Acute toxicity of curative radiotherapy for intermediate- and high-risk localised prostate cancer in the EORTC trial 22991.

INTRODUCTION: This trial randomly assessed short-term adjuvant hormonal therapy added to radiotherapy (RT) for intermediate- and high-risk (UICC 1997 cT2a or cT1b-c with high PSA or Gleason score) localised prostate cancer. We report acute toxicity (CTCAE v2) assessed weekly during RT in relation to radiation parameters. PATIENTS AND METHODS: Centres selected the RT dose (70, 74 or 78Gy) and RT technique. Statistical significance is at 0.05. RESULTS: Of 791 patients, 652 received 3D-CRT (70Gy: 195, 74Gy: 376, 78Gy: 81) and 139 received IMRT (74Gy: 28, 78Gy: 111). During RT, grade 3 gastrointestinal (GI) and genitourinary (GU) toxicities were reported by 7 (0.8%) and 50 (6.3%) patients, respectively. No grade 4 was reported. The risk of grade 2 GI toxicity increased significantly with increasing D50%-rectum (p=0.004) and that of grade 2 GU toxicity correlated only to Dmax-bladder (p=0.051). 3D-RT technique, increasing total dose and V95% >400 cc increased D50% and Dmax. One month after RT, only 14 patients (1.8%) reported grade 3 toxicity. AST did not seem to influence the risk of GU or GI acute toxicity. CONCLUSION: RT up to 78Gy was well tolerated. Dmax-bladder and D50%-rectum influenced the risk of grade 2 GU toxicity and GI toxicity, respectively. Both were lower with IMRT but remained high for an irradiated RT volume>400 cc for 3D-RT and for a dose of 78Gy. Hormonal treatment did not influence acute toxicity.

Adverse gastrointestinal effects of arginine and related amino acids

Oral supplements of arginine and citrulline increase local nitric oxide (NO production in the small intestine and this may be harmful under certain circumstances. Gastrointestinal toxicity was therefore reviewed with respect to the intestinal physiology of arginine, citrulline, ornithine, and cystine (which shares the same transporter) and the many clinical trials of supplements of the dibasic amino acids or N-acetylcysteine (NAC. The human intestinal dibasic amino acid transport system has high affinity and low capacity. L-Arginine (but not lysine, ornithine, or D-arginine) induces water and electrolyte secretion that is mediated by NO, which acts as an absorbagogue at low levels and as a secretagogue at high levels. The action of many laxatives is NO mediated and there are reports of diarrhea following oral administration of arginine or ornithine ihine. The clinical data cover a wide span of arginine intakes f rom 3 g/d to > 100 g/d, but the standard of reporting adverse effects (e.g. nausea, vomiting, and diarrhea) was variable. Single doses of 3-6 g rarely provoked side effects and healthy athletes appeared to be more susceptible than diabetic patients to gastrointestinal symptoms at individual doses >9 g. This may relate to an effect of disease on gastrointestinal motility and pharmacokinetics. Most side effects of arginine and NAC occurred at single doses of >9 g in adults >140 mg/kg) often when part of a daily regime of similar to>30 g/d (>174 mmol/d). In the case of arginine, this compares with the laxative threshold of the nonabsorbed disaccharide alcohol, lactitol (74 g or 194 mmol). Adverse effects seemed dependent on the dosage regime and disappeared if divided doses were ingested (unlike lactitol). Large single doses of poorly absorbed amino acids seem to provoke diarrhea. More research is needed to refine dosage strategies that reduce this phenomenon. It is suggested that dipeptide forms of arginine may meet this criterion.

Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data

BACKGROUND The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including DPYD*2A and c.2846A>T. Three other variants-DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A-have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity. METHODS We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction). FINDINGS 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08-9·30, p<0·0001), as was c.1236G>A/HapB3 (1·59, 1·29-1·97, p<0·0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86-2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40-23·33, p=0·015; and 2·04, 1·49-2·78, p<0·0001, respectively) and haematological toxicity (adjusted RR 9·76, 95% CI 3·03-31·48, p=0·00014; and 2·07, 1·17-3·68, p=0·013, respectively), but not with hand-foot syndrome. DPYD*2A and c.2846A>T were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75-4·62, p<0·0001; and 3·02, 2·22-4·10, p<0·0001, respectively). INTERPRETATION DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines. FUNDING None.

