Treatment Schedule Research Articles

Patient preferences for CDK4/6 inhibitor treatments in HR+/HER2- early breast cancer: a discrete choice survey study.

Adding CDK4/6 inhibitors (CDK4/6is) to endocrine therapy (ET) for HR+/HER2- early breast cancer (EBC) demonstrated statistically significant invasive disease-free survival (iDFS) benefits in monarchE (node positive, high risk, stage II/III) and NATALEE (select N0 and all macroscopic N1, stage II/III). This study evaluated patient preferences for EBC treatment attributes and how these may translate for CDK4/6i selection. A web-based discrete choice experiment survey was conducted among US-based adult women with self-reported stage II/III HR+/HER2- EBC. Eight attributes were included, informed by 14 qualitative interviews (to identify most relevant attributes), expert clinical input, and differentiating features between CDK4/6is: efficacy (5-year iDFS), adverse events (venous thromboembolic event [VTE], diarrhea, fatigue), number of blood tests, number of electrocardiograms (EKGs), treatment duration, and schedule. Participants selected scenarios that best reflected their preferences from 10 choice cards, each displaying a pair of hypothetical treatment profiles. A conditional logit regression model was used to estimate preference weights and relative importance (RI) of attributes. A total of 409 women participated. Patient preferences, from high to low RI, were higher efficacy, lower diarrhea risk, lower fatigue risk, shorter treatment duration, and lower VTE risk. Number of blood tests, number of EKGs, and treatment schedule were less important. Utility scores were higher for reconstructed treatment profiles that resembled ribociclib. This study demonstrated that patients prefer adjuvant treatment with higher efficacy and lower risk of adverse events. These data will aid shared decision-making when discussing the addition of CDK4/6is to adjuvant ET for eligible patients with HR+/HER2- EBC.

The Role of the DNA Methyltransferase Family and the Therapeutic Potential of DNMT Inhibitors in Tumor Treatment

Members of the DNA methyltransferase (DNMT) family have been recognized as major epigenetic regulators of altered gene expression during tumor development. They establish and maintain DNA methylation of the CpG island of promoter and non-CpG region of the genome. The abnormal methylation status of tumor suppressor genes (TSGs) has been associated with tumorigenesis, leading to genomic instability, improper gene silence, and immune evasion. DNMT1 helps preserve methylation patterns during DNA replication, whereas the DNMT3 family is responsible for de novo methylation, creating new methylation patterns. Altered DNA methylation significantly supports tumor growth by changing gene expression patterns. FDA-approved DNMT inhibitors reverse hypermethylation-induced gene repression and improve therapeutic outcomes for cancer. Recent studies indicate that combining DNMT inhibitors with chemotherapies and immunotherapies can have synergistic effects, especially in aggressive metastatic tumors. Improving the treatment schedules, increasing isoform specificity, reducing toxicity, and utilizing genome-wide analyses of CRISPR-based editing to create personalized epigenetic therapies tailored to individual patient needs are promising strategies for enhancing therapeutic outcomes. This review discusses the interaction between DNMT regulators and DNMT1, its binding partners, the connection between DNA methylation and tumors, how these processes contribute to tumor development, and DNMT inhibitors’ advancements and pharmacological properties.

Impact of education on clinical confidence utilizing HER2-targeted therapies in colorectal cancer.

225 Background: Novel targeted therapies entered the treatment landscape in patients with HER2-positive metastatic colorectal cancer (mCRC). To ensure that these therapies are used effectively, clinicians must assess tumor HER2 status and recognize how HER2-directed treatment modalities fit into the current paradigm. To further enable clinicians to integrate HER2-targeted therapies, an educational program was designed in 2023. Methods: A one-hour online, video-based program was designed for clinicians and their teams and hosted on MedLive from February 2023 for one year. Knowledge and competence questions were administered pre-, and immediate post-activity. Additional questions assessed attitudes, barriers, and intended practice changes related to HER-positive mCRC. Results: Over 4,000 participants engaged in the educational activity, 67% of whom were physicians, and 63% noting their specialty as oncology. Approximately 68% identified as treaters seeing 14 patients with CRC per week with 78% of those patients have HER2-positive CRC. All pre-post questions showed significant improvements in knowledge and competence related to HER2 amplification testing methodologies, trial eligibility criteria, identification of patients who would benefit from anti-HER2 targeted regimens, and adverse events associated with anti-HER2 agents. Following the activity, 51% were more likely to incorporate testing for HER2 expression level or amplification prior to the selection of targeted therapy for their patients. The greatest challenges faced when managing patients with HER2-positive mCRC were affordability of therapy for patients (50%), adherence to treatment schedules (25%) and patient anxiety about treatment efficacy (24%). The most common barriers to patient enrollment in clinical trials identified by clinicians were lack of trials at their institutions (35%), lack of trials in their geographic region (21%), and patient lack of interest (20%). Qualitative insights on intended practice changes were shared by learners post-activity. Conclusions: The outcomes of this educational activity demonstrate the effectiveness of education in improving knowledge and confidence from testing to adverse event management to better integrate new regimens into practice. Encouraging practice changes were also seen from the write-in responses from learners. Additional needs were also identified to further solidify HER2 testing as a prerequisite for anti-HER2 targeted therapies, selecting eligible patients, and timely management of adverse events.

