Irinotecan often causes unpredictably severe, occasionally fatal, toxicity involving leukopenia or diarrhea. It is converted by carboxyesterase to an active metabolite, SN-38, which is further conjugated and detoxified to SN-38-glucuronide by UDP-glucuronosyltransferase (UGT). We genotyped the UGT1A7 gene by direct sequencing analysis and polymerase chain reaction-restriction fragment length polymorphism in 118 cancer patients and 108 healthy subjects. All the patients had received irinotecan-containing chemotherapy and were evaluated to see whether the variant UGT1A7 genotype would increase the likelihood of severe toxicity of irinotecan consisting of grade 4 leukopenia and/or grade 3 or more diarrhea. Among the 26 patients with severe toxicity, the allele frequencies were 61.5% for UGT1A7 * 1, 15.4% for UGT1A7 * 2, and 23.1% for UGT1A7 * 3. On the other hand, the frequencies were 63.6% for UGT1A7 * 1, 15.8% for UGT1A7 * 2, and 20.7% for UGT1A7 * 3 among the 92 patients without severe toxicity. None of the 118 patients had UGT1A7 * 4. Neither univariate analysis (odds ratio, 1.13; 95% confidential interval, 0.46-2.75) nor multivariate logistic regression analysis (odds ratio, 0.74; 95% confidential interval, 0.26-2.07) found any significant association between carrying at least one of the variant alleles and the occurrence of severe toxicity. The distribution of UGT1A7 genotypes in 108 healthy subjects was not significantly different from that in the patients (P = = = =0.99 and 0.86 for those with and without severe toxicity, respectively), but significantly less than that in Caucasians reported previously (P < < < <0.001). The results suggested that determination of UGT1A7 genotypes would not be useful for predicting severe toxicity of irinotecan.

Accuracy in the assessment of performance status by oncologists has not been well evaluated. We investigated possible discrepancies in the assessment of performance status among patients, nurses, and oncologists, and evaluated the prognostic importance of each assessment. Two hundred and six inpatients with inoperable, advanced non-small cell lung cancer were investigated prospectively. Weighted Kappa statistics for inter-observer agreement were 0.53 between oncologists and patients and 0.63 between oncologists and nurses. There was a significant difference among the assessments by the three groups (P < 0.001). Oncologists gave the healthiest performance status assessment, nurses an intermediate assessment, and patients the poorest. When included separately in the Cox model, the assessment by each group was significantly correlated with survival. However, the assessment by the patients themselves failed to distinguish survival of patients with performance status 1 and 2. Among the three models including patient-, nurse-, and oncologist-assessed PS, that including oncologist-assessed PS best fitted to the observed survival data. These results showed that the assessment by the patients themselves is different from those by the nurses and the oncologists and provided additional support for the use of the assessment by oncologists in clinical oncology. © 2001 Cancer Research Campaign http://www.bjcancer.com

ContextImmune checkpoint inhibitors, including anti–programmed cell death-1 (PD-1) antibodies, have become promising treatments for a variety of advanced malignancies. However, these medicines can cause immune-related adverse events (irAEs), including endocrinopathies.ObjectiveThis study examined the incidence of endocrine irAEs induced by nivolumab.Patients and Main Outcome MeasuredSixty-six patients treated with nivolumab at Nagoya University Hospital were prospectively evaluated for pituitary hormones, thyroid function, antithyroid antibodies (Abs), and glucose levels every 6 weeks after the initiation of nivolumab for 24 weeks.ResultsFour out of 66 patients developed destructive thyroiditis, and three patients developed hypothyroidism requiring levothyroxine replacement. The prevalence of positive anti-thyroglobulin Abs (TgAbs) and/or anti–thyroid peroxidase Abs (TPOAbs) at baseline was significantly higher in the group that developed destructive thyroiditis (3/4) compared with the group that did not develop thyroiditis (3/62; P = 0.002). There were no significant differences in other clinical variables between the groups. There were no endocrine irAEs other than destructive thyroiditis during the 24 weeks. The prevalence of TgAbs and/or TPOAbs at baseline was not associated with the development of other irAEs, including pneumonitis, colitis, or skin reactions.ConclusionsOur real-world data showed that destructive thyroiditis was an endocrine irAE that was frequently induced by nivolumab and was significantly associated with positive TgAbs and/or TPOAbs before treatment. Our findings indicate that evaluating these Abs before treatment may help identify patients with a high risk of thyroidal irAEs and may have important clinical benefit.

