Choice of Capecitabine or S1 in Combination with Oxaliplatin based on Thymidine Phosphorylase and Dihydropyrimidine Dehydrogenase Expression Status in Patients with Advanced Gastric Cancer

PURPOSE: To study the efficacy of capecitabine or S-1 plus oxaliplatin (CAPOX or SOX) for treating thymidine phosphorylase (TP)- or dihydropyrimidine dehydrogenase (DPD)-positive advanced gastric cancer.MATERIALS AND METHODS: Eighty-six patients with stage IIIC to IV gastric cancer were assessed for TP and DPD expression by immunohistochemistry. The association between CAPOX or SOX efficacy and TP/DPD expression was retrospectively analyzed.RESULTS: There were no significant differences in the objective remission rate (ORR, 52.27% vs. 47.62%; P>0.05), disease control rate (72.73% vs. 73.81%, P>0.05), progression-free survival (hazard ratio [HR], 1.119; 95% confidence interval [CI], 0.739–1.741; P=0.586), and overall survival (OS; HR, 0.855; 95% CI, 0.481–1.511; P=0.588) between CAPOX and SOX. A higher number of stage IV patients showed TP positivity, while DPD-positive patients predominantly showed intestinal type of gastric cancer. In TP-positive patients, the ORRs associated with CAPOX and SOX treatments were 57.14% and 38.10%, respectively; OS was better with CAPOX than with SOX (HR, 0.447; 95% CI, 0.179–0.978; P=0.046). Among DPD-positive patients, the SOX treatment-associated ORR (60.87%) was significantly higher than the CAPOX treatment-associated ORR (43.48%). Furthermore, SOX treatment resulted in better OS than did CAPOX treatment (HR, 2.020; 95% CI, 1.019–4.837; P=0.049).CONCLUSIONS: No significant difference in clinical efficacy was found between CAPOX and SOX. TP-positive patients might respond better to CAPOX while DPD-positive patients may respond better to SOX. Our findings might serve as a guide for personalized chemotherapy for gastric cancer.

Comparison of the efficacy and safety of capecitabine or tegafur, gimeracil and oteracil potassium capsules combined with oxaliplatin chemotherapy regimens in the treatment of advanced gastric cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To observe the efficacy and safety of chemotherapy regimens oxaliplatin combined with capecitabine (CAPOX) or oxaliplatin combined with tegafur, gimeracil and oteracil potassium capsules (S-1)(SOX), and to investigate the value of expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) proteins in tumor tissue for predicting the efficacy of CAPOX and SOX regimens in advanced gastric cancer patients.</p><p><b>METHODS</b>A total of 107 newly-diagnosed, stage Ⅲc/Ⅳ gastric cancer patients (no surgical indication, ECOG performance scores 0-2 and expected survival time ≥3 months) were recruited with 101 patients evaluated. The patients were randomly divided into two groups. One was study group in which the patients received CAPOX regimen. The other was control group received SOX regimen. Each patient received four cycles, at least two cycles chemotherapy every three weeks and followed up until death or lost. Tumor biopsies were obtained by gastroscopy for immunohistochemical examination of the expression of TP and DPD proteins before chemotherapy. Response rate (ORR), overall survival (OS) and time to tumor progression (TTP) of the patients were assessed.</p><p><b>RESULTS</b>The objective response rate (ORR) of the study and control groups was 49.0% (5/51) vs. 46.0% (23/50), respectively (P>0.05). The overall survival (OS) was 357.36±24.69 days in the study group and 349.87±22.63 days in the control group, and the time-to-progression (TTP) was 216.75±19.32 days in the study group and 220.54±18.47 days in the control group (P>0.05 for both). Stratified analysis showed that the ORR of TP-positive patients in the study group was significantly higher than that in the control group (72.0 % vs. 41.7 %, P=0.032). There was no significant difference in ORR between the TP-negative patients in the study and control groups (26.9% vs. 50.0%, P=0.087), while the ORR of DPD-positive patients in the control group was significantly higher than that of the study group (51.9% vs. 34.6%, P=0.046). There was no significant difference in the ORR between DPD-negative patients in the study and control groups (64.0% vs. 39.1%, P=0.084). The follow-up showed that the OS (378.42±22.56 days) and TTP (271.77±24.92 days) in the TP-positive patients of the study group were significantly longer than those of the control group (OS: 326.57±19.84 days, and TTP: 229.13±22.68 days)( P<0.05). The OS was 371.25±23.97 days and TTP was 264.66±21.36 days in the DPD-positive patients of control group, significantly longer than those of the study group (OS: 334.73±21.47days, and TTP: 208.58±20.70 days) (P<0.05). But there was no significant difference in the OS and TTP between the TP- and DPD-negative patients in the two groups (P>0.05). In respect of adverse events, both the rates of hematological and non-hematological toxicities were low and similar between the two groups (P>0.05), and well-tolerated by the patients.</p><p><b>CONCLUSIONS</b>Both CAPOX and SOX regimens are effective chemotherapeutic protocols in treatment of patients with advanced gastric cancer. The expression levels of TP and DPD in tumor tissue can be used as a predictive factor for the efficacy of capecitabine or tegafur, gimeracil and oteracil potassium capsules combined with oxaliplatin regimens. CAPOX chemotherapy regimen is more suitable for the TP-positive gastric cancer patients, and SOX regimen is more suitable for the DPS-positive gastric cancer patients.</p>

