Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing.

BACKGROUND: Colorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection. The search for predictive biomarkers is often performed on primary tumours tissue. In order to assess the effectiveness of tailored treatment in regard to the primary tumour the differences in the genomic profile needs to be clarified. METHODS: Fresh-frozen tissue from primary tumours, synchronous liver metastases and adjacent normal liver was collected from 21 patients and analysed by whole-exome sequencing on the Illumina HiSeq 2500 platform. Gene variants designated as 'damaging' or 'potentially damaging' by Ingenuity software were used for the subsequent comparative analysis. BAM files were used as the input for the analysis of CNAs using NEXUS software. RESULTS: Shared mutations between the primary tumours and the synchronous liver metastases varied from 50 to 96%. Mutations in APC, KRAS, NRAS, TP53 or BRAF were concordant between the primary tumours and the metastases. Among the private mutations were well-known driver genes such as PIK3CA and SMAD4. The number of mutations was significantly higher in patients with right- compared to left-sided tumours (102 vs. 66, p = 0.004). Furthermore, right- compared to left-sided tumours had a significantly higher frequency of private mutations (p = 0.023). Similarly, CNAs differed between the primary tumours and the metastases. The difference was mostly comprised of numerical and segmental aberrations. However, novel CNAs were rarely observed in specific CRC-relevant genes. CONCLUSION: The examined primary colorectal tumours and synchronous liver metastases had multiple private mutations, indicating a high degree of inter-tumour heterogeneity in the individual patient. Moreover, the acquirement of novel CNAs from primary tumours to metastases substantiates the need for genomic profiling of metastases in order to tailor metastatic CRC therapies. As for the mutational status of the KRAS, NRAS and BRAF genes, no discordance was observed between the primary tumours and the metastases.

Primary tumor location and bevacizumab effectiveness in patients with metastatic colorectal cancer.

BACKGROUND: There is an unmet need for predictive markers for the antiangiogenic agent bevacizumab in metastatic colorectal cancer (mCRC). We aimed to assess whether the location of the primary tumor is associated with bevacizumab effectiveness when combined with capecitabine and oxaliplatin (CAPEOX) in the first-line treatment of patients with mCRC. PATIENTS AND METHODS: A cohort of 667 consecutive patients with mCRC from the general community treated from 2006 to 2011 with CAPEOX and bevacizumab as standard first-line therapy was compared with a cohort of 213 patients treated with CAPEOX from 2003 to 2006, before bevacizumab was approved. Main outcome measures were progression-free survival (PFS) and overall survival (OS). Differences in outcome were tested using Kaplan-Meier curves and log-rank tests, and multivariate analyses were carried out using Cox Proportional Hazards models. RESULTS: Patients treated with CAPEOX and bevacizumab with primary tumors originating in the sigmoid colon and rectum had a significantly better outcome than patients with primary tumors originating from the cecum to the descending colon, both for PFS (median PFS 9.3 versus 7.2 months; hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.56-0.82) and for OS (median OS 23.5 versus 13.0 months; HR 0.47, 95% CI 0.38-0.57). This difference was confirmed in multivariate analyses after adjustment for other potentially prognostic factors. For patients treated with CAPEOX, there was no association between primary tumor location and outcome, neither in unadjusted nor adjusted analyses. CONCLUSIONS: The addition of bevacizumab to CAPEOX in first-line treatment of patients with mCRC may primarily benefit patients with primary tumors originating in the rectum and sigmoid colon. This hypothesis needs to be validated in data from completed randomized trials. CLINICALTRIALSGOV IDENTIFICATION NUMBER: NCT00212615.

Socioeconomic position, stage of lung cancer and time between referral and diagnosis in Denmark, 2001-2008.

