Poor Tolerance Research Articles

Physical rehabilitation program for cardiorespiratory health and quality of life among breast cancer survivors in UAE: protocol for a randomized control trial

BackgroundCancer is a medical condition where some cells of the body reproduce uncontrollably and metastasize to other parts of the body. The burden of the disease is significantly high both at the global and national levels. In UAE, cancer was found to be the third leading cause of death. Breast cancer has been ranked first due to its prevalence, incidence, and mortality in UAE. Breast cancer survivors have significantly poor cardiovascular tolerance which affects their quality of life (QoL), even after the carcinoma has been treated or removed. Thus, the protocol aims to analyze the changes in cardiovascular endurance and QoL domains for breast cancer survivors in the United Arab Emirates using a long-term 2-month physical rehabilitation.MethodsA total of 60 breast cancer survivors would be included in the study using a randomized controlled allocation of a 2-month physical rehabilitation intervention program with 3 months of follow-up. The intervention would target the cardiovascular endurance component of the participants to improve their physical well-being and quality of life ultimately.DiscussionThe findings of the study would have high clinical significance among breast cancer survivors in the UAE. The proposed physical rehabilitation program could be beneficial in improving cardiovascular endurance and thereby reduce the risk of mortality among breast cancer survivors. In addition, the physiological benefits of the exercise program could improve their quality-of-life domains including physical, mental, and social well-being. On a larger view, it could also help to reduce the economic burden on the health system due to associated complications.Trial registrationClinicalTrials.gov NCT06013527. Registered on 28 August 2023.

Individual sol-gel microencapsulation of benzoyl peroxide and tretinoin enables controlled release onto the skin

A combination of benzoyl peroxide (BPO) and tretinoin is recommended for treating acne; however, concurrent administration can be irritating, and coformulation is prevented by BPO-mediated oxidation of tretinoin. In rosacea, benzoyl peroxide has been shown to be efficacious; however, its use has been limited by poor tolerability. To overcome these limitations, the active ingredients can be encapsulated within silica microcapsules. The US Food and Drug Administration has approved 2 products using this technology, a combination of encapsulated benzoyl peroxide and encapsulated tretinoin product for acne vulgaris and encapsulated benzoyl peroxide to treat inflammatory lesions in rosacea. The active ingredients are released through small channels in the silica shell, gradually releasing the active ingredients to the skin. This study describes the stability and release profiles of encapsulated tretinoin and encapsulated benzoyl peroxide from the silica shell in physiologically relevant conditions and provides differentiation from traditional formulations.

Evaluation of drug tolerability as a function of toxicity and quality of life in patients enrolled on I-SPY2.

11113 Background: Patient-reported outcomes (PROs) are valuable for understanding treatment tolerability and toxicity. I-SPY2 is a phase-II neoadjuvant clinical trial for breast cancer with electronic PROs and quality of life (QOL) assessments. We sought to understand how well the GP5 self-reported tolerability item reflected toxicity burden and QOL during treatment and follow-up in I-SPY 2 participants. Methods: Our study included 306 patients who completed the FACIT Item GP5 and answered PROMIS surveys at two or more timepoints. Analysis timepoints included screening (SC), inter-regimen (IR), pre-surgery (PS), 1-month post-surgery (FU1), and 6-months post-surgery (FU2). Symptoms were assessed weekly using PRO-CTCAE and CTCAEv4.0. QOL was evaluated using PROMIS. The GP5: “I am bothered by side effects of treatment,” was used to estimate tolerability, where worse tolerability is a higher score. Odds ratios, Spearman correlation, and regularized multi-variate regression were used to evaluate the associations between individual symptoms and adverse events with GP5 scores. Results: Demographic information was available for 243 of the 306 (70.2%) participants (median age=47,73.7% white). In the 306, tolerability scores worsened over study treatment, with a maximum mean score of 1.71 at Cycle 11. Tolerability improved after treatment cessation at FU1(1.09). Mean tolerability at week 6 was 1.53. The only clinical factor that was associated with early change in tolerability (week 6 to PS) was age >50 (mean score ranged from 1.55-1.70 vs 1.29-1.45 (age<50), p<0.05). PRO-CTCAE and GP5 correlative analysis suggested that higher grade abdominal pain, decreased appetite, dizziness and blurry vision significantly associated with higher GP5 scores at multiple timepoints (p<0.05). Symptoms not associated with tolerability were nail loss, acne, hair loss, and rash (p>0.05). Additionally, the total number of low-grade (mild to moderate) symptoms a patient experienced during study treatment was significantly correlated to poor tolerability (p<0.00001). Among patients with CTCAE data, 9% had adrenal insufficiency, and higher GP5 was found across all study timepoints in those with (compared to without) adrenal insufficiency (mean GP5 = [1.7-1.9] vs [1.3-1.5] respectively). Similarly, among patients with neuropathy (14%), higher GP5 scores were reported across all study timepoints (mean GP5 = [1.8-2.3] vs [1.3-1.5] respectively). Higher GP5 scores during treatment were correlated with higher fatigue scores at PS and FU1 (p<0.02 and p<0.001) and lower physical functioning at PS (p<0.01). Conclusions: TheGP5 measure is associated with self-reported symptoms, higher grade adverse events and quality of life scores. Furthermore, greater accumulation of lower grade symptoms can lead to poor tolerability. The single measure GP5 composite score reflects multiple components of treatment toxicity.