A clinical audit of the prescribing of celecoxib and rofecoxib in Australian rural general practice

Aims The new cyclooxygenase-2 (COX-2) selective inhibitors, celecoxib (Celebrex®) and rofecoxib (Vioxx®), have been widely prescribed since their launch. No reviews currently appear in the literature of prescribing patterns in Australia. This paper describes a self-audit of the clinical use of selective COX-2 inhibitor therapy undertaken with rural general practitioners (GPs) in Australia. Methods A structured audit form was developed and distributed to interested GPs. The form was self-administered and focused on issues about COX-2 inhibitors and the types of patients who were receiving them, e.g. indications, patient demographics, risk factors and drug interactions. Results A total of 627 patients were recruited (569 celecoxib and 58 rofecoxib). A range of doses was prescribed. Osteoarthritis was the most common indication (68.1%). Risk factors known for the nonselective nonsteroidal anti-inflammatory drugs were identified in 65.1% of patients, with the most common being advanced age, hypertension and previous peptic ulcer disease. Potential drug interactions were common. A variety of reasons for initiation of therapy was identified; these included perceived increased efficacy, safety and failure of other treatment. Conclusions These results show that COX-2 inhibitors are being prescribed for patients with multiple risk factors that may place the patient at increased risk of adverse drug reactions to a COX-2 inhibitor. The perception of improved safety and efficacy was common and is of concern. Limitations of the study include the reliance on self-reporting.

Keratinocyte Growth factor (KGF) in hematology and oncology

Keratinocyte Growth factor (KGF) is an epithelial cell growth factor of the fibroblast growth factor family and is produced by fibroblasts and microvascular endothelium in response to proinflammatory cytokines and steroid hormones. KGF is a heparin binding growth factor that exerts effects on epithelial cells in a paracrine fashion through interaction with KGF receptors. Preclinical data has demonstrated that KGF can prevent lung and gastrointestinal toxicity following chemotherapy and radiation and preliminary clinical data in the later setting supports these findings. In the experimental allogeneic bone marrow transplant scenario KGF has shown significant ability to prevent graft-versus-host disease by maintaining gastrointestinal tract integrity and acting as a cytokine shield to prevent subsequent proinflammatory cytokine generation. Within this setting KGF has also shown an ability to prevent experimental idiopathic pneumonia syndrome by stimulating production of surfactant protein A, promoting alveolar epithelialization and attenuating immune-mediated injury. Perhaps most unexpectantly, KGF appears able to maintain thymic function during allogeneic stern cell transplantation and so promote T cell engraftment and reconstitution. These data suggest that KGF will find a therapeutic role in the prevention of epithelial toxicity following intensive chemotherapy and radiotherapy protocols and in allogeneic stem cell transplantation.

Combinations of vascular endothelial growth factor pathway inhibitors with metronomic chemotherapy: Rational and current status.

Chemotherapy given in a metronomic manner can be administered with less adverse effects which are common with conventional schedules such as myelotoxicity and gastrointestinal toxicity and thus may be appropriate for older patients and patients with decreased performance status. Efficacy has been observed in several settings. An opportunity to improve the efficacy of metronomic schedules without significantly increasing toxicity presents with the addition of anti-angiogenic targeted treatments. These combinations rational stems from the understanding of the importance of angiogenesis in the mechanism of action of metronomic chemotherapy which may be augmented by specific targeting of the vascular endothelial growth factor (VEGF) pathway by antibodies or small tyrosine kinase inhibitors. Combinations of metronomic chemotherapy schedules with VEGF pathway targeting drugs will be discussed in this paper.

