Is a pretreatment radiological staging system feasible for suggesting the optimal extent of resection and predicting prognosis in glioblastoma? An observational study.

To assess the value of resection in glioblastoma based on pre-surgical tumor characteristics and a subsequent staging system. The lack of a staging system for glioblastoma hinders the analysis of treatment outcome. We classified 292 uniformly treated glioblastoma patients as stage I, II, or III based on tumor size, location, and eloquence and then analyzed the impact of the extent of resection. We classified 62% of patients as stage I, 25.3% as stage II, and 12.7% as stage III. Gross total resection (GTR) was performed mainly in stage I rather than stage II or III patients (79.2% vs. 14.6% vs. 6.3%; P < 0.001). Overall survival (OS) was 17.7, 14.6, and 10.8 months for stage I, II, and III patients, respectively (P = 0.005). Longer OS was significantly associated with greater extent of resection, younger age, KPS ≥ 70%, MGMT methylation, lower stage, and tumor ≤ 5 cm. In the subgroups of stage I (P = 0.04) and stage II (P < 0.001)-but not stage III-patients, GTR and partial resection (PR) were associated with longer OS. We constructed several multivariable models including different variables, and greater extent of resection, smaller tumor size, and MGMT methylation consistently emerged as independent markers of longer OS. This staging system provides a feasible tool for comparison of results. We confirmed the value of partial resection in stage I and II patients, in contrast to some reports suggesting that biopsy only is sufficient when gross total resection cannot be safely achieved.

Ocular involvement in pemphigus vulgaris - a retrospective study of a large Spanish cohort.

BACKGROUND AND OBJECTIVES: Ocular/periocular involvement in pemphigus vulgaris (OPV) has rarely been reported. The objective of the present study was to investigate the pattern of OPV and define the prognostic value of its manifestation. PATIENTS AND METHODS: From 1985 to 2014, a total of 167 patients with pemphigus vulgaris (PV) were treated at four tertiary Spanish hospitals. In this retrospective study, we included all patients with OPV. Clinical data and information on associated symptoms were obtained from patients' medical records. RESULTS: Only 24 (14.3 %) of all PV patients had ocular lesions. In most cases, -ocular involvement was preceded by PV lesions at various other sites (mean duration: 33.7 months). Ocular PV lesions occurred during flares of mucocutaneous pemphigus, and was never the only mucosal manifestation. The most common clinical signs were conjunctival hyperemia (87.5 %), erosions on the eyelids (41.6 %) as well as of the palpebral/bulbar conjunctiva (33.3 %) and at the medial epicanthus (20.8 %). The most relevant associated symptoms included local pain/stinging (71.4 %), irritation (47.6 %), photophobia (38.1 %), and epiphora (23.9 %). Ocular PV improved with systemic and adjuvant topical therapies. Only two patients experienced sequelae. CONCLUSIONS: In patients with PV, ocular involvement is an exception. Ocular PV is associated with greater disease activity, and usually follows a benign course. Sites affected are the conjunctiva, the eyelids, or both.

Augenbeteiligung beim Pemphigus vulgaris - retrospektive Studie an einer großen spanischen Kohorte.

