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Background Denosumab has been shown to reduce tumor size and progression, reform mineralized bone, and increase intralesional bone density in patients with giant cell tumor of bone (GCTB); however, radiologic assessment of tumors in bone is challenging. The study objective was to assess tumor response to denosumab using three different imaging parameters in a prespecified analysis in patients with GCTB from two phase 2 studies. Methods The studies enrolled adults and adolescents (skeletally mature and at least 12 years of age) with radiographically measurable GCTB that were given denosumab 120 mg every 4 weeks, with additional doses on days 8 and 15 of cycle 1. The proportion of patients with an objective tumor response was assessed using either Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST), European Organisation for Research and Treatment of Cancer response criteria (positron emission tomography [PET] scan criteria), or inverse Choi density/size (ICDS) criteria. Target lesions were measured by computed tomography or magnetic resonance imaging (both studies), PET (study 2 only), or plain film radiograph (study 2 only). Results Most patients (71.6%) had an objective tumor response by at least one response criteria. Per RECIST, 25.1% of patients had a response; per PET scan criteria, 96.2% had a response; per ICDS, 76.1% had a response. 68.5% had an objective tumor response ≥ 24 weeks. Using any criteria, crude incidence of response ranged from 56% (vertebrae/skull) to 91% (lung/soft tissue), and 98.2% had tumor control ≥ 24 weeks. Reduced PET avidity appeared to be an early sign of response to denosumab treatment. Conclusion Modified PET scan criteria and ICDS criteria indicate that most patients show responses and higher benefit rates than modified RECIST, and therefore may be useful for early assessment of response to denosumab. Trial registration ClinicalTrials.gov Clinical Trials Registry NCT00396279 (retrospectively registered November 6, 2006) and NCT00680992 (retrospectively registered May 20, 2008).

Chimeric antigen receptor (CAR) T cells can achieve sustained clinical benefit in B cell malignancies and autoimmune diseases. Despite the many potential advantages over autologous products, allogeneic CAR T cells carry a higher risk of rejection, which may limit persistence and therapeutic efficacy. We report the design and evaluation of an optimized CD70 CAR that prevents rejection of allogeneic CAR T cells by targeting activated alloreactive lymphocytes. Co-expression of this CD70 CAR with a CD19 CAR resulted in sustained CAR T cell persistence in the presence of alloreactive lymphocytes and prolonged antitumor activity in a CD19 antigen escape model. In vivo, CD19/CD70 dual CAR T cells eliminated B cells and CD70 T cells derived from patients with systemic lupus erythematosus in humanized mouse models, resulting in reduced immunoglobulin production. An allogeneic CD19/CD70 dual CAR T cell therapy may therefore broaden clinical applicability while enabling the use of less intensive lymphodepleting conditioning regimens prior to CAR T cell infusion.

Background Surgical resection with curative intent for giant cell tumor of bone (GCTB) may be associated with severe morbidity. This interim analysis evaluated reduction in surgical invasiveness after denosumab treatment in patients with resectable GCTB. Methods Patients with primary or recurrent GCTB, for whom the initially planned surgery was associated with functional compromise or morbidity, received denosumab 120 mg subcutaneously every 4 weeks (additional doses on days 8 and 15 of the first cycle). Planned and actual GCTB-related surgical procedures before and after denosumab treatment were reported. Patients were followed for surgical outcome, adverse events, and recurrence following resection. Results Overall, 222 patients were evaluable for surgical downstaging (54 % were women; median age 34 years). Lesions (67 % primary and 33 % recurrent) were located in the axial (15 %) and appendicular skeleton (85 %). At the data cutoff date, most patients had not yet undergone surgery ( n  = 106; 48 %) or had a less morbid procedure ( n  = 84; 38 %) than originally planned. Median (interquartile range) time on denosumab was 19.5 (12.4–28.6) months for the 106 patients who had not undergone surgery and were continuing on monthly denosumab. Native joint preservation was 96 % ( n  = 24/25) for patients with planned joint/prosthesis replacement and 86 % ( n  = 30/35) for patients with planned joint resection/fusion. Of the 116 patients who had surgery (median postsurgical follow-up 13.0 [8.5–17.9] months), local recurrence occurred in 17 (15 %) patients. Conclusion For patients with resectable GCTB, neoadjuvant denosumab therapy resulted in beneficial surgical downstaging, including either no surgery or a less morbid surgical procedure.

Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6) 1 . Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4 + T cells. Using single-cell sequencing, we identify a rare population of HHV-6 ‘super-expressors’ (about 1 in 300–10,000 cells) that possess high viral transcriptional activity, among research-grade allogeneic chimeric antigen receptor (CAR) T cells. By analysing single-cell sequencing data from patients receiving cell therapy products that are approved by the US Food and Drug Administration 2 or are in clinical studies 3 – 5 , we identify the presence of HHV-6-super-expressor CAR T cells in patients in vivo. Together, the findings of our study demonstrate the utility of comprehensive genomics analyses in implicating cell therapy products as a potential source contributing to the lytic HHV-6 infection that has been reported in clinical trials 1 , 6 – 8 and may influence the design and production of autologous and allogeneic cell therapies. Genomics analyses reveal that in vitro culture of CAR T cells can lead to reactivation of a latent herpesvirus, which might be involved in complications in patients receiving associated cell therapies.

Crohn’s disease is a chronic disorder associated with a high rate of recurrence and morbidity. New therapies have been developed over the last few decades that have improved both induction of remission and lowered recurrence rates which led to improved outcomes. An overarching set of principles connects these therapies with prevention of recurrence being the top priority. To achieve the best outcomes, patients must be carefully chosen, optimized, and the correct surgery performed by an experienced and multidisciplinary team at the appropriate time. We seek to outline the current evidence-based approach to the surgical management of Crohn’s disease.

Mechanisms of chimeric antigen receptor (CAR) T cell-mediated antitumor immunity and toxicity remain poorly characterized because few studies examine the intact tumor microenvironment (TME) following CAR T cell infusion. Axicabtagene ciloleucel is an autologous anti-CD19 CAR T cell therapy approved for patients with large B cell lymphoma. We devised multiplex immunostaining and ISH assays to interrogate CAR T cells and other immune cell infiltrates in biopsies of diffuse large B cell lymphoma following axicabtagene ciloleucel infusion. We found that a majority of intratumoral CAR T cells expressed markers of T cell activation but, unexpectedly, constituted ≤5% of all T cells within the TME 5 days or more after therapy. Large numbers of T cells without CAR were also activated within the TME after axicabtagene ciloleucel infusion; these cells were positive for Ki-67, IFN-γ, granzyme B (GzmB), and/or PD-1 and were found at the highest levels in biopsies with CAR T cells. Additionally, non-CAR immune cells were the exclusive source of IL-6, a cytokine associated with cytokine release syndrome, and were found at their highest numbers in biopsies with CAR T cells. These data suggest that intratumoral CAR T cells are associated with non-CAR immune cell activation within the TME with both beneficial and pathological effects.

Or perhaps literary impressionism describes the attempt to capture in densely descriptive prose the unique settings characteristic of Impressionist canvases, as in the mock-pastoral romance of Maupassants A Day in the Country, which evokes the vulgar suburban gaiety of a Renoir boating party, complete with a drunken dejeuner sur ľherbe and randy canotiers (Renoirs son, Jean, directed a film adaptation of the story in 1936 starring Sylvia Rataille that deliberately pays homage to his fathers paintings). The scholar Jesse Matz, whose work has been influential in defining the term and making it a fruitful subject of critical discussion, writes that literary impressionism \"is still a dominant style of mainstream literary fiction\" and cites Zadie Smith's NW as a work so completely impressionist \"that it might seem to be a throwback.\" The first usage of the term is often credited to the literary critic Ferdinand Brunetiere, who defined literary impressionism in an 1879 review of a novel by Alphonse Daudet as \"a systematic transposition of the means of expression of one art, which is the art of painting, into the domain of another art, which is the art of writing.\" Pound's dictate echoed the more foreboding language of the critic Max Nordau, who felt that the intermixture of the art of the painter and the art of the poet made impressionism in literature the height of fin de siede decadence, \"an example of that atavism which we have noticed as the most distinctive feature in the mental life of degenerates.\"

