Upper Limit For Age Research Articles

Abstract 4137009: Treating Elderly Cardiogenic Shock Patients with a Microaxial Flow Pump; Is It DANGERous?

Background: The Danish German Cardiogenic Shock trial (DanGer Shock) recently showed a reduction in all-cause mortality when treating selected patients with ST-segment elevation myocardial infarction (STEMI) and cardiogenic shock with a microaxial flow pump (mAFP). Whether there is an age-related differential survival benefit is unknown. Objective: To assess the influence of age on 180-day all-cause mortality in patients with STEMI and cardiogenic shock randomized in DanGer Shock. Methods: In DanGer Shock (an open-label, international, multicenter trial), 355 adult patients (aged ≥18 years with no upper age limit) with STEMI and cardiogenic shock were included and randomized to a mAFP (Impella CP) plus standard care or standard care alone. Patients were stratified in quartiles according to age, and logistic regression analyses were used to assess mortality according to age quartiles, and to evaluate whether age modified the treatment effect of the mAFP. Results: From lowest to highest quartile, patients’ ages ranged from 31-59, 60-69, 70-76, and 77-92, respectively. There were no differences in blood pressure, lactate level, left ventricular ejection fraction and shock severity across age groups. However, the proportion of females (41%) and the prevalence of hypertension (64%) was higher in patients aged ≥77 years (highest quartile), while more patients aged <60 years (lowest quartile) had been resuscitated before randomization. Mortality increased incrementally from the lowest quartile to the highest (31% vs. 47% vs. 61% vs. 73%, p log-rank <0.001), with an adjusted odds ratio for death at 180 days of 5.50 (95%CI 2.65-11.8, p<0.001) in the highest quartile compared to the lowest. Patients in the three lower quartiles had a lower absolute mortality at 180 days if randomized to the mAFP group, whereas patients in the highest quartile had a higher mortality if randomized to the mAFP group, p=0.028 for interaction, Figure. Conclusion: In patients with STEMI-related cardiogenic shock, the overall mortality increased with advancing age, and treatment benefit of the mAFP appeared to diminish in the eldest patients. (DanGer Shock, NCT01633502)

Headache/migraine-related stigma, quality of life, disability, and most bothersome symptom in adults with current versus previous high-frequency headache/migraine and medication overuse: results of the Migraine Report Card survey

BackgroundHigh-frequency headache/migraine (HFM) and overuse of acute medication (medication overuse [MO]) are associated with increased disability and impact. Experiencing both HFM and MO can potentially compound impacts, including stigma; however, evidence of this is limited. The objective of this report was to evaluate self-reported stigma, health-related quality of life (HRQoL), disability, and migraine symptomology in US adults with HFM + MO from the Harris Poll Migraine Report Card survey.MethodsUS adults (≥ 18 yrs., no upper age limit) who screened positive for migraine per the ID Migraine™ screener completed an online survey. Participants were classified into “current HFM + MO” (≥ 8 days/month with headache/migraine and ≥ 10 days/month of acute medication use over last few months) or “previous HFM + MO” (previously experienced HFM + MO, headaches now occur ≤ 7 days/month with ≤ 9 days/month of acute medication use). Stigma, HRQoL, disability, and most bothersome symptom (MBS) were captured. The validated 8-item Stigma Scale for Chronic Illnesses (SSCI-8) assessed internal and external stigma (scores ≥ 60 are clinically significant). Raw data were weighted to the US adult population. Statistically significant differences were determined by a standard t-test of column proportions and means at the 90% (p < 0.1) and 95% (p < 0.05) confidence levels.ResultsParticipants (N = 550) were categorized as having current (n = 440; mean age 41.1 years; 54% female; 57% White, not Hispanic; 24% Hispanic; 11% Black, not Hispanic) or previous (n = 110; mean age 47.2 years; 49% female; 75% White, not Hispanic; 13% Hispanic; 4% Black, not Hispanic) HFM + MO. Compared to those with previous HFM + MO (21%), adults with current HFM + MO were more likely to experience clinically significant levels of stigma (47%). Men with current HFM + MO (52% compared to men with previous HFM + MO [25%] and women with current [41%] or previous [18%] HFM + MO), non-Hispanic Black (51% compared to White, not Hispanic [45%] and Hispanic [48%] current HFM + MO groups and White, not Hispanic previous HFM + MO [12%]), current HFM + MO aged 18–49 years (50% compared to those with current HFM + MO aged ≥ 50 years [33%] and those with previous HFM + MO aged 18–49 [34%] and ≥ 50 years [4%]), and employed respondents (53% current and 29% previous compared to those not employed [32% current and 12% previous]) reported higher rates of clinically significant stigma. Those with current HFM + MO were more likely to have worse HRQoL and disability due to headache/migraine. Respondents aged ≥ 50 years with current HFM + MO were more likely than respondents aged 18–49 years with current HFM + MO to indicate that their overall quality of life (66% vs. 52%) and their ability to participate in hobbies/activities they enjoy were negatively impacted by headache/migraine (61% vs. 49%). Pain-related symptoms were identified as the MBS.ConclusionsTogether these data suggest that current and previous HFM + MO can be associated with undesirable outcomes, including stigma and reduced HRQoL, which were greatest among people with current HFM + MO, but still considerable for people with previous HFM + MO.Graphical abstract

The history of vaccine and vaccination against influenza in Poland

The influenza virus is an important cause of morbidity, complications and mortality worldwide. Anyone can be infected, regardless of latitude or age. The paper describes the history of obtaining a modern influenza vaccine that does not deviate from current World Health Organization standards in Poland. Dozens of studies assessing the post-vaccination humoral response for different types of influenza vaccine, measuring levels of anti-haemagglutinin and anti-neuraminidase antibodies (although not in all of the studies) have been presented. The research was conducted mainly in high-risk populations, regardless of the age of vaccine recipients. What is noteworthy, the paper presents specific examples that may help promote prevention and encourage healthcare personnel to protect not only patients, but also their relatives. Prophylaxis in the form of vaccination is the cheapest and most effective form of preventing both dangerous complications and mortality. Infection caused by the influenza virus should be viewed not only in the context of exacerbation of a pre-existing disease or causing a new disease, but also in terms of measurable public costs. There are many types of imported influenza vaccines available on the Polish pharmaceutical market, from the inactivated intramuscular split or subunit vaccine to the intranasal live vaccine obtained from strains adapted to lower replication temperatures. Currently, quadrivalent influenza vaccines, i.e. containing two influenza A virus subtypes (A/H1N1/pdm09, A/H3N2) and two influenza B virus lineages (Victoria and Yamagata), are used. Depending on the type of vaccine, immunisation is recommended from the age of 6 months, whereas the upper age limit is not specified. The composition of vaccines is updated every epidemic season.

