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Biomedical subjects

J Reifenberger

Publications and source records attributed to J Reifenberger.

At least 37 records · Page 2Linked to original sources
PubMed2005

Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from a randomized vehicle-controlled phase III study in Europe.

BACKGROUND: Imiquimod is an immune response modifier that acts through toll-like receptor 7 to induce cytokine production and a subsequent innate and adaptive cell-mediated immune response. Clinical studies have demonstrated clinical and histological clearance of superficial basal cell carcinoma (sBCC) after treatment with imiquimod 5% cream. OBJECTIVES: To evaluate the safety and clinical efficacy of imiquimod (Aldaratrade mark; 3M Pharmaceuticals, St Paul, MN, U.S.A.) 5% cream for the treatment of sBCC in a multicentre, randomized, parallel, vehicle-controlled, double-blind, phase III clinical study conducted at 26 centres in Europe. METHODS: Subjects who had at least one histologically confirmed sBCC tumour were randomized to apply imiquimod or vehicle cream to the target tumour once daily, seven times per week (7 x/week) for 6 weeks. The target tumour location was identified with an indelible ink mark before treatment initiation. The treated tumour site was clinically assessed for treatment response at 12 weeks post-treatment and was then excised for histological evaluation. Efficacy assessments included the composite response rates (proportion of subjects with clinical and histological clearance) and response rates solely based on histology (proportion of subjects with histological clearance). Safety assessments, which included adverse events and scoring of local skin reactions (LSRs), were carried out throughout the study. RESULTS: In total, 166 subjects were enrolled in this study. For the intent-to-treat dataset, there was a statistically significant difference between imiquimod and vehicle groups for both composite clearance rates (clinical and histological assessments) and histological clearance rates. Composite clearance was demonstrated in 77% and 6% of subjects treated with imiquimod and vehicle cream, respectively. Histological clearance was demonstrated in 80% and 6% of subjects treated with imiquimod and vehicle cream, respectively. The most frequently reported safety findings were investigator-assessed LSRs and spontaneous reports by subjects of application site reactions, which occurred more frequently in the imiquimod group than in the vehicle group. CONCLUSIONS: Imiquimod 5% cream administered 7 x/week for 6 weeks is a safe and effective treatment for sBCC when compared with vehicle cream.

Adult↗
PubMed2004

[Hereditary tumor syndromes. Cutaneous manifestations and molecular pathogenesis of Gorlin and Cowden syndromes].

Several hereditary tumor syndromes are associated with characteristic skin lesions which may facilitate an early diagnosis. We summarize clinical features and recent progress in understanding the etiology and pathogenesis of two selected tumor syndromes, namely nevoid basal cell carcinoma syndrome (Gorlin syndrome) and Cowden syndrome. Both are autosomal dominantly inherited disorders. Nevoid basal cell carcinoma syndrome is characterized by the early onset of multiple basal cell carcinomas as as well as developmental defects and a predisposition for other benign and malignant tumors. The syndrome is caused by germline mutations in the PTCH tumor suppressor gene. Cowden syndrome is associated with pathognomonic mucocutaneous lesions, such as facial trichilemmomas, acral keratoses, and mucocutaneous papillomatosis. In addition, Cowden patients are predisposed to carcinomas of the thyroid, breast and endometrium. Cowden syndrome is caused by germline mutations in the PTEN tumor suppressor gene. Identification of the genes causing hereditary tumor syndromes as well as generation of genetically engineered mouse models have greatly advanced our understanding of the molecular pathogenesis of these diseases. Furthermore, novel pathogenesis-based pharmacological strategies are being developed that promise to improve prevention and therapy.

Animals↗
PubMed2004

[Neurocutaneous melanosis and malignant melanoma].

A 36-year-old man presented with a giant congenital melanocytic nevus and multiple disseminated melanocytic nevi. After he had developed neurological symptoms (grand mal seizures), a cerebral metastasis of a malignant melanoma without a primary melanoma was found. The patient was diagnosed as having a neurocutaneous melanosis with a cerebral metastasis. In spite of a variety of therapeutic attempts (surgery, radiation therapy and chemotherapy) he followed a rapidly progressive, lethal course with increased intracranial pressure, hydrocephalus and spinal metastases.

Adult↗
PubMed2004

[Ulcus terebrans. Therapy options and their limits].

