Loss of p16 expression is a risk factor for recurrence in sinonasal inverted papilloma.

BACKGROUND: The purpose of this study was to evaluate p16, p53, EGFR, pEGFR protein expression and HPV infection as possible markers of tumor progression in a series of sinonasal inverted papilloma (SNIP) and sinonasal squamous cell carcinoma (SNSCC). METHODS: A series of 49 SNIP, 11 SNSCC associated with SNIP (SNIP-SNSCC) and 52 SNSCC not associated with SNIP were analyzed for p16, p53, EGFR, and phosphorylated EGFR (pEGFR) expression by immunohistochemistry. Human papillomavirus (HPV) infection status was evaluated by DNA-PCR. Results were correlated to clinical and follow-up data. RESULTS: Reduced or loss of p16 expression was observed in 18% SNIP, 64% SNIP-SNSCC and 87% of SNSCC. Reduced or loss p16 staining in SNIP correlated with shorter recurrent SNIP-free follow-up. In contrast, p16 expression was not predictive of recurrent SNSCC in cases with SNIP-SNSCC and SNSCC. P53, EGFR, and pEGFR expression did not differ between the tumor groups, nor were they related to recurrent SNIP-free follow-up or recurrent SNSCC. Oncogenic HPV types 16 and 18 were detected in 5% of SNIP and 18% of SNIP-SNSCC, but not in SNSCC. There was no correlation between HPV infection and >70% p16 immunostaining. CONCLUSIONS: HPV infection appears to play a minor role in SNIP and SNSCC and p16 immunostaining does not appear a valid surrogate marker for HPV. However, reduced or loss p16 expression may have prognostic value as a risk marker for recurrent SNIP.

Factors facilitating or hindering meaningful staff-client interactions in people with intellectual disabilities and challenging behaviour: A systematic mixed studies review using thematic synthesis.

BACKGROUND: Interactions with professional caregivers affect the quality of support and life of people with intellectual disabilities and contribute to the occurrence of challenging behaviour. The present literature review provides an overview of factors facilitating or hindering meaningful staff-client interactions in people with borderline to profound intellectual disabilities and challenging behaviour. METHOD: Database searches, reference list and citation screening, and expert consultations were undertaken. A thematic synthesis of 28 studies was performed. RESULTS: Factors were identified at the client (i.e. behaviour, emotions and (dis)abilities), staff (i.e. interactive principles, knowledge, psychological resources, attributions, attitudes and (coping with) emotions) and context levels (i.e. group size, team and organization). CONCLUSIONS: The present overview provides insights into factors that facilitate or hinder meaningful staff-client interactions with people with intellectual disabilities and challenging behaviour. The results support the need to combine client, staff and contextual factors when considering staff-client interactions in research and practice.

EGFR mutation and HPV infection in sinonasal inverted papilloma and squamous cell carcinoma.

BACKGROUND: To evaluate the involvement of EGFR signalling and HPV infection in a cohort of inverted sinonasal papilloma (ISP) and sinonasal squamous cell carcinoma (SNSCC) and their value for prognosis and clinical treatment. METHODS: We analysed 55 ISP, 14 SNSCC associated with ISP (SNSCC-isp) and and 60 SNSCC not associated with ISP (SNSCC-novo) for EGFR gene mutation and copy number gain, protein expression of EGFR and phosporylated EGFR (pEGFR), and HPV-infection and KRAS mutation. Findings were correlated to clinico-pathological and follow-up data. RESULTS: We found EGFR exon 20 mutations in 38% (7/18) ISP, in 50% (6/12) SNSCC-isp and in 5% (1/19) SNSCC-novo. EGFR was expressed in 92% of ISP, while pEGFR was observed in 54% (21/39). SNSCC-isp and SNSCC-novo demonstrated comparable expression of EGFR (57% and 33%) and of pEGFR (44% and 38%). We observed an inverse relation between EGFR exon 20 mutation and pEGFR expression. Four of 39 (10%) ISP carried HPV-16. Oncogenic HPV was detected in 3/12 (25%) SNSSC-isp and in 1/8 (13%) SNSCC-novo. KRAS mutations were not detected in any of the samples. HPV infection was inversely correlated with pEGFR expression but not with EGFR mutation. ISP with EGFR activation by mutation or by phosphorylation had longer ISP-free survival, however, neither EGFR exon 20 mutation, pEGFR expression nor HPV infection demonstrated prognostic value in SNSCC. CONCLUSIONS: EGFR exon 20 mutation is frequent in ISP and SNSCC-isp, while activation of EGFR through phosphorylation also plays an important role. Our data indicate that a large proportion of SNSCC patients could benefit from therapy with modern EGFR inhibitors.

