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Biomedical subjects

J Lundin

Publications and source records attributed to J Lundin.

At least 19 recordsLinked to original sources

Treatment of severe refractory autoimmune hemolytic anemia in B-cell chronic lymphocytic leukemia with alemtuzumab (humanized CD52 monoclonal antibody).

Progressive B-cell chronic lymphocytic leukemia (B-CLL) is often complicated by autoimmune hemolytic anemia (AIHA), which in some cases may be refractory to conventional therapy such as corticosteroids, rituximab and splenectomy. We report here on 5 patients (median age 66 years, range 59-69) with advanced B-CLL, all of whom developed severe transfusion-dependent AIHA resistant to conventional therapy and received subcutaneous (SC) or intravenous (IV) alemtuzumab, a humanized monoclonal antibody that targets the CD52 antigen as salvage treatment for AIHA. Alemtuzumab was well tolerated with only minor 'first dose' reactions. All 5 patients responded with a >or=2.0 g/dl rise in hemoglobin (Hb) concentration, in the absence of further transfusions, after a median time of 5 weeks (range 4-7), and the mean Hb increased from 7.2 g/dl at baseline to 11.9 g/dl at end of treatment. All patients remained stable, without further AIHA episodes, after a median follow-up time of 12 months with a mean Hb of 12.5 g/dl (range 12.2-12.9). For patients with severe, refractory CLL-related AIHA, who have not previously responded to conventional therapy, alemtuzumab is an effective agent.

Aged↗

Using high-power lasers for detection of elastic photon-photon scattering.

The properties of four-wave interaction via the nonlinear quantum vacuum is investigated. The effect of the quantum vacuum is to generate photons with new frequencies and wave vectors, due to elastic photon-photon scattering. An expression for the number of generated photons is derived, and using state-of-the-art laser data it is found that the number of photons can reach detectable levels. In particular, the prospect of using the high-repetition Astra Gemini system at the Rutherford Appleton Laboratory is discussed. The problem of noise sources is reviewed, and it is found that the noise level can be reduced well below the signal level. Thus, detection of elastic photon-photon scattering may for the first time be achieved.

Journal Article↗

Decreased xanthine oxidoreductase is a predictor of poor prognosis in early-stage gastric cancer.

BACKGROUND: Xanthine oxidoreductase (XOR) is a key enzyme in the degradation of DNA, RNA and high-energy phosphates. About half of the patients with breast cancer have a decrease in XOR expression. Patients with breast cancer with unfavourable prognosis are independently identified by the loss of XOR. AIM: To assess the clinical relevance of XOR expression in gastric cancer. METHODS: XOR levels were studied by immunohistochemistry in tissue microarray specimens of 337 patients with gastric cancer and the relation between XOR expression and a series of clinicopathological variables, as well as disease-specific survival, was assessed. RESULTS: XOR was moderately decreased in 41% and was undetectable in another 14% of the tumours compared with the corresponding normal tissue. Decreased XOR was associated with advanced stage, deep tumour penetration, diffusely spread tumour location, positive lymph node status, large tumour size, non-curative disease, cellular aneuploidy, high S-phase fraction and high cyclooxygenase-2 expression, but not with p53 expression or Borrmann classification. Down regulation of XOR was associated with unfavourable outcome, and the cumulative 5-year gastric cancer-specific survival in patients with strong XOR expression was 47%, compared with 22% in those with moderate to negative expression (p<0.001). This was also true in patients with stage I-II (p = 0.01) and lymph node-negative (p = 0.02) disease, as well as in patients with smaller (< or =5 cm) tumours (p = 0.02). CONCLUSION: XOR expression in gastric cancer may be a new marker for a more aggressive gastric cancer biology, similar to that previously reported for breast cancer.

Adenocarcinoma↗

Epithelial syndecan-1 expression is associated with stage and grade in colorectal cancer.

