Genetic alterations of 9p24 in lymphomas and their impact for cancer (immuno-)therapy

Abstract

Chromosome 9 harbors several relevant oncogenes related to hematolymphoid malignancies and one specific region, 9p24, has come into the focus of attention in the last years as it contains recurrently mutant genes of therapeutic interest. The most prominent genes of this locus are programmed death ligands 1 and 2 (PDL1/PDL2), with the amplification of PDL1 being a hallmark of both classical Hodgkin and primary mediastinal B cell lymphoma, and Janus kinase 2 (JAK2), which is point-mutated in myeloproliferative neoplasms and other myeloid malignancies, and rearranged in PCM1-JAK2-positive myeloid/lymphoid neoplasms with eosinophila. Finally, this locus contains the lysine (K)-specific demethylase 4C (KDM4C/JMJD2C), which is also relevant for oncogenesis. Activation of these genes is effectuated, as exemplified, by multiple mechanisms, which is rather unique to oncogenes, since they are usually affected by just one type of mutation, and points towards the central role of these genes in tumor initiation and growth. Amplifications and, less frequently, translocations are the most common findings for PDL1/PDL2 and JAK2 in lymphomas. In this review, we describe the role of genes located on chromosome 9p24 and their derived proteins in diverse subtypes of lymphomas, with a special focus on PDL1 and PDL2, which are becoming a central target of immunotherapy, not only in classical Hodgkin lymphoma but also in various types of solid cancers. We also elucidate the role of the surgical pathologists in this setting — concerning what they can contribute — both diagnostically and predictively.

https://ift.tt/2PnMLYK

Patterns of failure in high-metastatic node number human papillomavirus-positive oropharyngeal carcinoma

Publication date: October 2018

Source: Oral Oncology, Volume 85

Author(s): Nicholas C.J. Lee, Jacqueline R. Kelly, Henry S. Park, Yi An, Benjamin L. Judson, Barbara A. Burtness, Zain A. Husain

Abstract

Background

The 8th edition American Joint Committee on Cancer staging system for resected HPV-positive oropharynx carcinoma (HPV+ OPC) highlights high node number as a critical determinant of survival. We sought to characterize outcomes and patterns of failure in patients with high pathologically involved node number oropharynx cancer.

Methods

We retrospectively identified 116 HPV+ OPC patients sequentially treated with neck dissection and either resection or intraoperative brachytherapy of the primary tumor between 2010 and 2016. External beam radiation was given based on the pathologic findings. Cox proportional hazards regression was used for multivariate analysis.

Results

With a median follow-up of 27 months, the 3-year overall survival and progression free survival (PFS) were 89% and 81%, respectively. On multivariate analysis, ≥5 involved lymph nodes was significantly associated with worse PFS (hazard ratio 4.3, 95% confidence interval (CI) 1.5–12.0, P = 0.001). Rates of 3-year locoregional recurrence (LRR) in patients with ≤4 vs ≥5 were 6% and 22% (log-rank P = 0.12). Rates of 3-year distant metastases (DM) were 12% and 53% between ≤4 and ≥5 (log-rank P < 0.001).

Conclusion

Our findings confirm that patients with 5 or more involved lymph nodes appear to have substantially worsened rates of disease recurrence. While these patients appear to be at high risk of both LRR and DM, the predominant mechanism of failure is distant, and the rate of DM in this group was over 50%. Dedicated clinical trials in this patient population are warranted with a focus on mitigating the high DM rate.

https://ift.tt/2LcAnHV

Management of otitis media with effusion in children. Société française d’ORL et de chirurgie cervico-faciale clinical practice guidelines

Publication date: August 2018

Source: European Annals of Otorhinolaryngology, Head and Neck Diseases, Volume 135, Issue 4

Author(s): F. Blanc, D. Ayache, M.N. Calmels, O. Deguine, M. François, N. Leboulanger, E. Lescanne, R. Marianowski, J. Nevoux, R. Nicollas, S. Tringali, N. Tessier, V. Franco-Vidal, P. Bordure, M. Mondain

Abstract

The Société française d'ORL et de chirurgie cervico-faciale clinical practice guidelines concern the management of otitis media with effusion (OME) in children under the age of 12 years. They are based on extensive review of MEDLINE and Cochrane Library publications in English or French from 1996 to 2016 concerning the methods of diagnosis and assessment of otitis media with effusion, as well as the efficacy of tympanostomy tubes and medical and surgical treatments of OME.

https://ift.tt/2nS40Fb

Editorial Board

Publication date: August 2018

Source: European Annals of Otorhinolaryngology, Head and Neck Diseases, Volume 135, Issue 4

Author(s):

https://ift.tt/2LdIofw

Contents

Publication date: August 2018

Source: European Annals of Otorhinolaryngology, Head and Neck Diseases, Volume 135, Issue 4

Author(s):

https://ift.tt/2nThxMI

Utility of Skin Biopsy in a Case of Progressive Myoclonic Epilepsy: Answer

No abstract available

https://ift.tt/2N756YO

Grover Disease With Epidermal Dysmaturation Pattern: A Common Histopathologic Finding

Background: Grover disease is an entity whose diagnosis is based on clinicopathologic correlation. Histopathologically, focal acantholysis is the most common finding. In some cases, there is prominent squamous atypia which can prove to be very challenging and the lesion may be confused with an epidermal neoplasm. Objective: To report on atypical histopathological changes in Grover disease and to provide helpful clues to differentiate between the epidermal atypia seen in some cases of Grover disease and epithelial neoplasms. Material and Methods: We analyzed 33 cases of Grover disease histologically diagnosed at Wake Forest Baptist Medical Center, NC, between 2011 and 2017. Atypical changes in keratinocytes were defined as epithelial buds, nuclear pleomorphism, and dyskeratosis in all layers of epidermis or altered granular layer. Results: Twenty cases (64%) showed foci with alteration of the normal keratinocytic maturation, whereas 18 cases demonstrated nuclear pleomorphism. Buds of epithelial cells emanating from the basal layer of the epidermis and granular cell alteration was present in 19 cases. Conclusions: The findings especially the presence of an altered granular layer may represent a diagnostic clue in cases of Grover disease with atypical changes.

https://ift.tt/2PqWnSv

An Unusual Vesiculopustular Eruption: Challenge

No abstract available

https://ift.tt/2N7Y9q7

PD-L1 Expression is Increased in Metastasizing Squamous Cell Carcinomas and Their Metastases

Abstract: Programmed cell death ligand 1 (PD-L1) expression by tumor cells plays an important role in the inhibition of T cell–mediated immune response in cancer. PD-L1 expression by tumor cells has been linked to poor prognosis in a wide variety of cancers. However, PD-L1 expression in cutaneous squamous cell carcinoma (cSCC) has been scarcely studied, and its role as a prognosis biomarker remains controversial. The association of PD-L1 expression and the metastatic risk in a series of cSCC was assessed. PD-L1 and CD8 immunostainings of full excision sections of 99 primary tumors and 24 lymphatic metastases were semiquantitatively evaluated. Primary cSCCs were grouped according to the development of lymphatic metastatic spread [metastasizing squamous cell carcinoma (MSCC)] (n = 48) or the absence of progression [nonmetastasizing squamous cell carcinoma (NMSCC)] (n = 51). PD-L1–positive expression (cut off ≥1%) was found in 26% NMSCCs and in 50% MSCCs (P = 0.02). PD-L1 association with an increased metastatic risk was confirmed in the multivariate analysis (P

https://ift.tt/2PqVYPZ

Cytotoxic CD8+ Granulomatous Cutaneous T-Cell Lymphoma Associated With Human Immunodeficiency Virus Infection: A Diagnostic Challenge

No abstract available

https://ift.tt/2N7XULJ

Using Stratum Corneum Thickness and Configuration to Distinguish Lichenoid Dermatoses

Background: Clues in the stratum corneum (SC) can aide in histopathologic diagnosis of many conditions. Objective: To determine if SC configuration and thickness could help differentiate the lichenoid dermatoses. Methods: A retrospective study was performed. A total of 305 cases (55 lichenoid keratosis, 51 lichen planus, 7 hypertrophic lichen planus, 40 lichenoid drug eruption, 19 lichenoid graft-vs.-host disease, 14 hypertrophic lupus, 46 lichenoid actinic keratosis, 73 lentigo maligna) fulfilled the selection criteria. Cases were digitally scanned using the 40× (0.23 μm/pixel) mode of a Hamamatsu NanoZoomer 2.0-HT Slide Scanner (Hamamatsu Photonics, Hamamatsu City, Japan), allowing for the creation of virtual (digital) slides. SC thicknesses and configuration were assessed for each case. Results: Mixed SC patterns were common in cases of lichenoid keratoses. Compact parakeratosis was the most common pattern in lichenoid drug eruption. Tiered parakeratosis was the most predominant pattern in cases of lichenoid graft versus host disease and lichenoid actinic keratosis. Hypertrophic lupus had the highest average SC thickness. Limitations: The sample size for cases of hypertrophic lupus and hypertrophic lichen planus was low. Conclusions: SC thickness and configuration can be utilized to help differentiate the lichenoid dermatoses.

https://ift.tt/2PqVSYD

Erythematous Nodule on the Face of a Child: Answer

No abstract available

https://ift.tt/2N4Xg1I

Role of Direct Immunofluorescence in Cutaneous Small-Vessel Vasculitis: Experience From a Tertiary Center

Abstract: Skin is commonly affected by vasculitic process and often subjected to biopsy. Cutaneous vasculitis can be either primary or part of a systemic vasculitic process. This study was conducted to evaluate the diagnostic utility of direct immunofluorescence (DIF) in determination of etiology of cutaneous vasculitis. All histologically proven cases of cutaneous vasculitis over the past two and half years were retrospectively analyzed along with their clinical and DIF findings (IgG, IgA, IgM, and C3). Within this study period, a total of 198 cases of small-vessel vasculitis were diagnosed based on skin biopsy and DIF findings. The mean age of patients was 31.2 years (range 1–84 years) with slight male dominance (M:F ratio 1.06:1). Henoch–Schonlein purpura/IgA vasculitis was the commonest clinical diagnosis (31%), followed by urticarial vasculitis (11%) and others. Idiopathic vasculitis was suspected in 33% cases. Overall, DIF was positive in 60% (119/198) cases, with vascular deposition of IgA being commonest, followed by C3. The clinical diagnosis of Henoch–Schonlein purpura could be confirmed in 61.5% (40/65) cases by DIF, whereas another 20 unsuspected cases were picked up as IgA vasculitis based on DIF findings. DIF findings confirmed lupus vasculitis in 50% cases. Other cases showed variable nonspecific deposition of C3 and IgM in 42% cases. DIF can be highly useful to classify cutaneous vasculitis, with maximum efficacy for diagnosis of IgA vasculitis and lupus vasculitis. It can aid in the accurate diagnosis even when the histological changes are minimal. All cases of suspected cutaneous vasculitis should be subjected to DIF.

https://ift.tt/2PqVlWD

Epidermal Calcinosis: A New Pattern

No abstract available

https://ift.tt/2N40faK

Practice of Teledermatopathology: A Systematic Review

Introduction: Teledermatopathology has the potential to revolutionize the practice of diagnosing skin diseases. This review provides an overview of the advantages, limitations, and future directions of teledermatopathology. Methods: MEDLINE was searched via PubMed and Google Scholar databases for relevant articles published from 2012 to the present. Additional articles were also identified by hand-searching. Results: A total of 2675 citations were identified in the initial search. Two thousand five hundred seventy-three were excluded based on duplicates and review of titles and abstracts. Eighty studies failed to meet the inclusion criteria, resulting in a total of 22 articles for analysis. Nine additional articles were hand-searched. Conclusions: Recent studies report that telepathology increases access to specialists, reduces interpretive errors and health care expenditures, improves the efficiency of workflow, and optimizes patient outcomes. It also facilitates international collaboration by widening global access to dermatopathology services and providing educational resources in underserved areas. However, the quality and regulations of digital slide imaging in teledermatopathology need to be improved.