Phase 1 Study of Autologous Sirpα-Low Macrophages (SIRPant-M) Administered By Intratumoral Injection Alone or in Combination with External-Beam Radiotherapy in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma (NCT05967416)

Background and Significance. While a sentinel role of macrophages in channeling immune responses has long been recognized, the opportunity to harvest, harness and deploy macrophages for therapeutic potential has been underappreciated clinically. Most currently marketed and development-stage cell therapies target a single tumor-associated antigen, permitting activation of resistance and tumor escape mechanisms that frequently lead to relapse. High rates of CRS and neurotoxicity (ICANS) associated with CAR-T therapies complicate usage, with associated product labeling that includes a Risk Evaluation and Mitigation Strategy (REMS), mandating hospitalization and post-therapy monitoring with attendant administrative burden that precludes widespread use in community-based settings. Moreover, many subtypes of lymphoma (NHL) lack a readily druggable target. The current first-in-human Phase 1 study advances a novel paradigm in cell-therapy, deploying SIRPα-depleted activated macrophages, manufactured from an autologous mononuclear apheresis (SIRPant-M). In the context of macrophages, SIRPα acts as a strong negative regulator of (i) phagocytosis and (ii) productive pro-inflammatory T cell stimulation; therefore abrogation of SIRPα-activity serves as a necessary precondition for robust neo-antigen-specific anti-tumor responses. Requiring no genetic modification, in pre-clinical models these SIRPα-depleted macrophages orchestrated an immune response that targets multiple individual-specific and tumor-unique neo-antigens in parallel. SIRPant-M elicits a multi-pronged polyclonal immune response that transforms the tumor microenvironment (TME) by fostering a pro-inflammatory milieu that provides for unencumbered and orchestrated targeting of cancer cells via both cellular and humoral effector mechanisms. Manufactured and subsequently frozen as 3 aliquots from a single apheresis, activation of macrophages is brought about by conditioning the macrophages during ex vivo culture with a proprietary cytokine cocktail (PhagoAct™) with the added effect of modulating activity of SIRPα. This combination of product attributes permits the same cell product to have potential clinical applications in both solid tumor and hematologic malignancies. While this initial Phase 1 study administers the macrophages by intra-tumoral injection (ITI), subsequent studies aim to explore IV-dosing. Study design, methods and patients. This is a multicenter open-label Phase 1 study of SIRPant-M monotherapy, with sequential cohorts receiving low [90×10 6] and high [300×10 6] ITI cell doses. Cell product is administered alone or combined with focal external-beam radiotherapy (XRT). Each cell dose is administered in 3 ITI-fractions on days 1, 3, and 5 over 1 cycle. Upon confirmation of safety as a single agent, subsequent cohorts receive cell product concurrent with focally directed radiation in three 2.5 Gy fractions (7.5 Gy total). The primary end point, Dose Limiting Toxicity, is assessed over 30 days and dose escalation is gated by a standard 3+3 dose escalation design, overseen by a Safety Monitoring Committee. The enrollment target is 12-24 DLT-evaluable patients. The study enrolls an “all comers” B- and T-cell NHL population, including systemic and cutaneous histologies (CTCL), with relapsed or progressive disease following a minimum of 2- but no maximum number of prior therapies. Minimum age is 18, with no upper age limit. Prior CAR-T, bi-specific antibody and/or autologous/allogeneic transplant is allowed after recovery from treatment-related AEs. Patients must not receive immuno-suppression for GVHD and must have at least 1 target lesion that is 1.5 to 5 cm in diameter and accessible for safe ITI, ECOG ≤ 2, life expectancy &amp;gt; 3 months, renal/hepatic/coagulation parameters and blood counts that are standard for Phase 1 studies at baseline. Secondary and Exploratory Endpoints. Tumor response, including abscopal response, is evaluated by Lugano criteria or other Workgroup criteria as appropriate for the tumor type at the end of the DLT-period (Day 30), Week 12 and per SOC thereafter. Serial blood samples and a tumor biopsy before and 16 days after treatment are collected for multi-parameter analyte detection including pro-inflammatory cytokines, multiplex flow cytometry, scRNA sequencing, and ctDNA analysis to investigate pharmacodynamics and mechanism of action.

Equality, diversity, and inclusion in oncology clinical trials: an audit of essential documents and data collection against INCLUDE under-served groups in a UK academic trial setting.

Clinical trials should be as inclusive as possible to facilitate equitable access to research and better reflect the population towards which any intervention is aimed. Informed by the UK's National Institute for Health and Care Research (NIHR) Innovations in Clinical Trial Design and Delivery for the Under-served (INCLUDE) guidance, we audited oncology trials conducted by the Clinical Trials and Statistics Unit at The Institute of Cancer Research, London (ICR-CTSU) to identify whether essential documents were overtly excluding any groups and whether sufficient data were collected to assess diversity of trial participants from groups suggested by INCLUDE as under-served by research in the UK. Thirty cancer clinical trials managed by ICR-CTSU and approved between 2011-2021 were audited. The first ethics approved version of each trial's protocol, patient information sheet, and patient completed questionnaire, together with the first case report forms (CRFs) version were reviewed. A range of items aligned with the INCLUDE under-served groups were assessed, including age, sex and gender, socio-economic and health factors. The scope did not cover trial processes in participating hospitals. Data relating to participants' age, ethnic group and health status were well collected and no upper age limit was specified in any trials' eligibility criteria. 23/30 (77%) information sheets used at least one gendered term to address patients. Most CRFs did not specify whether they were collecting sex or gender and only included male or female categories. The median reading age for information sheets was 15-16 years (IQR: 14-15 - 16-17). Socio-economic factors were not routinely collected and not commonly mentioned in trial protocols. No systemic issues were identified in protocols which would explicitly prevent any under-served group from participating. Areas for improvement include reducing use of gendered words and improving readability of patient information. The challenge of fully assessing adequate inclusion of under-served populations remains, as socio-economic factors are not routinely collected because they fall beyond the data generally required for protocol-specified trial endpoint assessments. This audit has highlighted the need to agree and standardise demographic data collection to permit adequate monitoring of the under-served groups identified by the NIHR.