INTRODUCTION: We investigated the association between socioeconomic position, stage at diagnosis, and length of period between referral and diagnosis in a nationwide cohort of lung cancer patients. METHODS: Through the Danish Lung Cancer Register, we identified 18,103 persons diagnosed with lung cancer (small cell and non-small cell) in Denmark, 2001-2008, and obtained information on socioeconomic position and comorbidity from nationwide administrative registries. The odds ratio (OR) for a diagnosis of advanced-stage lung cancer (stages IIIB-IV) and for a diagnosis >28 days after referral were analysed by multivariate logistic regression models. RESULTS: The adjusted OR for advanced-stage lung cancer was reduced among persons with higher education (OR, 0.92; 95% confidence interval (CI), 0.84-0.99), was increased in persons living alone (OR, 1.06; 95% CI, 1.01-1.13) and decreased stepwise with increasing comorbidity. Higher education was associated with a reduced OR for >28 days between referral and diagnosis as was high income in early-stage patients. Male gender, age and severe comorbidity were associated with increased ORs in advanced-stage patients. INTERPRETATION: Differences by socioeconomic position in stage at diagnosis and in the period between referral and diagnosis indicate that vulnerable patients presenting with lung cancer symptoms require special attention.

Prognostic factors in small cell lung cancer: multivariate model based on 778 patients treated with chemotherapy with or without irradiation.

The relationships between prognostic factors and duration of survival in small cell lung cancer were investigated in a consecutive series of 874 patients treated with combination chemotherapy with or without irradiation. The series included 443 patients with limited and 431 patients with extensive stage disease based on staging including bone marrow examination and peritoneoscopy with liver biopsy but no routine scans. The median durations of survival for the two disease categories were 48 and 30 weeks, respectively. The influence on survival of various pretreatment factors was investigated by use of univariate methods and Cox's multivariate regression model. Patients in each stage were treated according to one of three controlled trials. Variations among the applied treatment regimens did not result in significant differences in duration of survival among patients with limited disease. An alternating regimen was superior to continuous therapy in patients with extensive disease and raised serum lactate dehydrogenase. Prognosis was correlated with disease extent. Surgical resection as well as limited stage disease thus both contributed to survival. Poor performance status, reduced hemoglobin concentration, and raised values for serum lactate dehydrogenase were significantly associated with a reduced duration of survival in both stages. Females with limited disease lived significantly longer than males while advanced age was a negative prognostic factor in extensive disease. Plasma sodium and serum urate were both predictive of survival in limited disease. Proved metastatic disease affecting specific sites or total number of metastatic sites did not carry significant prognostic information in a model including a general variable characterizing stage of disease. Fifty of the 778 patients, on whom the multiple regression model was based, were alive and disease free 2 years after the start of the treatment. Two-year survival rates were strongly correlated to groupings based on prognostic factors, and information about disease extent was not mandatory for predicting the probability of long term disease-free survival.

Determinants of complete remission induction and maintenance in chemotherapy with or without irradiation of small cell lung cancer.

The possible influence of pretreatment patient characteristics upon the probabilities of complete remission (CR) induction and maintenance was investigated in a series of 815 nonresected patients with small cell lung cancer. All patients underwent pretreatment staging which enabled allocation of 391 patients to trials for limited stage disease and 424 patients to trials for extensive disease. Three controlled trials for each disease stage were conducted between 1973 and 1981. All therapeutic regimens consisted of combinations of between three and six agents (lomustine, cyclophosphamide, methotrexate, vincristine, doxorubicin, etoposide) with or without irradiation. Thirty-five % of the limited stage patients and 18% of the extensive stage patients were alive and had achieved a complete remission 16 weeks after initiation of the treatment, i.e., after four cycles of chemotherapy. Relationships between pretreatment characteristics and the probability to pass this benchmark were examined by logistic regression analysis. The probability of CR was negatively related to increased serum lactate dehydrogenase and male sex in both disease stages. Pretreatment anemia (less than 12 g/liter) and poor performance status were associated with a reduced CR rate in limited and extensive stage disease, respectively. Factors related to the maintenance of complete remission were subsequently examined in the 211 complete responders by use of Cox's regression analysis. Complete responders with extensive disease prior to treatment had greater cumulative risk of relapse than those with limited disease (P less than 0.01). Hyponatremia had a significant negative influence on the remission duration in limited disease while age greater than 60 years and bone marrow metastases had significantly negative influence in extensive disease. Using the models it was possible to identify subgroups of patients with CR rates ranging from 5 to 55% and to stratify complete responders according to estimated risks of subsequent relapse.

