Breast Cancer in Young Women: Is It Different? A Single-Center Retrospective Cohort Study.

Introduction: Breast cancer (BC) is one of the commonest cancers among women worldwide. Differences regarding tumor biology, presentation, genetics, and molecular subtypes may contribute to the relatively poorer prognosis among younger women. Limited information exists regarding pathologic characteristics and long-term outcomes among this group. Methods: This retrospective cohort study included 695 BC patients diagnosed over a 10-year period and investigated the clinicopathological characteristics and long-term disease outcomes among patients diagnosed at age less than or equal to 40 years compared with older ones. Cox regression analysis was performed, and Kaplan-Meier curves were generated to assess overall survival (OS). Results: Compared with the younger patients (⩽40 years) estrogen receptor (ER) and progesterone receptor (PR) expression was mainly positive in older patients (>40 years) (76.2% vs 61.3% and 64.2% vs 49.6%, respectively). The most common molecular subtype in both age groups was luminal B (44.1% in older and 40.3% in younger). A clinical complete remission after neoadjuvant therapy was observed more frequently in older patients (76.7%; N = 442) in comparison with the younger patients (66.4%; N = 79) (P = .018). Recurrence and disease progression were significantly more likely to occur among younger patients accounting for 12.6% and 29.4% of the cases, compared with 6.3% and 18.2% in older patients (P = .016 and P = .006, respectively). The overall mortality was 132 (19%) of 695, with 88% cancer-related deaths. Estrogen receptor and PR expression (P ⩽ .001 and P = .003, respectively), molecular subtype (P = .002), tumor grade (P = .002), and N stage (P = .038) were the variables that were found to be significantly influenced by age. The OS was not statistically different among 2 age groups, but younger patients with luminal A molecular subtype showed significantly poor outcome (P = .019). Conclusion: Overall survival in women diagnosed with BC at age less than or equal to 40 years is not significantly worse than older patients. However, among patients with luminal A subtype, younger women had relatively poor survival. Further research is needed to understand this age-based disparity in outcomes.

Measurement of Exam Anxiety Levels Among Medical Students and Their Association With the Influencing Factors.

Introduction Studying medical science is a demanding task, often leading to exam anxiety among medical students. This study aims to measure anxiety levels among medical students and their relationship with gender, age, grades, study time, year of study, and learning methods. Methods It is a cross-sectional study involving third- to sixth-year medical students, who filled in the questionnaire related to the personal data, studying methods, and the Westside Test Anxiety Scale, to estimate the exam anxiety levels before the final examinations of the academic year 2020-2021. Completed questionnaires were reviewed, entered in Microsoft Excel, and analyzed using SPSS.  Results We found a significant association between gender and high-test anxiety (p < 0.001), with a higher prevalence among females (47.9%) compared to males (22.5%). Although non-significant, its prevalence was higher among the 20 years old (34%) and those with a GPA 4.00-4.49 (37.9%). Anxiety decreased as the students progressed to higher years of studies (37.9% in the third year to only 9.1% in sixth year, p=0.073), with the lower incidence among those who studied five days or more per week (26.7%) and no significant difference was observed whether students studying in a group or individually. Though insignificant (p=0.754), learning through textbooks was found to be less stressful (29% vs 33%). Conclusion Our findings suggest that mediocre and female students are more vulnerable to exam high-test anxiety. Progression to senior years and use of textbooks were associated with lower anxiety levels. A cohort longitudinal study to establish an association between specific factors and anxiety levels is recommended.

Assessing the Correlation of Rate of Pathological Complete Response and Outcome in Post Neoadjuvant Chemotherapy Setting and Molecular Subtypes of Breast Cancer.

