Discontinuation Period Research Articles

Reporting of late-onset immune-related adverse events with immune checkpoint inhibitors in VigiBase.

To date, evidence on late-onset immune-related adverse events (irAEs) with immune checkpoint inhibitors (ICIs) is limited to a small number of clinical cases. This study aimed to identify drug- and patient-related characteristics potentially associated with the reporting of late-onset irAEs with ICIs in VigiBase, the WHO global database of individual case safety reports (ICSRs). Observational study comparing deduplicated ICSRs with ICIs reporting late-onset irAEs (occurred >90 days after ICI discontinuation) versus ICSRs with ICIs not reporting late-onset irAEs, collected in VigiBase from 2011 to December 31, 2022. Logistic regression was used to model the relationship between drug-related and patient-related characteristics of ICSRs and the reporting of late-onset irAEs. Significance was determined for variables with the lower bound of the 95% CI of the reporting OR (ROR) higher than 1 and a p value <0.05. The study population consisted of 6006 ICSRs with ICI-related irAEs (4574, 76.2%, originated from Europe; 3900, 64.9%, involved males; median patient age was 67 years, IQR 59-74 years). Of these, 344 (5.7%) ICSRs reported a total of 388 late-onset irAEs, among which the most frequent were thyroiditis (n=45), pneumonitis (n=37), interstitial lung disease (n=25), hepatitis (n=23) and vitiligo (n=19). Median time to onset since ICI discontinuation was 167 days (IQR 115-294 days), with negligible proportion (3.2%) of co-reported antineoplastic agents during the discontinuation period. Logistic regression models showed disproportionate reporting of late-onset irAEs with ICI combination therapy (ROR 2.33, 95% CI 1.19 to 4.57), reporting of multiple irAEs (ROR 3.96, 95% CI 2.85 to 5.52), reporting of cutaneous irAEs (ROR 1.83, 95% CI 1.24 to 2.71), and melanoma (ROR 1.47, 95% CI 1.04 to 2.06). This global pharmacovigilance study provides the largest case series of late-onset irAEs with ICIs to date and identifies characteristics of ICSRs associated with disproportionate reporting. Dedicated prospective observational studies focused on long-term sequelae, quality of life and survival of patients developing late-onset irAEs with ICIs should be planned to confirm whether these reporting characteristics are predictors of actual occurrence. Furthermore, translational research should be encouraged to clarify the molecular mechanisms underlying late-onset irAE development.

The impact of antidepressant discontinuation prior to treatment with psilocybin for treatment-resistant depression

It has been suggested that the recent use and discontinuation of antidepressant drugs compromises the action of psilocybin. As evidence is only available from small or uncontrolled samples, this post hoc analysis investigated this using data from the largest, phase II, randomized controlled trial of psilocybin treatment to date. Data from 233 participants with treatment-resistant depression (TRD) who received 25 mg, 10 mg, or 1 mg of investigational drug COMP360 psilocybin (a proprietary, pharmaceutical-grade synthetic psilocybin formulation, developed by the sponsor, Compass Pathfinder Ltd.), administered with psychological support, were compared for groups of participants who either discontinued one or more antidepressant drugs during screening or entered the trial antidepressant drug free. Measures of depression symptom severity change during the antidepressant drug discontinuation period, baseline suicidality, acute subjective psychedelic effects, and the study's primary endpoint (change in depression symptom severity between Baseline and Week 3) are described for both groups. Antidepressant drug discontinuation was not related to worsening of depression severity before Baseline. Suicidality was comparable between groups at Baseline. Psilocybin treatment efficacy and the subjective psychedelic experience did not appear to be compromised by antidepressant drug discontinuation. Thus, it does not limit the feasibility of psilocybin treatment for the future. These findings also support the overall homogeneity of our findings with psilocybin treatment as a monotherapy for TRD. The prior contradictory reports may come to appear misleading.

52501 4-year long-term drug survival of dupilumab analyzed by treatment period and predictive factors of discontinuation in moderate to severe atopic dermatitis patients: A real-world retrospective study

52501 4-year long-term drug survival of dupilumab analyzed by treatment period and predictive factors of discontinuation in moderate to severe atopic dermatitis patients: A real-world retrospective study

Chidamide plus R-GDP for relapsed/refractory diffuse large B-cell lymphoma in patients ineligible for autologous transplantation: A prospective, single-arm, phase II study.

In relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), a negative prognosis is frequently linked to heightened epigenetic heterogeneity. Chidamide, a selective histone deacetylase inhibitor, shows promise as a targeted therapy for R/R DLBCL by targeting abnormal epigenetic changes associated with poor prognosis. A cohort of 27 ineligible patients with R/R DLBCL participated in an open - label, single - arm study. Chidamide was administered orally at a dose of 30 mg twice weekly for one week during the induction monotherapy phase. The subsequent combination therapy phase involved oral chidamide at a dose of 20 mg twice weekly for two weeks, followed by a one-week discontinuation period, in conjunction with intravenous R-GDP every 21 days. Among the cohort of 31 patients who underwent screening (median age: 67 years), 27 were ultimately included in the study, with 14 individuals successfully completing six cycles of C-R-GDP treatment. The overall best objective response rate was determined to be 79.1% (95% CI: 75.1%-83.3%), comprising a complete response rate of 45.8% (95% CI: 41.6%-49.9%) and a partial response rate of 33.3% (95% CI: 29.3%-37.4%). Within the subgroup of 14 patients who completed the full treatment regimen, the best objective response rate reached 100%, with 71.4% achieving complete response (n = 10) and 28.6% achieving partial response (n = 4). The median follow-up period for these patients was 17.0 months, ranging from 3.5 to 55 months. Progression-free survival was 5.9 months and overall survival was 48.3 months. Anemia was the most common adverse event, affecting all patients. Thrombocytopenia led to treatment interruption or dose reduction in 13 patients. Other common adverse events included hypocalcemia, hyponatremia, and hypokalemia. Three patients experienced grade 3 pneumonitis and one had grade 3 skin rash. Chidamide combined with R-GDP is a safe and effective treatment option for patients with R/R DLBCL who are not eligible for autologous stem cell transplantation.

Abstract PO4-27-02: Pandemic Shifts: How did elective breast cancer care change?

Abstract Introduction: As the COVID-19 pandemic began, concerns arose that timely utilization of elective breast cancer care would decrease due to state moratoriums, travel restrictions, or fear, resulting in poorer long-term outcomes. Advances in telemedicine provided a new avenue for care; however, rapid implementation brought concerns about variable uptake and disparities. To support longitudinal clinical and epidemiological studies, this analysis described elective breast cancer care utilization during the first year of the pandemic, including patient, hospital, and geographic barriers and facilitators. Methods: The Multidisciplinary Breast Reconstruction Research Program team reviewed all breast cancer surgeries and procedures at The University of Texas MD Anderson Cancer Center during the pre-pandemic (March 1, 2019 to February 29, 2020) and pandemic (March 1, 2020 to February 28, 2021) periods. The team identified procedures that were deemed elective or preference-sensitive, and summarized the timeline of pandemic milestones and changes, including the implementation of telemedicine appointments. A data analyst summarized the distributions of completed, canceled, rescheduled, and never completed procedures. T tests and analyses of variance tested differences between the pre-pandemic and pandemic year. Generalized linear models assessed patient, hospital, and geographic factors that correlated with successful access to, and completion of, procedures. Two focus groups reviewed data and informed the interpretation of results. Results: During the first pandemic year, 30 breast care procedures were identified that were postponed during March-April, July-August, and December-January. Surprisingly, no decrease in overall utilization of elective care procedures was observed; in fact, 19% more elective breast cancer care surgeries and procedures were scheduled (4752 pre-pandemic vs 4003 pandemic) in 13% more episodes of care (2723 pre-pandemic vs 2415 pandemic). As expected, rescheduling of procedures increased 98% (from 14% pre-pandemic to 27% pandemic); however, the majority of procedures were able to be completed by the end of the year (72% pre-pandemic, 73% pandemic). Telemedicine did not significantly mediate successful completion, as the majority of procedures were prophylactic or reconstructive surgeries. However, extended hours (p = 0.03) and proximity to the hospital facilitated access and successful completion of care (p&amp;lt; 0.01). The most common procedures that were not able to be performed within the first year of the pandemic were autologous breast reconstruction, revision, and mastopexy. Notably, patients reported slightly improved rates of anxiety and depression during the initial pandemic year (11% vs 14%, p = 0.04), possibly due to relative privation or comparison bias. Clinicians and patients/survivors noted several “lessons learned” that may inform access and preference-sensitive care delivery. Conclusions: Despite three periods of state-mandated discontinuation of elective care procedures, the majority of patients were able to access and successfully complete elective breast cancer care during the first year of the COVID-19 pandemic. Future studies and initiatives may use this information to explore innovations in care delivery and short- and long-term effects on health outcomes. Citation Format: Haoqi Wang, Greg Reece, Mary Catherine Bordes, Mia Markey, Aubri Hoffman. Pandemic Shifts: How did elective breast cancer care change? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-27-02.

Early identification of golimumab-treated patients with higher likelihood of long-term retention.

The early identification of patients' profiles most likely to respond to and maintain long-term therapy with a biological drug can have clinical and cost-effectiveness implications. To evaluate the utility of an innovative approach for early identification of patient profiles associated with long-term persistence of golimumab, a tumour necrosis factor inhibitor, in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (SpA) under real-world conditions. Retrospective non-interventional database analysis. Kaplan-Meier curves of golimumab retention over 8 years from the BIOBADASER registry, overall and by indication, were analysed using a novel approach (a two-phase decay model) to identify the point at which the golimumab retention curve shifted from rapid (indicating high golimumab discontinuation rate) to slow decay (low discontinuation rate). Factors associated with golimumab retention at these time points were identified using Cox regression, and retention rates for different patient profiles were calculated. 885 patients were included. The golimumab retention curve shifted from rapid to slow decay at month 10 for the overall population (retention rate: 73.4%), at month 24 for RA patients (retention: 45.0%), and at month 8 for SpA, including axial SpA and PsA (81.6%). Factors associated with golimumab discontinuation at these early points were, overall, similar to those previously identified at year 8 (RA diagnosis, golimumab as second- or third-line of biological therapy, disease activity over the median and treatment with corticosteroids at golimumab initiation, advanced age [in RA], and female gender [in SpA]). With this novel approach, the factors associated with long-term retention were identified in the initial period of rapid discontinuation of golimumab.

