Claims for compensation after injuries related to airway management: a nationwide study covering 15 years.

BACKGROUND: Securing the airway is one of the most important responsibilities in anaesthesia. Injuries related to airway management can occur. Analysis from closed claims can help to identify patterns of injury, risk factors and areas for improvement. METHODS: All claims to The Norwegian System of Compensation to Patients from 1 January 2001 to 31 December 2015 within the medical specialty of anaesthesiology were studied. Data were extracted from this database for patients and coded by airway management procedures. RESULTS: Of 400 claims for injuries related to airway management, 359 were classified as 'non-severe' and 41 as 'severe'. Of the severe cases, 37% of injuries occurred during emergency procedures. Eighty-one claims resulted in compensation, and 319 were rejected. A total of €1,505,344 was paid to the claimants during the period. Claims of dental damage contributed to a numerically important, but financially modest, proportion of claims. More than half of the severe cases were caused by failed intubation or a misplaced endotracheal tube. CONCLUSION: Anaesthesia procedures are not without risk, and injuries can occur when securing the airway. The most common injury was dental trauma. Clear patterns of airway management that resulted in injuries are not apparent from our data, but 37% of severe cases were related to emergency procedures which suggest the need for additional vigilance. Guidelines for difficult intubation situations are well established, but adherence to such guidelines varies. Good planning of every general anaesthesia should involve consideration of possible airway problems and assessment of pre-existing poor dentition.

Ethnicity differences in breast cancer stage at the time of diagnosis in Norway.

BACKGROUND AND AIMS: Several studies have demonstrated that breast cancer survival rates differ with ethnicity. Most of these studies analyzed discrepancies between African-American and Caucasian-American women and were performed in the United States. There are increasing concerns about differences in breast cancer survival among immigrants from Asia and Africa living in Europe, including those living in Scandinavian countries. There are few data on breast cancer survival in relation to race or ethnicity in Scandinavian countries, even though immigrants from Asia and Africa have lived in Scandinavian countries for decades. The aim of this study was to identify variations in breast cancer incidence, treatment modalities, relapse, and survival among women from Pakistan, Sri Lanka, and Somalia compared to ethnic Norwegian women. MATERIAL AND METHODS: The incidence, treatment modalities, relapse, and survival of breast cancer were analyzed in women from Pakistan, Sri Lanka, and Somalia in a nation-based study over a period of 7 ears. Results for women from Pakistan, Sri Lanka, and Somalia were compared with those from a group of ethnic Norwegian women during the same period. In our study, 63 patients from Pakistan, Sri Lanka, and Somalia were diagnosed with breast cancer during the period 2002-2009 in Norway. RESULTS AND CONCLUSION: Comparison between women from Pakistan, Sri Lanka, and Somalia and ethnic women from Norway revealed significant differences in cancer stage at the time of diagnosis, age at diagnosis, type of surgical treatment, and relapse and breast cancer mortality rates. The findings of this study demonstrate that the outcome after a breast cancer diagnosis is significantly worse for women from Pakistan, Sri Lanka, and Somalia than for ethnic Norwegian women. In addition, the mean age at the breast cancer diagnosis was lower for women from Pakistan, Sri Lanka, and Somalia, especially those from Sri Lanka and Somalia, than for ethnic Norwegian women.

Short term results of complete (D3) vs. standard (D2) mesenteric excision in colon cancer shows improved outcome of complete mesenteric excision in patients with TNM stages I-II.

