Traditional risk factors and nodal yield-still relevant with high-quality risk-adapted adjuvant treatment for locally advanced head and neck cancer?

OBJECTIVE: Patients with locally advanced head and neck cancer (LAHNC) often undergo multimodal therapy including radical resection of the primary tumor and neck dissection (ND) followed by risk-adapted adjuvant radio(chemo)therapy (R(C)T). Quality parameters influencing local control and survival of these patients have been postulated: resection status (R status), extranodal extension (ENE), interval to adjuvant treatment ≤6 weeks, R(C)T given when indicated, and nodal yield (NY) ≥18 lymph nodes per neck. For other solid tumors the trend is towards less extensive lymph node surgery to avoid toxicity such as lymphedema, damage to peripheral nerves, dysesthesia, or paresthesia. The present study aims to investigate whether the number of nodes removed during neck dissection for LAHNC is still predictive for outcome when patients receive risk-adapted adjuvant treatment according to current guidelines. METHODS: Between 2008 and 2015, 468 patients with LAHNC undergoing R(C)T with curative intent were prospectively registered in a database (UICC III/IV). Among them, 359 patients received adjuvant treatment and 295 underwent neck dissection. There were 119 (40%) patients with an oropharyngeal primary, 49 (17%) with cancer of the larynx/hypopharynx, 88 (30%) of the oral cavity, and 39 (13%) of the nasal/paranasal sinuses and cancer of unknown primary (CUP). Median follow-up was 45.6 months. Histopathology revealed an R1 status in 65 (22%) cases and ENE in 93 (31%) cases. 150 (51%) patients received RCT; the median time to adjuvant treatment from the day of tumor resection was 44 days (35-54) and overall treatment time (OTT; time from surgery to the last day of R(C)T) was 90 days (82-101). Factors influencing disease-free survival (DFS) were adjusted and analyzed using CART analysis (removed nodes, number of positive nodes, body mass index (BMI), ENE, T and N classification, R status, and primary site). Local control (LC), distant metastases-free survival (DMFS), and overall survival (OS) were analyzed using Kaplan-Meier statistics and multivariate analysis (MVA) for factors predictive for DFS and OS. RESULTS: CART analysis (Classification and Regression Trees) showed that T classification (T3/4) is the most important predictor for DFS, followed by age (> 61 years) and BMI (< 17.4). Primary site (OPC vs. other) and number of removed nodes (< 17) were shown to be less important for DFS, while ECE, N classification, and R status seem to be of little relevance. MVA revealed number of positive nodes, non-OPC, and T3/4 to be negative predictive factors for DFS. For OS, the number of positive nodes and non-OPC primary were predictive. Five-year rates were 86.1% for LC, 87.9% DMFS, 76.5% DFS, and 67.2% for OS. CONCLUSION: In this patient cohort, the number of removed nodes is not relevant for DFS and OS, while the number of positive nodes and T classification have a negative impact on these endpoints. The high-risk factors positive resection margin and ECE seem to lose their negative impact on DFS and OS. High-quality care in head and oncology is only possible within a close multidisciplinary team and network.

[Musculoskeletal disorders among urologists-is there an association with open pelvic surgery? : Results of a national survey]. / Muskuloskelettale Erkrankungen bei Operateuren in der Urologie ­ besteht ein Zusammenhang mit der offenen Beckenchirurgie? : Ergebnisse einer nationalen Erhebung.

