Thulium Fiber Laser Versus Holmium:Yttrium Aluminum Garnet for Lithotripsy: A Systematic Review and Meta-analysis.

CONTEXT: Thulium fiber laser (TFL) emerged as a competitor of holmium:yttrium aluminum garnet (Ho:YAG) laser for the treatment of urinary stones. OBJECTIVE: To compare the efficacy between Ho:YAG and TFL for laser lithotripsy of renal and ureteral stones. EVIDENCE ACQUISITION: A literature search was conducted using PubMed/Medline, Embase, and Web of Science databases to identify reports published until May 2023. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed to identify eligible studies. The primary outcome was to compare the stone-free rate (SFR) between Ho:YAG and TFL for laser lithotripsy. EVIDENCE SYNTHESIS: Eleven studies met our inclusion criteria, and data from 1286 and 880 patients who underwent, respectively, Ho:YAG and TFL laser lithotripsy were reviewed. Most studies included ureteroscopy (URS) and retrograde intrarenal surgeries as procedures, two included percutaneous nephrolithotomy, and one included URS exclusively. Only two studies reported results in pediatric patients. TFL was associated with a higher SFR (odds ratio [OR] 1.84, 95% confidence interval [CI]: 1.06-3.20; p = 0.031) when no residual fragment is considered, but not when SFR refers to the presence of fragments <3 mm (OR 2.48, 95% CI: 0.98-6.29; p = 0.055) or when only Ho:YAG with MOSES is considered (p = 0.068). According to the stones' location, TFL was associated with higher SFRs than Ho:YAG for renal (OR 3.14, 95% CI: 1.69-5.86; p < 0.001) but not for ureteral (p = 0.8) stones. TFL was associated with a lower intraoperative complication rate (OR 0.34, 95% CI: 0.19-0.63; p < 0.001). No difference was found in major (p = 0.4) or overall (p = 0.4) complication rate, operative time (p = 0.051), and laser time (p = 0.9). CONCLUSIONS: TFL is a promising laser for the treatment of urinary stones with some advantages over Ho:YAG. Further high-quality studies are needed to confirm these findings and optimize the surgical settings. PATIENT SUMMARY: The use of thulium fiber laser rather than holmium:yttrium aluminum garnet permits to reach a higher stone-free rate in stones located in the kidney rather than in the ureter.

Role, Cost, and Availably of Urinary pH Monitoring for Kidney Stone Disease-A Systematic Review of the Literature.

PURPOSE OF REVIEW: Urinary pH is an important factor related to renal stone disease, and it plays an essential role in stone prevention. Monitoring of urinary pH by patients at home provides information that can help to assess the treatment needed by each patient. We conducted a systematic review is to assess the available evidence concerning urinary pH monitoring methods along with their accuracy, cost, and usefulness by patients with urolithiasis. RECENT FINDINGS: A total of 9 articles were included (1886 urinary pH measurements). They reported information about urinary dipsticks, portable electronic pH meters and electronic strip readers, amongst other methods. Accuracy was compared with a laboratory pH meter (gold standard). Urinary dipsticks were found to be not accurate enough to guide clinical decision making and portable electronic pH meters showed promising results. Urinary dipsticks are neither precise nor accurate enough. Portable electronic pH meters seem to be more accurate, easy to use, and cost-effective. They are a reliable source for patients to use at home in order to prevent future episodes of nephrolithiasis.

Use of Moses 2.0 with extended frequency and optimized Moses vs. high-power laser in MiniPCNL: a randomized controlled trial.

