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BACKGROUND: We recently reported better wheat-protein utilization and a higher apparent lysine requirement than would be predicted, because of adaptive mechanisms of lysine conservation. However, such findings may be subject to the feeding protocol of frequent small meals. OBJECTIVE: We used a [1-13C]leucine balance, large single-meal protocol to estimate the utilization of wheat and the consequent lysine requirements. DESIGN: Wheat and milk utilization were compared in 5 adults infused for 9 h with L-[1-13C]leucine, in the postabsorptive (0-3 h) and postprandial (3-9 h) states after ingestion of a single meal of either milk (30.4 kJ/kg; 32% of energy as protein) or a mixture of wheat gluten and whole wheat (29.2 kJ; 26.7% of energy as protein). Premeal nitrogen balance was predicted from [1-13C]leucine oxidation and postmeal balance predicted from cumulative increased leucine oxidation, enabling evaluation of the metabolic demand for protein, the efficiency of postprandial protein utilization (PPU), and the requirements for wheat protein and lysine. RESULTS: Mean (+/-SD) PPU was 0.61 +/- 0.03 and 0.93 +/- 0.02 for wheat and milk (P < or = 0.001), respectively, and the estimated average wheat-protein requirement (0.6 g x g(-1) x d(-1)/PPU) was 0.98 +/- 0.05 g x kg(-1) x d(-1), indicating a lysine requirement of 18.3 +/- 1.0 mg x kg(-1) x d(-1). CONCLUSIONS: Measured wheat utilization efficiency at 0.61 was considerably higher than the value predicted from wheat lysine intake and milk protein lysine deposition (ie, 0.222 +/- 0.004). These results confirm our previous finding that lysine conservation allows wheat protein to be utilized more efficiently than expected and is consistent with a lysine requirement in fully adapted individuals of 19 mg x kg(-1) x d(-1), as indicated by recalculated nitrogen balance data. Copyright © 2002 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Introduction: Sarcopenia is a known risk factor for adverse outcomes across multiple disease states, including severe trauma. Factors such as age, hyperinflammation, prolonged immobilization, and critical illness may not only exacerbate progression of this disease but may also contribute to the development of induced sarcopenia, or sarcopenia secondary to hospitalization. This study seeks to (1) determine the effects of severe traumatic injury on changes in skeletal muscle mass in older adults; (2) test whether changes in skeletal muscle mass are associated with clinical frailty, physical performance, and health-related quality of life; and (3) examine trauma-induced frailty and temporal changes in myokine and chemokine profiles., Methods: A prospective, longitudinal cohort study of 47 critically ill, older (≥45 years) adults presenting after severe blunt trauma was conducted. Repeated measures of computed tomography-based skeletal muscle index, frailty, and quality of life were obtained in addition to selected plasma biomarkers over 6 months., Results: Severe trauma was associated with significant losses in skeletal muscle mass and increased incidence of sarcopenia from 36% at baseline to 60% at 6 months. Severe trauma also was associated with a transient worsening of induced frailty and reduced quality of life irrespective of sarcopenia status, which returned to baseline by 6 months after injury. Admission biomarker levels were not associated with skeletal muscle index at the time points studied but demonstrated distinct temporal changes across our entire cohort., Conclusions: Severe blunt trauma in older adults is associated with increased incidence of induced sarcopenia and reversible induced frailty. Despite muscle wasting, functional decline is transient, with a return to baseline by 6 months, suggesting a need for holistic definitions of sarcopenia and further investigation into long-term functional outcomes in this population., Competing Interests: Conflicts of Interest/Disclosure The authors have no related conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Epigenetics has been shown to be relevant in oncology: BMI1 overexpression has been reported in leukemias, EZH2 mutations have been found in follicular lymphoma, and USP22 seems to stabilize BMI1 protein. In this study, we measured the expression of BMI1, EZH2, and USP22 in lymph nodes from 56 diffuse large B-cell lymphoma (DLBCL) patients., Methods: A new multiplex digital droplet PCR (ddPCR) has been set up to measure the expression of 4 genes (BMI1, EZH2, USP22, and GAPDH) in the same reaction on RNA extracted from paraffin-embedded tissues., Results: The specificity of ddPCR was confirmed by a 100% alignment on the BLAST platform and its repeatability demonstrated by duplicates. A strict correlation between expression of BMI1 and EZH2 and BMI1 and USP22 has been found, and high expression of these genes was correlated with extra-nodal