https://ift.tt/2PqVKID

Unusual Case of Dactylitis With Nail Unit Involvement: Challenge

No abstract available

https://ift.tt/2N7DkLw

Unusual Neuroendocrine Differentiation in a Small Round Cell Angiosarcoma: A Potential Histologic Mimicker of Superficial Ewing Sarcoma

Abstract: Neuroendocrine differentiation or aberrant expression of neuroendocrine markers is very uncommon in angiosarcomas (AS) and creates a challenging differential diagnosis with other superficial or soft tissue tumors. Herein, we report a new case of superficial AS presenting as a tumor lesion on the little finger of the right hand of a 52-year-old man. The tumor displayed CD56, chromogranin-A, and synaptophysin immunoreactivity. Tumor cells were positive for vascular markers (CD31, FLI1, ERG, D2-40, VE-cadherin, VEGR1,2, and 3), CD99, and EMA, but were negative for S100, CK (AE1/AE3), CK20, polyomavirus, and myogenic (desmin and myogenin) and melanocyte markers (melan-A and HMB45). Ki67 immunostains indicated high proliferative activity (>50%). The whole-body computed tomography did not reveal distant disease. The initial assessment considered several tumor subtypes as possible histological diagnoses, including Ewing sarcoma, Ewing-like sarcoma, Merkel cell carcinoma, and undifferentiated "small round cell sarcoma". Fluorescence in situ hybridization analysis was negative for EWSR1 translocation and molecular analysis failed to detect any EWSR1, CIC, SYT or BCOR rearrangement. As a follow-up investigation, we tested 17 cutaneous/superficial AS for neuroendocrine markers; however, only one of these showed focal CD56 and synaptophysin expression. In conclusion, the present findings indicate that neuroendocrine differentiation is a very infrequent feature in AS. We report an AS of the finger with an uncommon histological appearance and immunohistochemical profile: predominant round cell tumor proliferation and neuroendocrine differentiation. Pathologists should be aware of these potential histological and immunohistochemical pitfalls in AS.

https://ift.tt/2PqVglN

Pilomatrixoma: A Comprehensive Review of the Literature

Introduction: Pilomatrixoma, also known as calcifying epithelioma of Malherbe, is a superficial benign skin tumor that arises from hair follicle matrix cells. Although pilomatrixomas are well-recognized lesions, clinically they are frequently misdiagnosed as other skin conditions. By reviewing all the literature over the past 10 years, the aims of this article are to analyze the cause, clinical presentation, management, and outcome of pilomatrixoma among children and adults to gain a more complete understanding of this lesion in today's clinical context. Methods: A MEDLINE and EMBASE search was conducted from January 2005 to February 2015 using a combination of the terms: "child," "childhood," "adult," and keywords: "pilomatrixoma," "pilomatricoma," and "calcifying epithelioma of Malherbe." A total of 150 articles were reviewed. Results: The lesions occurred most commonly in the first and second decades (mean age 16 years and 7 months). The commonest presentation was of an asymptomatic, firm, slowly growing, mobile nodule. Only 16% were accurately diagnosed on clinical examination. Imaging in the form of ultrasound, computed tomography, and magnetic resonance imaging has been reported. Pathological diagnosis was achieved through incision, punch, and shave biopsies. Pathological findings are discussed and summarized in this review. Conclusion: Pilomatrixomas are thought to arise from mutation in the Wnt pathway and has been linked to several genetic conditions. It is commonly misdiagnosed preoperatively; however, with better awareness of the lesion, it can be appropriately treated while avoiding unnecessary diagnostic tests. Complete surgical excision with clear margins is almost always curative.

https://ift.tt/2N4LmVo

T-Lymphoblastic Leukemia/Lymphoma With Annular Skin Rash and Epidermotropism

Abstract: Leukemia cutis is uncommon in patients with acute lymphoblastic leukemia. It typically presents with dermal papules or subcutaneous nodules, with no epidermal or upper papillary dermal involvement on histopathology. We present an unusual clinical presentation of leukemia cutis, with annular plaques and epidermotropism.

https://ift.tt/2PqVCZF

An Unusual Case of Dactylitis With Nail Unit Involvement: Answer

No abstract available

https://ift.tt/2N7D9jk

A Case of a Malignant Cutaneous Mixed Tumor (Chondroid Syringoma) of the Scapula Treated With Staged Margin-Controlled Excision

Abstract: Cutaneous mixed tumor (chondroid syringoma) is the cutaneous counterpart of pleomorphic adenoma of salivary glands, comprised of both epithelial and mesenchymal components. Malignant transformation is exceptionally rare, with only a few cases reported. We report a case of a malignant cutaneous mixed tumor in an 86-year-old white man who presented with a pink indurated plaque on his left scapula. He had a history of nonmelanoma skin cancers, a stage IB malignant melanoma of a lower extremity and Gleason 4 + 3 prostate cancer treated with brachytherapy, external beam irradiation, and bicalutamide. A shave biopsy was performed and histologic examination revealed infiltrative single-unit atypical cells and small ducts in a superficially transected sclerotic dermis suggestive of a poorly differentiated adenocarcinoma. No epidermal connection was identified. Immunohistochemical studies revealed that the tumor was positive for CK7, CAM5.2, and mCEA and negative for CK20, epithelial membrane antigen, P63, prostate-specific antigen, prostatic specific acid phosphatase, and alpha-methylacyl-coenzyme A racemase. A metastasis of the breast or upper digestive tract was favored, although a primary eccrine carcinoma was also considered. Imaging was performed and no other masses were identified. A slow Mohs excision was performed with negative margins. Microscopic examination revealed a biphasic neoplasm comprised of infiltrative epithelial strands and tubules consistent with an eccrine carcinoma in a hyalinized and chondromyxoid stroma within the dermis, arising from a well-circumscribed chondroid syringoma located in the deep dermis and subcutis. Areas of clear cell change, intracytoplasmic vacuolization, and mucin pools were noted. Multiple foci of perineural invasion were identified. Additional immunohistochemical studies revealed that the tumor was positive for S100 and negative for CK5/6, calponin, glial fibrillary acidic protein, GATA3, GCDFP-15, and mammoglobin. Based on the morphologic features and immunoprofile, this was diagnosed as a malignant cutaneous mixed tumor. This case highlights the importance of obtaining adequate tissue for histologic evaluation, as they can be confused with other skin neoplasms because of their clinically ambiguous presentations. Although rare, an accurate diagnosis is important given that long-term follow-up is recommended because of the risk of local recurrence and both lymph node and distant metastases.

https://ift.tt/2PqV4TB

An Unusual Vesiculopustular Eruption: Answer

No abstract available

https://ift.tt/2N40enc

Livedoid Vasculopathy Presenting in a Patient With Sickle Cell Disease

Abstract: We report a case in which a 43-year-old African American male with medical history of sickle cell disease (SCD) presented with a nonhealing ulcer. Biopsy revealed features of livedoid vasculopathy. Previously, livedoid vasculopathy had only been described in a patient with sickle cell trait, but never in a patient with SCD. Livedoid vasculopathy most commonly affects the distal lower extremities and is characterized by irregular, punched-out, painful ulcers that heal with stellate white scars of atrophie blanche. Histologically, it reveals segmental hyalinizing vessels, focal thrombosis, and endothelial proliferation. The etiology is currently unclear, but it has been shown to be related to procoagulant states and a diagnosis of livedoid vasculopathy should prompt a thorough hypercoagulable workup, including testing for SCD in high-risk patients.

https://ift.tt/2PqUTHV

Cutaneous Metastases of Melanoma Mimicking Interstitial Granulomatous Processes

No abstract available

https://ift.tt/2N0CwIm

Rare Variant of Agminated Spitz Nevi on a Hypopigmented Background and Segmental Distribution: Case Report and Review of Literature

Abstract: Spitz nevus is a type of melanocytic nevus that can arise as a solitary lesion or as multiple lesions either disseminated or agminated (grouped) in different skin backgrounds (eg, grossly normal, hyperpigmented, or hypopigmented). Agminated Spitz nevi have been rarely reported and are even rarer in a background of hypopigmented skin. We present the case of a 2-month-old girl with multiple, grouped, dome-shaped, red papules arising on a hypopigmented patch with a segmental distribution. Biopsy of 2 lesions showed findings characteristic of Spitz nevus, confirming the diagnosis. We also review 4 other cases of agminated Spitz nevi arising on hypopigmented skin reported in the literature.

https://ift.tt/2Po2VBw

Serum antibodies against the insulin-like growth factor-1 receptor (IGF-1R) in Graves’ disease and Graves’ orbitopathy

Abstract

Background

A role of the insulin-like growth factor-1 receptor (IGF-1R) in the pathogenesis of Graves' orbitopathy (GO) has been proposed, but the existence and function of anti-IGF-1R-antibodies (IGF-1R-Abs) are debated.

Methods

We designed a cross-sectional investigation to measure serum IGF-1R-Abs by a commercial assay in consecutive patients with Graves' disease (GD) compared with healthy subjects and patients with autoimmune thyroiditis (AT). A total of 134 subjects were screened including 27 healthy subjects, 80 GD patients (54 of whom with GO), and 27 AT patients. The main outcome measure was the prevalence of positive serum IGF-1R-Abs in GO, compared with GD without GO and with the other study groups.

Results

Having established a cut-off value at 55.2 ng/ml for positive tests, positive IGF-1R-Abs were more frequent in GD (25%), than in AT (3.7%, P = 0.003) and healthy subjects (0%, P = 0.006). Within GD, there was no difference between patients with or without GO. Serum levels of IGF-1R-Abs differed across the study population (P < 0.0001), reflecting their higher concentrations in GD (P < 0.0001 vs both AT and healthy subjects), but with no difference between patients with or without GO. In patients with GO, there was an inverse correlation between serum IGF-1R-Abs and CAS (R = − 0.376, 95% CI: from − 0.373 to − 0.631; P = 0.005), the significance of which remains to be investigated.

Conclusions

Serum autoantibodies against the IFG-1R are present in one-fourth of GD patients, regardless of the presence of GO. Further functional studies are needed to investigate the significance of their inverse correlation with GO activity.

https://ift.tt/2nUEHT5

Hypermucoviscous Klebsiella pneumoniae liver abscess requiring liver resection

Description 

A 41-year-old healthy woman from China presented to her local hospital with a 4-day history of fevers, malaise and epigastric pain. On examination, she had localised right upper quadrant abdominal pain on palpation. Laboratory investigations showed leukocytosis (13.8x10⁹/L), thrombocytopaenia (82x10⁹/L) and elevated alanine transaminase (184 U/L). An abdominal CT scan revealed a 10x8x9 cm multiloculated collection within the right liver lobe, with a second nodular septated collection under the left subcapsular region (figure 1). Her blood cultures returned positive for Klebsiella pneumoniae, resistant to ampicillin and susceptible to cefazolin, ciprofloxacin and meropenem. She was admitted to hospital and started on ceftriaxone.

Figure 1

Abdominal CT showing large multiloculated liver abscesses in segments 2/3 of the left liver lobe (white arrow) and segments 6/7 of the right liver lobe (black arrow).

