Squamous cell carcinoma of the uroepithelium: CT evaluation

Fourteen cases of primary squamous cell carcinoma (SCC) originating in the uroepithelium were studied with computed tomography (CT). Nine cases were of vesical origin, three were of renal pelvic origin, and two were of ureteral origin. CT scans of eight of the 14 cases, including four cases of vesical origin and four cases of renal pelvic or ureteral origin, demonstrated predominantly extraluminal extension with invasion into adjacent organs or the renal parenchyma. CT scans of the remaining six cases showed almost equal extra- and intraluminal tumor growth and no predominantly intraluminal extension. An associated urinary stone was demonstrated in four of the five cases of SCC of renal pelvic or ureteral origin. Two of these cases were diagnosed as urinary stones before CT was performed. Eight of the nine cases of SCC of vesical origin and four of the five cases of SCC of renal pelvic or ureteral origin were correctly staged with the aid of CT.     

Some aspects of size-dependent differential drug response in primary and metastatic tumors

Summary The response of cancer to various anticancer drugs is tumor-size dependent in many aspects. In general, problems stem partly from the fact that the entire tumor cell populations do not respond equally to a certain treatment. As a result of recent progress in cancer biology, it has become evident that cellular heterogeneity of the tumor underlies the difficulties of treating primary and metastatic tumors with chemotherapy. Moreover, as tumors grow, marked diversity develops on the tissue level as well. An uneven distribution with an increase of areas of lower growth fraction and of poorer drug delivery is more distinct in larger tumors. Heterogeneous distribution and low levels of tumor blood flow are considered to be causally related to the heterogeneous nature of tumor tissue. Considering the lack of evidence of a lymphatic system within the tumor, increased interstitial fluid pressure may be a natural result that further impedes blood flow in the tumor. The fact that the temporary and selective increase in tumor tissue blood flow by angiotensin-induced hypertension produces a remarkable chemotherapeutic effect should vividly indicate that delivery of the drug to the tumor is really the bottleneck of cancer chemotherapy. Tumor-size-related change in the transvascular and extravascular transport of molecules and its relevance to chemotherapy are also discussed in this article.     

Phase I study of CPT-11 and bolus 5-FU/<Emphasis Type="Italic">l</Emphasis>-leucovorin in patients with metastatic colorectal cancer

Background Irinotecan (CPT-11) and bolus 5-fluorouracil (5-FU)/leucovorin (LV) administered weekly for 4 weeks every 42 days (Saltz regimen) is active but substantially toxic in patients with metastatic colorectal cancer (CRC). The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC.Methods We investigated the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) for CPT-11 given i.v. (90-min infusion) and bolus 5-FU plus biologically active l-LV administered weekly for 3 weeks every 28 days (modified Saltz regimen) in Japanese patients with metastatic CRC. Eighteen patients with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and adequate organ functions were enrolled.Results At dose level 2 (CPT-11, 100mg/m²; 5-FU, 400mg/m²; and l-LV, 25mg/body), 1 of 6 patients had DLT (febrile neutropenia). At dose level 3 (CPT-11, 100mg/m²; 5-FU, 500mg/m²; and l-LV, 25mg/body), 2 of 6 patients had DLT (febrile neutropenia and grade 4 neutropenia lasting more than 4 days). To determine whether level 3 was the MTD level, an additional 3 patients were treated at this level, but no DLT was observed. Consequently, 2 of 9 patients had DLT at level 3, this level thus being considered as the RD. At this level, grade 3–4 neutropenia was common but manageable. Nonhematological toxicities were mild. Seven partial responses were observed in the 18 enrolled patients (response rate [RR], 39%), and 8 patients (44%) experienced stable disease.Conclusion This CPT-11/5-FU/l-LV regimen administered weekly for 3 weeks every 28 days has substantial antitumor activity, with manageable toxicities. A multicenter phase II study is currently underway.     

Dose escalation study of paclitaxel in combination with fixed-dose irinotecan in patients with advanced non-small cell lung cancer (JCOG 9807)

BACKGROUND: Both irinotecan (CPT) and paclitaxel (Pac) are effective against non-small cell lung cancer (NSCLC), and besides, preclinical studies have demonstrated an additive or synergistic interaction between camptothecin and taxane. METHODS: We conducted a phase I/II study of combination chemotherapy consisting of Pac and CPT to determine qualitative and quantitative toxicities and efficacy of the combination against advanced NSCLC. We fixed the dose of CPT at 60 mg/m(2) and escalated the Pac dose in 10 or 20 mg/m(2) increments from a starting dose of 80 mg/m(2), and repeated the cycle every 2 weeks. Prophylactic G-CSF was also administered. RESULTS: Between February 1999 and April 2001, 24 patients were registered in the study. None of the patients had a history of prior chemotherapy, but surgical resection had been performed in 3 of them. None of the patients experienced dose-limiting toxicity (DLT) up to and including level 6. At dose level 7 of Pac, 180 mg/m(2), 2 patients experienced DLT, that is grades 2 and 3 dyspnea due to pneumonitis. Another patient experienced grade 1 dyspnea due to pneumonitis. Neutropenia, diarrhea, and other toxicities were mild; however, we concluded that dose level 7 of Pac was the maximum-tolerated dose. An objective response was observed in 58.3%. The median survival time was 370 days, and the 1-year survival rate was 54.2%. CONCLUSION: Pneumonitis was the DLT in this study, and Pac 160 mg/m(2) and CPT 60 mg/m(2) every 2 weeks are recommended for the phase II study. This combination shows appreciable activity against NSCLC.     

