A 49-year-old male was referred to our hospital because of an abnormal shadow in his left lower lung field on chest X-ray. Magnetic resonance imaging scans revealed a large mass on the left diaphragm. The tumor was surgically extirpated. The tumor, encapsulated and growing from the center of the left diaphragm, measured 18 x 8 x 4 cm and weighed 440 g. Microscopic examination revealed a solitary fibrous tumor with mitotic activity of 7/ 50 hpf. Immunohistochemically, the tumor was negative for cytokeratin, s-100 protein, desmin, and alpha-smooth muscle actin, while positive for vimentin and CD34. On a histoculture drug response assay using the resected tissue, the tumor was sensitive to 5-FU, adriamycin, mitomycin C and docetaxel, and resistant to cisplatin, irinotecan, and gemcitabine.

This review summarizes drug induced nephrotic syndrome. Major drugs which induce drug related nephrotoxicity are antibiotics, NSAID, radiocontrast media, anticancer drug and antirheumatic drug. Drug induced nephropathy can show various forms of renal diseases. The nephropathy consists of acute tubular necrosis, acute tubulointerstitial nephritis, pre-renal type renal failure, obstructive renal failure, chronic tubulointerstitial nephritis and glomerular damage. Major drugs which induce nephrotic syndrome and glomerular damage are gold, penicillamine, bucillamine and NSAID. In the nephrotic syndrome due to these drugs, the major type of renal disease is the membranous glomerulonephritis and the nephropathy resolves completely when the drug is withdrawn; renal function does not deteriorate, and corticosteroids are unnecessary.

The clinical efficacy and safety of gemcitabine (GEM) monotherapy were studied retrospectively in the patients with recurrent or metastatic pancreatic cancer. The subjects were 30 patients who were treated with GEM at our center between May 2001 and August 2003. The objective overall response rate was 11% (3/28; 95% confidence interval, 2.3-28%). The disease control rate (CR+PR+SD) was 54%. Grade 3 or 4 neutropenia was most frequently seen in 46%. Non-hematological toxicities were mild. The median survival time was 4.8 months. One-year survival rate was 15%. This study showed the reproducible activity and safety of GEM in practice.

Thymidylate synthase (TS) is a target enzyme of 5-fluorouracil (5-FU), and the TS expression level of cancer tissues is a potential predictor of the response to 5-FU-based chemotherapy. The TS gene has a polymorphic tandem-repeat sequence, which is associated with its protein expression. Therefore, the TS polymorphism may also be a predictor of the response to 5-FU-based chemotherapy. In this study, we analyzed the TS genotype, TS protein level, and sensitivity to 5-fluoro-5'-deoxyuridine (5'-dFUrd) in 10 human gastric cancer cell lines. TS genotype was classified into 2R-homozygote (2R/2R, n=3), 3R-homozygote (3R/3R, n=5), and 2R/3R-heterozygote (2R/3R, n=2). The cell lines with 3R/3R showed a significantly higher IC50 value compared to those with 2R/2R or 2R/3R genotype. There was no relationship between TS protein level and 5'-dFUrd sensitivity. However, a statistically significant relationship was revealed between them when the subgroup with the genotypes of 2R/2R or 2R/3R was considered (r=0.815, p<0.05). In this subgroup, the cell lines with higher TS protein showed higher IC50 value for 5'-dFUrd, indicating less sensitivity to 5'-dFUrd. An identical relationship between the TS protein level and IC50 was also observed in the subgroup with 3R/3R genotype, although it did not reach statistical significance (r=0.745, p=0.09). These results suggest that the TS gene polymorphism and TS protein level may be independent predictors for 5-FU-based chemotherapy.

We discussed the future direction of studies on psycho-oncology by reviewing relevant previous findings regarding treatment, early detection, and prevention of psychiatric disorders experienced by cancer patients. PSYCHIATRIC DISORDERS IN CANCER PATIENTS: It is reported that the common psychiatric disorders among cancer patients are adjustment disorder, major depression, and delirium. In addition, prevalence of adjustment disorder and major depression is higher among advanced cancer patients than that among patients with early stage cancer, and that delirium is the most common disorder among patients with terminally ill cancer.

The feasibility and anti-tumor activity of gemcitabine in postoperative adjuvant chemotherapy were evaluated retrospectively.