lymphomas. Progression-free survival (PFS) and overall survival (OS) were conditioned by IPI, bone marrow infiltration, and the complete response achievement. High levels of BMI1 and USP22 did not condition the response to therapy, but impaired the PFS, especially for patients defined at "high risk" based on the cell of origin (no germinal center [GCB]), high BCL2 expression, and IPI 3-5. In this subgroup, the probability of relapse/progression was twice higher than that of patients carrying low BMI1 and USP22 levels., Conclusion: High expression of BMI1 and of USP22 might be a poor prognostic factor in DLBCL, and might represent the target for novel inhibitors., (© 2024 The Author(s). International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Metronomic chemotherapy (mCHEMO), based on frequent, regular administration of low, but pharmacologically active drug doses, optimizes antitumor efficacy by targeting multiple targets and reducing toxicity of antineoplastic drugs. This minireview will summarize preclinical and clinical studies on cytotoxic drugs given at weekly, daily, or at continuous metronomic schedules alone or in combination with novel targeted agents for hematological malignancies, including lymphoma, multiple myeloma, and leukemia. Most of the preclinical in vitro and in vivo studies have reported a significant benefit of both mCHEMO monotherapy and combinatorial regimens compared with chemotherapy at the maximum tolerated dose. However, the combination of mCHEMO with targeted drugs is still little explored in the hematologic clinical setting. Data obtained from preclinical studies on low dose metronomic chemotherapy in hematological malignancies clearly suggested the possibility to clinically investigate more tolerable and effective strategies for the treatment of patients with advanced hematological malignancies, or at least for those frail and elderly patients, who are not eligible or resistant to standard treatments., Competing Interests: Declaration of competing interest none., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The EANM Research Ltd. (EARL) guidelines give recommendations for harmonization of [ 18 F]FDG PET-CT image acquisition and reconstruction, aiming to ensure reproducibility of quantitative data between PET scanners. Recent technological advancements in PET-CT imaging resulted in an updated version of the EARL guidelines (EARL2). The aim of this study is to compare quantitative [ 18 F]FDG uptake metrics of the primary tumor and lymph nodes in patients with head and neck squamous cell carcinoma (HNSCC) on EARL2 versus EARL1 reconstructed images and to describe clinical implications for nodal staging and treatment., Methods: Forty-nine consecutive patients with HNSCC were included. For all, both EARL1 and EARL2 images were reconstructed from a singular [ 18 F]FDG PET-CT scan. Primary tumors and non-necrotic lymph nodes ≥ 5 mm were delineated on CT-scan. In the quantitative analysis, maximum standardized uptake values (SUV max ) and standardized uptake ratios (SUR max , i.e., SUV max normalized to cervical spinal cord uptake) were calculated for all lesions on EARL1 and EARL2 reconstructions. Metabolic tumor volume (MTV) and total lesion glycolysis were compared between EARL1 and EARL2 using different segmentation methods (adaptive threshold; SUV2.5/3.5/4.5; SUR2.5/3.5/4.5; MAX40%/50%). In the qualitative analysis, each lymph node was scored independently by two nuclear medicine physicians on both EARL1 and EARL2 images on different occasions using a 4-point scale., Results: There was a significant increase in SUV max (16.5%) and SUR max (9.6%) of primary tumor and lymph nodes on EARL2 versus EARL1 imaging (p < 0.001). The proportional difference of both SUV max and SUR max between EARL2 and EARL1 decreased with increasing tumor volume (p < 0.001). Absolute differences in MTVs between both reconstructions were small (< 1.0 cm 3 ), independent of the segmentation method. MTVs decreased on EARL2 using relative threshold methods (adaptive threshold; MAX40%/50%) and increased using static SUV or SUR thresholds. With visual scoring of lymph nodes 38% (11/29) of nodes with score 2 on EARL1 were upstaged to score 3 on EARL2, which resulted in an alteration of nodal stage in 18% (6/33) of the patients., Conclusions: Using the EARL2 method for PET image reconstruction resulted in higher SUV max and SUR max compared to EARL1, with nodal upstaging in a significant number of patients., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

