Expression of DSG1 and DSC1 are prognostic markers in anal carcinoma patients.

BACKGROUND: Our purpose was to investigate if dysregulation of cell adhesion molecules could be linked to prognosis in squamous cell carcinomas (SCCs) of the anal region. METHODS: Protein expression of desmoglein-1 (DSG1), desmocollin-1 (DSC1) and E-cadherin was studied by immunohistochemistry in a cohort of 53 anal carcinoma patients treated by radiation alone or combined with 5-fluorouracil and mitomycin C. RESULTS: Univariate analyses identified, among others, negative membranous DSG1 staining (P=0.009), negative cytoplasmic DSC1 staining (P=0.012) and negative DSG1 (membranous)+negative DSC1 (cytoplasmic) staining (P=0.004) to be associated with improved cancer-specific survival (CSS). On multivariate analyses positive DSG1 (membranous)+DSC1 (cytoplasmic) staining (HR 6.95, P=0.044), large tumour size and lymph node metastases (HR 6.44, P=0.004) and radiation without chemotherapy (HR 6.73 P=0.004) were associated with worse CSS. On univariate analysis, improved disease-free survival was associated with negative membranous staining of DSG1 (P=0.047), and negative DSG1 (membranous)+negative DSC1 (cytoplasmic) staining (P=0.025), among others. CONCLUSION: Membrane negativity for DSG1 and cytoplasmic negativity for DSC1 are favourable markers for CSS in SCCs of the anal region.

MicroRNA-15b is induced with E2F-controlled genes in HPV-related cancer.

BACKGROUND: MicroRNAs (miRNAs) are important regulators of cellular processes and are found to be deregulated in many cancers. We here analysed the miRNA expression in anal carcinomas. In a previous study, we found that our anal carcinoma tumours were divided into two groups based on the expression of E2F-regulated genes. Therefore, we searched for miRNAs that could reproduce this grouping. METHODS: A global screen of the miRNA population was performed using real-time quantitative PCR (RT-qPCR) array methods and differentially expressed miRNAs were identified. Real-time-qPCR was used to verify the expression levels of selected miRNAs and genes in a larger collection of biopsies. A siRNA-mediated knockdown of human papilloma virus (HPV)16 E7 in a cervical cell line was performed to assess the effect of E7 on miR-15b. RESULTS: The grouping of tumours into two groups based on the expression of E2F-controlled genes was confirmed in a larger collection of anal carcinoma tumours. The expression of miR-15b was shown to be highly correlated with that of five selected E2F-induced genes (CCNA2, CCNB1, CCNB2, MSH6 and MCM7). A knockdown of HPV16 E7 resulted in decreased levels of miR-15b in Ca Ski cells. CONCLUSION: MiR-15b expression correlates with E2F-regulated genes in anal carcinoma and appears to be part of the E2F-regulatory network.

Rectal cancer with macroscopic peritoneal involvement--clinical challenges and consequences.

OBJECTIVE: In gastrointestinal cancer, serosal involvement indicates advanced disease. We looked at the possible role of clinical peritoneal involvement (CPI) in local recurrences (LRs) and the overall survival of patients with rectal cancer (RC). METHOD: Between 1993 and 2002, 6404 patients were diagnosed with RC. Based on macroscopic findings at surgery and corresponding histological findings, 166 patients (3%) had CPI. Surgery was stratified according to type and extent of operation: as resective or nonresective surgery and as curative (R0) or noncurative (R1 or R2) resection. RESULTS: The presence of CPI was a negative factor for survival with a median of 15 months (95% CI, 12-19) in the presence of CPI compared with 65 months (95% CI, 61-70) without it (P < 0.001). In R0 resections, the median survival was 97 months (95% CI, 90-102) in patients without CPI compared with 48 months (95% CI, 22-74) in patients with CPI (P < 0.001). In R1 or R2 resections, the median survival was 16 months (95% CI, 15-17) in the absence of CPI and 9 months (95% CI, 8-10) in the presence of CPI. The LR rate in patients without CPI was 10.2% compared with 15.7% in patients with CPI (P = 0.022). CONCLUSIONS: Clinical peritoneal involvement is a significant detrimental prognostic factor for the LR of RC and survival in the absence of metastases. Observations from this large national cohort add to what is known about peritoneal involvement. Diagnosed CPI should be taken into consideration when adjuvant treatment strategies are addressed.

