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.     

RadGenomics project

Human health conditions are largely determined by a complex interplay among genetic susceptibility, environmental factors, and aging. The RadGenomics project, which began in April 2001, promotes analysis of genes in response to irradiation, identification of their allelic variants in the human population, development of an effective procedure for quantitating individual radio-sensitivity, and analysis of the interrelationship between genetic heterogeneity and susceptibility to irradiation. Major groups of genes with which the project will concern itself include DNA repair genes, cell cycle genes, oncogenes, tumor suppressor genes, genes for programmed cell death, genes for signal transduction, and genes for oxidative processes. The outcome of the RadGenomics project should lead to improved protocols for personalized radiotherapy and reduce the possible side effects of treatment. The project will contribute to future research on the molecular mechanisms of radiation sensitivity in humans and stimulate the development of new high-throughput technology for a broader application of the biological and medical sciences. Identification of functionally important polymorphisms in the radiation response genes may determine individual differences in sensitivity to radiation exposure. The staff members, who are specialists in a variety of fields including genome science, radiation biology, medical science, molecular biology, and bioinformatics, have come to the RadGenomics project from various universities, companies, and research institutes.     

Intrapulmonary lymph nodes: thin-section CT features of 19 nodules

PURPOSE: The purpose of this study was to describe the thin-section CT features of intrapulmonary lymph nodes that accompanied primary or metastatic lung tumors. METHOD: A retrospective analysis of thin-section CT features was performed on 19 nodules in 16 patients with pathologically confirmed intrapulmonary lymph nodes that accompanied primary or metastatic lung tumors. RESULTS: Of the 16 patients, 13 had a solitary nodule and 3 had two nodules. All nodules were distributed in the middle lobe, lingula, or lower lobe. On thin-section CT images, the nodule was located abutting the visceral pleura (n = 10) or within 8 mm of the visceral pleura (n = 9). The thin-section CT findings showed that most of the nodules were well circumscribed (n = 18), homogeneous (n = 19), ovoid (n = 10), or round (n = 9) and smaller than 12 mm in maximal diameter. The surrounding lung field was normal (n = 16). CONCLUSION: Intrapulmonary lymph nodes are subpleural in the lower lung field. On thin-section CT, they are well circumscribed, homogeneous, round or ovoid, and smaller than 12 mm in maximal diameter. In the differential diagnosis of subpleural nodules located in the lower lung field, it should be kept in mind that they may be intrapulmonary lymph nodes even though the patient has malignancy.     

Clinical and radiological features in four adolescents with nutcracker syndrome

We describe four adolescents with the nutcracker syndrome. In three patients, the nutcracker syndrome was detected through mass urinary screening; the other patient was diagnosed after a sudden onset of dark urine. All patients underwent magnetic resonance angiography (MRA) for diagnosis of the nutcracker syndrome, which revealed dilatation of the left renal vein ranging between 7.4 and 13 mm at the hilar portion. A renal biopsy, performed in three patients, showed no remarkable abnormalities in the glomerulus or tubulointerstitial tissue. The patients complained of physical discomfort, including headache, abdominal pain, fainting, and tachycardia mimicking clinical symptoms of an orthostatic disturbance. However, no chronic systemic diseases were detected in any of the patients after repeated laboratory examinations. An orthostatic disturbance preceded diagnosis in three patients. This report indicates that the nutcracker syndrome may cause serious physical ailments that clinically mimic an orthostatic disturbance. It may be important to identify the nutcracker syndrome among children who manifest non-specific physical complaints. MRA could be a safe and reliable method for diagnosing the nutcracker syndrome.     