The presence of a serum paraprotein (PP) is usually associated with plasma-cell dyscrasias, Waldenstrom Macroglobulinemia/lymphoplasmacytic lymphoma, and cryoglobulinemia. However, PP is also often reported in other high- and low-grade B-cell malignancies. As these reports are sparse and heterogeneous, an overall view on this topic is lacking, Therefore, we carried out a complete literature review to detail the characteristics, and highlight differences and similarities among lymphoma entities associated with PP. In these settings, IgM and IgG are the prevalent PP subtypes, and their serum concentration is often low or even undetectable without immunofixation. The relevance of paraproteinemia and its prevalence, as well as the impact of IgG vs. IgM PP, seems to differ within B-NHL subtypes and CLL. Nonetheless, paraproteinemia is almost always associated with advanced disease, as well as with immunophenotypic, genetic, and clinical features, impacting prognosis. In fact, PP is reported as an independent prognostic marker of poor outcome. All the above call for implementing clinical practice, with the assessment of paraproteinemia, in patients' work-up. Indeed, more studies are needed to shed light on the biological mechanism causing more aggressive disease. Furthermore, the significance of paraproteinemia, in the era of targeted therapies, should be assessed in prospective trials.

Introduction: Identifying effective cancer drugs remains an inefficient process. Drug efficacy in traditional preclinical cancer models translates poorly into therapy in the clinic. Implementation of preclinical models that incorporate the tumor microenvironment (TME) is needed to improve selection of active drugs prior to clinical trials., Areas Covered: Progression of cancer results from the behavior of cancer cells in concert with the host's histopathological background. Nonetheless, complex preclinical models with a relevant microenvironment have yet to become an integral part of drug development. This review discusses existing models and provides a synopsis of active areas of cancer drug development where implementation would be of value. Their contribution to finding therapeutics in immune oncology, angiogenesis, regulated cell death and targeting tumor fibroblasts as well as optimization of drug delivery, combination therapy, and biomarkers of efficacy is considered., Expert Opinion: Complex tumor models in vitro (CTMIVs) that mimic the organotypic architecture of neoplastic tumors have boosted research into TME influence on traditional cytoreductive chemotherapy as well as the detection of specific TME targets. Despite advances in technical prowess, CTMIVs can only address specific aspects of cancer pathophysiology.

Introduction: Classical Hodgkin Lymphoma (HL) is a lymphoproliferative disease typically diagnosed in the young. The excellent results obtained with current treatment lead to long survival with age-related complications affecting patients' survival and quality of life. One issue affecting HL patients is infertility. This problem can be easily overcome in males with seminal liquid cryopreservation, however, in females it is more complex either in terms of the quality of the cryopreserved material or the patients' age at diagnosis. Moreover, not all chemo- or radio-therapies have the same negative impact on fertility.The main objectives of this study was to collect epidemiological information on HL patients involved in fertility preservation counseling and to analyze the impact of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine), the standard treatment for HL, on ovarian function, hormonal levels and ovarian and uterine tissue morphologies. Patterns of fertility preservation were also reported., Methods: Data were obtained from 270 female patients at HL onset who were interested in fertility counseling prior to therapy initiation. Each patient was assessed at HL diagnosis for levels of Anti-Mullerian Hormone (AMH), Follicle Stimulating Hormone (FSH), and 17β-oestradiol (17β-oe), with additional assessments at 6 and 12 months after chemotherapy. Patients were evaluated with ultrasound scans to study the number of ovarian follicles and the degree of uterine thickness at the same timepoints., Results: The average patient AMH level showed a statistically significant reduction at 6 months after chemotherapy (p=0.05) and by the 12 month time point returned to near pre-chemotherapy values. FSH and 17β-oe levels did not significantly vary throughout the study period. ABVD chemotherapy was associated with a significant reduction of both ovarian follicles and endometrial thickness at the 6 month time point followed by a recovery at the 12 time point in both ovaries. Different results were observed when patients changed treatment to a more intensive one., Discussion: Based on the results from the hormonal measurements and the follicle echography, it appears that the toxic effect of ABVD on fertility is transient, whereas, in contrast, more intensive therapies may potentially be more harmful and long-lasting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ciccarone, Cavaceppi, Tesei, Brunetti, Pulsoni, Annibali, Gasparoli, Battistini, Hohaus, Pelliccia, Tafuri, Cox, Cantonetti, Rigacci and Abruzzese.)

