Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study.

BACKGROUND: Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up. PATIENTS AND METHODS: ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: At data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib. CONCLUSIONS: These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer.

Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations.

BACKGROUND: Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung cancer (NSCLC). It is critical to analyze RET mutants resistant to these drugs and unravel the molecular basis to improve patient outcomes. PATIENTS AND METHODS: Cell-free DNAs (cfDNAs) were analyzed in a RET-mutant medullary thyroid cancer (MTC) patient and a CCDC6-RET fusion NSCLC patient who had dramatic response to selpercatinib and later developed resistance. Selpercatinib-resistant RET mutants were identified and cross-profiled with pralsetinib in cell cultures. Crystal structures of RET-selpercatinib and RET-pralsetinib complexes were determined based on high-resolution diffraction data collected with synchrotron radiation. RESULTS: RETG810C/S mutations at the solvent front and RETY806C/N mutation at the hinge region were found in cfDNAs of an MTC patient with RETM918T/V804M/L, who initially responded to selpercatinib and developed resistance. RETG810C mutant was detected in cfDNAs of a CCDC6-RET-fusion NSCLC patient who developed acquired resistance to selpercatinib. Five RET kinase domain mutations at three non-gatekeeper residues were identified from 39 selpercatinib-resistant cell lines. All five selpercatinib-resistant RET mutants were cross-resistant to pralsetinib. X-ray crystal structures of the RET-selpercatinib and RET-pralsetinib complexes reveal that, unlike other TKIs, these two RET TKIs anchor one end in the front cleft and wrap around the gate wall to access the back cleft. CONCLUSIONS: RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations.

Selective RET kinase inhibition for patients with RET-altered cancers.

Background: Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations. Patients and methods: Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly. Results: LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein -/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and tumor-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved. Conclusions: These results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.

Hearing and vestibular disorders in patients with systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) is associated with several comorbidities, including hearing and vestibular disorders. We recently described an increase of SLE prevalence in patients with Menierés disease (MD). The aim of this study is to explore if a subset of SLE patients may have a common inner ear disorder and determine the potential relationship with migraine. METHODS; Eighty-nine patients with SLE (according to the American College of Rheumatology criteria for the diagnosis of SLE) were evaluated for audiovestibular symptoms by a telephone interview carried out by two experienced otoneurologists. Twenty-one patients with SLE were referred to the otoneurology clinic for a detailed clinical history for criteria assessment for MD and a complete audiovestibular examination (audiogram, oculomotor, and caloric testing with video-oculography). RESULTS: Recurrent headache was found in 50/89 patients, and 26 of them had diagnostic criteria for migraine. Twenty-four percent of patients reported sensorineural hearing loss (SNHL) or episodic vertigo. Among the eight patients (9%) with episodic vertigo, one had criteria for definite MD and another two patients had criteria for possible MD. SNHL was found to be associated with a history of episodic vertigo (Fisher's test, p=0.02), but not with headache or migraine. SLE and episodic vertigo were not associated with tinnitus, migraine, lupus nephritis, antinuclear antibodies or antiphospholipid syndrome. CONCLUSIONS: Migraine, SNHL and episodic vertigo are comorbid conditions in patients with SLE, but migraine is not associated with SNHL or vertigo in these patients. However, SNHL and vertigo are associated conditions in SLE, suggesting a common audiovestibular dysfunction.

Optimizing therapy for radioactive iodine-refractory differentiated thyroid cancer: current state of the art and future directions.

The majority of patients with differentiated thyroid cancer are cured with standard primary treatments including surgery, radioactive iodine and TSH suppression. A small proportion of patients who develop radioactive iodine-refractory metastatic disease have few treatment options. Recent discovery of the molecular mechanisms that contribute to thyroid cancer tumorigenesis and its progression have revealed key targets that are currently being evaluated in clinical trials. In the last decade several novel targeted therapies have shown encouraging results and have brought hope to patients with advanced disease. However, identifying the subpopulation of patients who may benefit from systemic therapies remains a challenge as the use of these therapeutic modalities is associated with high toxicity rates and most patients have a long indolent phase where the tumor is stable or slowly progressive and asymptomatic. The objective of this review is to summarize the management of patients with metastatic, radioactive iodine refractory differentiated thyroid cancer.

