Genetic immunization with mouse thyrotrophin hormone receptor plasmid breaks self-tolerance for a murine model of autoimmune thyroid disease and Graves' orbitopathy.

Experimental models of Graves' hyperthyroid disease accompanied by Graves' orbitopathy (GO) can be induced efficiently in susceptible inbred strains of mice by immunization by electroporation of heterologous human TSH receptor (TSHR) A-subunit plasmid. In this study, we report on the development of a bona fide murine model of autoimmune Graves' disease induced with homologous mouse TSHR A-subunit plasmid. Autoimmune thyroid disease in the self-antigen model was accompanied by GO and characterized by histopathology of hyperplastic glands with large thyroid follicular cells. Examination of orbital tissues showed significant inflammation in extra-ocular muscle with accumulation of T cells and macrophages together with substantial deposition of adipose tissue. Notably, increased levels of brown adipose tissue were present in the orbital tissue of animals undergoing experimental GO. Further analysis of inflammatory loci by 19 F-magnetic resonance imaging showed inflammation to be confined to orbital muscle and optic nerve, but orbital fat showed no difference in inflammatory signs in comparison to control ß-Gal-immunized animals. Pathogenic antibodies induced to mouse TSHR were specific for the self-antigen, with minimal cross-reactivity to human TSHR. Moreover, compared to other self-antigen models of murine Graves' disease induced in TSHR knock-out mice, the repertoire of autoantibodies to mouse TSHR generated following the breakdown of thymic self-tolerance is different to those that arise when tolerance is not breached immunologically, as in the knock-out models. Overall, we show that mouse TSHR A-subunit plasmid immunization by electroporation overcomes tolerance to self-antigen to provide a faithful model of Graves' disease and GO.

TRPC1 regulates fMLP-stimulated migration and chemotaxis of neutrophil granulocytes.

Neutrophils form the first line of defense of the innate immune system and are rapidly recruited by chemotactic signals to sites of inflammation. Understanding the mechanisms of neutrophil chemotaxis is therefore of great interest for the potential development of new immunoregulatory therapies. It has been shown that members of the transient receptor potential (TRP) family of cation channels are involved in both cell migration and chemotaxis. In this study, we demonstrate that TRPC1 channels play an important role in fMLP mediated chemotaxis and migration of murine neutrophils. The knock-out of TRPC1 channels leads to an impaired migration, transmigration and chemotaxis of the neutrophils. In contrast, Ca²âº influx but not store release after activation of the TRPC1(-/-) neutrophils with fMLP is strongly enhanced. We show that the enhanced Ca²âº influx in the TRPC1(-/-) neutrophils is associated with a steepened front to rear gradient of the intracellular Ca²âº concentration with higher levels at the cell rear. Taken together, this paper highlights a distinct role of TRPC1 in neutrophil migration and chemotaxis. We propose that TRPC1 controls the activity of further Ca²âº influx channels and thus regulates the maintenance of intracellular Ca²âº gradients which are critical for cell migration. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.

Identification of novel NOTCH1 mutations: increasing our knowledge of the NOTCH signaling pathway.

BACKGROUND: Alterations in the NOTCH1 signaling pathway are found in about 60% of pediatric T-ALL, but its impact on prognosis remains unclear. PROCEDURE: We extended the previously published CoALL cohort (n = 74) to a larger cohort (n = 127) and additionally included 38 Argentine patients from ALL IC-BFM to potentially identify novel mutations and decipher a stronger discriminatory effect on the genotype/phenotype relationship with regard to early treatment response and long-term outcome. RESULTS: Overall, 101 out of 165 (61.2%) T-ALL samples revealed at least one NOTCH1 mutation, 28 of whom had combined NOTCH1 and FBXW7 mutations. Eight T-ALL samples (4.8%) exclusively revealed FBXW7 mutations. Fifty-six T-ALL (33.9%) exhibited a wild-type configuration of either gene. Four novel NOTCH1 mutations were identified localized in the C-terminal PEST domain, in the rarely affected LNR repeat domain and in the ankyrin domain. Novel LNR mutations may contribute to a better understanding of the structure of the NOTCH1 negative regulatory region (NRR) and the R1946 mutation in the ankyrin domain may represent an unusual loss-of-function mutation. CONCLUSIONS: Overall, NOTCH1 pathway mutations did not affect the relapse rate and outcome of the extended T-ALL cohort uniformly treated according to CoALL protocols, although NOTCH1 mutations were associated with good response to induction therapy (P = 0.009). Individually, HD and PEST domain mutations might exert distinct functional effects on cellular homeostasis under treatment NOTCH1 pathway activity with prognostic implications.