Continuous versus alternating combination chemotherapy for advanced small cell carcinoma of the lung.

In a 2-year period, 146 patients with small cell carcinoma of the lung, staged as having extensive disease, were randomized to receive either continuous chemotherapy consisting of (a) 1-(2-chloroethyl-3-cyclohexyl-1-nitrosourea, cyclophosphamide, methotrexate, and vincristine followed by (b) 4'-demethylepipodophyllotoxin 9-[4,6-O-(R) ethylidene-beta-D-glucopyranoside] and doxorubicin at progression of disease or a regimen of (a) alternating with (b). Seventy-six patients received the continuous regimen; 70 patients received alternating treatment. Response rates were 68 and 72%, respectively. The median duration of response was 16 weeks in patients receiving continuous treatment compared to 28 weeks in patients receiving alternating treatment (p less than 0.05). No survival time difference was observed between the groups, median survival being 36 and 38 weeks, respectively. Four patients became long-term survivors (5.6 +, 5.5 +, 5.1, and 4.7 + years). All received alternating therapy. Six toxic deaths were observed among patients receiving continuous therapy compared to only one death among those in the alternating regimen. In conclusion, alternating combination chemotherapy leads to prolonged duration of remission. Duration of survival is not prolonged in uncured patients, but an increased possibility of long-term disease-free survival cannot be precluded.

Urokinase and plasminogen activator inhibitor type 1 in pulmonary adenocarcinoma.

The urokinase pathway of plasminogen activation is involved in proteolytic degradation of various tissues, including dissolution of the extracellular matrix and basement membranes during the process of cancer cell invasion. We have studied the prognostic value of urokinase-type plasminogen activator (uPA) and type-1 plasminogen activator inhibitor (PAI-1) in tumor extracts from 106 patients with adenocarcinoma of the lung. uPA and PAI-1 levels were determined by sandwich enzyme-linked immunosorbent assays. No correlation was found between uPA and PAI-1 (r = 0.23). High PAI-1 levels were significantly associated with short-duration overall survival (P = 0.017), while uPA levels showed no significant association with overall survival. Relating the levels of PAI-1 to other prognostic factors such as stage and age, no significant correlations were found. The prognostic impact of uPA and PAI-1 were investigated together with other prognostic factors in Cox multivariate analysis. PAI-1 was found to be an independent prognostic variable for survival, the relative risks being 1.5 (low versus medium PAI-1 values (95% confidence interval, 1.2-1.8) and 2.2 (low versus high (95% confidence interval, 1.8-2.6)). In patients with stage I disease (69 patients) high levels of PAI-1 were significantly associated with poor prognosis compared to low levels (P = 0.037). These data indicate that PAI-1 is a potentially important prognostic factor in pulmonary adenocarcinoma and may as such be used to select patients with low stage and poor prognosis for adjuvant therapy subsequent to complete surgical resection.

Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue.

We have studied the prognostic value of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), and type 1 plasminogen activator inhibitor (PAI-1) in tumor extracts from 84 patients with squamous cell lung carcinoma and 38 patients with large cell lung carcinoma, measuring each molecule with sandwich enzyme-linked immunosorbent assays. High uPAR levels were significantly associated with short overall survival in patients with squamous cell lung carcinomas when the median value was used as a cutoff point (P = 0.038), while no statistically significant prognostic impact of uPA and PAI-1 levels was found in this group of patients. The combination of high uPAR and high PAI-1 levels did, however, have a particular significant association with short overall survival (P = 0.008). None of the 3 components was found to have a statistically significant prognostic impact in the group of 38 large cell lung cancer patients. There was a positive correlation between uPAR and PAI-1 levels in both groups and between uPA and uPAR levels in the large cell carcinoma patients. In a multivariate analysis, high uPAR was found to be an independent prognostic variable in squamous cell carcinoma patients, with a relative risk of 2.1 (95% confidence interval, 1.1-4.0) and tumor size the only other significant prognostic parameter. These data suggest that uPAR is an important prognostic factor in squamous cell lung carcinoma. In addition to the potential direct clinical usefulness, this information could be helpful in understanding the biology of this disease and developing new therapeutic approaches.

