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2.
  • Meng, Wen-Jian, et al. (author)
  • MicroRNA Expression Profile Reveals miR-17-92 and miR-143-145 Cluster in Synchronous Colorectal Cancer
  • 2015
  • In: Medicine. - : Lippincott Williams & Wilkins. - 0025-7974 .- 1536-5964. ; 94:32
  • Journal article (peer-reviewed)abstract
    • The expression of abnormal microRNA (miRNA, miR) is a ubiquitous feature of colorectal cancer (CRC). The pathological features and clinical behaviors of synchronous CRC have been comprehensively described; however, the expression profile of miRNA and small nucleolar RNA (snoRNA) in synchronous CRC has not been elucidated. In the present study, the expression profile of miRNA and snoRNA in 5 synchronous CRCs, along with the matched normal colorectal tissue was evaluated by microarray. Function and pathway analyses of putative targets, predicted from miRNA-mRNA interaction, were performed. Moreover, we analyzed clinicopathological and molecular characteristics of 22 patients with synchronous CRC and 579 solitary CRCs in a retrospective cohort study. We found a global dysregulation of miRNAs, including an oncogenic miR-17-92 cluster and oncosuppressive miR-143-145 cluster, and snoRNAs in synchronous CRC. Differential miRNA rather than snoRNA expression was robust enough to distinguish synchronous cancer from normal mucosa. Function analysis of putative targets suggested that miRNA clusters may modulate multiple effectors of oncogenic pathways involved in the pathogenesis of synchronous CRC. A comparison of normal mucosa between synchronous and solitary CRC suggested a differential genetic background of synchronous CRC from solitary CRC during carcinogenesis. Compared with solitary cancer patients, synchronous cases exhibited multiple extra-colonic cancers (P=0.012), coexistence of adenoma (P=0.012), microsatellite instability (P=0.024), and less glucose transporter 1 (P=0.037). Aberrant miRNA expression profiles could potentially be used as a diagnostic tool for synchronous CRC. Our findings represent the first comprehensive miRNA and snoRNA expression signatures for synchronous CRC, implicating that the miRNAs and snoRNAs may present therapeutic targets for synchronous CRC.
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3.
  • Wang, Mo-Jin, et al. (author)
  • Prognostic significance and molecular features of colorectal mucinous adenocarcinomas : A strobe-compliant study
  • 2015
  • In: Medicine. - : Lippincott Williams & Wilkins. - 0025-7974 .- 1536-5964. ; 94:51
  • Journal article (peer-reviewed)abstract
    • Mucinous adenocarcinoma (MC) is a special histology subtype of colorectal adenocarcinoma. The survival of MC is controversial and the prognostic biomarkers of MC remain unclear. To analyze prognostic significance and molecular features of colorectal MC. This study included 755,682 and 1001 colorectal cancer (CRC) patients from Surveillance, Epidemiology, and End Results program (SEER, 1973 2011), and Linkoping Cancer (LC, 1972-2009) databases. We investigated independently the clinicopathological characteristics, survival, and variety of molecular features from these 2 databases. MC was found in 9.3% and 9.8% patients in SEER and LC, respectively. MC was more frequently localized in the right colon compared with nonmucinous adenocarcinoma (NMC) in both SEER (57.7% vs 37.2%, P < 0.001) and LC (46.9% vs 27.7%, P < 0.001). Colorectal MC patients had significantly worse cancer-specific survival (CSS) than NMC patients (SEER, P < 0.001; LC, P = 0.026), prominently in stage III (SEER, P < 0.001; P=0.023). The multivariate survival analysis showed that MC was independently related to poor prognosis in rectal cancer patients (SEER, hazard ratios [HR], 1.076; 95% confidence intervals [CI], 1.057-1.096; P < 0.001). In LC, the integrated analysis of genetic and epigenetic features showed that that strong expression of PINCH (HR, 3.954; 95% CI, 1.493-10.47; P = 0.013) and weak expression of RAD50 (HR 0.348, 95% CT, 0.106-1.192; P=0.026) were significantly associated with poor CSS of colorectal MC patients. In conclusion, the colorectal MC patients had significantly worse CSS than NMC patients, prominently in stage III. MC was an independent prognostic factor associated with worse survival in rectal cancer patients. The PINCH and RAD50 were prognostic biomarkers for colorectal MC patients.
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4.
  • Wang, Mo-Jin, et al. (author)
  • The prognostic factors and multiple biomarkers in young patients with colorectal cancer
  • 2015
  • In: Scientific Reports. - : Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group. - 2045-2322. ; 5:10645
  • Journal article (peer-reviewed)abstract
    • The incidence of colorectal cancer (CRC) in young patients (less than= 50 years of age) appears to be increasing. However, their clinicopathological characteristics and survival are controversial. Likewise, the biomarkers are unclear. We used the West China (2008-2013, China), Surveillance, Epidemiology, and End Results program (1973-2011, United States) and Linkoping Cancer (1972-2009, Sweden) databases to analyse clinicopathological characteristics, survival and multiple biomarkers of young CRC patients. A total of 509,934 CRC patients were included from the three databases. The young CRC patients tended to have more distal location tumours, fewer tumour numbers, later stage, more mucinous carcinoma and poorer differentiation. The cancer-specific survival (CSS) of young patients was significantly better. The PRL (HR = 12.341, 95% CI = 1.615-94.276, P = 0.010), RBM3 (HR = 0.093, 95% CI = 0.012-0.712, P = 0.018), Wrap53 (HR = 1.952, 95% CI = 0.452-6.342, P = 0.031), p53 (HR = 5.549, 95% CI = 1.176-26.178, P = 0.045) and DNA status (HR = 17.602, 95% CI = 2.551-121.448, P = 0.001) were associated with CSS of the young patients. In conclusion, this study suggests that young CRC patients present advanced tumours and more malignant pathological features, while they have a better prognosis. The PRL, RBM3, Wrap53, p53 and DNA status are potential prognostic biomarkers for the young CRC patients.
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5.
  • Yang, Lie, et al. (author)
  • Efficacy of Surgery and Adjuvant Therapy in Older Patients With Colorectal Cancer A STROBE-compliant article
  • 2014
  • In: Medicine. - : Lippincott, Williams andamp; Wilkins. - 0025-7974 .- 1536-5964. ; 93:28
  • Journal article (peer-reviewed)abstract
    • The present study aimed to assess the efficacy of surgery and adjuvant therapy in older patients (age greater than= 70 years) with colorectal cancer (CRC). Older CRC patients are under-represented in available clinical trials, and therefore their outcomes after receiving surgery and adjuvant therapy are unclear. From two prospective Swedish databases, we assessed a cohort of 1021 patients who underwent curative surgery for stage I, II, or III primary CRC, with or without adjuvant chemotherapy/ radiotherapy. Of the patients with colon cancer (n = 467), 182 (39%) were aged less than70 years, 162 (35%) aged 70 to 80 years, and 123 (26%) were aged greater than= 80 years. Of rectal cancer patients (n = 554), 264 (48%) were aged less than70 years, 234 (42%) aged 70 to 80 years, and 56 (10%) aged greater than= 80 years. Older patients with either colon or rectal cancer had higher comorbidity than did younger patients. Older patients with colon cancer had equivalent postoperative morbidity and 30-day mortality to younger patients. Rectal cancer patients aged greater than= 80 years had a higher 30-day mortality than younger patients (odds ratio OR], 2.37; 95% confidence interval CI], 1.6-4.55; P = 0.03). For either colon or rectal cancer, adjuvant chemotherapy compromised the 5-year overall survival (OS) of older patients with stage II disease and had no effect on those with stage III disease. Receiving adjuvant chemotherapy was a poor factor of OS for older patients with either colon (HR 1.88, 95% CI: 1.20-4.35, P = 0.03) or rectal cancer (HR 1.72, 95% CI: 1.052.26, P = 0.004). Preoperative short-course radiotherapy improved both OS and local control for older patients with stage III rectal cancer and had no effect on those with stage II disease. Radiotherapy was a favorable factor for the OS of the older patients with rectal cancer (HR 0.42, 95% CI: 0.21-3.57, P = 0.01). In conclusion, Older CRC patients had equal safety of surgery as younger patients, except rectal cancer patients aged greater than= 80 years that had a higher mortality. Adjuvant 5FU-based chemotherapy did not benefit older CRC patient, while neoadjuvant radiotherapy improved the prognosis of older patients with stage III rectal cancer.
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6.
