Dysfunctions of innate and adaptive immune tumor microenvironment in Waldenström macroglobulinemia

Waldenström macroglobulinemia (WM) is a rare subtype of non-Hodgkin lymphoma characterized by malignant lymphoplasmacytic cells in the bone marrow (BM). To dissect the pathophysiology of WM, we evaluated clonal cells by mapping of B cell lymphomagenesis with adaptive and innate immune tumor microenvironment (TME) in the BM of WM patients using mass cytometry (CyTOF). In-depth immunophenotypic profiling of WM cells exhibited profound expansion of clonal cells in both unswitched and switched memory B cells and also plasma cells with aberrant expression variations. WM B lymphomagenesis was associated with reduction of most B cell precursors assessed with the same clonally restricted light chain and phenotypic changes. The immune TME was infiltrated by mature monocytes, neutrophils and adaptive T cells, preferentially subsets of effector T helper, effector CTL and effector memory CTL cells that were associated with superior overall survival (OS), in contrast to progenitors of T cells and myeloid/monocytic lineage subsets that were suppressed in WM cohort. Moreover, decrease in immature B and NKT cells was related to worse OS in WM patients. Innate and adaptive immune subsets of WM TME were modulated by immune checkpoints, including PD-1/PD-L1&PD-L2, TIGIT/PVR, CD137/CD137-L, CTLA-4, BTLA and KIR expression. The response of ibrutinib treatment to the reduction of clonal memory B cell was associated with high levels of immature B cells and effector memory CTL cells. Our study demonstrates that CyTOF technology is a powerful approach for characterizing the pathophysiology of WM at various stages, predicting patient risk and monitoring the effectiveness of treatment strategies.     

Clinical Utilization of Chimeric Antigen Receptor T Cells in B Cell Acute Lymphoblastic Leukemia: An Expert Opinion from the European Society for Blood and Marrow Transplantation and the American Society for Blood and Marrow Transplantation

On August 30, 2017 the US Food and Drug Administration approved tisagenlecleucel (Kymriah; Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present, ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring, and disease assessments. To address these issues experts representing the American Society for Blood and Marrow Transplant, the European Society for Blood and Marrow Transplantation, the International Society of Cell and Gene Therapy, and the Foundation for the Accreditation of Cellular Therapy formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.     

Postpartum optic neuritis: etiologic and pathophysiologic considerations.

The clinical course of four patients with visual loss in the postpartum period due to acute optic neuritis is described. Factors that disclosed the underlying etiology and expression of disease are discussed. The clinical records of four women examined and managed for visual loss after uncomplicated pregnancies and term deliveries were reviewed. Neurodiagnostic examination, treatment modalities, and outcomes were assessed. These four women with varied and confounding medical histories, all with optic neuropathy, eventually were demonstrated to harbor demyelinating disease. Although visual loss in the postpartum period evokes differential diagnostic considerations, the authors' experience suggests that puerperal immune-mediated changes are responsible for activation of optic neuritis associated with relapsing multiple sclerosis.     

Peptide receptor radioligand therapy is an effective treatment for the long-term stabilization of malignant gastrinomas

BACKGROUND:

Gastrinomas, a rare group of neuroendocrine tumors, are responsible for severe peptic disease and diarrhea. Although symptomatic control may be achieved with proton‐pump inhibitors (PPIs) and somatostatin analogues (SSAs), data are limited regarding the possible antitumor effect of the peptide receptor radioligand therapy (PRRT) with radiolabeled SSAs in gastrinoma patients. The goal of this study was to assess the effect of PRRT on symptoms, gastrin secretion, and tumor load in patients with progressive malignant gastrinomas.

METHODS:

We retrospectively studied 11 patients with metastatic gastrinomas followed for a mean period of 6 years. All patients were symptomatically treated with PPIs, and 9 of 11 patients received monthly injections of SSAs; all patients had an Eastern Cooperative Oncology Group score of 0‐1, and received PRRT (⁹⁰Yttrium‐ or ¹⁷⁷Lutetium‐DOTATOC) for progressive disease. Serum gastrin measurements and radiological assessment (using the Response Evaluation Criteria in Solid Tumors criteria) were performed before and every 3‐6 months following PRRT.

RESULTS:

PRRT induced symptomatic improvement in all patients. The mean serum gastrin decreased significantly from 4831 mI/L to 932.6 mI/L (normal, 40‐108 mI/L; P < .001). Periodic radiological surveillance showed complete response in 1 (9%) patient, partial tumor response in 5/11 (45%) patients, and tumor stabilization in 5/11 (45%) patients. In 7/11 (64%) patients, the antitumor effect of PRRT persisted after a median period of 14 months. Four of 11 (36%) patients died due to tumor progression (median time to progression, 11 months); in this group, the mean survival time after the last PRRT was 14 ± 6.9 months.

CONCLUSIONS:

PRRT seems to be a promising tool for the management of patients with inoperable or progressive metastatic gastrinomas. Cancer 2011. © 2010 American Cancer Society.     

