The immune microenvironment: a major player in human cancers.

Cancer is a major public health issue and figures among the leading causes of death in the world. Cancer development is a long process, involving the mutation, amplification or deletion of genes and chromosomal rearrangements. The transformed cells change morphologically, enlarge, become invasive and finally detach from the primary tumor to metastasize in other organs through the blood and/or lymph. During this process, the tumor cells interact with their microenvironment, which is complex and composed of stromal and immune cells that penetrate the tumor site via blood vessels and lymphoid capillaries. All subsets of immune cells can be found in tumors, but their respective density, functionality and organization vary from one type of tumor to another. Whereas inflammatory cells play a protumoral role, there is a large body of evidence of effector memory T cells controlling tumor invasion and metastasis. Thus, high densities of memory Th1/CD8 cytotoxic T cells in the primary tumors correlate with good prognosis in most tumor types. Tertiary lymphoid structures, which contain mature dendritic cells (DC) in a T cell zone, proliferating B cells and follicular DC, are found in the tumor stroma and they correlate with intratumoral Th1/CD8 T cell and B cell infiltration. Eventually, tumors undergo genetic and epigenetic modifications that allow them to escape being controlled by the immune system. This comprehensive review describes the immune contexture of human primary and metastatic tumors, how it impacts on patient outcomes and how it could be used as a predictive biomarker and guide immunotherapies.

Green light laser (KTP, 80 W) for the treatment of benign prostatic hyperplasia.

AIM: An attractive alternative for the management of benign prostate hyperplasia (BPH) is the use of 80 W potassium titanyl phosphate (KTP). We evaluated the efficacy and safety of this procedure in patients with bladder outlet obstruction (BOO). METHODS: A total of 171 patients with obstructive BPH underwent the 80 W potassium-titanyl-phosphate laser procedures. Preoperatively the international prostate symptom score (IPSS), the maximal urinary flow rate (Qmax), prostate volume and the post-void residual urine volume (PVR) were determined. Perioperative complications and postoperative blood loss, hospitalization, catheterization time, Qmax and PVR were also assessed. RESULTS: From the 171 patients, who underwent KTP laser procedure, 143 have been evaluated. The mean preoperative prostate volume was 43.9+/-17.1 (15-76). Eighty-nine patients (62.2%) were on chronic oral anticoagulant therapy (Coumarin or Aspirin 100). The mean applied energy was 170+/-65 kJ (100-275). There was no significant blood loss or fluid absorption during the KTP procedure. The mean Qmax values preoperatively and postoperatively were 3.4+/-4.3 and 16.3+/-7.3, respectively. PVR decreased from 74+/-47.7 mL preoperatively, to 16.6+/-21.5 mL postoperatively. Catheteriza-tion time was 1.4+/-0.8 days (0-5). CONCLUSION: KTP laser for the prostate represents a safe and effective treatment for patients with BPH. The procedure has a low rate of postoperative complications. It can be used for high risk patients especially for them who are receiving oral anticoagulation therapy.

[Cryoablation of prostate cancer]. / Die Kryoablation des Prostatakarzinoms.

Because of continuous technical development for more than half a century, followed by better clinical results with minimal side effects, cryoablation of the prostate for localized prostate cancer has evolved as a true alternative therapeutic option in selected cases. Today's form of cryotherapy has almost nothing in common with those versions established in the 1970s and further developed in the 1990s. Nowadays it shows minimal invasiveness and high efficacy for treatment of high-risk carcinomas and failures of other therapeutic modalities. Cryoablation of the prostate is indicated if there are absolute or relative contraindications for radical surgery. In localized prostate cancer, cryoablation is the therapy of choice for salvage cases; standardisation of the procedure, definition of freeze-thaw cycles, and structured training programs have led to this status.

Author Correction: Checkpoint blockade immunotherapy reshapes the high-dimensional phenotypic heterogeneity of murine intratumoural neoantigen-specific CD8+ T cells.

