[Does radiation therapy for prostate cancer increase the risk of second cancers?] / La radiothérapie du cancer de la prostate augmente-t-elle le risque de seconds cancers ?

PURPOSE: The increased risk of second cancer after prostate radiotherapy is a debated clinical concern. The objective of the study was to assess the risk of occurrence of second cancers after prostate radiation therapy based on the analysis the literature, and to identify potential factors explaining the discrepancies in results between studies. MATERIALS AND METHODS: A review of the literature was carried out, comparing the occurrence of second cancers in patients all presenting with prostate cancer, treated or not by radiation. RESULTS: This review included 30 studies reporting the occurrence of second cancers in 2,112,000 patients treated or monitored for localized prostate cancer, including 1,111,000 by external radiation therapy and 103,000 by brachytherapy. Regarding external radiation therapy, the average follow-up was 7.3years. The majority of studies (80%) involving external radiation therapy, compared to no external radiation therapy, showed an increased risk of second cancers with a hazard ratio ranging from 1.13 to 4.9, depending on the duration of the follow-up. The median time to the occurrence of these second cancers after external radiotherapy ranged from 4 to 6years. An increased risk of second rectal and bladder cancer was observed in 52% and 85% of the studies, respectively. Considering a censoring period of more than 10 years after irradiation, 57% and 100% of the studies found an increased risk of rectal and bladder cancer, without any impact in overall survival. Studies of brachytherapy did not show an increased risk of second cancer. However, these comparative studies, most often old and retrospective, had many methodological biases. CONCLUSION: Despite numerous methodological biases, prostate external radiation therapy appears associated with a moderate increase in the risk of second pelvic cancer, in particular bladder cancer, without impacting survival. Brachytherapy does not increase the risk of a second cancer.

[Combination radiotherapy-immunotherapy in genitourinary cancer]. / Combinaison radiothérapie-immunothérapie en cancérologie génito-urinaire.

Immunotherapy occupies a growing place in urologic oncology, mainly for kidney and bladder cancers. On the basis of encouraging preclinical work, the combination of immunotherapy with radiotherapy aims to increase the tumor response, including in metastatic tumors, which raises many hopes, which this article reviews.

Performance comparison of modified ComBat for harmonization of radiomic features for multicenter studies.

Multicenter studies are needed to demonstrate the clinical potential value of radiomics as a prognostic tool. However, variability in scanner models, acquisition protocols and reconstruction settings are unavoidable and radiomic features are notoriously sensitive to these factors, which hinders pooling them in a statistical analysis. A statistical harmonization method called ComBat was developed to deal with the "batch effect" in gene expression microarray data and was used in radiomics studies to deal with the "center-effect". Our goal was to evaluate modifications in ComBat allowing for more flexibility in choosing a reference and improving robustness of the estimation. Two modified ComBat versions were evaluated: M-ComBat allows to transform all features distributions to a chosen reference, instead of the overall mean, providing more flexibility. B-ComBat adds bootstrap and Monte Carlo for improved robustness in the estimation. BM-ComBat combines both modifications. The four versions were compared regarding their ability to harmonize features in a multicenter context in two different clinical datasets. The first contains 119 locally advanced cervical cancer patients from 3 centers, with magnetic resonance imaging and positron emission tomography imaging. In that case ComBat was applied with 3 labels corresponding to each center. The second one contains 98 locally advanced laryngeal cancer patients from 5 centers with contrast-enhanced computed tomography. In that specific case, because imaging settings were highly heterogeneous even within each of the five centers, unsupervised clustering was used to determine two labels for applying ComBat. The impact of each harmonization was evaluated through three different machine learning pipelines for the modelling step in predicting the clinical outcomes, across two performance metrics (balanced accuracy and Matthews correlation coefficient). Before harmonization, almost all radiomic features had significantly different distributions between labels. These differences were successfully removed with all ComBat versions. The predictive ability of the radiomic models was always improved with harmonization and the improved ComBat provided the best results. This was observed consistently in both datasets, through all machine learning pipelines and performance metrics. The proposed modifications allow for more flexibility and robustness in the estimation. They also slightly but consistently improve the predictive power of resulting radiomic models.

