Metastatic Tumor Nodules Research Articles

Memory T Cells in Human Tumor and Chronic Inflammatory Microenvironments: Sleeping Beauties Re-awakened by a Cytokine Kiss

Human tumors often progress and spread in spite of the presence of large numbers of CD4+ and CD8+ T cells with activated or memory cell phenotypes. The T cells in the microenvironment of human lung tumors fail to be activated in response to stimulation via the T cell receptor and CD28 under conditions that fully activate T cells derived from the peripheral blood of the cancer patients. A combination of regulatory mechanisms which are also observed in a variety of different chronic inflammatory conditions may contribute to the T cell unresponsiveness, and to their inability to respond to and kill tumor cells. The non-responsiveness of memory T cells isolated from human lung tumors and non-malignant chronic inflammatory tissues can be reversed in vitro by a brief pulse with IL-12, and the local and sustained release of exogenous IL-12 into the microenvironment of human tumor xenografts in SCID mice re-activates the tumor-associated T cells in situ. In the later case, the T cells proliferate, secrete interferon-γ and initiate a cascade of events that culminate in the eradication of tumor cells from the xenograft. In transplantable and spontaneously developing tumors of mice the injection of a single tumor nodule with IL-12 loaded biodegradable microspheres activates tumor-associated T cells to kill tumor cells in situ, and provokes a systemic anti-tumor response that results in the eradication of distant metastatic tumor nodules that are not treated with the cytokine. These mice exhibit a systemic tumor specific immunity as they resist a second challenge with the same (but not a different) tumor. These findings suggest that it will be possible to provoke a systemic anti-tumor immunity in cancer patients by the direct injection of IL-12 loaded biodegradable microspheres or liposomes to locally deliver very low but sustained doses of IL-12 into a single tumor site. This strategy which is based upon the ability of IL-12 to re-activate tumor-associated T cells is termed in situ tumor vaccination.

Clusterin plays an important role in hepatocellular carcinoma metastasis

To identify genes associated with tumor metastasis in hepatocellular carcinoma (HCC), gene expression profiles between a pair of primary HCC (H2-P) and their matched metastatic HCC (H2-M) were compared. Overexpression of clusterin (CLU) was found in H2-M cells. To determine the roles CLU played in HCC metastasis, CLU was transfected into H2-P cells. Overexpression of CLU in H2-P cells increased cell migration by twofold in vitro and formation of metastatic tumor nodules in liver by eightfold in vivo. To evaluate the correlation of CLU expression with HCC metastasis, the expression levels of CLU in HCCs were investigated using a tissue microarray (TMA) containing 104 pairs of primary HCCs and their matched metastases. The frequency of CLU overexpression increased significantly in metastatic HCCs (59.1%) compared with that in primary tumors (32.6%, P<0.001). To gain additional insight into the function of CLU, the expression profile of H2P-CLU was compared with vector-transfected H2-P cells by cDNA microarray. A total of 35 upregulated and 14 downregulated genes were detected in H2P-CLU. One of the upregulated genes known as YKL-40, which is implicated in matrix-remodeling and metastasis, was further studied using TMA. A significant correlation (P<0.001) between the expression levels of YKL-40 and CLU was observed, implying that the CLU-YKL-40 pathway may play an important role in HCC metastasis.

167. Both Oncolysis and Tumor Immunity Are Involved in an Autitumoral Efficacy by Intratumoral Injection of Recombinant Vaccinia Virus (TK Deleted, hGM-CSF Inserted Wyeth Strain) in a VX2 Rabbit Model

