Reasons for non-feasibility of therapeutic drug monitoring of oral targeted therapies in oncology - an analysis of the closed cohorts of a multicentre prospective study.

BACKGROUND: Therapeutic drug monitoring (TDM) - performing dose adjustments based on measured drug levels and established pharmacokinetic (PK) targets - could optimise treatment with drugs that show large interpatient variability in exposure. We evaluated the feasibility of TDM for multiple oral targeted therapies. Here we report on drugs for which routine TDM is not feasible. METHODS: We evaluated drug cohorts from the Dutch Pharmacology Oncology Group - TDM study. Based on PK levels taken at pre-specified time points, PK-guided interventions were performed. Feasibility of TDM was evaluated, and based on the success and practicability of TDM, cohorts could be closed. RESULTS: For 10 out of 24 cohorts TDM was not feasible and inclusion was closed. A high incidence of adverse events resulted in closing the cabozantinib, dabrafenib/trametinib, everolimus, regorafenib and vismodegib cohort. The enzalutamide and erlotinib cohorts were closed because almost all PK levels were above target. Other, non-pharmacological reasons led to closing the palbociclib, olaparib and tamoxifen cohort. CONCLUSIONS: Although TDM could help personalising treatment for many drugs, the above-mentioned reasons can influence its feasibility, usefulness and clinical applicability. Therefore, routine TDM is not advised for cabozantinib, dabrafenib/trametinib, enzalutamide, erlotinib, everolimus, regorafenib and vismodegib. Nonetheless, TDM remains valuable for individual clinical decisions.

Evaluating the Clinical Impact and Feasibility of Therapeutic Drug Monitoring of Pazopanib in a Real-World Soft-Tissue Sarcoma Cohort.

INTRODUCTION AND OBJECTIVE: Pazopanib is registered for metastatic renal cell carcinoma and soft-tissue sarcoma (STS). Its variable pharmacokinetic (PK) characteristics and narrow therapeutic range provide a strong rationale for therapeutic drug monitoring (TDM). Prior studies have defined target levels of drug exposure (≥ 20.5 mg/L) linked to prolonged progression-free survival (PFS), but the added value of using TDM remains unclear. This study investigates the effect of TDM of pazopanib in patients with STS on survival outcomes and dose-limiting toxicities (DLTs) and evaluates the feasibility of TDM-guided dosing. METHODS: A TDM-guided cohort was compared to a non-TDM-guided cohort for PFS, overall survival (OS) and DLTs. PK samples were available from all patients, though not acted upon in the non-TDM-guided cohort. We evaluated the feasibility of TDM by comparing the proportion of underdosed patients in our TDM cohort with data from previous publications. RESULTS: A total of 122 STS patients were included in the TDM-guided cohort (n = 95) and non-TDM-guided cohort (n = 27). The average exposure in the overall population was 30.5 mg/L and was similar in both groups. Median PFS and OS did not differ between the TDM-guided cohort and non-TDM-guided cohort (respectively 5.5 vs 4.4 months, p = 0.3, and 12.6 vs 10.1 months, p = 0.8). Slightly more patients in the non-TDM-guided cohort experienced DLTs (54%) compared to the TDM-guided cohort (44%). The proportion of underdosed patients (13.3%) was halved compared to historical data (26.7%). CONCLUSION: TDM reduced the proportion of patients with subtherapeutic exposure levels by ~ 50%. Nonetheless, the added value of TDM for achieving target trough levels of ≥ 20.5 mg/L for pazopanib on survival outcomes could not be confirmed in STS patients.

Improvement of perioperative outcomes of gastric gastrointestinal stromal tumour (GIST) resections and the influence of minimal invasive surgery.

