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Background: The popularization of all-inside (AI) meniscal repair devices has led to a shift away from the historical gold standard of inside-out (IO) meniscal repair without comparative studies to support the change. Purpose: To compare the failure rate and time to failure of AI and IO meniscal repair performed in elite athletes. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective review was performed of all professional and national- and international-level amateur athletes who underwent meniscal repair, with a minimum of 2-year follow-up between January 2013 and September 2019. Meniscal repair was classified as AI or IO depending on the surgical technique performed. Treatment failure was defined as patients having to undergo subsequent surgery to address a persistent meniscal tear after repair. Cox proportional hazards modeling was used to determine if meniscal repair failure rates differed by the location and technique of meniscal repair. Models were controlled for known risk factors such as age, sex, sport, and concurrent cruciate ligament reconstruction. Results: A total of 192 (135 lateral and 57 medial) meniscal repairs were performed in elite athletes during the study period. Overall, 41 (21%) meniscal repairs met the criteria for failure. Medial meniscal tears repaired with the AI technique failed at a significantly higher rate (18/31 [58%]) than medial meniscal tears repaired with the IO technique (6/26 [23%]) or lateral meniscal tears repaired with the AI (9/76 [12%]) or IO (8/59 [14%]) technique ( P < .001). Cox proportional hazards modeling revealed that a medial meniscal tear repaired with the AI technique had an almost 8 times greater hazard of failure than a lateral meniscal tear repaired with the AI technique ( P < .001). At 1 year postoperatively, 8% of lateral meniscal repairs had failed (regardless of technique), while medial meniscal tears failed at a rate of 16% with the IO technique and 42% with the AI technique. By 2 years, 53% of medial meniscal tears repaired with the AI technique had failed, and by 5 years, 63% had failed. Conclusion: AI repair of medial meniscal tears led to a higher rate of failure than IO repair of medial or lateral meniscal tears in elite athletes. Medial meniscal repair failed at a higher rate than lateral meniscal repair.

The ACL is a complex ribbon-like structure, which is approximately 3.5 times larger at the tibial and femoral insertions than at the midpoint. Accordingly, it is impossible to recreate with a single cylindrical graft. However, this has not stopped surgeons from using the term 'anatomic' to describe multiple ACL reconstruction techniques inserting at a number of different locations within the original ACL footprint, causing confusion. The term 'anatomic' should be discarded and replaced by an anatomic description of the tunnel placements on the tibia and femur. Current ACL reconstruction techniques cite anatomical studies that identified 'direct and indirect fibres' of the ACL. The 'direct fibres' bear 85-95% of the load and provide the main resistance to both anterior tibial translation and internal rotation/pivot shift. On the femur these fibres insert in a line just posterior to the intercondylar ridge and comprise the portion of the ACL that surgeons should strive to restore. Placement of the graft just posterior to the intercondylar ridge creates a line of placement options from the anteromedial bundle to the 'central' position, and finally to the posteromedial bundle position. The authors prefer placing the femoral tunnel in the isometric anteromedial position and addressing a high-grade pivot shift at the IT-band with a lateral extra-articular tenodesis. As with the femoral tunnel, the native ACL footprint on the tibia is much larger than the ACL graft and thus can be placed in multiple 'anatomic' locations. The authors prefer placement of the tibial tunnel in the anterior most position of the native footprint, that does not cause impingement in the femoral notch. Additional research is needed to determine the ideal tunnel positions on the femur and tibia and validating the technique with patient outcomes. However, this cannot be accomplished without describing tunnel placement with specific anatomical locations so other surgeons can replicate the technique.

The purpose of the study is to assess return to play rate and timing of elite athletes treated for multi-ligament knee injuries with modern surgical techniques.A retrospective review was performed of all professional or national/international level athletes treated for a multi-ligament knee injury by the senior author in the period from February 2001 to October 2019, with a minimum of 2-year follow-up. The study cohort consisted of 136 elite athletes who underwent surgery of two or more knee ligaments. Outcomes measures were return to play (RTP), defined as return to elite level sport, return to play time, and further surgical procedures.One hundred and twenty (88.2%) athletes returned to elite level sport at an average of 12.8 months from operation. In unicruciate injuries, ACL and PCL-based injuries had similar return to play rates (89.1% vs. 87.5% respectfully, n.s.) although mean RTP time was longer in those with PCL-based injuries (15.2 vs. 11.9 months, p 0.01). Bicruciate injuries had longer RTP times compared to unicruciate injuries (mean RTP 16.0vs. 12.4 months, p 0.05) but were able to return at a similar rate (83.3% vs. 88.9%, n.s.). Medial and lateral sided injuries had similar RTP rates (89.3% vs. 87.9%, n.s.) though lateral sided injuries took longer before returning to play (13.4 vs. 11.6 months, p 0.05). Further surgery was required in 54 (39.9%) patients including 25 (18.4%) manipulations under anaesthesia. Four (2.9%) of the athletes underwent revision ligament surgery.Modern surgical techniques used in the treatment of multi-ligament knee injuries can lead to high return to play rates in elite athletes.IV.