The upfront treatment of very elderly and frail patients with diffuse large B-cell lymphoma (DLBCL) is still a matter of debate. Herein, we report results of the metronomic all-oral DEVEC [prednisolone/deltacortene®, vinorelbine (VNR), etoposide (ETO), cyclophosphamide] combined with i.v. rituximab (R). This schedule was administered as a first line therapy in 22 elderly/frail DLBCL subjects (median age = 84.5 years). In 17/22 (77%) patients, the Elderly-IPI-score was high. After a median follow-up of 24 months, 15 patients had died: seven (50%) for causes unrelated to DLBCL or its treatment, six (40%) for progression, and two (13%) for multiorgan failure. Six treatment-pertinent serious-adverse-events occurred. At the end of induction, 14/22 (64%) achieved complete remission; overall survival and event-free survival at 24 months were both 54% (95% CI = 32−72%), while the time to progression was 74% (95% CI = 48−88%). Furthermore, antiproliferative and proapoptotic assays were performed on DLBCL/OCI-LY3 cell-line using metronomic VNR and ETO and their combination. Both metronomic VNR and ETO had concentration-dependent antiproliferative (IC50 = 0.036 ± 0.01 nM and 7.9 ± 3.6 nM, respectively), and proapoptotic activities in DLBCL cells. Co-administration of the two drugs showed a strong synergism (combination index < 1 and dose reduction index > 1) against cell proliferation and survival. This low-dose schedule seems to compare favourably with intravenous-CHEMO protocols used in the same subset. Indeed, the high synergism shown by metronomic VRN+ETO in in vitro studies, explains the remarkable clinical responses and it allows significant dose reductions.

Antibody-drug conjugates (ADC) have emerged as one of the pillars of clinical disease management in oncology. The biggest hurdle to widespread development and application of ADCs has been a narrow therapeutic index. Advances in antibody technologies and formats as well as novel linker and payload chemistries have begun to facilitate structural improvements to ADCs. However, the interplay of structural characteristics with physiologic and pharmacologic factors determining therapeutic success has garnered less attention. This review elaborates on the pharmacology of ADCs, the pathophysiology of cancerous tissues, and the reciprocal consequences on ADC properties and functions. While most currently approved ADCs utilize either microtubule inhibition or DNA damage as primary mechanisms of action, we present arguments to expand this repertoire and highlight the need for payload mechanisms that exploit disease-specific vulnerabilities. We promote the idea that the choice of antibody format, targeting antigen, linker properties, and payload of an ADC should be deliberately fit for purpose by taking the pathophysiology of disease and the specific pharmacology of the drug entity into account, thus allowing a higher probability of clinical success., (©2022 American Association for Cancer Research.)