BACKGROUND: Safety of minimally invasive surgery (MIS) for gastrointestinal stromal tumours (GISTs) is still under debate since it might increase the risk of tumour rupture, especially in larger tumours. The aim of this study was to investigate trends in treatment and perioperative outcomes of patients undergoing resections of gastric GISTs over time. METHODS: This was a multicentre retrospective study of consecutive patients who underwent wedge resection or partial gastrectomy for localized gastric GIST at five GIST reference centres between January 2009 and January 2022. To evaluate changes in treatment and perioperative outcomes over time, patients were divided into four equal periods. Perioperative outcomes were analysed separately and as a novel composite measure textbook outcome (TO). RESULTS: In total 385 patients were included. Patient and tumour characteristics did not change over time, except for median age (62-65-68-68 years, p = 0.002). The proportion of MIS increased (4.0%-9.8%-37.4%-53.0 %, p < 0.001). Postoperative complications (Clavien Dindo ≥2; 22%-15%-11%-10 %, p = 0.146), duration of admission (6-6-5-4 days, p < 0.001) and operating time (92-94-77-73 min, p = 0.007) decreased over time while TO increased (54.0%- 52.7%-65.9%-76.0 %, p < 0.001). No change was seen in perioperative ruptures (6.0%- 3.6%-1.6%-3.0 %, p = 0.499). MIS was correlated with less CD ≥ 2 complications (p = 0.006), shorter duration of admission (p < 0.001) and more TO (p < 0.001). Similar results were observed in tumours ≤5 cm and >5 cm. CONCLUSION: A larger percentage of gastric GIST were treated with MIS over time. MIS was correlated with less complications, shorter duration of admission and more TO. Tumour rupture rates remained low over time.

Levels of circulating tumor DNA correlate with tumor volume in gastro-intestinal stromal tumors: an exploratory long-term follow-up study.

Patients with gastro-intestinal stromal tumors (GISTs) undergoing tyrosine kinase inhibitor therapy are monitored with regular computed tomography (CT) scans, exposing patients to cumulative radiation. This exploratory study aimed to evaluate circulating tumor DNA (ctDNA) testing to monitor treatment response and compare changes in ctDNA levels with RECIST 1.1 and total tumor volume measurements. Between 2014 and 2021, six patients with KIT proto-oncogene, receptor tyrosine kinase (KIT) exon-11-mutated GIST from whom long-term plasma samples were collected prospectively were included in the study. ctDNA levels of relevant plasma samples were determined using the KIT exon 11 digital droplet PCR drop-off assay. Tumor volume measurements were performed using a semi-automated approach. In total, 94 of 130 clinically relevant ctDNA samples were analyzed. Upon successful treatment response, ctDNA became undetectable in all patients. At progressive disease, ctDNA was detectable in five out of six patients. Higher levels of ctDNA correlated with larger tumor volumes. Undetectable ctDNA at the time of progressive disease on imaging was consistent with lower tumor volumes compared to those with detectable ctDNA. In summary, ctDNA levels seem to correlate with total tumor volume at the time of progressive disease. Our exploratory study shows promise for including ctDNA testing in treatment follow-up.

Timing of surgery in acute deep partial-thickness burns: A study protocol.

For deep partial-thickness burns no consensus on the optimal treatment has been reached due to conflicting study outcomes with low quality evidence. Treatment options in high- and middle-income countries include conservative treatment with delayed excision and grafting if needed; and early excision and grafting. The majority of timing of surgery studies focus on survival rather than on quality of life. This study protocol describes a study that aims to compare long-term scar quality, clinical outcomes, and patient-reported outcomes between the treatment options. A multicentre prospective study will be conducted in the three Dutch burn centres (Rotterdam, Beverwijk, and Groningen). All adult patients with acute deep-partial thickness burns, based on healing potential with Laser Doppler Imaging, are eligible for inclusion. During a nine-month baseline period, standard practice will be monitored. This includes conservative treatment with dressings and topical agents, and excision and grafting of residual defects if needed 14-21 days post-burn. The subsequent nine months, early surgery is advocated, involving excision and grafting in the first week to ten days post-burn. The primary outcome compared between the two groups is long-term scar quality assessed by the Patient and Observer Scar Assessment Scale 3.0 twelve months after discharge. Secondary outcomes include clinical outcomes and patient-reported outcomes like quality of life and return to work. The aim of the study is to assess long-term scar quality in deep partial-thickness burns after conservative treatment with delayed excision and grafting if needed, compared to early excision and grafting. Adding to the ongoing debate on the optimal treatment of these burns. The broad range of studied outcomes will be used for the development of a decision aid for deep partial-thickness burns, to fully inform patients at the point of consent to surgery and support optimal person-centred care.