The aim of the study was to compare standard high-power laser (with < 80 Hz) to extended frequency (> 100 Hz) lithotripsy during miniPCNL. 40 patients were randomized in to two groups undergoing MiniPCNL. For both groups, the Holmium Pulse laser Moses 2.0 (Lumenis) was used. For group A, standard high-power laser with < 80 Hz, with Moses distance was set using up to 3 J. For Group B, extended frequency (100-120 Hz) was used allowing up to 0.6 J. All patients underwent MiniPCNL using an 18 Fr balloon access. Demographics were comparable between groups. Mean stone diameter was 19 mm (14-23) with no differences between groups (p = 0.14). Mean operative time was 91 and 87 min for group A and B (p = 0.71), mean laser time was similar in both groups, 6.5 min and 7.5 min, respectively (p = 0.52) as well as the number of laser activations during the surgery (p = 0.43). Mean Watts used was 18 and 16 respectively being similar in both groups (p = 0.54) as well as the total KJoules (p = 0.29). Endoscopic vision was good in all surgeries. The endoscopic and radiologic stone free rate was achieved in all patients expect for two in both groups (p = 0.72). Two Clavien I complications were seen, a small bleeding for group A and a small pelvic perforation in group B. The use of high-power holmium laser with extended frequency and optimized Moses was effective and safe being comparable to standard high-power laser for MiniPCNL allowing more versatility with the setting range.

Bowel Perforation after Extracorporeal Wave Lithotripsy: A Review of the Literature.

INTRODUCTION: Extracorporeal wave lithotripsy (ESWL) is considered a first-line treatment for renal and ureteral stones up to 10-20 mm in diameter. Complications are uncommon, with a reported rate of 0-6% in the literature. Bowel perforation has only been described in a few case reports but requires rapid diagnosis and treatment. METHODS: A review of the literature from PubMed/Medline, Embase, Cochrane, and Web of Science databases was performed including studies reporting bowel perforation secondary to ESWL between January 1990 and June 2022. RESULTS: We found 16 case reports of intestinal perforation in the literature. Although some patients had previously undergone abdominal surgery or had inflammatory intestinal disease, others were without comorbidities that could lead to complications. Abdominal pain was the main symptom and imaging was required to confirm the diagnosis, which usually necessitated a surgical intervention. As regards the ESWL technique, it appears that the combination of a high energy level and the prone position constitutes a risk factor for these rare complications. At the authors' centre, only one case has been reported among 24,000 ESWL procedures over 20 years: A 59-year-old female who underwent ESWL for a distal right ureteral stone presented acute abdominal pain and free intraperitoneal pelvic fluid on ultrasound. A CT scan revealed a small bowel perforation requiring open laparotomy with primary closure. CONCLUSIONS: In conclusion, although bowel perforation after ESWL is rare, progressive abdominal pain with tenderness at physical examination requires proper imaging evaluation to exclude bowel perforation and prompt intervention if required.

New Generation Pulse Modulation in Holmium:YAG Lasers: A Systematic Review of the Literature and Meta-Analysis.

(1) Background: New pulse modulation (PM) technologies in Holmium:YAG lasers are available for urinary stone treatment, but little is known about them. We aim to systematically evaluate the published evidence in terms of their lithotripsy performance. (2) Methods: A systematic electronic search was performed (MEDLINE, Scopus, and Cochrane databases). We included all relevant publications, including randomized controlled trials, non-randomized comparative and non-comparative studies, and in-vitro studies investigating Holmium:YAG lithotripsy performance employing any new PM. (3) Results: Initial search yielded 203 studies; 24 studies were included after selection: 15 in-vitro, 9 in-vivo. 10 In-vitro compared Moses with regular PM, 1 compared Quanta's, 1 Dornier MedTech's, 2 Moses with super Thulium Fiber Laser, and 1 compared Moses with Quanta PMs. Six out of seven comparative studies found a statistically significant difference in favor of new-generation PM technologies in terms of operative time and five out of six in fragmentation time; two studies evaluated retropulsion, both in favor of new-generation PM. There were no statistically significant differences regarding stone-free rate, lasing and operative time, and complications between Moses and regular PM when data were meta-analyzed. (4) Conclusions: Moses PM seems to have better lithotripsy performance than regular modes in in-vitro studies, but there are still some doubts about its in-vivo results. Little is known about the other PMs. Although some results favor Quanta PMs, further studies are needed.

mTOR Inhibition and T-DM1 in HER2-Positive Breast Cancer.

