Neurology and the histiocytoses: a case of Rosai-Dorfman-Destombes disease.

The histiocytoses are a group of rare disorders characterised by the accumulation of neoplastic or non-neoplastic activated histiocytes in various tissues. Phenotypes vary widely from cutaneous lesions or lymphadenopathy that regress spontaneously to disseminated disease with poor prognosis. Neurological symptoms can be a presenting feature or appear during the course of disease. We present a challenging diagnostic and management case of Rosai-Dorfman-Destombes disease in a 48-year-old woman with a relapsing, partially steroid-responsive syndrome comprising patchy, non-length-dependent radiculoneuropathy with diffuse pachymeningitis and widespread systemic disease, and recent dramatic response to novel mitogen-activated kinase pathway inhibition. We discuss the clinical characteristics, diagnosis, recent breakthroughs in pathogenesis and emerging treatment options for Rosai-Dorfman disease and for the histiocytoses with neurological sequelae, including Langerhans cell histiocytosis and Erdheim-Chester disease.

High inter-follicular spatial co-localization of CD8+FOXP3+ with CD4+CD8+ cells predicts favorable outcome in follicular lymphoma.

The spatial architecture of the lymphoid tissue in follicular lymphoma (FL) presents unique challenges to studying its immune microenvironment. We investigated the spatial interplay of T cells, macrophages, myeloid cells and natural killer T cells using multispectral immunofluorescence images of diagnostic biopsies of 32 patients. A deep learning-based image analysis pipeline was tailored to the needs of follicular lymphoma spatial histology research, enabling the identification of different immune cells within and outside neoplastic follicles. We analyzed the density and spatial co-localization of immune cells in the inter-follicular and intra-follicular regions of follicular lymphoma. Low inter-follicular density of CD8+FOXP3+ cells and co-localization of CD8+FOXP3+ with CD4+CD8+ cells were significantly associated with relapse (p = 0.0057 and p = 0.0019, respectively) and shorter time to progression after first-line treatment (Logrank p = 0.0097 and log-rank p = 0.0093, respectively). A low inter-follicular density of CD8+FOXP3+ cells is associated with increased risk of relapse independent of follicular lymphoma international prognostic index (FLIPI) (p = 0.038, Hazard ratio (HR) = 0.42 [0.19, 0.95], but not independent of co-localization of CD8+FOXP3+ with CD4+CD8+ cells (p = 0.43). Co-localization of CD8+FOXP3+ with CD4+CD8+ cells is predictors of time to relapse independent of the FLIPI score and density of CD8+FOXP3+ cells (p = 0.027, HR = 0.0019 [7.19 × 10-6 , 0.49], This suggests a potential role of inter-follicular CD8+FOXP3+ and CD4+CD8+ cells in the disease progression of FL, warranting further validation on larger patient cohorts.

227Th-Labeled Anti-CD22 Antibody (BAY 1862864) in Relapsed/Refractory CD22-Positive Non-Hodgkin Lymphoma: A First-in-Human, Phase I Study.

Background: BAY 1862864 is an α-particle emitting 227Th-labeled CD22-targeting antibody. This first-in-human dose-escalation phase I study evaluated BAY 1862864 in patients with CD22-positive relapsed/refractory B cell non-Hodgkin lymphoma (R/R-NHL). Materials and Methods: BAY 1862864 intravenous injections were administered at the starting 227Th radioactivity dose of 1.5 MBq (2 or 10 mg antibody), and the radioactivity dose escalated in ∼1.5 MBq increments (10 mg antibody) until the maximum tolerated dose (MTD) was reported. The primary objective was to determine the safety, tolerability, and MTD. Results: Twenty-one patients received BAY 1862864. Two dose-limiting toxicities (grade 3 febrile neutropenia and grade 4 thrombocytopenia) were reported in one patient in the 4.6 MBq (10 mg antibody) cohort. The MTD was not reached. Ten (48%) patients reported grade ≥3 treatment-emergent adverse events, with the most common being neutropenia, thrombocytopenia, and leukopenia, each occurring in 3 (14%) patients. Pharmacokinetics demonstrated the dose proportionality and stability of BAY 1862864 in the blood. The objective response rate (ORR) was 25% (5/21 patients) according to the LUGANO 2014 criteria, including 1 complete and 4 partial responses. The ORR was 11% (1/9) and 30% (3/10) in patients with relapsed high- and low-grade lymphomas, respectively. Conclusions: BAY 1862864 was safe and tolerated in patients with R/R-NHL. Clinical Trial Registration numbers: NCT02581878 and EudraCT 2014-004140-36.

