Biomedical subjects

M Loda

Publications and source records attributed to M Loda.

At least 55 records · Page 3Linked to original sources

PubMed1999

p27 expression in inflammatory bowel disease-associated neoplasia. Further evidence of a unique molecular pathogenesis.

The cyclin-dependent kinase inhibitor p27 is a negative regulator of the transition from G1 to S phase of the cell cycle, protects against inflammatory injury and promotes epithelial differentiation. Because p27 protein has been shown to be abnormally expressed both in dysplasia associated with Barrett's esophagus and in sporadic colorectal adenomas, we used immunohistochemistry to evaluate p27 expression in inflammatory bowel disease (IBD)-associated dysplasia and carcinomas. Normal, inflamed, and transitional mucosa, sporadic adenomas, and sporadic colonic carcinomas were studied as controls. In normal colonic epithelium p27 expression was restricted to the superficial, terminally differentiated cells. In colitic and inflamed diverticular mucosa p27 was expressed in the base of the crypts in 86 and 70% of cases, respectively. Similarly, in transitional mucosa adjacent to sporadic carcinomas p27 was expressed in the base of the crypts in all cases. Strong p27 expression extended more frequently from the base of the crypts to superficial cells in IBD-associated dysplasia than in sporadic adenomas (P < 0.007). Twenty of 20 (100%) IBD-associated carcinomas showed low p27 expression (<50% nuclei positive) compared to 6 of 20 (30%) stage-matched sporadic colorectal carcinomas (P < 0.001). We conclude (i) aberrant p27 protein expression in inflamed and IBD-associated nondysplastic mucosa is indistinguishable from that found in transitional mucosa adjacent to sporadic carcinomas; (ii) p27 is overexpressed in dysplastic lesions, perhaps as an attempt to counterbalance proliferative stimuli; and (iii) IBD-associated colorectal carcinomas have significantly lower p27 expression, commonly associated with poor prognosis, than stage-matched sporadic colorectal carcinomas. These findings further substantiate the existence of divergent molecular pathogenetic pathways between these types of carcinomas and suggest an intrinsically more aggressive behavior of IBD-associated colon carcinomas compared to sporadic ones.

Cell Cycle↗

PubMed1999

Detection of concurrent/recurrent non-Hodgkin's lymphoma in effusions by PCR.

A subset of patients with non-Hodgkin's lymphoma (NHL), present with or subsequently develop lymphocytic effusions. Differential diagnosis between reactive lymphocytosis and recurrent low-grade NHL is difficult by cytology alone. We studied the use of polymerase chain reaction (PCR)-based techniques to detect concurrent/recurrent NHL. Both primary tumors and atypical lymphocytic effusions of 12 low-grade B-NHL patients and 4 T-NHL patients were studied. Six pleural effusions (reactive/carcinomatous), in patients with no history of NHL, were included. Samples were amplified by PCR, using Fr3, Fr2, LJH, and VLJH primers specific for the immunoglobulin heavy chain (IgH) gene and Vgamma-8, Vgamma9, Vgamma10, Vgamma11 and Jgamma1/Jgamma2 consensus primers specific for the T-cell receptor gamma (TCR-gamma) gene. IgH gene PCR products were analyzed by polyacrylamide gel electrophoresis (PAGE). TCR-gamma gene PCR products were analyzed using a novel nonradioactive single-strand conformational polymorphism (SSCP) procedure. IgH gene rearrangement analysis demonstrated monoclonality in 11/12 primary low-grade B-NHLs. Identical monoclonal bands were found in both primary tumor and effusion in 9 patients. TCR-gamma gene rearrangement analysis demonstrated monoclonality in 4 of 4 primary T-NHLs. Identical monoclonal banded patterns were found in both primary tumor and effusion in 3 patients. Our results strongly support the diagnosis of concurrent/recurrent NHL in 13 of 16 (81%) cases of atypical lymphocytic effusions. IgH/PAGE and TCR-gamma/SSCP analyses are useful tools in the diagnoses of lymphocytic effusions in patients with NHL.