Gene expression reveals two distinct groups of anal carcinomas with clinical implications.

Human papillomavirus (HPV) is a major aetiological agent in anal carcinomas. We here present a study of global gene expression using microarray hybridisation in a collection of anal carcinoma biopsies. Quantitative PCR was used to verify expression of selected genes. All biopsies contained integrated DNA of human papillomavirus subtype 16 (HPV16) and expressed HPV16 E7 mRNA. No other subspecies of HPV were detected in these 13 biopsies as assessed by PCR amplification and DNA sequencing. Unsupervised cluster analysis, based on global mRNA expression, divided the tumour biopsies into two distinct groups. Cluster analysis based on a number of high-risk HPV and/or E2F-regulated genes reproduced this biopsy grouping, suggesting that integrated HPV16 substantially influenced global gene expression in approximately half the biopsies studied. The levels of HPV16 E7 mRNA were significantly different between the two groups, but with considerable overlap. Thus, influence on global gene expression could not be absolutely ascribed to the expression level of HPV16. To investigate whether this distinction in gene expression had prognostic impact, we studied protein expression in an independent cohort of 55 anal carcinomas not included in the microarray study of two differentially expressed candidate genes, minichromosome maintenance complex component 7 (MCM7) and cyclin-dependent kinase inhibitor 2A (CDKN2A or p16). HPV status was assessed by in situ hybridisation. There was a significant association between in situ staining for HPV E7 mRNA and immunostaining for CDKN2A (p16) and MCM7 protein. CDKN2A (p16) mRNA was found significantly differentially expressed between the two tumour groups. However, cluster analysis on genes directly regulated by CDKN2A (p16) could not reproduce this split of biopsies into two groups, suggesting that the transcriptional regulatory activity of CDKN2A in these biopsies is inhibited. Furthermore, protein expression of CDKN2A (p16) could not be associated with survival. MCM7 is directly regulated by E2F and induced by HPV, and its mRNA was found differentially expressed between the two tumour groups. High level of MCM7 protein was found to be associated with both improved relapse-free survival (RFS, P=0.02) and cancer-specific survival (CSS, P=0.03) in anal cancer patients treated with radiation with or without additional chemotherapy.

Palliative surgery for rectal cancer in a national cohort.

OBJECTIVE: Whether resection of the primary tumour is of benefit to patients with incurable rectal cancer (RC) remains a matter of debate. In this study we analyse prospectively recorded data from a national cohort. METHOD: Among 4831 patients diagnosed with RC between 1997 and 2001, 838 (17%) patients were treated with palliative surgery. Patients were stratified according to disease stage, age and type of surgery. RESULTS: A significantly longer median survival, 12 (range 10-13) months, was observed in patients treated with resection of the primary tumour compared with 5 (range 4-6) months in patients treated with nonresective procedures (P < 0.001). Median survival in months was significantly (P < 0.001) related to age (13; < 60 years of age, 10; 60 to 69 years, 7; 70 to 79 years, 6; >/= 80 years of age). In patients over 80 years, survival was similar regardless of the treatment. Thirty-day mortality varied from 2.5% to 20%, according to age groups. CONCLUSION: The longer survival observed in patients with resection of the primary tumour may partly be explained by patient selection. Elderly patients (>/= 80 years) had a similar survival, irrespective of resection of the primary tumour or not. Careful consideration of the individual patient, extent of disease and treatment-related factors are important in decision-taking for palliative treatment for patients with advanced RC.

Local resection of rectal tumors by transanal endoscopic microsurgery: experience with the first 70 cases.