Background Neoadjuvant chemotherapy (NAC) is being widely used in treating breast cancer (BC). This study aimed to analyze the correlation between clinicopathological features, immunohistochemistry (IHC)-based molecular subtypes, and the pathological response to NAC and its relationship with disease-free survival (DFS) and overall survival (OS). Materials and methods A retrospective analysis of 211 breast cancer patients who received NAC between 2008 and 2018 was performed. Tumors were classified by IHC into luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and triple-negative subtypes. The chi-square test was used to assess the association between pathological response and clinicopathological parameters. Cox regression analysis was used to assess factors related to DFS and OS. Results Post NAC, 19.4% of patients achieved a pathologic complete response (pCR). Estrogen receptor (ER), progesterone receptor (PR), HER2 (p<0.001, 0.005, and 0.02), Ki67 (p=0.03), molecular subtypes (p<0.001), T stage (p=0.04), and N stage (p=0.01) were significantly associated with pathological response. The rate of pCR was highest among HER2-enriched and triple-negative tumors (45.2% and 28%, respectively) with OR=0.13 and p<0.001 for the HER2-enriched subtype. Patients with pCR were 61% less likely to develop metastasis (adjusted hazard ratio [aHR]=0.39, p=0.06, 95% CI=0.14-1.06) and were significantly associated with better OS (aHR=0.07, p=0.02, 95% CI=0.01-0.61). Patients who were ≤40 years old (aHR=2.1, p=0.01), with T4 (aHR=3.4, p=0.02), grade 3 (aHR=2.5, p=0.01), and node-positive disease (HR=2.24, p=0.02) were at an increased risk of developing metastasis. High Ki67 was found to be significantly associated with better DFS (p=0.006). Conclusion HER2-enriched and triple-negative BC were associated with a higher rate of pCR. Patients with pCR had significantly better DFS and OS. Younger age, advanced stage, higher grade, and lymph node involvement were risk factors for metastasis.

A Shifting Trend Towards Endovascular Intervention in the Treatment of Acute Mesenteric Ischemia.

Background Acute mesenteric ischemia (AMI) is a vascular emergency with a quite low incidence, but it is associated with disproportionately more severe morbidity and mortality. The aim of this study was to assess the current trend in the treatment of AMI and to see if endovascular intervention is an effective treatment modality in the selected group of patients. Methods A retrospective review of patients admitted with AMI between 2007 and 2018 was performed. Outcome measures were length of stay (LOS) at hospital and intensive care unit (ICU), and post-treatment mortality. Results A total of 98 patients with AMI were admitted during the study period. Patients undergoing endovascular treatment compared with surgery were younger (62.9 ± 13.7 years vs. 69.5 ± 12.8 years; p = 0.01). Shorter LOS in hospital and ICU was observed for those treated with endovascular approach (6.8 ± 3.4 and 3.25 ± 0.5 days) compared to the surgical group (25 ± 8.6 and 12.8 ± 26.8 days; p < 0.001). Out of 39 patients requiring ICU admission, 48.7% were surgically treated and 10.2% underwent endovascular intervention (p < 0.001). Mortality associated with surgery was 30.6% compared to only 6.6% with endovascular intervention (p < 0.001). Between 2007 and 2012, only one patient underwent endovascular intervention and 20 underwent surgery compared to 14 patients treated with endovascular approach and 16 with surgery between 2013 and 2018. Conclusion In this non-randomized, retrospective case series, patients with endovascular treatment fared clinically better and the intervention was found to be safe and feasible in the selected group of patients. We suggest a preference for this modality where possible. At our hospital, a trend favoring this approach is apparent during the last six years.

Can disseminated intravascular coagulation scores predict mortality in COVID-19 patients?

OBJECTIVES: Complications related to coronavirus disease 2019 (COVID-19) may lead to disseminated intravascular coagulation (DIC), which has been reported to be among the known causes of mortality in such patients. This study aims to analyse the incidence of DIC in COVID-19 non-survivors and to assess the association between DIC and its comorbidities. METHODS: The medical records of 154 non-survivors of COVID-19, hospitalised between April 2020 and July 2020, were retrospectively analysed. The International Society on Thrombosis and Haemostasis (ISTH) criteria for DIC were applied to identify the occurrence of coagulopathy. The receiver-operating characteristic (ROC) analysis was used to assess the association between DIC and its comorbidities. RESULTS: Out of 154 non-survivors, non-overt DIC was observed in 94.8% of the patients, whereas only 5.2% fulfilled the overt criteria of DIC with a mean age 64.6 years. The mortality rate was 4.5 times higher among men than women. The D-dimer level was >250 ng/ml in 68.8% of the patients including 88.9% of the non-overt and 100% of the overt DIC patients. Prothrombin time (PT) in non-overt and overt DIC cases was 17.3 s and 24.4 s, respectively. Thrombotic event and chronic kidney disease were found to be the main predictors of DIC (p < 0.0001 and 0.03, respectively) followed by diabetes mellitus (DM) and hypertension (statistically insignificant). CONCLUSIONS: Our study concludes that the ISTH DIC score cannot predict mortality as the COVID-19 related DIC differs from the sepsis-induced DIC. Among the seriously ill, older patients with comorbidities, increased levels of D-dimer and prolonged PT are more reliable parameters among COVID-19 non-survivors.