Individualized Dosing Patterns in the Treatment of Older Patients with Gastrointestinal Stromal Tumors: Results of a Registry-Based Observational National Cohort Study Including 871 Patients.

BACKGROUND: While the effectiveness of tyrosine kinase inhibitors (TKIs) seems similar in older patients with gastrointestinal stromal tumors (GIST) compared with younger patients, toxicities in older patients treated with TKIs more often lead to discontinuation of treatment. OBJECTIVE: To better understand the age-related pharmacology and pharmacodynamic differences in patients with GIST treated with TKIs, the primary aim of this study was to evaluate TKI dosing patterns in older patients with GIST, while the secondary aims were to evaluate differences in imatinib trough plasma concentrations between age groups and to compare the overall survival (OS) in patients with and without dose reductions in all treatment lines in a palliative setting. METHODS: Patients (18 years of age or older) with histologically proven GIST diagnosed between January 2009 and June 2021 and treated with one or more lines of TKIs were selected from the Dutch GIST Registry (DGR) database. Age groups were divided into younger patients (age <70 years) and older patients (age ≥70 years). All imatinib trough plasma concentrations of blood withdrawals taken from initiation of imatinib until a maximum of 1 year of treatment with imatinib were collected. Reasons for first adjustment of treatment were classified as adverse event, dose modification, progressive disease and other reasons. The next treatment steps after first adjustment of treatment were defined as dose escalation, dose reduction, dose interruption, or end of treatment. The association of dose reduction and OS was analyzed using the landmark approach. RESULTS: Overall, 871 patients were included in this study, including 577 younger patients and 294 older patients. Older patients more often had an adverse event as the reason for first adjustment of treatment with both imatinib (45.6%; p < 0.001) and sunitinib (58.6%; p = 0.224) compared with younger patients (19.5% and 42.7%, respectively). Adjustment of imatinib and sunitinib after starting on a standard dose because of an adverse event most often resulted in dose reduction in both age groups. Median trough plasma concentrations of all samples taken within the first year after initiation of imatinib were higher in older patients (1228 ng/mL, interquartile range [IQR] 959-1687) compared with younger patients (1035 ng/mL [IQR 773-1377]; p < 0.001). No significant differences were seen between OS in patients with or without dose reduction in all treatment lines (imatinib: p = 0.270; sunitinib: p = 0.547; and regorafenib: p = 0.784). CONCLUSION: Older patients showed higher imatinib trough plasma concentrations compared with younger patients and also had earlier and more often adverse events as the reason for first adjustment of treatment with imatinib followed by dose reduction. However, in a landmark analysis, patients with imatinib dose reductions had no poorer outcomes compared with patients not requiring a dose reduction.

Local treatment in metastatic GIST patients: A multicentre analysis from the Dutch GIST Registry.

BACKGROUND: The added value of local treatment in selected metastatic GIST patients is unclear. This study aims to provide insight into the usefulness of local treatment in metastatic GIST by use of a survey study and retrospective analyses in a clinical database. METHODS: A survey study was conducted among clinical specialists to select most relevant characteristics of metastatic GIST patients considered for local treatment, defined as elective surgery or ablation. Patients were selected from the Dutch GIST Registry. A multivariate Cox-regression model for overall survival since time of diagnosis of metastatic disease was estimated with local treatment as a time-dependent variable. An additional model was estimated to assess prognostic factors since local treatment. RESULTS: The survey's response rate was 14/16. Performance status, response to TKIs, location of active disease, number of lesions, mutation status, and time between primary diagnosis and metastases, were regarded the 6 most important characteristics. Of 457 included patients, 123 underwent local treatment, which was associated with better survival after diagnosis of metastases (HR = 0.558, 95%CI = 0.336-0.928). Progressive disease during systemic treatment (HR = 3.885, 95%CI = 1.195-12.627) and disease confined to the liver (HR = 0.269, 95%CI = 0.082-0.880) were associated with worse and better survival after local treatment, respectively. CONCLUSION: Local treatment is associated with better survival in selected patients with metastatic GIST. Locally treated patients with response to TKIs and disease confined to the liver have good clinical outcome. These results might be considered for tailoring treatment, but should be interpreted with care because only specific patients are provided with local treatment in this retrospective study.

