Intensification Treatment Research Articles

Therapeutic inertia and contributing factors among ambulatory patients with hypertension

BackgroundTherapeutic inertia refers to the failure of healthcare providers to initiate or intensify therapy based on current evidence-based guidelines, even when the desired treatment goal is not achieved. Despite poorly controlled hypertension, clinicians often hesitate to intensify treatment. Therapeutic inertia is currently receiving more attention as a significant reason for clinicians’ inability to effectively manage hypertension. However, in our setting, there is limited knowledge about therapeutic inertia and its contributing factors.ObjectivesThe aim of this study was to investigate therapeutic inertia and contributing factors among ambulatory patients with hypertension.MethodA prospective observational study was conducted at the cardiac clinic of Ayder comprehensive specialized hospital in the Tigray region of northern Ethiopia. Patients were recruited into the study during their medication refilling appointments using a simple random sampling technique. All patients were followed for a minimum of 6 months to assess therapeutic inertia, which was defined as the healthcare providers’ failure to initiate or intensify therapy based on current evidence-based guidelines when therapeutic goals were not achieved. Data were collected through patient interviews and review of their medical records. We utilized binary logistic regression analysis to determine factors associated with therapeutic inertia.ResultThe study included 282 participants, with an equal male-to-female ratio. The mean age of the participants was 56.6 ± 12.3 years. Among all participants, a majority (67.4%) had uncontrolled hypertension. The study revealed that 72% of patients with uncontrolled hypertension experienced therapeutic inertia. In response to this issue, we recommended dose escalation for 73% of the patients and the initiation of additional drug therapy for 27% of them. Multivariable analysis indicated that having three or more medications (AOR = 4.74, 95%CI = 1.94–11.61) and having stage II hypertension (AOR = 3.06, 95%CI = 1.32–7.08) were identified as independent predictors of therapeutic inertia.ConclusionThe findings of our study indicated that a large proportion of the patients had poorly controlled hypertension, and a significant number of these patients also demonstrated therapeutic inertia. The number of medications and stage II hypertension were identified as independent predictors of therapeutic inertia. Therefore, it is crucial to prioritize patients at risk of therapeutic inertia and provide them with additional support. Moreover, practice based training should be given to clinicians in order to enhance treatment intensification and overall treatment outcome among ambulatory patients with hypertension.

Investigation on the cavitation characteristic of a novel cylindrical rotational hydrodynamic cavitation reactor

Hydrodynamic cavitation reactors are of great promise for the applications of chemical process intensification and water treatment. In this work, a novel cylindrical rotational hydrodynamic cavitation reactor (CRHCR) with rectangular grooves and oblique tooth protrusions on the rotor surface was studied. The three-dimensional characterization of cavitation within the CRHCR was observed from the front and left views by the high-speed camera experiments. Interestingly, a new phenomenon of simultaneous formation of the attached cavitation and shear cavitation was found in the CRHCR. The synergistic effect of attached cavitation and shear cavitation contributes to the enhancement of the cavitation performance of CRHCR. In addition, the evolution of attached cavitation is explored. It is found that attached cavitation forms a trapezoidal-shaped cavitation cloud in the groove, which undergoes three various stages: incipient, development, and collapse. Finally, the pulsation frequency and cavitation intensity of shear cavitation in the chamber were investigated. The results show that the cavitation pulsation frequency is the same at the same rotational speed in the chamber near diverse oblique teeth. As the rotational speed increases, the cavitation pulsation frequency increases linearly. These findings in this paper are of great benefit to understanding the mechanism of the cavitation effect of CRHCR.

NOTCH1 fusions in pediatric T-cell lymphoblastic lymphoma: Ahigh-risk subgroup with CCL17 (TARC) levels as diagnostic biomarker.

Twenty percent of children with T-cell lymphoblastic lymphoma (T-LBL) will relapse and have an extremely poor outcome. Currently, we can identify a genetically low-risk subgroup in pediatric T-LBL, yet these high-risk patients who need intensified or alternative treatment options remain undetected. Therefore, there is an urgent need to recognize these high-risk T-LBL patients through identification of molecular characteristics and biomarkers. By using RNA sequencing which was performed in 29/49 T-LBL patients who were diagnosed in the Princess Maxima Center for Pediatric Oncology between 2018 and 2023, we discovered a previously unknown high-risk biological subgroup of children with T-LBL. This subgroup is characterized by NOTCH1 gene fusions, found in 21% of our T-LBL cohort (6/29). All patients presented with a large mediastinal mass, pleural/pericardial effusions, and absence of blasts in the bone marrow, blood, and central nervous system. Blood CCL17 (C-C Motif Chemokine Ligand 17, TARC) levels were measured at diagnosis in 26/29 patients, and all six patients with NOTCH1 gene fusions patients exclusively expressed highly elevated blood CCL17 levels, defining a novel and previously not known clinically relevant biomarker for T-cell lymphoblastic lymphoma. Four out of these six patients relapsed during therapy, a fifth developed a therapy-related acute myeloid leukemia during maintenance therapy. These data indicate that T-LBL patients with a NOTCH1 fusion have a high risk of relapse which can be easily identified using a blood CCL17 screening at diagnosis. Further molecular characterization through NOTCH1 gene fusion analysis offers these patients the opportunity for treatment intensification or new treatment strategies.

