Acute Autonomic Nervous System Response to Direct Sacral Nerve Root Stimulation in Lower Urinary Tract Dysfunction: A New Approach to Understand the Mechanism of Action of Sacral Nerve Modulation.

PURPOSE: Our goal was to assess acute autonomic nervous system (ANS) response to direct sacral nerve root (SNR) stimulation in the context of lower urinary tract dysfunction. MATERIALS AND METHODS: In this retrospective monocentric study, patients undergoing 2-stage sacral nerve modulation for overactive bladder, nonobstructive urinary retention, or chronic bladder pain syndrome between March 2022 and June 2023 were analyzed. A standardized stimulation protocol was applied during the lead implantation, each of the 4 contact points being sequentially stimulated at the amplitude required to elicit anal motor response. Stimulations were labeled as StimA, StimB, StimC, and StimD, ordered by ascending order of minimum amplitude required for anal motor response. Heart rate variability parameters were collected using PhysioDoloris Monitor, and computed through the time-domain (standard deviation of normal-to-normal intervals [SDNN], root mean square of successive differences), the frequency-domain (low frequency, high frequency) and the graphical (Analgesia Nociception Index [ANI]) methods. RESULTS: Fifty patients were analyzed, including 35 females. Twelve patients had an underlying neurological disease. Efficacy was deemed achieved in 54% of patients. SDNN variability significantly increased during StimA to StimC, while maximum SDNN significantly increased only during StimA. ANI variability significantly increased during all 4 stimulations, while maximum ANI significantly increased only during StimA. CONCLUSIONS: Direct stimulation of SNR is responsible for a significant increase in ANS and relative parasympathetic nervous system activity, with a greater effect observed when the stimulation was delivered closer to the SNR. These results shed light on potential mechanisms underlying sacral nerve modulation, particularly regarding the treatment of ANS dysregulation in lower urinary tract dysfunction.

Motor Response Matters: Lead Placement and Urologic Efficacy Linked in Sacral Neuromodulation.

OBJECTIVES: This study aimed to characterize the pelvic floor muscles (PFM) motor response provoked during sacral neuromodulation (SNM) lead placement, determining its utility in improving therapy delivery. MATERIALS AND METHODS: A prospective pilot study (January 2018-September 2021) was performed including patients with overactive bladder or nonobstructive urinary retention-a very homogeneous group without any medical history interfering with bladder function-who underwent SNM. An external pulse generator was connected for three weeks. Success was defined as ≥50% improvement. PFM electromyography was recorded using a multiple array probe. Differences in electrical PFM motor response (peak-to-peak amplitude, area under the curve [AUC] or latency) among different electrical stimulation levels up to 10V (and the clinically relevant intensities up to 3V) and different parts (four sides, three depths) of the pelvic floor were modeled using linear mixed model analysis (LMM). RESULTS: The study population comprised 26 women (overall success 81%). With increasing improvement in voiding diary data, higher peak-to-peak amplitudes and AUC were seen for up to 10V stimulation intensities (LMM: p value 0.0046 and 0.0043, respectively) and up to 3V stimulation intensities (LMM: p value 0.0261 and 0.0416, respectively). Subanalysis of the different parts of the PFM showed all different sides (first corrected p value < 0.0125) and depths (first corrected p value < 0.0167) presented with statistically significant differences in favor of those with higher percentage improvement for the 10V and 3V analyses, with only two exceptions: peak-to-peak amplitude at the posterior layer at the clinically relevant stimulation intensities (LMM: p value: 0.0752) and AUC at the posterior layer for the stimulation intensities on 10V (LMM: p value: 0.0557). No statistically significant differences were found for the overall mean peak-to-peak amplitude and AUC based on dichotomous outcome (responders vs nonresponders). CONCLUSIONS: Intraoperative PFM electromyography obtained during lead placement aids in more accurate targeting of the lead to the nerve. To our knowledge, this is the first study to correlate tined lead placement based on electrodiagnostic testing and outcome in SNM. It has been proved to be a reliable measurement tool, serving as a physiological biomarker of treatment response during the test phase. A strong motor response can make the surgeon confident that the correct position of the lead has been established for maximal benefit.