Individual patient data (IPD) pooled analysis on the optimal therapeutic management of patients with microsatellite instability-high (MSI) resectable gastroesophageal adenocarcinoma (GEA).

455 Background: Patients with resectable MSI/dMMR GEA showed improved survival and modest if any benefit from chemotherapy. Preoperative treatment with immune checkpoint inhibition (ICI) showed high rate of major-complete pathologic response in single arm trials possibly allowing the design of chemotherapy/surgery-free approaches. Methods: This was a multinational IPD analysis including patients with resectable GEA with MSI/dMMR status enrolled in INFINITY and NEONIPIGA phase II trials, with dual CTLA-4/PD-(L)1 ICI followed by surgery +/- adjuvant ICI; PROSECCO retrospective study, with perioperative FLOT chemotherapy and surgery, and the dataset of our previous IPD analysis on MAGIC, CLASSIC, ARTIST and ITACA-S randomized trials of patients treated with surgery alone or plus older perioperative/adjuvant chemo(radio)therapy regimen. Primary endpoint was the evaluation of rates of pathologic complete response (pCR) defined as TRG1a Becker and major-complete pathologic response (pCR/MPR) defined as TRG1a/b Becker according to preoperative treatment schedule in patients who underwent surgery. Univariable and multivariable analyses were conducted using a random effects logistic model adjusted with propensity score. Secondary endpoints were event-free survival (EFS) and overall survival (OS) according to the therapeutic strategy in the overall study population. Multivariable mixed-effects Cox models weighted with propensity score were performed. Results: The IPD included 197 patients. Of these, 49 received ICI +/- surgery, 27 FLOT chemotherapy plus surgery, 33 surgery alone and 88 older chemo(radio)therapy regimens plus surgery. In the 69 patients resected after neoadjuvant ICI or FLOT standard of care treatment, ICI demonstrated a higher rate of pathologic response compared to chemotherapy (pCR 61.9% vs 3.7%, OR 54.8 p=0.002; pCR/MPR 78.6% vs 10%, OR 39.3 p<0.001). In ITT population, no significant difference in OS and EFS was shown in patients treated with ICI, FLOT plus surgery, old chemo(radio)therapy plus surgery or surgery alone. Conclusions: In resectable MSI/dMMR GEA, upfront ICI showed comparable survival outcomes to surgery alone, with limitations of study design and sample size. The impact on survival of ICI versus surgery alone should be investigated prospectively to avoid overtreatment or identify specific risk categories with benefit. The high rate of major-complete pathologic response may allow to study or perform organ sparing surgery procedures or non-operative management to reduce surgical morbidity/mortality and improve quality of life. OS EFS HR 2.5-97.5% CI p HR 2.5-97.5% CI p Ref: Surgery only - - - - - - Chemo+surgery 1.16 0.27-4.98 0.84 1.10 0.39-3.07 0.85 FLOT+surgery 1.10 0.19-6.22 0.92 2.38 0.90-6.27 0.08 ICI +/- surgery 1.97 0.43-8.96 0.38 1.39 0.51-3.77 0.52

The Effectiveness of Budesonide Once Daily as Maintenance Treatment of Eosinophilic Esophagitis.