Genotype; Cancer phenotypes; Genetic tumour Genotip; Fenotips del càncer; Tumor genètic Genotipo; Fenotipos del cáncer; Tumor genético Background Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype–phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing. Methods This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype–phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test. Findings From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1–93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66–57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18–29·39], p=0·0017) and gastric cancer (7·81 [2·03–29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004). Interpretation CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria. Funding European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme. European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme.

Modern ACL reconstruction (ACL-R) techniques have led to improved outcomes in professional footballers. The aim of this study was to identify and assess patient, surgical and post-operative factors that affected rates and time to return to play (RTP) as well as ACL re-rupture rates. A retrospective review of consecutive ACL-R undertaken in professional footballers between 2005 and 2018. Two-hundred and thirty-two knees in 215 professional footballers (17 bilateral) were included. 205 (88.9%) were male and average age at surgery was 23.3 ± 4.4 years. Two-hundred and twenty-two (96.1%) returned to professional football, with 209 (90.1%) returning to the same or higher Tegner level. Subgroup analysis revealed three factors that independently affected RTP rate: (1) Players under 25 years had a higher rate of RTP (99.3% vs 90.2%. p = 0.001); (2) a subsequent operation prior to RTP decreased RTP rate from 98.2 to 89.7% (p = 0.009).; (3) undergoing meniscal surgery at ACL-R decreased RTP rate (p = 0.002). The mean time to RTP from surgery was 10.5 ± 3.6 months. Factors found to increase RTP time included age under 25 (11.0 vs 9.7 months, p = 0.005), recurrent effusions (11.4 vs 10.2 months, p = 0.035), and medial meniscal repair at ACL-R compared to meniscectomy (12.5 vs 9.6 months, p = 0.022). The surgical technique varied over the study period in relation to graft type, femoral tunnel position and addition of lateral extra-articular tenodesis (LET). Overall, the re-rupture rate was 8.2% at 2 years. Patella tendon autograft in an anteromedial bundle femoral tunnel position with addition of LET has the lowest re-rupture rate (2.0%). Primary ACL-R in professional footballers yields high rates of RTP (96.1%), with 90.1% at the same level or higher, at a mean 10.5 months. Patients under 25 years not only had a significantly higher RTP rate, but also had a lengthier period of rehabilitation. Level IV.

Background: There is growing evidence that anterolateral procedures can reduce the risk of rerupture in high-risk recreational athletes undergoing primary anterior cruciate ligament (ACL) reconstruction (ACLR). However, this effectiveness has never been evaluated in elite athletes. Purpose: The purpose of this study was to evaluate the effectiveness of lateral extra-articular tenodesis (LET) in reducing revision rates in primary ACLR in elite athletes. Additionally, this study evaluated whether LET had a greater effect when combined with ACLR utilizing a hamstring or patellar tendon graft. Study Design: Cohort study; Level of evidence, 3. Methods: A consecutive cohort of elite athletes with an isolated ACL tear undergoing autograft patellar or hamstring tendon reconstruction with or without Lemaire LET were analyzed between 2005 and 2018. A minimum 2-year follow-up was required. The association between the use of LET and ACL graft failure as defined by revision ACLR was evaluated with univariate and multivariate logistic regression models. Results: A total of 455 elite athletes (83% men and overall age 22.5 ± 4.7 years) underwent primary ACLR with (n = 117) or without (n = 338) a LET procedure. Overall, 36 athletes (7.9%) experienced ACL graft failure, including 32 (9.5%) reconstructions without a LET and 4 (3.4%) with a LET. Utilization of LET during primary ACLR reduced the risk of graft failure by 2.8 times, with 16.5 athletes needing LET to prevent a single ACL graft failure. Multivariate models showed that LET significantly reduced the risk of graft rupture (relative risk = 0.325; P = .029) as compared with ACLR alone after controlling for sex and age at ACLR. Including graft type in the model did not significantly change the risk profile, and although a patellar tendon graft had a slightly lower risk of failure, this was not statistically significant ( P = .466). Conclusion: The addition of LET reduced the risk of undergoing revision by 2.8 times in elite athletes undergoing primary ACLR. This risk reduction did not differ significantly between the patellar tendon and hamstring tendon autografts. With these results, status as an elite athlete should be included in the indications for a LET, as they are at increased risk for ACL graft failure.