Discontinuation of long-term growth hormone treatment in adults with growth hormone deficiency: a survey of UK practice.

We conducted a survey of UK endocrine clinicians between June 2022 and August 2022 to understand current practices regarding GH treatment discontinuation in adults with growth hormone deficiency. Using Survey Monkey®, a web-based multiple-choice questionnaire was disseminated to the UK Society for Endocrinology membership. It consisted of 15 questions on demographics, number of patients receiving GH and current practice on GH treatment discontinuation. In total, 102 endocrine clinicians completed the survey. Of these, 65 respondents (33 endocrinologists and 32 specialist nurses) indicated active involvement in managing patients with growth hormone deficiency. In total, 27.7% of clinicians were routinely offering a trial of GH discontinuation to adults receiving long-term GH therapy. Only 6% had a clinical guideline to direct such practice. In total, 29.2% stated that GH discontinuation should be routinely offered as an option to patients on long-term treatment, whilst 60% were not clearly in favour or against this approach but stated that it should probably be considered, and 9.2% were against. During the GH withdrawal period, most clinicians monitor signs and symptoms (75.4%), measure IGF-1 (84.6%), and complete a quality-of-life assessment (89.2%). The practice of offering a trial of GH discontinuation in growth hormone deficiency adults on long-term GH therapy is highly variable, reflecting the lack of high-quality evidence. Around a quarter of clinicians offer GH withdrawal for a number of reasons, but only a few have a local clinical guidance. A further 60% of clinicians stated they would probably consider such an approach. Methodologically sound studies underpinning the development of safe and cost-effective guidance are needed. In this UK survey of endocrine clinicians managing adults with growth hormone deficiency on long-term GH therapy, we explored for the first-time current practice and views on offering GH treatment discontinuation. In total, 27.7% of clinicians were routinely offering this option for a variety of reasons. Only 6% have local clinical guideline available to direct their practice on this. The majority of clinicians (60%), were not clearly in favour or against this approach but indicated it should probably be considered. In the absence of robust evidence on consequences of GH withdrawal, clinicians proposed monitoring of various clinical, biochemical and quality-of-life parameters during the period of discontinuation. Methodologically sound studies that will underpin the development of a safe, cost-effective guidance are needed.

Impact of multiple treatment cycles with anti-CGRP monoclonal antibodies on migraine course: focus on discontinuation periods. Insights from the multicenter, prospective, I-GRAINE study.

While a single 12-month treatment cycle (TrC) with anti-CGRP mAbs is not disease-modifying for most patients, there is limited understanding of the effects of multiple TrCs on migraine course. We evaluated whether a second TrC might modify the migraine course by comparing the occurrence of migraine relapse after discontinuation of the second TrC to that following the cessation of the first TrC. In a real-life, multicenter, prospective study we considered all consecutive patients diagnosed with high-frequency episodic migraine (HFEM) or chronic migraine (CM) with > 3 treatment failures and treated with any anti-CGRP mAbs for ≥ 2 consecutive 12-month TrCs who were responders at week 12. The primary endpoint was the change in monthly migraine days (MMD) for HFEM or monthly headache days (MHD) for CM at the first month of treatment discontinuation after the second TrC (D2) compared to the first TrC (D1). Secondary endpoints included variations in monthly analgesic medications (MAM), Numeric Rating Scale (NRS), and Headache Impact Test (HIT-6) scores, ≥ 50%, ≥ 75%, and 100% response rates, and relapse from episodic migraine to CM and from no-medication overuse (MO) to MO at D2 vs. D1. One-hundred-seventy-eight patients completed two 12-month TrCs with anti-CGRP mAbs. At D2, patients experienced a significant reduction in MMD (-0.6, p = 0.028), MHD (-2.6, p < 0.001), monthly analgesic medications (-2.0, p < 0.001), and HIT-6 score (-2.2, p < 0.001) compared to D1, indicating improved effectiveness. The ≥ 50% response rate at weeks 45-48 during the first TrC was 95.5%, while at weeks 45-48 of the second TrC was 99.4%. Corresponding rates at D1 was 20.2% whereas at D2 was 51.6% (p < 0.0001). No statistical difference emerged in ≥ 75% and 100% responders. The relapse rate from episodic migraine to CM at D2 was lower than at D1 (12.3% vs 30.4%; p = 0.0002) Fewer patients experienced relapse from no-MO to MO at D2 compared to D1 (29.5% vs 68.7%; p = 0.00001). A second TrC with anti-CGRP mAbs demonstrated clinical improvements compared to the first one, as indicated by a milder migraine relapse at D2 compared to D1. Multiple TrCs with anti-CGRP mAbs could progressively modify migraine evolution by reducing CGRP-dependent neuroinflammatory nociceptive inputs to the brain.