Real-world Outcomes With Rituximab-based Therapy for Posttransplant Lymphoproliferative Disease Arising After Solid Organ Transplant.

BACKGROUND: Optimal upfront therapy for posttransplant lymphoproliferative disease (PTLD) arising after solid organ transplant remains contentious. Rituximab monotherapy (R-Mono) in unselected patients has shown a lack of durable remissions. Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-based chemotherapy confers improved response rates, although concerns exist about toxicity. METHODS: This multicenter retrospective study reports outcomes for adults with biopsy-proven B-cell PTLD treated initially with R-Mono or Rituximab plus CHOP (R-CHOP). Selection of therapy was made according to physician preference. RESULTS: Among 101 patients, 41 received R-Mono and 60 had R-CHOP. Most (93%) had undergone renal or liver transplantation. R-CHOP showed a trend toward improved complete (53% versus 71%; P = 0.066) and overall (75% versus 90%; P = 0.054) response rates. In the R-Mono group, 13 of 41 (32%) subsequently received chemotherapy, while 25 of 41 (61%) remained progression-free without further therapy. With median follow-up of 47 months, overall survival (OS) was similar for R-Mono and R-CHOP, with 3-year OS of 71% and 63%, respectively (P = 0.722). Non-PTLD mortality was 3 of 41 (7%) and 4 of 60 (7%) within 12 months of R-Mono or R-CHOP, respectively. The International Prognostic Index was statistically significant, with low- (0-2 points) and high-risk (≥3 points) groups exhibiting 3-year OS of 78% and 54%, respectively (P = 0.0003). In low-risk PTLD, outcomes were similar between therapies. However, in high-risk disease R-Mono conferred an inferior complete response rate (21% versus 68%; P = 0.006), albeit with no impact on survival. CONCLUSIONS: Our data support R-Mono as initial therapy for PTLD arising after renal or liver transplantation. However, upfront R-CHOP may benefit selected high-risk cases in whom rapid attainment of response is desirable.

Haemophagocytic lymphohistiocytosis in adult critical care.

Haemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune dysregulation, characterised by extreme inflammation, fever, cytopaenias and organ dysfunction. HLH can be triggered by conditions such as infection, autoimmune disease and malignancy, among others. Both a familial and a secondary form have been described, the latter being increasingly recognised in adult patients with critical illness. HLH is difficult to diagnose, often under-recognised and carries a high mortality. Patients can present in a very similar fashion to sepsis and the two syndromes can co-exist and overlap, yet HLH requires specific immunosuppressive therapy. HLH should be actively excluded in patients with presumed sepsis who either lack a clear focus of infection or who are not responding to energetic infection management. Elevated serum ferritin is a key biomarker that may indicate the need for further investigations for HLH and can guide treatment. Early diagnosis and a multidisciplinary approach to HLH management may save lives.

Do Women Know Their Prepregnancy Weight?

OBJECTIVE: Prepregnancy weight may not always be known to women. A model was developed to estimate prepregnancy weight from measured pregnancy weight. METHODS: The model was developed and validated using participants from two studies (Project Viva, n = 301, model development; and Fit for Delivery [FFD], n = 401, model validation). Data from the third study (Programming Research in Obesity, Growth, Environment and Social Stressors [PROGRESS]), which included women from Mexico City, were used to demonstrate the utility of the newly developed model to objectively quantify prepregnancy weight. RESULTS: The model developed from the Project Viva study validated well with low bias (R2 = 0.95; y = 1.02x - 0.69; bias = 0.68 kg; 95% CI: -4.86 to 6.21). Predictions in women from FFD demonstrated good agreement (R2 = 0.96; y = 0.96x + 4.35; bias = 1.60 kg; 95% CI: -4.40 to 7.54; error range = -11.25 kg to 14.73 kg). High deviations from model predictions were observed in the Programming Research in PROGRESS (R2 = 0.81; y = 0.89x + 9.61; bias = 2.83 kg; 95% CI: -7.70 to 12.31; error range = -39.17 kg to 25.73 kg). The model was programmed into software (https://www.pbrc.edu/research-and-faculty/calculators/prepregnancy/). CONCLUSIONS: The developed model provides an alternative to determine prepregnancy weight in populations receiving routine health care that may not have accurate knowledge of prepregnancy weight. The software can identify misreporting and classification into incorrect gestational weight gain categories.

