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.

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 localized prostate cancer. Current state]. / Kryoablation des lokalisierten Prostatakarzinoms. Aktueller Stand.

Due to continuous technical developments 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. The current version of cryoablation has almost nothing in common with those versions established in the 1960s and 1970s and further developed in the 1980s and 1990s. The present version is minimally invasive and has a high efficacy for treatment of high risk carcinomas and failure of other therapeutic modalities. Cryoablation of the prostate is indicated if there are absolute or relative contraindications for radical surgery. In salvage cases cryoablation is the therapy of choice for localized prostate cancer. Standardization of the procedure, definition of freeze-thaw cycles and structured training programs have led to this status.

[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.

[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.

[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.

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.

Alpha-fetoprotein-producing renal cell carcinoma.

Alpha-fetoprotein (AFP) is recognized as a tumor marker of yolk sac tumors, liver cancer and some other cancers of the digestive organs. Renal cell carcinoma (RCC) producing AFP is a rare entity. A case of AFP-producing RCC with solitary bone metastasis, but without liver involvement, is reported. The stain specific to AFP proved the presence of AFP in the cytoplasms of more cells of the renal tumors. Additionally, the other published cases are reviewed. These cases indicate that mesoderm-originating malignant tumors such as RCCs can produce AFP in some situations. So, AFP is probably more universal than believed, although it is generally a popular and useful tumor marker for hepatocellular carcinomas and yolk sac tumors.

Antegrade percutaneous endoluminal treatment of non-malignant ureterointestinal anastomotic strictures following urinary diversion.

OBJECTIVE: We report our experience on antegrade percutaneous incision of ureterointestinal anastomosis strictures after urinary diversion. MATERIALS AND METHODS: Since 1994, we have evaluated retrospectively 18 patients with 22 ureterointestinal anastomosis strictures (UAS), who were treated with cold-knife incision. After placement of an 8-french nephrostomy tube, a 0.035-inch guide wire bypassed the stricture under guidance of a centrally opened (5-french) ureter catheter. A wire-mounted cold-knife was pulled through the strictured area retrogradely under fluoroscopic control. Routinely, following the incision, an 8-french external stent was left in place for 6-8 weeks. RESULTS: After stent removal as a primary procedure, the ureteroenteric area has remained patent in 14 of 19 (74%) UAS. In 3 cases undergoing a secondary or repeated procedure, treatment failed. The average follow-up was 23.5 (range 12-39) months. Failures were associated with radiogenic injury of the ureter in 5 UAS and unexplained in 2. No complication was observed. CONCLUSION: Percutaneous endourological management of UAS with the cold-knife incision, when used as a primary treatment, is a safe and effective alternative to open surgical repair and should be considered as an initial approach.

[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.

A comparison of urinary nuclear matrix protein-22 and bladder tumour antigen tests with voided urinary cytology in detecting and following bladder cancer: the prognostic value of false-positive results.

OBJECTIVES: To evaluate the diagnostic and prognostic value of the nuclear matrix protein-22 (NMP22) and bladder tumour antigen (BTAstat) tests compared with voided urinary cytology (VUC) in detecting and following bladder cancer, assessing particularly the prognostic value of false-positive test results in patients followed up for bladder cancer. PATIENTS AND METHODS: From 739 patients suspected of having bladder cancer, voided urine samples for the NMP22 and BTAstat tests, and for VUC and urine analysis, were collected before cystoscopy. All patients underwent transurethral resection of bladder lesions or mapping. and were followed for a mean (range) of 27.3 (3-65) months. RESULTS: In the 406 patients with bladder cancer, the overall sensitivity was 85% for NMP22, 70% for BTAstat and 62% for VUC. For histological grades 1-3 the sensitivity in detecting transitional cell carcinoma was 82%, 89% and 94% for NMP22, 53%, 76% and 90% for BTAstat, and 38%, 68% and 90% for VUC, respectively. Although the sensitivity in detecting invasive carcinoma was >85% for all the tests. NMP22 and BTAstat were statistically more sensitive than VUC for superficial tumours. The optimal threshold value for NMP22, calculated using the receiver operating characteristics curve was 8.25 U/mL. The specificity was 68% for NMP22, 67% for BTAstat, and 96% for VUC. The specificity of VUC remained >87% and was independent of benign histological findings. In contrast, in patients with no apparent genitourinary disease on histology, NMP22 and BTAstat had significantly higher specificity (94% and 92%, respectively: P=0.003) than in the group with chronic cystitis (52% for both tests). Forty patients having no bladder cancer at biopsy had a recurrence after a mean (range) follow-up of 7.7 (3-15) months: all had a previous history of bladder cancer. According to subsequent recurrence, the prognostic positive and negative predictive values were 18% and 91% for NMP22, 13% and 88% for BTAstat, and 79% and 91% for VUC. Both false-positive VUC and NMP22 tests predicted recurrence (log-rank test, P<0.001 and P=0.004, respectively), but the BTAstat test produced no similar correlation (P=0.778). CONCLUSION: The NMP22 and BTAstat tests are better than VUC for detecting superficial and low-grade bladder cancer but they have significantly lower specificity. After excluding diseases with the potential to interfere in these tests the overall specificity of both tests is increased considerably. False-positive results from NMP22 and VUC but not from BTAstat in patients followed up for bladder cancer correlate with future recurrences.