The Level of Agreement Among Medical Oncologists on Adjuvant Chemotherapy Decision for Breast Cancer in Pre and Post-Oncotype DX Settings.

INTRODUCTION: The Oncotype DX assay plays an important role in the identification of the specific subset of hormone receptor (HR)-positive and node-negative breast cancer (BC) patients, who would benefit the most from adjuvant chemotherapy. The current study aimed at assessing the level of agreement among medical oncologists on adjuvant chemotherapy decisions before and after Oncotype DX, as well as the intra-observer agreement of each medical oncologist's decision of prescribing adjuvant chemotherapy based on clinicopathological and immunohistochemical parameters only and followed by Oncotype DX recurrence score (RS) results. METHODS: A retrospective analysis of data related to clinicopathological and immunohistochemical parameters, and Oncotype DX RS result for 145 female, estrogen receptor (ER)-positive, HER2 negative, and both node-negative and positive BC patients was performed. Initially, the data without Oncotype DX RS was sent to 16 oncologists in multiple centers in the Middle East. After one week, the same data with the shuffling of cases were sent to the oncologists with the addition of the Oncotype DX RS result for each patient. The inter and intra-observer agreement (kappa and Fleiss multi-rater kappa) among oncologists' decision of prescribing adjuvant chemotherapy pre and post-Oncotype DX RS results were assessed. Oncotype DX risk scores were used as continuous variables as well as based on old RS grouping, categorized into low (0-17), intermediate (18-30), and high risk (≥ 31) groups. A test with a p-value of < 0 .05 will be considered statistically significant. RESULTS: The mean age ± SD of the cohort was 51.9 ± 9.4 years. Sixty-nine patients (47.6%) were premenopausal whereas 76 patients (52.4%) were postmenopausal. The mean Oncotype DX RS was 17.8 ± 8.6 and 54.5% had low recurrence risk (RR), 37.9% had intermediate RR and only 7.6% had high RR. The majority of our cases were grade two (53.1%) and T stage one (49%), whereas 29.7% had positive one to three lymph nodes. The addition of Oncotype DX results improved the agreement among oncologists' decision from fair to moderate (kappa = 0.52; p <0.001). On average, an oncologist's decision of prescribing adjuvant chemotherapy pre and post-Oncotype DX had an agreement in 70.6% of the cases, with agreement observed mostly for cases where the initial decision of adjuvant chemotherapy was (no) and it was retained with post-Oncotype DX assay (46.1%), compared to 24.5% cases where the initial decision was (yes) and it was retained with post-Oncotype DX assay (kappa = 0.39; p <0.001). The addition of the Oncotype DX RS result avoided chemotherapy in 20.4% of cases and identified 9% of cases as candidates for adjuvant chemotherapy (kappa = 0.38; p <0.001). The disagreement was highest among cases with intermediate RR (33.6%) followed by high and low RR (31.3% and 21.6%) with a statistical significance of <0.001. CONCLUSION: We conclude that the Oncotype DX RS significantly influenced the decision to prescribe adjuvant chemotherapy among HR-positive, HER2 negative, and both node-negative and positive patients, as it increased the level of agreement among oncologists and led to a decrease in the use of adjuvant chemotherapy compared to the pre-Oncotype recommendations.

Phyllodes tumor of the breast clinical experience and outcomes: A retrospective cohort tertiary hospital experience.