Several approaches to gene therapy for cancer have yielded promising results in rodent models. The translation of these results to the clinical realm has been delayed by the lack of tumor models in large animals. We investigated the efficacy of thymidine kinase (TK) deleted human GM-CSF inserted mutants of Wyeth strain of vaccinia virus (JX-594) using in VX-2 rabbit hepatoma model. VX-2 rabbit carcinoma cells were maintained by serial transplantation in the thigh muscles of New Zealand White rabbits, and VX-2 tumor fragment (1mm3) was injected into left hepatic lobe. The primary tumor formation was detected by U/S on week 2 to week 3 post VX-2 injection. JX-594 (10^9 pfu) was injected by U/S guide immediately after tumor detection (<1.5 cm2 in a diameter) into intratumorally (IT) or intravenously, and then CT was taken every a week to monitor hepatoma growth. The tumor growth after both IT or IV injection significantly was significantly inhibited. Furthermore, the metastatic tumor nodule was not observed after IT or IV JX-594 injection while 100 % was observed in rabbits without vv administration. Serum human GM-CSF was maintained to at least one week both in IT and IV injected groups, and the degree of therapeutic efficacy was related with GM-CSF production. Based on in vitro and in vivo tumor-specific replication capacity of JX-594 replication capacity, both direct viral growth and increased tumor immunity by GM-CSF produced by JX-594 might be responsible for antitumoral efficacy and antimetastatic effect. This preclinical study of hepatoma treatment shows JX-594 acts as an oncolytic vaccinia virus suggesting that JX-594 might be potent and safe viral vector for the clinical application for tumor-directed gene therapy.

Osteopontin in Melanocytic Lesions—A First Step Towards Invasion?

Determination of the earliest molecular changes that occur during the process of cellular transformation is of intense interest to the field of tumor biology but represents a considerable technical challenge in that it is not normally amenable to pathological examination. As the transition from melanocyte hyperplasia to primary cutaneous melanoma often occurs within dysplastic nevi at the dermal–epidermal junction on sun exposed sites of the skin, it presents a unique opportunity to examine these initial stages of tumor progression. Aberrant changes associated with this transition can be identified via gene expression profiling using high-density DNA microarrays probed with samples prepared from melanocytic lesions or cell lines (Carr et al, 2003) or conversely using immunohistochemical staining to determine expression in tissue section microarrays from defined stages (Pacifico et al, 2004). Genes identified as being differentially expressed in this way provide prognostic markers as well as insight into the process of cellular transformation. The combination of both of these techniques were used in the report ofZhou et al (2005), in order to discover genes highly upregulated in melanocytic lesions. Comparison of metastatic tumor nodules with benign nevi has found over 190 genes potentially implicated in this process of early stage transformation, with the osteopontin gene already recognized for its involvement in transformation of a number of diverse tumor types (Wai and Kuo, 2004) showing the highest abundance of differential expression.

Phase I Study of MetXia-P450 Gene Therapy and Oral Cyclophosphamide for Patients with Advanced Breast Cancer or Melanoma

MetXia-P450 is a novel recombinant retroviral vector that encodes the human cytochrome P450 type 2B6 gene (CYP2B6), Escherichia coli lacZ, and neomycin resistance marker genes. Cytochrome P450 enzymes are primarily expressed in the liver and convert the prodrug cyclophosphamide to an active phosphoramide mustard and acrolein. Gene-based delivery of CYP2B6 to the tumor site leads to local prodrug activation and higher concentrations of the active metabolites at the target site. MetXia-P450 was directly injected into metastatic cutaneous tumor nodules on days 1 and 2 and nodules biopsied on day 7. Oral cyclophosphamide (100 mg/m(2)) was administered between days 8 and 22. Subsequent cycles of oral cyclophosphamide were repeated for 2 of 4 weeks. Gene transfer levels in biopsy samples were measured by histologic and quantitative PCR analyses. Safety assessments were made using PCR for vector dissemination to the blood after injection and using PCR and serologic analyses to detect replicating virus. Secondary end points included clinical response, toxicity, and evaluation of antitumor immune responses by measurement of carcinoembryonic antigen and 5T4 antibodies. Twelve patients with breast cancer (n = 9) and melanoma (n = 3) received three dose levels of MetXia-P450 ( approximately 8 x 10(5), approximately 8 x 10(6), and approximately 8 x 10(7) lacZ transferring units/mL). The product was safe and well tolerated. The lacZ transgene was detected in biopsy material by immunohistochemistry in 10 of 12 patients and integrated viral sequences by PCR in 3 of 6 patients. One (8%) patient with breast cancer had a partial response and received 7 months of oral cyclophosphamide. Four (33%) patients had stable disease for > or =3 months and the rest had progressive disease. Preliminary immunologic analyses were suggestive of an antitumor response in two patients (partial response in one patient and stable disease in one patient). MetXia was safe and well tolerated. Gene transfer was detected at all dose levels, and the initial suggestion of an antitumor response indicates that MetXia-P450 should undergo further clinical assessment.