Evaluating the significance of next-generation sequencing (NGS) testing in Indian patients with advanced malignancies: An observational study on clinical outcomes and treatment costs.

e15091 Background: The widespread use of Next-Generation Sequencing (NGS) panels to guide targeted therapy in advanced malignancies has raised questions regarding their real-world impact on clinical outcomes and affordability. Methods: This observational study included 126 patients, conducted between January 2022 and December 2023 aimed to assess the utility of NGS testing in both the initial and subsequent lines of treatment for Indian patients facing advanced malignancies. Results: In the first-line setting, NGS was extensively employed for patients with metastatic Colorectal Cancer (mCRC) and Non-Small Cell Lung Cancer (NSCLC). Analysis of RAS and BRAF mutations in mCRC patients (n=21) informed the choice between EGFR and VEGFR-directed therapy, resulting in a median Progression-Free Survival (PFS) of 7.5 months. In NSCLC patients (n=37), the NGS identified targetable mutations in 30 cases, leading to significantly improved mPFS (12 months vs 6 mo with chemotherapy alone). NGS was also employed for HRR, HRD and BRCA testing in advanced breast (n=45) and ovarian carcinoma (n=11), which helps in determining prognosis, role of targeted therapy and genetics. No adverse events noted till date. For patients undergoing subsequent lines of treatment (n=12), NGS detected targetable mutations in 9 cases. NGS revealed actionable mutations (ERBB2, CD74/NRG1fusion and KRAS12C mutation) in metastatic NSCLC patients (n=3), leading to appropriate treatment and PFS of 4-6 months. In metastatic NSCLC patients, T790M mutation was detected in 1 patient confering PFS of 6 months with change to Osimertinib and EGFR exon 20 insertion mutation detected in another, survival didn't improve with addition of amivantamab due to poor general condition. Alpelisib was started for PIK3CA mutation in metastatic Ca Breast (HR+,HEr2-), which was discontinued due to poor tolerance after 3 months. In Metastatic Neuroendocrine Carcinoma (NEC) Lung, detection of EGFR l858R mutation did not confer a PFS benefit despite the addition of Geftinib to chemotherapy. Due to financial constraints, targeted therapy couldn't be started for 2 patients with pathogenic target detected. Conclusions: The study's findings suggest that NGS testing offers tangible clinical benefits in both initial and subsequent lines of treatment for advanced malignancies in the Indian population. Despite the varying costs of NGS in India (ranging from 240 to 1800 USD), the data implies an overall affordability, making it a viable option for patients with advanced malignancies. However, NGS didn't improve outcomes in patients with rapidly progressing disease, poor general condition and financial constraints.

Clinical efficacy and safety of mTOR inhibitor in patients with advanced unresectable epithelioid hemangioendothelioma (EHE).