Burst Stimulation Evokes Increased Bladder and Urethral Pressure in Patients With Sacral Neuromodulation, Indicating Potential Activation of the Autonomic Nervous System: A Pilot Study.

OBJECTIVES: Currently, sacral neuromodulation (SNM) outcomes are often suboptimal, and changing stimulation parameters might improve SNM efficacy. Burst stimulation mimics physiological burst firing of the nervous system and might therefore benefit patients treated with SNM. The purpose of the present pilot study was to evaluate the effect of various Burst SNM paradigms on bladder and urethral pressure in patients with overactive bladder (OAB) or nonobstructive urinary retention (NOUR). MATERIALS AND METHODS: The bladder was filled to 50% of its capacity under general anesthesia in six patients with an implanted sacral lead for SNM purposes. Bladder pressure, and mid- and proximal urethral pressure were measured using conventional (Con-) SNM and various Burst SNM paradigms (10-20-40 Hz interburst frequency) with increasing amplitudes up to 5 mA for Con-SNM and 4 mA for Burst SNM. RESULTS: Burst SNM caused a substantial increase in both bladder and urethral pressure. In contrast, Con-SNM caused a milder increase in urethral pressure, and only one patient showed a modest increase in bladder pressure. Furthermore, the pressure increase was higher in the proximal urethra than in the midurethra using Burst-SNM, whereas Con-SNM caused comparable increases in proximal and midurethra pressure. CONCLUSIONS: Burst SNM induces bladder contraction compared with Con-SNM and induces higher pressure increases in bladder and proximal urethra than does Con-SNM in patients with OAB or NOUR, indicating a higher degree of autonomic nervous system stimulation. The observed responses could not be fully explained by the total charge of the Burst SNM paradigms, which suggests the importance of individual Burst SNM parameters, such as frequency and amplitude. Future studies should assess the feasibility and efficacy of Burst SNM in awake patients.

The effect of tranexamic acid on perioperative blood loss in transurethral resection of the prostate: A double-blind, randomized controlled trial.

BACKGROUND: Bleeding and bleeding-related complications remain common after bipolar transurethral resection of the prostate (TURP) for benign prostatic hyperplasia. This may possibly lead to prolonged postoperative irrigation, catheterization, and hospital stay. The objective of this trial was to evaluate the effect of high-dose tranexamic acid (TXA) on perioperative blood loss in patients treated with bipolar TURP for prostate sizes between 30 and 80 g. METHODS: We conducted a single-center, prospective, double-blind, randomized controlled trial. Eighty patients were screened for inclusion between March 2020 and January 2023. After exclusion, 65 patients were randomized in two comparable groups. The TXA group (31 patients) received a TXA intravenous loading dose of 10 mg/kg over 30 min before induction, followed by a maintenance dose of 5 mg/kg/h over 12 h. The placebo group (34 patients) received an equal dose of saline infusion. We measured age, weight, preoperative prostate size, anticoagulant use, 5-alpha reductase inhibitor use, preoperative urinary tract infection, American Society of Anesthesiologists score, difference in pre- and 24 h postoperative hemoglobin and hematocrit levels, operative time, resected adenoma weight, duration of postoperative irrigation, total amount of postoperative irrigation fluid, indwelling catheter time, duration of hospital stay, blood transfusion rate, and 4-week complication rate. RESULTS: Baseline characteristics in both groups were comparable. Postoperative hemoglobin decrease in TXA versus placebo group was 1 versus 1.6 mg/dL, respectively (p = 0.04). In addition, the amount of postoperative irrigation fluid (10.7 vs. 18.5 L), irrigation time (24.3 vs. 37.9 h), catheterization time (40.8 vs. 53.7 h), and hospital stay (46.9 vs. 59.2 h) were statistically significant in favor of TXA use. No blood transfusions were carried out. Four-week complication rate was comparable between the two groups. CONCLUSIONS: Perioperative high-dose TXA seems beneficial in reducing hemoglobin loss, postoperative irrigation, catheterization time, and hospital stay in bipolar TURP for prostate sizes between 30 and 80 g, without increased risk of TXA-related thromboembolic events.

