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Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them achieves long-term benefit from trastuzumab-based upfront strategy. To advance precision oncology, we investigated the therapeutic efficacy of different HER2-targeted strategies, in HER2 “hyper”-amplified (≥ 8 copies) tumors. We undertook a prospective evaluation of HER2 targeting with monoclonal antibodies, tyrosine kinase inhibitors and antibody–drug conjugates, in a selected subgroup of HER2 “hyper”-amplified gastric patient-derived xenografts (PDXs), through the design of ad hoc preclinical trials. Despite the high level of HER2 amplification, trastuzumab elicited a partial response only in 2 out of 8 PDX models. The dual-HER2 blockade with trastuzumab plus either pertuzumab or lapatinib led to complete and durable responses in 5 (62.5%) out of 8 models, including one tumor bearing a concomitant HER2 mutation. In a resistant PDX harboring KRAS amplification, the novel antibody–drug conjugate trastuzumab deruxtecan (but not trastuzumab emtansine) overcame KRAS-mediated resistance. We also identified a HGF-mediated non-cell-autonomous mechanism of secondary resistance to anti-HER2 drugs, responsive to MET co-targeting. These preclinical randomized trials clearly indicate that in HER2-driven gastric tumors, a boosted HER2 therapeutic blockade is required for optimal efficacy, leading to complete and durable responses in most of the cases. Our results suggest that a selected subpopulation of HER2-“hyper”-amplified GC patients could strongly benefit from this strategy. Despite the negative results of clinical trials, the dual blockade should be reconsidered for patients with clearly HER2-addicted cancers.

Purpose: Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents. Experimental Design: We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX). Results: The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that EGFR amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy-number gain and that coamplification of other receptor tyrosine kinases or KRAS is associated with worse response. Preclinical trials performed on EGFR-amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR-amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition. Conclusions: This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors. See related commentary by Openshaw et al., p. 2964

The glenohumeral joint is the most dislocated articulation, accounting for more than 50% of all joint dislocations. The reason behind shoulder instability should be investigated in detail for successful management, and the treatment plan should be individualized for all patients. Several classification systems have been proposed for glenohumeral instability. A physical exam is mandatory no matter what classification system is used. When treating patients with anterior shoulder instability, surgeons need to be aware of the critical size of the bone loss, which is commonly seen. The glenoid track concept was clinically adopted, and the measurement of the glenoid track for surgical decision-making is recommended. Detailed assessment of existing soft tissue injury to the labrum, capsule, glenohumeral ligaments, and rotator cuff is also mandatory as their presence influences the surgical outcome. Rehabilitation, arthroscopic repair techniques, open Bankart procedure, capsular plication, remplissage, Latarjet technique, iliac crest, and other bone grafts offer the surgeon different treatment options according to the type of patient and the lesions to be treated. Three-dimensional (3D) technologies can help to evaluate glenoid and humeral defects. Patient-specific guides are low-cost surgical instruments and can be used in shoulder instability surgery. 3D printing will undoubtedly become an essential tool to achieve the best results in glenohumeral instability surgery.

SummarySARS-CoV-2 infections lead to a high risk of hospitalization and mortality in diabetic patients. Why diabetic individuals are more prone to develop severe COVID-19 remains unclear. Here, we established a novel human kidney organoid model that mimics early hallmarks of diabetic nephropathy. High oscillatory glucose exposure resulted in metabolic changes, expansion of extracellular membrane components, gene expression changes determined by scRNAseq, and marked upregulation of angiotensin-converting enzyme 2 (ACE2). Upon SARS-CoV-2 infection, hyperglycemic conditions lead to markedly higher viral loads in kidney organoids compared to normoglycemia. Genetic deletion of ACE2, but not of the candidate receptor BSG/CD147, in kidney organoids demonstrated the essential role of ACE2 in SARS-CoV-2 infections and completely prevented SARS-CoV-2 infection in the diabetogenic microenvironment. These data introduce a novel organoid model for diabetic kidney disease and show that diabetic-induced ACE2 licenses the diabetic kidney to enhanced SARS-CoV-2 replication.