BACKGROUND: Phyllodes tumor (PT) accounts for <1% of all breast tumors worldwide. Based on their microscopic features, these tumors are classified into benign, borderline, and malignant. This study aimed at evaluating the clinical experience and the clinicopathologic features of PT. METHODS: A retrospective cohort study of 46 female patients with histologically diagnosed PT. Data collection and evaluation was done on patient demographics, preoperative radiological assessment and pathology, surgical procedure, post-surgery pathological evaluation, radiation therapy (RT), and follow-up. RESULTS: The median age at diagnosis was 42 years and young premenopausal patients (median age 35 years) had malignant PT. Forty-five patients underwent core needle biopsy (CNB) with high sensitivity and the positive predictive value (82.2% and 97.4% respectively). Thirty-nine patients (86.7%) underwent conservative surgery and 6 (13.3%) had a mastectomy. Twenty-seven (58.6%) were classified as benign, 11 (23.9%) as borderline and only 8 (17.4%) as malignant PT. Malignant PT had the greatest median tumor size (13 cm). Mortality and recurrence rates were 4.3% and 2.2% respectively. RT was administered in 6 patients (13.0%), 5 having malignant and 1 borderline PT. The metastatic rate was found to be 6.5%. CONCLUSION: PT are rare breast tumors with variable biologic behavior and heterogenous clinicopathological findings. Young, premenopausal women with large tumors may have malignant PT with a risk of recurrence and metastasis. Core needle biopsy is a reliable tool for diagnosis of PT with strict follow-up recommended for large tumors diagnosed as fibroadenoma on CNB. Surgical management must ensure a tumor-free margin on excision to reduce recurrence.

Predictability of 21-Gene Recurrence Score Assay by Using Pathological and Immunohistochemical Parameters in Breast Cancer.

BACKGROUND: Oncotype Dx is used to predict the long-term recurrence risk in patients with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative invasive breast cancer (BC). This study aimed at establishing a correlation between clinicopathological parameters and recurrence score (RS), subsequently improving predictability and ultimately justifying the use of the multigene assay. MATERIALS AND METHODS: A retrospective analysis of the pathology and clinical data of 114 female patients with BC who had Oncotype Dx testing between 2012 and 2019. The pathological parameters included are tumor cell type, tumor grade, pathological stage, and mitotic index (MI). The expression of ER, progesterone receptor (PR), HER2, and Ki67 was assessed by immunohistochemistry. A univariate and multivariate linear regression analysis was performed to assess the correlation between these parameters and the RS. RESULTS: In univariate analysis, age (˂40 years), higher tumor grade, and low PR expression were significantly associated with higher RS (P = .02; ˂.001; and ˂.001, respectively). Both MI and Ki67 were also strongly correlated with an increase in the RS with a P value of .01 (Spearman correlation 0.34 and 0.33). In multivariate linear regression analysis, age, MI, and Ki67 lost their significance, but both higher grade and PR remained significantly associated with a higher RS along with the tumor stage (P ˂ .001; ˂.001; and .04, respectively). CONCLUSIONS: Tumor grade and PR immunohistochemical expression are the main predictors of RS in our study population. Other clinicopathological features were not significant predictors of change in RS in multivariate analysis.

Age and pro-inflammatory gene polymorphisms influence adjacent segment disc degeneration more than fusion does in patients treated for chronic low back pain.

PURPOSE: Does lumbar fusion lead to accelerated adjacent segment disc degeneration (ASDD) or is it explained by genetics and aging? The influence of genetics on ASDD remains to be explored. This study assesses whether the disc space height adjacent to a fused segment is associated with candidate gene single nucleotide polymorphisms (SNPs). METHODS: Patients with low back pain from four RCTs (N = 208 fusion; 77 non-operative treatment) underwent standing plain radiography and genetic analyses at 13 ± 4 years follow-up. Disc space height was measured using a validated computer-assisted distortion-compensated roentgen analysis technique and reported in standard deviations from normal values. Genetic association analyses included 34 SNPs in 25 structural, inflammatory, matrix degrading, apoptotic, vitamin D receptor and OA-related genes relevant to disc degeneration. These were analysed for their association with disc space height (after adjusting for age, gender, smoking, duration of follow-up and treatment group) first, separately, and then together in a stepwise multivariable model. RESULTS: Two SNPs from the IL18RAP gene (rs1420106 and rs917997) were each associated with a lower disc space height at the adjacent level (B = -0.34, p = 0.04 and B = -0.35, p = 0.04, respectively) and the MMP-9 gene SNP rs20544 was associated with a greater disc space height (B = 0.35, p = 0.04). Age (p < 0.001) and fusion (p < 0.008) were also significant variables in each analysis. The total explained variance in disc space height was for each SNP model 13-14 %, with 11-12 % of this being accounted for by the given SNP, 64-67 % by age and 19-22 % by fusion. In the multivariable regression analysis (with nine SNPs selected for entry, along with the covariates) the total explained variance in disc space height was 23 %, with the nine SNPs, age and fusion accounting for 45, 45 and 7 % of this, respectively. CONCLUSIONS: Age was the most significant determinant of adjacent segment disc space height followed by genetic factors, specifically inflammatory genes. Fusion explained a statistically significant but small proportion of the total variance. Much of the variance remained to be explained.