Venetoclax and Blinatumomab for Adult Patients with Relapsed/Refractory or MRD Positive Ph-Negative B-Precursor ALL: First Results of the GMALL-Bliven Trial

Introduction Prognosis of adult patients with relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia (BCP-ALL) remains poor. Monotherapy with Blinatumomab in ALL induced a complete remission (CR) in 44% of patients and measurable residual disease (MRD) negative molecular remission (MOL-CR) in 33%. Median overall survival of 7.7 months remains unsatisfactory. In the MRD setting, median survival was 36 months in the context of subsequent allogeneic stem cell transplantation (SCT). The combination of Blinatumomab with Venetoclax may be an effective option in ALL. Objectives In this multicenter phase 1 clinical trial the GMALL study group evaluates the safety of Blinatumomab in combination with Venetoclax in R/R or MRD positive BCP-ALL (NCT05182385). Using RNA sequencing, functional intracellular BH3 profiling, T cell immunomonitoring and effector cell cytotoxicity assays we aim to further elucidate synergy of this combination. Methods The BLIVEN trial includes patients with CD19-positive Ph-negative BCP-ALL aged 18 years and older, with no upper age limit. Eligible patients had either R/R ALL (bone marrow blasts &amp;gt;5%) or molecular failure/relapse (MRD &amp;gt;1xE-04). To assess safety, we determined maximum tolerated dose (MTD) as primary endpoint of the phase I part of the trial as designated recommended phase 2 dose (RP2D). Key secondary endpoint was the MOL-CR rate. Treatment consisted of oral Venetoclax in continuous dosing on day -7 to day 42 of target doses ranging between 200-800 mg once daily, and Blinatumomab as continuous intravenous infusion of 28 µg/d 4 weeks on and 2 weeks off, starting on day 1. For patients with R/R ALL, a cautionary dose step of 9 µg/d Blinatumomab was implemented for one week. MRD was analyzed in the reference laboratory using real-time quantitative PCR (RQ-PCR) of immunoglobulin and T-cell receptor (IG/TR) rearrangements. Results Between February 2022 and May 2023 a total of 7 patients were enrolled in the phase I part at four German centers (Figure 1). Venetoclax target doses were 400 mg (n=3), 600 mg (n=3), and 800 mg (n=1). Median age was 48.5 years (range 22 - 72 years). MRD assessment was available in 7/7 patients. Molecular BCP-ALL subtypes were identified by RNA sequencing in 5/5 analyzed patients, including ZNF384-rearranged ALL (n=2), BCR::ABL1-like (n=2; IGH::CRLF2 rearranged), and KMT2A-rearranged ALL (n=1). Three of seven patients were treated for hematological relapse, while 4/7 patients had molecular failure/relapse at time of enrolment. Among patients with R/R ALL, 2/3 were refractory to front-line therapy with intensive GMALL induction/consolidation therapy, while 1/3 suffered relapse shortly after failure of second allogeneic SCT. CTCAE grade IV neutropenia was identified as adverse reaction related to Venetoclax in one patient. Neutropenia resolved before dose limiting toxicity (DLT) evaluation time (i.e. 42 days after Venetoclax initiation). Overall, no DLT was identified throughout the trial and MTD was not reached. No treatment interruption was noted during cycle 1. Two of seven patients received one treatment cycle of BLIVEN only due to treatment failure, 5/7 patients received two treatment cycles. Response assessment was available for 7/7 patients. Treatment with Blinatumomab/Venetoclax of R/R ALL resulted in CR in 1/3 patients, with the responding patient showing a MOL-CR. The MOL-CR rate in molecular failure/relapse patients was 3/4. Conclusion Salvage therapy with Blinatumomab and Venetoclax exhibited good tolerability without treatment-related mortality. No treatment withdrawals were attributed to safety concerns. Two patients did not respond to BLIVEN combination therapy. Interestingly, both patients exhibited IGH::CRLF2 fusion transcripts.The remaining 5 patients obtained MRD responses, including complete MRD responses, of which 2/2 occurred in ZNF384 rearranged BCP-ALL. Further follow-up and larger patient numbers are needed to establish the potential benefit of this regimen in molecular driver subtypes of BCP-ALL. Enrollment to complete phase I of the BLIVEN trial is currently ongoing. Updated results including RP2D will be presented at the meeting. Acknowledgments This is an independent academic early phase I clinical trial conducted under the sponsor role of the Goethe University, Frankfurt, Germany. It received financial support and supply of Venetoclax by AbbVie Inc..

