Survival after resection for primary lung cancer: a population based study of 3211 resected patients.

BACKGROUND: Very few population based results have been presented for survival after resection for lung cancer. The purpose of this study was to present long term survival after resection and to quantify prognostic factors for survival. METHODS: All lung cancer patients diagnosed in Norway in 1993-2002 were reported to the Cancer Registry of Norway (n = 19 582). A total of 3211 patients underwent surgical resection and were included for analysis. Supplementary information from hospitals (including co-morbidity data) was collected for patients diagnosed in 1993-8. Five year observed and relative survival was analysed for patients diagnosed and operated in 1993-9. Factors believed to influence survival were analysed by a Cox proportional hazard regression model. RESULTS: Five year relative survival in the period 1993-9 was 46.4% (n = 2144): 58.4% for stage I disease (n = 1375), 28.4% for stage II (n = 532), 15.1% for IIIa (n = 133), 24.1% for IIIb (n = 63), and 21.1% for stage IV disease (n = 41). The high survival in stage IIIb and IV was due to the contribution of multiple tumours. Cox regression analysis identified male sex, higher age, procedures other than upper and middle lobectomy, histologies such as adenocarcinoma and large cell carcinoma, surgery on the right side, infiltration of resection margins, and larger tumour size as non-favourable prognostic factors. CONCLUSIONS: Survival was favourable for resected patients in a population based group including subgroups such as elderly patients, those with advanced stage, small cell lung cancer, tumours with nodal invasion, and patients with multiple tumours. These results question the validity of the current TNM system for lung cancer with regard to tumour size and categorization of multiple tumours.

Anastomotic leakage following routine mesorectal excision for rectal cancer in a national cohort of patients.

OBJECTIVE: Mesorectal excision is successfully implemented as the standard surgical technique for rectal cancer resections in Norway. This technique has been associated with higher rates of anastomotic leakage (AL) and the purpose of this study was to examine AL in a large national cohort of patients. METHODS: This was a prospective national cohort study of 1958 patients undergoing rectal cancer surgery with anterior resection in Norway from November 1993 to December 1999. RESULTS: The overall rate of AL was 11.6% (228 of 1958 patients). In a multivariate analysis, the risk of AL was significantly higher in males (odds ratio (OR) 1.6, 95% confidence interval (CI) 1.1-2.2), in patients receiving pre-operative radiotherapy (OR 2.2, CI 1.0-4.7) and in low level (4-6 cm) (OR 3.5, CI 1.6-7.7) and ultra-low level (< or = 3 cm) anastomoses (OR 5.4, CI 2.3-12.9). The presence of a diverting stoma was associated with a 60% reduction in the risk of AL (OR 0.4, CI 0.3-0.7) for anastomoses 6 cm and below. 30-day mortality was significantly higher for the patients with AL (7.0%, CI 3.7-10.3) compared with no AL (2.4%, CI 1.7-3.2) AL had no significant effect on local recurrence rate (log rank P=0.608). CONCLUSION: Low anastomoses should be defunctioned to avoid AL and the associated high perioperative mortality. No effect of AL on local recurrence was found in this large cohort.

Trends in colorectal cancer incidence in Norway by gender and anatomic site: an age-period-cohort analysis.

The purpose of this study was to examine the secular trend of colorectal cancer in Norway by gender and subsite. All new cases of cancer in proximal colon, distal colon and rectum diagnosed between 1958 and 1997 in Norway were included in the study, altogether 34 202 and 34 097 cases for men and women, respectively. The incidence data were fitted separately for each gender and subsite to an age-period-cohort model. An increase in incidence of colorectal cancer was seen from 1958 to 1997 for both men and women, although a moderate attenuation of the increase has taken place in the last 15-20 years. This observation is most pronounced for cancer of the distal colon, but is also evident for proximal colonic and rectal cancers. For the distal colon and rectum, the period effect is more important than the cohort effect for both genders, whilst opposite for the proximal colon. The main estimated trend for cohort effects is a steady increase for both men and women, apart from an unexpected drop in incidence among the cohorts born during or shortly after World War II. These findings indicate that different aetiological risk factors may act on cancers of the proximal and distal part of the large bowel and further suggest that exogenous risk factors acting very early in life may play a more important role for colorectal cancer than previously recognized.