Novel drugs are rapidly moving forward the treatment-paradigm of non-Hodgkin-lymphomas (NHLs). Notwithstanding, especially in aggressive subtypes, chemotherapy remains the pillar of treatment. Indeed, the combination of highly effective Maximum-Tolerated-Dose Chemotherapy (MTD-CHEMO) + "novel drugs", has so far, fallen short from expectations, often because it caused excessive toxicity. Metronomic chemotherapy (mCHEMO), which is the frequent, long-term administration of low dose cytotoxic drugs, may allow more effective and tolerable combinations. mCHEMO pharmacodynamics, has been described as pleiotropic. In fact, it may have different cellular and molecular targets, when drugs or their schedules are modified. Although mCHEMO has been little explored in NHLs, pre-clinical studies - in lymphoma models - which addressed the activity of mCHEMO in combination with novel drugs, have shown very promising results. These included inhibitors of histone deacetylase, mTOR and PI3K/mTOR, as well as the immune checkpoint inhibitor anti-PD-L1. Moreover, a few impressive reports have recently shown all-oral mCHEMO schedules, with or without rituximab, can effectively shrink both B and T-cell aggressive NHLs. Indeed, these regimens allowed elderly-frail patients to achieve sustained remission, while toxicity proved manageable. In our opinion, all-oral mCHEMO, is an active, easy-to start, well-tolerated, and inexpensive therapeutic approach, which deserves further investigation. Most importantly, mCHEMO, holds promise to empower the activity of novel targeted therapies, without causing excessive toxicity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Sarcopenia is a known risk factor for poor outcomes across many chronic diseases. The impact on outcomes of both pre-existing sarcopenia and acute muscle wasting (AMW) in acute critical illness caused by sepsis remain unclear., Methods: We conducted a prospective longitudinal cohort study of critically ill patients with intra-abdominal sepsis utilizing abdominal computed tomography at sepsis onset to determine baseline skeletal muscle index (SMI). Biomarkers of inflammation and catabolism were measured through 28 days while hospitalized. We performed follow-up evaluations of strength and physical function at 3, 6, and 12 months, with interval CT analyses at 3 and 12 months to evaluate changes in muscle mass. Measured clinical outcomes included development of chronic critical illness (≥14 days in intensive care with persistent organ dysfunction), long-term functional status, and 1 year mortality., Results: Among 47 sepsis patients enrolled (mean age 53 ± 14 years), half (n = 23; 49%) were sarcopenic at baseline. Overall, sepsis patients exhibited acute and persistent muscle wasting with an average 8% decrease in SMI from baseline at 3 months (P = 0.0008). Sarcopenic (SAR) and non-sarcopenic (NSAR) groups were similar in regards to age and comorbidity burden. SAR patients had greater acute physiologic derangement (APACHE II, 18 vs. 12.5), higher incidence of multiple organ failure (57% vs. 17%), longer hospital (21 vs. 12 days) and intensive care unit length of stays (13 vs. 4 days), and higher inpatient mortality (17% vs. 0%; all P < 0.05). Pre-existing SAR was a strong independent predictor of early death or developing chronic critical illness (odds ratio 11.87, 95% confidence interval CI 1.88-74.9; P = 0.009, area under the curve 0.880) and was associated with significantly higher risk of 1-year mortality (34.9% vs. 4.2%, p = 0.007). Lower baseline SMI was also predictive of poor functional status at 12 months (OR 0.89, 95% confidence interval 0.80-0.99; p = 0.039, area under the curve 0.867). Additionally, SAR patients had AMW with persistent muscle mass loss at 3 months that was associated with decreased health-related quality of life and SF-36 physical function domains (P < 0.05). Persistent AMW at 3 months was not predictive of mortality or poor functional status, with return to near-baseline muscle mass among sepsis survivors by 6 months., Conclusions: Critically ill patients have an acute and persistent loss of muscle mass after intra-abdominal sepsis, which is associated with decreased health-related quality of life and physical function at 3 months. However, pre-existing sarcopenia, rather than persistent acute muscle mass loss at 3 months after sepsis, is independently associated with poor long-term functional status and increased 1 year mortality., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

The current standard preclinical oncology models are not able to fully recapitulate therapeutic targets and clinically relevant disease biology, evidenced by the 90% attrition rate of new therapies in clinical trials. Three-dimensional (3D) culture systems have the potential to enhance the relevance of preclinical models. However, the limitations of currently available cellular assays to accurately evaluate therapeutic efficacy in these models are hindering their widespread adoption. We assessed the compatibility of the lactate dehydrogenase (LDH) assay in 3D spheroid cultures against other commercially available readout methods. We developed a standardized protocol to apply the LDH assay to ex vivo cultures, considering the impact of culture growth dynamics. We show that accounting for growth rates and background release levels of LDH are sufficient to make the LDH assay a suitable methodology for longitudinal monitoring and endpoint assessment of therapeutic efficacy in both cell line-derived xenografts (xenospheres) and patient-derived explant cultures. This method has the added value of being non-destructive and not dependent on reagent penetration or manipulation of the parent material. The establishment of reliable readout methods for complex 3D culture systems will further the utility of these tumor models in preclinical and co-clinical drug development studies., (© 2021. The Author(s).)

