Tore B. Halvorsen

Oligodendroglioma. Histologic Evaluation and Prognosis

Abstract All oligodendrogliomas registered in Norway during a 25-year period (1953–1977) were studied to establish the frequency of different histologic features and to compare them with survival data of the patients. The minimum observation time was five years. The original tumor specimens from 208 patients were independently reexamined by two pathologists. The characteristic Oligodendroglioma of this series was of medium cell density (53% of lesions), with moderate nuclear atypia, with vascular endothelial proliferation (53%), calcification (56%), with from one to five mitotic figures per ten high power fields, and without microcystic degenerative changes (58%). Subpial tumor cell infiltration, perivascular lymphocytic infiltration and local leptomeningeal invasion were present in a minority of cases. In 11 cases autopsy material was the only source of diagnosis. Microcysts, necrosis, and cell density were the only histologic features of prognostic significance. Subpial infiltrative growth was of suggestive prognostic value. There was no significant association between the number of mitotic figures and survival. Vascular endothelial proliferation, calcification, pronounced nuclear atypia, perivascular lymphocytic infiltration and local leptomeningeal invasion were of no significant prognostic value. Age at operation did not alter these conclusions, neither did sex nor duration of preoperative symptoms.

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 (⩾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.

Ki‐67 As a Prognostic Marker in Adenoid Cystic Carcinoma Assessed With the Monoclonal Antibody MIB1 in Paraffin Sections

The monoclonal antibody MIB1 recognizing the Ki‐67 antigen in formalin‐fixed, paraffin‐embedded tissue was used to study the proliferative activity in 44 adenoid cystic carcinomas of the salivary glands. The antigen expression was compared with clinical factors, histopathological grading, and prognosis. The Ki‐67 value was significantly higher in tumors from patients suffering from treatment failure than in nonfailures (P < 0.001). The Ki‐67 expression was also higher in tumors exhibiting areas more than 30% of the solid growth pattern and higher in sinonasal tumors than in other locations. By Cox regression analysis, Ki‐67 more than 4% was the strongest prognostic indicator (P <0.005). Clinical stage and violation of surgical margins were also found to be independent significant prognostic indicators. We conclude that Ki‐67 expression estimated by the use of MIB1 is a powerful tool for predicting the short‐term prognosis for patients with adenoid cystic carcinoma.

Final results of a randomised phase III study on adjuvant chemotherapy with 5 FU and levamisol in colon and rectum cancer stage II and III by the Norwegian Gastrointestinal Cancer Group

Background. The recommendation of adjuvant chemotherapy for colon cancer with lymph node metastases, based on two studies from USA, was reluctantly accepted by Norwegian medical doctors. It was therefore decided to assess the role of adjuvant therapy with 5fluorouracil (5-FU) combined with levamisole (Lev) in a confirmatory randomised study. Material and methods. Four hundred and twenty five patients with operable colon and rectum cancer, Stage II and III (Dukes’ stage B and C), were from January 1993 to October 1996, included in a randomised multicentre trial in Norway. The age limits were 18–75 years. Therapy started with a loading course of bolus i.v. 5-FU (450 mg/m2) daily for 5 days and p.o. doses of Lev (50 mg x 3) for 3 days. From day 28 a weekly i.v. 5-FU dose (450 mg/m2) were administered for 48 weeks. From day 28 also p.o. doses of Lev (50 mg x 3) for 3 days were given every 14 days. In total 214 patients were randomised to 5FU/Lev and 211 were included in the control group with surgery alone. Some did not comply with the inclusion and exclusion criteria, thus leaving 206 evaluable patients in each group. Results. There was no significant survival difference between the two groups at 5 years: Disease-free survival (DFS) was 73% after chemotherapy, 68% (p=0.24) in the control group, and corresponding cancer specific survival (CSS) 75% and 71%, respectively (p=0.69). There was no difference between the two groups when analysed for colon and rectum separately. However, the subgroup of colon cancer with stage III exhibited a statistically significant difference both for DFS, 58% vs. 37% (p=0.012) and CSS, 65% vs. 47% (p=0.032) in favour of adjuvant chemotherapy. The benefit was further statistically significant for women but not for men. Toxicity was generally mild and acceptable with no drug related fatalities. Conclusions. Colon cancer patients with lymph node metastases benefit from adjuvant chemotherapy with 5-FU/Lev with acceptable toxicity. In a subgroup analysis females did better than males. Rectal cancer does not benefit from this regimen.

