ALK+ histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

ALK-related histiocytosis (formerly ALK-positive histiocytosis) is a rare subtype of histiocytic neoplasm first described in 2008 in three infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-related histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-related histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (seven and twelve from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and ALK, and often conferred strong expression of phosphorylated-ERK, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, while CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, ten with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-related histiocytosis, and provides guidance for the clinical management of this emerging histiocytic entity.

Download Full-text

Treatment of a BRAF V600E Positive Ameloblastoma in a Pediatric Patient with MEK Inhibitor Monotherapy

FACE ◽

10.1177/27325016211005126 ◽

2021 ◽

pp. 273250162110051

Author(s):

Steven Daws ◽

Kongkrit Chaiyasate ◽

Arshi Lehal

Keyword(s):

Mapk Pathway ◽

Case Reports ◽

Radical Resection ◽

Mek Inhibitor ◽

Braf V600e Mutation ◽

Braf V600e ◽

Targeted Chemotherapy ◽

Odontogenic Epithelium ◽

Genetic Landscape ◽

Frequent Presence

Ameloblastomas are uncommon tumors of the odontogenic epithelium standardly treated with radical resection. Recent studies of the genetic landscape of ameloblastoma have revealed the frequent presence of the BRAF V600E mutation, suggesting a possible role for targeted chemotherapy. We present the case of a primary mandibular ameloblastoma found in a 13-year-old female with confirmed BRAF V600E mutation. Prior to invasive surgical intervention she was treated for 8 weeks with the MEK inhibitor trametinib, but her tumor demonstrated little radiographic, clinical, or histologic response. Previous case reports have shown ameloblastoma in adult patients to be responsive to other agents targeting the MAPK pathway. Our observations in the presented case demonstrate the need for further research into the utility of targeted chemotherapy in ameloblastoma treatment.

Download Full-text

Cutaneous Side Effects of BRAF Inhibitors in Advanced Melanoma: Review of the Literature

Dermatology Research and Practice ◽

10.1155/2016/5361569 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 27

Author(s):

Bilgen Gençler ◽

Müzeyyen Gönül

Keyword(s):

Side Effects ◽

Metastatic Melanoma ◽

Mapk Pathway ◽

Case Reports ◽

Mitogen Activated Protein Kinase ◽

Braf V600e ◽

Braf Inhibitors ◽

Braf Mutations ◽

Cutaneous Side Effects ◽

Downstream Signaling

The incidence of melanoma has recently been increasing. BRAF mutations have been found in 40–60% of melanomas. The increased activity of BRAF V600E leads to the activation of downstream signaling through the mitogen-activated protein kinase (MAPK) pathway, which plays a key role as a regulator of cell growth, differentiation, and survival. The use of BRAF inhibitors in metastatic melanoma with BRAF mutation ensures clinical improvement of the disease. Vemurafenib and dabrafenib are two selective BRAF inhibitors approved by the Food and Drug Administration (FDA). Both drugs are well tolerated and successfully used in clinical practice. However, some adverse reactions have been reported in patients in the course of treatment. Cutaneous side effects are the most common adverse events among them with a broad spectrum. Both the case reports and several original clinical trials reported cutaneous reactions during the treatment with BRAF inhibitors. In this review, the common cutaneous side effects of BRAF inhibitors in the treatment of metastatic melanoma with BRAF V600E mutation were reviewed.

Download Full-text

Is L5/S1 interbody fusion necessary in long-segment surgery for adult degenerative scoliosis? A systematic review and meta-analysis

Journal of Neurosurgery Spine ◽

10.3171/2021.9.spine21883 ◽

2021 ◽

pp. 1-8

Keyword(s):

