Thulium fiber laser vs Ho:YAG in RIRS: a prospective randomized clinical trial assessing the efficacy of lasers and different fiber diameters (150 µm and 200 µm).

INTRODUCTION: The aims of the study: (1) to compare the Super Pulse Thulium Fiber Laser (SP TFL) and the holmium: yttrium-aluminium-garnet (Ho:YAG) lasers in retrograde intrarenal surgery (RIRS); (2) to compare the efficacy of SP TFL laser fibers of different diameters (150 µm and 200 µm). METHODS: A prospective randomized single-blinded trial was conducted. Patients with stones from 10 to 20 mm were randomly assigned RIRS in three groups: (1) SP TFL (NTO IRE-Polus, Russia) with fiber diameter of 150 µm; (2) SP TFL with 200-µm fiber; and (3) Ho:YAG (Lumenis, USA) with 200-µm fiber. RESULTS: Ninety-six patients with kidney stones were randomized to undergo RIRS with SP TFL using a 150-µm fiber (34 patients) and a 200-µm fiber (32 patients) and RIRS with Ho:YAG (30 patients). The median laser on time (LOT) in the 200-µm SP TFL group was 9.2 (6.2-14.6) min, in 150-µm SP TFL-11.4 (7.7-14.9) min (p = 0.390), in Ho:YAG-14.1 (10.8-18.1) min (p = 0.021). The total energy consumed in 200-µm SP TFL was 8.4 (5.8-15.2) kJ; 150-µm SP TFL - 10.8 (7.3-13.5) kJ (p = 0.626) and in Ho:YAG-15.2 (11.1-25.3) kJ (p = 0.005). CONCLUSIONS: Irrespective of the density, RIRS with SP TFL laser has proven to be both a safe and effective procedure. Whilst the introduction of smaller fibers may have the potential to reduce the duration of surgery, SP TFL results in a reduction in the LOT and total energy for stone ablation in RIRS compared with Ho:YAG.

A Prospective Comparison of Transrectal Standard, Cognitive, Transperineal Fusion, and Mapping Prostate Biopsy for Cancer Detection.

Purpose: The aim of this research was to compare the clinically significant prostate cancer (csPCa) detection rate (International Society of Urological Pathology [ISUP] ≥2) for the four biopsy methods: transrectal ultrasound-guided biopsy (TRUS-GB), cognitive transrectal biopsy (COG-TB), fusion transperineal biopsy (FUS-TB), and transperineal template mapping biopsy (TPMB). Materials and Methods: The inclusion criteria were as follows: prostate-specific antigen (PSA) >2 ng/mL, and/or positive digital rectal examination (DRE), and/or suspicious lesion on transrectal ultrasound (TRUS) and Prostate Imaging Reporting and Data System (Pi-RADS) v2.1 ≥ 3 score. In total, 102 patients were enrolled in the study. Biopsies were performed by two urologists. In a single procedure, the first urologist performed a FUS-TB and TPMB followed by second urologist who performed TRUS-GB and COG-TB. All specimens were obtained within a single procedure. Results: The csPCa detection rate and overall cancer detection rate (CDR) per patient were comparable among the respective biopsy methods (p > 0.05). Compared with other biopsy methods, a lower clinically insignificant prostate cancer (cisPCa) was detected using COG-TB (p = 0.004). The positive cores percentage ratio (p < 0.001) as well as positive cores containing csPCa percentage ratio (p < 0.001) significantly increased for the targeted biopsy methods. The median maximum cancer core length (MCCL; p = 0.52) as well the median for the MCCL of csPCa (p = 0.47) did not differ significantly among the respective biopsy methods. Concordance of the Gleason scores between biopsy and postprostatectomy pathology did not differ significantly among biopsy methods (p = 0.87). For TRUS-GB, FUS-TB, and TPMB, the common predictive factors for csPCa were positive DRE, suspicious lesion on ultrasound and Pi-RADS 5. As for COG-TB, the only predictor was Pi-RADS 5. Conclusion: The targeted methods did not show an increase in detection of csPCa and overall CDR over systematic ones in patients with Pi-RADS ≥3. A lower cisPCa was detected using COG-TB in comparison with the other methods. The sampling efficiency increased for the targeted biopsy methods, which used only a proportion of positive cores and cores containing csPCa. There was no statistical difference in histology concordance among the biopsies. One common predictive factor of increased csPCa detection for all biopsy methods was Pi-RADS 5.