We evaluated the reliability of CTC v 2.0 based on source documents and also studied the degree of inconsistency in toxicity grading. Five clinical research coordinators from the National Cancer Center Hospital independently reviewed source documents from 17 patients and graded toxicities in the following common adverse events: diarrhea, nausea, stomatitis/pharyngitis, vomiting, febrile neutropenia, infection, infection unknown source, and sensory neuropathy. If grading was already documented on the medical chart, it was masked so that the coordinator could perform the evaluation without information bias. After the completion of toxicity grading, the participating coordinators discussed each case, and a consensus was reached for final toxicity grading. The proportion of agreement for each toxicity criteria are as follows: diarrhea; 0.59 (95%CI 0.35-0.82), nausea; 0.47 (0.23-0.71), stomatitis/pharyngitis; 0.59 (0.35-0.82), vomiting; 0.71 (0.49-0.92), febrile neutropenia; 0.88 (0.73-1.04), infection; 0.82 (0.64-1.01), infection by unknown source; 0.82 (0.64-1.01), sensory neuropathy; 0.65 0.42-0.87). The cause of variability largely depended on the differences in individual clinical assessment, and misunderstanding of toxicity criteria by coordinators has been observed. Even in a single institution environment, variability exists in the toxicity assessment and grading. Good training and education on toxicity assessment using common criteria and development of translated manual, including the interpretation of criteria assessment, may help reduce variability.

Cytotoxic drug-induced nausea and vomiting are the side effects most feared by cancer patients. Emesis is an instinctive defense reaction caused by the somato-autonomic nerve reflex, which is integrated in the medulla oblongata. Emesis caused by anticancer drugs is associated with an increase in the concentration of serotonin (5-HT) (5-HT) in the intestinal mucosa and brainstem. 5-HT released from the enterochromaffin (EC) cells, which synthesize and secrete 5-HT, stimulates the 5-HT receptors on the adjacent vagal afferent nerves. The depolarization of the vagal afferent nerves stimulates the vomiting center in the brainstem and eventually induces a vomiting reflex. 5-HT released from EC cells appears to mediate the cisplatin-induced emesis sensitive to 5-HT(3) receptor antagonists. The precise role of 5-HT in the occurrence of vomiting has not been fully elucidated. The present review describes the role of 5-HT in anticancer drug-induced emesis from the viewpoint of 5-HT release and afferent vagal nerve activity. Various models and methods for predicting emesis are also evaluated.

The proteasome is a multicatalytic proteinase complex responsible for the degradation of most intracellular proteins, including crucial to cell cycle regulation, cell growth, and apoptosis. Bortezomib (Vercade; formerly known as PS-341) is a novel dipeptide boronic acid that is the first proteasome inhibitor to have progressed to clinical trials. Below we discuss the mechanism of bortezomib for cancer therapy, review the clinical data, and introduce the potent effect on ATL cells.

Tamoxifen, an anti-estrogen, has been used for a long time as an adjuvant therapy in cases of estrogen receptor positive breast cancer. Tamoxifen also demonstrates some weak estrogenic activity. A small increase in serum triglycerides is commonly found after tamoxifen administration. Herein we report 3 cases of sever hypertriglyceridemia due to tamoxifen. Case 1 recovered with tamoxifen withdrawal. Tamoxifen was replaced with toremifene in case 2. The level of triglyceride decreased significantly after the change of agent. Tamoxifen was discontinued and anastrozole administration was started in the third patient. Her triglyceride levels improved. Tamoxifen-induced severe hypertriglyceridemia seen in these patients was an effect of its estrogen action. Anastrozole has been used to treat postmenopausal metastatic breast cancer, and several clinical trials in the adjuvant setting are ongoing. Anastrozole does not affect lipid metabolism. Therefore, anstrozole might be safe for patiens with abnormal triglyceride profiles during tamoxifen treatment. We recommended that a periodic serum triglyceride check is needed for patients treated with tamoxifen.

Cancer metastasis involves the complicated steps of tumor growth, angiogenesis, invasion and adhesion. At present new drugs targeting particular molecule (s) responsible for such cancer progression and metastasis have been developed in clinics. Major endpoints for cancer treatment should be prolongation of survival and maintenance of QOL. However, clinical development of such molecular-target based drugs is associated with difficulties in evaluating the efficacy in phase I/II studies prior to entering phase III study, because many of the targeted drugs seem cytostatic rather than cytocidal to tumors. New approaches incorporating technologies of genomics and proteomics may provide an expanding repertoire of molecular targeted therapeutics for clinical evaluation. In this review, the significance and problems of biomarkers available for clinical evaluation of molecular targeted drugs are discussed.