The original version of this Article omitted a declaration from the competing interests statement, which should have included the following: 'R.D.S. is a cofounder, stock holder, and scientific advisory board member of Jounce Therapeutics and Neon Therapeutics, and a member of the scientific advisory boards of BioLegend, Constellation, Lytix, and NGM. He also received research funding from Janssen and Agios.'. This has now been corrected in both the PDF and HTML versions of the Article.

Checkpoint blockade immunotherapy reshapes the high-dimensional phenotypic heterogeneity of murine intratumoural neoantigen-specific CD8+ T cells.

The analysis of neoantigen-specific CD8+ T cells in tumour-bearing individuals is challenging due to the small pool of tumour antigen-specific T cells. Here we show that mass cytometry with multiplex combinatorial tetramer staining can identify and characterize neoantigen-specific CD8+ T cells in mice bearing T3 methylcholanthrene-induced sarcomas that are susceptible to checkpoint blockade immunotherapy. Among 81 candidate antigens tested, we identify T cells restricted to two known neoantigens simultaneously in tumours, spleens and lymph nodes in tumour-bearing mice. High-dimensional phenotypic profiling reveals that antigen-specific, tumour-infiltrating T cells are highly heterogeneous. We further show that neoantigen-specific T cells display a different phenotypic profile in mice treated with anti-CTLA-4 or anti-PD-1 immunotherapy, whereas their peripheral counterparts are not affected by the treatments. Our results provide insights into the nature of neoantigen-specific T cells and the effects of checkpoint blockade immunotherapy.Immune checkpoint blockade (ICB) therapies can unleash anti-tumour T-cell responses. Here the authors show, by integrating MHC tetramer multiplexing, mass cytometry and high-dimensional analyses, that neoantigen-specific, tumour-infiltrating T cells are highly heterogeneous and are subjected to ICB modulations.

[Cryoablation of prostate cancer]. / Kryoablation des Prostatakarzinoms.

BACKGROUND: Due to continuous technical developments for more than 60 years followed by better clinical results with minimal side effects, cryoablation of the prostate for localized prostate cancer has evolved as a true alternative therapeutic option for selected patients. THEMATA: The current form of cryoablation has almost nothing in common with those established in the 1960s and 1970s, which were further developed in the 1980s and 1990s. Nowadays it is a minimally invasively and highly effective treatment for high-risk carcinomas and failure of other therapeutic modalities. CONCLUSION: Thus, cryoablation of the prostate is indicated if there are absolute or relative contraindications for radical surgery. In salvage cases for localized prostate cancer, cryoablation is the therapy of choice. Cryoablation is also an option for focal therapy. Standardization of the procedure, definition of freeze-thaw cycles, and structured training programs have led to this status.

Malignant fibrous histiocytoma of the renal capsule.

We report about an extremely rare case of malignant fibrous histiocytoma (MFH) of the renal capsule. The tumor is composed of fibroblast-like cells arranged in a storiform pattern and histiocyte-like cells with multinucleated giant cells, both showing no iron reaction. Characteristic of the histiocytic quality of the tumor are numerous PAS-positive intracytoplasmic droplets which can be identified as erythrophagosomes only under the electron microscope. Emphasis is put on the preoperative differential diagnosis of the tumor from renal cell carcinoma as well as on its histogenesis and prognosis.

In vitro chemosensitivity testing of renal cell cancer. Short-term culture technique.

In an attempt to solve the problem of chemosensitivity testing of renal cell carcinoma in vitro, a modified short-term culture technique was developed. The kinetic study of hypernephroma cells and normal renal cells showed that the uptake of H3-uridine and H3-thymidine is at its maximum after eighty hours. The effect of doxorubicin, cisplatinum, vinblastine, and mitomycin C in different concentrations was tested. Tumors generally showed more resistance than sensitivity. Some tumors showed sensitivity to one or more drugs, but no one drug was persistently effective in all tumors. Our short-term culture technique solved the discrepancy between cell kinetics and test duration found in the Volm test and the problem of nongrowth in the clonogenic assay.

Effect of lectins on KK-47 bladder cancer cell line.