Activation of the beta-catenin gene by interstitial deletions involving exon 3 as an early event in colorectal tumorigenesis

beta-Catenin has been identified as an oncogene in several tumors including colorectal cancers. beta-Catenin gene is activated by interstitial deletions involving exon 3 in colorectal carcinomas of Japanese population, in contrast to amino acid substitutions detected among Caucasian population. The aim of this study was to examine the type and frequency of beta-catenin gene mutation during early stages of colorectal tumorigenesis. We screened 100 colorectal adenomas for somatic mutations in the beta-catenin gene by single-strand conformation polymorphism method, as well as polymerase chain reaction amplification. In cases with mutations, sequencing analyses and immunohistochemical staining were also performed. Somatic interstitial deletions of 272-413 bp, each of which included all parts of exon 3, were detected in three tumors. However, no adenoma carried missense mutations. We confirmed accumulation of aberrant beta-catenin protein in cytoplasm and nuclei of adenoma cells by immunohistochemical analysis. Our results suggested that activation of the beta-catenin gene by interstitial deletions involving exon 3 might be less frequent compared with frequent alterations of adenomatous polyposis coli (APC) gene, but could be an early event in colorectal tumorigenesis equivalent to APC gene alterations in the Japanese population.     

Efficacy of oncolytic reovirus against liver metastasis from pancreatic cancer in immunocompetent models

Liver metastasis is common in pancreatic cancer patients, and the current treatments are insufficient to improve the clinical outcome. Recently, tumor-targeted replication-competent viruses have been developed as cancer therapy. The aim of this study was to clarify the efficacy of oncolytic reovirus against liver metastases from pancreatic cancer in immunocompetent models. Reovirus serotype 3 and three hamster pancreatic cancer cell lines (HPD1NR, HPD2NR, and HaP-T1) were used in this study. The susceptibility of reovirus to these cell lines was examined. The effect of intraportal administration of reovirus against metastatic liver tumors was evaluated in vivo. Reovirus infected all cell lines and propagated via an activated Ras signalling pathway in vitro. In syngeneic hamster models using the HPD2NR cell line, intraportal administration of reovirus significantly decreased the number and size of treated tumors in comparison with non-treated tumors. Immunohistochemical examination revealed reovirus replication within the tumor cells but not in the surrounding normal tissue and organs. There were no reovirus-related toxicities and deaths. Our results indicate that intraportal administration of reovirus is effective and safe in immunocompetent and syngeneic hamster models of liver metastases from pancreatic cancer, suggesting that reovirus can be developed into an effective therapeutic modality in future.     

Potential in a single cancer cell to produce heterogeneous morphology, radiosensitivity and gene expression

Morphologically heterogeneous colonies were formed from a cultured cell line (KYSE70) established from one human esophageal carcinoma tissue. Two subclones were separated from a single clone (clone13) of KYSE70 cells. One subclone (clone13-3G) formed mainly mounding colonies and the other (clone 13-6G) formed flat, diffusive colonies. X-irradiation stimulated the cells to dedifferentiate from the mounding state to the flat, diffusive state. Clone 13-6G cells were more radiosensitive than the other 3 cell lines. Clustering analysis for gene expression level by oligonucleotide microarray demonstrated that in the radiosensitive clone13-6G cells, expression of genes involved in cell adhesion was upregulated, but genes involved in the response to DNA damage stimulus were downregulated. The data demonstrated that a single cancer cell had the potential to produce progeny heterogeneous in terms of morphology, radiation sensitivity and gene expression, and irradiation enhanced the dedifferentiation of cancer cells.     

CT findings of surgically resected large cell neuroendocrine carcinoma of the lung in 38 patients

