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Background: TAS-102, a new treatment option for patients with metastatic colorectal cancer that is refractory or intolerant to standard therapies, has been improving survival with acceptable tolerability and adverse events. Adverse hematological events associated with TAS-102 treatment were extensively profiled in the RECOURSE trial, but pulmonary toxicities associated with TAS-102 therapy are distinctly uncommon. In a recent early post-marketing phase vigilance on TAS-102 in Japan, seven cases of pulmonary disease were reported, but patient follow-up in this study was incomplete. Here, we present the first case of interstitial lung disease occurring in association with TAS-102 treatment., Case Presentation: A 57-year-old Japanese man who had previously received two standard treatments was admitted in 2014, at which time we administered TAS-102 (110 mg/day) as a third-line chemotherapy. He was safely treated with TAS-102 for the first planned cycle; however, approximately 4 days after receiving the second cycle of TAS-102, he complained of high fever and subsequent dyspnea with severe hypoxemia and went to the emergency room. A chest X-ray revealed diffuse coarse reticular shadows with ground-glass opacity on both lungs. Furthermore, a chest computed tomography scan showed thickening of the bronchovascular bundles with extensive ground-glass opacification and pleural effusions in both lung fields. In addition, a peripheral blood lymphocyte stimulation test with TAS-102 showed higher values compared with control samples. Consequently, we suspected drug-induced interstitial pneumonia, and discontinued treatment. Our patient was given an initial administration of high-dose methylprednisolone (1000 mg/day) for 3 days and oxygen. Our patient was discharged with oral prednisolone (20 mg/day) and improved symptomatically and radiologically., Conclusions: These findings suggest that interstitial pneumonia is a rare complication of TAS-102 chemotherapy, but the possibility of interstitial pneumonia should always be considered when a patient presents with a respiratory disorder while undergoing TAS-102 systemic chemotherapy. Prompt discontinuation of TAS-102 and treatment with high-dosage corticosteroids is needed to avoid exacerbating respiratory symptoms.

The "Cancer Chemotherapy and its Management" subcommittee at the Ehime Cancer Care Network Priority Hospitals (Ehime Cancer Kyoten Hospitals)with a focus on medical expenses associated with chemotherapy, surveyed awareness among 98 clinicians regarding certifications of eligibility for Limited Health Insurance Payments during cancer treatment. This committee also lists social and clinical problems encountered at the Ehime Cancer Care Network Priority Hospitals. In our survey, 78% of clinicians were consulted about medical expenses associated with chemotherapy and were actively involved in resolving medical expense problems and resulting correspondences. However, only 38% of clinicians could explain the details of the Japanese guideline on the catastrophic cap and the certifications of eligibility for Limited Health Insurance Payments. This knowledge deficit was more pronounced in younger residents. From our analyses of the awareness about medical expenses among clinicians, we recommend the establishment of the following systems for the management of cancer patients. First, establish a reporting system and early consultation on the catastrophic cap and the certifications of eligibility before initiating cancer treatment. Second, education regarding medical expenses should be mandatory for clinicians, especially for young residents. Third, patients with cancer suffering in the interval of the medical expense and the social system should be relieved with new systems.

