Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis.

BACKGROUND: Enhancer of zeste homologue 2 (EZH2) is a member of the Polycomb group of genes that is involved in epigenetic silencing and cell cycle regulation. METHODS: We studied EZH2 expression in 409 patients with colorectal cancer stages II and III. The patients were included in a randomised study, and treated with surgery alone or surgery followed by adjuvant chemotherapy. RESULTS: EZH2 expression was significantly related to increased tumour cell proliferation, as assessed by Ki-67 expression. In colon cancer, strong EZH2 expression (P=0.041) and high proliferation (>or=40%; P=0.001) were both associated with better relapse-free survival (RFS). In contrast, no such associations were found among rectal cancers. High Ki-67 staining was associated with improved RFS in colon cancer patients who received adjuvant chemotherapy (P=0.001), but not among those who were treated by surgery alone (P=0.087). In colon cancers stage III, a significant association between RFS and randomisation group was found in patients with high proliferation (P=0.046), but not in patients with low proliferation (P=0.26). Multivariate analyses of colon cancers showed that stage III (hazard ratio (HR) 4.00) and high histological grade (HR 1.80) were independent predictors of reduced RFS, whereas high proliferation indicated improved RFS (HR 0.55). CONCLUSION: Strong EZH2 expression and high proliferation are associated features and both indicate improved RFS in colon cancer, but not so in rectal cancer.

Intravenous cyclophosphamide in patients with chronic systemic inflammatory diseases: morbidity and mortality.

BACKGROUND: Few data exist concerning the development of malignancies and haemorrhagic cystitis in patients with systemic autoimmune diseases previously treated with intravenous (iv) cyclophosphamide (CYC). The use of mesna prophylaxis is also controversial. METHODS: The medical records of all patients with chronic systemic inflammatory diseases treated with iv or oral CYC at Stavanger University Hospital from 1985 to 1999 were reviewed. Eighty-five patients were identified, of whom 75 patients had been treated with iv CYC only and were thus included in this study. Of these 75 patients, 20 (27%) had died and 55 (73%) were alive. Forty-two (76%) out of the 55 patients consented to undergo a comprehensive clinical examination, including a cystoscopy in 33 of them. The medical history of the patients not clinically examined was based solely on medical records. Data from the Cancer Registry of Norway and Statistics Norway were used for comparison with normative data in the general population. RESULTS: Six patients (8%) developed malignant disease compared with an expected number of 4.5, giving a standard incidence ratio of 1.5 [95% confidence interval (CI) 0.7-3.2]. The observed number of deaths was 23 compared to an expected number of 6.3, giving a standard mortality ratio of 3.7 (95% CI 2.4-5.5). CONCLUSIONS: The standard incidence ratio of cancer following iv CYC was increased, although not statistically significantly. No urinary bladder cancer or haemorrhagic cystitis developed even though mesna prophylaxis was not given.

Comparing subjective and digital image analysis HER2/neu expression scores with conventional and modified FISH scores in breast cancer.

BACKGROUND: HER2/neu expression and fluorescence in situ hybridisation (FISH) amplification have therapeutic significance. AIMS: To compare subjective HER2/neu expression scores with digital image analysis (DIA) and conventional and modified FISH scores in breast cancer. METHODS: Sixty HercepTest-immunostained breast carcinomas, prospectively scored as consensus 2+ and 3+ (DAKO protocol) by two observers, were analysed with DIA, and conventional (Vysis) and modified FISH scoring protocols. RESULTS: With consensus scoring, 23 (38%) of the 60 cases were 2+ and 37 (62%) were 3+. Agreement with DIA scores was 100%. With conventional FISH scoring, 4 of the 3+ cases did not show amplification, but all of those negative cases had high HER2/neu copy numbers. With the modified FISH scoring protocol, all HercepTest immunohistochemical 3+ cases were amplified. Of the 2+ cases, 3 were amplified with the modified FISH protocol and 4 with the conventional FISH protocol. CONCLUSIONS: Modified FISH scores were better correlated with HercepTest 3+ consensus and DIA scores than were conventional FISH scores. HER2/neu DIA scoring is a cost-effective supplementary tool in surgical pathology.

Proliferation markers and DNA content analysis in urinary bladder TaT1 urothelial cell carcinomas: identification of subgroups with low and high stage progression risks.