e23540 Background: Epithelioidhemangioendothelioma is a rare vascular soft tissue sarcoma, 90% of which contains WWTR1-CAMTA1 fusion gene. Studies have shown that mTOR inhibitors may have a certain effect on EHE patients. Methods: A retrospective analysis of the efficacy and safety of mTOR inhibitor everolimus in the treatment of advanced unresectable epithelioidhemangioendothelioma in our hospital in the past one year. Patients with advanced epithelioidhemangioendothelioma (EHE) confirmed by consultation in the pathological center received this regimen, everolimus 10mg, once a day orally for 28 days, every 4 weeks as a treatment cycle until the disease progressed or showed intolerable toxicity. Results: There were 3 females and 5 males, and their average age was 41.8 years old. All of them were unresectable with liver, lung, and shoulder primary lesions, and lungs, liver, pleura and bone metastasis. Ki67 is from 2% to 10%. 3 patients who received molecular pathological examination were all identified the WWTR1-CAMTA1 fusion gene, and one of them also had EWSR1 chromosome translocation. Previous antineoplastic treatments included gemcitabine, cisplatin, albumin paclitaxel, epirubicin, dacarbazine chemotherapy, anlotinib targeting, and toripalimab immune therapy. 5 patients were treated with first-line drugs, 2 cases with second-line and 1 case with third-line. In terms of overall efficacy, 1 case was not evaluated, 2 cases lost follow-up due to poor tolerance and economic factors, 2 cases were included in the clinical trails after reaching tumor control for 3 months, and the other 3 cases achieved tumor remission with a median PFS of 11.0 months, and the best curative effect was SDa. Severe oral mucositis can greatly affect the medication experience of patients, which can be relieved after symptomatic medication, or when interstitial pneumonia and hemogram decrease significantly, we can consider the oral administration of everolimus 5mg. Conclusions: At present, there is no standard treatment for EHE, we can roughly see the efficacy of mTOR inhibitor everolimus in some EHE patients, mainly disease stability. Emphasis on side effect management, improve tolerance, and systematic treatment of EHE needs to be further explored.

Лечение колхицинрезистентной периодической болезни: ретроспективное когортное исследование

Lifelong administration of colchicine is the mainstay of treatment for familial Mediterranean fever (FMF), whereas canakinumab, a monoclonal antibody that blocks the effects of interleukin (IL)-1β, can be used in case of colchicine resistance or its poor tolerability.

Dietary restriction rescues 5-fluorouracil-induced lethal intestinal toxicity in old mice by blocking translocation of opportunistic pathogens

ABSTRACT Chemotherapy remains a major treatment for malignant tumors, yet the application of standard dose intensity chemotherapy is limited due to the side effects of cytotoxic drugs, especially in old populations. The underlying mechanisms of cytotoxicity and strategies to increase the safety and tolerance of chemotherapy remain to be explored. Using 5-fluorouracil (5-FU), a cornerstone chemotherapeutic drug, we demonstrate that the main cause of death in ad libitum (AL) fed mice after 5-FU chemotherapy was infection caused by translocation of intestinal opportunistic pathogens. We show that these opportunistic pathogens greatly increase in the intestine after chemotherapy, which was closely related to loss of intestinal lysozyme. Of note, two weeks of dietary restriction (DR) prior to chemotherapy significantly protected the loss of lysozyme and increased the content of the beneficial Lactobacillus genera, resulting in a substantial inhibition of intestinal opportunistic pathogens and their translocation. The rescue effect of DR could be mimicked by Lysozyme or Lactobacillus gavage. Our study provides the first evidence that DR achieved a comprehensive protection of the intestinal physical, biological and chemical barriers, which significantly improved the overall survival of 5-FU-treated mice. Importantly, the above findings were more prominent in old mice. Furthermore, we show that patients over 65 years old have enriched opportunistic pathogens in their gut microbiota, especially after 5-FU based chemotherapy. Our study reveals important mechanisms for the poor chemotherapy tolerance of the elderly population, which can be significantly improved by short-term DR. This study generates new insights into methods for improving the chemotherapeutic prognosis by increasing the chemotherapy tolerance and safety of patients with malignant tumors.

Solvent Tolerance Improvement of Lipases Enhanced Their Applications: State of the Art.

Lipases, crucial catalysts in biochemical synthesis, find extensive applications across industries such as food, medicine, and cosmetics. The efficiency of lipase-catalyzed reactions is significantly influenced by the choice of solvents. Polar organic solvents often result in a decrease, or even loss, of lipase activity. Conversely, nonpolar organic solvents induce excessive rigidity in lipases, thereby affecting their activity. While the advent of new solvents like ionic liquids and deep eutectic solvents has somewhat improved the activity and stability of lipases, it fails to address the fundamental issue of lipases' poor solvent tolerance. Hence, the rational design of lipases for enhanced solvent tolerance can significantly boost their industrial performance. This review provides a comprehensive summary of the structural characteristics and properties of lipases in various solvent systems and emphasizes various strategies of protein engineering for non-aqueous media to improve lipases' solvent tolerance. This study provides a theoretical foundation for further enhancing the solvent tolerance and industrial properties of lipases.