Abstract 2560: Genomic biomarkers of survival in patients (pts) with metastatic castrate-sensitive prostate cancer (mCSPC) undergoing androgen deprivation therapy (ADT) intensification (ADTi)

Abstract Background: ADTi with androgen receptor pathway inhibitors (ARPI) with or without docetaxel improves survival outcomes in pts with mCSPC. Even with ADTi, 20% of these pts progress within a year and experience poor overall survival (OS). Identifying baseline genomic biomarkers predicting poor survival outcomes in pts receiving ADTi remains an unmet need. Methods: In this IRB-approved retrospective study, pts with a new diagnosis of mCSPC who underwent comprehensive genomic profiling of primary prostate tissue or metastatic site or cell-free DNA and treated with ADTi (ADT with ARPI or docetaxel) were included. Genomic alterations with an incidence > 5% were included in the analysis. Study endpoints: progression-free survival (PFS) was defined from the start of therapy for mCSPC to progression (per PCWG-2) or death from any cause. OS was defined from the start of therapy for mCSPC to the date of death from any cause or censored at the last follow-up. A multivariable analysis using the Cox proportional hazards model was used, adjusting for age at mCSPC diagnosis, disease volume (high vs. low), Gleason score (≥ 8 vs. < 8), Log2PSA at baseline, and initial timing of metastasis (de novo vs. non de novo). A subgroup analysis by intensification treatment received (ARPI vs. docetaxel) was also performed. Missing baseline characteristics such as volume of disease, Gleason score, and Log2PSA were multiply imputed on 50 chained equations using “mice” package in R. All the analyses were done using R version 4.3.1. Results: A total of 289 pts were included in the study. The baseline characteristics of the cohort will be presented in the meeting. The alterations included in the analysis were TP53 (31.8%), TMPRSS2 (30.4%), PTEN (17%), APC (10.4%), SPOP (9%), RB1 (6.2%), BRCA2 (5.2%), and CDK12 (5.2%). In the multivariable analysis, TP53 (HR 1.87, 95% CI 1.29-2.72, p = 0.001), RB1 (HR 2.56, 95% CI 1.45-4.53, p = 0.001), PTEN (HR 1.77, 95% CI 1.15-2.72, p = 0.009), and BRCA2 (HR 2.68, 95% CI 1.47-4.89, p = 0.002) were associated with significantly shorter PFS while TP53 (HR 1.78, 95% CI 1.1-2.88, p = 0.019), RB1 (HR 4.78, 95% CI 2.53-9.02, p < 0.001), and PTEN (HR 2.37, 95% CI 1.37-4.1, p = 0.003) were associated with significantly worse OS. Results of the subgroup analysis by intensification treatment (ARPI vs. docetaxel) will also be presented in the meeting. Conclusions: In this real-world study, we identified genomic biomarkers that could be associated with shorter PFS and OS in pts with mCSPC treated with ADTi. Upon external validation, these results may aid in developing a clinical-genomic risk stratification model, patient counseling, and treatment selection. Citation Format: Arshit Narang, Georges Gebrael, Chadi Hage Chehade, Nicolas Sayegh, Yeonjung Jo, Beverly Chigarira, Nishita Tripathi, Ayana Srivastava, Clara Tandar, Benjamin L. Maughan, Umang Swami, Neeraj Agarwal. Genomic biomarkers of survival in patients (pts) with metastatic castrate-sensitive prostate cancer (mCSPC) undergoing androgen deprivation therapy (ADT) intensification (ADTi) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2560.

Sustainable intensification of climate-resilient maize–chickpea system in semi-arid tropics through assessing factor productivity

Global trends show that the rapid increase in maize production is associated more with the expansion of maize growing areas than with rapid increases in yield. This is possible through achieving possible higher productivity through maize production practices intensification to meet the sustainable production. Therefore, a field experiment on “Ecological intensification of climate-resilient maize–chickpea cropping system” was conducted during consecutive three years from 2017–2018 to 2019–2020 at Main Agricultural Research Station, Dharwad, Karnataka, India. Results of three years pooled data revealed that ecological intensification (EI) treatment which comprises of all best management practices resulted in higher grain yield (7560 kg/ha) and stover yield compared to farmers’ practice (FP) and all other treatments which were deficit in one or other crop management practices. Similarly, in the succeeding winter season, significantly higher chickpea yield (797 kg/ha) was recorded in EI. Further EI practice recorded significant amount of soil organic carbon, available nitrogen, phosphorus, potassium, zinc, and iron after completion of third cycle of experimentation (0.60%, 235.3 kg/ha,21.0 kg/ha,363.2 kg/ha,0.52 ppm and 5.2 ppm respectively). Soil enzymatic activity was also improved in EI practice over the years and improvement in each year was significant. Lower input energy use was in FP (17,855.2 MJ/ha). Whereas total output energy produced was the highest in EI practice (220,590 MJ ha−1) and lower output energy was recorded in EI–integrated nutrient management (INM) (149,255 MJ/ha). Lower energy productivity was noticed in EI-INM. Lower specific energy was recorded in FP and was followed by EI practice. Whereas higher specific energy was noticed is EI–INM. Each individual year and pooled data showed that EI practice recorded higher net return and benefit–cost ratio. The lower net returns were obtained in EI-integrated weed management (Rs. 51354.7/ha), EI-recommended irrigation management (Rs. 56,015.3/ha), integrated pest management (Rs. 59,569.7/ha) and farmers’ practice (Rs. 67,357.7/ha) which were on par with others.