Improved Efficacy of First-Line Imatinib in Advanced Gastrointestinal Stromal Tumors (GIST): The Dutch GIST Registry Data.

BACKGROUND: Patients with unresectable and metastasized gastrointestinal stromal tumor (GIST) experienced a remarkable improvement of progression-free survival (PFS) and overall survival (OS) after the introduction of imatinib. Our hypothesis is that the outcomes of treatment with imatinib are even better nowadays compared with the registration trials that were performed two decades ago. To study this, we used real-life data from a contemporary registry. METHODS: A multicenter, retrospective study was performed by exploring clinical data from a prospective real-life clinical database, the Dutch GIST Registry (DGR). Patients with advanced GIST treated with first-line imatinib were included and PFS (primary outcome) and OS (secondary outcome) were analyzed. Results of our study were compared with published results of the European Organisation for Research and Treatment of Cancer (EORTC) 62005 trial, which marked the first era of imatinib in the treatment of GIST. RESULTS: Overall, 420 of the 435 patients treated with imatinib in the DGR had recorded response evaluation and were included in the analysis. During a median follow-up of 35.0 months (range 2.0-136.0), progression of GIST was eventually observed in 217 patients (51.2%). The DGR cohort showed a longer median PFS (33.0 months, 95% confidence interval [CI] 28.4-37.6) compared with the EORTC 62005 trial (an estimated PFS of 19.5 months). Additionally, the median OS of 68.0 months (95% CI 56.1-80.0) was longer than the exposed median OS (46.8 months) published in the long-term follow-up results of the EORTC 62005 trial (median follow-up duration 10.9 years). CONCLUSION: This study provides an update on outcomes of imatinib in the treatment of advanced GIST patients and demonstrates improved clinical outcomes since the first randomized studies of imatinib 2 decades ago. Furthermore, these results represent outcomes in real-world clinical practice and can serve as a reference when evaluating effectiveness of imatinib in patients with advanced GIST.

Local recurrence in primary localised resected gastrointestinal stromal tumours: A registry observational national cohort study including 912 patients.

BACKGROUND AND OBJECTIVES: Previous literature showed a high risk of recurrence following surgical treatment in patients with gastrointestinal stromal tumours (GISTs). However, little is known about the patient- and treatment characteristics of local recurrences (LRs) in GIST patients. Therefore, this study aimed to better understand patterns of LR in surgically treated localised GIST and to describe treatment options based on our Dutch GIST Registry (DGR). METHODS: Data of primary surgically treated localised GIST between January 2009 until July 2021 were retrospectively retrieved from the DGR. RESULTS: Of 1452 patients registered in the DGR, 912 patients were included in this study. Only 3.8% (35/912) of patients developed LR, including 20 patients with LR only and 15 patients with simultaneous LR and distant metastases (DM). Median time to LR was 30 (interquartile range 8-53) months from date of surgery. Eleven percent (100/912) of patients developed only DM. A total of 2.3% (6/259) of patients treated with adjuvant treatment developed an LR during adjuvant therapy. Seventy percent of patients with LR only (14/20) were treated with surgery (85.7% R0), which was mostly combined with systemic treatment. CONCLUSIONS: Patients with primary surgically treated localised GIST have a limited risk of developing recurrence. Fifteen percent developed recurrence, of which one quarter developed an LR. Therefore, less intensified follow-up schedules could be considered, especially during treatment with adjuvant imatinib. In patients with LR only, potentially curative treatment strategies, including surgical (re-)resection, are often possible as treatment for LR.

