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Background: Bullous pemphigoid (BP) affects elderly individuals with multiple comorbidities, making conventional treatments unsuitable., Objectives: Evaluate the effectiveness and safety of dupilumab in the treatment of BP., Methods: A multicentre ambispective cohort study was conducted across 34 hospitals. Patients with BP treated with dupilumab were included. Most of the patients (97.1%) received an initial 600-mg dose followed by 300 mg every 2 weeks. The primary outcome was the proportion of patients achieving complete remission (CR) within 4 weeks, defined as an Investigator's Global Assessment score of 0 or 1. CR at weeks 16, 24 and 52, adverse events (AEs), reductions in Peak Pruritus Numerical Rating Scale (PP-NRS) and systemic glucocorticoid use were also assessed., Results: The study included 103 patients with a median age of 77.3 years; 58.3% were male. CR was achieved by 53.4% within 4 weeks and 95.7% by week 52. The PP-NRS score reduced by 70.0% by week 4 and was completely controlled by week 24. Thirteen patients presented with AEs, most of which were mild. Systemic glucocorticoid use reduced by 82.1% by week 52. Shorter disease duration and exclusive cutaneous involvement predicted better response at 16 weeks. No differences in response rates to dupilumab were observed between drug-associated BP and idiopathic cases. No significant difference in response rates was observed between patients treated with dupilumab in monotherapy and those receiving dupilumab with concomitant treatments., Conclusions: Dupilumab is effective, rapid and safe in managing BP, reducing the need for corticosteroids and other treatments. Early initiation and exclusive skin involvement predict better outcomes., Competing Interests: Conflicts of interest: C.M.-V. has served as a speaker for Leo Pharma and Sanofi. M.A.B.M. has participated as a principal investigator or sub-investigator in clinical trials for bullous pemphigoid funded by Argnx, AstraZeneca and Regeneron. J.S. has served as a medical advisor, speaker and/or has received research funding from Abbvie, Leo Pharma, Lilly, Noucor, Novartis and Sanofi Genzyme. C.M.C. has received funding from Sanofi for activities related to her work. S.M.-S. has received funding from Sanofi for attending congresses. J.M.M.Jr has served as a speaker or consultant for ADIMYF, Astra Zeneca, Bocentium Consulting, Fundacio Clinic Per La Recerca, Fundació Institut de Recerca Hospital de la Santa Creu i Sant Pau, Fundacion Piel Sana de la AEDV, Grupo Español de Trasplantes Hematopoyéticos y Terapia Celular, Janssen, Laboratorios Viñas, MFAR, Organon Salud, Sanofi-Aventis and Viatris Pharmaceuticals, all outside the submitted work. He has participated as principal investigator in clinical trials for bullous pemphigoid funded by AstraZeneca. L.C.-B. has served as a speaker, medical advisor and/or consultant for Abbvie, Leo Pharma, Lilly, Novartis and Sanofi., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The current available evidence on the management of metastatic renal cell cancer (mRCC) in real life is scarce in our environment. We present a summary of the existing real-world data and the results of an analysis describing the clinical characteristics, treatments, and health outcomes of patients with mRCC in northern Spain., Methods: Retrospective observational study. Adult patients diagnosed with mRCC between Jan 2007 and Dec 2019 were included. Epidemiological, efficacy and toxicity data were collected. Median overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan-Meier method., Results: A total of 829 patients were included (median age at diagnosis:63 years;73% men). Median follow-up was 180 months. The preponderant histology was clear cell (85%). In 50% the initial diagnosis was advanced disease. The distribution according to IMDC prognosis was good (24%), intermediate (50%) and poor (26%). The most frequent metastatic locations were lung (68.3%) and lymph node (41.0%). Most patients (95%) received a first line (1L) systemic treatment, 60% were treated with a second line (2L) of therapy and 37% received third line (3L). A VEGFR-TKIs was the most common treatment (1L: 90%, n = 507; 2L: 49%, n = 233; 3L: 54%, n = 156) followed by mTOR inhibitors (1L: 2%, n = 4; 2L: 27%, n = 126; 3L: 23%, n = 68) and immunotherapy (1L: 3.7%, n = 25; 2L: 27%, n = 126). Median OS was 24.5 months in the general population. According to IMDC prognostic groups, OS was 52.5, 25.7 and 9 months respectively. From the start of the 1L, 2L, and 3L treatment, median PFS was: 1L: 7.8 (6.8-9.0); 2L: 4.9 (4.3-5.5); 3L: 4.3 (3.8-4.8) months. No unexpected toxicity was reported., Conclusions: The Real-World Data on the management of mRCC in Northern Spain are comparable in epidemiology, efficacy, and safety to studies conducted in other areas of the world. The significant reduction in the number of patients receiving second and subsequent lines of therapy hampers the access to new therapies developed in this context., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Nanosystems that simultaneously contain fluorescent and magnetic modules can offer decisive advantages in the development of new biomedical approaches. A biomaterial that enables multimodal imaging and contains highly efficient nanoheaters together with an intrinsic temperature sensor would become an archetypical theranostic agent. In this work, we have designed a magneto-luminescent system based on Fe 3 O 4 NPs with large heating power and thermosensitive rhodamine (Rh) fluorophores that exhibits the ability to self-monitor the hyperthermia degree. Three samples composed of highly homogeneous Fe 3 O 4 NPs of ∼25 nm and different morphologies (cuboctahedrons, octahedrons, and irregular truncated-octahedrons) have been finely synthesized. These NPs have been thoroughly studied in order to choose the most efficient inorganic core for magnetic hyperthermia under clinically safe radiofrequency. Surface functionalization of selected Fe 3 O 4 NPs has been carried out using fluorescent copolymers composed of PMAO, PEG and Rh. Copolymers with distinct PEG tail lengths (5-20 kDa) and different Rh percentages (5, 10, and 25%) have been synthesized, finding out that the copolymer with 20 kDa PEG and 10% Rh provides the best coating for an efficient fluorescence with minimal aggregation effects. The optimized Fe 3 O 4 @Rh system offers very suitable fluorescence thermosensitivity in the therapeutic hyperthermia range. Additionally, this sample presents good biocompatibility and displays an excellent heating capacity within the clinical safety limits of the AC field (≈ 1000 W/g at 142 kHz and 44 mT), which has been confirmed by both calorimetry and AC magnetometry. Thus, the current work opens up promising avenues toward next-generation medical technologies.