  • Adell, Gunnar C. E., 1953-, et al. (author)
  • Apoptosis in rectal carcinoma : Prognosis and recurrence after preoperative radiotherapy
  • 2001
  • In: Cancer. - 0008-543X .- 1097-0142. ; 91:10, s. 1870-1875
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Rectal carcinoma is common, with considerable local recurrence and death rates. Preoperative radiotherapy and refined surgical techniques can improve local control. The aim of this study was to investigate the interaction between apoptosis and the outcome of rectal carcinoma, with and without short-term preoperative radiotherapy.METHODS: Specimens were from 162 patients from the Southeast Swedish Health Care region included in the Swedish Rectal Cancer Trial between 1987-1990. New sections from the paraffin blocks of the preoperative biopsies and the surgical specimens were examined for apoptosis using the terminal deoxynucleotidyl transferase mediated digoxigenin nick end labeling (TUNEL) method.RESULTS: The mean percentage of apoptotic cells was 0.3% (0-4%) and 1.1% (0-14.5%) for the preoperative biopsy and the surgical specimen, respectively. The authors analyzed the surgical specimens from nonirradiated patients and divided them into three groups by apoptotic index (AI) as follows: 0%, 0-1%, and > 1%. A high AI was associated with a decreased local recurrence rate compared with an intermediate or a low AI (P = 0.024). There was no significant relation between AI and survival. There was a significant reduction in the local recurrence rate for irradiated patients compared with the nonirradiated in the low (P = 0.015) and intermediate (P = 0.038) AI groups. In the high AI group, there were few recurrences and no significant difference was observed between irradiated and nonirradiated patients. The relative risk of death from rectal carcinoma in Dukes A-C patients was not significantly decreased by radiotherapy, but, in the intermediate AI group, there was a trend (P = 0.08) in favor of the irradiated patients.CONCLUSION: A high AI in rectal carcinoma indicated a decreased local recurrence rate.
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7.
  • Adell, Gunnar, 1953-, et al. (author)
  • Decreased tumor cell proliferation as an indicator of the effect of preoperative radiotherapy of rectal cancer
  • 2001
  • In: International Journal of Radiation Oncology, Biology, Physics. - 0360-3016 .- 1879-355X. ; 50:3, s. 659-663
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Rectal cancer is a common malignancy, with significant local recurrence and death rates. Preoperative radiotherapy and refined surgical technique can improve local control rates and disease-free survival.PURPOSE: To investigate the relationship between the tumor growth fraction in rectal cancer measured with Ki-67 and the outcome, with and without short-term preoperative radiotherapy.Method: Ki-67 (MIB-1) immunohistochemistry was used to measure tumor cell proliferation in the preoperative biopsy and the surgical specimen.MATERIALS: Specimens from 152 patients from the Southeast Swedish Health Care region were included in the Swedish rectal cancer trial 1987-1990.RESULTS: Tumors with low proliferation treated with preoperative radiotherapy had a significantly reduced recurrence rate. The influence on death from rectal cancer was shown only in the univariate analysis. Preoperative radiotherapy of tumors with high proliferation did not significantly improve local control and disease-free survival. The interaction between Ki-67 status and the benefit of radiotherapy was significant for the reduced recurrence rate (p = 0.03), with a trend toward improved disease-free survival (p = 0.08). In the surgery-alone group, Ki-67 staining did not significantly correlate with local recurrence or survival rates.CONCLUSION: Many Ki-67 stained tumor cells in the preoperative biopsy predicts an increased treatment failure rate after preoperative radiotherapy of rectal cancer.
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8.
  • Adell, Gunnar, 1953- (author)
  • Indicators of colorectal cancer prognosis and response to preoperative radiotherapy
  • 2000
  • Doctoral thesis (other academic/artistic)abstract
    • Colorectal cancer is one of the three most common malignant diseases in Sweden, with about 5,000 new cases each year. Thirty-five percent of these are rectal cancer, for which local recurrence after surgery has been a serious problem. The five-year survival rate in colorectal cancer has improved from about 40% in 1960 to 55% in 1995. Adjuvant chemotherapy of colon cancer, preoperative radiotherapy and improved surgical techniques in rectal cancer have contributed to the improved  results. To select patients best suited for pre- or postoperative therapy, we need indicators of both prognosis and response to therapy.Using antibodies against cytokeratin, we found that 39% of patients with colorectal carcinoma that had penetrated the muscularis propria but without lymph-node metastases by routine light microscopy, had got micrometastases. Survival among patients with micrometastases was not significantly different from that among patients without such metastases.We also identified subsets of tumour-infiltrating mononuclear cells and studied their pattern of distribution in relation to regressive tumour areas and Dukes class. Our interpretation is that the subsets of tumourinfiltrating mononuclear cells change with advancing Dukes class, indicating gradual deterioration of the local immune control.We also investigated the interaction between p53, Ki-67, apoptosis and the outcome in rectal cancer with and without short-term preoperative radiotherapy. The expression of nuclear p53 protein seemed to be a significant predictive factor for local treatment failure after preoperative radiotherapy. Low tumour cell proliferation measured with Ki-67 in the preoperative biopsy correlated with improved local control and disease-free survival after preoperative radiotherapy.High apoptotic index was associated with improved local control of rectal cancer even without pre-operative radiotherapy, whereas local control of tumours with low and intermediate apoptotic index was significantly improved by preoperative radiotherapy.In conclusion, micrometastases in regional lymph nodes are an interesting phenomenon but with limited prognostic value. The subsets of tumour-infiltrating mononuclear cells change with advancing Dukes class, and its seems that the local immune control is gradually broken down. In rectal cancer, p53 expression, tumour proliferation measured with Ki-67 and apoptotic index seem to be interesting indicators of rectal cancer prognosis and response to preoperative radiotherapy.
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9.
  • Adell, Gunnar, et al. (author)
  • Occurrence and prognostic importance of micrometastases in regional lymph nodes in Dukes' B colorectal carcinoma : an immunohistochemical study
  • 1996
  • In: European Journal of Surgery. - 1102-4151 .- 1741-9271. ; 162:8, s. 637-642
  • Journal article (peer-reviewed)abstract
    • OBJECTIVE: To evaluate the incidence and prognostic importance of micrometastatic disease in regional lymph nodes from Dukes' B colorectal carcinomas.DESIGN: Retrospective study.SETTING: University hospital, Sweden.SUBJECTS: 100 patients operated on for primary colorectal carcinoma, classified as Dukes' B lesions.INTERVENTIONS: The regional lymph nodes were re-examined immunohistochemically using monoclonal antibodies against cytokeratin.OUTCOME MEASURES: Incidence and prognostic importance of micrometastases.RESULTS: Micrometastases were found in 39% (39/100) of the patients. The number of positive cells in the lymph nodes examined varied from 1 to over 100. They appeared as single cells or small clusters of cells located within the capsule or in the peripheral sinus of the lymph node. At least three sections from each of three lymph nodes had to be examined to identify 95% of the patients with lymph node micrometastases. The outcome of the patients with micrometastases was not significantly different from that of patients with no epithelial cells in the lymph nodes.CONCLUSION: Micrometastases in regional lymph nodes are a interesting phenomenon but clinically seem to be of only weak prognostic value.
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10.
  • Adell, Gunnar, 1953-, et al. (author)
  • p53 status : an indicator for the effect of preoperative radiotherapy of rectal cancer.
  • 1999
  • In: Radiotherapy and Oncology. - 0167-8140 .- 1879-0887. ; 51:2, s. 169-174
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Rectal carcinoma is a common malignancy, with a history of high local recurrence rates following surgery. In recent years. preoperative radiotherapy and refined surgical technique have improved local control rates.AIM: To investigate the relationship between expression of nuclear p53 protein and the outcome in rectal carcinoma, with and without short-term preoperative radiotherapy.MATERIAL: Specimens from 163 patients from the Southeast Swedish Health Care region included in the Swedish rectal cancer trial between 1987-1990.METHOD: New sections from the paraffin blocks of the preoperative biopsy and the surgical specimen were examined immunohistochemically using a p53 antibody (PAb 1801).RESULT: Expression of nuclear p53 protein was seen in 41% of the tumours. The p53 negative patients treated with preoperative radiotherapy had a significant reduction of local failure compared with the non-irradiated p53 negative patients (P = 0.0008). In contrast, p53 positive patients showed no benefit from preoperative radiotherapy. The interaction between p53 status and the benefit of radiotherapy was statistically significant (P = 0.018).CONCLUSION: Expression of nuclear p53 protein in rectal carcinoma seems to be a significant predictive factor for local treatment failure after preoperative radiotherapy. Further investigations are necessary to select patients for preoperative treatment based on analysis of the preoperative biopsies.
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11.
  • Arlehag, L, et al. (author)
  • ATM expression in rectal cancers with or without preoperative radiotherapy
  • 2005
  • In: Oncology Reports. - 1021-335X .- 1791-2431. ; 14:2, s. 313-317
  • Journal article (peer-reviewed)abstract
    • Patients with ATM (Ataxia-Telangiectasia mutated) mutation show increased sensitivity to radiation and have a higher risk of developing malignancies. The present study aimed to investigate whether ATM expression was related to radiotherapy, and clinicopathological and biological variables in rectal cancers. ATM expression was immunohistochemically examined in 78 rectal cancers from patients who participated in a Swedish rectal cancer trial of preoperative radiotherapy. Of 78 patients, 44 underwent surgery alone, and 34 underwent both preoperative radiotherapy and surgery. Fifty-eight cases had normal rectal mucosa adjacent to the tumour. The results showed that, compared to normal mucosa, tumours had less nuclear (p=0.03) but more cytoplasmic expression of ATM (p=0.004). In tumours, less expression of ATM, either in the nucleus (p=0.07) or in the cytoplasm (p=0.02 for staining intensity, and p=0.07 for staining percentage), tended to be correlated with male patients. Also, ATM expression was not related to radiotherapy or other clinicopathological and biological variables (p > 0.05). In conclusion, the pattern of ATM expression was changed from normal mucosa to tumour. Less expression of ATM may be related to males.