Recurrent DNA copy number alterations in intestinal-type sinonasal adenocarcinoma.

BACKGROUND: Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare tumour related to occupational wood dust exposure. Few studies have described recurrent genetic changes on a genome-wide scale. The aim of this study was to obtain a high resolution map of recurrent genetic alterations in ITAC. MATERIAL AND METHODS: Copy number alterations were evaluated by microarray CGH and MLPA in 37 primary tumours. The results were correlated with pathological characteristics and clinical outcome. RESULTS: Microarray CGH identified the following recurrent aberrations, in descending order: gains at 5p15 (22 cases, 60%), 8q24 (21 cases, 57%), 20q13 (20 cases, 54%), 20q11, and 8q21 (19 cases, 51%), 20p13, and 7p11 (16 cases, 43%), and losses at 5q11-qter, 8p12-pter, and 18q12-23 (15 cases, 40%), and 17p13, and 19p13 (13 cases, 35%). MLPA analysis confirmed this global pattern of gains and losses. Chromosomal loss at 4q32-ter and gains at 1q22, 6p22 and 3q29, as well as deletion of TIMP2 and CRK correlated with unfavourable clinical outcome. CONCLUSION: ITACs have a unique pattern of chromosomal abnormalities. The four different histological subtypes of ITAC appeared genetically similar. Four chromosomal gains and losses and two specific genes showed prognostic value and may be involved in tumour progression.

The human degree of care. Professional loving care for people with a mild intellectual disability: an explorative study.

BACKGROUND: Research has shown that care staff are not always able to offer quality care. Commercialisation and market forces within the care sector are often pointed to as an explanation for this shortcoming. In the present study, insight is gained into the possible connections between the commercialisation of care, on the one hand, and the shrinkage of possibilities and motivation to offer professional loving care, on the other hand, from the perspective of care staff working with people with mild intellectual disabilities. METHOD: Semi-structured qualitative interviews were conducted with 28 care staff working with people with mild intellectual disabilities. Scientific research methods were combined with normative ethical reflection to examine the internal morals of the care staff. RESULTS: According to participating care staff, an affiliation with and recognition of the client form the basis for professional loving care. Care staff recognise that their profession is increasingly being built upon manageability and accountability, and this is making their jobs more difficult. CONCLUSION: We conclude that care staff perceive the precedence given to the smooth running of production processes over investment in direct contact with clients to be a real threat to the quality of care. Concerns about declining motivation and loss of work satisfaction as a result of the commercialisation of care are only partly acknowledged by care staff. While shrinkage of space for professional loving care is recognised, one can hardly speak of declining motivation.

Signet-ring cell change in adenoid cystic carcinoma: a clinicopathologic and immunohistochemical study of four cases.

AIMS: Signet-ring cell (SRC) change has not been reported in adenoid cystic carcinomas (ACC). This study describes the clinicopathological and immunohistochemical findings in four cases of ACC with SRCs (ACC-SRC), in which the relative proportion of the SRC component ranged from 25% to 50%. METHODS AND RESULTS: The median age was 58 years (range: 48 to 81 y) and all patients were women. The involved sites were sinonasal, lip and submandibular. Two patients developed lung metastasis and one died of disease 63 months after tumor resection. Neither mucinous nor lipid substances were detected in the SRCs. These were positive for AE1/AE3, CK14 and EMA; which highlighted the intracytoplasmic vacuole borders. The SRC nests were surrounded by α-SMA and p63 positive myoepithelial cells. When compared to the conventional component, the SRCs exhibited similar p53 positivity but lower Ki-67 and mitotic indices. SRCs were C-Myb negative. Ultrastructural examination revealed that the intracytoplasmic vacuoles were lumens lined by microvilli. CONCLUSIONS: ACC-SRC is a nonmucin and nonlipid producing phenomenon, possibly related to disturbed differentiation of ductal/luminal cells. This cellular modification in ACC apparently does not change the biological behavior of the tumor but it may cause significant diagnostic problems, particularly in incisional biopsies. © 2012 Blackwell Publishing Ltd.