Randomized prospective trial of the severity of irritative symptoms after HoLEP vs ThuFLEP.

PURPOSE: To compare the short-term postoperative functional outcomes and severity of irritative symptoms following holmium and thulium fiber laser enucleation (HoLEP and ThuFLEP). METHODS: This prospective randomized single-blinded study was performed in accordance with CONSORT. The inclusion criteria were IPSS > 20 or Qmax < 10 ml/s. Patients were randomized between HoLEP and ThuFLEP. Demographics, objective data (PSA, prostate volume, etc.), data on urinary and sexual function (IPSS, IIEF, QoL, QUID, Qmax, ICIQ-MLUTS) were collected. Detailed perioperative information and postoperative data on functional outcomes at 1, 2, 3, 4, 6, 8, 10, 12 weeks and 6 months were collected. RESULTS: Data on 163 participants were included (77-HoLEP, 86-ThuFLEP). No differences were found in surgery duration; number of postoperative complications (Clavien-Dindo I-III), catheterization time and hospital stay. Functional outcomes up to 6 months didn't differ between the groups (IPPS, IIEF, QoL, QUID, ICIQ-MLUTS, Qmax, p > 0.05). Total ICIQ-MLUTS, bother and voiding scores at 1 and 3 months significantly increased compared with the baseline in both groups (p < 0.05). No difference between the groups were observed. In HoLEP the SUI series rate was 1.3% and 1.3% after 3 and 6 months following the procedure; in ThuFLEP: it was 3.5% and 2.3% respectively (p = 0.35 and p = 0.54). CONCLUSION: The preliminary results of the study showed no apparent differences in functional outcomes (IPSS, Qmax), rate of SUI or irritative symptoms. Both ThuFLEP and HoLEP are efficient ways of treating benign prostatic obstruction. Both surgeries are comparable in terms of duration and postoperative complication rates.

EAU, AUA and NICE Guidelines on Surgical and Minimally Invasive Treatment of Benign Prostate Hyperplasia: A Critical Appraisal of the Guidelines Using the AGREE-II Tool.

OBJECTIVE: To critically appraise the methodological rigour of the clinical practice guidelines (CPGs) vis-à-vis BPH surgery as used by specialist research associations in the US, Europe and UK, and to compare whether the guidelines cover all or only some of the available treatments. METHODS: The current guidelines issued by the EUA, AUA and NICE associations have been analyzed by 4 appraisers using the AGREE-II instrument. We also compared the recommendations given in the guidelines for surgical and minimally invasive treatment to find out which of these CPGs include most of the available treatment options. RESULTS: According to the AGREE II tool, the median scores of domains were: domain 1 scope and purpose 66.7%, domain 2 stakeholder involvement 50.0%, domain 3 rigor of development 65.1%, domain 4 clarity of presentation 80.6%, domain 5 applicability 33.3%, domain 6 editorial independence 72.9%. The overall assessment according to AGREE II is 83.3%. The NICE guideline scored highest on 5 out of 6 domains and the highest overall assessment score (91.6%). The EAU guideline scored lowest on 4 out of 6 domains and has the lowest overall assessment score (79.1%). CONCLUSIONS: The analyzed CPGs comprehensively highlight the minimally invasive and surgical treatment options for BPH. According to the AGREE II tool, the domains for clarity of presentation and editorial independence received the highest scores. The stakeholder involvement and applicability domains were ranked as the lowest. Improving the CPG in these domains may help to improve the clinical utility and applicability of CPGs.

Nephrometric score based on 3D modeling (3D nephrometry score) for the probability prediction of intra- and postoperative complications for kidney surgery.

