Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling.

T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell leukemia 1A (TCL1A) oncogene distinguishes the (pre)leukemic cell from regular postthymic T cells. We assessed activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent noncanonical patterns. Virtually all T-PLL expressed a T-cell receptor (TCR) and/or CD28-coreceptor without overrepresentation of specific TCR clonotypes. The highly activated leukemic cells also revealed losses of negative-regulatory TCR coreceptors (eg, CTLA4). TCR stimulation of T-PLL cells evoked higher-than-normal cell-cycle transition and profiles of cytokine release that resembled those of normal memory T cells. More activated phenotypes and higher TCL1A correlated with inferior clinical outcomes. TCL1A was linked to the marked resistance of T-PLL to activation- and FAS-induced cell death. Enforced TCL1A enhanced phospho-activation of TCR kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses. This reduced the input thresholds for IL-2 secretion in a sensitizer-like fashion. Mice of TCL1A-initiated protracted T-PLL development resembled such features. When equipped with epitope-defined TCRs or chimeric antigen receptors, these Lckpr-hTCL1Atg T cells gained a leukemogenic growth advantage in scenarios of receptor stimulation. Overall, we propose a model of T-PLL pathogenesis in which TCL1A enhances TCR signals and drives the accumulation of death-resistant memory-type cells that use amplified low-level stimulatory input, and whose loss of negative coregulators additionally maintains their activated state. Treatment rationales are provided by combined interception in TCR and survival signaling.

TOX expression in cutaneous T-cell lymphomas: an adjunctive diagnostic marker that is not tumour specific and not restricted to the CD4(+) CD8(-) phenotype.

BACKGROUND: TOX (thymocyte selection-associated high-mobility group box) was shown to be aberrantly expressed in mycosis fungoides (MF) and Sézary syndrome (SS) and is suggested to have additional diagnostic value. However, data on expression in other types of cutaneous T-cell lymphoma (CTCL) are scarce and it is unknown whether TOX is expressed only by MF with a CD4(+)  CD8(-) phenotype. OBJECTIVES: To investigate TOX expression in various types of CTCL with different T-cell phenotypes. METHODS: Immunohistochemical expression of TOX was evaluated on 153 skin biopsies of 132 patients with CTCL and 60 patients with benign inflammatory dermatoses (BIDs). RESULTS: TOX was expressed by > 50% of the neoplastic T cells in 49 of 59 patients (83%) with MF and in 19 of 22 patients (86%) with SS. The TOX(+) cases of MF included 34 of 35 cases (97%) with a CD4(+)  CD8(-) phenotype, but also five of eight cases (63%) with a CD4(-)  CD8(+) phenotype and 10 of 16 cases (63%) with a CD4(-)  CD8(-) phenotype. TOX expression in other types of CTCL was common but showed variable intensity. Although only one of 60 patients (2%) with a BID expressed TOX in > 50% of the skin-infiltrating T cells, some caution is warranted, as the majority of BIDs had TOX(+) T cells varying between 11% and 50%. CONCLUSIONS: TOX expression is not tumour specific, is not restricted to CTCL with a CD4(+)  CD8(-) phenotype, and, on its own, is insufficient for diagnosis of CTCL. However, it may have an adjunctive diagnostic role in conjunction with other clinical and histological data.

Tumor-infiltrating lymphocytes and immune-related adverse events in advanced melanoma.

Background: The predictive value of tumor-infiltrating lymphocytes (TILs) in immune-related adverse event (irAE) development remains unknown, although an association between tumor immunogenicity and irAEs has been suggested. We investigated the association between TIL abundance in pretreatment primary and metastasis specimens and the subsequent development of severe irAEs. Patients and methods: We retrospectively identified patients with advanced cutaneous melanoma who received first-line anti-programmed cell death protein 1 (PD-1) with or without anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) from 10 hospitals in the Netherlands. TILs were scored on representative hematoxylin and eosin (H&E) stains of the primary melanoma and pretreatment melanoma metastasis as 'absent', 'nonbrisk', or 'brisk'. A univariable logistic regression analysis was carried out to assess the association between the TIL scores and the development of severe irAEs. Fine and Gray subdistribution hazard models were used to estimate the cumulative incidence of severe irAEs. Results: Of the 1346 eligible patients, 536 patients had primary melanoma specimens available, and 613 patients had metastasis specimens available. Severe irAEs occurred in 15% of anti-PD-1-treated patients and 49% of anti-PD-1 + anti-CTLA-4-treated patients. The presence of TILs was not associated with the occurrence of grade ≥3 irAEs in primary melanoma specimens (P = 0.70) nor pretreatment metastasis specimens (P = 0.91). In the univariable analysis, patients with brisk TILs did not have a higher chance of developing severe irAEs compared with patients with absent TILs, for both primary specimen (odds ratio 1.15, 95% confidence interval 0.60-2.18) and metastasis specimen (odds ratio 0.77, 95% confidence interval 0.37-1.59). There was also no significant difference in the lifetime risk or timing of the development of severe irAEs in patients with TILs present compared with patients with TILs absent. Conclusion: There was no association between the TIL scores on H&E-stained slides from the primary melanoma or pretreatment metastasis and the development of grade 3 or higher irAEs. Additionally, no correlation was found between the presence of TILs and the timing of irAEs.