AIMS: To evaluate whether in situ biomarkers Ki67, mitotic activity index (MAI), p53, mean area of the 10 largest nuclei (MNA10), and whole genome DNA ploidy by flow and image cytometry (FCM and ICM, respectively) have independent prognostic value in urinary bladder urothelial cell carcinomas (UCs). METHODS: Ki67 and p53 immunoquantitation was performed in TaT1 consensus diagnosis UCs. MAI and MNA10 were also determined. Single cell suspensions were stained (DAPI for FCM; Feulgen for ICM). There was enough material for all measurements in 171 cases. Kaplan-Meier curves and multivariate survival analysis (Cox) were used to assess the prognostic value of all features (including classic clinicopathological risk factors, such as stage, grade, multicentricity, carcinoma in situ). RESULTS: Thirteen (7.6%) patients progressed. Of the classic factors, grade was strongly prognostic in univariate analysis, as were all the biomarkers. In multivariate analysis, the strongest independent combinations for progression were MNA10 (threshold (T) = 170.0 micro m(2)) plus MAI (T = 30), or MNA10 (T = 170.0 micro m(2)) plus Ki67(T = 25.0%). p53 (T = 35.2%) plus Ki67 (T = 25.0%) also predicted progression well, with high hazard ratios, but p53 measurements were not as reproducible as the other features. The prognostic value of the quantitative biomarkers exceeded that of the classic risk factors and DNA ploidy. The sensitivity, specificity, positive, and negative predictive values of MNA10/MAI or MNA10/Ki67 at the thresholds mentioned were 100%, 79%, 57%, and 100%, respectively. These feature combinations were also strongest prognostically in the high risk treatment subgroup. CONCLUSIONS: The combined biomarkers MNA10/Ki67 or MNA10/MAI are more accurate and reproducible predictors of stage progression in TaT1 UCs than classic prognostic risk factors and DNA ploidy.

Incidence of acute nonperforated and perforated appendicitis: age-specific and sex-specific analysis.

This prospective study was performed to investigate epidemiological characteristics in terms of the age- and sex-specific incidence in patients with perforated and nonperforated appendicitis. The study population comprised 1486 consecutive patients who underwent appendectomy for suspected acute appendicitis between 1989 and 1993. Two patient cohorts [n = 544 (37%)] were analyzed with regard to prehospitalization duration of symptoms and in-hospital observation time. The crude incidence of acute appendicitis was 86 per 100,000 per year. Although the incidence of nonperforated appendicitis was highest among adolescents and young adults (13-40 years of age), perforated appendicitis occurred at almost the same incidence in all sex and age groups. The diagnostic accuracy was 76%. Perforated appendicitis occurred in 19%, with higher rates in small children and the elderly, irrespective of gender. A high diagnostic accuracy was not associated with an increased rate of perforation. In small children and the elderly, the diagnostic accuracy was low and the perforation rate high. Patients with perforation had a significantly longer duration of symptoms as well as in-hospital observation time than did patients with nonperforated appendicitis. Perforated appendicitis showed a different incidence pattern than nonperforated appendicitis and was associated with a significantly longer duration of symptoms and in-hospital observation time, probably due to patient-related factors. We suggest this observation deserves attention regarding clinical diagnosis and treatment decision-making for patients with suspected acute appendicitis.

Thrombotic microangiopathy in a patient with chronic myelogenous leukemia on hydroxyurea.

We describe the case of a 57-year-old woman with chronic myelogenous leukemia who was on hydroxyurea and developed a fatal thrombotic microangiopathy with renal, retinal and central nervous system involvement. There was no evidence of medullary or extramedullary leukemia transformation. Repeated examinations of the peripheral blood film revealed only minimal morphological changes of microangiopathic hemolysis. The diagnosis was made by postmortem examination of the kidneys, brain, meninges and retina. The underlying etiology may have been a paraneoplastic phenomenon of the chronic phase of CML or may have indicated the beginning of transformation to an accelerated phase. A late side effect of hydroxyurea therapy cannot be excluded.

A prospective study of the length of the distal margin after low anterior resection for rectal cancer.

The length of distal margin between the lower border of the tumour and the level of division during low anterior resection may be related to the rate of local recurrence. The method of measuring the distal clearance is not usually stated in reports of the operation. The distal margin was measured prospectively in 5 different ways in 20 patients. A difference was observed between various methods of measurement of the same specimen in situ, unpinned and pinned out before and after fixation. The margin was significantly less (p less than 0.001) in unpinned compared with pinned specimens. There was poor correlation between the in situ measurement and that determined by the pathologist in both unpinned and pinned specimens. There was no significant difference before and after fixation if the specimen had been pinned but significant (p less than 0.001) shrinkage occurred with fixation when the specimen had not been pinned.