E-cadherin, a

Simple Summary An unexpectedly high number of early-onset diffuse gastric and lobular breast cancer in apparently unrelated families carrying the same CDH1 c.1901C>T variant (formerly known as missense p.A634V) in Northern Portugal suggested a founder effect in this region. We demonstrated that c.1901C>T is a truncating variant triggered by cryptic splicing, calculated its mutational age, and characterized the tumour spectrum and age of onset in affected families. Abstract Hereditary diffuse gastric cancer (HDGC) caused by CDH1 variants predisposes to early-onset diffuse gastric (DGC) and lobular breast cancer (LBC). In Northern Portugal, the unusually high number of HDGC cases in unrelated families carrying the c.1901C>T variant (formerly known as p.A634V) suggested this as a CDH1-founder variant. We aimed to demonstrate that c.1901C>T is a bona fide truncating variant inducing cryptic splicing, to calculate the timing of a potential founder effect, and to characterize tumour spectrum and age of onset in carrying families. The impact in splicing was proven by using carriers’ RNA for PCR-cloning sequencing and allelic expression imbalance analysis with SNaPshot. Carriers and noncarriers were haplotyped for 12 polymorphic markers, and the decay of haplotype sharing (DHS) method was used to estimate the time to the most common ancestor of c.1901C>T. Clinical information from 58 carriers was collected and analysed. We validated the cryptic splice site within CDH1-exon 12, which was preferred over the canonical one in 100% of sequenced clones. Cryptic splicing induced an out-of-frame 37bp deletion in exon 12, premature truncation (p.Ala634ProfsTer7), and consequently RNA mediated decay. The haplotypes carrying the c.1901C>T variant were found to share a common ancestral estimated at 490 years (95% Confidence Interval 445–10,900). Among 58 carriers (27 males (M)–31 females (F); 13–83 years), DGC occurred in 11 (18.9%; 4M–7F; average age 33 ± 12) and LBC in 6 females (19.4%; average age 50 ± 8). Herein, we demonstrated that the c.1901C>T variant is a loss-of-function splice-site variant that underlies the first CDH1-founder effect in Portugal. Knowledge on this founder effect will drive genetic testing of this specific variant in HDGC families in this geographical region and allow intrafamilial penetrance analysis and better estimation of variant-associated tumour risks, disease age of onset, and spectrum.

BackgroundFamilial intestinal gastric cancer (FIGC) remains genetically unexplained and without testing/clinical criteria. Herein, we characterised the age of onset and disease spectrum of 50 FIGC families and searched for genetic causes potentially underlying a monogenic or an oligogenic/polygenic inheritance pattern.MethodsNormal and tumour DNA from 50 FIGC probands were sequenced using Illumina custom panels on MiSeq, and their respective germline and somatic landscapes were compared with corresponding landscapes from sporadic intestinal gastric cancer (SIGC) and hereditary diffuse gastric cancer cohorts.ResultsThe most prevalent phenotype in FIGC families was gastric cancer, detected in 138 of 208 patients (50 intestinal gastric cancer probands and 88 unknown gastric cancer histology relatives), followed by colorectal and breast cancers. After excluding benign and intronic variants lacking impact in splicing, 12 rare high-quality variants were found exclusively in 11 FIGC probands. Only two probands carried potentially deleterious variants, but lacked somatic second-hits, weakly supporting the monogenic hypothesis for FIGC. However, FIGC probands developed gastric cancer at least 10 years earlier and carried more TP53 germline common variants than SIGC (p=4.5E-03); FIGC and SIGC could be distinguished by specific germline and somatic variant profiles; there was an excess of FIGC tumours presenting microsatellite instability (38%); and FIGC tumours displayed significantly more somatic common variants than SIGC tumours (p=4.2E-06).ConclusionThis study proposed the first data-driven testing criteria for FIGC families, and supported FIGC as a genetically determined, likely polygenic, gastric cancer-predisposing disease, with earlier onset and distinct from patients with SIGC at the germline and somatic levels.