Management of muscle-invasive bladder cancer.

The incidence of muscle-invasive bladder cancer (MIBC) is increasing. Many different and multimodal novel treatment options were brought on the way since the beginning of a new era in the early 1980s, when the neobladder as a common option for urinary diversion had been induced. In addition to open radical cystectomy and urinary diversion, recently, minimal invasive surgery has been implemented in experienced centers and led to promising results in short term follow-up, awaiting confirmation in larger cohorts. Pelvic lymphnode dissection can cure patients with low metastatic load. Expansion of pelvic lymphonodal dissection and its influence on survival was discussed intensively with trends to a moderate enlargement of the standard field. Outcome in nodal positive disease is remaining poor, while 90% of patients with multiple lymphnode metastases will suffer from systemic progress 5 years after diagnosis. In the last decade, treatment regimens based on neoajuvant or adjuvant chemotherapy were published with different results on efficiency. To decide whether to treat with surgery alone, or to offer perioperative systemic cytostatic therapy, is one of the unanswered questions. Furthermore, bladder preserving techniques are still optional for patients with small unifocal lesions or the medically unfit cohort. This review summarizes current data and aims to help guiding through several available recommendations on therapy and management of MIBC.

[New S3 guideline prostate cancer 2021 (version 6.2)-What has changed in advanced prostate cancer?] / Neue S3-Leitlinie Prostatakarzinom 2021 (Version 6.2) ­ Was hat sich beim fortgeschrittenen Prostatakarzinom geändert?

There have been numerous new findings from clinical trials in recent years regarding the treatment of metastatic hormone-sensitive or castration-resistant prostate cancer. The newly approved treatment options make therapy planning and therapy sequencing more challenging. In addition, local therapy of metastatic prostate cancer is becoming increasingly important. In the new German guidelines on prostate cancer (version 6.2, October 2021), new developments in the recommendations for the treatment of mHSPC and mCRPC were implemented, and their most important resulting recommendations for the clinical practice are presented in this review.

Effects of glyceryl glucoside on AQP3 expression, barrier function and hydration of human skin.

BACKGROUND/AIM: Aquaporins (AQPs) present in the epidermis are essential hydration-regulating elements controlling cellular water and glycerol transport. In this study, the potential of glyceryl glucoside [GG; alpha-D-glucopyranosyl-alpha-(1->2)-glycerol], an enhanced glycerol derivative, to increase the expression of AQP3 in vitro and ex vivo was evaluated. METHODS: In vitro studies with real-time RT-PCR and FACS measurements were performed to test the induction by GG (3% w/v) of AQP3 mRNA and protein in cultured human keratinocytes. GG-containing formulations were applied topically to volunteer subjects and suction blister biopsies were analyzed to assess whether GG (5%) could penetrate the epidermis of intact skin, and subsequently upregulate AQP3 mRNA expression and improve barrier function. RESULTS: AQP3 mRNA and protein levels were significantly increased in cultured human keratinocytes. In the studies on volunteer subjects, GG significantly increased AQP3 mRNA levels in the skin and reduced transepidermal water loss compared with vehicle-controlled areas. CONCLUSION: GG promotes AQP3 mRNA and protein upregulation and improves skin barrier function, and may thus offer an effective treatment option for dehydrated skin.

Mind your head: two cases of mucosal metastasis of BRAF-mutated melanoma of the scalp.