OBJECTIVES: Loss of epithelial heparan sulfate proteoglycan syndecan-1 has been associated with a more aggressive behavior in various cancer forms, but the prognostic significance of syndecan-1 expression in colorectal cancer is unclear. The aim of this study was to evaluate the prognostic value of immunohistochemical syndecan-1 expression in a series of 237 patients with colorectal cancer. METHODS: Paraffin-embedded formalin-fixed specimens were stained with a syndecan-1-specific monoclonal antibody, and both the epithelial and stromal expression were analyzed. RESULTS: Epithelial expression of syndecan-1 was seen in 222 tumors (94%), and it was associated with low stage of disease (p = 0.002) and low histological differentiation grade (p = 0.048). The cumulative 5-year survival of patients with weak and strong syndecan-1 expression was 49 and 54 %, respectively (p = 0.234). Syndecan-1 stromal immunoreactivity was observed in 138 tumors (58%), but lacked prognostic significance. Staining pattern and distribution can be viewed from digitized representative microscope slides (virtual slides) at http://www.webmicroscope.net/supplements/syndecan. CONCLUSIONS: The results are in line with previous reports in that low epithelial syndecan-1 expression was associated with a higher histological grade and a more advanced clinical stage of the patients. This study shows that syndecan-1 is expressed also in stromal tissue of colorectal cancer, but it does not support the proposed role of stromal syndecan-1 expression as a marker of poor clinical outcome.

Adult↗

High tissue expression of tumour-associated trypsin inhibitor (TATI) associates with a more favourable prognosis in gastric cancer.

AIMS: The tumour-associated trypsin inhibitor (TATI) is a 6-kDa protease inhibitor with potential inhibitory effects on tissue degradation. In serum, increased levels have been associated with adverse prognosis in different forms of cancer. We assessed the tumour tissue expression and prognostic value of TATI in a surgically treated, single-institution series of patients with gastric cancer. METHODS AND RESULTS: Using a monoclonal anti-TATI antibody, immunohistochemistry was performed on formalin-fixed paraffin-embedded tumour specimens from 336 patients. TATI expression was observed in 265 (79%) of the tumours. There was a significant association between high TATI expression and low stage (P = 0.007), superficial tumours (P = 0.005), and absence of nodal (P = 0.015) and of distant metastases (P = 0.022). In univariate analysis, patients with high TATI expression had a significantly more favourable 5-year cumulative survival compared with patients with negative to moderate immunostaining (43% and 28%, respectively, P = 0.006). On multivariate survival analysis stratified for estimated cure of surgery, stage (P < 0.0001) and age (P = 0.022) at the time of surgery were independent prognostic factors. CONCLUSIONS: High TATI expression in tumour tissue was detected more frequently in patients with early-stage gastric cancer and seems to correlate with a favourable outcome.

Adenocarcinoma↗

Cellular immune reconstitution after subcutaneous alemtuzumab (anti-CD52 monoclonal antibody, CAMPATH-1H) treatment as first-line therapy for B-cell chronic lymphocytic leukaemia.

Little information is available on long-term immune reconstitution after therapy with alemtuzumab in B-CLL patients. We present long-term follow-up data for blood lymphocyte subsets analysed by flow cytometry in previously untreated B-CLL patients who received alemtuzumab subcutaneously as first-line therapy. All lymphoid subsets were significantly (P<0.001) and profoundly reduced; the median end-of-treatment counts for CD4(+), CD8(+), CD3(-)56(+) (natural killer (NK)), CD3(+)56(+) (NK-T) and CD19(+)5(-) (normal B) cells were 43, 20, 4, 1 and 8 cells/microl, respectively. The median cell count of all subsets remained at <25% of the baseline values for >9 months post-treatment. CD4(+) and CD8(+) levels in blood had reached >100 cells/microl in >50% of the patients at 4 months after the end of treatment. One patient had a cytomegalovirus reactivation and one patient developed Pneumocystis carinii pneumonia during therapy. No opportunistic or other major infections were recorded during unmaintained, long-term follow-up. There was no correlation between the cumulative dose of alemtuzumab and the severity or length of immunosuppression. CD52(-) T-cell subsets occurred during the treatment and comprised >80% of all CD4(+) and CD8(+) cells in the blood at the end of therapy. These subpopulations declined gradually during unmaintained follow-up. The relationship between these observations and the safety/antitumour effects of alemtuzumab is discussed.

Adult↗

Apoptotic tumor cells are superior to tumor cell lysate, and tumor cell RNA in induction of autologous T cell response in B-CLL.

