Efficacy of adjuvant immune checkpoint inhibitors pembrolizumab or nivolumab in melanoma patients ≥ 75 years: results of a real-world cohort including 456 patients.

BACKGROUND: Immune checkpoint inhibitors (ICI) applied in patients with melanoma in an adjuvant setting have proven safety and efficacy in several studies, but data on elderly patients aged 75 years or more is scarce. Aim of this study was to investigate efficacy and safety of adjuvant ICI in patients aged ≥ 75 years compared to patients < 75 years in a real-world setting. METHODS: We retrospectively analyzed clinical data, including occurrence of immune-related adverse events (irAE) and outcome of 456 patients that had been treated with adjuvant ICI between January 1st, 2018 and December 20th, 2022. We then compared patients aged ≥ 75 years (n = 117) to patients < 75 years (n = 339) in terms of safety and disease-free survival (DFS). RESULTS AND CONCLUSION: ICI were well tolerated in both groups, with no significant difference observed in the overall occurrence of irAE. However, within the elderly subgroup, there was a significantly higher proportion of skin or nephrological toxicity and colitis/diarrhea compared to the other group. In terms of efficacy, a significantly shorter DFS in patients aged ≥ 75 years was observed. Adjuvant ICI in patients ≥ 75 years was less effective and furthermore associated with an increased risk for skin, renal or bowel toxicity. Therefore, in elderly patients, adjuvant ICI should be used with precaution.

Impact of off-label use regulations on patient care in dermatology - a prospective study of cost-coverage applications filed by tertiary dermatology clinics throughout Germany.

BACKGROUND: In dermatology, a medical speciality with a relatively high number of rare diseases, physicians often have to resort to off-label treatment options. To avoid claims, physicians in Germany can file a cost-coverage request (off-label application, OL-A). OBJECTIVES: Our aim was to investigate the extent to which the current regulations affect patient care. MATERIAL AND METHODS: Prospective cohort study among tertiary dermatology clinics throughout Germany, consecutively including OL-As (05/2019-09/2020) and assessing the follow-up correspondence. We modelled regressions to assess factors associated with cost-coverage decisions and the time needed by health insurers to process the OL-As. RESULTS: Thirteen clinics provided data on 121 OL-As, two of which applied for on-label treatments. Of the remaining 119 OL-As, 70 (58.8%) were immediately approved and 44 (37.0%) rejected. Including cases with one or more appeals, 87 of 119 OL-As (73.1%) were finally approved and 26 (21.9%) rejected. There was an association of the final approval rate with (1) the class of medication/treatment, with approval rates being significantly lower for JAK inhibitors than for biologics (OR 0.16, 95%-CI: 0.03-0.82); (2) German state, with approval rates being lower in eastern than in western states (OR 0.30, 95%-CI 0.12-0.76); and (3) cost of the intervention (no linear trend). However, none of these predictors was significant in our multiple logistic regression models. The median health insurer's processing time (first response) was 29 days (IQR 22-38). Our analyses showed no evidence of an association with the predictors we assessed. In cases approved, the median time from the decision to file an OL-A to the actual initiation of the treatment was 65.5 days (IQR 51-92). CONCLUSIONS: Our study points to substantial delays and inequalities in the provision of timely health care for dermatological patients with rare diseases, often involving treatments for which there is no adequate approved therapy.

Adherence to the EAU guideline recommendations for systemic chemotherapy in penile cancer: results of the E-PROPS study group survey.

OBJECTIVES: To validate the adherence of urologists to chemotherapy recommendations given in the EAU guidelines on PeCa. The European Association of Urology (EAU) guidelines on penile cancer (PeCa) are predominantly based on retrospective studies with low level of evidence. MATERIALS AND METHODS: A 14-item-survey addressing general issues of PeCa treatment was developed and sent to 45 European hospitals. 557 urologists participated in the survey of which 43.5%, 19.3%, and 37.2% were in-training, certified, and in leading positions, respectively. Median response rate among participating departments was 85.7% (IQR 75-94%). Three of 14 questions addressed clinical decisions on neoadjuvant, adjuvant, and palliative chemotherapy. Survey results were analyzed by bootstrap-adjusted multivariate logistic-regression-analysis to identify predictors for chemotherapy recommendations consistent with the guidelines. RESULTS: Neoadjuvant, adjuvant, and palliative chemotherapy was recommended according to EAU guidelines in 21%, 26%, and 48%, respectively. For neoadjuvant chemotherapy, urologists holding leading positions or performing chemotherapy were more likely to recommend guideline-consistent treatment (OR 1.85 and 1.92 with p(bootstrap) = 0.007 and 0.003, respectively). Supporting resources (i.e., guidelines, textbooks) were used by 23% of survey participants and significantly improved consistency between treatment recommendations and Guideline recommendations in all chemotherapy settings (p(bootstrap) = 0.010-0.001). Department size and university center status were no significant predictors for all three endpoints. CONCLUSIONS: In this study, we found a very low rate of adherence to the EAU guidelines on systemic treatment for PeCa. Further investigations are needed to clarify whether this missing adherence is a consequence of limited individual knowledge level or of the low grade of guideline recommendations.

