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Correction to: Nature Communications; https://doi.org/10.1038/s41467-018-06863-1, published online 5 November 2018.

Background: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. Patients: and methods We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201).Results: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type.Conclusions: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.

A series of 55 randomly chosen radical prostatectomy specimens was analyzed for expression of prostate-specific antigen (PSA) by immunohistochemical techniques. Tissue sections were selected in such a manner that in addition to glandular benign prostatic hyperplasia (BPH), one or more different prostatic tumour growth patterns were present. Four monoclonal antibodies, directed against three different PSA epitopes, and one polyclonal anti-PSA antiserum were used. Expression of PSA was compared with that of prostate-specific acid phosphatase (PAP), recognized by two different polyclonal antisera. A critical dilution aimed at a maximum of staining intensity on BPH tissue sections was chosen for all antibodies. Anti-PSA and anti-PAP antisera stained essentially all BPH samples (over 90%). Irrespective of the nature of the antibodies used, PSA expression was found to be decreased in prostatic carcinoma. A clear cut relationship was found between immunoreactivity for PSA and the degree of differentiation of the tumour area. Under the experimental conditions used the PSA monoclonal antibodies stained only 1 out of 10 undifferentiated carcinomas, whereas 50% to 70% of the well- and moderately-differentiated carcinomas showed immunoreactivity. This correlation was less pronounced with the PAP staining pattern. If the PSA antibody titer was raised the percentage of clearly staining undifferentiated carcinomas could be considerably increased (up to 60%-100%), indicating that PSA expression is not absent, but lowered in most (if not all) undifferentiated carcinomas.

Purpose The randomized controlled European Organisation for Research and Treatment of Cancer (EORTC) trial 22911 studied the effect of radiotherapy after prostatectomy in patients with adverse risk factors. Review pathology data of specimens from participants in this trial were analyzed to identify which factors predict increased benefit from adjuvant radiotherapy. Patients and Methods After prostatectomy, 1,005 patients with stage pT3 and/or positive surgical margins were randomly assigned to a wait-and-see (n = 503) and an adjuvant radiotherapy (60 Gy conventional irradiation) arm (n = 502). Pathologic review data were available for 552 patients from 11 participating centers. The interaction between the review pathology characteristics and treatment benefit was assessed by log-rank test for heterogeneity (P < .05). Results Margin status assessed by review pathology was the strongest predictor of prolonged biochemical disease-free survival with immediate postoperative radiotherapy (heterogeneity, P < .01): by year 5, immediate postoperative irradiation could prevent 291 events/1,000 patients with positive margins versus 88 events/1,000 patients with negative margins. The hazard ratio for immediate irradiation was 0.38 (95% CI, 0.26 to 0.54) and 0.88 (95% CI, 0.53 to 1.46) in the groups with positive and negative margins, respectively. We could not identify a significant impact of the positive margin localization. Conclusion Provided careful pathology of the prostatectomy is performed, our results suggest that immediate postoperative radiotherapy might not be recommended for prostate cancer patients with negative surgical margins. These findings require validation on an independent data set.

Objective: To assess the magnitude of prostate cancer detection by serendipity (the coincidental detection of prostate cancer during the evaluation of an abnormal screening test result) when a digital rectal examination (DRE) and transrectal ultrasonography (TRUS) are used as initial screening tests for prostate cancer in men with low levels of prostate-specific antigen (PSA; 0.0-3.9 ng/mL). Patients and methods: In all, 117 participants of a population-based screening study were diagnosed with prostate cancer after a standard evaluation of an abnormal screening test result; 49 underwent radical prostatectomy. Serendipity was defined as either: (i) the presence of prostate cancer opposite to the side that raised suspicion for cancer on DRE and/or TRUS; (ii) a negative lesion-directed biopsy while cancer was present in one or more of the cores of the sextant biopsy; (iii) a tumour volume of