After 1990's, the development of new generation anti-cancer agents produced encouraging improvement of prognosis in inoperable or relapsed stomach cancer and colorectal cancer. However, non-hematological toxicity, such as peripheral neuropathies, become a new dose-limiting toxicity. In several new generation drugs, measures for controlling peripheral neuropathy had not been established besides dose modification or schedule modification. We tried to control the peripheral neuropathy induced by anti-cancer agents with the assistance of an adjuvant analgesics ladder. A total of 18 digestive cancer patients who presented with peripheral neuropathy of grade 1 or more(NCI-CTCAE ver 3.0), in the chemotherapy including Taxol or Oxaliplatin, were enrolled. The first stage of the adjuvant analgesics ladder was set as the antidepressant(amoxapin), the second stage was anticonvulsive drugs(valproic acid or clonazepam) and the third stage was antiarrhythmic drug(mexiletine). In each stage, if the drug turned out to be ineffective after two / weeks follow-up, it shifted to the next stage. The response rate of each step was 61.1%(11/18)of the first stage, 50.0%(5/10)of the 2nd stage, 50.0%(2/4)of the 3rd stage, and the overall response rate was 77.8%. The discontinuance of cancer treatment by peripheral neuropathy was observed only in 1 patient 5.5%(1/18)in the Taxol administered group. The toxicity profile was skin eruption and drowsiness, but the skin eruption was observed only in 1 patient at the 3rd stage and the drowsiness in 2 patients at the 2nd stage. It appears that the method to control the peripheral neuropathy induced by anti-cancer agents with the assistance of adjuvant analgesics ladder was effective and safe, but a large-scale clinical trial was warranted.

A novel hydrophilic gold compound, tetrakis((trishydroxymethyl)phosphine)gold(I) chloride 1, has been investigated for its antitumor properties. In vitro studies demonstrate that 1 is active against HCT-15, AGS, PC-3, and LNCaP tumor cells. Cell cycle analysis of the HCT-15 cells by flow cytometry revealed elongation of the G1 phase of the cell cycle leading to growth inhibition. Administration of 1 to Balb/C mice inoculated with syngenic meth/A cells demonstrated statistically significant dose-dependent survival time.

A gold compound, which is an anti-rheumatoid agent, was clinically applied to patients showing a high level of tumor-associated antigens. Two patients showed no clear evidence of recurrence except for a high level of tumor-associated antigens. The gold compound was injected i.m. every week at the dose of 25 mg/body for 10 times to a patient showing a high CEA level that had arisen eight years after cervical dissection for a tongue carcinoma. It was also administered every other week for 30 times at the dose of 25 mg/body to a patient showing high CA19-9 and SLX levels five years after palliative left pulmonary resection followed by radiation therapy for left pulmonary carcinoma. The CEA level dropped to the normal limit after 10 injection and remained at that level after cessation of the gold treatment. SLX and CA19-9 levels of the second patient showed lower than initial values, although SLX did not fall to the normal range after the 30 injections. No side effects such as lowering of white blood cell count, BUN elevation, or kidney dysfunction were seen.

Tannic acid which was found earlier to have growth suppressive activity against cultured tumor cells, was given to Balb/c mice p.o. The mice had been inoculated with syngeneic tumor cells (Meth/A) i.p. When tannic acid was suspended in drinking water and given daily at doses of approximately 875 mg/kg/day and 1750 mg/kg/day, the respective survival rates were 59% and 48%, with that of the control mice being 29%. To study the cytotoxicity of tannic acid, we administered the tannic acid to mice at 875 and 1750 mg/kg/day for 35 days. The weight gain for each dose was lower than that of the control, although the difference was not significant. When tannic acid was given at 8750 mg/kg/day, the weight gain was significantly lower than the control. A histologic study did not show any pathological findings in the kidney, liver, or lungs in the mice given tannic acid at the above doses.

Tannic acid was cultured together with tumor cells that had originated from human malignant tumors (HCT-15 & AGS). Significant suppression of tumor growth was observed. The 50% suppression was observed at the concentration between 50 micrograms/ml and 12.5 micrograms/ml. When tannic acid was injected into HCT-15 cells by electroporation at 1180 mu p and 200 ohm, the suppression rate was 34.3% at the concentration of 50 micrograms/ml in HBS solution. The suppression rate of cells only in contact with tannic acid solution for one hour under the same conditions as used for electroporation, was 26.1%. Histographic findings suggested that tannic acid almost completely blocked the S phase of the cell cycle.