Systematic Review ◽

Interbody Fusion ◽

Case Reports ◽

Adult Spinal Deformity ◽

Meta Analysis ◽

Lumbar Interbody Fusion ◽

Lumbosacral Junction ◽

Pelvic Fixation ◽

Group 2 ◽

Group 1

OBJECTIVE There is no consensus regarding the best surgical strategy at the lumbosacral junction (LSJ) in long constructs for adult spinal deformity (ASD). The use of interbody fusion (IF) has been advocated to increase fusion rates, with additional pelvic fixation (PF) typically recommended. The actual benefit of IF even when extending to the pelvis, however, has not been vigorously analyzed. The goal of this work was to better understand the role of IF, specifically with respect to arthrodesis, when extending long constructs to the ilium. METHODS A systematic review of the PubMed and Cochrane databases was performed to identify the relevant studies in English, addressing the management of LSJ in long constructs (defined as ≥ 5 levels) in ASD. The search terms used were as follows: “Lumbosacral Junction,” “Long Constructs,” “Long Fusion to the Sacrum,” “Sacropelvic Fixation,” “Interbody Fusion,” and “Iliac Screw.” The authors excluded technical notes, case reports, literature reviews, and cadaveric studies; pediatric populations; pathologies different from ASD; studies not using conventional techniques; and studies focused only on alignment of different levels. RESULTS The PRISMA protocol was used. The authors found 12 retrospective clinical studies with a total of 1216 patients who were sorted into 3 different categories: group 1, using PF or not (n = 6); group 2, using PF with or without IF (n = 5); and group 3, from 1 study comparing anterior lumbar interbody fusion versus transforaminal lumbar interbody fusion. Five studies in group 1 and 4 in group 2 had pseudarthrosis rate as primary outcome and were selected for a quantitative analysis. Forest plots were used to display the risk ratio, and funnel plots were used to look at the risk of publication bias. The summary risk ratios were 0.36 (0.23–0.57, p < 0.001) and 1.03 (0.54–1.96, p = 0.94) for the PF and IF, respectively; there is a protective effect of overall pseudarthrosis for using PF in long constructs for ASD surgeries, but not for using IF. CONCLUSIONS The long-held contention that L5/S1 IF is always advantageous in long-construct deformity surgery is not supported by the current literature. Based on the findings from this systematic review and meta-analysis, PF with or without additional L5/S1 interbody grafting demonstrates similar overall construct pseudarthrosis rates. The added risk and costs associated with IF, therefore, should be more closely considered on a case-by-case basis.

Download Full-text

EFFICACY OF FREQUENT NEBULIZED IPRATROPIUM BROMIDE ADDED TO FREQUENT HIGH-DOSE ALBUTEROL THERAPY IN SEVERE CHILDHOOD ASTHMA

PEDIATRICS ◽

10.1542/peds.98.2.342 ◽

1996 ◽

Vol 98 (2) ◽

pp. 342-342

Author(s):

Thad H. Joos

Keyword(s):

Ipratropium Bromide ◽

Treatment Protocol ◽

Forced Expiratory Volume ◽

High Dose ◽

Entire Cohort ◽

Asthmatic Children ◽

Group 3 ◽

Group 2 ◽

Sick Children ◽

Double Blinded

Purpose of the Study. High-dose nebulized albuterol has become the standard of treatment for the severely wheezing asthmatic child. The role, dose, and frequency of administration of ipratropium bromide in this same group of children requires further definition. Methods. From the Emergency Department of the Hospital for Sick Children in Toronto, Ontario, Canada, 120 children 5 to 17 years of age with severe asthma as determined by a forced expiratory volume in 1 second (FEV1) of less than 50% predicted normal were equally divided and entered into a double-blinded, placebo-controlled treatment protocol. All groups received 0.15 mg albuterol/kg/dose nebulized every 20 minutes χ3. Group 1 had 250 µg of ipratropium bromide added to each treatment. Group 2 had the same amount of ipratropium bromide added to only the initial aerosol with a like amount of saline added to aerosols 2 and 3. Group 3 had only saline added to each aerosol. No corticosteroids were administered to any patient in the first hour. The entire cohort was meticulously monitored for oxygen saturation, heart rate, respiratory rate, accessory muscle use, cyanosis, wheezing and pulmonary function test parameters by a skilled research nurse. Results. As expected, all patients improved to a degree but those with the lowest FEV1s who were treated with ipratropium in each aerosol responded the best and were admitted to the hospital less frequently. No serious untoward side effects were observed in any patient. Reviewer's Comment. I feel the article is a must read for all physicians caring for acutely wheezing asthmatic children.

Download Full-text

Can Endocrine Dysfunction Be Reliably Tested in Aged Horses That Are Experiencing Pain?