[Distant metastases in head and neck cancer]. / Metástasis a distancia en el cáncer de cabeza y cuello.

INTRODUCTION: The presence of distant metastasis (DM) after the initial treatment of head and neck squamous cell carcinoma (HNSCC) is not considered a common event and it is associated to a poor outcome. PURPOSE: To investigate the prevalence and risk factors associated with the diagnosis of distant metastasis in SCC. METHODS AND MATERIALS: A retrospective study of 633 patients with HNSCC to describe the clinical characteristics of the DM. RESULTS: During the follow-up period after the initial treatment, 6.2% of the patients were diagnosed of having distant metastasis. The site of primary tumor was hypopharynx in 14.4%, unknown origin in 11.8% and oropharynx in 8.5%. The most common sites of DM were the lungs (58%) and the bone (22%). Three year overall survival in patients with DM was 2.5% (versus 49,5% in the control group). CONCLUSIONS: This study confirms that DM have an adverse impact in survival. There is a need of guidelines for screening of distant metastases in patients with HNSCC in order to get an early diagnosis and a more effective treatment. Because of the poor prognosis of DM, protocols including adjuvant chemotherapy should be investigated.

Metástasis a distancia en el cáncer de cabeza y cuello / Distant metastases in head and neck cancer

Introducción: La presencia de metástasis a distancia (MD) no es un evento muy frecuente en los carcinomas de cabeza y cuello (CECC) y se asocia con muy mal pronóstico. Objetivo: Investigar la las principales características clínicas y factores de riesgo asociados con el diagnóstico de MD en CECC. Material y método: Estudio retrospectivo de 633 pacientes con CECC para describir las características clínicas de las MD. Resultados: Se observan en el 6,2% de los CECC. Las localizaciones que más las originan son la hipofaringe (14,4%), los primarios de origen desconocido (11,8%) y la orofaringe (8,5%), apareciendo con mayor frecuencia en pulmón (58%) y hueso (22%). Determinan un gran impacto en la supervivencia, reduciéndola al 2,5% a los 3 años (49,5% en el grupo control a los 5 años). Conclusiones: Es preciso realizar un seguimiento adecuado para su detección precoz y tratamiento eficaz, investigando nuevos protocolos terapéuticos que incluyan la quimioterapia

Introduction: The presence of distant metastasis (DM) after the initial treatment of head and neck squamous cell carcinoma (HNSCC) is not considered a common event and it is associated to a poor outcome. Purpose: To investigate the prevalence and risk factors associated with the diagnosis of distant metastasis in SCC. Methods and Materials: A retrospective study of 633 patients with HNSCC to describe the clinical characteristics of the DM. Results: During the follow-up period after the initial treatment, 6.2% of the patients were diagnosed of having distant metastasis. The site of primary tumor was hypopharynx in 14.4%, unknown origin in 11.8% and oropharynx in 8.5%. The most common sites of DM were the lungs (58%) and the bone (22%). Three year overall survival in patients with DM was 2.5% (versus 49,5% in the control group). Conclusions: This study confirms that DM have an adverse impact in survival. There is a need of guidelines for screening of distant metastases in patients with HNSCC in order to get an early diagnosis and a more effective treatment. Because of the poor prognosis of DM, protocols including adjuvant chemotherapy should be investigated

Replacement of intravenous administration of anti-D by subcutaneous administration in patients with autoimmune thrombocytopenia.

