Meeting the Shortage of Human Cells and Tissues: The Andalusian Quality Assurance Programme for Tissue Donation.

Background A quality assurance programme for the tissue donation process was launched in Andalusia in 2020 to facilitate the integration of tissue donation into end-of-life care, and to respond to the growing need for human tissue for therapeutic purposes. The results of this programme are presented here. Methods After identifying the hospital departments in which to intensify the detection of tissue donors, expanding training activities and designing a specific data collection system for possible tissue donors who do not donate their tissues, the results of the donation activity were quantified and the causes of non-donation were analysed by applying the critical pathway for deceased tissue donation methodology. Results After an initial drop in activity, which coincided with the coronavirus pandemic, the number of tissue donors increased by 48.4% in 2022 compared to 2019. From the eligible donors, 83% were actual tissue donors and 71% were utilised donors. The modifiable causes of tissue donation loss, in order of frequency, were family refusal, followed by organisational or logistical issues, failure to notify or failure to identify possible donors, and failure to complete donor evaluation. Conclusion As a result of the collaboration of the various professionals involved in the programme, tissue donation activity has increased remarkably, the potential and effectiveness of the donation process have been evaluated, and areas for improvement have been identified, which we hope will lead to continuous improvement of the process.

Oxidative Effects in Early Stages of Embryo Development Due to Alcohol Consumption.

Alcohol, a widely consumed drug, exerts significant toxic effects on the human organism. This review focuses on its impact during fetal development, when it leads to a spectrum of disorders collectively termed Fetal Alcohol Spectrum Disorders (FASD). Children afflicted by FASD exhibit distinct clinical manifestations, including facial dysmorphism, delayed growth, and neurological and behavioral disorders. These behavioral issues encompass diminished intellectual capacity, memory impairment, and heightened impulsiveness. While the precise mechanisms underlying alcohol-induced fetal damage remain incompletely understood, research indicates a pivotal role for reactive oxygen species (ROS) that are released during alcohol metabolism, inciting inflammation at the cerebral level. Ethanol metabolism amplifies the generation of oxidant molecules, inducing through alterations in enzymatic and non-enzymatic systems responsible for cellular homeostasis. Alcohol consumption disrupts endogenous enzyme activity and fosters lipid peroxidation in consumers, potentially affecting the developing fetus. Addressing this concern, administration of metformin during the prenatal period, corresponding to the third trimester of human pregnancy, emerges as a potential therapeutic intervention for mitigating FASD. This proposed approach holds promise for ameliorating the adverse effects of alcohol exposure on fetal development and warrants further investigation.

Promoting the ethical use of safe and effective cell-based products: the Andalusian plan on regenerative medicine.

With regard to regenerative medicine, the expectations generated over the last two decades and the time involved in developing this type of therapies, together with the availability of devices that allow point-of-care treatments through the rapid isolation of cellular or plasma products from patients in the operating theater, represent the perfect breeding ground for the offering of unproven or unregulated therapies on a global scale. A multidisciplinary approach-one based on the collaboration of institutions that, from the perspective of their area of competence, can contribute to reversing this worrying situation-to this problem is essential. It is a priority for local health authorities to take measures that are adapted to the particular situation and regulatory framework of their respective territory. In this article, the authors present the regenerative medicine action plan promoted by the Andalusian Transplant Coordination (i.e., the action plan for the largest region in Spain), highlighting the aspects the authors believe are fundamental to its success. The authors describe, in summary form, the methodology, phases of the plan, actions designed, key collaborators, important milestones achieved and main lessons they have drawn from their experience so that this can serve as an example for other institutions interested in promoting the ethical use of this type of therapy.

Hereditary breast and ovarian cancer in Andalusian families: a genetic population study.