Efeito da revascularização renal sobre a evolução da disfunção renal na nefropatia isquêmica aterosclerótica / Effect of renal revascularization on the development of renal dysfunction in atherosclerotic ischemic nephropathy

A doença renal crônica (DRC) é caracterizada por uma perda progressiva da função renal e suas principais causas são hipertensão arterial (HA) e diabete melito. Entre as causas de HA, podemos destacar a doença renal aterosclerótica (DRA). O desenvolvimento de DRC nos pacientes com DRA parece ser decorrente não apenas do acometimento das artérias renais principais, mas também da microcirculação renal, o que pode justificar o fato de o sucesso do procedimento não garantir uma melhora da evolução da DRC. Até o presente momento, não existe evidência de benefício da angioplastia em relação ao tratamento clínico exclusivo nos pacientes com DRA. O presente trabalho analisa os estudos mais significantes sobre os desfechos renais em pacientes portadores de DRA submetidos à revascularização ou ao tratamento clínico exclusivo.

Chronic kidney disease (CKD) is characterized by a progressive loss of renal function and its main causes are hypertension and diabetes mellitus. Among the causes of hypertension is atherosclerotic renal disease (ARD). The development of CKD in patients with ARD appears to be due not only to the involvement of the main renal arteries, but also of the renal microcirculation, which may explain the fact that the success of the procedure does not guarantee an improvement in the progression of CKD. To date there is no evidence of benefit of angioplasty compared to medical treatment alone in patients with ARD. The present paper analyzes the most significant studies on renal outcomes in patients with ARD undergoing revascularization or medical treatment alone.

Influence of Apical Enlargement in Cleaning of Curved Canals Using Negative Pressure System

This study aimed to evaluate, by scanning electron microscopy (SEM), the cleaning of canal walls with moderate curvature subjected to biomechanical preparation with different final diameters using apical negative pressure irrigation. Thirty-two mesiobuccal roots of molars were divided into 4 groups (n=8) according to the instrument's final diameter: GI: 30.02, GII: 35.02, GIII: 40.02 and GIV: 45.02. Irrigating procedure was performed at each change of instrument with 1% NaOCl using the Endovac system. Final irrigation was conducted with 17% EDTA for 5 min. The SEM photomicrographs were evaluated under 35× and 1000× magnification, by three calibrated examiners, in a double-blind design. Data were submitted to Kruskal-Wallis and Dunn's post hoc tests (α=0.05). Canals instrumented with 30.02 and 35.02 final diameters showed more debris, statistically different from the other groups (p<0.05). Comparing each root canal third, for the cervical and apical portions no statistically significant difference (p>0.05) was found among the four groups. Regarding the presence of smear layer, canals with 30.02 final diameter showed the highest scores, statistically different from the 45.02 group (p<0.05) and similar to the 35.02 and the 40.02 groups (p>0.05). Although none of the studied diameters completely removed debris and smear layer, it may be concluded that instrumentation with higher final diameters was more effective in cleaning the root canals with moderate curvature.