Intravenous (IV) administration of anti-D in patients with autoimmune thrombocytopenia (AITP) may result in severe hemolysis and even death. Over a 3-year period, we gave anti-D only subcutaneously (SC), and none of our patients have developed any acute adverse reaction. Most importantly, SC delivery of anti-D produces largely the same beneficial effect as obtained by IV anti-D. We recommend replacement of IV administration of anti-D by SC administration in AITP.

[Second primary tumors in head and neck cancer]. / Segundos tumores primarios en el cáncer escamoso de cabeza y cuello.

INTRODUCTION: The development of second primary tumors (SPT) in patients with head and neck squamous cell carcinoma (HNSCC) has become an increasingly important factor in clinical treatment decisions. PURPOSE: To define favourable clinical characteristics for overall survival, in patients with SP head and neck cancer. MATERIAL AND METHOD: Records of 633 patients with SCC treated from 1984 to 2004 were reviewed to describe clinical characteristics of the SPT. RESULTS: The overall incidence of SPT was 11%. The incidence of the index tumors was as follows: supraglottic cancer 21% and oral cancer 16%. The most common SPT occurred in head and neck area in 47%, lung in 32% and esophagus in 11%. Second primary was associated with a poor 5 years survival in patients with HN-SCC (23 versus 53% in control group). CONCLUSION: Because of the high rate of second primary tumors, protocols including chemoprophylaxis should be investigated. Prevention and early detection are indicated.

DNA copy number changes at 8q11-24 in metastasized colorectal cancer.

BACKGROUND: C-Myc, a well-known oncogene located on 8q24.12-q24.23, is often amplified and over-expressed in both primary and metastasizing colorectal cancer. In addition, PRL-3 (also known as PTP4A3), a tyrosine phosphatase located on 8q24.3, is amplified in colorectal cancer metastasis. Beside PRL-3 and c-myc, other oncogenes located on the 8q23-24 region might be involved in this process. Therefore, the present study aims to correlate DNA copy number status of a series of genes at 8q23-24 in colorectal cancer at high resolution in correlation to metastatic disease. MATERIALS AND METHODS: Thirty-two cases of colorectal cancer, 10 stage B1, 10 B2 and 12 D (Astler-Coller) with their corresponding liver metastasis and one colorectal cell line (colo205, previously analyzed by array-CGH), were included in this study. A chromosome 8 specific MLPA probe mixture was used to analyze the presence of DNA copy number changes. The probe mixture contained 29 probes covering 25 genes on chromosome 8, as well as 6 control probes on other chromosomes. RESULTS AND DISCUSSION: MLPA results obtained of the colo205 colorectal cell line were comparable with previous array-CGH results, thus validating the MLPA probe mixture. Astler-Coller B1 and B2 colorectal cancers differed significantly in DNA copy number of the genes, MOS (p=0.04), MYC (p=0.007), DDEF1 (p=0.004), PTK2 (p=0.02) and PTP4A3 (p=0.04). When comparing these with Astler-Coller D primary tumors, significant differences were seen for several genes as well (MYC (p<0.000), DDEF1 (p<0.000), SLA (p<0.000), PTK2 (p<0.000), PTP4A3 (p=0.002), and RECQL4 (p=0.01)). When comparing primary Astler-Coller D tumors and their corresponding liver metastases, a similar pattern of gains and losses was observed. Most of the liver metastases showed higher DNA copy number ratios than the corresponding primary tumors, but this difference was only significant for TPD52 (p=0.02) and EIF3S6 (p=0.007). CONCLUSION: In addition to c-myc, multiple genes on chromosome 8 differed significantly between primary colorectal cancers with and without liver metastases. This observation is consistent with the concept that clinical behaviour, like risk of liver metastasis, is determined by the genomic profile that is already present in the primary tumor.

Auricular acupuncture for pain relief after total hip arthroplasty - a randomized controlled study.