BACKGROUND: In urology, the health implications of open pelvic surgery (OPS) on the patient have been the subject of numerous studies. However, health effects on the surgeon have not yet been sufficiently considered. The present study investigates the relationship between musculoskeletal disorders in urological surgeons and their activity in OPS. MATERIALS AND METHODS: From the point of view of occupational physiology, exemplary operations in OPS were examined using the key indicator method (KIM). In addition, a web-based survey among German clinicians was carried out. From the collected variables, models for the prediction of the endpoints pain and disc herniation (DH) were generated by multivariate logistic regression. RESULTS: Risk assessment of the operations with KIM could show that OPS presents a significantly increased physical workload and thus potential physical overstraining. Of the 605 participants in the survey, 35.4% were urologists performing OPS, 32.0% were urologists not performing OPS and 32.6% were gastroenterologists (control groups). Activity in OPS had an odds ratio (OR) of 1.09 (confidence interval [CI]: 0.72-1.66, p = 0.69) for predicting pain, and an OR of 1.14 for prediction of DH CI: 0.66-1.94; p = 0.64). Statistically significant factors influencing the perception of pain were BMI, gender and work ability index (WAI), whereas age and WAI were significant for the occurrence of DH. CONCLUSION: Our survey could not show that surgeons practicing OPS have a significantly increased rate of musculoskeletal disorders or, in particular, an increased rate of DH in comparison to the control groups. Nevertheless, the rate of reported complaints among all clinicians surveyed is high, and the random risk assessment of the examplary OPS operations could also demonstrate the risk of physical overstraining. Further considerations should therefore be made as to how reduce the strain on the musculoskeletal system.

Standard of Care Versus Metastases-directed Therapy for PET-detected Nodal Oligorecurrent Prostate Cancer Following Multimodality Treatment: A Multi-institutional Case-control Study.

BACKGROUND: Most prostate cancer (PCa) patients with a biochemical failure following primary multimodality treatment (surgery and postoperative radiotherapy) relapse in the nodes. OBJECTIVE: To perform a matched-case analysis in men with lymph node recurrent PCa comparing standard of care (SOC) with metastasis-directed therapy (MDT). DESIGN, SETTING, AND PARTICIPANTS: PCa patients with a prostate-specific antigen (PSA) progression following multimodality treatment were included in this retrospective multi-institutional analysis. INTERVENTION: The SOC cohort (n=1816) received immediate or delayed androgen deprivation therapy administered at PSA progression. The MDT cohort (n=263) received either salvage lymph node dissection (n=166) or stereotactic body radiotherapy (n=97) at PSA progression to a positron emission tomography-detected nodal recurrence. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint, cancer-specific survival (CSS), was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. RESULTS AND LIMITATIONS: At a median follow-up of 70 (interquartile range: 48-98) mo, MDT was associated with an improved CSS on univariate (p=0.029) and multivariate analysis (hazard ratio: 0.33, 95% confidence interval [CI]: 0.17-0.64) adjusted for the year of radical prostatectomy (RP), age at RP, PSA at RP, time from RP to PSA progression, Gleason score, surgical margin status, pT- and pN-stage. In total, 659 men were matched (3:1 ratio). The 5-yr CSS was 98.6% (95% CI: 94.3-99.6) and 95.7% (95% CI: 93.2-97.3) for MDT and SOC, respectively (p=0.005, log-rank). The main limitations of our study are its retrospective design and lack of standardization of systemic treatment in the SOC cohort. CONCLUSIONS: MDT for nodal oligorecurrent PCa improves CSS as compared with SOC. These retrospective data from a multi-institutional pooled analysis should be considered as hypothesis-generating and inform future randomized trials in this setting. PATIENT SUMMARY: Prostate cancer patients experiencing a lymph node recurrence might benefit from local treatments directed at these lymph nodes.

Loss of PTEN-assisted G2/M checkpoint impedes homologous recombination repair and enhances radio-curability and PARP inhibitor treatment response in prostate cancer.