In patients with trastuzumab-resistant HER2-positive breast cancer, the combination of everolimus (mTORC1 inhibitor) with trastuzumab failed to show a clinically significant benefit. However, the combination of mTOR inhibition and the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) remains unexplored. We tested T-DM1 plus everolimus in a broad panel of HER2-positive breast cancer cell lines. The combination was superior to T-DM1 alone in four cell lines (HCC1954, SKBR3, EFM192A, and MDA-MB-36) and in two cultures from primary tumor cells derived from HER2-positive patient-derived xenografts (PDX), but not in BT474 cells. In the trastuzumab-resistant HCC1954 cell line, we characterized the effects of the combination using TAK-228 (mTORC1 and -2 inhibitor) and knockdown of the different mTOR complex components. T-DM1 did not affect mTOR downstream signaling nor induct autophagy. Importantly, mTOR inhibition increased intracellular T-DM1 levels, leading to increased lysosomal accumulation of the compound. The increased efficacy of mTOR inhibition plus T-DM1 was abrogated by lysosome inhibitors (chloroquine and bafilomycin A1). Our experiments suggest that BT474 are less sensitive to T-DM1 due to lack of optimal lysosomal processing and intrinsic resistance to the DM1 moiety. Finally, we performed several in vivo experiments that corroborated the superior activity of T-DM1 and everolimus in HCC1954 and PDX-derived mouse models. In summary, everolimus in combination with T-DM1 showed strong antitumor effects in HER2-positive breast cancer, both in vitro and in vivo. This effect might be related, at least partially, to mTOR-dependent lysosomal processing of T-DM1, a finding that might apply to other ADCs that require lysosomal processing. IMPLICATIONS: Inhibition of mTOR increases the antitumor activity of T-DM1, supporting that the combination of mTOR inhibitors and antibody-drug conjugates warrants clinical evaluation in patients with HER2-positive breast cancer.

Systematic Review and Meta-Analysis Comparing Fluoroless Ureteroscopy and Conventional Ureteroscopy in the Management of Ureteral and Renal Stones.

Context: Stone recurrence is frequent in stone formers, and repeated diagnostic and therapeutic procedures in recurrent stone formers place patients and urologists at a significant risk of radiation-related effects. Objective: To assess the efficacy and safety of fluoroless ureteroscopy (fURS) compared with conventional ureteroscopy (cURS) in the management of ureteral and renal stones. Evidence Acquisition: A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies providing data on the stone-free rate (SFR), secondary procedures, operative time (OT), and complication rate for fURS and cURS were included. An overall analysis and a subgroup analysis based on the stone target (ureteral stones, renal stones, or a combination thereof) were performed. Evidence Synthesis: A total of 23 studies were included, recruiting 4029 patients. Pooled data showed that in comparison with cURS, fURS exhibited a similar SFR (odds ratio [OR]: 0.99; 95% confidence interval [CI]: 0.92 to 1.06; p = 0.709), without significant differences in overall intraoperative complication rate (OR: 0.73; 95% CI: 0.33 to 1.63; p = 0.446), overall postoperative complication rate (OR: 0.98; 95% CI: 0.59 to 1.63; p = 0.949), major postoperative complication rate (Clavien ≥3; OR: 0.46; 95% CI: 0.14 to 1.53; p = 0.205), OT (standardized mean difference [SMD]: 0.07; 95% CI: -0.15 to 0.29; p = 0.537), hospital stay (SMD: -0.12; 95% CI: -0.26 to 0.02; p = 0.084), or secondary procedures (OR: 1.20; 95% CI: 0.58 to 2.49; p = 0.616). The subgroup analysis revealed no differences in outcomes according to the stone target. We also identified a rate of conversion to the conventional technique of 5% (95% CI: 3% to 7%). Conclusions: The available data suggest that for the treatment of ureteral and renal stones, fURS offers a similar SFR to that provided by the cURS without any increase in complication rate, OT, hospital stay, or secondary procedures. Critical review of the dogmatic routine use of fluoroscopy during ureteroscopy may be warranted.

