Domino liver transplantation with double piggyback: is this the best technique? A case report.

Sequential or domino liver transplantation is a well-established procedure for patients with familial amyloidotic polyneuropathy (FAP). Donation for domino liver transplantation imposed the resection of the inferior vena cava along with the liver, requiring complete suprarenal vena cava clamping and usually the use of venovenous bypass. We describe a successful case in which it was possible to perform the FAP hepatectomy by the piggyback technique.

Fractionated administration of irinotecan and cisplatin for treatment of non-small-cell lung cancer: a phase II study of Okayama Lung Cancer Study Group.

A phase II study of fractionated administration of irinotecan (CPT-11) and cisplatin (CDDP) in patients with non-small-cell lung cancer (NSCLC) was conducted. Between January 1996 and January 1998, 44 previously untreated patients with stage IIIB or IV NSCLC were enrolled. CDDP at a dose of 60 mg x m(-2) was given first and followed by CPT-11 at a dose of 50 mg x m(-2). Both drugs were given by 1-hour infusion on days 1 and 8, and repeated every 4 weeks up to 4 cycles. 42 patients were evaluated for response and 44 for survival and toxicity. 20 patients (48%: 95% confidence interval 32-63%) achieved an objective response. The median duration of responses was 8 months, and the median survival time and the 1-year survival rate were 12.5 months and 56.8%, respectively. Major toxicities were neutropenia and diarrhoea. Grade 3 or 4 neutropenia occurred in 70.5% of the patients and one patient died of sepsis. Grade 3 or 4 diarrhoea was experienced in 25.0%, but manageable by conventional therapy. In conclusion, fractionated administration of CPT-11 and CDDP was highly effective for advanced NSCLC with manageable toxicities.

Intramedullary spinal cord recurrence after high-dose chemotherapy and autologous peripheral blood progenitor cell transplantation for limited-disease small cell lung cancer.

Intramedullary spinal cord metastasis is very rare in small-cell lung cancer (SCLC), and develops in only 2% of neurological disorders associated with SCLC according to previous reports. We describe here a patient with SCLC who developed intramedullary spinal cord recurrence after high-dose chemotherapy (HDCT) followed by autologous blood progenitor cell transplantation (ABPCT). A 59-year-old Japanese male was referred to us for diagnosis and treatment of an abnormal shadow on a chest radiograph. Based on transbronchial biopsy and staging procedures, he was diagnosed with limited-disease (LD)-SCLC. He received concurrent chemoradiotherapy followed by late intensification with HDCT supported by ABPCT. He achieved complete response and was discharged after receiving prophylactic cranial irradiation (PCI). However 6 months later, he noticed rapidly progressive weakness of the left lower extremity and bowel/bladder dysfunction. Magnetic resonance imaging (MRI) of the spinal cord disclosed an intramedullary tumor exhibiting an enhancement effect with Gd-DTPA at the 11-12th level of the thoracic vertebra. Immediately, radiotherapy to the spinal cord metastasis was given at a dose of 30 Gy, and his neurological disorders were completely resolved. At this time of reporting, he is doing well without recurrence. This case indicates that intramedullary spinal cord is one of the recurrence sites implicated after HDCT and PCI in LD-SCLC.

Combination of nedaplatin and vindesine for treatment of relapsed or refractory non-small-cell lung cancer.