Purpose The purpose of this study was to establish consensus statements via a modified Delphi process on revision surgery, rehabilitation and return to play, and clinical follow-up for anterior shoulder instability. Methods A consensus process on the treatment using a modified Delphi technique was conducted, with 65 shoulder surgeons from 14 countries across 5 continents participating. Experts were assigned to one of 9 working groups defined by specific subtopics of interest within anterior shoulder instability. Results The primary relative indications for revision surgery include symptomatic apprehension or recurrent instability, additional intra-articular pathologies, and symptomatic hardware failure. In revision cases, the differentiating factors that dictate treatment are the degree of glenohumeral bone loss and rotator cuff function/integrity. The minimum amount of time before allowing athletes to return to play is unknown, but other factors should be considered, including restoration of strength, range of motion and proprioception, and resolved pain and apprehension, as these are prognostic factors of reinjury. Additionally, psychological factors should be considered in the rehabilitation process. Patients should be clinically followed up for a minimum of 12 months or until a return to full, premorbid function/activities. Finally, the following factors should be included in anterior shoulder instability-specific, patient-reported outcome measures: function/limitations impact on activities of daily living, return to sport/activity, instability symptoms, confidence in shoulder, and satisfaction. Conclusion Overall, 92% of statements reached unanimous or strong consensus. The statements that reached unanimous consensus were indications and factors affecting decisions for revision surgery, as well as how prior surgeries impact procedure choice. Furthermore, there was unanimous consensus on the role of psychological factors in the return to play, considerations for allowing return to play, as well as prognostic factors. Finally, there was a lack of unanimous consensus on recommended timing and methods for clinical follow-up. Level of Evidence Level V, expert opinion.

Purpose The purpose of this study was to establish consensus statements via a modified Delphi process on the Latarjet procedure, remplissage, and glenoid-bone grafting for anterior shoulder instability. Methods A consensus process on the treatment utilizing a modified Delphi technique was conducted, with 65 shoulder surgeons from 14 countries across 5 continents participating. Experts were assigned to one of 9 working groups defined by specific subtopics of interest within anterior shoulder instability. Results The technical approaches identified in the statements on the Latarjet procedure and glenoid bone-graft were that a subscapularis split approach should be utilized, and that it is unclear whether a capsular repair is routinely required. Furthermore, despite similar indications, glenoid bone-grafting may be preferred over the Latarjet in patients with bone-loss greater than can be treated with a coracoid graft, and in cases of surgeon preference, failed prior Latarjet or glenoid bone-grafting procedure, and epilepsy. In contrast, the primary indications for a remplissage procedure was either an off-track or engaging Hill-Sachs lesion without severe glenoid bone loss. Additionally, in contrast to the bone-block procedure, complications following remplissage are rare, and loss of shoulder external rotation can be minimized by performing the tenodesis via the safe-zone and not over medializing the fixation. Conclusion Overall, 89% of statements reached unanimous or strong consensus. The statements that reached unanimous consensus were the prognostic factors that are important to consider in those undergoing a glenoid bone-grafting procedure including age, activity level, Hill-Sachs Lesion, extent of glenoid bone-loss, hyperlaxity, prior surgeries, and arthritic changes. Furthermore, there was unanimous agreement that it is unclear whether a capsular repair is routinely required with a glenoid bone graft, but it may be beneficial in some cases. There was no unanimous agreement on any aspect related to the Latarjet procedure or Remplissage. Level of Evidence Level V: expert opinion.

