Clinical and genetic factors involved in Porto-sinusoidal vascular disorder after oxaliplatin exposure.

BACKGROUND AND AIMS: Oxaliplatin (OX) has been described as a potential etiologic agent for porto-sinusoidal vascular disorder (PSVD). Our aim was to describe the natural history of PSVD due to OX in colon cancer (CRC) and identify risk factors for its development. METHODS: We made a multicenter retrospective case-control (ratio 1:3) study with patients diagnosed of PSVD-OX. Baseline data, end of treatment, years of follow-up and diagnosis of PSVD were collected and compared to controls (without PSVD). Besides, 16 different SNPs were selected from bibliography and analyzed by genotyping in the case group to identify potential genetic risk factors. RESULTS: 41 cases were identified, with a median time to PSVD diagnosis after the end of OX of 34 months. Spleen diameter was the strongest predictor of PSVD during treatment (OR 43.94 (14.48-133.336); p < 0.0001). Additionally, thrombocytopenia (<150 × 10^9) at one year was a significant disease risk marker (OR 9.35; 95% CI: 3.71-23.58; p = 0.001). We could not establish any significant association between the selected SNPs and PSVD diagnosis. CONCLUSION: The increase of spleen diameter is the strongest predictor of PSVD in patients treated with OX for CRC. These patients could be candidates for a specific follow-up of portal hypertension-related complications.

Efficacy of an aloe vera, chamomile, and thyme cosmetic cream for the prophylaxis and treatment of mild dermatitis induced by radiation therapy in breast cancer patients (the Alantel study).

Objectives: Radiation-induced dermatitis (RD) is one of the most common toxicities in radiation therapy (RT) patients. Corticosteroids, immunosuppressants, and natural products (NPs) have been used as treatment. The objective was to evaluate the efficacy of a NPs-based cream (Alantel®) to reduce the incidence of RD in women with breast cancer undergoing RT treatment. Design: We conducted a controlled, randomized, double-blind clinical trial. Setting: Radiation Oncology Unit of the Reina Sofía Hospital and 5 Primary Care centers of the Cordoba and Guadalquivir Health District (Spain). Interventions: Patients assigned to the experimental group (GTA) were treated with Alantel, while those in the control group (GTE) were treated with a moisturizer and emollient cream. Main outcome measures: The primary outcome variable was the incidence of RD. RD-free time, duration of RD, quality of life, and product safety were also assessed. Results: Seventy patients were included in the study, 35 in the GTA and 35 in the GTE. The incidence of RD was lower in the GTA (71.4%) than in the GTE (91.4%) after 4 weeks of follow-up (RR = 0.78; NNT = 5; p < 0.031). The Skindex-29 questionnaire showed differences in the statement: "My skin condition makes it hard to work or do hobbies" (17.1% in the GTE vs. 2.9% in GTA; p = 0.024). Conclusions: The higher efficacy of Alantel® compared to the control cream in reducing the incidence of RD in women with breast cancer has been demonstrated.

Dose and volume de-escalation of radiotherapy in head and neck cancer.

Radiotherapy plays a key role in the treatment of head and neck cancer. However, irradiation of the head and neck region is associated with high rates of acute and chronic toxicity. Technological advances have led to better visualisation of target volumes and critical structures and improved dose conformality in the treatment volume. Despite this, acute toxicity has not been substantially reduced and late toxicity has a significant impact on patients' quality of life. The greater radiosensitivity of tumours associated with the HPV and the development of new imaging techniques have encouraged research into new deintensified strategies to reduce the side effects of radiotherapy. The aim of this paper is to review the literature on the strategies of de-escalated treatment in dose and/or volume in head and neck cancer.

Impact of WALANT Hand Surgery in a Secondary Care Hospital in Spain. Benefits to the Patient and the Health System.

