Three inverted nasal papillomas were cytogenetically investigated after short-term culture. Two o... more Three inverted nasal papillomas were cytogenetically investigated after short-term culture. Two of the cases were characterized by a single abnormal clone with t(1;8)(p36;q11) and trisomy 7, respectively, whereas the third papilloma showed extreme cytogenetic heterogeneity: of 852 analyzed cells, 329 belonged to 36 unrelated clones, 344 had non-clonal changes, and 179 had a normal chromosome constitution. The polyclonal papilloma was further analyzed during in vitro passage of 3 lines (L1-L3) cultured independently since initiation of the primary cultures and found to have 6, 16 and 6 unrelated clones at analysis of primary cultures. At passage 1, each line was further subdivided into 2 sub-lines (L1A and B, L2A and B, and L3A and B), which were cultured separately until the cells spontaneously stopped dividing. After 4 to 7 passages, each sub-line was dominated (83-98% of the cells) by a single clone. The cell populations that took over the cultures were the same within each set of...
Moderately differentiated neuroendocrine carcinoma of the larynx is morphologically distinct from... more Moderately differentiated neuroendocrine carcinoma of the larynx is morphologically distinct from the classic carcinoid and small-cell carcinoma. It is composed of medium to large polyhedral cells with an insular, trabecular, or acinar growth pattern, variable pleomorphism, and a tendency to metastasize to skin and bone. We describe the clinicopathological features of the tumor in two patients in whom tumor dissemination resulted in death 13 and 33 months after diagnosis. Both tumors occurred above the glottis and metastasized to bone but not to regional tissues. In one case, the diagnosis was confirmed when the aspiration cytological specimen from a rib lesion suggested a neuroendocrine carcinoma resembling medullary thyroid cancer (triangular cytoplasm, double nuclei, and fine red cytoplasmic granules on May-Grünwald-Giemsa staining). Both tumors were originally misdiagnosed as squamous cell carcinoma, as acinic cell cancer, or as suggesting metastasis of melanoma. Immunohistochem...
The t(14;18)(q21;q32) is the most common recurrent genetic defect in follicle center cell lymphom... more The t(14;18)(q21;q32) is the most common recurrent genetic defect in follicle center cell lymphoma (FCC). Conflicting reports exist in regard to a possible prognostic significance for the translocation. In a single center, 102 patients with either low-grade (n = 50) or high-grade (n = 52) FCC (Kiel classification) and a median follow-up of 82 months were retrospectively studied to determine survival in relation to t(14;18) as shown by either PCR of the bcl-2 rearrangement in paraffinized tissue or karyotype analysis. t(14;18) was detected in 30 of 50 (60%) low-grade FCC and in 12 of 52 (23%) high-grade FCC. The presence of the t(14;18) was not related to morphologic bone marrow involvement or other clinical parameters, but it was related to age: in low-grade FCC, patients with t(14;18) were an average of 17 years younger (p = 0.002) than those without the translocation. In the group with high-grade histology, 30% survived beyond 60 months regardless of t(14;18) status (p = 0.92). Pa...
We used the polymerase chain reaction on 63 tissue specimens of histologically staged classic Kap... more We used the polymerase chain reaction on 63 tissue specimens of histologically staged classic Kaposi's sarcoma (KS) from 40 patients, 14 specimens from 14 acquired immune deficiency syndrome (AIDS)-KS cases (all from the same geographic area over a 10-year period), and peripheral blood mononuclear cells from 1 of the non-AIDS KS patients to amplify a specific 210-bp genomic sequence of the newly discovered KS-associated herpesvirus (KSHV). Also tested were 86 benign and malignant endothelial lesions, which potentially simulated each KS histological stage and were further matched by age approximation and by sex with a classical KS specimen. The lesions included hemangioma, lymphangioma, pyogenic granuloma, and angiosarcoma. KSHV was also sought in multiple well characterized vascular endothelial cell lines from AIDS-KS lesions and in 20 mainly cutaneous benign and malignant lesions from 15 immunosuppressed transplant patients. Overall, 92% of KS tissue specimens, representing 88%...