Background The medial coracoclavicular ligament (MCCL), is a structure that shows defined morphologic and histologic features. However, little attention has been paid to the MCCL to date. This study was conducted to (1) determine whether the MCCL is a constant structure, (2) analyze its mechanical properties, and (3) determine its possible role in acromioclavicular (AC) stability. Methods AC joints, lateral coracoclavicular ligaments (LCCLs; conoid and trapezoid), and MCCLs were dissected in 30 fresh frozen upper limbs. In 6 of these specimens, we performed a sequential sectioning following the aforementioned order. A 20-N cephalad force was applied to the lateral clavicle at each step, recording the AC distance and coracoclavicular space and their variation. In 6 other specimens, we evaluated the anteroposterior motion of the clavicle following the MCCL section. Biomechanical testing was performed in 8 specimens, comparing the resistance of the MCCL to the LCCLs. Results The MCCL in all of the specimens featured a sharp-edge bundle stretching from the coracoid process to the clavicle and subclavius sheath. It showed ligament-like mechanical properties although less tensile resistance than the LCCLs. Once the AC and LCCLs were sectioned, transection of the MCCL determined a significant increase in both cephalad and posterior displacement. Conclusion The MCCL is a constant structure with the mechanical behavior of a ligament. It may act as the last container of the coracoclavicular space both in cephalad and posterior directions, precluding additional displacement in the absence of the LCCLs.

ObjetivoEl ligamento de Caldani o córacoclavicular medial (LCCM) ha sido estudiado anatómicamente pero no hemos hallado mención alguna sobre su identificación imagenológica. El objetivo del presente trabajo es presentar una técnica original de resonancia magnética que hemos desarrollado para identificarlo, y describir las imágenes correspondientes.Materiales y Métodos Se incluyeron en el protocolo de investigación a 7 voluntarios sin patología de hombro conocida. Se utilizó un Resonador Magnético PHILLIPS INGENIA de una intensidad de campo magnético de 1.5 Tesla Versión 4.1, diámetro de Gantry (túnel del resonador) de 70 cm, bobina Sense específica para Hombro de 8 canales con imágenes de alta resolución. Se realizaron las secuencias de búsqueda del ligamento en tres planos.ResultadosEl LCCM fue identificado en todos los casos, extendiéndose oblicuamente desde la apófisis coracoides a la clavícula coincidiendo con las descripciones de la bibliografía anatómica consultada. Presentó una señal hipointensa en todas las secuencias, indicando el poco espacio entre fibras y correspondiendo a tejido colágeno compacto. Su longitud promedio fue de 41,15mm (entre 34mm y 47mm, desvío standard de 4,40). El espesor promedio fue de 2,11mm (entre 1,3mm y 3,2mm, desvío standard de 0,66).ConclusiónEl LCCM puede ser observado en imágenes de resonancia magnética mediante la técnica original que describimos. La posibilidad de localizar y observar el LCCM mediante resonancia magnética abre las puertas al estudio del mismo en futuras investigaciones, no sólo de compresiones neurovasculares sino también en lesiones traumáticas acromioclaviculares, especialmente en las tipo V de la clasificación de Rockwood.

Background Mesenchymal stromal cells (MSCs) from different sources possess great therapeutic potential due to their immunomodulatory properties associated with allograft tolerance. However, a crucial role in this activity resides in extracellular vesicles (EVs) and signaling molecules secreted by cells. This study aimed to evaluate the immunomodulatory properties of donor and recipient MSCs isolated from adipose tissue (AD) or bone marrow (BM) and their EVs on kidney outcome in a rat kidney transplant model. Methods The heterotopic-kidney-transplant Fisher-to-Lewis rat model (F-L) was performed to study mixed cellular and humoral rejection. After kidney transplantation, Lewis recipients were assigned to 10 groups; two control groups; four groups received autologous MSCs (either AD- or BM- MSC) or EVs (derived from both cell types); and four groups received donor-derived MSCs or EVs. AD and BM-EVs were purified by ultracentrifugation. Autologous cell therapies were administered three times intravenously; immediately after kidney transplantation, 4 and 8 weeks, whereas donor-derived cell therapies were administered once intravenously immediately after transplantation. Survival and renal function were monitored. Twelve weeks after kidney transplantation grafts were harvested, infiltrating lymphocytes were analyzed by flow cytometry and histological lesions were characterized. Results Autologous AD- and BM-MSCs, but not their EVs, prolonged graft and recipient survival in a rat model of kidney rejection. Autologous AD- and BM-MSCs significantly improved renal function during the first 4 weeks after transplantation. The amelioration of graft function could be associated with an improvement in tubular damage, as well as in T, and NK cell infiltration. On the other side, the application of donor-derived AD-MSC was harmful, and all rats died before the end of the protocol. AD-EVs did not accelerate the rejection. Contrary to autologous MSCs results, the single dose of donor-derived BM-MSCs is not enough to ameliorate kidney graft damage. Conclusion EVs treatments did not exert any benefit in our experimental settings. In the autologous setting, BM-MSCs prompted as a potentially promising therapy to improve kidney graft outcomes in rats with chronic mixed rejection. In the donor-derived setting, AD-MSC accelerated progression to end-stage kidney disease. Further experiments are required to adjust timing and dose for better long-term outcomes.