BACKGROUND: The aim of the present study was to investigate whether the new method of complete mesocolic excision (CME) with a high (apical) vascular tie (D3 resection) had an immediate effect compared with a conventional (standard) approach even in those patients without lymph node metastases. METHODS: A cohort of 189 consecutive patients with tumour-nodal-metastasis (TNM) stages I-II and a mean age of 73 years were operated on in the period from January 2007 to December 2008 in three community teaching hospitals. The CME approach (n = 89), used in hospital A, was compared to the standard technique used (n = 105) in two other hospitals, B and C. Lymph node yields from the specimens were used as a surrogate measure of radical resections. Outcome was analysed after a median follow-up of 50.2 months. RESULTS: In-hospital mortality rate was 2.8 % in the CME group and 8.6 % in the standard group. The 3-year overall survival (OS) in the CME group was 88.1 versus 79.0 % (p = 0.003) in the standard group, and the corresponding disease-free survival (DFS) was 82.1 versus 74.3 % (p = 0.026). Cancer-specific survival was 95.2 % in the CME group versus 90.5 % in the standard group (p = 0.067). Age, operative technique, and T category were significant in multiple Cox regressions of OS and DFS. CONCLUSIONS: Compared with the standard (D2) approach, introduction of CME surgical management of colon cancer resulted in a significant immediate improvement of 3-year survival for patients with TNM stage I-II tumours as assessed by OS and DFS.

Preoperative body size and composition, habitual diet, and post-operative complications in elective colorectal cancer patients in Norway.

BACKGROUND: Both malnutrition and obesity are related to worsened post-operative outcomes after colorectal surgery. Obese cancer patients may be malnourished as a result of short-term weight loss. The present study aimed to evaluate preoperative nutritional status, body composition and dietary intake related to post-operative complications (POC) and post-operative hospital days (POHD) in elective colorectal cancer (CRC) patients. METHODS: Anthropometry, body composition measured by bioelectric spectroscopy and dietary habits assessed by a validated food-frequency questionnaire were examined in 100 newly-diagnosed CRC patients. Data from 30-day POC and POHD were collected from medical records. Nonparametric and chi-squared tests and logistic regression were used to analyse associations between body and dietary variables and post-operative outcome. RESULTS: Twenty-nine patients had at least one POC. The median POHD was six. Body size and composition measures and short-term weight loss were no different between patients with and without POC, or between patients with POHD <7 and ≥7. Dietary variables were otherwise no different between patients with and without POC, although the median intake of marine n-3 polyunsaturated fatty acids (PUFA, the sum of eicosapentaenoic and docosahexaenoic acids) was significantly lower in patients with versus without POC (0.7 versus 1.2 g day(-1) , P = 0.04). CONCLUSIONS: We found that preoperative body size, body composition and short-term weight loss were not related to 30-day post-operative outcomes in CRC patients. A high content of marine n-3 PUFA in preoperative habitual diets may protect against POC after CRC surgery.

Disseminated tumour cells as a prognostic biomarker in colorectal cancer.

BACKGROUND: The study was performed to determine detection rate and prognostic relevance of disseminated tumour cells (DTC) in patients receiving curatively intended surgery for colorectal cancer (CRC). METHODS: The study population consisted of 235 patients with CRC prospectively recruited from five hospitals in the Oslo region. Bone marrow (BM) aspirates were collected at the time of surgery and the presence of DTC was determined by two immunological methods; immunomagnetic selection (using an anti-EpCAM antibody) and immunocytochemistry (using a pan-cytokeratin antibody). Associations between the presence of DTC and metastasis-free, disease-specific and overall survival were analysed using univariate and multivariate methods. RESULTS: Disseminated tumour cells were detected in 41 (17%) and 28 (12%) of the 235 examined BM samples by immunomagnetic selection and immunocytochemistry, respectively, with only five samples being positive with both methods. The presence of DTC was associated with adverse outcome (metastasis-free, disease-specific and overall survival) in univariate and multivariate analyses. CONCLUSION: The presence of DTC was associated with adverse prognosis in this cohort of patients curatively resected for CRC, suggesting that DTC detection still holds promise as a biomarker in CRC.

The prognostic value and overexpression of cyclin A is correlated with gene amplification of both cyclin A and cyclin E in breast cancer patient.