Crude methanol extracts of red and white wines were added to diethyl ether in order to divide them into the anthocyanin fraction (insoluble in diethyl ether) and fractions containing other flavonoids and their derivatives (soluble in diethyl ether). However, the white wine did not contain anthocyanins (all of the methanol extract was soluble in diethyl ether). When HCT-15 cells, derived from human colon cancer or AGS cells, derived from human gastric cancer, were cultured with these fractions, the anthocyanin fraction from the red wine and the non-anthocyanic substances extracted from red and white wines suppressed the growth of the cells, and the suppression rate by the anthocyanin fraction was significantly higher than that of the other fractions. Thin-layer chromatographic analysis revealed mostly delphinidin in the anthocyanin fraction. The other fractions contained mostly flavonoids and their derivatives. The sugars in all fractions were mainly glucose, fucose, and fructose. Flow cytometric study suggested that the anthocyanin fraction blocked mostly S, G2, and M phase, and the non-anthocyanic flavonoids also blocked these phases, although the histographic pattern varied depending on the fractions. Methanol insoluble but water soluble fractions (mostly free sugars) of red and white wines did not show such suppressive effects.

Sodium aurothiomalate (monogold monosodium mono-hydrogen sulfidobutanedioate), an anti-rheumatoid gold agent, was injected s.c. every other day for three times or given in drinking water daily for two weeks to Balb/C mice that were inoculated with syngeneic Meth/A cells i.p. As the control, cisplatinum was injected s.c. Survival curve was then observed and significance was determined by Wilcoxon's method. Statistically significant effects on survivals was obtained by 30 mg/kg/day s.c. or 75 mg/kg/day p.o. of gold. A dose of less than 12.5 mg/kg/day s.c. adversely affected the survival. Cisplatinum was significantly effective at the dose of 12.5 mg/kg/day, but markedly toxic at the dose of 125 mg/kg and adversely effective at 6 mg/kg/day s.c. The range of dose effectiveness of cisplatinum on survival was narrower than that of gold. Gold was effective when given s.c. or p.o. No significant toxicity of gold was observed at doses up to 125 mg/kg/day.

Gold agents have been widely used for the treatment of rheumatoid arthritis. We studied the growth inhibiting effect of such an agent on malignant cells in vitro. HCT-15, AGS cells derived from a human malignancy, and Meth/A cells from a malignant lymphoma of Balb/C mice were cultured separately with gold agent at concentrations of 2 micrograms/ml. Four days after the cultures had been incubated in a 5% CO2 incubator at 37 degrees C, cell counts were made; and significance of differences was analyzed by Student's t test. Additionally, HCT-15 cells were cultured with gold for two days, and then the cells were analyzed by flow cytometry. The growth of HCT-15, AGS, and Meth/A cells was suppressed by gold. Fifty percent suppression was observed at a concentration between 50 micrograms/ml and 10 micrograms/ml for HCT-15 cells, between 125 micrograms/ml and 50 micrograms/ml for AGS cells, and between 125 micrograms/ml and 50 micrograms/ml for Meth/A cells. Fifty percent suppression of HCT-15 cell growth by cisplatinum was found between 50 micrograms/ml and 10 micrograms/ml. Flow cytometric findings showed a significant rise in the tetraploid peak, a mild rise in the resion between diploid and tetraploid peaks, and an increase in cells with a ploidy greater than four. These data suggest that gold blocks the S phase, G2 to M phase, and M phase as well. To observe the cytotoxicity of gold, each of 10 of 4 week-old Balb/C mice was injected s.c. at a dose of 10 mg/kg or 2 mg/kg every other day for a total of 3 injections, or was administered the gold at 30 mg/kg/day p.o. for 10 days. All mice were still alive after 20 days of observation. Cisplatinum at a dose of 10 mg/kg was also injected s.c. one time into each of 10 mice, and 60% of the animals died within 10 days after the injection.