Auricular acupuncture (AA) is known to be effective in treatment of various pain conditions, but still there have been no randomized controlled studies of AA for treatment of acute postoperative pain. Therefore we tested whether AA of specific points is superior to sham acupuncture for complementary analgesia after total hip arthroplasty in a patient-anesthesiologist-evaluator-analyst blinded study. The patients were randomly allocated to receive true AA (lung, shenmen, thalamus and hip points) or sham procedure (4 non-acupuncture points on the auricular helix). Permanent press AA needles were retained in situ 3 days after surgery. Postoperative pain was treated with intravenous piritramide (opioid receptor agonist with analgesic potency of 0.7 compared with morphine) using a patient-controlled analgesia (PCA) pump. The time to the first analgesic request, the amount of postoperative piritramide via PCA and pain intensity on a 100-mm visual analogue scale (VAS-100) were used to evaluate postoperative analgesia. Intraoperative anesthetic requirement, incidence of analgesia-related side effects, inflammation parameters and success of patients' blinding were also recorded. Fifty-four patients (29 AA and 25 controls) completed the study. Piritramide requirement during 36 h after surgery in AA group was lower than in control: 37+/-18 vs. 54+/-21 mg; mean+/-SD; P=0.004. Pain intensity on VAS-100 and incidence of analgesia-related side effects were similar in both groups. The differences between the groups as regard patients' opinions concerning success of blinding were not significant. Findings from our study demonstrate that AA could be used to reduce postoperative analgesic requirement.

Chromosomal instability in flat adenomas and carcinomas of the colon.

Flat adenomas are flat or slightly elevated dysplastic lesions of the colorectal mucosa, mostly with a tubular architecture. Compared with polypoid adenomas of similar size, flat adenomas show a higher frequency of high-grade dysplasia and rapid submucosal invasion. The aim of this study was to survey whether flat colorectal lesions differ in their pattern of chromosomal aberrations from their polypoid counterparts. Six flat adenomas and 12 flat carcinomas were analysed by comparative genomic hybridization (CGH) and the pattern of chromosomal aberrations was compared with a previously published series of 112 polypoid adenomas and 82 polypoid carcinomas. In addition, multiplex ligation-dependent probe amplification (MLPA) for identifying DNA copy number changes of 25 individual genes on chromosome 20 was performed on 14 flat and 15 polypoid tumours. With CGH, flat adenomas showed on average 1.8 gains (range 1-4) and 3.2 losses (range 0-4), and the flat carcinomas 4.5 gains (range 0-8) and 3.5 losses (range 1-6). In both adenomas and carcinomas, high frequencies of 20q gain (83% and 92%, respectively) and 18q loss (83% and 92%, respectively) were found. This correlation between 20q gain and 18q loss had previously been observed in a subgroup of polypoid colorectal tumours. Both flat and polypoid colorectal tumours with 20q gains by CGH showed similar patterns of copy number ratios for the individual genes tested. TOP1, BCL2L1, and E2F1 had median copy number ratios of 2 or higher, while ZNF217 had a ratio around 3. In conclusion, flat adenomas and carcinomas of the large intestine show a similar pattern of chromosomal aberrations to that observed in a specific subgroup of polypoid lesions. The transcription factor ZNF217 is an important candidate for driving the 20q gain.

Genomics and proteomics in cancer.

Cancer development is driven by the accumulation of DNA changes in the approximately 40000 chromosomal genes. In solid tumours, chromosomal numerical/structural aberrations are common. DNA repair defects may lead to genome-wide genetic instability, which can drive further cancer progression. The genes code the actual players in the cellular processes, the 100000-10 million proteins, which in (pre)malignant cells can also be altered in a variety of ways. Over the past decade, our knowledge of the human genome and Genomics (the study of the human genome) in (pre)malignancies has increased enormously and Proteomics (the analysis of the protein complement of the genome) has taken off as well. Both will play an increasingly important role. In this article, a short description of the essential molecular biological cell processes is given. Important genomic and proteomic research methods are described and illustrated. Applications are still limited, but the evidence so far is exciting. Will genomics replace classical diagnostic or prognostic procedures? In breast cancers, the gene expression array is stronger than classical criteria, but in endometrial hyperplasia, quantitative morphological features are more cost-effective than genetic testing. It is still too early to make strong statements, the more so because it is expected that genomics and proteomics will expand rapidly. However, it is likely that they will take a central place in the understanding, diagnosis, monitoring and treatment of (pre)cancers of many different sites.

