Novel agents in relapsed/refractory diffuse large B-cell lymphoma.

Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), ineligible for or relapsing after autologous stem-cell transplant or chimeric antigen-receptor T-cell therapies have poor outcomes. Several novel agents, polatuzumab vedotin, tafasitamab, loncastuximab tesirine, and selinexor, have been approved and offer new opportunities for this difficult to treat population. Studies are evaluating combination of these agents with chemotherapy and other emerging therapies. Additionally, advances in our understanding of DLBCL biology, genetics, and immune microenvironment have allowed for the identification of new therapeutic targets like Ikaros and Aiolos, IRAK4, MALT1, and CD47 with several agents in ongoing clinical trials. In this chapter we review updated data supporting the use of the approved agents and discuss other emerging novel therapies for patients with R/R DLBCL.

Waveguide-integrated mid-infrared photodetection using graphene on a scalable chalcogenide glass platform.

The development of compact and fieldable mid-infrared (mid-IR) spectroscopy devices represents a critical challenge for distributed sensing with applications from gas leak detection to environmental monitoring. Recent work has focused on mid-IR photonic integrated circuit (PIC) sensing platforms and waveguide-integrated mid-IR light sources and detectors based on semiconductors such as PbTe, black phosphorus and tellurene. However, material bandgaps and reliance on SiO2 substrates limit operation to wavelengths λ ≲ 4 µm. Here we overcome these challenges with a chalcogenide glass-on-CaF2 PIC architecture incorporating split-gate photothermoelectric graphene photodetectors. Our design extends operation to λ = 5.2 µm with a Johnson noise-limited noise-equivalent power of 1.1 nW/Hz1/2, no fall-off in photoresponse up to f = 1 MHz, and a predicted 3-dB bandwidth of f3dB > 1 GHz. This mid-IR PIC platform readily extends to longer wavelengths and opens the door to applications from distributed gas sensing and portable dual comb spectroscopy to weather-resilient free space optical communications.

Imaging metasurfaces based on graphene-loaded slot antennas.

Spectral imagers, the classic example being the color camera, are ubiquitous in everyday life. However, most such imagers rely on filter arrays that absorb light outside each spectral channel, yielding ∼1/N efficiency for an N-channel imager. This is especially undesirable in thermal infrared (IR) wavelengths, where sensor detectivities are low. We propose an efficient and compact thermal infrared spectral imager comprising a metasurface composed of sub-wavelength-spaced, differently-tuned slot antennas coupled to photosensitive elements. Here, we demonstrate this idea using graphene, which features a photoresponse up to thermal IR wavelengths. The combined antenna resonances yield broadband absorption in the graphene exceeding the 1/N efficiency limit. We establish a circuit model for the antennas' optical properties and demonstrate consistency with full-wave simulations. We also theoretically demonstrate ∼58% free space-to-graphene photodetector coupling efficiency, averaged over the 1050 cm-1 to 1700 cm-1 wavenumber range, for a four-spectral-channel gold metasurface with a 0.883 µm by 6.0 µm antenna pitch. This research paves the way towards compact CMOS-integrable thermal IR spectral imagers.

Evaluation of the prognostic utility of bone marrow biopsy in diffuse large B-Cell lymphoma in the SEER-Medicare dataset.

Positron emission tomography-computed tomography (PET-CT) has become the primary modality for staging in diffuse large B-cell lymphoma (DLBCL), whereas the role of staging bone marrow biopsy (BMB) has become less clear. In this analysis, we included 7,005 DLBCL patients in SEER-Medicare who received either PET-CT without BMB (PET-CT w/o BMB), CT with BMB (CT w/ BMB), or both PET-CT and BMB (PET-CT w/ BMB). The proportion of patients undergoing PET-CT increased across years of diagnosis, while the proportion undergoing CT or BMB decreased. In a fully adjusted Cox proportional hazards model, PET-CT w/ BMB was associated with a marginally superior OS compared to PET-CT w/o BMB. Notably, the association between PET-CT w/ BMB and OS was strongest in patients ≤70 years, but was not present when looking at individual stage of diagnosis. Overall, these data do not provide sufficient support to eliminate staging BMB in patients who undergo PET-CT.

Plasmonic antenna coupling to hyperbolic phonon-polaritons for sensitive and fast mid-infrared photodetection with graphene.