Mutagenicity of urinary metabolites of benzidine and benzidine-based azo dyes

Summary The mutagenicity of urinary metabolites of benzidine and benzidine-based azo dyes was studied by using urine samples. The azo dyes studied were Direct Deep Black EX and Congo Red, both containing a 4,4′-diazobiphenyl group. After benzidine and the azo dyes had been administered orally to rats, urine was collected and extracted with ether. Mutagenicity of the urine extracts was tested in the Salmonella/mammalian-microsome assay. The results of the mutagenicity assay and the GC analysis of the urine extracts suggested that the azo dyes might decompose and release benzidine in the intestine of the rats. It was found that the urinary metabolites of benzidine, both N-acetylbenzidine, and N,N′-diacetylbenzidine, show stronger mutagenicity than benzidine itself. It was also found that the urine extracts from four men who had undergone “gastroscopy with Congo Red” were mutagenic.     

Aortic valve replacement in a patient with myelodysplastic syndrome and interstitial pneumonia.

There are a few reports of cardiac surgery in patients with myelodysplastic syndrome (MDS). It is difficult to control bleeding and prevent infection in the presence of pancytopenia. Interstitial pneumonia, which is treated by steroid medication, is also a risk factor in cardiac surgery. Aortic valve replacement was successfully performed in a patient with severe thrombocytopenia associated with MDS, interstitial pneumonia and scleroderma.     

A Randomized Cross-over Trial of Granisetron and Dexamethasone versus Granisetron Alone: The Role of Dexamethasone on Day 1 in the Control of Cisplatin-induced Delayed Emesis

We studied the role of dexamethasone (DEX) administered on day1 in controlling cisplatin-induced delayed emesis. Forty patientswere randomly allocated to receive either granisetron (GRN)and DEX on day 1, or the same dose of CRN alone. On days 2–5,all the patients received metoclopramide and DEX. They werecorssed over to the other antiemetic regimen with their secondcourse of chemotherapy. Thirty-one patients were evaluable forefficacy. The mean visual analogue scale scores for nausea ondays 1 and 2 were 9.1 and 18.8 mm for GRN and DEX, and 16.3and 28.5 mm for GRN alone, respectively (P > 0.05 on day2). The mean numbers of emetic episodes on days 1–3 were0.036, 0.46 and 0.36 for GRN and DEX, and 0.39, 0.89 and 0.57for GRN alone, respectively (P > 0.01 on day 1). Hiccupsand restlessness were noted in 38% and 33% of cycles, respectively.Addition of DEX to GRN on day 1 thus enhanced the control ofdelayed emesis.     

A Kampo medicine "Juzen-taiho-to"--prevention of malignant progression and metastasis of tumor cells and the mechanism of action

Juzen-taiho-to is a Kampo (Japanese and Chinese traditional) medicine, and is a nourishing agent, a so-called "Hozai" (in Japanese), that is used for improving disturbances and imbalances in the homeostatic condition of the body. This drug is administered to patients in various weakened conditions, including post-surgery patients and patients with chronic illnesses, where it can alleviate general symptoms such as extreme fatigue, pale complexion, loss of appetite, dry or scaly skin, night sweating, and dryness of the mouth. Currently, Juzen-taiho-to is often administered to cancer patients, and has been shown to possess various biological activities, such as enhancement of phagocytosis, cytokine induction, antibody production, induction of the mitogenic activity of spleen cells, anti-tumor effects when combined with surgical excision, anti-tumor effects with or without other drugs, and protection against the deleterious effects of anti-cancer drugs as well as radiation-induced immunosuppression and bone marrow toxicity. This article focuses on the antitumor and antimetastatic properties of Kampo formulations and describes the effect of Juzen-taiho-to and related formulations on tumor development, progression and metastasis in vivo. We also discuss the mechanism of the inhibitory action and the importance of the formulation and the constituent drugs in determining the efficacy.     

Orotate phosphoribosyltransferase levels measured by a newly established enzyme-linked immunosorbent assay in gastric carcinoma

A number of enzymes have been shown to be involved in the process of activation and/or degradation of 5-fluorouracil (5-FU), and are potential candidates for predicting chemosensitivity to 5-FU. Among these, orotate phosphoribosyltransferase (OPRT EC 2.4.2.10) is a key enzyme related to the first-step activation process of 5-FU and has been shown to be an important enzyme that helps to predict sensitivity to 5-FU and its related derivatives. We developed a new enzyme-linked immunosorbent assay (ELISA) to accurately assess intratumoral activity of OPRT. A new sandwich ELISA was established using anti-OPRT polyclonal antibodies obtained from the rabbit immunized with the recombinant human peptides of the OPRT molecule. OPRT levels were measured in eight human cancer xenografts and in 75 gastric cancer tissues using both a newly established ELISA and a conventional enzyme assay, using radiolabeled 5-FU as a substrate. There was a significant correlation between OPRT levels measured by this ELISA and OPRT enzyme activity the in eight human cancer xenografts (r2 = 0.782) and gastric carcinoma tissue (r2 = 0.617). The ELISA system for OPRT requires a minimal amount of carcinoma tissue, making it an easy-to-use assay system to predict sensitivity to 5-FU and its derivatives in gastric carcinoma. There was a significant correlation between tumor growth inhibition rates against the oral administration of oral-uracil/tegafur (UFT) and OPRT enzyme activity in the human cancer xenografts (r2 = 0.574). These results suggest that this newly developed sandwich ELISA system for the quantification of OPRT levels is technically simple, feasible and a useful tool to predict sensitivity to fluoropyrimidine-based anticancer chemotherapy in patients with gastric carcinoma and other cancers.