HINTERGRUND UND ZIELE: Es gibt nur wenige Berichte zur Beteiligung der okulären/periokulären Region beim Pemphigus vulgaris (PV). Ziel der vorliegenden Studie war es, das Krankheitsbild des okulären PV (OPV) zu untersuchen und seinen prognostischen Wert zu definieren. PATIENTEN UND METHODIK: Zwischen 1985 und 2014 wurden insgesamt 167 Patienten mit Pemphigus vulgaris an vier tertiären spanischen Krankenhäusern behandelt. Wir haben alle Patienten mit OPV in diese retrospektive Studie aufgenommen. Klinische Daten sowie Informationen zu Begleitsymptomen wurden den Krankenakten der -Patienten entnommen. ERGEBNISSE: Lediglich 24 (14.3 %) PV-Patienten hatten okuläre Läsionen. Meist gingen dem okulären Befall PV-Läsionen an verschiedenen anderen Stellen voraus (durchschnittliche Dauer: 33,7 Monate). Okuläre PV-Läsionen traten während der Schübe eines mukokutanen Pemphigus auf und waren niemals die einzige Mukosa-Manifestation. Die häufigsten klinischen Symptome waren konjunktivale Hyperämie (87,5 %) und Erosionen an den Augenlidern (41,6 %), sowohl an der palpebralen/bulbären Konjunktiva (33,3 %) als auch am medialen Epikanthus (20,8 %). Zu den wichtigsten Begleitsymptomen gehörten lokale Schmerzen/Brennen (71,4 %), Reizung (47,6 %), Photophobie (38,1 %) und Epiphora (23,9 %). Der OPV besserte sich unter systemischer und unterstützender topischer Behandlung. Lediglich bei zwei Patienten traten Spätfolgen auf. SCHLUSSFOLGERUNGEN: Bei Patienten mit PV sind die Augen nur in Ausnahmefällen betroffen. Ein okulärer PV ist mit größerer Krankheitsaktivität assoziiert und hat in der Regel einen gutartigen Verlauf. Betroffen sind die Konjunktiva und/oder die Augenlider.

[Low field intra-operative magnetic resonance imaging for brain tumour surgery: preliminary experience]. / Resonancia magnética intraoperatoria de bajo campo para la cirugía de neoplasias cerebrales: experiencia preliminar.

OBJECTIVES: Intra-operative magnetic resonance imaging (iMRI) is a recently introduced tool in the most advanced neurosurgical operating rooms worldwide. We present our preliminary experience in brain tumour surgery with low field PoleStar N30® intraoperative MRI since its introduction in 2013 in the Barcelona Clinic Hospital. MATERIAL AND METHODS: A prospective non-randomised study was conducted on cases operated on using iMRI and intention of complete removal up to October 2015. A record was made of the data as regards surgical times, resection rates, histological diagnosis, hospital stay, and survival rates during follow-up. RESULTS: The study included 50 patients, with a mean age of 55 years (±13.7), a preoperative mean Karnofsky of 92 (being 81 post-operatively), and a mean follow-up of 10.5 months (±6.5). There were 26% re-operations due to recurrence. High-grade gliomas were reported in 56%, low-grade gliomas in 24%, and 20% "Other" tumours. Overall hospital stay was 10 days (±4.5). Depending on the histologiacl diagnosis, the "Others" group had a longer hospital stay. Overall, there were 52% complete removal, 18% of maximum removals, and 30% of partial removals. The overall survival rates during follow-up was 84%. CONCLUSIONS: iMRI is a safe and effective tool for brain tumour surgery. Its use allows an increase in resection rates, and minimises post-operative complications. Its implementation involves an increase in surgical time, which improves with the characteristic learning curve. More studies are needed to establish its role in the long-term survival of patients.

Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international panel of experts.

Mucous membrane pemphigoid encompasses a group of autoimmune bullous diseases with a similar phenotype characterized by subepithelial blisters, erosions, and scarring of mucous membranes, skin, or both. Although knowledge about autoimmune bullous disease is increasing, there is often a lack of clear definitions of disease, outcome measures, and therapeutic end points. With clearer definitions and outcome measures, it is possible to directly compare the results and data from various studies using meta-analyses. This consensus statement provides accurate and reproducible definitions for disease extent, activity, outcome measures, end points, and therapeutic response for mucous membrane pemphigoid and proposes a disease extent score, the Mucous Membrane Pemphigoid Disease Area Index.

[Diagnostic yield and postoperative management of patients submitted to brain biopsy in a university hospital]. / Eficacia diagnóstica y manejo posoperatorio de los pacientes sometidos a biopsia cerebral en un hospital universitario.