Significance of Continuous Low-Dose Lenvatinib for the Treating of the Patients with Unresectable Thyroid Carcinoma.

The tyrosine kinase inhibitor lenvatinib has been confirmed as an effective treatment option for patients with unresectable thyroid carcinoma. We conducted a retrospective analysis of the significance of the effect of continued lenvatinib treatment for the longest duration possible at a reasonable daily dose and with a minimum discontinuation period in 42 patients with unresectable thyroid carcinoma treated with lenvatinib between 2015 and 2020. A Cox proportional hazard model-based analysis revealed that the overall survival of the patients treated with a <8 mg/day mean dose of lenvatinib was significantly better than that of the patients treated with 8-24 mg/day (hazard ratio [HR] 0.38 for 1.14-4.54 mg/day, and HR 0.01 for 4.56-7.97 mg/day) adjusted for various factors (e.g., sex, age, drug interruption period). The cumulative dose of lenvatinib administered tended to be higher in the patients treated with low doses (< 8 mg/day) than in the patients treated with relatively high doses (8-24 mg/day). Considering its adverse events, the continuation of lenvatinib treatment with an adequate daily dose and drug interruption may help prolong the survival of patients with unresectable thyroid carcinoma.

P414 Timing of biologics discontinuation is not associated with postoperative complications (POCs), infective complications, bleeding, or intra-abdominal septic complications (IASCs) after primary ileocecal resection for Crohn’s Disease: a retrospective analysis of 237 patients in a tertiary centre

Abstract Background The role of biologics on postoperative complications in Crohn’s Disease (CD) is still debated. Recent studies showed that preoperative adalimumab, infliximab, ustekinumab, and vedolizumab were not associated with increased POCs and IASCs. While some studies defined a 12-week cut-off based on pharmacodynamics principles, the safest timing for biologics discontinuation remains unknown. We aimed to analyse different timing of biologics discontinuation and POCs, infective complications, bleeding and IASCs after primary ileocecal resection for CD. Methods This is a retrospective single-centre study including all consecutive patients undergoing primary ileocecal resection for CD between 2004-2022 and exposed preoperatively to biologics. Patients were divided into four groups according to the number of weeks between the last dose of biologics and surgery: Group 1 (≤6 weeks), Group 2 (&amp;gt;6 and ≤12 weeks), Group 3 (&amp;gt;12 and ≤30 weeks), Group 4 (&amp;gt;30 weeks). The primary aim was POCs. Secondary aims were postoperative Clavien-Dindo≥III complications, infective complications, bleeding and IASCs. Uni- and multivariable logistic regression analyses were performed. Results We included 237 patients who underwent primary ileocecal resection for CD with previous exposition to biologics. Group 1 (≤6w) included 42 patients, Group 2 (≤12w) 41, Group 3 (≤30w) 47, and Group 4 (&amp;gt;30w) 107. Patients received adalimumab (128 pts, 54%), infliximab (82 pts, 35%), ustekinumab (15 pts, 6%) or vedolizumab (11 pts, 5%). Ileocecal resection with primary anastomosis was performed in 233 patients (98%) and 31 patients (13%) had a stoma. Groups were different in age, BMI, smoking, preoperative antibiotics, Albumin, Haemoglobin, and laparoscopy with Group 1 having higher rates of major risk factors for POCs. However, POCs, postoperative Clavien-Dindo≥III complications, infective complications, bleeding and IASCs were not different among the groups. Other general characteristics and postoperative outcomes of the four groups were reported in Table 1. Logistic regression analyses comparing the study outcomes among the groups were not able to detect differences as shown in Table 2 Conclusion The present study compared outcomes of different timing of biologics discontinuation for primary ileocecal resection for CD. No difference was found in POCs, postoperative Clavien-Dindo≥III complications, infective complications, bleeding and IASCs. Considering that patients treated with biologics ≤ 6 weeks before surgery had also a higher rate of risk factors for POCs and IASCs, biologics discontinuation seems not to have any impact on them. Large prospective multicentre studies are needed to confirm the safest period of preoperatory biologics discontinuation.

Effects of Serum Antibody Test Reagent Discontinuation on Diagnosis of Amebiasis in Japan: Interrupted Time-Series Analysis.

