Tobias Grimm

A New Concept for Early Recovery after Surgery for Patients Undergoing Radical Cystectomy for Bladder Cancer: Results of a Prospective Randomized Study

PURPOSE Early recovery after surgery concepts have gained wide acceptance in various surgical specialties. However, limited data are available for radical cystectomy. A new early recovery after surgery concept was compared to a more conservative regimen in patients undergoing radical cystectomy for bladder cancer. MATERIALS AND METHODS A total of 101 consecutive patients were prospectively randomized to early recovery after surgery (62) or a conservative regimen (39) (intended randomization ratio was 2 early recovery after surgery-to-1 conservative regimen). Primary end points were differences in quality of life, and secondary end points included postoperative morbidity, demand for analgesics, time spent in the intermediate care unit, mobility and number of gastrointestinal events during hospital stay. RESULTS Quality of life parameters, as measured by the EORTC (European Organization for the Research and Treatment of Cancer) Quality of Life questionnaire QLQ-30 did not change significantly between postoperative days 3 and 7 and at discharge from hospital in the conservative regimen group, whereas a significant improvement was observed in the early recovery after surgery group. Postoperative morbidity was lower in the early recovery after surgery group in terms of wound healing disorders (p = 0.006), fever (p = 0.004) and thrombosis (p = 0.027). The demand for analgesics was significantly lower in the early recovery after surgery group. The amount of food consumed in relation to the amount of food offered was significantly higher for the early recovery after surgery group as early as day 3 (p = 0.02). Time spent in the intermediate care unit was significantly shorter for the early recovery after surgery group (p <0.001). There were no significant differences between the groups with respect to gastrointestinal events. The main limitations of this study were the lack of long-term data as well as the single center approach. CONCLUSIONS Early recovery after surgery of patients who underwent radical cystectomy appears to have significant benefits compared to a conservative regimen in terms of postoperative morbidity, quality of life, use of analgesics and time spent in the intermediate care unit.

Prognostic Features for Objectively Defined Urinary Continence after Radical Cystectomy and Ileal Orthotopic Neobladder in a Contemporary Cohort

Purpose: We objectively quantified daytime and nocturnal continence rates, and defined predictive features for favorable continence outcomes after radical cystectomy and orthotopic ileal neobladder creation. Materials and Methods: At 1 institution 1,012 cystectomies were performed between 2004 and 2015. Questionnaires evaluating the continence status were sent to 244 patients. To objectify postoperative urine loss daytime and nocturnal pad tests were performed. Continence was defined as the need for up to 1 safety pad and urine loss 10 gm or less per test. Predefined associative features were tested for an influence on continence outcomes. Statistical analysis was done with the Fisher exact and Mann‐Whitney U tests, and linear logistic regression models. Significance was considered at p <0.05. Results: A total of 188 patients (77.0%) returned the questionnaires. Median followup was 61 months. Median daytime pad use was 1 pad per day (range 0 to 9). Median daily urine loss based on standardized pad testing was 8 gm (range 0 to 2,400). During the night a median of 1 pad (range 0 to 7) was used and median nocturnal urine loss was 28.5 gm (range 0 to 1,220). The continence rate was 54.3% during the day and 36.3% at night. On multivariate analysis good preoperative ECOG (Eastern Cooperative Oncology Group) status (OR 2.987, p = 0.010), retained sensation of bladder filling (OR 6.462, p = 0.003) and preoperative coronary heart disease (OR 0.036, p = 0.002) were independent predictors of daytime success. Based on preoperative risk factors a simple predictive score for daytime continence was created (AUC 0.725, p <0.001). Conclusions: Continence rates after orthotopic ileal neobladder creation are lower than previously described when objective continence definitions are applied. Patients with good performance status, without coronary heart disease and with retained sensation of orthotopic ileal neobladder filling have better daytime continence outcomes.

Dramatic impact of blood transfusion on cancer-specific survival after radical cystectomy irrespective of tumor stage

