IL-23 secreted by myeloid cells drives castration-resistant prostate cancer.

Patients with prostate cancer frequently show resistance to androgen-deprivation therapy, a condition known as castration-resistant prostate cancer (CRPC). Acquiring a better understanding of the mechanisms that control the development of CRPC remains an unmet clinical need. The well-established dependency of cancer cells on the tumour microenvironment indicates that the microenvironment might control the emergence of CRPC. Here we identify IL-23 produced by myeloid-derived suppressor cells (MDSCs) as a driver of CRPC in mice and patients with CRPC. Mechanistically, IL-23 secreted by MDSCs can activate the androgen receptor pathway in prostate tumour cells, promoting cell survival and proliferation in androgen-deprived conditions. Intra-tumour MDSC infiltration and IL-23 concentration are increased in blood and tumour samples from patients with CRPC. Antibody-mediated inactivation of IL-23 restored sensitivity to androgen-deprivation therapy in mice. Taken together, these results reveal that MDSCs promote CRPC by acting in a non-cell autonomous manner. Treatments that block IL-23 can oppose MDSC-mediated resistance to castration in prostate cancer and synergize with standard therapies.

Fetal Cystoscopy and Vesicoamniotic Shunting in Lower Urinary Tract Obstruction: Long-Term Outcome and Current Technical Limitations.

BACKGROUND: In utero therapeutic approaches for lower urinary tract obstruction (LUTO) have been developed to salvage the fetal kidney function. OBJECTIVE: The aim of this work was to report the long-term survival, nephrological, and urological outcome of children treated prenatally for LUTO using operative fetal cystoscopy (FC) and vesicoamniotic shunting (VAS) or both. METHODS: A retrospective study of 48 procedures (23 FC, 25 VAS) was performed on 33 patients (between 2008 and 2018). Reviewed data included prenatal management and clinical follow-up by a pediatric nephrologist and a pediatric urologist. Both intention-to-treat and per-protocol analyses were conducted. RESULTS: The median follow-up was 3.6 years (0.5-7) for FC and 2.5 years (1.1-5.1) for VAS. There was no difference between FC and VAS in terms of survival (92 vs. 83%, p = 1), complication rate (74 vs. 92%, p = 0.88), or chronic kidney disease (58 vs. 50%, p = 1). The number of procedures was higher in the VAS group: 1.7 (1-3) versus 1.1 (1-2), p = 0.01. With a 30% rate of technical failure, FC added diagnostic value in 3 out of 21 cases. CONCLUSIONS: No difference was found between FC and VAS regarding survival, long-term kidney function, or urological outcome. Despite overly optimistic reports on FC, it lacks reproducibility due to posterior-urethra inadequate visualization and inappropriate instrumentation.

CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo.

The mechanisms by which prostate cancer shifts from an indolent castration-sensitive phenotype to lethal castration-resistant prostate cancer (CRPC) are poorly understood. Identification of clinically relevant genetic alterations leading to CRPC may reveal potential vulnerabilities for cancer therapy. Here we find that CUB domain-containing protein 1 (CDCP1), a transmembrane protein that acts as a substrate for SRC family kinases (SFKs), is overexpressed in a subset of CRPC. Notably, CDCP1 cooperates with the loss of the tumor suppressor gene PTEN to promote the emergence of metastatic prostate cancer. Mechanistically, we find that androgens suppress CDCP1 expression and that androgen deprivation in combination with loss of PTEN promotes the upregulation of CDCP1 and the subsequent activation of the SRC/MAPK pathway. Moreover, we demonstrate that anti-CDCP1 immunoliposomes (anti-CDCP1 ILs) loaded with chemotherapy suppress prostate cancer growth when administered in combination with enzalutamide. Thus, our study identifies CDCP1 as a powerful driver of prostate cancer progression and uncovers different potential therapeutic strategies for the treatment of metastatic prostate tumors.

Elastic stabile intramedullary nailing (ESIN) of diaphyseal femur fractures in children and adolescents: A strobe-compliant study.