Oral Acidification with l-Methionine as a Noninvasive Treatment for Encrusted Uropathy.

Background: Encrusted uropathy (EU) is a rare disease caused by urea-splitting bacteria, most commonly Corynebacterium urealyticum, whose incidence is increasing. Standard treatment is based on pathogen-directed antibiotic therapy, urinary diversion, bladder instillations, and surgical resection of urinary calcifications. Case Presentation: We present the case of a 60-year-old man with symptomatic bilateral encrusted pyelitis and cystitis with acute renal failure. We initially treated the patient with antibiotic therapy, urinary diversion, and oral acidification with acetohydroxamic acid, achieving negative urinary cultures. Because of the persistence of encrusted pyelitis, the patient was discharged on oral l-methionine 500 mg bid and 12 months later the encrustations had almost disappeared. Finally, we performed right retrograde intrarenal surgery to remove a persistent small calcification. Conclusion: Oral urinary acidification with l-methionine is a valid treatment for urinary encrustations in EU, with no complications reported. Complete resolution of the calcifications may be achieved without the need for invasive processes and unnecessary manipulation of the urinary system.

The relationship between calcium oxalate lithiasis and chronic proinflammatory intestinal dysbiosis pattern: a prospective study.

The objective is to establish whether a pattern of intestinal dysbiosis exists in calcium oxalate (CaOx) lithiasis and, if so, to identify its characteristics and explore whether there are differences in the pattern between CaOx dihydrate (COD) and monohydrate (COM) lithiasis. With this aim 24 patients diagnosed with CaOx lithiasis by means of optical microscopy and spectrometry were prospectively recruited. Faecal analysis was carried out by means of RT-PCR 16S rRNA assay and agar plate culture according to the methodology proposed by the Institute of Microecology (Herborn, Germany). The total number of bacteria was depleted due to COD lithiasis (p = 0.036). The mean values of immunoregulating microbiota were normal, but the percentage of normal values was lower in the COD group (30%) than in the COM group (69.2%) (p = 0.062). The total mean values of protective microbiota were normal in both groups. There was a large decrease in the mean values of the muconutritive microbiota Akkermansia muciniphila and Faecalibacterium prausnitzii, the most intense decline being observed in the COD group (p = 0.019). Levels of proteolytic microbiota were elevated in both groups, without differences between them. We conclude that patients with CaOx lithiasis have a chronic pro-inflammatory intestinal dysbiosis pattern characterised by a reduction in the total number of bacteria, a reduction in immunoregulating microbiota and a large reduction in muconutritive microbiota that is significantly more intense in COD lithiasis than in COM lithiasis.

The role of PIGF blockade in the treatment of colorectal cancer: overcoming the pitfalls.

Introduction: In colorectal cancer, anti-VEGF agents have demonstrated a survival benefit when combined with chemotherapy. However, development of resistance is very common. One of the mechanisms is due not to a failure in the VEGFR blockade, but rather to development of compensatory mechanisms of resistance, such as hypoxia-triggered upregulation of other proangiogenic factors, like placental growth factor (PlGF).Areas covered: This article summarizes the fundamental role of PlGF in the development of resistance to antiangiogenic treatment as well as the efficacy of aflibercept, ramucirumab, and regorafenib.Expert opinion: Aflibercept functions as a soluble decoy receptor precluding VEGFs and PlGF from binding to native VEGFR, and therefore preventing the emergence of resistance. Bevacizumab limits its function to preventing the interaction between VEGF-A and VEGFR. In combination with FOLFIRI (VELOUR trial), aflibercept improves survival in patients with metastatic CRC who are resistant or have progressed to oxaliplatin-based chemotherapy. Ramucirumab, a fully humanized immunoglobulin G1 (IgG-1) monoclonal antibody and regorafenib, a multikinase inhibitor, have significant improvement for overall survival as well as for progression-free survival in chemotherapy refractory settings.