Este estudo buscou avaliar, por meio de microscopia eletrônica de varredura (MEV), a limpeza das paredes de canais com curvatura moderada, submetidos ao preparo biomecânico com diferentes diâmetros finais utilizando-se irrigação por pressão apical negativa. Trinta e duas raízes mésio-vestibulares de molares foram divididas em 4 grupos (n=8) de acordo com o diâmetro final dos instrumentos: GI: 30.02, GII: 35.02, GIII: 40.02 e GIV: 45.02. O procedimento de irrigação foi realizado a cada troca de instrumento com NAOCl 1% utilizando o sistema EndoVac. A irrigação final foi conduzida com EDTA 17% por 5 min. As microfotografias de MEV foram avaliadas sob aumentos de 35× e 1000×, por três examinadores calibrados, em estudo duplo-cego. Os dados foram submetidos ao teste de Kruskal-Wallis e pós-teste de Dunn (=0,05). Os canais instrumentados com diâmetros finais de 30.02 e 35.02 demonstraram mais debris, estatisticamente diferente dos demais grupos (p<0,05). Comparando-se cada terço do canal radicular, para as porções cervical e apical não foi encontrada diferença estatisticamente significante (p>0,05) entre os quatro grupos. Com relação à presença de smear layer, canais com diâmetro final de 30.02 demonstraram os maiores scores, estatisticamente diferente do grupo 45.02 (p<0,05) e similar aos grupos 35.02 e 40.02 (p>0,05). Apesar de nenhum dos diâmetros estudados ter removido completamente os debris e a smear layer, pode ser concluído que a instrumentação com diâmetros finais maiores foi mais efetiva na limpeza dos canais radiculares com curvatura moderada.

Effect of jianpi liqi recipe on mRNA expressions of TP, DPD, and CYP3A4 in mice with human gastric cancer transplanted tumor / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To study the effect of Jianpi Liqi Recipe (JLR) on 5-fluorouracil (5-FU) relevant metabolic enzymes and CYP3A4 (the same enzyme of many chemotherapeutics) of mice with human gastric cancer transplanted tumor.</p><p><b>METHODS</b>Totally 80 mice were randomly divided into the model group, the chemotherapy group, the JLR group, and the combination group (using chemotherapy combined JLR), 20 in each group. The human gastric cancer transplanted tumor mouse model was duplicated by hypodermic inoculating MKN-8 tumor cell suspension from the left armpit. Physiological saline or JLR was given to those in the model group or the JLR group at 0.25 mL each time, twice daily by gastrogavage from the 2nd day after transplantation. Mice in the chemotherapy group were given 0.25 mL physiological saline, twice daily by gastrogavage 2 days after transplantation, for 5 days in succession, and then they were peritoneal injected with 5-FU at the daily dose of 20 mg/kg, once daily for 5 days in succession from the 7th day of transplantation. Those in the combination were given 0.25 mL JLR, twice daily by gastrogavage, for 5 days in succession, and then they were peritoneal injected with 5-FU at the daily dose of 20 mg/kg, once daily for 5 days in succession from the 7th day of transplantation. The mRNA expressions of thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), and CYP3A4 were detected using RT-PCR.</p><p><b>RESULTS</b>Compared with the model group and the chemotherapy group, mRNA expressions of TP and CYP3A4 obviously increased, mRNA expression of DPD obviously decreased in the JLR group and the combination group (P < 0.01). There was no statistical difference in mRNA expressions of TP, DPD, and CYP3A4 between the JLR group and the combination group (P > 0.05).</p><p><b>CONCLUSION</b>JLR could promote the activation of 5-FU, suppress the decomposition and inactivation of 5-FU in the tumor tissue of mice, and improve the chemotherapeutic efficacy through up-regulating mRNA expressions of TP and CYP3A4, and suppressing the mRNA expression of DPD.</p>

Screening of Dihydropyrimidine Dehydrogenase Genetic Variants by Direct Sequencing in Different Ethnic Groups