Integrating and manipulating the nano-optoelectronic properties of Van der Waals heterostructures can enable unprecedented platforms for photodetection and sensing. The main challenge of infrared photodetectors is to funnel the light into a small nanoscale active area and efficiently convert it into an electrical signal. Here, we overcome all of those challenges in one device, by efficient coupling of a plasmonic antenna to hyperbolic phonon-polaritons in hexagonal-BN to highly concentrate mid-infrared light into a graphene pn-junction. We balance the interplay of the absorption, electrical and thermal conductivity of graphene via the device geometry. This approach yields remarkable device performance featuring room temperature high sensitivity (NEP of 82 pW[Formula: see text]) and fast rise time of 17 nanoseconds (setup-limited), among others, hence achieving a combination currently not present in the state-of-the-art graphene and commercial mid-infrared detectors. We also develop a multiphysics model that shows very good quantitative agreement with our experimental results and reveals the different contributions to our photoresponse, thus paving the way for further improvement of these types of photodetectors even beyond mid-infrared range.

Remaining challenges in predicting patient outcomes for diffuse large B-cell lymphoma.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and is an aggressive malignancy with heterogeneous outcomes. Diverse methods for DLBCL outcomes assessment ranging from clinical to genomic have been developed with variable predictive and prognostic success.Areas covered: The authors provide an overview of the various methods currently used to estimate prognosis in DLBCL patients. Models incorporating cell of origin, genomic features, sociodemographic factors, treatment effectiveness measures, and machine learning are described.Expert opinion: The clinical and genetic heterogeneity of DLBCL presents distinct challenges in predicting response to therapy and overall prognosis. Successful integration of predictive and prognostic tools in clinical trials and in a standard clinical workflow for DLBCL will likely require a combination of methods incorporating clinical, sociodemographic, and molecular factors with the aid of machine learning and high-dimensional data analysis.

Insurance status impacts overall survival in Burkitt lymphoma.

The impact of insurance status on clinical outcomes in Burkitt (BL) and plasmablastic (PBL) lymphomas remains unknown. We used the National Cancer Database to examine insurance status' effect on overall survival (OS) in adults diagnosed with these lymphomas between 2004 and 2014. BL patients with private insurance had significantly better OS compared to those without. In patients aged <65 years, hazard ratios were 1.4 for uninsured status (95% confidence interval 1.2-1.7), 1.2 for Medicaid (95% CI 1.0-1.4), and 1.5 for Medicare (95% CI 1.2-1.9). For patients aged >65 years, hazard ratio for uninsured status was 8.4 (95% CI 2.5-28.3). Conversely, underinsured PBL patients experienced no difference in OS. Thus, expanding insurance-related access to care may improve survival in BL, for which curative therapy exists, but not PBL, where more effective therapies are needed. Our findings add to mounting evidence that adequate health insurance is particularly important for patients with curable cancers.

Nonfatal Hyperammonemic Encephalopathy as a Late Complication of Roux-en-Y Gastric Bypass.

Roux-en-Y gastric bypass (RYGB) is the most common weight loss procedure performed in the US. Gastric bypass-related hyperammonemia (GaBHA) is a potentially fatal entity, characterized by encephalopathy associated with hyperammonemia and various nutritional deficiencies, which can present at variable time intervals after RYGB. Twenty-five cases of hyperammonemic encephalopathy after bariatric surgery have been previously reported in the literature. We describe the case of a 48-year-old Hispanic woman with no prior history of liver disease, presenting with nonfatal hyperammonemic encephalopathy as a late postoperative complication 20 years after undergoing a RYGB. Hyperammonemic encephalopathy in the absence of known hepatic dysfunction presents a diagnostic dilemma. An early diagnosis and intervention are crucial to decrease morbidity and mortality.

PET-derived tumor metrics predict DLBCL response and progression-free survival.

[18F] fluorodeoxyglucose (FDG) - positron emission tomography (PET)/computed tomography (CT) is used to stage and assess response in diffuse large B-cell lymphoma (DLBCL), though the prognostic value of tumor metrics calculated from interim scans remains unsolved. We investigated the predictive value of interim and end-of-treatment (EOT) metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on progression-free survival (PFS) at 24 months in patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Controlling for pretreatment MTV, a positive interim MTV was highly correlated with (0.86) and a significant predictor of a positive EOT MTV (p = .03). Interim MTV > 0 (HR 5.51, CI 1.13, 26.79) and EOT MTV > 4.68 (HR 10.75, CI 1.31, 105.48) were significant predictors of PFS24. Our data show PET-derived metrics of pretreatment and interim MTV offer significant predictive value for EOT response and PFS, and can guide future response-adapted treatment approaches for DLBCL patients that build on the R-CHOP backbone.

A population-based multistate model for diffuse large B-cell lymphoma-specific mortality in older patients.