Background: The objective of this prospective randomized pilot study is to compare, by computed tomography (CT), the mobility of syndesmosis after static fixation (SF) or dynamic fixation (DF) in ankle fractures with syndesmotic rupture (AFSR) in adults, and to compare this mobility with that of healthy ankles., Methods: Forty-two patients with an AFSR were randomized to 2 groups: SF (N=21) or DF (N=21). Seven patients were lost to follow-up. Ultimately, 35 patients (SF, N=20; DF, N=15) were analyzed. The clinical results were assessed with the American Orthopedic Foot and Ankle Society scale. To assess syndesmosis mobility, CT in 30° of plantar flexion (PFlex) and 20° of dorsal flexion (DFlex) was performed on both ankles one year after the fracture. Four parameters were measured: anterior tibiofibular distance, posterior tibiofibular posterior distance, angle of fibular rotation (AFR), and anteroposterior fibular translation., Results: The AFR between DFlex and PFlex was more similar to the non-affected side in the DF group. The other three parameters showed no statistical differences between types of fixation. The mean loss of AFR compared with the non-affected side was 1.2° in the SF group and 0.1° in the DF group. No clinical differences between the SF group and the DF group were found. No correlation between clinical and radiological results was observed., Conclusion: The AFR was more similar to the non-affected side in the DF group. However, this finding did not correlate with a better clinical result.