Long-term disease-free survival in small-cell carcinoma of the lung: a study of clinical determinants.

The influence of treatment and of pretreatment patient characteristics on the probability of long-term disease-free survival in small-cell lung cancer (SCLC) was investigated in a consecutive series of 874 patients. The patients were included in six controlled treatment trials from 1973 to 1981, using different combinations of chemotherapy with or without irradiation. All patients underwent pretreatment staging, including bronchoscopy, peritoneoscopy with liver biopsy, and bone marrow examination. The same procedures were repeated in patients without overt signs of disease 18 months from initiation of treatment, and patients without evidence of SCLC were regarded as long-term survivors. Seventy-two patients were disease-free at restaging, corresponding to 13% of 443 patients with limited-stage disease and 3% of 431 patients with extensive-stage disease. The possible relationship between different pretreatment variables and the probability of 18 months' disease-free survival was investigated by multiple regression analysis. Disease extent was the most important determinant of long-term survival. Being a woman was a positive factor and hypouricemia had negative influence on the long-term results, while features such as performance status and serum lactate dehydrogenase (LDH) did not have significant influence in the regression model. Differences between the efficacy of the applied treatment regimens were less in limited disease than they were in extensive disease, in which six-agent regimens of alternating chemotherapy was significantly better than treatment with three- or four-agent regimens. Accordingly, disease extent seems to be the most pivotal determinant of long-term survival in SCLC, but influence of the patient's sex and serum urate concentration should also be considered.

Mortality and morbidity in long-term surviving patients treated with chemotherapy with or without irradiation for small-cell lung cancer.

Mortality and morbidity was investigated in a consecutive series of 72 patients with small-cell lung cancer (SCLC) who were found to be disease-free at restaging after 18 months of treatment. These patients were all the long-term survivors among 874 patients included in one of six trials between 1973 and 1981. All studies used combination chemotherapy with or without irradiation. Follow-up of the patients varied between 4 and 11 years. The estimated 5-year survival rate subsequent to discontinuation of therapy was 0.24, corresponding to a death rate of 0.25 per year or ten times greater than the expected mortality for persons of the same age group. This high mortality was primarily related to recurrent SCLC, the estimated cumulative risk of relapse reaching 46% at the time of the latest recurrence 5 years from diagnosis. The risk of relapse was generally independent of the pretreatment disease stage although it was reduced in patients with resectable disease and was greater in those with pretreatment liver or bone marrow metastases. Equal risks of relapse were related to the use of regimens with and without radiotherapy. The cumulative risk of relapse in patients surviving 3 years from initiation of the treatment was less than 15% and accordingly, 3 years of follow-up seems sufficient for comparison of long-term results obtained in different trials. The second factor resulting in death or disease was second cancer, for which the cumulated risk increased to 32%, the latest occurring 5.4 years from the diagnosis of SCLC. Five of these cases were non-small-cell lung cancers and three were secondary leukemias. The estimated mortality related to non-neoplastic conditions was just significantly greater than expected. In spite of the increased mortality in this series, 38 of 54 2-year disease-free survivors and 20 of 22 5-year survivors resumed a lifestyle similar to that before diagnosis of SCLC.

Metastatic patterns in small-cell lung cancer: correlation of autopsy findings with clinical parameters in 537 patients.