Swallowed topical corticosteroids (STC) are an effective first-line therapy for patients with eosinophilic esophagitis (EoE), both for induction and maintenance of remission. All interventional trials with STC used twice-daily dosing regimens. However, in other inflammatory gastrointestinal disorders, corticosteroids are given once daily (OD) with equal outcomes and improved compliance. To evaluate the effectiveness of topical budesonide maintenance treatment in a once-daily dosing schedule. Retrospective analysis of confirmed patients with EoE, treated with topical budesonide as maintenance therapy OD, with adequate follow-up available. Patients currently treated with budesonide were contacted to fill out online questionnaires regarding symptoms and health-related quality of life (HRQOL). The primary end point was histologic remission, defined as peak eosinophil count (PEC) <15 eosinophils per high power field (HPF) after >12 weeks of budesonide OD. We included 29 patients on STC OD (1mg, N=28; 0.5mg, N=1), either budesonide orodispersible tablet (BOT, Jorveza, Dr. Falk Pharma; N=12) or budesonide viscous solution (BVS; N=17). After a median follow-up of 767 days on OD dosing (range: 103 to 2396), 86% of patients were in histologic remission. Four patients had histologic disease activity, of which one was treated with BOT. Two patients experienced a slight increase in PEC after dose reduction of BVS to OD (to PEC of 25 and 35/HPF, respectively). However, after switching the formulation to BOT OD they achieved histologic remission. In this retrospective study, we demonstrated favorable results in the majority of patients treated with budesonide 1mg OD as maintenance treatment for eosinophilic esophagitis.

From pro-re-nata to fixed-interval regimen: evolving real-world treatment paradigms in anti-VEGF therapy for neovascular AMD.

To evaluate the impact of evolving treatment paradigms for neovascular age-related macular degeneration (nAMD) by comparing outcomes between two patient cohorts treated with different anti-vascular endothelial growth factor (anti-VEGF) regimens over a decade apart. This retrospective cohort study included 200 treatment-naive nAMD patients divided into two cohorts. Cohort 1 (2009-2010) was treated with a pro re nata (PRN) regimen, involving three initial monthly injections followed by as-needed treatments based on monthly monitoring. Cohort 2 (2019-2021) received a fixed-interval regimen, consisting of three initial monthly injections followed by bimonthly maintenance doses. Primary outcomes included changes in best corrected visual acuity (BCVA) and central retinal thickness (CRT) at 12 months. Secondary outcomes included the number of injections, follow-up visits, and adherence to treatment schedules. Cohort 2 demonstrated significantly greater improvement in BCVA (+5.5 vs -2.0 ETDRS letters, p < 0.001) and CRT reduction (-101.7 vs -26.5 μm, p < 0.001) compared to Cohort 1. Patients in Cohort 2 received more injections (7.7 vs 4.8, p < 0.001) but required fewer monitoring visits (3.2 vs 5.1, p < 0.001). Adherence to treatment schedules was markedly higher in Cohort 2 (78% vs 0%, p < 0.001). The transition from a PRN to a fixed-interval anti-VEGF regimen significantly improved visual and anatomical outcomes in nAMD patients. Fixed-interval regimens not only enhanced treatment efficacy but also optimized resource utilization, suggesting a superior approach for managing nAMD in a real-world clinical setting.

Lipid-Lowering Efficiency and Safety of Alirocumab 300 mg Using a 2-mL Autoinjector Device in Real-World Practice: The MARS Study.