Contribuição para o estudo do linfoma no cão em Portugal : análise da casuística em dois centros de referência

O linfoma é um grupo heterogéneo de neoplasias que apresentam morfologia variável e apresentações clínicas diversas, exigindo diferentes abordagens diagnósticas e terapêuticas. O prognóstico difere bastante entre os canídeos afectados. A presente dissertação refere-se a um estudo retrospectivo (2008-2012), de 50 canídeos com linfoma, com o objectivo de comparar os resultados obtidos com a bibliografia publicada, determinando ainda o impacto do imunofenótipo (B ou T) na sobrevida de cães com linfoma. Foi registado o mesmo número de machos e fêmeas e as raças mais frequentes foram o Boxer, Rottweiller e Cocker Spaniel. O diagnóstico da doença foi realizado maioritariamente por histopatologia de linfonodo (56%), revelando 84% de linfomas da forma multicêntrica. Quando determinado, o imunofenótipo mais frequente foi o de células B (69%). A maioria dos canídeos estava em estadios avançados da doença (III-V) (98%) no momento do diagnóstico, revelando 54% dos casos sub-estadio "b" segundo a OMS. O tratamento quimioterápico mais utilizado foi o protocolo CHOP (n=26) seguido do COP (n=9). A toxicidade hematológica e gastrointestinal secundárias à quimioterapia estiveram em igual número (22% cada), não se observando efeitos adversos em 56% dos cães com linfoma. Por último, o tempo médio de sobrevivência registado foi de 393 dias. Não foi encontrada uma relação estatísticamente significativa entre as variáveis (raça, sub-estadio e sexo) e o imunofenótipo de linfoma, sendo os tempos médios de sobrevivência de linfomas T e B semelhantes, 388 e 463 dias, respectivamente. No nosso caso, as principais diferenças encontradas, relativamente à bibliografia publicada, foram uma quantidade elevada de pacientes em sub-estadio "b" e os tempos médios de sobrevivência semelhantes para os diferentes imunofenótipos.

Advances in prodrug design

The background of prodrug design is presented herein as the basis for introducing new and advanced latent systems, taking into account mainly the versatility of polymers and other macromolecules as carriers. PDEPT (Polymer-Directed Enzyme Prodrug Therapy); PELT (Polymer-Enzyme Liposome Therapy); CDS (Chemical Delivery System); ADEPT(Antibody-Directed Enzyme Prodrug Therapy); GDEPT/VDEPT (Gene-Directed Enzyme Prodrug Therapy/Virus-Directed Enzyme Prodrug Therapy); ODDS (Osteotropic Drug Delivery System) and LEAPT (Lectin-directed enzyme-activated prodrug therapy) are briefly described and some examples are given. © 2005 Bentham Science Publishers Ltd.

Liposomal daunorubicin and dexamethasone as a treatment for multiple myeloma - The DD protocol

Context and Objective: Lipasomial daunorubicin has been used to treat hematological malignancies, including multiple myelomo (MM). The goal was to evaluate efficacy, side-effects and toxicity of liposomal daunorubicin and dexamethasone (DD Protocol). Design and Setting: Prospective study of Sírio-Libonês, São Camilo, Brasil and Alemão Oswaldo Cruz hospitals. Methods: Twenty consecutive patients with active MM received four cycles of liposomal daunorubicin intravenously for two hours (25-30 mg/m 2/day) on three consecutive days per month, with oral dexamethasone, (10 mg every six hours) on four consecutive days three times a month. Results: The male/female ratio was 1:1 and median age 60. Nine patients were stage IIA, ten IIIA and one IIIB. The median from diagnosis to starting DD was 13 months. All patients received four cycles, except one. Fifteen had already received chemotherapy before DD. Responses of > 50% reduction in serum monoclonal paraprotein were observed in six patients after first cycle (30%), six after second (30%) and four after third (20%), while four (20%) did not obtain this. Initially, 17 patients (85%) had anemia: 12 (70%) achieved correction. Progressive disease was observed in three patients (15%), while one had minimal response, four (20%) partial and 12 (60%) complete. Hemotologlical toxicity was acceptable: three patients (15%) had neutrophils < 1,000/mm 3; none had thrombocyfopenia. Gastrointestinal toxicity was mild: nausea (10%), anorexio (15%) and no vomiting. Conclusions: This treatment has mild toxicity and good response rate. It may therefore be feasible before autologous bone marraw transplantation.