[Image-guided radiotherapy contribution and patient setup for anorectal cancer treatment]. / Apport de la radiothérapie guidée par l'image et repositionnement du patient dans le cancer anorectal.

Intensity-modulated radiation therapy is recommended in anal squamous cell carcinoma treatment and is increasingly used in rectal cancer. It adapts the dose to target volumes, with a high doses gradient. Intensity-modulated radiation therapy allows to reduce toxicity to critical normal structures and to consider dose-escalation studies or systemic treatment intensification. Image-guided radiation therapy is a warrant of quality for intensity-modulated radiation therapy, especially for successful delivery of the dose as planned. There is no recommended international or national anorectal cancer image-guided radiation therapy protocol currently available. Dose-escalation trials or expert opinions about intensity-modulated/image-guided radiation therapy good practice guidelines recommend daily volumetric imaging throughout the treatment or during the five first fractions and weekly thereafter as a minimum. Image-guided radiation therapy allows to reduce margins related to patient setup errors. Internal margin, related to the internal organ motion, needs to be adapted according to short- or long-course radiotherapy, gender, rectal location; it can be higher than current recommended planning target volume margins, particularly in the upper and anterior part of mesorectum, which has the most significant movement. Image-guided radiation therapy based on volumetric imaging allows to take target volume shrinkage into account and to develop adaptive strategies, in particular for mesorectum shrinkage during rectal cancer treatment. Lastly, the emergence of new image-guided radiation therapy technologies including MRI (which plays a major role in pelvic tumours assessment and diagnosis) opens up interesting perspectives for adaptive radiotherapy, taking into account both organs' movements and tumour shrinkage.

KDIGO Guidelines and Kidney Transplantation: Is the Cystatin-C Based Recommendation Relevant?

The KDIGO guidelines propose a new approach to diagnose chronic kidney disease (CKD) based on estimated glomerular filtration rate (GFR). In patients with a GFR value comprised between 45 and 59 mL/min/1.73 m(2) as estimated by the CKD-EPI creatinine equation (eGFRcreat ), it is suggested to confirm the diagnosis with a second estimation using the CKD-EPI cystatin C-based equations (eGFRcys /eGFRcreat-cys) . We sought to determine whether this new diagnostic strategy might extend to kidney transplant recipients (KTR) and help to identify those with decreased GFR. In 670 KTR for whom a measured GFR was available, we simulated the detection of CKD using the two-steps approach recommended by the guidelines in comparison to the conventional approach relying on creatinine equation. One hundred forty-five patients with no albuminuria had eGFRcreat between 45 and 59 mL/min/1.73 m(2) . Among them, 23% had inulin clearance over 60 mL/min/1.73 m(2) and were thus incorrectly classified as CKD patients. When applying the Kidney Disease: Improving Global Outcomes (KDIGO) strategy, 138 patients were confirmed as having a GFR below 60 mL/min with eGFRcreat-cys . However, 21% of them were misclassified in reference to measured GFR. Our data do no not support the use of cystatin C as a confirmatory test of stage 3 A CKD in KTR.

Angioplasty and stenting of the extracranial carotid arteries.

We performed percutaneous transluminal angioplasty and stenting in patients with carotid artery stenosis to determine the efficacy of these techniques as an alternative to surgical endarterectomy. From April 1995 through July 1999, 315 carotid angioplasty procedures were performed (right, 151; left, 164) in 290 patients ranging in age from 40 to 93 years. Of these patients, 42% were symptomatic and 58% were asymptomatic. Twenty-five patients underwent bilateral procedures. The mean percentage of stenosis was 82.3%+/-8.7% SD. Angioplasty and stenting were performed without cerebral protection in 165 arteries and with protection in 150. Two methods of protection were used: the Theron technique and the PercuSurge Guardwire temporary occlusion and aspiration system. Balloon dilation and stent placement were successful in 289 patients; in the last patient, severe arterial tortuosity prevented catheterization and stenting. We observed 13 periprocedural neurologic complications due to ischemia (4.2%): 4 transient ischemic attacks (1.3%), 4 minor strokes (1.3%), and 5 major strokes (1.6%), including 1 death. At 6 months, 210 patients had a follow-up angiogram (155) or duplex ultrasound (55). There were 10 restenoses (4.7%), 1 of which was symptomatic and 2 of which showed mild compression of a Palmaz stent without marked stenosis. Primary and secondary 4-year patency rates were 96% and 99%, respectively. These results demonstrate acceptable mortality and morbidity rates related to carotid angioplasty and stenting. However, we found the risk of embolic stroke to be substantial. Cerebral protection may improve the results of carotid angioplasty and expand the indications for this procedure.

