Autoimmune cerebellar hypermetabolism: Report of three cases and literature overview.

We report three cases of vermian cerebellar hypermetabolism in patients with autoimmune encephalitis. One of our patients was positive for anti-Ma2 antibodies and one for anti-Zic4 antibodies while the remaining patient did not present any known antibodies. The seronegative patient deteriorated after immune checkpoint inhibitor treatment for a pulmonary adenocarcinoma and improved with immunosuppressive drugs, which is in favour of an underlying autoimmune mechanism. They all presented with subacute neurological symptoms. Brain magnetic resonance imaging was normal except in one patient, where hyperintensities were present on FLAIR sequence around the third ventricle and the cerebral aqueduct. 18F-FDG brain positron emission tomography with computed tomography (18F-FDG PET-CT) demonstrated an unusual vermian cerebellar hypermetabolism in the three cases. While cerebellar hypermetabolism on 18F-FDG PET-CT has been described in various neurological diseases, such vermian - and more broadly cerebellar - hypermetabolism was seldom described in previous studies on autoimmune encephalitis. When differential diagnoses have been ruled out, this pattern may be of interest for the positive diagnosis of autoimmune encephalitis in difficult diagnostic cases.

Robot-sewn ileoileal anastomosis during robot-assisted cystectomy.

PURPOSE: To analyze the feasibility and perioperative results of patients undergoing robot-assisted cystectomy with intracorporeal urinary diversion and robot-sewn ileoileal anastomosis. METHODS: This is a mono-centric analysis of perioperative data from 48 consecutive patients undergoing robot-assisted cystectomy with intracorporeal urinary diversion and robot-sewn ileoileal anastomosis. Data include the preoperative variables, operative and postoperative course and complication rates related to bowel anastomosis. End points were time spent for anastomosis and intra- and postoperative complication rates. RESULTS: Median operating time was 23.0 (13-60) min for the ileoileal anastomosis. Median overall operating time was 295 (200-780) min, with a median of 282 (200-418) min and 414.0 (225-780) min for the ileum conduit (N = 35) and ileal neobladder (N = 13). Two patients developed paralytic ileus; in another patient acute peritonitis occurred, but was caused by urinary leakage and therefore unrelated to the bowel anastomosis. No anastomotic leakage was noticed. Costs for the robot-sewn anastomosis was 8€ compared to 1250€ for a stapled anastomosis which was performed in previous cases. Limitations are the non-comparative nature of the analysis and the limited number of patients. CONCLUSIONS: Robot-sewn ileoileal anastomosis is feasible with low complication rates. Compared to the stapled anastomosis, a robot-sewn ileoileal anastomosis may serve as an alternative and cost-saving approach.

Does Gleason score at initial diagnosis predict efficacy of abiraterone acetate therapy in patients with metastatic castration-resistant prostate cancer? An analysis of abiraterone acetate phase III trials.