BACKGROUND: The BRCA1/2 mutation profile varies in Spain according to the geographical area studied. The mutational profile of BRCA1/2 in families at risk for hereditary breast and ovarian cancer has not so far been reported in Andalusia (southern Spain). METHODS: We analysed BRCA1/2 germline mutations in 562 high-risk cases with breast and/or ovarian cancer from Andalusian families from 2010 to 2015. RESULTS: Among the 562 cases, 120 (21.4%) carried a germline pathogenic mutation in BRCA1/2; 50 in BRCA1 (41.7%) and 70 in BRCA2 (58.3%). We detected 67 distinct mutations (29 in BRCA1 and 38 in BRCA2), of which 3 in BRCA1 (c.845C > A, c.1222_1223delAC, c.2527delA) and 5 in BRCA2 (c.293 T > G, c.5558_5559delGT, c.6034delT, c.6650_6654delAAGAT, c.6652delG) had not been previously described. The most frequent mutations in BRCA1 were c.5078_5080delCTG (10%) and c.5123C > A (10%), and in BRCA2 they were c.9018C > A (14%) and c.5720_5723delCTCT (8%). We identified 5 variants of unknown significance (VUS), all in BRCA2 (c.5836 T > C, c.6323G > T, c.9501 + 3A > T, c.8022_8030delGATAATGGA, c.10186A > C). We detected 76 polymorphisms (31 in BRCA1, 45 in BRCA2) not associated with breast cancer risk. CONCLUSIONS: This is the first study reporting the mutational profile of BRCA1/2 in Andalusia. We identified 21.4% of patients harbouring BRCA1/2 mutations, 58.3% of them in BRCA2. We also characterized the clinical data, mutational profile, VUS and haplotype profile.

Pattern of recurrence of early breast cancer is different according to intrinsic subtype and proliferation index.

INTRODUCTION: Recurrence risk in breast cancer varies throughout the follow-up time. We examined if these changes are related to the level of expression of the proliferation pathway and intrinsic subtypes. METHODS: Expression of estrogen and progesterone receptor, Ki-67, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR) and cytokeratin 5/6 (CK 5/6) was performed on tissue-microarrays constructed from a large and uniformly managed series of early breast cancer patients (N = 1,249). Subtype definitions by four biomarkers were as follows: luminal A (ER + and/or PR+, HER2−, Ki-67 <14), luminal B (ER + and/or PR+, HER2−, Ki-67 ≥14), HER2-enriched (any ER, any PR, HER2+, any Ki-67), triple-negative (ER−, PR−, HER2−, any Ki-67). Subtype definitions by six biomarkers were as follows: luminal A (ER + and/or PR+, HER2−, Ki-67 <14, any CK 5/6, any EGFR), luminal B (ER + and/or PR+, HER2−, Ki-67 ≥14, any CK 5/6, any EGFR), HER2-enriched (ER−, PR−, HER2+, any Ki-67, any CK 5/6, any EGFR), Luminal-HER2 (ER + and/or PR+, HER2+, any Ki-67, any CK 5/6, any EGFR), Basal-like (ER−, PR−, HER2−, any Ki-67, CK5/6+ and/or EGFR+), triple-negative nonbasal (ER−, PR−, HER2−, any Ki-67, CK 5/6−, EGFR−). Each four- or six-marker defined intrinsic subtype was divided in two groups, with Ki-67 <14% or with Ki-67 ≥14%. Recurrence hazard rate function was determined for each intrinsic subtype as a whole and according to Ki-67 value. RESULTS: Luminal A displayed a slow risk increase, reaching its maximum after three years and then remained steady. Luminal B presented most of its relapses during the first five years. HER2-enriched tumors show a peak of recurrence nearly twenty months post-surgery, with a greater risk in Ki-67 ≥14%. However a second peak occurred at 72 months but the risk magnitude was greater in Ki-67 <14%. Triple negative tumors with low proliferation rate display a smooth risk curve, but with Ki-67 ≥14% show sharp peak at nearly 18 months. CONCLUSIONS: Each intrinsic subtype has a particular pattern of relapses over time which change depending on the level of activation of the proliferation pathway assessed by Ki-67. These findings could have clinical implications both on adjuvant treatment trial design and on the recommendations concerning the surveillance of patients.

Laboratory Cross-Comparison and Ring Test Trial for Tumor BRCA Testing in a Multicenter Epithelial Ovarian Cancer Series: The BORNEO GEICO 60-0 Study.