[Attending physicians in urology working at university centers or non-university centers-what are the differences? : Results of a web-based cross-sectional study at German hospitals]. / Urologische Oberärztinnen und Oberärzte an universitären oder nicht-universitären Kliniken ­ welche Unterschiede gibt es? : Ergebnisse einer webbasierten Querschnittstudie an deutschen Kliniken.

BACKGROUND: Attending physicians (AP) in urology represent a very heterogeneous group covering various clinical priorities and career objectives. To date, there are no reliable data on professional, personal and position-linked aspects of AP in urology working in university centers (univ-AP) opposed to those working in non-university centers (n-univ-AP). MATERIALS AND METHODS: The objective of this study was to analyze individual professional perspectives, professional and personal settings, specific job-related activities and individual professional goals of univ-AP opposed to n­univ-AP. Thus, a web-based survey containing 55 items was designed to perform a cross-sectional study that was then forwarded using a link which was sent via a mailing list of the German Society of Urology. The survey was available for completion by AP at German urological centers from February to April 2019. Group-specific differences were evaluated using bootstrap-adjusted multivariate logistic regression models. RESULTS: Of the 192 evaluable surveys, 61 (31.8%) and 131 (68.2%) were part of the univ-AP and n­univ-AP study group, respectively. Participating n­univ-AP compared to univ-AP held the position of AP (p = 0.022) significantly longer and were on call significantly more frequently (p < 0.001). AP in urology (self)-assessed themselves as autonomously confident in performing robotic, laparoscopic, open, endo-urologic, and plastic-reconstructive surgery in 12.4%, 25%, 59.6%, 92.1%, and 25.7%, respectively, with no significant differences between the two groups among all above mentioned surgical subdomains based on multivariate analysis. AP in urology were (very) content in 92% concerning the choice of their discipline, in 73.9% concerning their actual working circumstances, and in 60.2% concerning their level of surgical expertise. Only 27.1% and 19.9% were (very) content with the amount of available time for their personal professional development and for private affairs, respectively. As opposed to n­univ-AP, univ-AP would choose a career in clinical centers once again significantly more frequently (OR 2.87; p(BS) = 0.041), but assess the position of AP as their definitive career goal significantly less frequently (OR 0.42; p(BS) = 0.40). Univ-AP state significantly more frequently that they were running for the position of head of department or full professor (OR 5.64; p(BS) = 0.001). CONCLUSION: In this first survey study world-wide on AP in urology divided according to their academic background, similarities and variances were analyzed, baring the potential to further improve identification of AP for a career in clinical centers.

Mechanical thrombectomy for the treatment of acute ischaemic stroke following pulmonary lobectomy.

Acute ischaemic stroke is a devastating postoperative complication that significantly impacts upon a patient's quality of life. Endovascular retrieval of thromboembolic material from proximal cerebral arteries by mechanical thrombectomy is the new standard of care for patients presenting with a proximal artery occlusion. We report the case of a patient developing an acute ischaemic stroke following pulmonary lobectomy, who was transferred to the regional neurosciences unit, despite the absence of an established referral pathway, to undergo mechanical thrombectomy, with significant prognostic neurological benefit. We would advocate all cardiothoracic centres identify their regional neurosciences unit and initiate discussion to establish a referral pathway.

[Recurrent bleeding of a duodenal ulcer in a 55-year-old man after heart transplantation]. / Rezidivierende Blutungen aus einem Ulcus duodeni bei einem 55-jährigen Patienten nach Herztransplantation.