OBJECTIVE: To assess the diagnostic yield and the incidence of perioperative complications in patients undergoing an open or closed cerebral biopsy and to determine the length of intensive care monitoring, for early diagnosis and fast management of perioperative complications. MATERIAL AND METHOD: This was a retrospective analysis of all the patients that underwent brain biopsy between January 2006 and July 2012. We recorded demographic data, comorbidities, modality of biopsy, intraoperative clinical data, histological results, computed tomography scanning findings and occurrence, and type of perioperative complications and moment of appearance. RESULTS: Seventy-six brain biopsies in 75 consecutive patients (51 closed and 25 open) were analysed. Diagnostic yield was 98% for closed biopsies and 96% for open biopsies. Mortality related to the procedures was 3.9 and 4%, respectively. The incidence of major complications was 3.9% for closed biopsies and 8% for open biopsies; half of these appeared within the first 24 postoperative hours, during patient stay in the Intensive Care Unit. Age was the only risk factor for complications (P=.04) in our study. No differences in morbimortality were found between the studied groups. CONCLUSIONS: Diagnostic yield was very high in our series. Because the importance of early diagnosis of complications for preventing long-term sequelae, we recommend overnight hospital stay for observation after open or closed brain biopsy.

Ultrasound-Oriented Surgical Planning ("UOSP") for Intracranial Lesions: A Systematic Integration to the Standard Preoperative Planning.

OBJECTIVE: Intraoperative ultrasound (iUS) is a well-established technique whose aim is to provide real-time visualization of deep lesions during brain surgery. The lack of definition of anatomic semeiotics and the unusual direction of the insonation plane make interpretation and orientation challenging for the surgeon who newly approaches to such a tool. We propose a novel protocol to be applied during the surgical planning for intracranial lesions surgery, a so-called ultrasound-oriented surgical planning ("UOSP") protocol, and we provide a retrospective analysis of 21 patients who underwent surgery for an intracranial lesion in which UOSP was applied. To further enlighten different surgical orientation strategies and possible limitations given by the technique, we discuss 3 illustrative cases assigned to 3 categories ("basic," "intermediate," and "challenging" lesions) with progressively growing difficulty in anatomic orientation during a surgical procedure. METHODS: A total of 21 patients operated between March 2021 and July 2021 and where the UOSP protocol was applied during surgical planning were evaluated retrospectively. The UOSP protocol was performed the days before the surgical intervention by the same surgical team. RESULTS: The UOSP protocol was successfully applied in all 21 patients. In all cases, the preoperative imaging obtained during surgical planning corresponded to the images observed during the application of iUS. CONCLUSIONS: The introduction of the UOSP protocol during the planification of the surgical intervention for an intracerebral lesion may serve as a key factor to overcome the actual limitations inherent to the iUS technique. Utilization of this protocol may facilitate wider use of iUS in neurosurgery.

Prospective evaluation of intense pulsed light treatment for meibomian gland dysfunction and blepharitis due to ocular rosacea

Background: Ocular rosacea is a common skin condition leading to dry eye that is difficult to manage. Objectives: To estimate the efficacy and safety of a new intense pulsed light device, Thermaeye Plus, for meibomian gland dysfunction and blepharitis due to ocular rosacea. Materials & Methods: This prospective, longitudinal study included 74 eyes of 37 consecutive patients with ocular rosacea, with mean age of 45.6±11.7 years. Four consecutive sessions were undertaken, including14 flashes with 10 J/cm² on the periocular area and facial cheeks on Day 1, 14, 28, and 49. Clinical evaluation was based on: ocular surface disease index (OSDI) and symptom score questionnaires, quality of live and facial severity degree, non-invasive tear meniscus height, non-invasive tear break up time, corneal fluorescein staining and eyelid margin and meibomian gland assessment. Adverse effects on the eye and periocular area, and systemic complications were evaluated. Results: The OSDI questionnaire showed a decrease in symptoms, achieving normal values in 91.9% of patients. The symptom score showed amelioration, with the most significant changes relating to dryness, foreign body sensation, light sensitivity, and pain. Longitudinal analysis showed the most significant improvement between baseline at Day 1 and 49. All eyelid signs improved, most significantly for telangiectasia/vascularity and blepharitis, leading to a 78% clearance of facial rosacea and 81.1% reduction of flushing. In total, 100% of the patients reported an improvement in their quality of life after treatment and 94.6% a very significant improvement (p<0.001). Conclusion: These results demonstrate that Thermaeye Plus is an effective and safe treatment for ocular rosacea.