Mucosal melanomas are rare and only a small portion bear BRAF mutations while cutaneous melanomas have a much higher prevalence and often harbor BRAF mutations. We present two cases in which, after a malignant melanocytic mucosal lesion with a BRAF mutation was found, the primary cutaneous source was identified and clonality confirmed between the lesions. In both cases, primary lesions occurred on the scalp, an often-overlooked site. Both lesions showed signs of regression implying that in due time these lesions could have been fully regressed and might never have been detected. In that case, the metastatic mucosal lesion would erroneously be identified as a BRAF-mutated mucosal melanoma. These cases give warrant; a careful dermatological inspection should be instigated when confronted with a BRAF-mutated mucosal melanoma. We hypothesize that some BRAF-mutated mucosal melanomas might actually represent metastases of regressed cutaneous melanomas.

Antioxidant efficacy on human skin in vivo investigated by UVA-induced chemiluminescence decay analysis via induced chemiluminescence of human skin.

BACKGROUND/AIMS: Exogenous factors (e.g. physical: UV irradiation; or chemical: hydrogen peroxide) and endogenous metabolic processes (e.g. cellular respiration, oxidative burst, etc.) generate oxidative stress in living tissues which are in balance with enzymatic antioxidative systems and ingested antioxidants under normal conditions. These complex biological reactions are accompanied by chemiluminescence (ultraweak photon emission). However, knowledge about the chemiluminescence decay characteristics of human skin and the modulatory influence of topically applied antioxidants is still scarce. METHODS: Using ICL-S (induced chemiluminescence of human skin), a highly sensitive in vivo method, the decay characteristics of UVA-induced photon emission caused by different UVA doses were investigated in detail. In addition, modulatory properties of topical antioxidant pretreatment were examined for 2 weeks. RESULTS: UVA-induced chemiluminescence signals were generally characterized by two distinct decay phases: an initial burst (0-5 s), contributing approximately 80% of the complete signal with an inverse dose-response relationship (UVA dose vs. chemiluminescence intensity), followed by a second decay phase (delayed chemiluminescence, 5-200 s) showing a direct correlation. Antioxidant pretreatment caused a reduction in signal intensity of approximately 50%, which was calculated by signal integration and confirmed using the modulation of the intersection point of decay curves resulting from irradiation with different UVA doses at constant intensity with and without treatment. CONCLUSION: In addition to the established UVA filter testing (independent from UVB filter content) on human skin in vivo, ICL-S is also a valuable tool for the efficacy testing of topically applied antioxidants under in vivo conditions in humans. The first rapid, but short, decay phase not only provides approximately 80% of the complete chemiluminescence signal, but is also essential for the investigation of antioxidant-mediated effects. Chemiluminescence signal modulations induced by UVA intensity reduction (e.g. UV filters in daily care products) can be clearly distinguished from antioxidant-mediated signal modulations. The probe head dimensions permit comprehensive in vivo testing in humans on practically every skin area (e.g. arms, legs, back, abdomen and face).

[Immunostimulatory CpG oligodeoxynucleotides (CpG-ODN) in an orthotopic murine transitional cell carcinoma (TCC) model. Effect on local cytokine expression]. / Immunstimulative CpG-Oligodeoxynukleotide (CpG-ODN) im orthotopen murinen Transitionalzellkarzinom (TCC)-Modell. Effekt auf die lokale Zytokinexpression.

CpG-oligodeoxynucleotides (CpG-ODN) are potent stimulators of the innate immune system. They promote a Th1-biased immune response with antineoplastic potential. We recently demonstrated antitumoral effects of CpG-ODN in murine transitional cell carcinoma (TCC) models. The purpose of the present work was to more precisely define the immunological nature of this immunotherapeutic approach to TCC.MB-49 TCC was established in female C57/Bl6 mice by intravesical tumor cell instillation after poly-L-lysine conditioning of the bladder (day 0) as described previously. Three groups of six mice were treated: intravesical instillation of 50 microl PBS on days 1, 3, 5, and 7 (group 1, untreated control); 10 nmol CpG 1668 on days 1, 3, 5, and 7 (group 2); and 10 nmol GpC 1668 on days 1, 3, 5, and 7 (group 3). Six native bladders served as no-treatment/no-tumor controls (group 4). Mice were sacrificed on day 11; bladders and draining lymph nodes were removed, and mRNA was prepared for quantitative real-time polymerase chain reaction. Samples were analyzed on a Bio-Rad iCycler for IL 10, TGF-beta, IL 12, and IFNgamma expression; threshold values were compared to beta-actin as housekeeping gene.Tumor take was 100%. Three animals in group 1 had to be sacrificed in advance due to rapid tumor progression. Relative cytokine expression was comparable in groups 1 and 4. IL-10, IL-12, TGF-beta, and IFNgamma were overexpressed in groups 2 and 3. CpG-ODN treatment of murine TCC results in overexpression of both classic Th1 cytokines (IL 12 and IFNgamma) and the Th2 marker IL 10. TGF-beta expression is increased as well. These phenomena are not induced by the growing TCC but by CpG-ODN therapy. They are accompanied by an objective clinical response, as we were able to show recently. Immunostimulatory DNA holds promise to be a novel therapeutic agent in TCC.