B cell chronic lymphocytic leukemia (B-CLL) is a chronic leukemia manifested by increased numbers of B cells in circulation. The slow, smouldering nature of the disease in a significant proportion of the cases makes it an ideal target for immunotherapy. Dendritic cell (DC)-based immunotherapy is emerging as an exciting modality with significant clinical potential. In this study, three strategies for delivering antigens to DC, namely apoptotic bodies (Apo-DC), tumor lysates, and tumor RNA were studied in an autologous setting. In all six CLL patients, Apo-DC induced higher HLA-restricted, T cell responses than DC pulsed with tumor lysate or RNA. Real-time PCR confirmed higher expression of genes for IL-2 and IFN-gamma in T cells stimulated with Apo-DC. Concurrently, no IL-10 and low IL-4 responses indicated that the immune response was primarily of the Th1 type. Enzyme-linked immunospot assay revealed high IFN-gamma secretion by T cells when Apo-DC was used to stimulate autologous T cells in all patients. Our data suggest that cellular vaccines with DC loaded with apoptotic bodies may be a suitable approach for immunotherapy of B-CLL.

Aged↗

Tenascin C expression is upregulated in pancreatic cancer and correlates with differentiation.

BACKGROUND: Tenascin C is a large, hexameric, extracellular matrix protein that is present during embryonic development but essentially absent in adult tissues. It is involved in remodelling processes, such as wound healing and tumour development. Tissue expression of tenascin C correlates with prognosis in colorectal, cervical, and breast cancer and in carcinoma of the papilla of Vater. AIM: To study the expression of tenascin C in pancreatic cancer and to compare the staining results with the patients' clinicopathological data. MATERIAL AND METHODS: Formalin fixed, paraffin wax embedded specimens from 146 patients with pancreatic adenocarcinoma were stained with an anti-tenascin C monoclonal antibody. RESULTS: Tenascin C immunoreactivity was seen in most samples of pancreatic carcinoma: staining was weak in 72 (49%), moderate in 52 (36%), strong in 10 (7%), and negative in 12 (8%) samples. Tenascin C expression correlated with age (< or = 66 v >66 years) and poor differentiation (grades 1-2 v 3). There was no correlation between tenascin C expression and survival, clinical stage, tumour size, nodal status, distant metastasis, tumour location, or sex. CONCLUSION: Tenascin C expression was increased in most pancreatic carcinomas, but contrary to the results in other cancers, it is not a prognostic factor in pancreatic cancer.

Adenocarcinoma↗

A digital atlas of breast histopathology: an application of web based virtual microscopy.

AIMS: To develop an educationally useful atlas of breast histopathology, using advanced web based virtual microscopy technology. METHODS: By using a robotic microscope and software adopted and modified from the aerial and satellite imaging industry, a virtual microscopy system was developed that allows fully automated slide scanning and image distribution via the internet. More than 150 slides were scanned at high resolution with an oil immersion x 40 objective (numerical aperture, 1.3) and archived on an image server residing in a high speed university network. RESULTS: A publicly available website was constructed, http://www.webmicroscope.net/breastatlas, which features a comprehensive virtual slide atlas of breast histopathology according to the World Health Organisation 2003 classification. Users can view any part of an entire specimen at any magnification within a standard web browser. The virtual slides are supplemented with concise textual descriptions, but can also be viewed without diagnostic information for self assessment of histopathology skills. CONCLUSIONS: Using the technology described here, it is feasible to develop clinically and educationally useful virtual microscopy applications. Web based virtual microscopy will probably become widely used at all levels in pathology teaching.

Breast↗

Loss of p27 expression is associated with poor prognosis in stage I-II pancreatic cancer.