Duodenal ulcers are most often caused by Helicobacter pylori (HP) infection, followed by nonsteroidal anti-inflammatory drugs and hypoperfusion. Posttransplant lymphoproliferative disorder (PTLD) occurs in about 1-6.3% of patients with a heart transplant under immunosuppression therapy. Up to 25% of cases of PTLD have gastrointestinal involvement. Due to a wide spectrum of clinical symptoms and pathological entities, the diagnosis can be challenging. We report the case of a 55-year-old man 12 years after receiving a heart transplant being treated with immunosuppressive agents (tacrolimus) who presented with recurrent bleeding from peptic duodeni. Immunohistochemistry revealed a rare Epstein-Barr-virus-associated polymorphic PTLD. Rarely, PTLD can manifest only with isolated lesions of the duodenal bulb. The course was progressive, going from an incidental finding requiring transfusion anemia to a perforation within 1 month. Repeated endoscopic interventions were unsuccessful. After a surgical intervention the patient died in the course of multiple organ failure. Retrospectively, a reduction of immunosuppression in polymorphic PTLD would have been a treatment option.

Impact of surgeon's experience on outcome parameters following ureterorenoscopic stone removal.

Within the BUSTER trial, we analyzed the surgeon's amount of experience and other parameters associated with URS procedures regarding the stone-free rate, complication rate, and operative time. Patient characteristics and surgical details on 307 URS procedures were prospectively documented according to a standardized study protocol at 14 German centers 01-04/2015. Surgeon's experience was correlated to clinical characteristics, and its impact on the stone-free rate, complication rate, and operative time subjected to multivariate analysis. 76 (25%), 66 (21%) and 165 (54%) of 307 URS procedures were carried out by residents, young specialists, and experienced specialists (> 5 years after board certification), respectively. Median stone size was 6 mm, median operative time 35 min. A ureteral stent was placed at the end of 82% of procedures. Stone-free rate and stone-free rate including minimal residual stone fragments (adequate for spontaneous clearance) following URS were 69 and 91%, respectively. No complications were documented during the hospital stays of 89% of patients (Clavien-Dindo grade 0). According to multivariate analysis, experienced specialists achieved a 2.2-fold higher stone-free rate compared to residents (p = 0.038), but used post-URS stenting 2.6-fold more frequently (p = 0.023). Surgeon's experience had no significant impact on the complication rate. We observed no differences in this study's main endpoints, namely the stone-free and complication rates, between residents and young specialists, but experienced specialists' stone-free rate was significantly higher. During this cross-sectional study, 75% of URS procedures were performed by specialists. The experienced specialists' more than two-fold higher stone-free rate compared to residents' justifies ongoing efforts to establish structured URS training programs.

[Interrater reliability and clinical impact of the Post-Ureteroscopic Lesion Scale (PULS) grading system for ureteral lesions after ureteroscopy : Results of the German prospective multicenter BUSTER project]. / Interrater-Übereinstimmung und klinischer Nutzen der "Post-Ureteroscopic Lesion Scale" (PULS) zur Graduierung von intraoperativen Harnleiterverletzungen einer Ureterorenoskopie : Ergebnisse der deutschen prospektiv-multizentrischen BUSTER-Studie.

BACKGROUND: The Post-ureteroscopic Lesion Scale (PULS) was designed as a standardized classification system for ureteral lesions after uretero(reno)scopy (URS). This study evaluates its routine use and a possible clinical impact based on a representative patient cohort. MATERIALS AND METHODS: Data of 307 patients in 14 German centers within the BUSTER project were used to test 3 hypotheses (H): PULS score shows a high interrater reliability (IRR) after independent assessment by urologic surgeon and assistance personnel (H1); PULS score is correlated with the frequency of postoperative complications during hospital stay (H2); post-URS stenting of the ureter is associated with higher PULS scores (H3). RESULTS: Median age of patients was 54.4 years (interquartile range [IQR] 44.4-65.8; 65.5% male). Median diameter of index stones was 6 mm (IQR 4-8) with 117 (38.4%) pyelo-caliceal and 188 (61.6%) ureteral stones. Overall, 70 and 82.4% of patients had pre-stenting and post-URS stenting, respectively. Stone-free status was achieved in 68.7% after one URS procedure with a complication rate of 10.8% (mostly grade 1-2 according to Clavien-Dindo). PULS scores 0, 1, 2 and 3 were assessed in 40%, 52.1%, 6.9% and 1% of patients, respectively, when estimated by urologic surgeons. PULS score showed a high IRR between the urologic surgeon and assistance personnel (κ = 0.883, p < 0.001), but was not significantly correlated with complications (ρ = 0.09, p = 0.881). In contrast, a significant positive correlation was found between PULS score and post-URS stenting (ρ = 0.287, p < 0.001). A PULS score of 1 multiplied the likelihood of post-URS stenting by 3.24 (95% confidence interval 1.43-7.34; p = 0.005) as opposed to PULS score 0. CONCLUSIONS: Removal of upper urinary tract stones using URS is safe and efficacious. Real-world data provided by this study confirm a high IRR of the PULS score and its clinical impact on the indication for post-URS stenting. A future prospective randomized trial should evaluate a possible standardization of post-URS stenting based on PULS score assessment.