High serum levels of ustekinumab are associated with better clinical outcomes during maintenance treatment for inflammatory bowel disease.

Ustekinumab (UST) is an effective treatment option in Crohn's disease (CD) and ulcerative colitis (UC). However, it still remains unclear if therapeutic drug monitoring could be helpful to guide clinicians. The aim of our study was to analyze the relationship between UST through levels (USTTL) and clinical outcomes in real-world inflammatory bowel disease (IBD) patients. We performed a unicentric retrospective study including patients with IBD under UST treatment with at least one level determination. The following variables were analyzed at the initiation of UST and at each USTTL measurement: clinical response and remission using the Harvey-Bradshaw Index (HBI) for CD and the Partial Mayo Score (pMayo) for UC; biochemical response and remission using fecal calprotectin and C-reactive protein, among others. Two periods were considered: P1 (time between induction and the first determination of USTTL) and P2 (time between USTTL1 and the second determination of USTTL). We included 125 patients, 117 with CD. In P1, 62.4% of patients were on subcutaneous maintenance, and the median USTTL1 was 3.1 μg/mL (1.6-5.3). In 44.8% of CD patients (48/117), clinical remission was achieved, with USTTL1 significantly higher than those who did not achieve remission (3.7 μg/mL (2.3-5.4) vs 2.3 μg/mL (1.1-5.2); p = 0.04). In the 46 patients with two determinations, statistically significant differences were found between variables in P2 versus P1: clinical remission (73.9% vs 21.7%; p = 0.001); USTTL (7.2 μg/mL (4.7-11.7) vs 3.4 μg/mL (1.9-6.4); p < 0.001), HBI (4 (4-4.3) vs 8 (4-9); p < 0.001), pMayo (1 (1-3.3) vs 4.5 (3-5); p = 0.042), and corticosteroid use (26.1% vs 41.3%; p = 0.024). Receiver-Operating-Characteristic (ROC) curves were calculated for clinical remission in P2, with USTTL cutoff value of 6.34 μg/mL for clinical remission and a high rate of intensified patients (98%). High serum levels of UST were associated with clinical remission during treatment for IBD under intensification treatment, with a cutoff point of 6.3 μg/mL.

Impact of Neoadjuvant Radiochemotherapy on Pathological Complete Response for Locally Advanced Rectal Cancer: A Mono Institutional Experience.

Neoadjuvant radiochemotherapy followed by surgery is a standard of care in locally advanced rectal cancer (LARC). Only a subgroup of patients can obtain a pathological complete response (pCR) and achieve good local control. However, the role of pCR on patient survival is debated. The aim of the study was to evaluate the impact of pCR on clinical outcomes and toxicities in LARC patients treated with dose intensification and concomitant capecitabine treatment in a neoadjuvant radiochemotherapy schedule. This was a single Institution retrospective study including 178 patients. Mandard tumor regression grade (TRG) and pTNM staging system were used to classify pathological response and define pathological complete response (pCR). Patients were divided in: pCR (pT0N0) and Not-pCR (pT>0N>0), according to pTNM and in good responders (TRG1-2) and partial/not responders (TRG3-5), according to Mandard TRG. The Kaplan-Meier method was used to estimate OS, CSS, DFS and LC. A low severe toxicity rate was observed. Acute Grade 3 lower bowel toxicity and Grade 3 cutaneous toxicity were reported in 2 (1.1%) patients, respectively. Late Grade >3 lower bowel toxicity was reported in 6 patients (3%) and late Grade >3 cutaneous toxicity was registered in one patient. No other severe acute and late toxicities were reported. The 5- and 10-year OS, CSS, DFS and LC rates were 85% and 75%, 94% and 92%, 83% and 81%, 88% and 88%, respectively. We observed a pCR rate of 36% and a good responders rate of 62%, in our study population. Both groups showed better rates for each analyzed clinical outcome. Neoadjuvant radiochemotherapy with dose intensification in LARC patients resulted in favorable long-term oncological outcomes, pCR rate showed an optimal impact on OS and DFS with an acceptable toxicity.

Is Interim PET a Useful and Used Tool in Classical Hodgkin Lymphoma? Results from a Retrospective Multicenter Italian Experience