After the declaration of the coronavirus disease 2019 (COVID-19) pandemic, gynecological surgery joins the readjustment process that this great global health crisis implies. In the light of current literature, the five steps towards its resilience are described as below; (1) Dynamic prioritization of surgical indications and reintroduction of elective surgeries: Diverse surgical prioritization lists are published including the most common gynecological pathologies. (2) Minimally invasive surgery through laparoscopy and robotic assistance: Some authors suggest a theoretical but unproven risk of viral transmission during these approaches because of the aerosol generation. These theories are opposed to the well-proven advantages of these approaches compared to open surgery. (3) Optimization of surgical procedures, according to the recommendations of different societies aimed at reducing the dispersion of aerosols and surgical smoke. (4) Clinical, epidemiological and microbiological screening of all patients awaiting prompt surgery: This screening should be adapted to the local alert state. (5) Protection through the reduction of number of persons present in the operating room, and the use of adapted personal protective equipment according to physical proximity to the patient., Competing Interests: CONFLICT OF INTEREST None., (Copyright © 2020 The Journal of Minimally Invasive Surgery. All rights reserved.)

Oral bisphosphonates are commonly used to improve bone density in patients who suffer from a variety of pathologies. However, they have also been known to cause bisphosphonate-related osteonecrosis of the jaws (BRONJ). The aim of this clinical case presentation is to (1) determine whether the currently recommended length of time that oral bisphosphonates should be discontinued, before performing dental implant surgery, is sufficient to prevent BRONJ and (2) to describe an alternative treatment for BRONJ. A 65-year-old female patient developed BRONJ after receiving mandibular dental implants 5 months after discontinuing alendronic acid (Fosamax). The BRONJ was treated by surgical osteotomy and plasma rich in growth factors (PRGF), and the patient was followed up with biweekly examinations, which included 0.2% chlorhexidine mouthwashes and removal of any remaining necrotic bone. The dental implants were loaded 41 weeks after surgery and followed up with periapical radiographs and implant stability quotient measurements at 3, 6, 12, and 24 months postloading. Although the Association of Oral and Maxillofacial Surgeons protocols for suspension of presurgical oral bisphosphonates were followed, this patient still developed BRONJ after implant surgery. While a multitude of treatments have been described in the literature, there is not enough scientific evidence to support any one treatment. Based on this clinical case, it can be concluded that the potential adverse effects of oral bisphosphonates on the jaws could be greater than expected and that treatment with PRGF produces promising results, although more long-term studies are necessary to confirm these findings.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers due to its late diagnosis with the main risk factor being liver cirrhosis (LC). Glycan structures from glycoproteins are usually altered in cancer. Blood plasma from 111 healthy and sick donors was analyzed to determine the post-translational modifications (PTM) of intact Aα-, Bβ-, and γ-subunits of fibrinogen, a glycoprotein predominantly produced in liver cells. Glycosylation and phosphorylation of the protein species were quantified by liquid chromatography coupled to mass spectrometry to correlate PTMs to pathological cases. Quantities of the PTMs were used for statistical classification by principal component analysis (PCA) and multivariate analysis of variance (MANOVA). As relevant clinical finding, patients with liver disease (HCC and/or LC) were distinguished from individuals without relevant chronic liver disease with 91% sensitivity and 100% specificity. Within the group of patients with liver disease, a robust separation between LC and HCC was not possible. In more detail, the phosphorylation of Aα-subunit is decreased in HCC patients, whereas the monophosphorylated state is significantly increased in LC patients. In terms of glycosylation, the amount of O-glycans in the Aα-subunit is decreased in LC patients, while sialylation and fucosylation of N-type glycans of Bβ- and γ-subunits are increased in LC and HCC. Based on PTM of fibrinogen, starting from plasma we can assign the status of an individual as healthy or as liver disease in less than 3 h.

