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Understanding the dynamics of evolution of Follicular Lymphoma (FL) clones during disease progression is important for monitoring and targeting this tumor effectively. Genetic profiling of serial FL biopsies and examples of FL transmission following bone marrow transplant suggest that this disease may evolve by divergent evolution from a common ancestor cell. However where this ancestor cell resides and how it evolves is still unclear. The analysis of the pattern of somatic hypermutation of the immunoglobulin gene (Ig) is traditionally used for tracking the physiological clonal evolution of B cells within the germinal center and allows to discriminate those cells that have just entered the germinal center and display features of ancestor cells from those B cells that keep re-circulating across different lymphoid organs. Here we investigated the pattern of somatic hypermutation of the heavy chain of the immunoglobulin gene (IgH-VH) in 4 flow-sorted B cells subpopulations belonging to different stages of differentiation, from sequential lymph node biopsies of cases displaying diverse patterns of evolution, using the GS-FLX Titanium sequencing platform. We observed an unexpectedly high level of clonality, with hundreds of distinct tumor subclones in the different subpopulations from the same sample, the majority detected at a frequency <10-2. By using a lineage trees analysis we observed in all our FL and t-FL cases that the oligoclonal FL population was trapped in a narrow intermediate stage of maturation that maintains the capacity to undergo SHM, but was unable to further differentiate. The presence of such a complex architecture highlights challenges currently encountered in finding a cure for this disease.

Background The study objectives were to assess the prognostic value of quantitative PET and to test whether combining baseline metabolic tumour burden with early PET response could improve predictive power in DLBCL. Methods A total of 147 patients with DLBCL underwent FDG-PET/CT scans before and after two cycles of RCHOP. Quantitative parameters including metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were measured, as well as the percentage change in these parameters. Cox regression analysis was used to test the relationship between progression-free survival (PFS) and the study variables. Receiver operator characteristics (ROC) analysis determined the optimal cut-off for quantitative variables, and Kaplan–Meier survival analysis was performed. Results The median follow-up was 3.8 years. As MTV and TLG measures correlated strongly, only MTV measures were used for multivariate analysis (MVA). Baseline MTV (MTV-0) was the only statistically significant predictor of PFS on MVA. The optimal cut-off for MTV-0 was 396 cm 3 . A model combing MTV-0 and Deauville score (DS) separated the population into three distinct prognostic groups: good (MTV-0 < 400; 5-year PFS > 90 %), intermediate (MTV-0 ≥ 400+ DS1-3; 5-year PFS 58.5 %) and poor (MTV-0 ≥ 400+ DS4-5; 5-year PFS 29.7 %) Conclusions MTV-0 is an important prognostic factor in DLBCL. Combining MTV-0 and early PET/CT response improves the predictive power of interim PET and defines a poor-prognosis group in whom most of the events occur.

Jessica Okosun, Csaba Bödör and colleagues performed whole-genome or whole-exome sequencing on 10 follicular lymphoma and transformed follicular lymphoma pairs, followed by deep sequencing of 28 target genes in an additional 122 cases. They identify recurrent mutations in linker histone genes and genes involved in JAK-STAT signaling, NF-κB signaling and B cell development. Follicular lymphoma is an incurable malignancy 1 , with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma–transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes ( CREBBP , EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling ( MYD88 and TNFAIP3 ) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy.

Background Using an updated dataset with more patients and extended follow-up, we further established cancer patient characteristics associated with COVID-19 death. Methods Data on all cancer patients with a positive reverse transcription-polymerase chain reaction swab for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) at Guy’s Cancer Centre and King’s College Hospital between 29 February and 31 July 2020 was used. Cox proportional hazards regression was performed to identify which factors were associated with COVID-19 mortality. Results Three hundred and six SARS-CoV-2-positive cancer patients were included. Seventy-one had mild/moderate and 29% had severe COVID-19. Seventy-two patients died of COVID-19 (24%), of whom 35 died <7 days. Male sex [hazard ratio (HR): 1.97 (95% confidence interval (CI): 1.15–3.38)], Asian ethnicity [3.42 (1. 59–7.35)], haematological cancer [2.03 (1.16–3.56)] and a cancer diagnosis for >2–5 years [2.81 (1.41–5.59)] or ≥5 years were associated with an increased mortality. Age >60 years and raised C-reactive protein (CRP) were also associated with COVID-19 death. Haematological cancer, a longer-established cancer diagnosis, dyspnoea at diagnosis and raised CRP were indicative of early COVID-19-related death in cancer patients (<7 days from diagnosis). Conclusions Findings further substantiate evidence for increased risk of COVID-19 mortality for male and Asian cancer patients, and those with haematological malignancies or a cancer diagnosis >2 years. These factors should be accounted for when making clinical decisions for cancer patients.