INTRODUCTION Interim PET (iPET) scan after 2 cycles has been proved a useful tool in order to escalate treatment in the setting of advanced stage (AS) classical Hodgkin Lymphoma (cHL) treated with ABVD as first-line therapy. However, few data are known regarding the use of iPET and the adoption of intensification treatment strategies in real life. MATERIALS AND METHODS We conducted a retrospective, multicenter study in which we collected consecutive, newly diagnosed AS cHL patients (pts) treated between January 2010 and December 2018. Pts could be included if aged 18 to 80 years old, if treated with ABVD/ABVD-like schemes and if pre-treatment and interim PET scans were available. Primary endpoint was the frequence of intensification after a positive iPET. Secondary endpoints were Progression Free Survival (PFS) and Overall Survival (OS) of pts undergoing iPET-based intensification strategies. iPET was defined as positive or negative based on the assessment by the local investigator. When available, Deauville Score (DS) was also collected. Continuous covariates were summarized as median, interquartile distance (IQR) and range, categorical variables were summarized as absolute and percentage frequencies. Survival functions were defined as the time between the date of iPET to the date of progression (PFS) or death for any cause (PFS/OS) or last clinic control (PFS/OS) for censored cases. The survival functions were computed by means of Kaplan-Meier method. Comparisons between groups were done using the log-rank test; the effect of covariates was estimated using the Cox proportional hazard regression model and was expressed as hazard ratio (HR), with 95%CI. All the p-values reported were two-sided. RESULTS Detailed characteristics of the 399 enrolled pts are listed in Table 1. iPET was positive in 68 pts (17%), of whom 17 (25%) were immediately shifted to intensified therapies: 8 escBEACOPP (eB), 8 chemo+ASCT (cA), 1 other salvage regimens (oSR). DS was reported in 220 (55%) pts. In iPET-positive pts, DS was reported in 35/68 pts (51,4%): 25 were DS4 and 10 were DS5, respectively. Among the 51 iPET positive pts who didn't change treatment after iPET, 31 (61%) underwent a subsequent iPET after 4 cycles. iPET4 was positive in 17 pts (55%), of whom 12 (70%) were shifted to intensified treatments: 2 eB, 8 cA, 2 oSR. Overall, 29/68 iPET-positive pts (43%) were intensified either immediately after iPET or after a subsequent iPET4 positivity and the most commonly used intensification was cA (16/29 cases). After a median follow up of 6 years (0.2 - 12), 5-y PFS was 76% (95% CI 72 to 80%), and 5-y OS was 94% (95% CI 91 to 96%). In univariable analysis, iPET positivity (5y PFS 60% versus 80% for iPET negative pts, p &amp;lt; 0.001), stage IV, age (continuous form) and not receiving radiotherapy were significantly associated with worse PFS; iPET positivity (5y OS 82% versus 96% in iPET-negative pts, p=0.003), stage IV, age ≥ 60, IPS, B symptoms, male gender and not receiving radiotherapy were significantly associated with worse OS. PFS and OS were similar (p=0.851 and 0.520, respectively) for iPET-positive pts undergoing or not undergoing immediate intensification (59% versus 61%, and 84% versus 81%, respectively) [Figure 1]. The 5-y PFS and OS were significantly different between pts with iPET negativity and iPET positivity, as reported above. Remarkably, among iPET+ pts, no treatment modification after iPET positivity (either after 2 or 4 cycles) was associated with worse 5-Y PFS and OS (72% and 82% respectively) if compared to PET negative pts. Moreover, there were no differences in terms of both PFS and OS for iPET pts who modified treatment after either iPET or iPET4. CONCLUSIONS In AS cHL pts undergoing ABVD first line treatment, iPET positivity is 17%, but few pts shifted to intensification strategies and most pts didn't change treatment and underwent to iPET4. iPET4 was positive in 17/31 pts, of whom 70% shifted to salvage treatments, mainly cA. iPET prognostic role was confirmed, since PFS and OS were strongly correlated with iPET status, but early intensification didn't provide any PFS and/or OS advantages. Due to the high prognostic role of iPET positivity, AS cHL pts might benefit from more intensive first line treatments that could reduce iPET positive cases (e.g. AVD combos with anti-PD1 or brentuximab vedotin) or from more efficacious second line therapies (e.g. Brentuximab Vedotin and/or anti-PD1 based combination strategies)

Would, early, versus late hydroxocobalamin dose intensification treatment, prevent cognitive decline, macular degeneration and ocular disease, in 5 patients with early-onset cblC deficiency?

In early-onset (EO) cblC deficiency (MMACHC), hydroxocobalamin dose-intensification (OHCBL-DI) improved biochemical and clinical outcome. In mammals, Cobalamin is reduced, in a reaction mediated by MMACHC. Pathogenic variants in MMACHC disrupt the synthesis pathway of methyl-cobalamin (MetCbl) and 5′-deoxy-adenosyl-cobalamin (AdoCbl), cofactors for both methionine synthase (MS) and methyl-malonyl-CoA mutase (MCM) enzymes. In 5 patients (pts.), with EO cblC deficiency, biochemical and clinical responses were studied following OHCbl-DI (mean ± SD 6,5 ± 3,3 mg/kg/day), given early, before age 5 months (pts. 1, 2, 3 and 4) or lately, at age 5 years (pt. 5). In all pts., total homocysteine (tHcy), methyl-malonic acid (MMA) and Cob(III)alamin levels were measured. Follow-up was performed during 74/12 years (pts. 1, 2, 3), 33/12 years (pt. 4) and 34/12 years (pt. 5). OHCbl was delivered intravenously or subcutaneously. Mean ± SD serum Cob(III)alamin levels were 42,2 × 106 ± 28, 0 × 106 pg/ml (normal: 200–900 pg/ml). In all pts., biomarkers were well controlled. All pts., except pt. 5, who had poor vision, had central vision, mild to moderate nystagmus, and with peri-foveolar irregularity in pts. 1, 2 and 4, yet none had the classic bulls' eye maculopathy and retinal degeneration characteristic of pts. with EO cblC deficiency. Only pt. 5, had severe cognitive deficiency. Both visual and cognitive functions were better preserved with early than with late OHCBL-DI. OHCBL-DI is suggested to bypass MMACHC, subsequently to be rescued by methionine synthase reductase (MSR) and adenosyl-transferase (ATR) to obtain Cob(I)alamin resulting in improved cognitive and retinal function in pts. with EO cblC deficiency.