Estudo sobre a necessidade e preferência sobre orientações de enfermagem ao paciente oncológico adulto em quimioterapia

Most cancer types are treated by antineoplastic chemotherapy, which can be performed conjointly with other treatments, such as radiotherapy and surgery. Due to its action, chemotherapy provides the possibility of cure, but it also leads to a number of adverse effects, such as myelosuppression, cutaneous and gastrointestinal toxicity, etc. Patients undergoing chemotherapy must receive constant information concerning how to prevent or minimize these effects in order to achieve better quality of life and, consequently, a more successful treatment. Hence, this study aimed at investigating the need and preference for different forms of information by oncologic patients submitted to chemotherapy. It is a cross-sectional, descriptive and quantitative study conducted at the chemotherapy division of the Botucatu School of Medicine University Hospital/SP on a sample of 50 patients older than 18 years. After previous knowledge of the study and formalization of Free Consent, the individuals answered a questionnaire containing 12 questions related to the importance attributed to the information received, from which professional and when to receive it. Data were analyzed by Fisher’s exact test and showed that 62% of the patients were females, and the remaining 38% were males of whom 46% were older than 60 years, 26% were from 50 to 60 years old, 24% from 30 to 50, and only 4% were younger than 30 years old. The patients had lymphatic (23.4%) and solid (76.6%) tumors. All the respondents reported that receiving information about the disease and its treatment was extremely important. As regards information related to side effects, 98% of patients answered that receiving it was extremely important, and only 2% answered that it was little important. Correlations were made between age, gender, and tumor type with the answers obtained for the best moment, how and from whom to receive such informatio... (Complete abstract click electronic access below)

Obtenção e caracterização de nanopartículas lipídicas sólidas como sistema de transporte para ibuprofeno

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Analysis of the feasibility of early hospital discharge after autologous hematopoietic stem cell transplantation and the implications to nursing care

Autologous hematopoietic stem cell transplantation is a conduct used to treat some hematologic diseases and to consolidate the treatment of others. In the field of nursing, the few published scientific studies on nursing care and early hospital discharge of transplant patients are deficient. Knowledge about the diseases treated using hematopoietic stem cell transplantation, providing guidance to patients and caregivers and patient monitoring are important nursing activities in this process. Guidance may contribute to long-term goals through patients' short-term needs. To analyze the results of early hospital discharge on the treatment of patients submitted to autologous transplantation and the influence of nursing care on this conduct. A retrospective, quantitative, descriptive and transversal study was conducted. The hospital records of 112 consecutive patients submitted to autologous transplantation in the period from January to December 2009 were revisited. Of these, 12 patients, who remained in hospital for more than ten days after transplantation, were excluded from the study. The medical records of 100 patients with a median age of 48.5 years (19-69 years) were analyzed. All patients were mobilized and hematopoietic stem cells were collected by leukapheresis. The most common conditioning regimes were BU12Mel100 and BEAM 400. Toxicity during conditioning was easily managed in the outpatient clinic. Gastrointestinal toxicity, mostly Grades I and II, was seen in 69% of the patients, 62% of patients had diarrhea, 61% of the patients had nausea and vomiting and 58% had Grade I and II mucositis. Ten patients required hospitalization due to the conditioning regimen. Febrile neutropenia was seen in 58% of patients. Two patients died before Day +60 due to infections, one with aplasia. The median times to granulocyte and platelet engraftment were 12 days and 15 days, respectively, with median red blood cell and platelet transfusions until discharge of three and four units, respectively. Twenty-three patients required rehospitalization before being discharged from the outpatient clinic. The median time to granulocyte engraftment was 12 days and during the aplasia phase few patients were hospitalized or suffered infections. The toxicity of the conditioning was the leading cause of rehospitalization. The nursing staff participated by providing guidance to patients and during the mobilization, transplant and outpatient follow-up phases, thus helping to successfully manage toxicity.

