanism should be further explored.

Tuberculous cerebral vasculitis: retrospective study of 10 cases.

BACKGROUND: Tuberculous cerebral vasculitis is a complication of tuberculous meningitis. This study was undertaken to determine the epidemiological characteristics, context, diagnostic means and outcomes under treatment of tuberculous cerebral vasculitides. METHODS: All consecutive patients diagnosed with tuberculous cerebral vasculitis were identified from the databases of three Internal Medicine, one Neurology and one Infectious Disease Departments in three suburban Parisian hospitals. RESULTS: We describe 10 cases: five men and five women (median age 33.5 [range: 27-55] years). Two were infected with the human immunodeficiency virus. Nine patients had tuberculous meningitis, eight with extraneurological involvement. The following manifestations led to the diagnosis: motor deficit, acute confusional state, headaches, involvement, coma and/or seizures. The cerebral vasculitis revealed tuberculosis in three patients, but tuberculosis was already known when vasculitis was diagnosed for the seven others. The cerebral computed-tomography scan showed cerebral infarctions in five patients, hydrocephalus and tuberculomas in four, while magnetic resonance imaging detected infarctions and leptomeningitis in nine patients, pachymeningitis in one, hydrocephalus and tuberculomas in seven. Therapy combined antituberculous agents with oral corticosteroids for all patients, preceded by a methylprednisolone pulse for five patients. Outcome was favorable for nine patients. CONCLUSION: We described the non-negligible frequency of tuberculous cerebral vasculitides, their clinical manifestations and their potential severity, and the diagnostic and monitoring contributions of magnetic resonance imaging and magnetic resonance angiography.

Ribosome protection prevents azithromycin-mediated quorum-sensing modulation and stationary-phase killing of Pseudomonas aeruginosa.

In Pseudomonas aeruginosa, azithromycin has been shown to reduce virulence factor production, to retard biofilm formation, and to exhibit bactericidal effects on stationary-phase cells. In this study we analyzed whether these azithromycin-mediated effects require interaction with the ribosome. We blocked the access of azithromycin to the ribosome in P. aeruginosa PAO1 by expressing the 23S rRNA methylase ErmBP from Clostridium perfringens. Ribosome protection prevented the azithromycin-mediated reduction of elastase and rhamnolipid production, as well as the inhibition of swarming motility. Ribosome protection also prevented the killing of stationary-phase cells, suggesting that the cell-killing effect of azithromycin does not result solely from membrane destabilization. We further show that rhamnolipids are involved in cell killing, probably by increasing the uptake of the hydrophobic azithromycin molecule. These results have important implications for the treatment with azithromycin of patients chronically colonized by P. aeruginosa and might explain the variability in the efficacy of azithromycin treatments.

Development and persistence of antimicrobial resistance in Pseudomonas aeruginosa: a longitudinal observation in mechanically ventilated patients.

Intubated patients frequently become colonized by Pseudomonas aeruginosa, which is subsequently responsible for ventilator-associated pneumonia. This pathogen readily acquires resistance against available antimicrobials. Depending on the resistance mechanism selected for, resistance might either be lost or persist after removal of the selective pressure. We investigated the rapidity of selection, as well as the persistence, of antimicrobial resistance and determined the underlying mechanisms. We selected 109 prospectively collected P. aeruginosa tracheal isolates from two patients based on their prolonged intubation and colonization periods, during which they had received carbapenem, fluoroquinolone (FQ), or combined beta-lactam-aminoglycoside therapies. We determined antimicrobial resistance phenotypes by susceptibility testing and used quantitative real-time PCR to measure the expression of resistance determinants. Within 10 days after the initiation of therapy, all treatment regimens selected resistant isolates. Resistance to beta-lactam and FQ was correlated with ampC and mexC gene expression levels, respectively, whereas imipenem resistance was attributable to decreased oprD expression. Combined beta-lactam-aminoglycoside resistance was associated with the appearance of small-colony variants. Imipenem and FQ resistance persisted for prolonged times once the selecting antimicrobial treatment had been discontinued. In contrast, resistance to beta-lactams disappeared rapidly after removal of the selective pressure, to reappear promptly upon renewed exposure. Our results suggest that resistant P. aeruginosa is selected in less than 10 days independently of the antimicrobial class. Different resistance mechanisms lead to the loss or persistence of resistance after the removal of the selecting agent. Even if resistant isolates are not evident upon culture, they may persist in the lung and can be rapidly reselected.