Purpose: The aim of this study is to compare patient benefits and economic costs of hand surgeries using the wide-awake local anesthesia no tourniquet (WALANT) technique versus a conventional major outpatient suite and review outcomes and complications in a series of cases of patients operated on using the WALANT technique. Methods: A prospective cohort study was first conducted comparing 150 cases of ambulatory hand surgery (carpal tunnel syndrome and trigger finger) using the WALANT technique and not requiring an operating room setting with 150 cases of outpatient surgery performed in an operating room involving a preoperative evaluation and the use of sedation and tourniquet. Preoperative, intraoperative, and postoperative pain was monitored, and days requiring postoperative analgesia were recorded. The resources and costs were evaluated. and patient satisfaction was assessed using a specific survey.Subsequently, 580 patient medical records were retrospectively reviewed, including 419 carpal tunnel syndrome and 197 trigger finger interventions (616 WALANT surgeries). Results: Intraoperative pain was equivalent for both groups, and postoperative pain was significantly lower in the WALANT group, with a reduced need for analgesics. Satisfaction was greater for the local anesthesia group. The use of personnel resources and hospital materials was reduced in the WALANT group, with a total estimated cost savings of 1.019 USD per patient.There were no complications related to the WALANT technique and the lidocaine and adrenaline combination. We found a complication rate of 5.58%, and, in line with the literature, most complications were minor, managed conservatively, and not related to the anesthetic technique. Conclusions: Procedures such as carpal tunnel and trigger finger surgeries can be safely performed using wide-awake surgery. Patient satisfaction is higher than with the conventional procedure performed in the operating room. Pain control is excellent, especially during the postoperative period. Clinical relevance: Hand surgery patients benefit from the WALANT technique in terms of comfort and timeliness because there is no need for preoperative tests or evaluations. In addition, it represents significant savings in hospital resources. In our case series, complications were in line with those previously reported with other anesthetic techniques.

Activating de novo monoallelic variants causing inborn errors of immunity in two unrelated children born of HIV-seroconcordant couples.

INTRODUCTION: Around 20% of all inborn errors of immunity (IEI) are autosomal dominant or monoallelic, either by haploinsufficiency, negative dominance, or gain of function (GOF). GOF phenotypes usually include autoinflammation, autoimmunity, lymphoproliferation, allergies, and some infections. CASE SERIES: We describe the cases of two unrelated patients born of HIV-seroconcordant parents. Both patients are HIV-negative but carry de novo GOF missense variants that resulted in inflammatory lymphoproliferative IEI diseases: signal transducer and activator of transcription 3 (STAT3)-GOF and phosphatidylinositol 3-kinase, catalytic delta (PIK3CD)-GOF. Both variants were found through whole-exome sequencing and confirmed by Sanger.An 11-year-old male with recurrent sinopulmonary infections, dysmorphism, growth delay, bronchiectasis, and mild mental retardation, as well as lymphopenia, thrombocytopenia, and high immunoglobulin M. Both his parents were known to be HIV-positive under anti-retroviral treatment. HIV infection was repeatedly ruled out in the patient, whom through whole-exome sequencing was found to have a heterozygous missense variant in exon 24 of PIK3CD, a hotspot transition, and the most reported variant in PIK3CD-GOF patients.A 6-year-old male with autoimmune hemolytic anemia, lymphoproliferation, short stature, and intractable diarrhea. Both his parents were found to be HIV-positive. HIV was repeatedly ruled out in the patient by ELISA and viral load. He was found to have a heterozygous missense/splice variant in exon 22 of STAT3, a hotspot transition, and the most reported variant in STAT3-GOF patients. DISCUSSION: The AID/APOBEC3 A-H family of proteins are cytidine deaminases that induce G>A hypermutation in both the invading viral DNA and the host genome, which results in stop codons inside the endogenized retroviral sequence. Both variants found in our patients are G to A transitions. Retroviral infection might thus have resulted in host genome instability, and our patients' rare congenital diseases are the unfortunate consequence of somatic hypermutation in one of their parents' gametes.