[Gender-specific characteristics and survival of renal cell carcinoma]. / Geschlechtsspezifische Charakteristika und Prognose des Nierenzellkarzinoms.

BACKGROUND: Renal cell carcinoma (RCC) occurs twice as often in men as in women; however, the influence of gender on stage, grade, subtype and prognosis has not been studied in detail. METHODS: This study included 780 patients treated by (partial) nephrectomy at our institution in Marburg between 1990 and 2005. The mean follow-up was 5.44 years. RESULTS: Of the 780 patients, 486 (62%) were men and 294 (38%) were women. Women were significantly older (mean, 65.3 vs. 62.2 years; p<0.001, t-test), presented at lower T stages (p=0.046, chi(2)) and suffered metastasis less frequently at diagnosis (p=0.026, chi(2)). In addition, women more frequently had clear cell tumours (85.2% vs. 78.3%) and less frequently papillary tumours (11.0% vs. 18.8%) than men (p=0.026, chi(2)). In contrast, men had an increased risk of death from RCC (HR 1.23, CI 0.92-1.63); Kaplan-Meier curves revealed a significant difference in tumour-specific survival between men and women (p=0.033, log rank; 5-year survival 74% vs. 83%). However, unlike tumour stage and tumour grade, gender could not be retained as a significant independent prognostic marker in multivariate analysis. CONCLUSION: In general, RCC in men is characterized by higher tumour stages and more frequent metastasis at diagnosis along with inferior tumour-specific survival. However, as gender failed to qualify as an independent prognostic marker for tumour-specific survival, delayed diagnosis due to insufficient routine medical check-up and/or a more aggressive tumour biology might be be a concurrent cause. Thorough regular medical check-ups for men, also with regard to RCC, are thus mandatory.

[Transitional cell carcinoma of the bladder. Evaluation of plasma levels of cellular fibronectin as a stage-dependent marker]. / Das Transitionalzellkarzinom der Harnblase. Evaluation von zellulärem Fibronektin im Plasma als stadienabhängiger Marker.

Up to now markers for transitional cell carcinoma of the bladder (TCC) are missing. Fibronectin (FN) seems to play a key role in progression and invasion of malignant tumors. The aim of this study was to assess the value of cellular FN (cFN), a more specific subform of produced FN, in different stages of TCC.cFN was determined using a highly sensitive immunoassay which we developed. Blood samples were taken of 45 patients with the first diagnosis of TCC before undergoing TUR-B and 6 patients with metastatic TCC before chemotherapy; 70 patients with nonmalignant urological disorders served as a control group.Patients with TCC showed significantly elevated cFN plasma levels compared to controls (p<0.05). Patients with muscle-invasive disease (n=15) showed significantly higher cFN plasma levels compared to the group with superficial TCC. Patients with metastatic TCC showed the highest, but not significantly elevated cFN plasma levels compared to patients with muscle-invasive TCC.The elevated cFN plasma levels in TCC underline the important role of cFN for tumor progression and its potential role as a marker for TCC. Upcoming investigations are necessary to prove the value of the potential marker cFN during follow-up and its impact as a prognostic factor for recurrence and progression of TCC.

[Selective cervical lymph node dissection for primary, node-negative, oral squamous cell carcinoma: oncologic assessment and clinical relevance of prognostic factors for secondary local metastasis]. / Selektive Halslymphknotenausräumung beim primär klinisch und histopathologisch metastasenfreien Plattenepithelkarzinom der Mundhöhle: Onkologische Wertigkeit und Analyse prognostischer Faktoren und ihrer klinischen Relevanz.