Background Cell therapies and derived products have a high potential in aiding tissue and organ repairing and have therefore been considered as potential therapies for treating renal diseases. However, few studies have evaluated the impact of these therapies according to the stage of chronic kidney disease. The aim of this study was to evaluate the renoprotective effect of murine bone marrow mesenchymal stromal cells (BM-MSCs), their extracellular vesicles (EVs) and EVs-depleted conditioned medium (dCM) in an aggressive mouse model of chronic cyclosporine (CsA) nephrotoxicity in a preventive and curative manner. Methods After 4 weeks of CsA-treatment (75 mg/kg daily) mice developed severe nephrotoxicity associated with a poor survival rate of 25%, and characterized by tubular vacuolization, casts, and cysts in renal histology. BM-MSC, EVs and dCM groups were administered as prophylaxis or as treatment of CsA nephrotoxicity. The effect of the cell therapies was analyzed by assessing renal function, histological damage, apoptotic cell death, and gene expression of fibrotic mediators. Results Combined administration of CsA and BM-MSCs ameliorated the mice survival rates (6-15%), but significantly renal function, and histological parameters, translating into a reduction of apoptosis and fibrotic markers. On the other hand, EVs and dCM administration were only associated with a partial recovery of renal function or histological damage. Better results were obtained when used as treatment rather than as prophylactic regimen i.e., cell therapy was more effective once the damage was established. Conclusion In this study, we showed that BM-MSCs induce an improvement in renal outcomes in an animal model of CsA nephrotoxicity, particularly if the inflammatory microenvironment is already established. EVs and dCM treatment induce a partial recovery, indicating that further experiments are required to adjust timing and dose for better long-term outcomes.

Patient-Derived Xenografts (PDXs) are, so far, the best preclinical model to validate targets and predictors of response to therapy. While subcutaneous implantation very rarely allows metastatic dissemination, orthotopic implantation (Patient-Derived Orthotopic Xenograft-PDOX) increases metastatic capability. Using a modified tool to analyze model validity, we performed a systematic review of Embase, PubMed, and Web of Science up to December 2018 to identify all original publications describing gastric cancer (GC) PDOXs. We identified ten studies of PDOX model validation from January 1981 to December 2018 that fulfilled the inclusion and exclusion criteria. Most models (70%) were derived from human GC cell lines rather than tissue fragments. In 90% of studies, the implantation was performed in the subserosal layer. Tumour engraftment rate ranged from 0 to 100%, despite the technique. Metastases were observed in 40% of PDOX models implanted into the subserosal layer, employing either cell suspension or cell line-derived tumour fragments. According to our modified model validity tool, half of the studies were defined as unclear because one or more validation criteria were not reported. Available GC PDOX models are not adequate according to our model validity tool. There is no demonstration that the submucosal site is more effective than the subserosal layer, and that tissue fragments are better than cell suspensions for successful engraftment and metastatic spread. Further studies should strictly employ model validity tools and large samples with orthotopic implant sites mirroring as much as possible the donor tumour characteristics.

