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Aggressive variant prostate cancer and transdifferentiated neuroendocrine prostate cancer: from diagnosis to therapy

Aggressive variants of prostate cancer (AVPC) comprise aheterogeneous group of prostate carcinomas characterized by androgen-independent, aggressive tumor growth. Clinically, they are characterized by prostate-specific antigen (PSA)-negative progression and an atypical metastatic pattern with increased visceral and osteolytic metastasis. Based on immunohistochemistry and transcriptome profiling, AVPC are divided into four subgroups: neuroendocrine prostate cancer (NEPC), amphicrine prostate cancer, androgen receptor-low expressing prostate cancer and double-negative prostate cancer. However, differentiating between the subgroups can be challenging. For the transformation process of an adenocarcinoma into an AVPC, so-called transdifferentiation, the inactivation of the tumor suppressor genes RB1, PTEN and TP53 plays acrucial role. Epigenetic changes contribute to the development of stem cell-like properties. AVPC is mostly treated with platinum-based chemotherapy, depending on the subtype in combination with etoposide or ataxane. New therapeutic approaches are investigating the use of chemotherapy combinations with PARP inhibitors, checkpoint inhibitors or immunomodulators. In addition, T‑cell engagers have achieved initial promising results, particularly in NEPC. Treatment of AVPC patients in trials is desirable to improve evidence for this aggressive form of prostate cancer.

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Functional disorders of the lower urinary tract following urogynecologic and abdominal surgery

Bladder dysfunction is divided into storage and emptying disorders, which can also be the result of surgical interventions in the small pelvis, either individually or in combination. Neuroirritants from alloplastic implants are often associated with urge complaints and pelvic pain. Removal of the irritant agent carries the risk of incalculable collateral damage and recurrence of the symptoms that initially led to surgery. Conservative measures, on the other hand, are often lengthy, multimodal, and yet frustrating. Iatrogenic denervation of the lower urinary tract-mainly due to damage to the pelvic plexus-can be asymptomatic for years and remain undetected, because detrusor hypo- or acontractility can be compensated for by using alternative emptying mechanisms (Valsalva maneuver, pressureless micturition via pelvic floor relaxation). Neuromodulative therapeutic approaches require residual contractility of the detrusor, in the case of complete acontractility, only intermittent self-catheterization and suprapubic urinary diversion remain as therapeutic options. Iatrogenic urogenital fistulas occur most frequently after hysterectomies in benign indications, and the risk of afistula following vaginal hysterectomy is tenfold with laparoscopic approaches. Due to the heterogeneity of fistulas, acorrespondingly broad range of therapies must also be provided and, in addition to conservative permanent catheterization, also include vaginal or transabdominal fistula closure strategies.

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Functional disorders of the lower urinary tract: Parkinson's disease

Parkinson's disease (PD) is acommon neurodegenerative disease that is associated with considerable socioeconomic burden. Due to neurogenic detrusor overactivity, which challenges more the urinary storage phase than the voiding phase, these patients mainly suffer from urinary urgency, increased urinary frequency (both during the day-time and particularly at night-time), and incontinence. Besides dopaminergic agents, which have an effect on motor symptoms but only aslight effect on lower urinary tract dysfunction (LUTD), antimuscarinics are generally used as first-line treatment. However, treatment benefit is limited by central side effects (i.e., dry mouth, constipation, cognitive impairment), which occur in approximately 60% of treated PD patients. Moreover, simultaneous supplementation of antimuscarinics and PD medication is limited by negative interactions. Intradetrusor onabotulinumtoxinA (OnabotA) injections have emerged as an effective, minimally invasive, well-tolerated, and widely accepted treatment for refractory neurogenic detrusor overactivity incontinence. Recently, intradetrusor OnabotA injections were noted to effectively alleviate detrusor overactivity in patients with spinal cord injury and multiple sclerosis. Intradetrusor OnabotA injections seem to effectively alleviate LUTD in patients diagnosed with PD, while maintaining voluntary voiding.

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