Background and Purpose: In rectal cancer patients, radiotherapy in prone position using a belly board can reduce the dose to organs at risk. For this patient group we investigated inter-fraction shape variation of the mesorectal part of the clinical target volume (CTV) and determined planning target volume (PTV) margins., Materials and Methods: Patients with rectal cancer receiving neoadjuvant (chemo)radiotherapy were eligible. For each patient a planning computed tomography (pCT) and five cone-beam CT (CBCT) scans were acquired in prone position using a belly board. The mesorectal CTV was delineated on all scans. Mesorectal shape variation was quantified relative to the pCT. PTV margins were derived locally and averaged for separate subregions of the mesorectal CTV. For each patient a total PTV was constructed using our clinical margins for mesorectal and lymph node CTVs. An artificial dose distribution conforming to this PTV was used to calculate the coverage for the mesorectal CTV using the CBCT delineations., Results: In 19 rectal cancer patients the derived PTV margins were smallest in the upper-lateral region (6 mm) and largest in the upper-anterior region (16 mm). PTV margins for the upper-anterior region were larger for female patients (19 mm) compared to male patients (14 mm). Clinical margins for the total PTV were sufficient for a coverage of at least 97% of the mesorectal CTV for all patients., Conclusions: Mesorectal shape variation is heterogeneous and largest in the upper-anterior region, in rectal cancer patients irradiated in prone position and using a belly board., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Background: Older patients account for a significant proportion of patients undergoing colorectal cancer surgery and are vulnerable to a number of preoperative risk factors that are not often present in younger patients. Further, three preoperative risk factors that are more prevalent in older adults include frailty, sarcopenia, and malnutrition. Although each of these has been studied in isolation, there is little information on the interplay between them in older surgical patients. A particular area of increasing interest is the use of urine metabolomics for the objective evaluation of dietary profiles and malnutrition., Objective: Herein, we describe the design, cohort, and standard operating procedures of a planned prospective study of older surgical patients undergoing colorectal cancer resection across multiple institutions in the United Kingdom. The objectives are to determine the association between clinical outcomes and frailty, nutritional status, and sarcopenia., Methods: The procedures will include serial frailty evaluations (Clinical Frailty Scale and Groningen Frailty Indicator), functional assessments (hand grip strength and 4-meter walk test), muscle mass evaluations via computerized tomography morphometric analysis, and the evaluation of nutritional status via the analysis of urinary dietary biomarkers. The primary feasibility outcome is the estimation of the incidence rate of postoperative complications, and the primary clinical outcome is the association between the presence of postoperative complications and frailty, sarcopenia, and nutritional status. The secondary outcome measures are the length of hospital stay, 30-day hospital readmission rate, and mortality rate at days 30 and 90., Results: Our study was approved by the National Health Service Research Ethics Committee (reference number: 19/WA/0190) via the Integrated Research Application System (project ID: 231694) prior to subject recruitment. Cardiff University is acting as the study sponsor. Our study is financially supported through an external, peer-reviewed grant from the British Geriatrics Society and internal funding resources from Cardiff University. The results will be disseminated through peer-review publications, social media, and conference proceedings., Conclusions: As frailty, sarcopenia, and malnutrition are all areas of common derangement in the older surgical population, prospectively studying these risk factors in concert will allow for the analysis of their interplay as well as the development of predictive models for those at risk of commonly tracked surgical complications and outcomes., International Registered Report Identifier (irrid): PRR1-10.2196/16846., (©Nia Angharad Humphry, Thomas Wilson, Michael Christian Cox, Ben Carter, Marco Arkesteijn, Nicola Laura Reeves, Scott Brakenridge, Kathryn McCarthy, John Bunni, John Draper, Jonathan Hewitt. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 17.08.2021.)