Energy expenditure and body composition in a hibernator, the alpine marmot.

Visceral organs and tissues of 89 free-living alpine marmots (Marmota marmota) shot during a population control program in Switzerland, were collected. Between emergence from hibernation in April to July, the gastrointestinal tract (stomach to colon) gained 51% of mass and the liver mass increased by 24%. At the same time, the basal metabolic rate (BMR), determined with a portable oxygen analyzer, increased by 18%. The organ masses of the digestive system (stomach, small intestine, caecum, large intestine) were all significantly correlated with BMR. Interestingly, the mass of abdominal white adipose tissue (WAT) and of the remaining carcass (mainly skin and bones) were also significantly correlated with BMR. These results indicate that the gastrointestinal tract and organs involved in digestive function are metabolically expensive. They also show that it is costly to maintain even tissues with low metabolic rate such as WAT, especially if they are large. Heart and kidneys and especially brain and lungs did not explain a large proportion of the variance in BMR. Marmots increased the uptake of fat prior to hibernation, both by selective feeding and enhanced gastrointestinal capacity. Large fat reserves enable marmots to hibernate without food intake and to reproduce in spring, but at the cost of an elevated BMR. We predict that climate changes that disturb energy accumulation in summer, increase energy expenditure in winter, or delay the emergence from hibernation in spring, such as the occurrence of storms with increasing frequency, will increase mortality in alpine marmots.

Dutch Gastrointestinal Stromal Tumor (GIST) Registry Data Comparing Sunitinib with Imatinib Dose Escalation in Second-Line Advanced Non-KIT Exon 9 Mutated GIST Patients.

BACKGROUND: The prognosis of patients with advanced gastrointestinal stromal tumor (GIST) has improved greatly after the introduction of imatinib. However, primary or secondary resistance to imatinib occurs in the majority of patients. Sunitinib is the standard second line treatment in exon-9 mutated GIST. OBJECTIVE: We compared the clinical outcomes of sunitinib with imatinib dose escalation in patients with progressive advanced non-KIT exon 9 mutated GIST after failure of first line imatinib. PATIENTS AND METHODS: A retrospective study was performed, retrieving data from a real-life database (Dutch GIST Registry) including patients with GIST treated with sunitinib or imatinib dose escalation after failure on first line imatinib 400 mg daily. Primary outcome measures were progression free survival (PFS) and overall survival (OS). RESULTS: In total, 110 patients were included, 72 (65.5%) patients were treated with sunitinib (group A) and 38 (34.5%) received an imatinib dose escalation (group B). Important prognostic features at baseline, such as tumor size, stage at diagnosis, mitotic count and localization were equally distributed in both groups. No significant difference (p = 0.88) between median PFS in group A [8.7 months (95% CI 5.6-11.3)] and group B [5.6 months, (95% CI 2.6-8.7)] was observed. Moreover, the OS was similar between group A and group B; 63.2 months and 63.4 months, respectively. CONCLUSION: This study represents a proper sample size cohort containing detailed data on mutational status of patients with advanced GIST. We illustrated that imatinib dose escalation could serve as a good alternative for sunitinib as second-line treatment in patients with a non-KIT exon 9 mutation.

Learning curve and functional outcomes after laser enucleation of the prostate for benign prostate hyperplasia according to surgeon's caseload.