BackgroundSeveral immune-related adverse events (irAEs) are reported to be associated with therapeutic efficacy of immune checkpoint inhibitors, yet whether pituitary dysfunction, a life-threatening irAE, affects overall survival (OS) in patients with malignancies is unclear. This prospective study examined the association of pituitary dysfunction (pituitary-irAE) with OS of patients with non-small cell lung carcinoma (NSCLC) or malignant melanoma (MM).MethodsA total of 174 patients (NSCLC, 108; MM, 66) treated with ipilimumab, nivolumab, pembrolizumab, or atezolizumab at Nagoya University Hospital were evaluated for OS and the development of pituitary-irAE. Kaplan-Meier curves of OS as a function of the development of pituitary-irAE were produced with the log-rank test as a primary endpoint.ResultsPituitary-irAE was observed in 16 patients (4 (3.7%) with NSCLC, 12 (18.2%) with MM) having two different disease types: hypophysitis with deficiency of multiple anterior pituitary hormones accompanied by pituitary enlargement, and isolated adrenocorticotropic hormone (ACTH) deficiency without pituitary enlargement. Among these patients, 6 developed pituitary-irAE while being treated with ipilimumab (6/25 patients (24.0%) treated with ipilimumab) and 10 developed pituitary-irAE during treatment with nivolumab or pembrolizumab (10/167 (6.0%)). All 16 patients had ACTH deficiency and were treated with physiological doses of hydrocortisone. The development of pituitary-irAE was associated with better OS in patients with NSCLC (not reached vs 441 (95% CI not calculated) days, p<0.05) and MM (885 (95% CI 434 to 1336) vs 298 (95% CI 84 to 512) days, p<0.05).ConclusionsIn our study cohort, the incidence of pituitary-irAE was higher than previously reported and the development of pituitary-irAE predicted better prognosis for both NSCLC and MM when patients were treated with physiological doses of hydrocortisone.Clinical trials registrationUMIN000019024.

S-1 is an oral anticancer agent composed of tegafur (FT),S -1 (Taiho Pharmaceutical, Tokyo, Japan) is an oral anticancer agent. This anticancer drug is currently one of the most widely prescribed agents for treatment of gastric cancer in Japan, as a standard option for chemotherapy.(1-3) S-1 is a formulation of FT, CDHP, and Oxo in a molar ratio of 1:0.4:1. (4) FT is a pro-drug for cytotoxic 5-FU. The biotransformation of FT to 5-FU is demonstrated to be catalyzed by the liver drug-metabolizing enzyme CYP2A6.(5,6) The addition of CDHP increases the plasma level of 5-FU, as CDHP prevents degradation of 5-FU by competitively inhibiting DPD, (7) which is a rate-limiting enzyme responsible for 5-FU detoxification.(8) Oxo reduces the gastrointestinal toxicity caused by the active 5-FU by blocking the orotate phosphoribosyltransferase pathway, which relates to further activation of 5-FU. (9,10) CYP2A6 is a polymorphic enzyme that shows considerable interindividual variability in its activity.(11-18) CYP2A6*1 is defined as the wild-type allele. CYP2A6*4 is a complete deletion of the CYP2A6 gene.(11-13) Among the CYP2A6*4 variants, CYP2A6*4A is a major variant seen in the Japanese population.(12,13) CYP2A6*7 is a single nucleotide polymorphism (1412T>C) causing an amino acid change (I471T) that decreases enzymatic activity.(14) CYP2A6*9 has a -48T>G nucleotide substitution in the TATA box of the 5′ flanking region of the CYP2A6 gene, which reduces the expression levels of CYP2A6 mRNA and protein in human livers.(15,16) These CYP2A6 polymorphisms are seen frequently in Japanese people with allele frequencies of approximately 20% for CYP2A6*4A, 6% for CYP2A6*7, and 20% for CYP2A6*9. (13,17,18) Thus, it was postulated that these CYP2A6 genetic polymorphisms in Japanese people influenced the PK variability of FT and 5-FU and susceptibility to adverse effects as well as S-1 anticancer activity. The results obtained by Daigo et al. partly support this hypothesis. (19) They found that the four-fold higher AUC of FT seen in one patient compared with four other patients was attributed to the simultaneous presence of CYP2A6*4A and CYP2A6*11 (S224P), causing reduced catalytic activity in the patient. This implies that CYP2A6 genetic polymorphisms alter the PK of FT.Because CDHP has been reported to be predominantly excreted in the urine, (20) interindividual variability of the plasma level of CDHP caused by renal function was expected to occur. The variability in the plasma concentration of CDHP that thus occurred was assumed to affect the PK of 5-FU. Ikeda et al. have suggested this point with data obtained from four patients. (21) Taking these considerations into account, the PK of 5-FU were expected to be influenced by polymorphisms in the CYP2A6 gene, (11)(12)(13)(14)(15)(16)(17)(18) and the PK of CDHP. Therefore, in the present study, the effects of CYP2A6 genotype and plasma

