Endogenous and exogenously-induced immunomodulation of tumour-host responsiveness

In spite of the availability of multiple effector mechanisms of the immune system to combat tumour growth and metastases, their impairment frequently accompanies the appearance of cancer. Factors contributing to this impairment may be related to properties of the host and/or the tumour itself and may be with respect to their origin -endogenous or exogenour. Based on the unique biological behavior of prostate cancer (PCa), and its apparent escape from immune surveillance in the presence of tumour immuno genicity, continuing investigation of endogenous and exogenous factors thought to be relevant to its pathogenesis have been made. For this purpose further studies of the suggested role of human seminal plasma (SePl) and the synthetic oestrogen, diethylstiboestrol (DES), as representative endogenous and exogenous immunomodulatory factors (IMF) of tumour-host responsiveness, together with evaluation of human prostatic tissue extracts and leuprolide (the luteinizing-hormone-releasing-hormone proposed as an alternate to DES therapy) have been made by evaluating their effect on the lytic activity of natural killer (NK) cells. SePl and prostate extracts significantly suppressed NK cell lysis. Physicochemical studies suggest SePl and prostate IMF to be associated with high and low molecular weight macromolecules; and implicate the participation of transglutaminase and prostaglandins. Comparative study of therapeutic levels of DES vs. leuprolide on NK cell lysis demonstrated significant suppression by DES vs. a negligible effect of leuprolide. Metastases are highly prevalent in PCa, and contribute significantly to its morbidity and mortality. Further knowledge of the range of effects of endogenous and exogenous IMF on effector mechanisms of tumour-host responsiveness, to include suppression of NK cells, and elucidation of their nature, may contribute toward our understanding of the unique biological behavior of tumours of the prostate, in addition to improvement in their clinical management.

Low-Dose Vascular Photodynamic Therapy Decreases Tumor Interstitial Fluid Pressure, which Promotes Liposomal Doxorubicin Distribution in a Murine Sarcoma Metastasis Model.

INTRODUCTION: Solid tumors are known to have an abnormal vasculature that limits the distribution of chemotherapy. We have recently shown that tumor vessel modulation by low-dose photodynamic therapy (L-PDT) could improve the uptake of macromolecular chemotherapeutic agents such as liposomal doxorubicin (Liporubicin) administered subsequently. However, how this occurs is unknown. Convection, the main mechanism for drug transport between the intravascular and extravascular spaces, is mostly related to interstitial fluid pressure (IFP) and tumor blood flow (TBF). Here, we determined the changes of tumor and surrounding lung IFP and TBF before, during, and after vascular L-PDT. We also evaluated the effect of these changes on the distribution of Liporubicin administered intravenously (IV) in a lung sarcoma metastasis model. MATERIALS AND METHODS: A syngeneic methylcholanthrene-induced sarcoma cell line was implanted subpleurally in the lung of Fischer rats. Tumor/surrounding lung IFP and TBF changes induced by L-PDT were determined using the wick-in-needle technique and laser Doppler flowmetry, respectively. The spatial distribution of Liporubicin in tumor and lung tissues following IV drug administration was then assessed in L-PDT-pretreated animals and controls (no L-PDT) by epifluorescence microscopy. RESULTS: L-PDT significantly decreased tumor but not lung IFP compared to controls (no L-PDT) without affecting TBF. These conditions were associated with a significant improvement in Liporubicin distribution in tumor tissues compared to controls (P < .05). DISCUSSION: L-PDT specifically enhanced convection in blood vessels of tumor but not of normal lung tissue, which was associated with a significant improvement of Liporubicin distribution in tumors compared to controls.