Migrating foreign body granulomas after rupture of a breast implant

AbstractWe present the case of an 80‐year‐old female with a history of bluish streaks and painful lumps on her left arm, initially misdiagnosed as a soft tissue infection. Further investigation revealed granulomatous infiltrates in the arm and a ruptured breast implant. Upon presentation, nodular and painful swelling prompted a new biopsy. Histology and electron spectroscopy confirmed silicone deposits within granulomas. The rupture of the breast implant was identified as the likely source of silicone migration to the arm, possibly exacerbated by a past fall. Treatment challenges included the extensive size of the granuloma, leading to a trial of methotrexate therapy with initial improvement but subsequent discontinuation due to poor tolerance. This case underscores the potential for silicone migration from ruptured breast implants to induce distant granulomatous reactions, necessitating individualised treatment approaches.

Impact of Antiretroviral Therapy on the Progression of EBV-Associated Lymphomas

Objective — to determine the impact of antiretroviral therapy (ART) on the progression of lymphomas induced by Epstein—Barr virus (EBV) in patients infected with human immunodeficiency virus (HIV). Materials and methods. We analysed clinical-epidemiological, laboratory and serological indicators of 57 HIV-infected patients with clinically and laboratory-confirmed EBV co-infection. Patients were divided into two groups: the primary group consisted of 9 patients with lymphomas (66.7 % of whom received ART without concurrent chemotherapy with cytostatic antitumor agents, while the rest did not receive ART), and the control group included 48 patients without neoplasms. Results and discussion. To assess the effectiveness of ART in treating EBV-induced lymphomas, we analysed the general clinical, immunological and virological indicators of patients at the start of observation and after 6 months of therapy. In patients with EBV-associated lymphomas receiving ART, there was an increase in CD4+ lymphocytes, a decrease in HIV viral load, an increase in hemoglobin levels (p < 0.05), and a significant reduction in EBV viral load (p < 0.01). In patients with EBV-associated lymphomas who did not receive ART, there was a further decrease in CD4+ lymphocytes and an increase in EBV viral load. Two clinical cases are presented: in one, a patient received palliative chemotherapy according to the CHOP regimen but did not receive ART due to an absolute refusal because of poor drug tolerance; in the other case, the patient received ART without cytostatic antitumor drugs due to an absolute refusal. Conclusions. The study results established that the use of ART in patients with EBV-associated lymphomas not only improved the primary indicators characteristic of HIV but also significantly reduced the EBV viral load (p < 0.01). The dynamics of the main immunological and virological indicators in patients with EBV-associated lymphomas who did not receive ART were negative, as evidenced by the further decrease in CD4+ lymphocytes and an increase in EBV viral load. From the clinical cases presented, it can be concluded that the timely administration of ART to patients with EBV-associated lymphomas is a crucial therapeutic tool that not only facilitates positive immunological and virological changes in HIV infection but also affects the quality and duration of life in patients with EBV-associated lymphomas.

Enhancing Rate Capability, Capacity, and Durability of Co‐Doped Germanium Phosphide Anodes for Li‐Ion Batteries

AbstractWhile germanium‐based anodes for Li‐ion batteries (LIBs) have potential to offer high energy density, their commercialization is impeded by low ionic and electronic conductivity and poor tolerance to volume change during cycling. Here a new quaternary CuGeSiP3 anode is reported to simultaneously overcome these limitations. Synthesized via ball milling process, CuGeSiP3 displays high ionic and electronic conductivity and excellent flexibility to accommodate volume change, attributed to increased structural entropy and reversible formation of favorable intermediates of both electronic and Li ion conductors, as confirmed by experimental measurements and theoretical calculations. When used as an LIB anode, CuGeSiP3 demonstrates large reversible capacity, high Coulombic efficiency, robust cycling stability, and high‐rate capability because it undergoes a reversible lithiation process that involves intercalation and conversion reaction. When composited with layered graphite, the electrode demonstrates exceptional cycling stability (1 261 mA h g−1 after 600 cycles at 400 mA g−1 and 861 mA h g−1 after 1 450 cycles at 20 00 mA g−1) and ultrahigh rate capability (448 mA h g−1 at 20 000 mA g−1). Further, the quaternary, pentanary, and hexanary cation‐disordered phosphides are also synthesized, all having similar Li‐storage superiority, implying the multiple co‐doping strategy is applicable to other material systems.

