Phase I study of combination chemotherapy with 5-fluorouracil (5-FU) and nedaplatin (NDP): adverse effects and eecommended dose of NDP administered after 5-FU

When nedaplatin (NDP) was used as a single agent in the phase I study, the dose-limiting toxicity (DLT) was thrombocytopenia and the recommended dose (RD) was 100 mg/m2. However, the DLT, maximum tolerated dose (MTD) and RD of NDP used in combination with 5-fluorouracil remained unknown. Therefore, we performed this study to assess the DLT and RD of NDP administered after 5-fluorouracil (5-FU). In this study, 5-FU was administered to 38 patients at a fixed dose (700 mg/m2/d on days 1-5) and NDP administered on day 6 at an initial dose of 80 mg/m2, which was subsequently increased to 100, 120, 130, 140, 150, and 160 mg/m2. The DLT of NDP was leukopenia and its MTD and RD were 160 and 150 mg/m2, respectively. Concerning impairment of renal function, only two patients had a grade I increase in serum creatinine. There were 19 responders (50%, 19/38) achieving partial response or complete response in the evaluation of antitumor effect. The result of this study is notable in that administration of 5-FU before NDP allows the dose of NDP to be substantially increased.     

Brain metastases from esophageal carcinoma: natural history, prognostic factors, and outcome

BACKGROUND: Brain metastases from esophageal carcinoma are extremely rare, and information regarding the natural history, results of treatment, and possible prognostic factors in these patients is limited. METHODS: The records of 36 patients with brain metastases from esophageal carcinoma who were treated between 1986 and 2000 were reviewed. For brain metastases, 12 patients (33%) were treated with surgical resection followed by radiation therapy (S+RT), and the remaining 24 patients were treated with radiation therapy alone. RESULTS: At the initial diagnosis of esophageal carcinoma, the median primary tumor length was 8 cm (range, 2-19 cm), and 26 of 32 available patients (81%) had clinical Stage III-IV tumors according to the International Union Against Cancer 1997 criteria. At time brain metastases appeared, lung metastases were not demonstrated in 25 of 36 patients (69%) who were assessed by chest computed tomography (CT) scans. The overall median survival for all patients was 3.9 months (range, 0.6-36.8 months), and the actuarial survival rates at 12 months and 24 months were 14% and 3%, respectively. In univariate analysis, treatment modality, Karnofsky performance status (KPS), and extracranial disease status each had a statistically significant impact on survival, and, in multivariate analysis, treatment modality and KPS were statistically significant prognostic factors for survival. Five patients (14%) survived more than 1 year, all of whom were treated with S+RT. These five patients had inactive extracranial disease and, four of five patients (80%) had a 90-100% KPS. CONCLUSIONS: Brain metastases from esophageal carcinoma tended to occur in patients with a large primary tumors and/or disease in advanced clinical stages. With the appearance of brain metastases, an absence of lung metastasis frequently was observed on chest CT scans. The prognoses for these patients were generally poor, although selected patients may survive longer with intensive brain tumor treatment.     

Current and future state of chemoradiotherapy for head and neck cancer

Radiation therapy was the conventional treatment for locally advanced, nonresectable head and neck cancer. However, therapeutic results were poor with this treatment modality, and chemoradiotherapy has been used in an effort to improve therapeutic results. Improved local-regional control and disease-free or overall survival have been shown in several randomized trials using a concurrent or alternative approach. Induction chemotherapy (neoadjuvant chemotherapy), however, has not been shown to improve local-regional control or survival. Induction chemotherapy followed by definitive radiotherapy may be useful in the selection of patients who are likely to benefit from non-surgical organ preservation treatment schemes. Further clinical trials are needed to clarify the most suitable combination of chemotherapy and radiation. Intraarterial chemotherapy combined with radiation therapy for head and neck cancer has been attempted for many years. However, the indications, clinical significance, and selection of suitable anti-cancer drugs remain unclarified. The modern superselective intraarterial approach should be re-evaluated. Many head and neck cancers have been found to overexpress the receptor to epidermal growth factor (EGFR). Antibodies such as IMC-C225 that specifically target EGF receptors with radiotherapy and/or chemotherapy may prove to be valuable contributors to the treatment of advanced head and neck cancer.     