Alirocumab is a fully human monoclonal antibody to proprotein convertase subtilisin kexin type 9 used for the reduction of low-density lipoprotein cholesterol (LDL-C) in high-risk patients not reaching their LDL-C target. Recently, a 2-mL prefilled autoinjector has been developed to support the monthly 300-mg dosing regimen with a single-injection administration. Monthly application of 300 mg AlirRocumab (Praluent®) using the 2-mL SYDNEY Device (MARS) is a non-interventional, open, prospective, multi-center cohort study conducted in Germany between 2021 and 2023 with an observational period of 12 weeks. Patients included had primary hypercholesterolemia (heterozygous familial or non-familial) or mixed dyslipidemia and confirmed vascular disease and other risk factors or confirmed familial heterozygous hypercholesterolemia. Primary objectives were to assess the effectiveness of the 2-mL SYDNEY autoinjector measured by the lipid-lowering effect of alirocumab and to document therapy satisfaction, patient adherence, and persistence. Secondary objectives were to assess safety (adverse events) and tolerability. A total of 146 patients were analyzed: 110 (75.3%) patients were proprotein convertase subtilisin kexin type 9 inhibitor naïve and 36 (24.7%) were pre-treated with a proprotein convertase subtilisin kexin type 9 inhibitor. Patient mean age was 65.6 years with a preponderance of male gender (59.6%). At 12 weeks, the LDL-C value had decreased by a median of 59.5 mg/dL (1.5 mmol/L) in naïve patients (median relative decrease: -52.0%). In the pre-treated group, the LDL-C value remained mainly unchanged (median slight numerical relative increase: 1.6%). Treatment satisfaction was rated similarly in both groups with most patients being satisfied/very satisfied and rating the injection as effective, safe, and easy to handle. Twenty-three adverse events in 13 patients (8.0%) were documented. Three patients experienced one serious adverse event each; for five patients, an adverse drug reaction was observed, although none was serious. The occurrence of adverse events was similar in both groups. Alirocumab 300 mg administered with the 2-mL SYDNEY autoinjector was safe and effective in lowering LDL-C after 12 weeks in a routine clinical setting in Germany. The treatment schedule was perceived to be beneficial with excellent device acceptance and satisfaction, potentially increasing patient adherence. Clinicaltrials.gov: NCT05129241.

Computed tomography-based nomogram for estimating progression-free survival probability in bladder cancer patients undergoing partial cystectomy.

To establish a prognostic model to estimate progression-free survival (PFS) probability in bladder cancer (BCa) patients undergoing partial cystectomy. Consecutive patients who underwent partial cystectomy between August 2012 and April 2021 were enrolled. The primary endpoint was PFS during the follow-up. The following features were assessed: tumor location, amount, size, tortuous blood vessels around or within the lesions, perivesical fat stranding, stalk, computed tomography (CT) enhancement, calcification, cystic degeneration, CT reported lymph nodes status, and presence of hydronephrosis. Univariate Cox regression and LASSO regression, followed by backward stepwise multivariable Cox, were used to construct the nomogram. A total of 106 patients were enrolled. Gender, histology, tortuous blood vessels, and perivesical fat stranding were used to fit the nomogram. The overall Harrell's concordance index (C-index) was 0.752. The area under the receiver operator characteristic curves (AUC) at 1-year, 2-year and 3-year were 0.733, 0.789 and 0.833, respectively. The calibration curves showed remarkable consistency. A nomogram model constructed based on the CT features and clinical risk factors is potentially feasible for predicting the PFS within 3years after PC for BCa, which can assist in the choice of treatment and follow-up scheduling.

The fractionation dependence of tumor control in proton therapy for early-stage non-small cell lung cancer.

The relative biological effectiveness (RBE) of tumor control for proton beam therapy (PBT) compared to photon radiotherapy (RT) is typically assumed to be independent of fractionation. To test this, we modeled published PBT outcome results for early-stage non-small cell lung cancer (NSCLC) treatments across a range of fractionation schedules. All published and analyzable cohorts were included (399 patients, 413 treated lesions). Two models were used to fit the data: a previously published tumor simulation model that fits photon RT results of NSCLC across all fractionation regimes and the Fowler LQ model with a kick-off time term. The treatment effect of each cohort was referenced to the photon equivalent dose through mechanistic model simulations in a 2 Gy/weekday scenario, with radiobiological parameters determined to simultaneously best-fit all fractionation results. The tumor control RBE of each published treatment schedule, compared to the modeled photon RT effect of the same schedule, was then estimated. For cohorts whose treatments lasted less than three weeks (i.e., 12 fractions or less), the RBE of PBT was in the range of 1.08 to 1.11. However, for fractionated treatments stretching over four weeks or more (20-25 fractions), the relative effectiveness was much lower, with RBEs in the range of 0.82-0.89. This conclusion was unchanged using the simpler Fowler LQ + time model. The proton RBE for hypo-fractionated schedules was 20-30% higher than for conventional schedules. The derived radiobiological parameters of PBT differ significantly from those of photon RT, indicating that PBT is influenced differentially by radiobiological mechanisms which require further investigation.

The Determinants of Toxicity in the Treatment of Prostate Cancer with a Focal, Intraprostatic "Microboost".

