p53, p21 and mdm2 expression vs the response to radiotherapy in transitional cell carcinoma of the bladder

OBJECTIVE: To identify, in a retrospective study, possible molecular markers predictive of radioresponsiveness in patients with transitional cell carcinoma (TCC) of the bladder. PATIENTS AND METHODS: Patients with T2-T4a TCC treated with preoperative radiotherapy and cystectomy were included in the study if their cystectomy specimen was pT3b (in 42) or pT0 (in 17). Because treatment schedules changed over time, radiotherapy was given either as 2 Gy x 23 over 4-5 weeks with cystectomy 4-5 weeks later (in 23), or as 4 Gy x 5 during 1 week with cystectomy in the following week (in 36 patients). Protein expression of p53, mdm2 and p21 (CDKN1 A/WAF1/CIP1/SDI1) was assessed immunohistochemically in biopsies taken before radiotherapy. RESULTS: There was no difference in protein expression when comparing all patients with pT0 and pT3b. However, for patients receiving 46 Gy, increased p53 expression (but not p21 or mdm2) predicted the absence of residual tumour (P = 0.005): six of seven patients with > 50% p53 expression had pT0 in the cystectomy specimen, whereas 10 of 12 patients with < or = 5% expression had pT3b. Over-expression of p53 correlated with longer overall (P = 0.045) and cancer-specific survival (P = 0.020). CONCLUSION: The expression of mdm2 or p21 did not predict radioresponsiveness in patients with TCC of the bladder. The role of p53 remains unclear; the view that p53 over-expression confers radioresistance in bladder cancer is not supported.     

Patients with focal full-thickness cartilage lesions benefit less from ACL reconstruction at 2–5?years follow-up

Purpose

To investigate differences in patient-reported outcome after anterior cruciate ligament (ACL) reconstruction between patients with and without a concomitant full-thickness cartilage lesion.

Methods

30 primary ACL-reconstructed patients with an isolated concomitant full-thickness cartilage lesion and 59 matched controls without cartilage lesions were identified in the Norwegian National Knee Ligament Registry and included in the present study. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was used as the outcome measure. At a median follow-up of 2.1?years (range, 2–5?years) after ACL reconstruction, 80 (90%) of the patients completed the KOOS.

Results

Preoperatively, there were no differences in KOOS between the study group and the control group. At follow-up, patients with full-thickness cartilage lesions reported significantly decreased scores compared to patients without cartilage lesions in the KOOS subscales pain (mean difference, 8.1; 95% confidence interval [CI], 0.8–15.3), activities in daily living (mean difference, 5.8; 95% CI, 0.3–11.2), sport/recreation (mean difference, 19.8; 95% CI, 5.3–34.3) and quality of life (mean difference, 17.2; 95% CI, 4.2–30.1). Patients with full-thickness cartilage lesions reported significantly less improvement from preoperative to follow-up than patients without cartilage lesions for the KOOS subscales pain (mean difference, 11.6; 95% CI, 3.2–19.9), sport/recreation (mean difference, 20.6; 95% CI, 8.1–33.1) and quality of life (mean difference, 16.3; 95% CI, 3.8–28.7).

Conclusions

ACL-injured patients with full-thickness cartilage lesions reported worse outcomes and less improvement after ACL reconstruction than those without cartilage lesions at 2–5?years follow-up.

Level of evidence

Prognostic; prospective cohort study, Level I.     

Microfracture technique versus osteochondral autologous transplantation mosaicplasty in patients with articular chondral lesions of the knee: a prospective randomized trial with long-term follow-up

Purpose

To compare long-term functional and radiological outcome following microfracture technique (MF) versus osteochondral autologous transplantation (OAT) mosaicplasty for treating focal chondral lesions of the knee.

Methods

Twenty-five patients (mean age 32.3 years, SD 7.7) with a full-thickness (International Cartilage Repair Society grade 3 or 4) chondral lesion of the articulating surface of the femur were randomized to either MF (n = 11) or OAT mosaicplasty (n = 14). At a median follow-up of 9.8 years (range 4.9–11.4), the patients were evaluated using Lysholm score (n = 25), Knee Injury and Osteoarthritis Outcome Score (KOOS, n = 25), isokinetic quadriceps measurement and hamstring strength measurement (n = 22) and standing radiographs (n = 23).

Results

There were no significant differences in Lysholm score, KOOS, isokinetic muscle strength or radiographic osteoarthritis between MF-treated patients and OAT mosaicplasty-treated patients at follow-up. Mean Lysholm score at follow-up was 69.7 [95 % confidence interval (CI), 55.1–84.4] for the MF group and 62.6 (95 % CI, 52.6–72.6) for the OAT mosaicplasty group.

Conclusion

At long-term follow-up, there were no significant differences between patients treated with MF and patients treated with OAT mosaicplasty in patient-reported outcomes, muscle strength or radiological outcome.

Level of evidence

Therapeutic study, Level II.     