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12.
  • Bisgin, Atil, et al. (author)
  • Interaction of CD200 Overexpression on Tumor Cells with CD200R1 Overexpression on Stromal Cells: An Escape from the Host Immune Response in Rectal Cancer Patients
  • 2019
  • In: Journal of Oncology. - : HINDAWI LTD. - 1687-8450 .- 1687-8469. ; 2019
  • Journal article (peer-reviewed)abstract
    • CD200 imparts an immunoregulatory signal through its receptor, CD200R1, leading to the suppression of tumor specific immunity. The mechanism of CD200:CD200R1 signaling pathway is still uncertain. Our aim was to investigate the expression and localization of CD200 and its receptor CD200R1 and their clinical significance in rectal cancer patients. We examined the immunohistochemical expressions and localizations of CD200 and CD200R1 in 140 rectal cancer patients. Among the patients, 79 underwent the preoperative radiotherapy and the others were untreated prior to the surgery. In addition, 121 matched normal rectal mucosa samples were evaluated. The results of immunohistochemical analysis showed a strikingly high level of CD200 in tumor cells (p=0.001) and CD200R1 expression in normal mucosal epithelium and stromal cells. Importantly, CD200R1 was overexpressed in stromal cells of the metastatic cancer patients compared to patients without metastases (p=0.002). More than that, 87% of metastatic patients had a phenotype of upregulated CD200 in tumor cells accompanied by overexpressed CD200R1 in stromal cells. In addition, low levels of CD200 were correlated with improved overall survival in untreated patients. We showed that tumor-stroma communication through CD200 and its receptor interaction is selected in patients with high risk of relapse. High levels of these molecules support instigation of the far and local metastatic nest that provides solid ground for metastasis. Our current data also disclose a mechanism by which CD200:CD200R1 affects tumor progression and may strengthen the feasibility of targeting CD200 or CD200R1 as anticancer strategy.
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13.
  • Ding, Zhen-Yu, et al. (author)
  • Livin expression is an independent factor in rectal cancer patients with or without preoperative radiotherapy
  • 2013
  • In: Radiation Oncology. - London, United Kingdom : BioMed Central. - 1748-717X. ; 8:1
  • Journal article (peer-reviewed)abstract
    • Background: This study was aimed to investigate the expression significance of Livin in relation to radiotherapy (RT), clinicopathological and biological factors of rectal cancer patients.Methods: This study included 144 primary rectal cancer patients who participated in a Swedish clinical trial of preoperative radiotherapy. Tissue microarray samples from the excised primary rectal cancers, normal mucosa and lymph node metastases were immunostained with Livin antibody. The proliferation of colon cancer cell lines SW620 and RKO was assayed after Livin knock-down.Results: The expression of Livin was significantly increased from adjacent (P = 0.051) or distant (P = 0.028) normal mucosa to primary tumors. 15.4% (2/13) and 39.7% (52/131) patients with Livin-negative and positive tumors died at 180 months after surgery, and the difference tended to be statistically significant (P = 0.091). In multivariate analyses, the difference achieved statistical significance, independent of TNM stage, local and distant recurrence, grade of differentiation, gender, and age (odds ratio = 5.09, 95% CI: 1.01-25.64, P = 0.048). The in vitro study indicated colon cancer cells with Livin knock-down exhibited decreased proliferation compared with controls after RT.Conclusions: The expression of Livin was was independently related to survival in rectal cancer patients, suggesting Livin as a useful prognostic factor for rectal cancer patients.
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14.
  • Flejmer, Anna M. (author)
  • Radiation burden from modern radiation therapy techniques including proton therapy for breast cancer treatment - clinical implications
  • 2016
  • Doctoral thesis (other academic/artistic)abstract
    • The purpose of this thesis was to study the clinical implications of modern radiotherapy techniques for breast cancer treatment. This was investigated in several individual studies.Study I investigated the implications of using the analytical anisotropic algorithm (AAA) from the perspective of clinical recommendations for breast cancer radiotherapy. Pencil beam convolution plans of 40 breast cancer patients were recalculated with AAA. The latter plans had a significantly worse coverage of the planning target volume (PTV) with the 93% isodose, higher maximum dose in hotspots, higher volumes of the ipsilateral lung receiving doses below 25 Gy and smaller volumes with doses above 25 Gy. AAA also predicted lower doses to the heart.Study II investigated the implications of using the irregular surface compensator (ISC), an electronic compensation algorithm, in comparison to three‐dimensional conformal radiotherapy (3D‐CRT) for breast cancer treatment. Ten breast cancer patients were planned with both techniques. The ISC technique led to better coverage of the clinical target volume of the tumour bed (CTV‐T) and PTV in almost all patients with significant improvement in homogeneity.Study III investigated the feasibility of using scanning pencil beam proton therapy for regional and loco‐regional breast cancer with comparison of ISC photon planning. Ten patients were included in the study, all with dose heterogeneity in the target and/or hotspots in the normal tissues outside the PTV. The proton plans showed comparable or better CTV‐T and PTV coverage, with large reductions in the mean doses to the heart and the ipsilateral lung.Study IV investigated the added value of enhanced inspiration gating (EIG) for proton therapy. Twenty patients were planned on CT datasets acquired during EIG and freebreathing (FB) using photon 3D‐CRT and scanning proton therapy. Proton spot scanning has a high potential to reduce the irradiation of organs‐at‐risk for most patients, beyond what could be achieved with EIG and photon therapy, especially in terms of mean doses to the heart and the left anterior descending artery.Study V investigated the impact of physiological breathing motion during proton radiotherapy for breast cancer. Twelve thoracic patients were planned on CT datasets during breath‐hold at inhalation phase and breath‐hold at exhalation phase. Between inhalation and exhalation phase there were very small differences in dose delivered to the target and cardiovascular structures, with very small clinical implication.The results of these studies showed the potential of various radiotherapy techniques to improve the quality of life for breast cancer patients by limiting the dose burden for normal tissues.
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15.
  • Gudjonsson, Sigurdur, et al. (author)
  • Should All Patients with Non-Muscle-Invasive Bladder Cancer Receive Early Intravesical Chemotherapy after Transurethral Resection? The Results of a Prospective Randomised Multicentre Study.
  • 2009
  • In: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 55, s. 773-780
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: To decrease recurrences in non-muscle-invasive bladder cancer (NMIBC), the European Association of Urology (EAU) guidelines recommend immediate, intravesical chemotherapy after transurethral resection (TUR) for all patients with Ta/T1 tumours. OBJECTIVE: To study the benefits of a single, early, intravesical instillation of epirubicin after TUR in patients with low- to intermediate-risk NMIBC. DESIGN, SETTING, AND PARTICIPANTS: In this prospective randomised multicentre trial, 305 patients with primary as well as recurrent low- to intermediate-risk (Ta/T1, G1/G2) tumours were enrolled between 1997 and 2004. Patients were randomly allocated to receive 80mg of epirubicin in 50ml of saline intravesically within 24h of TUR or no further treatment after TUR. MEASUREMENTS: The primary end point was time to first recurrence. RESULTS AND LIMITATIONS: A total of 219 patients remained for analysis after exclusions. The median follow-up time was 3.9 yr. During the study period, 62% (63 of 102) of the patients in the epirubicin group and 77% (90 of 117) in the control group experienced recurrence (p=0.016). In a multivariate model, the hazard ratio (HR) for recurrence was 0.56 (p=0.002) for early instillation of epirubicin versus no treatment. In a subgroup analysis, the treatment had a profound recurrence-reducing effect on patients with primary, solitary tumours, whereas it provided no benefits in patients with recurrent or multiple tumours. Furthermore, patients with a modified European Organisation for Research and Treatment of Cancer (EORTC) risk score of 0-2 with and without single instillation had recurrence rates of 41% and 69%, respectively (p=0.003), whereas the corresponding rates for those with a risk score of >/=3 were 81% and 85%, respectively (p=0.35). CONCLUSIONS: A single, early instillation of epirubicin after TUR for NMIBC reduces the likelihood of tumour recurrence; however, the benefit seems to be minimal in patients at intermediate or high risk of recurrence. Future trials will determine the value of early instillation in addition to serial instillations in NMIBC.
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16.