BACKGROUND: Despite effective therapies, outcomes for diffuse large B-cell lymphoma (DLCBL) remain heterogeneous in older individuals due to comorbid diseases and variations in disease biology. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, the authors conducted a multistate survival analysis of 11,780 patients with DLBCL who were aged ≥65 years at the time of diagnosis (2002-2009). Cox proportional hazards models were used to specify the impact of prognostic factors on overall survival and cause-specific deaths, and the Aalen-Johansen estimator was used to project the course of DLBCL over time with or without standard therapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). RESULTS: Advanced age (hazard ratio [HR] for ages 71-75 years: 1.25; HR for ages 76-80 years: 1.46; HR for ages 81-85 years: 1.88; and HR for age ≥86 years: 2.26), DLBCL stage (HR for Ann Arbor stage II: 1.28; HR for stage III: 1.54; and HR for stage IV: 1.95), Charlson Comorbidity Index (CCI) ≥1 (HR for CCI of 1, 1.15; and HR for CCI >1, 1.37), and not being married (HR, 1.12) were associated with an increased risk of DLBCL-specific death. Being female (HR, 0.91) and of higher socioeconomic status (HR, 0.91) were associated with a lower risk of DLBCL-related mortality after therapy. For patients treated with R-CHOP (3610 patients), the risk of death due to DLBCL was 14.0% and 18.6%, respectively, at 2 and 5 years of treatment and plateaued afterward, confirming a 5-year "cure" point while receiving R-CHOP among older patients. CONCLUSIONS: Conducting a survival analysis over a large data set, the current study evaluated competing risks for death within a multistate modeling framework, and identified age, sex, and CCI as risk factors for DLBCL-specific and other causes of death.

Assessing the Effectiveness of Treatment Sequences for Older Patients With High-risk Follicular Lymphoma With a Multistate Model.

BACKGROUND: Disease progression within < 2 years of initial chemoimmunotherapy and patient age > 60 years have been associated with poor overall survival (OS) in follicular lymphoma (FL). No standard treatment exists for these high-risk patients, and the effectiveness of sequential therapies remains unclear. PATIENTS AND METHODS: We studied the course of FL with first-, second-, and third-line treatment. Using large population-based data, we identified 5234 patients with FL diagnosed in 2000 to 2009. Of these patients, 71% had received second-line therapy < 2 years, and 29% had received no therapy after first-line therapy, with a median OS of < 3 years. Treatment included rituximab, R-CVP (rituximab, cyclophosphamide, vincristine), R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine), R-Other (other rituximab-containing), and other regimens. The Aalen-Johansen estimator and Cox proportional hazards models were used to quantify the outcomes and assess the effects of the clinical and sociodemographic factors. RESULTS: R-CHOP demonstrated the most favorable 5-year OS among first- (71%), second- (55%), and third-line (61%) therapies. First-line R-CHOP improved OS (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.50-0.64) and reduced the mortality risks after first-line (HR, 0.60; 95% CI, 0.47-0.77), second-line (HR, 0.40; 95% CI, 0.29-0.53), and third-line (HR, 0.63; 95% CI, 0.53-0.76) treatments. B-symptoms, being married, and histologic grade 1/2 were associated with the use of earlier second-line therapy. Early progression from second- to third-line therapy was associated with poor OS. The repeated use of R-CHOP or R-CVP as first- and second-line treatment yielded high 2-year mortality rates (R-CHOP + R-CHOP, 17.3%; R-CVP + R-CVP, 21.1%). CONCLUSION: Our multistate approach assessed the effect of sequential therapy on the immediate and subsequent treatment-line outcomes. We found that R-CHOP in any line improved OS for patients with high-risk FL.

Rural and urban patients with diffuse large B-cell and follicular lymphoma experience reduced overall survival: a National Cancer DataBase study.

We examined 83,108 patients with diffuse large B-cell lymphoma (DLBCL) and 43,393 patients with follicular lymphoma (FL) to investigate disparities related to geographic population density, stratified as rural, urban, or metropolitan. We found that urban and rural patients less commonly had private insurance and high socioeconomic status. Urban and rural DLBCL patients were more likely to receive treatment within 14 days of diagnosis (OR 0.93, 95% confidence interval [CI] 0.89-0.98; and OR 0.81, 95% CI 0.72-0.91) while urban FL patients were more likely to have treatment >14 days after diagnosis (OR 1.08, 95% CI 1.01-1.16). Multivariable analyses demonstrated that rural and urban patients had worse overall survival with DLBCL (hazard ratio [HR] 1.09; 95% CI 1-1.19 and HR 1.08; 95% CI 1.04-1.11) and FL (HR 1.11; 95% CI 1.04-1.18 and HR 1.2; 95% CI 1.02-1.41), respectively, suggesting needs for focused study and interventions for these populations.