BackgroundNecroptosis is a form of programmed cell death that is accompanied by release of intracellular contents, and reportedly contributes to various diseases. Here, we investigate the significance of necroptosis in pancreatic cancer. MethodsWe used immunohistochemistry and western blot analysis to evaluate expression of the key mediators of necroptosis-receptor-interacting serine/threonine protein kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL)-in human pancreatic cancer. We also tested the effects of conditioned media (CM) from necroptotic cells on pancreatic cancer cells in Transwell migration and Matrigel invasion assays. Protein array analysis was used to investigate possible mediators derived from necroptotic cells. ResultsRIP3 and MLKL are highly expressed in human pancreatic cancer tissues compared with normal pancreas. MLKL expression was particularly intense at the tumor invasion front. CM derived from necroptotic cells promoted cancer cell migration and invasion, but not CM derived from apoptotic cells. C-X-C motif chemokine 5 (CXCL5) was upregulated in CM derived from necroptotic cells compared with CM derived from control or apoptotic cells. Moreover, expression of the receptor for CXCL5, C-X-C-motif chemokine receptor-2 (CXCR2), was upregulated in pancreatic cancer cells. Inhibition of CXCR2 suppressed cancer cell migratory and invasive behavior enhanced by necroptosis.

Cancer-associated fibroblasts (CAFs) promote the progression of pancreatic ductal adenocarcinoma (PDAC) via tumor-stromal interactions. Neutrophil extracellular traps (NETs) are extracellular DNA meshworks released from neutrophils together with proteolytic enzymes against foreign pathogens. Emerging studies suggest their contribution to liver metastasis in several types of cancer. Herein, in order to investigate the role of NETs in liver metastasis in PDAC, the effects of NET inhibitors on spontaneous PDAC mouse models were evaluated. It was demonstrated that DNase I, a NET inhibitor, suppressed liver metastasis. For further investigation, further attention was paid to liver micrometastasis and an experimental liver metastasis mouse model was used that was generated by intrasplenic tumor injection. Furthermore, DNase I also suppressed liver micrometastasis and notably, CAFs accumulated in metastatic foci were significantly decreased in number.In vitro experiments revealed that pancreatic cancer cells induced NET formation and consequently NETs enhanced the migration of hepatic stellate cells, which was the possible origin of CAFs in liver metastasis. On the whole, these results suggest that NETs promote liver micrometastasis in PDAC via the activation of CAFs.

Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6, related to reduced catalytic and transcriptional activities of UGTs, is associated with the decreased glucuronosyltransferase activity for SN-38 in Japanese patients with cancer.