Postmortem material from 537 patients included in various protocols of intensive combination chemotherapy or chemoradiotherapy for the management of small-cell anaplastic carcinoma of the lung (SCLC) has been reviewed. Patterns of residual or recurrent disease were analyzed in relation to pretreatment clinical parameters. Residual primary tumor (P less than .05), regional lymph node involvement (P less than .01), hepatic (P less than .01), bone (P less than .05), and renal metastases (P less than .05) were all significantly less frequent among patients with initially limited-stage disease compared with extensively staged patients. The frequency of residual intrathoracic tumor and metastatic pattern did not significantly differ between partial responders (PRs) and nonresponders (NRs). Patients with limited disease achieving a complete remission had a lower frequency of intrathoracic tumor (P less than .001) at autopsy compared with limited-stage PRs. However, for extensive-stage patients the pattern of residual disease was essentially independent of tumor response. Prior surgery was associated with a reduced burden of metastases only in those who underwent a radical resection. The addition of radiotherapy to the primary tumor and mediastinum failed to modify the autopsy distribution of residual tumor compared with that in patients treated with chemotherapy alone. Metastatic patterns were similar with or without prophylactic abdominal radiotherapy, while prophylactic cranial irradiation (PCl) did not prevent the development of cerebral metastases in patients whose systemic response to treatment was either partial or nonexistent. However, a beneficial effect of PCl in compete responders (CRs) was not excluded.

Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years--an analysis of 1,714 consecutive patients.

PURPOSE: To describe in patients with small-cell lung cancer (SCLC) the characteristics of those who survive for > or = 5 years, to identify long-term prognostic factors, to analyze survival data of 5-year survivors, and to study 10-year survival in patients entered before 1981. PATIENTS AND METHODS: A total of 1,714 unselected patients with SCLC were treated with combination chemotherapy in nine consecutive clinical trials from 1973 to 1991. All medical records were reviewed and follow-up data obtained to analyze and compare pretreatment and posttreatment characteristics. RESULTS: Sixty patients survived longer than 5 years. Late relapses occurred in 15.0% of 5-year survivors and secondary malignancies in 20.0%. Twenty-six patients are still alive and disease-free 5 to 18 years (median, 9.5 years) from initiation of treatment. Extensive-stage disease, performance status (PS) more than 2, liver and bone marrow metastases, and elevated lactate dehydrogenase (LDH) and alkaline phosphatase levels were all negative prognostic factors. The 5-year survival rate was 3.5% (limited-stage disease, 4.8%; extensive-stage disease, 2.3%), and the 10-year survival rate was 1.8% (limited-stage disease, 2.5%; extensive-stage disease, 1.2%). CONCLUSION: Long-term survival can be achieved for both stages of SCLC, but without any change in survival rates over the last decade. Long-term survivors continuously seem to have considerable mortality due to late relapses and secondary malignancies, especially tobacco-related cancers and other tobacco-related diseases.

The superiority of combination chemotherapy including etoposide based on in vivo cell cycle analysis in the treatment of extensive small-cell lung cancer: a randomized trial of 288 consecutive patients.

Two hundred and eighty-eight patients with extensive small-cell carcinoma of the lung (SCCL) were entered into a three-arm prospective randomized trial. The purpose was both to compare etoposide with methotrexate (MTX) in a combination chemotherapy regimen otherwise consisting of vincristine (VCR), lomustine (CCNU), and cyclophosphamide (CTX) and to evaluate a treatment design based on cell kinetic observations suggesting enhanced sensitivity to etoposide three to six days after administration of VCR, CCNU, and CTX. In all three treatment arms, VCR, CCNU, and CTX were administered on day 1 of a 28-day cycle. In arm A, MTX was administered on days 14 and 17, while in arm B, MTX was replaced by etoposide administered on days 14 through 17. In arm C, MTX was also replaced by etoposide, but administered on days 3 through 6. Overall survival was significantly longer for patients treated with "early" etoposide (arm C; median, 33 weeks) as compared with arm A (MTX; median, 23 weeks) (P less than .05), but not statistically different from "late" etoposide administration (arm B; median, 27 weeks). However, for patients with initial favorable performance status (0 + 1), a significantly longer survival was obtained for those treated with early etoposide (arm C. median, 51 weeks) as compared with patients in arm A (median, 32 weeks) and arm B (median, 36 weeks) (P less than .05). Two-year survival was obtained in six patients (7%) in arm C compared with three patients (3%) in arm B and none in arm A. The study confirmed that etoposide is an active drug in the treatment of SCCL and when combined with CTX, CCNU, and VCR, the cell kinetic approach of an early administration yields the best results.

p53 protein in non-small cell lung cancer as quantitated by enzyme-linked immunosorbent assay: relation to prognosis.

