Autoantibody signature differentiates Wilms tumor patients from neuroblastoma patients

Several studies report autoantibody signatures in cancer. The majority of these studies analyzed adult tumors and compared the seroreactivity pattern of tumor patients with the pattern in healthy controls. Here, we compared the autoimmune response in patients with neuroblastoma and patients with Wilms tumor representing two different childhood tumors. We were able to differentiate untreated neuroblastoma patients from untreated Wilms tumor patients with an accuracy of 86.8%, a sensitivity of 87.0% and a specificity of 86.7%. The separation of treated neuroblastoma patients from treated Wilms tumor patients' yielded comparable results with an accuracy of 83.8%. We furthermore identified the antigens that contribute most to the differentiation between both tumor types. The analysis of these antigens revealed that neuroblastoma was considerably more immunogenic than Wilms tumor. The reported antigens have not been found to be relevant for comparative analyses between other tumors and controls. In summary, neuroblastoma appears as a highly immunogenic tumor as demonstrated by the extended number of antigens that separate this tumor from Wilms tumor.     

Cytotoxic dendritic cells generated from cancer patients

Known for years as professional APCs, dendritic cells (DCs) are also endowed with tumoricidal activity. This dual role of DC as killers and messengers may have important implications for tumor immunotherapy. However, the tumoricidal activity of DCs has mainly been investigated in animal models. Cancer cells inhibit antitumor immune responses using numerous mechanisms, including the induction of immunosuppressive/ tolerogenic DCs that have lost their ability to present Ags in an immunogenic manner. In this study, we evaluated the possibility of generating tumor killer DCs from patients with advanced-stage cancers. We demonstrate that human monocyte-derived DCs are endowed with significant cytotoxic activity against tumor cells following activation with LPS. The mechanism of DC-mediated tumor cell killing primarily involves peroxynitrites. This observed cytotoxic activity is restricted to immature DCs. Additionally, after killing, these cytotoxic DCs are able to activate tumor Ag-specific T cells. These observations may open important new perspectives for the use of autologous cytotoxic DCs in cancer immunotherapy strategies.     

Anti-P53 antibodies in Brazilian brain tumor patients

Gliomas of astrocytic origin are the most common primary brain tumors, accounting for over 40 to 50% of all central nervous system tumors. The TP53 tumor suppressor gene is the most frequently mutated gene found in human malignancies. A mutation of this gene can lead to an increased half-life of the resulting protein and loss of biological function. High levels of p53 have been detected in the serum of colon cancer patients, although p53 protein has not been detected in the serum of brain tumor patients. Besides circulating p53, several studies have detected antibodies against p53 in patients with lung and breast cancer, as well as those with other types of cancer. We studied p53 protein and anti-p53 antibodies in the plasma of Brazilian brain tumor patients. Plasma samples were drawn from 24 untreated brain tumor patients and from 15 healthy donors without clinical signs of cancer. Western blotting techniques were used to detect p53 protein and anti-p53 antibodies. We found anti-p53 antibodies in 5/24 brain tumor patients. Age appears to affect the immune response, as four of six tumor patients under 16 years old had detectable anti-p53 antibodies, while these were found in only 1 of 18 adults (over 16 years old). We found no p53 protein in any of the serum samples from the brain tumors. Possibly the presence of this protein is affected by tumor type or by the organs that are sampled.     

Decreased tumstatin-mRNA is associated with poor outcome in patients with NSCLC

Tumstatin is a candidate tumor suppressor that plays an important role in tumor growth and angiogenesis. The purpose of this study was to evaluate the correlation between tumstatin-mRNA expression and the clinicopathologic characteristics, tumor angiogenesis, outcome of patients with non-small cell lung cancer (NSCLC). Specimens from 68 patients with NSCLC were recruited in this study. Tumstatin-mRNA expression and protein level in tumor tissues were quantified respectively by quantitative RT-PCR and ELISA. Microvessel density (MVD) was determined by CD34 immunostaining. The correlation of tumstatin-mRNA expression levels with clinicopathologic variables, tumor angiogenesis, and prognosis was analyzed. Tumstatin-mRNA expression levels were decreased in tumor. Tumstatin-mRNA expression level was significantly correlated with its protein level in tumor (r = 0.562; P = 0.001). Tumstatin-mRNA expression levels in poorly differentiated tumor tissues were significantly lower than in well-differentiated tumor tissues (P < 0.004). Furthermore, tumor tumstatin-mRNA expression were also significantly related to tumor pathologic stage (P = 0.032) and MVD (r = -0.77, P < 0.0001). Overall survival (OS) and disease-free survival (DFS) analysis indicated that NSCLC patients with low tumstatin-mRNA expression had poorer OS and DFS than those with high expression (P = 0.015 and 0.037; respectively). Multivariable Cox regression analysis revealed that the tumstatin-mRNA expression could be an independent prognostic indicators in both DFS and OS. Tumstatin-mRNA expression levels are down-regulated in NSCLC tissues. Tumstatin-mRNA expression level correlates with prognosis, which suggests that tumstatin-mRNA is a new potential independent marker of favorable prognosis in NSCLC.     

