Quality of life in adults with lymphedema cholestasis syndrome 1.

BACKGROUND: LCS1 (Lymphedema Cholestasis Syndrome 1/Aagenaes syndrome) is a rare, hereditary disorder, where the highest known prevalence is in Norway. The disorder is characterized by lymphedema and periodic cholestasis from birth or the neonatal period. This study aimed to examine internal reliability of the SF-36, in addition to the group's overall- and health related quality of life (OQoL and HRQoL) and psychosocial well-being. METHODS: Twenty adults (aged 18-65) in Norway have been diagnosed with LSC1. Eighteen of these patients were included in the study and completed four questionnaires on overall and health related quality of life and psychosocial well-being: Cantril's Ladder (CL), The Kaasa Test, the SF-36, and a lymphedema anamnesis questionnaire. Demographic data were registered, and 15 of the patients underwent a physical examination of the lymphedema. SF-36 scores were compared with those of 360 age and gender matched controls drawn from an earlier survey of the Norwegian general population. The Mann-Whitney U test and Chi-square (χ2) test were used to test internal differences in the patient group. RESULTS: Health-related quality of life (HRQOL) was significantly reduced in patients with LSC1 compared to controls, in three out of eight areas, role physical, general health and mental health. Females scored significantly better than males in the patient group in two areas of SF-36, in CL, and in one of three scales of The Kaasa Test. Severe lymphedema was found to be significantly correlated to bodily pain and reduced mental health. The level of education was positively correlated to mental health. CONCLUSION: Overall quality of life (OQoL), health related quality of life (HRQoL) and psycho-social well-being were good in the patient group, but some dimensions of HRQoL were reduced. More severe extent of lymphedema was associated with poorer HRQoL.

Unmet needs for healthcare and social support services in patients with Huntington's disease: a cross-sectional population-based study.

BACKGROUND: In order to plan and improve provision of comprehensive care in Huntington's disease (HD), it is critical to understand the gaps in healthcare and social support services provided to HD patients. Research has described utilization of healthcare services in HD in Europe, however, studies systematically examining needs for healthcare services and social support are lacking. This study aims to identify the level and type of met and unmet needs for health and social care services among patients with HD, and explore associated clinical and socio-demographic factors. METHODS: Eighty-six patients with a clinical diagnosis of HD living in the South-Eastern region of Norway were recruited. Socio-demographic and clinical characteristics were collected. The Needs and Provision Complexity Scale (NPCS) was used to assess the patients' needs for healthcare and social services. Functional ability and disease stage was assessed using the UHDRS Functional assessment scales. In order to investigate factors determining the level of total unmet needs and the level of unmet needs for Health and personal care and Social care and support services, multivariate logistic regression models were used. RESULTS: A high level of unmet needs for health and personal care and social support services were found across all five disease stages, but most marked in disease stage III. The middle phase (disease stage III) and advanced phase (disease stages IV and V) of HD increased odds of having a high level of total unmet needs by 3.5 times and 1.4 times respectively, compared with the early phase (disease stages I and II). Similar results were found for level of unmet needs in the domain Health and personal care. Higher education tended to decrease odds of high level of unmet needs in this domain (OR = 0.48) and increase odds of higher level of unmet needs in the domain of Social care and support (OR = 1.3). Patients reporting needs on their own tended to decrease odds of having unmet needs in Health and personal care (OR = 0.57). CONCLUSIONS: Needs for healthcare and social services in patients with HD should be assessed in a systematic manner, in order to provide adequate comprehensive care during the course of disease.

Expression of cancer-testis (CT) antigens in placenta.

Besides their variable presence in fetal and adult germ cells, CT antigens have occasionally been detected in placental tissue. However, these data are scarce and solely based on mRNA analyses; nothing is known about their presence at the protein level. Here, we analyzed the expression of various CT antigens in placental tissues from gestational age week 5 to week 42 using monoclonal antibodies to various antigens of the MAGE-A and -C families, NY-ESO-1, as well as GAGE. We show that CT antigen expression in placenta varies widely for the various antigens, ranging from completely negative to abundant. Since little is known about the function and biology of CT antigens, interpretation of this highly variable expression pattern is purely speculative. However, our data indicate that the various CT antigens have different functions during placental development.