PURPOSE: A phase II study of nedaplatin and vindesine was conducted to evaluate their efficacy and safety for treatment of relapsed or refractory non-small-cell lung cancer (NSCLC). METHODS: Between August 1996 and September 1998, 48 patients who had previously received chemotherapy, thoracic radiotherapy, and/or surgery were enrolled in the study. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 to 2 and an age between 20 and 79 years. Treatment consisted of nedaplatin (80 mg/m2, day 1) and vindesine (3 mg/m2, days 1 and 8) every 3 to 4 weeks. RESULTS: Of 48 patients, 7 (14.6%) exhibited an objective response. Four (50%) of eight chemotherapy-naive patients had a partial response. However, of the 40 patients who had received prior chemotherapy, a partial response was observed in only 3 (7.5%). At a median follow-up time of 85.1 weeks, the median survival time was 43.6 weeks (95% confidence interval 34.4-52.7) for patients who had received chemotherapy, with a survival rate of 40% at 1 year. Grade 3 or 4 neutropenia occurred in 43 of 48 patients (90%), and neutropenic fever was observed in 3 of the 43 patients, one of whom died of sepsis. Pharmacokinetic and pharmacodynamic analyses of platinum were performed in 43 patients during the first cycle of chemotherapy. Percent reduction in absolute neutrophil count was correlated not only with the area under the plasma ultrafilterable platinum concentration versus time curve (r = 0.41, P = 0.007) but also with the duration of ultrafilterable platinum concentration above 1 microg/ml (r = 0.41, P = 0.007). Patients with progressive disease exhibited a shorter duration of ultrafilterable platinum concentration over 1 microg/ml (P = 0.046) than those with other responses. CONCLUSION: A combination of nedaplatin and vindesine was unsatisfactory as second-line chemotherapy for NSCLC, although the combination was well tolerated. The duration of ultrafilterable platinum concentration above 1 microg/ml was an important pharmacokinetic parameter for predicting both chemotherapy-induced neutropenia and treatment outcome.

Detection of occult tumor cells in peripheral blood from patients with small cell lung cancer by reverse transcriptase-polymerase chain reaction.

The reverse transcriptase-polymerase chain reaction (RT-PCR) of tumor-specific or -associated genes is a sensitive assay for detecting a minimal number of tumor cells in peripheral blood (PB) or bone marrow (BM). In this study, we determined whether mRNA of bombesin receptors is detectable in PB or peripheral blood progenitor cell (PBPC) samples from patients with small cell lung cancer. Among three bombesin-like peptide receptors, we used the neuromedin B receptor (NMB-R) gene as a target, because of the most frequent expression on SCLC cell lines. The lower limit of detection was one tumor cell in one million normal PB cells and there was no detection in normal PB or BM cells unlike a cytokeratin 19 gene. The NMB-R gene was detected in 14 (31.8%) of 44 PB samples from patients with SCLC at diagnosis and 2 (15.4%) of 13 samples of PBPC collected during a recovery phase after chemotherapy followed by administration of G-CSF (filgrastim). At diagnosis, patients whose PB was positive for the NMB-R gene had a significantly shorter survival than those who were negative. Our observation suggests that this assay may be useful in diagnosing metastatic disease and monitoring minimal residual disease in patients with SCLC.

(-)-Epigallocatechin gallate can prevent cisplatin-induced lung tumorigenesis in A/J mice.

Risks of secondary lung cancer in patients with non-small cell lung cancer and small cell lung cancer are estimated to be 1-2% and 2-10% per patient per year, respectively. Cisplatin is widely used in the treatment of lung cancer and is also known as a carcinogen in experimental animals. In this study, the effect of (-)-epigallocatechin gallate (EGCG) on cisplatin-induced lung tumors in A/J mice was investigated. Female A/J mice (4 weeks old) were divided into four groups: group 1, control without treatment; group 2, EGCG treatment (1 mg/ml in tap water); group 3, weekly cisplatin treatment (1.62 mg/kg body wt, i.p.) for 10 weeks; group 4, cisplatin plus EGCG treatment (EGCG was started 2 weeks before cisplatin treatment). Four groups of mice were killed at week 30 after treatment. Tumor incidence was 26.3% (5/19) in group 1, 30% (6/20) in group 2, 100% (19/19) in group 3 and 94.4% (17/18) in group 4. Tumor multiplicity (the number of tumors per mouse, mean +/- SD) was 0.4 +/- 0.8 in group 1, 0.4 +/- 0.8 in group 2, 5.1 +/- 2.1 in group 3 and 2.8 +/- 2.3 in group 4. Tumor multiplicity was significantly reduced by adding EGCG to cisplatin-treated mice (P < 0.01). Furthermore, EGCG significantly reduced cisplatin-induced weight loss from 24.7-26.3% (cisplatin treatment) to 10.8-11.6% (cisplatin plus EGCG treatment) (P < 0.01). These findings suggest that EGCG can inhibit cisplatin-induced weight loss and lung tumorigenesis in A/J mice.