BACKGROUND: Transanal endoscopic microsurgery (TEM) can access the whole rectum up to 20 cm from the anal verge. Due to its excellent view and accurate dissection, TEM is useful for the removal of adenoma and selected low risk cancers of the rectum. We report our experience with the first 70 patients presenting. METHODS: A prospective descriptive study of 70 patients treated for rectal tumor with TEM from December 99 until October 2002 at Haukeland University Hospital. RESULTS: TEM was performed in 37 men and 33 women, median age 70.5 (19-90) years, for anticipated adenoma (n = 64), adenocarcinoma (n = 3), rectal ulcer (n = 1), and re-resection after snare resection of rectal polyp with adenocarcinoma (n = 1) and carcinoid tumor (n = 1). The median observation time was 12 (1-33) months. The distance from the anal verge to the lower tumor border was 5.5 (2.5-14) cm. The median resected area was 15.4 (1.5-132) cm(2). 56 of the 64 anticipated adenomas were true adenoma, resected without recurrences; 8 (12.5%) were unexpected adenocarcinoma. Three of these underwent a secondary rectal resection and 5 patients have been observed without recurrence. Of the 3 patients with known adenocarcinoma, there was one recurrence which was treated with a secondary curative rectal resection. CONCLUSIONS: TEM can access tumors in the whole rectum. Large tumors may be removed with low frequency of per- and postoperative complications and short hospital stay. TEM is highly useful for removal of rectal adenoma. A role for primary treatment of selected low-risk rectal cancers may emerge.

Dieulafoy's vascular malformation: role of endoscopic ultrasonography in therapeutic decision-making.

BACKGROUND: Dieulafoy's vascular malformation may cause severe, potentially life-threatening gastrointestinal bleeding. Endoscopic diagnosis may be difficult because of minute mucosal lesions, and additional intramural abnormalities are usually not encountered. Endoluminal high-frequency ultrasonography is a new modality for imaging intramural and perivisceral structures. METHODS: We report two cases of recurrent severe gastric bleeding in which different endosonographic modalities were used in the diagnosis of Dieulafoy's malformation, and the impact of endosonography on therapeutic strategy is discussed. In the first case a radial-scanning 7.5/12-MHz echoendoscope and a linear 20-MHz miniature probe were applied for B-mode imaging in a stable-state patient who had undergone previous endoscopic sclerotherapy, and arterial flow signals from the small intramural lesion were recorded using a 10-MHz transendoscopic pulsed Doppler probe. In the other case urgent endosonography was performed shortly after a bleeding episode, disclosing an aberrant large-calibre artery entering the gastric wall with a long submucosal branch. RESULTS: Both patients were successfully operated on with a transabdominal approach. CONCLUSION: Endosonography is a quick and safe diagnostic method and should be considered when vascular malformations are suspected as the cause of gastric bleeding.

Smoking and ulcer perforation.

BACKGROUND: The use of ulcerogenic drugs is the only well documented risk factor for peptic ulcer perforation, but accounts for only a quarter of the events. Smoking is a well known risk factor for uncomplicated ulcer disease, and patients with ulcer bleeding have increased death rates from smoking related disorders. AIM: To assess the role of smoking in ulcer perforation. SUBJECTS: A total of 168 consecutive patients with gastroduodenal ulcer perforation and 4469 control subjects from a population based health survey. METHODS: The association between ulcer perforation and smoking habits was analysed by logistic regression while adjusting for age and sex. RESULTS: Current smoking increased the risk for ulcer perforation 10-fold in the age group 15-74 years (OR 9.7, 95% CI 5.9 to 15.8) and there was a highly significant dose-response relationship (p < 0.001). The results were similar in men (OR 9.3, 95% CI 4.9 to 17) and women (OR 11.6, 95% CI 5.3 to 25), and for gastric (OR 10.5, 95% CI 4.5 to 25) and duodenal (OR 8.6, 95% CI 4.9 to 15.4) ulcer perforation. No increase in risk was found in previous smokers (OR 0.8, 95% CI 0.2 to 2.2). CONCLUSION: Our findings suggest that smoking is a causal factor for ulcer perforation and accounts for a major part of ulcer perforations in the population aged less than 75 years.

[High frequency ultrasonography of the gastrointestinal wall]. / Høyfrekvent ultrasonografi av gastrointestinalkanalens vegg.

If an ultrasound probe comes close to the area of interest, high ultrasound frequencies can be applied. Endoscopic ultrasonography is performed by means of echoendoscopes or miniature probes using ultrasound frequencies between 7 and 30 MHz. A high frequency ultrasound image of the normal gastrointestinal wall usually shows five layers corresponding closely to the histological layers of the wall. Corrections have to be made, however, for interface echoes between layers with different acoustic impedances. We describe studies performed with the aim of correlating ultrasound images of the normal and diseased gastrointestinal wall with the histology. Ultrasound images of the normal gastrointestinal wall and pathological changes like ischemia, ulcers, tumours and inflammation are presented.