Photodynamic therapy : a pathway for enhanced delivery of liposomal doxorubicin to tumors

Abstract Part I : Background : Isolated lung perfusion (ILP) was designed for the treatment of loco-regional malignancies of the lung. In contrast to intravenous (IV) drug application, ILP allows for a selective administration of cytostatic agents such as doxorubicin to the lung while sparing non-affected tissues. However, the clinical results with ILP were disappointing. Doxorubicinbased ILP on sarcoma rodent lungs suggested high overall doxorubicin concentrations within the perfused lung but a poor penetration of the cytostatic agent into tumors. The same holds true for liposomal-encapsulated macromolecular doxorubicin (LiporubicinTM) In specific conditions, low-dose photodynamic therapy (PDT) can enhance the distribution of macromolecules across the endothelial bamer in solid tumors. It was recently postulated that tumor neovessels were more responsive to PDT than the normal vasculature. We therefore hypothesized that Visudyne®-mediated PDT could selectively increase liposomal doxorubicin (LiporubicinTM) uptake in sarcoma tumors to rodent lungs during intravenous (IV) drug administration and isolated lung perfusion (ILP). Material and Methods : A sarcoma tumor was generated in the left lung of Fisher rats by subpleural injection of a sarcoma cell ,suspension via thoracotomy. Ten days later, LiporubicinTM is administered IV or by single pass antegrade ILP, with or without Visudyne® -mediated low-dose PDT pre-treatment of the sarcoma bearing lung. The drug concentration and distribution were assessed separately in tumors and lung tissues by high pressure liquid chromatography (HPLC) and fluorescence microscopy (FNI~, respectively. Results : PDT pretreatment before IV LiporubicinTM administration resulted in a significantly higher tumor drug uptake and tumor to lung drug ratio compared to IV drug injection alone without affecting the blood flow and drug distribution in the lung. PDT pre-treatment before LiporubicinTM-based ILP also resulted in a higher tumor drug uptake and a higher tumor to lung drug ratio compared to ILP alone, however, these differences were not significant due to a heterogeneous blood flow drug distribution during ILP which was further accentuated by PDT. Conclusions : Low-dose Visudyne®-mediated PDT pre-treatment has the potential to selectively enhance liposomal encapsulated doxorubicin uptake in tumors but not in normal lung tissue after IV drug application in a rat model of sarcoma tumors to the lung which opens new perspectives for the treatment of superficially spreading chemoresistant tumors of the chest cavity such as mesothelioma or malignant effusion. However, the impact of PDT on macromolecular drug uptake during ILP is limited since its therapeutic advantage is circumvented by ILP-induced heterogeneicity of blood flow and drug distribution Abstract Part II Background : Photodynamic therapy (PDT) with Visudyne® acts by direct cellular phototoxicity and/or by an indirect vascular-mediated effect. Here, we demonstrate that the vessel integrity interruption by PDT can promote the extravasation of a macromolecular agent in normal tissue. To obtain extravasation in normal tissue PDT conditions were one order of magnitude more intensive than the ones in tissue containing neovessels reported in the literature. Material and Methods : Fluorescein isothiocyanate dextran (FITC-D, 2000kDa), a macromolecular agent, was intravenously injected 10 minutes before (LKO group, n=14) or 2 hours (LK2 group, n=16) after Visudyne® mediated PDT in nude mice bearing a dorsal skin fold chamber. Control animals had no PDT (CTRL group, n=8). The extravasation of FITC-D from blood vessels in striated muscle tissue was observed in both groups in real-time for up to 2500 seconds after injection. We also monitored PDT-induced leukocyte rolling in-vivo and assessed, by histology, the corresponding inflammatory reaction score in the dorsal skin fold chambers. Results : In all animals, at the applied PDT conditions, FITC-D extravasation was significantly enhanced in the PDT treated areas as compared to the surrounding non-treated areas (p<0.0001). There was no FITC-D leakage in the control animals. Animals from the LKO group had significantly less FITC-D extravasation than those from the LK2 group (p = 0.0002). In the LKO group FITC-D leakage correlated significantly with the inflammation (p < 0.001). Conclusions: At the selected conditions, Visudyne-mediated PDT promotes vascular leakage and FITC-D extravasation into the interstitial space of normal tissue. The intensity of vascular leakage depends on the time interval between PDT and FITC-D injection. This concept could be used to locally modulate the delivery of macromolecules in vivo. Résumé : La perfusion cytostatique isolée du poumon permet une administration sélective des agents cytostatiques sans implication de la circulation systémique avec une forte accumulation au niveau du poumon mais une faible pénétration dans les tumeurs. La thérapie photodynamique (PDT) qui consiste en l'application d'un sensibilisateur activé par lumière laser non- thermique d'une longueur d'onde définie permet dans certaines conditions, une augmentation de la pénétration des agents cytostatiques macromoléculaires à travers la barrière endothéliale tumorale. Nous avons exploré cet avantage thérapeutique de la PDT dans un modèle expérimental afin d'augmenter d'une manière sélective la pénétration tumorale de la doxorubicin pegylée, liposomal- encapsulée macromoléculaire (Liporubicin). Une tumeur sarcomateuse a été générée au niveau du poumon de rongeur suivie d'administration de Liporubicin, soit par voie intraveineuse soit par perfusion isolée du poumon (ILP). Une partie des animaux ont reçus un prétraitement de la tumeur et du poumon sous jacent par PDT avec Visudyne comme photosensibilisateur. Les résultats ont démontrés que la PDT permet, sous certaines conditions, une augmentation sélective de Liporubicin dans les tumeurs mais pas dans le parenchyme pulmonaire sous jacent. Après administration intraveineuse de Liporubicin et prétraitement par PDT, l'accumulation dans les tumeurs était significative par rapport au poumon, et aux tumeurs sans PDT. Le même phénomène est observé après ILP du poumon. Cependant, les différences avec ou sans PDT n'étaient pas significatives lié à und distribution hétérogène de Liporubicin dans le poumon perfusé après ILP. Dans une deuxième partie de l'expérimentation, nous avons exploré la microscopie intra-vitale pour déterminer l'extravasion des substances macromoléculaires (FITS) à travers la barrière endothéliale avec ou sans Visudyne-PDT au niveau des chambres dorsales des souris nues. Les résultats montrent qu'après PDT, l'extravasion de FITS a été augmentée de manière significative par rapport au tissu non traité. L'intensité de l'extravasion de FITS dépendait également de l'intervalle entre PDT et injection de FITS. En conclusion, les expérimentations montrent que la PDT est capable, sous certaines conditions, d'augmenter de manière significative l'extravasion des macromolécules à travers la barrière endothéliale et leur accumulation dans des tumeurs mais pas dans le parenchyme pulmonaire. Ces résultats permettent une nouvelle perspective de traitement pour des tumeurs superficielles intrathoraciques chimio-résistent comme l'épanchement pleural malin ou le mésothéliome pleural.