Simultaneous and synchronous bilateral endoscopic treatment of urolithiasis: a multicentric study.

INTRODUCTION: The general prevalence of bilateral urolithiasis has risen to 15% and bilateral non-simultaneous treatment has been reported to have good outcomes. The objective of this study was to evaluate the effectiveness and safety of simultaneous bilateral endoscopic surgery (SBES). MATERIAL AND METHODS: An international multicenter analysis was performed between May 2015 and December 2017. All patients with bilateral stone disease that underwent SBES were included. Patients were treated under general anesthesia in either the supine or lithotomy position. Demographic, clinical, intraoperative and postoperative data were analyzed. RESULTS: A total of 47 patients were included. Mean age was 53.8 years and 70% of the patients were males. The mean American Society of Anesthesiology (ASA) score was 2. The mean diameter of right- and left-sided stones was 29.43 mm (2-83 mm) and 31.15 (4-102 mm), respectively. Staghorn stones were treated in 18 cases (8 right-sided and 10 left-sided), four of them were defined as complete staghorn. The procedures performed were 42 cases of bilateral URS and PCNL and ureteroscopy. Additionally, 5 bilateral flexible ureteroscopy (fURS) cases were described. Intraoperative complications occurred in five patients: four of them were classified as Clavien-Dindo (CD) I and one as CD II. Postoperatively, there were two cases with CD I, 6 with CD II and one CD IIIa.The stone-free status was 70%. Residual stones (30%) were detected only on the side treated for high-volume (complete) staghorn calculi. CONCLUSIONS: SBES is a feasible, effective and safe procedure. It may potentially avoid repeated anesthetic sessions as needed for staged procedures and reduce the length of patients' hospital stay.

HER-Family Ligands Promote Acquired Resistance to Trastuzumab in Gastric Cancer.

Despite the clinical benefit of trastuzumab, eventually all HER2-amplified gastric cancer tumors develop drug resistance. We aimed to identify molecular mechanisms of acquired resistance to trastuzumab in gastric cancer by using well-established cell line-based preclinical models, as well as samples from patients with HER2-positive gastric cancer treated with trastuzumab. We studied trastuzumab resistance in NCI-N87 and OE19, two gastric cancer cell lines that overexpress HER2 receptor and are trastuzumab sensitive. Differences at protein, DNA, and RNA levels between the parental and resistant cells were characterized and functional studies were performed. Paired pre- and post-trastuzumab blood and tissue samples from patients with gastric cancer treated with trastuzumab were analyzed. We found that resistant cells were associated with increased activation of MAPK/ERK and PI3K/mTOR pathways driven by SRC activation. Upstream, resistant cells showed increased coexpression of multiple HER-family ligands that allowed for compensatory activation of alternative HER receptors upon HER2 blockade. Simultaneous inhibition of EGFR, HER2, and HER3 by the novel antibody mixture, Pan-HER, effectively reverted trastuzumab resistance in vitro and in vivo Similarly, an increase in HER-family ligands was observed in serum and tumor from patients with gastric cancer after trastuzumab therapy. We propose that trastuzumab resistance in gastric cancer is mediated by HER-family ligand upregulation that allows a compensatory activation of HER receptors and maintains downstream signaling activation despite trastuzumab therapy. Resistance is reverted by simultaneous inhibition of EGFR, HER2, and HER3, thereby revealing a potential therapeutic strategy to overcome trastuzumab resistance in patients with gastric cancer.

First clinical evaluation of the new single-use flexible and semirigid Pusen ureteroscopes.