The prognostic value of p53 protein in tumor extracts as measured by ELISA was studied retrospectively in 228 non-small cell lung cancer (NSCLC) patients. The assay measures both wild-type and mutated p53. The specimens on which this study was performed have been used earlier to analyze the prognostic impact of components of the plasminogen activation system, which enabled an analysis of relationships between these components and p53 protein. The median of the p53 protein values in the 228 patients was 0.10 (range, 0-0.70) ng/mg protein. Survival analysis comparing patients with p53 levels below versus above the median showed no significant difference (P = 0.67). When analyzing the histological types, adenocarcinoma (n = 106), squamous cell carcinoma (n = 84), and large cell carcinoma of the lung (n = 38) separately, similarly, no significant differences in survival between patients having low versus high tumor p53 levels were found. When comparing levels of p53 protein in the three histological types, a significant difference (P < 0.0001) was found, with adenocarcinomas having the lowest levels. There was a weak positive correlation (r = 0.22) between p53 protein and plasminogen activator inhibitor type 1 (PAI-1). Multivariate analysis proved no impact of p53 on survival; tumor size, PAI-1, and lymph node involvement were the only variables with significant influence on survival. These data indicate that p53 protein quantitated with a sandwich ELISA in tumor extracts from NSCLC has no prognostic value, but the observed statistically significant difference of p53 protein content between histological subgroups may be related to differences in etiology and biology in different NSCLC subtypes. In addition, the weak association found between p53 protein and the independent prognostic marker PAI-1 could suggest yet undefined interactions in lung cancer.

Growth pattern of colorectal liver metastasis as a marker of recurrence risk.

Despite improved therapy of advanced colorectal cancer, the median overall survival (OS) is still low. A surgical removal has significantly improved survival, if lesions are entirely removed. The purpose of this retrospective explorative study was to evaluate the prognostic value of histological growth patterns (GP) in chemonaive and patients receiving neo-adjuvant therapy. Two-hundred-fifty-four patients who underwent liver resection of colorectal liver metastases between 2007 and 2011 were included in the study. Clinicopathological data and information on neo-adjuvant treatment were retrieved from patient and pathology records. Histological GP were evaluated and related to recurrence free and OS. Kaplan-Meier curves, log-rank test and Cox regression analysis were used. The 5-year OS was 41.8% (95% CI 33.8-49.8%). Growth pattern evaluation of the largest liver metastasis was possible in 224 cases, with the following distribution: desmoplastic 63 patients (28.1%); pushing 77 patients (34.4%); replacement 28 patients (12.5%); mixed 56 patients (25.0%). The Kaplan-Meier analyses demonstrated that patients resected for liver metastases with desmoplastic growth pattern had a longer recurrence free survival (RFS) than patients resected for non-desmoplastic liver metastases (p=0.05). When patients were stratified according to neo-adjuvant treatment in the multivariate Cox regression model, hazard ratios for RFS compared to desmoplastic were: pushing (HR=1.37, 95% CI 0.93-2.02, p=0.116), replacement (HR=2.16, 95% CI 1.29-3.62, p=0.003) and mixed (HR=1.70, 95% CI 1.12-2.59, p=0.013). This was true for chemonaive patients as well as for patients who received neo-adjuvant treatment.

Inflammation and uPAR-Expression in Colorectal Liver Metastases in Relation to Growth Pattern and Neo-adjuvant Therapy.