Efficacy and safety of certolizumab pegol induction therapy in an unselected Crohn's disease population: results of the FACTS survey.

Background: Switzerland was the first country to approve certolizumab pegol (Cimzia, CZP) for the treatment of patients with moderate to severe Crohn's disease (CD) in September 2007. This phase IV study aimed to evaluate the efficacy and safety of CZP in a Swiss multicenter cohort of practice-based patients. Methods: Baseline and Week 6 evaluation questionnaires were sent to all Swiss gastroenterologists in hospitals and private practices. Disease activity was assessed with the Harvey-Bradshaw Index (HBI) and adverse events were evaluated according to WHO guidelines. Results: Fifty patients (31 women, 19 men) were included; 56% had complicated disease (stricture or fistula) and 52% had undergone prior CD-related surgery. All patients. had prior exposure to systemic steroids, 96% to immunomodulators, 78% to infliximab, and 50% to adalimumab. A significant decrease in HBI was observed at Week 6 (versus Week 0) following induction therapy with CZP 400 mg subcutaneously at Weeks 0, 2, and 4 (12.6 +/- 4.7 Week 0 versus 6.2 +/- 4.4 Week 6, P < 0.001). Response and remission rates at Week 6 were 54% and 40%, respectively. We identified 8/11 CD patients undergoing a 50% fistula response (P = 0.021). The frequency of adverse drug reactions attributed to CZP was 6%. CZP was continued in 80% of patients beyond Week 6. Conclusions: In a population of CD patients with complicated disease behavior, CZP induced a response and remission in 54% and 40% of patients, respectively. This series provides the first evidence of the effectiveness of CZP in perianal fistulizing CD.

Tumor necrosis factor (TNF) signaling, but not TWEAK (TNF-like weak inducer of apoptosis)-triggered cIAP1 (cellular inhibitor of apoptosis protein 1) degradation, requires cIAP1 RING dimerization and E2 binding.