Maxizymes, novel allosterically controllable ribozymes, can be designed to cleave various substrates.

We demonstrated previously that an allosterically controllable novel ribozyme, designated the maxizyme, is a powerful tool for disruption of an abnormal chimeric RNA target [BCR-ABL (b2a2) mRNA], and we proposed that it might provide the basis for future gene therapy for the treatment of chronic myelogenous leukemia (Kuwabara et al. Mol. Cell 1998, 2, 617-627). The maxizyme has sensor arms that can recognize a specific sequence and, in the presence exclusively of such a specific sequence, it can form a cavity for capture of catalytically indispensable Mg2+ ions. Cleavage of the target RNA then occurs at a site distant from the specific sequence. Clearly, the specific sequences recognized by sensor arms should not be limited to those of the above mentioned abnormal chimeric target. Thus, to demonstrate the general applicability of maxizyme technology, we constructed maxizymes targeted to other mRNAs, such as PML-RAR alpha mRNA, sDLST mRNA, and BCR-ABL (b1a2) mRNA, that are not cleaved with high specificity by the wild-type hammerhead ribozyme. Specific and efficient cleavage in vitro of these mRNAs by the custom-designed maxizymes demonstrated clearly that maxizyme technology is not limited to a specific case but may have broad general applicability in molecular biology and, also, in a clinical setting.

Two cases of intrapulmonary lymph node presenting as a peripheral nodular shadow: diagnostic differentiation from lung cancer.

We present two cases of intrapulmonary lymph node. The patients were a 44-year-old woman and a 71-year-old man each with a small peripheral nodule in the lung. On computed tomography (CT) scans, both nodules were spiculated. Since histological diagnosis could not be obtained by bronchoscopic examination or CT-guided needle biopsy, they underwent video-assisted thoracoscopic surgery. Histological examination of the resected material revealed that both nodules were composed of lymph node. Intrapulmonary lymph node has until recently been assigned no clinical significance; however, differential diagnosis of this lesion from lung cancers and other metastatic tumors is now clinically important.

Serum CD44 levels in patients with non-small cell lung cancer and their relationship with clinicopathological features.

Serum CD44 standard and CD44 variant 6 levels were measured in 45 non-small cell lung cancer (NSCLC) patients and 33 patients with benign lung disease by enzyme-linked immunosorbent assay (ELISA). Expression of CD44 variant 6 in trans-bronchial biopsy specimens from the NSCLC patients was studied by an immunoperoxidase method. CD44 standard and CD44 variant 6 levels in NSCLC patients were not significantly different from those in benign lung disease patients. However, serum CD44 variant 6 level in squamous cell carcinoma patients (226.8 +/- 152.7 ng/ml) was significantly higher than in patients with benign lung disease (154.8 +/- 46.4 ng/ml) (P = 0.011). Neither the serum level of CD44 standard nor that of CD44 variant 6 was correlated with disease Stage and metastasis. CD44 variant 6 expression was most frequently observed in squamous cell carcinoma (P = 0.00058); 15 (79%) of 19 squamous cell carcinoma cases were positive, as were five (22%) of 23 adenocarcinoma cases and two (67%) of three large cell carcinoma cases. Serum CD44 variant 6 levels were 217.1 +/- 143.1 and 156.1 +/- 48.8 ng/ml in patients with and without positive expression of CD44 variant 6, respectively (P = 0.020). Serum CD44 standard and CD44 variant 6 levels are not useful indicators of tumor burden and metastasis in patients with NSCLC. CD44 variant 6 expression might be associated with histological features of NSCLC.

Risk factors for development of radiation pneumonitis following radiation therapy with or without chemotherapy for lung cancer.