The cost-effectiveness of immediate treatment or watch and wait with deferred chemotherapy for advanced asymptomatic follicular lymphoma.

Recent evidence has shown that immediate treatment with rituximab induction, with and without maintenance, substantially reduces the need for further treatment in patients with advanced asymptomatic follicular lymphoma. This analysis estimates the cost-effectiveness of immediate treatment approaches in comparison to a watch and wait approach from the perspective of the UK National Health Service. A Markov decision model was developed to estimate the cost-effectiveness of treatment strategies in patients with asymptomatic follicular lymphoma. The model was populated using effectiveness data from a systematic literature review with the key clinical data sourced from a randomised trial, in which the treatment strategies were compared. Costs were estimated using UK national sources. In comparison to watchful waiting, both rituximab strategies were found to be more effective and cost saving. In comparison to rituximab induction, the addition of rituximab maintenance marginally increased effectiveness but substantially increased costs, resulting in an incremental cost-effectiveness ratio (ICER) of £69 406 per quality-adjusted life year (QALY). In probabilistic sensitivity analysis, rituximab induction was found to have a 68% probability of being cost-effective at a threshold of £20 000 per QALY. In conclusion, active treatment with rituximab induction is a cost-effective strategy to adopt in patients with asymptomatic follicular lymphoma.

Does cell-of-origin or MYC, BCL2 or BCL6 translocation status provide prognostic information beyond the International Prognostic Index score in patients with diffuse large B-cell lymphoma treated with rituximab and chemotherapy? A systematic review.

We examined the additional prognostic value for survival of cell-of-origin, and MYC, BCL2 and BCL6 translocation status to that provided by the International Prognostic Index in newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients treated firstline with rituximab-containing immunochemotherapy. We searched Medline, Premedline, Embase, the Cochrane Library, Web of Science, and ISI Proceedings (2000-2015) and assessed study risk-of-bias using a prognostic study checklist. Forty-four studies of moderate-high risk of bias with 100-712 participants were included. Immunohistochemistry-determined cell-of-origin, and BCL2 and BCL6 translocation status added no additional prognostic value. Half of the studies on gene expression profiling-determined cell-of-origin and MYC translocation status found that germinal center B-cell-like (GCB) and no translocation were associated with better overall survival (OS) whereas the remaining studies found no effect of these covariates. Further studies are required to ensure that biological information assessed using newer technologies can be reliably used for studies that incorporate newer agents targeting distinct molecular abnormalities identified in high-risk DLBCL patients.

Yoga Therapy in Children with Cystic Fibrosis Decreases Immediate Anxiety and Joint Pain.

This study was designed to determine whether yoga might alleviate symptoms of pain, sleep disturbance, anxiety, and depression in children with cystic fibrosis (CF). CF is the most common genetic, life-limiting chronic disease among Caucasian populations. It primarily affects the lungs but also many other secretory organs and consequently leads to significant morbidities. Research has shown that children with CF have significantly increased depression, anxiety, and pain compared to their healthy counterparts. Subjects participated in six one-on-one sessions over a 10-week period with a certified instructor who designed each yoga practice based on a preestablished list of 30 yoga asanas. Questionnaires evaluating pain, sleep disturbance, sustained anxiety, immediate anxiety, and depression were administered. Differences between premeasures and postmeasures were evaluated using a two-sided test. Twenty subjects were assessed (12 females/8 males), median age of 11 (7-20) years. Mean immediate anxiety scores decreased (before session to after session 29 to 23.6, respectively, p < 0.001). Joint pain improved (3.25 to 3.65, p = 0.028). CFQ-R emotion subscale improved from 79.2 to 85 (p = 0.073), and the respiratory subscale improved from 66.7 to 79.2 (p = 0.076). Other results were less notable. We conclude that yoga may reduce immediate anxiety and joint pain in patients with CF.

Maternal source of false-positive fetal sex chromosome aneuploidy in noninvasive prenatal testing.