Dihydropyrimidine dehydrogenase (DPYD) is an enzyme that regulates the rate-limiting step in pyrimidine metabolism, especially catabolism of fluorouracil, a chemotherapeutic agent for cancer. In order to determine the genetic distribution of DPYD, we directly sequenced 288 subjects from five ethnic groups (96 Koreans, 48 Japanese, 48 Han Chinese, 48 African Americans, and 48 European Americans). As a result, 56 polymorphisms were observed, including 6 core polymorphisms and 18 novel polymorphisms. Allele frequencies were nearly the same across the Asian populations, Korean, Han Chinese and Japanese, whereas several SNPs showed different genetic distributions between Asians and other ethnic populations (African American and European American). Additional in silico analysis was performed to predict the function of novel SNPs. One nonsynonymous SNP (+199381A > G, Asn151Asp) was predicted to change its polarity of amino acid (Asn, neutral to Asp, negative). These findings would be valuable for further research, including pharmacogenetic and drug responses studies.

Screening of Dihydropyrimidine Dehydrogenase Genetic Variants by Direct Sequencing in Different Ethnic Groups

Dihydropyrimidine dehydrogenase (DPYD) is an enzyme that regulates the rate-limiting step in pyrimidine metabolism, especially catabolism of fluorouracil, a chemotherapeutic agent for cancer. In order to determine the genetic distribution of DPYD, we directly sequenced 288 subjects from five ethnic groups (96 Koreans, 48 Japanese, 48 Han Chinese, 48 African Americans, and 48 European Americans). As a result, 56 polymorphisms were observed, including 6 core polymorphisms and 18 novel polymorphisms. Allele frequencies were nearly the same across the Asian populations, Korean, Han Chinese and Japanese, whereas several SNPs showed different genetic distributions between Asians and other ethnic populations (African American and European American). Additional in silico analysis was performed to predict the function of novel SNPs. One nonsynonymous SNP (+199381A > G, Asn151Asp) was predicted to change its polarity of amino acid (Asn, neutral to Asp, negative). These findings would be valuable for further research, including pharmacogenetic and drug responses studies.

Polymorphisms of dihydropyrimidine dehydrogenase gene and clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in Chinese population / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Dihydropyrimidine dehydrogenase (DPD), a key enzyme involved in the catabolism of 5-fluorouracil (5-FU), is the attractive candidate for pharmacogenetic research on efficacies and toxicities of 5-FU. The aim of this study is to explore the association between polymorphisms of dihydropyrimidine dehydrogenase gene (DPYD) and clinical outcomes of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in the Chinese population.</p><p><b>METHODS</b>Three hundred and sixty-two patients with gastric cancer in the Chinese population were treated with fluorouracil-based adjuvant chemotherapy. The single nucleotide polymorphic genotypes of DPYD were determined by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) using DNA samples isolated from peripheral blood collected before treatment.</p><p><b>RESULTS</b>The average response rate for chemotherapy was 46.7%. A significantly different distribution of the rs1801159 (c2=8.76, P=0.012) genotypes was observed. Homozygous genotype rs1801159A/A was over-represented in responsive patients. Conversely, carriers of the rs1801159A/G genotype were prevalent in non-responsive patients. In the haplotype association analysis, there was significant difference in global haplotype distribution between the groups (c2=3.96, P=0.0465).</p><p><b>CONCLUSIONS</b>These results suggest that polymorphisms of rs1801159 in DPYD may be used as valuable predictors of the response to fluorouracil-based chemotherapy for gastric cancer patients in the Chinese population. Well-designed, comprehensive, and prospective studies on determining these polymorphisms of DPYD as predictive markers for gastric cancer in response to fluorouracil-based therapies are warranted.</p>

Expression of dihydropyrimidine dehydrogenase negatively correlated with the prognosis of pancreatic ductal adenocarcinoma / 中华外科杂志