How Donor and Surgical Factors Affect the Viability and Functionality of Human Hepatocytes Isolated From Liver Resections.

Liver resections are a significant source of primary human hepatocytes used mainly in artificial liver devices and pharmacological and biomedical studies. However, it is not well known how patient-donor and surgery-dependent factors influence isolated hepatocytes' yield, viability, and function. Hence, we aimed to analyze the impact of all these elements on the outcome of human hepatocyte isolation. Patients and methods: Hepatocytes were isolated from liver tissue from patients undergoing partial hepatectomy using a two-step collagenase method. Hepatocyte viability, cell yield, adhesion, and functionality were measured. In addition, clinical and analytical patient variables were collected and the use or absence of vascular clamping and its type (continuous or intermittent) plus the ischemia times during surgery. Results: Malignant disease, previous chemotherapy, and male gender were associated with lower hepatocyte viability and isolation cell yields. The previous increase in transaminases was also associated with lower yields on isolation and lower albumin production. Furthermore, ischemia secondary to vascular clamping during surgery was inversely correlated with the isolated hepatocyte viability. An ischemia time higher than 15 min was related to adverse effects on viability. Conclusion: Several factors correlated with the patient and the surgery directly influence the success of human hepatocyte isolation from patients undergoing liver resection.

Mortality and Causes of Death After Liver Transplantation: Analysis of Sex Differences in a Large Nationwide Cohort.

In the last few years, several studies have analyzed sex and gender differences in liver transplantation (LT), but none have performed a disaggregated analysis of both mortality and causes of death. Data from 15,998 patients, 11,914 (74.5%) males and 4,069 (25.5%) females, transplanted between 2000 and 2016 were obtained from the Liver Transplantation Spanish Registry. Survival analysis was applied to explore recipient sex as a risk factor for death. The causes of death at different follow-up duration were disaggregated by recipient sex for analysis. Short-term survival was higher in males, whereas long-term survival was higher in females. Survival at 1, 5 and 10 years post-transplant was 87.43%, 73.83%, and 61.23%, respectively, in males and 86.28%, 74.19%, and 65.10%, respectively, in females (p = 0.05). Post-LT mortality related to previous liver disease also presented sex differences. Males had 37% increased overall mortality from acute liver failure (p = 0.035) and 37% from HCV-negative cirrhosis (p < 0.001). Females had approximately 16% increased mortality when the liver disease was HCV-positive cirrhosis (p = 0.003). Regarding causes of death, non-malignancy HCV+ recurrence (6.3% vs. 3.9% of patients; p < 0.001), was more frequently reported in females. By contrast, death because of malignancy recurrence (3.9% vs. 2.2% of patients; p = 0.003) and de novo malignancy (4.8% vs. 2.5% of patients; p < 0.001) were significantly more frequent in male recipients. Cardiovascular disease, renal failure, and surgical complications were similar in both. In summary, male patients have lower short-term mortality than females but higher long-term and overall mortality. In addition, the post-LT mortality risk related to previous liver disease and the causes of mortality differ between males and females.

Identification of hereditary breast and ovarian cancer germline variants in Granada (Spain): NGS perspective.

