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Treatment of hematologic malignancies with patient-derived anti-CD19 chimeric antigen receptor (CAR) T-cells has demonstrated long-term remissions for patients with otherwise treatment-refractory advanced leukemia and lymphoma. Conversely, CAR T-cell treatment of solid tumors, including advanced gastric cancer (GC), has proven more challenging due to on-target off-tumor toxicities, poor tumor T-cell infiltration, inefficient CAR T-cell expansion, immunosuppressive tumor microenvironments, and demanding preconditioning regimens. We report the exceptional results of autologous Claudin18.2-targeted CAR T cells (CT041) in a patient with metastatic GC, who had progressed on four lines of combined systemic chemotherapy and immunotherapy. After two CT041 infusions, the patient had target lesion complete response and sustained an 8-month overall partial response with only minimal ascites. Moreover, tumor-informed circulating tumor DNA (ctDNA) reductions coincided with rapid CAR T-cell expansion and radiologic response. No severe toxicities occurred, and the patient’s quality of life significantly improved. This experience supports targeting Claudin18.2-positive GC with CAR T-cell therapy and helps to validate ctDNA as a biomarker in CAR T-cell therapy.Clinical Insight: Claudin18.2-targeted CAR T cells can safely provide complete objective and ctDNA response in salvage metastatic GC.

Hodgkin lymphoma variant of Richter’s transformation (HvRT) is a rare complication for patients with chronic lymphocytic leukemia (CLL), with an overall poor prognosis. We present the first known case series of patients with HvRT treated with the combination of brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A + AVD). In our series of 4 patients, two patients treated with A + AVD for HvRT had durable remissions of 40 and 42 months, while two patients had disease progression and ultimately died. Continued investigation into the optimal management for patients with HvRT is still needed.

Abstract This letter presents an 11 b 200 MS/s 28 nm CMOS 2b/cycle successive‐approximation register (SAR) analogue‐to‐digital converter (ADC). The offset calibration technique is proposed to reduce the comparator offset mismatch that degrades the linearity of the high‐resolution 2b/cycle SAR ADC. The offset mismatch is reduced to within 0.25 least significant bit (LSB) by generating a compensation voltage from capacitor‐resistor (C‐R) hybrid digital‐to‐analogue converters (DACs). The prototype ADC implemented in a 28‐nm CMOS process demonstrates measured differential and integral non‐linearities within 0.6 LSB and 1.73 LSB at 11 b resolution, respectively. The measured signal‐to‐noise‐and‐distortion ratio (SNDR) and spurious‐free dynamic range (SFDR) are 50.9 dB and 66.2 dB at Nyquist, respectively. The prototype ADC occupies an active die area of 0.115 mm2 and consumes 3.98 mW at a 1.1‐V supply voltage.

Introduction: Prior cross-sectional studies suggest that health-related quality of life (HRQOL) worsens with more severe glomerular disease. This longitudinal analysis was conducted to assess changes in HRQOL with changing disease status. Methods: Cure Glomerulonephropathy (CureGN) is a cohort of patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA vasculitis, or IgA nephropathy. HRQOL was assessed at enrollment and follow-up visits 1 to 3 times annually for up to 5 years with the Patient-Reported Outcomes Measurement Information System (PROMIS). Global health, anxiety, and fatigue domains were measured in all; mobility was measured in children; and sleep-related impairment was measured in adults. Linear mixed effects models were used to evaluate HRQOL responsiveness to changes in disease status. Results: A total of 469 children and 1146 adults with PROMIS scores were included in the analysis. HRQOL improved over time in nearly all domains, though group-level changes were modest. Edema was most consistently associated with worse HRQOL across domains among children and adults. A greater number of symptoms also predicted worse HRQOL in all domains. Sex, age, obesity, and serum albumin were associated with some HRQOL domains. The estimated glomerular filtration rate (eGFR) was only associated with fatigue and adult physical health; proteinuria was not associated with any HRQOL domain in adjusted models. Conclusion: HRQOL measures were responsive to changes in disease activity, as indicated by edema. HRQOL over time was not predicted by laboratory-based markers of disease. Patient-reported edema and number of symptoms were the strongest predictors of HRQOL, highlighting the importance of the patient experience in glomerular disease. HRQOL outcomes inform understanding of the patient experience for children and adults with glomerular diseases.