Catechol-O-methyltransferase (COMT) gene polymorphisms are associated with baseline disability but not long-term treatment outcome in patients with chronic low back pain.

PURPOSE: To examine the association between COMT and OPRM1 gene polymorphisms and pain and disability at baseline and long-term follow-up in patients treated for chronic low back pain (LBP). METHODS: 371 of 767 unrelated European patients recruited from four randomised trials underwent genetic analyses at mean 11.4 years follow-up. 274 patients had fusion and 97 had non-operative treatment. Association analyses included disability, pain, five single nucleotide polymorphisms (SNPs) in the COMT gene, and one SNP in the OPRM1 gene. Analyses were adjusted for age, gender, smoking, analgesics and treatment. RESULTS: Disability at baseline was significantly associated with COMT SNPs rs4818 (p = 0.02), rs6269 (p = 0.007), rs4633 (p = 0.04) rs2075507 (p = 0.009), two haplotypes (p < 0.002), age, gender and smoking (p ≤ 0.002). No significant associations with clinical variables were observed for OPRM1, or for COMT at long-term follow-up. CONCLUSIONS: Results suggest that genetic factors are partly responsible for the variation in disability levels in patients presenting with chronic LBP being considered for surgery; in contrast, genetics has no influence on the long-term outcome of treatment.

Treatment outcome of chronic low back pain and radiographic lumbar disc degeneration are associated with inflammatory and matrix degrading gene variants: a prospective genetic association study.

BACKGROUND: Inflammatory and matrix degrading gene variants have been reported to be associated with disc degeneration. Some of these variants also modulate peripheral pain. This study examines the association of these genetic variants with radiographic lumbar disc degeneration and changes in pain and disability at long-term after surgical and cognitive behavioural management. METHODS: 93 unrelated patients with chronic low back pain (CLBP) for duration of >1 year and lumbar disc degeneration were treated with lumbar fusion or cognitive intervention and exercises. Standardised questionnaires included the Oswestry Disability Index (ODI) and Visual Analog Score (VAS) for CLBP, were filled in by patients both at baseline and at 9 years follow-up. Degenerative changes at baseline Magnetic Resonance Imaging and Computed Tomography scans, were graded as moderate and severe (N=79). Yield and quality of blood and saliva DNA was assessed by nano drop spectrophotometry. Eight SNPs in 5 inflammatory and matrix degrading genes were successfully genotyped. Single marker and haplotype association with severity of degeneration, number of discs involved, changes in ODI and VAS CLBP, was done using Haploview, linear regression and R-package Haplostats. RESULTS: Association analysis of individual SNPs revealed association of IL18RAP polymorphism rs1420100 with severe degeneration (p = 0.05) and more than one degenerated disc (p = 0.02). From the same gene two SNPs, rs917997 and rs1420106, were found to be in strong linkage disequilibrium (LD) and were associated with post treatment improvement in disability (p = 0.02). Haplotype association analysis of 5 SNPs spanning across IL18RAP, IL18R1 and IL1A genes revealed significant associations with improvement in disability (p=0.02) and reduction in pain (p=0.04). An association was found between MMP3 polymorphism rs72520913 and improvement in pain (p = 0.03) and with severe degeneration (p = 0.006). CONCLUSIONS: The findings of the current study suggest a role of variation at inflammatory and matrix degrading genes with severity of lumbar disc degeneration, pain and disability.

Genetic contribution of catechol-O-methyltransferase variants in treatment outcome of low back pain: a prospective genetic association study.

