Side Effects Of Long-term Treatment Research Articles

Eight-year follow-up of patient-reported outcomes in patients with breast cancer participating in exercise studies during chemotherapy.

Numerous randomized controlled trials (RCTs) have shown beneficial exercise effects on fatigue, anxiety and depression and health-related quality of life (HRQoL) in breast cancer (BC) patients during and shortly after treatment. Here, we investigated the long-term effects of exercise during chemotherapy for BC on these outcomes. We invited participants of two highly comparable RCTs that investigated the effects of exercise (EX) (versus usual care (UC)) during chemotherapy in patients with non-metastatic BC (N = 357) to participate in an 8-year follow-up. In both trials, fatigue, anxiety and depression and HRQoL were assessed using the same questionnaires, at multiple timepoints. Linear mixed-effect models were used to compare study arms over time. In total, 156 participants (EX = 82; UC = 74) completed the follow-up questionnaires. EX reported comparable general (between-group difference 0.73, 95% confidence interval (- 0.35; 1.80), ES = 0.18) and physical fatigue (0.55 (- 0.55; 1.65), ES = 0.13), small but statistically significantly higher levels of anxiety (1.24 (0.47 to 2.00), ES = 0.39) and depression (1.10 (0.34; 1.85), ES = 0.38), significantly lower global HRQoL (- 5.99 (- 10.65; - 1.32), ES = 0.34) and comparable summary HRQoL (- 1.90 (- 4.70; 0.89), ES = 0.16) compared to UC. No long-term beneficial effects of exercise during chemotherapy on BC patients' fatigue, anxiety, depression or HRQoL were observed. The less favourable outcomes for mood and HRQoL that were observed 8years after participation in an exercise intervention may be explained by selective loss-to-follow-up. The results highlight the need to incorporate strategies that promote physical activity maintenance after participation in an exercise programme to also counteract long-term detrimental side effects of cancer treatment.

Psychosocial and supportive care concerns of young women living with advanced breast cancer: baseline findings from a prospective virtual support intervention study.

Adolescent and young adults (AYAs) with metastatic breast cancer (MBC) experience high physical and psychosocial burdens compounded by a disrupted life trajectory. We sought to determine the psychosocial and supportive care concerns of this population to better understand and address unmet needs. AYAs diagnosed with MBC (18-39years) participating in a prospective interventional study (Young, Empowered, and Strong) at Dana-Farber Cancer Institute completed an electronic survey following enrollment. Measures evaluated sociodemographics, health behaviors, quality of life, and symptoms, among others. We used two-sided Fisher's exact tests to determine associations between concerns (e.g., cancer progression, side effects, lifestyle, finances, fertility) and demographic variables. Among 77 participants enrolled from 9/2020-12/2022, average age at MBC diagnosis and survey was 35.9 (range: 22-39) and 38.3years (range: 27-46), respectively. Most were non-Hispanic white (83.8%) and 40.3% reported their diagnosis caused some financial problems. Many were concerned about fertility (27.0%), long-term treatment side effects (67.6%), exercise (61.6%), and diet (54.1%). Select concerns varied significantly by age, race/ethnicity, and education. Younger women at survey reported greater concern about familial cancer risk (p = 0.028). Women from minority racial/ethnic groups more frequently reported issues talking about their cancer to family/friends (p = 0.040) while those with more education were more frequently concerned with long-term effects of cancer on their health (p = 0.021). Young women living with MBC frequently report psychosocial, health, and cancer management concerns. Tailoring supportive care and communications to address prevalent concerns including disease progression and treatment side effects may optimize wellbeing.