Diagnosis, Differential↗

PubMed1999

Nodular lymphoid lesion of the liver: an immune-mediated disorder mimicking low-grade malignant lymphoma.

Three cases of unusual lymphoid infiltrate forming nodular macroscopic masses in the liver were studied in the authors' surgical pathology laboratory. These lesions posed difficulty in diagnosis, and their differentiation from low-grade lymphoma was not possible on histopathologic evaluation alone. The liver masses were analyzed histologically and immunohistochemically as well as for clonal immunoglobulin heavy chain (IgH) and T-cell receptor gamma (TCR-gamma) gene rearrangements. The lesions were seen as solitary grossly distinct firm nodules in all three patients, measuring 0.4, 0.7, and 1.5 cm, respectively, in their greatest dimensions. Two were found in livers removed because of end-stage primary biliary cirrhosis at the time of orthotopic liver transplantation, and the third was an incidental finding during laparotomy. Microscopically, these were nodules composed of small lymphocytes, plasma cells, and immunoblasts, with varying degrees of admixed acute inflammatory cells and scattered lymphoid follicles. By immunohistochemistry and molecular studies, these were found to be reactive lymphoid proliferations. All patients are alive and well at 2, 4, and 13 years, respectively. It is concluded that these cases represent a unique type of nodular lymphoid lesion, which is probably an immune-mediated benign reactive hyperplasia. It constitutes an entity by itself and must be distinguished from low-grade lymphoma. For a definitive diagnosis, immunohistochemistry and molecular studies are required.

Diagnosis, Differential↗

PubMed1999

P53 and beta catenin expression in chronic ulcerative colitis--associated polypoid dysplasia and sporadic adenomas: an immunohistochemical study.

In patients with chronic ulcerative colitis (CUC), polypoid dysplastic lesions (PDLs) are morphologically similar to sporadic adenomas (SAs), but may be biologically distinct from them and are managed differently. p53 mutations have been shown to occur at an earlier phase in the progression of CUC-associated neoplasia when compared with sporadic colon carcinogenesis. In contrast, APC gene mutations are common and occur at an earlier stage in the development of SA. beta catenin is a cell membrane protein that accumulates in the nucleus of colon cancer cells in response to APC gene mutations. This study was performed to test the hypothesis that CUC-associated PDLs have a different molecular profile than do CUC-associated SAs and therefore may be distinguished on this basis. Mucosal biopsy specimens of 38 benign polypoid epithelial neoplasms (17 CUC-associated PDLs and 21 CUC-associated SAs) from 33 patients with CUC and 13 SAs from patients without CUC (controls) were immunohistochemically stained for p53 and beta catenin and graded as follows: 0 = no staining, 1+ = <50% of cells positive, and 2+ = > or =50% of cells positive. The results were correlated with the clinical and histologic features and compared between the two CUC-associated polyp subgroups. Overall, six (16%) polyps were p53-positive, of which five were CUC-associated PDLs (one 1+ and four 2+) and one was a CUC-associated SA (1+) (p = 0.05). Strong (2+) p53 positivity was detected, however, in only CUC-associated PDLs (4 of 5; 80%). Nine of 32 polyps evaluated for beta catenin were positive and included 1 (8%) of 12 CUC-associated PDLs and 8 (40%) of 20 CUC-associated SAs (p = 0.06). Two of the nine beta catenin polyps were strongly positive, and both were CUC-associated SAs. Non-CUC-associated (control) SAs were positive for p53 and beta catenin in 2 (15%) of 13 and 6 (46%) of 13 cases, but none in a strong (2+) fashion. No differences were observed in p53 or beta catenin staining, between CUC-associated and non-CUC-associated SAs. Neither p53 nor beta catenin expression correlated with any clinical or pathologic features, including size and degree of dysplasia of the polyps. CUC-associated PDLs and CUC-associated SAs may have a different molecular genotype. In patients with CUC, the combination of strong p53 expression and absent or weak beta catenin expression is evidence in favor of a CUC-associated PDL in diagnostically difficult lesions. Furthermore, CUC-associated and non-CUC-associated SAs have a similar P53 and beta catenin immunophenotype and thus provide evidence that they are pathogenetically related neoplasms regardless of the presence or absence of colitis.