BACKGROUND: Treatment outcome of low back pain (LBP) is associated with inter-individual variations in pain relief and functional disability. Genetic variants of catechol-O-methyltransferase (COMT) gene have previously been shown to be associated with pain sensitivity and pain medication. This study examines the association between COMT polymorphisms and 7-11 year change in Oswestry Disability Index (ODI) and Visual Analog Score (VAS) for LBP as clinical outcome variables in patients treated with surgical instrumented lumbar fusion or cognitive intervention and exercise. METHODS: 93 unrelated patients with chronic LBP for duration of >1 year and lumbar disc degeneration (LDD) were treated with lumbar fusion (N = 60) or cognitive therapy and exercises (N = 33). Standardised questionnaires assessing the ODI, VAS LBP, psychological factors and use of analgesics, were answered by patients both at baseline and at 7-11 years follow-up. Four SNPs in the COMT gene were successfully genotyped. Single marker as well as haplotype association with change in ODI and VAS LBP, were analyzed using Haploview, linear regression and R-package Haplostats. P-values were not formally corrected for multiple testing as this was an explorative study. RESULTS: Association analysis of individual SNPs adjusted for covariates revealed association of rs4633 and rs4680 with post treatment improvement in VAS LBP (p = 0.02, mean difference (ß) = 13.5 and p = 0.02, ß = 14.2 respectively). SNPs, rs4633 and rs4680 were found to be genotypically similar and in strong linkage disequilibrium (LD). A significant association was found with covariates, analgesics (p = 0.001, ß = 18.6); anxiety and depression (p = 0.008, ß = 15.4) and age (p = 0.03, mean difference per year (ß) = 0.7) at follow-up. There was a tendency for better improvement among heterozygous patients compared to the homozygous. No association was observed for the analysis of the common haplotypes, these SNPs were situated on. CONCLUSIONS: Results suggest an influence of genetic variants of COMT gene in describing the variation in pain after treatment for low back pain. Replication in large samples with testing for other pain related genes is warranted.

An Association Study of Interleukin 18 Receptor Genes (IL18R1 and IL18RAP) in Lumbar Disc Degeneration.

OBJECTIVES: To examine association of candidate genetic variants in structural, inflammatory, matrix modifying, vitamin D receptor genes and variants associated with osteoarthritis, with surgical candidates and surgical patients with lumbar disc degeneration (LDD), in light of their previously reported susceptibility for LDD. METHODS: Genotyping of 146 Norwegian LDD patients and 188 Norwegian controls was performed for 20 single-nucleotide polymorphisms (SNPs) from collagen, aggrecan, interleukin, VDR, MMP3 and COX2 genes and 7 SNPs from osteoarthritic genes. RESULTS: The neighboring genes IL18R1 and IL18RAP polymorphisms (rs2287037 and rs1420100), showed a statistically non-significant risk for developing LDD (OR 1.36 [95 % CI 0.99 - 1.87]; p=0.06 and OR 1.33 [95 % CI 0.98-1.81]; p=0.07). Homozygosity of these risk alleles was associated with LDD (p=0.023 and p=0.027). The non-risk alleles at these SNPs were situated on a haplotype negatively associated with LDD (p=0.008). Carriage of at least one non-risk allele at both loci also reduces the risk of developing LDD (OR 0.51 [95 % CI 0.33-0.80]; p=0.003). CONCLUSION: Our findings support the polygenic nature of LDD and suggest that variation in interleukin 18 receptor genes could affect the risk of severe LDD and associated low back pain.

Organ specific regulation of tumour invasiveness and gelatinolytic activity at the invasive front.

Proteolytic enzymes play a complex role in tumour growth and invasion. To explore the impact of tumour stroma on invasiveness and expression of proteolytic enzymes, we used a xenograft mouse model where tumours in tongue and skin were established from various human cancer cell lines. Gelatinolytic activity in the tumours was investigated by a novel in situ zymography technique which enables high image resolution. In vivo and in vitro expression of various proteolytic enzymes were analysed at transcriptional and protein level using RT-qPCR, immunohistochemistry and SDS-PAGE substrate zymography. At the mRNA level all cell lines were found to express MMP-2, -7, -14, uPA and uPAR. In addition, two out of three cell lines expressed MMP-9. Histological analyses revealed that tongue tumours had an invasive growth pattern, associated with reduced E-cadherin expression. In contrast, the skin tumours established from the same cell lines were non-invasive. Tongue tumours of all cell lines showed strong gelatinolytic activity especially at the invasive front, which was not seen in the non-invasive skin tumours. Our results show a close relationship between tumour invasiveness and gelatinolytic activity at the tumour front. Furthermore, in our model, both invasiveness and activity of tumour-associated proteolytic enzymes were more dependent on the tumour microenvironment than on inherent properties of the cancer cells.