PURPOSE: To evaluate the impact of surgical caseload on safety, efficacy, and functional outcomes of laser enucleation of the prostate (LEP) applying a structured mentoring program. METHODS: Patient characteristics, perioperative data, and functional outcomes were analyzed descriptively. Linear and logistic regression models analyzed the effect of caseload on complications, functional outcomes and operative speed. Within the structured mentoring program a senior surgeon was present for the first 24 procedures completely, for partial steps in procedures 25-49, and as needed thereafter. RESULTS: A total of 677 patients from our prospective institutional database (2017-2022) were included for analysis. Of these, 84 (12%), 75 (11%), 82 (12%), 106 (16%), and 330 patients (49%) were operated by surgeons at (A) < 25, (B) 25-49, (C) 50-99, (D) 100-199, and (E) ≥ 200 procedures. Preoperative characteristics were balanced (all p > 0.05) except for prostate volume, which increased with caseload. There was no significant difference in change of IPSS, Quality of life, ICIQ, pad usage, peak urine flow, residual urine, and major complications (Group A: 8.3 to E: 7.6%, p = 0.2) depending on the caseload. Caseload was not associated (Odds ratio: 0.7-1.4, p > 0.2) with major complications in the multivariable logistic regression model. Only operating time was significantly shorter with increasing caseload in the multivariable analysis (111-55 min, beta 23.9-62.9, p < 0.001). CONCLUSION: With a structured mentoring program, the safety and efficacy of LEP can be ensured even during the learning curve with very good outcome quality. Only the operating time decreases significantly with increasing experience of the surgeon.

Multimodality treatment of undifferentiated pleomorphic soft tissue sarcoma of the extremity (eUPS) in the elderly.

INTRODUCTION: This subgroup analysis of undifferentiated pleomorphic soft tissue sarcoma of the extremity (eUPS) from the PERSARC collaborative group aimed to achieve a more personalized multimodality treatment approach for primary eUPS in elderly patients. MATERIAL AND METHODS: A multicenter retrospective study including primary high-grade eUPS surgically treated with curative intent between 2000 and 2016. Overall survival (OS), local recurrence (LR) and distant metastasis (DM) curves were calculated by Kaplan Meier analysis. Cox proportional hazard models were used to determine the effect of radiotherapy. RESULTS: From a total of 2511 patients with extremity soft tissue sarcoma (eSTS) of the PERSARC study collaborative; 703 patients with eUPS were included in this study. In elderly patients with eUPS 5-year OS, LR and DM were 35.4 (95%CI 29.3-42.8), 17.7 (95%CI 12.7-22.6) and 24.6 (95%CI 19.1-30.1). eUPS was significantly less treated with radiotherapy compared with other eSTS, especially in elderly patients. Patients with R1-R2 margins treated with radiotherapy had about half the risk of developing LR compared with patients treated without radiotherapy (HR = 0.454, p = 0.033). CONCLUSION: Elderly patients with eUPS were less often treated with radiotherapy and showed higher LR. Nowadays, given an increasing life expectancy in elderly patients, multimodality treatment should be considered.

Additivity of apparent and standardized ileal amino acid digestibility of corn and soybean meal in broiler diets.

A total of 144 male Ross 308 broiler chickens were used in a digestibility bioassay to determine the additivity of apparent or standardized amino acid (AA) digestibility values for corn, soybean meal (SBM), or a mixture of corn and SBM. Following the receipt of a standard commercial starter diet from days 1 to 21, broilers were divided into 4 treatments (6 cages per treatment; 6 birds per cage) and received semi-purified diets based on corn, SBM, or a mixture of corn and SBM or a nitrogen-free diet (for the estimation of basal endogenous AA losses). Apparent and standardized ileal AA digestibility values were determined on day 28 and the measured values for the mixture of corn and SBM were statistically compared to calculated values based on the digestibility of the individual raw materials and their concentration in the mixed diet. The use of apparent ileal AA digestibility values for single ingredients resulted in an underestimation (P < 0.05) of the digestibility of the mixed feed for nitrogen, Lys, Arg, Thr, Asp, and Gly. Correction of apparent digestibility values to standardized values entirely corrected the underestimation in the mixed feed and resulted in a predictable linearity from single ingredients to the mixed diet. It can be concluded that standardized ileal AA digestibility values are more additive than apparent values and should be used, where possible, to enhance the accuracy of feed formulation and reduce both the diet cost and the environmental impact of nitrogenous pollution.

Long-term results of ProACT primary and repeat implantation for treatment of stress urinary incontinence in men.