Germline and tumor BRCA testing constitutes a valuable tool for clinical decision-making in the management of epithelial ovarian cancer (EOC) patients. Tissue testing is able to identify both germline (g) and somatic (s) BRCA variants, but tissue preservation methods and the widespread implementation of NGS represent pre-analytical and analytical challenges that need to be managed. This study was carried out on a multicenter prospective GEICO cohort of EOC patients with known gBRCA status in order to determine the inter-laboratory reproducibility of tissue sBRCA testing. The study consisted of two independent experimental approaches, a bilateral comparison between two reference laboratories (RLs) testing 82 formalin-paraffin-embedded (FFPE) EOC samples each, and a Ring Test Trial (RTT) with five participating clinical laboratories (CLs) evaluating the performance of tissue BRCA testing in a total of nine samples. Importantly, labs employed their own locally adopted next-generation sequencing (NGS) analytical approach. BRCA mutation frequency in the RL sub-study cohort was 23.17%: 12 (63.1%) germline and 6 (31.6%) somatic. Concordance between the two RLs with respect to BRCA status was 84.2% (gBRCA 100%). The RTT study distributed a total of nine samples (three commercial synthetic human FFPE references, three FFPE, and three OC DNA) among five CLs. The median concordance detection rate among them was 64.7% (range: 35.3-70.6%). Analytical discrepancies were mainly due to the minimum variant allele frequency thresholds, bioinformatic pipeline filters, and downstream variant interpretation, some of them with consequences of clinical relevance. Our study demonstrates a wide range of concordance in the identification and interpretation of BRCA sequencing data, highlighting the relevance of establishing standard criteria for detecting, interpreting, and reporting BRCA variants.

Complement component 4d immunostaining in liver allografts of patients with de novo immune hepatitis.

De novo immune hepatitis (DNIH) is a form of late graft dysfunction after liver transplantation. The fine mechanisms leading to the development of DNIH are not known, and whether this hepatitis is a form of rejection or a result of an auto/alloimmune injury has not been established. In our patients, DNIH was always preceded by the production of donor-specific antibodies against the glutathione S-transferase T1 (GSTT1) enzyme because of a genetic mismatch in which the donors carried the wild-type gene and the recipients displayed the null genotype. Complement component 4d (C4d) immunopositivity in 12 paraffin-embedded liver biopsy samples from 8 patients diagnosed with DNIH associated with anti-GSTT1 antibodies was retrospectively evaluated. Six patients with a diagnosis of chronic rejection (CR) and 7 patients with hepatitis C virus recurrence were included as control groups. Among the patients with DNIH, 7 showed C4d-positive immunostaining localized in the portal tracts, whereas in the tested biopsy samples of the 2 control groups, this staining pattern was absent. Four biopsy samples of the CR group showed C4d-positive sinusoidal staining. This study confirms the activation of the complement pathway in the presence of donor-specific antibodies, which was shown by the deposition of C4d elements in liver biopsy samples of patients with DNIH. The use of C4d as a marker of antibody-mediated rejection in liver allografts in the presence of antidonor antibodies is discussed, and it may contribute to improved differential diagnoses based on biopsy findings.

Outcome of small invasive breast cancer with no axillary lymph node involvement.

The prognosis and need or not for adjuvant therapy in patients with small breast tumors (≤1cm N0) is the subject of controversy as regards the clinical benefit obtained, toxicity, and the economical costs generated. A retrospective analysis was made of 238 patients with early-stage breast cancer (pT1≤1 cm N0M0) diagnosed between January 1993 and May 2008. As regards the systemic adjuvant treatments provided, (a) 122 (51%) received no treatment, (b) 102 (43%) received hormone therapy, (c) 9 (4%) chemotherapy, and (d) 5 (2%) received both hormone therapy and chemotherapy. An analysis was made of disease-free survival (DFS) and breast cancer-specific survival in our series of patients, and of their correlation to clinicopathological factors (age, tumor size, histological grade, estrogen receptor (ER) expression, HER-2 overexpression, and systemic adjuvant therapy). The median follow-up of this cohort was 63months (range 5-145). Some type of relapse was recorded in 4.2% of the patients (six patients presented local recurrence in all cases subjected to rescue treatment with surgery and/or radiotherapy, three patients developed distant metastases, and one patient presented a resected local recurrence followed by systemic relapse). The 5year DFS was 96%, and the 5year breast cancer-specific survival was 99.6%. A univariate analysis was made of the clinicopathological variables and their association to DFS. None of the variables was seen to be significantly correlated to shorter DSF except for an association between HER-2 overexpression and poor outcome borderline significance (p=0.07). The prognosis of our pT1≤1cm N0M0 tumors was excellent, although the absence of systemic adjuvant therapy in one-half of the patients.

[The regenerative medicine and stem cell business: confusion with legal implications]. / El negocio de la medicina regenerativa y las células madre: confusión con implicaciones legales.