A Propensity Score Weighting Analysis Emphasizes the Progress of the Gimema Approach in Adult Ph-Positive Acute Lymphoblastic Leukemia in the TKI Era

Introduction. In 2000, the GIMEMA cooperative study group launched the first frontline protocol with a tyrosine kinase inhibitor (TKI) alone plus steroids and without systemic chemotherapy for elderly (&amp;gt;60 years) Ph+ acute lymphoblastic leukemia (ALL) patients (LAL0201-B; Vignetti et al, Blood 2007). Thereafter, 4 academic clinical trials were conducted for adult patients (&amp;gt;18 years). In all studies, the induction was always based on a TKI alone plus steroids and CNS prophylaxis without systemic chemotherapy. In the GIMEMA LAL0904 trial, patients (18-60 years) received imatinib followed by chemotherapy in the post-induction phase (Chiaretti et al, Haematologica 2016). In the GIMEMA LAL1205 trial (no upper age limit), patients received dasatinib plus steroids, while the post-induction treatment was left to the investigator's choice (Foà et al, Blood 2011). In the GIMEMA LAL1509 total therapy protocol, patients (18-60 years) received dasatinib plus steroids followed by dasatinib alone in patients in complete molecular response (CMR) or chemotherapy and/or allogeneic transplant for those who did not reach a CMR (Chiaretti et al, Haematologica 2021). In the last LAL2116 trial, dasatinib plus glucocorticoids were administered in induction followed by at least two blinatumomab cycles as consolidation (Foà et al, N Engl J Med 2020). The rates of hematologic CR were comparable in the four trials, ranging from 96 to 100%. Methods. In order to perform a reliable comparison, patient-level data from the Ph+ ALL patients enrolled in the LAL0904 (n=51), LAL1205 (n=63), LAL1509 (n=60) and LAL2116 (n=63) protocols were used to conduct a multilevel propensity score weighting analysis. The median follow-up was similar in LAL0904, LAL1509 and LAL2116 - namely, 51.8, 57.4, 52.9 months - while LAL1205 had a shorter follow-up of 24.8 months, due to the trial design. Survival estimates were thus calculated at 24 months, representing the minimum median follow-up within the 4 trials. The weights were calculated with a multinomial logistic regression model. The variables age at diagnosis, gender, WBC, BCR::ABL1 isoform and allogenic transplant rate were included in this propensity score model. Differences in MRD rates were computed after the TKI alone induction using the chisq test. Given that the post-remission strategy was not defined in all protocols, the comparison of post-induction MRD was not appropriate. Survival curves were compared by standard and pairwise log-rank test. Results. Among the balancing weights methods, the matching weights produced the best balance, with standardized mean differences &amp;lt;0.2 for all variables. As shown in Table 1, before weighting the baseline features were uneven; upon weighting, the 4 cohorts were balanced in terms of age, gender, WBC, BCR::ABL1 isoform and transplant rate. After weighting, the MRD negativity rates at the end of induction were as follows: LAL0904 0%, LAL1205 23.9%, LAL1509 18.4%, LAL2116 29% (p=0.0007), mostly sustained by the different effect of dasatinib vs imatinib on the early molecular clearance. Survival outcomes after weighting underlined the superiority of the LAL2116 approach in comparison with the other protocols and the worse outcome for patients treated according to the LAL1205 scheme, presumably due to the lack of a uniform post-induction strategy. Indeed, the OS at 24 months was 89.8% in LAL2116, 71.2% in LAL1509, 52.9% in LAL1205, 66.2% in LAL0904 (p=0.001). Likewise, DFS at 24 months was 84.3% in LAL2116, 53.7% in LAL1509, 32.4in LAL1205, 61.1% in LAL0904 (p=0.001). Conclusions. By using a multilevel propensity score weighting approach, we were able to compare with statistical accuracy the results of 4 GIMEMA protocols for the frontline treatment of adult Ph+ ALL patients. After weighting, two results clearly emerged: on the one hand the markedly superior survival of patients enrolled in the LAL2116 protocol and on the other hand the unfavorable outcome of LAL1205. The marked improvement observed with the LAL2116 trial is ascribable to the consolidation strategy based on blinatumomab, since LAL2116 shared with the earlier LAL1509 and LAL1205 protocols the same induction strategy (dasatinib). It also appears evident that a center-specific post-induction strategy - as in LAL1205 - is not beneficial.

Studies Of Prescription Digital Therapeutics Often Lack Rigor And Inclusivity.

Little is known about the evidence to support prescription digital therapeutics, which are digital tools that rely primarily on software for diagnosis or treatment that have indications for use regulated by the Food and Drug Administration (FDA) and require a clinician's prescription. We conducted the first retrospective cross-sectional analysis of clinical studies of twenty prescription digital therapeutics authorized by the FDA and available on the market as of November2022. Our analysis found that just two prescription digital therapeutics had been evaluated in at least one study that was randomized and blinded and that used other rigorous standards of evidence. Two-thirds of clinical studies of prescription digital therapeutics were conducted on a postmarket basis, with less rigorous standards of evidence than the standards used in premarket studies. More than half of studies did not report data on participants' race, and more than 80percent did not report their ethnicity. More than one-third required English proficiency, and nearly half of nonpediatric studies had an upper age limit. These results suggest the need for a more rigorous and inclusive approach to clinical research supporting FDA-authorized prescription digital therapeutics. A stronger evidence base would increase confidence in these technologies' effectiveness and would enable more informed decision making about their clinical use and coverage.

Dissecting the complexity of pediatric blood transfusions and risk of adverse reactions in Aotearoa New Zealand.

Children have different clinical and physiological drivers for transfusion from adult recipients. However, adverse transfusion reactions (ATRs) in pediatric patients are usually reported using the same criteria as for adults. Broad assessments of pediatric ATRs neglect substantial variation in different developmental stages. This retrospective study included 342,950 patients, ~2.43 million transfusions, and 5,540 ATR reports collated from New Zealand hospitals between 2005 and 2021. Using 16 years as the upper age limit, 138,856 pediatric transfusions and 402 pediatric ATR reports were identified and dissected at three levels: pediatric as a whole, pediatric developmental stage (i.e., neonate, infant, preschool, and school), and chronological age to identify patients at high risk of ATRs. Multivariate logistic regression analysis was followed to quantify risk factors. Pediatric recipients had a higher ATR risk than adults (p=6.9-07) but the high risk was associated mainly with children older than 2 years. Neonates and infants accounted for 75.0% of pediatric recipients but had much lower ATR rates than adults. Pediatric transfusion recipients showed a clear male bias prior to age 11 years and then a female bias. However, gender difference in experiencing ATRs was significant only after age 13 years (p=2.3-04). Analyses focusing on the high-risk group revealed allergic reactions being the cause of the elevated risk and identified the main risk factors of number of transfusions (p=4.5-10) and multiple types of components transfused (p=2.0-13). The identified ATR risk factors signal linkage with the biological drivers for transfusion. Low ATR rates in infancy could also be attributed to use of neonatal components, low transfusions per patient, and less developed immunity. The relative increase in female recipients from age 11 may be associated with increased red blood cell demand following puberty.