Proteolytic activity and inflammation in the tumour microenvironment affects cancer progression. In colorectal cancer (CRC) liver metastases it has been observed that three different immune profiles are present, as well as proteolytic activity, determined by the expression of urokinase-type plasminogen activator (uPAR).The main objectives of this study were to investigate uPAR expression and the density of macrophages (CD68) and T cells (CD3) as markers of inflammation in resected CRC liver metastases, where patients were neo-adjuvantly treated with chemotherapy with or without the angiogenesis inhibitor bevacizumab. Chemonaive patients served as a control group. The markers were correlated to growth patterns (GP) of liver metastases, i.e. desmoplastic, pushing and replacement GP. It was hypothesised that differences in proteolysis and inflammation could reflect tumour specific growth and therapy related changes in the tumour microenvironment. In chemonaive patients, a significantly higher level of uPAR was observed in desmoplastic liver metastases in comparison to pushing GP (p = 0.01) or replacement GP (p = 0.03). A significantly higher density of CD68 was observed in liver metastases with replacement GP in comparison to those with pushing GP (p = 0.01). In liver metastases from chemo treated patients, CD68 density was significantly higher in desmoplastic GP in comparison to pushing GP (p = 0.03). In chemo and bevacizumab treated patients only a significant lower CD3 expression was observed in liver metastases with a mixed GP than in those with desmoplastic (p = 0.01) or pushing GP (p = 0.05). Expression of uPAR and the density of macrophages at the tumour margin of liver metastasis differ between GP in the untreated patients. A higher density of T cells was observed in the bevacizumab treated patients, when desmoplastic and pushing metastases were compared to liver metastases with a mix of the GP respectively, however no specific correlations between the immune markers of macrophages and T cells or GP of liver metastases could be demonstrated.

Histopathological features in stage I non-seminomatous testicular germ cell tumours correlated to relapse. Danish Testicular Cancer Study Group.

156 patients with stage I non-seminomatous testicular germ cell tumour entered a countrywide randomized study comparing the effect of postoperative irradiation of retroperitoneal lymph nodes with surveillance only. A total of 150 patients were included in this investigation of factors associated with increased risk of relapse. Thirty-four patients (23 per cent) had a relapse, i.e. 11/67 (16 per cent) in the former and 23/83 (28 per cent) in the latter group. Histopathological studies of the orchidectomy specimens were performed in order to identify features associated with relapse. Pure embryonal carcinoma and vascular involvement were significantly associated with increased risk of relapse. Thus, the relapse rate in the observation group in patients with pure embryonal carcinomas was 50 per cent (5/10) and 36 per cent (19/53) in all patients with tumours with vascular involvement.

Factors confounding evaluation of treatment effect in lung cancer.

Disease extent, performance status (PS), and serum lactate dehydrogenase (LDH) are the most important prognostic factors in both inoperable non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Hyponatremia and serum alkaline phosphatase play an additional role in SCLC. Many different stratification algorithms have been proposed in SCLC but a general consensus cannot be achieved before it is decided whether stage of disease should rank above or be included in an algorithm, along with other prognostic factors.

Outcome of combination chemotherapy in extensive stage small-cell lung cancer: any treatment related progress?

During the past two decades many different treatment regimens of combination chemotherapy have been applied in extensive stage small-cell lung cancer (SCLC). This study was carried out to identify whether these modifications have resulted in an improved overall survival for extensive stage during the past two decades. In total, 1111 patients with extensive stage SCLC were included in six consecutive randomised trials in our setting from 1973 until 1992. Of these, 526 patients treated in the early period (1973-1981) were compared with 585 patients treated in the late period (1981-1992) with respect to pretreatment prognostic factors, staging, treatment and outcome. No change in the distribution of prognostic factors was detected and the frequency of patients with extensive stage was equal in the two periods, and no difference in overall response rates and survival was observed (P = 0.49). Median survival in the two periods was 208 days and 215 days, respectively. No stage migration or treatment-related improved outcome was observed in extensive disease. We suggest restricting aggressive treatment to patients with favorable prognosis and long-term survival as a realistic aim.

Controlled trial of RSV, herbs or placebo as adjuvants to complete resection of squamous cell lung cancer.

152 completely resected patients with high or intermediate differentiated squamous cell lung cancer were randomized to receive 6 months adjuvant therapy with RSV (1, 2-diphenyl-alpha beta-diketone) herbs or placebo. No significant differences were observed in duration of survival or relapse rates between the three groups.