Engineering Lipid Vesicles of Enhanced Intratumoral Transport Capabilities: Correlating Liposome Characteristics with Penetration into Human Prostate Tumor Spheroids

Liposomes have been widely used delivery systems, particularly relevant to the development of cancer therapeutics. Numerous liposome-based drugs are in the clinic or in clinical trials today against multiple tumor types; however, systematic studies of liposome interactions with solid or metastatic tumor nodules are scarce. This study is describing the in vitro interaction between liposomes and avascular human prostate (LNCaP-LN3) tumor spheroids. The ability of fluorescently labelled liposomal delivery systems of varying physicochemical characteristics to penetrate within multicellular tumor spheroids has been investigated by confocal laser scanning microscopy. A variety of liposome characteristics and experimental parameters were investigated, including lipid bilayer composition, duration of liposome-spheroid interaction, mean liposome size, steric stabilization of liposomes. Electrostatic binding between cationic liposomes and spheroids was very efficient; however, it impeded any significant penetration of the vesicles within deeper layers of the tumor spheroid. Small unilamellar liposomes of neutral surface character did not bind as efficiently but exhibited enhanced penetrative transport capabilities closer to the tumor core. Polymer-coated (sterically stabilised) liposomes exhibited almost no interaction with the spheroid, indicating that their limited diffusion within avascular tissues may be a limiting step for their use against micrometastases. Multicellular tumor spheroids were used as models of solid tumor interstitium relevant to delivery systems able to extravasate from the microcapillaries or as models of prevascularized micrometastases. This study illustrates that interactions between liposomes and other drug delivery systems with multicellular tumor spheroids can offer critically important information with respect to optimizing solid or micrometastatic tumor delivery and targeting strategies.

Liposomal vector mediated delivery of the 3p FUS1 gene demonstrates potent antitumor activity against human lung cancer in vivo.

Lung cancer is one of the leading causes of death in the world. The underlying cause for lung cancer has been attributed to various factors that include alteration and mutation in the tumor suppressor genes. Restoration of normal function of the tumor suppressor gene is a potential therapeutic strategy. Recent studies have identified a group of candidate tumor suppressor genes on human chromosome 3p21.3 that are frequently deleted in human lung and breast cancers. Among the various genes identified in the 3p21.3 region, we tested the antitumor activity of the FUS1 gene in two human non-small-cell lung cancer (NSCLC) xenografts in vivo. Intratumoral administration of FUS1 gene complexed to DOTAP:cholesterol (DOTAP:Chol) liposome into subcutaneous H1299 and A549 lung tumor xenograft resulted in significant (P = .02) inhibition of tumor growth. Furthermore, intravenous injections of DOTAP:Chol-FUS1 complex into mice bearing experimental A549 lung metastasis demonstrated significant (P = .001) decrease in the number of metastatic tumor nodules. Finally, lung tumor-bearing animals when treated with DOTAP:Chol-FUS1 complex demonstrate prolonged survival (median survival time: 80 days, P = .01) compared to control animals. This result demonstrates the potent tumor suppressive activity of the FUS1 gene and is a promising therapeutic agent for treatment of primary and disseminated human lung cancer.

Low dose hyper-radiosensitivity in metastatic tumors

Introduction The laboratory phenomenon of low dose hyper-radiosensitivity (LDHRS) describes excess cell kill at doses below 1 Gy relative to that predicted by the linear quadratic model. These data have stimulated the investigation of whether LDHRS can be exploited clinically. Methods Patients with metastatic tumor nodules to skin were recruited. The nodules were measured in three dimensions, consecutively numbered according to volume, and randomized, in matched pairs, to receive either conventionally fractionated radiotherapy (1.5 Gy/day) or ultrafractionated radiotherapy (0.5 Gy TDS: 4-h gap). Both groups were treated for 12 days. Measurements were taken Days 0, 5, 8, 12, and 26 and monthly until regrowth occurred. Tumor volumes were normalized to those on Day 0 and plotted against time from the start of treatment. Time to regrowth to original volume was calculated and compared between groups using the Wilcoxon signed rank test. Results Eight patients with a total of 40 paired nodules were analyzed; 36 nodules have regrown and are therefore evaluable. Analysis of the whole data set demonstrates a two-tailed p-value of 0.14 in favor of the “ultrafractionated” treatment. Analysis of the tumors generally accepted as being radioresistant and known to show LDHRS in vitro demonstrates a two-tailed p value of 0.009. Conclusions LDHRS can be demonstrated in tumors clinically. An “ultrafractionated” radiotherapy regime produces significantly increased growth delay in radioresistant malignant tumors.