Here we report that PTEN contributes to DNA double-strand break (DSB) repair via homologous recombination (HR), as evidenced by (i) inhibition of HR in a reporter plasmid assay, (ii) enhanced sensitivity to mitomycin-C or olaparib and (iii) reduced RAD51 loading at IR-induced DSBs upon PTEN knockdown. No association was observed between PTEN-status and RAD51 expression either in-vitro or in-vivo in a tissue microarray of 1500 PTEN-deficient prostate cancer (PC) samples. PTEN depletion and sustained activation of AKT sequestered CHK1 in the cytoplasm, thus impairing the G2/M-checkpoint after irradiation. Consistently, AKT inhibition recovered the G2/M-checkpoint and restored HR efficiency in PTEN-depleted cells. We show that, although PTEN loss correlates with a worse prognosis, it may predict for improved response of PC patients to radiotherapy. Further, we provide evidence for the use of PTEN as a biomarker for predicting the response to PARP inhibitors as radiosensitizing agents in prostate cancer. Collectively, these data implicate PTEN in maintaining genomic stability by delaying G2/M-phase progression of damaged cells, thus allowing time for DSB repair by HR. Furthermore, we identify PTEN-status in PC as a putative predictor of (i) radiotherapy response and (ii) response to treatment with PARP inhibitor alone or combined with radiotherapy.

No impact of blood transfusion on oncological outcome after radical prostatectomy in patients with prostate cancer.

PURPOSE: To assess the association between blood loss, blood transfusion (BT) and biochemical recurrence (BCR)-free, metastasis-free and overall survival after radical prostatectomy (RP) in a large single-center cohort of patients. Perioperative BT at oncologic surgery has been reported to be a potential risk factor for cancer recurrence and survival in several cancer entities. Current studies addressing the relationship between BT, blood loss and BCR-free survival in prostate cancer patients are controversial and include only series with fairly small patient cohorts. MATERIALS AND METHODS: The data of 11,723 patients who underwent RP between 01/1992 and 08/2011 were analyzed. Cox regression analysis, including preoperative PSA level, pT stage, lymph node status, Gleason score, margin status, blood loss, transfusion rate (allogeneic or autologous), tested the relationship between blood loss, transfusion and BCR-free, metastasis-free and overall survival. Additionally, propensity score-matching analysis was performed to adjust differences in tumor characteristics. RESULTS: There was no statistically significant relationship between blood loss or BT and BCR-free, metastasis-free or overall survival. In multivariate analysis PSA level, pT stage, Gleason score, margin status and lymph node status were independent factors for a BCR (p < 0.0001). These results were identical after propensity score matching analysis, comparing patients with and without BT. CONCLUSIONS: This large-scale analysis revealed no correlation between blood loss, blood transfusion and oncological outcome in prostate cancer patients treated with RP. Therefore, the association between higher blood loss or transfusion rate and cancer recurrence as described in other surgical treated tumor entities seems to be irrelevant in prostate cancer patients.

Does HistoScanning™ predict positive results in prostate biopsy? A retrospective analysis of 1,188 sextants of the prostate.

PURPOSE: The role of HistoScanning™ (HS) in prostate biopsy is still indeterminate. Existing literature is sparse and controversial. To provide more evidence according to that important clinical topic, we analyzed institutional data from the Martini-Clinic, Prostate Cancer Center, Hamburg. METHODS: Patients who received prostate biopsy and who also received HS were included in the study cohort. A single examiner, blinded to pathological results, re-analyzed all HS data in accordance with sextants of the prostate. Each sextant was considered as an individual case. Corresponding results from biopsy and HS were analyzed. The area under the receiver-operating characteristic curve (AUC) for the prediction of a positive biopsy by HS was calculated. Furthermore, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were assessed according to different HS signal volume cutoffs (>0, >0.2 and >0.5 ml). RESULTS: Overall, 198 men were identified and 1,188 sextants were analyzed. The AUC to predict positive biopsy results by HS was 0.58. Sensitivity, specificity, PPV and NPV for HS to predict positive biopsy results per sextant, depending on different HS signal volume cutoffs (>0, >0.2 and >0.5 ml) were 84.1, 27.7, 29.5 and 82.9 %, 60.9, 50.6, 28.8 and 79.7 %, and 40.1, 73.3, 33.1 and 78.8 %, respectively. CONCLUSIONS: Positive HS signals do not accurately predict positive prostate biopsy results according to sextant analysis. We cannot recommend a variation of well-established random biopsy patterns or reduction of biopsy cores in accordance with HS signals at the moment.