Adenoma↗

PubMed1999

Clonality of cutaneous B-cell infiltrates determined by microdissection and immunoglobulin gene rearrangement.

Diagnosis of primary cutaneous B-cell lymphoma (PCBCL) is supported by the demonstration of a monoclonal B-cell population. Immunoglobulin heavy chain (IgH) gene-rearrangement analysis by polymerase chain reaction (PCR) is a reliable technique to detect B-cell monoclonality in paraffin-embedded tissue, but the presence of numerous reactive B lymphocytes in PCBCL may complicate the interpretation of clonality test results. To test this hypothesis, IgH gene-rearrangement analysis by PCR was performed on paraffin-embedded whole tissue sections of 19 cutaneous B-cell infiltrates diagnosed either as consistent with PCBCL (10 specimens) or unclassified lymphoid infiltrates (ULI) (9 specimens). In specimens that did not show monoclonal bands by IgH gene-rearrangement on DNA extracted from whole tissue sections, clonality assays were repeated on microdissected B-cell subpopulations suspicious for neoplastic cells. In the analysis of whole tissue sections, 4 (40%) of 10 specimens consistent with PCBCL showed one or two monoclonal bands, whereas 9 of 9 ULI specimens showed either a ladder or a smear. Clonality analysis of microdissected B-cell subpopulations showed 3 additional PCBCL specimens (total, 7 of 10) and 1 ULI specimen (total, 1 of 9) with unequivocal and reproducible monoclonal bands. Addition of microdissection increases the sensitivity of PCR-based B-cell clonality assay in PCBCL compared with analysis performed on the whole section (70% versus 40% monoclonal cases) and allows the recognition of a dominant clone in ULI specimens, possibly representing early PCBCL.

B-Lymphocyte Subsets↗

PubMed1998

Identification of genes expressed differentially by LNCaP or PC-3 prostate cancer cell lines.

The transition from androgen-dependent to aggressive androgen-independent growth is an important development in prostate cancer, and the identification of genes expressed differentially between these two phenotypes could provide new therapeutic targets as well as prognostic markers. Using a subtractive approach designated linker capture subtraction, we have now isolated several genes expressed differentially between the human prostate carcinoma cell lines LNCaP and PC-3, which are androgen-dependent and androgen-independent, respectively. In addition to 10 known genes that may be involved in signal transduction, tumor growth, tumor invasion, and metastasis, 3 novel genes were isolated. One of these, designated NPG-1, was expressed by the majority of primary tumors examined. Moreover, the degree of NPG-1 expressed correlated with an aggressive histopathology.

Gene Expression↗

PubMed1998

Loss or altered subcellular localization of p27 in Barrett's associated adenocarcinoma.