Lamotrigine induced subacute cutaneous lupus erythematous.

A 48-year-old woman developed drug-induced subacute lupus erythematosus while taking lamotrigine. The eruption resolved after discontinuance of lamotrigine, suggesting this drug as the cause.

[Salmon patch: a descriptive study]. / Mancha salmón: estudio descriptivo.

BACKGROUND AND OBJECTIVES: salmon patch is a congenital venous malformation that usually affects the midline. Although it is very common, few studies have analyzed its prevalence or predisposing factors. The aim of this study was to determine the prevalence and clinical characteristics of salmon patch in a group of newborn infants from a health care area in northwest Spain and to assess its association with neonatal and maternal variables. PATIENTS AND METHODS: a descriptive study was undertaken of live newborn children seen in the neonatal unit of the Department of Pediatrics at Hospital Arquitecto Marcide, Ferrol, Spain between May 1, 2008 and January 31, 2009. The study protocol included collection of data on neonatal variables (including gestational age, sex, ethnic origin, weight, and presence and anatomical site of salmon patch) and maternal variables (including age and number of previous pregnancies). RESULTS: of the 600 newborn infants included in the study, 59% had salmon patches. The most commonly affected sites were the nape of the neck (226 infants, 37.6%) and eyelids (211 infants, 35.1%). In a number of cases, more than one part of the body was affected. There was a higher prevalence of salmon patch in full-term or post-term births, in girls, white children, heavier children, and infants born to mothers aged between 30 and 34 years or who had not been pregnant previously. CONCLUSIONS: salmon patch occurred most frequently on the nape of the neck, the eyelids, and the glabella. Its prevalence was associated with certain neonatal and maternal factors.

[Prevalence of birthmarks and transient skin lesions in 1,000 Spanish newborns]. / Prevalencia de marcas de nacimiento y lesiones cutáneas transitorias en 1.000 recién nacidos españoles.

BACKGROUND AND OBJECTIVES: Almost all newborn children have some sort of birthmark or transient benign skin lesion. Few studies, however, have analyzed their frequency, particularly in Spain. The aims of this study were to determine their prevalence in 1000 newborn children in the health care area of Ferrol in northwest Spain and to compare the results with those of 9 other studies with similar characteristics. PATIENTS AND METHODS: We undertook a descriptive study of 1000 newborn infants seen in the first 3 days of life at the neonatal clinic in the Department of Pediatrics, Hospital Arquitecto Marcide, Ferrol, Spain. Each infant was examined for the presence of 19 different transient benign skin lesions and 11 birthmarks. RESULTS: Birthmarks or benign skin lesions were present in 994 neonates (99.4%). Transient skin lesions were present in 99.2% and birthmarks in 72%. The 5 most prevalent lesions were sebaceous hyperplasia (75%), salmon patch (64.2%), hypertrichosis (59%), sucking calluses (54%), and palatine cysts (53.7%). CONCLUSIONS: The results of this study show that most neonates have benign skin lesions. The findings of studies to assess their frequency are influenced not only by geographic location (affecting variables such as climate, social and health care conditions, and ethnic group) but also by the timing of examination, the inclusion criteria applied, and the terminology used.

[Prevalence and clinical features of congenital melanocytic nevi in 1,000 Spanish newborns]. / Prevalencia y características clínicas de los nevos melanocíticos congénitos en 1.000 recién nacidos españoles.