Cellular inhibitor of apoptosis (cIAP) proteins, cIAP1 and cIAP2, are important regulators of tumor necrosis factor (TNF) superfamily (SF) signaling and are amplified in a number of tumor types. They are targeted by IAP antagonist compounds that are undergoing clinical trials. IAP antagonist compounds trigger cIAP autoubiquitylation and degradation. The TNFSF member TWEAK induces lysosomal degradation of TRAF2 and cIAPs, leading to elevated NIK levels and activation of non-canonical NF-kappaB. To investigate the role of the ubiquitin ligase RING domain of cIAP1 in these pathways, we used cIAP-deleted cells reconstituted with cIAP1 point mutants designed to interfere with the ability of the RING to dimerize or to interact with E2 enzymes. We show that RING dimerization and E2 binding are required for IAP antagonists to induce cIAP1 degradation and protect cells from TNF-induced cell death. The RING functions of cIAP1 are required for full TNF-induced activation of NF-kappaB, however, delayed activation of NF-kappaB still occurs in cIAP1 and -2 double knock-out cells. The RING functions of cIAP1 are also required to prevent constitutive activation of non-canonical NF-kappaB by targeting NIK for proteasomal degradation. However, in cIAP double knock-out cells TWEAK was still able to increase NIK levels demonstrating that NIK can be regulated by cIAP-independent pathways. Finally we show that, unlike IAP antagonists, TWEAK was able to induce degradation of cIAP1 RING mutants. These results emphasize the critical importance of the RING of cIAP1 in many signaling scenarios, but also demonstrate that in some pathways RING functions are not required.

Photodynamic therapy enhances liposomal doxorubicin distribution in tumors during isolated perfusion of rodent lungs.

BACKGROUND: Photodynamic therapy (PDT) at low drug-light conditions can enhance the transport of intravenously injected macromolecular therapeutics through the tumor vasculature. Here we determined the impact of PDT on the distribution of liposomal doxorubicin (Liporubicin™) administered by isolated lung perfusion (ILP) in sarcomas grown on rodent lungs. METHODS: A syngeneic methylcholanthrene-induced sarcoma cell line was implanted subpleurally in the left lung of Fischer rats. Treatment schemes consisted in ILP alone (400 μg of Liporubicin), low-dose (0.0625 mg/kg Visudyne®, 10 J/cm(2) and 35 mW/cm(2)) and high-dose left lung PDT (0.125 mg/kg Visudyne, 10 J/cm(2) and 35 mW/cm(2)) followed by ILP (400 μg of Liporubicin). The uptake and distribution of Liporubicin in tumor and lung tissues were determined by high-performance liquid chromatography and fluorescence microscopy in each group. RESULTS: Low-dose PDT significantly improved the distribution of Liporubicin in tumors compared to high-dose PDT (p < 0.05) and ILP alone (p < 0.05). However, both PDT pretreatments did not result in a higher overall drug uptake in tumors or a higher tumor-to-lung drug ratio compared to ILP alone. CONCLUSIONS: Intraoperative low-dose Visudyne-mediated PDT enhances liposomal doxorubicin distribution administered by ILP in sarcomas grown on rodent lungs which is predicted to improve tumor control by ILP.

Kaposi sarcoma herpes virus antibody response and viremia following highly active antiretroviral therapy in the Swiss HIV Cohort study.

OBJECTIVE: To describe the effect of HAART on Kaposi sarcoma herpes virus (KSHV) antibody response and viremia among HIV-positive MSM. DESIGN: A follow-up study of 272 HIV-positive MSM (including 22 with Kaposi sarcoma) who first initiated HAART between January 1996 and July 2004 in the Swiss HIV Cohort Study. METHODS: For each individual, two serum samples, one at HAART initiation and another 24 months later, were tested for latent and lytic KSHV antibodies using immunofluorescence assays, and for KSHV viremia using PCR. Factors associated with changes in KSHV antibody titers and viremia were evaluated. RESULTS: At HAART initiation, 69.1 and 75.0% of patients were seropositive to latent and lytic KSHV antibodies, respectively. Seropositivity was associated with the presence of Kaposi sarcoma, older age, lower CD8 cell count and higher CD4/CD8 ratio. Prevalence of KSHV viremia at HAART initiation was 6.4%, being significantly higher among patients with Kaposi sarcoma (35.0%), and those with HIV viral loads 100 000 copies/ml (11.7%) or higher. At 24-month follow-up, geometric mean titers (GMTs) among KSHV seropositive patients increased and antibody seroprevalence was higher. Having Kaposi sarcoma and/or CD4 cell counts less than 50 cells/microl at HAART initiation was associated both with higher probability for antibody titers to increase (including seroconversion) and larger increases in GMTs. Only one of 17 viremic patients at HAART initiation had viremia at 24-month follow-up. CONCLUSION: HAART increases KSHV-specific humoral immune response and clearance of viremia among HIV-infected MSM, consistent with the dramatic protection offered by HAART against Kaposi sarcoma.