Diagnostic and therapeutic ultrasound-guided 10F drains were inserted into both abscesses...

https://ift.tt/2LcHnnZ

Paediatric parapharyngeal ganglioneuroma

A 17-year-old man initially presented to his primary care physician with throat pain for 1 week and was started on amoxicillin. After four additional days of ongoing pain and difficulty swallowing with decreased oral intake, he presented to the emergency department. Exam showed fullness to the right posterior oropharynx and palpable mass in the right neck without stridor. Initial imaging was soft tissue neck CT with contrast, which showed cystic 8 cm mass in the parapharyngeal space. Patient additionally underwent MRI, which showed an 8.6 cm mass in the right posterior oropharynx with obliteration of the vallecula. Differential diagnosis included abscess; therefore, ear, nose, and throat (ENT) specialist was consulted for possible drainage. Intraoperatively, there was no abscess; alternatively a biopsy was obtained, which was identified by pathology as a ganglioneuroma. Patient was referred to paediatric ENT specialist, underwent extensive resection confirming diagnosis of ganglioneuroma and did well postoperatively.

https://ift.tt/2Plm0Em

Euglycaemic diabetic ketoacidosis in bariatric surgery patients with type 2 diabetes taking canagliflozin

A 52-year-old type 2 diabetic man previously on canagliflozin developed severe anion gap metabolic acidosis and markedly elevated beta-hydroxybutyrate on postoperative day (POD) 2 status post laparoscopic Roux-en-Y gastric bypass. An insulin drip and aggressive intravenous fluid repletion were initiated, and electrolytes were monitored and repleted. His anion gap closed, and he was discharged on POD 4. This euglycaemic diabetic ketoacidosis prolonged his hospital stay by 2 days.

https://ift.tt/2LdKrQM

Bowel perforation in chronic idiopathic megarectum and megacolon

Description 

A 24-year-old man with autism spectrum disorder presented to accident and emergency complaining of a 1-week history of abdominal pain and diarrhoea. He had a history of chronic constipation with multiple previous admissions stretching 4 years back. On examination, he had a tender, distended abdomen with quiet bowel sounds. His CT scan on admission (figure 1) showed a dilated (up to 18 cm) rectum and sigmoid colon filled with faeces. The patient was managed conservatively with oral laxatives and regular enemas. However, the patient refused the enemas and was maintained on oral laxatives. Two days later, the patient complained of worsening abdominal pain. On examination, he had a peritonitic abdomen and reduced consciousness level. Biochemical investigations revealed worsening renal function and that the patient was now acidotic. A chest X-ray revealed free air beneath the diaphragm. A repeat CT scan (figures 2 and 3

https://ift.tt/2nThDUr

Asymptomatic dysphagia causing recurrent aspiration pneumonia

52-year-old male patient with known bipolar disorder and innate cerebral palsy causing widespread spasticity problems. Treated for 2 years with antidepressants and electroconvulsive therapy. He repeatedly presented with—and was treated for—pneumonia resulting in more than 20 episodes of hospital admission. He underwent numerous examinations until a diagnosis of dysphagia was established using video fluoroscopic swallowing examination (modified barium swallow). Eventually, as all other treatment regimens had proven effortless, percutaneous gastrostomy feeding tube was inserted and intensive training with a specialised occupational therapist was started. This treatment regimen caused the recurrent episodes of pneumonia to vanish. It is important to acknowledge that otherwise silent dysphagia may cause recurrent pneumonia.

https://ift.tt/2N2rdPP

Trisomy 5 as the sole chromosomal anomaly in acute lymphoblastic leukaemia

Trisomy 5 as the sole cytogenetic aberration in acute lymphoblastic leukaemia (ALL) is exceedingly rare. As such, its prognostic and therapeutic relevance remains unknown. We report a case of an 18-year-old young man who was diagnosed with B cell ALL with trisomy 5 as the sole chromosomal abnormality. He was treated with chemotherapy and went into complete remission. On the 14th month of treatment, he relapsed with central nervous system involvement characterised by leukaemic infiltration of the optic nerve and facial palsy. He subsequently underwent reinduction chemotherapy with aggressive intrathecal chemotherapy followed by posterior globe and whole brain radiation therapy. He is currently on his 26th month of treatment, in second remission, with complete resolution of leukaemic infiltrative optic neuropathy and facial paralysis. As more cases of this nature are reported, we will be able to determine the relevance of this distinct cytogenetic entity.

https://ift.tt/2nU9E9L

Colobronchial fistula: a rare cause of non-resolving pneumonia in Crohns disease

We discuss the case of a 44-year-old man with a refractory left lower lobe pneumonia progressing to a pulmonary abscess caused by a colobronchial fistula, a rare complication of underlying Crohn's disease. The patient presented with weight loss and signs of a pulmonary consolidation, which responded incompletely to the targeted antibiotic treatment. The causative colobronchial fistula was demonstrated by CT-guided puncture and retrograde injection of contrast medium. After fistula excision, the patient recovered rapidly with a weight gain of 4 kg within a few weeks.

https://ift.tt/2N7JpI9

Charcot osteoarthropathy of the knee secondary to neurosyphilis: a rare condition managed by a challenging arthrodesis

The Charcot joint or neuropathic osteoarthropathy was first described as an arthritic sequela of neurosyphilis (tabes dorsalis). It results in significant joint destruction and instability. Nowadays, it is a very rare condition and represents a considerable challenge to the orthopaedic surgeon. The authors describe the case of a patient diagnosed with neurosyphilis who was requested an orthopaedic consultation for an enlarged and unstable knee. The diagnosis of Charcot knee was made and based on the clinical and radiographical findings combined with the patient's medical history. Knee arthrodesis was the surgical treatment chosen to preserve the limb and only succeeded at second attempt. At 4 years of follow-up, it proved to be an effective surgical treatment. In this article, we focus on the importance of early recognition of joint changes in these patients in order to prevent irreversible joint loss.

https://ift.tt/2PrISC7

Quadruple torsion of the fallopian tube in an 18-year-old virgin: a rare twist

In this report, we describe an 18-year-old nulliparous virgo, with no medical history, who presented herself at the emergency department with symptoms of lower abdominal pain and nausea with vomiting. On examination, an echogenic unilocular cyst with possible relation to the right ovary was found. The working diagnosis was an ovarian torsion. She underwent a diagnostic laparoscopy which revealed a quadruple torsion of the fallopian tube with hydrosalpinx. Detorsion of the tube was performed, and the tube was drained using diathermic incision. After the surgery, the patient recovered rapidly. Ultrasonic evaluation 38 days later showed an echogenic area measuring 2x3 cm suspected for persistent hydrosalpinx. Because of the asymptomatic postoperative period, the patient was treated conservatively, and no further treatment was performed.

https://ift.tt/2Lb9Z1a

Non-cutaneous AIDS-associated Kaposis sarcoma presenting as recurrent rectal abscesses

Kaposi's sarcoma is a fatal disease that typically presents with cutaneous manifestations in immunocompromised individuals. There are a small number of documented cases where patients diagnosed with this disease present without cutaneous lesions. We present a 35-year-old man with recurrent rectal abscesses and fistula-in-ano, which required multiple drainage procedures. Further investigation revealed a diagnosis of HIV-AIDS, and biopsy of a rectal mass confirmed the diagnosis of visceral Kaposi's sarcoma, despite the absence of cutaneous involvement. Workup revealed hepatic metastasis and a second pulmonary primary malignancy. The patient denied chemotherapy or further intervention and was subsequently lost to follow-up. Prompt diagnosis of Kaposi's sarcoma and initiation of treatment is vital to decrease disease progression. A high index of suspicion should be present in immunocompromised patients, and clinicians must recognise atypical presentations in order to improve long-term survival.

https://ift.tt/2Pou0Vf

Primary amelanotic malignant melanoma of cervix masquerading as squamous cell carcinoma presenting with extensive metastases

Amelanotic melanoma of cervix is a rare and aggressive neoplasm and only few cases have been reported in the literature. We report a rare case of an amelanotic melanoma of the uterine cervix with extensive metastases and multiple subcutaneous nodules. Due to the unusual site and amelanotic nature of the lesion, chances of misdiagnosis are high and immunohistochemical markers for melanoma help establish the diagnosis. The possibility of metastasis from a primary malignant melanoma of the skin needs to be ruled out. The present case was initially misdiagnosed and treated on the regimen for squamous cell carcinoma, but progressed despite chemotherapy. After a thorough re-evaluation and applying extensive panel of immunohistochemistry, the diagnosis of an amelanotic malignant melanoma of uterine cervix was established.

https://ift.tt/2LcF5oT

Internal iliac artery transposition for vascular reconstruction in a patient with life-threatening iatrogenic common iliac artery injury

Major vascular injury during surgery is life threatening and can be a nightmare for any surgeon.

We share our experience of a 42-year-old woman where right common iliac artery and both common iliac veins were accidentally injured during lumbar discectomy leading to haemorrhagic shock. Patient was resuscitated and explored. A 4 cm segment of right common iliac artery was found lacerated along with perforations of both iliac veins. Proximal segment of internal iliac artery was mobilised quickly and vascular continuity was restored by end-to-end anastomosis of this segment to the proximal segment of common iliac artery after excising the damaged segment. Iliac veins were repaired primarily. Patient made an uneventful recovery. We share this technique as it was found expeditious and effective and may benefit surgeons working in this field.

https://ift.tt/2nWh4tk

Fever in a returning traveller: visceral leishmaniasis triggering haemophagocytic lymphohistiocytosis

We present the case of a 23-year-old student admitted with fever, night sweats and splenomegaly. These non-specific signs and symptoms posed a diagnostic challenge which was further complicated by a history of recent foreign travel. The range of potential diagnoses required a variety of investigations in order to reach the final diagnosis. The incidental finding of an incompetent bicuspid aortic valve and an inflamed gallbladder further clouded the diagnostic process. Despite treatment with broad spectrum antibiotics, the patient continued to deteriorate. Serological testing finally provided a diagnosis of visceral leishmaniasis. The patient subsequently developed haemophagocytic lymphohistiocytosis, a life-threatening immune hyperactivity state that very rarely complicates leishmaniasis infection. With the use of amphotericin B and high-dose steroids, the patient made an excellent recovery.

https://ift.tt/2N7NpYP

Progressive supranuclear palsy responding to intravenous thiamine: superimposed Wernickes encephalopathy?