Comparative genomic hybridisation divides retinoblastomas into a high and a low level chromosomal instability group.

BACKGROUND: Retinoblastoma is the most common intraocular malignancy in childhood and is responsible for approximately 1% of all deaths caused by childhood cancer. AIMS/METHODS: Comparative genomic hybridisation was performed on 13 consecutive, histologically confirmed retinoblastomas to analyse patterns of chromosomal changes and correlate these to clinicopathological variables. Six cases were hereditary and seven cases were sporadic. RESULTS: In 11 of the 13 tumours chromosomal abnormalities were detected, most frequently gains. Frequent chromosomal gains concerned 6p (46%), 1q (38%), 2p, 9q (30%), 5p, 7q, 10q, 17q, and 20q (23%). Frequent losses occurred at Xq (46%), 13q14, 16q, and 4q (23%). High level copy number gains were found at 5p15 and 6p11-12. A loss at 13q14 occurred in three cases only. Relatively few events occurred in the hereditary cases (27) compared with the non-hereditary cases (70 events). The number of chromosomal aberrations in these 13 retinoblastomas showed a bimodal distribution. Seven tumours showed less than four chromosomal aberrations, falling into a low level chromosomal instability (CIN) group, and six tumours showed at least eight aberrations, falling into a high level CIN group. In the low level CIN group the mean age was half that seen in the high level CIN group, there were less male patients, and there were more hereditary and bilateral cases. Microsatellite instability was not detected in either of the two groups. CONCLUSION: Despite the complex pattern of genetic changes in retinoblastomas, certain chromosomal regions appear to be affected preferentially. On the basis of the number of genetic events, retinoblastomas can be divided in low and a high level chromosomal instability groups, which have striking differences in clinical presentation.

[Co-maintenance with propofol and midazolam: sympathoadrenergic reactions, hemodynamic effects, stress response, EEG and recovery]. / Die "Co-Maintenance" mit Propofol und Midazolam: Sympatho-adrenerge Reaktionen, Kreislaufeffekte, Stressreaktion, EEG und Aufwachverhalten.

OBJECTIVE: The study was undertaken to investigate the influence of TIVA with propofol, midazolam and fentanyl (comaintenance, COM-group) or TIVA with propofol and fentanyl (control-group) on sympathoadrenergic and hemodynamic reactions, stress response, EEG and recovery. METHODS: After ethical approval, 2 x 20 patients of ASA-risk I - III over 55 years of age undergoing visceral surgery were investigated in a prospective randomized design. For induction of anesthesia, patients of the COM-group received 0,05 mg/kg BW midazolam und 1,0 mg/kg BW propofol, and anesthesia was maintained with 0,05 mg/kg BW/h midazolam (until 15 - 30 min before the end of the operation) together with propofol in decreasing doses of 10 - 5 - 2 mg/kg BW/h. In the control-group, 2,0 mg/kg BW propofol were used for induction followed by decreasing doses of 10 - 5 - 2 mg/kg BW/h as well. Premedication (0,1 mg/kg BW midazolam orally) and weight-dependent doses of fentanyl (2,5 microgram/kg BW for induction, 1,25 microgram/kg BW 2 min before skin incision, further repetition doses of 1,25 - 2,5 microgram/kg/BW as required) and vecuronium were equal in both groups. Beyond consumption of anesthetics and recovery, sympathoadrenergic, other endocrine and hemodynamic reactions and SEF 90 were investigated at 7 time points before induction and postoperative recovery. alpha 70 years) and duration of anesthesia and operation were comparable in both groups. Consumption of midazolam was higher in the COM-Group (14,8 vs. 7,5 mg; p = 0,004), whereas doses of fentanyl and vecuronium were comparable in both collectives. Recovery was significantly (p = 0,004) delayed in the COM-group: observing of simple orders 12,6 vs. 5,8 min, orientation with respect to person 19,8 vs. 9,9 min, local orientation 23,1 vs. 11,3 min. Mean arterial pressure in the COM-group was throughout lower than in the control-group, whereas heart rate was higher during the course of operation. Endocrine stress parameters (adrenaline, noradrenaline, antidiuretic hormone, adrenocorticotropic hormone, cortisol) and spectral edge frequency (SEF 90; Dräger-pEEG) were comparable in group level and time course between both groups. Plasma-concentrations of midazolam were significantly higher in the COM-group. CONCLUSION: In elderly patients undergoing visceral surgery in TIVA and when compared with propofol alone, no benefit of coinduction and comaintenance with midazolam and propofol could be demonstrated with respect to hemodynamic reactions and sympathoadrenergic and other endocrine stress response as well. Recovery was significantly delayed after administration of midazolam.