The effect of three lectins, Ricinus communis agglutinin (RCA II), concanavalin agglutinin (ConA), and wheat germ agglutinin (WGA), on KK-47 bladder cancer cell line was studied, RCA II showed effective inhibition of H3-uridine and H3-thymidine uptake by KK-47. ConA showed a stimulatory effect in all three concentrations used. WGA also showed stimulatory effect, but it was less pronounced than ConA.

Birth of two infants with normal karyotype after intracytoplasmic injection of sperm obtained by testicular extraction from two men with nonmosaic Klinefelter's syndrome.

OBJECTIVE: To report two births of a healthy male and a healthy female baby after use of testicular spermatozoa from two patients with nonmosaic Klinefelter's syndrome. DESIGN: Case report. SETTING: General academic hospital with IVF center and university institute of human genetics. PATIENT(S): Two couples with primary infertility in which the men had secretory azoospermia and nonmosaic 47,XXY karyotype. Both women had a normal karyotype and no gynecologic abnormalities. INTERVENTION(S): ICSI was performed using testicular spermatozoa after ovarian stimulation and transvaginal ultrasonography-guided oocyte pick-up. MAIN OUTCOME MEASURE(S): Normal fertilization, embryo cleavage, clinical pregnancy outcome, and peripheral blood karyotype of the newborn. RESULT(S): In each case, 13 metaphase II oocytes were injected, of which 7 fertilized normally. Three good-quality embryos (4-cell stage) were transferred into the uterine cavity. Both women conceived, and normal pregnancies followed. Genetic analysis of the neonates revealed normal 46,XX and 46,XY karyotypes. CONCLUSION(S): These case reports reaffirm that patients with nonmosaic Klinefelter's syndrome produce normal spermatozoa with fertilization potential. Although it is premature to make conclusions about the rate of transmission of this aneuploidy because of the low number of the published cases, this report substantiates the idea that rates of transmission of this gonosomal aneuploidy are low.

Angioma-like pseudometamorphosis in Wilms' tumors subjected to preoperative radio- and chemotherapy.

Six Wilms' tumors (stage III-V), which had undergone preoperative irradiation and chemotherapy, were examined histologically. While mesenchymal and differentiated epithelial tumor elements were preserved to a large extent, blastemic tumor structures were almost completely lacking. Instead, pseudoangioma-like structures similar to cavernous hemangioma prevailed. As demonstrated by transitional pictures, the pseudoangioma-like pattern is a result of the fact that blastemic tumor elements are replaced by blood after therapy-induced necrosis and lysis. The clinical advantages of preoperative treatment are briefly discussed, especially for patients with advanced tumors.

[The demonstration and staging of bladder carcinoma. A comparative study between magnetic resonance tomography, computed tomography and radioimmunoscintigraphy]. / Nachweis und Stadieneinteilung des Harnblasenkarzinoms. Eine vergleichende Untersuchung zwischen Magnetresonanztomographie, Computertomographie und Radioimmunszintigraphie.

The purpose of the present study was to compare the effectiveness of MRI, CT and radioimmunoscintigraphy in the staging and detection of bladder cancers in 28 patients. We distinguish two groups: Group I included the tumour stages CIS-T3A and the second group the deep infiltrative tumours T3B-T4. MRI was slightly superior to CT in respect of tumour staging (75% correct results as compared to 63%). No understaging occurred with MRI, whereas in 22% of the cases the stage of the tumour was underestimated using CT diagnostics. Overstaging occurred in 25% of the MRI and 15% of the CT-diagnostics, respectively. RIS cannot distinguish the tumour groups, and hence this method is useful only for the detection of the primary tumour and metastases. In 77% of cases the tumour was detected and in 15% the tumour could be safely excluded.

[Radioimmunoscintigraphy and magnetic resonance tomography in the diagnosis of urinary bladder cancer]. / Radioimmunoszintigraphie und Magnetresonanz-tomographie in der Diagnostik des Harnblasenkarzinoms.