Adjuvant tamoxifen for pre- and postmenopausal women with estrogen receptor positive, node positive breast cancer: a randomized study.

370 patients with operable, axillary node positive breast cancer, were randomized to receive tamoxifen (TAM) 20 mg/day for 2 years or no adjuvant hormone therapy. All patients had estrogen receptor (ER) positive (ER > 10 pmol/g) primary tumours. 350 patients, 93 younger than 50 years of age and 257 patients 50 years or older, were evaluable for the study. After a median follow up of 76 months, significantly (p = 0.0001) fewer loco-regional, but not distant (systemic), relapses have been recorded in the TAM group. Overall survival was also improved, but even though the study was designed to give maximum benefit from TAM statistically significant effect of TAM seemed to be limited to patients 50 years of age and older.

[Colonoscopy. In investigation, treatment and control of gastrointestinal diseases]. / Kolodkopi. I utredning, behandling og kontroll av gastrointestinale sykdommer.

Colonoscopy is the initial examination for patients with manifest or occult rectal bleeding, inflammatory bowel disease and colorectal polyps. In addition to polypectomy, colonoscopy is useful in decompression of adynamic colonileus and laser palliation of intractable tumours. In adenoma patients controls should be limited to high risk patients, i.e. those with large and multiple tubular adenomas, villous adenomas, multiple hyperplastic polyps (> 30), and first degree relatives of patients with colorectal carcinomas. Control after radical surgical treatment of colorectal cancer is offered during the first two years after the operation and to persons younger than 40 years. The efficacy of control programmes for hereditary nonpolyposis colorectal cancer families have to be evaluated in controlled series. Rectosigmoidoscopies could probably replace some total colonoscopies to examine ulcerative colitis patients for cancer, since cancer usually occurs in the distal colon. Complications are rare after diagnostic and therapeutic colonoscopies, but perforation, bleeding and injury to surrounding organs can be experienced.

Progesterone binding cyst protein in hormone receptor positive breast cancer; a predictive factor for effect of adjuvant tamoxifen treatment.

Progesterone binding cyst protein (PBCP) was measured in breast cancer cytosols from 128 pre- and post-menopausal women with operable node positive (pN+) breast cancer Stage II. All patients were included in a national multicenter study on the effect of adjuvant tamoxifen treatment in hormone sensitive breast cancer, i.e. estrogen receptor content of at least 10 pmol/g cytosol protein. Patients were randomised to receive adjuvant tamoxifen 20 mg once daily for two years or no endocrine treatment. At a median follow-up of 60 months, we found PBCP content in the primary tumor to be an important factor with regard to the effect of adjuvant tamoxifen treatment. The benefit of adjuvant tamoxifen treatment on relapse-free survival and overall survival was confined to the subpopulation of patients with PBCP negative tumors. PBCP should be further evaluated as a predictive factor for the effect of tamoxifen treatment.

Androgen receptors in operable breast cancer: relation to other steroid hormone receptors, correlations to prognostic factors and predictive value for effect of adjuvant tamoxifen treatment.

Steroid hormone receptors have been evaluated as independent prognostic factors as well as predictive factors for endocrine manipulation in the clinical management of breast cancer. The contribution of each receptor or combinations of different receptors remains controversial. In cytosols from 224 patients with operable breast cancer (stages I & II), estrogen receptor (ER), progesterone receptor (PgR) and androgen receptor (AR) content have been measured. An improved AR-assay has been used in order to circumvent some of the problems inherent in other methods. In this study, 91.1% of the patients were classified as AR 'positive' (i.e. greater than or equal to 10 pmol/g). The steroid hormone receptors were significantly correlated (P less than 0.001). Taking the median value of AR as cut-off (50.5 pmol/g), a significantly higher incidence (P = 0.004) of node negative patients was found in the group with a lower AR content. In a multivariate analysis the AR category (median value used as cut-off) was shown to be an independent predictor of the likelihood of axillary metastases (P = 0.001). AR category, however, did not reveal any significant prognostic information concerning relapse free survival. A subpopulation of node positive patients with ER positive tumors, have been included in a randomized trial on the role of tamoxifen as an adjuvant treatment compared with no endocrine treatment. In a multivariate analysis, PgR status was shown to be a single independent prognostic factor (P = 0.016) for relapse free survival in patients with a lower AR content (less than median value). The improved AR assay used in the present study may provide a basis for more correct estimation of the AR content in an individual tumor. The present study suggests that AR analysis and the use of a well-chosen cut-off level may add information about tumor biology to increase our understanding of breast cancer biology and treatment.