Basal cell carcinoma (BCC) is the most common tumor in humans and is defined as a slow-growing, locally invasive, epithelial skin tumor which rarely metastasizes. The first line treatment is surgical excision with histologic examination of the tumor margins, but numerous alternative therapies are available. A 75-year old patient with the most destructive form of BCC, ulcus terebrans, involving the scalp and invading the frontal bone. We discuss the problems and therapeutic limitations for this unusual BCC variant.

Aged↗
PubMed2003

[Cutaneous epithelial tumors. Molecular biology and pathogenesis-based therapy].

Basal cell carcinomas and squamous cell carcinomas are the most common human cancers and increasing in incidence. The development of novel, pathogenesis-based therapies requires a better knowledge of the molecular mechanisms leading to the development of these tumors. Basal cell carcinomas are characterized by aberrant activation of Sonic-Hedgehog (SHH) signaling due to mutations in the PTCH or SMOH genes. In addition, about 50% of the cases carry mutations in the TP53 tumor suppressor gene. Squamous cell carcinomas lack alterations of SHH signaling, while TP53 mutations are detectable in virtually all cases. Alterations in cell cycle regulatory genes, such as CDKN2A, are also common. Recently, specific inhibitors of the SHH-signaling pathway have been developed and shown promising results in preclinical studies on experimental basal cell carcinomas. However, the clinical significance of such targeted molecular therapy remains to be evaluated. Another successful pathogenesis-based therapy, which is already in clinical use, is the administration of topic immune response modifier imiquimod. This drug can eradicate non-melanoma skin cancers by different mechanisms, including cytokine-mediated stimulation of the anti-tumor immune response, as well as the induction of tumor cell apoptosis.

Adjuvants, Immunologic↗
PubMed2003

Cowden's disease: clinical and molecular genetic findings in a patient with a novel PTEN germline mutation.

We report a 54-year-old woman with Cowden's disease (CD) who was found to carry a novel germline mutation in the PTEN gene. The mutation (c.334C-->G) introduced a splice donor site within exon 5 that caused the expression of an aberrant transcript lacking 159 nucleotides corresponding to codons 112-164. Clinically, the patient showed multiple benign hamartomatous lesions of the skin, papillomatosis of the lips and oral mucosa, polyposis coli and bilateral fibrocystic disease of the breast. In addition, she developed different types of malignant neoplasms, including bilateral carcinomas of the breast and malignant melanomas of the skin. Molecular genetic analysis of a benign skin hamartoma and an invasive ductal breast carcinoma revealed loss of heterozygosity (LOH) at microsatellite markers on chromosome 10 in the carcinoma but not in the hamartoma. The breast carcinoma additionally carried a somatic TP53 point mutation (c.466C-->G; R156G) that was associated with LOH on 17p and nuclear p53 protein accumulation. Taken together, our findings indicate that benign hamartomas in CD may develop without loss of the second (wild-type) PTEN allele, whereas the pathogenesis of malignant tumours, such as breast carcinomas, appears to require the complete inactivation of Pten as well as further alterations such as the loss of p53-dependent growth control.

Breast Neoplasms↗
PubMed2002

Type 1 segmental cutaneous leiomyomatosis.

Cutaneous leiomyomas are rare benign tumours of the skin, which present in multiple disseminated, segmental or solitary forms. The pathogenesis of segmental cutaneous leiomyomatosis is not yet fully known. Most recently two types of segmental manifestation of autosomal dominant inherited diseases were postulated. Type 1 reflects heterozygosity for the underlying mutation with a clinical picture similar to that in a non-mosaic phenotype. In type 2, loss of heterozygosity leads to homo- or hemizygosity with a pronounced segmental manifestation of lesions in the affected segment. In our patient the lesions were restricted to one segment and therefore she most probably has a type 1 segmental cutaneous leiomyomatosis.

Adult↗
PubMed2001

Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors.