The rise of regenerative medicine and the growth of the offer of autologous therapies, obtained from blood, cells or tissues of the patients, have been favoured by the current availability of an increasing number of commercial devices. Most of these devices are easy to use, allowing the elaboration of products and its application within the same procedure. Regardless of the questionable efficacy and safety of many of the treatments offered under the claim of stem cells or regenerative medicine, most of the centres and professionals offering these treatments are unaware of the legal requirements and implications of their use. A common confusion consists in not distinguishing between the authorization required by the equipment itself, considered a medical device, and the authorization for the use of the product obtained, usually considered a medicinal product (whether advanced therapy or not) or a transplant. Moreover, these treatments frequently have an experimental nature. In that case, in addition to requiring the corresponding ethical evaluation and the authorization of various regulatory bodies, their administration must be offered free of charge, obtaining the patient's informed consent and after contracting a specific insurance policy. In this article we present a brief summary of the main requirements for the application of these autologous biological products with the aim of serving as a guide both for the professionals who prescribe them and for those who inspect the centres where the products are administered. Finally, we include some recommendations for patients.

Machine learning and natural language processing (NLP) approach to predict early progression to first-line treatment in real-world hormone receptor-positive (HR+)/HER2-negative advanced breast cancer patients.

BACKGROUND: CDK4/6 inhibitors plus endocrine therapies are the current standard of care in the first-line treatment of HR+/HER2-negative metastatic breast cancer, but there are no well-established clinical or molecular predictive factors for patient response. In the era of personalised oncology, new approaches for developing predictive models of response are needed. MATERIALS AND METHODS: Data derived from the electronic health records (EHRs) of real-world patients with HR+/HER2-negative advanced breast cancer were used to develop predictive models for early and late progression to first-line treatment. Two machine learning approaches were used: a classic approach using a data set of manually extracted features from reviewed (EHR) patients, and a second approach using natural language processing (NLP) of free-text clinical notes recorded during medical visits. RESULTS: Of the 610 patients included, there were 473 (77.5%) progressions to first-line treatment, of which 126 (20.6%) occurred within the first 6 months. There were 152 patients (24.9%) who showed no disease progression before 28 months from the onset of first-line treatment. The best predictive model for early progression using the manually extracted dataset achieved an area under the curve (AUC) of 0.734 (95% CI 0.687-0.782). Using the NLP free-text processing approach, the best model obtained an AUC of 0.758 (95% CI 0.714-0.800). The best model to predict long responders using manually extracted data obtained an AUC of 0.669 (95% CI 0.608-0.730). With NLP free-text processing, the best model attained an AUC of 0.752 (95% CI 0.705-0.799). CONCLUSIONS: Using machine learning methods, we developed predictive models for early and late progression to first-line treatment of HR+/HER2-negative metastatic breast cancer, also finding that NLP-based machine learning models are slightly better than predictive models based on manually obtained data.

Maintenance treatment with pegylated liposomal doxorubicin versus observation following induction chemotherapy for metastatic breast cancer: GEICAM 2001-01 study.

This randomized multicenter phase III trial evaluated the role of maintenance therapy with pegylated liposomal doxorubicin (PLD) after induction chemotherapy in patients with metastatic breast cancer (MBC). Patients without disease progression following first-line induction chemotherapy consisting of three cycles of doxorubicin (75 mg/m(2)) followed by three cycles of docetaxel (100 mg/m(2)) both every 21 days, were randomized to PLD (40 mg/m(2)) every 28 days for six cycles or to observation. Time to progression (TTP) was the primary endpoint. 288 patients were enrolled and received induction first-line chemotherapy. One hundred and fifty-five achieved response or stable disease and were randomized to maintenance PLD (n = 78) or observation (n = 77). With a median follow-up of 20 months from randomization (range 1-56), disease progression occurred in 94% of patients. PLD significantly improved TTP by 3.3 months (8.4 vs. 5.1 months; hazard ratio [HR] = 0.54, 95% CI: 0.39 to 0.76, P = 0.0002) compared with observation. Overall survival was not significantly prolonged with PLD (24.8 vs. 22.0 months, respectively; HR = 0.86, 95% CI: 0.58-1.27, P = 0.44). PLD-induced toxicity was mild and manageable with up to 5% of patients experiencing grade 3/4 non-hematologic events (fatigue, mucositis, palmar-plantar erythrodysesthesia). Grade 3/4 neutropenia occurred in 12% of patients; two patients developed febrile neutropenia. This phase III trial demonstrated that maintenance chemotherapy with PLD is well tolerated and offers improved TTP in patients with MBC following first-line chemotherapy.