Detailed Investigation of Bladder Diary Parameters During Sacral Neuromodulation in Patients With Overactive Symptoms.

AIMS: Sacral neuromodulation (SNM) is a well-accepted, minimally invasive modality for patients with overactive bladder (OAB). Successful response to SNM is defined as at least 50% improvement in key symptoms, evaluated in a bladder diary (BD). BDs provide much useful information on bladder behavior during daily life. The aim of this study is to investigate BD parameter changes during SNM therapy in patients with OAB. MATERIALS AND METHODS: The International Consultation on Incontinence Questionnaires (ICIQ)-BD was filled out by 34 patients with OAB, for three days at baseline and after three weeks of subthreshold sensory stimulation. The patients were considered responders for SNM when 50% improvement was seen in the BD. They underwent implantation of an internal pulse generator (IPG), and subsequently, an ICIQ-BD and a visual analog scale (VAS) evaluating bladder satisfaction during three days were filled out six weeks, six months, and one year after IPG implantation. RESULTS: IPGs were implanted in 29 patients (85%). The BD showed a significant decrease in 24-hour leakage at three weeks from 4.2 to 0.6 (-86%, p < 0.001), similar significant decreases at six weeks and six months, and at one year (-80%). Voided volume (VV) at corresponding bladder sensation codes was not different between baseline and at three weeks of tined-lead procedure (TLP) (p > 0.05), and at six weeks (p > 0.05), six months (p > 0.1), and one year of IPG (p > 0.08). After three weeks of TLP, urgency episodes decreased from 4.8 to 3.4 (-30%, p = 0.025), with 59% reduction at six-weeks IPG (p < 0.001) and 49% at six-months IPG (p = 0.013). At one year, a decrease from 4.7 to 2.3 (52% reduction, p = 0.017) was noted. VAS showed the strongest correlation with urgency (p < 0.001) and frequency (p = 0.006). No significant correlation was found with VV (p = 0.87). CONCLUSIONS: Our study describes how bladder sensation parameters change over time in patients on SNM. VV does not significantly increase, nor does frequency significantly decrease over the first year. Leaks and the percentage of urgency episodes significantly decrease, reaching a plateau level between six-weeks and six-months SNM.

The Influence of Electrode Configuration Changes on the Sensory and Motor Response During (Re)Programming in Sacral Neuromodulation.

OBJECTIVES: This study aimed to assess the neurophysiological basis behind troubleshooting in sacral neuromodulation (SNM). Close follow-up of SNM patients with program parameter optimization has proven to be paramount by restoring clinical efficacy and avoiding surgical revision. MATERIALS AND METHODS: A total of 34 successful SNM patients (28 overactive bladder wet, six nonobstructive urinary retention) with an implantable pulse generator were included. All possible bipolar and monopolar electrode settings were tested at sensory threshold (ST) to evaluate sensory (mapped on a perineal grid with 1 cm2 coordinates) and motor (peak-to-peak amplitude and latency of muscle action potential) responses of the pelvic floor. Pelvic floor muscle electromyography was recorded using a multiple array probe, placed intravaginally. Parametric tests were used for paired data: repeated-measures ANOVA or t-test. A nonparametric test was used for paired data: Friedman ANOVA or Wilcoxon signed rank (WSR) test; p < 0.05 was considered statistically significant. If significant, ANOVA was followed by Dunn-Bonferroni post hoc analysis. RESULTS: Monopolar configurations showed significantly lower STs-1.38 ± 0.73 V vs 1.76 ± 0.89 V (paired t-test: p < 0.0001)-and presented with significantly higher peak-to-peak amplitudes-115.67 ± 79.03 µV vs 90.77 ± 80.55 µV (WSR: p = 0.005)-than bipolar configurations. When polarity was swapped, configurations with the cathode distal to the anode showed significantly lower STs, 1.73 ± 0.91 V vs 1.85 ± 0.87 V (paired t-test: p = 0.003), and mean peak-to-peak amplitudes, 81.32 ± 72.82 µV vs 100.21 ± 90.22 µV (WSR: p = 0.0001). Cathodal changes resulted in more changes in sensory responses than anodal changes (χ2 test: p = 0.044). In cathodal changes only, peak-to-peak amplitudes were significantly higher when the distance between electrodes was maximally spread (WSR: p = 0.046). CONCLUSIONS: From a neurophysiological point of view, monopolar configurations stimulated more motor nerve fibers at lower STs, therefore providing more therapeutic efficiency. Swapping polarity or changing the position of the cathode led to different sensory and motor responses, serving as potential reprogramming options.