Comparative evaluation of different oral iron salts in the management of iron deficiency anemia.

Anemia affects one-fourth of the world's population and is caused mostly by iron deficiency. Iron supplementation is the most essential strategy for preventing iron deficiency anemia. Conventional oral iron salts have many drawbacks such as poor absorption & bioavailability, and poor tolerability resulting in poor clinical outcomes. To compare the effectiveness and safety of ferrous ascorbate, ferrous fumarate, ferrous bis-glycinate, and Sucrosomial iron in the management of iron deficiency anemia. The study is a retrospective observational clinical study comprising 260 subjects with hemoglobin between 7-10g/dl. The patients were divided into four groups I, II, III, and IV, and received ferrous fumarate, ferrous ascorbate, ferrous bis-glycinate, and Sucrosomial iron respectively. Hematological profile and iron store indices were measured at baseline and month 3. One-way ANOVA followed by Tukey multiple comparison test was used to assess statistical significance (P < 0.05) using GraphPad Prism V.9.3.1 software. The observational study showed that hemoglobin levels were significantly increased in the ferrous ascorbate group (11.86 ± 0.09; P < 0.0001), ferrous fumarate group (11.72 ± 0.08; P < 0.0001), ferrous bis-glycinate group (11.69 ± 0.11; P = 0.0003) and Sucrosomial iron group (12.20 ± 0.1; P < 0.0001) compared to the baseline. The Sucrosomial iron-supplemented group showed significantly higher improvement in hemoglobin levels and serum ferritin levels compared to conventional oral iron salts (P < 0.05) with a better safety profile. The Sucrosomial iron showed significantly higher improvement in hemoglobin levels and higher improvement in iron store indices parameters along with a good tolerability profile compared to other conventional oral iron salts.

Genotoxicity Associated with Retroviral CAR Transduction of ATM-Deficient T Cells.

Somatic variants in DNA damage response genes such as ATM are widespread in hematologic malignancies. ATM protein is essential for double-strand DNA break repair. Germline ATM deficiencies underlie ataxia-telangiectasia (A-T), a disease manifested by radiosensitivity, immunodeficiency, and predisposition to lymphoid malignancies. Patients with A-T diagnosed with malignancies have poor tolerance to chemotherapy or radiation. In this study, we investigated chimeric antigen receptor (CAR) T cells using primary T cells from patients with A-T (ATM-/-), heterozygote donors (ATM+/-), and healthy donors. ATM-/- T cells proliferate and can be successfully transduced with CARs, though functional impairment of ATM-/- CAR T-cells was observed. Retroviral transduction of the CAR in ATM-/- T cells resulted in high rates of chromosomal lesions at CAR insertion sites, as confirmed by next-generation long-read sequencing. This work suggests that ATM is essential to preserve genome integrity of CAR T-cells during retroviral manufacturing, and its lack poses a risk of chromosomal translocations and potential leukemogenicity. Significance: CAR T-cells are clinically approved genetically modified cells, but the control of genome integrity remains largely uncharacterized. This study demonstrates that ATM deficiency marginally impairs CAR T-cell function and results in high rates of chromosomal aberrations after retroviral transduction, which may be of concern in patients with DNA repair deficiencies.

Weekly Afatinib in the Treatment of Advanced Non-small Cell Lung Cancer with EGFR-G719C Mutation Followed by Lobectomy: A Case Report

Introduction: Lung cancer stands as the leading cause of cancer-related deaths worldwide. Over the past three decades, the advent of tyrosine kinase inhibitors (TKIs) has marked a significant turning point in the treatment of non-small cell lung cancer (NSCLC) harboring EGFR mutations. Notably, high response rates have been observed in cases with exon 19 deletions (Del19) and Exon 21 substitution L858R mutations. Conversely, the G719X mutation on exon 18 is less prevalent, with variable sensitivity across different generations of TKIs. Afatinib, a second-generation inhibitor, gained FDA approval for the initial treatment of EGFR-mutant metastatic NSCLC in 2013, though its role remains incompletely understood within a multidisciplinary treatment framework, particularly in combination with surgery. However, the standard daily dose of 40mg Afatinib has demonstrated poor tolerability, often resulting in adverse events such as diarrhea and skin toxicity, leading to treatment discontinuation. A recent strategy involving a weekly dose of 280mg Afatinib has shown promising outcomes and a reduced risk of adverse events. Case Presentation: This case report highlights a 50 - year-old female diagnosed with stage IVa right lung adenocarcinoma metastasizing to the left lung (cT3N0M1a), revealing the rare EGFR-G719C (exon18) mutation. Following this diagnosis, the patient underwent open lobectomy. Nine months post-surgery, a treatment approach involving 280mg weekly Afatinib was initiated. Subsequently, the patient was closely monitored for 16 months with no signs of recurrence. Conclusions: EGFR G719C exhibits sensitivity to Afatinib, endorsing the use of Afatinib with fewer adverse events compared to the traditional daily dosage. Our case further advocates for collaborative strategies between medical oncologists and surgeons in the management of advanced-stage NSCLC.