Analyses of dose-response in radiotherapy for patients with mature T/NK-cell lymphomas according to the WHO classification.

BACKGROUND AND PURPOSE: This study was conducted to analyze the influence of radiotherapy doses and chemotherapy doses and clinical parameters on in-field disease control in order to assess the optimal radiation doses for treatment of mature T/NK-cell lymphomas according to the newly proposed WHO classification. PATIENTS AND METHODS: Subjects consisted of 62 patients with mature T/NK-cell lymphomas treated with radiotherapy at four Japanese institutions between 1983 and 2002. We reevaluated all histopathological specimens of non-Hodgkin's lymphomas (NHL), using the WHO classification. Radiation therapy was usually delivered to the involved field. The majority of patients also received adriamycin-based chemotherapy such as CHOP, modified CHOP, or more intensive chemotherapy. RESULTS: There were no significant differences in radiosensitivity among subtypes of mature T/NK-cell lymphomas, at least between extranodal NK/T-cell lymphomas, nasal type and peripheral T-cell lymphomas, unspecified. There was a radiation dose-response in non-bulky mature T/NK-cell lymphomas, indicating that radiation doses of more than 52 Gy may be required to obtain in-field control. However, it was difficult to obtain local control of bulky T-cell lymphomas, even with high doses of irradiation. CONCLUSIONS: Mature T/NK-cell lymphomas were more radioresistant than B-cell lymphomas such as diffuse large B-cell lymphomas (DLBCL). The chemotherapy including adriamycin did not improve the in-field control of mature T/NK-cell lymphomas. These results were obtained by using non-randomized data and the significance of these results is limited by bias in data. However, our results suggest that the treatment strategy which is usually used for DLBCL, that is, a combined modality of CHOP and around 40 Gy of radiotherapy, may not be sufficiently effective for mature T/NK-cell lymphomas.     

Seven cases of breast cancer recurrence limited to the central nervous system without other visceral metastases

We report 7 rare cases of recurrent breast cancers who presented with central nervous system (CNS) metastases as the initial relapse site without any other organ metastases. The average age of the patients at surgery was 42.6 years old of age (median 45:range 32-60), and 6 of the 7 cases (86%) were premenopausal. The mean disease-free period was 25.7 months (median 22, range 2-60 months). The primary tumors were all invasive ductal carcinomas. The estrogen receptor and progesterone receptor status of the 3 tumors available for study were all negative. The metastatic CNS lesions included the cerebrum (4 cases), cerebellum, cervical spinal cord, and meninges. In 6 out of these 7 cases (86%), the CNS metastasis was the initial recurrent lesion. Multidisciplinary treatments including surgery, radiotherapy and systemic or intrathecal chemotherapy were given. Although the mean survival time from clinical manifestations of the metastases of the 4 deceased patients was 20 months (median 20.5; range 6-33), one patient treated with surgery and radiotherapy is been still alive18 years later. These cases were also notable for the fact that the only metastatic site was in the CNS only during the entire clinical course, except for 2 cases, one with ocular adnexa metastasis, and the other with cervical lymph node metastasis. Premenopausal patients with negative hormone receptor status are more likely to develop this type of recurrence, regardless of the histological type. It is necessary to pay attention to neurological symptoms and signs during follow-up of breast cancer patients.     

Phase I trial of weekly docetaxel and concurrent radiotherapy for head and neck cancer in elderly patients or patients with complications

OBJECTIVE: We planned a phase I study of radiotherapy combined with weekly docetaxel for elderly patients or patients with complications to find out the optimal dose. METHODS: Five consecutive weekly administrations of docetaxel were accompanied by radiotherapy for patients diagnosed with squamous cell carcinoma of the head and neck. The starting dose of docetaxel was 10 mg/m(2) with escalation at 2 mg/m(2) per step. RESULTS: Fifteen patients were enrolled in this trial. The maximal tolerated dose was 14 mg/m(2), so the recommended dose was determined as 12 mg/m(2). Hematological toxicity was sufficiently weak. Common dose-limiting toxicity was stomatitis within the radiation field. CONCLUSIONS: This protocol was thought to be practical for elderly patients or those with medical complications.     