Prostate-specific antigen value at 3 &amp; 7 months (PSA-3mo, PSA-7mo) and overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation (ADT) with or without orteronel (SWOG S1216).

5074 Background: Analysis of phase 3 studies of patients (pts) with mHSPC in the era of ADT, including in combination with docetaxel and/or androgen receptor axis targeted therapies have established PSA-7mo as a key prognostic marker. Our objective was to evaluate the association between PSA-3mo, PSA 7-mo and OS measured in the phase 3 S1216 trial in mHSPC comparing ADT + orteronel (treatment arm) vs ADT + bicalutamide (control arm) [NCT01809691]. Methods: Pts enrolled in the S1216 trial with available PSA-3mo &amp; PSA-7mo were included in this analysis. PSA responses were defined as complete response (CR) if PSA ≤ 0.2 ng/mL, partial response (PR) for PSA &gt;0.2 and ≤ 4ng/mL, and no response (NR) as PSA &gt;4 ng/mL at month 3 or 7. Landmark OS was measured and Cox regression model applied adjusting for stratification (performance status, extent of disease, early vs late start of treatment, treatment arm). Results: 1251 pts were alive and evaluable for PSA-3mo and 1231 pts were evaluable at 7 mo, out of a total of 1279 pts. The median age was 67 (range: 43-92), 10% of patients were black, 96% had a Zubrod performance status of 0-1. Median PSA at baseline was 29 ng/ml (range: 2-6710). Of pts on treatment vs.control arm, PSA-3mo CR, PR, and NR occurred in 52% vs 35%; 31% vs 42%, and 17% vs 23%, respectively. Of pts on treatment vs control arm, PSA-7mo CR, PR, and NR occurred in 61% vs 46%, 20% vs 26%, and 19% vs 29%, respectively. CR or PR at either timepoint led to significantly better outcomes than those with NR. No interaction between treatment arm and PSA response was observed in terms of OS. Conclusions: PSA-3mo and PSA-7mo are strong prognostic markers for pts with mHSPC. More pts on ADT with orteronel achieved CR at 3 and 7 mo. In addition to its use in counseling patients in the clinic, PSA-3mo and PSA-7mo may be used as parameters for designing future trials in pts with mHSPC, utilizing the next generation of intensification or de-intensification treatment regimens. Clinical trial information: NCT01809691 . [Table: see text]

Rotating Packed Bed Reactor Integrated with Plasma: Mass Transfer Intensification and Wastewater Treatment

When oxygen plasma contacts with liquid, abundant reactive species are generated to degrade the contaminant. Ozone is the main reactive species in the gas phase, but only part of it is utilized during wastewater treatment owing to its low solubility. In this work, a novel rotating packed bed reactor integrated with plasma (plasma-RPB) was developed to fully utilize ozone and enhance wastewater treatment. The ozone–water mass transfer efficiency of the plasma-RPB with different liquid distributor structures was evaluated. Subsequently, a dimensionless correlation for predicting the volumetric mass transfer coefficient of the plasma-RPB with the rotating cylinder was established, and the deviation between the predicted and experimental values was within ±6%. Employing the plasma-RPB, sulfamethoxazole and TOC removal efficiency reached up to 87.6 and 82.7% within 5 min, respectively, exhibiting prominent degradation performance compared with other advanced oxidation processes. This work provides an effective route for wastewater treatment.

Awareness Among Primary Care Physicians in Canada of Guideline Recommendations for Lowering LDL-Cholesterol in High-Risk Patients

BackgroundCardiovascular (CV) risk management for high-risk patients is often provided by primary care physicians (PCPs). We surveyed Canadian PCPs regarding their awareness and implementation of the 2021 Canadian Cardiovascular Society (CCS) lipid guideline recommendations for patients following an acute coronary syndrome (ACS) and those with diabetes but without CV disease. MethodsA committee of PCPs and specialists with lipid expertise, including some 2021 CCS lipid guideline coauthors, designed a survey to probe PCP awareness and practice patterns regarding CV risk management. From a national database, a total of 250 PCPs completed the survey between January and April 2022. ResultsAlmost all PCPs (97.2%) concurred that a post-ACS patient should be seen by their PCP within 4 weeks of hospital discharge (81.2% said within 2 weeks). Almost half (44.4%) responded that discharge summaries provided inadequate information, and 41.6% felt that lipid management post-ACS was the responsibility primarily of specialists. A total of 58.4% articulated that they face challenges when seeing a post-ACS patient, related to inadequate discharge information, complexities of polypharmacy and duration of therapies, and managing statin intolerance. A total of 63.2% and 43.6% correctly identified low-density lipoprotein cholesterol (LDL-C) intensification thresholds of 1.8 mmol/L in post-ACS patients, and 2.0 mmol/L in diabetes patients, respectively, and 81.2% incorrectly thought that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were indicated for patients with diabetes but without CV disease. ConclusionsOne year following publication of the 2021 CCS lipid guidelines, our survey reveals knowledge gaps among responding PCPs regarding intensification thresholds and treatment options for patients post-ACS, or those with diabetes. Innovative and effective knowledge-translation programs to address these gaps are desirable.