La terapia demetilante con 5-azacitidina nelle sindromi mielodisplastiche: esperienza clinica del Nostro Istituto e correlazione con i dati biologici

Sulla base delle evidenze della letteratura (Fenaux, 2009; Lyons, JCO 2009), a partire da Settembre 2004 nel Nostro Istituto sono stati trattati 57 pazienti affetti da Sindrome Mielodisplastica (MDS) mediante terapia demetilante con 5-Azacitidina. Sono stati utilizzati differenti regimi terapeutici a seconda della classe di rischio IPSS: i pazienti a rischio basso/intermedio-1 hanno ricevuto Azacitidina 75 mg/mq/die sottocute per 5 giorni/mese (schema 5) per 8 cicli; i pazienti a rischio alto/intermedio-2 hanno ricevuto Azacitidina 50 mg/mq/die sottocute per 10 giorni/mese (schema 5+2+5) o Azacitidina 75 mg/mq/die per 7 giorni/mese (schema 7) fino a perdita della risposta. Su una casistica totale di 57 pazienti (15 a rischio basso/int-1; 41 rischio alto/int-2), l’87.7% (50 pazienti) sono risultati valutabili. Tra questi le risposte osservate sono state del 68% (34 pazienti), di cui il 14% (7 pazienti) ha ottenuto una Remissione Completa (CR) ed il 54% (27 pazienti) ha ottenuto un Hematologic Improvement (HI). La valutazione della risposta è stata eseguita secondo i criteri dell’International Working Group 2006 (IWG, Cheeson 2006). Le principali tossicità osservate sono state rappresentate da reazioni cutanee locali nel sito d’iniezione, tossicità gastrointestinale (stipsi e/o diarrea), mielotossicità, neutropenia febbrile, sepsi (3 pazienti). Tra i pazienti trattati abbiamo osservato la presenza di risposta ematologica prolungata (≥ 20 mesi) in 10 pazienti (20% dei pazienti valutabili). Inoltre, grazie alla collaborazione con il Dipartimento di Anatomia Umana dell’Università di Bologna (Prof. L. Cocco, Dott.ssa M.Y. Follo), tutti i pazienti trattati sono stati valutati per i livelli di espressione genica e metilazione del gene della fosfolipasi PI-PLC-beta1. I dati biologici così ottenuti sono stati correlati con quelli clinici, evidenziando la presenza di una correlazione tra i livelli di espressione genica e mutilazione della PI-PLC-beta1 e la risposta alla terapia demetilante con 5-Azacitidina.

Avaliação dos efeitos secundários induzidos pela administração oral de ciclofosfamida em regime de quimioterapia metronómica em cães e gatos : estudo retrospetivo de 36 casos

Dissertação de Mestrado Integrado em Medicina Veterinária

Liver, Gastrointestinal, and Cardiac Toxicity in Intermediate Hepatocellular Carcinoma Treated With PRECISION TACE With Drug-Eluting Beads: Results From the PRECISION V Randomized Trial.

OBJECTIVE. The purpose of our study was to evaluate hepatic, gastrointestinal, and cardiac toxicity after PRECISION transarterial chemoembolization (TACE) with drug-eluting beads (DEB) versus conventional TACE with doxorubicin in the treatment of intermediate-stage hepatocellular carcinoma (HCC).SUBJECTS AND METHODS. Two hundred twelve patients (185 men and 27 women; mean age, 67 years) were randomized to TACE with DEB or conventional TACE. The majority of patients (67% in both groups) presented in a more advanced stage. Safety was measured by rate of adverse events (Southwest Oncology Group criteria) and changes in laboratory parameters. Cardiotoxicity was assessed with left ventricular ejection fraction (LVEF) mainly on MRI or echocardiography.RESULTS. The mean maximum postchemoembolization alanine transaminase increase in the DEB group was 50% less than in the conventional TACE group (p < 0.001) and 41% less in respect to aspartate transaminase (p < 0.001). End-of-study values returned to approximately baseline levels but with greater variability in conventional TACE patients. Treatment-emergent adverse events in the hepatobiliary system organ class occurred in 16.1% of DEB group patients compared with 25% of conventional TACE patients. There were fewer liver toxicity events in the DEB group. There was a small but statistically significant difference in mean change from baseline in LVEF between the two groups of 4 percentage points for the conventional TACE group (95% CI, 0.71-7.3; p = 0.018).CONCLUSION. PRECISION TACE with DEB loaded with doxorubicin offers a safe therapy option for intermediate-stage HCC, even in patients with more advanced liver disease.