Carotid stenting with cerebral protection: first clinical experience using the PercuSurge GuardWire system.

PURPOSE: To study the feasibility and safety of carotid angioplasty and stenting using a new cerebral protection device that temporarily occludes the distal internal carotid artery (ICA). METHODS: Forty-eight high-risk patients (39 men, mean age 69.1 +/- 8 years, range 54 to 86) with 53 ICA stenoses underwent percutaneous angioplasty and stenting via the femoral approach under cerebral protection afforded by a 0.014-inch GuardWire balloon occlusion device. Mean stenosis was 82.1% +/- 9.65% (range 70 to 96) and mean lesion length was 16.0 +/- 7.5 mm (range 6 to 50). Thirty-three (62%) lesions were calcified, and 38 (72%) were ulcerated. Thirty-two (60%) of the lesions were asymptomatic. With the occlusion balloon inflated in the distal ICA, the lesion was dilated and stented. The area was cleaned by aspiration and flushed via an aspiration catheter advanced over the wire. Blood samples were collected from the external carotid artery (ECA) and analyzed to measure the size and number of particles collected. Computed tomography and neurological examinations were performed the day after the procedure. RESULTS: Immediate technical success was achieved in all patients with the implantation of 38 Palmaz stents, 8 Expander stents, and 11 Wallstents. Carotid occlusion was well tolerated in all patients but 1 who had multiple, severe carotid lesions and poor collateralization. Mean cerebral flow occlusion time was 346 +/- 153 seconds during predilation and 303 +/- 143 seconds during stent placement. Total mean flow occlusion time was 542 +/- 243 seconds. One immediate neurological complication (transient amaurosis) occurred in a patient who had an anastomosis between the external carotid (EC) and ICA territories. Debris was removed in all patients with a mean 0.8-mm diameter catheter. CONCLUSION: Cerebral protection with the GuardWire device is easy, safe, and effective in protecting the brain from cerebral embolism. Larger studies are warranted.

Angioplasty and stenting of the extracranial carotid arteries.

PURPOSE: To study the feasibility and safety of stent-supported angioplasty in the treatment of atherosclerotic stenoses of the extracranial carotid arteries. METHODS: Carotid angioplasty was attempted in 174 arteries (163 patients: 126 males; mean age: 71 +/- 10 years, range 47 to 93). Mean lesion length was 15.1 +/- 4.1 mm, and mean percent stenosis was 83.8% +/- 7.3% (reference diameter 5.8 +/- 0.7 mm). The majority (106, 65%) were asymptomatic (51% of all patients had severe coronary disease, 32% had peripheral vascular diseases). Patients underwent independent neurological examination, computed tomography, duplex ultrasonography, and angiography preprocedurally, 24 hours after the procedure, and at 6-month follow-up intervals. Most (142, 82%) carotid arteries were treated without cerebral protection, but a protective triple coaxial catheter was used in 32 (18%) patients. Stents (primarily Palmaz and Wallstent) were deployed routinely in all cases; 18% were implanted without predilation. RESULTS: Immediate technical success was 173 of 174 (99.4%) (1 access failure referred electively to surgery). Eight (4.6%) neurological complications occurred in the periprocedural period: 3 transient ischemic attacks, 2 minor strokes, and 3 major strokes (1 amaurosis and 2 hemiplegias). Two major complications developed despite cerebral protection. There were no deaths or myocardial infarctions and only 3 cervical access site hematomas. Over a mean 12.7 +/- 9.2 month follow-up (range 1 to 36), no ipsilateral neurological complications have been seen. There were 4 (2.3%) restenoses (3 redilated, 1 treated medically) and 1 mild Palmaz stent compression, all found within the first 6 months. Primary and secondary patencies at 3 years are 96% and 99%, respectively. CONCLUSIONS: Angioplasty with routine stenting seems feasible and safe for treating certain types of carotid stenoses even in high-surgical risk patients; however, randomized trials are necessary before this treatment can be offered as an alternative to endarterectomy.