OBJECTIVE: p27 is a cyclin-dependent kinase inhibitor that prevents progression of the cell cycle from G1 phase. Postranscriptional loss of p27 correlates with poor prognosis in various solid tumors. In pancreatic cancer, the loss of p27 expression has been correlated with high tumor grade and advanced clinical stage, but data on its prognostic value are lacking. METHOD: In this retrospective study, the association between immunohistochemical p27 expression and prognosis was evaluated in 147 patients with pancreatic cancer using a commercial anti-Kip1/p27 monoclonal antibody. RESULT: p27 expression was generally low; in 103 of the 147 pancreatic cancer tumors examined, no nuclear staining was observed and in only 5 specimens did more than 50% of the nuclei stain, probably reflecting the aggressive nature of the disease. Loss of p27 expression was associated with poor prognosis in stage I-II pancreatic adenocarcinoma; the 5-year survival for p27 negative patients was 3.6% compared with 20% for p27-positive patients (p = 0.03). In a multivariate survival analysis in patients with stage I-II disease, p27 (HR 1.8) was a significant prognostic factor, independent of grade (RR 2.9). There was no association between p27 and other clinical variables. In conclusion, tissue expression of p27 is a significant predictor of 5-year survival in stage I-II pancreatic adenocarcinoma.

Aged↗

Tissue expression of human chorionic gonadotropin beta predicts outcome in colorectal cancer: a comparison with serum expression.

Production of the glycoprotein hormone human chorionic gonadotropin beta (hCGbeta) has been associated with more aggressive behavior in non-trophoblastic tumors. In this study, the prognostic value of immunohistochemical hCGbeta expression was evaluated in 239 patients with colorectal cancer. Paraffin-embedded, formalin-fixed specimens were stained with hCGbeta-specific monoclonal antibody, and the results were compared with serum levels determined with an assay based on the same antibody. hCGbeta immunoreactivity was seen in 52 of 239 tumors (22%). The difference in survival time between patients with histologically hCGbeta-negative (median survival 94 months) and -positive (median survival 27 months) tumors was statistically significant (p = 0.014). The risk ratio during follow-up for patients with positive hCGbeta tissue expression was 1.65 (95% CI 1.11-2.46). In a Cox multivariate analysis, Dukes' stage, hCGbeta and age remained independent prognostic factors. There was moderate agreement between immunohistochemical and serum expression levels of hCGbeta (kappa = 0.30). Using a combination of histological and serum levels of hCGbeta, the difference between survival rates was highly significant (p < 0.001). The accuracy when predicting 5-year survival status with the combined results of serum and tissue expression was 1.3% higher compared to hCGbeta tissue expression alone. Our results show that hCGbeta expression in both tumor tissue and serum has prognostic significance independent of other clinicopathological variables. Positive tumor staining does not always occur together with elevated serum levels, and the prognostic accuracy can slightly be increased by combining the results.

Adult↗

Epithelial and stromal syndecan-1 expression as predictor of outcome in patients with gastric cancer.

The prognostic value of the immunohistochemical expression of epithelial and stromal syndecan-1 was evaluated in 296 patients with gastric carcinoma. Formalin-fixed, paraffin-embedded specimens of gastric adenocarcinomas were stained with mouse monoclonal antibody B-B4 against human syndecan-1. Loss of immunoreactivity (syndecan-1 immunoreactivity correlated with a higher stage of disease (stages II-IV), tumour location in the upper third of the stomach, nodal metastases (N1 or N2), positive stromal syndecan-1 staining, deep tumour penetration (to subserosa or deeper = T2-T4), larger tumour size (> or = 5 cm) and intestinal type of cancer. No correlation between epithelial syndecan-1 immunoreactivity and age, gender, distant metastases, grade of differentiation or Borrmann classification was observed. Positive stromal syndecan-1 immunoreactivity correlated with decreased epithelial syndecan-1 expression, intestinal type of cancer and Borrmann type I. Patients with low epithelial syndecan-1 expression in cancer cells had worse overall survival than patients with strong epithelial syndecan-1 staining (p = 0.0012). Stromal syndecan-1-positive patients had a worse outcome than patients with syndecan-1-negative stroma (p = 0.0193). In Cox multivariate analysis, stromal syndecan-1 immunoreactivity was a prognostic factor independent of TNM stage, surgery for cure and tumour size. Thus, the immunohistochemical expression of syndecan-1 might be a predictor of outcome in patients with gastric adenocarcinoma.

Adenocarcinoma↗

Omission of histologic grading from clinical decision making may result in overuse of adjuvant therapies in breast cancer: results from a nationwide study.