Abstract Objective: The aim of the present study was to determine the influence of intraoperative and postoperative blood transfusion on cancer-specific outcome. Materials and methods: Follow-up data were collected from 722 patients undergoing radical cystectomy for urothelial carcinoma of the bladder (UCB) between 2004 and 2014. Median follow-up was 26 months (interquartile range 12–61 months). Outcome was analyzed in relation to the amount of intraoperative and postoperative blood transfusion and different tumor stages. The primary endpoint was cancer-specific survival (CSS) after cystectomy. Kaplan–Meier analysis with log-rank test and Cox regression models were used. Results: Intraoperative blood transfusion was given in 36% (263/722) and postoperative blood transfusion in 18% (132/722). In patients with and without intraoperative blood transfusion, 5 year CSS was 48% and 67%, respectively (p < .001). In patients with and without postoperative blood transfusion, 5 year CSS was 48% and 63%, respectively (p < .001). The number of transfused red blood cell (RBC) units [intraoperatively: hazard ratio (HR) = 1.08, 95% confidence interval (CI) 1.01–1.15, p = .023; postoperatively: HR = 1.14, 95% CI 1.07–1.21, p < .001] was an independent prognostic factor for CSS. The dose-dependent negative effect of transfusions was also found in favorable subgroups (pT1 tumor, hemoglobin ≥13 mg/dl, p = .004) and in a high-volume surgeon subgroup (n = 244, p < .001). Conclusions: Blood transfusions during and after radical cystectomy were independent prognostic factors for CSS in this retrospective study. Therefore, efforts should be made to reduce the necessity of intraoperative and postoperative blood transfusion in cystectomy patients.

Follow-up of high-risk bladder cancer—Is it safe to perform fluorescence endoscopy multiple times in the same patient?

PURPOSE As the use of fluorescence endoscopy is recommended today by different guidelines during the follow-up of high-grade non-muscle-invasive bladder cancer, the aim of this study is to analyze whether the multiple use of hexylaminolevulinate (HAL) for TUR-BT can be performed safely within the same patient over a time interval. METHODS Data of patients diagnosed and treated with HAL-TUR-B at our institute between 2008 and 2013 were analyzed. Special interest was given to side effects observed during the instillation of the substance, on the whole day of the instillation and during the entire hospital stay. We focussed on side effects associated with the use of HAL, such as allergic reactions, urinary tract infections, photosensitization of the skin, and relevant changes in blood pressure. RESULTS In the time between 2008 and 2013, 2480 HAL-TUR-BTs were performed in total at our institute. In 80 patients, HAL-TUR-BT was used at least 2 times, and on average 4 times (2-12 times). Only patients with multiple uses were included for our final analysis. We observed no allergizations in any of the treated patients. Minor side effects were urinary tract infections (n = 4), dysuria (n = 4), pollakisuria (n = 9), and bladder spasms (n = 17). CONCLUSION In our study cohort, the multiple use of HAL-TUR-BT within the same patient caused no major side effects or an induction of allergization against the substance. We, therefore, conclude that HAL-TUR-BT can be performed safely in the same patient during the follow-up of aggressive tumors as recommended by different guidelines today.

Prognostic Value of the Preoperative Platelet-to-leukocyte Ratio for Oncologic Outcomes in Patients Undergoing Radical Cystectomy for Bladder Cancer

Micro‐Abstract Emerging evidence underlines the importance of inflammatory processes in bladder cancer. We investigated the platelet‐to‐leukocyte ratio (PLR) as a prognostic marker in 665 patients undergoing radical cystectomy for urothelial carcinoma of the bladder. The PLR is a novel marker that significantly correlates with adverse oncologic outcomes. The combination of 2 key players of inflammation and its cost efficacy and availability make the PLR an interesting tool for further investigation. Background: Currently, stratification of patients with bladder cancer (BC) mainly relies on histopathologic and clinical staging. Furthermore, inflammation plays an important role in the pathogenesis of BC. With the preoperative platelet‐to‐leukocyte ratio (PLR), we introduce a novel prognostic marker based on routine hematologic values in patients undergoing radical cystectomy (RC). Patients and Methods: In our cohort of 665 patients undergoing RC (2004‐2015) for urothelial carcinoma of the bladder (UCB), we analyzed a variety of preoperative hematologic parameters. We investigated the effect of thrombocytosis, leukocytosis, and the PLR on the oncologic outcomes, including cancer‐specific survival (CSS), progression‐free survival (PFS), and overall survival (OS). Both univariate (log‐rank test) and multivariate (Cox regression) analysis were performed. The prevalence of thrombocytosis and leukocytosis and differences in the PLR was assessed using the Mann‐Whitney U test. The cutoff levels for leukocytosis, thrombocytosis, and the PLR were defined using receiver operating characteristic curve analysis, with the 5‐year CSS as the binary classifier. Results: A PLR of ≤ 28 (CSS, P = .033; OS, P = .029) and leukocytosis (CSS, P = .01; OS, P = .001; PFS, P = .003) were significantly associated with adverse oncologic outcomes using the log‐rank test. On multivariate regression analysis, the PLR (CSS, P = .022; OS, P = .025) remained a significant prognostic marker among the standard staging variables and hemoglobin level. Advanced BC disease was significantly more prevalent in the patient subgroup with a low PLR (pT2‐pT4, 35%; vs. pT ≤ 1, 24%; P = .006) and leukocytosis (pT2‐pT4, 46%; vs. pT ≤ 1, 30%; P < .001; pN+, 49%; vs. pN0, 39%; P < .047). Conclusion: To the best of our knowledge, the present study is the first report of the preoperative PLR as a prognostic factor in patients undergoing RC for UCB. Compared with other inflammatory markers in BC, the PLR can be assessed without additional effort. External validation and its combination with other parameters might improve current prognostication systems for UCB.