PURPOSE: To determine the risk factors contributing to development of radiation pneumonitis (RP) in patients with lung cancer who undergo radiation therapy to the thorax. METHODS AND MATERIALS: Development and severity of RP were retrospectively analyzed for 89 patients with lung cancer who underwent radiation therapy with or without chemotherapy at the National Shikoku Cancer Center Hospital between 1991 and 1995. The severity of RP was determined using a modified grading scale based on that of the Radiation Therapy Oncology Group and the European Organization for the Research and Treatment of Cancer. RESULTS: Fifty-two (58%) patients developed RP: 34 patients with Grade 1, 5 with Grade 2, 8 with Grade 3, and 5 with Grade 5 RP. Severe RP tended to develop earlier than less severe RP, but not to a significant extent (p = 0.151). On logistic regression analysis including both patient condition and treatment factors, development of Grade 1 or more severe RP was most frequently observed for Stage I-II disease (p = 0.011). The use of chemotherapy, large daily radiation dose, and once-daily fractionation (vs. twice-daily fractionation) were possibly related to the development of RP (p = 0.057, p = 0.069, and p = 0.092, respectively). For the group of 48 patients who underwent chemoradiation therapy, the use of large daily radiation dose was a significant risk factor for RP (p = 0.014). In addition, the use of once-daily fractionation was a marginally significant risk factor (p = 0.052). Among chemotherapy drugs administered, cisplatin was a favorable factor (p = 0.011), while adriamycin was a risk factor (p = 0.061). CONCLUSIONS: In radiation therapy for lung cancer, administration of a large daily dose should be avoided in order to prevent RP, particularly when radiation therapy is combined with chemotherapy.

Serum hepatocyte growth factor/scatter factor levels in small cell lung cancer patients.

Serum hepatocyte growth factor/scatter factor (HGF/SF) levels were measured in 25 patients with small cell lung cancer (SCLC), 16 patients with benign lung diseases and 15 healthy subjects with an enzyme-linked immunosorbent assay. The patients with SCLC did not have bacterial or interstitial pneumonia. Patients with benign lung diseases included eight with bacterial pneumonia, three with interstitial pneumonia, and five with benign lung tumor. Serum HGF/SF levels were significantly higher in patients with SCLC (mean +/- S.D.: 0.40 +/- 0.17 ng/ml) than in healthy subjects (0.26 +/- 0.093 ng/ml) (P = 0.0083). Patients with bacterial pneumonia had significantly higher serum HGF/SF (0.52 +/- 0.19 ng/ml) than did those with benign lung tumors (0.27 +/- 0.058 ng/ml) and healthy subjects (P = 0.013 and P = 0.0019, respectively). By clinical stage of SCLC, HGF/SF levels were 0.34 +/- 0.12 and 0.47 +/- 0.20 ng/ml in patients with limited disease and extensive disease, respectively; this difference was not significant (P = 0.080). Although serum HGF/SF levels were increased in patients with SCLC, this increase might not have been related to tumor burden.

The novel anti-rheumatic drug TA-383 has a macrophage migration enhancing activity.

We have investigated the effect of a novel anti-rheumatic drug, cis-2-(4-chlorophenyl)-4,5-diphenyl-2-imidazoline hydrochloride (TA-383), on macrophages. TA-383 (> or = 10(-9) M) significantly stimulated rabbit alveolar macrophage (AM) migration, and its migration-stimulatory activity was more potent than those of L-fucose (5 x 10(-3) M), lobenzarit disodium, bucillamine (SA-96) and salazosulfapyridine. In addition, TA-383 enhanced the production and/or release of macrophage migration enhancement factor by rabbit spleen cells. In vivo, TA-383 (0.4 mg/kg, p.o.) has suppressive effects on picryl chloride-induced delayed type hypersensitivity and type II collagen-induced arthritis in mice. These results suggest that the anti-rheumatic activity of TA-383 may be exerted through the dispersion of macrophages from inflammatory sites.

Measurement of serum p53 protein in patients with small cell lung cancer and results of its clinicopathological evaluation.