An Indirect Comparison of Basal Insulin Plus Once-Weekly Semaglutide and Fully Optimised Basal-Bolus Insulin in Type2 Diabetes.

To date, there have been few head-to-head comparisons between semaglutide once-weekly (OW) and short-acting meal-time insulin in participants with type2 diabetes (T2D) treated with basal insulin and requiring treatment intensification. This indirect comparison evaluated the effects of these regimens on glycated haemoglobin (HbA1c), body weight, hypoglycaemia, and other clinically relevant outcomes. A post-hoc, unanchored, individual participant data meta-analysis was conducted on the basis of data from single treatment arms in the SUSTAIN5 and DUAL7 trials. Semaglutide 0.5mg OW and 1.0mg OW plus basal insulin were compared with an optimised (treat-to-target) basal-bolus regimen of insulin glargine and insulin aspart over 26weeks, using regression adjustment to account for baseline differences between the trials. Over 26weeks, semaglutide 1.0mg OW plus basal insulin reduced mean HbA1c by significantly more than the basal-bolus regimen (treatment difference: - 0.36%; p = 0.003), while semaglutide 0.5mg OW plus basal insulin was comparable with basal-bolus insulin (treatment difference: 0.08%, p = 0.53). Both doses of semaglutide were associated with significant weight loss relative to insulin intensification (treatment differences: 6.8-9.4kg; p < 0.001). At both doses, semaglutide intensification required less basal insulin per day than bolus intensification, and more participants on semaglutide met HbA1c targets of < 7.0% and ≤ 6.5% without hypoglycaemia or weight gain (odds ratio [OR] for < 7.0%, 21.9; OR for ≤ 6.5%, 16.2; both p < 0.001). In T2D uncontrolled by basal insulin, intensification with semaglutide 1.0mg OW was associated with better glycaemic control, weight loss, and reduced hypoglycaemia versus a basal-bolus regimen, while limiting the treatment burden associated with frequent injections. Clinicians could consider treatment intensification with semaglutide when T2D is uncontrolled by basal insulin, especially when weight management is a priority. Effective glycaemic control coupled with weight management can alleviate the burden of diabetes-associated complications.

Awareness of lipid guideline recommendations for high-risk patients amongst primary care physicians in Canada

Abstract Background Lipid guidelines for cardiovascular (CV) risk reduction have evolved in recent years, particularly since the introduction of PCSK9 inhibitors. In many jurisdictions, CV risk management is provided by primary care physicians (PCPs). We surveyed Canadian PCPs regarding their awareness and implementation of the 2021 Canadian Cardiovascular Society (CCS) lipid guideline recommendations for patients following an acute coronary syndrome (ACS) or for those with diabetes but without CV disease. Methods and results From a national database of PCPs with interest and/or experience in CV medicine, we invited PCPs to complete a survey regarding lipid management in high-risk patients. A committee of PCPs and specialists with lipid expertise including several co-authors of the 2021 CCS lipid guidelines had designed the survey to probe awareness and practice patterns. A total of 203 PCPs from across Canada completed the survey between January and March 2022. 23.6% of respondents had previously prescribed a PCSK9 inhibitor. Almost all (96.5%) PCPs concurred that a post-ACS patient should be seen by their PCP within 4 weeks of hospital discharge (79.3% within 2 weeks). Almost half (45.3%) responded that discharge summaries provided inadequate information relevant for PCPs, and 43% felt that lipid management post-ACS was the primary responsibility of specialists. More than half (56%) articulated challenges when seeing a post-ACS patient, related to inadequate discharge information, complexities of polypharmacy and duration of therapies, and managing perceived or real statin intolerance. 62% correctly identified the LDL-C intensification threshold of 1.8 mmol/L in post-ACS patients, while 79% considered that PCSK9 inhibitors were indicated only for those patients who were already receiving statins plus ezetimibe or had substantially elevated LDL-C levels. 55.2% were able to correctly identify clinical features associated with greatest absolute benefit of PCSK9 inhibitors in post-ACS patients. For patients with diabetes but without ASCVD, 80% of PCPs incorrectly believed that PCSK9 inhibitors were indicated for LDL-C levels above threshold despite statin therapy, and only 42% correctly identified the LDL-C threshold for treatment intensification of 2.0 mmol/L. Conclusion While PCPs are aware of the urgency regarding lipid management in post-ACS patients, many encounter challenges after hospital discharge, frequently deferring lipid management to specialists. Thus, almost one year following publication of the 2021 CCS lipid guidelines, substantial knowledge gaps remain regarding intensification thresholds and treatment options for patients post-ACS or for those with diabetes. Innovative and effective knowledge translation programs are urgently required. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Amgen Canada

AWARENESS OF LIPID GUIDELINE RECOMMENDATIONS FOR HIGH-RISK PATIENTS AMONGST PRIMARY CARE PHYSICIANS IN CANADA

AWARENESS OF LIPID GUIDELINE RECOMMENDATIONS FOR HIGH-RISK PATIENTS AMONGST PRIMARY CARE PHYSICIANS IN CANADA

Hepatocellular carcinoma radiation segmentectomy treatment intensification prior to liver transplantation increases rates of complete pathologic necrosis: an explant analysis of 75 tumors.

