Reactive granulomatous dermatitis as a histological pattern including manifestations of interstitial granulomatous dermatitis and palisaded neutrophilic and granulomatous dermatitis: a study of 52 patients.

BACKGROUND: Confusion exists regarding interstitial granulomatous dermatitis (IGD) and palisaded neutrophilic and granulomatous dermatitis (PNGD). OBJECTIVE: To determine whether IGD and PNGD are two different entities, or whether they must be considered as two subtypes of the same reactive pattern, and thus whether the unification of the nomenclature is necessary. METHODS: Observational retrospective multicentre study of patients with IGD and PNGD evaluated between 1999 and 2019 and review of their clinical and histological features. RESULTS: We identified 52 patients (38 women and 14 men). Clinical and histological findings of IGD were observed in 88.4% of cases. The most common cutaneous lesions were plaques/macules (IGD) or annular plaques and papules/nodules (PNGD), located mostly on the limbs and trunk. The rope sign was developed in two patients with IGD that associated autoimmune disorders. Similar associated comorbidities (75%) were found in both entities, mainly autoimmune diseases (53.8%). In IGD, the infiltrate was predominantly lympho-histiocytic. Neutrophilic infiltrates, karyorrhexis and skin lesions with limited clinical course were mainly associated with PNGD biopsies. In biopsies with a limited recurrent course, a predominant lymphocytic inflammatory infiltrate was found. Collagen degeneration was present in 75.9% of cases. The floating sign was observed only in IGD type patients (63%). Overlapping histological findings were found in one fourth of cases, especially between IGD and interstitial granuloma annulare. Interface dermatitis, apparently unrelated to drug intake, was observed in 4 cases of IGD. CONCLUSION: We support the term reactive granulomatous dermatitis to unify both the clinical and histological findings of IGD and PNGD, and the overlapping between IGD and interstitial granuloma annulare. According to this, a spectrum of histological changes will be found depending on the clinical course of the skin lesions.

Clinical utility of plasma-based digital next-generation sequencing in patients with advance-stage lung adenocarcinomas with insufficient tumor samples for tissue genotyping.

BACKGROUND: Approximately 30% of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. We have analyzed the clinical utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) in patients with inadequate tumor samples for tissue genotyping. PATIENTS AND METHODS: We conducted the study in a multi-institutional prospective cohort of clinically unselected patients with advanced-stage lung adenocarcinomas with insufficient tissue for EGFR, ALK or ROS1 genotyping across 12 Spanish institutions (n = 93). ctDNA NGS was carried out by Guardant Health (Guardant360, Redwood City, CA), using a hybrid-capture-based 73-gene panel. Variants were deemed actionable if they were part of the OncoKB precision oncology knowledge database and classified in four levels of actionability based on their clinical or preclinical evidence for drug response. RESULTS: Eighty-three out of 93 patients (89%) had detectable levels of ctDNA. Potentially actionable level 1-4 genomic alterations were detected in 53 cases (57%), of which 13 (14%) had level 1-2A alterations (Food and Drug Administration-approved and standard-care biomarkers according to lung cancer guidelines). Frequencies of each genomic alteration in ctDNA were consistent with those observed in unselected pulmonary adenocarcinomas. The majority of the patients (62%), particularly those with actionable alterations (87%), had more than one pathogenic variant in ctDNA. The median turnaround time to genomic results was 13 days. Twelve patients (13%) received genotype-matched therapies based on ctDNA results, deriving the expected clinical benefit. Patients with co-occurring pathogenic alterations had a significantly shorter median overall survival as compared with patients without co-occurring pathogenic alteration (multivariate hazard ratio = 5.35, P = 0.01). CONCLUSION: Digital NGS of ctDNA in lung cancers with insufficient tumor samples for tissue sequencing detects actionable variants that frequently co-occur with other potentially clinically relevant genomic alterations, allowing timely initiation of genotype-matched therapies.

International Bullous Diseases Group: consensus on diagnostic criteria for epidermolysis bullosa acquisita.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a complex autoimmune bullous disease disease with variable clinical presentations and multiple possible diagnostic tests, making an international consensus on the diagnosis of EBA essential. OBJECTIVES: To obtain an international consensus on the clinical and diagnostic criteria for EBA. METHODS: The International Bullous Diseases Group (IBDG) met three times to discuss the clinical and diagnostic criteria for EBA. For the final voting exercise, 22 experts from 14 different countries voted on 50 different items. When > 30% disagreed with a proposal, a discussion was held and re-voting carried out. RESULTS: In total, 48 of 50 proposals achieved consensus after discussion. This included nine diagnostic criteria, which are summarized in a flow chart. The IBDG was unable to determine one procedure that would be applicable worldwide. A limitation of the study is that differential diagnosis of bullous systemic lupus erythematosus has not been addressed. CONCLUSIONS: This first international consensus conference established generally agreed-upon clinical and laboratory criteria defining the clinical classification of and diagnostic testing for EBA. Holding these voting exercises in person with the possibility of discussion prior to voting has advantages in reaching consensus over Delphi exercises with remote voting.