Advanced relationships between categories analysis as a qualitative research tool

The authors propose an advanced relationships between categories (RBC) model as an expansion of Tutty, Rothery, and Grinnell's ( 1996 ) qualitative tool for classifying RBC patterns as contained, temporal, and causal relationships. It is assumed that identification of the relationships obtained among categories of qualitative data paves the way for construction of a theory, even though few tools have been developed for this purpose to date. The advanced RBC model points to three additional relationship patterns: bilateral, trilateral, and quadrilateral relationships. These relationships reveal how the text itself links among its various components. The model serves as an innovative tool for systematic derivation of explanations based on the qualitative raw data, contributing to grounded theory and other interpretive studies. © 2010 Wiley Periodicals, Inc. J Clin Psychol: 66:1–11, 2010.     

Sarcoidosis Presenting as “Corset-like” Myelopathy: A Description of Six Cases and Literature Review

Sarcoidosis of the spinal cord is rare, even more so as the initial presentation of the disease. We describe six cases of spinal cord sarcoidosis and delineate a distinguishing feature which may allow for a timely diagnosis. All patients were admitted with complaints of a “corset-like” pressure in the lower chest and later developed cranial nerve palsies (two patients), parasthesias/paraparesis (two patients), fever of unknown origin (one patient), and bilateral proptosis (one patient). Serological tests, immunological screening, cerebrospinal fluid (CSF) analysis, bacteriological and viral testing were performed in all patients. Spinal and cerebral MRI, high-resolution computed tomography (HRCT) of the chest and gallium scan suggested the diagnosis of neurosarcoidosis of the spine while a biopsy of mediastinal lymph nodes, extra-ocular muscles, or spinal cord confirmed it. CSF showed inflammatory signs in 66% of patients and serum ACE levels were increased in a similar fraction. MRI revealed a gadolinium-enhanced thickening of the cord at the thoracic level in three patients whereas three other patients had normal spinal MRI despite similar symptoms. The presence of mediastinal lymphadenopathy on HRCT of the chest suggested the diagnosis in a third of patients. Patients were treated with steroid, immunosuppressive therapy and/or biologic therapies, with complete resolution in one case, improvement in four, and a somewhat deteriorating course, with development of spinal cord atrophy in the final case. As spinal cord involvement of sarcoidosis is extremely rare, making the diagnosis in the absence of systemic disease is challenging. The cases herein described suggest that sensory disturbance in a “corset-like” distribution may be indicative of neurosarcoidosis, especially when accompanied by extra-axial involvement such as cranial nerve palsies. This should prompt an evaluation for systemic involvement, keeping in mind that serum ACE and chest radiographs may be normal in the presence of primarily CNS-limited disease.     

Neonatal dacryocele with endonasal cyst: revisiting the management

Purpose

The aim of the study was to present a consecutive series of neonatal dacryocele with endonasal cyst diagnosed and treated in our institution and to compare our management regimen and outcome with those reported in the literature.

Methods

The study was conducted at a university-affiliated teaching hospital. Study population included 5 infants, ages 1 day to 1 month, with either noninfected or infected neonatal dacryocele with endonasal cyst. Management included antibiotic treatment (topical and/or systemic) and local lacrimal massage. When conservative treatment failed, endoscopic identification and incision of the endonasal cyst with subsequent lacrimal duct irrigation with fluorescein and antibiotics were carried out in the office. Main outcome measures included resolution of symptoms and recurrence rate.

Results

Between the years 2003 and 2007, 5 infants were diagnosed and treated. All had unilateral dacryocele with endonasal cyst. Female-to-male ratio was 4:1. Age ranged from 1 day to 1 month old. Three had dacryocystitis (60%) before treatment. None had symptoms of airway obstruction. One patient was successfully treated conservatively with firm massage by the ophthalmologist resulting in rupture of the endonasal cyst and did not require further treatment. Four patients were treated with a combined ophthalmology/otolaryngology surgical procedure. All patients were treated in an office setting without general anesthesia. One patient underwent computed tomographic imaging before treatment to confirm the diagnosis. Follow-up ranged from 1 month to 50 months with an average of 23 months. Complete resolution was observed in all patients without recurrence and without complications.

Conclusions

We report on the successful surgical treatment of neonatal dacryocele with endonasal cyst in an office setting without the use of general anesthesia, using endoscopic incision of the cyst and irrigation alone. The high success rate of this relatively benign office procedure encourages its use and further supports the approach of early surgical intervention, thus, helping to avoid infectious complications that can be severe at this age.     

Incidence of traumatic lumbar puncture: experience of a large, tertiary care pediatric hospital

The objective of this study was to establish the incidence of traumatic or unsuccessful lumbar punctures (LPs) in the authors' institution. This is a prospective study. Traumatic LP was defined as >400 red blood cells (RBCs) and unsuccessful LP as failure to obtain cerebrospinal fluid (CSF) after the first LP attempt. A total of 127 CSF were recorded over 1 year. The incidence of a traumatic LP was 27/103 (26.2%) using the sitting position and 3/24 (12.5%) in infants and children using the lying position. In total, 33 (26%) CSF samples had 0 RBCs. The incidence of traumatic LP was 24% when the procedure involved one LP and 50% when more than one attempt was required. RBC count was significantly lower in cases requiring only one attempt (P = .0074). Incidence of traumatic LP was independent of physicians' experience, sedation use or time of procedure, suggesting an intrinsic factor as the cause of traumatic LPs.