Serum p53 protein levels were measured in 36 patients with small cell lung cancer (SCLC) and 35 patients with benign lung diseases in order to evaluate the relationship of these levels to clinicopathological features of SCLC. Serum levels of p53 protein were measured by an enzyme-linked immunosorbent assay, p53 protein level was 23.92 +/- 6.78 pg/ml in patients with SCLC, and similar to that (17.47 +/- 2.86 pg/ml) in patients with benign lung diseases. By the clinical stage of SCLC, the mean level of p53 protein was 16.68 +/- 4.62 pg/ml in 21 patients with limited disease, and lower than that in 15 patients with extensive disease (34.05 +/- 14.84 pg/ml) (P = 0.23). The levels of p53 protein were not correlated with age, smoking index, or presence of cancer history for patients with SCLC. However, immunohistochemical examination disclosed a mild correlation between the expression of p53 protein by SCLC tumor and p53 protein serum level (r = 0.45, P = 0.02). Two patients with SCLC had an elevated serum level of p53 protein (> 2 S.D. above the mean for benign lung diseases). However, measurement of p53 protein serum level was not found to be clinically useful for detection of SCLC.

Clinical usefulness of serum cytokeratin 19 fragment as a tumor marker for lung cancer.

Serum soluble cytokeratin 19 fragment (CYFRA) levels were measured in 251 patients with lung cancer and 139 patients with benign lung diseases to determine the clinical usefulness of CYFRA level determination in the diagnosis and monitoring of lung cancer. Serum levels of CYFRA were measured by a 2-step sandwich ELISA method. When the cut-off value was defined as 3.5 ng/ml, which was associated with a specificity of 95% for benign lung diseases, CYFRA had a high sensitivity (53%) in all patients with lung cancer. Both the serum level of CYFRA and its sensitivity increased significantly with the increase in clinical stage. A comparison of areas under receiver operating characteristic curves showed that CYFRA had the most power of discrimination in the diagnosis of lung cancer among markers including carcinoembryonic antigen, squamous cell carcinoma antigen, carbohydrate antigen 19-9, and neuron-specific enolase. A good correlation was found between serial changes in serum CYFRA levels during therapy and clinical responses for 18 patients who underwent chemotherapy and/or radiotherapy. Our findings suggest that CYFRA may be a marker of choice for screening and monitoring of lung cancer, particularly squamous cell carcinoma.

A fibrous histiocytoma with a polypoid pattern of growth in a major bronchus.

A 47-year-old man was admitted to our hospital for abrupt onset of hemoptysis and dyspnea. Chest roentgenography revealed a left lower mass shadow with obstruction of the left main bronchus. However, on the third hospital day, he expectorated a coagulum-like substance which resembled bronchial tree, and his symptoms then dramatically subsided. Except for small amounts of bleeding from left B10a, the endobronchus was intact on bronchoscopic examination, and the pathologic diagnosis of the tumor using resected material was fibrous histiocytoma of low-grade malignancy. In addition, given the similarity in histologic findings between the expectorated substance and resected tumor, the expectorated substance was considered to be a part of the tumor which had grown along the endobronchial tree.

Primary lung cancer associated with diffuse granulomatous lesions in the pulmonary parenchyma.

A 60-year-old man was admitted to our hospital for productive cough. Chest roentgenography and CT scan disclosed a left hilar tumor invading the mediastinum, with mediastinal lymphadenopathy and diffuse micronodular shadows in both lung fields. A biopsied sample of the tumor revealed squamous cell carcinoma, while noncaseating epithelioid cell granulomas were observed in the samples obtained by transbronchial lung biopsy. The granulomas in the pulmonary parenchyma were determined to be sarcoid reactions secondary to lung cancer, since there was no evidence of sarcoidosis. Combination chemotherapy was effective for the tumor, and the granulomas disappeared after completion of the chemotherapy. These findings suggest the presence of a relationship between sarcoid reactions and lung cancer in this case.

Prognostic factors for patients with advanced non-small cell lung cancer: univariate and multivariate analyses including recursive partitioning and amalgamation.