The potential and controversy of targeting STAT family members in cancer.

The Signal Transducer and Activator of Transcription (STAT) family of proteins consists of transcription factors that play a complex and essential role in the regulation of physiologic cell processes, such as proliferation, differentiation, apoptosis and angiogenesis, and serves to organize the epigenetic landscape of immune cells. To date, seven STAT genes have been identified in the human genome; STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. They all account for diverse effects in response to extracellular signaling proteins, mainly by altering gene transcription in the effector cells. Members of the STAT family have been implicated in human cancer development, progression, metastasis, survival and resistance to treatment. Particularly STAT3 and STAT5 are of interest in cancer biology. They are currently considered as oncogenes, but their signaling is embedded into a complex and delicate balance between different (counteracting) transcription factors, and thus, in some contexts they can have a tumor suppressive role. Assessing STAT signaling mutations as well as screening for aberrant STAT pathway activation may have a role to predict sensitivity to immunotherapy and targeted STAT inhibition. In the present comprehensive review of the literature, we discuss in-depth the role of each STAT family member in cancer, assemble cutting-edge information on the use of these molecules as potential biomarkers and targets for treatment, and address why their clinical implementation is controversy.

A Supervised 3 Weeks Test Phase in Sacral Neuromodulation with a 1-Year Followup.

PURPOSE: We sought to determine whether prolonged interventional test phase increases cumulative success rate and compared success rates between early responders (ie within 1 week) and those in need for reprogramming (due to lack of efficacy) of sacral neuromodulation after 1-year followup. MATERIALS AND METHODS: In a single tertiary center prospective study (August 2015 to November 2018) 90 patients refractory to first line treatment were eligible for sacral neuromodulation, including 48 overactive bladder wet (53%), 8 overactive bladder dry (9%) and 34 nonobstructive urinary retention (38%). Patients were evaluated at weekly intervals during test phase and those not successful were reprogrammed. This could be repeated after the second week. Primary outcome was success rate after 3-week test phase and after 1-year followup. Statistical analysis was done by nonparametric tests for numeric (Mann-Whitney U) and categorical (chi2) data. RESULTS: After 3 weeks of test period 56 patients (62%) were considered successful. Prolonged interventional testing increased cumulative success. A 1-year followup showed no significant difference in success rate between early responders and those in need for reprogramming (chi2, p=0.562). There was no difference in age (Mann-Whitney U, p=0.222), sex (chi2, p=0.952) or indication (chi2, p= 0.975). CONCLUSIONS: A 3-week test phase with close followup increases cumulative success rate. During this supervised 3-week test phase 42% of the initial nonresponders after the first week became successful candidates after reprogramming. Patients who required this additional programming did equally as well as those without need for reprogramming. A supervised 3-week test phase is therefore strongly recommended.

Primary Posterior Cruciate Ligament Repair With The Novel Suture Tape Augmentation Technique.