BACKGROUND: Congenital melanocytic nevus is a benign proliferation of melanocytes that is present at birth or develops in the first months of life. Although such lesions are common, few studies have analyzed their prevalence in Spain. OBJECTIVES: The aim of this study was to define the prevalence and most frequent anatomical areas affected by congenital melanocytic nevi in our health service area. We also analyzed the influence of maternal and neonatal factors in the development of these lesions. PATIENTS AND METHODS: We performed a prospective study of 1000 consecutive neonates seen in the first 72hours of life in the perinatology clinic of the Pediatrics Department of Hospital Arquitecto Marcide in Ferrol, Spain, recording specific maternal and neonatal variables and the size and site of congenital melanocytic nevi if present. RESULTS: Fourteen infants (10 girls and 4 boys; 12 white European, 2 North African; 1.4% of the study population) presented at least 1 melanocytic nevus. None had more than 1 lesion. Eight of the nevi were located on the trunk, 2 on the face, 2 on the upper limbs, and 2 on the lower limbs. The diameter of the lesions was less than 1.5 cm in half of cases and between 1.5 and 3.5 cm in the remainder. CONCLUSIONS: There was a higher prevalence of congenital melanocytic nevi in preterm infants, females, and nonwhite infants. Maternal age, number of previous pregnancies, and birth weight do not appear to influence the prevalence of these lesions.

Clinical diagnosis of toenail onychomycosis is possible in some patients: cross-sectional diagnostic study and development of a diagnostic rule.

BACKGROUND: Suspected toenail onychomycosis is a frequent problem. Clinical diagnosis has been considered inadequate. OBJECTIVES: To assess the diagnostic accuracy of clinical findings for detecting fungi in toenails, and to develop and validate a clinical diagnostic rule aimed at improving dermatologists' diagnosis of onychomycosis. METHODS: A cross-sectional diagnostic study was performed including a total of 277 patients seen by 12 dermatologists. The gold standard was the presence of dermatophytes on culture or a positive nail plate biopsy. For each sign we described prevalence, sensitivity, specificity, positive and negative predictive values, and likelihood ratios for positive and negative results. We developed a diagnostic clinical rule and validated it in a subsample. RESULTS: Helpful findings to predict the presence of fungi are: previous diagnosis of fungal disease; abnormal plantar desquamation (affecting > 25% of the sole); onychomycosis considered the most probable diagnosis by a dermatologist; and presence of interdigital tinea. When dermatologists considered onychomycosis the most probable diagnosis and plantar desquamation was present (13% of patients), the positive predictive value for presence of fungi was 81%. When both signs were absent (34% of patients), the positive predictive value for absence of fungi was 71%. In other situations, clinical diagnosis might not give enough information to decide on therapy. CONCLUSIONS: In 13% of the patients (a large number in absolute terms), when dermatologists consider onychomycosis the most probable diagnosis and plantar desquamation is present, therapy should be started without any further test, as clinical diagnosis is at least as accurate as laboratory tests. In other situations, an optimal management strategy should be defined.

[Cutaneous collagenous vasculopathy: a case report and review of the literature]. / Vasculopatía colágena cutánea: aportación de un caso y revisión de la literatura.

Cutaneous collagenous vasculopathy is an idiopathic microangiopathy first described in 2000 by Salama and Rosenthal.It must not be confused with generalized essential telangiectasia. To date, all patients have been white men over the age of 50 years, most of whom had multiple pathologies, were taking multiple drugs, and had no family history of similar conditions or hemorrhagic disorders. The disease is characterized by the development of various numbers of telangiectases on the limbs, lower abdomen, chest, or back, with no involvement of the mucosas or nail bed. Histopathology shows dilated superficial cutaneous vessels with perivascular deposits of periodic acid-Schiff diastase-positive, eosinophilic hyaline material that exhibits positive immunoreactivity to collagen IV. We report a new case in a 68-year-old man with symmetrically distributed telangiectases on his forearms, lower abdomen, posterior thighs, lower legs, and dorsum of the feet.

Distinguishing Recurrent Thyroid Cancer from Residual Nonmalignant Thyroid Tissue Using Multiphasic Multidetector CT.