AIM: The purpose of the study is the development and evaluation of the informativeness of the author's 3D nephrometric score application to predict the probability of intraoperative and postoperative complications in kidney operations. MATERIAL AND METHODS: The study includes 264 patients who underwent surgical treatment of renal tumors, before that CT and 3D modeling were carried out. All patients underwent an analysis of the surgical intervention complexity on the C-index, PADUA, R.E.N.A.L., and developed 3D nephrometric score. To determine the set of variables that allow to classify patients, the method of discriminant analysis was used to predict the nature, volume of blood loss, duration of ischemia, and the number of complications. The sensitivity and specificity of the predictors were estimated with the help of ROC analysis. RESULTS: Indicators have been established to classify patients according to the probability of complications, the amount of blood loss and the duration of ischemia during surgery for kidney cancer. We have created linear models that predict the development of bleeding during surgery, the volume of blood loss of more than 200 ml and the duration of ischemia more than 20 min, as well as the likelihood of complications using discriminant functions. The proposed author's nephrometric score exceeds the capabilities of C-index, PADUA, R.E.N.A.L in many ways in blood loss and time of ischemia predicting, which allows us to recommend it for the assessment of resectability in kidney operations.

Prospective Single-Center Study of SuperPulsed Thulium Fiber Laser in Retrograde Intrarenal Surgery: Initial Clinical Data.

INTRODUCTION: The objective of this study was to present our clinical experience of using the thulium fiber laser in retrograde intrarenal surgery (RIRS). METHODS: A prospective clinical study performed after the IRB approval (Sechenov University, Russia). Patients with stones <30 mm were treated with SuperPulsed thulium fiber laser (SP TFL) (NTO IRE-Polus, Russia) through a 200-µm-diameter fiber. Stone size, density, the duration of the operation, and laser on time (LOT) were measured. Based on the surgeon's feedback, retropulsion and intraoperative visibility were also assessed (Likert scale). Stone-free rates (SFRs) were assessed with a low-dose CT scan 90 days after the operation. RESULTS: Between January 2018 and December 2019, 153 patients (mean age 54 ± 2.8 years) underwent RIRS with SP TFL (mean stone density 1,020 ± 382 HU). Median stone volume was 279.6 (139.4-615.8) mm3. Median LOT was 2.8 (IQR 1.6-6.6) min with median total energy for stone ablation 4.0 (IQR 2.1-7.17) kJ, median ablation speed was 1.7 (1.0-2.8) mm3/s, median ablation efficacy was 13.3 (7.3-20.9) J/mm3, and energy consumption was 170.3 (59.7-743.3) J/s. Overall, the SFR (at 3 months) was 89%. The overall complication rate was 8.4%. Retropulsion was present in 23 (15.1%) patients. Visibility was estimated as optimal in most patients, with poor visibility reported in only 13 (8.5%) patients. CONCLUSION: The SP TFL is a safe and efficient tool in lithotripsy, irrespective of the stone type and density. Retropulsion is minimal and visibility is maintained with SP TFL. Nonetheless, further clinical studies are needed to ensure optimal comparison with conventional holmium:YAG lithotripsy.

Retrograde intrarenal surgery versus percutaneous nephrolithotomy in larger kidney stones. Could SuperPulsed Thulium-fiber laser change the game?

INTRODUCTION: The aim of this article was to compare retrograde intrarenal surgery (RIRS) and percutaneous nephrolithotomy (PCNL) efficacy and safety with SuperPulsed Thulium-fiber laser (SP TFL) for stones 20 mm and larger. MATERIAL AND METHODS: Patients with large kidney stones (20 mm and larger) were recruited to undergo PCNL or RIRS with SP TFL lithotripsy. Both groups were comparable in terms of stone size and density, operation time, laser-on time (LOT), stone-free rate, residual fragments and complication rate. Stone retropulsion and visibility were assessed based on the surgeon's feedback using Likert scales. RESULTS: A total of 14 and 56 patients were included in the RIRS and PCNL groups, respectively. The mean stone density was 833.8 ±298.3 HU in the RIRS group and 882.3 ±408.5 HU in the PCNL group (p = 0.072). The median LOT was 11.7 (10.0-15.5) min for RIRS and 10.0 (6.0-12.1) min for PCNL (p = 0.207). The median total energy for stone ablation was 13.8 (11.8-25.0) kJ for RIRS and 12.0 (7.0-20.1) kJ for PCNL (p = 0.508). The median ablation speed was 3.9 (3.9-5.7) mm3/sec for RIRS and 5.0 (4.6-11.3) mm3/sec for PCNL (p = 0.085). We found a significant correlation between retropulsion and the type of surgery performed: with higher retropulsion in the PCNL (r = 0.298 with p = 0.012). The stone-free rate at 3-months was 85.7% in RIRS and 89.3% in PCNL (p = 0.505). CONCLUSIONS: SP TFL is a safe and effective modality for lithotripsy for both, RIRS and PCNL, achieving minimal retropulsion and good visibility. No discrepancies in procedure duration, complications, or LOT were identified between the different modalities.

hTERT, hTR and TERT promoter mutations as markers for urological cancers detection: A systematic review.