Digital sleep clinic: assessing efficacy of continuous positive airway pressure through sleep staging via connected devices: a study protocol

BackgroundObstructive sleep apnea (OSA) is a multisystemic chronic disease with disabling symptoms, cardiometabolic comorbidities and reduction in physical activity. Continuous positive airway pressure (CPAP) is the standard treatment for OSA. Only a few studies have characterized trajectories of sleep parameters upon initiation of CPAP and these are limited to one or two nights of polysomnographic recording in a sleep laboratory. This is due to the cost of carrying out these studies and poor tolerance by patients of multiple nights of polysomnographic recordings. No study has characterized sleep over multiple nights before and after CPAP initiation, assessing the multidimensional efficacy of CPAP on patient reported outcomes, objective and subjective sleep quality, oximetry, glucose control and physical activity.New digital technologies enable overnight sleep studies over several nights in the patient’s home, with a reliability of sleep characterization equivalent to polysomnographic recording.The primary aim of this study is to investigate objective slow wave sleep (SWS or N3) quality before CPAP and during the first month of the treatment.Secondary objectives are to assess changes in the following parameters before CPAP and during the first month of the treatment: other objective sleep parameters and sleep stages evolution (W, N1, N2 and REM), nocturnal oxygen desaturations, 24-h blood glucose profile, daily physical activity (the daily steps count), and patient reported outcomes.MethodsSeventy patients prescribed CPAP for OSA will be recruited at Grenoble Alpes University Hospital (France) and monitored for 5 weeks using validated innovative wearable connected devices (the Dreem 3 headband, a pedometer, an oximeter, and a continuous glucose sensor) enabling them to track their own sleep and physiological parameters at home before and after CPAP initiation.DiscussionBy pooling data from the CPAP telemonitoring and other connected devices we should be able to follow the multidimensional trajectories of patients after the initiation of CPAP. This will enable us to determine whether objective changes in sleep parameters in the first few weeks of CPAP treatment are associated with improvements in daytime sleepiness, quality of life, treatment adherence, glucose control and physical activity. The data will provide integrated markers of treatment efficacy and will allow adapted personalized management of OSA in the short and long-term.Trial registrationClinicaltrials (NCT05197855).

Mental fatigue and chronic fatigue syndrome in clinical practice

Fatigue is an extremely disabling symptom both in healthy people and in various diseases. Physical fatigue is characterized by limitations in physical functioning, while mental/cognitive fatigue involves difficulties in concentrating and performing cognitive tasks. Mental and physical fatigue exist in both pathological and physiological fatigue. Fatigue is primarily an adaptive physiological process. It is a signal to have a rest and helps conserve energy to prevent injury, which can be useful after intense work, or when the body’s defenses need to be redistributed, for example, during infectious disease. It is important to distinguish between fatigue or tiredness and chronic fatigue syndrome in clinical practice. Chronic fatigue syndrome has multisystem manifestations and affects millions of people globally. Although the exact aetiology of chronic fatigue syndrome is uncertain, the studies point to neurological, immunological, autonomic and energy disorders. The main sings of chronic fatigue syndrome are debilitating fatigue that is worsened by activity, poor exercise tolerance, unrefreshing sleep and cognitive impairment. Reduced information processing speed is the most common cognitive impairment in chronic fatigue syndrome. Other manifestations include decreased reaction time, working memory, and attention. These symptoms must persist for at least 3–6 months for a diagnosis to be made. As there are no specific tests for chronic fatigue syndrome, a diagnosis can be established on the basis of a medical history and physical examination.Although there are no standards-based methods specific to chronic fatigue syndrome, clinicians can reduce the severity of symptoms using pharmacological and non-pharmacological treatment approaches that have proved their efficacy in clinical practice. In particular, nootropics are widely used in asthenic conditions and chronic fatigue syndrome. Fonturacetam is a nootropic drug that directly activates brain integration activities, promotes memory consolidation, and improves concentration and mental activity.