The cyclin-dependent kinase inhibitor p27 is a negative regulator of the cell division cycle. It is expressed at the highest levels during the quiescent (G0) and prereplicative (G1) phases, and its degradation is required for entry into the S phase. Because lack of p27 is associated with aggressive behavior in a variety of tumors of epithelial and lymphoid origin, we used immunohistochemistry and in situ hybridization to evaluate the expression of p27 in metaplastic and dysplastic Barrett's epithelium and to assess its prognostic significance in Barrett's associated adenocarcinoma (BAA) of the esophagus. In metaplastic Barrett's epithelium, p27 protein and mRNA were restricted to the superficial third of glands in all cases and extended to the lower third in 4 cases. In contrast, expression of p27 message and protein was both increased and full-thickness, in the 23 cases with high-grade dysplasia adjacent to BAA and in carcinoma in situ. Although all invasive carcinomas had elevated levels of p27 mRNA, 45 (83%) of 54 invasive carcinomas had low p27 protein levels (<50% positive tumor cells). Low p27 protein correlated with higher histological grade (P < 0.0001), depth of invasion (P = 0.0120), presence of lymph node metastasis (P = 0.05), and survival (P = 0.0197). In addition to the nuclear staining, cytoplasmic staining of p27 was noted in 11 of 23 (48%) of cases of dysplasia and in 14 of 54 (26%) adenocarcinomas and confirmed, in a subset of cases, by subcellular fractionation of protein lysates obtained from fresh tumor tissues. Cytoplasmic localization of p27 was also associated with decreased survival (P = 0.0239). Loss of p27 conferred poor prognosis independently of proliferative index, as assessed by Ki-67 (MIB-1) immunostaining, which was not significantly different in survivors versus nonsurvivors. These results show that: (a) distribution of p27 message and protein parallel one another in metaplastic and dysplastic Barrett's epithelium, suggesting transcriptional regulation of the gene in the nonneoplastic setting; (b) p27 is inactivated in the majority of BAA as a result of either post-transcriptional modification or altered subcellular localization; and (c) loss of the cell cycle inhibitor p27 is associated with parameters of aggressive behavior and unfavorable outcome in BAA.

Adenocarcinoma↗

PubMed1998

Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer.

The identification of cell surface antigens is critical to the development of new diagnostic and therapeutic modalities for the management of prostate cancer. Prostate stem cell antigen (PSCA) is a prostate-specific gene with 30% homology to stem cell antigen 2, a member of the Thy-1/Ly-6 family of glycosylphosphatidylinositol (GPI)-anchored cell surface antigens. PSCA encodes a 123-aa protein with an amino-terminal signal sequence, a carboxyl-terminal GPI-anchoring sequence, and multiple N-glycosylation sites. PSCA mRNA expression is prostate-specific in normal male tissues and is highly up-regulated in both androgen-dependent and -independent prostate cancer xenografts. In situ mRNA analysis localizes PSCA expression in normal prostate to the basal cell epithelium, the putative stem cell compartment of the prostate. There is moderate to strong PSCA expression in 111 of 126 (88%) prostate cancer specimens examined by in situ analysis, including high-grade prostatic intraepithelial neoplasia and androgen-dependent and androgen-independent tumors. Flow cytometric analysis demonstrates that PSCA is expressed predominantly on the cell surface and is anchored by a GPI linkage. Fluorescent in situ hybridization analysis localizes the PSCA gene to chromosome 8q24.2, a region of allelic gain in more than 80% of prostate cancers. A mouse homologue with 70% amino acid identity and similar genomic organization to human PSCA has also been identified. These results support PSCA as a target for prostate cancer diagnosis and therapy.

Amino Acid Sequence↗

PubMed1998

Prognostic markers in rectal carcinoma.

Guidelines from two major organizations have recently supported the use of only the serological marker carcinoembryonic antigen (CEA) for the prognostication and monitoring of patients with colorectal carcinoma. However, in view of the exciting advances made recently in elucidating the molecular and cellular biology of adenocarcinoma of the rectum, the molecules that transform the well-ordered normal rectal epithelium into an invasive adenocarcinoma may yield information about the ultimate behavior of that cancer. Consequently, assessing the expression of molecules within a primary cancer may predict the probability of regional and distant metastasis, response to therapy, and outcome. This review analyzes the current state of intratumoral expression of several molecular markers for the management of rectal cancer and evaluates their potential for defining which patients may undergo rectal sphincter preservation and need adjuvant therapy.

Adenocarcinoma↗

PubMed1998

Mitogen-activated protein kinases and apoptosis in PIN.