The clinical relevance of telomerase subunits (human reverse transcriptase - hTERT, and human telomerase RNA - hTR) and TERT promotor mutations as biomarkers in genitourinary cancers was reviewed through the systematic analysis of the current literature. We performed a systematic literature search using 2 databases (Medline and Scopus) over the past 20 years. Primary outcomes were sensitivity and specificity of hTR, hTERT and TERT promoter mutations. Secondary outcomes were the biomarkers predictive values for tumor characteristics. Regarding bladder cancer, hTERT in urine showed high sensitivity (mean values: 55%-96%), and specificity (69%-100%): it correlated with bladder cancer grade and/or stage. hTR sensitivity ranged from 77% to 92%. With adapted cut-off, it demonstrated 72% to 89% specificity. TERT promoter mutation rate was up to 80% both in tissue and urine, resulting in 62%-92% sensitivity for primary tumors and 42% for relapse. Specificity ranged from 73% to 96%, no correlations with stage were observed. In prostate cancer, hTERT in tissue, prostate secretion and serum showed high sensitivity (97.9%, 36%, and 79.2%-97.5%, respectively) and specificity values (70%, 66%, 60%-100%). hTR showed very high sensitivity (88% in serum and 100% in tissue) although specificity values were highly variable depending on the series and techniques (0%-96.5%). In RCC, hTERT sensitivity on tissue ranged from 90 to 97%, specificity from 25 to 58%. There was an association of hTERT expression with tumor stage and grade. hTERT showed high accuracy in genitourinary cancers, while the value of hTR was more controversial. hTERT and TERT promotor mutations may have predictive value for bladder cancer and RCC staging and grading, while no such relationship was observed in CaP. Although telomerase subunits showed clinically relevant values in genitourinary cancers, developing fast and cost-effective methods is required before contemplating routine use.

Minimally invasive percutaneous nephrolithotomy with SuperPulsed Thulium-fiber laser.

We aimed to assess the efficacy and safety of minimally invasive percutaneous nephrolithotomy (PCNL) with SuperPulsed Thulium-fiber laser (SP TFL) using different frequency settings. 125 patients with solitary kidney calculi of up to 55 mm in the maximum diameter underwent mini-PCNL with the SP TFL. Stone-free rate, laser-on time, ablation efficacy, energy consumption, ablation speed and complications were all analyzed. Negative low-dose computed tomography scan or asymptomatic patients with stone fragments < 2 mm were the criteria for assessing the stone-free status. In 36 patients (28.8%) low frequency regimens were used (LF: 3-19 Hz-0.5-6 J), in 75 patients (60%) high frequency regimens were chosen (HF: 20-49 Hz-0.2-2 J) and in 14 (11.2%) patients higher frequency (HRF: 50-200 Hz-0.1-0.5 J) regimens were preferred. The mean age was 52 ± 1.8 years. Median stone diameter and median stone volume were larger at low frequency regimens compared to high frequency regimens. Ablation efficacy (J/mm3) was lower at low rather than at high frequency regimens. Ablation speed (mm3/sec) was higher at low compared to high frequency regimens. Surgeons reported minimal and absent retropulsion at higher frequency regimens. The best visibility was observed at high frequency regimens. The overall stone free rate (SFR) at 3 months was 85%. The majority of the postoperative complications were classified between Clavien grades I-II. SP TFL is an effective and safe tool for performing mini-PCNL regardless of the laser settings.