Gastric cancer with lymphoid stroma (GCLS) is characterized by prominent stromal infiltration of T-lymphocytes. The aim of this study was to investigate GCLS biology through analysis of clinicopathological features, EBV infection, microsatellite instability (MSI), immune gene-expression profiling and PD-L1 status in neoplastic cells and tumor immune microenvironment. Twenty-four GCLSs were analyzed by RNA in situ hybridization for EBV (EBER), PCR/fragment analysis for MSI, immunohistochemistry (PD-L1, cytokeratin, CD3, CD8), co-immunofluorescence (CK/PD-L1, CD68/PD-L1), NanoString gene-expression assay for immune-related genes and PD-L1 copy number alterations. CD3+ and CD8+ T-cell densities were calculated by digital analysis. Fifty-four non-GCLSs were used as control group. GCLSs displayed distinctive clinicopathological features, such as lower pTNM stage (p = 0.02) and better overall survival (p = 0.01). EBV+ or MSI-high phenotype was found in 66.7 and 16.7% cases, respectively. GCLSs harbored a cytotoxic T-cell-inflamed profile, particularly at the invasive front of tumors (p

Hereditary diffuse gastric cancer (HDGC) caused by CDH1 variants predisposes to early-onset diffuse gastric (DGC) and lobular breast cancer (LBC). In Northern Portugal, the unusually high number of HDGC cases in unrelated families carrying the c.1901C>T variant (formerly known as p.A634V) suggested this as a CDH1-founder variant. We aimed to demonstrate that c.1901C>T is a bona fide truncating variant inducing cryptic splicing, to calculate the timing of a potential founder effect, and to characterize tumour spectrum and age of onset in carrying families. The impact in splicing was proven by using carriers’ RNA for PCR-cloning sequencing and allelic expression imbalance analysis with SNaPshot. Carriers and noncarriers were haplotyped for 12 polymorphic markers, and the decay of haplotype sharing (DHS) method was used to estimate the time to the most common ancestor of c.1901C>T. Clinical information from 58 carriers was collected and analysed. We validated the cryptic splice site within CDH1-exon 12, which was preferred over the canonical one in 100% of sequenced clones. Cryptic splicing induced an out-of-frame 37bp deletion in exon 12, premature truncation (p.Ala634ProfsTer7), and consequently RNA mediated decay. The haplotypes carrying the c.1901C>T variant were found to share a common ancestral estimated at 490 years (95% Confidence Interval 445–10,900). Among 58 carriers (27 males (M)–31 females (F); 13–83 years), DGC occurred in 11 (18.9%; 4M–7F; average age 33 ± 12) and LBC in 6 females (19.4%; average age 50 ± 8). Herein, we demonstrated that the c.1901C>T variant is a loss-of-function splice-site variant that underlies the first CDH1-founder effect in Portugal. Knowledge on this founder effect will drive genetic testing of this specific variant in HDGC families in this geographical region and allow intrafamilial penetrance analysis and better estimation of variant-associated tumour risks, disease age of onset, and spectrum.

Contains fulltext : 182216.pdf (Publisher’s version ) (Open Access) Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.

ResumoIntroduçãoO adenoma nefrogénico da bexiga (ANB) é uma variante rara e benigna dos tumores uroteliais. A literatura existente é escassa relativamente à sua etiologia, clínica e terapêutica. Este trabalho apresenta o primeiro caso descrito de um doente com infeção por vírus da imunodeficiência humana tipo 1 (VIH‐1) a quem foi diagnosticado um ANB.Caso clínicoDoente do sexo feminino, 49 anos, seropositiva para VIH‐1. Seguida em consulta por quadro clínico consistente em polaquiúria, urgência miccional, sensação de esvaziamento vesical incompleto e episódios de hematúria intermitentes. Por apresentar uma lesão vesical suspeita foi submetida a uma RTU‐V. O exame anatomopatológico foi consistente com ANB. A doente encontra‐se em regime de follow‐up tendo completado um ano sem sinais de recidiva lesional.DiscussãoO ANB é uma lesão metaplásica do urotélio. A sua etiologia não está completamente esclarecida, encontrando‐se associada a processos inflamatórios crónicos ou a um estado de imunossupressão. O seu diagnóstico é histopatológico, caracterizando‐se pela presença de estruturas tubuloglandulares semelhantes aos túbulos renais. Este trabalho assume particular relevância pelo facto de ser o primeiro caso descrito de ANB numa doente imunodeprimida por infeção com VIH‐1.AbstractIntroductionNephrogenic adenoma of the urinary bladder (NAB) is a rare and benign urothelial tumor. The existing literature is scarce regarding its etiology, clinical symptoms and therapeutic options. This paper presents the first reported case of a patient with HIV‐1 infection to whom an NAB was diagnosed.Case ReportWe report a case of a female patient of 49 years old, seropositive for HIV‐1, with pollakiuria, mictional urgency, feeling of incomplete bladder emptying and intermittent macroscopic hematuria. The patient was submitted to TURB of a suspected intravesical lesion. Histopathological examination of the resected material was consistent with an NAB. The patient is in follow‐up, having completed one year with no sign of lesion recurrence.DiscussionNAB is a metaplastic lesion of the urothelial tissue. Its etiology is not fully understood. NAB is associated with chronic inflammatory processes or to a state of immunosuppression. Its diagnosis is histological, characterized by the presence of tubular structures similar to renal tubules. This work is particularly relevant because it is the first described case of NAB in a patient immunodepressed by HIV‐1 infection.