A single phase III trial has demonstrated that prostate radiotherapy with a focal, intra-prostatic "microboost" can improve disease control without an overall increase in toxicity. It is unclear how these results generalize to other treatment schedules and protocols. A systematic search of PubMed and the Cochrane Review was performed for studies published on or before September 1, 2023. A random-effects meta-analysis was used to pool the cumulative incidence of grade ≥2 (≥G2) acute and late genitourinary (GU) and gastrointestinal (GI) toxicity. Heterogeneity was assessed, and the association of trial-level covariates with toxicity were examined via subgroup analyses and meta-regression. Odds ratios (ORs) for dose metrics were reported per Gy EQD2. Thirty-eight patient cohorts were included. The pooled estimate of the cumulative incidence of ≥G2 acute and late GU toxicity was 25.3% (95% confidence interval [CI]: 19.1%-32.8%) and 21.1% (95% CI: 16.7%-26.3%), respectively. Late ≥G2 GI toxicity was less frequent, estimated at 5.6% (95% CI: 3.5%-8.7%) and 6.9% (95% CI: 4.6%-10.1%), respectively. Subgroup factors associated with at least one ≥G2 toxicity category were treatment technique, imaging used for boost volume definition, intrafraction motion management, trial phase, and toxicity grading. Rectal DMax was associated with acute ≥G2 GI toxicity (OR: 1.05 [95% CI: 1.02-1.08], p < 0.001). Additionally, urethral DMax was associated with late ≥G2 GU toxicity (OR: 1.02 [95% CI: 1.01-1.03], p < 0.001), and a stronger relationship was observed with the average plan urethral DMax (OR: 1.05 [95% CI: 1.03-1.07], p < 0.001). No association of toxicity with any bladder dose metric examined was observed. The utilization of a microboost appears tolerable across treatment protocols; however, subgroup factors, including the use of intrafraction motion management and the type of imaging modality utilized, may influence the probability of toxicity. Attention to rectal DMax constraints and urethral DMax dose constraints may help to mitigate GI and GU toxicity, respectively. No association between toxicity and bladder dose constraints was observed.

Ketamine and Ketamine-Assisted Psychotherapy for Psychiatric and Existential Distress in Patients with Serious Medical Illness: A Narrative Review.

Context: Psychiatric and existential distress are common and difficult-to-treat symptoms that are frequently encountered in the palliative care setting; current treatment options are limited in efficacy and tolerability. Psychedelic-assisted therapies (PAT) have gained public and scientific interest in their potential to induce rapid and effective reductions in psychiatric and existential distress in patients with serious medical illness, but remain available only in the research setting. Ketamine as a pharmacologic agent has a large body of evidence in the treatment of refractory depression. Objectives: To review the evidence that exists for use of ketamine or ketamine-assisted psychotherapy (KAP) for psychiatric and existential distress in patients with serious medical illness, aiming to identify therapeutic signals and gaps in research. Methods: A literature search identified publications of (1) ketamine or KAP, (2) psychiatric or existential distress, and (3) palliative care or patients with serious medical illness. Identified reports were carefully reviewed with attention to population and treatment-related factors, which were described in a narrative and aggregate format. Results: Nine studies and 12 case reports were identified that reported positive results and a good safety profile. There was significant variation in patient population, setting, route of administration, dosing schedule, and concurrent treatments. Most reports were of ketamine as a pharmacologic agent for symptoms of psychiatric distress. Conclusion: Evidence suggests that ketamine may induce rapid and transient improvements in psychiatric symptoms in patients with serious medical illness. A large gap in research exists for KAP and symptoms of existential distress. There is a signal that suggests ketamine could be used in a psychedelic therapy model with potential benefits over classical psychedelics.

P0783 High risk of adrenal insufficiency in patients with Inflammatory Bowel Disease treated with a conventional course of systemic corticosteroids: Results from a prospective study