[Prostate cancer]. / Prostatakarzinom.

For many clinical issues regarding prostate cancer magnetic resonance imaging (MRI) is gaining increasing importance for prostate diagnostics. The high morphological resolution of T2-weighted sequences is unsurpassed compared to other imaging modalities. It enables not only the detection and localization of prostate cancer but also allows the evaluation of extracapsular extensions. Functional MRI methods, such as diffusion-weighted imaging (DWI), dynamic contrast-enhanced (DCE) MRI and proton magnetic resonance spectroscopy ((1)H-MRS) increase the specificity and to a lesser extent, the sensitivity of diagnostics. In accordance with the interdisciplinary S3 guidelines, prostate MRI is recommended for patients with at least one negative biopsy for cancer detection. According to the guidelines areas suspected of being cancerous should be selectively biopsied in addition to the systematic biopsy. The transmission of findings about the suspected tumor areas according to the structured PI-RADS classification system has proven its worth. The localization and staging of prostate carcinoma is best achieved with the help of MRI and is recommended in the S3 guidelines especially for tumors with a clinical stage cT3/4 or with a Gleason grading system score ≥8. In addition to these applications MRI is mainly used under study conditions for local recurrence or active surveillance.

Influence of age on false positive rates of urine-based tumor markers.

INTRODUCTION: Several influencing factors on false positive rates (FPRs) of urine-based tumor markers in the detection of urothelial cancer (UC) have been identified. We evaluated age as a possible influencing factor. METHODS: Urinary cytology (Cyt), UroVysion (FISH), ImmunoCyt (uCyt+) and NMP22 were determined in 1,554 patients suspicious for UC of the bladder before cystoscopy and in case of cancer detection before TURB. Additionally, upper urinary tract imaging was performed. Maker sensitivity, specificity and FPRs were evaluated in the entire cohort and in subgroups divided by age into <50, ≥ 50-70 and ≥ 70 years. Contingency tables and the Cochrane Armitage tests were used for statistical comparisons. RESULTS: UC was found in 377 and no UC in 1,177 (75 %) patients. A total of 336 patients were diagnosed with UC of the bladder and 41 with UC of the upper urinary tract. Overall sensitivity and specificity for Cyt were 82 and 82 %: for FISH, 73 and 79 % and for uCyt+, 79 and 75 %, respectively. For NMP22, regardless of the exclusion criteria they were 72 and 34 % and after exclusion of urinary tract infection (UTI) or prior to manipulation 46 and 86 %, respectively. Significantly higher FPRs were found with increasing age for Cyt (p = 0.001), a trend to higher FPRs for uCyt+ (p = 0.11) and almost no difference for FISH (p = 0.63). For NMP22, differences became significant after exclusion of patients with UTI or prior manipulation (p = 0.02). CONCLUSIONS: The results of the present study give evidence that false positive rates of Cyt and NMP22 increase with age indicating that age should be respected for their correct interpretation.

Item analysis of G8 screening in uro-oncologic geriatric patients.

INTRODUCTION/BACKGROUND: The G8 score is a widespread screening tool for geriatric frailty in oncology. The aim of this study was to evaluate the scores and relevance of G8 items in a standard screening of geriatric patients with uro-oncologic diseases to better understand the results of the assessment. METHODS: Eighty-two consecutive uro-oncologic geriatric patients aged 75 years and older were evaluated. All patients underwent a G8 screening that consisted of 8 items. Patients with a G8 score above 14 were considered geriatric "fit", while others were considered to be "frail". Overall results and single item scores were evaluated. Clinical data were gathered from patients' charts. RESULTS: The mean age of the patients was 82 years (min. 75-max. 102). In 36 of the patients, the G8 score indicated "no-frailty", and in 46 patients, the G8 score indicated "frailty". The mean G8 score was 12.9 (min 4-max 17 pts). Item analysis revealed that points were most often lost in items H (polypharmacy), P (comparison of health status to peers) and Age. Fifty-nine, 56 and 52 patients lost points on item Age, item H and item P, respectively. In contrast, the majority of patients reached the maximum score for nutritional items [i.e., items A (food intake), B (weight loss) and F (body mass index (BMI))]. For item A, 73 patients reached the maximum score; for item B, 62 patients reached the maximum score; and for item F, 72 patients reached the maximum score. There were no differences in this distribution pattern when comparing tumour entities, sex, and patients with local vs. metastatic disease. CONCLUSION: The present study revealed a high percentage of suspicious test results. Potential reasons for these findings include the low threshold of the G8 overall score and the fact that in some items, points were easily lost. Modifications of the test should be considered.