Background: Diffuse gastric cancer (DGC) is associated with the reduction or absence of the expression of the cell adhesion protein E-cadherin (encoded by the CDH1 gene). Molecular characteristics are less well described for mixed gastric cancer (MGC). The main somatic alterations that have been described in the CDH1 gene are mutations, loss of heterozygosity (LOH) and promoter methylation. The aim was to analyze CDH1 somatic alterations in Mexican patients with diffuse and mixed gastric cancer. Methods: We searched for mutations in the CDH1 gene in tumor DNA from DGC (n = 13) and MGC (n = 7) patients by next generation sequencing (NGS). Validation of findings was performed using Sanger sequencing. LOH was analyzed using dinucleotide repeat markers surrounding the CDH1 gene, and methylation was investigated by DNA bisulfite conversion and sequencing. E-cadherin protein deficiency was analyzed by immunohistochemistry. Results: Seventeen point variants were identified by NGS, 13 of them were validated by Sanger sequencing. Only 1/13 had not been previously reported (c.-137C > A), and 12/13 were already reported as polymorphisms. Two DGC cases presented LOH at the locus 16q22.1 (13.3%). CDH1 promoter methylation was positive in (7/11) 63.6% and (4/6) 66.6% of the cases with DGC and MGC, respectively. E-cadherin protein deficiency was observed in 58.3% of DGC cases while 100% in MGC cases. Conclusions: While no pathogenic somatic mutations were found that could explain the diffuse histology of gastric cancer in DGC and MGC, methylation was the most common somatic inactivation event of the CDH1 gene, and LOH was rare. The previously unreported c.-137C > A variant modify the CDH1 gene expression since it alters the binding sites for transcription factors. This work was supported by the “Consejo Nacional de Ciencia y Tecnología (CONACYT)” (grant Ciencia Básica 2013–1-222972) and by the “Fondo de Investigación en Salud (FIS), Instituto Mexicano del Seguro Social (IMSS)” (grant FIS/IMSS/PROT/G13/1189), that contributed to the design of the study, collection, analysis, interpretation of data and writing the manuscript. We thank the following institutions: 1) Coordinación de Investigación en Salud (CIS), Instituto Mexicano del Seguro Social (IMSS) for the support given to ARBC, through the Professional Development in the International Research of Graduate Students (PRODESI) program; 2) Fundación IMSS, A.C. for the research grant awarded to JYSL and MTMT; 3) FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT/ Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274); 4) The project NORTE-01-0145-FEDER-000029, supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); 5) FCT fellowships (SFRH/BPD/86543/2012 to JC; SFRH/BPD/89764/2012 to PO; PD/ BD/128007/2016 to AS). IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT, the Portuguese Foundation for Science and Technology.

We present the clinical case of a 74-year-old woman with an urachal tumor diagnosed in 2004. The patient underwent a partial cystectomy of the dome with remotion of the urachal remnant and the umbilicus. She had been clinical well until 2011 when she had a kidney metastasis from the urachal tumor. Urachal tumors are very rare, comprising 0.17-0.34% of all bladder cancers. The most common sites of distant metastases are: lung, lymph nodes, bone, intestine, brain, liver, peritoneum, skin and spine. We describe an extremely rare case of a renal metastasis from an urachal cancer, seven years after the initial diagnosis. Usually, patients with localized disease have a good prognosis when treated with surgery. The prognosis gets worse for patients with metastases or local recurrence because a standard chemotherapy regimen does not exist.