Prognostic significance of the circumferential resection margin following total mesorectal excision for rectal cancer.

BACKGROUND: Knowledge of prognostic factors following resection of rectal cancer may be used in the selection of patients for adjuvant therapy. This study examined the prognostic impact of the circumferential resection margin on local recurrence, distant metastasis and survival rates. METHODS: A national population-based rectal cancer registry included all 3319 new patients from November 1993 to August 1997. Some 686 patients underwent total mesorectal excision with a known circumferential margin. This shortest radial resection margin was measured in fixed specimens. None of the patients had adjuvant radiotherapy. RESULTS: Following potentially curative resection and after a median follow-up of 29 (range 14--60) months, the overall local recurrence rate was 7 per cent (46 of 686 patients): 22 per cent among patients with a positive resection margin and 5 per cent in those with a negative margin (margin greater than 1 mm). Forty per cent of patients with a positive margin developed distant metastasis, compared with 12 per cent of those with a negative margin. With decreasing circumferential margin there was an exponential increase in the rates of local recurrence, metastasis and death. CONCLUSION: The circumferential margin has a significant and major prognostic impact on the rates of local recurrence, distant metastasis and survival. Information on circumferential margin is important in the selection of patients for postoperative adjuvant therapy.

[Examination, treatment and follow-up of ovarian cancer in Norway]. / Utredning, behandling og etterkontroll av eggstokkreft i Norge.

BACKGROUND: In order to improve our knowledge about the medical examination, treatment and follow of cancer patients, suggestions have been put forward for a system for quality assurance of clinical data on cancer in Norway (Government White Paper 20: 1997). MATERIAL AND METHODS: In spring 2000, a questionnaire was sent to 41 gynaecological departments with focus on ovarian cancer patients. Four of the departments were regional cancer centres. RESULTS: All gynaecological departments answered the questionnaire. Standard gynaecological examination, vaginal ultrasonography and CA-125 determination were included in the diagnostic procedures in all departments. Some differences were detected: Cytological examination of pleural effusions as part of the staging procedure was not performed by all hospitals. In one health region, hospitals used a Risk of Malignancy Index for referring women with suspected malignant pelvic masses to a centralised gynaecologic oncology unit for primary surgery. Sixteen hospitals out of 37 operated on patients with FIGO stage I disease without performing lympadenectomy. When operating on suspected FIGO stage II-IV disease, three out of 22 local hospitals never performed surgery of the intestines in order to achieve optimal tumour reduction. All regional hospitals gave adjuvant chemotherapy to high-risk FIGO stage I patients. Standard treatment in advanced stages was paclitaxel/carboplatinum. Some hospitals participated in randomized trials on chemotherapy. Third-line treatment depended on the patient's condition, earlier toxicity and response. One regional centre preferred not to give any third-line chemotherapy. Only a few hospitals recorded the patient's performance status (WHO or Karnofsky's grading table) during the treatment and follow-up. Most of the gynaecological departments referred the patients to the regional hospital at the time of recurrence. About half of the outpatient departments gave a written report to the regional hospital. INTERPRETATION: There are differences between the hospitals in how they handle ovarian cancer patients. One cannot, however, determine from this inquiry what kind of medical examination, treatment and follow-up is best. An extended registration of ovarian cancer organised by the Cancer Registry of Norway will be started with the aim of providing reliable population-based data (the OVANOR project).

Improved survival and local control after total mesorectal excision or D3 lymphadenectomy in the treatment of primary rectal cancer: an international analysis of 1411 patients.