Establishment of a protocol for large-scale gene expression analyses of laser capture microdissected bladder tissue.

PURPOSE: Lower urinary tract symptoms (LUTS) can be caused by structural and functional changes in different compartments of the bladder. To enable extensive investigations of individual regions even in small bladder biopsies, we established a combination protocol consisting of three molecular techniques: laser capture microdissection microscopy (LCM), RNA preamplification and quantitative polymerase chain reaction (qPCR). METHODS: Urinary bladders of ten mice were resected and frozen immediately or after a delay of 15 min. Cryosections were obtained and smooth muscle was isolated using the LCM technique. Then, RNA was extracted, including protocols with and without DNase digestion as well as with and without the addition of carrier RNA. Extracted RNA was either used for reverse transcriptase (RT)-PCR plus qPCR or for a combination of RNA preamplification and qPCR. RESULTS: Our data showed that with RNA preamplification, 10 µg cDNA can be regularly generated from 2.5 ng RNA. Depending on expression levels, this is sufficient for hundreds of pPCR reactions. The efficiency of preamplification, however, was gene-dependent. DNase digestion before preamplification lead to lower threshold cycles in qPCR. The use of partly degraded RNA for RNA preamplification did not change the results of the following qPCR. CONCLUSIONS: RNA preamplification strongly enlarges the spectrum of genes to be analyzed in distinct bladder compartments by qPCR. It is an easy and reliable method that can be realized with standard laboratory equipment. Our protocol may lead in near future to a better understanding of the pathomechanisms in LUTS.

Laparoscopic radical cystectomy: initial experience using the single-incision triangulated umbilical surgery (SITUS) technique.

INTRODUCTION: As could be demonstrated for simple and radical nephrectomy, single-incision triangulated umbilical surgery (SITUS) is an interesting alternative to laparoscopic single-site surgery. We present our initial experience with the SITUS technique in radical cystectomy. MATERIALS AND METHODS: Between September 2010 and September 2011, eight patients underwent SITUS radical cystectomy (SITUS Cx), pelvic lymph node dissection and extracorporeal urinary diversion. A cutaneous ureterostomy was performed in three, an ileum conduit in one and an ileal neobladder in four patients. Data were collected prospectively, including patients' characteristics, intraoperative parameters, pathological stage and postoperative outcome. RESULTS: Mean age of the patients was 67 years and the mean body mass index 24 kg/m(2). SITUS Cx was successfully completed in all patients without conversion to conventional laparoscopic or open surgery. Mean surgical time was 434 min and mean estimated blood loss 643 ml. No major intra- or postoperative surgical complications occurred. All patients recovered quickly reporting low postoperative pain levels. Mean hospital stay was 16 (7-24 days). Histopathological evaluation revealed a mean of 16 (6-33) retrieved lymph nodes and no positive margins. CONCLUSION: In the present experience, SITUS Cx proved to be feasible with surgical outcome comparable to conventional techniques. Because SITUS Cx combines the advantages of traditional laparoscopy (straight instruments and triangulation) with those of single-port surgery (superior cosmesis and minimal invasiveness), it presents an attractive alternative to other minimally invasive techniques.

Kidney-specific cadherin correlates with the ontogenetic origin of renal cell carcinoma subtypes: an indicator of a malignant potential?