The aim of this study was to assess the prevalence of germline variants in cancer-predisposing genes by either targeted (BRCA1/2) or multigene NGS panel in a high-risk Hereditary Breast and Ovarian Cancer (HBOC) cohort. Samples from 824 Caucasian probands were retrospectively collected and the impact of genetic diagnosis and genetic variants epidemiology in this cohort was evaluated. Performance of risk-reducing prophylactic measures, such as prophylactic mastectomy and/or prophylactic oophorectomy, was assessed through clinical follow-up of patients with a positive genetic result. Pathogenic variants predisposing to HBOC were identified in 11.9% (98/824) individuals at BRCA2 (47/98), BRCA1 (24/98), PALB2 (8/51), ATM (7/51), CHEK2 (6/51) MSH6, (2/51), RAD51C (2/51) and TP53 (2/386). Of them, 11 novel pathogenic variants and 12 VUS were identified, characterized, and submitted to ClinVar. Regarding clinical impact, the risk of developing basal or Her2 breast cancer was increased 15.7 times or 37.5 times for BRCA1 and MSH6 pathogenic variants respectively. On the contrary, the risk of developing basal or luminal A breast cancer was reduced to 81% or 77% for BRCA2 and BRCA1 pathogenic variants, respectively. Finally, 53.2% of individuals testing positive for class IV/V variants underwent prophylactic surgery (mastectomy, oophorectomy or both) being significantly younger at the cancer diagnosis than those undertaking prophylactic measures (p = 0.008). Of them, 8 carried a pathogenic/likely pathogenic variant in other genes different from BRCA1 and BRCA2, and the remaining (46.7%) decided to continue with clinical follow-up. No differences in pathogenicity or risk of developing cancer were found for BRCA1/2 between targeted and multigene sequencing strategies; however, NGS was able to resolve a greater proportion of high-risk patients.

Prognostic factors for complications after loop ileostomy reversal.

BACKGROUND: Defunctioning ileostomy creation and closure are both associated with morbidity. There is little data available about complications after ileostomy closure. The aim of this study was to evaluate morbidity related to loop ileostomy closure (LIC) and to determine if patients with postoperative complications in primary surgery suffer from more postoperative complications during stoma closure. METHODS: This was a retrospective study on prospectively registered consecutive patients undergoing elective LIC in a single centre in Spain between April 2010 and December 2017. Baseline characteristics, postoperative complications after primary surgery and after stoma closure were recorded. Primary surgery included any colorectal resection, elective or urgent associated with a diverting loop ileostomy either as a protective stoma or rescue procedure. A logistic regression model was used to assess the effects of baseline variables and postoperative complications after primary surgery on the existence of postoperative complications related to LIC. RESULTS: Four hundred and twenty-eight patients (288 men, median age 64.5 years [IQR 55.1-72.3 years]) were included in the study, and 37.4%, developed complications after LIC. The most common was paralytic ileus. Only chronic kidney disease (OR 2.31; 95% CI 1.03-5.33, p = 0.043), existence of postoperative complications after primary surgery (OR 2.25; 95% CI 1.41-3.66, p = < 0.001) and ileostomy closure later than 10 months after primary surgery (OR 1.52; 95% CI 1.00-2.33, p = 0.049) were statistically significant in the multivariate analysis. CONCLUSIONS: Patients with chronic kidney disease, those who had any complication after primary surgery and those who had LIC > 10 months after primary surgery have a significantly higher risk of developing postoperative complications.

Prevention and Management of Donor-transmitted Cancer After Liver Transplantation: Guidelines From the ILTS-SETH Consensus Conference.

As with any other intervention in health, liver transplantation (LT) entails a variety of risks, including donor-transmitted cancers (DTCs). At present, 2%-4% of used deceased organ donors are known to have a current or past history of malignancy. The frequency of DTCs is consistently reported at 3-6 cases per 10 000 solid organ transplants, with a similar frequency in the LT setting. A majority of DTCs are occult cancers unknown in the donor at the time of transplantation. Most DTCs are diagnosed within 2 y after LT and are associated with a 51% probability of survival at 2 y following diagnosis. The probability of death is greatest for DTCs that have already metastasized at the time of diagnosis. The International Liver Transplantation Society-Sociedad Española de Trasplante Hepático working group on DTC has provided guidance on how to minimize the occurrence of DTCs while avoiding the unnecessary loss of livers for transplantation both in deceased and living donor LT. The group endorses the Council of Europe classification of risk of transmission of cancer from donor to recipient (minimal, low to intermediate, high, and unacceptable), classifies a range of malignancies in the liver donor into these 4 categories, and recommends when to consider LT, mindful of the risk of DTCs, and the clinical condition of patients on the waiting list. We further provide recommendations to professionals who identify DTC events, stressing the need to immediately alert all stakeholders concerned, so a coordinated investigation and management can be initiated; decisions on retransplantation should be made on a case-by-case basis with a multidisciplinary approach.