In an attempt to determine the prognostic significance of pretreatment factors for patients with advanced non-small cell lung cancer (NSCLC), 24 pretreatment clinical variables were analyzed for 185 patients with NSCLC who underwent chemotherapy and/or radiotherapy between 1985 and 1994. Following univariate analysis, we applied two multivariate statistical techniques. In a Cox regression mode, independently significant factors influencing patient survival included performance status (PS), disease stage, hemoglobin level, and serum calcium level. Recursive partitioning and amalgamation (RPA) resulted in three distinct prognostic subgroups based on PS, stage, weight loss, and hemoglobin level. The best survival was observed for patients with a good PS and Stage III disease who had a hemoglobin level > 11 g/dl. The worst survival was observed for patients with a poor PS and presence of weight loss irrespective of stage. All other patients had an intermediate prognosis. Median survival times were 95.1 weeks, 17.1 weeks and 39.3 weeks, respectively (P < 0.00005). The results of our analyses show that three important prognostic subgroups could readily be discerned using RPA.

Primary adenoid cystic carcinoma of the trachea effectively treated with the endoscopic Nd-YAG laser followed by radiation.

We present a case of adenoid cystic carcinoma of the trachea. The tumor could not be resected due to extensive progression but it was effectively treated endoscopically with a Nd-YAG Laser followed by 70 Gy of conventional radiotherapy. Histologically-confirmed complete remission was achieved, and the patient has lived for nearly 9 years without recurrence of disease.

Enhanced expression of interleukin 6 in rat and murine arthritis models.

Interleukin 6 (IL-6) is a multifunctional cytokine and plays an important role in host defense mechanisms. Enhanced production of IL-6 has been reported in polyclonal B-cell abnormalities and autoimmune diseases such as rheumatoid arthritis (RA). To investigate the role of IL-6 inflammatory joint diseases, serum IL-6 levels of three animal models of RA, namely type II collagen (CII)-induced murine, rat arthritis and adjuvant-induced rat arthritis, were monitored. In these models, serum IL-6 increased with the development of arthritis. Serum IL-6 was not elevated by immunization with a non-arthritogenic immunogen such as bovine type I collagen (CI) and bovine serum albumin (BSA) to DBA/1J mice. The serum IL-6 level was correlated well with the severity of adjuvant-induced arthritis. The elevated IL-6 in sera may be associated with the overproduction of IL-6 at the arthritis paws, because higher IL-6 activity was detected in the homogenates of arthritic paws as compared with the control paws. Synovial fibroblasts were isolated from the arthritis knee joints of DBA/1J mice. These cells expressed type I interleukin 1 (IL-1) receptor constitutively and produced large amounts of IL-6 in response to IL-1 in vitro. Enhanced production of IL-1 was also detected at the arthritis paws. These results suggest that the elevated IL-6 in sera may be associated with the overproduced IL-6 in response to the increased IL-1 at the arthritic joints. Serum IL-6 may be a useful parameter for monitoring disease activity.

Effect of a novel anti-rheumatic drug, TA-383, on type II collagen-induced arthritis--suppressive effect of TA-383 on interleukin 6 production.

We have evaluated the effect of a novel anti-rheumatic drug, cis-2-(4-chlorophenyl)-4,5-diphenyl-2-imidazoline hydrochloride (TA-383), on type II collagen (CII)-induced arthritis in DBA/1J mice. Treatment with TA-383 (0.4 mg/kg/day) from the day of immunization with CII strongly suppressed the arthritic responses. Increased serum interleukin 6 (IL-6) level was lowered in parallel with the effect. Effect of TA-383 on IL-6 production was examined in vitro. TA-383 inhibited the production of IL-6 by murine synovial fibroblasts stimulated with recombinant interleukin 1 (IL-1) beta in a dose-dependent manner (0.1-10 microM). Neither the general protein synthesis nor the expression of type I IL-1 receptor was affected by TA-383. The results show that TA-383 possesses an inhibitory activity on IL-6 generation and suggest that the effect may partly contribute to the anti-arthritic effect of TA-383.