INTRODUCTION AND OBJECTIVES: To evaluate retrospectively kidney-specific cadherin (Ksp-cad) expression in renal cell carcinoma (RCC) subtypes and oncocytoma in correlation with its ontogenetic origin of distal and proximal tubules and to correlate Ksp-cad expression with tumour characteristics. MATERIALS AND METHODS: Membranous and cytoplasmic expression of Ksp-cad was determined in 40 clear cell (ccRCC), 25 papillary (pRCC), 19 chromophobe carcinomas (chRCC), 27 oncocytomas (oncocytomas) (n = 111) and 32 benign kidney parenchyma specimens separated in distal tubules (DT) and proximal tubules (PT) by immunohistochemistry using tissue microarray technique. Staining intensity was quantified as a score ranging from 0 to 12. Comparison of data and correlation with tumour characteristics were done by Wilcoxon/Kruskal-Wallis tests (post hoc Tukey-Kramer analysis). RESULTS: In benign renal tissue, membranous and cytoplasmic expression of Ksp-cad in the DT was significantly higher than that in the PT (12.0 ± 0 vs. 5.2 ± 0.3 and 6.3 ± 0.5 vs. 0.0 ± 0.0, respectively; (P < 0.05)). Membranous KSP-cad expression was significantly higher in chRCC (5.2 ± 0.8) and oncocytomas (3.7 ± 0.4) than that in ccRCC (0.8 ± 0.2) and pRCC (1.4 ± 0.4; P < 0.05), while expression between oncocytomas and chRCC did not differ significantly. In RCC, Ksp-cad expression was significantly associated with higher T stage and the occurrence of synchronous metastasis (P < 0.05). Higher N stages and grading tended to correlate with a lower Ksp-cad expression. CONCLUSIONS: In this cohort, the origin of tumour subtypes-chRCC and oncocytomas develop from DT and ccRCC and pRCC from PT cells-is mirrored by the respective Ksp-cad expression. This raises the question whether DT-derived tumours have a less malignant potential than PT-derived tumours.

Complications of a buried penis in an extremely obese patient.

The buried penis syndrome in adults is a rare condition of different aetiologies. Today extreme obesity is considered as a major contributor. We present a case of a 30-year-old extremely obese patient (BMI 65 kg/m(2)) with purulent infection of the penile cavity, a phlegmon of the mons pubis and urinary retention due to a buried penis. Whereas acute complications of a buried penis in obese patients include local infection and urinary retention, chronic problems are undirected voiding, disturbed vaginal penetration and erectile dysfunction. Even though several surgical techniques are described, weight reduction should be primarily preferred.

Age-resolving osteopetrosis: a rat model implicating microphthalmia and the related transcription factor TFE3.

Microphthalmia (Mi) is a basic helix-loop-helix-leucine zipper (b-HLH-ZIP) transcription factor implicated in pigmentation, mast cells, and bone development. Two dominant-negative mi alleles (mi/mi and Mior/Mior) in mice cause osteopetrosis. In contrast, osteopetrosis has not been observed in a number of recessive mi alleles, suggesting the existence of Mi protein partners important in osteoclast function. An osteopetrotic rat of unknown genetic defect (mib) has been described whose skeletal sclerosis improves dramatically with age and that is associated with pigmentation defects reminiscent of mouse mi alleles. Here we report that this rat strain harbors a large genomic deletion encompassing the 3' half of mi including most of the b-HLH-ZIP region. Osteoclasts from these animals lack Mi protein in contrast to wild-type rat, mouse, and human osteoclasts. Mi is not detectable in primary osteoblasts. In addition TFE3, a b-HLH-ZIP transcription factor related to Mi, was found to be expressed in osteoclasts, but not osteoblasts, and to coimmunoprecipitate with Mi. These results demonstrate the existence of members of a family of biochemically related transcription factors that may cooperate to play a central role in osteoclast function and possibly in age-related osteoclast homeostasis.

[Peyronie's disease-often a disabling disease for sexually active men]. / Maladie de la peyronie: une maladie invalidante pour tes hommes sexuettement actifs.

Peyronie's disease is an acquired penile condition characterized by fibrous plaques between the tunica albuginea and the subtunical tissue of the corpora cavernosa. Plaques are considered responsible for the main symptoms: penile pain and deviation. Even though several risk factors and associations with other diseases are known its exact aetiology remains unclear. Most commonly discussed hypotheses are micro traumata, inflammatory and/or ischemic processes. Currently different treatment forms exist raging form systemic or local medical treatment, to physical applications and surgery. All treatment forms are symptom based and evidence based treatment remains difficult to establish. Because conservative treatment is of limited success in many patients especially with severe deviations surgery becomes necessary.

Economic aspects of bladder cancer: what are the benefits and costs?