Progressive supranuclear palsy (PSP) may be a risk factor for thiamine deficiency. The classic symptoms of PSP (postural instability, supranuclear vertical gaze palsy and dementia) overlap with the clinical triad of Wernicke's encephalopathy (cognitive impairment, gait problems and ocular abnormality). Therefore, superimposed thiamine deficiency in patients with PSP may aggravate the pre-existing symptoms of PSP. Here, we are reporting a 64-year-old woman having supranuclear ocular palsy, gait instability and dementia for the past 2–3 years. The patient fulfilled the diagnostic criteria of PSP. In parallel, she fulfilled the Caine's criteria of Wernicke's encephalopathy. Her serum thiamine level was low. Supplementation of thiamine led to marked improvement in the symptoms which had been present for many years. These symptoms were originally presumed to be due to PSP. This case highlights the needs to identify superimposed thiamine deficiency in patients with PSP.

https://ift.tt/2Prldlq

Multiple renal calculi due to hypercalcaemia induced by over-the-counter vitamin D intoxication

Renal stone disease is a common and painful condition. Even though it is rarely fatal, patients describe it as the worst pain in their life. While dietary calcium may decrease the risk of stone formation, patients on supplemental calcium are at higher risk. Moreover, patients with diabetes are more prone to develop renal calculi. Hypervitaminosis D is a rare cause of hypercalcaemia. This is a case of an elderly diabetic man who developed multiple calcium oxalate renal stones due to hypercalcaemia following calcium–vitamin D supplementation.

https://ift.tt/2N7MYh9

Misplaced Foley catheter in ureter in a female with neurogenic bladder: a rare complication report

Accidental placement of Foley catheter in ureter is a rare phenomenon. It is more common in females with neurogenic bladder who have hypocontractile bladder or there can be iatrogenic placement during surgical procedures. We describe a case of a female suffering from upper motor neuronal lesion due to trauma at T8 level (American Spinal Injury grade A) following which she developed neurogenic bladder. A Foley catheter was unintentionally placed in the ureter and subsequently removed through a novel technique of percutaneous ultrasound-guided balloon puncture. It is not only imperative to diagnose and manage such an aberrant Foley catheter placement but also more importantly proper steps must be taken to prevent such a complication from occurring in these patients.

https://ift.tt/2N5HHH2

Mediastinal metastasectomy from a primary germ cell testicular tumour resulting in occult thoracic duct injury and chylothorax

A 22-year-old man underwent mediastinal metastasectomy for a testicular germ cell tumour via median sternotomy. Intraoperatively, the tumour was massive, measuring 88 mm in anterior-posterior (AP) diameter. It was densely adherent to the trachea and aggressive debulking resulted in tracheal injury. Therefore, the patient was kept nil by mouth for 3 days postoperatively and was discharged uneventfully. He represented only 2 days later with a large right-sided chylothorax. His chylothorax was managed conservatively with insertion of an intercostal catheter (ICC) and a low-fat diet. Over the course of 9 days, the ICC drained approximately 5 L of fluid. His admission was further complicated by severe gastroparesis requiring feeding Nasojejunal (NJ) tube placement. The delayed feeding in this case resulted in late detection of the occult thoracic duct injury. This case illustrates that conservative and multidisciplinary management of a postoperative chylothorax from a suspected thoracic duct injury achieves favourable outcomes avoiding further surgical intervention.

https://ift.tt/2nTkAof

Malignant proliferating trichilemmal tumour

Proliferating trichilemmal tumours are benign but locally aggressive skin neoplasms arising from hair follicles. Rarely, they can become malignant and must be appropriately managed to prevent recurrence and metastasis. One must have a low threshold for diagnosing this rare neoplasm.

https://ift.tt/2N5HjIA

Tracking a painful episode after a joint replacement using patient-reported outcome measures (PROMs)

Patient-reported outcome measures (PROMs) are an important tool in measuring the benefit of a surgery for patients and for clinicians. The results of such assessment tools can be used to monitor patient progress or initiate intervention. The scores also provide a reproducible evaluation of functional recovery and well-being after surgery. We report the case of a 68-year-old woman who underwent left unicondylar knee replacement in November 2011 followed by right unicondylar knee replacement in April 2012. Prospective, web-based electronic PROMs were used preoperatively and every 6–12 months postoperatively to monitor the improvement in pain and function symptoms. These outcome measures were beneficial in helping to monitor an episode of new pain in her left knee, without requiring invasive or extensive investigation.

https://ift.tt/2PnEUdI

Delirium and topographical disorientation associated with glioblastoma multiforme tumour progression into the isthmus of the cingulate gyrus

Since there is no cure for glioblastoma multiforme (GBM), the goal of treatment becomes prolonging the survival through cytoreduction while minimising neurological deficits. In this case report, laser interstitial thermal therapy (LITT) was used once the tumour progressed into the isthmus of the cingulate gyrus. One year after temporal lobectomy, disorders of memory, emotion, personality and navigation, likely related to limbic system involvement along with hallucinations and fluctuating cognition occurred as the tumour progressed. After ablation of the posterior cingulum, worsening of topographical disorientation was observed.

Per literature review, delirium has been noted in patients with strokes involving the right-sided temporo-parieto-occipital junction, and topographical disorientation has been associated with lesions of the right posterior cingulum. Alternative causes of these deficits were ruled out, leaving structural changes as the primary explanation. This is the first report of the neurological deficits associated with tumour progression and vasogenic oedema in this region.

https://ift.tt/2LbvnDa

CD200 expression is a feature of solid pseudopapillary neoplasms of the pancreas

Abstract

CD200 has been recently indicated as a robust marker of well-differentiated neuroendocrine neoplasms. Here, we evaluate its role in differential diagnosis of solid pancreatic neoplasms. We immunostained for CD200 22 solid pseudopapillary neoplasms (SPNs), 8 acinar carcinomas (ACs), 2 pancreatoblastomas (PBs), 138 neuroendocrine tumors (PanNETs), and 48 ductal adenocarcinomas. All SPNs showed strong cytoplasmic and membranous staining for CD200, while only one case of AC had focal positivity. The two PBs showed focal CD200 positivity, mainly located in squamoid nests. The vast majority of PanNETs (96%) showed strong cytoplasmic and membranous staining for CD200, whereas all PDACs were negative. As both PanNETs and SPNs express CD200, it has no role in the differential diagnosis between these two entities.

https://ift.tt/2whGQvF

Dupilumab improves symptoms, quality of life, and productivity in uncontrolled persistent asthma

Publication date: Available online 21 August 2018

Source: Annals of Allergy, Asthma & Immunology

Author(s): Jonathan Corren, Mario Castro, Pascal Chanez, Leonardo Fabbri, Vijay N. Joish, Nikhil Amin, Neil M.H. Graham, Vera Mastey, Adeline Abbé, Christine Taniou, Puneet Mahajan, Ariel Teper, Gianluca Pirozzi, Laurent Eckert

https://ift.tt/2MqK6Qt

Differences in airway structural changes assessed by three-dimensional computed tomography in asthma and asthma-COPD overlap

Publication date: Available online 21 August 2018

Source: Annals of Allergy, Asthma & Immunology

Author(s): Mitsuru Niwa, Tomoyuki Fujisawa, Masato Karayama, Kazuki Furuhashi, Kazutaka Mori, Dai Hashimoto, Hideki Yasui, Yuzo Suzuki, Hironao Hozumi, Noriyuki Enomoto, Yutaro Nakamura, Naoki Inui, Takafumi Suda

Abstract

Background: Asthma- COPD overlap (ACO) is a clinical phenotype sharing features of asthma and COPD. Multidetector row computed tomography (MDCT) can be used to evaluate the airway structure; however, differences between asthma and ACO seen on MDCT are poorly understood.

Objective: To investigate the difference in airway structural between asthma and ACO using MDCT in patients with clinical asthma.

Methods:Sixty-four patients with asthma were allocated to an asthma group (neversmokers and ex-smokers with a smoking history of <10 pack-years) or an ACO group (patients with a ≥10-pack-year smoking history and FEV1/ FVC <0.7). The asthma group was further divided into patients with airflow limitation (AL; FEV1/FVC <0.7) and those without AL. Wall thickness (WT) and airway inner luminal area in the third-generation to fifth-generation bronchi were evaluated using MDCT in both study groups and in 29 healthy controls.

Results: There were 43 patients in the asthma group (20 with AL, 23 without AL) and 16 in the ACO group. Patients with asthma and ACO had significantly greater WT than the healthy controls. WT in the third-generation bronchi was significantly greater in the ACO group than in the asthma group. The ACO group and the asthma with AL group were matched for age, disease duration, FEV1/FVC. WT in the third-generation bronchi was still greater in the ACO group than in the asthma with AL group.

Conclusion: Patients with ACO have a thicker airway wall than those with asthma, suggesting that airway remodeling is more prominent in ACO than in asthma.

https://ift.tt/2wkUfDs

Unintentional injection to the bone with a pediatric epinephrine auto-injector

Skin-to-bone distance (STBD) in children prescribed a pediatric epinephrine auto-injector (EAI) for anaphylaxis is not commonly measured in practice. Recent evidence suggests that children with STBD less than ...

https://ift.tt/2BuI3pl

Effects of compost containing oxytetracycline on enzyme activities and microbial communities in maize rhizosphere soil

Abstract

Veterinary antibiotics can enter agricultural fields via the application of livestock manure containing antibiotics. However, the response of soil microorganisms to compost containing antibiotics is not well understood. A 120-day pot experiment was conducted to investigate the impact of compost containing oxytetracycline (OTC) on the enzyme activities and microbial communities in maize rhizosphere soil. Swine manure was artificially spiked with OTC at four concentrations, 35, 70, 105, and 140 mg kg⁻¹, and combined with straw to produce compost. The compost products were applied to soil planted with maize. Rhizosphere soil samples were collected on days 1, 15, 30, 60, and 120. The results indicated that the urease activities first increased and then declined, while in contrast, the alkaline phosphatase activities first decreased and then increased slightly. Catalase exhibited dose-related activation during the maize growth period. At the end of the experiment, the soil enzyme activities were similar to their initial values, indicating that the soil enzymes showed a level of recovery. The carbon metabolic activity levels were higher in the soils with high OTC concentrations than in the control, whereas the Shannon diversity index was higher in the control soil. The results of principal component analysis (PCA) indicated that the application of compost containing OTC shifted the structure of the soil microbial community and negatively affected its stability. These results suggest that the compost containing OTC exerted selective pressure on enzyme activities and microbial communities in maize rhizosphere soil and decreased their resilience to antibiotic pollution.

https://ift.tt/2vX1OAu

Bullous erythroderma: novel association of pityriasis rubra pilaris with bullous pemphigoid

Clinical and Experimental Dermatology, EarlyView.


https://ift.tt/2MsYAPK

Bullous erythroderma: novel association of pityriasis rubra pilaris with bullous pemphigoid

Clinical and Experimental Dermatology, EarlyView.


https://ift.tt/2MsYAPK

Exceptional mucocutaneous manifestations with amyloid nephropathy: a case report

Amyloidosis is a very rare disease that is difficult to diagnose because of the unspecific early clinical manifestations of the disease. Accurate and early diagnosis is extremely important because the effect o...

https://ift.tt/2BuZia6

Neural therapy of an athlete’s chronic plantar fasciitis: a case report and review of the literature

The focus of this case report is on the role of inflammation as a contributor to pain in plantar fasciitis and its cure by the injection of local anesthetics.

https://ift.tt/2MGLRbe

Conventional cardiopulmonary resuscitation-induced refractory cardiac arrest due to latent left ventricular outflow tract obstruction due to a sigmoid septum: a case report

Patients with left ventricular outflow tract obstruction who do not exhibit a dynamic pressure gradient at rest, experience pressure gradient increases of ≥ 30 mmHg only during specific situations; this is cal...

https://ift.tt/2BwHyes

The challenges of treating tracheobronchitis in a laryngectomee due to nontypeable Haemophilus influenzae: a case report

Laryngectomees run the risk of developing severe respiratory tract infections especially during the winter and when they do not wear a stoma cover. A case of severe tracheobronchitis in a laryngectomee is pres...

https://ift.tt/2PqblbG

The potential for constructed wetland mechanisms to treat alkaline bauxite residue leachate: carbonation and precipitate characterisation

Abstract

Leachates emanating from bauxite residue disposal areas are alkaline and require neutralisation prior to discharge. The use of passive technologies such as constructed wetlands has received increasing interest as possible treatments for alkaline leachates, including bauxite residues. Mechanisms proposed for wetland effectiveness have included calcite precipitation but it is not clear if such a pathway is feasible in the relatively low Ca residue leachates. Carbonation of Ca-spiked residue leachate treatments was conducted to observe rates of pH decrease and precipitate formation. For all treatments, carbonation effectively decreased pH to ca. 10.5 which remained stable following aeration. Decreases in Al content of 83–93% were also observed. Precipitates retrieved from carbonation experiments and from a constructed wetland trial were characterised using XRD, SEM, XPS and EDX. Calcium carbonates formed in Ca-spiked treatments and dawsonite precipitation occur in the absence of Ca. Rinsing of precipitates removes surface calcium indicating soluble forms adsorbed on precipitates. The results demonstrate that carbonation of bauxite residue leachate is an important component of passive treatments and neutralisation.

https://ift.tt/2OUyySh

Identification of a novel de novo gain-of-function mutation of PIK3CD in a patient with activated phosphoinositide 3-kinase δ syndrome