Uptake of Long-Circulating Immunoliposomes, Directed Against Colon Adenocarcinoma Cells, by Liver Metastases of Colon Cancer

Radiolabeled ([3H]cholesteryloleyl ether) immunoliposomes directed against rat colon adenocarcinoma CC531 cells were prepared by random coupling of a tumor cell-specific antibody, CC52, via a thio–ether bond. In vitro binding experiments demonstrated a saturable and specific interaction of CC52-immunoliposomes, which could be inhibited by free non-coupled CC52 but not by irrelevant antibodies. The in vivo targeting potential of CC52-immunoliposomes, which were pegylated to achieve prolonged circulation times, was tested in an established rat liver CC531 metastasis model. Twenty-four hours after injection of the liposomes, 25% of the CC52-immunoliposomes were still present in the blood, which was comparable with the control liposomes (either with or without antibody). Liposomes were mainly taken up from the blood by the liver and the spleen, although hepatic uptake of the immunoliposomes was higher and splenic uptake was lower as compared to liposomes without antibody. Within the metastatic tumor nodules in the liver, uptake of both the CC52-immunoliposomes and non-specific immunoliposomes was significantly higher than that of control liposomes without antibody. Visualization of fluorescently or gold labeled CC52-immunoliposomes revealed that, although targeting to liver metastases was achieved, the immunoliposomes were mostly not associated with tumor cells but rather localized in tumor associated cells, probably macrophages.

Multiple nodular metastases in mesenteric panniculitis by uterine papillary serous adenocarcinoma (upsc):: CT Appearance of a case

Intra-abdominal panniculitis is a thickening of the mesentery of the small/large intestine due to infiltration of lipid-laden macrophages associated with a variable amount of fibrosis. This condition is rarely associated with malignant neoplasms. We report the computed tomography (CT) findings of a patient treated for uterine papillary serous adenocarcinoma (UPSC). She had mesenteric panniculitis where metastatic tumor nodules implanted. This was the only intraperitoneal recurrence. To our knowledge, no such finding has been reported in the gynecologic and radiologic literature to date. On CT images, the differential diagnosis is with cystic dilatations of mesenteric lymph vessels.

Matrilysin-specific antisense oligonucleotide inhibits liver metastasis of human colon cancer cells in a nude mouse model.

Human colon cancer frequently develops liver metastasis. Matrilysin (MMP-7), the smallest member of the matrix metalloproteinase (MMP) family, is commonly produced by human colon carcinoma cells and has been suggested to be involved in the progression and metastasis of this type of cancer. In the present study, we tested the effect of a matrilysin-specific antisense phosphorothioate oligonucleotide on liver metastasis of the human colon carcinoma cell line WiDr in nude mice. In culture, the antisense oligonucleotide moderately inhibited the secretion of matrilysin by WiDr cells. Injection of WiDr cells into the spleen of nude mice produced many metastatic tumor nodules in the liver. When the antisense oligonucleotide was injected daily into the mice for 11 days, the formation of the metastatic tumor nodules was strongly inhibited in a dose-dependent manner. An inhibition of liver metastasis of over 70% was obtained at a dose of 120 micrograms of the oligonucleotide per mouse. The antisense oligonucleotide did not inhibit tumor growth in spleen and in liver. A scrambled control oligonucleotide had no effect on liver metastasis of WiDr cells. Our results demonstrate an important role of matrilysin in liver metastasis of human colon cancer and the therapeutic potential of matrilysin antisense oligonucleotides for the prevention of metastasis.

A high level of prostaglandin E2 (PGE2) in the portal vein suppresses liver-associated immunity and promotes liver metastases.