Background The progression from acute to chronic antibody-mediated rejection in kidney transplant recipients is usually not prevented by current therapeutic options. Here, we investigated whether the use of tofacitinib (TOFA), a Janus kinase 3 inhibitor, was capable of preventing the progression of allograft dysfunction in a Fisher-to-Lewis rat model of kidney transplantation. Methods Rats were treated from the third week after transplantation to allow the development of rejection. Treatment was based on cyclosporin A, rapamycin or TOFA. Renal function was assessed at 1, 4, 8, and 12 weeks after transplantation, whereas rat survival, histological lesions, and infiltrating lymphocytes were analyzed at 12 weeks. Results Tofacitinib prolonged graft survival, preserved tubular and glomerular structures and reduced humoral damage characterized by C4d deposition. Tofacitinib was able to reduce donor-specific antibodies. In addition, T and natural killer cell graft infiltration was reduced in TOFA-treated rats. Although rapamycin-treated rats also showed prolonged graft survival, glomerular structures were more affected. Moreover, only TOFA treatment reduced the presence of T, B and natural killer cells in splenic parenchyma. Conclusions Tofacitinib is able to reduce the immune response generated in a rat model of kidney graft rejection, providing prolonged graft and recipient survival, better graft function, and less histological lesions.

Increasing evidence suggests that extracorporeal shockwave treatment (ESWT) is safe and effective for treating several musculoskeletal disorders.Two types of technical principles are usually included in ESWT: focused ESWT (F-ESWT) and radial pressure waves (RPW). These 2 technologies differ with res

Shoulder pain is one of the most common musculoskeletal pathologies. Treatment by ESWT (extracorporeal shockwave therapy) has emerged as an alternative when conservative treatment fails in rotator cuff calcific tendinopathy, prior to invasive procedures. The clinical efficacy of ESWT in non-calcific tendinopathy remains controversial. The good results in the treatment of rotator cuff calcifications, have led to indications of ESWT being expanded to other shoulder pathologies. We review the current state of indications and evidence based practice.

In this work we explore a set of image enhancement techniques for improving contrast and removing noise from digital images of cell activity. The cells studied were extracted from cancerous brain tissue and exposed to different chemo-therapeutic agents, as microbiologists aim to analyze the behavior of cells exposed to different chemo-therapies. To ease and improve the precision of such analysis, an automatic cell tracking framework is of great interest. Thus, in this work we focus on the first stage of such framework, which refers to image preprocessing, aiming to noise removal and contrast enhancement, in order to improve cell segmentation and tracking performance. We compared the segmentation precision using different image preprocessing techniques based on the Deceived Weighting Average Framework (DeWAFF), reaching improvements of around 15 percent of segmentation accuracy, over no preprocessed images.

Submitted manuscript version. Published version available in Bioorganic and Medicinal Chemistry (2017) 25(2), 646-657. Here we report a series of close analogues of our recently published scaffold-based tripeptidomimetic CXCR4 antagonists, containing positively charged guanidino groups in R1 and R2, and an aromatic group in R3. While contraction/elongation of the guanidine carrying side chains (R1 and R2) resulted in loss of activity, introduction of bromine in position 1 on the naphth-2-ylmethyl moiety (R3 ) resulted in an EC50 of 61 µM (mixture of diastereoisomers) against wild-type CXCR4; thus, the antagonistic activity of these tripeptidomimetics seems to be amenable to optimization of the aromatic moiety. Moreover, for analogues carrying a naphth-2-ylmethyl substituent, we observed that a Pictet-Spengler like cyclization side reaction depended on the nature of the R1 substituent.