Oncological long-term outcome of 4772 patients with prostate cancer undergoing radical prostatectomy: does the anaesthetic technique matter?

INTRODUCTION: Recent data suggest that using additional neuroaxial anaesthesia during oncological surgery is associated with favourable recurrence-free survival, when compared with general anaesthesia alone. We assessed the impact of adjunctive perioperative spinal anaesthesia and dose of opioids on the oncological long-term outcome of patients following radical prostatectomy. METHODS: We selected patients from our institutional review board-approved database who consecutively underwent radical prostatectomy between 2002 and 2007. Patients were stratified by type of anaesthesia, administered as general anaesthesia alone, or spinal anaesthesia in addition to general anaesthesia. Biochemical recurrence-free survival, metastasis-free survival and overall survival were analysed by a multivariate Cox regression model and by Kaplan-Meier analysis in propensity-score based matched cohorts, adjusted for standard clinico-pathological variables and year of surgery. RESULTS: Overall, 4772 patients were analysed. Regarding the type of anaesthesia no significant difference for biochemical recurrence-free survival, metastasis-free survival and overall survival was analysed by a multivariate Cox regression model (p = 0.5, 0.8 and 0.7). The Kaplan-Meier analyses after propensity-score matched based comparisons revealed no significant difference depending on type of anaesthesia for biochemical recurrence-free survival, metastasis-free survival and overall survival (p = 0.6, 0.1 and 0.4). The same accounted for a propensity-score matched model adjusted for the year of surgery on biochemical recurrence-free survival (p = 0.7). CONCLUSIONS: The oncological outcome after radical prostatectomy was not affected by the adjunctive use of spinal anaesthesia.

Comparison of prostate cancer volume measured by HistoScanning™ and final histopathological results.

PURPOSE: HistoScanning™ (HS) is an ultrasound-based tissue characterization technique with encouraging results in the detection of prostate cancer (PCa). The aim of this study was to evaluate the accuracy of total tumor volume measured by HS (TVHS) in patients with PCa. METHODS: In 148 patients with proven PCa, TVHS was measured prior to radical prostatectomy and compared with the total tumor volume in the final pathological report (TVP) using the rank-based spearman correlation test. Correlation was performed after stratification of the results by d'Amico risk categories, prostate volume, experience of HS examiner, distance of the ultrasound probe to the prostate (≤3.5 and >3.5 mm) and quality of initial HS. In addition, a re-analysis of HS data was performed by a single examiner and the TVHS from the unmodified HS data was acquired. RESULTS: TVP was approximately twofold higher compared to TVHS. Overall, there was no significant correlation (r s = -0.0083, p = 0.9) for the TVP and the TVHS. After adjusting for d'Amico risk categories, prostate volume, experience of examiner, distance of the ultrasound probe to the prostate and quality of initial HS, no significant correlation was found. After re-analyzing of all HS data by 1 examiner, the correlation remained not significant (r s = 0.039, p = 0.6). CONCLUSIONS: TVHS and TVP did not correlate in this cohort of patients. We cannot recommend the use of HS at least for imaging of the total tumor volume at this time. The controversial findings for prostate HS should initiate more studies to clarify these discrepancies.

Xerostomia after radiotherapy. What matters--mean total dose or dose to each parotid gland?