BACKGROUND: The usefulness of Gleason score (<8 or ≥8) at initial diagnosis as a predictive marker of response to abiraterone acetate (AA) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) was explored retrospectively. PATIENTS AND METHODS: Initial diagnosis Gleason score was obtained in 1048 of 1195 (COU-AA-301, post-docetaxel) and 996 of 1088 (COU-AA-302, chemotherapy-naïve) patients treated with AA 1 g plus prednisone 5 mg twice daily by mouth or placebo plus prednisone. Efficacy end points included radiographic progression-free survival (rPFS) and overall survival (OS). Distributions and medians were estimated by Kaplan-Meier method and hazard ratio (HR) and 95% confidence interval (CI) by Cox model. RESULTS: Baseline characteristics were similar across studies and treatment groups. Regardless of Gleason score, AA treatment significantly improved rPFS in post-docetaxel [Gleason score <8: median, 6.4 versus 5.5 months (HR = 0.70; 95% CI 0.56-0.86), P = 0.0009 and Gleason score ≥8: median, 5.6 versus 2.9 months (HR = 0.58; 95% CI 0.48-0.72), P < 0.0001] and chemotherapy-naïve patients [Gleason score <8: median, 16.5 versus 8.2 months (HR = 0.50; 95% CI 0.40-0.62), P < 0.0001 and Gleason score ≥8: median, 13.8 versus 8.2 months (HR = 0.61; 95% CI 0.49-0.76), P < 0.0001]. Clinical benefit of AA treatment was also observed for OS, prostate-specific antigen (PSA) response, objective response and time to PSA progression across studies and Gleason score subgroups. CONCLUSION: OS and rPFS trends demonstrate AA treatment benefit in patients with pre- or post-chemotherapy mCRPC regardless of Gleason score at initial diagnosis. The initial diagnostic Gleason score in patients with mCRPC should not be considered in the decision to treat with AA, as tumour metastases may no longer reflect the histology at the time of diagnosis. CLINICAL TRIALS NUMBER: COU-AA-301 (NCT00638690); COU-AA-302 (NCT00887198).

DEPROMP Trial: the additive value of PSMA-PET/CT-guided biopsy for prostate cancer management in biopsy naïve men-study protocol for a randomized trial.

BACKGROUND: The primary objective is to determine the proportion of men with suspected prostate cancer (PCA) in whom the management plans are changed by additive gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT) guided prostate biopsy (PET-TB) in combination with standard of care (SOC) using systematic (SB) and multiparametric magnetic resonance imaging-guided biopsy (MR-TB) compared with SOC alone. The major secondary objectives are to determine the additive value of the combined approach of SB + MR-TB + PET-TB (PET/MR-TB) for detecting clinically significant PCA (csPCA) compared to SOC; to determine sensitivity, specificity, positive and negative predictive value and diagnostic accuracy of imaging techniques, respective imaging classification systems, and each biopsy method; and to compare preoperatively defined tumor burden and biomarker expression and pathological tumor extent in prostate specimens. METHODS: The DEPROMP study is a prospective, open-label, interventional investigator-initiated trial. Risk stratification and management plans after PET/MR-TB are conducted randomized and blinded by different evaluation teams of experienced urologists based on histopathological analysis and imaging information: one including all results of the PET/MR-TB and one excluding the additional information gained by PSMA-PET/CT guided biopsy. The power calculation was centered on pilot data, and we will recruit up to 230 biopsy-naïve men who will undergo PET/MR-TB for suspected PCA. Conduct and reporting of MRI and PSMA-PET/CT will be performed in a blinded fashion. DISCUSSION: The DEPROMP Trial will be the first to evaluate the clinically relevant effects of the use of PSMA-PET/CT in patients with suspected PCA compared to current SOC. The study will provide prospective data to determine the diagnostic yields of additional PET-TB in men with suspected PCA and the impact on treatment plans in terms of intra- and intermodal changes. The results will allow a comparative analysis of risk stratification by each biopsy method, including a performance analysis of the corresponding rating systems. This will reveal potential intermethod and pre- and postoperative discordances of tumor stage and grading, providing the opportunity to critically assess the need for multiple biopsies. TRIAL REGISTRATION: German Clinical Study Register DRKS 00024134. Registered on 26 January 2021.

[Quality assurance for the treatment of muscle-invasive and metastasized bladder carcinoma in Germany : An initiative of the Working Groups Urological Oncology (AUO) and Internal Oncology (AIO) in the German Cancer Society (DKG)]. / Qualitätssicherung zur Therapie des muskelinvasiven und metastasierten Harnblasenkarzinoms in Deutschland : Eine Initiative der Arbeitsgemeinschaften Urologische Onkologie (AUO) und Internistische Onkologie (AIO) in der Deutschen Krebsgesellschaft (DKG).