Association between preoperative serum lactate concentrate with tumor cell proliferative index in primary brain tumor.

BACKGROUND: Elevated preoperative lactate levels have been reported in patients admitted for resection of brain tumors. As histologic type and tumor grade have also been linked to lactate concentration, we hypothesized that preoperative lactate concentration in patients with brain tumors may be associated with tumor proliferation. We describe the relationship between preoperative plasma lactate levels, and the cell proliferation marker Ki-67 in brain tumor surgery. METHODS: In this cross-sectional study, records of patients who underwent craniotomy between June 2017 and February 2018 at our Hospital were reviewed to select glioma and meningioma cases in which lactate concentrations in plasma and degree of cell proliferation were registered. Bivariable and linear regression analyses were used to assess the association between lactate concentrations and the Ki-67 Index. RESULTS: Lactate concentrations in plasma and Ki-67 Index were available in 55 patients. Meningioma cases had a mean concentration of 1.2 (0.1) mmol/L compared to diffuse astrocytic and oligodendroglial tumors cases with 1.7 (0.1) mmol/L (P<0.01). Both variables had a low positive correlation in meningiomas (Spearman's r, 0.29; 95% CI, -0.10-0.61; P=0.13) and a high correlation in gliomas (Spearman's r, 0.64; 95% CI, 0.33-0.82; P<0.01). The pooled analysis showed a high correlation index (Spearman's r, 0.61; 95% CI, 0.40-0.76; P<0.01). A linear regression model showed that the Ki-67 Index explained 43% of the variation in lactate (P<0.01). CONCLUSIONS: Brain tumors with higher rates of cell proliferation have higher plasma lactate levels. In this scenario, lactate concentrations may not only reflect systemic perfusion.

Activity and Resistance of a Brain-Permeable Paradox Breaker BRAF Inhibitor in Melanoma Brain Metastasis.

The therapeutic benefit of approved BRAF and MEK inhibitors (BRAFi/MEKi) in patients with brain metastatic BRAF V600E/K-mutated melanoma is limited and transient. Resistance largely occurs through the restoration of MAPK signaling via paradoxical BRAF activation, highlighting the need for more effective therapeutic options. Aiming to address this clinical challenge, we characterized the activity of a potent, brain-penetrant paradox breaker BRAFi (compound 1a, C1a) as first-line therapy and following progression upon treatment with approved BRAFi and BRAFi/MEKi therapies. C1a activity was evaluated in vitro and in vivo in melanoma cell lines and patient-derived models of BRAF V600E-mutant melanoma brain metastases following relapse after treatment with BRAFi/MEKi. C1a showed superior efficacy compared with approved BRAFi in both subcutaneous and brain metastatic models. Importantly, C1a manifested potent and prolonged antitumor activity even in models that progressed on BRAFi/MEKi treatment. Analysis of mechanisms of resistance to C1a revealed MAPK reactivation under drug treatment as the predominant resistance-driving event in both subcutaneous and intracranial tumors. Specifically, BRAF kinase domain duplication was identified as a frequently occurring driver of resistance to C1a. Combination therapies of C1a and anti-PD-1 antibody proved to significantly reduce disease recurrence. Collectively, these preclinical studies validate the outstanding antitumor activity of C1a in brain metastasis, support clinical investigation of this agent in patients pretreated with BRAFi/MEKi, unveil genetic drivers of tumor escape from C1a, and identify a combinatorial treatment that achieves long-lasting responses. SIGNIFICANCE: A brain-penetrant BRAF inhibitor demonstrates potent activity in brain metastatic melanoma, even upon relapse following standard BRAF inhibitor therapy, supporting further investigation into its clinical utility.