Publication date: Available online 20 August 2018

Source: Clinical Immunology

Author(s): Ying Luo, Yu Xia, Wenjing Wang, Zhichuan Li, Yan Jin, Yifeng Gong, Tingyan He, Qiu Li, Chengrong Li, Jun Yang

Abstract

Activated phosphoinositide 3-kinase δ (PI3Kδ) syndrome is a newly defined and relatively common primary immunodeficiency, which is caused by heterozygous gain-of-function (GOF) mutations in PIK3CD or PIK3R1. Here, we report a novel de novo GOF mutation (c.1570 T > A, p.Y524N) in PIK3CD in a 6-year-old Chinese girl. The patient suffered recurrent sinopulmonary infection, bronchiectasis, lymphoproliferation, herpesvirus infection, and distinctive nodular lymphoid hyperplasia of mucosal surfaces. Immunological analysis revealed increased CD4+ T cell senescence and B cell immaturity. Further analysis revealed an increase in almost all CD4+ T cell subsets to varying degrees, including effector T cells and Treg cells. Increased levels of plasma T cell-related cytokines corroborated these results. Hyperactivation of the PI3Kδ-Akt-mTOR signaling pathway was also confirmed. Treatment with rapamycin ameliorated the lymphoproliferative immunodeficiency caused by hyperactivation of mTOR. These results expand genetic spectrum of APDS and will facilitate further study of the genotype-phenotype correlation in those with PIK3CD mutations.

https://ift.tt/2w1b0UH

A Phase III Study to Compare the Efficacy and Safety of Paclitaxel Versus Irinotecan in Patients with Metastatic or Recurrent Gastric Cancer Who Failed in First‐line Therapy (KCSG ST10‐01)

AbstractLessons Learned. Irinotecan could not be proven noninferior to paclitaxel as a second‐line treatment for patients with metastatic or recurrent gastric cancer.The failure to demonstrate noninferiority may have been a result of insufficient patient enrollment.Both agents were tolerable but showed different toxicity profiles.Background.This phase III study compared the efficacy and safety of paclitaxel versus irinotecan in patients with metastatic or recurrent gastric cancer (MRGC) who had experienced disease progression following first‐line chemotherapy.Methods.Patients were randomized to receive either paclitaxel (70 mg/m2; days 1, 8, 15, every 4 weeks) or irinotecan (150 mg/m2 every other week). The primary endpoint was progression‐free survival (PFS).Results.This study was stopped early due to low accrual rate. A total of 112 patients were enrolled; 54 were allocated to paclitaxel and 58 to irinotecan. Median PFS for the paclitaxel and irinotecan groups was 3.5 and 2.1 months, respectively (hazard ratio [HR], 1.27; 95% confidence interval [CI], 0.86–1.88; p = .234). Noninferiority of irinotecan to paclitaxel was not proved because the upper boundary of the 95% CI (1.88) exceeded the predefined upper margin of noninferiority (1.32). Median overall survival (OS) was 8.6 months in the paclitaxel group and 7.0 months in the irinotecan group (HR, 1.39; 95% CI, 0.91–2.11; p = .126). Among toxicities greater than or equal to grade 3, neutropenia (11.5%) was the most common, followed by peripheral neuropathy (7.7%) in the paclitaxel group, and neutropenia (34.5%) followed by nausea, vomiting, and anemia (8.6%, respectively) in the irinotecan group.Conclusion.Although paclitaxel showed numerically longer PFS and OS compared with irinotecan, this was statistically insignificant. Both irinotecan and paclitaxel are valid second‐line treatment options in MRGC.

https://ift.tt/2PmxR5j

Clinicopathological and Molecular Characterization of Metastatic Gastrointestinal Stromal Tumors with Prolonged Benefit to Frontline Imatinib

AbstractBackground.Oncogenic KIT/PDGFRA signaling inhibition with imatinib achieves disease control in most patients with advanced/metastatic gastrointestinal stromal tumor (GIST), but resistance eventually develops after 20–24 months. Notably, a small subset of these patients obtain durable benefit from imatinib therapy.Methods.We analyzed clinical, pathological, and molecular characteristics and long‐term outcomes in patients with metastatic GIST treated with continuous daily dosing of frontline imatinib in a cohort of patients benefiting for ≥5 years. A control group was obtained from the national Spanish Group for Sarcoma Research database and used as comparator.Results.Sixty‐four imatinib long‐term responders (LTRs) and 70 control cases were identified. Compared with controls, LTRs at baseline had better performance status (PS) 0–1 (100% vs. 81%), lower mitotic count (median, 8 vs. 15), and tumor burden (number of metastases, 3 vs. 7). KIT exon 11 was the only region found mutated in LTRs. LTRs achieved 34% complete responses and a median progression‐free survival of 11 years, compared with 4% and 2 years, respectively, in the control cohort. Prognostic factors that independently predicted long‐term benefit with imatinib were PS, number of metastases prior to imatinib, and response to imatinib. Fifteen LTR patients developed new side effects attributable to imatinib after ≥5 years of continuous treatment. No resistance mutations were found in metastatic samples from three patients progressing on imatinib.Conclusion.GISTs in LTRs are a distinctive entity with less aggressive behavior and marked sensitivity to KIT inhibition. Patients reaching 5 or more years on imatinib have a higher chance of remaining progression free over time.Implications for Practice.This work demonstrates that clinical and inherent tumor characteristics define a subset of patients with gastrointestinal stromal tumor (GIST) with increased likelihood to achieve durable response to first‐line imatinib therapy. Patients reaching ≥5 years on imatinib have a greater chance of remaining progression free over time, although the disease is unlikely to be cured. Imatinib is well tolerated for >5 years, and emergent toxicities are overall manageable. Resistance to imatinib emerging in patients with GISTs after long‐term imatinib treatment does not involve polyclonal expansion of KIT secondary mutations.

https://ift.tt/2N4bDDz

Alerta Rosa: Novel Alert and Navigation Breast Cancer Program in Nuevo Leon, Mexico, for Reducing Health System Interval Delays

AbstractBackground.In Mexico, the median time between breast cancer (BC) symptom detection and treatment initiation is approximately 7 months. Alerta Rosa is a program that was developed with the intent of breaking down medical care barriers and reduce delays.Patients and Methods.Through several media campaigns, we reached out to patients with breast symptoms or abnormal imaging studies. Patients contacted our call center or Facebook page. A navigator recorded their main complaint and scheduled a medical consultation with a specialist. We prioritized patients according to clinical risk. Those diagnosed with BC were referred to their health affiliation unit for care.Results.To date, 656 patients have contacted our program. Median age was 44 years (range, 7–82). Patients reported becoming aware of Alerta Rosa mainly by word of mouth and TV. A total of 446 medical consultations were scheduled, and 309 patients attended their appointments. A biopsy procedure was solicited for 39 patients, and 22 were diagnosed with BC. Most patients had stage II (45%) or stage III (32%) disease. The median time from alert activation to treatment initiation was 33 days (range, 19–56) and from first medical evaluation to treatment initiation was 28 days (range, 16–48).Conclusion.In low‐ or middle‐income countries, where BC screening programs do not effectively reach the target population, it is crucial to focus efforts in identifying and prioritizing symptomatic patients or those with abnormal imaging studies to ultimately downstage BC. Alerta Rosa proved to be successful in reducing health system intervals and could be replicated and adapted for other limited resource settings.Implications for Practice.In countries such as Mexico, infrastructure and financial drawbacks limit the implementation of effective screening mammography programs. This article presents a novel and effective alternative to optimize resources and reduce health system intervals, so that patients in limited‐resource settings can have access to prompt quality care. This strategy for early breast cancer detection focused efforts in prioritizing symptomatic women and those with abnormal breast imaging studies. This article presents novel information that will be useful for the development of effective early breast cancer detection with a focus on opportunistic rather than population‐screening mammography in low‐resource settings.

https://ift.tt/2PqnJIz

Monitoring Serum VEGF in Neoadjuvant Chemotherapy for Patients with Triple‐Negative Breast Cancer: A New Strategy for Early Prediction of Treatment Response and Patient Survival

AbstractBackground.This study aimed to investigate the clinical utility of serum biomarker changes during neoadjuvant chemotherapy (NAC) for triple‐negative breast cancer (TNBC).Methods.A total of 303 patients with TNBC were included in this study. Serum samples were taken at three time points during NAC: baseline, prior to the third cycle, and prior to surgery. Luminex multibiomarker panel for 29 serum biomarkers was used to detect their correlation with NAC response. The predictive and prognostic value of each selected biomarker was then studied.Results.Vascular endothelial growth factor (VEGF) was the only biomarker that correlated with treatment response, with a decreasing trend in pCR patients relative to non‐pCR patients (p < .001). Univariable and multivariable analyses revealed that the relative change in VEGF prior to the third cycle of NAC had a remarkable predictive value for both pCR and pathological nonresponse with high sensitivity and specificity. VEGF was also independently correlated with disease‐free survival.Conclusion.Our findings indicate that monitoring serum VEGF could help identify patients with different responses at an early time point of NAC and at varying risk of disease relapse. Serum VEGF may also serve as an alternative to traditional response‐evaluating methodologies in tailoring and modifying the NAC strategy for both operable and advanced TNBCs.Implications for Practice.Neoadjuvant chemotherapy (NAC) followed by definitive surgery is a standard of care for locally advanced breast cancer. The identification of sensitive responders to neoadjuvant therapy is highly significant for breast cancer, especially triple‐negative breast cancer (TNBC). Results of this study indicate that the monitoring of serum vascular endothelial growth factor (VEGF) could identify patients with favorable or poor responses at an early time point of NAC. Furthermore, the prediction power of VEGF was better than traditional response‐evaluating methods. VEGF might serve as a complement or alternative to traditional imaging‐based response‐evaluating methodologies in tailoring systemic treatment strategies for both operable and advanced TNBCs.

https://ift.tt/2N4zJhj

A Phase II Trial of Sorafenib and Dacarbazine for Leiomyosarcoma, Synovial Sarcoma, and Malignant Peripheral Nerve Sheath Tumors

AbstractBackground.Sorafenib and dacarbazine have low single‐agent response rates in metastatic sarcomas. As angiogenesis inhibitors can enhance the efficacy of chemotherapy, we investigated the combination of sorafenib and dacarbazine in select sarcoma subtypes.Materials and Methods.Patients with leiomyosarcoma (LMS), synovial sarcoma (SS), or malignant peripheral nerve sheath tumors (MPNST) with up to two previous lines of therapy and adequate hepatic, renal, and marrow function received 3‐week cycles of sorafenib at 400 mg oral twice daily and dacarbazine 1,000 mg/m2 intravenously (later reduced to 850 mg/m2). Patients were evaluated for response every 6 weeks. The primary objective was to determine the disease control rate (DCR) of sorafenib plus dacarbazine in the selected sarcoma subtypes.Results.The study included 37 patients (19 female); median age was 55 years (range 26–87); and histologies included LMS (22), SS (11), and MPNST (4). The DCR was 46% (17/37). Median progression‐free survival was 13.4 weeks. The RECIST response rate was 14% (5/37). The Choi response rate was 51% (19/37). Median overall survival was 13.2 months. Of the first 25 patients, 15 (60%) required dacarbazine dose reductions for hematologic toxicity, with one episode of grade 5 neutropenic fever. After reducing the starting dose of dacarbazine to 850 mg/m2, only 3 of the final 12 (25%) patients required dose reduction.Conclusion.This phase II study met its primary endpoint with an 18‐week DCR of 46%. The clinical activity of dacarbazine plus sorafenib in patients with these diagnoses is modest.Implications for Practice.Metastatic soft tissue sarcomas are a heterogeneous group of relatively rare malignancies. Most patients are treated with cytotoxic chemotherapy or targeted therapy in the form of tyrosine kinase inhibitors. Response rates are relatively low, and there is a need for better therapies. This clinical trial demonstrates that combining a cytotoxic therapy (dacarbazine) with an antiangiogenic small molecule (sorafenib) is feasible and associated with favorable disease‐control rates; however, it also increases the potential for significant toxicity.