A randomized clinical trial of home telemonitoring in patients with advanced heart and lung diseases.

BRIEF SUMMARY: The addition of home monitoring to an integrated care model in patients with advanced chronic heart/lung diseases decreases mortality, hospital and emergency admissions, improves functional status, HRQoL, and is cost-effective. BACKGROUND: Telemonitoring is a promising implement for medicine, but its efficacy is unknown in patients with advanced heart and lung failure (AHLF). OBJECTIVE: To determine the efficacy of a telemonitoring system added to coordinated clinical care in patients with AHLF. DESIGN: Randomized phase 3 multicenter clinical trial with parallel groups in adult patients. PARTICIPANTS: Five spanish centers including patients with AHLF at discharge or in out-patient clinics. INTERVENTION: Patients were randomly assigned to receive a remote bio-parameters telemonitoring system (TELECARE) or best usual care (UCARE). TELECARE patients were provided with devices that collected symptoms and bio-parameters, and transferred them synchronously to a call-center, with a real-time health-care response. MAIN MEASURES: Primary end point was the need of admissions/emergency room visits at 45, 90, 180 days. Secondary end points included health care requirements, mortality, functional assessment, health related quality of life (HRQoL), perceived satisfaction, and cost-efficacy. RESULTS: 510 patients were included (54.5% women, median age 76.5 years; 63.1% suffered heart failure, 13.9% lung failure, and 22.9% both conditions). Clinical and functional features were comparable in both arms. TELECARE globally needed less admissions with respect UCARE after 45 days of inclusion (35.4% vs. 46.9%, p < 0.05). This tendency was maintained in the subgroups of patients with multimorbidity (34.2% vs. 46.9%, p < 0.05), intermediate risk of mortality (36.5% vs. 51.1%, p < 0.05), and those included after hospital discharge (34.9% vs. 50.5%, p < 0.01). HRQoL significantly improved (TELECARE/UCARE EuroQol baseline of 56.2 ± 18.2/55.1 ± 19.7, p = 0.054, and 64 ± 19.9/56.3 ± 21.6; p < 0.01 at the end), and perceived satisfaction was also higher (6.77 ± 0.52 vs. 6.62 ± 0.81, p < 0.001; highest possible score = 7). A trend to mortality decrease was also observed (12.9% vs. 19.3%, p = 0.13). TELECARE was cost-efficacious (TELECARE/UCARE QALY 3.94 Euros/0.81Euros). CONCLUSIONS: The addition of a telemonitoring system to an integrated care model in patients with AHLF decreases hospital and emergency admissions, improves functional status as well as HRQoL, and is cost-efficacious.

Deep Phenotypic Characterisation of CTCs by Combination of Microfluidic Isolation (IsoFlux) and Imaging Flow Cytometry (ImageStream).

The isolation of circulating tumour cells (CTCs) in colorectal cancer (CRC) mostly relies on the expression of epithelial markers such as EpCAM, and phenotypic characterisation is usually performed under fluorescence microscopy with only one or two additional markers. This limits the ability to detect different CTC subpopulations based on multiple markers. The aim of this work was to develop a novel protocol combining two platforms (IsoFluxTM and ImageStream®X) to improve CTC evaluation. Cancer cell lines and peripheral blood from healthy donors were used to evaluate the efficiency of each platform independently and in combination. Peripheral blood was extracted from 16 early CRC patients (before loco-regional surgery) to demonstrate the suitability of the protocol for CTC assessment. Additionally, peripheral blood was extracted from nine patients one month after surgery to validate the utility of our protocol for identifying CTC subpopulation changes over time. Results: Our protocol had a mean recovery efficiency of 69.5% and a limit of detection of at least four cells per millilitre. We developed an analysis method to reduce noise from magnetic beads used for CTC isolation. CTCs were isolated from CRC patients with a median of 37 CTCs (IQ 13.0-85.5) at baseline. CTCs from CRC patients were significantly (p < 0.0001) larger than cytokeratin (CK)-negative cells, and patients were stratified into two groups based on BRAFV600E and PD-L1 expression on CK-positive cells. The changes observed over time included not only the number of CTCs but also their distribution into four different subpopulations defined according to BRAFV600E and PD-L1 positivity. We developed a novel protocol for semi-automatic CTC isolation and phenotypic characterisation by combining two platforms. Assessment of CTCs from early CRC patients using our protocol allowed the identification of two clusters of patients with changing phenotypes over time.