BACKGROUND: A posterior cruciate ligament (PCL) rupture is less common than an anterior cruciate ligament (ACL) rupture. PCL reconstruction remains controversial with variable outcomes and problems. The encouraging results of the novel ACL repair techniques led to renewed interest in PCL repair. Primary arthroscopic PCL repair has been rarely discussed and literature is scarce. To the best of our knowledge, no PCL repair patient outcome has been reported with one of the novel PCL repair techniques. We present the first case report of two patients who have been treated with the novel PCL repair technique, the suture tape augmentation technique. CASE DESCRIPTION: Two patients who underwent primary PCL repair after an acute PCL rupture with a two-year follow up are presented. Patients were evaluated according to the Lysholm scale, the International Knee Documentation Committee (IKDC), and the Tegner activity scale. Follow up also included objective physical examinations-knee function and posterior drawer test using a rolimeter-and magnetic resonance imaging (MRI). Physical examinations were performed at three months, six months, one year, and two years after surgery. OUTCOMES: At two-year follow up, both patients had a full range of motion and experienced no pain, nor swelling. IKDC scores were 83% (good) and 100% (excellent), Lysholm scores were 99 and 100 two years after surgery. At three months postoperative, the Tegner activity scale equaled the preinjury Tegner activity scale. One patient was horseback riding within three months. There were some increased posterior translation differences after two years-+2 and +3mm-compared with six weeks postoperative. MRI showed a healed PCL in both cases. DISCUSSION: PCL repair could be a promising treatment option for acute PCL ruptures. Advantages of this technique are the retaining of the natural proprioceptive capacities due to preserving native PCL fibers, the surgical technique is less invasive compared to a reconstruction, and no donor graft morbidity is expected as no graft is needed. CONCLUSION: In these two cases, good subjective and objective results are demonstrated after PCL repair using the novel suture tape augmentation technique. MRI confirmed the healing of the PCL. Although this is a small case series, as PCL ruptures are less common compared to ACL ruptures, it is a stepping-stone for further PCL repair research.

Bladder perivascular epithelioid cell neoplasm: Review on clinical features of this rare tumor.

Perivascular epithelioid cell neoplasm (PEComa) is a rare mesenchymal tumor composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. They can arise in various localizations such as the bladder. A total of 36 case reports regarding bladder PEComa have been described in the literature. Eleven reviews regarding this tumor have been published in literature so far primarily focusing on anatomic pathology. Through these reviews, it is known that in bladder PEComa, the melanocytic marker Human Melanoma Black-45 is expressed in 100% of cases whereas variable expression can be seen in multiple other melanocytic and myoid markers such as smooth muscle actin, Melan-A, CD117, S100, CD31, and CD34. Since current reviews mainly emphasize anatomic pathology, we perform a review focusing on the clinical aspects of PEComa at the level of the clinician. A manual electronic search of the PubMed/Medline and Web of Science Core Collection databases was conducted. Search was done on (perivascular epithelioid cell neoplasms [MeSH terms]) AND (Bladder). All case reports and reviews were encompassed until March 15, 2023, to identify studies that assessed bladder PEComa. The age of presentation is relatively low with a median age of 37 years. There is a female predominance with a female/male ratio of 1.5. The tumor shows no preference in anatomical localization within the bladder. Even involvement of the bladder neck, proximal urethra, and distal ureter has been described. The clinical presentation consists in the majority of patients of symptoms related to the urinary tract such as hematuria, dysuria, passage of urine sediment, frequency, and urgency. Other symptoms include abdominal discomfort and dysmenorrhea. In clinical examination, an abdominal mass can be found based on the size and location of the tumor. Further examination usually encompasses cystoscopy due to the hematuria and radiological investigations such as ultrasound (US), computed tomography, and magnetic resonance imaging. These radiological investigations reveal a heterogeneous solid mass with clear borders. In our center, we performed a transvaginal US additionally in a patient with bladder PEComa, which was the only investigation in our patient that concluded the mass was located in the Retzius space. For treatment, transurethral resection of the bladder tumor and partial cystectomy were both described in equal numbers. The choice of treatment depends on the localization and size of the tumor. Follow-up consists of imaging, but clear guidelines on this matter are lacking. Bladder PEComa is a rare condition and usually presents itself with nonspecific symptoms. Radiological investigations will reveal the tumor, but the final diagnosis is based on cytological and immunohistochemical features. Since bladder PEComa is an entity with uncertain malignant potential, it is important to include this entity in the differential diagnosis when a patient presents with lower abdominal discomfort and lower urinary tract symptoms in combination with a mass in the pelvic region.