MALT Lymphoma of the Urinary Bladder Shows a Dramatic Female Predominance, Uneven Geographic Distribution, and Possible Infectious Etiology.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) of the urinary bladder is an extremely rare entity accounting for 0.2% of all malignant urinary bladder neoplasms, and the diagnosis could be challenging. We present here a patient with urinary bladder MALT lymphoma and review of all published case reports in the literature. We summarized the reported immunophenotype of the neoplasm, ancillary studies, therapy, and follow-up for all 59 patients in the table. The median patients' age was 57 years-old (range, 17 to 88), with female predominance in 50 of 59 patients representing a 1:5.6 ratio. Geographical distribution of the reported patients was as follows: 22 from Asia, of which more than a half (16) originated from Japan; 28 from Europe, of which 19 reported from the United Kingdom, and 3 patients were reported from the United States (including our patient). Twenty-three (77%) of 30 patients, for whom their clinical presentation was recorded, had symptoms of cystitis; Escherichia coli was the most common pathogen. We concluded that a prominent female predominance, uneven geographic distribution of urinary bladder MALT lymphoma, and a success of antibacterial therapy in selected cases suggest the link between urinary tract infection and urinary bladder MALT lymphoma.

Unusual Case of Anaplastic Large Cell Lymphoma Presenting as a Breast Mass in a Patient with no History of Breast Implants.

Adenocarcinoma is the most common malignant neoplasm involving breast tissue. In contrast to carcinomas, the other types of malignant neoplasms involving the breast are relatively uncommon. One of the examples of this rare entity is lymphoma. Traditionally, non-Hodgkin lymphomas (NHL) involving the breast are divided into primary lymphoma of the breast and systemic lymphoma, although the distinction could be challenging. Most of NHL involving breast tissue have B cell origin; T cell NHL represents less than 20% of all lymphoma cases. Anaplastic large cell lymphomas (ALCL) involving the breast accounts for even lower percentage of cases. Similar to ALCL involving other sites, there are several main types of ALCL identified: primary cutaneous ALCL and systemic ALCL, which is subdivided into ALK positive and ALK negative subtypes. Relatively recently, an additional distinct subtype of ALK-negative ALCL was described, which is associated with textured breast implants and needs to be considered as a differential diagnosis if patient has a history of breast implants. Here, we report a case of ALCL presented as a breast mass without history of breast implant and discuss similar cases published in the literature.

A systematic review of irreversible electroporation in localised prostate cancer treatment.

Irreversible electroporation is a treatment option used for focal therapy. In this systematic review, we summarise data on irreversible electroporation outcomes in patients with localised prostate cancer. We performed a literature search in 3 databases and included articles with own data on irreversible electroporation results in patients with localised prostate cancer. Primary outcome was procedure efficacy measured as the absence of cancer in the treatment area on the follow-up biopsy. Secondary outcomes were the absence of prostate cancer recurrence in the treatment area on MRI, out-of-field recurrence, complications and functional outcomes (erectile function and micturition). In-field recurrence rate was 0%-39% and out-field 6.4%-24%. In all studies, PSA level decreased: twice lower than baseline after 4 weeks and by 76% after 2 years. Most of the authors noted sexual and urinary toxicity during the first half year after surgery. However, functional outcomes recovered to baseline after 6 months with mild decrease in sexual function. Complication rates after irreversible electroporation were 0%-1% of Clavien-Dindo III and 5%-20% of Clavien-Dindo I-II. Irreversible electroporation has promise oncological outcomes, rate of post-operative complications and minimal-to-no effects on erectile and urinary function. However, medium and long-term data on cancer-specific and recurrence-free survival are still lacking.

Comparative results of cryoablation and laparoscopic radical prostatectomy in the treatment of localized prostate cancer.

AIM: To evaluate early prostate cancer cryoablation functional and oncological results in comparison with results of extraperitoneoscopic radical prostatectomy. MATERIALS AND METHODS: We analyzed early results of surgical treatment of 285 patients with prostate cancer: 42 of them had undergone total cryoablation (Group 1) while the rest of them had been treated by radical laparo- and extraperitoneoscopic prostatectomy. For comparative assessment of prostate cryoablation results, 42 patients from Group 2 randomized in accordance with their age, stage of disease, Gleason, prostate-specific antigen, and prostate volume were selected. In compliance with the results of pre-surgical examination, all the patients had low oncological risk and were not concerned in sexual function. Volume of prostate was from 22 to 65 cm3, prostate-specific antigen level was from 4.1 to 10 ng/mL, and level of neoplastic process differentiation using Gleason grading system was from 6 to 7a (3 + 4) scores. RESULTS: Patients after prostate cryoablation in early post-surgical period felt lower intensity of postoperative pain compared with those who had undergone prostatectomy. Follow-up period up to 12 months manifested significant true reduction of prostate-specific antigen level in both groups of patients. Frequency of stress-induced enuresis in Group 1 was not observed. CONCLUSION: Radical prostatectomy is still the traditional treatment of choice in the case of localized prostate cancer. But we can draw the conclusion that cryoablation is an effective low-invasive method for treatment of low oncological risk patients, which gives the opportunity both to achieve good oncological results and to preserve high life quality.