Surgical sepsis has evolved into two major subpopulations: patients who rapidly recover, and those who develop chronic critical illness (CCI). Our primary aim was to determine whether CCI sepsis survivors manifest unique blood leukocyte transcriptomes in late sepsis that differ from transcriptomes among sepsis survivors with rapid recovery. In a prospective cohort study of surgical ICU patients, genome-wide expression analysis was conducted on total leukocytes in human whole blood collected on days 1 and 14 from sepsis survivors who rapidly recovered or developed CCI, defined as ICU length of stay ≥ 14 days with persistent organ dysfunction. Both sepsis patients who developed CCI and those who rapidly recovered exhibited marked changes in genome-wide expression at day 1 which remained abnormal through day 14. Although summary changes in gene expression were similar between CCI patients and subjects who rapidly recovered, CCI patients exhibited differential expression of 185 unique genes compared with rapid recovery patients at day 14 ( p < 0.001). The transcriptomic patterns in sepsis survivors reveal an ongoing immune dyscrasia at the level of the blood leukocyte transcriptome, consistent with persistent inflammation and immune suppression. Furthermore, the findings highlight important genes that could compose a prognostic transcriptomic metric or serve as therapeutic targets among sepsis patients that develop CCI.

Background: Increased circulating myeloid-derived suppressor cells (MDSCs) are independently associated with poor long-term clinical outcomes in sepsis. Studies implicate subsets of MDSCs having unique roles in lymphocyte suppression; however, characterization of these cells after sepsis remains incomplete. We performed a pilot study to determine the transcriptomic landscape in MDSC subsets in sepsis using single-cell RNAseq (scRNA-seq)., Methods: A mixture of whole blood myeloid-enriched and Ficoll-enriched PBMCs from two late septic patients on post-sepsis day 21 and two control subjects underwent Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq)., Results: We successfully identified the three MDSC subset clusters-granulocytic (G-), monocytic (M-), and early (E-) MDSCs. Sepsis was associated with a greater relative expansion of G-MDSCs versus M-MDSCs at 21 days as compared to control subjects. Genomic analysis between septic patients and control subjects revealed cell-specific and common differential expression of genes in both G-MDSC and M-MDSC subsets. Many of the common genes have previously been associated with MDSC proliferation and immunosuppressive function. Interestingly, there was no differential expression of several genes demonstrated in the literature to be vital to immunosuppression in cancer-induced MDSC., Conclusion: This pilot study successfully demonstrated that MDSCs maintain a transcriptomic profile that is immunosuppressive in late sepsis. Interestingly, the landscape in chronic critical illness is partially dependent on the original septic insult. Preliminary data would also indicate immunosuppressive MDSCs from late sepsis patients appear to have a somewhat unique transcriptome from cancer and/or other inflammatory diseases., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