Prostaglandin E2 (PGE2) is generally accepted to be an immunosuppressant produced by cancer cells and their surrounding macrophages. Although several investigators have reported detecting high concentrations of PGE2 in the portal veins of patients with colorectal cancer, the relationship between these high concentrations of PGE2 in the portal vein and liver-associated immunity remains unclear. In this study, we attempted to determine if the portal administration of PGE2 suppresses the immune function of the liver in a rat model. Donryu rats were administered PGE2 via the portal vein for 7 days, following which the cytotoxic activity of hepatic sinusoidal lymphocytes (HSL) against natural killer (NK)-sensitive YAC-1 and rat syngeneic AH60C tumor cells was assessed. Purified HSL are spontaneously cytolytic; however, the continuous administration of PGE2 dramatically suppressed the cytotoxic activity of HSLs in a dose-dependent fashion. Flow cytometric analysis showed that the large granular lymphocyte (LGL) fraction, hepatic natural killer (pit) cells, and CD4-8+ killer/suppressor T cells were mainly reduced in number in the HSLs following PGE2 infusion. In this rat AH60C metastasis model, the continuous administration of PGE2 increased the number and size of metastatic tumor nodules in the liver, suggesting that high concentrations of PGE2 in the portal vein suppress liver-associated immunity and promote the formation of hepatic metastasis.

Antitumor effects of liposomal IL1? and TNF? against the pulmonary metastases of the B16F10 murine melanoma in syngeneic mice

Interleukin 1 alpha (IL1 alpha) and tumor necrosis factor alpha (TNF alpha) have been successfully incorporated into specific phosphatidylcholine (PC) and phosphatidylserine (PS) multilamellar vesicle (MLV) liposomes by modifying the concentration of calcium ion and pH of the encapsulation buffer. Under these conditions, some of the cytokines may attach to the exterior surface of the MLV and therefore be readily accessible to target cells for receptor binding and signal transduction. These cytokine-associated liposomes are stable for up to 2 weeks in serum-free buffer, and leakage of cytokines into medium containing 10% fetal bovine serum was about 50% at the end of a 3-day incubation period at 37 degrees C. The biological activities mediated by liposomal IL1 alpha and TNF alpha were specific: the stimulation of thymidine uptake in T-helper D10 lymphocytes and the cytolysis of TNF alpha-sensitive L929 target cells could be blocked by specific neutralizing antibodies in a dose-dependent fashion. When administered intravenously into C57BL/6 mice bearing the syngeneic B16F10 murine melanoma cells, dual entrapment of liposomal IL1 alpha and TNF alpha significantly reduced the number of metastatic tumor nodules in the lungs and prolonged the life span of the animals. Thus, liposomal IL1 alpha and TNF alpha displayed significant in vivo antitumor activity against the IL1 alpha- and TNF alpha-resistant B16F10 metastatic murine melanoma.

Impact of the Crohn's-like lymphoid reaction on staging of right-sided colon cancer: Results of multivariate analysis

The presence of lymphoid aggregates within the muscularis propria or pericolic fibroadipose tissue apposing invasive colorectal carcinoma, termed the Crohn's-like lymphoid reaction, has been related to improved patient length of survival according to univariate statistical analysis. We tested the Crohn's-like lymphoid reaction as an indicator of prognosis in a multivariate statistical analysis of 344 resected right-sided colonic cancers. Improved 5-year survival in univariate analysis was associated with low tumor grade, regular tubule configuration, expanding tumor growth pattern, prominent peritumoral lymphocytic infiltration, absence of tumoral invasion of extramural veins, all levels of intramural and extramural invasion short of widespread local tumor permeation, conspicuous Crohn's-like lymphoid reaction, and absence of both nodal metastasis and nodal-independent tumor nodules in pericolic fat. By the Cox proportional hazard model using the stepwise method, depth of tumor invasion, lymph node metastasis, Crohn's-like lymphoid reaction, and metastatic tumor nodules in pericolic fat retained independent prognostic significance. Combining the four variables to formulate pathological prognostic categories yielded a highly favorable prognostic group—92% 5-year survival and 95% confidence limits (88% to 96%)—encompassing 53% of the study population. It included all Dukes' stage A carcinomas, 66% of Dukes' stage B adenocarcinomas, and 11% of Dukes' stage C cancers. Lymph node metastases coupled with intramural and extramural extent of tumor invasion are the cornerstones of colorectal cancer staging. Addition of other variables improves prognostication for the cecum and ascending colon. From this study the Crohn's-like lymphoid reaction and metastatic tumor nodules in pericolic fat emerge as significant independent indicators of prognosis for right-sided colon cancer. Complex correlations of both indicators with nonselected variables were observed.