Abstract PO3-04-03: Drug Holidays in Patients with HER-2 Positive Metastatic Breast Cancer

Abstract Background Treatment of HER-2 positive metastatic breast cancer (MBC) involves the use of HER-2-targeted therapy in combination with cytotoxic chemotherapy and/or hormone therapy. Treatment duration for HER2-targeted agents is not standardized, and patients are often kept on these drugs indefinitely. Drug holidays can be initiated due to poor tolerance of drug or can be considered when trying to limit drug toxicity. Our study aims to determine the safety of utilizing drug holidays for patients receiving HER2-targeted therapies and the effect on overall survival and disease progression. Methods Study Design This retrospective study included patients who were diagnosed with metastatic HER2 positive breast cancer and had complete clinical and survival data available within UPMC Magee Women’s Hospital. The patients were divided into two groups based on whether they had a drug holiday or not. A drug holiday was defined as the temporary cessation of antiHER2 therapy for a minimum of three months in patients receiving HER2-targeted treatments. This involved the discontinuation of earlier- and later-line medications without considering the cessation of hormone therapy. Statistical Analysis The chi-square test or Fisher's exact test was used to compare categorical variables and the Mann-Whitney U test was used to compare continuous variables. The results were reported as proportions for categorical variables and as medians with 25th-75th percentiles for continuous variables. Survival rates and Hazard ratios were estimated using Kaplan-Meier log-rank tests and Cox models, respectively. The significance level was set at p &amp;lt; 0.05 for all analyses. Results 83 patients with HER2+ MBC treated with HER2-targeted therapy were identified, of which 54 patients were in the drug holiday group. Of noted patient variables, there was no significant difference in the tumor histology, distribution of estrogen receptor (ER) status (p= 0.38) and progesterone receptor (PR) status (p = 0.64). The use of hormonotherapy, immunotherapy, radiotherapy to the primary tumor, and radiotherapy to metastasis did not significantly differ between the two groups (p &amp;gt; 0.05 for all comparisons). Subgroup analysis was conducted within the hormonotherapy subgroup to assess the survival difference in the no drug holiday group and to evaluate the impact of drug holiday on antiHER2 therapy cessation while continuing hormonotherapy. There was a trend towards a higher proportion of patients who were deceased in the no drug holiday group (62%) compared to the drug holiday group (42%), although this difference did not reach statistical significance (p = 0.16). The disease status differed significantly between the two groups (p &amp;lt; 0.0001). In the no-drug holiday group, 72% of patients had progressive disease, while 20% had stable disease with the anti-HER2 therapy and 7% had no-evidence of disease. In contrast, the drug holiday group had a higher proportion of patients with no-evidence of disease (48%) compared to progressive disease (38%) and stable disease (14%). The drug holiday group demonstrated higher overall survival (61% with median follow-up 1719 days 25th-75th percentile: 963-2222) compared to the no drug holiday group (39% with median follow-up time of 803 days 25th-75th percentile: 216-1510) (p= 0.04). Conclusion Overall, our findings suggest that utilization of a drug holiday in stable and NED HER2+ MBC is not associated with decreased survival. Analysis within the hormonotherapy subgroup indicated no survival difference in the drug holiday group, highlighting the potential for cessation of antiHER2 therapy while continuing hormonotherapy in this specific subgroup. However further prospective studies with long drug holiday intervals, larger sample size, and control of other potential confounding factors are needed to validate these results. Citation Format: Saba Kurtom, Kazim Senol, Qurat Ul Ain Sabih, Efe Sezgin, Adam Brufsky, Vikram Gorantla, Shannon Puhalla, Atilla Soran. Drug Holidays in Patients with HER-2 Positive Metastatic Breast Cancer [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 PO3-04-03.