Study Objectives: Obstructive sleep apnea (OSA) prevalence increases with age, but whether OSA-related sleep disruption could interrupt the processing of previously encoded wake information thought to normally occur during sleep in cognitively normal older adults remains unknown. Methods: Fifty-two older (age = 66.9 ± 7.7 years, 56% female), community-dwelling, cognitively normal adults explored a 3-D maze environment and then performed 3 timed trials before (evening) and after (morning) sleep recorded with polysomnography with a 20-minute morning psychomotor vigilance test. Results: Twenty-two (22) participants had untreated OSA [apnea-hypopnea index (AHI4%) ≥ 5 events/h] where severity was mild on average [median (interquartile range); AHI4% = 11.0 (20.7) events/h] and 30 participants had an AHI4% < 5 events/h. No significant differences were observed in overnight percent change in completion time or in the pattern of evening presleep maze performance. However, during the morning postsleep trials, there was a significant interaction between OSA group and morning trial number such that participants with OSA performed worse on average with each subsequent morning trial, whereas those without OSA showed improvements. There were no significant differences in morning psychomotor vigilance test performance, suggesting that vigilance is unlikely to account for this difference in morning maze performance. Increasing relative frontal slow wave activity was associated with better overnight maze performance improvement in participants with OSA ( r = .51, P = .02) but not in those without OSA, and no differences in slow wave activity were observed between groups. Conclusions: OSA alters morning performance in spatial navigation independent of a deleterious effect on morning vigilance or evening navigation performance. Relative frontal slow wave activity is associated with overnight performance change in older participants with OSA, but not those without. Citation: Mullins AE, Williams MK, Kam K, et al. Effects of obstructive sleep apnea on human spatial navigational memory processing in cognitively normal older individuals. J Clin Sleep Med . 2021;17(5):939–948.

BackgroundTumor infiltrating lymphocyte (TIL) products made from tumor digests showed a high overall response rate (ORR; 67%) and complete response (CR) rate (19%) and a safety profile consistent with lymphodepletion and high-dose interleukin (IL)-2 in a retrospective analysis of a single center experience of TILs for compassionate use treatment of advanced cutaneous melanoma (n=21; Hawkins, et al. AACR 2021. ePoster LB150). This subanalysis assesses outcomes for patients who received TILs after prior checkpoint inhibition, a subset with limited treatment options.MethodsPatients with advanced cutaneous melanoma and no standard of care treatment options received lymphodepleting chemotherapy (cyclophosphamide ×2 days; fludarabine ×5 days) followed by TIL infusion and post TIL high-dose IL-2. Safety was assessed by clinically significant adverse events (AEs). Efficacy assessments included ORR, CR rate, and overall survival (OS).ResultsOf 21 patients who underwent treatment between October 2011 and August 2019, median age was 45 years, median number of disease sites was 4, 100% of patients had M1c or M1d disease (33% with M1d), average number of prior therapies was 3 (any checkpoint inhibitor, 91%; BRAF inhibitor [BRAFi], 52%; and MEKi, 24%), and 52% were BRAF-mutated. Twelve patients received prior PD-1i therapy and are reported herein. Baseline characteristics were similar between the overall and prior PD-1i subgroup populations. All patients in the prior PD-1i subgroup received prior CTLA-4i, and all BRAF-mutated patients received prior BRAFi alone ± MEKi. The most commonly reported AEs post-TIL infusion were consistent between the overall and prior PD-1i subgroup populations and included thrombocytopenia (62% and 75%, respectively), pyrexia (57% and 50%), and rigors (43% and 50%). No treatment-related deaths occurred. With a median follow-up of 45.5 months, the ORR and CR rate for the prior PD-1i subgroup were 58% and 8%, respectively. At data cutoff, 2 of 12 patients (17%) had durable ongoing responses (>30 months post-TIL infusion). Median OS in the prior PD-1i subgroup and overall population was 21.3 months.ConclusionsIn this subanalysis of patients with relapsed advanced melanoma after both PD-1i and CTLA-4i, and for some, BRAFi, outcomes of unselected autologous TILs were similar to those observed in all treated patients, with high response rates and a safety profile consistent with that of TIL therapy. Unselected TILs may address the unmet medical need for the poor-risk subset of patients with advanced melanoma who experience disease progression following checkpoint inhibition and, if applicable, targeted therapy.AcknowledgementsThe authors would like to thank all the staff within The Christie NHS Foundation Trust and The Christie Clinic who worked tirelessly to provide high–quality care to all the patients in this report. Medical writing support was provided by Christopher Waldapfel, PharmD, of Instil Bio, Inc. and Jennifer Yang, PhD, of Nexus GG Science, with funding from Instil Bio, Inc.Ethics ApprovalAs a compassionate use study, the treatment was approved by institutional review board and National Health Service commissioning.