Disparities in survival by insurance status in follicular lymphoma.

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma and most common indolent non-Hodgkin lymphoma. Lower socioeconomic status is associated with poor outcomes in FL, suggesting that access to care is an important prognostic factor; however, the association between insurance status and FL survival has not been sufficiently examined. The National Cancer Database, a nationwide cancer registry, was used to evaluate 43 648 patients with FL diagnosed between 2004 and 2014. All analyses were performed on 2 cohorts segmented at age 65 years to account for changes in insurance status with Medicare eligibility. Cox proportional hazard models calculated hazard ratios (HRs) with confidence intervals (CIs) for the association between insurance status and overall survival (OS) controlling for the available sociodemographic and prognostic factors. Kaplan-Meier curves display outcomes by insurance status for patients covered by private insurance, no insurance, Medicaid, or Medicare. When compared with patients younger than age 65 years with private insurance, patients younger than age 65 years with no insurance (HR, 1.96; 95% CI, 1.69-2.28), with Medicaid (HR, 1.82; 95% CI, 1.57-2.12), and with Medicare (HR, 1.96; 95% CI, 1.71-2.24) had significantly worse OS after adjusting for sociodemographic and prognostic factors. Compared with patients age 65 years or older with private insurance, those with Medicare only (HR, 1.28; 95% CI, 1.17-1.4) had significantly worse OS. For adults with FL, expanding access to care through insurance has the potential to improve outcomes.

Novel and emerging therapies for cholestatic liver diseases.

While bile acids are important for both digestion and signalling, hydrophobic bile acids can be harmful, especially when in high concentrations. Mechanisms for the protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signalling, among others. By altering or overwhelming these defence mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation. While PBC is currently treated with ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), many fail treatment, and we have yet to find an effective therapy for PSC. Novel therapies under evaluation target nuclear and surface receptors including FXR, transmembrane G-protein-coupled receptor 5 (TGR5), peroxisome proliferator-activated receptor (PPAR) and pregnane X receptor (PXR). Modulation of these receptors leads to altered bile composition, decreased cytotoxicity, decreased inflammation and improved metabolism. This review summarizes our current understanding of the role of bile acids in the pathophysiology of cholestatic liver diseases, presents the rationale for already approved medical therapies and discusses novel pharmacologic therapies under investigation.

Informatics Approaches to Address New Challenges in the Classification of Lymphoid Malignancies.

Purpose: Lymphoid malignancies are remarkably heterogeneous, with variations in outcomes and clinical, biologic, and histologic presentation complicating classification according to the World Health Organization guidelines. Incorrect classification of lymphoid neoplasms can result in suboptimal therapeutic strategies for individual patients and confound the interpretation of clinical trials involving personalized, class-based treatments. This review discusses the potential role of pathology informatics in improving the classification accuracy and objectivity for lymphoid malignancies. Design: We identified peer-reviewed publications examining pathology informatics approaches for the classification of lymphoid malignancies, reviewed developments in the lymphoma classification systems, and summarized computational methods for pathologic assessment that can impact practice. Results: Computer-assisted pathology image analysis algorithms in lymphoma most commonly have been applied to follicular lymphoma to address biologic heterogeneity and subjectivity in the process of classification. Conclusion: Objective methods are available to assist pathologists in lymphoma classification and grading, and have been demonstrated to provide measurable benefits in specific contexts. Future validation and extension of these approaches will require datasets that link high resolution pathology images available for image analysis algorithms with clinical variables and follow up outcomes.

Expression of Blimp-1 in dendritic cells modulates the innate inflammatory response in dextran sodium sulfate-induced colitis.

A single nucleotide polymorphism of PRDM1, the gene encoding Blimp-1, is strongly associated with inflammatory bowel disease. Here, we demonstrate that Blimp-1 in CD103(+) dendritic cells (DCs) critically contributes to the regulation of macrophage homeostasis in the colon. Dextran sodium sulfate (DSS)-exposed Blimp-1(cko) mice with a deletion of Blimp-1 in CD103(+) DCs and CD11c(hi) macrophages exhibited severe inflammatory symptoms, pronounced weight loss, high mortality, robust infiltration of neutrophils in epithelial regions of the colon, an increased expression of proinflammatory cytokines and a significant decrease in CD103(+) DCs in the colon compared with DSS exposed wild-type (WT) mice. Purified colonic macrophages from Blimp-1(cko) mice expressed increased levels of matrix metalloproteinase 8, 9 and 12 mRNA. WT macrophages cocultured with colonic DCs but not bone marrow-derived DCs from Blimp-1(cko) produced increased matrix metalloproteinases in an interleukin (IL)-1ß- and IL-6-dependent manner. Treatment of Blimp-1(cko) mice with anti-IL-1ß and anti-IL-6 abrogated the exaggerated clinical response. Overall, these data demonstrate that Blimp-1 expression in DCs can alter an innate inflammatory response by modulating the activation of myeloid cells. This is a novel mechanism of contribution of Blimp-1 for the pathogenesis of inflammatory bowel diseases, implicating another therapeutic target for the development of inflammatory bowel disease.