Amebiasis is a notifiable infectious disease in Japan, and the number of reported cases had been on the rise, but since the discontinuation of insurance-covered serum antibody testing reagent in 2017, concerns have arisen regarding the decrease in reported cases. This study aimed to investigate changes occurring after discontinuation of the serum antibody test reagent production. We retrospectively analyzed amebiasis cases from January 2014 to December 2019 using the National Center for Epidemiology of Infectious Diseases system. Interrupted time-series regression analysis was used to evaluate trends in weekly amebiasis cases before and after the discontinuation period. The study period was divided into prediscontinuation (2014-2017) and discontinuation (2018-2019) periods. A total of 6,179 amebiasis cases were reported. The average numbers of weekly cases were 21.5 during 2014-2017 and 16.3 during 2018-2019. The frequency of diagnoses decreased in the discontinuation period (prevalence rate ratio = 0.78; 95% CI, 0.67-0.89; P < 0.01). Subgroup analysis showed lower diagnostic rates, particularly for extraintestinal amebiasis (prevalence rate ratio = 0.37; 95% CI, 0.22-0.55; P < 0.01). We observed a significant decrease in the number of reported amebiasis cases per week after discontinuation of the serum antibody test reagent in Japan. Our findings hold significance for both public health policy and practice in Japan, underscoring the requirement for enhanced amebiasis diagnostic tools and strategies. To ensure accurate diagnosis, availability of antibody reagents for serum testing, covered by insurance, should be encouraged.

Effects of Lactiplantibacillus plantarum CCFM1214 and Ligilactobacillus salivarius CCFM1215 on halitosis: a double-blind, randomized controlled trial.

The purpose of this study was to evaluate the effects of known probiotic species Lactiplantibacillus plantarum CCFM1214 and Ligilactobacillus salivarius CCFM1215 on halitosis, the oral status, and the oral microbiome. In a double-blind, randomized controlled trial that lasted for five weeks, 43 participants were divided into an oral probiotics group and a control group and given probiotics or control powder for the first four weeks, with the fifth week being the discontinuation period. 33 participants (probiotics group = 21, control group = 12) completed the entire experiment in the end. Oral samples were taken as part of oral health examinations during the baseline period (day 0) and four weeks after (day 28). The nucleotide sequence of the V3-V4 region of 16S rRNA was determined to examine the impact of intervention and time on the oral microbiome. The effects of L. plantarum CCFM1214 and L. salivarius CCFM1215 on the number of Fusobacterium nucleatum in gingival crevicular fluid (GCF) samples of participants were detected by quantitative PCR. After the intervention, L. plantarum CCFM1214 and L. salivarius CCFM1215 significantly reduced the levels of volatile sulfur compounds (VSCs) and the quantity of F. nucleatum in GCF samples, where the average DNA copy number per ng (log) of F. nucleatum decreased from 7.12 ± 0.04 to 6.01 ± 0.09. The β diversity of the probiotics group, on the whole, tended to be more concentrated and stable after the intervention. In addition, after probiotic intervention, the abundance of Lactobacillus and Bifidobacterium increased, while the abundance of Fusobacterium, Acinetobacter, Porphyromonas, and Aggregatibacter decreased significantly. In general, L. plantarum CCFM1214 and L. salivarius CCFM1215 can alleviate halitosis and considerably lower the value of VSCs and improve the oral microbiota in participants with halitosis.

The fluctuation of pig prices and the identification of major drivers in China.

In recent years, the domestic live pig price has risen and fallen rapidly and fluctuated frequently, which has greatly impacted the live pig industry. The level of price volatility in the pig market has served as a significant indication of the progress of the agricultural sector. Identifying the dominant factors affecting the fluctuation of pig prices has become more important. Based on the monthly data of the pig industry from February 2009 to December 2022, this paper constructs an index system of influencing factors of pig price from four aspects: uncertain impact, supply factors, demand factors, and macro-environment factors. By using the transfer model of the Markov regime (MS-VAR), we obtained the probability plot of zone transition for pig price volatility, the impulse response effect diagram of factors affecting pig price, and the cumulated impulse response effect diagram of factors affecting pig price, and analyze the reasons for the ups and downs of pig price according to the above results. The findings indicate prominent features of zone transition in the price fluctuation of China's pig market. From 2017 to 2022, the domestic pig price frequently switches between rising and falling zones, and the "falling pig price stage" and "rising pig price stage" in the non-stationary state last for a relatively short and discontinuous period. There is little probability that the price of live pigs will directly change from rising to falling, and there will be a smooth buffer stage in the price rise and fall process. Among the factors that affect the fluctuation of live pig prices, the dominant factor of frequent and large fluctuation of pig prices is the pig epidemic situation in external factors. Among the internal influencing factors, the changes in farming costs have the greatest significant influence on the fluctuation of pig prices. These results provide a decision-making reference for legislators to carry out epidemic risk prevention and control better, stabilize the market pig price, and provide empirical evidence for market participants to accurately avoid price risks through multiple channels and ways and ensure stable profitability.

Improvement of osteoblast adhesion, viability, and mineralization by restoring the cell cytoskeleton after bisphosphonate discontinuation in vitro.