PURPOSE: To investigate the influence of routinely performed histologic grading on breast cancer outcome prediction and patient selection for adjuvant therapy. PATIENTS AND METHODS: The analysis is based on a cohort of 2,842 women diagnosed with breast cancer and comprising 91% of all breast cancers diagnosed in five defined geographical regions in Finland in 1991 through 1992. Data on clinicopathologic factors and follow-up were collected from hospital case records and national registries. Histologic grade assessed at diagnosis and other clinicopathologic data were available for 1,554 operable unilateral invasive carcinomas. The relative value of grade with respect to competing prognostic factors was estimated with the Cox proportional hazards model and logistic regression. Interactions and nonlinearity of factors were accounted for by using an artificial neural network. RESULTS: Histologic grade was correlated strongly with survival in the entire series and in all subgroups studied. Women with well-differentiated node-negative cancer had a 97% 5-year distant disease-free survival rate as compared with 78% for women with poorly differentiated cancer. Grade was an independent prognostic factor in multivariate models and increased the predictive accuracy of a neural network model. Inclusion of grade data in a Cox multivariate model based on tumor size and hormone receptor status in node-negative cancer increased the proportion of patients with 5% or less risk for distant recurrence at 5 years from 15% to 54%. CONCLUSION: Even when assessed by pathologists who have no special training in breast cancer pathology, histologic grade has substantial and independent prognostic value in breast cancer. Omission of grading from clinical decision making may result in considerable overuse of adjuvant therapies.

Adult↗

p27 expression correlates with short-term, but not with long-term prognosis in breast cancer.

UNLABELLED: New prognostic and predictive factors are needed to adjust more appropriate therapy for individual patients after operation. p27 is a cell cycle regulator, and a low tissue expression of this protein has been shown to correlate with poor prognosis in colorectal, lung, gastric, prostate, and breast cancer. In this study on 197 breast cancer patients with a median follow-up of 17 years, the prognostic value of immunohistochemical p27 expression was evaluated. After 5 years of follow-up patients with a p27 expression in less than 50% of the tumor cells had a significantly lower survival rate than those with an expression above this level (p = 0.01). However, after longer follow-up the difference decreased and was no longer significant at 7 years (p = 0.1) or when the entire follow-up period was examined (p=0.67). Tests for associations showed that a low p27 expression correlated with a high histologic grade, a high S-phase fraction (SPF), an advanced TNM stage and negative hormone receptor status. IN CONCLUSION: Tissue expression of p27 is a significant predictor of 5-year, but not of 10- or 15-year breast cancer specific survival.

Adult↗

Amplification of c-myc oncogene by chromogenic and fluorescence in situ hybridization in archival breast cancer tissue array samples.

Fluorescence in situ hybridization (FISH) is currently considered to be the most specific and sensitive method for detection of oncogene amplifications in human tumor samples. However, FISH requires fluorescence microscopy, which is tedious and does not allow histopathologic evaluation of the cells and tissues examined. Here we compared FISH with the newly developed chromogenic in situ hybridization (CISH), which uses peroxidase enzyme for probe detection instead of fluorescent dyes. CISH was found to be highly concordant with FISH in a tissue array series of 177 archival breast cancer samples. This was true both when comparing CISH with single-color and two-color FISH, the latter including the chromosome 8 centromere probe as reference (the kappa coefficients were 0.67 and 0.76, respectively). Clinicopathologic correlations of c-myc amplification as detected by FISH and CISH were generally the same. By both methods, c-myc amplification was significantly associated with high histologic grade, negative progesterone receptor status, DNA aneuploidy, and high S-phase fraction. c-myc amplification was strongly associated with poor distant metastasis-free survival when amplification was detected by CISH (p = 0.0013), but this association was weaker when FISH was used (p = 0.16 for two-color FISH and p = 0.065 for single-color FISH). These data suggest that CISH is at least as sensitive and specific as FISH in the detection of oncogene amplification in human tumor samples. The possibility for concomitant tissue architecture evaluation using an ordinary transmitted light microscope may favor the use of CISH over FISH in oncogene amplification detection in large tumor series, and tissue arrays and, ultimately, in routine clinical diagnostics.

Archives↗