Progression of urothelial carcinoma in situ of the urinary bladder: a switch from luminal to basal phenotype and related therapeutic implications

The stratification of bladder cancer into luminal and basal tumors has recently been introduced as a novel prognostic system in patient cohorts of muscle-invasive bladder cancer or high-grade papillary carcinomas. Using a representative immunohistochemistry panel, we analyzed luminal and basal marker expression in a large case series (n = 156) of urothelial carcinoma in situ (CIS), a precancerous lesion that frequently progresses to muscle-invasive disease. The majority of CIS cases was characterized by a positivity for luminal markers (aberrant cytokeratin (CK) 20 85% (132/156), GATA3 median Remmele score (score of staining intensity (0–3) multiplied with percentage of positive cells (0–4)): 12, estrogen receptor (ER) β Remmele score > 2: 88% (138/156), human epidermal growth factor receptor 2 (Her2) Dako score 3+ 32% (50/156), Her2 Dako score 2+ 33% (51/156)), and marginal expression of basal markers (CK5/6+ 2% (3/156), CK14+ 1% (2/156)). To further investigate phenotypic stability during disease progression, we compared 48 pairs of CIS and invasive tumors from the same biopsy. A highly significant loss of luminal marker expression (p < 0.001) was observed in the course of progression whereas an increase of basal marker expression (p < 0.01) was noted in the invasive compartment. Importantly, 91% of CIS cases demonstrated a positivity for at least one of the two predictive markers Her2 and ERβ, indicating that the analysis of Her2 and ERβ may help to identify CIS-patient subgroups prone to more efficient targeted treatment strategies. Larger prospective and biomarker-embedded clinical trials are needed to confirm and validate our preliminary findings.

Diagnostic and Prognostic Implications of FGFR3high/Ki67high Papillary Bladder Cancers

Prognostic/therapeutic stratification of papillary urothelial cancers is solely based upon histology, despite activated FGFR3-signaling was found to be associated with low grade tumors and favorable outcome. However, there are FGFR3-overexpressing tumors showing high proliferation—a paradox of coexisting favorable and adverse features. Therefore, our study aimed to decipher the relevance of FGFR3-overexpression/proliferation for histopathological grading and risk stratification. N = 142 (n = 82 pTa, n = 42 pT1, n = 18 pT2-4) morphologically G1–G3 tumors were analyzed for immunohistochemical expression of FGFR3 and Ki67. Mutation analysis of FGFR3 and TP53 and FISH for FGFR3 amplification and rearrangement was performed. SPSS 23.0 was used for statistical analysis. Overall FGFR3high/Ki67high status (n = 58) resulted in a reduced ∆mean progression-free survival (PFS) (p < 0.01) of 63.92 months, and shorter progression-free survival (p < 0.01; mean PFS: 55.89 months) in pTa tumors (n = 50). FGFR3mut/TP53mut double mutations led to a reduced ∆mean PFS (p < 0.01) of 80.30 months in all tumors, and FGFR3mut/TP53mut pTa tumors presented a dramatically reduced PFS (p < 0.001; mean PFS: 5.00 months). Our results identified FGFR3high/Ki67high papillary pTa tumors as a subgroup with poor prognosis and encourage histological grading as high grade tumors. Tumor grading should possibly be augmented by immunohistochemical stainings and suitable clinical surveillance by endoscopy should be performed.

What’s New in TIND?