Purpose: Cabozantinib (XL184), a multi-targeted oral tyrosine kinase inhibitor with activity against MET, VEGFR2, AXL, and other tyrosine kinases, was assessed in a cohort of metastatic breast cancer (MBC) patients in a phase II randomized discontinuation trial (RDT)., Methods: Patients received 100 mg cabozantinib daily during a 12-week lead-in stage. Those with stable disease per modified Response Evaluation Criteria in Solid Tumors version 1.0 at 12 weeks were randomized to either continue cabozantinib or receive placebo. Primary endpoints were objective response rate (ORR) during the 12-week lead-in stage and progression-free survival (PFS) after randomization. Patients were also followed for overall survival (OS)., Results: Forty-five patients with MBC and a median of three prior lines of chemotherapy for metastatic disease were enrolled. The ORR during the lead-in stage was 13.6 % (95 % confidence interval [CI] 6-25.7 %), and the disease control rate at week 12 was 46.7 % (95 % CI 31.7-61.6 %). Per the initial RDT study design, patients with stable disease at week 12 were randomized to cabozantinib or placebo. Following a Study Oversight Committee recommendation, randomization was suspended. Patients in the lead-in stage continued on open-label cabozantinib. Patients in the randomization stage were subsequently unblinded. The overall median PFS for all MBC patients was 4.3 months. Median OS was 11.4 months (95 % CI 10.5-16.5 months). The most common grade 3/4 adverse events in the lead-in stage were palmar-plantar erythrodysesthesia (13 %) and fatigue (11 %). One death from respiratory failure was reported as drug-related during the lead-in stage., Conclusions: In heavily pretreated MBC patients, cabozantinib monotherapy demonstrated clinical activity including objective response and disease control., Competing Interests: SMT has received support for clinical research from Exelixis. HN has received support for clinical research from Exelixis. I-GR has no conflicts to report. PS has received institutional research support from Exelixis, and received travel support and honoraria for participation in educational and advisory functions from Exelixis and SOBI. AA has no conflicts to report. CAY has no conflicts to report. ADL was an employee and stockholder of Exelixis. BO was an employee and stockholder of Exelixis. GIS has received support for clinical research from Exelixis. EPW has received support for clinical research from Exelixis.

Lung cancer is a highly lethal disease. Targeted therapies have been developed in last years, however survival rates are not improving due to the delay in the diagnosis, making biomarkers one of the most interesting fields of study in cancer. Liquid biopsy has raised as an alternative to tissue biopsy due to improvements in analytical techniques for circulating tumor cells (CTCs), cell free DNA and exosomes. Among all, exosomes have raised as one of the most promising tools to understand the tumor due to their stability in the blood and their similarity to the cells of origin. In the last years, different alterations have been described inside the exosomes derived from non-small cell lung cancer (NSCLC) cells mirroring the processes inside these tumoral cells, such as EGFR mutation, translocations or microRNA (miRNA) deregulation. All these studies have opened the window to a new world of possibilities in the study of tumor biomarkers., Competing Interests: The authors have no conflicts of interest to declare.

The Chiari malformation type I (CM-I) has been associated with sleep-disordered breathing, especially central sleep apnea syndrome. We report the case of a 44-year-old female with CM-I who was referred to our sleep laboratory for suspected sleep apnea. The patient had undergone decompressive surgery 3 years prior. An arterial blood gas analysis showed hypercapnia. Polysomnography showed a respiratory disturbance index of 108 events/h, and all were central apnea events. Treatment with adaptive servo-ventilation was initiated, and central apnea was resolved. This report demonstrates the efficacy of servo-ventilation in the treatment of central sleep apnea syndrome associated with alveolar hypoventilation in a CM-I patient with a history of decompressive surgery.

The behavioral effects of the kappa-opioid receptor agonist U69593 were examined in lactating rats. On day 5 of lactation, animals were treated with 0.1 mg/kg of U69593 to determine whether it influences general activity and maternal latencies toward pups. Because little attention has been given to the possibility that pre-mating treatment with morphine may modulate the response to kappa-opioid receptor stimulation, another group of animals was submitted to the same acute challenge after abrupt withdrawal from repeated treatment with morphine sulfate during the pre-mating period (5 mg/kg on alternate days for a total of five doses). Acute kappa-opioid stimulation reduced total locomotion, rearing frequency, and time spent self-grooming and increased immobility duration. These kappa agonist effects were not observed in animals pretreated with morphine. Similarly, latencies to retrieve pups were longer only in animals pretreated with saline and challenged acutely with U69593. None of these effects were observed in morphine sulfate-pretreated animals. The present results suggest that pre-mating repeated exposure to morphine produces a tolerance-like effect on behavioral responses to low-dose kappa-opioid receptor stimulation in active reproductive females.