Abstract Background Corticosteroids (CS) remain the first-line treatment for inflammatory bowel disease (IBD) although they can cause adrenal insufficiency (AI) due to the alteration of the hypothalamic-pituitary-adrenal (HPA) axis. Assessing this risk is essential, as these patients are often in stressful situations, and AI can mimic IBD symptoms, leading to misdiagnosis. However, there is a lack of studies adequately assessing adrenal function in these patients. The objectives of this study were to determine the proportion of IBD patients who present HPA axis suppression following CS treatment, assess the time required for axis recovery, and identify risk factors for AI. Methods A prospective observational study was conducted including adult patients with active IBD who started systemic CS treatment and with no exposure to CS within the last 6 months. They all followed a pre-defined regimen of 1 mg/kg/day of prednisone (maximum 60mg) for 2 weeks, tapering by 10 mg weekly until reaching 20 mg, then tapering by 5 mg weekly. The HPA axis was assessed 24 hours after CS discontinuation by the measurement of baseline cortisol and ACTH, and cortisol 30 and 60 minutes after stimulation with 250 mcg of ACTH. HPA axis recovery was evaluated 3 and 6 months after CS discontinuation. The association between clinical and demographic variables and the occurrence of AI was analysed. Results Ninety-two patients were included (58% Crohn's disease, 39% ulcerative colitis, mean age 39.8±16 years, 50% women), who received a total CS dose of 2000.7±543.1 mg for 63.5±14.1 days. Forty patients (43.5%) were diagnosed with AI (32 partial, 8 complete). The recovery test was not performed in 10/40 patients (5 due to loss of follow-up, 5 due to need of a new course of CS). 23/30 patients recovered the adrenal function 3 months after stopping CS, and 27/30 patients after 6 months. In the univariate analysis, only fecal calprotectin at the end of CS treatment was associated with AI (P=0.026). Conclusion A high proportion of IBD patients treated with a conventional CS treatment schedule develop HPA axis suppression, although most of them recover adrenal function within six months. The development of AI was not associated with any of the studied variables, except for faecal calprotectin levels. Our results highlight the potential risks associated with prolonged CS use and underscore the importance of considering AI in this context, particularly when the patient faces physical stress.

Optimization of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin therapy for Japanese patients with urothelial carcinoma.

Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) regimen has been established as a systemic chemotherapy for patients with urothelial carcinoma. However, it is rarely used in Japan owing to the challenges associated with managing the related adverse events. This study aimed to optimize the dd-MVAC protocol for Japanese patients. Criteria were developed to adjust the doses of anticancer drugs used in dd-MVAC. In this regimen, the initial cycle of methotrexate and cisplatin was administered at 75% of the full dose. Patients who did not experience significant toxicities during the first cycle subsequently received the full dose starting from the second cycle. Additionally, the doses of methotrexate and cisplatin were adjusted according to the Cockcroft-Gault creatinine clearance. Based on these criteria, patients with urothelial carcinoma underwent dd-MVAC between August 2018 and May 2023, and all patients were scheduled to undergo six cycles. A total of 86 patients received dd-MVAC, with 36, 15, and 35 patients receiving it as neoadjuvant, adjuvant, and salvage chemotherapy, respectively. Fifty-nine patients (68.6%) completed the six scheduled cycles. Grade≥3 toxicities of Common Terminology Criteria for Adverse Events were observed in 76 (88.4%) patients; however, most were manageable. In the neoadjuvant cohort, the pathological complete response rate was 52.2% among patients with clinical N0 lower tract urothelial carcinoma. High levels of alkaline phosphatase at the initiation of treatment were correlated with failure to complete six cycles of dd-MVAC. Adjusting the dd-MVAC regimen based on renal function and significant adverse events may result in a high completion rate of scheduled treatments in Japanese patients with urothelial carcinoma.

The Missing Link in Antiamyloid Therapy.

Alzheimer's disease (AD) impacts millions of elderly adults worldwide causing cognitive decline and severe deterioration of activities of daily life. The popular causal hypotheses for several decades include beta-amyloid (Aβ) deposition and tau hyperphosphorylation. AD research and more than 34% of clinical trials in AD are based on these two hypotheses. A phase-III clinical trial of lecanemab in early AD and mild cognitive impaired (MCI) patients reported a delay in cognitive decline of 27% over an 18-month treatment schedule. This multicenter trial found high specificity of lecanemab toward toxic protofibrils and subsequent clearance of beta-amyloid. There were, however, adverse events, which included cerebral edema and intracerebral hemorrhages in 23.1% of patients compared to 9.3% for those who received a placebo. Suboptimal clinical outcomes, brain volume loss, and adverse events in lecanemab treatment prompted a search for an alternative etiopathogenic explanation. Our research and others have focused on the oxidative stress (OS) hypothesis in AD. Autopsy studies have found significant depletion of the master antioxidant glutathione (GSH) in the hippocampal region, and is believed to be an early event in AD progression. Hippocampal GSH depletion is positively correlated with memory impairment. We have confirmed non-invasively with magnetic resonance spectroscopy (MRS) the depletion of GSH in patients with MCI and AD. We therefore propose a combinational therapy involving oral supplementation of gamma-glutamylcysteine (GGC), an early precursor of glutathione, to replenish brain GSH in addition to lecanemab, potentially to maximize desirable outcomes from combined therapeutic approach.