https://ift.tt/2Pqo3af

Osimertinib for EGFR‐Mutant Lung Cancer with Brain Metastases: Results from a Single‐Center Retrospective Study

AbstractIntroduction.Osimertinib is a third‐generation tyrosine kinase inhibitor, initially approved for epidermal growth factor receptor (EGFR) mutant non‐small cell lung cancer (NSCLC) with T790M acquired resistance, and now approved in the first‐line setting. However, data supporting the use of osimertinib in untreated brain metastases are limited, although it has established central nervous system (CNS) activity. Our study compares the clinical outcomes of patients experiencing progressing brain metastases treated with cranial irradiation and osimertinib with those treated with osimertinib alone.Methods.Forty patients who were treated with osimertinib at the Stanford Cancer Center from November 2015 to December 2016 were identified by searching an electronic medical record database. Eleven patients had progressing brain metastases and did not receive radiation (group A), 9 patients had progressing brain metastases and received radiation when starting osimertinib (group B), and 20 patients had stable brain metastases at the time of initiating osimertinib (group C). Patient and disease characteristics, radiographic responses, and survival outcomes were evaluated retrospectively for the three groups.Results.The CNS response rate was 32.3%. Median time to treatment failure (TTF), overall progression‐free survival (PFS), and overall survival (OS) were 10.0 months (95% confidence interval [CI], 4.5–11.8), 8.8 months (95% CI, 6.2–12.1), and 16.2 months, respectively. Median TTF was 15.1 months for group A (95% CI, 1.7–28.5), 7.7 months for group B (95% CI, 0–15.5), and 10.7 months for group C (95% CI, 9.0–12.5). The median PFS was 8.8 months for group A (95% CI, 4.3–13.4), not reached for group B, and 8.4 months for group C (95% CI, 5.6–11.1). The median OS was not reached for group A and C, and was 16.2 months for group B. There was no apparent difference in TTF, PFS, or OS between the three groups.Conclusion.Receiving radiation prior to starting osimertinib for patients with progressing brain metastases did not prolong TTF, PFS, or OS in our series. To minimize the risks of radiation‐related toxicity, delaying radiation could be considered for some patients with EGFR‐mutant NSCLC with brain metastases who initially respond to osimertinib in the second‐line setting.Implications for Practice.Osimertinib is a third‐generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor recently approved for the first‐line treatment of EGFR‐mutant non‐small cell lung cancer. Although it appears to have central nervous system (CNS) activity, most clinical trials have excluded patients with untreated, progressing brain metastases. This study included patients with stable and progressing CNS metastases treated with osimertinib and found no apparent differences in median time to treatment failure, time to progression, and overall survival in patients who received osimertinib alone compared with those who received osimertinib and radiosurgery. This may support a clinician's decision to defer radiation for selected patients with untreated brain metastases who are candidates for osimertinib therapy.

https://ift.tt/2N559nV

Efficacy and safety of ixekizumab, an interleukin-17A monoclonal antibody, in real-world patients with psoriasis: 12-week results from a Canadian multicenter retrospective study

Background: The discovery of targeted therapies that selectively bind to interleukin (IL)-17A and neutralize the bioactivity of this cytokine has led to the development of the next generation of biologic treatments for psoriasis. Most recently, ixekizumab, an IL-17A monoclonal antibody was approved for the treatment of moderate to severe plaque psoriasis in adult patients. Current efficacy and safety data are limited to results from phase III randomized controlled trials (RCT). Although these studies have shown unprecedented outcomes, how dermatologist prescribe and monitor ixekizumab in the real world is based on results obtained from patients enrolled in clinical trials.

https://ift.tt/2Pry6vZ

Hydroa vacciniforme–like lymphoma in an adult resident of the United States

Introduction: Hydroa vacciniforme–like lymphoproliferative disorders (HVLPDs) are a spectrum of diseases resulting from chronic Epstein-Barr virus (EBV) infection of T cells and natural killer cells. These include classic hydroa-vacciniforme (HV), severe HV, and HV-like lymphoma (HVLL). The latter 2 conditions rarely occur outside Asian and Latin American youth. Here we present an unusual case of adult-onset HVLPD in the United States.

https://ift.tt/2N3Xvu1

Is apremilast a promising treatment for psoriasis and psoriatic arthritis?

Introduction and objective: Apremilast (APR), is a small molecule that selectively inhibits the phosphodiesterase 4 (PDE-4) which modulates the release of pro- and antiinflammatory mediators. it was approved in February 2015 in Italy for the treatment of moderate-to-severe psoriasis and psoriatic arthritis (PsA) in adults. The aim of the authors is to assess the efficacy as well as the safety of the PDE-4 inhibitor apremilast both in PsA and psoriasis (Pso).

https://ift.tt/2N0XXsL

Evaluation of the protection of a broad-spectrum SPF50+ sunscreen against DNA damage

Introduction and objectives: UV exposure causes many skin damages. UV damages DNA, proteins, and lipids, which can result in harmful consequences, such as carcinogenesis and skin aging. Formation of DNA photoproducts caused by UV exposure needs to be investigated in vivo to assess sunscreens' level of protection against solar genotoxicity. The objective of the present study was to evaluate how the tested broad-spectrum sunscreen protect against the formation of photoproducts.

https://ift.tt/2MBF7eY

Dermatology boot camp: A model for initiating new residents into dermatology clinical care

Entering dermatology residency is an immersive experience requiring specialty-specific skills that are not routinely emphasized in medical school and internship training. To provide a practical introduction to dermatologic clinical care emphasizing ACGME dermatology milestones, we developed a concentrated 8-hour curriculum for first-year dermatology residents that encompasses 3 pillars of patient care: clinical visit competencies, procedural techniques, and professionalism and collegiality. A variety of diverse teaching approaches are employed, emphasizing respect for one another and patients, to allow instruction in pertinent practical and intellectual skills.

https://ift.tt/2N3XupX

Gender differences for those who have second primary malignancies within the first year of survival after malignant melanoma diagnosis: A United States population-based study

Introduction: Little has been reported about gender differences in those with second primary malignancies (SPM) within 1 year of melanoma (MM) diagnosis. The aim of this study is to explore gender differences as evidenced by tumor type within the first year of MM survival status using the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database.

https://ift.tt/2Bv3I0w

Endoglin is highly expressed in human mast cells

Background: CD 105 is a glycoprotein of cell membrane, for which an immunohistochemical antibody has been used as marker of endothelial cells from capillaries in proliferation. Mast cells originate from hematopoietic stem cells located in the bone marrow and migrate through the blood stream to target tissues. These cells are a component of normal tissue, though they play an important role in the regulation of several processes, including inflammation, allergy and neoplasia. The aim of this study was to evaluate the use of CD105 as a biologic marker of mast cells compared with the criterion standard stain.

https://ift.tt/2Pn4f7D

Disseminated pruritic papules

A 60-year-old Arabic man with a medical history of diabetes mellitus was admitted to the hospital for an unprovoked deep vein thrombosis with pruritus, nonproductive cough, and abdominal pain. His pruritus had been ongoing over the preceding four months and he has developed diffuse erythematous to hyperpigmented papules with some having a central keratotic core and others with hemorrhagic crusting. He had minimal to no improvement in his pruritus on mid-potency topical corticosteroids in combination with antihistamines.

https://ift.tt/2BtDADi

Cutaneous nontuberculous mycobacteria infection: A retrospective study of 78 cases

Introduction: The incidence of cutaneous nontuberculous Mycobacteria (NTM) infection is increasing in both immunosuppressed and immunocompetent patients. These infections are often misdiagnosed due to nonspecific presentation.

https://ift.tt/2Prgiku

Köhlmeier-Degos disease: Does the benign form really exist?

A 46-year-old woman was referred to us for evaluation of asymptomatic erythematous papules with central umbilication and atrophy in trunk and extremities. Histologic features were compatible with Degos disease. She had no systemic manifestations and the laboratory and the radiologic findings were no significant. 6 years after the diagnosis the patient complained of headache and weakness. Initial evaluation revealed a subdural hygroma on CT. Then she developed a hemiparesis, and MRI showed a subacute ischemia in the territory supplied by the middle cerebral artery.

https://ift.tt/2N9waX2

Infantile myofibromatosis: A diagnostic conundrum

A 2-day-old boy was referred to dermatology with a history of skin lesions present since birth. He was born at 39+6 weeks by cesarean section owing to failure to progress to a primiparous mother with gestational diabetes. On examination, he had 6 firm, tumid, red-violaceous nodules on the body. The largest was on the left side of the neck which had reportedly grown since birth; ultrasound did not reveal any Doppler flow. In addition, similar lesions were noted on the torso, with smaller nodules on the groin, lower abdomen and calf.

https://ift.tt/2MBpPXw

Impact of genital lichen sclerosus treatments on occurrence of vulvar neoplasms in 275 adult women

Background: Lichen sclerosus (LS) is a chronic inflammatory disease most commonly affecting the genital area of women. LS-associated vulvar neoplasms are known to occur. Treatment of LS is thought to reduce malignancy risk. A recent report showed reduction in vulvar neoplasms in those compliant with maintenance therapy. We performed a single-institution, retrospective chart review to identify vulvar neoplasm occurrence in women with biopsy-proven genital LS and to determine whether a correlation exists between LS treatments and vulvar neoplasm occurrence.

https://ift.tt/2N3ScL1

Hallopeau’s continuous acrodermatitis: Management

Introduction: Hallopeau's continuous acrodermatitis (ACH) is a chronic inflammatory disease affecting the fingers and/or toes, characterized by an erythematous-desquamative plaque with sterile pustular eruptions. It is a rare or perhaps underdiagnosed and more frequent pathology in middle-aged women, according to the few cases reported.

https://ift.tt/2PqGhIM

Familial aplasia cutis congenita: A case report

Introduction: Aplasia cutis congenita is a rare congenital disorder. The incidence has been estimated at 1 per 10,000 live births. It is characterized by the absence of certain layers of the skin. At birth, it commonly presents as a solitary well localized lesion on the scalp. Infrequently, a widespread area can be involved. The etiology remains unclear. Genetic factors, environmental causes and teratogens have been implicated.

https://ift.tt/2Buzhrv

Erlotinib-induced erosive pustular dermatosis of the scalp complicated by MRSA infection

Introduction: Erosive pustular dermatosis (EPD) of the scalp is a rare entity characterized by erosive, follicular, papulopustular eruptions with nonspecific chronic inflammatory findings on histopathology. EPD of the scalp has been associated with epidermal growth factor receptor (EGFR) inhibitor therapy such as gefitinib or erlotinib with only a few reported cases. Herein, we report an impressive presentation of EPD of the scalp complicated by secondary methicillin-resistant Staphlococcus aureus (MRSA) infection during treatment with erlotinib for stage IV lung cancer.

https://ift.tt/2MJSdXo

Efficacy of sinecatechins 10% as proactive sequential therapy of external and perianal genital warts after laser therapy: An exploratory trial

Background: External genital warts (EGW) are the most common viral sexually transmitted infection. Ablative treatments like cryotherapy, curettage and CO2 laser therapy offer rapid onset of effect, fast clearance, and reduction of virus load. However, these procedures are associated with high recurrence rates (RR) of 20%-77% in the short and medium term and do not provide sustained clearance. After laser therapy removal of EGW a RR up to 60% has been reported. Topical sinecatechins 10% is a patient-applied regimen for the treatment of EGW with a low RR (6.5%) at 3 months after completion of the therapy in the pivotal trials conducted so far.