The long-term survival of patients with advanced stage aggressive lymphoma has not improved signi... more The long-term survival of patients with advanced stage aggressive lymphoma has not improved significantly during the last twenty years. In a randomised trial, the efficacy of MACOP-B, a six-drug weekly chemotherapy regimen, was compared to CHOP, the current standard regimen, in terms of overall and failure-free survival, toxicity and health related quality of life. Four hundred five patients with aggressive lymphoma, stage II-IV, age 18-67, were randomised to receive either 12 weeks of MACOP-B or 8 courses of CHOP over 24 weeks. Special emphasis was put in the definition of Ann Arbor stage in extranodal disease. A subset of 95 patients also entered a quality of life study, based on the EORTC QLQ-C30. Thirty-one patients were ineligible. Among the remaining 374 patients, the median age was 52 years. According to the age-adjusted International Prognostic Index, 37% were 'high-intermediate' or 'high-risk' patients. No difference could be demonstrated, either in overall ...
The cell cycle consists of an initial growth phase (G1), DNA replication (S), a gap phase (G2), a... more The cell cycle consists of an initial growth phase (G1), DNA replication (S), a gap phase (G2), and mitosis (M), after which the cell may differentiate or enter the resting state (G0). The cycle is driven by a number of positive and negative regulatory phosphorylation and dephosphorylation events, involving protein kinases, protein phosphatases, cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors, that ultimately impinge on the activity of transcription factors. Unreplicated or damaged DNA blocks the progression of the cell cycle at checkpoints, including a late G1 checkpoint regulated by the dephosphorylated retinoblastoma protein and a late G2 checkpoint regulated by the phosphorylation of cyclin-dependent kinase 1 complexed with cyclin B. Many cell cycle regulator genes may be considered proto-oncogenes or tumor suppressor genes, and point mutations, amplifications, deletions, or rearrangements involving their loci, particularly those in the "RB pathway...
"Lethal midline granuloma" of the upper airways generally encompasses T-cell lymphoma a... more "Lethal midline granuloma" of the upper airways generally encompasses T-cell lymphoma and Wegener's granulomatosis in Western populations. Treatment and outcome for each is different, but their pathological distinction may not always be possible on routine biopsy specimens. Within a defined population between 1947 and 1994, we found 12 cases of primary sinonasal T-cell lymphoma, all with a CD20-, CD3+ immunophenotype in paraffin sections. We studied the occurrence of the Epstein-Barr virus RNA EBER1 using colorimetric in situ hybridization (ISH) with an oligoprobe. All available biopsy specimens from each patient were hybridized to detect the presence of EBER1 in relation to the phase of lymphoma progression. In addition, ISH was performed on 23 cases of nonspecific rhinitis and 10 cases of Wegener's granulomatosis to determine the specificity of the method in the differential diagnosis of inflammatory/ulcerative lesions. In ten cases of lymphoma, initial biopsy sp...
Poorly differentiated midline carcinoma with a translocation between chromosomes 15 and 19, i.e. ... more Poorly differentiated midline carcinoma with a translocation between chromosomes 15 and 19, i.e. t(15;19), has been recognized as a distinct clinical entity for over a decade. This tumor affects young individuals, shows a rapidly fatal clinical course despite intensive therapy. The t(15;19) results in the fusion oncogene BRD4-NUT. Information concerning treatment of this rare disorder is scarce. A 30-year-old woman was admitted with a rapidly progressing tumor in the mediastinum, cervical lymph nodes, vertebral column and the epidural space. Pathological, cytogenetic, FISH and PCR analysis revealed a glycogenated carcinoma rarely expressing cytokeratins and showing t(15;19) and BRD4-NUT gene rearrangement. The patient was initially treated with a Ewing sarcoma chemotherapy regimen, but had rapid progression after two cycles. She then received docetaxel and radiotherapy, which resulted in almost complete disappearance of the tumor. Docetaxel may be considered for initial chemotherapy...
Immunohistochemical staining for tumor-associated proteins is widely used for the identification ... more Immunohistochemical staining for tumor-associated proteins is widely used for the identification of novel prognostic markers. Recently, a tissue-conserving, high-throughput technique, tissue microarray, has been introduced. This technique uses 0.6-mm tissue core biopsy specimens, 500 to 1000 of which are brought into a new paraffin array block, which can be sectioned up to 100 times. We evaluated the tissue microarray technique for immunohistochemical analysis in 20 rectal cancers. Immunohistochemical staining was performed for the proliferation marker Ki-67 and the tumor suppressor protein p53 in whole tissue sections and in tissue core biopsy specimens. The whole tissue sections were assessed by counting all cells in 10 high-power fields (x40), which resulted in a mean fraction of Ki-67-expressing tumor cells of 0.81 (range, 0.54-1.0). p53 expression assessed in whole tissue sections showed nuclear staining in 15 (75%) of 20 rectal carcinomas. For the tissue microarray technique, ...
