Dose selection for radioiodine therapy of borderline hyperthyroid patients according to thyroid uptake of 99mTc-pertechnetate: applicability to unifocal thyroid autonomy?

PURPOSE: The aim of this study was to evaluate the feasibility of applying a previously described dose strategy based on (99m)Tc-pertechnetate thyroid uptake under thyrotropin suppression (TcTU(s)) to radioiodine therapy for unifocal thyroid autonomy. METHODS: A total of 425 consecutive patients (302 females, 123 males; age 63.1+/-10.3 years) with unifocal thyroid autonomy were treated at three different centres with (131)I, using Marinelli's formula for calculation of three different absorbed dose schedules: 100-300 Gy to the total thyroid volume according to the pre-treatment TcTU(s) (n=146), 300 Gy to the nodule volume (n=137) and 400 Gy to the nodule volume (n=142). RESULTS: Successful elimination of functional thyroid autonomy with either euthyroidism or hypothyroidism occurred at a mean of 12 months after radioiodine therapy in 94.5% of patients receiving 100-300 Gy to the thyroid volume, in 89.8% of patients receiving 300 Gy to the nodule volume and in 94.4% receiving 400 Gy to the nodule volume. Reduction in thyroid volume was highest for the 100-300 Gy per thyroid and 400 Gy per nodule strategies (36+/-19% and 38+/-20%, respectively) and significantly lower for the 300 Gy per nodule strategy (28+/-16%; p<0.01). CONCLUSION: A dose strategy based on the TcTU(s) can be used independently of the scintigraphic pattern of functional autonomous tissue in the thyroid.

Fixed-dose combination therapy for type 2 diabetes: sitagliptin plus pioglitazone

Importance of the field: Type 2 diabetes is typically associated with insulin resistance and dysfunction of insulin-secreting pancreatic beta-cells. Addressing these defects often requires therapy with a combination of differently acting antidiabetic agents. A potential novel combination in development brings together the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin with the thiazolidinedione pioglitazone into a fixed-dose single-tablet combination. The former component acts mainly to increase prandial insulin secretion; the latter improves insulin sensitivity.

Does radioiodine therapy in patients with differentiated thyroid cancer increase the frequency of another malignant neoplasm?

Objectives. To compare the frequency of another primary malignancy in patients with differentiated thyroid carcinoma (DTC) who received radioiodine therapy or not ((131)I). Material and Methods. 168 cases of DTC patients were retrospectively evaluated as to the frequency of another neoplasia by comparing patients with and without it, taking into account clinical, laboratory, and therapeutic parameters. Results. Another primary malignancy occurred in 8.9% of patients. Of these, 53.3% showed the malignancy before (131)I and 46.7% after it. By comparing both groups, the age at the moment of diagnosis of another neoplasia was 46.1 ± 20.2 years for the group before (131)I therapy and of 69.4 ± 11.4 years for the group after it (P = 0.02). Of the 148 patients treated with (131)I, 4.7% developed another malignancy. The latter were older (61 ± 17 years) than those who did not show another cancer type (44.1 ± 14.2 years) (P < 0.05). Conclusion. The frequency of another neoplasia found after (131)I was similar to that found before (131)I.

Low-dose cyclosporine therapy in triple-drug immunosuppression for heart transplant recipients

The toxicity of long-term immunosuppressive therapy has become a major concern in long-term follow-up of heart transplant recipients. In this respect the quality of renal function is undoubtedly linked to cyclosporin A (CsA) drug levels. In cardiac transplantation, specific CsA trough levels have historically been maintained between 250 and 350 micrograms/L in many centers without direct evidence for the necessity of such high levels while using triple-drug immunosuppression. This retrospective analysis compares the incidence of acute and chronic graft rejection as well as overall mortality between groups of patients with high (250 to 350 micrograms/L) and low (150 to 250 micrograms/L) specific CsA trough levels. A total of 332 patients who underwent heart transplantation between October 1985 and October 1992 with a minimum follow-up of 30 days were included in this study (46 women and 276 men; aged, 44 +/- 12 years; mean follow-up, 1,122 +/- 777 days). Standard triple-drug immunosuppression included first-year specific CsA target trough levels of 250 to 300 micrograms/L. Patients were grouped according to their average creatinine level in the first postoperative year (group I, < 130 mumol/L, n = 234; group II, > or = 130 mumol/L, n = 98). The overall 5-year survival excluding the early 30-day mortality was 92% (group I, 216/232) and 91% (group II, 89/98) with 75% of the mortality due to chronic rejection. The rate of rejection for the entire follow-up period was similar in both groups (first year: group I, 3.2 +/- 2.6 rejection/patient/year; group II, 3.6 +/- 2.7 rejection/patient/year; p = not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Fixed-dose combination therapy for type 2 diabetes:sitagliptin plus pioglitazone

Type 2 diabetes is typically associated with insulin resistance and dysfunction of insulin-secreting pancreatic beta-cells. Addressing these defects often requires therapy with a combination of differently acting antidiabetic agents. A potential novel combination in development brings together the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin with the thiazolidinedione pioglitazone into a fixed-dose single-tablet combination. The former component acts mainly to increase prandial insulin secretion; the latter improves insulin sensitivity.