PURPOSE: Xerostomia is a debilitating side effect of radiotherapy in patients with head and neck cancer. We undertook a prospective study of the effect on xerostomia and outcomes of sparing one or both parotid glands during radiotherapy for patients with squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Patients with locally advanced squamous cell carcinoma of the head and neck received definitive (70 Gy in 2 Gy fractions) or adjuvant (60-66 Gy in 2 Gy fractions) curative-intent radiotherapy using helical tomotherapy with concurrent chemotherapy if appropriate. Group A received < 26 Gy to the left and right parotids and group B received < 26 Gy to either parotid. RESULTS: The study included 126 patients; 114 (55 in group A and 59 in group B) had follow-up data. There were no statistically significant differences between groups in disease stage. Xerostomia was significantly reduced in group A vs. group B (p = 0.0381). Patients in group A also had significantly less dysphagia. Relapse-free and overall survival were not compromised in group A: 2-year relapse-free survival was 86% vs. 72% in group B (p = 0.361); 2-year overall survival was 88% and 76%, respectively (p = 0.251). CONCLUSION: This analysis suggests that reducing radiotherapy doses to both parotid glands to < 26 Gy can reduce xerostomia and dysphagia significantly without compromising survival. Sparing both parotids while maintaining target volume coverage and clinical outcome should be the treatment goal and reporting radiotherapy doses delivered to the individual parotids should be standard practice.

Expression of insulin-like growth factor II mRNA-binding protein 3 in squamous cell carcinomas of the head and neck.

BACKGROUND: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) was found overexpressed in various cancer types suggesting its possible role in carcinogenesis. Analysis of IMP3 expression in head and neck squamous cell carcinomas (HNSCC) is rare so that we evaluated it using tissue microarray method. METHOD: Immunohistochemical analysis of IMP3 was performed on samples from over 400 patients. The expression was measured semiquantitative, subsequently divided into four categories (negative, weak, medium, or strong) and correlated with several available clinicopathologic parameters. RESULTS: For HNSCC, positive IMP3 expression was observed in patients with all tumor stages (pT1-4) and nodal stages (pN0-3), showing also significant statistical correlation (P=0.023 and P=0.0013, respectively). No further correlations were found. Separate analysis according to tumor localization (oral cavity, oropharyngeal, and laryngeal) showed a significant correlation of positive IMP3 expression and overall survival (P=0.038) only in patients with tumors of the oral cavity. Multivariate analysis showed IMP3 as an independent predictive marker for oral squamous cell carcinomas (OSCC). CONCLUSION: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) expression might be used as an independent prognostic factor in the subgroup of OSCC.

EGFR gene copy number increase in vulvar carcinomas is linked with poor clinical outcome.

EGFR copy number increases have been frequently reported in cancer including vulvar carcinomas. Co-amplification of cancer genes plays an important role in the development of many tumour types. To better understand the effect of EGFR aberrations on vulvar cancer phenotype and patient prognosis, the authors analysed EGFR copy number changes using fluorescence in situ hybridisation and EGFR expression by immunohistochemistry in a tissue microarray containing 183 squamous cell carcinomas of vulva. Furthermore, the authors analysed the co-amplification frequency of EGFR with HER2, CCND1, MYC and PIK3CA, respectively. EGFR copy number increase was found in 39.3% of the tumours. Seventeen per cent of vulvar carcinomas showed EGFR high polysomy including 9% with amplification of the EGFR gene. Copy number gain of the EGFR locus was associated with non-basaloid phenotype (p=0.03), high-tumour stage (p<0.001), human papillomaviruse negativity of tumours (p=0.04) and the number of lymph node metastases (p=0.02). EGFR protein expression was statistically correlated to EGFR copy number increase (p<0.05). The observed co-amplification rate of EGFR with all four additionally examined oncogenes was much higher than statistically expected. There was a highly significant association between EGFR copy number increase and CCND1 amplifications (p<0.001) as well as the total number of gene amplifications (p=0.04). EGFR copy number gains were significantly related to unfavourable patient outcome in univariate analysis and multivariate Cox regression analysis. In conclusion, EGFR copy number increases are detectable in a substantial proportion of vulvar carcinomas with relationships to advanced tumour stages and the development of lymph node metastases. EGFR copy number aberrations are connected to other gene amplifications and probably define an human papillomaviruses-independent pathway in the development of vulvar carcinomas. These data support the potential utility of EGFR inhibitors as a therapeutic alternative in a subset of vulvar carcinomas.