Role of nitric oxide in depressed lymphoproliferative responses and altered cytokine production following thermal injury in rats.

Immunodeficiency follows extensive burns. We investigated some underlying mechanisms in rats, 10 days after a full-thickness skin burn affecting 20% of total body surface area. In both normal and burned rats the splenocyte proliferative response to Con A was linearly and negatively correlated with nitric oxide (NO) production. In all burned rats, the proliferative response was depressed by more than 80% and NO production corresponded to a nitrite concentration above 20 microM. Proliferative responses in burned rats were fully restored in the presence of 250 microM NG-monomethyl-L-arginine (NMMA). A time course study of NO production in response to Con A, LPS, anti-CD3, and IFN-gamma showed that splenic macrophages from burned rats responded to direct and indirect stimuli more rapidly and more intensively than normal macrophages. In the second part of this work, the effect of the overproduction of NO on the synthesis of immunoregulatory and proinflammatory cytokines was investigated. Although it was inhibited, IFN-gamma production by splenocytes from burned rats remained sufficient for NO synthase induction and was restored by NMMA. Concomitantly, IL-2 concentration was enhanced but returned to normal in the presence of NMMA. TNF production was halved after burn injury and NMMA partially restored it. In contrast, IL-6 production was enhanced and increased further in the presence of NMMA. Therefore, cytokines were differently affected by burn injury and variously regulated by NO.

Restoration of postburn impaired lymphocyte responsiveness by nonsteroidal anti-inflammatory drugs is independent of prostaglandin E2 inhibition.

Prostaglandin E2 (PGE2) has been implicated in postburn immunosuppression, which is responsible for septic complications. In the present work, seven non-steroidal anti-inflammatory drugs (NSAIDs), differing by their capacity to inhibit the cyclooxygenase pathway, were compared for their ability to restore T lymphocyte proliferative responses evaluated 4 days after thermal injury in rats. Salicylic acid, 5-aminosalicylic acid, and niflumic acid, given daily, fully restored spleen cell responses to concanavalin A (Con A) and phytohemagglutinin. These drugs were active only at doses that were below the anti-inflammatory doses and did not modify normal spleen cell responses. In these conditions, indomethacin slightly restored lymphocyte reactivity, whereas acetylsalicylic acid, ketoprofen, and piroxicam were ineffective. PGE2 production by Con A-stimulated spleen cells from untreated burned rats and after treatment with niflumic acid or 5-aminosalicylic acid did not correlate with the intensity of the proliferative response. Indomethacin, niflumic acid, and 5-aminosalicylic acid were added in vitro to spleen cells from normal and burned rats, at concentrations from 10(-7) to 10(-4) M. PGE2 production was strongly depressed by indomethacin and niflumic acid and not modified by 5-aminosalicylic acid. The proliferative response of normal spleen cells was depressed in a concentration-dependent manner by niflumic acid and slightly inhibited at the highest concentrations of indomethacin. In contrast, indomethacin concentration dependently restored the burn-impaired proliferative response, whereas niflumic acid further depressed it and 5-aminosalicylic acid had no effect. These results demonstrate that only some NSAIDs are able to restore T lymphocyte reactivity impaired after thermal injury and that this property is not related to inhibition of PGE2 production.

Inhibition of human monocyte TNF production by adenosine receptor agonists.

Adenosine receptor agonists and agents enhancing pericellular concentrations of adenosine possess antiinflammatory properties. In the present study, we found that R-phenylisopropyladenosine (R-PIA), 5'-N-ethylcarboxamido adenosine (NECA), other agonists of adenosine receptors and dipyridamole, an adenosine uptake inhibitor, inhibited tumor necrosis factor (TNF) production by endotoxin-stimulated human monocytes in a concentration-dependent manner with no inhibition of interleukin-6. The rank order of agonist potency is characteristic of neither A1 nor A2 receptors and suggests the involvement of another receptor subtype. The effect of R-PIA on TNF was in part abolished by the antagonist 8-sulfophenyltheophylline. In endotoxin-treated rats, R-PIA pretreatment (2.5 mg/kg) reduced serum TNF levels by 98%, with no modification of serum IL6 levels. TNF inhibition could be an important mechanism by which adenosine analogs exert their antiinflammatory action.