Testicular histology after treatment with LH-RH analogue for carcinoma of the prostate.

Orchiectomy was performed in 16 patients because of progression of prostatic cancer despite adequate medical castration with goserelin (Zoladex, ICI) over a mean period of 17.6 months. Severe tubular atrophy was seen in the testes. The Leydig cells also showed signs of atrophy, a fact that may indicate a direct effect of goserelin on these cells. In 1 patient, however, orchiectomy was postponed for 3 months after cessation of medical castration. The serum testosterone had resumed almost normal values and testicular histology revealed intact spermatogenesis and apparently normal Leydig cells.

Pleomorphic adenoma of the human breast with local recurrence.

Pleomorphic adenoma of the human breast is a rare, benign tumor for which the literature is sparse. A local recurrence has been reported only once before. The diagnostic challenge of this cancer-imitating lesion is emphasized in this report. Although local excision of the tumor is the treatment of choice, almost 50% of the patients reported have undergone fairly extensive surgery, i.e., simple or radical mastectomy. A paraffin secretion of the excised tumor is mandatory to confirm the benign nature of the lesion to avoid an unnecessary mastectomy for a benign condition.

Testicular seminoma: histological findings and their prognostic significance for stage II disease.

Risk factors, their interrelationship, and prognostic relevance for seminoma stage II disease have been examined. The size of the primary tumor was significantly correlated with the pT category, as was the presence of tumor invasion of small vessels. The pT category was correlated neither with clinical substage nor relapse rate. There was a poorer 3-year survival for anaplastic seminomas as compared to that of classical seminomas; the difference was not significant. The 5-year survival for seminomas rich in lymphocytes was better than those of poor lymphocytic infiltration, but this difference also was not significant. No difference in survival or relapse rate was found between HCG-producing and HCG-nonproducing seminomas.

Multicystic peritoneal mesothelioma.

A multicystic peritoneal mesothelioma in a 55-year-old man is reported. The large multicystic tumor was only partially removed. 36 months after the first presentation he is still working and his only complaint is abdominal swelling. The light microscopical, immunocytochemical and ultrastructural features are described and differential diagnoses discussed.

Salivary gland malignant neoplasms: treatment and prognosis.

A retrospective analysis of 183 patients with malignant salivary gland tumors treated between 1955 and 1978 is presented. The analysis showed that radiation therapy lowered the recurrence rates after surgery and controlled approximately one-third of the inoperable tumors. A dose-response relationship exists and the data suggest that the radiation dose should not be less than that corresponding to a CRE-value of 1950 reu (70 Gy/7 weeks). Histology, location and clinical stage are important prognostic factors.

Bilateral malignant testicular germ cell cancer.

Twenty-six of approximately 1300 patients (1.9%) with unilateral testicular cancer developed a second primary germ cell cancer (seminoma 18; non-seminoma 8). Patients with previous seminoma had a significantly higher risk of developing a new seminoma than those with a previous non-seminoma. The diagnosis of second primary was made within 3 years of the first diagnosis in only 50% of the patients. In patients with a history of undescended and/or atrophic testes the interval significantly decreased between the diagnosis of the two testicular cancers. The prognosis of bilateral testicular cancer is generally good. Patients in whom the second testicular cancer is at clinical stage I (no metastases) at diagnosis can safely be observed without further treatment after orchiectomy. A patient with unilateral testicular cancer should be informed of the increased risk of developing a second primary germ cell tumour and should be encouraged to perform regular examination of the remaining testis. The need for life-long follow-up visits for patients with testicular cancer is questionable.

Testicular seminoma: analysis of treatment and failure for stage II disease.

Seventy-three patients with seminoma testis stage II have been retrospectively analyzed with regard to prognostic factors and value of prophylactic mediastinal irradiation and chemotherapy. Although survival differences were seen between stage IIa, IIb and IIc, these were not statistically significant. Neither was there a significant difference between IIc patients with tumors greater than 10 cm and less than 10 cm in diameter. The incidence of HCG-producing seminomas in the present series was 16%. No significant difference in survival nor relapse rate was found between HCG-producing and HCG-non-producing seminomas. Prophylactic mediastinal irradiation did not influence the survival nor the relapse rate and may therefore be omitted. In the present series there was no significant improvement neither in relapse rate nor survival in patients receiving pre-irradiation chemotherapy. However, the total number of patients is small and optimal pre-irradiation chemotherapy still have to be defined.