Valproic acid related idiosyncratic drug induced hepatotoxicity in a glioblastoma patient treated with temozolomide.

Glioblastoma patients undergoing treatment with surgery followed by radiation and temozolomide chemotherapy often develop a state of immunosuppression and are at risk for opportunistic infections and reactivation of hepatitis and herpes viruses. We report the case of a 48-year-old glioblastoma patient who developed acute cholestatic hepatitis with hepatic failure during adjuvant treatment with temozolomide and the integrin inhibitor cilengitide. A viral hepatitis was excluded and valproic acid treatment was stopped. Upon normalisation of the liver tests, temozolomide treatment was resumed without perturbation of the liver tests. Valproic acid related idiosyncratic drug induced hepatotoxicity should be considered as a differential diagnosis in glioblastoma patients undergoing adjuvant therapy.

Angiotensin II receptor blockade prevents acute renal sodium retention induced by low levels of orthostatic stress.

BACKGROUND: Depending on its magnitude, lower body negative pressure (LBNP) has been shown to induce a progressive activation of neurohormonal, renal tubular, and renal hemodynamic responses, thereby mimicking the renal responses observed in clinical conditions characterized by a low effective arterial volume such as congestive heart failure. Our objective was to evaluate the impact of angiotensin II receptor blockade with candesartan on the renal hemodynamic and urinary excretory responses to a progressive orthostatic stress in normal subjects. METHODS: Twenty healthy men were submitted to three levels of LBNP (0, -10, and -20 mbar or 0, -7.5, and -15 mm Hg) for 1 hour according to a crossover design with a minimum of 2 days between each level of LBNP. Ten subjects were randomly allocated to receive a placebo and ten others were treated with candesartan 16 mg orally for 10 days before and during the three levels of LBNP. Systemic and renal hemodynamics, renal sodium excretions, and the hormonal response were measured hourly before, during, and for 2 hours after LBNP. RESULTS: During placebo, LBNP induced no change in systemic and renal hemodynamics, but sodium excretion decreased dose dependently with higher levels of LBNP. At -20 mbar, cumulative 3-hour sodium balance was negative at -2.3 +/- 2.3 mmol (mean +/- SEM). With candesartan, mean blood pressure decreased (76 +/- 1 mm Hg vs. 83 +/- 3 mm Hg, candesartan vs. placebo, P < 0.05) and renal plasma flow increased (858 +/- 52 mL/min vs. 639 +/- 36 mL/min, candesartan vs. placebo, P < 0.05). Glomerular filtration rate (GFR) was not significantly higher with candesartan (127 +/- 7 mL/min in placebo vs. 144 +/- 12 mL/min in candesartan). No significant decrease in sodium and water excretion was found during LBNP in candesartan-treated subjects. At -20 mbar, the 3-hour cumulative sodium excretion was + 4.6 +/- 1.4 mmol in the candesartan group (P= 0.02 vs. placebo). CONCLUSION: Selective blockade of angiotensin II type 1 (AT1) receptors with candesartan increases renal blood flow and prevents the antinatriuresis during sustained lower body negative pressure despite a modest decrease in blood pressure. These results thus provide interesting insights into potential benefits of AT1 receptor blockade in sodium-retaining states such as congestive heart failure.

Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells.