AIMS: Improved local control and survival in the treatment of rectal cancer have been reported after total mesorectal excision and after extended lymphadenectomy. Comparison of published results is difficult because of differences in patient populations and definitions. We compared three series of patients who underwent standardized surgery [i.e. total mesorectal excision (TME) or D3 lymphadenectomy] with patients who underwent conventional surgery, using actual patient data and uniform definitions. METHODS: TME was performed at Memorial Sloan-Kettering Cancer Center, New York, USA (n=254) and the North Hampshire Hospital, Basingstoke, UK (n=204). D3 lymphadenectomy was performed at the National Cancer Center, Tokyo (n=233). Conventional surgery was used in hospitals in Norway (n=366) and in hospitals of the Comprehensive Cancer Center West, The Netherlands (n=354). Only patients with a curatively resected primary TNM Stage II or Stage III rectal cancer within 12 cm from the anal verge were included. RESULTS: Five-year overall survival and cancer-specific survival were 62-75% and 75-80%, respectively, in the standardized surgery groups and 42-44% and 52%, respectively, in the conventional surgery groups. Local recurrence rates ranged from 4 to 9% in the standardized surgery groups and 32-35% in the conventional surgery groups. CONCLUSIONS: A 30% survival difference and 25% local recurrence difference is not likely to be caused by the shortcomings which are inherent in a non-randomized study: selection bias, assessment variability or stage migration. This study suggests that standardized surgery gives superior survival and local control when compared to conventional surgery.

Major histocompatibility complex class II-dependent antigen presentation by human intestinal endothelial cells.

BACKGROUND & AIMS: In the normal gut, human intestinal microvascular endothelial cells (HIMECs) express major histocompatibility complex (MHC) class II molecules. Enhanced expression is found in chronic inflammation. We examined the cytokine regulation of MHC class II molecules and the associated invariant chain (Ii) in HIMECs and investigated whether such cells can process and present a complex protein antigen to T cells. METHODS: Enzyme-linked immunosorbent assay, flow cytometry, immunoelectron microscopy, as well as T-cell activation assay with HIMECs and HLA-DR-restricted T-cell clones were employed. RESULTS: In unstimulated HIMEC monolayers, HLA-DR, -DP, and -DQ and Ii were undetectable at the protein level, but interferon gamma (IFN-gamma) (100 U/mL) induced expression that peaked for DR after 2-3 days, for DP after 4-6 days, for DQ after 10-12 days, and for Ii after 2-3 days. Tumor necrosis factor alpha had no effect alone but enhanced class II expression in combination with IFN-gamma, most notably for DQ and DP. HLA-DR3-restricted and Mycobacterium tuberculosis heat shock 65-kilodalton-specific T-cell clones were activated to produce IFN-gamma in response to relevant antigen presented by IFN-gamma-treated HIMECs. This response was inhibited by blocking monoclonal antibody to HLA-DR and by chloroquine when compared to professional antigen-presenting cells, HIMECs activated T-cell clones quite efficiently. CONCLUSIONS: These data suggest that microvascular endothelial cells can present complex protein antigens in the human gut.

Phenotypes of B and T cells in human intestinal and mesenteric lymph.