ABCE1, a member of ATP-binding cassette transporter gene, encodes peptides capable of inducing HLA-A2-restricted and tumor-reactive cytotoxic T lymphocytes in colon cancer patients

To provide a scientific basis for specific immunotherapy of colon cancer, this study focused on the identification of tumor-associated antigens recognized by HLA-A2-restricted and cancer-reactive cytotoxic T lymphocytes (CTLs) from tumor-infiltrating lymphocytes (TIL) of a colon cancer patient. We identified a gene coding a member of the ATP-binding cassette transporter (ABCE1), which is known as an inhibitor to the 2-5A/RNase L system, a central pathway of interferon action, and its gene expression is amplified in drug-resistant cells. The ABCE1 mRNA was ubiquitously expressed in tumor cell lines, as well as normal cells or tissues. Among 21 peptides with the HLA-A2 binding motifs, 2 ABCE1-derived peptides were recognized by the colon cancer-reactive CTLs in a dose-dependent manner. CTL precursors reactive to these 2 ABCE1 peptides were detected in the peripheral blood mononuclear cells (PBMCs) of the colon cancer patient, from whom the TILs had been obtained. In addition, these ABCE1 peptides had the potential to generate HLA-A2-restricted and colon cancer-reactive CTLs from the PBMCs of colon cancer patients, but not from those of healthy donors. Their cytotoxicity against colon cancer was mainly ascribed to peptide-specific and CD8+ CTLs. No definite cytotoxicity was observed against normal T cell blasts, irrespective of the expression of the ABCE1 mRNA. These results indicate that the ABCE1 and its peptides could be target molecules in specific immunotherapy for HLA-A2(+) colon cancer patients.     

A new method for measuring total coronary blood flow using the lithium dilution method

BACKGROUND: The aim in this study is to evaluate a new method of measuring total coronary blood flow (TCBF) in (1) an in vitro model and in (2) an animal model by the lithium dilution method. METHODS: (1) Ringer's solution was circulated in a closed circuit with the main flow as a systemic circulation, and the side flow as a coronary circulation by a roller pump. Two peaks originating from the main and side flow were recorded by the lithium dilution method. The flow was calculated using the Fick principle based on the ratio of the areas under the curve. The validity of this method was evaluated by Bland Altman analysis. (2) Four beagles were anesthetized and subjected to insertion of two pulmonary artery catheters. The position of the catheters was confirmed as being in the pulmonary artery and in the right atrium. Lithium chloride solution was injected into the pulmonary artery and the change in lithium concentration at the right atrium was recorded. TCBF was estimated by the method used in the in vitro study. RESULTS: (1) The calculated flow correlated well with the actual flow (r2 = 0.86). (2) The estimated TCBF at baseline, with low-dose nitroglycerin, and with high-dose nitroglycerin was 206 +/- 43.0 mL/min, 304 +/- 50.3 mL/min, and 348 +/- 50.1 mL/min, respectively (mean +/- SE). TCBF was significantly increased by nitroglycerin infusion. CONCLUSION: A new method of measuring TCBF using the lithium dilution method was reliable and useful both in vitro and in an animal model. This may be clinically useful method for measuring TCBF.     

Intraluminal ureteral hematoma complicating anticoagulant therapy

Intraluminal ureteral hematoma is a rare disease and only a few cases have been previously described. We report a case of intraluminal ureteral hematoma induced by anticoagulant therapy. A 65-year old man having the oral anticoagulant therapy for prevention of secondary thrombolism following atrial fibrillation was referred to us for gross hematuria. Ultrasound sonography (US) revealed right renal mild wide pelvis. Computed tomography (CT) showed the right ureteral submucosal hematoma. This ureteral hematoma penetrated the ureteral mucosa and caused macrohematuria. The patient had been anticoagulated on Warfarin with Bucolome for 18 days, so the prothrombin times (PT) was found to be excessively prolonged beyond the normal therapeutic range. The oral anticoagulation was stopped and intravenous Vitamin K2 was given, so PT was normalized. Though estimate hemorrhage quantity reached 1,200 ml, we had no blood transfusion. The hematoma was completely diminished 4 months later, no reccurence has been occurred. Bucolome has especially pharmacokinetic positive interaction to Warfarin, so we must check PT-INR frequently.