Survival in squamous cell carcinoma of the head and neck (HNSCC) was compared with overexpression... more Survival in squamous cell carcinoma of the head and neck (HNSCC) was compared with overexpression and mutation of the p53 gene. Archival tissue from 77 tumours was analysed for protein expression using immunohistochemistry (IHC) with the monoclonal antibody Do-7, and for the presence of mutation in exons 5-8 using single-stranded conformation polymorphism (SSCP), followed by DNA sequencing in SSCP-positive cases. p53 expression was scored as high (>70% nuclei stained) in 25 (32%) tumours, as intermediate (10-70% nuclei stained) in 19 (25%) tumours and as low (<10% nuclei stained) in 33 (43%) tumours. Twelve (18%) tumours exhibited gene mutation (ten missense and two nonsense mutations) and an additional five tumours contained changes that could not result in amino acid substitution or protein truncation. There was no correlation between gene expression and mutation, mutations being equally frequent in tumours with either high (4/25), intermediate (4/19) or low protein expressi...
The nature of Kaposi sarcoma (KS) (vascular malignancy vs. discordant angiogenesis) and lineage o... more The nature of Kaposi sarcoma (KS) (vascular malignancy vs. discordant angiogenesis) and lineage of the progenitor cell remain unclear. Therefore, AIDS-KS enzyme isolate cultures were prepared from excised skin lesions. Endothelial marker positivity for Factor VIII related antigen (F8RAg), Ulex europaeus agglutinin (UEA), and angiotensin-converting enzyme (ACE) were determined by fluorescence microscopy (FM) and flow cytometry (FCM). DNA cell-cycle analysis was performed using FCM. KS lesions showed large thick-walled channels (F8RAg and UEA strongly +), narrow vascular slits and thin-walled lakes (F8RAg and UEA weakly +), and non-prominent spindle cells (F8RAg and UEA almost uniformly negative). KS cultures yielded heterogenous populations of spindle, stellate, and flattened endothelial-like cells, displaying positivity for F8RAg (64 +/- 3%; mean +/- SE), UEA (40 +/- 9%), and ACE (81 +/- 9%). When injected subcutaneously in the nude mouse these cells failed to produce tumors. During...
Short-term cultures from 12 non-squamous cell carcinomas (NSCCs) of the head and neck were cytoge... more Short-term cultures from 12 non-squamous cell carcinomas (NSCCs) of the head and neck were cytogenetically investigated. Three tumours were acinic cell carcinomas, two adenoid cystic carcinomas, three mucoepidermoid carcinomas, two carcinomas in pleomorphic adenoma, and two adenocarcinomas. Clonal chromosome aberrations were detected in all but one adenocarcinoma. Including our data, a total of 40 head and neck NSCCs with clonal aberrations have been described. Deletions of the long arm of chromosome 6 are the most common aberrations (11/40 cases); they have been detected in all types of NSCC except carcinoma in pleomorphic adenoma. Two aberrations seem to be closely associated with tumour type: t(6;9)(q21-24;p13-23), which has been seen in three of 11 adenoid cystic carcinomas (in two as the sole aberration), and structural rearrangements of 8q12-13, which have been detected in three of four carcinomas in pleomorphic adenoma.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2010
Genetic alterations underlying the development of the cancer of the nose and paranasal sinuses (s... more Genetic alterations underlying the development of the cancer of the nose and paranasal sinuses (sinonasal cancer, SNC), a rare cancer that can be included in the group of head and neck cancers, are still largely unknown. We recently reported that TP53 mutations are a common feature of SNC, with an overall frequency of 77%, and they show association to adenocarcinoma and wood-dust exposure . In this study, we report in detail the sequence change for 159 TP53 mutations identified by direct sequencing. More than half of the mutations (60%, 95/159) were missense mutations; there were also 28 (18%) frameshift or nonsense mutations, and 36 (23%) intronic or silent mutations. In coding region, the most common base change detected was C → T transition (43/125; 34% of base changes in the coding region). G → T transversions occurred at a frequency of 10% (12/125), which is less than reported in mutation databases for head and neck squamous cell carcinoma (24%). Characteristically, in our SNC series, the mutations were scattered over a large number of codons, codon 248 being the most frequent target of base substitution. Codon 135 was the second most frequently mutated codon; this nucleotide position has not been reported before as frequently mutated in head and neck cancer or human cancer in general. About half of all tumours with TP53 mutations carried more than one mutation. Interestingly, 86% (19/22) of the silent mutations detected had occurred in tumours with multiple mutations.