OBJECTIVE: We sought to assess the CT features of surgically resected large cell neuroendocrine carcinoma of the lung. MATERIALS AND METHODS: The cases of all patients who underwent surgical resection for primary lung cancer in a single institution from 1993 to 2000 and who received an initial diagnosis of poorly differentiated non-small cell lung carcinoma, small cell carcinoma, carcinoid tumor, and large cell neuroendocrine carcinoma were histologically reviewed. The findings for 43 patients were histologically reclassified and confirmed as large cell neuroendocrine carcinoma. The CT scans available for 38 patients were evaluated by two observers. RESULTS: In the 38 patients, six central tumors and 32 peripheral tumors, with diameters ranging from 12 to 92 mm (mean +/- SD, 32 +/- 19 mm), were identified. None of the tumors had air bronchograms or calcification in the mass or nodule. Of the 19 patients with thin-section CT scans, 14 (74%) showed the tumor-lung interface as well defined and five (26%) showed the interface to be ill defined. Lobulation was identified on 15 scans (79%) and spiculation was evident on six scans (32%). On contrast-enhanced CT scans, inhomogeneously enhanced tumors appeared to be larger (51 +/- 18 mm) than homogeneously enhanced tumors (25 +/- 10 mm; p < 0.001). At histopathologic examination, gross necrosis was noted in 20 of 28 patients who had undergone contrast-enhanced CT, and the cause of inhomogeneous enhancement on CT scans was determined to be intratumoral necrosis. Multiple microscopic necroses were present in all 28 patients. CONCLUSION: Large cell neuroendocrine carcinoma usually appears as a well-defined and lobulated tumor with no air bronchograms or calcification. The inhomogeneous enhancement (caused by necrosis) seen in large cell neuroendocrine carcinomas with large diameters is not necessarily apparent in small-diameter (< 33 mm) large cell neuroendocrine carcinomas, even if the tumor contains necrosis.     

Pulmonary dirofilariasis: computed tomography findings and correlation with pathologic features

OBJECTIVE: The purpose of this study was to describe the computed tomography (CT) and pathologic features of 5 nodules of pulmonary dirofilariasis in 4 patients. METHODS: Four patients with 5 nodules of pathologically confirmed pulmonary dirofilariasis who under went CT were enrolled, and the imaging interpretations were retrospectively compared with the histopathologic characteristics. RESULTS: Three of the 4 patients had a solitary nodule, and the remaining patient had 2 nodules. All the nodules were distributed in the right lower lobe and were attached to the pleura. They were all round or oval in shape and ranged in size from 11 to 22 mm in largest diameter (mean=17 mm). On thinner section CT, the nodules had a well-defined smooth margin with or without a shallow notch; they were connected to the arterial branch and, occasionally, to the venous branch. On contrast-enhanced CT, all the nodules contained a homogeneous low-attenuation area, which corresponded to areas of coagulative necrosis on histopathologic examination. CONCLUSION: Although the CT findings of a pulmonary dirofilariasis nodule are nonspecific, awareness of the findings on contrast-enhanced CT and the pathologic appearance of this rare benign condition may facilitate its differentiation from a malignant nodule.     

Formalin-fixed tumor cells effectively induce antitumor immunity both in prophylactic and therapeutic conditions

BACKGROUND: Autologous whole tumor cell-based vaccinations would seem to be ideal since such vaccinations, in contrast to vaccination with a single defined antigen, have the potential to elicit a broad type of T-cell immune response to tumor-associated antigens. OBJECTIVE: We modified formaldehyde (formalin)-fixed mouse melanoma cells and investigated the utility of those cells as sources of tumor antigens for immunotherapy. METHODS: C57BL/6 or the proteasome activator PA28alpha-knockout mice were intradermally inoculated with 1% formalin-fixed B16 cells three times at weekly intervals either before or after tumor challenge. Simultaneously, interleukin-12 gene was transferred into the skin around immunization sites using gene gun technology. The effects were evaluated by tumor growth, antigen-specific interferon-gamma production in splenic lymphocytes, and activation of dendritic cells. RESULTS: Fixed cells directly induced production of tumor necrosis factor-alpha in dendritic cells more effectively than did frozen and thawed cells. More than 60% of the mice immunized with fixed cells and interleukin-12 rejected the challenged B16 tumor. CD4+ T cells from those mice produced a significant amount of interferon-gamma in response to melanoma cells. Furthermore, this combined treatment showed antitumor immunity initiated by CD8+ and CD4+ T cells in the therapeutic experiments. PA28alpha/beta appeared not to be required for the development of CD8+ T cells, although it is known to be essential for the development of CD8+ T cells specific for tyrosinase-related protein-2, one of melanocyte-lineage differentiated antigens. CONCLUSION: These results suggest that formalin-fixed autologous melanoma cells have a potential to function as effective antigen sources for immunotherapy.