Primitive neuroectodermal tumors (PNETs) represent the most frequent malignant brain tumors in childhood. The majority of these neoplasms occur in the cerebellum and are classified as medulloblastomas (MB). Most PNETs develop sporadically; however, their incidence is highly elevated in patients carrying germline APC gene mutations. The APC gene encodes a central component of the WNT/wingless developmental signaling pathway. It regulates the levels of cytoplasmic beta-catenin protein that plays a central role in neural development and cell proliferation. We analyzed 87 sporadic PNETs and 10 PNET cell lines for mutations of the APC gene and beta-catenin (CTNNB1) gene using single strand conformational polymorphism (SSCP) and sequencing analysis. We examined the mutation cluster region of APC (codons 1255--1641) for germline variants and somatic mutations. The medulloblastoma cell line MHH-MED-2 carried a Glu1317Gln missense germline variant and a sporadic MB sample showed a somatic Pro1319Leu substitution. Mutational analysis of exon 3 of CTNNB1 uncovered 4 PNETs (4.8%) with somatic missense mutations. These mutations caused amino acid substitutions in 3 of 80 medulloblastomas (Ser33Phe, Ser33Cys and Ser37Cys) and 1 of 4 supratentorial PNETs (Gly34Val). All mutations affected GSK-3 beta phosphorylation sites of the degradation targeting box of beta-catenin and resulted in nuclear beta-catenin protein accumulation. Deletions of CTNNB1 were not detected by PCR amplification with primers spanning exons 1--5. Our data indicate that inappropriate activation of the WNT/wingless signaling pathway by mutations of its components may contribute to the pathogenesis of a subset of PNETs.

Adenomatous Polyposis Coli Protein↗
PubMed2001

Oligodendroglial tumors frequently demonstrate hypermethylation of the CDKN2A (MTS1, p16INK4a), p14ARF, and CDKN2B (MTS2, p15INK4b) tumor suppressor genes.

We investigated 34 oligodendroglial tumors (7 oligodendrogliomas, 11 anaplastic oligodendrogliomas, 8 oligoastrocytomas, and 8 anaplastic oligoastrocytomas) for deletion, mutation, hypermethylation, and expression of the CDKN2A (MTS1, p16INK4a), p14ARF, and CDKN2B (MTS2, p15INK4b) tumor suppressor genes at 9p21. One anaplastic oligoastrocytoma carried a homozygous deletion including all 3 genes. None of the tumors demonstrated point mutations in any of the genes. Methylation-specific polymerase chain reaction (MSP) analysis and sequencing of bisulfite-modified DNA, however, revealed frequent hypermethylation of the 5'-CpG islands in CDKN2A, p14ARF, and CDKN2B. Partial or complete methylation of the majority of CpG sites analyzed from each gene was detected in 32% of the tumors at the CDKN2A gene and at a similar percentage (41%) of the tumors at the p14ARF gene and the CDKN2B gene. Most tumors with CDKN2A, p14ARF, and/or CDKN2B hypermethylation either lacked detectable transcripts from these genes or had lower mRNA levels than those determined for non-neoplastic brain tissue. There was a significant correlation between hypermethylation of these genes and the presence of allelic losses on chromosomal arms 1p and 19q. In addition, p14ARF hypermethylation was predominantly found in tumors without a demonstrated TP53 mutation. Taken together, our results indicate that hypermethylation of CDKN2A, p14ARF, and CDKN2B is an important epigenetic mechanism by which oligodendroglial tumors may escape from p53- and pRb-dependent growth control.

Adolescent↗
PubMed2001

Long-term survival of a patient with giant cell glioblastoma. Case report.

The authors report on a patient who had undergone resection of a left-sided temporal giant cell glioblastoma at the age of 69 years and who survived for more than 17 years. This man had not undergone postoperative radiotherapy or adjuvant chemotherapy. He died at the age of 86 years without clinical evidence of tumor recurrence. Histologically, the lesion was characterized by highly pleomorphic tumor cells (including bizarre multinucleated giant cells) with high mitotic activity, large necroses, and prominent mononuclear infiltration. A point mutation in the TP53 tumor suppressor gene (c.524G>A; R175H) and no epidermal growth factor receptor gene amplification were revealed on molecular genetic analysis. No diagnostic chromosomal imbalances were identified on comparative genomic hybridization, although the average ratio profile for chromosome 10 indicated loss of 10p15 in a subpopulation of tumor cells. This patient is exceptional because tumor resection, probably in conjunction with a marked antitumor immune response, apparently resulted in eradication of the lesion.

Aged↗
PubMed2000

[Progressive cicatricial psoriatic alopecia in AIDS].