BACKGROUND: The S3-guideline on bladder cancer recommends radical cystectomy and cisplatin-based perioperative chemotherapy (POC) for muscle-invasive bladder cancer (MIBC). Recommendation for metastatic urothelial cancer (mUC) is cisplatin-based or immuno-oncological (IO) treatment in platinum-ineligible patients (pts) or as 2nd-line therapy. OBJECTIVES: Aim of the study was to obtain representative data on clinical routine treatment of MIBC and mUC in Germany. MATERIALS AND METHODS: A nationwide survey was performed to obtain data on stage-related patient volume in hospitals and office-based physicians. Based on these results, a representative sample of treatment data was collected retrospectively from pts with MIBC and mUC. RESULTS: Data from 956 pts (MIBC 576; mUC: 380) were collected. Of the MIBC pts, 49.8% received a systemic therapy (80.4% of them received cisplatin/gemcitabine) and 50.2% were treated with a cystectomy without POC. Significant factors for cystectomy without POC were higher age > 75 years (odds ratio [OR] 4.91, 95% confidence interval [CI] 3.01-8.11, p < 0.001) and platinum-ineligible pts (OR 2.15, 95% CI 1.30-3.59; p = 0.003). Treatment decision without interdisciplinary tumor board was also correlated with no POC (OR 2.43, 95% CI 1.65-3.61, p < 0.001). In mUC platinum-pretreated pts generally receive IO therapy (OR 12.07, 95% CI 6.94-21.82, p < 0.001). Other significant factors are positive PD-L1 status (OR 3.72, 95% CI 1.30-5.71, p < 0.001), higher age > 75 years (OR 2.83, 95% CI 1.43-5.73, p = 0.003) and platinum-ineligible pts (OR 2.57, 95% CI 1.30-5.71, p = 0.007). CONCLUSIONS: The "gold standard" cisplatin/gemcitabine is established in Germany if pts are treated with POC. Nonetheless half of the MIBC pts did not receive a POC, especially if the treatment decision is not discussed in a tumor board. In mUC IO therapy is established as 2nd-line therapy after a platinum-based treatment. Although the guideline recommendations are largely implemented, there is potential for optimization, especially in the establishment of interdisciplinary tumor boards.

Outcome of treatment discontinuation in patients with metastatic renal cell carcinoma and no evidence of disease following targeted therapy with or without metastasectomy.

BACKGROUND: It is unknown if discontinuation of targeted therapy (TT) and readministration in case of recurrence is feasible in patients with metastatic renal cell carcinoma (mRCC) in which complete response (CR) is achieved by TT alone or no evidence of disease (NED) with additional resection of residual metastases. PATIENTS AND METHODS: Patients in whom TT was discontinued after CR to TT alone or NED after additional metastasectomy were included in this retrospective analysis. Outcome criteria evaluated were time off TT, recurrence of metastases and response to re-exposure to TT. Univariate and multivariate analyses were carried out to identify variables potentially predictive of outcome. RESULTS: In 36 patients with CR or NED under TT with sunitinib (22), sorafenib (11), bevacizumab/interferon (2) and temsirolimus (1), TT was discontinued. Recurrence was observed in 24 patients (66.7%). Re-exposure to TT was effective in 86.9% of these cases. Twelve patients (33.3%) remained recurrence free at a median follow-up of 12 months (range 3-31). Median time off TT was 7 months (range 1-31). Factors that correlate with outcome could not be identified. CONCLUSIONS: In the majority of patients with mRCC and CR or NED, discontinuation of TT was followed by recurrence, but re-exposure to TT was effective.

Sequential therapies with sorafenib and sunitinib in advanced or metastatic renal cell carcinoma.