Progesterone-binding cyst protein (PBCP) in operable breast cancer: correlations with prognostic factors and predictive value for effect of adjuvant tamoxifen treatment.

Progesterone-binding cyst protein (PBCP) is a secretory protein which has been found in varying concentrations and incidence in cytosols from benign breast tumors, primary breast cancer and metastasis. In order to evaluate its correlation to other prognostic factors, PBCP was analysed in tumor cytosols from 386 women with stage I and stage II breast cancer. The incidence of PBCP negative (i.e. PBCP = 0) tumors was significantly decreased in node negative patients as compared to node positive (p = 0.012). An inverse correlation between estrogen receptor content and PBCP was found (p = 0.001). In a multivariate analysis PBCP category was found to be an independent predictor of the likelihood of axillary nodal involvement (p = 0.015). In spite of this association, PBCP did not reach statistical significance as an independent prognostic factor with regard to relapse-free survival. To evaluate PBCP category as a possible predictive factor for response to adjuvant endocrine treatment, a subpopulation of node positive patients with ER positive tumors was analysed; in patients with PBCP negative tumors, adjuvant treatment with tamoxifen proved to increase the relapse-free survival significantly (p = 0.011). We suggest that PBCP may have a place among other biochemical parameters in breast cancer, to provide an extended basis for understanding of tumor biology and a better selection of patients for endocrine treatment.

Palpation of the axillary nodes in breast cancer: what does the surgeon feel?

The findings on routine pre-operative palpation of the axilla in patients with infiltrative breast carcinoma are compared to the results of histological quantitation of the nodal lymphoid tissue and its tumour deposits in 91 consecutive cases in which a standardized axillary dissection had been carried out. The study demonstrates that lymphoid tissue, even when present in large amounts (up to 6 cm2 on histology), is seldom palpable. What the clinician identifies in favourable cases is the tumour deposit itself. When little lymphoid tissue is present very small tumour deposits (0.2 cm2) may be found on palpation, but large deposits (1 cm2) may be missed when surrounded by sufficient lymphoid tissue. These findings go far to explain the well documented unreliability of the nodal findings on axillary palpation in breast cancer.

Standardized treatment of colorectal cancer. A prospective study.

304 patients with colorectal adenocarcinoma underwent standardized, aggressive treatment which included wide resection, adjuvant radio- or chemotherapy and management of advanced disease. The mean age of the patients was 68 years; 50% were older than 70 years, and 17% above 80 years. The resectability rate was 86.2%. Overall postoperative mortality was 7.3%, in patients operated on for cure 5.7%, and in patients more than 80 years 16.3%. The highest postoperative mortality was seen following right hemicolectomy and deaths were mainly caused by anastomotic leakage and myocardial infarction. In patients with primarily inoperable rectal cancer treated with irradiation and followed by attempted curative surgery, the estimated 5-year survival was 38%. In patients with operable rectal cancer treated with preoperative irradiation followed by surgery the 5 year survival was 69% as compared to 45% for those treated with surgery only. Adjuvant cytostatic therapy in patients with colonic tumours of Dukes B and C stages did not improve survival.

Risk of carcinoma following gastric operations for benign disease. A historical cohort study of 3470 patients.

The risk of stomach cancer was analysed in a cohort of 3470 patients who had had gastric surgery for benign disease between 1900 and 1969. In 87 patients (2.2%) stomach-stump cancer was diagnosed in the follow-up period 1970-84. By comparison with the total incidence of stomach cancer in the same region during the same time period, the observed versus expected ratio in the post-surgery group was 2.1 (p less than 0.001) and did not differ between men and women. At 5-10 years postoperative the risk of cancer was no different from that in the total population, whereas after 40-45 years it was 7.3-fold higher. The risk was unrelated to primary diagnosis or type of operation.