Expression of cancer-testis antigens in endometrial carcinomas using a tissue microarray.

Cancer-testis (CT) antigens are expressed in a variety of malignant tumors, but in normal adult tissue, they are only expressed in testicular germ cells. Owing to this tumor-associated expression pattern, these antigens are of major interest as potential targets for immunotherapy and possibly for diagnostic purposes. This study was performed to analyze the expression of four CT antigens, NY-ESO-1, MAGE-A3, MAGE-A4, and CT7/MAGE-C1, in endometrial carcinoma using immunohistochemistry, and to correlate expression with histologic subtypes, grade, and expression of WT1 and p53. Formalin-fixed paraffin-embedded tissues of 130 endometrial carcinomas of the following types and grades were analyzed using a tissue microarray: 85 endometrioid carcinomas (FIGO grade 1, 39; grade 2, 11; and grade 3, 35), 18 papillary serous carcinomas, 12 clear cell carcinomas, 13 malignant mixed mullerian tumors, one mucinous adenocarcinoma, and one undifferentiated carcinoma. The following anti-CT monoclonal antibodies/antigens were studied by immunohistochemistry: monoclonal antibody ES121/NY-ESO-1, monoclonal antibody M3H67/MAGE-A3, monoclonal antibody 57B/MAGE-A4, and monoclonal antibody CT7-33/CT7. The CT expression data were compared to WT1 and p53 protein expression as analyzed in a previous study. Positive staining with anti-CT monoclonal antibodies was graded as follows: focal, <5% positive cells; 1+, 5-25% cells; 2+, 26-50% cells; 3+, 51-75%; and 4+, >75% cells. The 3+ and 4+ staining patterns were considered homogeneous patterns of potential clinical significance and were scored positive for statistical analysis. In low-grade tumors, the most immunoreactivity was seen with mAb M3H67 but little labeling was observed with the other monoclonal antibodies. In high-grade tumors, monoclonal antibodies M3H67 (25%), 57B (23%), and CT7-33 (20%) showed the highest reactivity, while ES121 showed the lowest immunoreactivity (6%). The staining pattern was mostly heterogeneous. Statistical significance was found solely for the correlation of monoclonal antibody 57B staining and p53 expression. No correlation was found for any anti-CT monoclonal antibody staining and clinical stage or for anti-CT staining and WT1 expression. CT antigens CT7, MAGE-A3 and MAGE-A4, but not NY-ESO-1, are expressed in high-grade endometrial carcinomas, and expression of MAGE-A4 is correlated with the presence of overexpressed p53.

Expression and significance of cancer testis antigens in primary mucosal melanoma of the head and neck.

BACKGROUND: Cancer testis antigens (CTAs) are T-cell-defined tumor-associated antigens encoded by the genes and gene families such as MAGE, NY-ESO-1, and others. Their expression in a wide variety of malignant neoplasms but absence in all normal adult tissue except testicular germ cells makes them attractive targets for immunotherapy of cancer. Primary mucosal melanomas of the head and neck (HNMM) are rare aggressive malignant tumors that are usually difficult to treat. CTAs may provide useful targets for therapy; however, their expression in HNMM is not known. METHODS: We analyzed 40 initial, 15 recurrent, and 15 metastatic HNMM to nonmucosal locations from 64 patients (oral, n = 30; sinonasal, n = 34). Immunohistochemistry was performed on archival tissue with monoclonal antibodies 57B, CT7-33, and ES121 to the following CTAs: MAGE-A4, CT7 (MAGE-C1), and NY-ESO-1, respectively. RESULTS: CT7, MAGE-A4, and NY-ESO-1 expression was seen in 73%, 61%, and 24% of tumors, respectively, with 81% of the tumors expressing at least one of the CTAs. CT7 and MAGE-A4 were significantly more frequently expressed in tumors composed of epithelioid cells than spindle cells (p = .05). CTA expression did not correlate with disease progression, overall survival, and disease-specific survival. CONCLUSIONS: CT7, MAGEA4, and NY-ESO-1 are frequently expressed in HNMM and may be potential targets for CTA-based immunotherapy. The expression does not seem to have prognostic significance.