Minimizing cardiotoxicity while optimizing treatment efficacy with trastuzumab: review and expert recommendations.

Numerous clinical studies have demonstrated the therapeutic benefit of trastuzumab in women with breast cancer. However, a small but not insignificant proportion of patients have experienced trastuzumab-associated cardiotoxicity during these trials. This phenomenon is generally characterized by an asymptomatic reduction in left ventricular ejection fraction (LVEF) or, less often, congestive heart failure (CHF). Concomitant anthracycline therapy significantly increases the risk for cardiotoxicity during trastuzumab treatment, and such regimens are therefore not recommended. The cardiac dysfunction associated with trastuzumab is most often reversible upon discontinuation of treatment and initiation of standard medical therapy for CHF. Prior to treatment initiation, a risk-benefit analysis should be performed for each individual patient, including a thorough assessment of potential risk factors and cardiac function. Cardiac monitoring should be continued throughout trastuzumab therapy and the follow-up period, because early recognition of trastuzumab-associated cardiac dysfunction can allow effective medical intervention. Following the occurrence of asymptomatic LVEF reduction or CHF and appropriate medical intervention, reintroduction of trastuzumab may be considered in patients following resolution of normal cardiac function, or in those for whom the benefit of antitumor therapy outweighs the risk for CHF.

Geographic Information System Analysis: Promoting the Organ Donation Process in Andalusia.

OBJECTIVE: The objective is to study the geographic distribution of public awareness and acceptance of organ donation in Andalusian municipalities and determine its relationship with each population and the rate of aging. METHODS: Data on organ donors from the Information System for Autonomous Regional Transplant Coordination in Andalusia were analyzed from 2006 to 2017. The geographic analysis was performed using free software from the Generalitat Valenciana Geographic Information System (gvGIS, Valencia, Spain). Data from the Spanish National Statistics Institute for the year 2017 were used as a reference for population estimates and calculating the rate of aging. RESULTS: From 2006 to 2017, a total of 3698 donors were registered in Andalusia, 28 of whom were residing in another autonomous community and 120 who were not censored as residents of their municipality, leaving a final total of 3550 donors. The rate of aging in 2017 was 1.02. Choropleth mapping was used to identify donors in each municipality. Population and aging rate in 2017 for these areas were also analyzed. CONCLUSION: Georeferenced data on organ donation not only reveals spatial differences in the distribution of public acceptance; it also provides insight into the relationship between this distribution and the sociodemographic characteristics of each community. In this study, areas with the least number of donors seem to coincide with difficult accessibility, higher aging index, and low population rates. These maps can assist transplant coordinators in targeting areas for public education and information campaigns to heighten awareness of the positive results of organ donation and potentiate its acceptance.

Continuing Training Accreditation in the Organ Donation Process in Andalusia: Results From the Education and Training Unit of the Regional Transplant Organization of Andalusia.

OBJECTIVE: The objective of this study is to evaluate the results obtained by the Training Unit of the Regional Transplant Organization of Andalusia from 2015 to 2017. METHODS: The following indicators were analyzed: number of activities carried out, number of students trained per year, students who do not complete the course, student and teacher satisfaction, learning assessment via postformation test, and transfer of training to the workplace. RESULTS: Between the years 2015 to 2017, 86 courses were carried out, and 2600 students were trained (1325 doctors, 1064 nurses, and 211 students with other degrees). A total of 83 students (3.2%) withdrew from training after its initiation. The overall assessments from teachers and students were 95/100 and 92/100, respectively. Student scores from the postformation test to assess learning averaged 77 points. CONCLUSION: It is worth noting the elevated number of courses offered and students trained over this 3-year period. We believe this has had a strong impact on the donation rate in Andalusia, which rose from 37.5 donors per million inhabitants in 2014 to 52.5 donors in 2018. Although student and teacher satisfaction was very high, it is clear that the transfer of new skills to the workplace could benefit from improvements in teamwork, communication with the transplant coordinator, the overall work environment, and the resources at their disposal.

False-Positive Tumor During Organ Retrieval: All Cats Are Gray in the Dark.