General order kinetics model for OSL rock surface exposure dating

Dating of rock surface using optically stimulated luminescence (OSL) is an emerging tool to estimate exposure age and post exposure erosion rates. The present study points out the lacuna in the mathematical model that is used for this method. So far, all existing research, use first order kinetics (FOK) model. The FOK model predicts an exponential decay of OSL signal of polymineral rock with sunlight exposure, which is contrary to the observation. The non-exponential decay of OSL signal, more precisely infrared stimulated luminescence (IRSL) of feldspar, can be better explained by general order kinetics (GOK). Thus, we propose a new GOK model for OSL surface exposure dating. Present theoretical study shows, for FOK model the OSL (IRSL) depth profile propagates faster with time of light exposure than actual. Consequently, the FOK model predicts lower exposure age. The propagation of OSL profile with time depends on order of kinetics of the GOK model. We demonstrate how the order of kinetics can be constrained through laboratory bleaching experiment. The impact of the GOK model on exposure age and upper age limit, for different order of kinetics are presented. We apply this new GOK model on experimental data, available in the literature (Luo et al. in Geophysical Research Letter 49: e2022GL099526, 2022), of OSL depth profile on exposed fault scarp and reevaluate the exposure ages for different order of kinetics to validate the GOK model. We conclude that the GOK model better explains the IRSL of feldspar than the FOK model and should be preferred for OSL rock surface dating.

Exclusion of older adults from randomized controlled trials in rheumatoid arthritis.

To assess eligibility criteria that either explicitly or implicitly exclude older patients from randomized controlled trials (RCTs) in RA. Our analysis included RCTs of pharmacological interventions registered with ClinicalTrials.gov and started between 2013 and 2022. Co-primary outcomes were proportions of trials with an upper age limit and the eligibility criteria indirectly increasing risk of the exclusion of older adults. A total of 143/290 (49%) trials had an upper age limit of 85 years or less. Multivariable analysis showed that the odds of an upper age limit were significantly lower in trials performed in the USA [adjusted odds ratio (aOR), 0.34; CI, 0.12-0.99; P = 0.04] and intercontinental trials (aOR, 0.4; CI, 0.18-0.87; P = 0.02). In total, 154/290 (53%) trials had at least one eligibility criterion implicitly excluding older adults. These included specific comorbidities (n = 114; 39%), compliance concerns (n = 67; 23%), and broad and vague exclusion criteria (n = 57; 20%); however, we found no significant associations between these criteria and trial characteristics. Overall, 217 (75%) trials either explicitly or implicitly excluded older patients; we also noted a trend towards increasing proportion of these trials over time. Only one trial (0.3%) enrolled solely patients aged 65 and older. Older adults are commonly excluded from RCTs in RA based on both age limits and other eligibility criteria. This seriously limits the evidence base for the treatment of older patients in clinical practice. Given the growing prevalence of RA in older adults, relevant RCTs should be more inclusive to them.

Filizchay pyrite-polymetallic deposit (the southern slope of the Greater Caucasus) – as a typical representative of the SEDEX type pyrite deposits

&#x0D; &#x0D; &#x0D; The article has been devoted to one of the largest deposits of the southern slope of the Greater Caucasus – the Filizchay pyrite-polymetallic deposit. It has been found that the main morphology peculiarity of the pyrite-polymetallic deposit of the Filizchay deposit is that it is a single, compact sheet-like body composed mainly (at 90-95%) by the aggregates of the sulfide ores which are based on pyrite, sphalerite, galena and to a far lesser extent chalcopyrite and pyrrhotite. The carbonate minerals played a subordinate role in the deposit composition and quartz, sericite and chlorite – even less. The pyrite –polymetalic ores of the deposit are characterized by the following main mineralogical-textural varieties of ores: layered-bedded pyrite-polymetallic, massive sulfur-pyrite, massive pyrite-polymetallic, spotted-disseminated pyrite-polymetallic and vein-disseminated pyrite-polymetallic. The vein-disseminated ores are adjacent to the deposit on the footwall and are considered as independent bodies. Two industrial-techno- logical types of ores, oxidized and pyrite-polymetallic, have been distinguished at the deposit. The latter is in turn divided into two grades: mixed and primary ores. These three varieties of ores differ in the content of the oxidized lead forms. The ores with a content of the oxidized lead speciation above 60% have been classed as oxidized ores, those from 20% to 60% as mixed and those below 20% as primary. The Filizchay deposit consists of thin-bedded massive sulfides with shales, siltstones or sandstones interbeds («ore flysch») which have been formed exclusively or mainly as a result of the exhalative processes on the seabed and differ from massive sulfide deposits in volcanic rocks. On the basis of this and also according to the geological structure, the reserves of the valuable Zn + Pb components of the deposit belong to the SEDEX type that is the most important source of lead, zinc and silver. The deposit had been developing for a long time starting from the period of sedimentation and up to the ore’s formation of the copper-pyrrhotite stage. The lower age limit of the mineralization is determined by the presence of the hydrothermal-sedimentary ores of the Upper Pliensbachian. The upper age limit is established by the presence of the pebbles of the hydrothermally altered rocks and by their sulfide ores in the conglomerates underlying the deposits of the lower parts of the Upper Jurassic.&#x0D; &#x0D; &#x0D;

Shedding a Light on the Challenges of Adolescents and Young Adults with Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a typical tumour of childhood but can occur at any age. Several studies have reported that adolescent and young adult (AYA) patients with RMS have poorer survival than do younger patients. This review discusses the specific challenges in AYA patients with pediatric-type RMS, exploring possible underlying factors which may influence different outcomes. Reasons for AYA survival gap are likely multifactorial, and might be related to differences in tumor biology and intrinsic aggressiveness, or differences in clinical management (that could include patient referral patterns, time to diagnosis, enrolment into clinical trials, the adequacy and intensity of treatment), as well as patient factors (including physiology and comorbidity that may influence treatment tolerability, drug pharmacokinetics and efficacy). However, improved survival has been reported in the most recent studies for AYA patients treated on pediatric RMS protocols. Different strategies may help to further improve outcome, such as supporting trans-age academic societies and national/international collaborations; developing specific clinical trials without upper age limit; defining integrated and comprehensive approach to AYA patients, including the genomic aspects; establishing multidisciplinary tumor boards with involvement of both pediatric and adult oncologists to discuss all pediatric-type RMS patients; developing dedicated projects with specific treatment recommendations and registry/database.

