Investigating and modeling positron emission tomography factors associated with large cell transformation from low‐grade lymphomas

Abstract Low‐grade lymphomas have a 1%–3% annual risk of transformation to a high‐grade histology, and prognostic factors remain undefined. We set to investigate the role of positron emission tomography (PET) metrics in identification of transformation in a retrospective case‐control series of patients matched by histology and follow‐up time. We measured PET parameters including maximum standard uptake value (SUV‐max) and total lesion glycolysis (TLG), and developed a PET feature and lactate dehydrogenase (LDH)‐based model to identify transformation status within discovery and validation cohorts. For our discovery cohort, we identified 53 patients with transformation and 53 controls with a similar distribution of follicular lymphoma (FL). Time to transformation and control follow‐up time was similar. We observed a significant incremental increase in SUV‐max and TLG between control, pretransformation and post‐transformation groups (P < 0.05). By multivariable analysis, we identified a significant interaction between SUV‐max and TLG such that SUV‐max had highest significance for low volume cases (P = 0.04). We developed a scoring model incorporating SUV‐max, TLG, and serum LDH with improved identification of transformation (area under the curve [AUC] = 0.91). Our model performed similarly for our validation cohort of 23 patients (AUC = 0.90). With external and prospective validation, our scoring model may provide a specific and noninvasive tool for risk stratification for patients with low‐grade lymphoma

Cellular and humoral immune response to SARS-CoV-2 vaccination and booster dose in immunosuppressed patients: An observational cohort study.

BackgroundHumoral and cellular immune responses to SARS-CoV-2 vaccination among immunosuppressed patients remain poorly defined, as well as variables associated with poor response.MethodsWe performed a retrospective observational cohort study at a large Northern California healthcare system of infection-naïve individuals fully vaccinated against SARS-CoV-2 (mRNA-1273, BNT162b2, or Ad26.COV2.S) with clinical SARS-CoV-2 interferon gamma release assay (IGRA) ordered between January through November 2021. Humoral and cellular immune responses were measured by anti-SARS-CoV-2 S1 IgG ELISA (anti-S1 IgG) and IGRA, respectively, following primary and/or booster vaccination.Results496 immunosuppressed patients (54% female; median age 50 years) were included. 62% (261/419) of patients had positive anti-S1 IgG and 71% (277/389) had positive IGRA after primary vaccination, with 20% of patients having a positive IGRA only. Following booster, 69% (81/118) had positive anti-S1 IgG and 73% (91/124) had positive IGRA. Factors associated with low humoral response rates after primary vaccination included anti-CD20 monoclonal antibodies (P&nbsp;&lt;&nbsp;0.001), sphingosine 1-phsophate (S1P) receptor modulators (P&nbsp;&lt;&nbsp;0.001), mycophenolate (P&nbsp;=&nbsp;0.002), and B cell lymphoma (P&nbsp;=&nbsp;0.004); those associated with low cellular response rates included S1P receptor modulators (P&nbsp;&lt;&nbsp;0.001) and mycophenolate (P&nbsp;&lt;&nbsp;0.001). Of patients who had poor humoral response to primary vaccination, 35% (18/52) developed a significantly higher response after the booster. Only 5% (2/42) of patients developed a significantly higher cellular response to the booster dose compared to primary vaccination.ConclusionsHumoral and cellular response rates to primary and booster SARS-CoV-2 vaccination differ among immunosuppressed patient groups. Clinical testing of cellular immunity is important in monitoring vaccine response in vulnerable populations

The embryo as moral work object: PGD/IVF staff views and experiences

Copyright @ 2008 the authors. This article is available in accordance with the Creative Commons Deed, Attribution 2.5, see http://creativecommons.org/licenses/by-nc-nd/2.5/deed.en_CA.We report on one aspect of a study that explored the views and experiences of practitioners and scientists on social, ethical and clinical dilemmas encountered when working in the field of preimplantation genetic diagnosis (PGD) for serious genetic disorders. The study produced an ethnography based on observation, interviews and ethics discussion groups with staff from two PGD/IVF Units in the UK. We focus here on staff perceptions of work with embryos that entails disposing of ‘affected’ or ‘spare’ embryos or using them for research. A variety of views were expressed on the ‘embryo question’ in contrast to polarised media debates. We argue that the prevailing policy acceptance of destroying affected embryos, and allowing research on embryos up to 14 days leaves some staff with rarely reported, ambivalent feelings. Staff views are under-researched in this area and we focus on how they may reconcile their personal moral views with the ethical framework in their field. Staff construct embryos in a variety of ways as ‘moral work objects’. This allows them to shift attention between micro-level and overarching institutional work goals, building on Casper's concept of ‘work objects’ and focusing on negotiation of the social order in a morally contested field.The Wellcome Trust Biomedical Ethics Programme, who funded the projects‘Facilitating choice, framing choice: the experience of staff working in pre-implantation genetic diagnosis’ (no: 074935), and ‘Ethical Frameworks for Embryo Donation:the views and practices of IVF/PGD staff’ (no: 081414)

The development of a scale of the Guttman Type for the assessment of mobility disability in multiple sclerosis

Objective: The aim of the study was to develop a valid and reliable unidimensional scale of the Guttman type for the assessment of mobility disability in multiple sclerosis (MS). Subjects: Sixty-eight subjects with a definite diagnosis of MS participated.They were attending as outpatients at a MS unit at a District General Hospital. Thirty had the primary progressive pattern of disease, and 38 had the relapsing-remitting pattern. Methods: Formal assessments used for neurological disability were inspected, and 14 test items of gross motor function were extracted and ordered according to two criteria. These were that actions progressed from lying, to sitting, to standing and walking tasks, and that they progressed from broader to narrower bases of support. All subjects carried out all test items which were scored as ‘pass’ or ‘fail’. Analysis: Data were tested for internal consistency, reliability, inter item correlation, reproducibility and scalability. On the basis of the results, the items were re-ordered in rank, and reduced to eleven tests. The eleven item scale was re-analysed. Results: Results showed that the scale had an internal consistency of 0.88 (alpha coefficient) and a coefficient of reproducibility (CR) of 0.95 and above for both MS subject groups. The coefficient of scalability (CS) for items was 0.78 for primary progressive subjects and 0.74 for the relapsing-remitting group. Reliability ranged from good (kappa = 0.49) for one item, to perfect for six items. Conclusion: The scale was demonstrated to be a hierarchical scale of the Guttman type exhibiting homogeneous unidimensionality and good reliability. The high CR indicated that scores may be summed, and the very acceptable levels of CS indicated that the cumulative scores are meaningful within the defined concept of hierarchy used in this study

Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling.

The scarcity of malignant Hodgkin and Reed-Sternberg (HRS) cells hamper tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). Liquid biopsies, in contrast, show promise for molecular profiling of cHL due to relatively high circulating tumor DNA (ctDNA) levels. Here, we show that the plasma representation of mutations exceeds the bulk tumor representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumors, we demonstrate HRS ctDNA shedding to be shaped by DNASE1L3, whose increased tumor microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R-mutations that are dependent on IL13 signaling and therapeutically targetable with IL4R blocking antibodies. Finally, using PhasED-Seq we demonstrate the clinical value of pre- and on-treatment ctDNA levels for longitudinally refining cHL risk prediction, and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL as well as capturing molecularly distinct subtypes with diagnostic, prognostic, and therapeutic potential