UNLABELLED: Deregulation of cell cycle control is a hallmark of cancer. The primary cyclins (A, B1, D1, D3 and E) are crucial for cell cycle progression. Secondary cyclins (C and H) have putative indirect effects on cell cycle propulsion and are not previously evaluated in breast cancer. We have examined protein expression and gene amplification of cyclins in breast carcinomas and correlated the findings with clinical follow-up data. We have previously demonstrated that over-expression of cyclin A is associated with poor prognosis in breast cancer patients. In this study we wanted to evaluate the mechanisms behind overexpression of cyclin A, as well as the impact of other cyclins, both at the gene level and at the protein level, on prognosis of breast cancer patients. The impact of TP53 gene mutations on gene amplification of cyclins was also evaluated. METHODS: Real-Time Quantitative PCR was used to detect gene amplification of cyclins in tumour tissue from 86 patients operated for invasive breast carcinomas, while immunohistochemistry was applied to detect protein expression of the same cyclins. RESULT: Of the 80-breast tumour samples available for cyclin A gene amplification analyses, 26.7% (23/80) was defined to have cyclin A gene amplification. 37.2% (32/79) had cyclin B1 gene amplification, 82.6% (71/82) of the samples harboured amplification of cyclin C gene, 74.4% (64/82) had cyclin D1 gene amplification, 41.9% (36/86) had cyclin D3 gene amplification, 29.1% (25/81) of the patients had cyclin E gene amplification and 9.3% (8/86) of the samples showed amplification of the cyclin H gene. When correlation between gene amplification and protein expression was evaluated, we observed a statistical significant correlation between gene amplification and protein expression of cyclin A (p=0.009) and cyclin D3 (p<0.001). However, the correlation between gene amplification and protein expression of cyclin A, as well as the prognostic value of cyclin A overexpression, was affected by gene amplification of cyclin E. Gene amplification of none of the other cyclins was associated with patient prognosis. There was a statistical significant correlation between TP53 gene mutations and gene amplification of cyclins A, D3 and B1. No correlation was observed between gene amplification of secondary cyclins (H and C) and TP53 gene mutations. CONCLUSIONS: The overexpression of cyclin A is correlated to gene amplification of both cyclin A and cyclin E. Over-expression of cyclin A is associated with poor prognosis in breast cancer patients. When analysed in a multivariate analyses model, gene amplification as well as protein expression of none of the other cyclins than cyclin A are associated with patient prognosis in breast carcinomas. TP53 gene mutation seems to correlate with gene amplification of primary, but not secondary cyclins.

Expression and gene amplification of primary (A, B1, D1, D3, and E) and secondary (C and H) cyclins in colon adenocarcinomas and correlation with patient outcome.

BACKGROUND/AIMS: Deregulation of cell cycle control is a hallmark of cancer. The primary cyclins (A, B1, D1, D3, and E) are crucial for cell cycle progression. Secondary cyclins (C and H) have putative indirect effects on cell cycle progression and have not previously been evaluated in colon cancer. This study examined cyclin protein expression and gene amplification in colon adenocarcinoma and the correlation with patient outcome. METHODS: Immunohistochemistry and real time quantitative polymerase chain reaction were used to determine cyclin expression and gene amplification in 219 tumours. The results were compared with clinical variables and patient outcomes. RESULTS: Cyclin H was overexpressed in all tumours, cyclin C in 88%, cyclin B1 in 58%, cyclin A in 83%, cyclin D3 in 36%, cyclin E in 25%, and cyclin D1 in 11% of the tumours. Extra gene copies of cyclin A were seen in 6.2% of the tumours, cyclin B1 in 9%, cyclin C in 26.9%, cyclin D1 in 55%, cyclin D3 in 20.5%, cyclin E in 19.1%, and cyclin H in 5.1%. A significant correlation between protein overexpression and gene amplification was seen for cyclin C only. High expression of cyclin A was independently associated with improved survival. Amplification of cyclin C was independently associated with an unfavourable prognosis. CONCLUSIONS: Amplification of the cyclin C gene was related to an unfavourable prognosis and high protein expression of cyclin A was associated with a better outcome in colon adenocarcinoma.

Presence of isolated tumour cells in mesenteric lymph nodes predicts poor prognosis in patients with stage II colon cancer.