Mitogen-activated protein (MAP) kinases are key elements of the signalling systems needed to transduce different extracellular messages into cellular responses. At least three parallel MAP kinase pathways have been identified: one, stimulated by serum and growth factors to activate extracellular signal-regulated protein kinases (ERKs) by dual tyrosine and threonine phosphorylation, triggers cell proliferation or differentiation; the other two, induced by a variety of cellular stresses to activate c-jun N-terminal kinases (JNKs) and reactivating kinase (p38/RK), result in growth arrest and induction of apoptosis. Mitogen-activated protein kinase phosphatases (MKPs) inactivate MAP kinases through dephosphorylation and, thus, can modulate the MAP kinase pathways. Expression of JNK-1, ERK-1, p38/RK and MKP-1 proteins was investigated by immunohistochemistry and expression of MKP-1 mRNA by in situ hybridisation in 50 cases of high-grade prostatic intraepithelial neoplasia (PIN), thought to represent the precursor of prostate cancer. The frequency of apoptotic cells was also determined in these cases. Overexpression of the three MAP kinases and MKP-1 mRNA was found in all cases of high-grade PIN compared with normal prostate. Immunoreactivity for MKP-1 protein was found to be as intense as in normal glands in 30% and weaker in 56% of the PIN cases. Fourteen per cent of PIN cases did not stain with MKP-1 antibody. The proportion of apoptosis was significantly higher (P < 0.008) in PIN lesions that did not express MKP-1 protein than in those that did. These results are consistent with our previous demonstration of preferential inhibition of the apoptosis-related kinases by MKP-1 and further support the contention that MKP-1, even in PIN, may shift the balance existing between cell proliferation and death. When expressed, it may inhibiting those pathways that lead to apoptosis.

Adenocarcinoma↗

PubMed1998

Down-regulation of p27 is associated with development of colorectal adenocarcinoma metastases.

The cyclin-dependent kinase inhibitor p27 is a negative regulator of the cell cycle and a potential tumor suppressor gene. Because we had previously demonstrated that loss of p27 protein is associated with aggressive behavior in colorectal adenocarcinomas, we used immunohistochemistry and in situ hybridization to evaluate the potential role of alterations in p27 expression in primary and metastatic colorectal adenocarcinomas. Parallel immunostaining was performed for Ki-67 and p53. We evaluated 13 cases of metachronous and 23 cases of synchronous primary and metastatic colorectal tumor pairs. In the synchronous subgroup (Stage IV tumors), 57% of the primary tumor and metastases pairs did not express p27 protein and the remainder were low expressors. In the metachronous subgroup, 54% of the primary tumors were low expressors and the remainder high expressors of p27 protein. There was a significant reduction in the expression of p27 in the metachronous metastases (mean positive cells: 14.5%) when compared to the corresponding primary tumors (mean positive cells: 41.8%), P = 0.0023. All the primary and metastatic tumors in the metachronous subgroup showed high levels of p27 mRNA expression. There was no association between loss of p27 and either Ki-67 count or p53 expression. Because p27 is known to be up-regulated when epithelial cells are grown in suspension, the down-regulation of p27 in circulating tumor cells may confer the ability to grow in an environment of altered extracellular matrix or intercellular adhesion properties, two situations which may facilitate metastases.

Adenocarcinoma↗

PubMed1998

Clinical and molecular prognostic factors in sphincter-preserving surgery for rectal cancer.

As many as a third of patients with rectal cancers may be candidates for sphincter preservation surgery. The goal of the conservative management of adenocarcinoma of the distal rectum is to preserve rectal sphincter function without sacrificing local tumor control. To achieve this goal, a combined modality approach is necessary because multimodality therapy for more advanced disease has improved both local control and survival. Candidates for local excision are those with adenocarcinomas with a maximal diameter of less than 4 cm, mobile, and not poorly differentiated or mucinous and within 10 cm of the anal verge--usually within 6 cm. These criteria should be defined objectively by biopsy combined with state-of-the-art endorectal imaging. Newer molecular markers that are associated with prognosis and response to therapy may also be important for assessing prognosis, probability of local recurrence, and whether conservative treatment is appropriate. Patients with T0-3 N0 lesions meeting these standard clinicopathologic criteria have been treated successfully with wide local excision combined with chemotherapy and radiotherapy. Patients with larger or more advanced lesions may undergo low anterior resection with coloanal anastomosis. After resection, radiotherapy to at least 45 to 50 Gy is delivered to the pelvis and tumor bed often with concomitant chemotherapy. The overall rate of local failure in prospective single-institution trials in which local excision is performed with postoperative chemoradiotherapy has been 5% for T1 lesions, 7% for T2 lesions and 24% for T3 lesions. Although single-institution studies have supported the concept of conservative therapy, the safety and efficacy of this approach must still be confirmed in a multicenter, prospective trial, such as that underway in several of the cooperative oncology groups, before it may be considered a standard of practice.