Rituximab has become the mainstay of systemic therapy for patients with follicular lymphoma and is associated with an improved outcome at both diagnosis and relapse, either as induction or maintenance therapy. The challenge lies in maximizing the benefit of this drug in a condition characterized by multiple relapses.

Abstract Case report - Introduction IgG4-related disease (IgG4-RD) is increasingly recognised in rheumatology practice. We describe a case of orbital swelling initially diagnosed as IgG4-RD. It was exquisitely steroid responsive and she was treated with 6 years of immunosuppression but her symptoms later deteriorated. She developed worsening left eye swelling that required debulking surgery; histopathology demonstrated IgG4-positive lymphoma. She had an excellent response to localised radiotherapy and remains in remission. Although her initial presentation was typical of IgG4-RD, her subsequent lack of response to steroids prompted reconsideration of the initial diagnosis and re-examination of her previous biopsy specimen, confirming IgG4-positive Iymphoma at both timepoints. Case report - Case description A 25-year-old lady presented in 2008 with a swollen left eye. She had a history of childhood eczema, asthma and sinusitis. Diagnostic excision was undertaken; histology was considered to show chronic inflammation, scattered eosinophils, dense fibrosis and no granulomas. She was diagnosed with a ‘granulomatosis with polyangiitis-like’ orbital pseudotumour. It was exquisitely steroid responsive; mycophenolate mofetil was added from an early stage of treatment. The patient was referred to rheumatology 3 years after diagnosis as she was unable to reduce her prednisolone below 5mg daily. Her immunology screen was negative. Although her plasma IgG4 levels were normal at 0.14g/L, the original histology was reviewed and immunostained for IgG4. This demonstrated more than 80% of plasma cells to be IgG4 positive, with the previously noted dense fibrosis and chronic inflammatory infiltrate. Her diagnosis was revised to orbital IgG4-RD. She commenced azathioprine as she was planning a pregnancy. Following an uncomplicated pregnancy in 2014, her symptoms significantly deteriorated, with worsening pain, discharge and swelling in her left eye. A repeat MRI scan showed a new cuff of abnormal tissue within the lateral aspect of the left orbit. She was referred to ophthalmology and underwent left anterior orbitotomy with debulking. Histopathology at this time was consistent with extranodal marginal zone lymphoma (EMZL) of MALT (mucosa-associated lymphoid tissue) type, IgG4 positive. An extraordinary feature was an abundance of crystal-storing histiocytes, presumed to contain ingested IgG4. To investigate whether she had an IgG4-secreting lymphoma from the beginning or whether there had been malignant transformation of her orbital IgG4-RD, the histology from 2009 was reviewed. This was considered to indicate a MALT-type EMZL. The patient was referred to haematology and she was treated with localised radiotherapy with an excellent response. She remains in remission following this and she has subsequently been discharged from haematology follow-up. Case report - Discussion IgG4-RD is a condition involving fibroinflammatory lesions that can affect any organ in the body. As a newly recognised condition, the role of IgG4 in IgG4-RD is still not fully understood. Questions that remain unanswered include whether or not IgG4 is directly pathogenic and whether there is an increased risk of malignancy in patients with IgG4-RD. Our patient’s case demonstrates how IgG4-positive lymphoma can mimic IgG4-RD. It is important to keep a broad differential diagnosis in complex cases, and to support the eventual diagnosis with blood results, imaging studies and histology. It is essential to involve colleagues in radiology and histopathology so that a multidisciplinary decision can be made with regards to management. IgG4-RD is a steroid-responsive condition. When there is poor response to conventional treatment, this should raise doubts regarding the diagnosis, and it would be prudent to consider a repeat biopsy as well as obtaining previous pathology specimens so that they can be re-reviewed. Ocular adnexal lymphomas form 1—2% of non-Hodgkin lymphomas and 8% of extranodal lymphomas. Over recent decades the incidence has increased, partly reflecting better diagnostic techniques. The most common subtype of ocular adnexal lymphomas are EMZL of MALT type, as in our patient. There are several case reports of lymphoma arising in patients with established IgG4-RD, raising the question of potential lymphomagenesis in IgG4-RD. The earliest reports come from Asia and most have been reported in patients with ocular IgG4-RD. However, the link between malignancy and IgG4-RD is still being investigated. It is important to consider a potential malignancy when managing patients with IgG4-RD, especially if there is a lack of response to steroids. Case report - Key learning points There is no single diagnostic test for IgG4-RD. Diagnosis should be based on the overall clinical picture, supported by blood results, imaging and histopathology. IgG4-RD is a steroid-responsive disease. If there is a poor response to treatment, the diagnosis should be re-considered. Re-examination of previous biopsy specimens can be invaluable, especially in patients refractory to standard treatment. The link between IgG4-RD and malignancy has not been established and it is important to remain vigilant. As ocular adnexal lymphomas are not uncommon, it is important to keep this differential diagnosis in mind when reviewing patients with eye swelling thought to be secondary to IgG4-related ocular disease.