CONTEXT There is growing interest in minimally invasive (MI) treatment options for male lower urinary tract symptoms (LUTS). Among these options, the temporary implantable nitinol device (TIND; Medi-Tate, Or Akiva, Israel) is a novel instrument used to alleviate symptoms by creating incisions in the prostate via mechanical stress. OBJECTIVE To review recent data for TIND as an MI procedure to improve LUTS. EVIDENCE ACQUISITION Medline, PubMed, the Cochrane Database, and Embase were screened for clinical trials, randomized controlled trials, and review articles on the use of TIND in patients with male LUTS. EVIDENCE SYNTHESIS There are currently two studies available, one being a follow-up of the first pilot study. Both 12-mo and 36-mo results suggest at least medium-term effects of TIND in terms of symptom improvement (International Prostate Symptom Score, IPSS) and maximum urinary flow (Qmax). IPSS was improved by 41% after 12mo (p<0.001) and worsened only insignificantly after 36mo compared to baseline values. Qmax increased by 4.4ml/s after 12mo (p<0.001) and did not decrease significantly after 36mo. Postoperative complications were mild and included urinary tract infection and urinary retention. CONCLUSIONS Preliminary data suggest that TIND is a safe and effective MI technique for patients with male LUTS. Symptom relief and increase in urinary flow after 36mo are promising. However, long-term results are needed. PATIENT SUMMARY Various treatment options for male patients suffering from urinary voiding symptoms are emerging. TIND, a temporary implantable nitinol device, appears to be a safe option that improves symptoms without affecting sexuality.

Surgical High-risk Patients With ASA ≥ 3 Undergoing Radical Cystectomy: Morbidity, Mortality, and Predictors for Major Complications in a High-volume Tertiary Center

Background: The purpose of this study was to investigate major complications and risk factors for adverse clinical outcome in surgical high‐risk (American Society of Anesthesiologists [ASA] 3‐4) patients undergoing radical cystectomy (RC) in a high‐volume setting. Patients and Methods: A total of 1206 patients underwent RC between 2004 and 2017 in our institution and were included. We assessed complications graded by the Clavien‐Dindo‐Classification system (CDC) in addition to the 90‐day mortality rate and stratified results by the ASA classification. In a multivariate analysis, risk factors for high‐grade complications (CDC ≥ 3) were tested. Additionally, outcome parameters were compared between 2004 to 2010 and 2010 to 2017. Results: Patients with ASA ≥ 3 presented with more locally advanced tumors pT ≥ 3 (52.1% vs. 42.4%; P = .002) and positive lymphatic spread N1 (27.2% vs. 23.5%; P = .001) compared with patients with ASA ≤ 2. High‐grade complications were significantly (P < .001) more prevalent in patients with ASA ≥ 3 compared with patients with ASA ≤ 2: CDC3 (14.6% vs. 9.4%), CDC4 (10.2% vs. 5.4%), and CDC5 (2.5% vs. 1.0%). The 90‐day mortality rate (7.6% vs. 3.2%; P = .002) and perioperative reinterventions (23.5% vs. 13.1%; P < .001) were elevated in patients with ASA ≥ 3. ASA (odds ratio [OR], 2.701, 95% confidence interval [CI], 1.089‐6.703; P = .032), previous abdominal operations (OR, 1.683; 95% CI, 1.188‐2.384; P = .003), and body mass index ≥ 30 (OR, 1.533; 95% CI, 1.021‐2.304; P = .039) proved to function as independent predictors for major complications. CDC ≥ 3 complications (31.7% vs. 24.3%; P = .029) and 90‐day mortality (10.4% vs. 5.6%; P = .018) were significantly lower in the second half of the study period. Conclusions: Mortality and morbidity in surgical high‐risk patients with ASA 3 to 4 undergoing RC is about twice as high compared with patients with ASA 1 to 2. ASA, previous abdominal operations, and elevated body mass index independently predict adverse clinical outcome in patients with ASA 3 to 4. Our results may help to weigh the surgical risk of RC in multimorbid patients.

Diagnostik und Therapie des Harnblasenkarzinoms

ZusammenfassungDas Urothelkarzinom der Harnblase zählt zu den häufigsten Malignomen des unteren Harntrakts und nimmt bis zu 7% aller Krebserkrankungen in der westlichen Welt ein. Es kann durch mehrere exogene Noxen begünstigt oder ausgelöst werden. Als Hauptrisikofaktor gilt Tabakkonsum. Das Kardinalsymptom ist die schmerzlose Hämaturie. In der Diagnostik nimmt die Urethrozystoskopie neben der Sonografie den wichtigsten Stellenwert ein. Bei Tumornachweis sollte eine nachfolgende transurethrale Resektion der Blase (TUR-B) durchgeführt werden. Bei nicht-muskelinvasiven Tumoren kann eine Nachresektion und/oder eine adjuvante Instillationstherapie der Blase nötig sein. Bei muskelinvasiven Tumoren stellt die radikale Zystektomie nach einer neoadjuvanten systemischen Chemotherapie die kurative Therapie der Wahl dar. Im metastasierten Krankheitsstadium nimmt die palliative Chemotherapie den größten Stellenwert ein.