BACKGROUND AND PURPOSE: During thyroidectomy incomplete resection of the thyroid gland may occur. This complicates the imaging surveillance of these patients as residual thyroid needs to be distinguished from local recurrence. Therefore, the purpose of this study was to determine if multiphasic multi-detector computed tomography (4D-MDCT) can differentiate residual nonmalignant thyroid tissue and recurrent thyroid carcinoma after thyroidectomy. MATERIALS AND METHODS: In this retrospective study, Hounsfield unit values on multiphasic multidetector CT in precontrast, arterial (25 seconds), venous (55 seconds), and delayed (85 seconds) phases were compared in 29 lesions of recurrent thyroid cancer, 29 with normal thyroid, and 29 with diseased thyroid (thyroiditis/multinodular thyroid). The comparison of Hounsfield unit values among lesion types by phase was performed using ANOVA. The performance of Hounsfield unit values to predict recurrence was evaluated by logistic regression and receiver operating characteristic analysis. RESULTS: All 3 tissue types had near-parallel enhancement characteristics, with a wash-in-washout pattern. Statistically different Hounsfield unit density was noted between the recurrence (lowest Hounsfield unit), diseased (intermediate Hounsfield unit), and normal (highest Hounsfield unit) thyroid groups throughout all 4 phases (P < .001 for each group and in each phase). Dichotomized recurrence-versus-diseased/normal thyroid tissue with univariate logistic regression analysis demonstrated that the area under the receiver operating characteristic curve for differentiating benign from malignant thyroid for the various phases of enhancement was greatest in the precontrast phase at 0.983 (95% CI, 0.954-1), with a cutoff value of ≤62 (sensitivity/specificity, 0.966/0.983) followed by the arterial phase. CONCLUSIONS: Recurrent thyroid carcinoma can be distinguished from residual nonmalignant thyroid tissue using multiphasic multidetector CT with high accuracy. The maximum information for discrimination is in the precontrast images, then the arterial phase. An optimal clinical protocol could be built from any number of phases but should include a precontrast phase.

Observer agreement in toenail disorders: implications for diagnosis and clinical research.

BACKGROUND: Toenail disorders are frequent, especially onychomycosis. The interobserver variability of nail signs needs to be known before these signs can be confidently applied for diagnosis. OBJECTIVES: To describe observer agreement in toenail findings as described by dermatologists in standard clinical practice, focusing on signs that could be useful for diagnosis of onychomycosis. METHODS: Prospective cross-sectional study in five dermatology departments. Eighty-six patients with abnormal toenails that could have onychomycosis as a differential diagnosis were independently examined by a pair of dermatologists using a predefined questionnaire, to describe the presence of 10 findings on previous history and 14 physical signs. RESULTS: Agreement was fine for previous history findings: it was very good (kappa > 0.81) for previous diagnosis of diabetes, smoking and use of public dressing rooms or swimming pools. Agreement was good (kappa 0.61-0.80) for immune suppression (drugs or cancer), previous diagnosis of fungal disease and worsening in the last year. It was moderate (kappa 0.41-0.60) for previous diagnosis of arterial disease, trauma induced by work or sports, and distal vs. proximal or lateral vs. central start of the lesion. Agreement was worse for physical signs: we found good agreement for the presence of the same disease in fingernails, abnormal plantar desquamation, deformity causing nail trauma, and subungual hyperkeratosis. It was moderate for the presence of nail destruction, tinea interdigitalis, onycholysis, and the type of material obtained by subungual curettage (dust vs. hard). Agreement was fair (kappa 0.21-0.40) for the presence of longitudinal or transverse striae, trachyonychia, pachyonychia, and change in colour of the nail plate. Pitting was too infrequent to allow for kappa calculation. Chance expected agreement was between 51% and 84% for all signs except pitting. CONCLUSIONS: Agreement is adequate for most signs. It is low for the presence of longitudinal or transverse striae, trachyonychia, and change in colour of the nail plate. Pitting is rare in toenails.