Temporoparietal fascia flap for auricular reconstruction. / Colgajo de fascia temporoparietal para reconstrucción auricular.

INTRODUCTION: Microtia is a congenital malformation of the auricle. The most common complication of microtia surgical repair is costal cartilage exposure. We describe the case of a patient with costal cartilage exposure and the use of temporoparietal fascia flap (TPFF) for covering purposes. CLINICAL CASE: 12-year-old male patient with right microtia undergoing two auricle reconstruction surgeries. One month following the second surgery, costal cartilage exposure was noted, with loss of grafted skin. A TPFF and a scalp skin graft were performed to cover the exposed cartilage. COMMENTS: An adequate and critical management of costal cartilage exposure is required to avoid cartilage reabsorption. TPFF represents a useful tool in ear reconstruction surgeries and should be considered in potential face reconstruction surgeries.

INTRODUCCION: La microtia es una malformación congénita del pabellón auricular. Dentro de las complicaciones de la reparación quirúrgica, la más frecuente es la exposición del cartílago costal. Describimos el caso de un paciente con exposición del cartílago costal y la utilización del colgajo de fascia temporoparietal (CFTP) para su cobertura. CASO CLINICO: Paciente varón de 12 años con microtia derecha intervenido de primer y segundo tiempo de reconstrucción del pabellón auricular. Al mes de la segunda cirugía se evidencia exposición del cartílago costal, con pérdida de la piel injertada. Se realiza un CFTP e injerto de piel de cuero cabelludo para cubrir el cartílago expuesto. COMENTARIOS: Un manejo adecuado y crítico de la exposición del cartílago costal es necesario para evitar la reabsorción de dicho cartílago. El CFTP representa una herramienta para cirugías reconstructivas de la oreja y se ha de conocer para eventuales cirugías de reconstrucción facial.

Proposal for a preventive protocol for medication-related osteonecrosis of the jaw.

BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse reaction experienced by some patients exposed to certain drugs (antiresorptives such as bisphosphonates or denosumab, and antiangiogenic drugs). From a review of the literature it appears that there is no uniform criterion when selecting preventive measures; these vary according to author. Likewise, the measures recommended are usually general, so that in few cases they result in specific actions to be applied depending on the different variables involved such as the type of drug used, the duration of its application, the underlying pathology, the presence or absence of risk factors, etc. The aim of this study has been to design a preventive protocol which can be easily applied in any clinic or by any dental care service. MATERIAL AND METHODS: We undertook an exhaustive literature review to find any articles related to the topic of study, namely, preventive measures for medication-related osteonecrosis of the jaw, on the one hand generically and on the other focusing on dental implant treatment. The most part the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. From 3946 items, we selected a total of 21 items. RESULTS: From the analysis of the selected articles, several protocols have been developed that are easy to apply in a dental clinic.: Protocol 1. Before starting treatment with antiresorptives (Patients who are going to be treated for osteoporosis / Patients who are going to be treated for cancer). Protocol 2. Once treatment is initiated with antiresorptives (Patients being treated for osteoporosis / Patients being treated for cancer). CONCLUSIONS: The application of these protocols requires an interdisciplinary team which can handle the various treatments and apply the measures contained in them. Along with a team of well-educated and trained dentists, it is equally important to maintain contact with the medical team involved in the treatment of the underlying pathology, especially rheumatologists, oncologists, internists and gynaecologists. All the above requires a great staff learning and organization effort, continuous training and coordination of the whole team involved in the preventive management of these patients.