Adenocarcinoma↗

PubMed1998

Thymosin beta15 expression in tumor cell lines with varying metastatic potential.

We previously isolated thymosin beta15 from highly metastatic Dunning rat prostatic carcinoma cells. Immunohistochemical study of human prostate cancer specimens revealed a general correlation between Gleason grade and thymosin beta15 expression, with high-grade (more malignant) tumors showing increased staining compared to low-grade tumors. To determine whether thymosin beta15 may be differentially expressed in cancer cells with different metastatic potential other than in the prostatic carcinoma cells, we examined thymosin beta15 mRNA levels in tumor cell lines from different species. We also examined thymosin beta15 protein levels in human breast cancer samples. Thymosin beta15 was upregulated in the highly metastatic mouse lung and human breast cancer cell lines in comparison to the nonmetastatic counterparts. Immunohistochemical staining showed the evidence of upregulation of thymosin beta15 in malignant human breast carcinomas as compared to benign breast tumors. The expression of thymosin beta15 was correlated with the metastatic potential of the mouse lung carcinoma and human breast carcinoma cells in addition to the prostatic carcinomas. Thymosin beta15 may be a useful marker to predict metastatic potential of certain human cancers.

Animals↗

PubMed1998

Automated in situ hybridization: diagnostic and research applications.

Although in situ hybridization has been in use for almost 30 years, its technically demanding nature, the requirements for optimal tissue fixation and preservation, and the turnaround time for the experiments have prevented this technique from becoming widely used in the surgical pathology setting. The use of nonisotopic reporter molecules, the possibility of performing hybridization on archival material, and very recently, automation of the procedure have brought in situ hybridization to the forefront of diagnostic and experimental pathology. We describe our experience with nonradioactive, automated in situ hybridization, compare the technique with traditional manual procedures, and briefly outline its potential applications in diagnostic pathology and in the research setting.

Automation↗

PubMed1998

Low p27 expression predicts poor disease-free survival in patients with prostate cancer.

PURPOSE: p27 is an inhibitor of the cell cycle with potential tumor suppressor function. Decreased levels of p27 protein expression have been correlated with poor prognosis in patients with breast and colorectal carcinomas. Although as many as a third of patients with clinically localized prostate cancer will have relapse after radical prostatectomy, predicting who will have recurrence remains enigmatic. We examined the ability of p27 protein levels to predict outcome in patients with clinically localized disease who underwent radical prostatectomy. MATERIALS AND METHODS: p27 protein expression was evaluated in 86 patients with clinical stage T1-2 prostate cancer who were treated with radical prostatectomy. Archived paraffin embedded specimens were sectioned and immunostained with p27 antibody, and scored by 2 independent observers in a blinded fashion. The absence or presence of p27 protein was then correlated with biochemical relapse in univariate and multivariate analyses. RESULTS: In a multivariate analysis that included age, preoperative prostate specific antigen, Gleason score and pathological stage p27 was a strong independent predictor of disease-free survival (p = 0.0184, risk ratio 3.04), second only to pathological stage (p = 0.0001, risk ratio 6.73). Even more strikingly, multivariate analysis demonstrated that p27 was the strongest predictor of biochemical recurrence (p = 0.0081, risk ratio 4.99) among factors studied in patients with pathological T2a-T3b disease. CONCLUSIONS: Absent or low levels of p27 protein expression appear to be an adverse prognostic factor in patients with clinically organ confined disease treated by radical prostatectomy. This marker appears to be especially useful in those patients in whom surgery is believed to be potentially curative, that is patients with pathological T2-T3b disease. Patients with low or absent p27 protein expression may be candidates for novel adjuvant therapies.