Expression of the epidermal growth factor receptor family in normal and malignant urothelium

OBJECTIVE: To compare the immunohistochemically assessed expression of the epidermal growth factor receptor (EGFR) family in normal and malignant bladder urothelium, and suggest new hypotheses about their function in the development and progression of transitional cell carcinoma (TCC). PATIENTS AND METHODS: EGFR, ERBB2, ERBB3 and ERBB4 were evaluated immunohistochemically in normal urothelium (NU, 15), primary non-metastasized invasive TCC (NMC, 19) and in primary invasive TCCs with corresponding metastases (MC, 51, both specimens). RESULTS: All NU samples expressed ERBB4, none expressed ERBB2 and two expressed EGFR; all staining was uniform throughout all cell layers. ERBB2 expression increased and ERBB4 decreased from normal samples to carcinomas. There was no difference between NMCs and MCs in ERBB2, ERBB3 and ERBB4, but the NMCs expressed more EGFR than both NU and MC samples. There were no associations with T category, grade or survival. All combinations of expression levels for the four receptors were detected, with no dominant profile. CONCLUSION: We hypothesise that: (i) ERBB4 is important for differentiation in NU; (ii) ERBB2 is up-regulated with carcinogenesis in the urinary bladder but does not discriminate between bladder cancer with or without metastases; (iii) EGFR may be a marker of indolent disease. A current hypothesis, that superficial layers of NU do not express EGFR and thus protect the basal cells from the mitogenic effect of urinary EGF, is challenged.     

No difference in the level of physical activity between children who have or have never sustained a fracture

This study investigates whether children with an acute fracture have a different level of physical activity compared to children who have never sustained a fracture, as measured by the Physical Activity Questionnaire for older children (PAQ‐C). The PAQ‐C scores of 683 children (295 girls) aged 6–12 years (mean age 9.4 years) who presented to our institution with an acute fracture were compared to the PAQ‐C scores of 151 random children (81 girls) aged 6–12 years (mean 9.1 years) in the same area who had never sustained a fracture. Multivariate regression analysis was employed, controlling for age and gender. The mean PAQ‐C score of the children who presented to the institution with an acute fracture was 2.85 (95% confidence interval [CI], 2.80–2.91). For the children who had never sustained a fracture, the mean PAQ‐C score was 2.78 (95% CI, 2.69–2.87). If there is a true difference in the level of physical activity between children who have or have never sustained a fracture, the PAQ‐C questionnaire is not sensitive enough to identify it.     

TP53 and p21WAF1/CIP1 Behave Differently in Euploid versus Aneuploid Bladder Tumours Treated with Radiotherapy

The aim of this study was to examine any relation between DNA ploidy and previously detected TP53 (p53) or p21^WAF1/CIP1 expression in 94 patients with muscle-invasive transitional cell carcinoma of the urinary bladder and to associate these factors with survival. DNA ploidy was determined by image cytometry. In a subgroup of patients, the mutational status of the TP53 gene was assessed by temporal temperature gradient electrophoresis (TTGE) or perpendicular denaturant gradient gel electrophoresis (DGGE) and subsequent sequencing. Significantly more aneuploid than euploid tumours showed TP53 accumulation (p = 0.003). Patients with aneuploid tumours lived longer than patients with euploid tumours (p = 0.003). In the euploid, but not in the aneuploid group, TP53 and p21^WAF1/CIP1 were associated with cancer-specific survival (p = 0.002 and 0.02, respectively). Patients with > 50% TP53 expression had the longest survival time. Mutation analyses showed acceptable concordance with TP53 expression. We conclude that DNA aneuploidy may confer increased radiosensitivity in bladder cancer patients and that TP53 accumulation may confer increased radiosensitivity, but its effect is detectable only in euploid tumours.     

No negative effect on patient-reported outcome of concomitant cartilage lesions 5–9 years after ACL reconstruction

Purpose

To compare patient-reported outcome 5–9 years after anterior cruciate ligament (ACL) reconstruction in patients with and without a concomitant full-thickness [International Cartilage Repair Society (ICRS) grade 3–4] cartilage lesion.

Methods

This is a prospective follow-up of a cohort of 89 patients that were identified in the Norwegian National Knee Ligament Registry and included in the current study in 2007, consisting of 30 primary ACL-reconstructed patients with a concomitant, isolated full-thickness cartilage lesion (ICRS grade 3 and 4) and 59 matched controls without cartilage lesions (ICRS grade 1–4). At a median follow-up of 6.3 years (range 4.9–9.1) after ACL reconstruction, 74 (84 %) patients completed the Knee Injury and Osteoarthritis Outcome Score (KOOS), which was used as the main outcome measure. Secondary outcomes included radiographic evaluation according to the Kellgren–Lawrence criteria of knee osteoarthritis (OA).

Results

At follow-up, 5–9 years after ACL reconstruction, no statistically significant differences in KOOS were detected between patients with a concomitant full-thickness cartilage lesion and patients without concomitant cartilage lesions. Radiographic knee OA of the affected knee, defined as Kellgren and Lawrence ≥2, was significantly more frequent in subjects without a concomitant cartilage lesion (p = 0.016).

Conclusion

ACL reconstruction performed in patients with an isolated concomitant full-thickness cartilage lesion restored patient-reported knee function to the same level as ACL reconstruction performed in patients without concomitant cartilage lesions, 5–9 years after surgery. This should be considered in the preoperative information given to patients with such combined injuries, in terms of the expected outcome after ACL reconstruction and in the counselling and decision-making on the subject of surgical treatment of the concomitant cartilage lesion.

Level of evidence

Prognostic; prospective cohort study, Level I.