BACKGROUND The behavior and mechanisms of colorectal carcinoma in solid organ transplantation have not been well characterized. Our aim was to determine the clinical and molecular phenotypes of colorectal carcinoma in kidney transplant recipients and compare with those in the nonimmunosuppressed population. For the first time, we analyzed the impact of KRAS and BRAF mutations in kidney transplantation. METHODS Kidney transplant recipients with colorectal carcinoma were diagnosed and followed up from 1992 to 2007. Twelve patients fulfilled inclusion criteria and were matched with the general population with colorectal cancer. To assess the possible mechanisms involved in the clinical behavior of colorectal carcinoma, we compared the tumoral expression by immunohistochemical analysis of molecule markers of mammalian target of rapamycin (mTOR) pathway, angiogenesis and proliferation, and the role of activating mutations in KRAS and BRAF genes. RESULTS Colorectal carcinoma was more prevalent and exhibited a trend for worse prognosis in transplant patients. Although the mTOR pathway was activated in both populations, activation was lower in transplant patients because of relatively higher phosphatase and tensin homolog expression in the former. Angiogenesis was activated in colorectal carcinoma in both groups. KRAS mutations were found in transplant recipients treated with calcineurin inhibitors and with high expression of phosphatase and tensin homolog. CONCLUSION The activation of oncogenic pathways could be responsible for the clinical behavior of posttransplant colorectal carcinoma. The mutation status of the KRAS gene is likely involved in mTOR pathway and to be a prognosis marker for colorectal cancer in kidney transplantation.

Fire is an ecological factor in ecosystems around the world, made increasingly more critical by unprecedented shifts in climate and human population pressure. The knowledge gradually acquired on the subject is needed to improve fire behaviour understanding and to enhance fire management decision-making. This issue (Volume 28, issue 7, International Journal of Wildland Fire) is Part 2 of a special issue aimed at synthesising ongoing research on preventive management and post-fire restoration, including characterisation of the wildland–urban interface (WUI) and assessing the post-fire restoration of wilderness and WUI areas. Landscape management was also investigated using remote sensing techniques and simulation modelling to improve ecosystem resilience. As in Part 1 (Volume 28, issue 5, International Journal of Wildland Fire), the current issue covers diverse forest settings under scenarios of changing climate and land use. The broad geographical range of these studies highlights key similarities of wildfire issues around the world, but detailed data show unique local circumstances that must be considered. The new information from these six papers helps advance fire ecology and management during a period of rapid change.

Although fire is an intrinsic factor in most terrestrial biomes, it is often perceived as a negative disturbance that must be suppressed. The application of successful fire prevention policies can lead to unsustainable fire events for ecosystems adapted to a specific fire regime. In addition, new climate and land use scenarios are influencing fire parameters and ecosystem services. Consequently, adaptive forest and landscape management must include knowledge on vulnerability, resistance and resilience of terrestrial ecosystems. To help address this need, we convened a special issue (divided in two separate parts) to synthesise ongoing research focused on obtaining a better understanding of wildfire response decisions and actions, including preventive management and post-fire restoration. We conceived a collection of research studies covering a wide diversity of geographical settings characterised by different climates and forest types, under scenarios of changing climate and land use. Here, we summarise the key findings from the six papers published in the first section of the special issue. They deal with diverse topics and assessments, such as adaptions to fire regimes, the effects of burn severity on the plant–soil interface, and post-fire management taking advantage of indices obtained from satellite images (dNBR, NDVI), dendrochronology, soil sampling and analysis of biological indicators. We highlight the new knowledge developed to enhance fire management decision making in a time of rapidly changing scenarios around the world.

Background Sirolimus (SRL) is a potent and specific immunosuppressive drug used in organ transplantation, as basic therapy or in combination with calcineurin inhibitors. Although SRL is a nonnephrotoxic drug, many reports have related its use with the development of proteinuria, especially after conversion. Therefore, the aim of this study was to elucidate the interrelation between early and late SRL administration on the development of glomerular hypertrophy and proteinuria in a model of renal mass reduction (RMR). Methods Rats underwent 2/3 cryoablation of the left kidney and subsequent right nephrectomy (n=42) or sham operations (n=29). Two weeks before (early study) or 12 weeks after (late study) surgery, SRL or vehicle was administered three times weekly. Creatinine clearance and proteinuria were determined throughout the study, and a complete histologic analysis was performed at the end of the study. Results Treatment with SRL had no effect on creatinine clearance, independently of the administration time. Four weeks after RMR, a significant increase in proteinuria was observed. Proteinuria was stabilized after early and late SRL administration, whereas vehicle-treated animals showed a further increase in proteinuria. Glomerular hypertrophy was strongly associated with proteinuria, and early SRL introduction prevented glomerular enlargement. The histologic analysis showed less structural damage in the two groups of animals treated with SRL than in the control group. Conclusion Although early SRL introduction blocked glomerular hypertrophy, SRL treatment revealed the potential to halt progression of proteinuria and histologic damage at any time of administration in a model of RMR.