Aged↗

PubMed1998

Proliferation, apoptosis and cell cycle regulation in prostatic carcinogenesis.

Cancer progression occurs because of imbalance in the processes of proliferation, differentiation and programmed cell death. In prostate cells, these processes are regulated at least in part by androgens. Structural alterations occur in a variety of genes regulating such processes. In order to obtain meaningful information on the biologic behavior of prostate cancers, it is important to assess androgen dependence and alterations in key genes regulating cell cycle kinetics as well as the aberrant response in cellular proliferation and death that such genetic events bring about. Most genetic alterations resulting in cancer progression alter normal cell cycle progression. Assessment of cell division cycle alterations by means of quantitative methods may have prognostic value, while interference with cell cycle regulatory proteins may result in powerful therapeutic tools. Here we review the methodologies utilized in the assessment of cell cycle kinetics and the abnormalities in proliferation and apoptosis encountered in prostate cancer. In addition, alterations in novel, important genes likely to have an impact on the behavior of prostate cancer and its precursor lesions are discussed. Molecular assessment of genetic alterations in genes that play a pivotal role in prostate cancer coupled with quantitative cytometry of cell kinetics may be utilized for a more precise evaluation of biologic behavior of prostate neoplasms.

Animals↗

PubMed1997

Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer.

Despite its potential role as a tumor suppressor, p27 gene, a member of the Cip/Kip family of cyclin-dependent kinase inhibitor genes, has never been found mutated in human tumors. We investigated p27 protein expression in a series of 108 non-small cell lung cancers (57.4% stage 1, 16.7% stage 2, and 25.9% stage 3) to determine whether the lack or altered expression of this protein correlates with neoplastic transformation and/or progression. We performed immunohistochemistry and Western blot analysis of each specimen. We found that tumors expressing low to undetectable levels of p27 contained high p27 degradation activity. When we evaluated the outcome of the patients in relationship to p27 expression, we found p27 to be a prognostic factor correlating with the overall survival times (P = 0.0012). The possibility of a simple assay, such as the immunohistochemical analysis of p27 expression on routinely formalin-fixed, paraffin-embedded specimens, has considerable value for the prognosis of patients who undergo surgical resection. In addition, confirmation of the involvement of the proteasome-mediated proteolysis in p27 degradation should stimulate new strategies of nonsurgical treatments of non-small cell lung cancer.

Adenocarcinoma↗

PubMed1997

The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a,b) invasive breast carcinomas.

Breast carcinomas < or = 1 cm in size (T1a,b) are being detected more frequently as a result of screening. Because traditional prognostic parameters are either lacking (tumor size) or rare (nodal metastases), a marker(s) is needed to identify the subset of patients who could benefit from adjuvant therapy. A retrospective series of 202 patients with stage T1a,b invasive breast carcinomas was evaluated. The clinicopathological features (age, histological grade, extensive in situ carcinoma, hormone receptor status, and nodal metastasis) as well as microvessel density and the expression of c-erb-B2, p53, MIB-1/Ki-67, and cdc25B were assessed. In addition, expression of the cell cycle inhibitor p27 was evaluated. Nineteen patients (18% of patients who had axillary dissection) had locoregional lymph node metastases. Forty-two % of them died of disease (median survival, 112 months), whereas mortality was 11% in node-negative patients (median survival, 168 months; P = 0.0055). Patients with low p27 expression had a median survival of 139 months (17% mortality) versus 174 months (9% mortality) in the group with high p27 expression (P = 0.0233). Lack of p27 was associated with poor prognosis when node-positive patients were excluded (P = 0.0252). Nodal status and low p27 were found to be the only independent prognostic parameters by both univariate and multivariate analysis, with relative risks of dying of disease of 4.9 (P = 0.001) and 3.4 (P = 0.0306), respectively. Assessment of p27, which yields prognostic information in node-negative patients, could be useful to identify patients with small, invasive breast carcinomas who might benefit from adjuvant therapy.

Age Factors↗