Magnetic resonance tomography is a method which is sufficiently precise to demonstrate morphological changes for tumor staging of carcinoma of the urinary bladder. The stage of the tumor was correct in 68 resp. 86% of the patients. The RIS shows organ and lymph node metastases and has the capability to differentiating between scar and tumor after transurethral resection. The local spread, especially the infiltration depth of the tumor, is not visible. In 90% of the patients a primary tumor was detected, only in 5 cases a false-negative and in 2 cases a false-positive finding was made.

[Alloplastic ureter substitution and limitations in clinical application. A status analysis]. / Alloplastischer Ureterersatz und Grenzen des klinischen Einsatzes. Eine Standortanalyse.

Operative ureteral replacement with the patient's own body tissue or by reconstructive ureteral surgery is indicated relatively often. The operative methods applied vary: they include pelvic flap pyeloplasty, caudal transposition of the kidney, interposition of the small intestine, trans-ureterostomy, calico-ureterostomy, of bladder flap transplantation and autotransplantation of the kidney. When the indications are correctly observed with reference to the kind and location of the ureteral lesion all these methods are successful. The methods of alloplastic replacement of the ureter, in contrast, have lost clinical importance and should be performed only in rare, isolated cases, mainly as a short-term solution. Possible indications are a poor general condition in patients for whom alloplastic ureteral replacement is the only alternative to permanent nephrostomy and malignant tumours requiring immediate irradiation, which cannot be postponed until definitive wound healing has taken place following a plastic operation. It is important that problems of biocompatibility have now been largely overcome. Segmental ureteral replacement with alloplastic materials is not possible, however, and the functional difficulties with urinary transport have not been solved in the long term, even in models with pumps and reflux-preventing mechanisms.

[Orthotopic urinary bladder replacement in the woman. Initial clinical experiences]. / Der orthotope Harnblasenersatz bei der Frau. Erste klinische Erfahrungen.

Ileum neobladder after cystectomy is mainly reserved for male patients. Female patients are normally excluded from this kind of urinary diversion for fear of incontinence following orthotopic bladder substitution. In addition as in the male, the question of urethral recurrence of urothelial carcinoma is still not settled. We report on seven cases of successful orthotopic bladder reconstruction in females by means of an ileum neobladder according to Hautmann with follow up of up to 4.5 years. One of these patients had a complicated bladder-vaginal fistula and almost complete loss of bladder function because of a shrunken bladder after radiation therapy for a cervical carcinoma and the other six had undergone radical cystectomy because of bladder carcinoma. The ileum neobladder is anastomosed with the preserved urethral stump. The original method of ileum neobladder is extended by a colposuspension plasty according to Marshall-Marchetti, which is the means of achieving continence. The first results are encouraging and open further possibilities for bladder reconstruction in the female.

[Antegrade percutaneous endoluminal therapy of nonmalignant strictures of ureterointestinal anastomoses after urinary diversion]. / Antegrade perkutane endoluminale Therapie der nichtmalignen Strikturen von ureterointestinalen Anastomosen nach Harnableitung.

We report our experience on the use of antegrade percutaneous incision of ureterointestinal anastomosis strictures after urinary diversion. Since 1994, we evaluated 9 patients with 12 ureterointestinal anastomosis (UAS) strictures who were treated with a cold-knife incision. After placement of an 8-Fr nephrostomy tube, a 0.035-in guide wire was passed through the stricture under guidance of a central opened ureter catheter (5 Fr). A wire-mounted cold-knife was pulled through the strictured area in the retrograde way under fluoroscopic control. Routinely, following the incision, an 8-Fr external stent was left in place for 6-8 weeks. After removal of the stent, the ureteroenteric area remained patent in 7 UAS (58%) cases versus 7 of 9 (78%) patients, with average follow-up of 18 months (range 13-25 months). Failures were associated with radiogenic injury of the ureter in three UAS cases and unexplained in two. No complication was observed. Percutaneous endourological management of ureterointestinal anastomotic strictures with the cold-knife incision is a safe and effective alternative to open surgical repair and should be tried as an initial approach.

[Prediction of calculus clearance after extracorporeal shock wave lithotripsy of calculi in the inferior kidney calices. Application of the artificial neural network]. / Prädiktion der Steinfreiheit nach extrakorporaler Stosswellenlithotripsie bei unteren Nierenkelchsteinen. Einsatz eines artifiziellen neuronalen Netzwerks.