Differential gene expression analysis, using high-density microarray chips, demonstrated 300 - 40... more Differential gene expression analysis, using high-density microarray chips, demonstrated 300 - 400 genes to be deregulated in mantle cell lymphomas (MCLs) compared with normal B-cell populations. To inves- tigate the significance of this genetic signature in lymphoma etiology and diagnostics, we selected 90 annotated genes involved in a number of cellular functions for further analysis. Our findings demonstrated a nor-
In the last 2 years, the discovery that the suspected causative agent of Kaposi&#39;s sarcoma... more In the last 2 years, the discovery that the suspected causative agent of Kaposi&#39;s sarcoma (KS) is a new gamma-herpesvirus, called human herpesvirus type 8 (HHV8) or Kaposi&#39;s sarcoma-associated herpesvirus (KSHV), has been followed by studies showing it to be a sine qua non of all clinical forms of KS and a specific marker for KS in the differential diagnosis of angioproliferative lesions. Reports that the virus is ubiquitous have been based on the polymerase chain reaction and appear to be contradicted by serological studies of blood donors and patients with acquired immunodeficiency syndrome (AIDS)-related and classical KS. Further serological surveys and the application of molecular probes in histological sections should resolve the issue. The recent descriptions of KSHV RNA molecules and several viral mimickers of human cytokines offer the chance to map the viral latent-lytic cycle and will change the direction of cytokine research in KS. These discoveries suggest that the increase of endemic classical KS noted in Nordic countries before the AIDS epidemic was due to spread of KSHV by unknown routes. The aggregate data should force a paradigm shift away from the notion that human immunodeficiency virus infection has a necessary role to play in AIDS-KS other than as a cause of progressive immunodeficiency.
transmission of HIV in 39 pregnancies between 1989 and 1993 among 37 HIV-1-infected women without... more transmission of HIV in 39 pregnancies between 1989 and 1993 among 37 HIV-1-infected women without zidovudine prophylaxis. HIV-1 was detected in 12 of 37 (31%) placentas by immunohistochemistry and in 3 of 18 by PCR. Altogether 14 39 (36%) placentas bore evidence of HIV-1 infection, although there was no relation with the outcome of HIV infection in the child. Neither was there a relation between placental infection and either CD4 cell counts or HIV-1 RNA levels. However, HIV-1 was isolated from plasma in 20 of 39 (50%) pregnancies, which was inversely related to the presence of HIV in the placenta. When HIV-1
Mutations in the p53 tumour suppressor gene and amplification of the cyclin D1 (CCND1) oncogene h... more Mutations in the p53 tumour suppressor gene and amplification of the cyclin D1 (CCND1) oncogene have been commonly reported in various malignancies. In the present study of 39 squamous cell carcinomas of the head and neck, p53 mutations were manifest in 11 (28%) of the cases, whereas CCND1 amplification was seen in 6 (16%) of 37 analysed tumours. The 10 mutations occurring in coding sequences of p53 were found in exon 5 (4 cases), exon 6 (3 cases),f and exon 8 (3 cases). No mutation was found in exon 7. Eight of the 10 exon nucleotide substitutions were missense mutations and two were nonsense mutations. All six tumours with CCND1 amplification also had p53 mutations, while an additional five tumours manifested p53 mutations in the absence of CCND1 amplification. There was a statistically significant positive correlation between these two gene alterations. This raises the possibility that mutation of p53 precedes CCND1 amplification in carcinogenesis.
Tongue squamous cell carcinoma makes up a large percentage of head and neck cancers, and the inci... more Tongue squamous cell carcinoma makes up a large percentage of head and neck cancers, and the incidence among young patients is increasing. The aim of this study was to reveal the correlation between cyclin D1 (CCND1) expression and clinical and histologic features. We performed an immunohistochemical study on the level of CCND1 expression in tumor specimens obtained from 94 patients with tongue squamous cell carcinoma. The relationship between the expression and the following features such as age, sex, smoking and alcohol intake history, T, N, histologic grade, and multiple primary cancer was analyzed. Eighteen patients (19%) showed CCND1 overexpression (tumor cell nuclei positivity &gt;/=50%). The 5-year survival rate of high CCND1 expressors was 39%, which was significantly poor (p=0.04). N classification correlated with CCND1 expression. CCND1 overexpression is associated with poor survival associated with progression of lymph node spread in patients with tongue squamous cell carcinomas. CCND1 expression may be a useful biologic marker for prognosis.