<p><b>OBJECTIVE</b>To detect the expression of dihydropyrimidine dehydrogenase (DPD) in pancreatic ductal adenocarcinoma (PDAC), and to investigate the relationships between DPD expression and the prognosis of PDAC.</p><p><b>METHODS</b>Immunohistochemistry and tissue microarray techniques were used to exam the expression of DPD in the cancerous tissue in 156 patients admitted from January 2005 to December 2009, including 89 males and 67 females, with the age ranging from 35 to 81 years. The median age was 55 years.</p><p><b>RESULTS</b>With the positive rate of DPD 55.1%, the expression of DPD was correlated with the differentiation (P = 0.001), TNM staging of tumor (P = 0.021). No relationship was observed between the vessel invasion (P = 0.265), lymphatic metastasis (P = 0.123), neural invasion (P = 0.598) and DPD expression. In the follow-up 117 patients the overall median survival time was 14.2 months, in 58 cases expressed negative, the median survival time was 20.6 months; 39 cases expressed "+" and "++", the median survival time was 12.3 months; 20 cases expressed "+++", the median survival time was 6.8 months. The expression of DPD in pancreatic cancer was correlated with the prognosis of patients, those with higher expression pattern exhibited shorter survival time (P < 0.05). Univariate survival analysis revealed that DPD expression, TNM staging, lymphatic metastasis and neural invasion were factors related to prognosis (P < 0.05), while differentiation levels and vessel invasion were not. Multivariate survival analysis revealed that DPD expression (P = 0.002), lymphatic metastasis (P = 0.000) were two independent prognostic factors.</p><p><b>CONCLUSIONS</b>The expression levels of DPD was correlated to differentiation levels of pancreatic cancer and TNM staging; those with higher expression of DPD showed shorter survival time. DPD expression, lymphatic metastasis were independent prognostic factors for pancreatic cancer.</p>

Detection of single nucleotide polymorphisms of mthfr and dpyd genes in leukemia cell lines K562 and K562/A02 / 中国实验血液学杂志

This study was purposed to detect single nucleotide polymorphisms (SNP) of 2 pharmacokinetics-related genes in K562 and K562/A02 cell lines. Leukemia cell line K562 and its resistant line K562/A02 were cultured, the genomic DNA was isolated by QIAamp DNA Blood Mini kit, primers were designed, the related DNA fragments were amplified by PCR. The SNP genotyping of mthfr gene rs1801131, rs1801133 and rs2274976 and dpyd gene rs1801159, rs1801160 and rs17376848 was performed by means of matrix assisted laser desorption ionization-time of flight mass spectrometry method (MALDI-TOFMS). The results showed that the genotype of mthfr gene locus 1801131 was AC, rs1801133 was CC, rs2274976 was GG, genotype of dpyd gene locus 1801159 was GG, rs1801160 was GG, rs17376848 was AA in both K562 and K562/A02 cell lines. It is concluded that the above-mentioned loci of mthfr and dpyd genes in K562 and K562/A02 cell lines are not expressed differently.

Restrição calórica e mitocôndrias: papel no envelhecimento de Saccharomyces cerevisiae / Caloric Restriction and Mitochondria: Role in Saccharomyces cerevisiae aging / Restriction calorique et mitochondrie: rôle dans le vieillissement de Saccharomyces cerevisiae

A restrição calórica (RC) é uma intervenção dietética capaz de estender a longevidade de vários organismos. O modelo para RC em Saccharomyces cerevisiae consiste da diminuição da concentração de glicose no meio de cultura e mostra um aumentado tanto do tempo de vida cronológico quanto replicativo. Nosso objetivo foi investigar experimentalmente a ação da RC, focando principalmente nas causas e consequências das modificações de geração de EROs mitocondriais e como estas estão associadas ao processo de envelhecimento. Em um primeiro período de estudos, verificamos quais as fontes mitocondriais de EROs, e comprovamos que uma quantidade significativa se origina de proteínas da matriz mitocondrial, e não da cadeia de transporte de elétrons. Nós estudamos a participação de glicose e de outras fontes de carbono sobre o tempo de vida cronológico em leveduras e mostramos que o aumento da longevidade promovida pela RC está associado à uma mudança de metabolismo fermentativo para respiratório, com participação da via de sinalização de glicose. No estágio realizado no laboratório do Professor Francis Sluse na Université de Liegè, Bélgica, estudamos a ação da RC em leveduras focando nas consequências das modificações no proteoma mitocondrial. Em nosso estudo proteômico, encontramos grandes modificações em proteínas envolvidas com o metabolismo de aminoácidos. Monitoramos a atividade de enzimas relacionadas ao metabolismo de aminoácidos e o tempo de vida cronológico de S. cerevisiae e as mutantes nulas bat2Δ, gdh1Δ, gdh2Δ e gdh3Δ, que codificam a aminotransferase de aminoácidos de cadeia ramificada citosólica, NADP glutamato desidrogenase citosólica, a NAD glutamato desidrogenase mitocondrial, e a NADP glutamato desidrogenase mitocondrial, respectivamente. A atividade da NAD glutamato desidrogenase é aumentada em RC, mas a de NADP glutamato desidrogenase decresce em células controle. Aumentos do tempo de vida cronológico foram observados nas mutantes...