PURPOSE: To investigate whether patients with metastatic renal cell carcinoma benefit from sequential therapies with the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib. PATIENTS AND METHODS: A total of 89 patients were treated in nine German centres between 2002 and 2009. The TKI sequence started as first-, second- or third-line therapy after prior chemo- or immunotherapy. When progression was diagnosed, treatment was switched to the second TKI until further progression. RESULTS: Overall progression-free survival (PFS) of patients receiving sunitinib followed by sorafenib shows no statistically significant difference to patients receiving sorafenib followed by sunitinib (15.4 months vs. 12.1 months). The secondary use of sorafenib resulted in a median PFS of 3.8 months if the TKI sequence had been started as a first-line treatment and of 3.5 months if the TKI sequence had been started second-line treatment. The secondary use of sunitinib resulted in a median PFS of 3.4 and 4.0 months, respectively. OS was 28.8 months for all patients, without a statistically significant difference between the two groups. CONCLUSIONS: This study endorses the notion of a clinical benefit of the sequential use of sorafenib and sunitinib and supports observations from previous studies. In terms of the optimal succession of the two TKIs, the study does not allow a definite answer.

[Combination therapy for metastatic hormone-sensitive prostate cancer: What? When? For whom?] / Kombinierte Systemtherapie beim metastasierten hormonsensitiven Prostatakarzinom: Was? Wann? Bei wem?

Novel combination therapies are currently the standard systemic treatment for metastatic hormone-sensitive prostate cancer. As a result, the overall survival of patients can be extended by approximately 1.5 years. The taxane docetaxel, the CYP17 inhibitor abiraterone and the second generation antiandrogen apalutamide can currently be used as a combination partner for classic androgen deprivation. While the de novo synthesis of testosterone is the rationale for abiraterone or apalutamide combination, taxanes offer a promising approach in the presence of primarily androgen-independent prostate cancer cells. Due to the increased rate of side effects caused by combination therapy, it is important to clarify in daily clinical practice which patient group benefits in particular from the respective combination therapy. Hereby, the metastatic pattern, general condition and age play an important role. While there is good evidence of the use of docetaxel or abiraterone in visceral metastasis, apalutamide offers a very wide range of uses. Ultimately, the recommendation for combination therapy is always an individual decision that needs to be discussed with the patient, considering the benefits and risks.

[Algorithms for systemic therapy of prostate cancer, transitional cell carcinoma and renal cell carcinoma]. / Algorithmen zur Systemtherapie bei Prostata­, Urothel- und Nierenzellkarzinom.

Systemic therapy in uro-oncology is currently undergoing major changes. In the past, drug therapies only showed good treatment results in metastasized testicular tumors. New developments indicate that an improved understanding of tumor biology will lead to targeted treatment strategies for metastatic prostate, urothelial and renal cell carcinoma. In the following article, we summarize the practice-relevant innovations in systemic therapy in the guidelines on prostate cancer, transitional cell carcinoma of the bladder and renal cell carcinoma.

[Androgen deprivation for advanced prostate cancer]. / Androgendeprivation in der Therapie des Prostatakarzinoms.

Androgen deprivation (ADT) by medical or surgical castration represents the standard therapeutic approach for managing prostate cancer (PCA) with systemic or locoregional metastases. Although ADT has been successfully used for more than 60 years, there are still major controversies with regard to the initiation (early versus delayed), type (complete versus monotherapy), and duration (continuous versus intermittent) of treatment. It is the purpose of this review to critically present the results of the various ADT options. Bilateral orchiectomy and subcutaneous application of luteinising hormone-releasing hormone (LHRH) analogues represent the guideline-recommended standard treatment for metastatic PCA, whereas estrogens are no longer recommended because of significant cardiovascular side effects despite comparable therapeutic efficacy. Antiandrogen monotherapy with bicalutamide is comparable to LHRH analogues in men with minimal tumour burden. However, survival rates are inferior in patients with extensive metastatic disease, in whom medical or surgical castration should be favoured. Complete ADT results in a median survival benefit of about 5% in men with low metastatic tumour burden, and it cannot be recommended for routine use. Early ADT is associated with a significant advantage in terms of symptom-free survival and prevention of metastasis-associated complications, but it does not result in a prolonged progression-free and overall survival when compared with delayed ADT. Despite encouraging results, intermittent ADT remains an experimental therapeutic approach that should be considered on an individual basis in carefully selected patients. Adjuvant ADT is still discussed controversially for men after radical prostatectomy, whereas it has become the standard approach in patients who undergo external beam radiation for locally advanced PCA.