  • Holmqvist, Annica, 1974- (author)
  • Biological and histological factors as predictors in rectal cancer patients : A study in a clinical trial of preoperative radiotherapy
  • 2011
  • Doctoral thesis (other academic/artistic)abstract
    • With improved surgical techniques and preoperative radiotherapy (RT) the local recurrence rate in rectal cancer patients has been reduced, however the mortality rate is still high and there is a huge variation in the response to preoperative RT in patients with the same tumour stage. To improve patient’s survival, it is of great importance to identify good prognostic and predictive factors that help us to select the best suited patients for preoperative RT in the future.For many years, studies of neoplastic transformation have mainly focused on tumour cells. In recent years, researchers have realised that the stroma around tumour cells and their extracellular matrix components also play an important role in tumour carcinogensesis.The aim of this thesis was to investigate the biological factors, survivin and particularly interesting new cysteine-histidine rich protein (PINCH), histological factors, inflammatory infiltration, fibrosis, necrosis, mucinous content, angiogenesis and lymphangiogenesis as well as their relationships to preoperative RT and to clinical variables in rectal cancer patients who participated in a Swedish rectal cancer trial of preoperative RT.In paper I, the expression of survivin and its relationship to preoperative RT and clinical factors were investigated in 98 primary rectal tumours and adjacent normal mucosa. In all patients, positive survivin expression was independently related to worse survival compared to negative survivin expression in a multivariate analysis.In paper II, PINCH expression and its relationship to RT, clinical, histological and biological factors were investigated at the invasive margin and inner tumour area in 137 primary rectal tumours and in cell line of fibroblasts. In patients without RT, strong PINCH expression was independently related to worse survival in a multivariate analysis. No survival relationship was found in the patients with RT, and there was no difference in PINCH expression between the subgroups of non-RT and RT at the invasive margin/inner tumour area. In patients with RT, strong PINCH expression at the inner tumour area was related to a high level of lymphatic vessel density (LVD).In paper III, the frequency of LVD/blood vessel density (BVD) was analysed at the periphery, the inner tumour area and the invasive margin of 138/140 primary rectal tumours and correlated to RT, clinical, histological and biological factors. In all patients, LVD at the periphery of the tumour was independently related to better survival compared to LVD at the inner tumour area/invasive margin. In all patients, a higher LVD at the periphery was related to negative (wild type) p53 expression.In paper IV, the inflammatory infiltration, fibrosis, necrosis and mucinous content were studied in relation to RT, clinical and biological parameters in preoperative biopsies (n = 153) and in primary tumours (n = 148). In all patients and in the subgroups of non-RT and RT a higher grade of inflammatory infiltration was independently related to improved survival compared to weak inflammatory infiltration in a multivariate analysis.In this thesis, survivin, PINCH, LVD and inflammatory infiltration are independent prognostic factors in rectal cancer patients who participated in a clinical trial of preoperative RT. This information may help us to improve patient’s survival by selecting the best suited patients for preoperative RT in the future.
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17.
  • Holmqvist, A, et al. (author)
  • The location of lymphangiogenesis is an independent prognostic factor in rectal cancers with or without preoperative radiotherapy
  • 2010
  • In: ANNALS OF ONCOLOGY. - : Elsevier BV. - 0923-7534. ; 21:3, s. 512-517
  • Journal article (peer-reviewed)abstract
    • Background: Lymphangiogenesis and angiogenesis are essential for tumour development and progression. The lymphatic vessel density (LVD) and blood vessel density (BVD) and their relationship to outcome have been studied extensively, however the clinical significance of the location of LVD/BVD in tumour is not known. In the present study, the location and degree of LVD/BVD and their relationship to preoperative radiotherapy (RT), clinicopathological, histopathological and biological factors were studied in rectal cancer patients participating in a Swedish clinical trial of preoperative RT. Patients and methods: The location and degree of LVD/BVD were analysed in primary tumours (n = 138/140) and in their subgroups of non-RT (n = 74) and RT (n = 64/66). Further, the degree of LVD/BVD was examined in the corresponding distant normal mucosa (n = 35/31) and adjacent normal mucosa (n = 72/91). All sections were immunohistochemically examined by using D2-40 and CD34 antibodies. Results: In the whole series of the patients, a higher LVD at the periphery was related to negative p53 expression (P = 0.03) and favourable survival independent of tumour-node-metastasis stage, differentiation and p53 expression (P = 0.03). LVD was increased in p53-negative tumours after RT (P = 0.01). Conclusion: LVD at the periphery of the tumour was an independent prognostic factor in rectal cancer patients.
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18.
  • Holmqvist Knutsen, Annica, 1974-, et al. (author)
  • PINCH is an independent prognostic factor in rectal cancer patients without preoperative radiotherapy : A study in a Swedish rectal cancer trial of preoperative radiotherapy
  • 2012
  • In: BMC Cancer. - : BioMed Central. - 1471-2407. ; 12:65
  • Journal article (peer-reviewed)abstract
    • Background and Purpose: The clinical significance between particularly interesting new cysteine-histidine rich protein (PINCH) expression and radiotherapy (RT) in tumours is not known. In this study, the expression of PINCH and its relationship to RT, clinical, pathological and biological factors were studied in rectal cancer patients. Material and Methods: PINCH expression determined by immunohistochemistry was analysed at the invasive margin and inner tumour area in 137 primary rectal adenocarcinomas (72 cases without RT and 65 cases with RT). PINCH expression in colon fibroblast cell line (CCD-18 Co) was determined by Western blot. Results: In patients without RT, strong PINCH expression at the invasive margin of primary tumours was related to worse survival, compared to patients with weak expression, independent of TNM stage and differentiation (p = 0.03). No survival relationship in patients with RT was observed (p = 0.64). Comparing the non-RT with RT subgroup, there was no difference in PINCH expression in primary tumours (invasive margin (p = 0.68)/inner tumour area (p = 0.49). Conclusions: PINCH expression at the invasive margin was an independent prognostic factor in patients without RT. RT does not seem to directly affect the PINCH expression.  
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19.
  • Håkansson, L., et al. (author)
  • Infiltration of mononuclear inflammatory cells into primary colorectal carcinomas : an immunohistological analysis
  • 1997
  • In: British Journal of Cancer. - 0007-0920 .- 1532-1827. ; 75:3, s. 374-380
  • Journal article (peer-reviewed)abstract
    • Local immunoregulation mediated by mononuclear tumour-infiltrating cells is considered of importance for tumour progression of colorectal cancer, although the balance between immunosuppressor and cytotoxic activities is unclear. Colorectal cancers from 26 patients were investigated using a panel of monoclonal antibodies in order to identify subsets of mononuclear inflammatory cells and to study their pattern of distribution in relation to tumour stage and cytotoxic immune reactivity against the tumour. In all but five tumours, mononuclear cells, lymphocytes or monocytes were present in fairly large numbers, particularly in the stroma. The infiltration of CD4+ mononuclear cells predominated over the CD8+ subset. Infiltration near the tumour cells was found in four cancers only. Stromal infiltration of CD11c+ macrophages was found in all but eight tumours. Small regressive areas, in which the histological architecture of the tumours was broken down, were found in 17 tumours with intense or moderate infiltration by CD4+ lymphocytes or CD11c+ macrophages. Probably this destruction of tumour tissue was caused by cytotoxic activity of the tumour-infiltrating mononuclear cells. In Dukes' class A and B tumours, CD4+ lymphocytes predominated over CD4+ cells with macrophage morphology, but the latter were increasingly found in Dukes' class C and D disease. The occurrence of MHC II-positive macrophages and lymphocytes in different Dukes' classes was similar to that of CD4+ cells. In contrast to this, CD11c+ and CD11a+ cells were more frequent in Dukes' A and B class tumours compared with Dukes' C and D. Four out of nine tumours of the latter stages showed a poor inflammatory reaction. The interpretation of our results is that the subsets of tumour-infiltrating mononuclear cells change with advancing Dukes' class and that the local immune control is gradually broken down in progressive tumour growth, even if some cytotoxic activity is still present.
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20.
  • Knutsen Holmqvist, Annica, 1974-, et al. (author)
  • Inflammatory infiltration, fibrosis, necrosis and mucinous content in relation to clinicopathological and molecular factors in rectal cancers with or without preoperative radiotherapy.
  • 2006
  • In: Oncology Reports. - 1021-335X .- 1791-2431. ; 16:2, s. 321-327
  • Journal article (peer-reviewed)abstract
    • The association between inflammatory infiltration, fibrosis, necrosis and mucinous content in rectal cancers, and their relationship to preoperative radiotherapy (RT) clinicopathological and biological factors (p53, apoptosis and Cox-2) is not fully characterised. We analysed these histopathological parameters and their relationships in rectal cancer patients who participated in a clinical trial of preoperative RT. One hundred and forty-eight preoperative biopsies and 153 surgically resected tumours were examined. Of the surgical specimens, 81 had surgery alone and 72 received RT before surgery. A higher grade of inflammatory infiltration was related to favourable survival in the whole group of patients (p=0.004, for multivariate analysis p=0.01) as well as in the subgroups of patients with (p=0.04) or without RT (p=0.01). After RT, tumours showed a decreased infiltration (p=0.0003) and increased necrosis (p=0.006), strong necrosis was related to favourable survival (p=0.046). Necrosis (p=0.054) and fibrosis (p=0.06) tended to be increased in p53-negative tumours after RT. Inflammatory infiltration was a strong prognostic factor in rectal cancer patients, regardless of RT. RT tended to induce necrosis and fibrosis in p53-negative tumours.
  •  
21.