The purpose of this retrospective study was to define prognostic factors which determine the stone clearance (SC) for lower caliceal stones after extracorporeal shock wave lithotripsy (ESWL) and to compare the prediction accuracy of artificial neural network analysis (ANNA) and standard computational methods. Since January 1995, 321 renal units in 310 patients with single or multiple inferior caliceal calculi of all sizes and compositions have been treated with ESWL (Lithotriptor: Piezolith 2500, Wolf company). The classification accuracy of ANNA in the test set was 94%, with a sensitivity of 95%, a specificity of 92%, and a receiver operating characteristic curve area of 0.966, results significantly better than those yielded by a logistic regression analysis (classification accuracy 77%, sensitivity 75%, specificity 81%, and ROC curve area 0.779). Patients with lower renal caliceal stones appear to have the best chance of successful ESWL when their body mass index (BMI) and urinary transport (UT) are normal, the infundibular width (IW) is 5 mm or more, and the infundibular ureteropelvic angle (IUPA) is 45 degrees or more. Stone size and composition, as factors of SC, are not statistically significant. After determining the angle, width, and UT in patients with optimal age and body mass suitable for ESWL, SC can be achieved irrespective of stone size and composition.

[Complexity-oriented surgical strategies in vesicovaginal fistulas]. / Komplexitätsorientierte Operationsstrategien bei vesiko-vaginalen Fisteln.

Since 1975 a total of 55 patients with vesicovaginal fistulas have undergone surgery at the Clinic of Urology, University of Saarland, Homburg/Saar. A majority (55%) of the cases were complicated. In 9 cases supravesical urinary diversion was necessary. Successful closure of the fistula was achieved in 45 patients (81.8%); only in one case is the fistula still present. In 5 patients with uncomplicated fistulas successful closure was accomplished by a vaginal approach. In the presence of complications, e.g., previous radiotherapy or accompanying lesions of the ureter or rectum, a transvesical/transabdominal approach was preferred; surgery was successful in 93.3% of such cases.

[History of ureteropelvic junction obstruction repair (pyeloplasty). From Trendelenburg (1886) to the present]. / Die Geschichte der operativen Behandlung der Harnleiterabgangsstenose (Pyeloplastik). Von Trendelenburg (1886) bis zur Gegenwart.

The first reconstructive procedure for ureteropelvic junction (UPJ) obstruction was performed by Trendelenburg in 1886. The important milestones in the reconstruction of UPJ are discussed and all available historical papers and reports since 1886 are reviewed. Kuster published the first successful dismembered pyeloplasty 5 years later, but his technique was prone to strictures. In 1892, the application of the Heineke-Mickulicz principle by Fenger resulted in bulking and kinking with obstruction. Plication of the renal pelvis, first introduced by Israel in 1896, was modified by Kelly in 1906. After the principle of the Finney pyloroplasty, von Lichtenberg designed his pyeloplasty in 1921, best suited to cases of high implantation of the ureter. Foley modified flap techniques, first introduced by Schwyzer in 1923 after the application of the Durante pyloroplasty principle, successfully to Y-V pyeloplasty in 1937. Culp and de-Weerd introduced the spiral flap in 1951. Scardino and Prince reported about the vertical flap in 1953. Patel published the extra-long spiral flap technique in 1982. In order to decrease the likelihood of stricture, Nesbit, in 1949, modified Kuster's procedure by utilizing an elliptic anastomosis. In the same year, Anderson and Hynes, published their technique. With the advent of endourology, several minimally invasive procedures were applied: antegrade or retrograde endopyelotomy, balloon dilation, and laparoscopic pyeloplasty. The concept of full-thickness incision of the narrow segment followed by prolonged stenting was first described in 1903 by Albarran and was popularized by Davis in 1943. Several basic principles must be applied in order to ensure successful repair: the resultant anastomosis should be widely patent, performed in a watertight fashion without tension. Endopyelotomy represents an alternative to open surgery.