Alloreactive donor T cells undergo extensive metabolic reprogramming to become activated and induce graft-versus-host disease (GVHD) upon alloantigen encounter. It is generally thought that glycolysis, which promotes T cell growth and clonal expansion, is employed in this process. However, conflicting data have been reported regarding the requirement of glycolysis to induce T cell-mediated GVHD due to the lack of T cell-specific treatments using glycolysis inhibitors. Importantly, previous studies have not evaluated whether graft-versus-leukemia (GVL) activity is preserved in donor T cells deficient for glycolysis. As a critical component affecting the clinical outcome, it is necessary to assess the anti-tumor activity following treatment with metabolic modulators in preclinical models. In the present study, we utilized T cells selectively deficient for glucose transporter 1 (Glut1T-KO), to examine the role of glycolysis exclusively in alloreactive T cells without off-targeting effects from antigen presenting cells and other cell types that are dependent on glycolysis. We demonstrated that transfer of Glut1T-KO T cells significantly improved acute GVHD outcomes through increased apoptotic rates, impaired expansion, and decreased proinflammatory cytokine production. In addition to impaired GVHD development, donor Glut1T-KO T cells mediated sufficient GVL activity to protect recipients from tumor development. A clinically relevant approach using donor T cells treated with a small molecule inhibitor of glycolysis, 2-Deoxy-D-glucose ex vivo, further demonstrated protection from tumor development. These findings indicate that treatment with glycolysis inhibitors prior to transplantation selectively eliminates alloreactive T cells, but spares non-alloreactive T cells including those that protect against tumor growth. The present study has established a definitive role for glycolysis in acute GVHD and demonstrated that acute GVHD can be selectively prevented through targeting glycolysis.

BackgroundSupporting healthy lifestyle changes is a key aim of cardiovascular and pulmonary rehabilitation programs. SMS text messaging programs have demonstrated effectiveness in cardiovascular disease risk reduction, weight loss, increasing physical activity, and smoking cessation. The optimization of SMS text messaging programs may deliver greater population benefits as mobile phone use becomes ubiquitous. Visual messaging (ie, image-based messages) has the potential to communicate health messages via digital technology and result in enhanced engagement. ObjectiveThis study aims to determine and understand patient preferences for lifestyle-focused visual text messages that support cardiovascular and pulmonary rehabilitation. MethodsA discrete choice experiment was conducted in a 4-stage iterative process to elicit patient preferences for visual message features. Attribute and level development yielded 3 attributes (purpose, image type, and web address), and 16 choice sets were subsequently constructed according to a full factorial design. Patients participating in cardiovascular and pulmonary rehabilitation were surveyed (on the web) for their preferences regarding the visual message choice sets. Respondents were asked to choose among 16 pairs of visual messages regarding key lifestyle behaviors, namely, physical activity and nutrition. The data were analyzed using a conditional logit model. ResultsThere was a total of 1728 observations from 54 unique respondents. Two factors that were associated with patient preference were gain-framed purpose compared with no purpose (odds ratio [OR] 1.93, 95% CI 1.40-2.65) and real images compared with cartoon images (OR 1.26, 95% CI 1.04-1.54). A loss-framed purpose was less preferred than no purpose (OR 0.55, 95% CI 0.42-0.74). Overall, patients preferred positive images that were colorful and engaged with text that supported the image and had a preference for images of real people rather than cartoons. ConclusionsA discrete choice experiment is a scientific method for eliciting patient preferences for a visual messaging intervention that is designed to support changes in lifestyle behaviors. SMS text messaging programs that use visual aids may result in greater patient satisfaction by using a gain frame, using real images, and avoiding a loss frame. Further research is needed to explore the feasibility of implementation and the health and behavioral outcomes associated with such visual messaging programs.