To verify the correlation between yttrium-90 glass microsphere radiation segmentectomy treatment intensification of hepatocellular carcinoma (HCC) and complete pathologic necrosis (CPN) at liver transplantation. A retrospective, single center, analysis of patients with HCC who received radiation segmentectomy prior to liver transplantation from 2016 to 2021 was performed. The tumor treatment intensification cohort (n = 38) was prescribed radiation segmentectomy as per response recommendations identified in a previously published baseline cohort study (n = 37). Treatment intensification and baseline cohort treatment parameters were compared for rates of CPN. Both cohorts were then combined for an overall analysis of treatment parameter correlation with CPN. Sixty-three patients with a combined 75 tumors were analyzed. Specific activity, dose, and treatment activity were significantly higher in the treatment intensification cohort (all p < 0.01), while particles per cubic centimeter of treated liver were not. CPN was achieved in 76% (n = 29) of tumors in the treatment intensification cohort compared to 49% (n = 18) in the baseline cohort (p = 0.013). The combined cohort CPN rate was 63% (n = 47). ROC analysis showed that specific activity ≥ 327Bq (AUC 0.75, p < 0.001), dose ≥ 446Gy (AUC 0.69, p = 0.005), and treatment activity ≥ 2.55 Gbq (AUC 0.71, p = 0.002) were predictive of CPN. Multivariate logistic regression demonstrated that a specific activity ≥ 327Bq was the sole independent predictor of CPN (p = 0.013). Radiation segmentectomy treatment intensification for patients with HCC prior to liver transplantation increases rates of CPN. While dose strongly correlated with pathologic response, specific activity was the most significant independent radiation segmentectomy treatment parameter associated with CPN.

The Evolving Neoadjuvant Treatment Paradigm for Patients with Locoregional mismatch Repair Proficient Rectal Cancer.

The standard of care for locally advanced rectal cancer (LARC) has included preoperative chemoradiation, total mesorectal excision surgery and post operative adjuvant chemotherapy based on histopathology. The current therapeutic landscape in LARC has many different options with different directions of travel - depending on the goal of treatment. Enthusiasm for delivering total neoadjuvant therapy (TNT) for patients with locally advanced rectal cancer (LARC) is increasing in the light of recently published randomised phase III trials - RAPIDO and PRODIGE-23. There is a wide diversity of different potential schedules and a multitude of approaches, which include induction neoadjuvant chemotherapy (NACT) with a range of chemotherapy options (CAPEOX, FOLFOX, FOLFOXIRI) and a varying duration of 6-18 weeks, or consolidation NACT. These schedules either precede or follow short-course preoperative radiation therapy (SCPRT) using 5 × 5Gy or long-course chemoradiation (LCCRT) using 45-60Gy respectively. The different strategies of induction and consolidation neoadjuvant chemotherapy have been compared and have similar long-term outcomes, but consolidation chemotherapy may facilitate organ-sparing. The results are driving novel paradigms with both intensification and de-intensification treatment strategies. The ideal combination, sequence or duration of such a TNT approach remains undefined. As yet, there are no robust clinical, genetic, molecular, immune or imaging features (alone or integrated), which either direct or aid these choices. Currently, the selection of neoadjuvant treatment is driven by the impact on avoidance or feasibility of surgery or reducing the risk of metastases rather than prevention of local recurrence. Most believe that TNT will improve overall survival, despite the present lack of evidence. Both the inherent heterogeneity in LARC and the observed range of different responses underline the need for response biomarkers to individually tailor therapy rather than 'a one size fits all' approach.

Treatment de-escalation for HPV+ oropharyngeal cancer: A systematic review and meta-analysis.

Human Papillomavirus (HPV) related oropharyngeal carcinoma (OPC) carries a better prognosis compared with HPV-counterparts, thereby pushing the adoption of de-intensification treatment approaches as new strategies to preserve superior oncologic outcomes while minimizing toxicity. We evaluated the effect of treatment de-intensification in terms of overall survival (OS), progression-free survival (PFS), locoregional and distant control (LRC and DM) by selecting prospective or retrospective studies, providing outcome data with reduced intensification versus standard curative treatment in HPV+ OPC patients, with a systematic analysis till September 2020. The primary outcome of interest was OS. Secondary endpoints were PFS, LRC, and DM expressed as HR. A total of 55 studies (from 1393 screened references) were employed for quantitative synthesis for 38 929 patients. Among n=48 studies with data available, de-intensified treatments reduced OS in HPV+ OPCs (HR=1.33, 95% CI 1.17-1.52; p < 0.01). In de-escalated treatments, PFS was also decreased (HR=2.11, 95% CI 1.65-2.69; p < 0.01). Compared with standard treatments, reduced intensity approaches were associated with reduced locoregional and distant disease control (HR=2.51, 95% CI 1.75-3.59; p < 0.01; and HR=1.9, 95% CI 1.25-2.9; p < 0.01). Chemoradiation improved survival in a definitive curative setting compared with radiotherapy alone (HR=1.42, 95% CI 1.16-1.75; p < 0.01). When adjuvant treatments were compared, standard and de-escalation strategies provided similar OS. In conclusion, in patients with HPV+ OPC, de-escalation treatments should not be widely and agnostically adopted in clinical practice, as therein lies a concrete risk of offering a sub-optimal treatment to patients.