Combining cisplatin and mitomycin with radiotherapy in anal carcinoma.

PURPOSE: The European Organization for Research and Treatment of Cancer (EORTC) phase II study No. 22953 demonstrated the feasibility of reducing the overall treatment time of chemoradiation, delivering mitomycin C twice rather than once and fluorouracil during the whole treatment. We tested the feasibility of chemoradiation in anal carcinoma with mitomycin and cisplatin in a phase II study. METHODS: Twenty-one patients with locally advanced anal carcinoma (15 women, 6 men) were treated. The first sequence of radiotherapy consisted of 36 Gy over four weeks. After a gap interval of 16 days, a second sequence of radiotherapy was given, delivering 23.4 Gy over 2.5 weeks. Mitomycin C was delivered at 10 mg/m(2) day 1 of each sequence and cisplatin was delivered at 25 mg/m(2)/week of each sequence. RESULTS: The compliance rates for the first sequence with radiation, mitomycinm, and cispaltin (dose and timing) were 100 percent. The median duration gap was 16 days (14-30 days). The compliance rates for the second sequence with radiation, mitomycin, and cisplatin (dose and timing) were 100, 76.2, and 85.7 percent, respectively. Grade > or = 2 acute toxicities of 62, 29, 25, and 5 percent were observed for skin, diarrhea, hematologic, and renal toxicities, respectively. Nineteen patients were in complete response (90.5 percent). CONCLUSIONS: Combining radiation with mitomycin and cisplatin in patients with locally advanced anal cancer is feasible. The results are promising. The EORTC is currently comparing this combination with mitomycin and 5-fluorouracil in a large phase II-III trial.

Cerebral ischemia during carotid artery cross-clamping: predictive value of phase-contrast magnetic resonance imaging.

The goal of this prospective study was to determine the utility of preoperative cerebral magnetic resonance imaging (MRI) in predicting cerebral ischemia during carotid artery cross-clamping for endarterectomy. Between January 2000 and December 2003, a total of 121 patients (95 men, 26 women) underwent three-dimensional phase-contrast MRI to assess collateral function prior to carotid endarterectomy. During regional anesthesia, patients were monitored to detect ischemic events and their timing in relation to cross-clamping and to determine mean intraoperative arterial pressure. These findings were then correlated with the collateral variations observed in the circle of Willis on preoperative MRI. Patients were classified into three groups according to neurological tolerance: normal tolerance (n = 106), immediate severe deficit (n = 9), and late deficit associated with arterial hypotension (n = 6). In the second group, a significant correlation was found between the absence of collateral circulation and neurological deficit (p < .0001). These results indicated that three-dimensional phase-contrast MRI is useful for predicting cerebral ischemia during carotid cross-clamping and selecting indications for shunting. Absence of visible collaterals of the circle of Willis on MRI is significantly predictive of early ischemia and an indication for systematic shunt placement.

Tumor volume as outcome determinant in patients treated with chemoradiation for locally advanced esophageal cancer.

OBJECTIVE: The currently used tumor-node metastasis (TNM) staging method is generally not applicable to patients with unresectable esophageal carcinomas. There is a need for both an efficient, easy-to-perform clinical classification and for identification of pretherapeutic prognostic factors that would be useful for oncologists, one of which is tumor volume. METHODS: Records of 148 patients, admitted to hospital during the period January 1993 to December 2001, were evaluated retrospectively. Median age was 65.7 years (range, 35.5-85.5 years). Most patients had SCC (84.5%). Using the computed tomography (CT) scan classification, tumors were recorded as follows: 1 T1, 42 T2, 93 T3, 6 T4, 2 Nx, 72 N0, 74 N1. Tumor volume from the CT scans was determined as the sum of 2 opposed truncated cones. Median tumor volume was 57.5 cm3 (range, 0.6-288 cm3). RESULTS: Median follow-up was 15.1 month (range, 0.3-82.8 months). Survival rates at 1, 2, and 3 years were 42.5%, 21.6%, and 8%, respectively. Prognostic factors identified by univariate analysis were: dysphagia grade > or =2, other histology than squamous cell, tumor location below the carina, age <65 years and tumor volume > or =100 cm3. Prognostic factors identified with multivariate analysis were: dysphagia grade > or =2 (P = 0.013), weight loss > or =10% (P = 0.047), tumor location below the carina (P = 0.002), and tumor volume > or =100 cm3 (P = 0.041). CONCLUSIONS: For patients that the TNM staging system is not applicable, tumor volume is a new powerful determinant of survival. Further clinical trials need to be carried out to validate this prospectively.