https://ift.tt/2BtJqEP

Eccrine poroma: An unusual presentation and evaluation with the use of dermoscopy and optical-coherence tomographic imaging

Eccrine poromas (EP) are benign cutaneous adnexal neoplasms that commonly present as solitary plaques, papules, or nodules on the lower extremities. Both clinically, and on dermoscopy, EP can be hard to distinguish from other skin tumors, including amelanotic melanoma and eccrine porocarcinoma. Dermoscopy and optical-coherence tomography (OCT) are 2 noninvasive imaging devices that can increase the diagnostic accuracy of benign and malignant cutaneous diseases. Thus, understanding the dermoscopic features of EP and characterizing it on OCT imaging may help improve diagnostic accuracy.

https://ift.tt/2ML4Odf

Diagnosis and management of childhood psoriasis: A prospective study

Retrospective studies show that approximately one third of adults with psoriasis recall onset in childhood however the true prevalence in children remains unknown. It affects 2.0%-3.5% of the population worldwide and has been reported as high as 8.5% depending on the population studied. Psoriasis can have a significant impact on quality of life in both children and adolescents by impacting self-esteem, family and social relations and school. Children suffering from psoriasis also have higher prevalence of obesity, hypertension, diabetes mellitus, rheumatoid arthritis, Crohn's disease and psychiatric disorders.

https://ift.tt/2Bu2McL

B Cell Defects Observed in Nod2 Knockout Mice Are a Consequence of a Dock2 Mutation Frequently Found in Inbred Strains [IMMUNE SYSTEM DEVELOPMENT]

Phenotypic differences among substrains of laboratory mice due to spontaneous mutations or pre-existing genetic variation confound the interpretation of targeted mutagenesis experiments and contribute to challenges with reproducibility across institutions. Notably, C57BL/6 Hsd mice and gene-targeted mice that have been backcrossed to this substrain have been reported to harbor a duplication in exons 28 and 29 of Dock2. In this study, we demonstrate the presence of this Dock2 variant in the widely used Nod2^–/– mice. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is a cytosolic innate immune receptor associated with inflammatory bowel disease susceptibility. Consistent with a role of NOD2 in an immunological disorder, Nod2^–/– mice bred at our institution displayed multiple B cell defects including deficiencies in recirculating B cells, marginal zone B cells, and B1a cells in vivo, as well as defects in class switch recombination in vitro. However, we found that these effects are due to the Dock2 variant and are independent of Nod2 deletion. Despite originating from the same gene-targeted founder mice, Nod2^–/– mice from another source did not harbor the Dock2 variant or B cell defects. Finally, we show that Dock2^–/– mice display the same B cell defects as mice harboring the Dock2 variant, confirming that the variant is a loss-of-function mutation and is sufficient to explain the alterations to the B cell compartment observed in Nod2^–/– mice. Our findings highlight the effects of confounding mutations from widely used inbred strains on gene-targeted mice and reveal new functions of DOCK2 in B cells.

https://ift.tt/2vWezeM

Targeting Antigen-Specific B Cells Using Antigen-Expressing Transduced Regulatory T Cells [IMMUNE REGULATION]

Controlling immune responses in autoimmunity and to biotherapeutics is an unmet need. In hemophilia, for example, up to one third of patients receiving therapeutic factor VIII (FVIII) infusions develop neutralizing Abs termed "inhibitors." To address this problem in a mouse model of hemophilia A, we used an Ag-specific regulatory T cell (Treg) approach in which we created a novel B cell–targeting chimeric receptor composed of an FVIII Ag domain linked with the CD28-CD3 transmembrane and signaling domains. We termed these "BAR" for B cell–targeting Ab receptors. CD4⁺CD25^hiCD127^low human Tregs were retrovirally transduced to express a BAR containing the immunodominant FVIII C2 or A2 domains (C2- and A2-BAR). Such BAR-Tregs specifically suppressed the recall Ab response of spleen cultures from FVIII-immunized mice in vitro and completely prevented anti-FVIII Ab development in response to FVIII immunization. Mechanistic studies with purified B cells and T cells from tolerized or control recipients demonstrated that the FVIII-specific B cells were directly suppressed or anergized, whereas the T cell response remained intact. Taken together, we report in this study a successful proof-of-principle strategy using Ag-expressing Tregs to directly target specific B cells, an approach which could be adapted to address other adverse immune responses as well.

https://ift.tt/2Brrsms

Id3 Restricts {gamma}{delta} NKT Cell Expansion by Controlling Egr2 and c-Myc Activity [IMMUNE SYSTEM DEVELOPMENT]

NKT cells are neonatal-derived T lymphocytes that are grouped together with invariant NKT cells based on their shared innate-like developmental program characterized by the transcription factor PLZF (promyelocytic leukemia zinc finger). Previous studies have demonstrated that the population size of NKT cells is tightly controlled by Id3-mediated inhibition of E-protein activity in mice. However, how E proteins promote NKT cell development and expansion remains to be determined. In this study, we report that the transcription factor Egr2, which also activates PLZF expression in invariant NKT cells, is essential for regulating NKT cell expansion. We observed a higher expression of Egr family genes in NKT cells compared with the conventional T cell population. Loss of function of Id3 caused an expansion of NKT cells, which is accompanied by further upregulation of Egr family genes as well as PLZF. Deletion of Egr2 in Id3-deficient NKT cells prevented cell expansion and blocked PLZF upregulation. We further show that this Egr2-mediated NKT cell expansion is dependent on c-Myc. c-Myc knockdown attenuated the proliferation of Id3-deficient NKT cells, whereas c-Myc overexpression enhanced the proliferation of Id3/Egr2–double-deficient NKT cells. Therefore, our data reveal a regulatory circuit involving Egr2–Id3–E2A, which normally restricts the population size of NKT cells by adjusting Egr2 dosage and c-Myc expression.

https://ift.tt/2BuQpNC

Effects of Masker Envelope Fluctuations on the Temporal Effect

ABSTRACT

Under certain conditions, detection thresholds in simultaneous masking improve when the onset of a short sinusoidal probe is delayed from the onset of a long masker. This improvement, known as the temporal effect, is largest for broadband maskers and is smaller or absent for narrowband maskers centered on the probe frequency. This study tests the hypothesis that small or absent temporal effects for narrowband maskers are due to the inherent temporal envelope fluctuations of Gaussian noise. Temporal effects were measured for narrowband noise maskers with fluctuating ("fluctuating maskers") and flattened ("flattened maskers") temporal envelopes as a function of masker level (Exp. I) and in the presence of fluctuating and flattened precursors (Exp. II). The temporal effect was absent for fluctuating narrowband maskers and as large as ~ 7 dB for flattened narrowband maskers. The AC-coupled power of the temporal envelopes of precursors and maskers accounted for 94 % of the variance in probe detection thresholds measured with fluctuating and flattened precursors and maskers. These results suggest that masker temporal envelope fluctuations contribute to the temporal effect and should be considered in future modeling efforts.

https://ift.tt/2vZ0jC2

Dupilumab improves symptoms, quality of life, and productivity in uncontrolled persistent asthma

Asthma is a heterogeneous disease consisting of phenotypes defined, in part, by clinical parameters such as age of onset, presence of allergic features, degree of airway obstruction, obesity, gender, and smoking history.1-3 These characteristics may be associated with outcome and treatment response.3 Poor asthma control has been associated with increased risk of asthma exacerbations, asthma-related hospitalization,4,5 poor quality of life (QoL),6 adverse impact on productivity,7,8 and possibly, increased risk of mortality.

https://ift.tt/2N6d6cy

Differences in airway structural changes assessed by three-dimensional computed tomography in asthma and asthma-COPD overlap

Background: Asthma- COPD overlap (ACO) is a clinical phenotype sharing features of asthma and COPD. Multidetector row computed tomography (MDCT) can be used to evaluate the airway structure; however, differences between asthma and ACO seen on MDCT are poorly understood.Objective: To investigate the difference in airway structural between asthma and ACO using MDCT in patients with clinical asthma.Methods:Sixty-four patients with asthma were allocated to an asthma group (neversmokers and ex-smokers with a smoking history of <10 pack-years) or an ACO group (patients with a ≥10-pack-year smoking history and FEV1/ FVC <0.7).

https://ift.tt/2Pmdl4N

Analysis of KIR3DP1 Polymorphism Provides Relevant Information on Centromeric KIR Gene Content [IMMUNOGENETICS]

Four killer cell Ig-like receptor (KIR) genes, collectively referred to as framework genes, characterize almost all KIR haplotypes. In particular, KIR3DL3 and KIR3DL2 mark the ends of the locus, whereas KIR3DP1 and KIR2DL4 are located in the central part. A recombination hot spot, mapped between KIR3DP1 and KIR2DL4, splits the haplotypes into two regions: a centromeric (Cen) region (spanning from KIR3DL3 to KIR3DP1) and a telomeric region (from KIR2DL4 to KIR3DL2), both varying in KIR gene content. In this study, we analyzed KIR3DP1 polymorphism in a cohort of 316 healthy, unrelated individuals. To this aim, we divided KIR3DP1 alleles into two groups by the use of a sequence-specific primer– PCR approach. Our data clearly indicated that KIR3DP1 alleles present on haplotypes carrying Cen-A or Cen-B1 regions differ from those having Cen-B2 motifs. Few donors (~3%) made exceptions, and they were all, except one, characterized by uncommon haplotypes, including either KIR deletions or KIR duplications. Consequently, as KIR2DL1 is present in Cen-A and Cen-B1 regions but absent in Cen-B2 regions, we demonstrated that KIR3DP1 polymorphism might represent a suitable marker for KIR2DL1 gene copy number analysis. Moreover, because Cen-B1 and Cen-B2 regions are characterized by different KIR3DP1 alleles, we showed that KIR3DP1 polymorphism analysis also provides information to dissect between Cen-B1/Cen-B1 and Cen-B1/Cen-B2 donors. Taken together, our data suggest that the analysis of KIR3DP1 polymorphism should be included in KIR repertoire evaluation.

https://ift.tt/2MCEi5A

A Convergent Immunological Holy Trinity of Adaptive Immunity in Lampreys: Discovery of the Variable Lymphocyte Receptors [PILLARS OF IMMUNOLOGY]

https://ift.tt/2vWeE24

Pre-Existing Maternal Antibodies Cause Rapid Prenatal Rejection of Allotransplants in the Mouse Model of In Utero Hematopoietic Cell Transplantation [TRANSPLANTATION]

In utero hematopoietic cell transplantation (IUHCT) is a nonmyeloablative nonimmunosuppressive alternative to postnatal hematopoietic stem cell transplantation for the treatment of congenital hemoglobinopathies. Anti-HLA donor-specific Abs (DSA) are associated with a high incidence of graft rejection following postnatal hematopoietic stem cell transplantation. We determine if DSA present in the mother can similarly cause graft rejection in the fetus following IUHCT. Ten million C57BL/6 (B6, H2k^b) bone marrow cells were transplanted in utero into gestational day 14 BALB/c (H2k^d) fetuses. The pregnant BALB/c dams carrying these fetuses either had been previously sensitized to B6 Ag or were injected on gestational days 13–15 with serum from B6-sensitized BALB/c females. Maternal–fetal Ab transmission, Ab opsonization of donor cells, chimerism, and frequency of macrochimeric engraftment (chimerism >1%) were assessed by flow cytometry. Maternal IgG was transmitted to the fetus and rapidly opsonized donor cells following IUHCT. Donor cell rejection was observed as early as 4 h after IUHCT in B6-sensitized dams and 24 h after IUHCT in dams injected with B6-sensitized serum. Efficient opsonization was strongly correlated with decreased chimerism. No IUHCT recipients born to B6-sensitized dams or dams injected with B6-sensitized serum demonstrated macrochimeric engraftment at birth compared with 100% of IUHCT recipients born to naive dams or dams injected with naive serum (p < 0.001). In summary, maternal donor–specific IgG causes rapid, complete graft rejection in the fetus following IUHCT. When a third-party donor must be used for clinical IUHCT, the maternal serum should be screened for DSA to optimize the chance for successful engraftment.