BACKGROUND & AIMS: Cells in lymph draining the human gut have not been characterized previously. The aim of this study was to phenotype B and T cells present in microlymphatics of Peyer's pathces and in mesenteric lymph. METHODS: The studies were conducted by multicolor immunohistochemistry, flow cytometry, and immunocytochemistry. RESULTS: In decreasing order of frequency, microlymphatics in Peyer's patches contained naive T (CD3+CD45RA+ alpha 4 beta 7low) and B (sIgD+CD20+ alpha 4 beta 7low) lymphocytes, memory T (CD45RO+ alpha 4 beta 7+) and B (sIgD-CD20+ alpha 4 beta 7+) lymphocytes, and B-cell blasts (CD19+CD38high alpha 4 beta 7high). Naive cells were usually positive for L-selectin, memory cells were either positive or negative, and B-cell blasts were usually negative. Mesenteric lymph contained naive T (approximately 60%) and B (approximately 25%) lymphocytes, memory T and B lymphocytes (approximately 10%), and B-cell blasts (approximately 2%). Cytospins confirmed these results and showed, in addition, that B-cell blasts contained cytoplasmic immunoglobulin (Ig) A, IgM, or IgG in overall proportions of 5:1: < 0.5. CONCLUSIONS: Our results are similar to the phenotypes previously described in animal thoracic or mesenteric lymph. A fraction of the B cells stimulated in Peyer's patches are near terminal differentiation (contain cytoplasmic Ig) before they enter peripheral blood. Many memory cells, and most if not all B-cell blasts entering lymph show an adhesion molecule profile (alpha 4 beta 7high L-selectin low) in keeping with the presumed phenotype of lymphoid cells destined for mucosal effector sites such as the gut lamina propria.

Expression of the L1 antigen (calprotectin) by tissue macrophages reflects recent recruitment from peripheral blood rather than upregulation of local synthesis: implications for rejection diagnosis in formalin-fixed kidney specimens.

The L1 antigen (calprotectin) is present in circulating monocytes but is restricted to certain subsets of tissue macrophages. Its expression is significantly increased in inflammatory bowel disease, apparently because of newly recruited monocytes. In vitro experiments were performed to substantiate lack of L1 upregulation in tissue macrophages, thereby justifying the use of this marker to detect newly recruited cells. Its reliability was further evaluated by studying mononuclear cell infiltrates characteristic of acute kidney rejection. After pro-inflammatory stimulation, monocytes matured in vitro (n = 12) as well as adherent mononuclear cells from normal small intestinal mucosa (n = 5) were examined for L1 expression by immunocytochemistry and by ELISA (cell lysates). In addition, peritubular mononuclear L1+ cells were examined by immunohistochemistry in routine biopsy specimens from transplanted kidneys with (n = 11) or without (n = 14) histopathologically diagnosed acute rejection. L1 was not upregulated in monocytes matured in vitro, nor in mucosal macrophages after stimulation with interferon-gamma, LPS, phorbol ester, or supernatant from activated leucocytes. In transplanted kidneys with signs of acute rejection, the fraction of L1+ macrophages was significantly increased (P < 0.001). Because L1 is persistently downregulated in mature tissue macrophages and is formalin-resistant, it identifies young infiltrating macrophages in routinely processed biopsy material. L1 should therefore be a valuable adjunct in the diagnosis of kidney rejection.

Human intestinal B-cell blasts and plasma cells express the mucosal homing receptor integrin alpha 4 beta 7.

Interactions between homing receptors on circulating leucocytes and endothelial addressins regulate tissue-specific cellular extravasation. Although integrin alpha 4 beta 7 appears to be the main receptor for gut-homing T lymphocytes, less is known about molecules mediating mucosal B cell homing. Expression of integrin alpha 4 beta 7 on B lymphocytes, B cell blasts, and plasma cells in human gut-associated lymphoid tissue (GALT; the Peyer's patches and appendix) and lamina propria was studied by multi-colour immunofluorescence applied on cryosections. Isolated mononuclear cells from the same tissue compartments were examined by flow cytometry and compared with peripheral blood B cells. Integrin alpha 4 beta 7 was expressed by IgA+ B cell blasts and plasma cells (CD38high) in the lamina propria, B cell blasts in GALT, and sIgD+ B lymphocytes in peripheral blood. In contrast, GALT sIgD+ B lymphocytes were negative or only weakly positive for alpha 4 beta 7. These results suggested that B lymphocytes down-regulate alpha 4 beta 7 upon extravasation in GALT but up-regulate this integrin after antigen-priming. Thus, alpha 4 beta 7 may be a homing receptor also for B cell blasts extravasating in the gut lamina propria, where this integrin is maintained on plasma cells, perhaps as a local retention factor.