Animals ◽

10.3390/ani10081426 ◽

2020 ◽

Vol 10 (8) ◽

pp. 1426

Author(s):

Heidrun Gehlen ◽

Nina Jaburg ◽

Roswitha Merle ◽

Judith Winter

Keyword(s):

Underlying Disease ◽

Pain Scale ◽

Stimulation Test ◽

Pars Intermedia ◽

Moderate Pain ◽

Disease Group ◽

Trh Stimulation ◽

Significant Difference ◽

Acth Concentration ◽

Group 2

The aim of the present study was to evaluate (i) the effects of different intensities and types of treated pain on the basal concentrations of adrenocorticotropic hormone (ACTH) and cortisol, and (ii) the thyrotropin-releasing hormone (TRH) stimulation test, to determine whether treated pain caused a marked increase of ACTH, which would lead to a false positive result in the diagnosis of pituitary pars intermedia dysfunction (PPID). Methods: Fifteen horses with treated low to moderate pain intensities were part of the study. They served as their own controls as soon as they were pain-free again. The horses were divided into three disease groups, depending on their underlying disease (disease group 1 = colic, disease group 2 = laminitis, disease group 3 = orthopedic problems). A composite pain scale was used to evaluate the intensity of the pain. This pain scale contained a general part and specific criteria for every disease. Subsequently, ACTH and cortisol were measured before and after the intravenous application of 1 mg of TRH. Results: There was no significant difference in the basal or stimulated ACTH concentration in horses with pain and controls, between different pain intensities or between disease groups. Descriptive statistics, however, revealed that pain might decrease the effect of TRH on the secretion of ACTH. There was an increase of ACTH 30 min after TRH application (p = 0.007) in the treated pain group, but this difference could not be statistically confirmed. Measuring the basal ACTH concentration and performing the TRH stimulation test for the diagnosis of PPID seem to be possible in horses with low to moderate pain.

Download Full-text

Does Surgery Improve the Survival of Patients with Advanced Anaplastic Thyroid Carcinoma?

Otolaryngology ◽

10.1177/019459989811800532 ◽

1998 ◽

Vol 118 (5) ◽

pp. 728-731

Author(s):

WEN-TSOUNG LU ◽

Jen-Der Lin ◽

Hong-So Huang ◽

Tzu-Chieh Chao

Keyword(s):

Thyroid Carcinoma ◽

Distant Metastases ◽

Anaplastic Thyroid Carcinoma ◽

Disease Group ◽

Localized Disease ◽

The Mean ◽

Group 2 ◽

Nonsurgical Patients ◽

Head Neck ◽

Group 1

Anaplastic thyroid carcinoma is one of the most lethal neoplasms, with poor prognosis being reported by most authors. The benefits of surgery for most cases of advanced disease remain controversial. In this study we asked the following question: Does surgical intervention alter outcomes for patients with advanced anaplastic thyroid carcinoma? Forty-six patients with advanced anaplastic thyroid carcinoma were analyzed. There were 20 patients with advanced localized disease (group 1), 15 of whom received surgery. Of the other 26 patients with evidence of distant metastases (group 2), 13 received surgery. For group 1 patients, the mean survival was 12.8 months versus 8.6 months in the surgical and nonsurgical subgroups ( p = 0.46). For group 2 patients, the mean survival was 3.5 months versus 2.8 months in the surgical and nonsurgical subgroups ( p = 0.72). These data suggest that surgery does not improve survival for patients with advanced anaplastic thyroid carcinoma. In conclusion, the mean survival showed no significant differences between surgical and nonsurgical patients ( p = 0.43). This study suggests that surgical resection does not improve the survival of patients with advanced anaplastic thyroid carcinoma. (Otolaryngol Head Neck Surg 1998;118:728–31.)

Download Full-text

Delayed internal capsule infarctions following radiofrequency pallidotomy

Journal of Neurosurgery ◽

10.3171/jns.1997.87.6.0955 ◽

1997 ◽

Vol 87 (6) ◽

pp. 955-960 ◽

Cited By ~ 24

Author(s):

Jae Y. Lim ◽

Antonio A. F. de Salles ◽

Jeff Bronstein ◽

Donna L. Masterman ◽

Jeffrey L. Saver

Keyword(s):