An angiomyofibroblastoma-like tumor is a rare mesenchymal tumor that arises in the scrotum, inguinal region or perineum in men. It is usually described as superficial, originating in subcutaneous tissues. In the present case we found an angiomyofibroblastoma-like tumor with a different clinical presentation. We describe a benign tumor that mimicked a testicular tumor clinically and in imaging exams. This tumor was herniated to the scrotum through an indirect inguinal hernia that had arisen from the omentum and the mesenteric/splanchnic circulation; these were the only structures it was linked to. Surgical excision is the recommended treatment and cure is obtained in most cases.

The purpose of this study was to evaluate the popcorn technique using a wide range of holmium laser settings and fiber sizes in a systematic in vitro assessment.Evaluations were done with 4 artificial stones in a collection tube. A fixed ureteroscope was inserted through a ureteral access sheath to provide constant irrigation flow and the laser was placed 1 mm from the bottom. Combinations of 0.5 to 1.5 J, 10 to 20 and 40 Hz, and long and short pulses were tested for 2 and 4 minutes. We used 273 and 365 μm laser fibers. All tests were repeated 3 times. The stones were weighed before and after the experiments to evaluate the setting efficiency. Significant predictors of a highly efficient technique were assessed.A total of 144 tests were performed. Mean starting weight of the stones was 0.23 gm, which was consistent among the groups. After the experiment the median weight difference was 0.07 gm (range 0.01 to 0.24). When designating a 50% reduction in stone volume as the threshold indicating high efficiency, the significant predictors of an efficient popcorn technique were a long pulse (OR 2.7, 95% CI 1.05-7.15), a longer duration (OR 11.4, 95% CI 3.88-33.29), a small (273 μm) laser fiber (OR 0.23, 95% CI 0.08-0.70) and higher power (W) (OR 1.14, 95% CI 1.09-1.20).Higher energy, a longer pulse, frequencies higher than 10 Hz, a longer duration and a smaller laser fiber predict a popcorn technique that is more efficient at reducing stone volume.

Neste trabalho, procurou-se avaliar o comportamento de concretos produzidos com adicoes minerais, quanto a corrosao das armaduras sob a acao de cloretos livres. Realizaram-se ensaios de absorcao capilar, absorcao por imersao e ensaio acelerado de corrosao, de modo a avaliar de forma comparativa as adicoes utilizadas. Para cada adicao foram feitos corpos de prova, variando a relacao agua/cimento (0,4 e 0,7), o tipo e o teor da adicao. Ao longo dos ensaios de absorcao capilar e absorcao por imersao, as grandezas medidas foram: massa dos corpos de prova (M) e Variacao da massa (Mv). O procedimento adotado possibilitou analisar de forma comparativa a capacidade de absorcao de liquidos. E no ensaio acelerado de corrosao, a grandeza medida foi:o potencial de corrosao. Desse modo, pode-se concluir que os corpos de prova com adicao de 7% de Silica, com tempo de cura de 28 dias e relacao agua/cimento 0,4, foram os que apresentaram menor absorcao de agua, por capilaridade e imersao, e, portanto, os que apresentaram um melhor desempenho contra os ions cloretos.

Introduction The pancreas is a rare metastization site for renal cell carcinoma (RCC); this paper reports a rare presentation of metastatic RCC, of obstructive jaundice secondary to a solitary synchronous pancreatic metastasis; the authors review the existing literature on pancreatic metastization of RCC in what concerns etiopathogenesis, clinics and therapeutic options. Clinical case A 53-year-old man was referenced to consultation for complains of weakness, dyspepsia, back pain, choluria, weight loss and jaundice; image exams revealed a single lesion on the head of the pancreas and a tumour in the left kidney; after elective pancreaticoduodenectomy and radical nephrectomy, histology revealed a RCC, and a metastatic lesion with endoluminal growth in Wirsung duct; the follow-up was uneventful with no evidence of recurrence at 6 months. Discussion Pancreatic metastization of RCC tend to occur many years after nephrectomy; computerize tomography imaging is the method of choice for its characterization; the R0 resection provide the longest disease-free survival possible; any patient with solitary metastatic RCC in the pancreas should be a candidate for complete surgical excision if technically feasible, for palliation and prognostic reasons.

Objective To describe and discuss the feasibility and the use of apnea during retrograde intrarenal surgery (RIRS). Materials and Methods A discussion of the current literature about the different anesthesia techniques and the use of apnea to improve RIRS by avoiding renal movements over diaphragmatic excursion was performed. Results To date, there are no mentions in the literature about the use of apnea as a mechanism to facilitate this procedure that requires extremely precise laser use. A description of the feasibility of apnea during RIRS is described as a technical consideration and discussed. Conclusion The use of apnea during RIRS has facilitated the procedure, avoiding renal movements, particularly in special cases where extremely precise maneuvers during laser use are required.