We developed various types of differentiation- and apoptosis-inducing agents against tumor cells and also studied the function and structure of synucleins and taste modifiers. Differentiation- and apoptosis-inducing agents are classified into DNA-damaging agents, Na(+), K(+)-ATPase inhibitors, agents affecting the redox states of tumor cells, agents affecting signal transduction pathways, isoprenoid compounds, and ATP-noncompetitive tyrosine kinase inhibitors. These include camptothecin, etoposide, cisplatin, transplantin, bufalin, arsenic trioxide, costunolide, C(2)- ceramide, daidzein, geranylgeranylacetone, geranylgeraniol, vitamin K(2), sophoranone, and beta-hydroxyisovalerylshikonin. The mechanisms of action of these differentiation- and apoptosis-inducing agents are described. The structure and function of synucleins are also reviewed for the development of potential antidementia agents. In addition, the structures of three purified taste modifiers are described.

Gemcitabine (GEM) is currently considered a standard drug for advanced pancreatic cancer and widely used for patients with this carcinoma. We report on 2 patients with unresectable pancreatic cancer who were able to survive for more than 2 years after GEM treatments. Case 1 was a 82-year-old woman with invasion to celiac artery and who was inoperable. During GEM administration, she had no symptoms and the tumor did not progress. However, because of the toxicities of heart failure, GEM administration was stopped after she took a total of 16,800 mg. After GEM administration was stopped, symptoms appeared and the tumor progressed. Case 2 was a 39-year-old man with obstructive jaundice with liver and lymph node metastases. He was treated with metallic stent in order to reduce cholestasis. During GEM administration, he had no symptoms and the tumor did not progress. As an adverse event, rash occurred after he took a total of 51,800 mg. GEM administration was then stopped. This patient sometimes developed cholestasis due to tumor ingrowths and sludge and was treated successful by endoscopy. GEM has shown to improve survival and show a clinically beneficial response in patients with advanced pancreatic cancer. However, toxic events can be expected to occur with long term GEM administration. We consider that management of complications such as obstructive jaundice is very important in the treatment of pancreatic cancer.

A multi-center cooperative clinical trial was undertaken to evaluate the safety and efficacy of weekly taxol (TXL) therapy combined with short-premedication as a pretreatment in an effort to determine if TXL can be used in ambulatory treatment. TXL was administered at 60 mg/m2 to patients with advanced recurrent breast cancer once a week without a rest or with a rest for 1 week after treatment for 3 weeks. A total of 36 patients were finally enrolled. The site of recurrence was the local region in 8 patients, lung/pleura in 24, liver in 9, bone in 16, lymph nodes in 15, epicardium in 2, and brain metastasis in 2. The response was CR in 2, PR in 12, NC in 9, PD in 8, and NE in 5, with a response rate of 45.2%. Grade 4 anorexia was reported as non-hematotoxicity. All other adverse reactions, such as myalgia/arthralgia and peripheral neuropathy, were mild (grade 1 or 2). Hematotoxic effects observed in this study included only grade 3 leukopenia in 5 patients, neutropenia in 4, and decreases in hemoglobin in 1.

To examine the feasibility of radiotherapy with a full dose of gemcitabine (1000 mg/m2 once a week) for unresectable pancreatic carcinoma, we treated 15 patients with 50 Gy/25 fractions/5 weeks concurrent chemoradiotherapy using a limited irradiation field. Eleven patients completed treatment. No lethal side effects were seen during and after these therapies. Two patients quit therapy because of tumor progression; one patient quit radiotherapy owing to general fatigue and nausea; and the other patient stopped gemcitabine administration owing to a grade 4 hematological adverse event. As only two patients stopped this protocol as a result of untoward effects of treatment, limited-field radiotherapy enabled us to treat pancreatic cancer with full-dose gemcitabine.

IMMUNOLOGICAL PARAMETER FOR CANCER PATIENTS: In this paper, we are the first to demonstrate that a disturbed immune system, especially imbalance between monocytes and T cells in peripheral blood mononuclear cells, is closely related to cancer recurrence. We have developed a parameter of immunocompetence in cancer patients, which we designated the monocyte/T cell(M/T) ratio. The M/T ratio was shown to be related to cytotoxic T lymphocyte activity in vitro. Furthermore, the M/T ratio should be useful for earlier detection of recurrence than conventional tumor markers. Early detection of recurrence would permit a timely retreatment decision and contribute to prolonged survival in cancer patients. IMMUNOLOGICAL EFFECTS OF KAMPO MEDICINE: Juzen-taiho-to (TJ-48) is a traditional kampo medicine used in Japan and China. We demonstrated in this paper that CD3+8+ cytotoxic T lymphocytes specific for autologous and HLA shared allogeneic tumor cells were induced from peripheral blood mononuclear cells stimulated by TJ-48 in vitro. Furthermore, we also demonstrated that the M/T ratio is decreased by administration of TJ-48 in patients with gynecologic cancer.