Bisphosphonates are prescribed to treat excessive bone resorption in patients with osteoporosis. However, its use is associated with potential adverse effects such as medication-related osteonecrosis of the jaw, prompting the introduction of the drug holiday concept in patients prior to dentoalveolar surgery. Furthermore, bisphosphonate discontinuation has been studied in vivo, in humans, and in animal models. However, it is not known whether this approach could affect bone cells in vitro. Therefore, the objective of this study was to investigate the potential effects of bisphosphonate discontinuation on pre-osteoblast and osteoblast activities in vitro. Pre-osteoblasts (MC3T3) and osteoblasts were treated with bisphosphonate (alendronate) at concentrations of 1, 5, and 10 µM. Alendronate was then withdrawn at different time points. The negative control consisted of untreated cells (0 µM), while the positive control consisted of cells incubated with alendronate throughout the experiment. Cell viability, cell adhesion, cell cytoskeleton, mineralization, and gene expressions were investigated. Pre-osteoblasts and osteoblasts showed a decrease in cell viability after treatment with 5-10 μM alendronate for 4 days or longer. Two days of alendronate discontinuation significantly increased cell viability compared with the positive control. However, these levels did not reach those of the negative control. Bone nodule formation was reduced by alendronate. Discontinuation of alendronate regained bone nodule formation. Longer periods of discontinuation were more effective in restoring nodule formation than shorter periods. Addition of alendronate resulted in an increase in the percentage of dead cells, which, in turn, decreased when alendronate was discontinued. Alendronate affected the cell cytoskeleton by disassembling actin stress fibers. Cell adhesion and cell morphological parameters were also affected by alendronate. Discontinuation of alendronate restored cell adhesion and these parameters. Overall, the highest improvement after alendronate discontinuation was seen at 10 µM. However, alendronate treatment and discontinuation did not affect osteoblast gene expression. Discontinuation of alendronate helps to reverse the negative effects of the drug on cell viability, cell adhesion, and mineralization by restoring the cell cytoskeleton. Our data suggest the benefits of drug holiday and/or intermittent strategies for alendronate administration at the cellular level.

Addition of Chidamide to a Sandwich Protocol, Pegaspargase, Gemcitabine and Oxaliplatin Chemotherapy Combined with Radiotherapy, As First-Line Treatment in Early Stage NK/T-Cell Lymphoma: Real World Outcomes in a Retrospective Study

Background: Extranodal NK/T-cell lymphoma, nasal type (ENKTL-NT) is a highly invasive tumor with a short doubling time and poor prognosis. Clinically, it usually involves the upper aerodigestive tract and mainly presents with early-stage. Initially, intensity modulated radiation therapy (IMRT) has been considered the preferred first-line therapy for early-stage ENKTL due to its high response rate. In recent years, more and more studies show that adding chemotherapy, especially asparaginase (ASP)-based regimens, provide survival benefit in early-stage patients. However, the optimal chemotherapy regimen has not been fully defined. Epigenetic regulatory mechanisms related to histone deacetylase (HDAC) have been found to play a role in the evolution and progression of ENKTL. Chidamide, a new HDAC inhibitor, has been confirmed to be effective and tolerable to treat lymphoma. Recently, Xue et al showed that chidamide in combination with cisplatin, etoposide or gemcitabine showed synergistic effect and reversed the chemotherapy resistance in the relapsed/refractory B-cell lymphoma. Here, we investigate the safety and efficacy of adding chidamide to a sandwich protocol, P-GEMOX (pegaspargase/gemcitabine/oxaliplatin) regimen (CP-GEMOX) combined with IMRT as first-line treatment in early-stage ENKTL-NT patients. Methods: We retrospectively reviewed data of early-stage ENKTL-NT patients in the first affiliated hospital of Soochow University from March 2020 to April 2023. A total of 21 patients diagnosed with early-stage (stage Ⅰ or Ⅱ) ENKTL-NT were enrolled and treated with 2 cycles of CP-GEMOX followed by IMRT and 1 or 2 cycles of CP-GEMOX sequentially as consolidation. After consolidation, chidamide was administrated as a maintenance therapy for 1 year. In the induction therapy phase, chidamide was administered orally at a dose of 20 mg twice a week for two weeks, with a one-week discontinuation period; During the maintenance treatment phase, the original dose of chidamide was still maintained and used without pause. The baseline clinical features for the 21 patients were summarized in Table 1. Results: Among 21 patients, 14 were males and 7 were females, and their median age was 57 (range, 41-75) years. Elevated lactate dehydrogenase, elevated β2-microglobulin, stage II disease and primary tumor invasion were present in 4.8% (1/21), 19.0% (4/21), 61.9% (13/21) and 61.9% (13/21) patients. According to the early stage-adjusted nomogram-revised risk index, the majority of patients (76.2%, 16/21) were classified into intermediate- (1-2) and high (≥3) risk groups. The baseline clinical features for the 21 patients were summarized in Table 1. During treatment, all patients were well-tolerated and the most common adverse events were hematological toxicities with neutropenia, thrombocytopenia and anemia. Among non-hematological adverse events, nausea, vomiting and reduced appetite were most common. Other side effects included coagulation dysfunction, skin reaction, diarrhea, serum amylase and alanine aminotransferas /aspartate aminotransferase /bilirubin elevation. No anaphylactic reaction to pegaspargase, hemophagocytic syndrome, pancreatitis or sepsis were observed during chemotherapy. Some patients had mucositis and xerostomia when receiving local radiotherapy. All side effects could be reversed with proper treatment, and there were no therapy related mortality. All patients completed 2 cycles of CP-GEMOX, 19 patients achieved complete remission (CR) and 2 patients achieved partial remission (PR) with a CR rate of 90.5% (19/21) and overall response rate (ORR) of 100.0% (21/21) after 2 cycles of CP-GEMOX. Among the 21 patients, 18 patients completed treatment and CR rate was improved to 100.0% (18/18), giving an ORR of 100% (18/18). After a median follow-up of 25.6(range, 2.6-39) months , all patients were alive except one patient relapsed 20 months after treatment and died of COVID-19 related pneumonia 1 month later. The 2-year progression-free survival and overall survival were all 91.5% (Figure 1). Conclusions: This study demonstrates that sandwich CP-GEMOX chemoradiotherapy is a safe and promising approach to managing patients with early-stage ENKTL-NT. Keywords: Extranodal NK/T-cell lymphoma; chidamide; pegaspargase; gemcitabine; radiation therapy.