Purpose: To prospectively validate the use of a simplified geriatric assessment (sGA) at diagnosis and to integrate it into a prognostic score for older patients with diffuse large B-cell lymphoma (DLBCL)., Methods: We conducted the prospective Elderly Project study on patients with DLBCL older than 64 years who underwent our Fondazione Italiana Linfomi original geriatric assessment (oGA) (age, Cumulative Illness Rating Scale for Geriatrics, activities of daily living, and instrumental activities of daily living) before treatment. Treatment choice was left to the physician's discretion. The primary end point was overall survival (OS) (ClinicalTrials.gov identifier: NCT02364050)., Results: We analyzed 1,163 patients (median age 76 years), with a 3-year OS of 65% (95% CI, 62 to 68). Because at multivariate analysis on oGA, age > 80 years retained an independent correlation with OS, we also developed a new, simplified version of the GA (sGA) that classifies patients as fit (55%), unfit (28%), and frail (18%) with significantly different 3-year OS of 75%, 58%, and 43%, respectively. The sGA groups, International Prognostic Index, and hemoglobin levels were independent predictors of OS and were used to build the Elderly Prognostic Index (EPI). Three risk groups were identified: low (23%), intermediate (48%), and high (29%), with an estimated 3-year OS of 87% (95% CI, 81 to 91), 69% (95% CI, 63 to 73), and 42% (95% CI, 36 to 49), respectively. The EPI was validated using an independent external series of 328 cases., Conclusion: The Elderly Project validates sGA as an objective tool to assess fitness status and defines the new EPI to predict OS of older patients with DLBCL., Competing Interests: Francesco MerliConsulting or Advisory Role: Janssen, Gilead Sciences, MSD, Takeda, RocheTravel, Accommodations, Expenses: Janssen, Gilead Sciences, EUSA Pharma, Celgene, Roche, Takeda Stefano LuminariConsulting or Advisory Role: Roche, Gilead Sciences, CelgeneTravel, Accommodations, Expenses: Janssen, Celgene Alessandra TucciConsulting or Advisory Role: Janssen, TakedaTravel, Accommodations, Expenses: Sandoz Annalisa ArcariConsulting or Advisory Role: Janssen-CilagTravel, Accommodations, Expenses: Janssen-Cilag, Takeda Luigi RigacciConsulting or Advisory Role: Roche, Gilead Sciences, Takeda, Janssen-Cilag, AbbVie, Celgene/Bristol-Myers Squibb, Merck, MenariniSpeakers' Bureau: Roche, Gilead Sciences, CelgeneTravel, Accommodations, Expenses: Takeda Eliza HawkesConsulting or Advisory Role: Merck Sharpe & Dohme, Roche/Genentech, AstraZeneca, Gilead SciencesSpeakers' Bureau: Roche/GenentechResearch Funding: AstraZeneca, Celgene, Merck KGaA, Janssen-Cilag, Gilead Sciences, Mundipharma, Bristol-Myers SquibbTravel, Accommodations, Expenses: Roche/Genentech Carlos S. ChiattoneConsulting or Advisory Role: Roche, Takeda, Janssen Federica CavalloHonoraria: Takeda, Janssen-Cilag, Gilead SciencesConsulting or Advisory Role: Janssen-Cilag, Gilead SciencesTravel, Accommodations, Expenses: Celgene Alberto FabbriHonoraria: Takeda, Servier/PfizerTravel, Accommodations, Expenses: Takeda Allison BarracloughTravel, Accommodations, Expenses: Roche Simone FerreroConsulting or Advisory Role: Janssen-Cilag, EUSA Pharma, Clinigen GroupSpeakers' Bureau: Janssen-Cilag, Servier, EUSA Pharma, Gilead SciencesTravel, Accommodations, Expenses: Roche, Servier, Sanofi, Janssen-Cilag, EUSA Pharma, Gentili Alice Di RoccoSpeakers' Bureau: Roche/GenentechTravel, Accommodations, Expenses: Roche, Novartis Stefan HohausConsulting or Advisory Role: MSD, EusaPharma, Servier, GentiliniTravel, Accommodations, Expenses: Roche Luca NassiEmployment: SanofiStock and Other Ownership Interests: Sanofi, MolMedConsulting or Advisory Role: Takeda Gerardo MusuracaConsulting or Advisory Role: Janssen Oncology, Servier Leonardo FlenghiTravel, Accommodations, Expenses: Roche, Janssen Michele SpinaEmployment: Bristol-Myers Squibb/Medarex, SanofiConsulting or Advisory Role: Gilead Sciences, IncyteNo other potential conflicts of interest were reported.