  • Knutsen Holmqvist, Annica, et al. (author)
  • Survivin expression is an independent prognostic factor in rectal cancer patients with and without preoperative radiotherapy
  • 2004
  • In: Journal of chromatography. B. - 1570-0232 .- 1873-376X. ; 60:1, s. 149-155
  • Journal article (peer-reviewed)abstract
    • Purpose: Survivin, as an inhibitor of apoptosis, is undetectable in normal tissues but expressed in tumors. Survivin expression in rectal cancer patients who have undergone preoperative radiotherapy (RT) alone has not been studied. We analyzed the relationships of survivin expression to RT, clinicopathologic variables, apoptosis, and p53 expression in rectal cancer patients who participated in a trial of preoperative RT. Methods and Materials: Survivin was immunohistochemically examined in 98 rectal tumors (74 had adjacent normal mucosa). Of 98 patients, 57 underwent surgery alone and 41 underwent RT before surgery. Results: Survivin positivity was related to worse survival, independent of Dukes' stage, local and distant recurrence, differentiation, gender, age, apoptosis, and p53 expression (p = 0.02). Survivin was not associated with survival in the patients without (p = 0.08) or with (p = 0.19) RT. After RT, survivin tended to be increased in adjacent normal mucosa (p = 0.057) but not in tumors (p = 0.71). Conclusion: Survivin was independently related to survival in rectal cancer patients who participated in a trial of preoperative RT, but not in either treatment group (surgery alone or surgery plus RT). Whether the effect of survivin on tumors is associated with RT and further related to patient survival needs to be investigated in a larger number of patients. (C) 2004 Elsevier Inc.
  •  
22.
  • Lewander, Andreas, et al. (author)
  • Expression of NF-kappa B p65 phosphorylated at serine-536 in rectal cancer with or without preoperative radiotherapy
  • 2011
  • In: Radiology and Oncology. - : Walter de Gruyter. - 1318-2099 .- 1581-3207. ; 45:4, s. 279-284
  • Journal article (peer-reviewed)abstract
    • Background. In the present study, we investigated NF-kappa B p65 phosphorylated at Serine-536 (phosphor-Ser536-p65) in rectal cancer and its relationship to preoperative radiotherapy (RT), clinicopathological variables and biological factors. Patients and methods. Expression of phosphor-Ser536-p65 was examined by using immunohistochemistry in 141 primary rectal cancers, 149 normal mucosa specimens and 48 metastases in the lymph nodes, from rectal cancer patients who participated in a Swedish clinical trial of preoperative RT. Results. The expression of phosphor-Ser536-p65 in the cytoplasm increased from normal mucosa to primary tumour (p<0.0001, for both the group that did and the group that did not received RT). The expression did not further increase from primary tumour to metastasis in either group (p>0.05). Expression of phosphor-Ser536-p65 was positively related to, or tended to be related to, the expression of tumour endothelium marker 1 (TEM1, p=0.02), FXYD-3 (p=0.001), phosphatase of regenerating liver (PRL, p=0.02), p73 (p=0.048) and meningioma associated protein (MAC30, p=0.05) in the group that received RT but there were no such relationships in the group that did not received RT (p>0.05). The expression of phosphor-Ser536-p65 was not related to clinicopathological factors including survival (p>0.05). Conclusions. The increased expression of phosphor-Ser536-p65 may be involved in rectal cancer development. After RT, phosphor-Ser536-p65 seems to be positively related to the biological factors, which associated with more malignant features of tumours. However, phosphor-Ser536-p65 was not directly related to the response of RT based on recurrence and survival.
  •  
23.
  • Liu, Na, et al. (author)
  • Nuclear expression of lysyl oxidase enzyme is an independent prognostic factor in rectal cancer patients.
  • 2017
  • In: Oncotarget. - : Impact journals. - 1949-2553. ; 8:36, s. 60015-60024
  • Journal article (peer-reviewed)abstract
    • Emerging evidence has implicated a pivotal role for lysyl oxidase (LOX) in cancer progression and metastasis. Whilst the majority of work has focused on the extracellular matrix cross-linking role of LOX, the exact function of intracellular LOX localisation remains unclear. In this study, we analysed the LOX expression patterns in the nuclei of rectal cancer patient samples and determined the clinical significance of this expression. Nuclear LOX expression was significantly increased in patient lymph node metastases compared to their primary tumours. High nuclear LOX expression in tumours was correlated with a high rate of distant metastasis and increased recurrence. Multivariable analysis showed that high nuclear LOX expression was also correlated with poor overall survival and disease free survival. Furthermore, we are the first to identify LOX enzyme isoforms (50 kDa and 32 kDa) within the nucleus of colon cancer cell lines by confocal microscopy and Western blot. Our results show a powerful link between nuclear LOX expression in tumours and patient survival, and offer a promising prognostic biomarker for rectal cancer patients.
  •  
24.
  • Loftas, Per, et al. (author)
  • EXPRESSION OF FXYD-3 IS AN INDEPENDENT PROGNOSTIC FACTOR IN RECTAL CANCER PATIENTS WITH PREOPERATIVE RADIOTHERAPY
  • 2009
  • In: INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS. - : Elsevier BV. - 0360-3016. ; 75:1, s. 137-142
  • Journal article (peer-reviewed)abstract
    • Purpose: FXYD-3 (MAT-8) is overexpressed in several types of cancers; however, its clinical relevance in rectal cancers has not been studied. Therefore, we examined FXYD-3 expression in rectal cancers from the patients who participated in a Swedish clinical trial of preoperative radiotherapy (RT) to determine whether FXYD-3 was overexpressed in rectal cancers and correlated with RT, survival, and other clinicopathologic variables. Methods and Materials: The study included 140 rectal cancer patients who participated in a clinical trial of preoperative RT, 65 with and 75 without RT before surgery. FXYD-3 expression was immumohistochemically examined in distant (n = 70) and adjacent (n = 101) normal mucosa, primary tumors (n = 140), and lymph node metastasis (n = 36). Results: In the whole cohort, strong FXYD-3 expression was correlated with infiltrative tumor growth (p = 0.02). In the RT group, strong FXYD-3 expression alone (p = 0.02) or combined with phosphatase of regenerating liver was associated with an unfavorable prognosis (p = 0.02), independent of both TNM stage and tumor differentiation. In tumors with strong FXYD-3 expression, there was less tumor necrosis (p = 0.02) and a trend toward increased incidence of distant metastasis (p = 0.08) after RT. None of these effects was seen in the non-RT group. FXYD-3 expression in the primary tumors tended to he increased compared with normal mucosa regardless of RT. Conclusion: FXYD-3 expression was a prognostic factor independent of tumor stage and differentiation in patients receiving preoperative RT for rectal cancer.
  •  
25.
  • Lööf, Jasmine, et al. (author)
  • Significance of an exon 2 G4C14-to-A4T14 polymorphism in the p73 gene on survival in rectal cancer patients with or without preoperative radiotherapy
  • 2009
  • In: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 92:2, s. 215-220
  • Journal article (peer-reviewed)abstract
    • Background and Purpose: An exon 2 G4C14→A4T14 polymorphism in the p73 gene was shown to be related to survival in several types of cancers, including colorectal cancer. The purpose was to investigate if this polymorphism was related to survival in rectal cancer patients with or without preoperative radiotherapy. Material and Methods: DNA extracted from tissue of 138 rectal cancer patients that received preoperative radiotherapy or had surgery alone was typed for the polymorphism by PCR using confronting two-pair primers. Results: Among patients, 69% had GC/GC genotype, 27% GC/AT and 4% AT/AT. In the radiotherapy group, patients carrying the AT (GC/AT+AT/AT) allele had stronger expression of p53 (p=0.001) and survivin protein (p=0.03) than those carrying the GC/GC genotype. Further, among patients receiving preoperative radiotherapy the GC/GC genotype tended to be related to better survival (p=0.20). Patients with GC/GC genotype, along with negative p53 and weak survivin expression showed better survival than the other patients (p=0.03), even after adjusting for TNM stage and tumor differentiation (p=0.01, RR, 7.63, 95% CI, 1.50-38.74). In the non-radiotherapy group, the polymorphism was not related to survival (p=0.74). Conclusions: Results suggest that the p73 G4C14→A4T14 polymorphism could be one factor influencing outcome of preoperative radiotherapy in rectal cancer patients.
  •  
26.
  •  
27.
  • Meng, Wen-Jian, et al. (author)
  • Expressions of miR-302a, miR-105, and miR-888 Play Critical Roles in Pathogenesis, Radiotherapy, and Prognosis on Rectal Cancer Patients : A Study From Rectal Cancer Patients in a Swedish Rectal Cancer Trial of Preoperative Radiotherapy to Big Database Analyses
  • 2020
  • In: Frontiers in Oncology. - : Frontiers. - 2234-943X. ; 10
  • Journal article (peer-reviewed)abstract
    • Differential expressions and functions of various micoRNAs (miRNAs) have been intensively studied in both colon and rectal cancers. However, the importance of miRNAs on radiotherapy (RT) response and clinical outcome in rectal cancer patients remains unclear. In this study, we used real-time polymerase chain reaction to examine the expressions of miR-302a, miR-105, and miR-888 in normal mucosa and cancer tissue from rectal cancer patients with and without preoperative RT. The biological function of miR-302a, miR-105, and miR-888 expression was further analyzed and identified through the public databases: TCGA (The Cancer Genome Atlas) and GEPIA (Gene Expression Profiling Interactive Analysis). The results showed that the expression of miR-105 in rectal cancer was higher than that in normal mucosa in RT (P = 0.042) and non-RT patients (P = 0.003) and was associated with mucinous histological type (P = 0.004), COX-2 (P = 0.042), and p73 expression (P = 0.030). The expression of miR-302a was shown more frequently in cancers with necrosis (P = 0.033) and with WRAP53 expression (P = 0.015), whereas miR-888 expression occurred more frequently in tumors with protein the expression of survivin (P = 0.015), AEG-1 (astrocyte elevated gene-1) (P = 0.003), and SATB1 (special AT-rich sequence binding protein 1) (P = 0.036). Moreover, TargetScan also predicted AEG-1 and SATB1 as putative targets for miR-888. The miRNA-gene network analysis showed that ABI2 was associated with all the three miRNAs, with lower expression and good diagnostic value in rectal cancers. The TCGA database demonstrated the association of miR-105 expression with high carcinoembryonic antigen level (P = 0.048). RT reduced the expressions of miR-302a, miR-105, and miR-888. Prognostic analysis showed that miR-888 expression was independently associated with worse survival of patients without RT [overall survival, P = 0.001; disease-free survival, P = 0.009]. Analysis of biological function revealed that the protein serine/threonine kinase activity and PI3K-AKT signaling pathway were the most significantly enriched functions and pathways, respectively. Our findings suggest that miR-105 is involved in rectal cancer pathogenesis and miR-888 is associated with prognosis. MiR-302a, miR-105, and miR-888 have potential influence on the pathogenesis, RT, and prognosis of rectal cancer.