Cutaneous leishmaniasis: 20 years' experience in a Spanish tertiary care hospital.

INTRODUCTION AND OBJECTIVES: Cutaneous leishmaniasis is the most common form of leishmaniasis, which is endemic in Spain. The aim of this study was to evaluate the epidemiological and clinical characteristics of cutaneous leishmaniasis seen in our hospital over a period of 20 years, with a particular focus on clinical differences according to immune status and origin of infection MATERIALS AND METHODS: We performed a chart review of 67 cases of cutaneous leishmaniasis diagnosed between 1992 and 2012. Follow-up data were available for 54 patients. RESULTS: Fifty-four patients with cutaneous leishmaniasis were included in the study. Of these, 26 had been diagnosed between 1992 and 2002 and 28 between 2003 and 2012. The mean age at diagnosis was 49 years, there was a predominance of male patients, and the mean time from onset of symptoms to consultation was 3 months. The most common clinical manifestations were plaques and ulcers. Most of the immunodepressed patients and patients with imported leishmaniasis had skin ulcers and/or multiple lesions. During the first decade of the study, diagnosis was based on clinical and histologic findings. These were supported by molecular techniques in the second decade. Pentavalent antimonials were the treatment of choice, producing good results and very few adverse effects CONCLUSION: The number of patients with cutaneous leishmaniasis and with compromised immune status was similar in the periods 1992-2002 and 2003-2013, but more cases of imported leishmaniasis were diagnosed in the second period. Patients with ulcers and/or multiple lesions should be evaluated to rule out immunosuppression or infection by Leishmania species from other parts of the world. Both systemic and intralesional meglumine antimonate was effective and safe.

Epidermolysis bullosa acquisita: a retrospective analysis of 12 patients evaluated in four tertiary hospitals in Spain.

BACKGROUND: Epidermolysis bullosa acquisita is an exceedingly rare subepidermal blistering disease caused by antibodies against type VII collagen. Studies summarizing the clinical and immunological features of this disease in large series of patients are scarce. OBJECTIVES: To analyse the clinical and immunopathological characteristics, treatment responses and outcomes of 12 patients with epidermolysis bullosa acquisita from four tertiary hospitals in Spain. METHODS: An extensive retrospective review of clinical charts. RESULTS: The mean age of onset was 48 years and the mean delay to diagnosis was 20·75 months. The classical phenotype occurred in 42% of cases, inflammatory in 42% and mixed in 17%. Mucosal involvement was present in 75%. Linear IgG deposition along the basement membrane zone was consistently present on direct immunofluorescence examination. Indirect immunofluorescence study was positive in 67% of the cases. Frequently associated diseases were neoplasms (25%), inflammatory bowel disease (25%), hepatitis C virus infection (17%) and thyroid dysfunction (17%). Therapeutic responses were variable. CONCLUSIONS: The prevalence of neoplasms was similar to that seen in inflammatory bowel disease. Multicentric prospective studies including larger numbers of patients are required for a better knowledge and management of this disease.

Treatment of bullous pemphigoid with low-dose oral cyclophosphamide: a case series of 20 patients.

BACKGROUND: Cyclophosphamide has been commonly used for the treatment of pemphigus vulgaris and mucous membrane pemphigoid with satisfactory results. Published data of this therapeutic approach for bullous pemphigoid are scant and showed significant morbidity and mortality. OBJECTIVE: To assess the clinical efficacy and safety of low-dose oral cyclophosphamide (CFM) (50-100 mg/day) in patients with refractory bullous pemphigoid. METHODS: We conducted a retrospective study including patients with bullous pemphigoid treated with CFM in the department of Dermatology in the Hospital Clínic of Barcelona, Spain. RESULTS: Complete response was observed in 11 (58%) over 19 evaluable patients. Cyclophosphamide at 50 mg/day was enough to achieve clinical remission in eight of these patients. Partial response was observed in four (21%) more patients. Bone marrow suppression appeared in 12 (60%) patients, but treatment discontinuation was only required in three (15%) cases. Gastrointestinal intolerance occurred in one (5%) patient. One patient died during therapy from heart failure (not attributed to CFM) and another patient developed acute myeloid leukaemia 1.5 years after CFM therapy. CONCLUSIONS: In our series, CFM had a marked therapeutic effect in bullous pemphigoid. These results of efficacy are similar to those described in other autoimmune blistering skin diseases. Only a few patients had to discontinue their treatment due to adverse effects. Therefore, we consider that low-dose oral CFM can be valuable therapeutic alternative in elderly patients with moderate-to-severe bullous pemphigoid.