OBJECTIVE: Efforts to expand the organ donor pool to meet growing transplant demands remains a top priority, as does maintaining the quality and safety standards of potential recipients. There is a short window of time from organ retrieval to decision making on organ acceptance, based on the available data. Furthermore, the limitations of intraoperative biopsy can often lead to donor or organ refusal due to a suspected tumor, which, if not confirmed in the final biopsy, results in the loss of a transplant opportunity. METHODS: Donor characteristics and organs discarded on suspicion of neoplastic disease at the time of extraction were analyzed in Andalusia between January 2014 and July 2018. The variable analysis included sociodemographic data, type of donor, location of the potential malignancy, histopathologic examination, and discarded organs. RESULTS: A total of 43 cases were identified. The organs of 33 donors (76.7%) were discarded. Kidneys were the most frequent location for a suspected tumor (44%), followed by the liver (21%). In 18 of the 43 cases (42%), the suspected malignancy was not confirmed, and of these, only 3 livers and 1 kidney were implanted. Sixty potentially transplantable organs were discarded, including those that would have been extracted and/or implanted in the absence of a suspected tumor. CONCLUSIONS: These results highlight the need not only to improve the accuracy of intraoperative biopsies but to seek new decision-making strategies for the short interval after organ retrieval. This involves avoiding both extremes of donation contraindications, while maintaining quality and safety standards.

Positive association of anticytoskeletal endothelial cell antibodies and cardiac allograft rejection.

Using an indirect immunofluorescence method on human umbilical vein endothelial cells (HUVEC), we investigated the presence of antiendothelial cell antibodies (AECA) in 136 pre- and posttransplant serum samples sequentially collected from 31 patients during the first year after cardiac transplantation. A healthy control group was also included (n = 87). Colocalization studies demonstrated a positive staining pattern of different cytoskeletal components (cytoskeletal-antiendothelial cell antibodies, CSK-AECA) including antivimentin, antiactin, antitubulin, and anticytokeratin among heart transplanted patients. Frequency of CSK-AECA in the control group and at day 0 in the transplant group was 18.3 and 22.5%, respectively (p = NS). A progressive increase in the frequency of CSK-AECA was observed after cardiac transplantation: 13.3% at day 15; 22.2% at day 30; 53.8% at day 90, and 58% at day 360. Interestingly, rejection episodes within the first year after transplantation occurred in 83.3% of CSK-AECA-positive and in 30.7% of CSK-AECA-negative patients (p = 0.0045). The presence of antibodies was detected prior to the rejection event and was associated with a poor clinical outcome: rejection episodes occurred at a mean of 36.14 +/- 17 days after transplantation in patients with preexisting AECA and 174.25 +/- 51.9 days after de novo antibody appearance in patients with no antibodies at day 0 (p = 0.029). In conclusion, a progressive increase in the frequency of CSK-AECA was observed following cardiac transplantation; the presence of these antibodies is strongly associated and precedes the rejection episodes. Thus, CSK-AECA could be a good marker for acute graft rejection.

Anti-glutathione S-transferase T1 antibody-mediated rejection in C4d-positive renal allograft recipients.

BACKGROUND: Chronic humoral rejection is a progressive form of graft injury, with defined diagnostic criteria, the crucial one being the evidence of circulating anti-donor antibodies. These antibodies are mainly directed against human leucocyte antigens (HLA), but other targets have also been described. We previously reported that antibodies against the Glutathione S-transferase T1 (GSTT1) enzyme appear in recipients without the GSTT1 gene who receive a graft from a GSTT1-positive donor. The primary aim of this study was to analyse the role of GSTT1 in cases of antibody-mediated rejection (AMR) in the absence of anti-HLA antibodies. A second objective was to describe the distribution of the GSTT1 enzyme in the human kidney. METHODS: Four renal biopsies from four renal transplanted patients with declined renal function and circulating anti-donor GSTT1 antibodies were studied for C4d deposits in sections of paraffin-embedded tissue samples. Anti-donor-specific HLA and MICA antibody detection was done with the Luminex platform and anti-GSTT1 antibodies were tested by indirect immunofluorescence on rat tissues and ELISA assay. DNA of the patients was extracted for GSTT1 genotyping. RESULTS: Four patients with the GSTT1 donor/recipient mismatch developed anti-GSTT1 antibodies 32, 42, 48 and 60 months after the transplant. One patient also had donor-specific anti-HLA antibodies. Their biopsies showed pathologic lesions compatible with chronic antibody-mediated rejection (CAMR), along with positive C4d deposition in peritubular capillaries in three of them, being no valuable in the other case. CONCLUSION: This is the first study reporting an association between the appearance of chronic antibody-mediated renal allograft rejection and the occurrence of de novo production of anti-GSTT1 antibodies, in the absence of anti-HLA donor-specific antibodies. This fact suggests a potential role of the GSTT1 system in anti-graft immune response.