Cyclooxyganase-2 (COX-2), a rate-limiting enzyme in the prostaglandin synthesis pathway, is overexpressed in many cancers and contributes to cancer progression through tumor cell-autonomous and paracrine effects. Regular use of non-steroidal anti-inflammatory drugs or selective COX-2 inhibitors (COXIBs) reduces the risk of cancer development and progression, in particular of the colon. The COXIB celecoxib is approved for adjunct therapy in patients with Familial adenomatous polyposis at high risk for colorectal cancer (CRC) formation. Long-term use of COXIBs, however, is associated with potentially severe cardiovascular complications, which hampers their broader use as preventive anticancer agents. In an effort to better understand the tumor-suppressive mechanisms of COXIBs, we identified MAGUK with Inverted domain structure-1 (MAGI1), a scaffolding protein implicated in the stabilization of adherens junctions, as a gene upregulated by COXIB in CRC cells and acting as tumor suppressor. Overexpression of MAGI1 in CRC cell lines SW480 and HCT116 induced an epithelial-like morphology; stabilized E-cadherin and β-catenin localization at cell-cell junctions; enhanced actin stress fiber and focal adhesion formation; increased cell adhesion to matrix proteins and suppressed Wnt signaling, anchorage-independent growth, migration and invasion in vitro. Conversely, MAGI1 silencing decreased E-cadherin and β-catenin localization at cell-cell junctions; disrupted actin stress fiber and focal adhesion formation; and enhanced Wnt signaling, anchorage-independent growth, migration and invasion in vitro. MAGI1 overexpression suppressed SW480 and HCT116 subcutaneous primary tumor growth, attenuated primary tumor growth and spontaneous lung metastasis in an orthotopic model of CRC, and decreased the number and size of metastatic nodules in an experimental model of lung metastasis. Collectively, these results identify MAG1 as a COXIB-induced inhibitor of the Wnt/β-catenin signaling pathway, with tumor-suppressive and anti-metastatic activity in experimental colon cancer.

Prophytaxie de l'ostéoporose cortisonique: qui, quand et quoi [Prevention of cortisone-induced osteoporosis: who, when and what?]

Glucocorticoid-induced osteoporosis is a known phenomenon with already an increased fracture risk at 2.5 mg of prednisone daily over 3 months. This risk appears to be independent of bone densitometry results, in contradiction with published guidelines. With the creation of our Department of Musculoskeletal Medicine, we wanted to edict clear recommendations for the prevention of steroid-induced osteoporosis. In addition to the standard general measures to prevent osteoporosis and calcium and vitamin D supplementation, we advocate the use of a specific treatment for osteoporosis in all cases when the duration of corticosteroid therapy is not strictly limited and shorter than 3 months. Bisphosphonates are the treatment of choice, while the analogue of parathyroid hormone remains an alternative in cases with a very high fracture risk.

Feasibility and efficacy of subcutaneous amifostine therapy in patients with head and neck cancer treated with curative accelerated concomitant-boost radiation therapy.

OBJECTIVE: To assess the feasibility and efficacy of subcutaneous amifostine therapy in patients with head and neck cancer treated with curative accelerated radiotherapy (RT). DESIGN: Retrospective study. SETTING: University of Lausanne, Lausanne, Switzerland. PATIENTS: Thirty-three consecutive patients (male-female ratio, 4.5; median age, 54 years [age range, 39-76 years]). INTERVENTIONS: Between November 2000 and January 2003, the 33 patients were treated with curative definitive (n = 19) or postoperative (n = 14) RT with (n = 26) or without (n = 7) chemotherapy. All patients received conformal RT. Fractionation schedule consisted of concomitant-boost (Friday afternoon session) accelerated RT using 70 Gy (2 Gy per fraction) in 6 weeks in patients treated with definitive RT and 66 Gy (2 Gy per fraction) in 5 weeks and 3 days in the postoperative setting. Parotid glands received at least 50 Gy in all patients. Amifostine was administered to a total dose of 500 mg subcutaneously, 15 to 30 minutes before morning RT sessions. RESULTS: All patients received their planned treatment (including chemotherapy). Ten patients received the full schedule of amifostine (at least 25 injections), 9 received 20 to 24 doses, 4 received 10 to 19 doses, 5 received 5 to 9 doses, and 5 received fewer than 5 doses. Fifteen patients (45%) did not show any intolerance related to amifostine use. Amifostine therapy was discontinued because of nausea in 11 patients (33%) and hypotension in 6 patients (18%), and 1 patient refused treatment. No grade 3, amifostine-related, cutaneous toxic effects were observed. Radiotherapy-induced grade 3 acute toxic effects included mucositis in 14 patients (42%), erythema in 14 patients (42%), and dysphagia in 13 patients (39%). Late toxic effects included grade 2 or more xerostomia in 17 patients (51%) and fibrosis in 3 patients (9%). Grade 2 or more xerostomia was observed in 8 (42%) of 19 patients receiving 20 injections or more vs 9 (64%) of 14 patients receiving fewer than 20 injections (P = .15). CONCLUSIONS: Subcutaneous amifostine administration in combination with accelerated concomitant-boost RT with or without chemotherapy is feasible. The major adverse effect of subcutaneous administration was nausea despite prophylactic antiemetic medication, and hypotension was observed in only 6 patients (18%).