Very few studies investigating COVID-19 in cancer patients have included cancer patients as controls. We aimed to identify factors associated with the risk of testing positive for SARS CoV2 infection in a cohort of cancer patients. We analyzed data from all cancer patients swabbed for COVID-19 between 1st March and 31st July 2020 at Guy’s Cancer Centre. We conducted logistic regression analyses to identify which factors were associated with a positive COVID-19 test. Results: Of the 2152 patients tested for COVID-19, 190 (9%) tested positive. Male sex, black ethnicity, and hematological cancer type were positively associated with risk of COVID-19 (OR = 1.85, 95%CI:1.37–2.51; OR = 1.93, 95%CI:1.31–2.84; OR = 2.29, 95%CI:1.45–3.62, respectively) as compared to females, white ethnicity, or solid cancer type, respectively. Male, Asian ethnicity, and hematological cancer type were associated with an increased risk of severe COVID-19 (OR = 3.12, 95%CI:1.58–6.14; OR = 2.97, 95%CI:1.00–8.93; OR = 2.43, 95%CI:1.00–5.90, respectively). This study is one of the first to compare the risk of COVID-19 incidence and severity in cancer patients when including cancer patients as controls. Results from this study have echoed those of previous reports, that patients who are male, of black or Asian ethnicity, or with a hematological malignancy are at an increased risk of COVID-19.

Anaemia is an independent, commonly under-recognised risk factor for delirium. Prompt management of anaemia and its underlying aetiology could result in recovery from delirium and associated psychotic manifestations. We report this unprecedented case of complete recovery from delirium and challenging behaviour, following treatment of autoimmune haemolytic anaemia with rituximab.

Understanding the dynamics of evolution of Follicular Lymphoma (FL) clones during disease progression is important for monitoring and targeting this tumor effectively. Genetic profiling of serial FL biopsies and examples of FL transmission following bone marrow transplant suggest that this disease may evolve by divergent evolution from a common ancestor cell. However where this ancestor cell resides and how it evolves is still unclear. The analysis of the pattern of somatic hypermutation of the immunoglobulin gene (Ig) is traditionally used for tracking the physiological clonal evolution of B cells within the germinal center and allows to discriminate those cells that have just entered the germinal center and display features of ancestor cells from those B cells that keep re-circulating across different lymphoid organs. Here we investigated the pattern of somatic hypermutation of the heavy chain of the immunoglobulin gene (IgH-VH) in 4 flow-sorted B cells subpopulations belonging to different stages of differentiation, from sequential lymph node biopsies of cases displaying diverse patterns of evolution, using the GS-FLX Titanium sequencing platform. We observed an unexpectedly high level of clonality, with hundreds of distinct tumor subclones in the different subpopulations from the same sample, the majority detected at a frequency <10-2. By using a lineage trees analysis we observed in all our FL and t-FL cases that the oligoclonal FL population was trapped in a narrow intermediate stage of maturation that maintains the capacity to undergo SHM, but was unable to further differentiate. The presence of such a complex architecture highlights challenges currently encountered in finding a cure for this disease.