Three inverted nasal papillomas were cytogenetically investigated after short-term culture. Two o... more Three inverted nasal papillomas were cytogenetically investigated after short-term culture. Two of the cases were characterized by a single abnormal clone with t(1;8)(p36;q11) and trisomy 7, respectively, whereas the third papilloma showed extreme cytogenetic heterogeneity: of 852 analyzed cells, 329 belonged to 36 unrelated clones, 344 had non-clonal changes, and 179 had a normal chromosome constitution. The polyclonal papilloma was further analyzed during in vitro passage of 3 lines (L1-L3) cultured independently since initiation of the primary cultures and found to have 6, 16 and 6 unrelated clones at analysis of primary cultures. At passage 1, each line was further subdivided into 2 sub-lines (L1A and B, L2A and B, and L3A and B), which were cultured separately until the cells spontaneously stopped dividing. After 4 to 7 passages, each sub-line was dominated (83-98% of the cells) by a single clone. The cell populations that took over the cultures were the same within each set of...
Moderately differentiated neuroendocrine carcinoma of the larynx is morphologically distinct from... more Moderately differentiated neuroendocrine carcinoma of the larynx is morphologically distinct from the classic carcinoid and small-cell carcinoma. It is composed of medium to large polyhedral cells with an insular, trabecular, or acinar growth pattern, variable pleomorphism, and a tendency to metastasize to skin and bone. We describe the clinicopathological features of the tumor in two patients in whom tumor dissemination resulted in death 13 and 33 months after diagnosis. Both tumors occurred above the glottis and metastasized to bone but not to regional tissues. In one case, the diagnosis was confirmed when the aspiration cytological specimen from a rib lesion suggested a neuroendocrine carcinoma resembling medullary thyroid cancer (triangular cytoplasm, double nuclei, and fine red cytoplasmic granules on May-Grünwald-Giemsa staining). Both tumors were originally misdiagnosed as squamous cell carcinoma, as acinic cell cancer, or as suggesting metastasis of melanoma. Immunohistochem...
The t(14;18)(q21;q32) is the most common recurrent genetic defect in follicle center cell lymphom... more The t(14;18)(q21;q32) is the most common recurrent genetic defect in follicle center cell lymphoma (FCC). Conflicting reports exist in regard to a possible prognostic significance for the translocation. In a single center, 102 patients with either low-grade (n = 50) or high-grade (n = 52) FCC (Kiel classification) and a median follow-up of 82 months were retrospectively studied to determine survival in relation to t(14;18) as shown by either PCR of the bcl-2 rearrangement in paraffinized tissue or karyotype analysis. t(14;18) was detected in 30 of 50 (60%) low-grade FCC and in 12 of 52 (23%) high-grade FCC. The presence of the t(14;18) was not related to morphologic bone marrow involvement or other clinical parameters, but it was related to age: in low-grade FCC, patients with t(14;18) were an average of 17 years younger (p = 0.002) than those without the translocation. In the group with high-grade histology, 30% survived beyond 60 months regardless of t(14;18) status (p = 0.92). Pa...
We used the polymerase chain reaction on 63 tissue specimens of histologically staged classic Kap... more We used the polymerase chain reaction on 63 tissue specimens of histologically staged classic Kaposi's sarcoma (KS) from 40 patients, 14 specimens from 14 acquired immune deficiency syndrome (AIDS)-KS cases (all from the same geographic area over a 10-year period), and peripheral blood mononuclear cells from 1 of the non-AIDS KS patients to amplify a specific 210-bp genomic sequence of the newly discovered KS-associated herpesvirus (KSHV). Also tested were 86 benign and malignant endothelial lesions, which potentially simulated each KS histological stage and were further matched by age approximation and by sex with a classical KS specimen. The lesions included hemangioma, lymphangioma, pyogenic granuloma, and angiosarcoma. KSHV was also sought in multiple well characterized vascular endothelial cell lines from AIDS-KS lesions and in 20 mainly cutaneous benign and malignant lesions from 15 immunosuppressed transplant patients. Overall, 92% of KS tissue specimens, representing 88%...