Coherent spin control of a nanocavity-enhanced qubit in diamond.

A central aim of quantum information processing is the efficient entanglement of multiple stationary quantum memories via photons. Among solid-state systems, the nitrogen-vacancy centre in diamond has emerged as an excellent optically addressable memory with second-scale electron spin coherence times. Recently, quantum entanglement and teleportation have been shown between two nitrogen-vacancy memories, but scaling to larger networks requires more efficient spin-photon interfaces such as optical resonators. Here we report such nitrogen-vacancy-nanocavity systems in the strong Purcell regime with optical quality factors approaching 10,000 and electron spin coherence times exceeding 200 µs using a silicon hard-mask fabrication process. This spin-photon interface is integrated with on-chip microwave striplines for coherent spin control, providing an efficient quantum memory for quantum networks.

A biomechanical analysis of point of failure during lateral-row tensioning in transosseous-equivalent rotator cuff repair.

PURPOSE: The purpose of this study was to determine the maximum load and point of failure of the construct during tensioning of the lateral row of a transosseous-equivalent (TOE) rotator cuff repair. METHODS: In 6 fresh-frozen human shoulders, a TOE rotator cuff repair was performed, with 1 suture from each medial anchor passed through the tendon and tied in a horizontal mattress pattern. One of 2 limbs from each of 2 medial anchors was pulled laterally over the tendon. After preparation of the lateral bone for anchor placement, the 2 limbs were passed through the polyether ether ketone (PEEK) eyelet of a knotless anchor and tied to a tensiometer. The lateral anchor was placed into the prepared bone tunnel but not fully seated. Tensioning of the lateral-row repair was simulated by pulling the tensiometer to tighten the suture limbs as they passed through the eyelet of the knotless anchor. The mode of failure and maximum tension were recorded. The procedure was then repeated for the second lateral-row anchor. RESULTS: The mean load to failure during lateral-row placement in the TOE model was 80.8 ± 21.0 N (median, 83 N; range, 27.2 to 115.8 N). There was no statistically significant difference between load to failure during lateral-row tensioning for the anterior and posterior anchors (P = .84). Each of the 12 constructs failed at the eyelet of the lateral anchor. Retrieval analysis showed no failure of the medial anchors, no medial suture cutout through the rotator cuff tendon, and no signs of gapping at the repair site. CONCLUSIONS: Our results suggest that the medial-row repair does not appear vulnerable during tensioning of the lateral row of a TOE rotator cuff repair with the implants tested. However, surgeons should exercise caution when tensioning the lateral row, especially when lateral-row anchors with PEEK eyelets are implemented. CLINICAL RELEVANCE: For this repair construct, the findings suggest that although the medial row is not vulnerable during lateral-row tensioning of a TOE rotator cuff repair, lateral-row anchors with PEEK eyelets appear vulnerable to early failure.

Tolerogenic function of Blimp-1 in dendritic cells.

Blimp-1 has been identified as a key regulator of plasma cell differentiation in B cells and effector/memory function in T cells. We demonstrate that Blimp-1 in dendritic cells (DCs) is required to maintain immune tolerance in female but not male mice. Female mice lacking Blimp-1 expression in DCs (DCBlimp-1(ko)) or haploid for Blimp-1 expression exhibit normal DC development but an altered DC function and develop lupus-like autoantibodies. Although DCs have been implicated in the pathogenesis of lupus, a defect in DC function has not previously been shown to initiate the disease process. Blimp-1(ko) DCs display increased production of IL-6 and preferentially induce differentiation of follicular T helper cells (T(FH) cells) in vitro. In vivo, the expansion of T(FH) cells is associated with an enhanced germinal center (GC) response and the development of autoreactivity. These studies demonstrate a critical role for Blimp-1 in the tolerogenic function of DCs and show that a diminished expression of Blimp-1 in DCs can result in aberrant activation of the adaptive immune system with the development of a lupus-like serology in a gender-specific manner. This study is of particular interest because a polymorphism of Blimp-1 associates with SLE.