A homozygote splice site PMS2 mutation as cause of Turcot syndrome gives rise to two different abnormal transcripts

Turcot syndrome is a rare, inherited disease predisposing of tumours in the central nerve system and in the colorectal system. This report describes a Turcot patient with an extraordinary clinical history. The patient is still alive at the age of 43. She was operated at the age of 10 by brain tumour and at the age of 16 by colorectal cancer. She has since then been treated for multiple cancers (gastrointestinal, endometrial, basal cell carcinomas), and removal of adenomatous polyps at several occasions. The aim of this work was to investigate if there was any specific genotype that explains her remarkable clinical history. Microsatellite instability and immunohistochemistry analysis for four DNA mismatch repair proteins were performed. DNA mutation analysis was done for genes involved in polyposis and mismatch repair by denaturing high performance liquid chromatography and sequencing. cDNA analysis was carried out for the mismatch repair gene PMS2. The patients genotype was found to be a homozygous splice site mutation in the PMS2 gene, c.989-1G<T, which resulted in two abnormal transcripts, not one as expected. The patient’s long time survival may in part be explained by meticulous follow up by health care professionals. The other importing factor is probably the nature of here genotype. cDNA analysis showed that the homozygous mutation led to two abnormal transcripts, of which one is perhaps less detrimental. Thus cDNA analysis is of prime importance for the full evaluation of the effect of putative splicing mutations.

Pharmacokinetics of ceftazidime in patients with biliary tract disease

SummaryAfter administration of ceftazidime as a 1 g i.v. bolus injection, its concentration was measured by HPLC at frequent intervals in serum, bile and tissue from different parts of the biliary tract in 32 patients undergoing operation for biliary tract disease. In bile from the functioning gallbladder and common bile duct, a high concentration of ceftazidime was found, mean 18.5 and 26.6 mg/l, respectively. In bile from the non-functioning gallbladder, a very low concentration was found (<1.5 mg/l). Ceftazidime in the gallbladder wall varied considerably with the type and degree of inflammation judged histologically; the mean level was 21.3 mg/kg. The elimination half-life of ceftazidime was 1.74 h, apparent volume of distribution 20.01 and total plasma clearance 133 ml/min. In bile from T-tube specimens a high concentration was found, the mean peak values being 27.2 mg/l. However, biliary excretion of the drug was low at less than 0.5% of the administered dose. These concentrations of ceftazidime were sufficient to inhibit the in-vitro growth of pathogens, namely theEnterobacteriaecae commonly responsible for biliary tract infection.

The Penetration of Ceftazidime into the Inflamed Rabbit Eye

Acute endophthalmitis was unilaterally induced in 8 rabbits by intravitreal injection of 5 micrograms Escherichia coli endotoxin. A reproducible increase in aqueous humour polymorphonuclear neutrophils and total protein content was observed after 24 h (mean +/- SD: 2400 +/- 274 X 10(6)/l and 3.7 +/- 0.4 g/l, respectively). In the opposite eye only minor changes occurred, making it suitable as a paired control. The intraocular penetration of ceftazidime was then studied in 30 rabbits after i.v. injection of 50 mg/kg body weight. The mean penetration into aqueous humour of the eyes with and without endophthalmitis was 64 and 10%, respectively. In the vitreous body the corresponding penetration was 5 and 1%. The concentration of ceftazidime achieved in the intraocular structures was sufficient to inhibit the growth of pathogens, i.e. Enterobacteriaceae, commonly responsible for intraocular infections.