恶性肿瘤化疗所致院内感染31例分析

目的探讨恶性肿瘤患者化疗后发生院内感染的相关因素及防治措施。方法对31例恶性肿瘤患者化疗后发生的院内感染作回顾性分析。结果恶性肿瘤患者化疗后发生院内感染与中性粒细胞减少程度及持续时间有关,感染的部位以呼吸道为主,主要采用粒细胞集落刺激因子（G-CSF）及抗生素治疗。结论恶性肿瘤患者化疗所致院内感染与中性粒细胞减少程度及持续时间密切相关,合理使用G—CSF及抗生素是预防和控制感染的重要措施。     

Serum gangliosides in patients with brain tumors

In order to determine possible differences in serum gangliosides content and composition before and after surgical removal of tumor, gangliosides isolated from preoperative and postoperative sera of patients with brain tumors were analyzed. Serum samples were collected from patients with glioblastoma, meningioma, acoustic neurinoma, haemangioma, oligodendroglioma and astrocytoma, one week before and one week after surgical removal of the tumor. Serum gangliosides were qualitatively and quantitatively analyzed by high performance thin layer chromatography and laser densitometry. Results showed changes of total gangliosides concentrations in analyzed postoperative sera comparing to preoperative sera. There was not a significant difference in ganglioside pattern of preoperative vs. preoperative sera. However, a postoperative decreased proportion of ganglioside GD3 was observed in sera derived from patients with complete tumor removal. The results of this study indicate that comparative quantitative and compositional analysis of both preoperative and postoperative serum gangliosides may provide useful information concerning tumor progression, surgical success and prognosis.     

Treatment-independent miRNA signature in blood of wilms tumor patients

ABSTRACT: BACKGROUND: Blood-born miRNA signatures have recently been reported for various tumor diseases. Here, we compared themiRNA signature in Wilms tumor patients prior and after preoperative chemotherapy according to SIOPprotocol 2001. RESULTS: We did not find a significant difference between miRNA signature of both groups. However both, Wilmstumor patients prior and after chemotherapy showed a miRNA signature different from healthy controls. Thesignature of Wilms tumor patients prior to chemotherapy showed an accuracy of 97.5% and of patients afterchemotherapy an accuracy of 97.0%, each as compared to healthy controls. CONCLUSION: Our results provide evidence for a blood-born Wilms tumor miRNA signature largely independent of fourweeks preoperative chemotherapy treatment.     

Tumor-reactive IgE antibodies in plasma of patients with gastrointestinal carcinomas

A total of 208 plasma samples from 115 patients with gastrointestinal carcinomas and nine patients with other intestinal disease were examined for the presence of IgE tumor antibodies by a solid-phase radioimmunoassay. Approximately one-third of the patients gave significant reactions with gastrointestinal carcinoma extracts compared with normal tissue extracts. Absorption with tumor and normal tissue extracts, with type AB human red cells, and with CEA indicated tumor specificity in some of the samples so examined. None of the 50 serum samples tested from normal blood donors contained tumor-specific IgE. IgE tumor antibodies decreased or completely disappeared in the majority of patients 8-13 days after surgical treatment.     

High-resolution studies in patients with aniridia-Wilms tumor association,Wilms tumor or related congenital abnormalities

Summary We attempted to determine wheter all cases of AWTA (anirida-Wilms tumor association) or any of the following groups of patients show 11p deletion: cases of Wilms tumor with congenital abnormalities other than aniridia, those without any congenital abnormalities, tumor itself in cases of Wilsm tumor without constitutional 11p deletion and cases of aniridia or hemihypertrophy without Wilms tumor. We studied a total of 29 index patients including five cases of AWTA, four cases of Wilms tumor with various congenital abnormalities, 16 cases of Wilms tumor without other abnormalities, three cases of aniridia in one of which Wilms tumor developed later and a case of hemihypertrophy.In all five cases of AWTA and in a case of aniridia who later developed Wilms tumor, 11p deletion involving the p13 band was detected. The mother of the latter also showed an identical 11p deletion. The common segment of deletion was the middle part of the p13. Two possible hypotheses on the mechanism through which Wilms tumor might develop were evaluated, based on the distribution of break points. All other cases, including five with tumor culture, showed a normal karyotype.     