BACKGROUND: The intent of noninvasive prenatal testing is to screen for fetal aneuploidies. The assumption is that overrepresented and underrepresented chromosomes are of fetal origin. However, this is not always the case. CASES: We report three cases in which maternal sex chromosome aneuploidy (confirmed by karyotype), two cases of which were previously unknown, resulted in false-positive results. In each, results were positive for fetal aneuploidy, but neonatal karyotypes confirmed normal karyotype. CONCLUSION: Noninvasive prenatal testing assesses the proportion of chromosomes 21, 18, 13, and sex chromosomes in maternal circulation. Intrinsic to the analysis is that the underrepresentations and overrepresentations are of fetal origin. We present three cases in which this assumption is not valid. We suggest that maternal sex chromosome aneuploidy be considered when results suggest fetal sex chromosome aneuploidies.

Rosai-Dorfman disease with spinal cord compression: a diagnostic challenge.

PURPOSE: Rosai-Dorfman disease (RDD) is an uncommon benign histiocytic proliferative disorder commonly involving the cervical lymph nodes and less frequently extranodal sites, including, rarely, the central nervous system, mainly intracranially. Spinal involvement is unusual. RDD is characterized by pathognomonic histopathological features, which are decisive in the definitive diagnosis. We present the case of a 75-year-old lady who presented with an isolated thoracic vertebral lesion. She underwent 3 CT-guided biopsies, all not confirmative for a definite diagnosis, and 2 open biopsies and debulking of the lesion. METHODS: The clinical notes, operation notes, investigations and clinic letters of the patient were reviewed. A literature search was performed using PubMed, with the keywords "Rosai-Dorfman disease", "sinus histiocytosis with massive lymphadenopathy", "histiocytic proliferative disorder". RESULTS: Only the histopathology after the last procedure was diagnostic for Rosai-Dorfman disease. The patient was treated with steroids with marked improvement in her clinical condition. CONCLUSIONS: This case demonstrates the challenge in making a diagnosis. RDD should be considered as a differential diagnosis in case of spinal lesion and non-diagnostic biopsy, especially in steroid sensitive lesions. The implications of the case are discussed.

EBV-driven diffuse large B-cell lymphoma confined to the liver in a patient with a history of idiopathic CD4 lymphocytopenia.

Idiopathic CD4 lymphocytopenia (ICL) is a rare immunodeficiency disorder. We describe a 49-year-old woman with a history of ICL who developed hepatic Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL). ICL was diagnosed at a time of her presentation with varicella-zoster virus (VZV) meningoencephalitis and chorioretinitis. Her CD4 count subsequently improved but remained at the lower limits of the normal range. Five years later she presented with cough, fever and night-sweat. She was found to have multiple liver nodules on MRI, fluorodeoxyglucose (FDG) avid on the positron emission tomography (PET) CT, histologically defined as DLBCL, EBV positive and of non-germinal centre type. To our knowledge this is the first reported case of EBV-positive DLBCL localised to the liver in the context of ICL. EBV-positive DLBCL typically occurs in immunocompromised individuals. The corticosteroid therapy she received for VZV meningoencephalitis may have contributed to the EBV reactivation with subsequent EBV-driven malignant transformation of B-cells.

Interim fluoro-2-deoxy-D-glucose-PET predicts response and progression-free survival in patients with Hodgkin lymphoma and HIV infection.

BACKGROUND: Interim PET scans in HIV-negative patients with Hodgkin lymphoma has emerged as one of the most important prognostic tools. However, equivalent studies in HIV-positive patients are yet to be performed. OBJECTIVE: We evaluated the prognostic value of interim [18F]-fluoro-2-deoxy-D-glucose-PET (18F-FDG PET) after two or three cycles of chemotherapy using adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) with concomitant HAART in HIV-positive patients with Hodgkin lymphoma. METHODS: Patients with advanced HIV-Hodgkin lymphoma (HIV-HL) from six UK centres were included. Interim PET scans after two or three cycles of ABVD (PET-2 or PET-3) were carried out. Prognostic analysis correlated the 2-year progression-free survival (PFS) rate with the interim PET result. RESULTS: Twenty-three evaluable patients were assessed, 21 achieved a negative interim PET and 22 achieved complete remission by computerized tomography scan criteria after ABVD therapy. After a median follow-up of 27 months (range 12-50), disease progression was seen in one patient. Treatment failure was seen in one of the two interim PET-positive patients and none of the interim PET-negative patients. The 2-year PFS for interim PET-positive patients was 50%, and 100% for interim PET-negative patients (P = 0.0012). CONCLUSION: A negative interim 18F-FDG PET result is highly predictive of treatment success in HIV-HL patients.