INTRODUCTION: Urinary incontinence in men after radical prostatectomy affects strongly quality of life. If conservative treatment fails, surgical treatment consists of implantable devices. If the requirement of manual dexterity in the artificial sphincter is to be avoided, the ProACT system offers a readjustable system, which shows good continence, but also high revision rates. Aim of our single-centre, single-surgeon study was to evaluate the success and revision rates of ProACT over long-term follow-up and if repeat ProACT implantation after failure would be a reasonable strategy. MATERIALS AND METHODS: In May 2017, follow-up of all patients who underwent ProACT implantation between 2003 and 2013 was obtained. Parameters were numbers of pads used, filling volume of balloons, and patient-reported satisfaction. Furthermore, revisions were noted. RESULTS: Between 2003 and 2013, 134 patients were implanted a ProACT system. Median age was 71 years; median follow-up was 118 months. 112 implantations were successful (82.6%) and the number of pads used decreased significantly (p < 0.005). 63 patients were revised and 49 were successful (77.8%). No differences in success rate, pads used, or filling volume were seen (all p > 0.8). In a second revision, again, no differences in success rate or pads used were noted (all p > 0.7). Patients' personal satisfaction was high despite the high revision rate. CONCLUSION: In the hands of an experienced surgeon, ProACT is a safe and effective therapy for post-prostatectomy incontinence especially if mayor surgery is to be avoided. Revision rates are high, but the results of ProACT reimplantation are comparable to the results after the first implantation.

Surgical treatment of large volume prostates: a matched pair analysis comparing the open, endoscopic (ThuVEP) and robotic approach.

OBJECTIVE: To compare open simple prostatectomy, endoscopic enucleation and laparoscopic, robot-assisted enucleation of high-volume prostate in terms of operation time, blood loss, transfusion and complication rates and early continence rates. MATERIAL AND METHODS: Patients with BPH treated endoscopically (ThuVEP, Hamburg and Hannover) or robotically (Mainz) were evaluated prospectively for prostate size, free flow and validated questionnaires (IPSS, QoL). 35 patients were matched to patients after open prostatectomy (Mainz) for age, prostate size, IPSS and QoL scores. Operation time was noted from the first cut to the last suture; blood loss was estimated by the drop of haemoglobin preoperatively and one day after surgery. Transfusion rates were documented. Early continence was estimated by pad use over the first 24 h after catheter removal. Statistical analysis was performed with SPSS 22.0. RESULTS: No significant differences in prostate size, age and preoperative questionnaires were found (p > 0.3). Postoperative flow and the results of the questionnaires were significantly improved (all p < 0.05), without difference between the approaches (p > 0.8). Endoscopic surgery showed superiority in operation time (both p < 0.05); blood loss and transfusion rates were significantly lower compared to open surgery (both p < 0.01) and lower than in robotic surgery without reaching significance (p = 0.18, p = 0.36). Similar results were seen in early continence rates. CONCLUSION: Due to our results, endoscopic surgery should be considered as first-line therapy unless there are comorbidities like diverticula and/or bladder calculi that can be easily treated simultaneously by robotic surgery. Against the background of these findings, indications favouring open surgery are getting sparse.

Survival outcomes in patients with large (≥7cm) clear cell renal cell carcinomas treated with nephron-sparing surgery versus radical nephrectomy: Results of a multicenter cohort with long-term follow-up.