  •  
28.
  • Meng, Wen-Jian, et al. (author)
  • Special AT-rich sequence binding protein 1 expression correlates with response to preoperative radiotherapy and clinical outcome in rectal cancer
  • 2015
  • In: Cancer Biology & Therapy. - : Taylor & Francis. - 1538-4047 .- 1555-8576. ; 16:12, s. 1738-1745
  • Journal article (peer-reviewed)abstract
    • Our recent study showed the important role of special AT-rich sequence binding protein 1 (SATB1) in the progression of human rectal cancer. However, the value of SATB1 in response to radiotherapy (RT) for rectal cancer hasn't been reported so far. Here, SATB1 was determined using immunohistochemistry in normal mucosa, biopsy, primary cancer, and lymph node metastasis from 132 rectal cancer patients: 66 with and 66 without preoperative RT before surgery. The effect of SATB1 knockdown on radiosensitivity was assessed by proliferation-based assay and clonogenic assay. The results showed that SATB1 increased from normal mucosa to primary cancer, whereas it decreased from primary cancer to metastasis in non-RT patients. SATB1 decreased in primary cancers after RT. In RT patients, positive SATB1 was independently associated with decreased response to preoperative RT, early time to metastasis, and worse survival. SATB1 negatively correlated with ataxia telangiectasia mutated (ATM) and pRb2/p130, and positively with Ki-67 and Survivin in RT patients, and their potential interaction through different canonical pathways was identified in network ideogram. Taken together, our findings disclose for the first time that radiation decreases SATB1 expression and sensitizes cancer cells to confer clinical benefit of patients, suggesting that SATB1 is predictive of response to preoperative RT and clinical outcome in rectal cancer.
  •  
29.
  • Moparthi, Satish Babu, et al. (author)
  • pRb2/p130 protein in relation to clinicopathological and biological variables in rectal cancers with a clinical trial of preoperative radiotherapy
  • 2009
  • In: INTERNATIONAL JOURNAL OF COLORECTAL DISEASE. - : Springer Science and Business Media LLC. - 0179-1958 .- 1432-1262. ; 24:11, s. 1303-1310
  • Journal article (peer-reviewed)abstract
    • pRb2/p130 plays a key role in cell proliferation and is a considerable progress about expression patterns of pRb2/p130 in number of malignancies. However, pRb2/p130 expression and its significance in rectal cancer remain unknown. The purpose of the present study was to investigate pRb2/p130 protein patterns and their correlations with clinicopathological and biological factors in rectal cancer patients with or without preoperative radiotherapy (RT). pRb2/p130 protein was examined by immunohistochemistry in 130 primary tumors, along with the corresponding 61 distant normal mucosa specimens, 85 adjacent normal mucosa specimens, 34 lymph node metastases, and 93 primary tumor biopsies from rectal cancer patients who participated in a Swedish clinical trial of preoperative RT. The pRb2/p130 protein was mainly localized in the cytoplasm of tumor cells. In nonradiated cases, the lack of pRb2/p130 was related to advanced tumor-node-metastases stage, poorer differentiation, weak fibrosis, less inflammatory infiltration, higher Ki-67, and positive Cox-2 expression (p andlt; 0.05). In radiated cases, the lack of pRb2/p130 was related to nonstaining of Cox-2 and survivin (p andlt; 0.05). pRb2/p130 protein in primary tumors tended to be increased after RT (27% vs 16%, p = 0.07). pRb2/p130 was mainly localized in the cytoplasm rather than in the nucleus in rectal cancer. After RT, pRb2/p130 protein seems to be increased in primary tumors, and further the relationship of the pRb2/p130 with the clinicopathological and biological variables changed compared to the nonradiated cases. However, we did not find that the pRb2/p130 was directly related to RT, tumor recurrence, and patients survival.
  •  
30.
  • Pachkoria, Ketevan, et al. (author)
  • Significance of Cox-2 expression in rectal cancers with or without preoperative radiotherapy
  • 2005
  • In: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier BV. - 0360-3016 .- 1879-355X. ; 63:3, s. 739-744
  • Journal article (peer-reviewed)abstract
    • Purpose: Radiotherapy has reduced local recurrence of rectal cancers, but the result is not satisfactory. Further biologic factors are needed to identify patients for more effective radiotherapy. Our aims were to investigate the relationship of cyclooxygenase-2 (Cox-2) expression to radiotherapy, and clinicopathologic/biologic variables in rectal cancers with or without radiotherapy. Methods and Materials: Cox-2 expression was immunohistochemically examined in distal normal mucosa (n = 28), in adjacent normal mucosa (n = 107), in primary cancer (n = 138), lymph node metastasis (n = 30), and biopsy (n = 85). The patients participated in a rectal cancer trial of preoperative radiotherapy. Results: Cox-2 expression was increased in primary tumor compared with normal mucosa (p < 0.0001), but there was no significant change between primary tumor and metastasis. Cox-2 positivity was or tended to be related to more p53 and Ki-67 expression, and less apoptosis (p ≤ 0.05). In Cox-2-negative cases of either biopsy (p = 0.01) or surgical samples (p = 0.02), radiotherapy was related to less frequency of local recurrence, but this was not the case in Cox-2-positive cases. Conclusion: Cox-2 expression seemed to be an early event involved in rectal cancer development. Radiotherapy might reduce a rate of local recurrence in the patients with Cox-2 weakly stained tumors, but not in those with Cox-2 strongly stained tumors. © 2005 Elsevier Inc.
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31.
  • Pathak, Surajit, et al. (author)
  • Association of MicroRNA-652 Expression with Radiation Response of Colorectal Cancer : A Study from Rectal Cancer Patients in a Swedish Trial of Preoperative Radiotherapy
  • 2023
  • In: Current Gene Therapy. - : Bentham Science Publishers. - 1566-5232 .- 1875-5631. ; 23:5, s. 356-367
  • Journal article (peer-reviewed)abstract
    • Background: Radiotherapy is a standard adjuvant therapy in patients with progressive rectal cancer, but many patients are resistant to radiotherapy, leading to poor prognosis. Our study identified microRNA-652 (miR-652) value on radiotherapy response and outcome in rectal cancer patients.Methods: miR-652 expression was determined by qPCR in primary rectal cancer from 48 patients with and 53 patients without radiotherapy. The association of miR-652 with biological factors and the prognosis was examined. The biological function of miR-652 was identified through TCGA and GEPIA database searches. Two human colon cancer cell lines (HCT116 p53(+/+) and p53(-/-)) were used for in vitro study. The molecular interactions of miR-652 and tumor suppressor genes were studied through a computational approach.Results: In RT patients, miR-652 expression was significantly decreased in cancers when compared to non-radiotherapy cases (P = 0.002). High miR-652 expression in non-RT patients was with increased apoptosis marker (P = 0.036), ATM (P = 0.010), and DNp73 expression (P = 0.009). High miR-652 expression was related to worse disease-free survival of non-radiotherapy patients, independent of gender, age, tumor stage, and differentiation (P = 0.028; HR = 7.398, 95% CI 0.217-3.786). The biological functional analysis further identified the prognostic value and potential relationship of miR-652 with apoptosis in rectal cancer. miR-652 expression in cancers was negatively related to WRAP53 expression (P = 0.022). After miR-652 inhibition, the estimation of reactive oxygen species, caspase activity, and apoptosis in HCT116 p53(+/+ )cells was significantly increased compared with HCT116 p53(-/-) cells after radiation. The results of the molecular docking analysis show that the miR652-CTNNBL1 and miR652-TP53 were highly stable.Conclusion: Our findings suggest the potential value of miR-652 expression as a marker for the prediction of radiation response and clinical outcome in rectal cancer patients.
  •  
32.