AIM: Most patients with stage I and stage II colon adenocarcinomas do not have disseminated disease, and the group is not offered adjuvant therapy. However, more than 30% of stage II colon adenocarcinoma patients get metastases to remote organs. Thus, it is important to identify patients in this group at risk of disease relapse. PATIENTS AND METHODS: We have examined the prognostic value of isolated tumour cells (ITC) in mesenteric lymph nodes in a consecutive series of 156 colon carcinoma patients with stage II disease. Immunohistochemistry, using antibodies to cytokeratins, and morphology were used to identify presence of ITC. RESULTS: ITC were detected in 59 (37.8%) patients. Presence of ITC in mesenteric lymph nodes was independently associated with reduced relative survival both in univariate (p=0.0199) and in a multivariate analysis (p=0.041). CONCLUSION: The results strongly suggest that presence of ITC in mesenteric lymph nodes is associated with reduced relative survival in colon carcinoma patients stage II, and that detection of ITC may be important in treatment of these patients.

Association between histology grade, expression of HsMCM2, and cyclin A in human invasive breast carcinomas.

AIM: Increased proliferation of tumour cells has prognostic value in human invasive breast carcinomas (IBCs), and high histology grade and cyclin A expression, which may reflect high proliferation rate, are associated with poor prognosis. Expression of HsMCM2 is related to cell proliferation. This study evaluates the correlation between the expression of cyclins A, D1, D3, and E, Ki-67, proliferating cell nuclear antigen (PCNA), histology grade, and HsMCM2 expression, in addition to the independent prognostic value of HsMCM2 expression in human IBCs. METHODS: Immunohistochemistry to evaluate HsMCM2, Ki-67, and PCNA expression in tumours from 147 patients with IBC. RESULTS: Nuclear staining for HsMCM2 was seen in 10-30% of the tumour cells in 30 samples, in 30-70% in 40 samples, in > 70% in 44 samples, and in < 10% in 33 samples. One way ANOVA showed a significant association between expression of HsMCM2 and cyclin A, D3, E, histology grade, and Ki-67. A borderline correlation was seen between HsMCM2 and PCNA. In multivariate analysis, the only association was with cyclin A, in addition to a borderline association with histology grade. In a Cox regression hazards model, expression of HsMCM2 was associated with poor patient survival, although it lost its independent prognostic value when cyclin A expression was included. Ki-67 and PCNA expression were not associated with patient survival. CONCLUSION: Cyclin A expression is independently associated with HsMCM2 expression, histology grade, and Ki-67. HsMCM2 expression is associated with poor patient survival, although it loses prognostic value when adjusted for cyclin A.

Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer.

The functional role and specificity of tumor infiltrating lymphocytes (TIL) is generally not well characterized. Prominent lymphocyte infiltration is the hallmark of the most common form of hereditary colon cancer, hereditary nonpolyposis colon cancer (HNPCC) and the corresponding spontaneous colon cancers with the microsatellite instability (MSI) phenotype. These cancers are caused by inherited or acquired defects in the DNA mismatch-repair machinery. The molecular mechanism behind the MSI phenotype provides a clue to understanding the lymphocyte reaction by allowing reliable prediction of potential T cell epitopes created by frameshift mutations in candidate genes carrying nucleotide repeat sequences, such as TGF beta RII and BAX. These tumors therefore represent an interesting human system for studying TIL and characterizing tumor-specific T cells. We here describe T cell reactivity against several T helper cell epitopes, representing a common frameshift mutation in TGF beta RII, in TIL and peripheral blood lymphocytes from patients with MSI(+) tumors. The peptide SLVRLSSCVPVALMSAMTTSSSQ was recognized by T cells from two of three patients with spontaneous MSI(+) colon cancers and from all three patients with HNPCC. Because such mutations are present in 90% of cancers within this patient group, these newly characterized epitopes provide attractive targets for cancer vaccines, including a prophylactic vaccine for individuals carrying a genetic disposition for developing HNPCC.

Over-expression of cyclin A is highly associated with early relapse and reduced survival in patients with primary breast carcinomas.