INTRODUCTION: The purpose of the present study was to clinically evaluate two new single-use Pusen ureteroscopes, one semirigid with a flexible tip (srURS) and one flexible (fURS). MATERIALS AND METHODS: During ten consecutive procedures (five srURS and five fURS), we subjectively evaluated on a scale from 0 (poor) to 10 (excellent), the scope's deflection, image quality, and maneuverability prior to, during and after the surgery. Patient demographics, complications with the devices, and troubleshooting were recorded. RESULTS: There were a total of ten patients, five of which were female while the other five were male. Mean age was 58.9 years. Seven patients had a single kidney stone with mean size of 9.6 mm (1.6-20 mm). Half of the patients were pre-stented. For the fURS, the preoperative image quality rating was 8.4 (8-10), compared with 6.8 (4-9) during surgery. The preoperative deflection rating was 9.6+ 0.9 (8-10), while during surgery this decreased to 8.0 (6-10) and to 6.0 (4-8) when using a laser fiber. The srURS had a preoperative image quality rating of 9.2 (8-10), which decreased to 7.6 (6-9) while using the scope. The deflection rating decreased from 9.4 (7-10) preoperatively to 7.0 (1-10) postoperatively, and a similar reduction was observed in the maneuverability rating, from 9.6 (8-10) to 7.4 (1-10). Ureteroscopy was considered as a standard in four of the fURS and three of the srURS procedures. The mean overall satisfaction rating was 6. CONCLUSIONS: The two new single-use ureteroscopes, one flexible and one semirigid, were considered to have allowed standard ureteroscopy in four and three out of the five procedures for each scope, respectively. The image quality, deflection, and maneuverability ratings decreased during the procedure for both scopes.

Chromium disrupts chromatin organization and CTCF access to its cognate sites in promoters of differentially expressed genes.

Hexavalent chromium compounds are well-established respiratory carcinogens used in industrial processes. While inhalation exposure constitutes an occupational risk affecting mostly chromium workers, environmental exposure from drinking water is a widespread gastrointestinal cancer risk, affecting millions of people throughout the world. Cr(VI) is genotoxic, forming protein-Cr-DNA adducts and silencing tumor suppressor genes, but its mechanism of action at the molecular level is poorly understood. Our prior work using FAIRE showed that Cr(VI) disrupted the binding of transcription factors CTCF and AP-1 to their cognate chromatin sites. Here, we used two complementary approaches to test the hypothesis that chromium perturbs chromatin organization and dynamics. DANPOS2 analyses of MNase-seq data identified several chromatin alterations induced by Cr(VI) affecting nucleosome architecture, including occupancy changes at specific genome locations; position shifts of 10 nucleotides or more; and changes in position amplitude or fuzziness. ATAC-seq analysis revealed that Cr(VI) disrupted the accessibility of chromatin regions enriched for CTCF and AP-1 binding motifs, with a significant co-occurrence of binding sites for both factors in the same region. Cr(VI)-enriched CTCF sites were confirmed by ChIP-seq and found to correlate with evolutionarily conserved sites occupied by CTCF in vivo, as determined by comparison with ENCODE-validated CTCF datasets from mouse liver. In addition, more than 30% of the Cr(VI)-enriched CTCF sites were located in promoters of genes differentially expressed from chromium treatment. Our results support the conclusion that Cr(VI) exposure promotes broad changes in chromatin accessibility and suggest that the subsequent effects on transcription regulation may result from disruption of CTCF binding and nucleosome spacing, implicating transcription regulatory mechanisms as primary Cr(VI) targets.

Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due to RAS and EGFR extracellular domain (ECD) mutations in metastatic colorectal cancer (mCRC). Some anti-EGFR-refractory patients retain tumor EGFR dependency potentially targetable by agents such as Sym004, which is a mixture of 2 nonoverlapping monoclonal antibodies targeting EGFR. OBJECTIVE: To determine if continuous blockade of EGFR by Sym004 has survival benefit. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, phase 2, randomized, clinical trial comparing 2 regimens of Sym004 with investigator's choice from March 6, 2014, through October 15, 2015. Circulating tumor DNA (ctDNA) was analyzed for biomarker and tracking clonal dynamics during treatment. Participants had wild-type KRAS exon 2 mCRC refractory to standard chemotherapy and acquired resistance to anti-EGFR monoclonal antibodies. INTERVENTIONS: Participants were randomly assigned in a 1:1:1 ratio to Sym004, 12 mg/kg/wk (arm A), Sym004, 9 mg/kg loading dose followed by 6 mg/kg/wk (arm B), or investigator's choice of treatment (arm C). MAIN OUTCOMES AND MEASURES: Overall survival (OS). Secondary end points included preplanned exploratory biomarker analysis in ctDNA. RESULTS: A total of 254 patients were randomized (intent-to-treat [ITT] population) (median age, 63 [range, 34-91] years; 63% male; n = 160). Median OS in the ITT population was 7.9 months (95% CI, 6.5-9.9 months), 10.3 months (95% CI, 9.0-12.9 months), and 9.6 months (95% CI, 8.3-12.2 months) for arms A, B, and C, respectively (hazard ratio [HR], 1.31; 95% CI, 0.92-1.87 for A vs C; and HR, 0.97; 95% CI, 0.68-1.40 for B vs C). The ctDNA revealed high intrapatient genomic heterogeneity following anti-EGFR therapy. Sym004 effectively targeted EGFR ECD-mutated cancer cells, and a decrease in EGFR ECD ctDNA occurred in Sym004-treated patients. However, this did not translate into clinical benefit in patients with EGFR ECD mutations, likely owing to co-occurring resistance mechanisms. A subgroup of patients was defined by ctDNA (RAS/BRAF/EGFR ECD-mutation negative) associated with improved OS in Sym004-treated patients in arm B compared with arm C (median OS, 12.8 and 7.3 months, respectively). CONCLUSIONS AND RELEVANCE: Sym004 did not improve OS in an unselected population of patients with mCRC and acquired anti-EGFR resistance. A prospective clinical validation of Sym004 efficacy in a ctDNA molecularly defined subgroup of patients with refractory mCRC is warranted. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2013-003829-29.

[Epidemiology of urolithiasis in Spain: Review of published demographic data in the period 1977-2016.] / Epidemiología de la urolitiasis en España: revisión de los datos demográficos publicadosen el periodo 1977­2016.

OBJECTIVE: Epidemiological data on urolithiasis in Spain have appeared in publications especially local and regional level, with few referrals to Spanish national territory. The aim of this paper is to review and systematize the epidemiological data published on urolithiasis in Spain. METHODS: We reviewed publications in national and international scientific journals, meetings and conferences, and research reports (1977-2016). PubMed search (indexed papers) and manual bibliography search (not indexed works) were performed. Bibliometric data evaluated: Year of publication, geographic area, number of cases, sample type, study design and publishing format. Demographic systematization of data: age, age and frequency distribution by gender, family history, social stratum, profession, place of residence, ethnics, seasonality and dietary habits. RESULTS: Publications revised: 79 corresponding to 56 main authors. Selected publications with original data: 42 (2 composed by Part I and II, and 2 composed by paper and thesis), corresponding to 35 authors. Bibliometric and demographic data of all publications are displayed in tables, sorted by variables. CONCLUSIONS: The comprehensive review of studies on epidemiology in Spain constitutes a solid basis for future research about epidemiology of urolithiasis.