Quadruplet Induction, Autologous Transplantation and Minimal Residual Disease Adapted Consolidation and Treatment Cessation in Older Adults ≥70y with Newly Diagnosed Multiple Myeloma: A Subgroup Analysis of the Master Trial

Background: Half of adults with newly diagnosed multiple myeloma (NDMM) in the US are ≥70y. This age group is often considered ineligible for intensive therapy and not routinely included in prospective clinical trials. The phase II MASTER trial (NCT03224507) for NDMM did not have an upper age limit as eligibility and showed high rates of minimal residual disease- (MRD) negativity among NDMM patients receiving quadruplet induction, autologous stem cell transplantation (ASCT) and response-adapted consolidation therapy (Costa LJ et al JCO 2021). Here, we conducted a post-hoc analysis comparing the outcomes of patients age ≥70y. vs <70y. Methods: The MASTER trial enrolled patients with NDMM, with ECOG ≤2, measurable disease and creatinine clearance ≥40 ml/min as key eligibility criteria. Patients received Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRD based induction, ASCT and response adapted Dara-KRD consolidation. The primary end point was achievement of MRD-negativity (<10-5) at any point during follow-up by NGS (ClonoSEQ®). Secondary endpoints included achievement of MRD <10-6 at any point, rate of MRD negativity post-induction, rate of complete response, progression-free survival (PFS) and overall survival (OS). Those who achieved two consecutive MRD-negative assessments underwent treatment free observation and MRD surveillance (MRD-SURE). For the current analysis, we compared the achievement of primary and secondary endpoints using intent-to-treat principle between the study cohorts. Results: Of the 123 enrolled patients, 24 (19.5%) were ≥70y at the time of diagnosis (5 were ≥75y). Baseline characteristics were similar between the two age groups (Table 1). All 24 patients received planned ASCT. Compared to younger adults, older adults had similar rates of MRD negativity post induction (36% vs 41%; p= 0.66), but lower rates of overall MRD negativity (<10-5) (65% vs 84%; p=0.03) and lower rates of complete response (71% vs 93%; p= 0.002) (Table 1). Older and younger patients had similar probability of achieving MRD-SURE (61% vs. 74%, P=0.18). Median time on protocol treatment was 11.7 (IQR 7.7-15.2) months (m) for older patients and 11.6 (IQR 8.0-14.7) m for younger patients (p=0.85). Grade ³3 treatment emergent adverse events occurred in 79% of older and 69% of younger patients (p=0.31). No patients in the older group permanently discontinued protocol therapy due to toxicity. At a median follow up of 35.9 (range 1-51) m, older vs younger adults had similar PFS (3-y PFS 86.3% vs 80.3%; p= 0.74)(Fig) and OS (3y OS 95.8% vs 88.7%; p= 0.53). Three deaths occurred during the treatment period, of which one patient was ≥70y (unwitnessed sudden death 2 m after ASCT and before consolidation). Conclusion: Our study demonstrates that older adults can be candidates for quadruplet induction, ASCT, and MRD-adapted consolidation therapy and can derive similar benefits as younger NDMM pts. While toxicity may be higher among older adults, it does not appear to compromise treatment continuation, PFS or OS. Chronologic age, by itself, should not be an eligibility criterion from trials utilizing higher intensity therapies. Future studies should focus on how to identify older adults who can benefit from intensive frontline MRD adapted therapies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 11453: Age, Sex, and Outcomes in Heart Failure With Reduced Ejection Fraction: Insights From the VICTORIA Trial

Background: Both patient age and sex influence heart failure (HF) treatment and outcomes. Given women are generally older in HF trials, we examined the associations of age and sex with clinical characteristics, background HF therapy, and response to vericiguat in VICTORIA. VICTORIA enrolled 5050 patients with HF with reduced ejection fraction (HFrEF) and recent worsening HF, was broadly inclusive without an upper age limit, and included 28% women (n=1208), and 31% (1568 ) were ≥75 years old with event rates exceeding most HF trials. Methods: Clinical characteristics were compared across age groups (&lt;65, 65 to &lt;75, ≥75 and &lt;75, ≥75 years) and sex ( Table ). Results: More women (37%) than men (29%) were age ≥75 years. Compared with younger patients, those ≥75 had higher EF and class III/IV symptoms, more comorbidities, higher NT-proBNP and lower eGFR, indicative of more advanced disease; however, this age group had the lowest use of triple therapy. Within each age group, women had higher EF and lower burden of some comorbidities (atrial fibrillation, hyperlipidemia, coronary artery disease) compared with men, but similar functional status and NT-proBNP. There were no sex differences in the use of triple therapy by age group; however, women ≥75 years less often achieved target doses of triple therapy than men of similar age. Women were also less likely to receive HF devices across all ages. The incidence of the primary composite endpoint (cardiovascular death or HF hospitalization) increased across age groups and was higher in men than women. Compared with the pre-specified age subgroup analysis (i.e., &lt;75, ≥75 years), the beneficial effect of vericiguat on the primary endpoint was not modified by age (continuous) and sex (3-way interaction; p=0.847). Conclusions: Women in VICTORIA were older than men, and while elderly women received less intense background HF therapy, their prognosis was nominally better than elderly men. Vericiguat’s benefit was independent of age and sex.