Oral solid dosage forms that contain APIs in the amorphous state have become commonplace because of many drug substances exhibiting poor water solubility, which negatively impacts their absorption in the human GI tract. While micronization, solvent spray-drying, and hot-melt extrusion can address solubility issues, spray coating of the APIs onto beads and tablets offers another option for producing amorphous drug products. High-level comparisons between bead and tablet coating technologies have the potential for simpler equipment and operation that can reduce the cost of development and manufacturing. However, spray coating directly onto tablets is not without challenges, especially with respect to meeting uniformity acceptance value (AV) criteria, comprising accuracy (mean) and precision (variance) objectives. The feasibility of meeting AV criteria is examined, based on mathematical models for accuracy and precision. The results indicate that the main difficulty in manufacturing satisfactory drug-layered tablets by spray coating is caused by the practical limitations of achieving the necessary coating precision. Despite this limitation, it is shown that AV criteria can be consistently met by appropriate materials monitoring and control as well as processing equipment setup, operation, and maintenance.

The utility of positron emission tomography-computed tomography (PET-CT) in distinguishing Richter’s transformation versus chronic lymphocytic leukemia (CLL) progression after ibrutinib and/or idelalisib was assessed in a post hoc analysis of a phase II study of venetoclax. Patients underwent PET-CT at screening and were not enrolled/treated if Richter’s transformation was confirmed pathologically. Of 167 patients screened, 57 met criteria for biopsy after PET-CT. Of 35 patients who underwent biopsy, eight had Richter’s transformation, two had another malignancy, and 25 had CLL. A PET-CT maximum standardized uptake value (SUVmax) ≥10 had 71% sensitivity and 50% specificity for detecting Richter’s transformation [Odds Ratio (OR): 2.5, 95%CI: 0.4-15; P=0.318]. Response rate to venetoclax was similar for screening SUVmax

PURPOSE:To create a standardized method for evaluating the video recordings of patients self-instilling eye drops and to determine the level of agreement of eye drop instillation efficacy, safety and efficiency ratings by three masked graders. DESIGN:Prospective cross-sectional study. PARTICIPANTS:78 patients with open-angle glaucoma or ocular hypertension who had at least 6 months of experience with the use of eye drop medications. METHODS:Participants were video recorded while self-instilling artificial tears sequentially to both eyes. Three masked observers graded these video recordings on three criteria: efficacy (the determination of whether an eye drop was instilled on the ocular surface), safety (assessment of whether the tip of the medication bottle made contact with the ocular surface or eyelids), and efficiency (the number of eye drops expressed from the bottle). MAIN OUTCOME MEASURES:After grading the video recordings based on efficacy, safety, and efficiency, kappa statistics were used to estimate inter-rater agreement. RESULTS:The mean kappa level of agreement for efficacy, safety, and efficiency was 0.64 (95% confidence interval (CI), 0.42-0.87), 0.73 (95% CI, 0.58-0.88), and 0.62 (95% CI, 0.42-0.81), respectively. CONCLUSIONS:We demonstrated good inter-rater reproducibility of the masked analysis of video recordings of patients self-instilling eye drops based on three criteria: efficiency, safety, and efficacy.

In humans de novo synthesis of 2′-deoxythymidine-5′-monophosphate (dTMP), an essential building block of DNA, utilizes an enzymatic pathway requiring thymidylate synthase (TSase) and dihydrofolate reductase (DHFR). The enzyme flavin-dependent thymidylate synthase (FDTS) represents an alternative enzymatic pathway to synthesize dTMP, which is not present in human cells. A number of pathogenic bacteria, however, depend on this enzyme in lieu of or in conjunction with the analogous human pathway. Thus, inhibitors of this enzyme may serve as antibiotics. Here, we review the similarities and differences of FDTS vs. TSase including aspects of their structure and chemical mechanism. In addition, we review current progress in the search for inhibitors of flavin dependent thymidylate synthase as potential novel therapeutics.