Abstract PO5-26-06: Understanding patient experiences to inform future studies to reduce treatment burden in breast cancer

Abstract Background Most patients with early breast cancer receive multimodality therapy, including surgery, chemotherapy, radiotherapy and endocrine therapy. Currently, not all patients benefit from the treatments they receive but many experience significant morbidities that substantially impact their quality of life. Personalised approaches to treatment offer the opportunity for patients to avoid treatments that do not offer oncological benefit without compromising breast cancer outcomes. Further studies are needed to evaluate these approaches; it is vital that future research is designed to optimise treatment benefit while remaining acceptable to patients. This survey aimed to understand experiences of patients who have received treatment for early breast cancer to inform future risk-adapted studies. Methods An online survey was co-developed with patient advocates to explore respondents’ experiences of treatments. Questions included simple demographics, treatments received and views about omitting therapies if it was safe to do so. Free-text boxes were provided for respondents to explain their decision. The survey was circulated via social media platforms from April-July 2023. Responses were summarised using simple descriptive statistics and free text was analysed thematically. Results 112 responses were received. Respondents were mostly aged 40-60 (n=88, 72.7%) and diagnosed with breast cancer between 1995 - 2023 (median 2017). Treatments received included surgery (n=107, 95.5%), radiotherapy (n=85, 75.9%), chemotherapy (n=69, 61.6%) and endocrine therapy (n=82, 73.2%). Of the 106 (94.6%) respondents who expressed a preference, 38 (35.8%) would omit chemotherapy; 34 (32.1%) would choose not to have endocrine therapy; 19 (17.9%) would prefer to avoid surgery and 11 (10.4%) would omit radiotherapy if safe to do so. Respondents opting to avoid chemotherapy highlighted the ‘brutal’ short-term side effects and their profound impact on their ability to continue with their daily lives. Hair loss was a common concern and chemotherapy was considered ‘very visible’, making them a ‘cancer patient’ in the eyes of others. Long-term effects of treatment such as peripheral neuropathy had lasting effects on respondents’ activities of daily living. Almost all respondents who would omit endocrine therapy cited the profound impact of side effects including joint/muscle pains, fatigue, hair loss, sleep disturbance and loss of libido on quality of life. Some respondents commented that the treatment itself was a daily reminder of their diagnosis. Surgery was identified as having long-term impacts on respondents’ physical and psychological well-being. Many expressed a desire to avoid ‘disfiguring’ procedures which had affected their relationships and quality of life. Respondents highlighted specific procedures they would choose to avoid including mastectomy due to the ‘trauma’ of losing a breast and axillary node clearance due to complications such as lymphoedema. Fewer women chose to avoid radiotherapy. Reasons to do so included both short and long-term side effects of treatment including chronic pain, difficulties travelling and attending for treatment over 5 weeks. Although there was generally a positive response to the concept of reducing unnecessary treatments, safety was a key concern. Several respondents commented that they would have any treatments considered necessary as survival was their ‘absolute priority’. Respondents felt that patients would need to be reassured that any reduction in treatment would not impact long-term outcomes. Conclusions This survey suggests patients would support studies aiming to reduce the burden of breast cancer treatment, and that different patients may wish to de-escalate different components of therapy. Studies developing an evidence base to allow treatment personalisation with a particular emphasis on reducing chemotherapy and endocrine therapy are research priorities. Citation Format: Shelley Potter, Mhairi MacTier, Katherine Fairhurst, Jacqui Gath, Hilary Stobart, Stuart McIntosh. Understanding patient experiences to inform future studies to reduce treatment burden in 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 PO5-26-06.

Abstract PO1-10-08: Building awareness of triple negative breast cancer: Results from the Canadian Breast Cancer Network national survey