BACKGROUND: The aim of this retrospective study was to evaluate prognostic factors for the development of secondary local lymph node metastases in patients with oral squamous cell carcinoma who had undergone selective neck dissection for primary node-negative disease. PATIENTS AND METHODS: The study included 331 patients with primary squamous cell carcinoma of the oral cavity who underwent 431 selective neck dissections between January 1986 and December 2002 in Germany at the Hannover Medical School's Department of Oral and Maxillofacial Surgery. Several potential prognostic factors were evaluated for their influence on the development of secondary metastases following primary neck dissection. RESULTS: No statistically significant relationship to the appearance of secondary local metastasis following selective neck dissection was detected concerning: patient age or sex, histopathologic tumor stage, primary tumor grade, or adjuvant therapies such as pre- or postoperative radiotherapy and radiochemotherapy. The only study factor with a statistically significant influence was the extent of lymphadenectomy, in which particularly the region of the carotid bifurcation played a decisive role. CONCLUSION: Significantly fewer secondary metastases occurred following neck dissections that included the carotid trigone. In light of these results, we recommend that neck dissection for primary oral squamous cell cancer always include the region of the carotid bifurcation, regardless of the above mentioned associated patient and tumor factors.

Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.

Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL.

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.

Different frequencies of angiotensin-converting enzyme genotypes in older hypertensive individuals.

The frequency of the D allele of an insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene has been reported to be elevated in myocardial infarction and other patients. We therefore hypothesized that death rate of DD individuals should be increased in the population as a whole and this should be evident as a decrease in DD frequency with age. This hypothesis was tested in 118 Caucasian subjects who were already at high risk of cardiovascular events by having severe, early onset, familial hypertension (HT). A group of 196 age-, sex- and body mass index-matched normotensives (NTs) was used as a control. In the NT group II, ID, and DD genotype frequencies were similar for different age groups. DD frequency was 0.42 in NTs, but in HTs was 0.28, 0.26, and 0.10 for the age groups < 50, 50-59, and > or = 60 yr, respectively. Corresponding D allele frequencies were 0.52, 0.46, and 0.40 in the respective age groups of HTs, compared with 0.61 in NTs (by chi 2-analysis, P = 0.1, 0.047, and 0.0006, respectively). In HTs aged > or = 60, DD frequency was only 14% of expected. Plasma ACE activity tracked similarly with I/D genotype in HTs (P = 0.027; n = 35) as in NTs (P = 0.0001; n = 94) and Michaelis constant was identical for DD and II. Neither blood pressure, body mass index, nor sex bore any relationship with I/D genotype. In conclusion, in a group of severely HT patients not selected for cardiac pathology, there appeared to be a marked, selective decrease, in subgroups of increasing age, in frequency of the ACE DD genotype. One possibility suggested by this data might be that DD increases risk of premature death, at least in HTs who have two HT parents.

[177Lu-PSMA therapy : Current evidence for use in the treatment of patients with metastatic prostate cancer]. / 177Lu-PSMA-Therapie : Aktuelle Evidenzlage beim Einsatz in der Behandlung von Patienten mit metastasiertem Prostatakarzinom.

BACKGROUND: Despite significant progress in the treatment of metastatic castration-resistant prostate cancer (mCRPC) in recent years (including agents targeting androgen receptor signaling, chemotherapy, and 223Ra), most of these patients still succumb to prostate cancer. Recently, 177lutetium prostate-specific membrane antigen radioligand therapy (177Lu-PSMA-RLT) has been increasingly used within compassionate use provisions in these patients in Germany and showed promising efficacy. OBJECTIVES: Establishment of the current position of 177Lu-PSMA-RLT in mCRPC in 2017. MATERIALS AND METHODS: Presentation of the therapy landscape in mCRPC and the current challenges within treatment and survey of the available data on 177Lu-PSMA-RLT after PubMed-based research. RESULTS: In several larger retrospective studies, 177Lu-PSMA-RLT seems to be an encouraging new option with the potential to extend overall survival while displaying a favorable toxicity profile. CONCLUSIONS: Prospective trials are urgently needed to confirm these encouraging results found in retrospective analyses with 177Lu-PSMA-RLT in the treatment of mCRPC.

[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.

[Use of the S3 guidelines for early detection of prostate cancer in urological practices]. / Anwendung der S3-Leitlinie zur Prostatakrebsfrüherkennung in urologischen Praxen.