LBMON198 Improving Knowledge And Implementation Of Healthcare Transition (HCT) Policy And Procedure For Transgender And Gender Diverse (TGD) Youth At The UCSF Child And Adolescent Gender Center (CAGC)

Abstract Introduction The UCSF CAGC has served TGD youth since 2009. Increased referrals coupled with an expanding young adult patient population has resulted in longer wait times and an increased need for transition to adult care services. As part of an ongoing quality improvement initiative to develop an equitable HCT program tailored to the unique needs of TGD youth at the UCSF CAGC, we developed and aimed to improve provider knowledge of a standardized policy and procedure for HCT from pediatric to adult gender care. Methods CAGC providers received training in 11/2021 on the HCT policy and procedure, including a standardized method to identify patients with whom to initiate HCT discussions. Providers completed pre- and post-training surveys evaluating knowledge and confidence regarding HCT practices. Knowledge was assessed with yes/no questions and confidence with 5-point Likert scales (1 = lowest, 5 = highest). Pre- and post-survey results were compared using proportions tests for dichotomous outcomes and Wilcoxon rank-sum tests for confidence levels. To evaluate effectiveness, baseline data on % of eligible TGD youth seen in the UCSF CAGC in 1-2/2021 with "Counseling for transition from pediatric to adult care provider" (Z71.89) added to their problem list in the electronic medical record were collected and compared to % of eligible TGD youth with Z71.89 added to their list the 4 consecutive months following the training session. Results Nine and 7 CAGC providers completed the pre- and post-training surveys, respectively. Knowledge increased in all areas although not all were statistically significant: Age limit for new patient referrals (78% to 100%, p = 0.18), upper age limit at which patients must transition to an adult provider (56% to 100%, p = 0. 04), standardized method to track patients with whom HCT discussions have been initiated (0% to 100%, p = 0. 0001), and list of criteria for assessing HCT readiness (11% to 100%, p = 0. 0004). Confidence increased in identifying patients with whom HCT has been initiated (median 2 to 4, p = 0. 02) but not in identifying patients ready to initiate the HCT process (median 4 to 4, p = 0.43). The % of eligible TGD youth seen in the UCSF CAGC with Z71.89 added to their problem list increased from 0% at baseline to 72%, 82%, 86%, and 90% in the 4 months consecutively following the training session. Conclusions Our findings indicate that standardized training led to increased provider knowledge, participation, patient identification, and implementation of HCT program policy and procedure tailored to our TGD youth population. Future initiatives will include collaboration with adult gender centers to transition TGD youth to adult care services and to evaluate the experiences of TGD youth and providers who receive them. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

587. ROLE OF THORACOSCOPIC HAND-SEWN ESOPHAGO-GASTRIC ANASTOMOSIS IN 2-STAGE TOTALLY MINIMALLY INVASIVE ESOPHAGECTOMY. REPORT OF 200 CONSECUTIVE CASES

Abstract Esophagectomy is the mainstay of treatment of esophageal and gastro-esophageal junction cancer. Minimally invasive esophagectomy has been introduced in the 2000s in an effort to reduce post-operative pulmonary and cardiac complications. 2-stage totally minimally invasive esophagectomy combines laparoscopic abdominal phase followed by thoracoscopic thoracic phase. The rate limiting step of the procedure is the construction of esophago-gastric anastomosis. We aim to present our technique and results on hand-sewn thoracoscopic esophago-gastric anastomosis in prone position. This is prospective analysis of consecutive patients that underwent 2-stage totally minimally invasive esophagectomy for esophageal and gastro-esophageal junction Siewert type I-II cancers. All operations were identical in terms of patient positioning, lymphadenectomy and type of anastomosis formed. Study included adult patients with no upper age limit (&amp;gt;18 years); all hybrid esophagectomies, esophagectomies for malignancy and emergency operations were excluded from the study. The anastomosis was manually facilitated thoracoscopic in prone position, in 2-layers, using barbed sutures. Primary endpoints were anastomotic leakage and anastomotic stricture rate. Secondary endpoints were 30- and 90-day mortality rates. During a 5-years-period, n=200 consecutive patients underwent 2-stage totally minimally invasive esophagectomy for cancer. Most patients were males. Median age was 65.5 years. Median operative time was 280 minutes while median suturing time for the anastomosis was 50 minutes. Anastomosis was thoracoscopic, hand-sewn constructed in prone position in all cases. There was no conversion to open. Anastomotic leak complicated n=5 patients (2.5%); n=4 were type I anastomotic leaks and n=1 was type I, which was treated with chest drainage. Anastomotic stricture was presented in n=13 patients (6.5%). 30-day mortality rate was 1% and 90-day mortality rate was 2.5%. Formation of the esophago-gastric anastomosis is one of the most challenging aspects during 2-stage totally minimally invasive esophagectomy. Most surgeons prefer the construction using circular or linear staplers. Our anastomotic technique, present a safe and effective anastomosis, with favorable clinical outcomes. It can be reproduced and established in the hand of experts, offering all the advantages of manual anastomosis and reduction of devastating post-operative anastomotic leakage, which still complicates stapled constructed anastomosis with significant incidence.