Progression through the mammalian cell cycle is facilitated by cyclin-cyclin-dependent kinase (cdk) complexes, which are activated at specific points during the cell cycle. Alteration in cyclin-cdk complexess may lead to altered cell cycle and tumorigenesis. In this study, we analyzed expression of cyclins A, D1, D3 and E in tumor tissue from 170 patients with primary invasive breast carcinomas. Immunohistochemical methods were used to detect protein expression of these cyclins. We detected positive immunoreactivity in 55 (32%), 22 (13%), 38 (22%) and 37 (21.8%) of the samples for cyclins A, D1, D3 and E, respectively. A highly statistically significant association was observed between expression of cyclin A and early relapse (p = 0.001 univariate analysis, p = 0.006 multivariate analysis) as well as cancer-specific death (p < 0.0001) during the follow-up time. No association was observed between cyclin D1 or cyclin E, respectively, and relapse of disease or survival, while cyclin D3 over-expression was associated with development of metastases during follow-up (p = 0.005 univariate analysis, p = 0.01 multivariate analysis). However, cyclin D3 did not show any statistically significant association when cancer-specific death was examined in a multivariate analysis (Cox regression for survival function).

Protein expression of p53, p21 (WAF1/CIP1), bcl-2, Bax, cyclin D1 and pRb in human colon carcinomas.

Tumour growth is regulated by a balance between proliferation, growth arrest and programmed cell death (apoptosis). Until recently, the majority of the studies dealing with oncogenesis has been focused on the regulation of cell proliferation. There is now growing understanding that control of growth arrest and apoptosis play key roles in the development of human cancer and in cancer treatment. Some of the more heavily studied proteins of importance for the control of growth arrest and apoptosis are p53, p21, bcl-2 and bax. Alterations in the p53 protein may lead to malignant transformation and defect therapy response, most likely as a result of defective p53-dependent apoptosis. In addition, p21 (WAF1/CIP1) is involved in cell-cycle arrest and probably in induction of p53-dependent apoptosis. Proteins belonging to the bcl-2 family are also important for normal apoptosis. Overexpression of bcl-2 protein is thought to reduce the apoptotic capacity, while bax protein seems to be necessary for induction of apoptosis. In this study, we have immunostained tissues from 93 primary colon carcinomas and have examined the expression of p53, p21 (WAF1/CIP1), bcl-2 bax, pRb and cyclin D1 for evaluation of their roles in colon-cancer progression. A highly significant association between p53 accumulation and downregulation of p21 (WAF1/CIP1) was seen. We also found a strong association between reduced/absent p21 and the development of metastases and death due to cancer disease. Cyclin D1, bcl-2 and bax protein failed to have independent prognostic impacts. Bcl-2 and bax protein levels showed an inverse relationship. The results of the present study indicate that reduced p21 protein levels play an important role in progression of colon cancer. We concluded that evaluation of p21 expression in primary colon carcinomas at the time of surgery might be a valuable tool in defining patients with a high risk of developing metastases.

Re-expression of E-cadherin, alpha-catenin and beta-catenin, but not of gamma-catenin, in metastatic tissue from breast cancer patients [seecomments].

Tumour cell invasion and metastasis are the processes which kill most cancer patients. Tumour cells with the greatest invasive and metastatic capacity may be those with the highest number of genetic aberrations. The present study has analysed the expression of several tumour-related proteins in both primary tumours and metastatic lesions from 34 breast cancer patients. Protein expression of p53, bcl-2, p21, cyclin D1, E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin was investigated by immunohistochemistry (IHC) using monoclonal antibodies. Metastatic tissue showed a different expression profile from the primary tumour in most patients. The most significant finding was the re-expression of E-cadherin, alpha-catenin, and beta-catenin, and increased down-regulation of gamma-catenin, in metastatic lesions. These results demonstrate that tumour cells, when released from the primary site and after regrowth elsewhere, are capable of re-expression of adhesion molecules. gamma-catenin may play a different role in metastatic lesions than in primary tumours, since it is selectively down-regulated in tumour tissue at the metastatic site.