[Usefulness of meal replacement: analysis of the principal meal replacement products commercialised in Spain]. / Características y utilidad de los sustitutos de la comida: análisis de los productos comercializados de uso habitual en nuestro entorno.

INTRODUCTION: Obesity has become a serious health problem. It is nowadays considered a pandemia and it is therefore a priority to develop different strategies on its prevention and treatment: lifestyle changes, community interventions as well as pharmacological and non-pharmacological activities. In this way, meal replacement products (energy reduced products designed to replace one or two regular meals providing a supously nutritionally balanced low fat meal) can be an alternative to traditional reduced calorie diet. OBJECTIVE: Our aim was to revise the literature on meal replacement and compare the nutritional composition and the different forms of presentation of the main meal replacement products commercialised in Spain. METHODOLOGY: We made a research in pharmacies, weight loss centers and big supermarkets of food products specially designed to replace a meal. We compared the nutritional composition regarding macronutrients and micronutrients of the thirty-two different products founded, including their different form of presentation (bars, powder, drink-shakes and crackers). In order to judge their nutritional composition, we compared one meal replaced with these products with the Recommended Dietary Allowances (RDA). RESULTS: The most common form of meal replacement products were bars (23 of 32 analyzed products), followed by powder for making shakes (6 products), bricks (2 products) and crackers (1 product). When we analysed a single meal replaced with these products, we founded that the global distribution of macronutrients was: 45% as carbohydrates, 29% as fats, 26% as proteins, and 4.45 grams of fiber. Their average energy was 266 Kcal per meal. Regarding micronutrients (vitamins and minerals), there was a great variability among the different products, but in average their composition was above the 33% of the RDA per meal specially in iron and vitamins B1, B6 and D. Calcium, magnesium, folic acid and vitamin B12 were the micronutrients less plentiful. CONCLUSION: Partial meal replacement can be an alternative or a complementary therapeutic option to conventional hipocaloric diets in obesity since they appear to have an easier understanding and follow up. It is therefore important to consider them in weight management programs and more studies are required to establish strict criteria on their nutritional composition by a legal normative.

Viral kinetics during the first month of treatment in patients with genotype 1 chronic hepatitis C.

OBJECTIVE: to identify predictive factors of response to pegylated interferon alpha-2b and ribavirin in patients with genotype 1 chronic hepatitis C. Viral kinetics were studied in weeks 2 and 4. METHODS: a prospective and consecutive study of patients with genotype 1 chronic hepatitis C referred to our Hepatology Clinic between January 2004 and October 2006 for antiviral treatment. Baseline data were recorded and viremia levels were determined hours before the weekly dose of pegylated interferon by qualitative and quantitative PCR. RESULTS: 57 patients were included in the study, although 3 of these were excluded during follow up; 65% were male (n = 35), with a mean age of 42 (26-65) years. Baseline viremia levels were > 800,000 IU/mL in 67% (n = 36). Liver biopsy was performed in 86% (n = 46), 22% (n = 12) had advanced fibrosis. Forty were naïve, 4 relapsing and 10 non-responders. Ribavirin dose was modified in one patient alone due to adverse effects. End treatment response and sustained virological response (SVR) were 59 and 41%, respectively. A univariate analysis revealed a statistically significant association of SVR with baseline viremia (p = 0.006), baseline GGT (p = 0.025), and a reduction in viremia > or =2 logs at 2, 4 and 12 weeks (p = 0.001). The extent of viremia reduction at week 2 was associated with 100% SVR, and at 4 weeks the positive predictive values was 84% and the negative predictive values was 96.5%. A subanalysis of the naïve group yielded analogous results. CONCLUSIONS: in our study, a reduction in viremia > or = 2 logs 2 weeks after treatment could ensure SVR. At 4 weeks, most non-responders could be identified.