Serum TARC Concentration Kinetic in Classical Hodgkin Lymphoma during First-Line Treatment

Introduction: Thymus and activation-regulated chemokine (TARC) has been recently identified as a promising predictor of response in patients (pts) with classical Hodgkin's Lymphoma (HL). A correlation between treatment response and early sTARC reduction in HL pts treated with PET-adapted strategy was reported (Guidetti A, Leuk Res, 2017; Viviani S, Hematol Oncol, 2020). In the current study, we analyzed the kinetic of sTARC in HL pts during first-line treatment, with the aim to evaluate its potential predictive value.Methods: We prospectively collected plasma samples of naïve HL pts. Pts were stratified according to GHSG risk categories. Localized HL were treated with 2-4 cycles of ABVD followed by involved field radiotherapy (IFRT); advanced HL underwent 6 cycles of ABVD. Pts with a positive PET-2 switched to an intensification treatment. Pts with positive end of treatment PET (EOT-PET) were treated with BeGEV followed by autologous stem cell transplantation (ASCT).sTARC levels were measured with a commercial TARC ELISA kit (R & D Systems, Minneapolis, US) according to manufactory instructions. Samples were collected immediately before treatment on day 1 of each ABVD cycle, before IFRT in localized stages, on day 1 of each cycle of salvage therapy, including ASCT, and 1 month after EOT. Samples were analyzed in duplicate. Statistical analysis was performed using IBM SPSS Statistic v.27 and GraphPad PRISM v.8; Continuous variables were compared by Mann-Whitney U test, categorical variables by χ 2 test. Statistical significance was defined as P=.05.Results: Of 43 pts enrolled in the study, 4 pts were excluded due to missing samples, and for 3 PET-2 positive pts data were unavailable at time of this analysis; overall evaluable pts were 36. Median age was 33.5 yr (range 17−65), 58% pts were male. B-symptoms were present in 50% of pts. Fourteen pts (39%) were early stage (IA, IB, IIA), 22 pts (61%) were advanced stage (IIB, III, IV). Four pts (11%) were refractory, documented by EOT-PET positivity. For the purposes of this analysis, pts were stratified in two subgroups including stage I pts (11%) and stage II-IV (89%).Median baseline sTARC was 35,454 pg/ml (range 273−183,225); levels were significantly lower in stage I compared to stages II-IV (524 vs 50,606 pg/ml, P=.001). Median sTARC after 2 ABVD cycles (sTARC-2) was 482 pg/ml (range 97−2,071) in the whole population, with a median logarithmic reduction (logRED) vs baseline of 1.83 (range -0.26−3.12). In stage II-IV a significant decrease of sTARC-2 (median 493 pg/ml; range 97−2,071), with a median logRED of 1.94 (range 0.73−3.12), was observed, unlike in stage I where sTARC-2 remained stable (median 393 pg/ml; range 279−805); median logRED -0.03 (range -0.27 to 0.57) (Fig 1A).We then compared sTARC in chemorefractory and chemosensitive stage II-IV pts. We observed an almost significant difference (P=.077) by considering baseline sTARC in the two groups, respectively 95,236 pg/ml (range 53,502−135,787) in chemorefractory and 35,454 pg/ml (range 5,475−183,225) in chemosensitive pts. However, sTARC-2 and the logRED of sTARC-2 were not significantly different between the two groups: 654 pg/ml (range 97−1,564) vs 463 (range 150−2,071) and 2.1 (range 1.6−3.1) vs 2.0 (range -0.7−2.6), respectively.Finally, sTARC measurements after PET-2 and before EOT-PET, and their log variation (logΔ) as compared to sTARC-2, were assessed in chemorefractory and chemosensitive subgroups. In refractory pts, a progressive increase of sTARC was observed: median sTARC was 32,202 pg/ml (range 14,362−71,807) at the time of biohumoral relapse compared to 373 pg/ml (range 166−1,102) in responding pts (P=.001). The corresponding log∆ values were -1.5 (range -2.9 to -1.1) and 0.1 (range -0.3−0.6) (P=.001), respectively (Fig 2B).Conclusions: The current study, with the limitations of small pts number, provides an analysis of sTARC prognostic implications in pts with HL. While sTARC is of limited value in pts with stage I disease, the kinetic of sTARC variation in pts with stage II-IV HL resulted well correlated with treatment response as assessed by EOT-PET. Specifically, an increase of sTARC during treatment after sTARC-2 may predict refractoriness at later cycles. Larger studies are needed to confirm that monitoring of sTARC in stage II-IV HL during treatment might provide prognostic and therapeutic insights.Supported by Legato Zottola, University of Florence [Display omitted] DisclosuresPuccini: Takeda: Membership on an entity's Board of Directors or advisory committees. Vannucchi: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Nassi: Incyte: Consultancy; Takeda: Consultancy; Roche: Consultancy; Kyowa Kirin: Consultancy.

Autologous Stem Cell Transplantation Versus Bortezomib-Melphalan-Prednisone for Newly Diagnosed Multiple Myeloma: Second Interim Analysis of the Phase 3 EMN02/HO95 Study

Autologous Stem Cell Transplantation Versus Bortezomib-Melphalan-Prednisone for Newly Diagnosed Multiple Myeloma: Second Interim Analysis of the Phase 3 EMN02/HO95 Study