We report a direct observation of the intrinsic magnetization behavior of Au in thiol-capped gold nanoparticles with permanent magnetism at room temperature. Two element specific techniques have been used for this purpose: X-ray magnetic circular dichroism on the L edges of the Au and 197Au Mössbauer spectroscopy. Besides, we show that silver and copper nanoparticles synthesized by the same chemical procedure also present room-temperature permanent magnetism. The observed permanent magnetism at room temperature in Ag and Cu dodecanethiol-capped nanoparticles proves that the physical mechanisms associated to this magnetization process can be extended to more elements, opening the way to new and still not-discovered applications and to new possibilities to research basic questions of magnetism.

We recently presented evidence showing that a human cementoblastoma-derived protein, named Cementum Protein 1 (CEMP1) may play a role as a local regulator of cementoblast differentiation and cementum-matrix mineralization. This protein was shown to be expressed by cementoblasts and progenitor cells localized in the periodontal ligament. In this study we demonstrate that transfection of CEMP1 into human gingival fibroblasts (HGF) induces mineralization and expression of bone and cementum-matrix proteins. The transfected HGF cells had higher alkaline phosphatase activity and proliferation rate and they expressed genes for alkaline phosphatase, bone sialoprotein, osteocalcin, osteopontin, the transcription factor Runx2/Cbfa1, and cementum attachment protein (CAP). They also produced biological-type hydroxyapatite. These findings indicate that the CEMP1 might participate in differentiation and mineralization of nonosteogenic cells, and that it might have a potential function in cementum and bone formation.

We studied the correlation between the efficacy of local external beam radiotherapy and the efficacy of strontium-89 in the palliation of osteoblastic metastatic bone pain in 43 patients with cancer. All 43 had been treated with hormonal or chemotherapy according to the primary malignancies and analgetic pharmacotherapy as needed, 36 received local external beam radiotherapy as a palliative before strontium-89 injection, and all 43 were ultimately treated with strontium-89 as salvage therapy. Responses to the first strontium treatment, and to the first radiation treatment if given, were taken from patient files. Pain was evaluated by Karnofsky performance status, analgesic dosage, and duration of response to treatment translated into numeric scores on a pain duration scale and an integrated response scale. The efficacy of limited field external radiation in metastatic bone pain palliation was 80.6% versus 58.1% for strontium-89. Patients treated with both external radiation and strontium had a positive correlation of 0.4 with a probability of P = 0.0158 between the responses to the 2 treatments, indicating that response to external radiotherapy could be viewed as an indicator of strontium-89 efficacy in metastatic osteoblastic bone pain palliation in the same patient. No significant correlation was found between strontium efficacy and gender, location of metastases to weight-bearing bones, duration of hormonal therapy or chemotherapy, or type of primary neoplasm.

The alteration of vancomycin pharmacokinetics during cardiopulmonary bypass (CPB) in patients undergoing cardiac surgery was studied. Eighteen patients were enrolled in the study. Vancomycin (1 g) was intravenously infused one to two hours before surgery. Blood samples were taken before, during, and after CPB. Serum drug concentrations were determined by an automated fluorescence polarization immunoassay and adjusted, with a bayesian analysis, to a bi-compartmental model implemented in a pharmacokinetic system program. Serum creatinine, hematocrit, and plasma proteins were also measured before, during, and after CPB. During CPB, serum creatinine, hematocrit, and plasma protein values all decreased significantly (p < 0.05). Serum vancomycin concentration also diminished abruptly with CPB (7.04 micrograms/mL; 95% confidence interval, 5.70-8.38 micrograms/mL) but increased moderately during the next 30 minutes, probably attributable to redistribution into plasma from tissue stores. Vancomycin's apparent volume of distribution showed an important increase during CPB (58.8%) (p < 0.0005), and its systemic clearance also increased significantly after CPB (19.7%) (p < 0.0005). The decrease in serum vancomycin concentration seems mediated by the hemodilution associated with the pump prime volume. Vancomycin's mean +/- S.D. nadir serum concentration before the next dose was 7.13 +/- 2.1 micrograms/mL. In patients undergoing cardiac surgery and treated prophylactically with a 1-g preoperative i.v. dose of vancomycin, the onset of CPB was associated with a drop in serum vancomycin concentration.