Classical pituitary apoplexy presentation and a follow-up of 13 patients

Thirteen patients who presented with signs and symptoms of pituitary disease gave a history of classical pituitary apoplexy. Six presented with acute symptoms and in 7 the history antedated the admission by a mean of 887 days (range 365-2,190 days). All patients had an enlarged eroded sella. CT scans revealed a bleed in the tumor in 11 (histologically confirmed in all 8 patients operated), evidence of residual tumor in 1 and an empty sella (ES) in 1 patient. Hypopituitarism was present in 9, 4 were endocrinologically normal, 8 had visual problems requiring decompressive surgery and radiotherapy (RT) was given to 7 patients. They were subsequently followed for a median period of 730 days (range 365-3,385 days). During this time an empty sella developed in 5, 2 of whom had no surgery or RT; 4 remained endocrinologically normal, and a second hemorrhage occurred in 2 patients. Histological evidence of previous bleeds was noted in 6 of the 8 patients treated surgically. We conclude that apoplexy (1) may produce complete or partial tumor destruction with or without preservation of endocrine function; (2) recurrent, often silent, bleeding into a pituitary tumor appears to be a common event; (3) RT should be withheld unless recurrent tumor is documented (since at least 2 patients in this study have experienced spontaneous resolution of the tumor); and (4) the presence of an enlarged eroded fossa with an ES is reasonable presumptive evidence of an infarction of a pre-existing pituitary tumor.     

Gas chromatographic profiling and pattern recognition analysis of urinary organic acids from uterine myoma patients and cervical cancer patients

An efficient organic acid profiling and pattern recognition method is described for the correlation between urinary organic acid profiles and uterine cervical cancer. After methoximation of keto acids in alkalinized urine samples, all free organic acids were recovered by a dual solid-phase extraction procedure, followed by conversion to tert.-butyldimethylsilyl derivatives for the profiling analysis by dual-capillary column gas chromatography (GC) with subsequent screening for acids by retention index (I) library matching. A total of 50 organic acids were positively identified in urine samples (0.25 ml) from 12 uterine myoma (benign tumor group) and 14 uterine cervical cancer (malignant tumor group) patients studied. When the GC profiles were simplified to their corresponding organic acid I spectra in bar graphical form, characteristic patterns were obtained for each average of benign and malignant tumor groups. Stepwise discriminant analysis performed on the GC data selected 16 acids as the variables discriminating between the two groups. Canonical discriminant analysis applied to these 16 variables correctly classified 26 urine samples into two separate clusters according to tumor types in the canonical plot.     

Cholesterol in cerebrospinal fluid of brain tumor patients

A sensitive method for assay of total cholesterol (free plus esterified) in one ml of CSF is presented. Patients with brain tumors showed much higher levels of this sterol in CSF than those with neoplasia external to the central nervous system. Repeated assay of CSF cholesterol in post-surgical follow-up of brain tumor patients undergoing chemotherapy may provide a biochemical tool for detection of renewed tumor activity.     

Modifications of default-mode network connectivity in patients with cerebral glioma

Purpose

The aim of the study was to evaluate connectivity modifications in the Default Mode Network (DMN) in patients with cerebral glioma, and to correlate these modifications to tumor characteristics.

Methods

Twenty-four patients with a left-hemisphere cerebral tumor (14 grade II and 10 grade IV gliomas) and 14 healthy age-matched right-hand volunteers were enrolled in the study. Subjects underwent fMRI while performing language tasks for presurgical mapping. Data was analyzed with independent component analysis in order to identify the DMN. DMN group maps were produced by random-effect analysis (p<0.001, FDR-corrected). An analysis of variance across the three groups (p<0.05) and post-hoc t-test contrasts between pairs of groups were calculated (p<0.05, FDR-corrected).

Results

All three groups showed typical DMN areas. However, reduced DMN connectivity was detected in tumor patients with respect to controls. A significantly increased and reduced integration of DMN areas was observed in the hippocampal and prefrontal regions, respectively. Modifications were closely related to tumor grading. Moreover, the DMN lateralized to the hemisphere contralateral to tumor in the low-grade, but not in the high-grade tumor patients.

Conclusion

Modifications of DMN connectivity were induced by gliomas and differed for high and low grade tumors.     