UNLABELLED The aim was to study the influence of sirolimus (SRL) on body weight in a rat model and in kidney transplant patients. Wistar rats (15 weeks old) were either treated with vehicle (VEH; n = 8) or SRL (n = 7) 1.0 mg/kg three times per week for 12 weeks. Body mass and food intake were measured weekly. Adipocyte diameter was determined in hematoxylin-eosin stains. The body mass index (BMI) obtained from clinical kidney transplant trials comparing SRL-based with cyclosporine-based therapy was analyzed. ANIMALS SRL produced a decrease of the weight gain curve. At the end of the study, mean body weight in the SRL group was lower than in the VEH group (356 vs. 507 g, P < 0.01) in spite of comparable food intake normalized for body weight was not different. Mean adipocyte diameter was 36 mum in VEH and 25 mum in SRL rats (P = 0.009). Mean SRL blood trough concentration was 38 ng/ml. Kidney transplant patients: Two years after transplantation, BMI was significantly lower in the SRL-based treatment arm compared to cyclosporine (24.17 +/- 2.99 vs. 25.97 +/- 5.01 kg/m(2), P = 0.031). SRL treatment leads to less body mass. Adipocyte cell diameter was reduced in SRL-treated animals. A possible explanation may be the effects of SRL on metabolic regulation and cell growth.

Kaposi's sarcoma (KS) is one of the most frequent transplant related tumors. Several pathways are involved; however, the impact of the molecular phenotype associated to the tumor stage and the behavior-depending resultant therapy is still unknown. The aim of our study was to analyze the role of HHV-8 and mTOR pathway in tumor stages of skin KS after renal transplantation. Twelve renal transplant recipients with cutaneous KS from five transplant centers (1980-2007) under reduction of immunosuppression or conversion to mTOR inhibitor were included. The expression of HHV-8, PTEN, TGFβ, VEGF, phospho-mTOR, and phospho-P70S6K in tumoral tissue was analyzed. KS lesions were classified as patch, plaque, and nodule state. HHV-8 infection was found in all tissue samples. KS lesions showed high activation of VEGF, p-mTOR and p-P70S6K, low PTEN, and null TGFβ expression. The only pathway activated in a staging-dependent manner was mTOR with higher p-mTOR and p-P70S6K expression in nodule versus patch stage. KS lesions disappeared after 5.24 months in all converted patients without any recurrence in 14.05 years of mean follow-up. The activation of mTOR pathway according to KS stages supports the rational of the mTOR inhibitor in post-transplant Kaposi.

SummaryCancer in transplant recipients represents a therapeutic challenge even when thepatient is already under mTOR inhibitors. A 78-year-old man received a deceaseddonor kidney transplant in 1993. After 6 months, he developed a multifocal cuta-neous and nonvisceral Kaposi’s Sarcoma while on cyclosporine immunosuppres-sant therapy. The patient was converted to sirolimus monotherapy in 2001 withsubsequent complete recovery within 2 years. In 2007, the patient was diagnosedwith an esophageal adenocarcinoma stage IIA. An esophagectomy was performedwithout requirement of further treatment. He has continued on sirolimus mono-therapy ever since, with no other incidents and no recurrences of either tumor. Inthis report, we describe an interesting case of a second cancer while on immuno-suppressive therapy with anticancer activity. Moreover, the present knowledge ofthe matter is discussed.BackgroundKidney transplantation is the best treatment for end-stagerenal disease. Modern immunosuppressive therapy has ledto advances in kidney transplantation, with lower acuterejection rates and excellent outcomes in patient and graftsurvival [1]. Nonetheless, more patients are at risk of theimmunosuppressive side effects, such as malignancy [2,3].In fact, cancer is responsible for 10–35% of all deaths aftertransplantation. For most common tumors, for example