Scarring alopecia is a rare complication of scalp psoriasis which in most cases occurs in areas of long-standing lesions. A HIV-positive 35 year-old Moroccan patient (CDC C3) developed scalp psoriasis with scarring alopecia within five weeks. Topical antipsoriatic therapy resulted in alleviation of psoriatic lesions and stopped the progression of the alopecia. This case report suggests potential pathogenic links between scalp psoriasis, scarring alopecia, and HIV-infection. In addition, early and efficient antipsoriatic treatment is recommended to prevent the disfiguring complication of scarring alopecia.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Allelic losses on chromosome arm 10q and mutation of the PTEN (MMAC1) tumour suppressor gene in primary and metastatic malignant melanomas.

Malignant melanomas frequently show loss of alleles on the long arm of chromosome 10. The PTEN (MMAC1) gene has been identified as a tumour suppressor gene at 10q23.3 that is mutated in various types of advanced human cancers. We have investigated a series of 40 sporadic melanomas from 37 patients (15 primary cutaneous melanomas and 25 melanoma metastases) for allelic losses on chromosome 10, as well as for deletion and mutation of the PTEN gene. Microsatellite analysis revealed loss of heterozygosity at loci located on 10q in tumours from 15 of 34 patients investigated (44%). Somatic PTEN mutations were identified in melanomas from 4 of 37 patients (11%), all of whom had metastatic disease. In two of these patients, the tumours had additionally lost one PTEN allele, indicating complete loss of wild-type PTEN in the tumour cells. Our findings corroborate that loss of heterozygosity on chromosome 10 is a frequent aberration in malignant melanomas and implicate PTEN as a tumour suppressor gene inactivated by somatic mutation in a fraction of these tumours.

Adult↗
PubMed1999

Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification.

We have previously reported on the amplification and overexpression of the MDM2 proto-oncogene in a subset of malignant gliomas without TP53 mutation (G. Reifenberger et al, Cancer Res., 53: 2736-2739, 1993). Here, we show that the MDM4 (MDMX) gene located on 1q32 is a further target for amplification in malignant gliomas. MDM4 codes for a Mdm2-related protein that can bind to p53 and inhibits p53-mediated transcriptional transactivation. We investigated a series of 208 gliomas (106 glioblastomas, 46 anaplastic gliomas, and 56 low-grade gliomas) and identified 5 tumors (4 glioblastomas and 1 anaplastic oligodendroglioma) with MDM4 amplification and overexpression. Several other genes from 1q32 were found to be coamplified with MDM4, such as GAC1 in five tumors, REN in four tumors, and RBBP5 in three tumors. Additional analyses revealed that the malignant gliomas with MDM4 amplification and overexpression carried neither mutations in conserved regions of the TP53 gene nor amplification of the MDM2 gene. Taken together, our data indicate that amplification and overexpression of MDM4 is a novel molecular mechanism by which a small fraction of human malignant gliomas escapes p53-dependent growth control.

Cell Division↗
PubMed1999

Multiple basal cell carcinomas associated with hairy cell leukaemia.

We report the case of a caucasian woman who, between the ages of 49 and 51 years, developed multiple (> 20) basal cell carcinomas (BCC). There was no family history of BCC. No abnormalities in the human homologue of the Drosophila segment polarity gene patched (PTCH), glutathione S-transferases T1 and M1, or cytochrome P450 1A1 were detected by polymerase chain reaction (PCR)-based molecular analysis. There was, however, actinic damage of the skin in sun-exposed areas. The patient was diagnosed as having hairy cell leukaemia (HCL) at the age of 51 years, based upon leucocyte morphology as assessed by light and electron microscopy, tartrate-resistant acid leucocyte phosphatase (TRAP) staining, fluorescence activated cell scanning of peripheral blood leucocytes and bone marrow histology. As the leukaemia slowly progressed over a 3-month period, the patient developed four further BCCs. Given that HCL is characterized by a profound defect in T-cell function, it is conceivable that T-cell immune dysregulation can contribute to the pathogenesis of BCC, possibly enhancing the aetiological effect of ultraviolet irradiation.

Basal Cell Carcinoma↗
PubMed1998

Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system.