Primary central nervous system lymphomas in immunocompetent patients

Primary Central nervous system lymphoma is a rare non-Hodgkin's tumor of the brain that has been traditionally found in patients with immunodeficiency syndromes. However, there are several immunocompetent patients that have also been reported with this neoplasm. In this group of patients, the mean age of diagnosis is around 60-year old, with a very slight predominance in women. Macroscopically, most of the tumors are unique and mainly located in the supratentorial region in the proximity of the cerebrospinal fluid circulation. The typical histological pattern is a perivascular distribution of tumor cells, within a network of reticulin fibers. Even though they are usually well defined masses, it is not rare to find tumor invasion beyond the macroscopic margin. Coagulative necrosis is not as common as in immunodeficiency-related cases. Immunohistochemistry has demonstrated that most of the tumor cells are B-lymphocytes and the electron microscopic findings do not differ from those reported in systemic non-Hodgkin's lymphomas. There are several histological classifications of these tumors, some of them with recent modifications to facilitate the analysis, but unfortunately, up now with a little or no clinical significance. The diagnosis is based on the histological study of the specimen obtained mainly through a Stereotactic biopsy. The treatment is based on a combination of chemotherapy followed by radiotherapy, but the mortality rate is still high.     

Cellular immunecompetence in patients with malignant melanoma

Summary The nonspecific immunecompetence of the peripheral blood lymphocytes of 29 patients with malignant melanoma and one with the benign condition of Riehl's melanosis was tested by means of a local xenogeneic graft-versus-host reaction and the E rosette test. The lymphocytes of 20 normal donors served as controls. Impairment of cellular immunecompetence was found in patients with invasive multiple primaries and those with invasive nodular malignant melanoma. Functional activity of T lymphocytes was normal in most of the patients who had an invasive melanoma with adjacent intraepidermal component of Hutchinson melanotic freckle or superficial spreading. In three cases with superficial spreading in which there had been an impairment of T cell function before removal of the tumor, there was an improvement following surgery. There was a clear correlation between the patient's cell-mediated immune response and the pathological type of the tumor, but not with the depth of invasion. It is suggested that cellular immunecompetence is a valuable parameter in the prognosis and treatment of malignant melanoma and should be measured in all patients with this type of tumor.     

Biochemical markers predicting response to radiation- and radiochemo-therapy in cancer patients

Ongoing studies carried out worldwide using banks of tumor and non-tumor samples give evidence that perspective markers predicting response of individual patients to intended radiation therapy may be found among some apoptotic indexes, spectrum of specialized proteins, and DNA-based microarray molecular profiling analysis as well determination of single nucleotide polymorphisms in genome of the patients. In the last years there is increasing interest in radiogenomics and characterization of gene expression profiles by DNA (micro)array technique that can predict radioresponse of tumor and non-tumor tissues. So far there are only a few reliable molecular markers predicting response of tumor and non-tumor tissues to radiation.     

Using extracellular biomarkers for monitoring efficacy of therapeutics in cancer patients: an update

Rapidly detectable and easily accessible markers of tumor cell death are needed for evaluating early therapeutic efficacy for immunotherapy and chemotherapy so that patients and their physicians can decide whether to remain with a given therapeutic strategy. Currently, image-based tests such as computed tomography scans and magnetic resonance imaging are used to visualize the response of a patient’s tumor, but often these evaluations are not conducted for weeks to months after treatment begins. While serum levels of secreted proteins such as carcinoembryonic antigen and prostate specific antigen are commonly monitored to gauge tumor status during therapy and between image evaluations, the levels of these proteins do not always correlate well with the actual tumor response. In laboratory studies, it has been shown that tumor cells undergoing apoptosis can release cellular components into cell culture media such as cytochrome c, nucleosomes, cleaved cytokeratin-18 and E-cadherin. Studies of patient sera have found that these and other macromolecules can be found in circulation during cancer therapy, providing a potential source of material for monitoring treatment efficacy. In the future, analysis of biofluids from severe combined immunodeficiency mice bearing patient tumor specimens treated with a targeted therapy such as Apo2L/tumor necrosis factor-related apoptosis-inducing ligand will be useful in the preclinical identification of therapy response markers. In this review, the current status of the identification of serum markers of tumor cell apoptosis is provided, as well as a discussion of critical research questions that must be addressed and the considerations necessary when identifying a marker that reflects true clinical outcome.     