  • Pathak, Surajit, et al. (author)
  • Tafazzin Protein Expression Is Associated with Tumorigenesis and Radiation Response in Rectal Cancer : A Study of Swedish Clinical Trial on Preoperative Radiotherapy
  • 2014
  • In: PLOS ONE. - San Francisco : Public Library Science. - 1932-6203. ; 9:5
  • Journal article (peer-reviewed)abstract
    • Background: Tafazzin (TAZ), a transmembrane protein contributes in mitochondrial structural and functional modifications through cardiolipin remodeling. TAZ mutations are associated with several diseases, but studies on the role of TAZ protein in carcinogenesis and radiotherapy (RT) response is lacking. Therefore we investigated the TAZ expression in rectal cancer, and its correlation with RT, clinicopathological and biological variables in the patients participating in a clinical trial of preoperative RT.Methods: 140 rectal cancer patients were included in this study, of which 65 received RT before surgery and the rest underwent surgery alone. TAZ expression was determined by immunohistochemistry in primary cancer, distant, adjacent normal mucosa and lymph node metastasis. In-silico protein-protein interaction analysis was performed to study the predictive functional interaction of TAZ with other oncoproteins.Results: TAZ showed stronger expression in primary cancer and lymph node metastasis compared to distant or adjacent normal mucosa in both non-RT and RT patients. Strong TAZ expression was significantly higher in stages I-III and non-mucinious cancer of non-RT patients. In RT patients, strong TAZ expression in biopsy was related to distant recurrence, independent of gender, age, stages and grade (p = 0.043, HR, 6.160, 95% CI, 1.063-35.704). In silico protein-protein interaction study demonstrated that TAZ was positively related to oncoproteins, Livin, MAC30 and FXYD-3.Conclusions: Strong expression of TAZ protein seems to be related to rectal cancer development and RT response, it can be a predictive biomarker of distant recurrence in patients with preoperative RT.
  •  
33.
  • Pfeifer, Daniella, et al. (author)
  • Expression of the p73 protein in rectal cancers with or without preoperative radiotherapy
  • 2006
  • In: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier. - 0360-3016 .- 1879-355X. ; 65:4, s. 1143-1148
  • Journal article (peer-reviewed)abstract
    • Purpose: To investigate p73 expression in normal mucosa, primary tumor, and metastasis in relation to radiotherapy (RT) response and clinicopathologic/biologic variables in rectal cancers. Methods and Materials: p73 was immunohistochemically examined on biopsies (unirradiated, n = 102), distant (from the large bowel, n = 82), and adjacent (adjacent to primary tumor, n = 89) normal mucosa samples, primary tumors (n = 131), and lymph node metastasis (n = 32) from rectal cancer patients participating in a clinical trial of preoperative RT. Seventy-four patients received surgery alone and 57 received additional RT. Results: Cytoplasmic p73 was increased in the primary tumor compared with the distant or adjacent mucosa (p ≤ 0.0001). Nuclear (p = 0.02) and cytoplasmic (p = 0.003) p73 was higher in irradiated distant mucosa samples than in unirradiated ones, and nuclear p73 tended to be increased in irradiated primary tumors compared with unirradiated ones (p = 0.06). p73 was positively related to cyclooxygenase-2 expression in irradiated tumors (p = 0.03). p73-negative tumors tended to have a lower local recurrence after RT compared with unirradiated cases (p = 0.06). Conclusions: Normal epithelial cells seem more sensitive to RT than tumor cells regarding p73 expression. Patients with p73-negative rectal tumors may have a lower risk of local recurrence after RT.
  •  
34.
  • von Dobeln, Gabriella Alexandersson, et al. (author)
  • Pulmonary function and cardiac stress test after multimodality treatment of esophageal cancer
  • 2016
  • In: Practical Radiation Oncology. - : Elsevier BV. - 1879-8500 .- 1879-8519. ; 6:3, s. E53-E59
  • Journal article (peer-reviewed)abstract
    • Purpose: Curative treatment of esophageal cancer is accompanied by frequent and sometimes severe side effects. However, prospectively collected data on side effects are scarce. The aim of this study was to evaluate if pulmonary function and exercise capacity were affected in the acute setting after neoadjuvant treatment and if there were long-lasting effects after neoadjuvant treatment and surgery. We also aimed to investigate whether the addition of radiation therapy to chemotherapy would aggravate side effects. Methods and materials: A cohort of 97 patients enrolled in the randomized NeoRes trial was used for the present analysis. The patients had been randomized to receive 3 cycles of cisplatin and fluorouracil with or without concurrent radiation therapy to 40 Gy. A cardiac stress test on a stationary bicycle and a spirometry were performed before and after neoadjuvant treatment and 1 to 2 years later after surgery provided that the cancer had not recurred. Results: We found impairment in pulmonary function measured as vital capacity and forced expiratory volume in 1 second and a decrease in exercise capacity after neoadjuvant treatment and 1 to 2 years later after surgery. We did not detect any differences between patients treated with chemoradiation therapy and those treated with chemotherapy alone. Conclusions: Multimodality treatment of esophageal cancer caused short-term and lasting impairments in pulmonary function and exercise capacity. The reductions were not aggravated by the addition of radiation therapy to neoadjuvant chemotherapy.
  •  
35.
  • Wallin, Åsa R., 1976-, et al. (author)
  • Expression of PRL proteins at invasive margin of rectal cancers in relation to preoperative radiotherapy
  • 2006
  • In: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier BV. - 0360-3016 .- 1879-355X. ; 65:2, s. 452-458
  • Journal article (peer-reviewed)abstract
    • Purpose: PRL-3 (phosphatase of regenerating liver) is involved in metastasis of colorectal cancer; however, its therapeutic implication in cancer patients has not been studied. We investigated the relationships of PRL expression to radiotherapy (RT) in rectal cancer patients.Methods and Materials: Phosphatase of regenerating liver expression was immunohistochemically examined in distant (n = 36) and adjacent (n = 82) normal mucosa, primary tumor (n = 125), biopsy specimens (n = 96), and lymph node metastasis (n = 30) from rectal cancer patients participating in a clinical trial of preoperative RT.Results: Phosphatase of regenerating liver expression was increased from the distant to adjacent mucosa and to the primary tumor (p < 0.05). PRL was highly expressed at the invasive margin in 28% of the primary tumors and 26% of the metastases. In the RT group, strong PRL expression at the invasive margin was related to distant recurrence (p = 0.006) and poor survival (p = 0.01), but not in the non-RT group. The survival significance remained even after adjusting for Dukes’ stage and differentiation (p = 0.02). Additional multivariate analyses showed that the correlation with prognostic significance of PRL differed between the RT and non-RT groups (p = 0.01).Conclusion: Phosphatase of regenerating liver expression (rather than PRL-3 alone) at the invasive margin predicted resistance to RT and unfavorable survival in rectal cancer patients with preoperative RT.
  •  
36.
  • Wang, Chao-Jie, et al. (author)
  • Prognostic value of nuclear FBI-1 in patients with rectal cancer with or without preoperative radiotherapy
  • 2019
  • In: Oncology Letters. - : Spandidos Publications. - 1792-1074 .- 1792-1082. ; 18:5, s. 5301-5309
  • Journal article (peer-reviewed)abstract
    • Factor that binds to the inducer of short transcripts of the human immunodeficiency virus-1 (FBI-1) represents as a crucial gene regulator in colorectal cancer; however, the correlation between FBI-1 and preoperative radiotherapy (RT) in rectal cancer (RC) has not yet been reported. The aim was to detect FBI-1 expression in patients with RC with or without RT, by immunohistochemistry and quantitative polymerase chain reaction, and to analyze its association with clinicopathological features and response to RT. The results from immunohistochemistry analysis (n=139) and reverse transcription-quantitative polymerase chain reaction (n=55) demonstrated that FBI-1 was overexpressed in patients with RC, whether they had received preoperative RT or not. Subsequently, the association between FBI-1 expression, and the clinicopathological features and response to RT in patients with RC was analyzed. Cytoplasmic FBI-1 was upregulated in non-RT (n=77) and RT (n=62) groups (17.7 vs. 74.0%, P<0.001; 41.1 vs. 69.4%, P=0.002, respectively) of patients with RC compared with normal mucosa. However, nuclear FBI-1 was downregulated (75.8 vs. 22.1%, P<0.001; 83.9 vs. 35.5%, P<0.001, respectively) in both groups. RT had no significant effect on FBI-1 expression in RC tissues. Furthermore, nuclear FBI-1 was positively associated with tumor-node-metastasis stage and distant recurrence (P=0.003 and P=0.010, respectively). In patients with stage I, II or III RC, higher nuclear FBI-1 expression was associated with poorer disease-free survival [hazard ratio (HR)=1.934, 95% confidence interval (CI): 1.055-3.579, P=0.033] and overall survival (HR=2.174, 95% CI: 1.102-4.290, P=0.025), independently of sex, age, growth pattern, differentiation and RT. In addition, FBI-1 was positively correlated with numerous biological factors, including p73 [Spearman's correlation coefficient (rs)=0.332, P=0.007], lysyl oxidase (rs=0.234, P=0.043), Wrap53 (rs=-0.425, P=0.0002) and peroxisome proliferator-activated receptor δ (rs=-0.294, P=0.026). In conclusion, the present study demonstrated that nuclear FBI-1 was an independent prognostic factor in patients with RC and correlated with numerous biological factors, which indicated that it may have multiple roles in RC.
  •  
37.