OBJECTIVE: Bladder cancer (BC) has the highest lifetime treatment costs per patient of all cancers. The high recurrence rate and ongoing invasive monitoring requirement are the key contributors to the economic and human toll of this disease. The purpose of this paper was to utilize the recent literature to identify opportunities for improving the benefits and costs of BC care. METHODS: A PubMed search was performed of recent publications concerning (BC) cost-effectiveness. We reviewed studies, reviews, opinion papers and cost-effectiveness analyses, focusing primarily on non-muscle-invasive bladder cancer (Ta/T1; NMIBC). RESULTS: New diagnostic tools such as urine markers may assist in more cost-effectively detecting BC at an earlier stage, however, these markers cannot replace the cystoscopy, which is the current standard of care. A photodynamic diagnostic tool (PDD) using hexylaminolevulinate (Hexvix) enhances tumor visibility and improves transurethral resection of bladder cancer (TURB) results, potentially reducing recurrence rates and lowering treatment costs. While the importance of BC research has been acknowledged, research investment has been continuously reduced during the last 5 years. CONCLUSIONS: The economic burden of BC is well-characterized in the literature. This study suggests that new technologies (i.e., urine-based tests, PDD) and therapeutic regimes (intravesical chemotherapy, adjuvant immunotherapy) have significant potential to improve the diagnosis, treatment and on-going monitoring of BC patients, with potential improvements in clinical outcomes and concurrent cost-savings. A renewed interest and investment in BC research are required to ensure future advancements.

Blended E-learning in a Web-based virtual hospital: a useful tool for undergraduate education in urology.

INTRODUCTION: E-learning is a teaching tool used successfully in many medical subspecialties. Experience with its use in urology, however, is scarce. We present our teaching experience with the INMEDEA simulator to teach urological care to medical students. METHODS: The INMEDEA simulator is an interactive e-learning system built around a virtual hospital which includes a department of urology. It allows students to solve virtual patient cases online. In this study, students were asked to prepare two urological cases prior to discussion of the cases in small groups. This blended teaching approach was evaluated by students through anonymous questionnaires. RESULTS: Of 70 4th year medical students 76% judged this teaching method as good or very good. Eighty-seven percent felt that it offered a good way to understand urological diseases better and 72% felt that learning with this method was fun. Nevertheless, 30 out of 70 free text statements revealed that further improvements of the program, including an easier and more comfortable navigation and a faster supply of information are necessary. CONCLUSIONS: Virtual patient cases offer a practicable solution for teaching based on problem solving in urology with a high acceptance rate by students.

Comparative Prey Spectra Analyses on the Endangered Aquatic Carnivorous Waterwheel Plant (Aldrovanda vesiculosa, Droseraceae) at Several Naturalized Microsites in the Czech Republic and Germany.

The critically endangered carnivorous waterwheel plant (Aldrovanda vesiculosa, Droseraceae) possesses underwater snap traps for capturing small aquatic animals, but knowledge on the exact prey species is limited. Such information would be essential for continuing ecological research, drawing conclusions regarding trapping efficiency and trap evolution, and eventually, for conservation. Therefore, we performed comparative trap size measurements and snapshot prey analyses at seven Czech and one German naturalized microsites on plants originating from at least two different populations. One Czech site was sampled twice during 2017. We recorded seven main prey taxonomic groups, that is, Cladocera, Copepoda, Ostracoda, Ephemeroptera, Nematocera, Hydrachnidia, and Pulmonata. In total, we recorded 43 different prey taxa in 445 prey-filled traps, containing in sum 461 prey items. With one exception, prey spectra did not correlate with site conditions (e.g. water depth) or trap size. Our data indicate that A. vesiculosa shows no prey specificity but catches opportunistically, independent of prey species, prey mobility mode (swimming or substrate-bound), and speed of movement. Even in cases where the prey size exceeded trap size, successful capture was accomplished by clamping the animal between the traps' lobes. As we found a wide prey range that was attracted, it appears unlikely that the capture is enhanced by specialized chemical- or mimicry-based attraction mechanisms. However, for animals seeking shelter, a place to rest, or a substrate to graze on, A. vesiculosa may indirectly attract prey organisms in the vicinity, whereas other prey capture events (like that of comparably large notonectids) may also be purely coincidental.

[Diagnostic procedures in upper urinary tract urothelial carcinoma]. / Diagnostik von Urothelkarzinomen des oberen Harntrakts.