Chromosomal instability in the lymphocytes of breast cancer patients

Genomic instability in the tumor tissue has been correlated with tumor progression. In the present study, chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBLs) of breast tumor patients were studied to assess whether chromosomal instability (CIN) in PBLs correlates with aggressiveness of breast tumor (i.e., disease stage) and has any prognostic utility. Cultured blood lymphocyte metaphases were scored for aberrations in 31 breast cancer patients and 20 healthy age and sex-matched controls. A variety of CAs, including aneuploidy, polyploidy, terminal deletions, acentric fragments, double minutes, chromatid separations, ring chromosome, marker chromosome, chromatid gaps, and breaks were seen in PBLs of the patients. The CAs in patients were higher than in controls. A comparison of the frequency of metaphases with aberrations by grouping the patients according to the stage of advancement of disease did not reveal any consistent pattern of variation in lymphocytic CIN. Neither was any specific chromosomal abnormality found to be associated with the stage of cancer. This might be indicative of the fact that cancer patients have constitutional CIN, which predisposes them to the disease, and this inherent difference in the level of genomic instability might play a role in disease progression and response to treatment.     

Histopathological analysis of metastatic melanoma deposits in patients receiving adoptive immunotherapy with tumor-infiltrating lymphocytes

Tumor-infiltrating lymphocytes (TIL) from a wide range of human and murine tumors can be expanded in vitro using interleukin-2 (IL-2). These TIL are cytolytic T lymphocytes with in vivo and in vitro antitumor activity in mice and in humans. TIL from human melanoma can recognize autologous tumor in an MHC-restricted fashion, localize in vivo after¹¹¹In labeling, and mediate regression of large metastatic deposits. Although studied extensively in vitro, less is known in vivo about TIL activity associated with tumor regression. This study was undertaken, in association with a study of TIL localization, to investigate mechanisms of TIL action by evaluating histopathological changes that occur at the tumor site during TIL administration. A total of 106 pre- and post-treatment pathological specimens from 25 patients enrolled in phase II TIL treatment and¹¹¹In-TIL imaging protocols were examined blindly by a single pathologist. Histological subtype, lymphocytic infiltration, melanin content, vascularity, and necrosis were documented for each tumor specimen. Average baseline and post-treatment parameters were compared. Any significant changes were evaluated for correlation with clinical response and¹¹¹In-TIL localization to tumor. Melanin content and vascularity of the tumor did not change as a result of therapy or correlate with either response or TIL localization. However, both increased lymphocytic infiltration and tumor necrosis were present after TIL administration (P=0.044 and 0.032 respectively). Furthermore, increases in lymphocytic infiltration correlated with tumor imaging using¹¹¹In-TIL, and with the percentage of¹¹¹In-labeled injectate present per gram of tumor specimen (P=0.036 and 0.0041 respectively). This suggests that TIL either account for the increased lymphocytes directly, or localize to tumor and recruit endogenous lymphocytes. We were unable to demonstrate any pretreatment histopathological predictors of response or variables that significantly correlated with subsequent clinical response, although peak and average values of necrosis were higher in responding patients compared to non-responding patients.     

131I]metaiodobenzylguanidine in neuroblastoma patients at diagnosis.

Treatment of resistant neuroblastoma with high dosage [131I]metaiodobenzylguanidine (131I-MIBG) appears effective since encouraging results have been obtained so far even in patients with very advanced, intensively pre-treated disease. We have already reported a stage III NB patient treated at diagnosis, who is at present in complete remission with a 4-year follow-up. To further explore the potential role of this new drug in untreated patients, we administered radionuclide to two children with stage III neuroblastoma. Both cases received 131I-MIBG at relatively low doses, and showed a significant reduction of the tumor mass and, interestingly enough, no evidence of 131I-MIBG uptake of a tracer dose in the remaining tumor. Particularly in case 1, the permanence and subsequent progression of the part of the tumor mass without 131I-MIBG uptake, after therapeutic doses of 131I-MIBG which apparently destroyed the 131I-MIBG-positive cell population, clearly suggest heterogeneity at diagnosis, with a dual neuroblastoma cell population, one with 131I-MIBG uptake and the other without. Aside from the biological implications of the heterogeneous MIBG uptake in neuroblastoma at diagnosis, our findings suggest that in stage III neuroblastoma patients even a relatively small dose of 131I-MIBG administered at diagnosis is sufficient to either completely destroy the primary tumor, as reported by our group, or to destroy that part of the tumor which shows 131I-MIBG uptake (as in the present cases), without any significant hematologic toxicity. Furthermore, a single course of 131I-MIBG at the dosage employed here does not appear to jeopardize the subsequent use of chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)