Sacral neuromodulation for the treatment of overactive bladder: systematic review and future prospects.

INTRODUCTION: Sacral Neuromodulation (SNM) is a minimally invasive treatment for OAB patients following failure of conventional interventions. Patient selection, lead placement, and testing technique are important pillars in optimizing success rates. AREAS COVERED: A comprehensive literature search was conducted on 'sacral neuromodulation' and 'overactive bladder.' There was no date restriction, with the last search dated 31 May 2021. Patient selection, lead placement, test phases, safety, efficacy, and available devices are thoroughly discussedLastly, future perspectives will be presented with the anticipated trajectory of sacral neuromodulation over the next five years. EXPERT OPINION/COMMENTARY: SNM has proved to be a safe and effective therapy on the short-, medium- and long-term without precluding any other treatment options. In all studies reviewed, no life threatening or major irreversible complications were presented. However, surgical re-intervention rates were high with a median of 33.2% (range: 8-34%) in studies with at least 24 months follow-up. No true consensus could be made regarding prognostic factors. However, optimized lead placement, consequent ideal motor thresholds, and the use of a curved stylet theoretically facilitates reaching maximal success with SNM. Test phase success rates increased to such a level that from a cost-effective point of view, single-stage implants could be considered.Abbreviations: OAB: overactive bladder; SNM: sacral neuromodulation; BoNT-A: Botulinum toxin A; PFM EMG: pelvic floor muscle electromyography; IPG: implantable pulse generator; PNE: percutaneous nerve evaluation; FSTLP: first-stage tined lead procedure; NLUTD: neurogenic lower urinary tract dysfunction; ITT: intention to threat; PPMC: per protocol modified completers; PPC: per protocol completers; AE: adverse event; MRI: magnetic resonance imaging; RCT: randomized controlled trial.

Intravascular double J stent migration: A case report, review, and management algorithm.

A double J stent (DJS) is the main therapy for ureteral obstruction when conservative treatment fails. Antegrade migration in the bladder - or retrograde migration in the ureter - are well-known complications. We present a case with intravascular migration of a DJS into the inferior vena cava. Inferior venocavagraphy confirmed the position of the stent, and thrombus formation was excluded at its tip. The stent was retracted endoscopically. After the procedure, limited contrast leakage was seen at the perforation site on venography. The current available literature is reviewed. Based on this, a management algorithm is drawn up.

The role of Nuclear Factor-kappa B signaling in human cervical cancer.

Background The Nuclear Factor kappaB (NF-kB) family consists of transcription factors that play a complex and essential role in the regulation of immune responses and inflammation. NF-kB has recently generated considerable interest as it has been implicated in human cancer initiation, progression and resistance to treatment. In the present comprehensive review the different aspects of NF-kB signaling in the carcinogenesis of cancer of the uterine cervix are discussed. NF-kB functions as part of a network, which determines the pattern of its effects on the expression of several other genes (such as crosstalks with reactive oxygen species, p53, STAT3 and miRNAS) and thus its function. Activation of NF-kB triggered by a HPV infection is playing an important role in the innate and adaptive immune response of the host. The virus induces down regulation of NF-kB to liquidate the inhibitory activity for its replication triggered by the immune system leading a status of persistant HPV infection. During the progression to high grade intraepithelial neoplasia and cervical cancer NF-KB becomes constitutionally activated again. Mutations in NF-kB genes are rare in solid tumors but mutations of upstream signaling molecules such as RAS, EGFR, PGF, HER2 have been implicated in elevated NF-kB signaling. NF-kB can stimulate transcription of proliferation regulating genes (eg. cyclin D1 and c-myc), genes involved in metastasis, VEGF dependent angiogenesis and cell immortality by telomerase. NF-kB activation can also induce the expression of activation-induced cytodine deaminase (AID) and the APOBEC proteins, providing a mechanistic link between the NF-kB pathway and mutagenic characteristic of cervical cancer. Inhibition of NF-kB has the potential to be used to reverse resistance to radiotherapy and systemic anti-cancer medication, but currently no clinicaly active NF-kB targeting strategies are available.