Calorie restriction (CR) is a dietary intervention capable of extending lifespans in a wide range of organisms. A yeast model of CR has been developed in which limiting the concentration of glucose in growth media of Saccharomyces cerevisiae leads to enhanced chronological and replicative life spans. Our aim was to experimentally investigate the effects of CR, focusing mainly on the causes and consequences of changes in mitochondrial reactive oxygen species (ROS) generation and how these are associated with the aging process. Initially, we looked for sources of mitochondrial ROS, and found that a significant amount of ROS comes from mitochondrial matrix enzymes and not from the electron transport chain. We studied the participation of glucose and other carbon sources in chronological lifespan and show that increased longevity promoted by CR is associated with a metabolism change from fermentation to respiration, with participation of glucose repression pathway. During studies performed in the laboratory of Professor Francis Sluse at the Université de Liège, Belgium, we studied the effect of CR in yeast with focus on the consequences of changes in the mitochondrial proteome. We found large proteomic changes in proteins involved in amino acid metabolism. We monitored the activity of enzymes related to amino acid metabolism and chronological life span of S. cerevisiae null mutants bat2Δ, gdh1Δ, gdh2Δ, and gdh3Δ, which encode for the cytosolic branched-chain amino acid aminotransferase, cytosolic NADP glutamate dehydrogenase, mitochondrial NAD glutamate dehydrogenase and mitochondrial NADP glutamate dehydrogenase, respectively. The activity of NAD glutamate dehydrogenase is increased in CR, but NADP glutamate dehydrogenase decreases in control cells. Increases in chronological life span due to RC were observed in bat2Δ and gdh1Δ mutants, but no significant difference was found in Gdh2p and Gdh3p null mutants in the stationary phase…

La restriction calorique (RC) est une intervention diététique capable de prolonger la durée de vie dans divers organismes. Un modèle de RC pour la levure a été developpé dans lequel limiter la concentration de glucose dans le milieu de culture de Saccharomyces cerevisiae a montré une augmentation de vieillessement chronologique et réplicative. Notre objectif était d’étudierexpérimentalement l’effet de la RC, en se concentrant principalement sur les causes et les conséquences des changements dans la production des espèces d’oxygène réactive (ROS) mitochondriales et de la façon dont elles sont associée au processus de vieillessement. Dans une première période d’études, qui a trouvé la source de ROS mitochondriale, nous montrons qu’une quantité importante vient d’enzyme de la matrice et pas de la chaîne de transport d’électrons. Nous avons étudié la participation de glucose et d’autres sources de carbone sur le vieillissement chronologique dans la levure et nous avons montré que l’augmentation de la longévité promure par RC est associée à un changement du métabolisme fermentaire à respiratoire, avec la participation de la voie de signalisation du glucose. Dans le laboratoire du professeur Francis Sluse à l’Université de Liège, en Belgique, nous avons étudié l’effet du RC dans la levure en se concentrant sur les conséquences des changements du protéome mitochondrial. Dans notre étude, nous avons constaté de grands changements des protéines impliquées dans le métabolisme des acides amines. Nous avons surveillé l’activité des enzymes liées au métabolisme des acides aminés et le vieillissement chronologique de S. cerevisiae et des mutants nul bat2Δ, gdh1Δ, gdh2Δ et gdh3Δ, qui codent aminotransférase pour les acides aminés à chaîne ramifiée cytosolique, NADP glutamate déshydrogénase cytologique, NAD glutamate déshydrogénase mitochondriale et NADP glutamate déshydrogénase mitochondriale, respectivement. L’activité de la NAD glutamate...

