Takashi Yoshioka

Hypometabolism in the limbic system of cancer patients observed by positron emission tomography.

Brain images obtained by a positron emission tomography with 18F‐fluorodeoxyglucose from 19 pretreatment cancer patients with variable cancers except brain cancers were compared with those from 17 inpatients with benign diseases. Relative reduction in regional cerebral metabolism of glucose was found mainly in the limbic structures including the bilateral orbitofrontal cortex, lateral frontal cortex, cingulate gyrus, thalamus, hippocampus and parahippocampal gyrus, insulae, and basal ganglia. The regional metabolism tended to be low in the patients who had severe pains which required opiates and morphines, and tended to be preserved in the patients who were already disclosed of their malignancy based on previous studies such as biopsy. Our findings would support that psychological deficits in cancer patients are associated with abnormalities in regional brain metabolism in the limbic system. Copyright

Dose escalation study of docetaxel and nedaplatin in patients with relapsed or refractory squamous cell carcinoma of the esophagus pretreated using cisplatin, 5-fluorouracil, and radiation

BackgroundDefinitive chemoradiation with cisplatin (CDDP) and 5-fluorouracil (5FU) has been playing an important role in the treatment of esophageal cancer, but some patients are not curable or have recurrent lesions. However, few chemotherapeutic regimens are available for such patients. Docetaxel and nedaplatin are active for esophageal cancer. We conducted a dose-escalation study of docetaxel and nedaplatin as second line-chemotherapy after definitive chemoradiation in patients with relapsed or refractory squamous cell carcinoma of the esophagus after chemoradiation.MethodsNedaplatin was administered on day 1 and docetaxel was administered on days 1 and 15, every 4 weeks. Dose escalation was based on the dose-limiting toxicity (DLT) observed during the first cycle.ResultsTwelve patients were enrolled. At a docetaxel dose of 30u2009mg/m2 and a nedaplatin dose of 80u2009mg/m2, one grade 4 neutropenia occurred and caused one treatment break longer than 2 weeks, but there were few DLTs. At doses of 35 and 80u2009mg/m2, respectively, two grade 4 neutropenias and one grade 2 thrombopenia occurred and caused three treatment breaks longer than 2 weeks. Therefore, the maximum tolerated dose was established at this dose level. Two grade 3 anorexias and one grade 3 nausea occurred, but other non-hematological toxicities were generally mild. Responses were seen in one-fourth of the 12 patients, including one complete remission.ConclusionThe recommended doses of docetaxel and nedaplatin were 30 and 80u2009mg/m2, respectively. This combination could be a potential second-line treatment for this target population.

A novel germline mutation of the LKB1 gene in a patient with Peutz-Jeghers syndrome with early-onset gastric cancer

The gene responsible for Peutz-Jeghers syndrome (PJS), LKB1 (also called STK11) was mapped to chromosome 19p13.3 and was found to encode a putative serine/threonine protein kinase, LKB1. As only a limited number (∼100) of germline mutations of the gene have been reported, and because the protein function is still unclear, information about LKB1 mutations and their expression should be accumulated to understand the phenotype-genotype correlation of this disease. Here we report a patient with sporadic PJS with early-onset gastric cancer. We found a novel germline frameshift mutation (757-758insT) in the LKB1 gene and a marked reduction in LKB1 protein expression in the carcinoma cells, suggesting that the loss of LKB1 function may have led to the carcinogenesis of the gastric cancer.

Phase I/II study of sequential therapy with irinotecan and S-1 for metastatic colorectal cancer

Background:Both irinotecan (CPT-11) and S-1 are active against colorectal cancer; however, as S-1 is a prodrug of 5-fluorouracil (5-FU), 5-FU and its metabolites might inhibit the antitumour effect of CPT-11. Therefore, we designed a sequential combination, in which CPT-11 infusion was given on day 1 and S-1 was given orally at 80u2009mgu2009m−2 per day on days 3–16 every 3 weeks.Methods:Twelve patients entered the phase I study, and the recommended doses were determined as a CPT-11 dose of 150u2009mgu2009m−2 and an S-1 dose of 80u2009mgu2009m−2.Results:In all, 36 patients entered the phase II study, of whom 4 and 16 had complete and partial responses. The overall response rate was 55.6% (95% confidence interval, 38.1–72.1%), and median progression-free survival was 7.7 months (95% confidence interval, 4.8–12.6 months). Grade 3 neutropenia was the most common haematological toxicity and occurred in 6.5% of 215 treatment courses. Grade 3 non-haematological toxicities included anorexia (1.4%) and diarrhoea (0.9%). There was no grade 4 toxicity of any kind.Conclusion:Our results suggest that this regimen is convenient, safe and promising, compared with conventional regimens for patients with metastatic colorectal cancer.

O-[18F]fluoromethyl-L-tyrosine is a potential tracer for monitoring tumour response to chemotherapy using PET: an initial comparative in vivo study with deoxyglucose and thymidine.