About one-third of sporadic basal cell carcinomas (BCCs) of the skin and 10-15% of primitive neuroectodermal tumors (PNETs) of the central nervous system show mutations in the PTCH tumor suppressor gene. The PTCH gene product (Ptch) functions as a transmembrane receptor for the Sonic hedgehog protein (Shh) and interacts with another transmembrane protein called Smoh. To further elucidate the significance of alterations in the Shh signaling pathway, we investigated 31 sporadic BCCs and 15 PNETs for the mutation and/or expression of SMOH, PTCH, SHH, and GL11. In addition, we fine-mapped the SMOH gene locus by fluorescence in situ hybridization to chromosomal band 7q32. Mutational analysis identified four BCCs with somatic missense mutations in SMOH affecting codon 535 (TGG==>TTG: Trp==>Leu) in three tumors and codon 199 (CGG==>TGG: Arg==>Trp) in one tumor. A missense mutation at codon 533 (AGC==>AAC: Ser==>Asn) was found in one PNET. PTCH mutations were detected in eight BCCs and one PNET. Two BCCs demonstrated mutations in both SMOH and PTCH. The majority of tumors showed an increased expression of SMOH, PTCH, and GL11 transcripts as compared with that of normal skin and nonneoplastic brain tissue, respectively. In contrast, only one BCC and one PNET expressed SHH mRNA at levels detectable by reverse transcription-PCR, and no SHH gene mutations were found. In summary, our results indicate that both PTCH and SMOH represent important targets for genetic alterations in sporadic BCCs and PNETs.

Adolescent↗
PubMed1998

Primitive neuroectodermal tumors of the cerebral hemispheres in two siblings with TP53 germline mutation.

AWe report on two siblings (brother and sister) who developed cerebral PNETs at the age of 5 years and 6 months, respectively. Both children were treated by operation followed by polychemotherapy. The brother also received cranio-spinal irradiation. Nevertheless, the children died about 12 months and 24 months post-operatively due to extensive cerebral tumor recurrences. Shortly after having lost both of her children, the mother developed an intra-abdominal tumor, which was resected and histologically diagnosed as ovarian carcinoma. Because of this unusual familial clustering of tumors and a positive history of brain tumors and other cancers in several maternal relatives, we analyzed DNA isolated from both PNETs and the ovarian carcinoma as well as constitutional (leukocyte) DNA from the whole family for mutation of the TP53 tumor suppressor gene. This analysis revealed that all tumors were homozygous for a missense mutation at codon 213 (CGA => TGG) resulting in an amino acid exchange from arginine to tryptophane. The same mutation was present in one TP53 allele in the constitutional DNA of the mother and the children, indicating that the mother had transmitted a TP53 germline mutation to both of her children. Analysis of loss of heterozygosity at microsatellite markers from 17p confirmed deletion of the paternal (wild-type) allele in both PNETs. Further investigation of the PNETs by comparative genomic hybridization revealed multiple chromosomal abnormalities. Interestingly, some genomic changes were common to both PNETs, while many others were not, a finding suggesting substantial genomic instability, probably as a consequence of p53 inactivation.

Adult↗
PubMed1998

Frequent inactivation of CDKN2A and rare mutation of TP53 in PCNSL.

Twenty primary central nervous system lymphomas (PCNSL) from immunocompetent patients (nineteen B-cell lymphomas and one T-cell lymphoma) were investigated for genetic alterations and/or expression of the genes BCL2, CCND1, CDK4, CDKN1A, CDKN2A, MDM2, MYC, RB1, REL, and TP53. The gene found to be altered most frequently was CDKN2A. Eight tumors (40%) showed homozygous and two tumors (10%) hemizygous CDKN2A deletions. Furthermore, methylation analysis of six PCNSL without homozygous CDKN2A loss revealed methylation of the CpG island within exon 1 of CDKN2A in three instances. Reverse transcription PCR analysis of CDKN2A mRNA expression was performed for 11 tumors and showed either no or weak signals. Similarly, immunocytochemistry for the CDKN2A gene product (p16) remained either completely negative or showed expression restricted to single tumor cells. None of the PCNSL showed amplification of CDK4. Similarly, investigation of CCND1 revealed no amplification, rearrangement or overexpression. The retinoblastoma protein was strongly expressed in all tumors. Only one PCNSL showed a mutation of the TP53 gene, i.e., a missense mutation at codon 248 (CGG to TGG:Arg to Trp). No evidence of BCL2 gene rearrangement was found in 11 tumors investigated. The bcl-2 protein, however, was strongly expressed in most tumors. None of the 20 PCNSL demonstrated gene amplification of MDM2, MYC or REL. In summary, inactivation of CDKN2A by either homozygous deletion or DNA methylation represents an important molecular mechanism in PCNSL. Mutation of the TP53 gene and alterations of the other genes investigated appear to be of minor significance in these tumors.

Aged↗