The BJC is owned by Cancer Research UK, a charity dedicated to understanding the causes, prevention and treatment of cancer and to making sure that the best new treatments reach patients in the clinic as quickly as possible. The journal reflects these aims. It was founded more than fifty years ago and, from the start, its far-sighted mission was to encourage communication of the very best cancer research from laboratories and clinics in all countries. The breadth of its coverage, its editorial independence and it consistent high standards, have made BJC one of the world's premier general cancer journals. Its increasing popularity is reflected by a steadily rising impact factor.

Case Study聽 Mr. D., a 55-year-old male, presented to the medical oncology service with a diagnosis of stage III adenocarcinoma of the sigmoid colon. He presented 7 weeks post sigmoid colectomy with lymph node resection and was initiated on adjuvant chemotherapy with CAPOX (capecitabine [Xeloda] and oxaliplatin [Eloxatin]). Standard dosing was used: oxaliplatin at 130 mg/m(2) on day 1 and capecitabine at approximately 2,000 mg/m(2)/day (rounded to the nearest 500-mg tablet size) for 14 days on and 7 days off (1 cycle = 21 days). A capped body surface area of 2.4 m2 was used, due to the patient's body habitus. Adverse Effects聽 Mr. D. did not report any complications of therapy during cycle 1, days 1-7, other than grade 1 diarrhea, which was amenable to diphenoxylate/atropine when taken. The next week, he reported significant malaise and fatigue associated with persistent diarrhea occurring every 30 minutes for 5 days. Mr. D. was instructed to go to the emergency room for an immediate evaluation, but he refused. Mr. D. presented to the clinic in poor condition on day 14 of cycle 1. His diarrhea had increased to grade 3 and was not controlled with either loperamide or diphenoxylate/atropine, though he was not taking his medications as directed. He had been instructed to take two 2-mg loperamide tablets after the first loose stool, followed by 1 tablet of diphenoxylate/atropine 2 hours later. He could then alternate this with loperamide every 2 hours as needed, not to exceed 8 tablets of loperamide per day. Instead, he had taken 2 tablets of loperamide after the first loose stool, but either waited 6 hours to take 1 tablet of diphenoxylate/atropine or otherwise chose not to alternate the medications at all despite continued diarrhea, depending on the day. Mr. D.'s timing in taking his supportive medications was inconsistent, and his explanations of this timing were not exact. He also reported persistent grade 3 nausea with vomiting for 5 days, which did not improve with ondansetron and prochlorperazine, though he again did not take these consistently. He was advised to alternate ondansetron and prochlorperazine every 4 hours as needed, but only took one or the other medication approximately 3 times per day. According to Mr. D., his adverse effects initially began on day 9 of cycle 1. He had lost approximately 14 kg (31 lb) during cycle 1. Clinically, he was found to have grade 2 mucositis and grade 1 hand-foot syndrome. At the time of this visit, his absolute neutrophil count was 3,000/矛L, his hemoglobin was 14.4 g/dL, his hematocrit 42.2%, and his platelet count was 139,000/矛L. His kidney function was within the normal range. Mr. D. refused hospitalization despite the primary team's recommendation. He also refused to undergo stool sampling for Clostridium difficile. He was given IV fluids along with adjustments in supportive medications, including a prescription for 10% tincture of opium. He was instructed to use 0.6 mL every 6 hours in addition to alternating loperamide with diphenoxylate/atropine as noted previously. He was advised to rinse his mouth with a baking soda solution for relief of his grade 1 mucositis, and alternation of antiemetics every 4 hours was reiterated. He was to return prior to initiation of cycle 2 for further evaluation. Worsening Symptoms聽 The next day, Mr. D.'s wife called the clinic to report that her husband's diarrhea continued despite the use of tincture of opium and that it was associated with hematochezia. He was also experiencing a worsening of his mucositis, with an associated swelling of the tongue. He was instructed to present to the emergency center, which he did on day 16 of cycle 1. By then, he was found to be febrile at 39.5掳C. He was tachycardic, with a heart rate of 126, and he was experiencing significant abdominal pain associated with the diarrhea. The mucositis was worsening, with new odynophagia. At this time, Mr. D.'s absolute neutrophil count had dropped dramatically to 160/矛L, his hemoglobin was 13.1 g/dL, his hematocrit was 39.2%, and his platelet count was 68,000/矛L. He was admitted to the inpatient service and started on empiric antibiotics. His blood cultures remained negative during hospitalization, but stool cultures were positive for C. difficile. His antimicrobial regimen was deescalated to oral vancomycin once his stool volume decreased. He was treated with an institutional compounded mouthwash of diphenhydramine, aluminum/magnesium hydroxide, and viscous lidocaine for the mucositis, which also slowly improved. He was given a dose of growth factor. Neutropenia eventually resolved, with an absolute neutrophil count of 4,820/矛L on the day of discharge. He was discharged 26 days after initiating cycle 1, at which time his myelosuppression and mucositis were also resolved. Throughout his course, he did not report any neurotoxicity. DPD Testing聽 Due to his severe symptoms of neutropenia, mucositis, and diarrhea, Mr. D. was tested for dihydropyrimidine dehydrogenase (DPD) deficiency. Testing confirmed a heterozygous IVS14+IG>A mutation. For this reason, all further adjuvant therapy was withheld, and he was followed on clinical surveillance only.