The long-term survival of patients with advanced stage aggressive lymphoma has not improved signi... more The long-term survival of patients with advanced stage aggressive lymphoma has not improved significantly during the last twenty years. In a randomised trial, the efficacy of MACOP-B, a six-drug weekly chemotherapy regimen, was compared to CHOP, the current standard regimen, in terms of overall and failure-free survival, toxicity and health related quality of life. Four hundred five patients with aggressive lymphoma, stage II-IV, age 18-67, were randomised to receive either 12 weeks of MACOP-B or 8 courses of CHOP over 24 weeks. Special emphasis was put in the definition of Ann Arbor stage in extranodal disease. A subset of 95 patients also entered a quality of life study, based on the EORTC QLQ-C30. Thirty-one patients were ineligible. Among the remaining 374 patients, the median age was 52 years. According to the age-adjusted International Prognostic Index, 37% were 'high-intermediate' or 'high-risk' patients. No difference could be demonstrated, either in overall ...
The cell cycle consists of an initial growth phase (G1), DNA replication (S), a gap phase (G2), a... more The cell cycle consists of an initial growth phase (G1), DNA replication (S), a gap phase (G2), and mitosis (M), after which the cell may differentiate or enter the resting state (G0). The cycle is driven by a number of positive and negative regulatory phosphorylation and dephosphorylation events, involving protein kinases, protein phosphatases, cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors, that ultimately impinge on the activity of transcription factors. Unreplicated or damaged DNA blocks the progression of the cell cycle at checkpoints, including a late G1 checkpoint regulated by the dephosphorylated retinoblastoma protein and a late G2 checkpoint regulated by the phosphorylation of cyclin-dependent kinase 1 complexed with cyclin B. Many cell cycle regulator genes may be considered proto-oncogenes or tumor suppressor genes, and point mutations, amplifications, deletions, or rearrangements involving their loci, particularly those in the "RB pathway...
"Lethal midline granuloma" of the upper airways generally encompasses T-cell lymphoma a... more "Lethal midline granuloma" of the upper airways generally encompasses T-cell lymphoma and Wegener's granulomatosis in Western populations. Treatment and outcome for each is different, but their pathological distinction may not always be possible on routine biopsy specimens. Within a defined population between 1947 and 1994, we found 12 cases of primary sinonasal T-cell lymphoma, all with a CD20-, CD3+ immunophenotype in paraffin sections. We studied the occurrence of the Epstein-Barr virus RNA EBER1 using colorimetric in situ hybridization (ISH) with an oligoprobe. All available biopsy specimens from each patient were hybridized to detect the presence of EBER1 in relation to the phase of lymphoma progression. In addition, ISH was performed on 23 cases of nonspecific rhinitis and 10 cases of Wegener's granulomatosis to determine the specificity of the method in the differential diagnosis of inflammatory/ulcerative lesions. In ten cases of lymphoma, initial biopsy sp...
Poorly differentiated midline carcinoma with a translocation between chromosomes 15 and 19, i.e. ... more Poorly differentiated midline carcinoma with a translocation between chromosomes 15 and 19, i.e. t(15;19), has been recognized as a distinct clinical entity for over a decade. This tumor affects young individuals, shows a rapidly fatal clinical course despite intensive therapy. The t(15;19) results in the fusion oncogene BRD4-NUT. Information concerning treatment of this rare disorder is scarce. A 30-year-old woman was admitted with a rapidly progressing tumor in the mediastinum, cervical lymph nodes, vertebral column and the epidural space. Pathological, cytogenetic, FISH and PCR analysis revealed a glycogenated carcinoma rarely expressing cytokeratins and showing t(15;19) and BRD4-NUT gene rearrangement. The patient was initially treated with a Ewing sarcoma chemotherapy regimen, but had rapid progression after two cycles. She then received docetaxel and radiotherapy, which resulted in almost complete disappearance of the tumor. Docetaxel may be considered for initial chemotherapy...
Immunohistochemical staining for tumor-associated proteins is widely used for the identification ... more Immunohistochemical staining for tumor-associated proteins is widely used for the identification of novel prognostic markers. Recently, a tissue-conserving, high-throughput technique, tissue microarray, has been introduced. This technique uses 0.6-mm tissue core biopsy specimens, 500 to 1000 of which are brought into a new paraffin array block, which can be sectioned up to 100 times. We evaluated the tissue microarray technique for immunohistochemical analysis in 20 rectal cancers. Immunohistochemical staining was performed for the proliferation marker Ki-67 and the tumor suppressor protein p53 in whole tissue sections and in tissue core biopsy specimens. The whole tissue sections were assessed by counting all cells in 10 high-power fields (x40), which resulted in a mean fraction of Ki-67-expressing tumor cells of 0.81 (range, 0.54-1.0). p53 expression assessed in whole tissue sections showed nuclear staining in 15 (75%) of 20 rectal carcinomas. For the tissue microarray technique, ...