[Feasibility of targeted therapy based on immunohistochemical expression analysis in androgen-independent prostate cancer]. / Molekular getriggerte Therapie des hormonrefraktären Prostatakarzinoms.

Targeted therapies present an interesting treatment option in prostate cancer. The aim of our study was to analyze the expression profile of several molecular markers that are candidates for targeted therapy in patients with progressive androgen-independent prostate cancer (AIPC). Based on the expression profile, the efficacy of a combination therapy with a signal transduction inhibitor (STI) and docetaxel was evaluated.Tumor tissue obtained from biopsy of the prostate or lymph node and visceral metastasis was analyzed for the immunohistochemical expression of epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor beta (PDGFRbeta), Her-2/neu, c-KIT, and vascular endothelial growth factor (VEGF). Patients with positive staining of one or more markers were treated with the corresponding STI and docetaxel.Fifty-one patients were included in the protocol, of whom 43 (84.3%) presented with progressive AIPC after first-line chemotherapy. Forty-six of these 51 patients (90.2%) showed expression of one or more of the analyzed markers. Expression of EGFR was found in 61.2%, PDGFRbeta in 57.1%, Her-2/neu in 16.3%, c-KIT in 25.0%, and VEGF in 74.5%. After request for cost coverage, 8/51 patients received the combination therapy and were evaluated for response. Four of the eight patients (50%) showed a decline in prostate-specific antigen of > or =50%, and median survival time was 13.5 months at a median follow-up of 23.6 (11-35) months.The results show that expression of molecular targets is found in about 90% of patients with AIPC. Based on the expression profile, an individual treatment strategy can be applied to each patient. Further clinical studies should determine the clinical efficacy of molecular targeted therapy in patients with AIPC.

[Current and established diagnostic modalities for bladder cancer]. / Aktuelle und etablierte Diagnoseverfahren beim Harnblasenkarzinom.

INTRODUCTION: In this paper, current guidelines regarding diagnostic and staging modalities of urothelial cancer of the bladder are summarized and an overview of endoscopic, imaging, and molecular methods currently being tested are outlined. METHODS: Relevant passages from current guidelines and recent literature as well as to a certain extent our own research are examined. RESULTS: Over the last decade, imaging mainly in the form of photodynamic diagnosis (PDD) has undergone further development and found its way into several guidelines. PDD-based transurethral resection of the bladder (TURB) proved to have a long-term effect regarding recurrence rate, progression and reduction of cystectomy in some patients. More light-filtering techniques and improvements in the screen resolution are currently being clinically tested. Molecular substaging using combinations of immunohistochemical biomarkers has the potential to change the clinical management of advanced urothelial cancer. CONCLUSION: New visualization techniques are likely to improve recurrence intervals and prognosis of bladder cancer. Molecular substaging will revolutionize prognostic assessment and therapeutic strategies of urothelial cancer.

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.

[Lethal course after chemotherapy with docetaxel. Acute liver failure with accompanying erythema multiforme major]. / Letaler Ausgang einer Chemotherapie mit Docetaxel. Akutes Leberversagen mit begleitendem Erythema exsudativum multiforme majus.

We report on the lethal course of a patient receiving low-dose, weekly docetaxel who developed acute liver failure accompanied by a Stevens-Johnson syndrome. After receiving the fifth application of his chemotherapy, the patient was admitted to hospital because of neutropenia and severe erythema. The course worsened towards an acute liver failure and an erythema multiforme major. Despite an interdisciplinary approach, the further course could not be influenced and the patient died 6 weeks after admission due the toxicity of docetaxel. This case report underlines the spectrum of toxicity of docetaxel even in the low-dose weekly schedule.