E-cadherin and alpha-, beta-, and gamma-catenin protein expression in relation to metastasis in human breast carcinoma.

In the metastatic process, various cell-cell adhesion molecules seem to play an important role. E-cadherin, a transmembrane protein with an extracellular and an intracellular domain, is one of the key players involved in cell-cell adhesion. The function of E-cadherin in preventing metastasis in tumour development is believed to be dependent on intracellular catenins. In a previous study, the expression of E-cadherin was examined in a series of human breast carcinomas. In that study, down-regulation of E-cadherin failed to correlate with lymph node and/or distant metastasis. In the present study, the expression of alpha-, beta-, and gamma-catenins has been examined in a subset of the same tumours in order to evaluate their possible role in breast cancer metastasis. Tumour tissues from 90 primary breast carcinomas were immunostained for alpha-, beta-, and gamma-catenins. Reduced or absent immunoreactivity in the tumour tissue was seen in 63 (70.0 per cent) for alpha-catenin, in 50 (55.6 per cent) for beta-catenin, and in 50 (55.6 per cent) for gamma-catenin. Reduced expression of each of the catenins alone failed to correlate to metastasis. However, when all of the four proteins (E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin) were analysed as one group, a significant association was seen between reduction in immunoreactivity of at least one of these four proteins and the presence of metastases. These results indicate that if one of these proteins is down-regulated, the function of the others in suppressing metastasis is altered. A significant association was seen between lobular invasive tumours and beta-catenin expression.

Expression of cyclin Ds in relation to p53 status in human breast carcinomas.

Cyclin D1 has been reported to be overexpressed in many tumours, including breast carcinomas. Cyclin D1 was first identified as a protooncogene (BCL1/PRAD1), and its overexpression was related to tumour proliferation. The product has also recently been identified as important in mediating cell cycle growth arrest via the p53 pathway in murin fibroblast cell lines. Ninety breast carcinomas previously analysed for p53 status were analysed for amplification of cyclin D1, D2 and D3 genes by Southern blot analysis and for protein expression by immunhistochemistry. In 10 samples gene amplification was detected at the cyclin D1 locus. No gene amplification was detected at the cyclin D2 and D3 loci. Immunoreactivity for cyclin D1 was detected in 38 (42.2%) tumour tissue samples. Fifty samples were immunostained for cyclin D2 and D3. Only 2 samples (4%) showed immunoreactivty for cyclin D2, and 9 samples (18%) for cyclin D3. Cyclin D1 protein overexpression was significantly more often found in tumours with wild type p53 and in tumours with higher grades of differentiation expressing ER. No association was seen between gene amplification of the cyclin D1 gene and p53 status. We conclude there is a relationship between wild type p53 and cyclin D1 protein overexpression in clinical material, indicating that cyclin D1 may be another downstream effector of p53.

Mutation screening of BRCA1 using PTT and LOH analysis at 17q21 in breast carcinomas from familial and non-familial cases.

Germline mutations in the BRCA1 gene predispose to breast and ovarian cancer. An estimated 45% of families with multiple breast cancer cases and more than 80% of breast-ovarian cancer families are linked to BRCA1. Mutation analyses by collaborative laboratories have revealed around 460 distinct BRCA1 sequence alterations, mostly germline mutations from familial cases. The majority of these alterations were nonsense and frame-shift mutations. In the present study, breast tumors of both sporadic and familial origin were investigated for allelic imbalance (AI) at the BRCA1 locus. AI was observed in 52% of the sporadic cases and in 17% of the familial cases. Furthermore, 104 breast carcinomas from patients with sporadic disease and 77 patients with positive family histories of breast and/or ovarian cancer were examined for translation-terminating mutations in exon 11 of the BRCA1 gene using the protein truncation test (PTT). No somatic mutations were detected in any of the tumors analysed, and only one BRCA1 mutation carrier was found among the familial cases. The result of this study gives no indication that truncating somatic mutations in exon 11 of BRCA1 play a major role in the tumorigenesis of the breast. Furthermore, the frequency of such mutation carriers in breast cancer populations with weak family histories of breast and/or ovarian cancer seems to be low.