AIMS: The oral fluoropyrimidine prodrug capecitabine is widely used in oncology. Capecitabine was designed to generate 5FU via the thymidine phosphorylase (TP) enzyme, preferentially expressed in tumoral tissues. Hand-foot syndrome (HFS) is a limiting toxicity of capecitabine. A pilot study on healthy volunteers was conducted in order to test the hypothesis that the occurrence of HFS could be related to tissue-specific expression of drug-metabolizing enzymes in the skin of the palm and sole. To this end, the expression of TP (activating pathway), dihydropyrimidine dehydrogenase (DPD, catabolic pathway) and cell proliferation (Ki67) were measured in the skin of the palm (target tissue for HFS) and of the lower back (control area). METHODS: Two paired 4-mm diameter punch biopsy specimens (palm and back) were taken in 12 healthy volunteers. Immunohistochemical analyses were performed on frozen tissues. RESULTS: Proliferation rate (Ki67 staining) was significantly higher in epidermal basal cells of the palm compared with the back (P = 0.008). Also, TP and DPD expression were significantly greater in the palm relative to the back (P = 0.039 and 0.012, respectively). TP and Ki67 expression were positively and significantly correlated in the palm. CONCLUSIONS: The high proliferation rate of epidermal basal cells in the palm could make them more sensitive to the local action of cytotoxic drugs. TP-facilitated local production of 5FU in the palm during capecitabine treatment could explain the occurrence of HFS. This observation may support future strategies to limit the occurrence of HFS during capecitabine therapy.

Sirs: Capecitabine is an oral prodrug that is converted to only one active metabolite, fluorouracil (5-FU), which is used to treat numerous types of neoplasms, such as those of the breast, esophagus, and larynx cancer, as well as metastatic breast cancer as either a single agent or in combination with docetaxel after the failure of prior anthracycline-based chemotherapy [ 1 ]. The Federal Drug Administration has recently approved the combination of capecitabine and lapatinib for the treatment of advanced or metastatic breast cancer overexpressing human epidermal growth factor receptor-2 [ 2 ]. We treated a 61-year-old female patient with breast cancer who, following a right mastectomy, homolateral axillary lymphoadenectomy, and radiotherapy, entered into remission. After 7 years of remission, metastatic progression of the disease was determined, and the patient received radiotherapy and anthracycline-based chemotherapy, which were only partially successful. A drug regimen of lapatinib [1250聽 ...

Abstract Systemic chemotherapy can be complicated by colonic toxicity, which usually determines the onset of pseudomembranous colitis and, rarely, of ischemic colitis in patients with cancer. This report describes the case of a 45-year-old man with advanced gastric cancer who developed severe ischemic colitis after chemotherapy with cisplatin and capecitabine. The patient developed symptoms of gastrointestinal toxicity with abdominal pain and bloody diarrhea. He had a normal white blood cell count throughout his illness; the assay of stool specimens for Clostridium difficile toxins and the stool cultures were both negative. An endoscopy showed a mild, transient ischemic colitis. Although cisplatin is related to severe colonic cytotoxicity, it has not been previously reported that capecitabine induces arterial thrombosis and necrosis of the gastrointestinal mucosa and inhibits angiogenesis. Pseudomembranous colitis is the most frequent complication in patients with cancer who undergo capecitabine-based chemotherapy and develop gastrointestinal toxicity. Once Clostridium difficile infection has been excluded, a diagnosis of ischemic colitis should be considered, especially in patients with cancer who have normal white blood cell counts.