BACKGROUND: Does the dogma of nephron sparing surgery (NSS) still stand for large renal masses? Available studies dealing with that issue are considerably biased often mixing imperative with elective indications for NSS and also including less malignant variants or even benign renal tumors. Here, we analyzed the oncological long-term outcomes of patients undergoing elective NSS or radical tumor nephrectomy (RN) for non-endophytic, large (≥7cm) clear cell renal carcinoma (ccRCC). METHODS: Prospectively acquired, clinical databases from two academic high-volume centers were screened for patients from 1980 to 2010. The query was strictly limited to patients with elective indications. Surgical complications were retrospectively assessed and classified using the Clavien-Dindo-classification system (CDS). Overall survival (OS) and cancer specific survival (CSS) were analyzed using the Kaplan-Meier-method and the log-rank test. RESULTS: Out of in total 8664 patients in the databases, 123 patients were identified (elective NSS (n = 18) or elective RN (n = 105)) for ≥7cm ccRCC. The median follow-up over all was 102 months (range 3-367 months). Compared to the RN group, the NSS group had a significantly longer median OS (p = 0.014) and median CSS (p = 0.04). CONCLUSIONS: In large renal masses, NSS can be performed safely with acceptable complication rates. In terms of long-term OS and CSS, NSS was at least not inferior to RN. Our findings suggest that NSS should also be performed in patients presenting with renal tumors ≥7cm whenever technically feasible. Limitations include its retrospective nature and the limited availability of data concerning long-term development of renal function in the two groups.

[Systemic immune checkpoint inhibition : A promising treatment for urological tumors?] / Systemische Immuncheckpoint-Inhibition : Eine vielversprechende Therapie urologischer Tumoren?

Improved understanding of the immunomodulatory interactions between tumor cells and immune cells has led to new and promising systemic therapeutic approaches in the first- and second-line therapy of urological tumors. Particularly in the case of urothelial carcinoma, for the first time in 20 years, checkpoint inhibitors (PD-1 and PDL-1 inhibitors) provide well-tolerated therapy that achieves response rates of >20% that can be sustained over the long term. This review explains the approach of immunotherapy and summarizes the current phase III clinical situation on urothelial carcinoma and renal cell carcinoma. The current immunomodulatory therapeutic approaches for prostate cancer are discussed. Finally, we highlight new immunomodulatory therapeutic approaches in basic research.

A meta-analysis on the effect of canthaxanthin on egg production in brown egg layers.

A meta-analysis was conducted to evaluate the effect of the carotenoid canthaxanthin on production performance in layer hens. The data set contained 576 performance measurements from 34 trials. The trials were all conducted according to a similar experimental protocol from 1997 to 2012. The age of the animals ranged from 21 to 65 weeks. The experimental diets were predominantly wheat/SBM based, fed in mash form ad libitum. Depending on the trial and the treatment group considered, canthaxanthin supplementation was in the range of 0 to 8 mg/kg of feed.Using a linear mixed model regression applied to all 34 trials simultaneously, significant dose-dependent increases were found in egg yolk mass (+0.53% per ppm of canthaxanthin inclusion in the feed, P < 0.001), in egg mass (+0.47% per ppm, P = 0.0132), egg weight (+0.17% per ppm, P = 0.046), and in feed intake (+0.32% per ppm, P = 0.0054). A numerical increase was found in egg production (+0.28%, P = 0.14). The FCR decreased numerically (-0.24% per ppm, P = 0.36). The deposition of canthaxanthin in the egg yolk was 2.25 ppm per ppm of canthaxanthin in the feed (P < 0.001). It is concluded that in addition to egg yolk pigmentation, antioxidant effect, enhanced reproduction, and immune-modulation, canthaxanthin can significantly increase egg mass, thereby enhancing the productivity of the flock. Mechanisms relating to carotenoid metabolism and functions in avian species are a new research area that will require further investigation to explain the observed effects.

[Splice variant AR-V7 : Is it time for its routine use as a predictive marker in prostate cancer?] / Spleißvariante AR-V7 : Ist die Zeit reif für ihre routinemäßige Anwendung als prädiktiver Marker beim Prostatakarzinom?

Androgen receptor splice variants (AR-Vs), if overexpressed, lack the ligand-binding domain conveying metastasized castration-resistant prostate cancer with a therapeutic resistance to androgen receptor signaling inhibitors. Particularly AR-V7 has recently been proposed as a potential predictive biomarker to identify patients who would probably benefit most from taxane-based cytotoxic treatment. Several assays to substantiate or quantify AR-V7 expression have recently been proposed. However, their broad clinical value is still debatable. This contemporary update aims to shed light on the current evidence in the field and draw distinct practical conclusions.