Survival in squamous cell carcinoma of the head and neck (HNSCC) was compared with overexpression... more Survival in squamous cell carcinoma of the head and neck (HNSCC) was compared with overexpression and mutation of the p53 gene. Archival tissue from 77 tumours was analysed for protein expression using immunohistochemistry (IHC) with the monoclonal antibody Do-7, and for the presence of mutation in exons 5-8 using single-stranded conformation polymorphism (SSCP), followed by DNA sequencing in SSCP-positive cases. p53 expression was scored as high (>70% nuclei stained) in 25 (32%) tumours, as intermediate (10-70% nuclei stained) in 19 (25%) tumours and as low (<10% nuclei stained) in 33 (43%) tumours. Twelve (18%) tumours exhibited gene mutation (ten missense and two nonsense mutations) and an additional five tumours contained changes that could not result in amino acid substitution or protein truncation. There was no correlation between gene expression and mutation, mutations being equally frequent in tumours with either high (4/25), intermediate (4/19) or low protein expressi...
The nature of Kaposi sarcoma (KS) (vascular malignancy vs. discordant angiogenesis) and lineage o... more The nature of Kaposi sarcoma (KS) (vascular malignancy vs. discordant angiogenesis) and lineage of the progenitor cell remain unclear. Therefore, AIDS-KS enzyme isolate cultures were prepared from excised skin lesions. Endothelial marker positivity for Factor VIII related antigen (F8RAg), Ulex europaeus agglutinin (UEA), and angiotensin-converting enzyme (ACE) were determined by fluorescence microscopy (FM) and flow cytometry (FCM). DNA cell-cycle analysis was performed using FCM. KS lesions showed large thick-walled channels (F8RAg and UEA strongly +), narrow vascular slits and thin-walled lakes (F8RAg and UEA weakly +), and non-prominent spindle cells (F8RAg and UEA almost uniformly negative). KS cultures yielded heterogenous populations of spindle, stellate, and flattened endothelial-like cells, displaying positivity for F8RAg (64 +/- 3%; mean +/- SE), UEA (40 +/- 9%), and ACE (81 +/- 9%). When injected subcutaneously in the nude mouse these cells failed to produce tumors. During...
Short-term cultures from 12 non-squamous cell carcinomas (NSCCs) of the head and neck were cytoge... more Short-term cultures from 12 non-squamous cell carcinomas (NSCCs) of the head and neck were cytogenetically investigated. Three tumours were acinic cell carcinomas, two adenoid cystic carcinomas, three mucoepidermoid carcinomas, two carcinomas in pleomorphic adenoma, and two adenocarcinomas. Clonal chromosome aberrations were detected in all but one adenocarcinoma. Including our data, a total of 40 head and neck NSCCs with clonal aberrations have been described. Deletions of the long arm of chromosome 6 are the most common aberrations (11/40 cases); they have been detected in all types of NSCC except carcinoma in pleomorphic adenoma. Two aberrations seem to be closely associated with tumour type: t(6;9)(q21-24;p13-23), which has been seen in three of 11 adenoid cystic carcinomas (in two as the sole aberration), and structural rearrangements of 8q12-13, which have been detected in three of four carcinomas in pleomorphic adenoma.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2010
Genetic alterations underlying the development of the cancer of the nose and paranasal sinuses (s... more Genetic alterations underlying the development of the cancer of the nose and paranasal sinuses (sinonasal cancer, SNC), a rare cancer that can be included in the group of head and neck cancers, are still largely unknown. We recently reported that TP53 mutations are a common feature of SNC, with an overall frequency of 77%, and they show association to adenocarcinoma and wood-dust exposure . In this study, we report in detail the sequence change for 159 TP53 mutations identified by direct sequencing. More than half of the mutations (60%, 95/159) were missense mutations; there were also 28 (18%) frameshift or nonsense mutations, and 36 (23%) intronic or silent mutations. In coding region, the most common base change detected was C → T transition (43/125; 34% of base changes in the coding region). G → T transversions occurred at a frequency of 10% (12/125), which is less than reported in mutation databases for head and neck squamous cell carcinoma (24%). Characteristically, in our SNC series, the mutations were scattered over a large number of codons, codon 248 being the most frequent target of base substitution. Codon 135 was the second most frequently mutated codon; this nucleotide position has not been reported before as frequently mutated in head and neck cancer or human cancer in general. About half of all tumours with TP53 mutations carried more than one mutation. Interestingly, 86% (19/22) of the silent mutations detected had occurred in tumours with multiple mutations.