Abstract Background: Assessing the education, information and support needs of Canadians diagnosed with breast cancer involves categorizing and tailoring topics and methods of delivery but, most importantly, it must be rooted in an understating of the patient. In 2022, the Canadian Breast Cancer Network (CBCN) initiated a project to identify the needs of the Canadian breast cancer population, determine differences between those diagnosed with triple negative breast cancer (TNBC) compared to non-TNBC patients and develop tailored, focused programs and materials as a result of the findings. Methods: CBCN conducted a series of 45-minute key informant interviews (7) with patients and oncologists to determine needs, gaps, programs, and materials for triple negative breast cancer patients in Canada. Five 90-minute patient focus groups (32 participants) were conducted to enhance the interviews. One group was specifically for metastatic patients. Findings from the interviews and focus groups were used to inform the questions for an online survey open to all Canadians diagnosed with breast cancer which was fielded May 1 to June 10, 2022. The data analysis began in September 2022 and is on-going. Results: While 47.9% of TNBC respondents (versus 51.3% of non-TNBC patients) said that they were aware of different types and subtypes of breast cancer, 70.6% of patients reported they were not aware of the term “triple-negative breast cancer” and only learned about at diagnosis. 69.9% of TNBC patients said that the person giving them their diagnosis used the term – triple-negative breast cancer. 54.5% reported being provided with specific details about their TNBC diagnosis. This included details about: the aggressive nature of TNBC (76.8%), treatments (67.6%), treatment goals (56.3%), and the urgency of beginning treatment (66.2%). TNBC patients reported that in retrospect, more information on clinical trials (41.7%), the long-term side effects of treatment (38.6%) and post-treatment follow-up (32.5%) should have been included in the discussion at diagnosis. Conclusions: Breast cancer is not a monolithic disease. TNBC impacts 10-20% of the breast cancer population. A majority of those diagnosed with TNBC in the survey were not even aware of this subtype. Building awareness of TNBC, its risk factors and different treatment needs in the public at large and among the breast cancer community could facilitate discussions with healthcare providers and assist researchers seeking new treatments and, most importantly, provide an informed voice for those with TNBC. Making the most current, evidence-based TNBC information and resources available to both patients and providers at diagnosis could build trust and understanding of the differences in treatment and follow up and instill confidence in the overall patient experience. Citation Format: Kathleen D. Swiger, Scott Richter, Bukun Adegbembo, Cathy Ammendolea. Building awareness of triple negative breast cancer: Results from the Canadian Breast Cancer Network national survey [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 PO1-10-08.

Safety and efficacy of a class II medical device based on highly purified and standardized plant extracts in the management of post-menopausal patients with vulvar and vaginal atrophy: a single-center prospective observational study.

Despite the gold standard treatment for genitourinary syndrome of menopause (GSM) is based on the use of local or systemic estrogen-containing products, the typical long-term side effects of hormonal treatments and, most importantly, the contraindications in patients with history of breast and endometrial neoplasms do limit in some extent its use. As hyaluronic acid and some highly purified botanicals have clearly demonstrated their anti-inflammatory and mucosa-protecting properties, we have tested, in women with GSM, a class II vaginal medical device containing hyaluronate gel and a mucoadhesive active enriched with purified alkylamides from Zanthoxylum bungeanum, triterpenes from Centella asiatica and high molecular weight polysaccharides from Tamarindus indica. Our single-center, open-label, prospective and observational study was conducted on 50 menopausal women enrolled at the Department of Maternal-Fetal Medicine at Umberto I Polyclinic Hospital in Rome, Italy. Gel administration lasted 150 days and was performed daily for the first 12 days and every 48 hours for the remaining 138 days. Clinical evaluations were performed at baseline and after 12, 57 and 150 days. Besides product safety, main outcomes of our study were: 1) vaginal health (by Vaginal Health Index score [VHI]); 2) sexual quality of life (by Female Sexual Distress Scale [FSDS]); and 3) percentage of women declaring regular sexual activity. The product was safe with no specific adverse events reported. It significantly improved VHI (about 5% after 57 days and 8% after 150 days), FSDS (about 7% after 57 days and 10% after 150 days), and sexual activity (about 20% after 150 days). It also reduced dryness, dyspareunia, burning, itching, and dysuria incidence, respectively by about 18%, 14%, 14%, 27% and 11% after 150 days. In women with GSM, the intravaginal administration of a hyaluronate-based gel enriched with purified botanical actives endowed with anti-inflammatory and mucosal-protecting properties, reduced painful sensation during sexual acts and increased regular sexual activity.