Elevated serum levels of vascular endothelial growth factor are associated with tumor-associated macrophages in primary breast cancer.

We analyzed serum and tumor samples from 133 patients with operable primary breast cancer to determine the possible relationship between presurgery and postsurgery circulating serum vascular endothelial growth factor (VEGF) levels and tumor-associated macrophage (TAM) numbers, tumor VEGF expression, and other immunohistochemical parameters. A significant positive correlation was observed between the number of TAM and postsurgery circulating VEGF values (P < .05). Moreover, patients with a p53+ tumor had higher postsurgery serum VEGF levels than those with a p53- tumor (P < .05), and tumor p53 overexpression correlated significantly with TAM number (P = .007). We observed no significant association between serum values and tumor VEGF expression. Although the macrophage index was higher in VEGF+ than in VEGF- tumors, the differences were not statistically significant. Our data show a positive interrelation between high circulating VEGF levels, the number of TAM, and p53 overexpression, a relationship that might have an important role in the enhanced angiogenesis processes in breast cancer.

El negocio de la medicina regenerativa y las células madre: confusión con implicaciones legales / The regenerative medicine and stem cell business: confusion with legal implications

El auge de la medicina regenerativa y el crecimiento de la oferta de terapias autólogas obtenidas a partir de sangre, células o tejidos de los propios pacientes se ha visto favorecido por la actual disponibilidad de diversos dispositivos comerciales de fácil manejo que permiten la elaboración de los productos y su aplicación dentro de un mismo procedimiento. Independientemente de las dudosas eficacia y seguridad de muchos de los tratamientos que se ofrecen bajo el reclamo de las células madre o la medicina regenerativa, la mayor parte de los centros y de los profesionales que ofrecen estos tratamientos desconocen los requisitos y las implicaciones legales de su uso. Una confusión frecuente consiste en no distinguir entre la autorización que requiere el propio dispositivo, considerado producto sanitario, y la autorización para el uso del producto obtenido, que en general se trata de un medicamento, ya sea de terapia avanzada o no, o de un trasplante. Por otra parte, es frecuente que estos tratamientos tengan un carácter experimental, por lo que su administración en ese caso, además de requerir la evaluación ética correspondiente y la autorización de diversos organismos reguladores, debe ofrecerse de forma gratuita y tras recabar el consentimiento informado del paciente y contratar una póliza de seguros específica. En este artículo se presentan, de forma resumida, los principales requisitos para la aplicación de estos productos biológicos autólogos, con el objetivo de que puedan servir de guía tanto para los profesionales que los prescriben como para aquellos que inspeccionan los centros donde se administran. Por último, se ofrecen algunas recomendaciones para los pacientes. (AU)

The rise of regenerative medicine and the growth of the offer of autologous therapies, obtained from blood, cells or tissues of the patients, have been favoured by the current availability of an increasing number of commercial devices. Most of these devices are easy to use, allowing the elaboration of products and its application within the same procedure. Regardless of the questionable efficacy and safety of many of the treatments offered under the claim of stem cells or regenerative medicine, most of the centres and professionals offering these treatments are unaware of the legal requirements and implications of their use. A common confusion consists in not distinguishing between the authorization required by the equipment itself, considered a medical device, and the authorization for the use of the product obtained, usually considered a medicinal product (whether advanced therapy or not) or a transplant. Moreover, these treatments frequently have an experimental nature. In that case, in addition to requiring the corresponding ethical evaluation and the authorization of various regulatory bodies, their administration must be offered free of charge, obtaining the patient's informed consent and after contracting a specific insurance policy. In this article we present a brief summary of the main requirements for the application of these autologous biological products with the aim of serving as a guide both for the professionals who prescribe them and for those who inspect the centres where the products are administered. Finally, we include some recommendations for patients. (AU)