Vascular Disease ◽

Disease Risk ◽

Internal Capsule ◽

High Risk Group ◽

Disease Group ◽

Content Type ◽

Posterior Limb ◽

Group 3 ◽

Group 2 ◽

Capsular Infarction

✓ The authors report on a series of patients with idiopathic Parkinson's disease (IPD) who underwent stereotactic radiofrequency (RF) pallidotomies, three of whom suffered delayed postoperative strokes. These three belonged to a group consisting of 42 patients with medically intractable IPD in whom 50 pallidotomies were performed. All three patients had significant previous vascular disease and were in a high-risk group for cerebral infarction. A postoperative magnetic resonance (MR) image was obtained immediately after the pallidotomy was performed to document the placement of the RF lesion and to rule out any hematoma. The delayed strokes occurred on postoperative Days 10, 51, and 117 in patients with previous vascular disease (Group 1, 11 patients). No strokes occurred in the group with the vascular disease risk factor (Group 2, 11 patients) or in the group with no risk factors for vascular disease (Group 3, 20 patients). This observation is statistically significant (p < 0.05). The T2-weighted MR images showed the lesions as high-intensity signals extending to the posterior limb of the internal capsule ipsilateral to the pallidotomy site. The poststroke T1-weighted images obtained in two patients showed persistent contrast enhancement of the RF lesion and no enhancement around the stroke lesion. Clinically and radiographically, these discrete new lesions represent delayed infarctions, suggesting that RF lesioning can induce delayed injury in adjacent tissue. Patients with previously identified vasculopathy may be at risk for delayed capsular infarction following RF pallidotomy.

Download Full-text

Bortezomib+Chemotherapy Based Salvage Combinations in Refractory AML, Preliminary Results

Blood ◽

10.1182/blood.v112.11.4000.4000 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4000-4000

Author(s):

Miklos Udvardy ◽

Attila Kiss ◽

Bela Telek ◽

Robert Szasz ◽

Peter Batar ◽

...

Keyword(s):

Cell Lines ◽

De Novo ◽

Case Reports ◽

Fatal Outcome ◽

Normal Karyotype ◽

Secondary Aml ◽

Poor Risk ◽

Group 2 ◽

De Novo Aml ◽

Group 1

Abstract Bortezomib (Velcade) proved to be the standard element of refractory myeloma 2nd and 3rd line treatment, while many studies are suggesting excellent results in 1st line. Proteasome inhibition, the block of angiogenesis, modification of the NF-kappa-B system seems to be a challenging target in other malignant diseases, including refractory acute myeloid leukemia (AML), as well. In vitro data clearly support, that bortezomib exerts antiproliferative and pro-apoptotic effects in different AML cell-lines, along with human AML cell cultures, and moreover bortezomib was able to restore, or at least improve anthracyclin and possibly ARA-C sensitivity in different cell-lines (including AML). More recently, a Phase I trial showed bortezomib monotherapy efficient (only in few percents) in childhood refractory acute leukemia. Some case reports were shown at ASH 2007. We have tried bortezomib containing first or second line combinations in 27 (14 female, 13 male, mean age 57.6 years) patients with refractory or poor risk AML, in a small retrospective survey. The combinations were as follows: HAM or Flag-Ida, combined with bortezomib 1,3 mg pro sqm, day O and seven). The following groups were considered as refractory or poor risk AML: De novo AML, 2nd line: No response/remission to first line standard treatment (“3+7”), n=2 (Velcade- Flag-Ida treatment) De novo AML 1st line: bilineal or biphenotypic (flow-cytometry) n=2 (Velcade-Flag- Ida treatment) De novo AML with complex (numerical or more than 3 abnormalities) karyotype or normal karyotype with flt-3 TKD mutation, n=9, 1st line (Velcade-Flag-Ida n=6, Velcade- HAM protocol, n=3) Secondary AML or AML with evidence of previous more than 6 mo duration high grade MDS, n=14, 1st line: (Velcade-Flag-Ida n=9, Velcade-HAM n=5) RESULTS: Complete remission (CR) 12/27, partial remission (PR) 9/27, no remission 5/27, progression during treatment: 1/27.Best responses were seen in de novo cases. CR had been achieved in all patients of group 1 (two standard risk patients not responding to 3+7 protocol), and group 2 (biphenotypic, bilineal). The CR rate was quite appreciable in group 3, i.e. 6/9 (complex karyotype or normal karyotype with FLt-3 mutation – the response rate was excellent with flt-3 mutated cases). In group 4. (MDS, secondary AML) the results were less impressive. There were no major differences according to protocol (Flag-Ida or HAM) Allogeneous stem cell transplantation could have been performed in 1st CR in two patients (one from group 1. and another from group 2.). One of them died due to relapse, the other one is in CR since then. The combinations seem to be relatively safe. Induction related death rate was low (1 elderly patient acute thrombocytopenic bleeding with refractory MDS-AML). 5 other patients had severe neutropenic sepsis (2 with fatal outcome). Pulmonary syndrome, which may follow Velcade+ARA-C had not been documented. Other adverse events did not differ from the pattern observed with standard induction therapies.