Differential gene expression analysis, using high-density microarray chips, demonstrated 300 - 40... more Differential gene expression analysis, using high-density microarray chips, demonstrated 300 - 400 genes to be deregulated in mantle cell lymphomas (MCLs) compared with normal B-cell populations. To inves- tigate the significance of this genetic signature in lymphoma etiology and diagnostics, we selected 90 annotated genes involved in a number of cellular functions for further analysis. Our findings demonstrated a nor-
In the last 2 years, the discovery that the suspected causative agent of Kaposi&#39;s sarcoma... more In the last 2 years, the discovery that the suspected causative agent of Kaposi&#39;s sarcoma (KS) is a new gamma-herpesvirus, called human herpesvirus type 8 (HHV8) or Kaposi&#39;s sarcoma-associated herpesvirus (KSHV), has been followed by studies showing it to be a sine qua non of all clinical forms of KS and a specific marker for KS in the differential diagnosis of angioproliferative lesions. Reports that the virus is ubiquitous have been based on the polymerase chain reaction and appear to be contradicted by serological studies of blood donors and patients with acquired immunodeficiency syndrome (AIDS)-related and classical KS. Further serological surveys and the application of molecular probes in histological sections should resolve the issue. The recent descriptions of KSHV RNA molecules and several viral mimickers of human cytokines offer the chance to map the viral latent-lytic cycle and will change the direction of cytokine research in KS. These discoveries suggest that the increase of endemic classical KS noted in Nordic countries before the AIDS epidemic was due to spread of KSHV by unknown routes. The aggregate data should force a paradigm shift away from the notion that human immunodeficiency virus infection has a necessary role to play in AIDS-KS other than as a cause of progressive immunodeficiency.
transmission of HIV in 39 pregnancies between 1989 and 1993 among 37 HIV-1-infected women without... more transmission of HIV in 39 pregnancies between 1989 and 1993 among 37 HIV-1-infected women without zidovudine prophylaxis. HIV-1 was detected in 12 of 37 (31%) placentas by immunohistochemistry and in 3 of 18 by PCR. Altogether 14 39 (36%) placentas bore evidence of HIV-1 infection, although there was no relation with the outcome of HIV infection in the child. Neither was there a relation between placental infection and either CD4 cell counts or HIV-1 RNA levels. However, HIV-1 was isolated from plasma in 20 of 39 (50%) pregnancies, which was inversely related to the presence of HIV in the placenta. When HIV-1
Mutations in the p53 tumour suppressor gene and amplification of the cyclin D1 (CCND1) oncogene h... more Mutations in the p53 tumour suppressor gene and amplification of the cyclin D1 (CCND1) oncogene have been commonly reported in various malignancies. In the present study of 39 squamous cell carcinomas of the head and neck, p53 mutations were manifest in 11 (28%) of the cases, whereas CCND1 amplification was seen in 6 (16%) of 37 analysed tumours. The 10 mutations occurring in coding sequences of p53 were found in exon 5 (4 cases), exon 6 (3 cases),f and exon 8 (3 cases). No mutation was found in exon 7. Eight of the 10 exon nucleotide substitutions were missense mutations and two were nonsense mutations. All six tumours with CCND1 amplification also had p53 mutations, while an additional five tumours manifested p53 mutations in the absence of CCND1 amplification. There was a statistically significant positive correlation between these two gene alterations. This raises the possibility that mutation of p53 precedes CCND1 amplification in carcinogenesis.
Tongue squamous cell carcinoma makes up a large percentage of head and neck cancers, and the inci... more Tongue squamous cell carcinoma makes up a large percentage of head and neck cancers, and the incidence among young patients is increasing. The aim of this study was to reveal the correlation between cyclin D1 (CCND1) expression and clinical and histologic features. We performed an immunohistochemical study on the level of CCND1 expression in tumor specimens obtained from 94 patients with tongue squamous cell carcinoma. The relationship between the expression and the following features such as age, sex, smoking and alcohol intake history, T, N, histologic grade, and multiple primary cancer was analyzed. Eighteen patients (19%) showed CCND1 overexpression (tumor cell nuclei positivity &gt;/=50%). The 5-year survival rate of high CCND1 expressors was 39%, which was significantly poor (p=0.04). N classification correlated with CCND1 expression. CCND1 overexpression is associated with poor survival associated with progression of lymph node spread in patients with tongue squamous cell carcinomas. CCND1 expression may be a useful biologic marker for prognosis.
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Papers by Michael Dictor