Disruption of E-cadherin (CDH1 gene) expression, subcellular localization or function arises during initiation and progression of almost 90% of all epithelial carcinomas. Nevertheless, the mechanisms through which this occurs are largely unknown. Previous studies showed the importance of CDH1 intron 2 sequences for proper gene and protein expression, supporting these as E-cadherin cis-modulators. Through RACE and RT-PCR, we searched for transcription events arising from CDH1 intron 2 and discovered several new transcripts. One, named CDH1a, with high expression in spleen and absent from normal stomach, was demonstrated to be translated into a novel isoform, differing from canonical E-cadherin in its N-terminal, as determined by mass-spectrometry. Quantitative and functional assays showed that when overexpressed in an E-cadherin negative context, CDH1a replaced canonical protein interactions and functions. However, when co-expressed with canonical E-cadherin, CDH1a increased cell invasion and angiogenesis. Further, interferon-induced genes IFITM1 and IFI27 levels were increased upon CDH1a overexpression. Effects on invasion and IFITM1 and IFI27 expression were reverted upon CDH1a specific knockdown. Importantly, CDH1a was de novo expressed in gastric cancer cell lines. This study presents a new mechanism by which E-cadherin functions are impaired by cis-regulatory mechanisms possibly with the involvement of inflammatory machinery. If confirmed in other cancer models, our data encloses potential for designing targeted therapies to rescue E-cadherin function. Fundação para a Ciência e Tecnologia

FUNDAMENTOS: Insuficiência cardíaca (IC) é uma doença comum com alta taxa de mortalidade. Anemia e insuficiência renal (IR) são frequentemente encontradas em portadores de IC associadas com maior gravidade da doença cardíaca e pior prognóstico. OBJETIVO: Avaliar a prevalência de anemia e insuficiência renal, bem como a associação entre esses dois quadros, em portadores de IC não hospitalizados. MÉTODOS: Foram observados pacientes acompanhandos na clínica de IC de um hospital universitário de julho de 2003 a novembro de 2006. Anemia foi definida como níveis de hemoglobina abaixo de 13 mg/dl para homens e de 12 mg/dl para mulheres. A função renal foi avaliada por meio da taxa de filtração glomerular (TFG), calculada pela fórmula simplificada do estudo MDRD (Modification of Diet in Renal Disease). RESULTADOS: Dos trezentos e quarenta e cinco pacientes incluídos neste estudo, 26,4% (n = 91) tinham anemia e 29,6% tinham insuficiência renal moderada a grave (TFG < 60 ml/min). A associação entre anemia e maior prevalência de insuficiência renal foi estatisticamente significante (41,8% vs. 25,2%; p = 0,005). Os pacientes em classe funcional III e IV apresentaram maior incidência de anemia (39,0% vs. 19,4%; p FUNDAMENTO: La insuficiencia cardiaca (IC) es una enfermedad común con alta tasa de mortalidad. La anemia y la insuficiencia renal (IR), encontradas frecuentemente en portadores de IC, son asociadas a mayor severidad de la enfermedad cardiaca y peor pronóstico. OBJETIVO: Evaluar la prevalencia de anemia e insuficiencia renal, así como la asociación entre esos dos cuadros, en portadores de IC no hospitalizados. MÉTODOS: Se observaron a pacientes seguidos en la clínica de IC de un hospital universitario de julio de 2003 a noviembre de 2006. Se definió la anemia como niveles de hemoglobina abajo de 13 mg/dl para varones y de 12 mg/dl para mujeres. La función renal se evaluó por medio de la tasa de filtración glomerular (TFG), calculada por la fórmula simplificada del estudio MDRD (Modification of Diet in Renal Disease). RESULTADOS: Teniendo en cuenta los trescientos y cuarenta y cinco pacientes incluidos en este estudio, el 26,4% (n = 91) tenía anemia y el 29,6% presentaba insuficiencia renal de moderada a severa (TFG < 60 ml/min). La asociación entre anemia y mayor prevalencia de insuficiencia renal fue estadísticamente significante (el 41,8% vs el 25,2%; p = 0,005). Los pacientes en clase funcional III e IV presentaron mayor incidencia de anemia (el 39,0% vs el 19,4%; p BACKGROUND: Heart Failure (HF) is a common disease with a high rate of mortality. Anemia and renal failure (RF) are often found in patients with HF associated with higher severity of the heart disease and a worse prognosis. OBJECTIVE: To evaluate the prevalence of anemia and RF, as well as the association between these two conditions, in non-hospitalized patients with HF. METHODS: Patients treated at the HF Outpatient Clinic of a university hospital were followed from July 2003 to November 2006. Anemia was defined as hemoglobin levels < 13 mg/dl for men and 12 mg/dl for women. Renal function was assessed by the glomerular filtration rate (GFR), calculated by the simplified formula of the MDRD (Modification of Diet in Renal Disease) study. RESULTS: Of the 345 patients included in this study, 26.4% (n = 91) had anemia and 29.6% had moderate to severe renal failure (GFR < 60 ml/min). The association between anemia and a higher prevalence of renal failure was statistically significant (41.8% vs. 25.2%; p = 0.005). The patients at functional class III and IV presented a higher incidence of anemia (39.0% vs. 19.4%; p