Prognostic significance of Fuhrman grade and age for cancer-specific and overall survival in patients with papillary renal cell carcinoma: results of an international multi-institutional study on 2189 patients.

PURPOSE: Because the prognostic impact of the clinical and pathological features on cancer-specific survival (CSS) and overall survival (OS) in patients with papillary renal cell carcinoma (papRCC) is still controversial, we want to assess the impact of clinicopathological features, including Fuhrman grade and age, on survival in surgically treated papRCC patients in a large multi-institutional series. METHODS: We established a comprehensive multi-institutional database of surgically treated papRCC patients. Histopathological data collected from 2189 patients with papRCC after radical nephrectomy or nephron-sparing surgery were pooled from 18 centres in Europe and North America. OS and CSS probabilities were estimated using the Kaplan-Meier method. Multivariable competing risks analyses were used to assess the impact of Fuhrman grade (FG1-FG4) and age groups (<50 years, 50-75 years, >75 years) on cancer-specific mortality (CSM). RESULTS: CSS and OS rates for patients were 89 and 81% at 3 years, 86 and 75% at 5 years and 78 and 41% at 10 years after surgery, respectively. CSM differed significantly between FG 3 (hazard ratio [HR] 4.22, 95% confidence interval [CI] 2.17-8.22; p < 0.001) and FG 4 (HR 8.93, 95% CI 4.25-18.79; p < 0.001) in comparison to FG 1. CSM was significantly worse in patients aged >75 (HR 2.85, 95% CI 2.06-3.95; p < 0.001) compared to <50 years. CONCLUSIONS: FG is a strong prognostic factor for CSS in papRCC patients. In addition, patients older than 75 have worse CSM than patients younger than 50 years. These findings should be considered for clinical decision making.

Do we need new high-risk criteria for surgically treated renal cancer patients to improve the outcome of future clinical trials in the adjuvant setting? Results of a comprehensive analysis based on the multicenter CORONA database.

BACKGROUND: Since there is still an unmet need for potent adjuvant strategies for renal cancer patients with high progression risk after surgery, several targeted therapies are currently evaluated in this setting. We analyzed whether inclusion criteria of contemporary trials (ARISER, ASSURE, SORCE, EVEREST, PROTECT, S-TRAC, ATLAS) correctly identify high-risk patients. METHODS: The study group comprised 8873 patients of the international CORONA-database after surgery for non-metastatic renal cancer without any adjuvant treatment. Patients were divided into potentially eligible high-risk and assumable low-risk patients who didn't meet inclusion criteria of contemporary adjuvant clinical trials. The ability of various inclusion criteria for disease-free survival (DFS) prediction was evaluated by Harrell's c-index. RESULTS: During a median follow-up of 53 months 15.2% of patients experienced recurrence (5-year-DFS 84%). By application of trial inclusion criteria, 24% (S-TRAC) to 47% (SORCE) of patients would have been eligible for enrollment. Actual recurrence rates of eligible patients ranged between 29% (SORCE) and 37% (S-TRAC) opposed to <10% in excluded patients. Highest Hazard Ratio for selection criteria was proven for the SORCE-trial (HR 6.42; p < 0.001), while ASSURE and EVEREST reached the highest c-index for DFS prediction (both 0.73). In a separate multivariate Cox-model, two risk-groups were identified with a maximum difference in 5-year-DFS (94% vs. 61%). CONCLUSION: Results of contemporary adjuvant clinical trials will not be comparable as inclusion criteria differ significantly. Risk assessment according to our model might improve patient selection in clinical trials by defining a high-risk group (28% of all patients) with a 5-year-recurrence rate of almost 40%.