A Novel EGFRvIII T-Cell Bispecific Antibody for the Treatment of Glioblastoma.

T-cell bispecific antibodies (TCB) are engineered molecules that bind both the T-cell receptor and tumor-specific antigens. Epidermal growth factor receptor variant III (EGFRvIII) mutation is a common event in glioblastoma (GBM) and is characterized by the deletion of exons 2-7, resulting in a constitutively active receptor that promotes cell proliferation, angiogenesis, and invasion. EGFRvIII is expressed on the surface of tumor cells and is not expressed in normal tissues, making EGFRvIII an ideal neoantigen target for TCBs. We designed and developed a novel 2+1 EGFRvIII-TCB with optimal pharmacologic characteristics and potent antitumor activity. EGFRvIII-TCB showed specificity for EGFRvIII and promoted tumor cell killing as well as T-cell activation and cytokine secretion only in patient-derived models expressing EGFRvIII. Moreover, EGFRvIII-TCB promoted T-cell recruitment into intracranial tumors. EGFRvIII-TCB induced tumor regression in GBM animal models, including humanized orthotopic GBM patient-derived xenograft models. Our results warrant the clinical testing of EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.

Immune cell profiling of the cerebrospinal fluid enables the characterization of the brain metastasis microenvironment.

Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8+ T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis.

Correlation of immunological profile with phenotype and disease outcome in pemphigus.

There has been no previous clinical-immunological study of pemphigus in Spain. The aim of this study was to perform a retrospective analysis of pemphigus patients who had been followed for a period of 18 years in our centre. We characterized the autoantibody response, compared diagnostic assays and correlated the immunobiological data with phenotype and prognosis. Clinical, epidemiological and immunopathological data were collected from 40 patients. Patients sera were characterized by indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA). Epidemiological and clinical findings were comparable to other series. Mortality during follow-up was 0% and 6% in pemphigus foliaceus and vulgaris, respectively. Importantly, higher indirect immunofluorescence titres and anti-desmoglein 3 ELISA values of samples from untreated patients correlated significantly with a potentially worse clinical course. Moreover, there was a positive correlation between indirect immunofluorescence titres and anti-desmoglein 3 ELISA levels in pemphigus vulgaris patients. Based on our findings, initial high anti-desmoglein 3 antibodies in pemphigus patients correlate with a more adverse prognosis, which raises the question as to whether a more aggressive initial therapy is indicated in patients with this immunological pattern.

GRP94 promotes brain metastasis by engaging pro-survival autophagy.

BACKGROUND: GRP94 is a glucose-regulated protein critical for survival in endoplasmic reticulum stress. Expression of GRP94 is associated with cellular transformation and increased tumorigenicity in breast cancer. Specifically, overexpression of GRP94 predicts brain metastasis (BM) in breast carcinoma patients with either triple negative or ErbB2 positive tumors. The aim of this study was to understand if microenvironmental regulation of GRP94 expression might be a hinge orchestrating BM progression. METHODS: GRP94 ablation was performed in a BM model BR-eGFP-CMV/Luc-V5CA1 (BRV5CA1) of breast cancer. In vitro results were validated in a dataset of 29 metastases in diverse organs from human breast carcinomas and in BM tissue from tumors of different primary origin. BM patient-derived xenografts (PDXs) were used to test sensitivity to the therapeutic approach. RESULTS: BMs that overexpress GRP94 as well as tumor necrosis factor receptor-associated factor 2 are more resistant to glucose deprivation by induction of anti-apoptotic proteins (B-cell lymphoma 2 and inhibitors of apoptosis proteins) and engagement of pro-survival autophagy. GRP94 ablation downregulated autophagy in tumor cells, resulting in increased BM survival in vivo. These results were validated in a metastasis dataset from human patients, suggesting that targeting autophagy might be strategic for BM prevention. Indeed, hydroxychloroquine treatment of preclinical models of BM from PDX exerts preventive inhibition of tumor growth (P < 0.001). CONCLUSIONS: We show that GRP94 is directly implicated in BM establishment by activating pro-survival autophagy. Disruption of this compensatory fueling route might prevent metastatic growth.