The pre-operative prediction of prognostic tumour features in the radical prostatectomy specimen using routine clinicopathological variables remains limited. The present study evaluated the predictive value of the cell-cycle protein p27kip1, the proliferation marker MIB-1, and the cell-adhesion protein CD44s, determined on the diagnostic needle biopsy of asymptomatic men screened for prostate cancer. Of 81 screen-detected prostate cancers, representative biopsy cores and matched radical prostatectomy specimens were immunohistochemically stained for these tissue markers. Conventional pre-operative and post-operative clinicopathological variables were assessed and cancers were divided according to a validated tumour classification model (potentially harmless, clinically significant). Low (kip1 expression, high (≥10%) MIB-1 expression, and low (kip1, MIB-1, and CD44s, respectively. The concordance in tissue marker assessment between the biopsy specimen and matched radical prostatectomy specimens was low for all three. The positive predictive value (PPV) of p27kip1 was 90.0%, remarkably higher than that of MIB-1 and CD44s (41.2% and 52.0%, respectively), indicating that a low radical prostatectomy p27kip1 score is expected if the biopsy p27kip1 score is low. Logistic regression analysis revealed that biopsy Gleason score (pkip1 assessment (pkip1 expression were found to have clinically significant disease after radical prostatectomy. The assessment of p27kip1 in the biopsy specimen might thus assist in distinguishing between potentially aggressive and potentially non-aggressive disease in prostate cancer screening.

Increasing data suggest that the skin nerve system is involved in wound healing. The objective of this study was to investigate the outgrowth of nerve fibers during the burn wound remodeling process and to analyze possible differences between normotrophic and hypertrophic burn wounds. In a prospective study, biopsies were taken from 22 patients with spontaneously healed partial-thickness burns at 1, 4 and 7-month post-burn. Nerve outgrowth and the expression of the neuropeptides substance P, neurokinin A, calcitonin gene-related peptide, vasoactive intestinal peptide and neuropeptide Y was monitored using immunohistochemistry. Our results showed that the number of nerve fibers gradually increased in both the dermis and the epidermis, but that they did not reach the levels of expression present in matched unburned skin of the same patient. A significantly higher number of nerve fibers were observed in normotrophic scars compared with hypertrophic scars. The number of neuropeptides-containing nerves in normotrophic and hypertrophic scars were similar. In conclusion: 7 months after wound closure, burn wound scars contain less nerve fibers than unburned skin. The significantly higher number of nerve fibers in normotrophic, compared with hypertrophic scars suggests a regulatory role for the skin nerve system in the outcome of burn wound healing.

Keratinocytes are increasingly recognized as key regulators of skin inflammation and remodeling, as they are capable of producing growth factors and cytokines that are important mediators in the wound healing process. We investigated the expression and distribution of TGF-β1 mRNA by mRNA in situ hybridization and of TGF-β1, TGF-β2, TGF-β3, bFGF and VEGF protein expression using immunohistochemistry in spontaneously healed, partial-thickness burns and compared this with the expression of these markers in matched unburned skin. This was done to assess their role in the remodeling phase of burn wound healing. Punch biopsies were taken from both partial-thickness burns after re-epithelialization and from matched, unburned skin. At 4 and 7 months post-burn, biopsies were taken of normotrophic and hypertrophic scars that had developed in these wounds. We observed a higher expression of all mentioned growth factors in keratinocytes in scars at 1 month post-burn compared with matched unburned skin. At 4 months, keratinocytes still displayed a higher expression of TGF-β3 and bFGF, but the expression of TGF-β1, TGF-β2 and VEGF was normalized. The expression of TGF-β3 in the epidermis of hypertrophic scars was slightly higher than in normotrophic scars. At 7 months post-burn, all growth factors studied showed a normal expression on keratinocytes. Our results suggest that keratinocytes are not only involved in re-epithelialization, but also in the scar maturation. The data support the idea that keratinocytes not only respond to cytokines and growth factors in an autocrine fashion, but also exert regulatory paracrine effects on contiguous cells.

Objectives : The effect of androgen deprivation therapy on the expression of androgen receptors (AR) and the proliferation-associated MIB-1 antigen in prostatic intraepithelial neoplasia (PIN) was investigated. Methods : Immunohistochemistry was performed on tissue sections of prostatectomy specimens of patients with prostate cancer who either were not treated prior to surgery or received androgen blockade therapy for 3 months. Immunohistochemistry on slides, selected for the presence of PIN was performed with an AR-specific monoclonal antibody and MIB-1 using a microwave antigen-retrieval method. Results : AR expression was present in a majority of cells in PIN of both untreated and treated prostatectomy specimens. In addition, a proportion of normal prostatic glandular cells retained AR expression. The basal cells in both untreated and treated PIN did not express AR. MIB-1-positive cells were identified in PIN of untreated and treated cases. Conclusions : PIN lesions that persist after 3 months of androgen deprivation therapy continue to express AR and may therefore retain the potential to expand after cessation of this therapy.