Download Full-text

Preconditioning with hyperbaric oxygen attenuates brain edema after experimental intracerebral hemorrhage

Neurosurgical FOCUS ◽

10.3171/foc.2007.22.5.14 ◽

2007 ◽

Vol 22 (5) ◽

pp. 1-6 ◽

Cited By ~ 21

Author(s):

Zhiyong Qin ◽

Shuijiang Song ◽

Guohua Xi ◽

Robert Silbergleit ◽

Richard F. Keep ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Brain Edema ◽

Hyperbaric Oxygen ◽

Mapk Pathway ◽

Autologous Blood ◽

Neurosurgical Procedures ◽

Sprague Dawley ◽

Edema Formation ◽

Group 2 ◽

Brain Edema Formation

Object Preconditioning with hyperbaric oxygen (HBO2) reduces ischemic brain damage. Activation of p44/42 mitogen-activated protein kinases (p44/42 MAPK) has been associated with preconditioning-induced brain ischemic tolerance. This study investigated if preconditioning with HBO2 protects against intracerebral hemorrhage (ICH)–induced brain edema formation and examined the role of p44/42 MAPK in such protection. Methods The study had three experimental groups. In Group 1, Sprague-Dawley rats received two, three, or five consecutive sessions of preconditioning with HBO2 (3 ata, 100% xygen, 1 hour daily). Twenty-four hours after preconditioning with HBO2, rats received an infusion of autologous blood into the caudate. They were killed 1 or 3 days later for brain edema measurement. Rats in Group 2 received either five sessions of preconditioning with HBO2 or control pretreatment and were killed 24 hours later for Western blot and immunohistochemical analyses. In Group 3, rats received an intracau-date injection of PD098059 (an inhibitor of p44/42 MAPK activation) before the first of five sessions of preconditioning with HBO2. Twenty-four hours after the final preconditioning with HBO2, rats received an intracaudate blood infusion. Brain water content was measured 24 hours after ICH. Results Fewer than five sessions of preconditioning with HBO2 did not significantly attenuate brain edema after ICH. Five sessions of preconditioning with HBO2 reduced perihematomal edema 24 and 72 hours after ICH (p < 0.05). Strong p44/42 MAPK immunoreactivity was detected in the basal ganglia 24 hours after preconditioning with BO2. Intracaudate infusion of PD098059 abolished HBO2preconditioning–induced protection against ICH-induced brain edema formation. Conclusions Preconditioning with HBO2 protects against brain edema formation following ICH. Activation of the p44/42 MAPK pathway contributes to that protection. Preconditioning with HBO2 may be a way of limiting brain injury during invasive neurosurgical procedures that cause bleeding.

Download Full-text

Neurologic Involvement in Scleroderma en Coup de Sabre

Autoimmune Diseases ◽

10.1155/2012/719685 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

Tiago Nardi Amaral ◽

João Francisco Marques Neto ◽

Aline Tamires Lapa ◽

Fernando Augusto Peres ◽

Caio Rodrigues Guirau ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Clinical Characteristics ◽

Case Reports ◽

Localized Scleroderma ◽

Resonance Imaging ◽

Disease Pathogenesis ◽

Neurologic Involvement ◽

Parry Romberg Syndrome ◽

Sclerotic Lesions

Localized scleroderma is a rare disease, characterized by sclerotic lesions. A variety of presentations have been described, with different clinical characteristics and specific prognosis. In scleroderma en coup de sabre (LScs) the atrophic lesion in frontoparietal area is the disease hallmark. Skin and subcutaneous are the mainly affected tissues, but case reports of muscle, cartilage, and bone involvement are frequent. These cases pose a difficult differential diagnosis with Parry-Romberg syndrome. Once considered an exclusive cutaneous disorder, the neurologic involvement present in LScs has been described in several case reports. Seizures are most frequently observed, but focal neurologic deficits, movement disorders, trigeminal neuralgia, and mimics of hemiplegic migraines have been reported. Computed tomography and magnetic resonance imaging have aided the characterization of central nervous system lesions, and cerebral angiograms have pointed to vasculitis as a part of disease pathogenesis. In this paper we describe the clinical and radiologic aspects of neurologic involvement in LScs.

Download Full-text