Supplemental digital content is available in the text., Background Sirolimus (SRL) has been associated with new-onset diabetes mellitus after transplantation. The aim was to determine the effect of SRL on development of insulin resistance and β-cell toxicity. Methods Lean Zucker rat (LZR) and obese Zucker rat (OZR) were distributed into groups: vehicle and SRL (0.25, 0.5, or 1.0 mg/kg) during 12 or 28 days. Intraperitoneal glucose tolerance test (IPGTT) was evaluated at days 0, 12, 28, and 45. Islet morphometry, β-cell proliferation, and apoptosis were analyzed at 12 days. Islets were isolated to analyze insulin content, insulin secretion, and gene expression. Results After 12 days, SRL treatment only impaired IPGTT in a dose-dependent manner in OZR. Treatment prolongation induced increase of area under the curve of IPGTT in LZR and OZR; however, in contrast to OZR, LZR normalized glucose levels after 2 hours. The SRL reduced pancreas weight and islet proliferation in LZR and OZR as well as insulin content. Insulin secretion was only affected in OZR. Islets from OZR + SRL rats presented a downregulation of Neurod1, Pax4, and Ins2 gene. Genes related with insulin secretion remained unchanged or upregulated. Conclusions In conditions that require adaptive β-cell proliferation, SRL might reveal harmful effects by blocking β-cell proliferation, insulin production and secretion. These effects disappeared when removing the therapy.

[Introduction]: Despite advances in therapeutics, graft loss associated with chronic allograft dysfunction (CAD) remains high. Urinary proteomic analysis is a noninvasive method that could be used to detect and evaluate CAD in renal transplant recipients. This study was aimed to establish the normal proteome map of stable transplant patients and to validate the utility of two-dimensional difference gel electrophoresis (2DE-DIGE) in identifying new candidates as urinary biomarkers of CAD. [Methods]: Morning spot urine samples that were collected from kidney transplant recipients with biopsy-proven interstitial fibrosis and tubular atrophy (IFTA) stages 0-I-II/III (n=8/group) under immunosuppressive treatment with tacrolimus plus mycophenolate with or without prednisone. 2DE silver staining and mass spectrometry analyses were used to establish the normal proteome map, and 2DE-DIGE and mass spectrometry were used to identify proteins exhibiting differential abundance. [Results and Conclusions]: This study defines the normal proteome of stable renal transplant patients, which is composed of several plasma proteins, as well as of immunologic proteins that are probably specific to transplant recipients. The 2DE-DIGE study showed 19 proteins with differential concentrations, depending on the IFTA histologic score. These 19 proteins could be used as urinary biomarkers of the severity of IFTA in renal transplant recipients. Copyright © 2010 by Lippincott Williams & Wilkins., This work was supported by Instituto de Salud Carlos III, Fondo Investigación Sanitaria (FIS 03/0557 and FIS 06/1222), REDINREN (Red de Investigación en Enfermedades Renales), and FRIAT (Fundación Renal Íñigo Álvarez de Toledo).

El objetivo del siguiente trabajo es evaluar, en forma prospectiva, los resultados del tratamiento de pacientes portadores de calcificaciones del manguito rotador mediante la aplicación de ondas de choque focales.Se incluyeron 44 casos consecutivos de calcificaciones sintomáticas localizadas en alguno de los tendones del manguito rotador, en 43 pacientes con cirugías fallidas o que habían sido tratados en forma previa por al menos 6 meses con persistencia de los síntomas.Evaluados al año, en 20 pacientes (45,5%), la calcificación desapareció completamente. En 13 casos (29,5%) existió un cambio significativo en su tamaño o densidad. En 11 casos (25 %) no hubo modificaciones.El dolor de acuerdo a la escala visual analógica descendió de un promedio de 5,5 a 1,4.( p El estudio sugiere que la terapia por onda de choque es una alternativa válida en pacientes en los que ha fallado el tratamiento conservador y aún el quirúrgico.