[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.

Regulation of prostatic smooth muscle contractility by intracellular second messengers: implications for the conservative treatment of benign prostatic hyperplasia.

The increased sympathetic neurotransmission in benign prostatic hyperplasia (BPH) results in a alpha 1C-adrenoceptor-mediated increase in prostatic smooth muscle tone which seems to be responsible for the dynamic infravesical obstruction occurring in BPH. The prostatic smooth muscle contractions evoked by norepinephrine can be efficiently blocked by alpha 1-adrenoceptor blockers. Moreover, an impressive number of clinical trials illustrated the beneficial results of alpha 1-adrenoceptor blockers in the treatment of BPH. However, despite knowledge of alpha 1-adrenergic neurotransmission and the clinical application of its blockade by selective alpha 1-adrenoceptor antagonists, very little is known about the intracellular pathways involved in the regulation of prostatic smooth muscle contractility. To study the intracellular mechanism of the alpha 1C-adrenoceptor-induced prostatic smooth muscle contraction, the patch-clamp technique in the whole-cell configuration mode combined with the Fura-II fluorescence technique was used in human, enzymatically isolated smooth muscle cells obtained from patients undergoing transurethral resection of the prostate because of symptomatic BPH. Furthermore changes in prostatic smooth muscle contractility were registered in organ bath experiments. Application of the selective alpha 1-adrenoceptor agonist phenylephrine (PE) increased the L-type Ca(2+)-channel current (ICa) dose dependently from 8 up to 18.5 microA/cm2, simultaneously elevating the free cytoplasmic Ca2+ concentration ([Ca2+]i) up to 1.9 microM. Pretreating the myocytes with pertussis toxin, an exotoxin of Bordetella pertussis which inactivates GTP-binding proteins (G proteins) of the Gi and G(o) family by ADP ribosylation, reduced the PE-induced ICa stimulation by 71.5 +/- 5.6% (n = 21). Dialysis of the cytosol with the second messenger inositol-1,4,5-trisphosphate (IP3), which releases Ca2+ from intracellular non-mitochondrial, IP3-sensitive Ca2+ pools, imitated the PE-evoked responses. Pretreating the myocytes with the Ca(2+)-release blockers ryanodine (10-100 microM, n = 8), thapsigargin (0.1 microM, n = 11) or low-molecular weight heparin (n = 14) largely attenuated the PE-evoked responses. The experimental results suggest a coupling of alpha 1-adrenoceptors to phospholipase C-converting phosphoinositol-4,5-bisphosphate into diacylglycerol, an endogenous activator of the protein kinase C and IP3 which releases Ca2+ from intracellular stores stimulating ICa via Ca(2+)-calmodulin-dependent protein kinase induced phosphorylation of voltage-dependent Ca2+ channels. This knowledge could be of interest for conservative treatment in symptomatic BPH.

Urinary undiversion after implantation of an alloplastic urethral sling for male continence.

A man in whom urinary diversion (colon conduit) was performed after 2 unsuccessful implantations of artificial urethral sphincters for treatment of iatrogenic incontinence became continent again after implantation of an alloplastic sling. Three months later the patient underwent urinary undiversion with augmentation cystoplasty. After 3 years ureteroneocystostomy was necessary due to distal ureteral stenoses. At 7-year followup the patient is continent. He has good bladder capacity, bladder emptying and a normal upper urinary tract.