Mortality of bullous pemphigoid in the first year after diagnosis: a retrospective study in a Spanish medical centre.

BACKGROUND: Prognosis of patients with bullous pemphigoid (BP) is controversial, with a 1-year mortality rate ranging from 6% to 48%. OBJECTIVE: To determine the mortality rate of a large cohort of patients with BP and to identify prognostic factors associated with early mortality. METHODS: Patients diagnosed with BP between January 1, 1990 and December 31, 2010 in a referral unit for blistering skin diseases at a university hospital in Spain were studied retrospectively. Outcome measures were mortality rate during the first year after diagnosis, standardized mortality rate and poor prognostic factors. RESULTS: A total of 101 patients were included in the study. The mean patient age at diagnosis was 77.8 years, and 52 (51.5%) were men. Overall mortality during the first year was 12.9%. We found a standardized mortality ratio of 2.33 [CI95 = (1.25-4.03)]. Advanced age (patient group >80 years old) was the only risk factor for lethal outcome found, with a multivariate risk estimate of 1.09 [CI95 = (1.02-1.16)]. No significant association with mortality was detected for comorbidities, hospitalization history or treatment received for BP. CONCLUSIONS: We found an increased mortality of our BP patients compared with the general population. The mortality rate of BP patients was 2.3 times the expected rate. Observed mortality rate was lower than described in previous European studies. Advanced age impacts the prognosis of patients with BP. Specific treatment for BP appeared not to influence survival.

Retrospective study of the clinical, histologic, and immunologic features of epidermolysis bullosa acquisita in 9 patients.

INTRODUCTION: Epidermolysis bullosa acquisita (EBA) is an autoimmune subepidermal blistering disease caused by autoantibodies to type VII collagen. The clinical presentation is variable, with skin and mucosal lesions that can cause significant dysfunction. Different treatment options exist, but the results are often unsatisfactory. OBJECTIVE: To review all the cases of epidermolysis bullosa acquisita (EBA) diagnosed at our hospital over a 26-year period. MATERIALS AND METHODS: We performed a retrospective review of the clinical, histologic, and immunologic features of EBA in 9 patients. RESULTS: Mean age at presentation was 37 years and 66.67% of the patients were women. EBA occurred in association with malignant tumors, inflammatory bowel disease, and autoimmune disorders. The most common variant was inflammatory EBA (6 of the 9 cases). In all 9 patients, histology revealed a subepidermal blister and direct immunofluorescence showed linear deposits of immunoglobulin G and C3 in the basement membrane zone. Indirect immunofluorescence performed on salt-split skin substrate was positive in 6 patients and showed a dermal pattern in all cases. Five patients were tested for autoantibodies to type VII collagen using enzyme-linked immunosorbent assay, with positive results in 2 cases. Immunoblotting using recombinant noncollagenous domains (NC1) of type VII collagen was positive in all 6 cases in which it was performed. Response to treatment was variable. CONCLUSIONS: EBA is a rare disease with a variable clinical presentation that can be confused with that of other subepidermal blistering diseases. Correct diagnosis requires a high level of clinical suspicion and the use of all available diagnostic tests. Thorough evaluation of cutaneous and mucosal involvement and prompt initiation of appropriate treatment will ensure the detection and prevention of dysfunction and treatment-related complications.

[A retrospective study of clinical, histological, and immunological characteristics in patients with dermatitis herpetiformis. The experience of Hospital Clinic de Barcelona, Spain, between 1995 and 2010 and a review of the literature]. / Estudio retrospectivo de las características clínicas, histológicas e inmunológicas de los pacientes con dermatitis herpetiforme. Experiencia del Hospital Clínic de Barcelona entre los años 1995 y 2010 y revisión de la literatura.

BACKGROUND AND OBJECTIVES: Dermatitis herpetiformis is a chronic bullous disease that is currently considered a cutaneous expression of gluten hypersensitivity. The aim of this study was to analyze and describe the clinical, histological, and immunopathological characteristics of patients with dermatitis herpetiformis assessed at Hospital Clinic de Barcelona, Spain between 1995 and 2010. MATERIAL AND METHODS: Demographic, clinical, serologic, and histopathological data were reviewed for 33 patients with dermatitis herpetiformis. RESULTS: The median age of the patients at the time of disease onset was 30 years and the majority were men. Associated autoimmune disease was present in 49% of patients. In 6 patients, celiac disease was diagnosed before dermatitis herpetiformis. Although excoriations were the most predominant lesions, 9 patients had blisters. Histological findings in skin lesions were compatible with dermatitis herpetiformis in 46% of cases. The most frequently observed staining pattern by indirect immunofluorescence was the presence of granular immunoglobulin A deposits in the basement membrane (62%). More than 80% of intestinal biopsies were compatible with celiac disease. Antibodies linked to gluten sensitivity were observed in 79% of patients. Only 1 malignant tumor was detected. CONCLUSIONS: Notable findings were the frequent presence of bullous lesions, the high prevalence of celiac disease, and the positive findings on intestinal biopsy, all of which are suggestive of late diagnosis. Our findings confirm the lack of specificity of conventional histology in dermatitis herpetiformis and the association of the disease with other immunological disorders.

Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients.

BACKGROUND: Promising results have been reported with immune checkpoint inhibitors (ICI) in a small proportion of MPM patients. MMR deficiency (dMMR) has been well described in several malignancies and was approved as a biomarker for anti-PD-1 inhibitors. Next generation sequencing (NGS) data demonstrated that 2% of MPM harbor microsatellite instability. The aim of this study is to characterize MMR by immunohistochemistry (IHC) in a series of MPM including a subset of patients treated with immunotherapy. METHODS: Tumors of 159 MPM p diagnosed between 2002 and 2017 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained for MLH1, MSH2, MSH6 and PMS2 and tumors were classified as dMMR (MMR protein expression negative) and MMR intact (all MMR proteins positively expressed). We retrospectively collected clinical outcomes under standard chemotherapy and experimental immunotherapy in the entire cohort. RESULTS: MMR protein expression was analyzed in 158 samples with enough tissue and was positive in all of the cases. Twenty two patients received ICI with anti-CTLA4 or anti-PD-1 blockade in clinical trials, 58% had a response or stable disease for more than 6 m, with median progression-free survival (PFS) of 5.7 m (2.1-26.1 m). The median overall survival (mOS) in all population was 15 months (m) (13.5-18.8 m). In a multivariable model factors associated to improved mOS were PS 0, neutrophil-lymphocyte ratio (NLR) < 5 and epithelioid histology (p < 0.001). CONCLUSIONS: In our series we were unable to identify any MPM patient with dMMR by IHC. Further studies are needed to elucidate potential predictive biomarkers of ICI benefit in MPM.

Direct quantification of inorganic iodine in seawater by mixed-mode liquid chromatography-electrospray ionization-mass spectrometry.

Atmospheric iodine plays a relevant role in climate change. Bearing in mind that most of this iodine comes from the oceans, analytical methods capable of determining iodine in a challenging matrix as seawater are necessary. In this work, the first method capable of direct determination of total inorganic iodine in seawater at subnanomolar level based on mixed-mode liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) without any sample treatment is presented. Analytical characteristics of the developed method were studied in terms of linear range, limits of detection and quantification, precision, trueness, matrix effect, and robustness. The detection limit for iodide was as low as 0.16 nM, injecting 5 µL of seawater without any sample treatment and the working linear range of four orders of magnitude was wide enough to cover the broad concentration range observed in seawater samples. Average values for repeatability and intermediate precision were 4.1% and 8.1%, respectively. The suitability of the method was demonstrated through its application to the analysis of several types of samples, including seawater samples taken at different locations along the Spanish Mediterranean coast and some domestic iodized salts. According to the results obtained, the method developed is rapid, easy to apply and to be automated, avoids sample treatment and requires only few microliters of sample. Furthermore, it has a low detection limit and allows the quantification of inorganic iodine over a wide concentration range.

Efficacy of conversion to sirolimus in posttransplantation Kaposi's sarcoma.

UNLABELLED: The increased incidence of Kaposi's sarcoma (KS) in organ transplantation has been related to the KS herpes virus and the permissive effect of immunosuppressive therapy. We postulated that conversion to SRL in renal recipients with KS favored regression of KS lesions without increasing the risk of graft rejection. METHODS: In this study we performed a retrospective chart review of 7 caucasian renal transplant recipients affected by KS to determine demographic data, etiology of ESRD, immunologic risk factors, immunosuppressive treatment, KS disease follow-up, and renal function before and after SRL conversion. RESULTS: All seven patients were under calcineurin inhibitor treatment at the onset of KS which was limited to the skin, without regression despite attempts to minimize immunosuppression. After conversion to SRL, six patients showed progressive regression of KS lesions, with only hyperpigmented atrophic cutaneous lesions remaining after a mean time of 8.1 months (2-18 months). The seventh patient has completed 9 months follow-up with a near complete regression of KS lesions. One patient returned to hemodialysis after 13 months following irreversible acute renal failure not directly related to SRL conversion; in the other six, renal function was stable. The mean serum creatinine was 1.87 +/- 0.64 versus 1.74 +/- 0.68 mg/dL, pre-conversion versus the end of follow up, respectively. Mean SRL blood level was 9.2 +/- 2.0 ng/mL. CONCLUSION: After SRL conversion, patients with KS showed progressive regression without an increased risk of acute rejection. SRL offers a promising approach to the management of posttransplantation KS and probably other malignancies in organ transplant recipients.