[Incidence and characteristics of adult-onset asthma]. / Incidencia y características del asma bronquial de inicio en la edad adulta.

OBJECTIVE: To determine the incidence of adult-onset asthma, along with lung function and immunologic characteristics, causes, and clinical course of the disease. PATIENTS AND METHODS: After identifying incident cases of asthma among adult residents of the district of North Barcelona, Spain, we proceeded to characterize the disease using a questionnaire, lung function tests, and skin allergy tests. Patients with an occupation associated with asthma, wheezing at work, and/or sensitization to workplace allergens were considered as having occupational asthma. The risk factors for developing chronic asthma were determined by multivariate analysis. RESULTS: In the 2-year study period, 218 incident cases of adult-onset asthma were identified (in a population of 68 067 adults, corresponding to an annual incidence of 160 per 100 000 per year). In total, 152 patients agreed to participate in the study (response rate, 70%); 140 reported wheezing and/or asthma in the last year (92%). The skin tests showed atopy in 57 cases (41%). Occupational asthma was diagnosed in 19 cases (14%). Domestic mammals were identified as causal agents in 8 patients (6%), drugs in 7 (5%), and environmental allergens in 44 (31%). Household cleaning was the occupation most frequently associated with the disease (26%). Of the 102 patients examined again after 2 years, 70 had chronic asthma (69%). Atopy (odds ratio [OR], 3.39; 95% confidence interval [CI], 1.15-9.99) and risk occupation when the disease was diagnosed (OR, 5.54; 95% CI, 1.05-29.11) were the factors associated with development of chronic disease. CONCLUSIONS: Occupation was related to adult-onset asthma in a little over 10% of the cases and was the main determinant of the development of chronic symptoms.

Bullous pemphigoid induced by dipeptidyl peptidase-4 inhibitors. Eight cases with clinical and immunological characterization.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors have increasingly been identified as causative agents of bullous pemphigoid. The clinical and immunological characteristics of this pemphigoid variant are still unclear. The objective of our study was to analyze the clinical and immunological features of patients with pemphigoid induced by DPP-4 inhibitors. METHODS: All patients diagnosed with DPP-4 inhibitor-associated bullous pemphigoid at dermatology departments in three Spanish centers during the period 2013 to 2015 were included. ELISA assays for the NC16A domain of BP180 and BP230 were performed. Immunoblot studies using epidermal/dermal extracts and the C-terminal, NC16A and LAD-1 regions of BP180 were also carried out. RESULTS: A total of eight patients were identified (5 treated with vildagliptin, 2 with linagliptin, and one with sitagliptin). Of these, four presented the classical inflammatory phenotype of bullous pemphigoid and four a noninflammatory phenotype. The ELISA for BP180 (NC16A domain) was positive in six patients at diagnosis. Most patients reacted to more than one BP180 antigenic site (LAD-1 and/or C-terminal domain) on the immunoblot. Two patients showed no reaction against the NC16A domain of BP180 on either the ELISA or immunoblot but recognized either LAD-1 or both LAD-1 and the C-terminal domain. Only one of the NC16A-negative patients had a noninflammatory subtype of bullous pemphigoid. CONCLUSIONS: Patients with DPP-4 inhibitor-induced BP may present either an inflammatory or a noninflammatory phenotype of BP. IgG response against other BP180 regions different from the NC16A domain, such as LAD-1 and the C-terminal domain, could be pathogenically relevant to the onset of DPP-4 inhibitor-induced BP.