  • Wang, Chao-Jie, et al. (author)
  • Survivin Expression Quantified by Image Pro-plus Compared With Visual Assessment
  • 2009
  • In: APPLIED IMMUNOHISTOCHEMISTRY and MOLECULAR MORPHOLOGY. - : Lippincott Williams & Wilkins. - 1062-3345 .- 1541-2016 .- 1533-4058. ; 17:6, s. 530-535
  • Journal article (peer-reviewed)abstract
    • Over the past decades, immunohistochemistry has gained significance and already taken a crucial position in diagnosis of diseases and prognosis of patients. However, manual interpretation of immunohistochemistry and reproducibility of the scoring systems can be highly Subjective. In the article, the immunohistochemical staining of survivin in 98 rectal cancers was analyzed by using Image Pro-Plus (IPP) [3 parameters: density mean, area sum, and integrated optical density (IOD)] and the results were compared with visual assessment (2 parameters: intensity and percentage). The correlations between the 2 methods were examined, significant correlations were observed between density mean and staining intensity (Spearman correlation coefficient, r(s) = 0.806, P andlt; 0.001) IOD and staining intensity (r(s) = 0.9147 P andlt; 0.001) area sum and staining percentage (r(s) = 0.883, P andlt; 0.001), IOD and staining percentage (r(s) = 0.884, P andlt; 0.001). There was no significant difference between survivin expression and clinicopathologic variables (P andgt; 0.05) by visual assessment. However, by IPP analysis, both the density mean and IOD were higher in better-differentiated cancers than in worse differentiated ones (P = 0.02 and 0.03). There was a substantial agreement between the 2 methods. Density mean and IOD of IPP were representative parameters to assess the immunostaining quantification, and increased sensitivity in scoring and provided a more reliable and reproducible analysis of protein expression, especially, more information of the protein expression in relation to clinicopathologic variables can be provided by IPP analysis.
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38.
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39.
  • Wen, Yugang, et al. (author)
  • Predictive Role of Biopsy Based Biomarkers for Radiotherapy Treatment in Rectal Cancer
  • 2020
  • In: Journal of Personalized Medicine. - : MDPI. - 2075-4426. ; 10:4
  • Journal article (peer-reviewed)abstract
    • Background and Purpose: Radiation therapy has long been contemplated as an important mode in the treatment of rectal cancer. However, there are few ideal tools available for clinicians to make a radiotherapy decision at the time of diagnosis for rectal cancer. The purpose of this study was to assess whether biomarkers expressed in the biopsy could help to choose the suitable therapy and provide predictive and/or prognostic information. Experimental Design: In total, 30 biomarkers were analyzed in 219 biopsy samples before treatment to discover the possibility of using them as an indicator for radiotherapy selection, diagnosis, survival and recurrence. Results: Twenty-two biomarkers (COX2-RT, COX2-NonRT, etc.; 36.67%) had diagnostic value. For survival, four biomarkers (NFKBP65, p130, PINCH and PPAR) were significant in regulating gene promoter activity and overall survival, while four had a trend (AEG1, LOX, SATB1 and SIRT6). Three biomarkers (COX2, PINCH and WRAP53) correlated with disease-free survival, while eight had a trend (AEG1, COX2, Ki67, LOX, NFKBP65, PPAR and SATB1). Four biomarkers (COX2-RT, NFKBP65cyto-RT, P130cyto-NonRT and PPARcyto-RT) were independent prognostic factors for recurrence. NFKBP65 and SIRT6 were significantly correlated with lymph node metastasis regardless of radiation. Patients with high AEG1, LOX, NFKBP65, PPAR and SATB1 had or showed a positive trend for better survival after radiotherapy, while those with positive PINCH and WRAP53 expression would not benefit from radiotherapy. Conclusions: AEG1, LOX, NFKBP65cyto, PPAR and SATB1 could be used as indicators for choosing radiotherapy. COX2-RT, COX2-NonRT and some other biomarkers may provide additional help for diagnosis.
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40.
  • Zhang, Hong, et al. (author)
  • WRAP53 is an independent prognostic factor in rectal cancer- a study of Swedish clinical trial of preoperative radiotherapy in rectal cancer patients
  • 2012
  • In: BMC Cancer. - : BioMed Central. - 1471-2407. ; 12:294
  • Journal article (peer-reviewed)abstract
    • Background: Expression of WRAP53 protein has oncogenic properties and it is up regulated in several types of tumors. less thanbrgreater than less thanbrgreater thanMethods: We examined expression of WRAP53 protein in rectal cancers and analyzed its relationship to the response to preoperative radiotherapy and patient survival. The WRAP53 protein was examined by immunohistochemistry in normal mucosa, primary tumors and lymph node metastases from 143 rectal cancer patients participated in a Swedish clinical trial of preoperative radiotherapy. less thanbrgreater than less thanbrgreater thanResults: Frequency of WRAP53 protein expression was increased in primary rectal cancer compared to the normal mucosa (p andlt; 0.05). In non-radiotherapy group positive WRAP53 in primary tumors (p = 0.03, RR, 3.73, 95% CI, 1.13-11.89) or metastases (p = 0.01, RR, 4.11, 95% CI, 1.25-13.14), was associated with poor prognosis independently of stages and differentiations. In radiotherapy group, positive WRAP53 in the metastasis correlated with better survival (p = 0.04). An interaction analysis showed that the correlations of WRAP53 with the prognostic significance with and without radiotherapy in the metastasis differed (p = 0.01). In the radiotherapy group, expression of WRAP53 in metastases gave a better outcome (p = 0.02, RR, 0.32, 95% CI, 0.13-0.84), and an interaction analysis showed significance between the two groups (p = 0.01). less thanbrgreater than less thanbrgreater thanConclusion: WRAP53 may be a new biomarker used to predict prognosis and to select suitable patients for preoperative radiotherapy.
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41.
  • Zhang, Zhiyong, et al. (author)
  • Endosialin expression in relation to clinicopathological and biological variables in rectal cancers with a Swedish clinical trial of preoperative radiotherapy
  • 2011
  • In: BMC CANCER. - : BioMed Central. - 1471-2407. ; 11:89
  • Journal article (peer-reviewed)abstract
    • Background: The importance of changes in tumour-associated stroma for tumour initiation and progression has been established. Endosialin is expressed in fibroblasts and pericytes of blood vessels in several types of tumours, and is involved in the progression of colorectal cancer. In order to see whether endosialin was related to radiotherapy (RT) response, and clinicopathological and biological variables, we investigated endosialin expression in rectal cancers from the patients who participated in a Swedish clinical trial of preoperative RT. Methods: Endosialin was immunohistochemically examined in normal mucosa, including distant (n = 72) and adjacent (n = 112) normal mucosa, and primary tumours (n = 135). Seventy-three of 135 patients received surgery alone and 62 received additional preoperative RT. Results: Endosialin expression in the stroma increased from normal mucosa to tumour (p andlt; 0.0001) both in RT and non-RT group. In the RT group, endosialin expression in the stroma was positively associated with expression of cyclooxygenase-2 (Cox-2) (p = 0.03), p73 (p = 0.01) and phosphates of regenerating liver (PRL) (p = 0.002). Endosialin expression in the tumour cells of both in the RT group (p = 0.01) and the non-RT group (p = 0.06) was observed more often in tumours with an infiltrative growth pattern than in tumours with an expansive growth pattern. In the RT group, endosialin expression in tumour cells was positively related to PRL expression (p = 0.02), whereas in the non-RT group, endosialin expression in tumour cells was positively related to p73 expression (p = 0.01). Conclusions: Endosialin expression may be involved in the progression of rectal cancers, and was related to Cox-2, p73 and PRL expression. However, a direct relationship between endosialin expression and RT responses in patients was not found.
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42.
  • Zhang, Zhiyong, 1970-, et al. (author)
  • Expression of MAC30 in rectal cancers with or without preoperative radiotherapy
  • 2007
  • In: Oncology. - : S. Karger AG. - 0890-9091 .- 0030-2414 .- 1423-0232. ; 71:3-4, s. 259-265
  • Journal article (peer-reviewed)abstract
    • Objective: Meningioma-associated protein (MAC30) is overexpressed in several types of cancers, but its therapeutic implication in the patients has not been studied. We examined the relationship of MAC30 with clinicopathological and biological factors in rectal cancer patients with or without radiotherapy (RT). Methods: MAC30 was immunohistochemically examined in 75 distant and 91 adjacent normal mucosa specimens, 132 primary tumours and 39 lymph node metastases from rectal cancer patients participating in a clinical trial of preoperative RT. Results: In the RT group, MAC30 was or tended to be positively correlated with infiltrated growth pattern (p = 0.02), PRL (phosphatase of regenerating liver, p = 0.01) and Ki-67 expression (p = 0.06). MAC30 at the invasive margin of the metastasis was related to poor survival (p = 0.02) in the whole group of patients. MAC30 in primary tumours was not related to recurrence and survival in the non-RT or RT group. Conclusions:MAC30 expression in metastasis was an indicator for poor survival. After RT, MAC30 seemed to be more related to aggressive morphological and biological factors, however, we did not find direct evidence that MAC30 expression was related to the outcome of patients with or without RT. Copyright © 2006 S. Karger AG.
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