Renal microvascular perfusion evaluated by single fibre laser Doppler flowmetry.

The single fibre laser Doppler flowmetry technique has been designed to perform continuous quantification of microvascular perfusion deep in tissue. In this study we have evaluated the use of the technique in renal tissue. A total number of 164 recordings were analyzed. Fluctuations in perfusion related to heart rate and respiration were observed. The possible nature of the low-frequency flow motion waves (10-12 min-1) is discussed. No significant difference in perfusion level could be detected between the upper, the middle and the lower parts of the kidneys (p greater than 0.69), or between the cortex and the medulla (p = 0.77). The spatial variation, expressed as the difference between two consecutive measurements, was large. The median and mean values of groups of data are however reproducible. When the renal artery is reopened after 30 sec of occlusion, the pre-occlusive flux levels are regained after approximately 1.5 sec. The single fibre laser Doppler flowmetry technique can be used for renal microcirculatory studies, but comparative studies with other methods have to be performed.

Circulating secretory component in relation to early diagnosis and treatment of liver metastasis from colorectal carcinomas.

AIMS: To evaluate serum secretory component in relation to early detection and clinical management of liver metastasis in patients with colorectal cancer. METHODS: Secretory component and carcinoembryonic antigen (CEA) were analysed in serial serum samples from 23 patients who had liver metastases as the only apparent recurrence, and in sera from 54 matched controls. Results of surgical treatment of recurrences were classified peroperatively as radical when no residual tumour was apparent and resection margins were free of disease. RESULTS: In total, 18 (78%) patients had increased secretory component during the whole follow up period (median 16 months); 12 (52%) had raised secretory component concentrations before clinical recurrence (median lead time 5.2 months). There was no difference before recurrence between circulating secretory component and CEA in sensitivity and lead times. Seventeen patients underwent surgery for hepatic metastasis; seven had radical hepatic resection of which only two (29%) showed increased secretory component concentrations before clinical recurrence; both had concurrent raised CEA values. By contrast, secretory component was raised in 83% of those cases considered inoperable. CONCLUSIONS: Although serum secretory component clearly increases in most patients with liver metastases, its clinical value seems questionable because secretory component apparently indicates mainly inoperable hepatic metastases.

Reactive oxygen metabolites produce pulmonary vasoconstriction in young pigs.

Reactive oxygen metabolites appear to modulate pulmonary vascular changes. To study the effects of free radical formation in vivo, we investigated five groups of young pigs by recording hemodynamic changes after xanthine oxidase infusion alone and after pretreatment with hypoxanthine or possible blocking agents. The pulmonary vascular pressure increased rapidly in the groups without inhibition reaching maximum levels 25 min after the start of the experiment. The pulmonary artery blood flow declined toward minimum values at the same time. Compared to baseline levels, the calculated vascular lung resistance increased by 300% when the pigs were pretreated with hypoxanthine, and by 150% when xanthine oxidase was given alone. These findings suggest enhanced pulmonary vasoconstriction as a result of high initial hypoxanthine levels probably capable of forming larger quantities of oxygen radicals. The vascular reaction was attenuated when the pigs were pretreated with indomethacin (cyclo-oxygenase inhibitor) or allopurinol (xanthine oxidase inhibitor). Furthermore, the presence of catalase (hydrogen peroxide scavenger) reduced the pulmonary vasoconstriction significantly. We observed less decline in arterial oxygen tension and oxygen saturation when the animals had been pretreated with inhibitory agents, compared to the blood gas changes found in the xanthine oxidase group. The systemic pressure recordings in the carotid artery remained at baseline levels in all groups. We conclude that oxygen radicals formed by the hypoxanthine-xanthine oxidase system produce severe pulmonary vascular constriction in young pigs.