Radical prostatectomy performed via robotic, transperitoneal and extraperitoneoscopic approaches: functional and early oncological outcomes.

INTRODUCTION: Oncological remission along with high postoperative functionality [continence and erectile function (EF)] are the main aspects of prostate cancer (PCa) treatment. The aim of this study was to compare functional and oncological treatment results achieved after a nerve-sparing radical prostatectomy (RP) via transperitoneal (TPRP), extraperitoneal (EPRP) and robot-assisted (RARP) approach. MATERIAL AND METHODS: From March 2015 to March 2016, 507 RP were performed at the Institute for Urology and Reproductive Health (Moscow, Russia). A total of 264 patients with localized (cТ1а-2с) prostate cancer [prostate-specific antigen (PSA) <20 ng/ml, Gleason score ≤7], intact prostate capsule (according to MRI), International Index of Erectile Function (IIEF-5) ≥19 and a life expectancy >10 years were included into the retrospective study. All the surgeries were performed by a single surgeon. The outcomes were evaluated after urethral catheter removal and 3-6-12 months after RP. RESULTS: Nerve preservation (NP) was performed for 153 patients without significant distinctions in time (р = 0.064) and blood loss (р = 0.073). The International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-SF) score was lower for NP: 9.23 ±6.59 and 3.86 ±5.38 after 3 and 12 months respectively compared with continence after RP without nerve preservation (NP): 14.27 ±5.1 vs. 6.15 ±4.76 (р <0.001). Continent was 52.2% vs. 83.3% vs. 81.8% in TPRP, RARP and EPRP groups; р <0.001. IIEF-5 scores were 14.67 ±9.4, 4.2 ±4.26 and 4.0 ±2.07 after RARP, TPRP and EPRP respectively (р = 0.002). After 12 months the PSA: TPRP = 0.11 ±0.19, RARP = 0.03 ±0.05 and EPRP = 0.53 ±1.87 ng/ml (р <0.001). Outcomes depend on surgical approach and was better in the RARP-group (AUC = 0.768 ±0.034 (CI 95% 0,701-0.834; р <0.001). CONCLUSIONS: We suggest RARP with NP as a method of choice for treatment of prostate cancer in patients interested in preservation of EF and quality of life in general.

Percutaneous US-guided renal cryoablation using 3D modeling.

INTRODUCTION: The article describes the first experience of performing percutaneous ultrasound (US)-guided cryoablation of renal tumor and assesses the safety and short-term results of treatment. MATERIALS AND METHODS: Twelve patients were subjected to US-guided cryoablation of renal tumor in 2015. The tumor size in 11 patients was up to 3.0 cm (T1а); in one female patient, 4.5 cm (T1b). Tumors were assessed according to the PADUA score. In eight patients, it was 6-7 (low); in three patients, 8-9 (average); in one, 10 (high). All the patients underwent US examination using a FlexFocus 800 apparatus with convex abdominal transducers. Before surgery and 6 months later, all the patients underwent renal Doppler US and contrast-enhanced computed tomography. RESULTS: The average cryoablation time was 60 min. Seven operations were performed under spinal anesthesia and five operations under local anesthesia. The follow-up period lasted 8 months on average. According to the ultrasonography and Doppler findings, after 6 months, the tumor (T1a) in 11 patients reduced in size by an average of 7-8 mm and had no blood supply.T1b patient's mass size reduces from 4.5 to 3.7 cm; however, a 1.5 cm area with a high attenuation gradient of the contrast medium was visualized. Later, the patient was subjected to laparoscopic renal resection. Histological finding revealed clear-cell carcinoma. CONCLUSIONS: We consider percutaneous US-guided cryoablation as a method of choice for patients with stage T1a renal tumor localized on the posterior or lateral surface in the inferior or middle segment without sinus involvement and PADUA <9.