MANAGEMENT OF CERVICAL SPONDYLOSIS THROUGH AYURVEDA: A RE-SEARCH STUDY

Cervical spondylosis is a common spinal problem that is seen nowadays. Though degeneration of cervical vertebrae is mostly seen in older adults, its prevalence also increases in early or middle age. In the present case study, a diagnosed case of cervical spondylosis has been included for its Ayurvedic management. Chief complaints were pain in the neck region radiating towards both shoulders, stiffness over the neck for 5 to 6 months, and on &amp; off episodes of dizziness. The effect of oral medication of Tab Trayodashanga guggulu, Tab Ekangaveera rasa, Ashwagandharishta, Dashmoola arista and external application of Kottamchukkadi oil on cervical spondylosis had been evaluated. Different parameters have been assessed during and after the treatment schedule. There is complete relief in the parameters like neck pain, stiffness &amp; vertigo, and it has also shown significant improvement.

Strategies to enhance management of HER2-positive breast cancer in the elderly: an expert consensus perspective.

Therapeutic decision-making for older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer highlights the importance of a comprehensive geriatric assessment (CGA). This assessment considers the functional status, comorbidities, and relevant conditions of the patient, and allows for an estimation of life expectancy, but it does not facilitate individualized treatment plans. There are also other challenges to consider related to the cardiac toxicity of the treatments and the under-representation of older patients in clinical trials. The Oncogeriatrics Section of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica, SEOM), the Spanish Group for Breast Cancer Research (Grupo Español de Investigación en Cáncer de Mama, GEICAM) and the Spanish Group of Study, Treatment and other Experimental Strategies in Solid Tumours (Grupo Español de Estudio, Tratamiento y otras Estrategias Experimentales en Tumores Sólidos, SOLTI) have gathered an expert committee to evaluate the scientific evidence on the management of older patients with HER2-positive breast cancer and to establish recommendations based on a comprehensive review of the existing literature. These recommendations underscore the importance of individualizing treatment plans based on the patient's physical status and tolerability to maximize efficacy while minimizing toxicity. Emphasis is placed on adapting neoadjuvant and adjuvant therapies according to geriatric assessment and specific patient needs. A careful selection of treatment schedules for advanced stages is needed to improve survival and quality of life, assuming that scientific evidence in this age group is limited.

Mathematic Modeling of Tumor Growth During [177Lu]Lu-PSMA Therapy: Insights into Treatment Optimization.

The treatment regimen for [177Lu]Lu-prostate-specific membrane antigen (PSMA) 617 therapy follows that of chemotherapy: 6 administrations of a fixed activity, each separated by 6 wk. Mathematic modeling can be used to test the hypothesis that the current treatment regimen for a radiopharmaceutical modality is suboptimal. Methods: A mathematic model was developed to describe tumor growth during [177Lu]Lu-PSMA therapy. The model examined alternative treatment schedules to maximize tumor mass reduction while still maintaining an acceptable biologically effective dose to kidneys. Median patients' pharmacokinetics from literature reports were used to obtain the dose rate over time. The model incorporates the Gompertz tumor growth and linear quadratic models to describe the effect of radiation-induced cell kill on tumor growth. For a fixed total activity of 44.4 GBq of [177Lu]Lu-PSMA-617 and a 6-wk interval between cycles, the efficacy of the standard fractionation (6-cycle) treatment schedule was compared with different treatment regimens for a distribution of published tumor masses. A treatment schedule whereby 7.4 GBq are administered in the first cycle, and the remaining activity (37 GBq) in the second cycle (1-2-cycle treatment), was examined. Results: When tumor mass nadir was used as the optimization metric, a lower tumor burden (e.g., <4 g) was insensitive to the number of cycles; the 6-cycle treatment was equivalent to the 1-2-cycle treatment. For larger masses, fewer cycles yielded better results. For a 7-g tumor, the 5-cycle, 4-cycle, 3-cycle and 1-2-cycle schedules were 24%, 50%, 76%, and 84% more efficacious, respectively, than the 6-cycle schedule. The absorbed doses to kidneys, parotid glands, lacrimal glands, and red marrow were 23, 16, 70, and 1 Gy, respectively. In all fractionated schedules, the biologically effective dose to kidneys was within tolerance (<40 Gy). Conclusion: On the basis of model-derived simulations, treatment delivered in a 1-2-cycle schedule is recommended to achieve better outcomes for patients undergoing [177Lu]Lu-PSMA therapy.