[A very rare cause of haemoptysis - coexistence of primary oncocytic adenoma of trachea with bronchial carcinoma]. / Eine äußerst seltene Ursache von Hämoptysen. Koexistenz eines primären onkozytären Adenoms der Trachea und eines Adenokarzinoms des linken Oberlappens.

HISTORY AND ADMISSION FINDINGS: A 70-year-old man with a past history of COPD stage GOLD D with home oxygen therapy and tracheotomy due to long-term ventilation (898 hours) 6 years ago was admitted for investigation of haemoptysis during oral anticoagulation. He suffered from peripheral arterial disease (PAD) with bypass and repeated thrombectomy due to recurrent bypass caps, despite effective warfarin therapy. He had all cardiovascular risk factors. INVESTIGATIONS: The suspicion of a bronchial carcinoma was confirmed by CT. Bronchoscopically a 2 cm lesion in the left upper lobe was biopsied. Additionally, bronchoscopy revealed an approximately erythematous, bloody discolored lesion (diameter 7 mm) at a tracheotomy scar. DIAGNOSIS, TREATMENT AND COURSE: The biopsies revealed an adenocarcinoma in the left upper lobe and an oncocytic adenoma of the trachea - an extremely rare adenoma. The staging result was cT1b cN0 cM0 G2 IASLC Ia. Because of his severe multiple diseases the patient was in an inoperable condition. An interdisciplinary tumor conference recommended an individualized approach with a definitive radiotherapy of the adenocarcinoma. Endoscopic control of the macroscopically completely removed oncocytic adenoma of the trachea shall be performed one year later. CONCLUSIONS: Oncocytoma is an extremely rare adenoma (of the trachea), which in this case, has caused haemoptysis in addition to lung cancer during anticoagulation. For tumor genesis a reactive or hyperplasic response after tracheotomy 6 years ago is considered. Resection is the treatment of choice because of the potential for infiltrative growth. But the decision to treat always depends on individual benefit.

[Rates of prostate-specific antigen testing for early detection of prostate cancer: a first comparison of German results with current international data]. / PSA-basierte Früherkennung des Prostatakarzinoms durch den Hausarzt: Erste deutsche Ergebnisse im internationalen Vergleich.

OBJECTIVE: Measurement of prostate-specific antigen (PSA) is not only used as a screening instrument by urologists, but also by general practitioners and internal specialists (GP-IS). Until now, there are neither data on the approach of German GP-IS in practicing this nor have data been classified in the context of available international literature on this topic. MATERIALS AND METHODS: Between May and December 2012, a questionnaire containing 16 items was sent to 600 GP-IS in Brandenburg and Berlin. The response rate was 65% (392/600). Six indicator questions (IQ1-6) were selected and results were set in the context of available international data. The quality of present studies was evaluated by the Harden criteria. RESULTS: Of the 392 responding physicians, 317 (81%) declared that they would use PSA testing for early detection of PCA (IQ1) and, thus, formed the study group. Of these GP-IS, 38% consider an age between 41 and 50 years as suitable for testing begin (IQ2), while 53% and 14% of the GP-IS perform early detection until the age of 80 and 90 years, respectively (IQ3). A rigid PSA cut-off of 4 ng/ml is considered to be reasonable by 47% of the involved GP-IS, whereas 16% prefer an age-adjusted PSA cut-off (IQ4). Patients with pathological PSA levels were immediately referred to a board-certified urologist by 69% of the GP-IS. On the other hand, 10% first would independently control elevated PSA levels themselves after 3-12 months (IQ5). Furthermore, 14% of the interviewed physicians consider a decrease of PCA-specific mortality by PSA screening as being proven (IQ6). Knowledge regarding PCA diagnostics is mainly based on continuous medical education for GP-IS (33%), personal contact with urologists (6%), and guideline studies (4%). While 53% indicated more than one education source, 4% did not obtain any PCA-specific training. The results provided by this questionnaire evaluating response of German GP-IS to six selected indicator questions fit well into the international context; however, further studies with sufficient methodical quality are required. CONCLUSIONS: Despite current findings and controversial recommendations of the two large PCA screening studies on this issue, German GP-IS still frequently use PCA screening by PSA measurement. Primary strategies of early detection as well as follow-up after assessment of pathologically elevated PSA levels poorly follow international recommendations. Thus, an intensification of specific education is justified.