Truncating somatic mutation in exon 15 of the APC gene is a rare event in human breast carcinomas. Mutations in brief no. 179. Online.

Inactivation of the adenomatous polyposis coli (APC) gene is an early event in sporadic colorectal cancer. Somatic mutations have also been detected in cancers of the stomach, pancreas, thyroid, ovary and breast. Over 95% of the mutations reported in the APC gene are frameshift and nonsense mutations. The large exon 15 accounts for 77% of the coding sequence. The APC gene product interacts with cytoplasmic beta-catenin, mediates its degradation and thereby downregulates transcription exerted by the beta-catenin-Tcf complex. In the absence of a functional APC protein, beta-catenin is stabilized and accumulates in the cytoplasm. This results in uncontrolled transcriptional activation of Tcf responsive genes which may contribute to cancer progression. In order to investigate whether this pathway is disrupted by APC mutations in breast carcinoma cells, we screened 227 breast tumors for truncating mutations in exon 15 using the protein truncation test (PTT). Only one mutation, 4678delA, which was shown to be somatic, was detected by this approach. The mutation resided just outside the mutation cluster region (MCR) and resulted in a premature stop in codon 1564. Our findings do not indicate that the suppressive function of APC is commonly abrogated by truncating mutations in human breast carcinomas.

Interaction between bcl-2 and p21 (WAF1/CIP1) in breast carcinomas with wild-type p53.

The bcl-2 protein is found to be over-expressed in many types of human tumours and is a potent inhibitor of apoptosis. The exact mechanism by which bcl-2 prevents apoptosis and exercises its oncogenic effect is still unclear. Other studies on cell lines have reported that bcl-2 over-expression is related to suppression of p21 (WAF1/CIP). We have investigated the relationship between bcl-2 protein over-expression and expression of the p21 protein in a series of human breast carcinomas. Selected tumour samples from 100 breast-cancer patients (38 with abnormal p53 status, scored as protein accumulation and/or mutation, and 62 without detectable p53 alterations), were immunostained for bcl-2 protein, the p21 protein and the oestrogen-receptor (ER) protein. A highly significant association was found between reduced p21-protein expression and over-expression of bcl-2 in tumours with no detectable p53 alterations (p < 0.001). A significant association was seen between ER immunoreactivity and expression of the bcl-2 protein, as well as between bcl-2 protein expression and tumours of the higher differentiation grade (grade-2 tumours). No association was seen between bcl-2 over-expression and the presence of metastases. Our findings indicate that down-regulation of p21 may be a result of up-regulation of bcl-2 independent of p53.

Loss of heterozygosity at 11q23.1 in breast carcinomas: indication for involvement of a gene distal and close to ATM.

Previous reports have suggested that heterozygotes for ataxia-telangiectasia (A-T) have an increased risk of cancer, in particular breast cancer. The ATM gene, responsible for A-T, was recently cloned. Loss of heterozygosity (LOH) in the chromosome band 11q23, where the ATM gene is located, has been reported in several types of tumours including breast carcinomas. Whether the ATM gene is the target, and the sole target, for the LOH seen in this region is not yet known. In this study, 169 primary breast carcinomas and 10 metastases were examined for allelic imbalance (AI) using 10 microsatellite markers mapping to 11q23.1. Nine of the markers reside within a 10 Mb region surrounding the ATM gene, whereas the tenth locus, APOC-3, is located more than 12 Mb telomeric from this region. The highest frequencies of alteration were found for APOC-3 (45%), and for two markers located approximately 200 and 900 kb telomeric from ATM, D11S1294 (44%) and D11S1818 (44%). The marker located within the ATM gene, D11S2179, was altered in 37% of the informative tumours. The present deletion map indicates that three distinct regions at 11q23.1 may be involved in breast cancer development; one between the markers D11S1294 and D11S1818, a second close to APOC-3, and a third that is possibly the ATM-gene itself.