Upper urinary tract transitional cell carcinomas represent 5-6% of all urothelial carcinomas. Macroscopic hematuria is the most common symptom. The diagnostic algorithm contains medical history, clinical investigation, cystoscopy, urinary cytology, ultrasound and intravenous urography. When suspected, a complementary retrograde pyeloureterography with collecting selective urinary cytology is conducted. When radiological findings are doubted or when conservative treatment is planned, an ureterorenoscopy for biopsy of the suspected area is indicated. Computed tomography and magnetic resonance tomography is used to define the local extension of invasive tumors and to detect metastases. The use of urinary markers in the diagnosis of upper urinary tract urothelial carcinoma has to be evaluated in prospective trials.

[Supplementary optical techniques for the detection of nonmuscle invasive bladder cancer]. / Unterstützende optische Verfahren zur Detektion nicht-muskelinvasiver Blasentumoren.

White light cystoscopy (WL) is the gold standard for the detection of bladder cancer. It can be performed using a rigid or flexible urethrocystoscope. With the more recent introduction of high definition (HD) techniques, WL cystoscopy has been decisively improved. Supplementary optical techniques are also used to improve the detection of bladder cancer. Among these are photodynamic diagnosis (PDD), narrow-band imaging (NBI), S­technologies of IMAGE1 S, optical coherence tomography (OCT), confocal laser endomicroscopy (CLE), and Raman spectroscopy. The aim of the present work is to introduce the techniques and to discuss their current role and future potential in the detection of bladder cancer.

RAS pathway mutations as a predictive biomarker for treatment adaptation in pediatric B-cell precursor acute lymphoblastic leukemia.

RAS pathway mutations have been linked to relapse and chemotherapy resistance in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, comprehensive data on the frequency and prognostic value of subclonal mutations in well-defined subgroups using highly sensitive and quantitative methods are lacking. Targeted deep sequencing of 13 RAS pathway genes was performed in 461 pediatric BCP-ALL cases at initial diagnosis and in 19 diagnosis-relapse pairs. Mutations were present in 44.2% of patients, with 24.1% carrying a clonal mutation. Mutation frequencies were highest in high hyperdiploid, infant t(4;11)-rearranged, BCR-ABL1-like and B-other cases (50-70%), whereas mutations were less frequent in ETV6-RUNX1-rearranged, and rare in TCF3-PBX1- and BCR-ABL1-rearranged cases (27-4%). RAS pathway-mutated cells were more resistant to prednisolone and vincristine ex vivo. Clonal, but not subclonal, mutations were linked to unfavorable outcome in standard- and high-risk-treated patients. At relapse, most RAS pathway mutations were clonal (9 of 10). RAS mutant cells were sensitive to the MEK inhibitor trametinib ex vivo, and trametinib sensitized resistant cells to prednisolone. We conclude that RAS pathway mutations are frequent, and that clonal, but not subclonal, mutations are associated with unfavorable risk parameters in newly diagnosed pediatric BCP-ALL. These mutations may designate patients eligible for MEK inhibitor treatment.

Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia.

Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased relapse risk. Their mutational and transcriptional landscape, as well as the respective patterns at relapse remain largely elusive. We, therefore, performed an integrated analysis of whole-exome and RNA sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway-activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic alterations affecting lymphoid development (58%) and cell cycle (39%) remained stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and increased from initially 36 to 58% in matched cases. IKZF1's critical role is further corroborated by its specific transcriptional signature comprising stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for relapse development and instead highlight the prominent rank of IKZF1 for relapse development by mediating self-renewal and homing to the bone marrow niche. Consequently, reverting aberrant IKAROS signaling or its disparate programs emerges as an attractive potential treatment option in these leukemias.

[Systemic therapy of malignant adrenal tumors]. / Systemische Therapie maligner Nebennierentumoren.

Systemic treatment of advanced-stage adrenal malignancies is most often only palliative. Mitotane alone or in combination with other chemotherapeutic agents such as cisplatin, etoposide, and vincristine are established therapeutic concepts for the treatment of metastatic adrenal cancer. Suramin and gossypol are rarely employed. New therapeutic options are tumor vaccination and treatment with antiangiogenic drugs. Metaiodobenzylguanidine as a radiotherapeutic drug or chemotherapeutic combination therapies that include cyclophosphamide, vincristine, and dacarbazine are applied for systemic treatment of malignant pheochromocytomas.. However, the clinical efficacy of the latter regimen needs further evaluation.