Elastic stabile intramedullary nailing (ESIN) is a well-established method to stabilize diaphyseal fracture of the femur (DFF) in children. We aimed to evaluate the minimal medullary canal diameter (MMCD) of the fractured femur relative to the diameter of the nails. We also analyzed the real anteversion angle (AVA) of the affected femur in comparison to the healthy femur.We retrospectively reviewed the medical records and plain X-ray images of children aged 2-15 years treated with ESIN for unstable femoral shaft fractures between 2004 and 2012. We measured MMCD on preoperative plain X-ray images. Nail diameter (ND) and any postoperative complications were extracted from the medical records. At follow-up conducted at a median of 40 months (range: 4-103 months) after the operation, we obtained Dunn X-ray images of both hips. Particular emphasis was placed on postoperative torsional differences in relation to age, weight, and maturity of the growth plate.We analyzed the relationship between postoperative rotational malalignment and the ratio of ND to MMCD.Median age of the 22 children at the time of injury was 7.5 years (range: 2-15 years). Median body weight was 25 kg (range: 13-57 kg). Median MMCD amounted to 8.6 mm (range: 5.5-11.0 mm). Median ND/MMCD was 36.9% (range: 27.3%-47.4%). Radiological analyses revealed a median of 27.0° (range: -22.0° to +49.0°) of real AVA in the affected leg and 32.5° (range: 18.0°-48.0°) in the healthy leg.Three children (13.6%) experienced a grade III complication (Clavien-Dindo classification of surgical complications; CDCSC). Two of these children suffered retrotorsion of the femoral neck, while the third child experienced diminished anteversion.Overall, 3 of 22 children (13.6%) suffered a CDCSC-grade III complication (i.e., retrotorsion of the femoral neck in two children and diminished anteversion of the femoral neck in one child). We recommend obtaining Dunn images at the end of the operation to confirm correct rotational alignment after stabilization with ESIN. Further prospective studies are required to confirm our findings.

Topical everolimus for facial angiofibromas in the tuberous sclerosis complex. A first case report.

BACKGROUND: Facial angiofibromas are present in most of the patients with the tuberous sclerosis complex and may cause severe disfiguration of the face. The tumor growth in tuberous sclerosis complex is promoted by the disinhibition of the mammalian target of rapamycin pathway. Thus, the systemic treatment with mammalian target of rapamycin inhibitors such as sirolimus and everolimus has recently been established to treat specific tuberous sclerosis complex-associated lesions. For patients who suffer from disfiguring facial angiofibromas only, there is a need for a topical use of mammalian target of rapamycin inhibitors. Sirolimus has been shown to be beneficial in treating facial angiofibromas. But the topical use of everolimus, which has the approval to treat tuberous sclerosis complex-associated tumors, namely giant cell astrocytomas and renal angiofibromas, has not been reported. PATIENTS AND RESULTS: We present a 10-year-old girl whose facial angiofibromas were successfully treated with an everolimus ointment without relevant side effects. In addition, we provide a short pharmacological overview of sirolimus and everolimus with focus on the topical use. CONCLUSIONS: Topical everolimus seems to be a favorable and safe option for patients with facial angiofibromas who do not require systemic treatment.

Replacement of a string jejunostomy if the suture is lost: first time a technique with no need to cut.

PURPOSE: The aim of the study was to present the first case of replacement of a string jejunostomy with an enteroscopic percutaneous technique after the string was lost. The replaceable string jejunostomy is a well-established method for the enteral feeding in patients where the swallowing process is impaired and gastroesophageal reflux impedes the option of a gastrostomy. In the frequent case of obstruction, rupture or malfunction of the jejunostomy, it is easily replaced in an outpatient setting without anesthesia, with the help of the string that holds the tip of the feeding tube in place. In our case the string was lost. MATERIALS AND METHODS: The jejunostomy was replaced with a fully percutaneous technique with the help of a pediatric cystoscope. RESULTS: This technique is well practicable and obviated the need for a laparotomy in a polymorbid patient. CONCLUSIONS: The technique seems promising, but we report an anecdotal case description. Further experience is needed to investigate its safety.

Curious foreign body in the bladder of an adolescent.

We report the case of a 14 year old boy who presented at our emergency department because of increasing alguria and dysuria one year after inserting a wire cable into his bladder for autoerotic purposes. Endoscopic transurethral removal of the foreign body proved to be impossible because the cable was of a stiff consistency and was trapped in scar tissue at the bladder neck. The foreign body therefore had to be extracted using a Pfannenstiel approach. Urethrocystoscopy and uroflow performed one week later were normal. Filiform intravesical foreign bodies can create particular challenges. Adequate diagnostic imaging, awareness of possible complications, and knowledge of the different available techniques are essential in planning safe extraction.