https://ift.tt/2w0YTXD

Mannose Metabolism Is Essential for Th1 Cell Differentiation and IFN-{gamma} Production [IMMUNE REGULATION]

Glucose-derived mannose is a common component of glycoproteins, and its deficiency leads to a severe defect in protein glycosylation and failure in basic cell functions. In this work, we show that mannose metabolism is essential for IFN- production by mouse Th1 cells. In addition, we demonstrate that the susceptibility of Th1 cells to glycolysis restriction depends on the activation conditions and that under diminished glycolytic flux, mannose availability becomes the limiting factor for IFN- expression. This study unravels a new role for glucose metabolism in the differentiation process of Th1 cells, providing a mechanistic explanation for the importance of glycolysis in immune cell functions.

https://ift.tt/2MDzqNn

Pillars Article: Somatic Diversification of Variable Lymphocyte Receptors in the Agnathan Sea Lamprey. Nature. 2004. 430: 174-180 [PILLARS OF IMMUNOLOGY]

https://ift.tt/2BuQz7G

Functional Evidence of Pulmonary Extracellular Vesicles in Infectious and Noninfectious Lung Inflammation [INNATE IMMUNITY AND INFLAMMATION]

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a highly complex process that can be triggered by both noninfectious (sterile) and infectious stimuli. Inflammatory lung responses are one of the key features in the pathogenesis of this devastating syndrome. How ALI/ARDS-associated inflammation develops remains incompletely understood, particularly after exposure to sterile stimuli. Emerging evidence suggests that extracellular vesicles (EVs) regulate intercellular communication and inflammatory responses in various diseases. In this study, we characterized the generation and function of pulmonary EVs in the setting of ALI/ARDS, induced by sterile stimuli (oxidative stress or acid aspiration) and infection (LPS/Gram-negative bacteria) in mice. EVs detected in bronchoalveolar lavage fluid (BALF) were markedly increased after exposure of animals to both types of stimuli. After sterile stimuli, alveolar type-I epithelial cells were the main source of the BALF EVs. In contrast, infectious stimuli–induced BALF EVs were mainly derived from alveolar macrophages (AMs). Functionally, BALF EVs generated in both the noninfectious and infectious ALI models promoted the recruitment of macrophages in in vivo mouse models. Furthermore, BALF EVs differentially regulated AM production of cytokines and inflammatory mediators, as well as TLR expression in AMs in vivo. Regardless of their origin, BALF EVs contributed significantly to the development of lung inflammation in both the sterile and infectious ALI. Collectively, our results provide novel insights into the mechanisms by which EVs regulate the development of lung inflammation in response to diverse stimuli, potentially providing novel therapeutic and diagnostic targets for ALI/ARDS.

https://ift.tt/2w0QDqx

The Evolving Erythrocyte: Red Blood Cells as Modulators of Innate Immunity [BRIEF REVIEWS]

The field of red cell biology is undergoing a quiet revolution. Long assumed to be inert oxygen carriers, RBCs are emerging as important modulators of the innate immune response. Erythrocytes bind and scavenge chemokines, nucleic acids, and pathogens in circulation. Depending on the conditions of the microenvironment, erythrocytes may either promote immune activation or maintain immune quiescence. We examine erythrocyte immune function through a comparative and evolutionary lens, as this framework may offer perspective into newly recognized roles of human RBCs. Next, we review the known immune roles of human RBCs and discuss their activity in the context of sepsis where erythrocyte function may prove important to disease pathogenesis. Given the limited success of immunomodulatory therapies in treating inflammatory diseases, we propose that the immunologic function of RBCs provides an understudied and potentially rich area of research that may yield novel insights into mechanisms of immune regulation.

https://ift.tt/2vZ3rhg

Correction: Both HIV-Infected and Uninfected Cells Express TRAILshort, Which Confers TRAIL Resistance upon Bystander Cells within the Microenvironment [CORRECTIONS]

https://ift.tt/2MJBcfY

Cutting Edge: Deletion of Ezrin in B Cells of Lyn-Deficient Mice Downregulates Lupus Pathology [CUTTING EDGE]

Genetic deletion of the Src family tyrosine kinase Lyn in mice recapitulates human systemic lupus erythematosus, characterized by hyperactive BCR signaling, splenomegaly, autoantibody generation, and glomerulonephritis. However, the molecular regulators of autoimmunity in Lyn-deficient mice and in human lupus remain poorly characterized. In this study, we report that conditional deletion of the membrane–cytoskeleton linker protein ezrin in B cells of Lyn-deficient mice (double knockout [DKO] mice) ameliorates B cell activation and lupus pathogenesis. B cells from DKO mice respond poorly to BCR stimulation, with severe downregulation of major signaling pathways. DKO mice exhibit reduced splenomegaly as well as significantly lower levels of autoantibodies against a variety of autoantigens, including dsDNA, histone, and chromatin. Leukocyte infiltration and deposition of IgG and complement component C3 in the kidney glomeruli of DKO mice are markedly reduced. Our data demonstrate that ezrin is a novel molecular regulator of B cell–associated lupus pathology.

https://ift.tt/2BuQwZy

NK Cell-Derived IFN-{gamma} Protects against Nontuberculous Mycobacterial Lung Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

In developed countries, pulmonary nontuberculous mycobacteria (NTM) infections are more prevalent than Mycobacterium tuberculosis infections. Given the differences in the pathogenesis of NTM and M. tuberculosis infections, separate studies are needed to investigate the pathological effects of NTM pathogens. Our previous study showed that anti–IFN- autoantibodies are detected in NTM-infected patients. However, the role of NK cells and especially NK cell–derived IFN- in this context has not been studied in detail. In the current study, we show that NK1.1 cell depletion increases bacterial load and mortality in a mouse model of pulmonary NTM infection. NK1.1 cell depletion exacerbates NTM-induced pathogenesis by reducing macrophage phagocytosis, dendritic cell development, cytokine production, and lung granuloma formation. Similar pathological phenomena are observed in IFN-–deficient (IFN-^–/–) mice following NTM infection, and adoptive transfer of wild-type NK cells into IFN-^–/– mice considerably reduces NTM pathogenesis. Injection of rIFN- also prevents NTM-induced pathogenesis in IFN-^–/– mice. We observed that NK cells represent the main producers of IFN- in the lungs and production starts as soon as 1 d postinfection. Accordingly, injection of rIFN- into IFN-^–/– mice 1 d (but not 2 wk) postinfection significantly improves immunity against NTM infection. NK cells also stimulate mycobacterial killing and IL-12 production by macrophages. Our results therefore indicate that IFN- production by NK cells plays an important role in activating and enhancing innate and adaptive immune responses at early stages of pulmonary NTM infection.

https://ift.tt/2MJBcwu

Human Extrafollicular CD4+ Th Cells Help Memory B Cells Produce Igs [CLINICAL AND HUMAN IMMUNOLOGY]

Follicular helper T (Tfh) cells are necessary for germinal center B cell maturation during primary immune responses; however, the T cells that promote humoral recall responses via memory B cells are less well defined. In this article, we characterize a human tonsillar CD4⁺ T cell subset with this function. These cells are similar to Tfh cells in terms of expression of the chemokine receptor CXCR5 and the inhibitory receptor PD-1, IL-21 secretion, and expression of the transcription factor BCL6; however, unlike Tfh cells that are located within the B cell follicle and germinal center, they reside at the border of the T cell zone and the B cell follicle in proximity to memory B cells, a position dictated by their unique chemokine receptor expression. They promote memory B cells to produce Abs via CD40L, IL-10, and IL-21. Our results reveal a unique extrafollicular CD4⁺ T cell subset in human tonsils, which specialize in promoting T cell–dependent humoral recall responses.

https://ift.tt/2vWeBTW

A Fixed Spatial Structure of CD8+ T Cells in Tissue during Chronic HSV-2 Infection [MUCOSAL IMMUNOLOGY]

Tissue-resident CD8⁺ T cells (T_rm) can rapidly eliminate virally infected cells, but their heterogeneous spatial distribution may leave gaps in protection within tissues. Although T_rm patrol prior sites of viral replication, murine studies suggest they do not redistribute to adjacent uninfected sites to provide wider protection. We perform mathematical modeling of HSV-2 shedding in Homo sapiens and predict that infection does not induce enough T_rm in many genital tract regions to eliminate shedding; a strict spatial distribution pattern of mucosal CD8⁺ T cell density is maintained throughout chronic infection, and trafficking of T_rm across wide genital tract areas is unlikely. These predictions are confirmed with spatial analysis of CD8⁺ T cell distribution in histopathologic specimens from human genital biopsies. Further simulations predict that the key mechanistic correlate of protection following therapeutic HSV-2 vaccination would be an increase in total T_rm rather than spatial reassortment of these cells. The fixed spatial structure of T_rm induced by HSV-2 is sufficient for rapid elimination of infected cells but only in a portion of genital tract microregions.

https://ift.tt/2w0cizr

Characterization of a Synovial B Cell-Derived Recombinant Monoclonal Antibody Targeting Stromal Calreticulin in the Rheumatoid Joints [CLINICAL AND HUMAN IMMUNOLOGY]

Rheumatoid arthritis (RA) is characterized by formation of synovial ectopic lymphoid structures (ELS) supporting B cell autoreactivity toward locally generated citrullinated (cit) antigens, including those contained in neutrophil extracellular traps (NETs). However, only a minority of RA-rmAbs from B cells isolated from ELS⁺ RA tissues react against NETs. Thus, alternative cellular sources of other potential autoantigens targeted by locally differentiated B cells remain undefined. RA fibroblast–like synoviocytes (FLS) have been implicated in the release of RA-associated autoantigens. In this study, we aimed to define stromal-derived autoantigens from RA-FLS targeted by RA-rmAbs. Seventy-one RA-rmAbs were screened toward RA-FLS by living-cell immunofluorescence (IF). Western blotting was used to identify potential autoantigens from RA-FLS protein extracts. Putative candidates were validated using colocalization immunofluorescence confocal microscopy, ELISA, immunoprecipitation assay, and surface plasmon resonance on unmodified/cit proteins. Serum immunoreactivity was tested in anti-citrullinated peptide/protein Abs (ACPA)⁺ versus ACPA^– RA patients. Ten out of 71 RA-rmAbs showed clear reactivity toward RA-FLS in immunofluorescence with no binding to NETs. One stromal-reactive RA-rmAb (RA057/11.89.1) decorated a ~58-kDa band that mass spectrometry and Western blotting with a commercial Ab identified as calreticulin (CRT). Confocal microscopy demonstrated significant cellular colocalization between anti-CRT RA057/11.89.1 in RA-FLS. RA057/11.89.1 was able to immunoprecipitate rCRT. Deimination of CRT to cit-CRT moderately increased RA057/11.89.1 immunoreactivity. cit-CRT displayed increased blocking capacity compared with unmodified CRT in competitive binding assays. Finally, anti–cit-CRT Abs were preferentially detected in ACPA⁺ versus ACPA^– RA sera. We identified a synovial B cell–derived RA-rmAb locally differentiated within the ELS⁺ RA synovium reacting toward CRT, a putative novel autoantigen recently described in RA patients, suggesting that FLS-derived CRT may contribute to fuel the local autoimmune response.

https://ift.tt/2BuQv7W