Urban and Rural Differences in Cancer Treatment Disruption Among Patients With COVID-19: An Analysis of the US ASCO COVID-19 in Oncology Registry.

Cancer patients in rural areas experience greater barriers to treatment access compared with patients in urban areas. There is limited research on how the COVID-19 pandemic affected cancer treatment delivery for rural patients who were also diagnosed with COVID-19. This study has two objectives: to assess (1) the urban-rural differences in cancer care and (2) the predictors of cancer treatment delay or discontinuation (TDD) among patients diagnosed with COVID-19. We used data from the American Society of Clinical Oncology Survey on COVID-19 in Oncology Registry (March 2020-September 2022), which included cancer patients with test-confirmed SARS-CoV-2 infection (N = 3797). Data included patient sociodemographic characteristics, COVID-19 diagnosis information, cancer clinical characteristics, and changes to cancer treatment. Cancer TDD was defined as any scheduled treatment by more than 2 weeks. Rurality was examined through both patient residence and oncology practice. We computed adjusted prevalence ratios (aPRs) using multivariable Poisson regressions to assess predictors of cancer TDD in urban and rural areas. During the study period, 44.1% of patients with COVID-19 experienced either cancer treatment delay or discontinuation and 5.7% experienced cancer treatment discontinuation. Controlling for other factors, receiving care in a rural oncology practice was associated with cancer TDD (aPR: 1.25, 95% CI: 1.01-1.55). Differences in cancer TDD were not found across rurality of patient residence. Among rural patients (N = 582), Hispanic/Latinx cancer patients had greater prevalence of cancer TDD (aPR: 1.55, 95% CI: 1.04-2.33) compared with non-Hispanic White cancer patients. Our findings can be used to inform programs and policies to minimize the impact of future public health emergencies on cancer care delivery in rural areas. Additional research is needed to explore potential differences in cancer care delivery across urban and rural oncology practices and patients.

Feasibility and time gain of implementing artificial intelligence-based delineation tools in daily magnetic resonance image-guided adaptive prostate cancer radiotherapy.

Daily magnetic resonance image (MRI)-guided radiotherapy plan adaptation requires time-consuming manual contour edits of targets and organs at risk in the online workflow. Recent advances in auto-segmentation promise to deliver high-quality delineations within a short time frame. However, the actual time benefit in a clinical setting is unknown. The current study investigated the feasibility and time gain of implementing online artificial intelligence (AI)-based delineations at a 1.5T MRI-Linac. Fifteen consecutive prostate cancer patients, treated to 60Gy in 20 fractions at a 1.5T MRI-Linac, were included in the study. The first 5 patients (Group 1) were treated using the standard contouring workflow for all fractions. The last 10 patients (Group 2) were treated with the standard workflow for fractions 1 up to 3 (Group 2 - Standard) and an AI-based workflow for the remaining fractions (Group 2 - AI). AI delineations were delivered using an in-house developed AI inference service and an in-house trained nnU-Net. The AI-based workflow reduced delineation time from 9.8 to 5.3min. The variance in delineation time seemed to increase during the treatment course for Group 1, while the delineation time for the AI-based workflow was constant (Group 2 - AI). Fewer occurrences of readaptation due to target movement occurred with the AI-based workflow. Implementing an AI-based workflow at the 1.5T MRI-Linac is feasible and reduces the delineation time. Lower variance in delineation duration supports a better ability to plan daily treatment schedules and avoids delays.

On the effect of heat treatment schedules on the structure-property behaviour of heat-affected zones of ASTM A335 steel: Gleeble thermal-mechanical simulation

On the effect of heat treatment schedules on the structure-property behaviour of heat-affected zones of ASTM A335 steel: Gleeble thermal-mechanical simulation