PurposeTo compare the utility of a new artificial amino acid, O-[18F]fluoromethyl-L-tyrosine ([18F]FMT), for monitoring cancer chemotherapy with deoxyglucose and thymidine.Methods[18F]FMT, [14C]deoxyglucose ([14C]DG) and [6-3H]thymidine ([3H]Thd) were applied in this study. A 2.5xa0mg/kg dose of mitomycin (MMC) was administered to AH272 rat hepatoma-bearing Donryu rats. Tumour uptake of each tracer was measured just before (baseline) and on daysxa01, 3, 5 and 7 after the MMC administration, 1xa0h after a mixture of [18F]FMT, [14C]DG and [3H]Thd had been injected, and was shown as DURs (% injected dose/gram tissue normalised for the rat body weight). Dual-tracer macroautoradiographs with [18F]FMT and [14C]DG were also prepared.ResultsThe tumour uptake for each tracer decreased earlier than did the tumour size. DURs (mean±SD) at baseline and on daysxa01, 3, 5 and 7 were as follows: [18F]FMT: 4.68±0.72, 3.34±0.66, 3.13±0.72, 3.42±0.45, 3.01±0.32; [14C]DG: 3.26±0.40, 3.09±0.55, 3.01±0.97, 2.28±0.35, 1.70±0.72; and [3H]Thd: 2.23±0.46, 1.54±0.45, 1.28±0.37, 1.35±0.20, 0.94±0.12. Decrease in [18F]FMT uptake compared with baseline was significant from dayxa01 (p<0.01), and the decrease in [3H]Thd uptake was also significant on dayxa01 (p<0.05) and days 3–7 (p<0.01). However, decrease in [14C]DG uptake was only significant from dayxa05 (p<0.01). Macroautoradiography suggested that the influence of inflammatory cells on the accumulation of [18F]FMT in tumours is smaller than that on the accumulation of [14C]DG.Conclusion[18F]FMT uptake shows a rapid and sensitive response to chemotherapy, comparable to that of [3H]Thd, suggesting that it may be applied as a powerful tracer for monitoring of proliferative activity after cancer chemotherapy using PET.

Biweekly administration regimen of docetaxel combined with CPT-11 in patients with inoperable or recurrent gastric cancer

AbstractBackground. Both docetaxel (TXT) and irinotecan (CPT-11) are active chemotherapeutic agents for gastric cancer. We designed a biweekly administration regimen of TXT combined with CPT-11 for 4 weeks as one cycle in patients with inoperable or recurrent gastric cancer, and conducted a dose-escalation study.n Methods. Patients with histologically confirmed gastric cancer were treated with the regimen. The dosage levels of TXT and CPT-11 were as follows: level 1, 30u2009mg/m2 and 50u2009mg/m2; level 2, 35 and 50u2009mg/m2; level 3, 40 and 50u2009mg/m2; level 4, 40 and 60u2009mg/m2; and level 5, 50 and 60u2009mg/m2. The dose escalation was based on the dose-limiting toxicity (DLT) observed during the first cycle.n Results. Grade 4 neutropenia was observed at level 3, but no other DLT was observed at less than level 4 during the first cycle. However, three patients at level 3 could not continue treatment without a decrease in the dosage after the second cycle. Based on these results, level 2 was considered to be the clinically recommended dosages.n Conclusion. Biweekly TXT and CPT-11 was well tolerated. The recommended dosages of TXT and CPT-11 for a phase II trial are 35u2009mg/m2 and 50u2009mg/m2, respectively.

Phase I-II study of biweekly paclitaxel administration with fixed-dose-rate cisplatin in advanced gastric cancer

BackgroundBoth paclitaxel (TXL) and cisplatin (CDDP) show efficacy against gastric cancer. The aim of this phase I-II study was to determine the maximum tolerated dose (MTD) and to evaluate the toxicity and efficacy of combination chemotherapy with these two agents.MethodsNineteen patients entered the phase I part of the study, and 21 patients entered the phase II part. TXL infusions were administered on days 1 and 15, with a fixed 3mg/m2 dose of CDDP.ResultsIn the phase I part of the study, we determined dose level 5, which represented a TXL dose of 18mg/m2, with CDDP 3mg/m2, to be the MTD. The recommended dose (RD) was level 4, with a TXL dose of 16mg/m2 with CDDP, 3mg/m2. In the phase II part of the study, the response rate was 25.0%; five patients had a partial response, seven had stable disease, 6 had progressive disease, and 2 were not evaluable. Grade 3 or 4 neutropenia was the most common adverse event and occurred in 65% of the patients. During treatment, 25% of the patients received granulocyte colony-stimulating factor, but febrile neutropenia was not shown in any of the patients. Major nonhematological toxicities were nausea/vomiting, anorexia, fatigue, alopecia, and sensory neuropathy. Adverse reactions of grade 3 or 4 were shown by two patients, one with anorexia (5%) and the other with sensory neuropathy (5%).ConclusionThe RD was determined to be TXL 14mg/m2, with CDDP 3mg/m2.

Performance study of a miniature gamma ray scintillationvivo probe for tumor localization

We have developed a miniature γ-ray endoscopic probe consisting of dual BGO detector probes for tumor detection inside the body cavities. The dual detector system was coupled with random coincidence to decrease the distant background radiation and to improve its spatial resolution for tumor localization.Method: The performance of the probe was investigated with a point source and a water phantom. A solution of positron emitting18F isotope was used as the source. Clinical trials of the probe were done to localize tumors on the skin surface of four subjects carrying tumors close to the body surfaces, into whom67Ga-citrate and18F-FDG radiopharmaceuticals were injected.Results: Measurements indicated that the spatial resolution of the dual detector probes is around 1.5 times better than the single detector probe, and both single and dual detector endoscopic probe systems are capable of localizing a tumor on a large photon background.Conclusion: The endoscopic probe may be easier to insert inside body cavities due to the small crystal size and the flexible light guides. A single detector probe with higher sensitivity may be useful in searching for tumors over a wide intracavity area but a dual detector probe can be used for precise tumor localization. The detector probe may also be suitable for intraoperative observation.