Effects of flecainide on exercise-induced ventricular arrhythmias and recurrences in genotype-negative patients with catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Conventional therapy with beta-blockers is incompletely effective in preventing arrhythmic events in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). We have previously discovered that flecainide in addition to conventional drug therapy prevents ventricular arrhythmias in patients with genotype-positive CPVT. OBJECTIVE: To study the efficacy of flecainide in patients with genotype-negative CPVT. METHODS: We studied the efficacy of flecainide for reducing ventricular arrhythmias during exercise testing and preventing arrhythmia events during long-term follow-up. RESULTS: Twelve patients with genotype-negative CPVT were treated with flecainide. Conventional therapy failed to control ventricular arrhythmias in all patients. Flecainide was initiated because of significant ventricular arrhythmias (n = 8), syncope (n = 3), or cardiac arrest (n = 1). At the baseline exercise test before flecainide, 6 patients had ventricular tachycardia and 5 patients had bigeminal or frequent ventricular premature beats. Flecainide reduced ventricular arrhythmias at the exercise test in 8 patients compared to conventional therapy, similar to that in patients with genotype-positive CPVT in our previous report. Notably, flecainide completely prevented ventricular arrhythmias in 7 patients. Flecainide was continued in all patients except for one who had ventricular tachycardia at the exercise test on flecainide. During a follow-up of 48±94 months, arrhythmia events (sudden cardiac death and aborted cardiac arrest) associated with noncompliance occurred in 2 patients. Flecainide was not discontinued owing to side effects in any of the patients. CONCLUSIONS: Flecainide was effective in patients with genotype-negative CPVT, suggesting that spontaneous Ca(2+) release from ryanodine channels plays a role in arrhythmia susceptibility, similar to that in patients with genotype-positive CPVT.

Recombinant erythropoietin in acute chemotherapy-induced anemia of children with cancer.

Chemotherapy-induced anemia in children with cancer is usually of acute onset. To investigate an alternate treatment to transfusion (Tx), we undertook a phase I-II clinical trial of daily administrations of recombinant erythropoietin (rHuEPO). Patients with a hemoglobin (Hgb) value < 75 g/l were treated for 14 days in cohorts of 3 at escalating daily doses of 25, 50, 70, 80, 90, and 100 U/kg respectively. The maximum-tolerated dose was not encountered. Of 18 courses given to 15 children aged 0.5-18 years, 7 (39%) were associated with increased or stable Hgb levels (courses without Tx), while 11 (61%) were terminated by a Tx, without evidence of a dose-response relationship. Changes in mean Hgb levels and absolute reticulocyte counts were paralleled by those of mean white blood cell, platelet, and absolute neutrophil counts during the first 7 days and when the end-points of the study were reached. Numbers of circulating burst-forming units-erythroid remained low throughout courses without Tx. No cumulative increase of serially determined serum EPO levels was observed and serum ferritin levels were elevated in both groups of courses. We conclude that daily administration of rHuEPO were safe but ineffective in our trial. Recovery of chemotherapy-induced myelosuppression appeared to be the rate-limiting factor for the outcome, without evidence of an enhanced stimulation of erythropoiesis. The lack of a proliferative response of specific progenitor cells suggested a mechanism of transient primary resistance to rHuEPO.