Primary malignant melanoma of the oesophagus: a clinical and pathological study with emphasis on the immunophenotype of the tumours for melanocyte differentiation markers and cancer/testis antigens.

SUMMARY: Primary malignant melanomas of the oesophageal squamous mucosa are exceedingly rare. We present here the clinical and pathological findings of 10 patients (mean age 64 years) with primary oesophageal melanoma, with emphasis on the immunophenotype of the tumours. The majority of melanomas were located in the mid to distal oesophagus and were large (mean tumour size at the time of diagnosis 6.2 cm; mean depth of invasion 1.86 cm). All but two of the melanomas were associated with an extensive in situ component. Half of the tumours were amelanotic. The histological spectrum was wide, including appearances mimicking lymphoma, poorly differentiated adenocarcinoma or sarcoma. Immunohistochemical studies were performed on six tumours using monoclonal antibodies (MAb) to S100 protein, tyrosinase (MAb T311), Melan-A (MAb A103), and gp100 (MAb HMB-45), as well as antibodies to five cancer/testis (CT) antigens (MAb CT7-33 to CT7/MAGE-C1, MAb ESO121 to NY-ESO-1, MAb 57B to MAGE-A4, MAb MA454 to MAGE-A1, and MAb M3H67 to MAGE-A3). Seven patients had metastatic disease at the time of presentation. All but one patient underwent resection of the tumour with negative surgical margins. Survival was poor, with a mean survival of 19.8 months. One patient, however, whose tumour was limited to the submucosa, is still alive 108 months post-oesophagectomy. All six melanomas examined by immunohistochemistry were positive for all the melanocyte differentiation markers tested. In addition, they were all positive for CT antigens, with MA454 being the most commonly found, suggesting that CT antigens may be a promising immunotherapeutic target for oesophageal melanomas.

Expression of cancer/testis (CT) antigens MAGE-A1, MAGE-A3, MAGE-A4, CT-7, and NY-ESO-1 in malignant gammopathies is heterogeneous and correlates with site, stage and risk status of disease.

Cancer/testis (CT) antigens are expressed in several malignant tumors, but not in normal tissues except for testicular germ cells. The expression of CT antigenic proteins in malignant gammopathies has not been characterized. We examined the expression of a panel of CT antigenic proteins in 29 patients with malignant gammopathies by immunohistochemistry using the following monoclonal antibodies (mAbs): mAb MA454 to MAGE-A1, mAb M3H67 to MAGE-A3, mAb 57B to MAGE-A4, mAb CT7-33 to CT7/MAGE-C1 and mAb ES121 to NY-ESO-1. We could detect at least one CT antigen in tumors from 27 of 29 patients. The expression pattern of MAGE-A1, -A3, -A4 and NY-ESO-1 is heterogeneous in most cases, revealing staining in <25% of the tumor cells. Monoclonal antibodies CT7-33 and M3H67 show the highest incidence of immunoreactivity. Importantly, CT-7 can also be detected on the surface of some myeloma cells by flow cytometry, and in one plasmacytoma case by immunohistochemistry. Expression of CT antigens is greater in patients with stage III extramedullary plasmacytoma or high-risk myeloma relative to other cohorts. These data suggest that CT antigens may have important biological implications in malignant gammopathies and that CT-7 may be a suitable target for T cell-based and possibly antibody-mediated immunotherapy of myeloma.

A monoclonal antibody recognizing human cancers with amplification/overexpression of the human epidermal growth factor receptor.