Epidemiología de la urolitiasis en España: revisión de los datos demográficos publicados en el período 1977-2016 / Current status of extracorporeal shock wave lithotripsy in urinary lithiasis. Epidemiology of urolithiasis in Spain: review of published demographic data in the period 1977-2016

OBJETIVO: Los datos epidemiológicos sobre urolitiasis en España han aparecido sobre todo en publicaciones de ámbito comarcal y autonómico, siendo escasas las de carácter nacional español. El objetivo de este trabajo es revisar y sistematizar los datos epidemiológicos publicados sobre urolitiasis en España en los distintos trabajos. MÉTODOS: Revisión de las publicaciones en revistas científicas nacionales e internacionales, reuniones y congresos, e informes de investigación (1977-2016). Búsqueda en PubMed (trabajos indexados) y rastreo bibliográfico manual (trabajos no indexados). Datos bibliométricos evaluados: año de publicación, zona geográfica, número de casos, tipo de muestra, diseño del estudio y formato de publicación. Datos demográficos sistematizados: edad, distribución de edad y frecuencia por género, antecedente familiar, estrato social, profesión, lugar de residencia, aspectos étnicos, estacionalidad y hábitos dietéticos. RESULTADOS: Publicaciones revisadas: 79, correspondientes a 56 autores principales. Publicaciones seleccionadas con datos originales: 42 (2 compuestas de parte I y II), correspondientes a 35 autores. Se muestran en tablas los datos bibliométricos y demográficos del conjunto de publicaciones, ordenados por variables. CONCLUSIONES: La revisión completa de trabajos sobre epidemiología en España constituye una base sólida para establecer futuras investigaciones epimiológicas sobre urolitiasis

OBJECTIVE: Epidemiological data on urolithiasis in Spain have appeared in publications especially local and regional level, with few referrals to Spanish national territory. The aim of this paper is to review and systematize the epidemiological data published on urolithiasis in Spain. METHODS: We reviewed publications in national and international scientific journals, meetings and conferences, and research reports (1977-2016). PubMed search (indexed papers) and manual bibliography search (not indexed works) were performed. Bibliometric data evaluated: Year of publication, geographic area, number of cases, sample systematization of data: age, age and frequency distribution by gender, family history, social stratum, profession, place of residence, ethnics, seasonality and dietary habits. RESULTS: Publications revised: 79 corresponding to 56 main authors. Selected publications with original data: 42 (2 composed by Part I and II, and 2 composed by paper and thesis), corresponding to 35 authors. Bibliometric and demographic data of all publications are displayed in tables, sorted by variables. CONCLUSIONS: The comprehensive review of studies on epidemiology in Spain constitutes a solid basis for future research about epidemiology of urolithiasis

Simple Laparoscopic Nephrectomy in Stone Disease: Not Always Simple.

OBJECTIVES: Simple nephrectomy is performed for a benign pathology that does not require the excision of either the adrenal gland or any adenopathies. When it is carried out in cases of stone disease, however, it is frequently not a "simple" technique owing to the presence of significant inflammation and infection. METHODS: Ninety-six simple laparoscopic nephrectomies performed because of stone disease between 2006 and 2015 were retrospectively studied. A descriptive statistical analysis was performed, as well as an evaluation of the associated complications. RESULTS: Of the 96 laparoscopic nephrectomies (62 left, 34 right), 7 (7.2%) had to be converted into open surgery owing to the impossibility of dissecting the renal hilum because of xanthogranulomatous pyelonephritis (n = 4) or major associated lesions (n = 3). The indication for nephrectomy was lumbar pain associated with urinary infection, with a partial renal function below 15% assessed by DMSA renal scan. There were three major complications. Pathologic assessment revealed chronic pyelonephritis with kidney atrophy and associated pyonephrosis in 85 cases, xanthogranulomatous pyelonephritis in 10, and pT4 squamous cell carcinoma in 1. CONCLUSIONS: Despite its high technical difficulty, simple laparoscopic nephrectomy for stones is a viable technique for advanced laparoscopists. Its principal advantage compared with open surgery is improved postsurgical recovery, and it is associated with an acceptable complication rate. Xanthogranulomatous pyelonephritis is not an initial contraindication to laparoscopy, but it is the most significant risk factor for conversion to open surgery.