Pseudocannabinoid H4CBD Reduces Cardiac Damage Indicator 4HNE in OLETF (Otsuka Long Evans Tokushima Fatty) Rats

Cardiovascular disease (CVD) is a leading cause of death globally and MetS is an associated precursor of CVD. Of the 6 known cluster factor conditions of MetS, obesity, and poor glucose tolerance are known to contribute to high lipid peroxidation, which can contribute to the generation of damaging free radical species and a pro-oxidant system. Cannabidiol (CBD) is a known antioxidant and a growing understanding of CBD analogs and pseudocannabinoids, like H4CBD, implicate similar antioxidant effects. However, little is known about the effects of CBD analogs on MetS-associated cardiac tissue damage. To better understand these effects during extreme metabolic dysfunction, 41-weeks-old animals were assigned into three groups, (n=8/group): (1) one-lean-strain control, Long Evans Tokushima Otsuka (LETO), (2) untreated OLETF, and (3) OLETF + H4CBD (200 mg/kg/day x 4 weeks). Our hypothesis focuses on the prospect that ongoing treatment with H4CBD in a MetS model using Otsuka Long-Evans Tokushima Fatty (OLETF) rats will reduce indicators of lipid peroxidation including 4-hydroxynonenal (4HNE), a toxic end product of lipid peroxidation. After the 4-week treatment, cardiac tissue was analyzed for 4-hydroxynonenal (4HNE) protein expression. We found that H4CBD decreased cardiac 4HNE protein expression in treated OLETF rats by 68% (p&lt;0.05) compared to OLETF control, which indicates H4CBD attenuated cardiac lipid peroxidation overall. Although the 4-week treatment of H4CBD was not suffcient to ameliorate MetS-associated hypertension, the reduction of 4HNE suggests that the attenuation of cardiac damage is independent of arterial pressure. These data indicate that H4CBD and its derivatives hold promise for therapeutic use in managing CVD and related metabolic syndrome-associated pathologies. Undergraduate Research Training Initiative for Student Enhancement (U-RISE), Center for Medical Cannabis Research. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Realizing efficient operations of Ni-cermet-based fuel cells on hydrocarbons via an in situ self-assembled metal/oxide nano-heterostructured catalyst

Operating Ni-cermet-based fuel cells on hydrocarbons is charming but largely hindered by poor coking tolerance and severe deterioration. Here, we report an effective metal/oxide nano-heterostructured catalyst with a nominal composition of Pr0.95Ru0.05O2-δ (PRO), which is in situ self-assembled to a Pr0.95Ru0.05-xO2-δ oxide frame coated with Ru metallic nanoparticles (denoted as Ru/PRO) under the operation condition. When applied to the Ni-cermet (Ni-YSZ) anodes, the cells achieve decent peak power densities of 1.784 and 1.870 W cm−2 on CH4 and C3H8 with only 3% H2O at 750 °C, respectively. Moreover, the cells with Ru/PRO-coated anode demonstrate excellent durability when operated on CH4 for ∼ 220 h and C3H8 for ∼115 h. It is demonstrated that the Ru/PRO generates hydroxyl species that react with carbon species, followed by the formation of COH intermediates on anode surfaces for removing the coking, as confirmed by experiments and computations.

Morular Metaplasia of the Endometrium: A Case Report and Literature Review: Care Pathways based on Molecular Biology

Background: Endometrial morular metaplasia, a clinical conundrum from a diagnostic and management angle given its rarity and low oncogenic potential has been linked to endometrial hyperplasia and carcinoma. Case report: A 77-year-old woman with no significant past medical history was found to have an asymptomatic thickened endometrium on pelvic imaging, after presenting with lower abdominal pain, 3 yrs ago. Diagnostic hysteroscopy identified an endometrial polyp within a pyometra. Histopathology showed focal complex hyperplasia without atypia with superimposed morular metaplasia (EMM) amongst negative microbiology. Following conservative management with a Multidisciplinary Team (MDT) overview, as per her choice with 6-monthly follow-up hysteroscopies, endometrial biopsies, and a short use of the Mirena IUS (discontinued due to poor tolerance), histopathology shows resolved hyperplasia with persistent EMM. She is considering a hysterectomy. Discussion: Current evidence suggests that a sub-type of EMM, a likely histological manifestation of beta-catenin (CTNNB1) gene mutation: could be a precursor of endometrial hyperplasia and low-grade endometrioid-endometrial carcinoma sub-type. Though low-grade in nature, the increased recurrence risk raises significant concerns. Management options which include conservative, hormonal, and surgery have been described in the literature. A few cases of premenopausal women have been managed conservatively, with one resulting in a pregnancy. However, due to the lack of a natural history timeline, the optimal frequency of endometrial sampling when uterine-sparing, is unclear, leading to a management conundrum. Conclusion: Management of morular endometrial metaplasia can be difficult but must reflect the woman’s choice with an MDT overview. Immuno-histochemical tools utilizing new molecular biological advances can simplify the diagnostic and prognostication processes, aiding clinical management.