Epidermal growth factor receptor (EGFR) has attracted considerable attention as a target for cancer therapy. Wild-type (wt)EGFR is amplified/overexpressed in a number of tumor types, and several mutant forms of the coding gene have been found, with DeltaEGFR, a deletion mutation lacking exons 2-7 of the external domain, being the most common and particularly associated with glioblastoma. We generated monoclonal antibodies (mAbs) against NR6(DeltaEGFR) (mouse fibroblast line NR6 transfected with DeltaEGFR). mAb 806 with selective reactivity for NR6(DeltaEGFR) in mixed hemadsorption assays, fluorescence-activated cell sorting, Western blot, and immunohistochemistry was analyzed in detail and compared with mAbs 528 (anti-wtEGFR) and DH8.3 (anti-DeltaEGFR). In xenograft tumors and molecularly pretyped glioblastomas, the reactivity pattern was as follows: 528 reactive with amplified and nonamplified wtEGFR; DH8.3 reactive with DeltaEGFR; and 806 reactive with amplified/overexpressed wtEGFR (with or without DeltaEGFR). In normal tissues, 528 but not DH8.3 or 806 was widely reactive with many organs, e.g., liver expressing high EGFR levels. In glioblastoma and non-CNS tumor panels, 806 was reactive with a high proportion of glioblastomas and a substantial number of epithelial cancers of lung and of head and neck. DH8.3 reactivity was restricted to DeltaEGFR-positive glioblastoma. Thus, 806 represents a category of mAbs that recognizes tumors with EGFR amplification/overexpression but not normal tissues or tumors with normal EGFR levels. Our study also indicates that DeltaEGFR is restricted to glioblastoma, in contrast to other reports that this mutation is found in tumors outside the brain.

CT7 (MAGE-C1) antigen expression in normal and neoplastic tissues.

CT7 (MAGE-C1) is a member of the cancer testis (CT) antigen family. The present study describes the generation of CT7-33, a monoclonal antibody (MAb) to CT7, and the preliminary protein expression analysis of CT7 in normal tissues and in a limited number of neoplastic lesions. CT7-33 was effective in frozen as well as formalin-fixed, paraffin-embedded tissues, and immunohistochemistry/reverse transcriptase polymerase chain reaction (RT-PCR) co-typing demonstrated antibody specificity. CT7-33 immunoreactivity in normal adult tissues is restricted to testicular germ cells. In neoplastic lesions, CT7-33 immunostaining is confined to tumor cells, and the frequency of CT7 protein expression mostly parallels previous mRNA analyses. Whereas colorectal and renal cell carcinomas, as well as sarcomas, exhibit poor or no CT7-33 staining, carcinomas of the mammary gland and ovary, nonsmall cell lung carcinoma and metastatic melanomas exhibit a high incidence of CT7 protein expression. However, as seen in previous analyses of other CT antigens, the expression pattern is mostly heterogeneous, and tumors with more than 50% of tumor staining are only infrequently encountered. In summary, our study presents a new serologic reagent for the analysis of CT7 on a protein level and confirms what is known with regard to the expression pattern of other CT antigens in tumors: frequent heterogeneity of antigen expression.

MAGE antigen expression in monophasic and biphasic synovial sarcoma.

Synovial sarcomas are high-grade malignant mesenchymal tumors carrying a pathognomonic cytogenetic alteration t(X;18) involving the SYT gene on chromosome 18 and either SSX1 or SSX2 on chromosome X. Morphologically, biphasic (BSS) and monophasic (MSS) variants can be distinguished. Cancer/testis (CT) antigens are expressed in a variety of malignant tumors, but not in normal tissues except in germ cells, primarily of the testis. Anti-MAGE monoclonal antibody (mAb) 57B previously showed a high incidence and homogenous reactivity pattern in a preliminary analysis of synovial sarcomas. This study was performed to analyze the expression of MAGE by immunohistochemistry with mAb 57B in 25 synovial sarcomas (12 monophasic, 13 biphasic), which were typed for the t(X;18)-derived fusion transcript by reverse transcriptase polymerase chain reaction (19 SYT-SSX1, 6 SYT-SSX2). 57B immunoreactivity was present in 22 of 25 (88%) cases, and antigen expression was homogeneous in 14 of 22 57B-positive cases. Both morphological variants and both translocation types were immunoreactive; three SYT-SSX1 tumors (one MSS, two BSS) were 57B negative. Our study demonstrates that MAGE is frequently and homogeneously expressed in synovial sarcomas of both morphological variants and both translocation types, making these tumors an attractive target for MAGE antigen-based immunotherapy.