Nitric oxide mediates the depression of lymphoproliferative responses following burn injury in rats.

Among the multiple biological activities of nitric oxide (NO) an immunoregulatory role consisting of the mediation of macrophage suppressive activity, has recently been evidenced. In the present work, we investigated whether NO was implicated in immunosuppression following burn injury. Thermal injury affecting 20-25% of the total body surface area in Wistar rats, provoked a biphasic depression of spleen cell proliferative responses to phytohemagglutinin (PHA) and concanavalin A (Con A). We show that these responses are fully restored on day 4 after burn and only by 55% on day 10 when spleen cells were stimulated in the presence of NG-monomethyl-L-arginine (NMMA), a potent inhibitor of the macrophage inducible NO synthase. Nitrite content in culture supernatant, as an indicator of NO release (in the absence of NMMA), was significantly augmented in Con A-stimulated spleen cells from burned rats as compared to normal spleen cells. These results show for the first time that NO is implicated, at least in part, in an immunosuppression state which is not linked to an infectious disease.

Polyamine binding sites in the rat brain hippocampus plasma membranes: MK 801 does not influence the binding process.

The study was undertaken to characterize the polyamine binding sites in rat brain hippocampus plasma membranes. There were two types of binding sites for putrescine, Bmax 650 and 100 pmol/mg protein, with Kd1 = 39.2 and Kd2 = 6.7 microM, respectively, while those for spermidine (Spd) and spermine (Spm) represented only one type of population with Bmax 2.55 and 15 nmol/mg protein, respectively. The Kd values for Spd and Spm were 34 and 30.3 microM, respectively. The maximum binding of polyamines was found at pH 8.0. The binding capacity of these molecules was curtailed at 4 degrees C, indicating that the binding is an energy-dependent phenomenon. The specific binding was not appreciably influenced by the addition of MK 801, an antagonist of NMDA receptor, indicating that there are polyamine-specific binding sites that are different from those for MK 801. Glycine also did not significantly influence the binding of these biogenic amines. Interestingly, the addition of polyamino acids (polylysine, polyornithine, and polyglutamic acid) inhibited the polyamine binding to their receptor sites, supporting the notion that positive charge of polyamines could be important factor in the binding process.

Coupling of Na+ with the spermidine transporter protein in NIH BALB/c 3T3 cells.

This study demonstrates that polyamine spermidine (Spd) transporter protein is directly coupled with the Na+ in a ternary complex form, Na(+)-Spd-carrier. The Spd is transported with Na+ in a 1:1 stoichiometry relationship. Interestingly, addition of 2-deoxyglucose in the assay medium did not influence significantly the Spd uptake demonstrating the ATP independency of Spd transport.

Polyamines and polyamino acids regulation of cytosolic tyrosine protein (Tyr-P) kinase from human erythrocytes.

In vitro regulation of cytosolic tyrosine protein (Tyr-P) kinase from human erythrocytes by polyamines, polyamino acids, negative charged compounds or by insulin using angiotensin II or poly (Glu-Tyr)4:1 as substrates was studied. All the three polyamines, putrescine (Put), spermidine (Spd) and spermine (Spm) stimulated the Tyr-P kinase activity in a dose dependent manner. Spm stimulated Tyr-P kinase activity higher than Put and Spd whether the substrate was angiotension II or poly (Glu-Tyr)4:1. Polyamino acids (polyornithine, polyarginine, polyglutamic acid and polyaspartic acid) did not affect significantly the Tyr-P kinase phosphorylation except polylysine which significantly stimulated the Tyr-P kinase activity. Negative charged compounds (chondroitin sulfate A, B and C) and heparin inhibited the Tyr-P kinase phosphorylation while insulin did not influence the enzyme activity in the presence of either substrates.