Quinones were studied for their growth inhibitory effect on cultured malignant cells. HCT-15 cells derived from human colon carcinoma were used for these experiments. Quinones used were arbutin in the benzoquinone group, juglone and lawsone in the naphthaquinone group, alizarin, emodin, 1,8-dihydroxyanthraquinone, and anthraquinone in the anthraquinone group, and xanthone. Cultured cells were incubated with various concentrations of the quinones for four days in a 5% CO2 incubator, after which cell numbers were counted and significance of differences was analyzed by Student's t test. Anthraquinones and naphthaquinones used in these experiments were more effective than the monocyclic quinone. The 50% suppression dose was less than 12.5 micrograms/ml for them. The number of OH groups seemed to play an important role in the degree of the cell growth inhibition: anthraquinones with 2 or 3 OH groups were more effective than those with no OH group like, 9,10-dioxoanthracene and xanthone. In fact, anthraquinones with no OH group and xanthone were not significantly effective. Flow cytometric histograms revealed a specific pattern; that is, lawsone and juglone in the naphthaquinone group and alizarin and 1,8-dihydroxy-anthraquinone in the anthraquinone group blocked mainly the S phase, and emodin in the anthraquinone group blocked the G1 to S phase of the cell cycle.

Melanoidin, which belongs to the melanin group of molecules, was extracted from the polysaccharide biological response modifier PSK. Melanoidin was cultured together with HCT-15 cells derived from human colon cancer and with AGS cells derived from human gastric carcinoma. After four days of culture, cell count was compared with that of the control cells. Significant suppression was observed, that is, 50% suppression was shown at concentrations of melanoidin between 200 and 100 micrograms/ml. A histogram generated by flow cytometry showed elevation of the tetraploid peak and of that between diploid and tetraploid peaks, suggesting blockage of S phase and G2 to M phase of the cell cycle. Thus, melanoidins contained in the immunomodulator PSK revealed to have a direct tumor cell growth inhibitory effect.

The 2''-O-, 3''-O- and 2'',3''-di-O-substituted derivatives (4a--p) of etoposide were prepared by nucleophilic substitution of 4'-O-benzyloxycarbonyletoposide (2) followed by deprotection. Controlled reaction (a limited amount of reagents and low temperature) was required for preparing the mono-O-substituted derivatives. In terms of ED125 values, doses which show 125% of T/C against P388 leukemia in mice, both the 2''-O-acetate (4a, ED125 = 0.18 mg/kg) and 3''-O-acetate (4b, 0.23 mg/kg) were nearly as active as etoposide (1, 0.19 mg/kg), while the 2'',3''-di-O-acetate (4c, 1.9 mg/kg) was somewhat less potent. In the replacement with other substituents, antitumor activity of the 2''-O-substituted derivatives was affected much more by the difference of the substituents as compared with that of the corresponding 3''-O-substituted derivatives. In the 2'',3''-di-O-substituted derivatives, the activity was decreased additively on the substituents.

We have previously reported the leukocyte migration inhibition (LMI) factor in cancer patients, which is one of the specific parameters of cell mediated immunity. Since interpretation of these results was sometimes difficult in human cancer because of the unknown participation in the reaction, the inbred mouse strains were used as an experimental animal. We studied how the LMI factor of murine spleen cells changed with immunization of tumor cells, and intraperitoneal injection of protein polysaccharide (PSK) and/or cyclophosphamide (CPA). Method. LMI was performed by Clausen's method. Mouse strain; C3H/Heston. Tumors; C3M2 (methylcholanthrene induced tumor) and MAC (spontaneous mammary tumor). Result. Migration cells of murine spleen cells were almost granulocytes. Migration inhibition was maximum in 2 to 3 weeks after immunization of tumor cells. In vivo studies as well as in vitro studies revealed that C3M2 and MAC were not crossreactive. Migration was accelerated with CPA and inhibited with PSK. Leukocyte migration was inhibited by injection of PSK after treatment of CPA at a dose of 50 mg/kg, while in the case of CPA at a dose of 200 mg/kg, preinjection of PSK inhibited leukocyte migration.