Capecitabine is an oral prodrug to 5-fluorouracil and is commonly used in the treatment of advanced breast, colon and stomach cancer. While gastrointestinal toxicity is common, enterocolitis and ischemic colitis are uncommon complications and the histologic features of capecitabine in the colonic mucosa have not been previously described. We present a case of colitis attributed to capecitabine toxicity in a 45-year-old man undergoing treatment of metastatic gastroesophageal adenocarcinoma. Possible pathophysiologic mechanisms of capecitabine toxicity are discussed and the histologic effects on the colon are described. (C) 2014 Elsevier GmbH. All rights reserved.

Despite many treatment advances, remains an incurable disease and is the third leading cause of -related in Europe. has become a standard treatment option for , as a single agent or in combination. and diarrhoea are the most frequently reported side effects, while -related is very rare. Deficiency of leads to severe toxicities after administration of or its . We report two cases of patients with who developed after treatment with . One patient had a gene abnormality.

This report here is the case of a 52-year-old male patient who suffered from extremely severe haematological toxicities (G4 neutropenia, G4 thrombocytopenia) while undergoing Xelox (Xeloda + Oxaliplatin) treatment for his multifocal hepatocarcinoma. Despite appropriate supportive treatment, his condition quickly deteriorated and led to death. It was hypothesized that dihydropyrimidine deshydrogenase (DPD) gene polymorphism could be, at least in part, responsible for this fatal outcome. To test this hypothesis, both phenotypic and genotypic studies were undertaken, and fully confirmed the DPD-deficient status of this patient. Uracil to dihydrouracil ratio in plasma was evaluated as a surrogate marker for DPD deficiency, and showed values out of the range previously recorded from a reference, non-toxic population. Interestingly, the canonical IVS14+1G>A single nucleotide polymorphism, usually associated with the most severe toxicities reported with 5-fluorouracil (5-FU), was not found in this patient, but further investigations showed instead a heterozygosity for the 1896C>T mutation located in the exon 14 of the DPYD gene. Taken together, the data strongly suggest for the first time that a toxic-death case after capecitabine-containing protocol could be, at least in part, linked with a DPD-deficiency syndrome. The case reported here warrants therefore systematic detection of patients at risk, including when oral capecitabine is scheduled.

5-氟尿嘧啶(5-Fu)目前已成为结直肠癌辅助化疗的首选药 物,80％以上的5-Fu都是由二氢嘧啶脱氢酶(DPD)代谢降解的.当编码DPD的基因即DPYD基因突变导致DPD部分或完全缺陷时,可引起5-Fu 不良反应,包括腹泻、口腔炎、手足综合征及神经毒性等.文章就DPYD基因变异的研究背景、研究现状及对临床的指导意义作一综述.

Severe toxicity in patients with a deficiency of dihydropyrimidine dehydrogenase(), an enzyme that reduces fluoropyrimidine, is very rare, and reports on this condition are few. Accordingly, diagnosis is very difficult. The patient was 70-year-old who was admitted for adjuvant chemotherapy with (3,600mg/day)for . He was admitted to our hospital because of severe (grade 3)and (grade 3). After hospitalization, he experienced complications with (grade 4)and thrombocytopenia(grade 4). The patient died 25 days after the onset of chemotherapy. Despite the measurement of the value in mononuclear of peripheral blood and urophanic and , we were unable to diagnose deficiency. However, we suspected a partial deficiency of on the basis of the clinical course.

目的 探讨胃癌和结肠癌患者二氢嘧啶脱氢酶(DPYD)基因多态性与5-氟尿嘧啶(5-FU)代谢及化疗后毒副反应的关系.方法 采用高效液相色谱法测定接受化疗的胃癌和结肠癌患者5-FU血药浓度,使用基因芯片检测技术测定DPYD基因多态性.结果 (1)75例患者中未检测到DPYD*2、*3、*4和*12多态性位点变异;*9多态性位点中,有杂合型7例(9.3%),野生型68例(90.7%);*5多态性位点中,发现突变型11例(14.67%),杂合型23例(30.67%),野生型41例(54.67%).(2)DPYD * 5突变型消除速率常数小于野生型,差异有统计学意义(P=0.022).(3)DPYD*5基因型中重度恶心呕吐、白细胞下降发生率从高到低依次均为突变型、杂合型和野生型,差异有统计学意义(P＜0.05);DPYD*9杂合型中重度恶心呕吐发生率高于野生型,差异有统计学意义(P＜0.05).结论 不同的DPYD基因多态性患者体内5-FU消除速率及化疗后毒副反应有差异,其芯片多态性检测可用于指导5-FU临床用药.

Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of the degradation of pyrimidine base, and plays a pivotal role in the pharmacogenetic syndrome of 5-fluorouracil (5-FU). Deficiency of DPD activity leads to severe toxicities, even death, following administration of 5-FU. Several studies have demonstrated that molecular defects of the dihydropyrimidine dehydrogenase gene (DPYD) lead to the deficiency of DPD activity and cause this pharmacogenetic syndrome. We present the analysis of DPYD genotyping in untreated Caucasian patients (control group) and Caucasian patients with 5-FU/CAP-related grade 3/4 toxicities (toxicity group) who underwent a capecitabine TheraGuide 5-FU testing.Full sequencing of DPYD was performed in the Myriad Genetic Laboratories, Inc. as part of TheraGuide 5-FU test.Among 227 patients from the toxicity group, 27 (12%) had deleterious mutations in DPYD: twelve (5%) had IVS14 +1 G>A, eleven (5%) had D949V and four (2%) had other mutations. Only 7/192 (4%) patients from the control group had DPYD genotype abnormalities: two (1%) had IVS14 +1 G>A, four (2%) had D949V and one (1%) had other mutation. Genotype abnormalities were observed more frequently in the toxicity group (p=0.001). Among 65 patients with toxicities due to capecitabine, nine (14%) had mutated DPYD, which was more frequent than in the control group (p=0.006).Mutated DPYD is frequently observed in Caucasian patients who experience toxicities while receiving 5-FU/capecitabine. Screening of patients for DPYD mutations prior to administration of 5-FU/capecitabine using new pharmacogenetic testing methods, may help for identify those patients who are at greatest risk for adverse effects, allowing a more individualized approach to their chemotherapy management.

Dear Editor: Fluoropyrimidines are widely used in oncology. 5-Fluorouracil (5-FU) is the reference drug in the treatment of more than 50聽% of the gastrointestinal, gynecological, and upper aerodigestive tract cancers. As most of anti-cancer drugs, it has a narrow therapeutic index leading to organ toxicities that could be lethal in 0.5聽% of cases. Toxicity is linked to some specific parameters to patients (age, comorbidities, treatment duration) and genetic polymorphisms that can affect dihydropyrimidine dehydrogenase (DPD) key enzyme of fluoropyrimidine catabolism. Some mutations significantly modify DPD activity with more or less clinical impact. We report the clinical course and outcome of a 63-year-old woman exhibiting a complete DPD deficiency, leading to death after administration of only one standard dose of 5-FU infusion. Case report A 63-year-old patient with no medical history underwent a sigmoidectomy because of a moderately differentiated Lieberk眉hnien adenocarcinoma (pT3pN1M0 ...

ABSTRACT 5-Fluorouracil (5-FU) is a mainstay for treating colorectal cancer, alone or more frequently as part of combination therapies. However, its efficacy/toxicity balance is often limited by the occurrence of severe toxicities, showing in about 15%-20% of patients. Several clinical reports have shown the deleterious effect of dihydropyrimidine dehydrogenase (DPD) genetic polymorphism, a condition that reduces the liver detoxification step of standard dosages of 5-FU, in patients undergoing fluoropyrimidine-based therapy. Admittedly, DPD deficiency accounts for 50%-75% of the severe and sometimes life-threatening toxicities associated with 5-FU (or oral 5-FU). However, technical consensus on the best way to identify patients with DPD deficiency before administrating 5-FU is far from being achieved. Consequently, no regulatory step has been undertaken yet to recommend DPD testing as part of routine clinical practice for securing the administration of 5-FU. This review covers the limits and achievements of the various strategies proposed so far for determining DPD status in patients scheduled for 5-FU therapy.

Dihydropyrimidine dehydrogenase (DPD) degrades approximately 85% of administered 5-fluorouracil (5-FU). With a reported high mortality rate, chemotherapy is generally contraindicated for patients with DPD deficiency.Chemotherapy was initiated for a 73-year-old man with DPD deficiency. Capecitabine was administered in incrementally increasing doses, beginning with a single pill while monitoring plasma 5-FU concentration, and neutrophil and platelet counts.DPD protein level was 2.35 U/mg. After increasing the capecitabine dose to 1,800 mg, oxaliplatin and bevacizumab were added. Subsequent DPD protein measurement showed that the level had increased to approximately 12-fold the one before chemotherapy. Sequencing of all 23 exons of DPYD gene revealed a mutation of guanine to thymine in exon 11 (1156 G>T).This is the first report to indicate that DPD activity can be induced. These findings may provide early indications of a new method for chemotherapy for DPD-deficient patients.