[Patients with metastatic prostate cancer : Recommendations for primary hormonal or chemohormonal therapy]. / Patienten mit metastasiertem Prostatakarzinom : Empfehlungen zur primären Hormon- oder Hormonchemotherapie.

The standard treatment for patients with metastatic, hormone-sensitive prostate cancer (mCSPC) has so far consisted of medical or surgical castration. However, two published clinical trials using docetaxel in combination with castration (CHAARTED and STAMPEDE) recently provided evidence for a substantial improvement in overall survival. The survival benefit was 14 and 22 months, respectively, in the two trials. In addition, the CHAARTED trial showed that patients with high-volume disease may benefit most from chemohormonal treatment. According to the current available evidence, the new standard of treatment for patients therefore consists of castration in combination with docetaxel-based chemotherapy, which should be offered to all patients who are fit to receive chemotherapy. With the results of the LATITUDE and a further study-arm of the STAMPEDE trial, the combination of androgen-deprivation therapy (ADT) plus abiraterone/prednisone has recently become an alternative treatment to chemohormonal treatment. This combination leads to an identical survival benefit compared to chemohormonal treatment and is recommended by expert panels. Based on the current evidence, it is not possible to decide which patient may benefit from chemohormonal treatment and who will benefit from the combination of ADT plus abiraterone/prednisone.

[Antihormonal therapy in prostate cancer : Side effects]. / Antihormonelle Therapie beim Prostatakarzinom : Nebenwirkungen.

Androgen deprivation is still standard therapy for prostate cancer, either as primary androgen deprivation therapy or with the use of secondary hormonal drugs including abiraterone and enzalutamide. However, especially the clinically occult side effects like metabolic changes or cardiovascular complications and effects on the psyche of the patient are often not recognized in daily practice. Active monitoring of such side effects is essential for prevention and early intervention. In addition, the efficacy of androgen deprivation therapies is limited by primary and secondary resistance. The underlying molecular mechanism including splice variants of the androgen receptor in contrast to mutations are usually reversible and should be regarded as a sign of efficacy of the current treatment. Therefore, the clever, timely use of androgen deprivation or even the use of a bipolar androgen therapy should enable reversal of resistance to again render tumor cells sensitive to androgen-deprivation therapy.

[Metastatic prostate cancer : Update: position paper for the use of chemotherapy]. / Metastasiertes Prostatakarzinom : Update: Positionspapier zum Einsatz der Chemotherapie.

BACKGROUND: Taxen-based chemotherapy has been established as an effective treatment option in castration-resistant metastatic prostate cancer (mCRPC). Randomized phase III studies, however, have shown that even in the hormone-naïve metastatic state, the early use of chemotherapy in addition to the classical androgen deprivation therapy (ADT) approach leads to a significant increase in median overall survival. OBJECTIVE: This position paper aims to provide current data and orientation in the evidence-based treatment of mPC patients in daily clinical practice. MATERIALS AND METHODS: A German group of clinical experts analyzed the current data and developed criteria for the treatment of mPC patients in daily clinical practice. RESULTS: In the current treatment of hormone-naïve mPC, a beneficial effect of chemotherapy in addition to ADT has become evident. Provided patients are in an appropriate condition, those with a high metastatic load should receive chemotherapy in addition to ADT. Especially in high-risk mCRPC patients (PSA >114 ng/ml, visceral metastasis, ADT response <12 months, tumor-associated complaints), first-line chemotherapy is indicated. After docetaxel failure, continuous treatment with cabazitaxel shows superior overall survival compared to sustained antihormonal therapy. CONCLUSION: Chemotherapy is firmly established in treating patients with mCRPC. Long-term, it will be important to identify molecular predictors. The authors suggest the early use of chemotherapy in hormone-naïve mPC, but note that the approval in this indication is currently nonexistent. After disease progression, patients should be treated analogous to mCRPC.