Isolated Pulmonary Giant Cell Vasculitis

An autopsy case of granulomatous vasculitis confined to the pulmonary vasculature in a 40-year-old woman with widespread ovarian carcinoma is reported. Although gross lesions were not identified in the lungs other than a few metastatic tumor nodules, vascular lesions were demonstrated microscopically throughout both lungs. Histopathologically, granulomatous vasculitis was present only in the large and medium-calibered pulmonary arteries of elastic type and in pulmonary veins. Granulomas were distributed mainly in the media and adventitia. The lumina of arteries and veins were free from any occlusion or dilatation. In the granulomas, multinucleated giant cells of both foreign body and Langhans' types containing asteroid body often appeared with slight infiltration by T-lymphocytes. Fibrinoid necrosis was absent in the granulomatous lesions, and neutrophils and eosinophils were also not present. The pulmonary granulomatous vasculitis in this case is distinctly different from the other pulmonary necrotizing and granulomatous vasculitides previously reported.

From dukes through jass: Pathological prognostic indicators in rectal cancer

In the recently described Jass staging system for resected adenocarcinoma of the rectum, peritumoral lymphocytic infiltration and tumor growth pattern are introduced as significant indicators of prognosis in conjunction with depth of tumor invasion and lymph node metastasis. The authors of this study have tested the applicability of the Jass system by reviewing 348 resected rectal cancers for 12 pathological variables, including two newly recognized features, namely the Crohn's-like lymphoid reaction and metastatic tumor nodules in pericolic fat. By univariate analysis improved 5-year survival rate was associated with tubular-type adenocarcinoma, low tumor grade, retention of tubule configuration and nuclear polarity, expanding tumor growth pattern, prominent peritumoral lymphocytic infiltration, absence of extramural vein invasion by tumor, all levels of intramural and extramural invasion short of widespread local tumor dissemination, a Crohn's-like lymphoid reaction pattern, and absence of both nodal metastasis and tumor nodules in perirectal fat. By Cox stepwise proportional hazards analysis, depth of tumor invasion, lymph node metastasis, Crohn's-like lymphoid reaction, and extramural venous invasion retained independent prognostic significance. Peritumoral lymphocytic infiltration and tumor growth pattern of the Jass staging system failed to compete successfully with other variables in the proportional hazards model, in part because of their correlation with the model's selected variables. Both intramural and extramural extent of tumor invasion coupled with lymph node metastasis form the cornerstones of rectal cancer staging. However, other factors do refine prognostication. From this study the Crohn's-like lymphoid reaction emerges as a significant new independent indicator of prognosis for survival from rectal cancer. Although the Crohn's-like lymphoid reaction and extramural vein invasion took precedence as staging variables in this study, a complex interrelationship with other parameters was observed.

Development of Anaplastic Changes in Low-Grade Astrocytomas of Childhood

The authors present their experience with six children who developed anaplastic astrocytomas after receiving treatment for low-grade astrocytomas. Five children were from a series of 55 children with optic chiasmatic-hypothalamic gliomas who have been studied since 1976. The sixth child initially had a low-grade astrocytoma of the thalamus. The mean age of the children at initial presentation was 5.3 years. Five children were treated with surgery and radiation therapy; one child with a chiasmatic-hypothalamic glioma received radiation therapy alone. The amount of external radiation therapy used in all children was 50-52.5 Gy delivered in standard fractionations over approximately 6 weeks to include the volume of the original tumor plus a margin of 2 cm. The time to anaplastic transformation varied between 2 and 10 years (mean, 6.4 years). At tumor recurrence, the children had seizures or symptoms and signs of raised intracranial pressure. The location of the second tumor in all patients was either at the primary site or within the field of radiation therapy. Five of the six children underwent a second craniotomy and subtotal resection of their malignant gliomas. One child had positive cerebrospinal fluid cytology and multiple intraspinal metastatic tumor nodules detected by magnetic resonance imaging. On histopathological examination, four children had anaplastic astrocytoma, and two had glioblastoma multiforme. Four of the six children have died of their anaplastic astrocytomas (mean time from diagnosis of anaplastic astrocytoma to death, 10 months). Two children underwent chemotherapy and spinal irradiation for their anaplastic astrocytomas, and are currently alive and undergoing treatment. The possible mechanisms by which anaplastic tumors have developed in children treated previously for low-grade astrocytomas is discussed. The data suggest that radiation therapy may have played an integral role in the genesis of anaplastic astrocytomas in these children.