Epilepsy and neurocysticercosis in rural Bolivia: a population-based survey.

PURPOSE: To evaluate the frequency of neurocysticercosis (NCC) in a well-defined prevalent cohort of epilepsy patients in the rural area of the Cordillera province. METHODS: We carried out a two-phase door-to-door neuroepidemiologic survey in a sample of 10,124 subjects in a rural area of the Cordillera Province, Bolivia, to detect the prevalence of the most common neurologic disorders including epilepsy. A team of health workers administered a standard screening instrument for neurologic diseases; subjects found positive at the screening phase underwent a complete neurologic examination. Epilepsy patients were diagnosed according to the definition proposed by the International League Against Epilepsy (ILAE, 1993). Epilepsy patients identified this way underwent electroencephalographic recording, computed tomography (CT) scan, and serologic evaluation to detect antibodies against Taenia solium by enzyme-linked immunoelectrotransfer blot. RESULTS: At the end of the survey, we detected 124 defined prevalent epilepsy patients. On the basis of the classification proposed by the ILAE in 1981, partial seizures were the most common type diagnosed (66 patients, 53.3%). Of the 124 patients, 105 underwent CT scan, and a serum sample was taken to detect antibodies against T. solium in 112 patients; for 97 patients, both neuroradiologic and serologic data were available. Considering radiologic, serologic, and clinical features, of these 124 patients, 34 (27.4%) fulfilled the diagnostic criteria for definitive or probable NCC proposed in 2001. Of these 34 patients 24 (70.6%) had partial seizures. CONCLUSIONS: Our data confirm a high frequency of NCC among a well-defined prevalent cohort of epilepsy patients.

[Locoregional recurrent rectal cancer: the place of radiotherapy]. / Récidives locorégionales des cancers du rectum: place de la radiothérapie.

Currently, locoregional recurrence of rectal cancer is rare due to the therapeutic progress of total mesorectal excision and pre-operative radiotherapy. Nevertheless, a curative treatment could be proposed provided that surgical removal is possible and complete. Here, we will discuss the position of both external and intra-operative radiotherapy, and concomitant chemotherapy. Actually, multimodal therapy provides the best results for local control and overall survival. Exclusive external radiotherapy is indicated for palliative treatment of unresectable cases of recurrence.

CzcR-CzcS, a two-component system involved in heavy metal and carbapenem resistance in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an environmental bacterium involved in mineralization of organic matter. It is also an opportunistic pathogen able to cause serious infections in immunocompromised hosts. As such, it is exposed to xenobiotics including solvents, heavy metals, and antimicrobials. We studied the response of P. aeruginosa upon exposure to heavy metals or antibiotics to investigate whether common regulatory mechanisms govern resistance to both types of compounds. We showed that sublethal zinc concentrations induced resistance to zinc, cadmium, and cobalt, while lethal zinc concentrations selected mutants constitutively resistant to these heavy metals. Both zinc-induced and stable zinc-resistant strains were also resistant to the carbapenem antibiotic imipenem. On the other hand, only 20% of clones selected on imipenem were also resistant to zinc. Heavy metal resistance in the mutants could be correlated by quantitative real time PCR with increased expression of the heavy metal efflux pump CzcCBA and its cognate two-component regulator genes czcR-czcS. Western blot analysis revealed reduced expression of the basic amino acid and carbapenem-specific OprD porin in all imipenem-resistant mutants. Sequencing of the czcR-czcS DNA region in eight independent zinc- and imipenem-resistant mutants revealed the presence of the same V194L mutation in the CzcS sensor protein. Overexpression in a susceptible wild type strain of the mutated CzsS protein, but not of the wild type form, resulted in decreased oprD and increased czcC expression. We further show that zinc is released from latex urinary catheters into urine in amounts sufficient to induce carbapenem resistance in P. aeruginosa, possibly compromising treatment of urinary tract infections by this class of antibiotics.