A Case of 5-Fluorouracil Induced Encephalopathy / Journal of the Korean Cancer Association, 대한암학회지

Patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at risk for experiencing serious adverse effects following 5-fluorouracil (5-FU) based chemotherapy. Neurotoxicity is considered an extremely rare side effect of 5-FU. We report here on an unusual case of 5-FU induced encephalopathy. A 38-year-old woman with advanced gastric carcinoma was treated with adjuvant chemotherapy that consisted of infused 5-FU (1,000 mg/m2) for 5 days and cisplatin (60 mg/m2) on day 1 following total gastrectomy. Nineteen days after starting chemotherapy, the patient displayed a sudden onset of slurred speech, confusion, cognitive disturbances and paranoia. A magnetic resonance image (MRI) of the brain showed no structural abnormalities, and the other laboratory tests provided no explanations for her symptoms, other than a slightly elevated ammonia level. The patient was treated with a lactulose retention enema and thiamine infusion, the 5-FU was halted and her symptoms then recovered after 7 days.

A Case of Fixed Drug Eruption Induced by Tegafur-Uracil(TEGASIL) / 대한피부과학회지

A mixture of tegafur and uracil (TEGASIL) is a common antineoplastic agent. Tegafur is a fluoropyrimidine structurally similar to 5-fluorouracil (5-FU); uracil slows the degradation of 5-FU by dihydropyrimidine dehydrogenase, which results in higher 5-FU concentrations in tumors. Mucocutaneous side effects induced by this agent are rare and include photosensitivity of lichenoid and eczematous types, acral erythema, hyperpigmentation and palmoplantar keratoderma. However, there have been no reports of fixed drug eruption associated with TEGASIL. We report here on a case of fixed drug eruption due to oral TEGASIL.

Neurotrophic keratitis in a patient with dihydroxypyrimidine dehydrogenase deficiency.

We describe a case of neurotrophic keratitis in association with dihydroxypyrimidine dehydrogenase (DHPD) deficiency. Ocular manifestations in patients with DHPD are rare and neurotrophic keratitis has never been reported before. A six-year-old boy who was a known case of DHPD deficiency and born of a consanguineous marriage presented to our clinic with non-healing corneal ulcers in both eyes. Reduced corneal sensations were detected and the patient was started on lubricating eye drops. The patient continues to be on lubricant eye drops and there has been no recurrence of the disease.

Unpredicted Severe Toxicity after 5-Fluorouracil Treatment due to Dihydropyrimidine Dehydrogenase Deficiency

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). Thus, patients with a DPD deficiency are at risk of developing severe 5-FU-associated toxicity. A 37-year-old female with gastric cancer underwent a curative operation, followed by adjuvant chemotherapy consisting of 5-FU and epirubicin. After the first cycle of chemotherapy, the patient manifested grade 2 mucositis and febrile neutropenia, and when her treatment was subsequently continued with doxifluridine she developed severe mucositis and febrile neutropenia. A PCR study revealed that her DPD mRNA level was lower than that in a control group. Thus, when considering the routine use of 5-FU for the treatment of cancer patients, an analysis of DPD activity or screening for DPD mutations is warranted in confined patients who experience unpredicted severe toxicity after initial 5-FU administration, even though DPD deficiency is a rare metabolic defect.