Obstrução de vias lacrimais associada ao tratamento radioiodoterápico de carcinoma de tireoide

OBJETIVO: Descrever uma série de pacientes portadores de obstrução do sistema lacrimal associado à radioiodoterapia para tratamento de carcinoma de tireoide, revisar os dados clínicos e a resposta ao tratamento cirúrgico desta rara complicação. MÉTODOS: Foi realizada uma análise retrospectiva dos achados oftalmológicos de pacientes com histórico de carcinoma de tireoide previamente submetidos à tireoidectomia e à RIT que foram encaminhados para cirurgia de vias lacrimais. RESULTADOS: Dezessete pacientes com carcinoma de tireoide tratados com tireoidectomia e RIT apresentaram obstrução do ducto nasolacrimal sintomática após período médio de 13,2 meses do tratamento do câncer. Onze pacientes tiveram epífora bilateral, 8 com mucocele de saco lacrimal. A idade dos pacientes variou entre 30 e 80 anos, sendo 10 com idade menor ou igual a 49 anos. A dose cumulativa média de radioiodo administrada foi de 571 mCi (variação entre 200-1200 mCi). Sintomas de obstrução nasal e aumento de glândulas salivares ocorreram em 53% dos pacientes. Todos os pacientes foram submetidos à dacriocistorrinostomia. Observou-se ainda que nos 3 pacientes mais jovens houve maior sangramento intraoperatótio e dilatação de saco lacrimal. A resolução completa da epífora e da dacriocistite ocorreu em 82,4%, e foi parcial em 17,6% (3 pacientes mantiveram queixa unilateral após a correção da obstrução bilateralmente). O seguimento médio foi de 6 meses (intervalo: 2-24 meses). CONCLUSÕES: Alta dose cumulativa de radioiodo, disfunção nasal e de glândulas salivares estão associadas à obstrução das vias lacrimais. Observa-se uma maior porcentagem de pacientes mais jovens apresentando quadro de dacriocistite quando comparado à dacrioestenose idiopática. A absorção de iodo radioativo pela mucosa do ducto nasolacrimal com subsequente inflamação, edema e fibrose parece ter relação direta com a obstrução do ducto nasolacrimal. O conhecimento desta complicação é importante para o estudo e abordagem correta desses pacientes.

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.

Proposta de metodologia para o gerenciamento de fonte radioativa e estimativa de dose efeiva em pacientes submetidos à terapia com iodeto de sódio I-131

Pós-graduação em Pesquisa e Desenvolvimento (Biotecnologia Médica) - FMB

The difficult-to-treat, therapy-resistant cough: Why are current cough treatments not working and what can we do?

Cough can persist despite exhaustive diagnostic and therapeutic effort and has been termed 'idiopathic' or 'unexplained' but perhaps 'difficult to treat' cough is a more appropriate description. In this article the reasons for poor treatment response are discussed. These include a lack of physician fidelity to management guidelines, patient non-adherence and the lack of effective medicines. A number of randomized controlled trials have been undertaken including low dose opiate therapy, the use of a speech pathology intervention, oral antibiotics and antidepressants. The success or otherwise of such interventions will be discussed. A number of approaches to deal with the problem of 'difficult to treat cough' will be considered.

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.

Relationship of glutathione S-transferase genotypes with side-effects of pulsed cyclophsphamide therapy in patients with systemic lupus erythematosus

Aims
Cyclophosphamide (CTX) is an established treatment of severe systemic lupus erythematosus (SLE). Cytotoxic CTX metabolites are mainly detoxified by multiple glutathione S-transferases (GSTs). However, data are lacking on the relationship between the short-term side-effects of CTX therapy and GST genotypes. In the present study, the effects of common GSTM1, GSTT1, and GSTP1 genetic mutations on the severity of myelosuppression, gastrointestinal (GI) toxicity, and infection incidences induced by pulsed CTX therapy were evaluated in patients SLE.
Methods
DNA was extracted from peripheral leucocytes in patients with confirmed SLE diagnosis (n = 102). GSTM1 and GSTT1 null mutations were analyzed by a polymerase chain reaction (PCR)-multiplex procedure, whereas the GSTP1 codon 105 polymorphism (Ile→Val) was analyzed by a PCR-restriction fragment length polymorphism (RFLP) assay.
Results
Our study demonstrated that SLE patients carrying the genotypes with GSTP1 codon 105 mutation [GSTP1*-105I/V (heterozygote) and GSTP1*-105 V/V (homozygote)] had an increased risk of myelotoxicity when treated with pulsed high-dose CTX therapy (Odds ratio (OR) 5.00, 95% confidence interval (CI) 1.96, 12.76); especially in patients younger than 30 years (OR 7.50, 95% CI 2.14, 26.24), or in patients treated with a total CTX dose greater than 1.0 g (OR 12.88, 95% CI 3.16, 52.57). Similarly, patients with these genotypes (GSTP1*I/V and GSTP1*V/V) also had an increased risk of GI toxicity when treated with an initial pulsed high-dose CTX regimen (OR 3.33, 95% CI 1.03, 10.79). However, GSTM1 and GSTT1 null mutations did not significantly alter the risks of these short-term side-effects of pulsed high-dose CTX therapy in SLE patients.
Conclusions
The GSTP1 codon 105 polymorphism, but not GSTM1 or GSTT1 null mutations, significantly increased the risks of short-term side-effects of pulsed high-dose CTX therapy in SLE patients. Because of the lack of selective substrates for a GST enzyme phenotyping study, timely detection of this mutation on codon 105 may assist in optimizing pulsed high-dose CTX therapy in SLE patients.