595. LAPAROSCOPIC HELLER’S MYOTOMY WITHOUT FUNDOPLICATION. CURRENT EVIDENCE

Abstract Achalasia is a rare esophageal motility disorder which affects the esophageal smooth muscle layer, causing absent or spastic peristalsis, and absent or partial lower esophageal sphincter (LES) relaxation with an increased LES tone. Laparoscopic Heller’s myotomy is the gold standard surgical therapy of esophageal achalasia. The role of fundoplication to minimize GERD after myotomy is debatable. We studied our experience with Laparoscopic Heller Myotomy Without Fundoplication (LHM) for the treatment of esophageal achalasia. A retrospective analysis of prospectively collected data regarding consecutive patients that underwent LHM without fundoplication for the treatment of esophageal achalasia was conducted. All patients were operated between September 1st 2018 and January 1st 2022. Patients included in this study were adults (&amp;gt;18 years old) without upper age limit. All participants completed a subjective dysphagia score questionnaire, received an Eckardt Score preoperatively, as well as at 6 and 12 months following the myotomy procedure. Patients that were treated with endoscopic dilation POEM or esophagectomy were excluded from the study. Twenty-five patients underwent LHM myotomy without fundoplication during the study period. Median age was 42 years (Range: 25-90 years). Median operative time was 70 min (Range: 60-80 min). There was no conversion. Median length of stay was 2 days (Range: 1-15 days). There was one (n=1) mucosal perforation, in a 28-year-old male patient due to overeating, 4 days post LHM. He was treated with laparoscopic primary suturing. There was n=1 (4%) pathologic GERD noted post-operatively. The Eckardt score decreased from 6.5 ± 1.7 to 0.9 ± 1.4 at 1 month and to a 0.8 ± 1.1 at 12 months. Therapy of esophageal achalasia focuses on decreasing the outflow resistance of the GEJ caused by the dysfunctional LES. LHM is considered as the gold-standard therapy for most achalasia patients. LHM is considered safe and effective, while it has been associated with excellent results regarding the relief of dysphagia. There is a reportedly low incidence of new gastroesophageal reflux symptoms. There is no need for fundoplication following LHM since the incidence of GERD is relatively low.

596. MINIMALLY INVASIVE ESOPHAGECTOMY FOR ESOPHAGEAL AND GASTRO-ESOPHAGEAL JUNCTION TUMORS. A SINGLE CENTER EXPERIENCE

Abstract Esophagectomy carries high rates of post-operative morbidity and mortality. Minimally invasive esophagectomy was introduced more than 20 years ago offering all the advantages of minimally invasive surgery and significantly reducing post-operative pulmonary and cardiac complications associated with open esophagectomy. Clinical and oncological outcomes are vastly improved standardizing this approach as inferior in the hand of experts. Herein, we aim to present our results of minimally invasive esophagectomy for esophageal and gastro-esophageal junction cancer. This is prospective analysis of consecutive patients that underwent 2-stage minimally invasive esophagectomy for esophageal and gastro-esophageal junction Siewert type I-II cancers. Operations included hybrid 2-stage esophagectomy (laparoscopic/open thoracotomic or open laparotomy/thoracoscopy) and 2-stage totally minimally invasive esophagectomy (laparoscopic/thoracoscopic). Study included adult patients with no upper age limit (&amp;gt;18 years). All esophagectomies for benign disease, as well as emergency operations were excluded from the study. Primary endpoints were 30- and 90-day mortality rate, anastomotic leak, anastomotic stricture, pulmonary complications, and length of hospital stay. Secondary endpoints were overall survival and progression-free survival rates respectively. During an 8-year-period, n=350 consecutive patients underwent 2-stage minimally invasive esophagectomy for cancer. Our team has a cumulative experience of more than 300 open-esophagectomies. Since September 1st, 2013, hybrid 2-stage esophagectomy program was initiated. On September 1st, 2016, the program offered 2-stage totally minimally invasive esophagectomy in-all comers. Most patients were males. Anastomotic leak complicated 5.1% of the patients; 10% of the patients presented anastomotic stricture post-operatively, while pulmonary and cardiac complications reached up to 25 and 12% respectively. Medial LOS was 8 days. Median follow-up was 60 months. OS survival rate was 53 months and PFS was 48 months. Advances in minimally invasive surgery can benefit all patients with esophageal and gastro-esophageal junction tumors. Hybrid and totally minimally invasive 2-stage esophagectomy are well established approaches, with safe and feasible profile in tertiary cancer centers. They can lead to significantly improved clinical and oncological outcomes comparing to open esophagectomy and its complications burden.

594. TOTALLY MINIMALLY INVASIVE 2-STAGE ESOPHAGECTOMY VERSUS HYBRID 2-STAGE ESOPHAGECTOMY. A SINGLE CENTER EXPERIENCE

Abstract Totally minimally invasive 2-stage esophagectomy (TMIE) eliminates the thoracotomy associated with hybrid 2-stage minimally invasive esophagectomy (hybrid-MIE). This has an important role in minimizing post-operative respiratory complications. There is ongoing growing evidence in published literature of improved clinical and oncological outcomes in totally MIE comparing to hybrid MIE, due to enhanced optics and extend of lymphadenectomy as well as to shorter length of hospital stay and surgical trauma associated to thoracoscopy. This is a retrospective analysis of consecutive patients that underwent 2-stage minimally invasive esophagectomy for esophageal and gastro-esophageal junction Siewert type I-II cancers. TMIE combines a laparoscopic and thoracoscopic approach while hybrid-MIE includes laparoscopic open thoracotomic phase. Study included adult patients with no upper age limit (&amp;gt;18 years). All esophagectomies for benign disease, as well as emergency operations were excluded from the study. Primary endpoints were 30- and 90-day mortality rate, anastomotic leak, anastomotic stricture, pulmonary complications, and length of hospital stay. Secondary endpoints were overall survival and progression-free survival rates respectively. During an 8-year-period, 150 patients underwent hybrid-MIE, while 200 underwent TMIE. Operative-time was shorter in the hybrid-MIE group (320 vs 280 min). Anastomotic leak was significantly reduced in the TMIE group comparing to the hybrid-MIE group (2.5% vs 9.5%). Respiratory complications were reduced in the TMIE group (10 vs 25%). Median LOS was similar (7 vs 7.5 days). Median number of resected-lymph nodes was increased in the TMIE group (28 vs 35 lymph nodes). OS survival rate was 60 versus 51 months and PFS was 52 vs 43 months in the TMIE and hybrid-MIE groups respectively. In general, TMIE was associated with moderately lower morbidity compared to hybrid-MIE, but randomized controlled evidence is lacking. The higher anastomotic leakage rate, higher rate of pulmonary complications and lower lymph node count that was found after hybrid-MIE in comparative analysis, indicate that TMIE can significantly improve clinical outcomes of patients undergoing esophagectomy. The findings of this study should be considered carefully by surgeons when moving from hybrid-MIE to TMIE.