A Phase II Study of Chidamide Plus R-GDP Salvage Chemotherapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Ineligible for Autologous Transplantation: Efficacy and Safety Analysis

Background: A significant subset of Diffuse large B-cell lymphoma (DLBCL) patients (30%-40%) face treatment failure, necessitating effective salvage chemotherapy. We conducted a phase II study evaluating the efficacy and safety of chidamide plus R-GDP (rituximab, gemcitabine, dexamethasone, cisplatin) in relapsed/refractory (r/r) DLBCL patients. Methods: This open-label, single-arm study included 27 patients with r/r DLBCL who were ineligible for autologous stem cell transplantation. Prior to the induction monotherapy phase, chidamide was administered orally at a dose of 30 mg twice a week for one week. The combination therapy phase consisted of oral chidamide at a dose of 20 mg twice a week for two weeks, with a one-week discontinuation period, along with intravenous administration of rituximab, gemcitabine, dexamethasone, and cisplatin on a 21-day cycle. Results: A total of 27 patients received at least one dose of Chidamide plus R-GDP and were evaluated for safety. The median follow-up period was 17.0 months (range: 3.5 to 55 months). Radiological response assessment was available for 24 patients, who constituted the efficacy population. Fourteen patients completed six cycles of chidamide plus R-GDP (per-protocol population), while 10 patients discontinued treatment at the data cutoff. The baseline characteristics of enrolled patients included a median age of 67 years, predominantly older than 65 years. Approximately half of the patients exhibited elevated lactate dehydrogenase levels. All patients had received prior therapy with R-CHOP or equivalent chemoimmunotherapy. The majority of cases were classified as stage III/IV and non-germinal center B-cell-like (non-GCB) type by immunohistochemistry. Refractory or relapsed DLBCL within 1 year since the last treatment was observed in 74.0% of patients. Efficacy Outcomes: The investigator-assessed best objective response rate (ORR) was 79.2% (95% CI: 75.1% to 83.3%), with a complete response (CR) rate of 45.8% (95% CI: 41.6% to 49.9%) and a partial response (PR) rate of 33.3% (95% CI: 29.3% to 37.4%). The median time to response was 1.2 months, and the median time to CR or CRu (unconfirmed complete response) was 3.9 months. The best disease control rate was 87.5%. Among the patients who completed six cycles of chidamide plus R-GDP, the best ORR was 100%, with 71.4% achieving CR and 28.6% PR. Kaplan-Meier plots reveal that the median investigator-assessed progression-free survival (PFS) for the efficacy population was 5.9 (95% CI, 3.1 to 12.4) months. The median overall survival was 48.3 (95% CI, 13.1 to not reach (NR)) months. Safety Outcomes: A total of 13 patients (48.1%) required treatment interruption, primarily due to adverse events (22.2%) and disease progression (18.5%). Among patients who completed six cycles of chidamide plus R-GDP, 57.1% required a chidamide dose reduction. The most frequent treatment-emergent adverse event was anemia, occurring in all patients. Thrombocytopenia was the most common grade ≥3 adverse event leading to treatment interruption or dose reduction, affecting 48.1% of patients. Non-hematologic events included hypocalcemia (59.3%), hyponatremia (55.6%), and hypokalemia (44.4%). Three patients experienced grade 3 pneumonitis, and one patient had grade 3 skin rash. Conclusion: Chidamide plus R-GDP salvage chemotherapy demonstrated promising efficacy (ORR: 79.2%; CR rate: 45.8%) in r/r DLBCL patients. Adverse events were manageable but necessitated monitoring. Larger trials are needed to validate these findings and establish chidamide plus R-GDP as a potential treatment option for this challenging population. Keywords: relapsed/refractory DLBCL, salvage chemotherapy, chidamide, R-GDP, efficacy, safety

Extending device noise measurement capacity for OFDM-based PLC systems: Design, implementation, and on-field validation

Noise measurement in power line communication (PLC) systems is a common activity performed by grid operators for network tuning operations. Usually, these measurements are carried out with portable devices that have a fixed sensing and storage capacity.In this context, this paper presents a software-only solution for enhancing the performance of noise measurements in PLC systems. In detail: (i) we extend the measurement capacity in terms of the maximum number of samples that can be detected continuously, by using a machine learning (ML)-powered low complexity algorithm; and, (ii) we reduce the discontinuity period between successive measurements. This latter feature enables the possibility of collecting more continuous data. To show the viability of our proposal, we conducted a field measurements campaign to measure the scheme’s accuracy and the measurement capacity extension ratio (MCER). The introduced approach is able to increase the MCER by up to 8 times, in the considered PLC environments, with an accuracy above 90%. While the proposed approach has a clear application – improving current devices’ noise measurements capability without requiring costly hardware upgrades –, the technique herein shown has a general applicability, and could hence pave the way for further applications in related fields.