The Polemic Diagnostic Role of TP53 Mutations in Liquid Biopsies from Breast, Colon and Lung Cancers.

Being minimally invasive and thus allowing repeated measures over time, liquid biopsies are taking over traditional solid biopsies in certain circumstances such as those for unreachable tumors, very early stages or treatment monitoring. However, regarding TP53 mutation status analysis, liquid biopsies have not yet substituted tissue samples, mainly due to the lack of concordance between the two types of biopsies. This needs to be examined in a study-dependent manner, taking into account the particular type of liquid biopsy analyzed, that is, circulating tumor cells (CTCs) or cell-free DNA (cfDNA), its involvement in the tumor biology and evolution and, finally, the technology used to analyze each biopsy type. Here, we review the main studies analyzing TP53 mutations in either CTCs or cfDNA in the three more prevalent solid tumors: breast, colon and lung cancers. We evaluate the correlation for mutation status between liquid biopsies and tumor tissue, suggesting possible sources of discrepancies, as well as evaluating the clinical utility of using liquid biopsies for the analysis of TP53 mutation status and the future actions that need to be undertaken to make liquid biopsy analysis a reality for the evaluation of TP53 mutations.

Diamond Blackfan anemia is mediated by hyperactive Nemo-like kinase.

Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency. DBA is characterized by anemia, congenital anomalies, and cancer predisposition. Treatment for DBA is associated with significant morbidity. Here, we report the identification of Nemo-like kinase (NLK) as a potential target for DBA therapy. To identify new DBA targets, we screen for small molecules that increase erythroid expansion in mouse models of DBA. This screen identified a compound that inhibits NLK. Chemical and genetic inhibition of NLK increases erythroid expansion in mouse and human progenitors, including bone marrow cells from DBA patients. In DBA models and patient samples, aberrant NLK activation is initiated at the Megakaryocyte/Erythroid Progenitor (MEP) stage of differentiation and is not observed in non-erythroid hematopoietic lineages or healthy erythroblasts. We propose that NLK mediates aberrant erythropoiesis in DBA and is a potential target for therapy.

Everolimus plus exemestane in hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer: incidence and time course of adverse events in the phase IIIb BALLET population.

BACKGROUND: The addition of everolimus to exemestane therapy significantly improves progression-free survival in postmenopausal patients with hormone-receptor (HR)-positive HER2-negative endocrine-resistant breast cancer. However, the safety profile of this schedule still might be optimized. METHODS: Patients included in the BALLET trial were assessed. The objectives of this analysis were to provide additional information on the safety profile of this schedule depending on prior anticancer therapies and to characterize the time course of adverse events (AEs) and serious AEs (SAEs) of clinical interest throughout the study period. Non-infectious pneumonitis (NIP), stomatitis, asthenia and weight loss were selected as AEs of clinical interest. RESULTS: The safety population of this analysis comprised 2131 patients. There were similar incidences of AEs and SAEs of clinical interest regardless of previous anticancer therapies. Most stomatitis and asthenia events occurred within the first three months. Incidence of weight loss appeared to plateau except in the case of grade 3-4 events, which occurred rarely. The incidence of any grade NIP (between 2 to 6%) and grade 3-4 NIP (between 0 to 1%) was low across the study, but steady. CONCLUSIONS: Everolimus plus exemestane is a well-known therapeutic option for aromatase inhibitor pretreated advanced breast cancer patients, and its toxicity profile is similar to that described in previous studies. Close monitoring, especially within the first three months, early intervention with preventive measures and patient education to help recognize the first signs and symptoms of AEs, will help to reduce their incidence and severity.