OBJECTIVES: The German S3 guideline on prostate cancer gives recommendations on early detection of prostate cancer. In this study we analyzed the adherence of urologists in private practice from the administrative district of Münster, Germany to this guideline. METHODS: Data were collected through a semistructured survey of 22 urologists based on the COREQ checklist (Consolidated criteria for reporting qualitative research) in four focus groups consisting of five or six urologists in private practice. We developed 23 questions relating to 12 recommendations of the paragraphs of the S3 guidelines dealing with early detection of prostate cancer and prostate biopsy. The recommendations of the guideline are subdivided in nine "strong", one "optional recommendation" and two "statements". The adherence to the guideline was investigated by using frequency and qualitative content analysis (Mayring) based on a mixed methods design. RESULTS: The urologists follow six of the nine "strong recommendations" of the guideline and deviate from three. Reasons for deviations from "strong recommendations" are the following: information about advantages and disadvantages of early detection for prostate cancer, recommendation of a prostate biopsy in case of PSA level ≥4 ng/ml, and indication for repeat biopsy. CONCLUSION: Most of the "strong recommendations" are followed by the interviewed urologists of the administrative district of Münster. Contextually relevant deviations from "strong recommendations" are justified, e. g., the only limited transferability of the PSA threshold of 4 ng/ml derived from population-based studies of asymptomatic men to men presenting in a urologist's office.

Second-line strategies for metastatic renal cell carcinoma: classics and novel approaches.

OBJECTIVES: Renal cell carcinoma is an aggressive malignancy with a high propensity for both early and metachronous regional and distant metastasis. While surgical resection is the mainstay of therapy for patients with localized disease, the prognosis for patients with distant metastasis is poor with a 5-year survival rate of less than 10%. Response rates to first-line immunotherapy or immunochemotherapy range from 10-35%; responses achieved are predominantly partial remissions of short duration. Until today, there is no standard therapeutic procedure for the growing number of patients who relapse following first-line therapy and desire further active treatment. MATERIALS AND METHODS: This article reviews classic and recent publications about second- and third-line approaches, their potential efficacy and toxicity. RESULTS: Several novel approaches have raised well-founded hope. Especially the application of monoclonal antibodies targeting VEGF signalling as well as different receptor tyrosine kinase inhibitors have the potential to change the face of second-line treatment of patients with metastatic RCC. Both groups of agents are focused in current phase III trials, either as mono- and/or combination therapy. CONCLUSIONS: Until today, second-line treatment of patients with metastatic RCC progressing under therapy with biological response modifiers remains an unresolved issue. The results of ongoing clinical trials evaluating novel targeted approaches can be expected with suspense.

Percutaneous radiofrequency ablation of pulmonary tumors--is there a difference between treatment under general anaesthesia and under conscious sedation?

OBJECTIVE: This retrospective study aimed to compare feasibility, complication rate and local tumor control after radiofrequency ablation (RFA) of pulmonary tumors under conscious analgo-sedation (AS) versus general anaesthesia (GA). MATERIALS AND METHODS: Within 36 months 21 patients had RFA (36 tumors, 26 treatment sessions). One patient suffered from NSCLC, 20 had metastases (breast (8/20), colorectal (6/20), renal cell (2/20), pharyngeal carcinoma (1/20), malignant melanoma (3/20)). Patients were no surgical candidates due to underlying comorbidities. Eleven of 26 treatments were performed under GA, while in 15 of 26 treatments AS was used. Follow-up was scheduled 24 h, 6 weeks, 3 months, 6 months and then every 6 months after treatment. RESULTS: RFA was feasible in all treatments under GA, while under AS targeting of the lesion was not possible in 2/15. Six adverse events occurred in the GA group (three major, three minor), while seven complications happened in the AS group (three major, four minor) (p=0.57). During follow-up of 3-36 months local recurrence was detected in 3 of 21 tumors in the GA group and in 2 of 15 tumors in the AS group (p=0.79). DISCUSSION: Hospitalization, complication rates and types, and the rate of local tumor control did not differ substantially among both groups. Furthermore, there was no significant difference in technical success and feasibility. CONCLUSION: RFA of pulmonary tumors under GA or AS did not result in different tumor control and complication rates, respectively. Therefore, AS should be used except in anxious or agitated patients.