Glycoproteins of the scavenger receptor cysteine-rich (SRCR) superfamily contain one or more protein modules homologous to the membrane-distal domain of macrophage scavenger receptor I. These domains can be found in the extracellular regions of membrane proteins and in secreted glycoproteins, from the most primitive species to vertebrates. A systematic, bioinformatics-based search for putative human proteins related to the forty-seven known human group B SRCR domains identified a new family member that we have called Soluble Scavenger with 5 Domains (SSc5D). SSc5D is a new soluble protein whose expression is restricted to monocytes/macrophages and T-lymphocytes, and is particularly enriched in the placenta. The gene encoding SSc5D spans 30kb of genomic DNA, and contains fourteen exons producing a 4.8kb-long mRNA. The mature polypeptide is predicted to consist of 1573 amino acids comprising, towards the N-terminus, five very similar SRCR domains that are highly conserved among non-marsupial mammals, and a large (>250nm), very heavily glycosylated, mucin-like sequence towards the C-terminus. Each of the SRCR domains is encoded by a single exon, and contains eight cysteine residues, as observed for all other group B SRCR domains. A shorter isoform encoded by a weakly expressed, alternatively spliced transcript, which lacks the mucin-like C-terminal region, was also identified. It seems likely that SSc5D has a role at the interface between adaptive and innate immunity, or in placental function.

Background & Aims Hereditary diffuse gastric cancer (HDGC) families carry CDH1 heterozygous germline mutations; their tumors acquire complete CDH1 inactivation through "2nd-hit" mechanisms. Most frequently, this occurs via promoter hypermethylation (epigenetic modification), and less frequently via CDH1 mutations and loss of heterozygosity (LOH). We quantified the different 2nd hits in CDH1 occurring in neoplastic lesions from HDGC patients. Methods Samples were collected from 16 primary tumors and 12 metastases from 17 patients among 15 HDGC families; CDH1 mutations, LOH, and promoter hypermethylation were analyzed. E-cadherin protein expression and localization were determined by immunohistochemistry. Results Somatic CDH1 epigenetic and genetic alterations were detected in lesions from 80% of HDGC families and in 75% of all lesions analyzed (21/28). Of the 28 neoplastic lesions analyzed, promoter hypermethylation was found in 32.1%, LOH in 25%, both alterations in 17.9%, and no alterations in 25%. Half of the CDH1 2nd hits in primary tumors were epigenetic modifications, whereas a significantly greater percentage of 2nd hits in metastases were LOH (58.3%; P = .0274). Different neoplastic lesions from the same patient frequently displayed distinct 2nd-hit mechanisms. Different 2nd-hit mechanisms were also detected in the same tumor sample. Conclusion The 2nd hit in CDH1 frequently occurs via epigenetic changes in HDGC primary tumors and LOH in metastases. Because of the concomitance and heterogeneity of these alterations in neoplastic lesions and the plasticity of hypermethylated promoters during tumor initiation and progression, drugs targeting only epigenetic alterations might not be effective, particularly in patients with metastatic HDGC.

The retrocaval ureter is a rare congenital entity, classically managed with open pyeloplasty techniques. The experience obtained with the laparoscopic approach of other more frequent causes of ureteropelvic junction (UPJ) obstruction has opened the method for the minimally invasive approach of the retrocaval ureter. In our paper, we describe a clinical case of a right retrocaval ureter managed successfully with laparoscopic dismembered pyeloplasty. The main standpoints of the procedure are described. Our results were similar to others published by other urologic centers, which demonstrates the safety and feasibility of the procedure for this condition.