Silicon substituted hydroxyapatite/VEGF scaffolds stimulate bone regeneration in osteoporotic sheep.

Silicon-substituted hydroxyapatite (SiHA) macroporous scaffolds have been prepared by robocasting. In order to optimize their bone regeneration properties, we have manufactured these scaffolds presenting different microstructures: nanocrystalline and crystalline. Moreover, their surfaces have been decorated with vascular endothelial growth factor (VEGF) to evaluate the potential coupling between vascularization and bone regeneration. In vitro cell culture tests evidence that nanocrystalline SiHA hinders pre-osteblast proliferation, whereas the presence of VEGF enhances the biological functions of both endothelial cells and pre-osteoblasts. The bone regeneration capability has been evaluated using an osteoporotic sheep model. In vivo observations strongly correlate with in vitro cell culture tests. Those scaffolds made of nanocrystalline SiHA were colonized by fibrous tissue, promoted inflammatory response and fostered osteoclast recruitment. These observations discard nanocystalline SiHA as a suitable material for bone regeneration purposes. On the contrary, those scaffolds made of crystalline SiHA and decorated with VEGF exhibited bone regeneration properties, with high ossification degree, thicker trabeculae and higher presence of osteoblasts and blood vessels. Considering these results, macroporous scaffolds made of SiHA and decorated with VEGF are suitable bone grafts for regeneration purposes, even in adverse pathological scenarios such as osteoporosis. STATEMENT OF SIGNIFICANCE: For the first time, the in vivo behavior of scaffolds made of silicon substituted hydroxyapatites (SiHA) has been evaluated under osteoporosis conditions. In order to optimize the bone regeneration properties of these bioceramics, 3D macroporous scaffolds have been manufactured by robocasting and implanted in osteoporotic sheep. Our experimental design shed light on the important issue of the biological response of nano-sized bioceramics vs highly crystalline bioceramics, as well as on the importance of coupling vascularization and bone growth processes by decorating SiHA scaffolds with vascular endothelial growth factor.

Effectiveness of a chat-bot for the adult population to quit smoking: protocol of a pragmatic clinical trial in primary care (Dejal@).

BACKGROUND: The wide scale and severity of consequences of tobacco use, benefits derived from cessation, low rates of intervention by healthcare professionals, and new opportunities stemming from novel communications technologies are the main factors motivating this project. Thus, the purpose of this study is to assess the effectiveness of an intervention that helps people cease smoking and increase their nicotine abstinence rates in the long term via a chat-bot, compared to usual practice, utilizing a chemical validation at 6 months. METHODS: Design: Randomized, controlled, multicentric, pragmatic clinical trial, with a 6-month follow-up. SETTING: Healthcare centers in the public healthcare system of the Community of Madrid (Madrid Regional Health Service). PARTICIPANTS: Smokers > 18 years of age who attend a healthcare center and accept help to quit smoking in the following month. N = 460 smokers (230 per arm) who will be recruited prior to randomization. Intervention group: use of a chat-bot with evidence-based contents to help quit smoking. CONTROL GROUP: Usual treatment (according to the protocol for tobacco cessation by the Madrid Regional Health Service Main variable: Continuous nicotine withdrawal with chemical validation (carbon monoxide in exhaled air). Intention-to-treat analysis. Difference between groups in continuous abstinence rates at 6 months with their corresponding 95% confidence interval. A logistic regression model will be built to adjust for confounding factors. RESULTS: First expected results in January 2020. DISCUSSION: Providing science-based evidence on the effectiveness of clinical interventions via information technologies, without the physical presence of a professional, is essential. In addition to being more efficient, the characteristics of these interventions can improve effectiveness, accessibility, and adherence to treatment. From an ethics perspective, this new type of intervention must be backed by scientific evidence to circumvent pressures from the market or particular interests, improve patient safety, and follow the standards of correct practices for clinical interventions. TRIAL REGISTRATION: ClinicalTrials.gov, reference number NCT03445507.