Neural Responses to Repeated Noise Structure in Sounds Are Invariant to Temporal Interruptions

ABSTRACT The ability to extract meaning from acoustic environments requires sensitivity to repeating sound structures. Yet, how events that repeat are encoded and maintained in the brain and how the brain responds to events that reoccur at later points in time is not well understood. In two electroencephalography experiments, participants listened to a longer, ongoing white-noise sound which comprised shorter, frozen noise snippets that repeated at a regular 2-Hz rate. In several conditions, the snippet repetition discontinued for a brief period after which the noise snippet reoccurred. The experiments aimed to answer whether neural activity becomes entrained by the regular repetition of noise snippets, whether entrained neural activity self-sustains during the discontinuation period, and how the brain responds to a reoccurring noise snippet. Results show that neural activity is entrained by the snippet repetition, but there was no evidence for self-sustained neural activity during the discontinuation period. However, the auditory cortex responded with similar magnitude to a noise snippet reoccurring after a brief discontinuation as it responded to a noise snippet for which the snippet repetition had not been discontinued. This response invariance was observed for different onset times of the reoccurring noise snippet relative to the previously established regularity. The results thus demonstrate that the auditory cortex sensitively responds to, and thus maintains a memory trace of, previously learned acoustic noise independent of temporal interruptions.

Continuous home cage monitoring of activity and sleep in mice during repeated paroxetine treatment and discontinuation.

Non-invasive home cage monitoring is emerging as a valuable tool to assess the effects of experimental interventions on mouse behaviour. A field in which these techniques may prove useful is the study of repeated selective serotonin reuptake inhibitor (SSRI) treatment and discontinuation. SSRI discontinuation syndrome is an under-researched condition that includes the emergence of sleep disturbances following treatment cessation. We used passive infrared (PIR) monitoring to investigate changes in activity, sleep, and circadian rhythms during repeated treatment with the SSRI paroxetine and its discontinuation in mice. Male mice received paroxetine (10mg/kg/day, s.c.) for 12days, then were swapped to saline injections for a 13day discontinuation period and compared to mice that received saline injections throughout. Mice were continuously tracked using the Continuous Open Mouse Phenotyping of Activity and Sleep Status (COMPASS) system. Repeated paroxetine treatment reduced activity and increased behaviourally-defined sleep in the dark phase. These effects recovered to saline-control levels within 24h of paroxetine cessation, yet there was also evidence of a lengthening of sleep bouts in the dark phase for up to a week following discontinuation. This study provides the first example of how continuous non-invasive home cage monitoring can be used to detect objective behavioural changes in activity and sleep during and after drug treatment in mice. These data suggest that effects of paroxetine administration reversed soon after its discontinuation but identified an emergent change in sleep bout duration, which could be used as a biomarker in future preclinical studies to prevent or minimise SSRI discontinuation symptoms.

Discontinuation of Car Seat Tolerance Screening and Postdischarge Adverse Outcomes in Infants Born Preterm

To study the association between discontinuing predischarge car seat tolerance screening (CSTS) with 30-day postdischarge adverse outcomes in infants born preterm. Retrospective cohort study involving all infants born preterm from 2010 through 2021 who survived to discharge to home in a 14-hospital integrated health care system. The exposure was discontinuation of CSTS. The primary outcome was a composite rate of death, 911 call-triggered transports, or readmissions associated with diagnostic codes of respiratory disorders, apnea, apparent life-threatening event, or brief resolved unexplained events within 30days of discharge. Outcomes of infants born in the periods of CSTS and after discontinuation were compared. Twelve of 14 hospitals initially utilized CSTS and contributed patients to the CSTS period; 71.4% of neonatal intensive care unit (NICU) patients and 26.9% of non-NICU infants were screened. All hospitals participated in the discontinuation period; 0.1% was screened. Rates of the unadjusted primary outcome were 1.02% in infants in the CSTS period (n=21 122) and 1.06% after discontinuation (n=20 142) (P=.76). The aOR (95% CI) was 0.95 (0.75, 1.19). Statistically insignificant differences between periods were observed in components of the primary outcome, gestational age strata, NICU admission status groups, and other secondary analyses. Discontinuation of CSTS in a large integrated health care network was not associated with a change in 30-day postdischarge adverse outcomes. CSTS's value as a standard predischarge assessment deserves further evaluation.