Relationship between Microsatellite Instability and Dihydropyrimidine Dehydrogenase Expression as a Predictor of Response to 5-Fluorouracil Chemotherapy for Colorectal Cancer

PURPOSE: Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in 5-FU catabolism, so the enzymatic activity of DPD reflects the 5-FU response. Moreover, recent studies have revealed that microsatellite instability (MSI) status correlates well with the prognosis and the 5-FU chemosensitivity in colorectal cancer (CRC). This study aimed to determine whether DPD mRNA expression is related with the MSI status of primary CRC as a prognostic predictor. METHODS: Tumor samples and adjacent normal colonic mucosal tissues were collected from 59 patients. DPD mRNA expression was calculated by using the real-time RT-PCR method. The MSI status was examined by using multiplex fluorescent PCR with five reference markers. The results of DPD mRNA expression and MSI status were compared with the clinicopathologic variables and with each other. RESULTS: The mean age of the 59 patients was 59 (range: 36~81) years. In 55 patients (93.2%), the colorectal cancers were histologically well or moderately differentiated. Forty-nine of the tumors (49, 83.1%) were located distal to the splenic flexure, and 46 patients (78%) had TNM stage II (n=17) or stage III (n=29) cancer. The DPD mRNA expression level was informative in all 59 cases. The median expression level was 2.5 (range: 0~67.33). There was no correlation between the DPD mRNA expression level and age, gender, location, or TNM stage. MSI status was informative in 43 cases (72.9%). Thirty-six cases (36, 83.7%) were microsatellite-stable (MSS), 4 cases (9.3%) showed low-level microsatellite instability (MSI-L), and 3 cases (7.0%) showed high-level microsatellite instability (MSI-H). Proximal CRC showed a higher proportion of MSI-H than distal CRC (25% vs. 2.9%, P=0.03). We could not find any correlation between the DPD mRNA expression level and the MSI status in tumor tissues (r=0.29, P=0.09). CONCLUSIONS: The expression level of DPD mRNA raried among the tumors studied. The relatively low frequency of MSI in distal CRC prohibits the use of MSI status as a predictor of 5-FU chemosensitivity. We suggest that a well-designed large-scale study would be helpful to confirm the relation between DPD mRNA expression and MSI status as a predictor of 5-FU chemosensitivity in CRC patients.

Expressions of thymidine phosphorylase, thymidylate synthase and dihydropyrimidine dehydrogenase in breast cancer and their correlations with prognosis / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To study the expression of thymidine phosphorylase (TP), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) mRNA in breast cancer and its correlation with prognosis.</p><p><b>METHODS</b>Expression levels of TP, TS and DPD mRNA in 86 micro-selected breast cancer tissues and 9 normal breast tissues were detected by real-time quantitative PCR.</p><p><b>RESULTS</b>The median expression levels of TP, TS and DPD mRNA in tumor tissue and in normal tissues were 16.54, 0.38, 2.47 and 11.75, 0.25, 8.33, respectively, there were no significant differences (P >0.05). The expression levels of TP, TS and DPD mRNA showed no association with tumor size, lymph node metastasis, pathological grade and clinical stage, except that of DPD showed a negative association with patients' ages. There was no significant difference in disease-free survival or overall survival between the patients with high and low TP or DPD mRNA levels. Disease-free survival tends to be better in the patients with low TS mRNA level than those with high TS mRNA, but the difference was not significant (P=0.069), while the overall survival showed a statistically difference (59.00 month and 70.30 month) (P=0.0496).</p><p><b>CONCLUSION</b>The expression level of TS mRNA may serve as a prognostic marker for breast cancer patients.</p>

The thymidine phosphorylase to dihydropyrimidine dehydrogenase ratio in pancreatic cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To determine the contents of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) in pancreatic cancer to provide a basis for the clinical use of capecitabine in pancreatic cancer patients.</p><p><b>METHODS</b>The contents of TP and DPD in pancreatic cancer and adjacent normal tissues from 20 patients were determined by ELISA and the TP to DPD ratios in the cancer and adjacent normal tissue were compared.</p><p><b>RESULTS</b>TP content was 5- to 283-fold higher in tumor tissue (mean 74-fold) than in the adjacent normal tissue (P < 0.01). DPD in the cancer tissue increased significantly. So did the TP to DPD ratio, when compared to that in normal pancreatic tissue (P < 0.01).</p><p><b>CONCLUSION</b>The increased TP to DPD ratio in pancreatic cancer suggests that capecitabine could be activated by the cancer, these capable of selectively kill the tumor cells.</p>