Clonally related but phenotypically divergent human cancer cell lines derived from a single follicular thyroid cancer recurrence (TT2609).

Starting from different regional samples taken from a heterogeneous follicular thyroid cancer recurrence in a male patient, a series of cell cultures was initiated. Three stable cancer cell lines were successfully established (TT2609-A02, TT2609-B02, and TT2609-C02) and kept in continuous culture for more than 3 years. The lines are each characterized by a unique set of biological parameters such as morphology, ploidy state, cell proliferation rate, ultrastructure, thyroid marker expression, p53 expression, karyogram, agar clonogenic capacity and tumorigenicity as xenografts in nude mice. These characterization studies point to a marked heterogeneity at the level of the clinical tumor recurrence. Karyotype analysis of the cell lines showed a pattern of aberrations indicating that the lines are clonally related and that the A02 and C02 lines are subsequently derived from the more "original" tumor cell type B02 after a tetraploidization event. It is concluded that the obtained cell lines represent an in vitro/in vivo model for human follicular thyroid cancer. The availability of a series of cell lines for human follicular thyroid cancer, mimicking the biological heterogeneity observed in patient tumors, enables both detailed fundamental investigation of thyroid cancer cell biology and the experimental exploration of new treatment approaches.

Comparative genomic hybridization of microdissected familial ovarian carcinoma: two deleted regions on chromosome 15q not previously identified in sporadic ovarian carcinoma.

The vast majority of familial ovarian cancers harbor a germline mutation in either the breast cancer gene BRCA1 or BRCA2 tumor suppressor genes. However, mutations of these genes in sporadic ovarian cancer are rare. This suggests that in contrast to hereditary disease, BRCA1 and BRCA2 are not commonly involved in sporadic ovarian cancer and may indicate that there are two distinct pathways for the development of ovarian cancer. To characterize further differences between hereditary and sporadic cancers, the comparative genomic hybridization technique was employed to analyze changes in copy number of genetic material in a panel of 36 microdissected hereditary ovarian cancers. Gains at 8q23-qter (18 of 36, 5 cases with high-level amplifications), 3q26.3-qter (18 of 36, 2 cases with high-level amplifications), 11q22 (11 of 36) and 2q31-32 (8 of 36) were most frequent. Losses most frequently occurred (in decreasing order of frequency) on 8p21-pter (23 of 36), 16q22-pter (19 of 36), 22q13 (19 of 36), 9q31-33 (16 of 36), 12q24 (16 of 36), 15q11-15 (16 of 36), 17p12-13 (14 of 36), Xp21-22 (14 of 36), 20q13 (13 of 36), 15q24-25 (12 of 36), and 18q21 (12 of 36). Comparison with the literature revealed that the majority of these genetic alterations are also common in sporadic ovarian cancer. Deletions of 15q11-15, 15q24-25, 8p21-ter, 22q13, 12q24 and gains at 11q22, 13q22, and 17q23-25, however, appear to be specific to hereditary ovarian cancer. Aberrations at 15q11-15 and 15q24-25 have not yet been described in familial ovarian cancer. In these regions, important tumor suppressor genes, including the hRAD51 gene, are located. These and other yet unknown suppressor genes may be involved in a specific carcinogenic pathway for familial ovarian cancer and may explain the distinct clinical presentation and behavior of familial ovarian cancer.