Development of Anaplastic Changes in Low-Grade Astrocytomas of Childhood

The authors present their experience with six children who developed anaplastic astrocytomas after receiving treatment for low-grade astrocytomas. Five children were from a series of 55 children with optic chiasmatic-hypothalamic gliomas who have been studied since 1976. The sixth child initially had a low-grade astrocytoma of the thalamus. The mean age of the children at initial presentation was 5.3 years. Five children were treated with surgery and radiation therapy; one child with a chiasmatic-hypothalamic glioma received radiation therapy alone. The amount of external radiation therapy used in all children was 50-52.5 Gy delivered in standard fractionations over approximately 6 weeks to include the volume of the original tumor plus a margin of 2 cm. The time to anaplastic transformation varied between 2 and 10 years (mean, 6.4 years). At tumor recurrence, the children had seizures or symptoms and signs of raised intracranial pressure. The location of the second tumor in all patients was either at the primary site or within the field of radiation therapy. Five of the six children underwent a second craniotomy and subtotal resection of their malignant gliomas. One child had positive cerebrospinal fluid cytology and multiple intraspinal metastatic tumor nodules detected by magnetic resonance imaging. On histopathological examination, four children had anaplastic astrocytoma, and two had glioblastoma multiforme. Four of the six children have died of their anaplastic astrocytomas (mean time from diagnosis of anaplastic astrocytoma to death, 10 months). Two children underwent chemotherapy and spinal irradiation for their anaplastic astrocytomas, and are currently alive and undergoing treatment. The possible mechanisms by which anaplastic tumors have developed in children treated previously for low-grade astrocytomas is discussed. The data suggest that radiation therapy may have played an integral role in the genesis of anaplastic astrocytomas in these children.

Combined Treatment of Adriamycin and Dipyridamole Inhibits Lung Metastasis of B16 Melanoma Cells in Mice

The combined effects of adriamycin (ADM) and dipyridamole (DP) on lung metastasis of B16 melanoma cells in mice were investigated. First, the antitumor effects of ADM and DP were examined both in vitro and in vivo. The clonogenicity of B16 melanoma cells was suppressed by the combination of ADM and the nontoxic dose of DP in vitro, and growth of the B16 melanoma solid tumor implanted subcutaneously in mice was inhibited with this drug combination, compared to findings with ADM alone in vivo. To examine events related to experimental lung metastasis, 2 X 10(5) B16 melanoma cells were given intravenously into the tail vein of mice and the efficacy was determined by counting the number of metastatic tumor nodules. DP in doses of 25-100 mg/kg given alone reduced the number of metastasis to about 85% that in the control group. ADM in doses of 1-4 mg/kg for 3 days inhibited the metastasis, in a dose-dependent manner. When combined with DP, the antimetastatic effect of ADM was enhanced and the number of metastasis prominently decreased, compared to single application of the drug (p less than 0.05). We speculate that ADM given concomitantly with DP may have the potential to inhibit metastatic growth of a tumor.

Membrane characteristics and functional activity of phagocytic alveolar macrophages

The intravascular (iv) or intramuscular (im) inoculations of a suspension of Lewis carcinoma cells induced metastatic tumor nodules in the lungs of C57Bl/6 mice. The administration of curantil (dipyridamole) (500 mg per 20 g-mouse, per os) once a week beginning one day after iv tumor cells inoculation (2 X 10(5) cells) reduced 4-fold the number of tumor nodules. The administration of curantil one day after im tumor cells inoculation (2 X 10(6) cells) reduced 2-fold the number of tumor nodules. The combined treatment of curantil (4-, 10-days after inoculation) and well-known inducer of interferon poly I:poly C (50 mg per 20 g-mouse, 1-, 7-, 14-days after inoculation tumor cells) had no synergistic effect.