Increasing access to fertility preservation for women with breast cancer: protocol for a stepped-wedge cluster randomized trial in France

BackgroundWith the increase in the number of long-term survivors, interest is shifting from cancer survival to life and quality of life after cancer. These include consequences of long-term side effects of treatment, such as gonadotoxicity. Fertility preservation is becoming increasingly important in cancer management. International recommendations agree on the need to inform patients prior to treatments about the risk of fertility impairment and refer them to specialized centers to discuss fertility preservation. However, the literature reveals suboptimal access to fertility preservation on an international scale, and particularly in France, making information for patients and oncologists a potential lever for action. Our overall goal is to improve access to fertility preservation consultations for women with breast cancer through the development and evaluation of a combined intervention targeting the access and diffusion of information for these patients and brief training for oncologists.MethodsFirstly, we will improve existing information tools and create brief training content for oncologists using a qualitative, iterative, user-centred and participatory approach (objective 1). We will then use these tools in a combined intervention to conduct a stepped-wedge cluster randomized trial (objective 2) including 750 women aged 18 to 40 newly treated with chemotherapy for breast cancer at one of the 6 participating centers. As the primary outcome of the trial will be the access to fertility preservation counselling before and after using the combined intervention (brochures and brief training for oncologists), we will compare the rate of fertility preservation consultations between the usual care and intervention phases using linear regression models. Finally, we will analyse our approach using a context-sensitive implementation analysis and provide key elements for transferability to other contexts in France (objective 3).DiscussionWe expect to observe an increase in access to fertility preservation consultations as a result of the combined intervention. Particular attention will be paid to the effect of this intervention on socially disadvantaged women, who are known to be at greater risk of inappropriate treatment. The user-centred design principles and participatory approaches used to optimize the acceptability, usability and feasibility of the combined intervention will likely enhance its impact, diffusion and sustainability.Trial registrationRegistry: ClinicalTrials.gov. Trial registration number: NCT05989776. Date of registration: 7th September 2023. URL: https://classic.clinicaltrials.gov/ct2/show/NCT05989776.Protocol versionManuscript based on study protocol version 2.0, 21st may 2023.

A single-armed proof-of-concept study of Lymfit: A personalized, virtual exercise intervention to improve health outcomes in lymphoma survivors in the pandemic.

Treatments of lymphoma can lead to reduced physical functioning, cancer-related fatigue, depression, anxiety, and insomnia. These side effects can negatively impact the cancer survivor's quality of life. Mounting evidence indicates that physical activities are highly therapeutic in mitigating the short- and long-term side effects of cancer treatments. Yet, lymphoma survivors' participation in physical activities remains suboptimal, which has been further exacerbated by the deleterious effects of isolation during the COVID-19 pandemic. The Lymfit intervention aims to offer motivational support, expert guidance, and a personalized exercise prescription to optimize physical activities among lymphoma survivors. This proof-of-concept study explores implementation feasibility (retention, technical and safety), and the preliminary effects of Lymfit on various health outcomes. This was a single-armed trial with a pre-and post-test design. Twenty lymphoma survivors were recruited to participate in the 12-week Lymfit intervention. Wearable activity trackers (Fitbit) were given to participants as a motivational tool and for data collection purposes. Participants received a personalized exercise prescription designed by a kinesiologist. Physiologic metrics were collected by the Fitbit monitors and were stored in the Lymfit database. Self-reported questionnaires measuring health outcomes were collected at baseline and post-intervention. The retention rate of this trial was 70%. Minimal technical issues and no adverse effects were reported. Lymfit led to significant improvements in sleep disturbances and the ability to participate in social activities and decreased fear of cancer recurrence. It also increased daily steps and decreased sedentary time in participants who did not meet the recommended physical activity guidelines. With access to resources and fitness centers being limited during the pandemic, the Lymfit intervention filled an immediate need to provide physical activity guidance to lymphoma survivors. Findings provide preliminary support that implementing the Lymfit intervention is feasible and demonstrated promising results.

Retraction for Angelakis et al., "Abnormal Weight Gain and Gut Microbiota Modifications Are Side Effects of Long-Term Doxycycline and Hydroxychloroquine Treatment".

Retraction for Angelakis et al., "Abnormal Weight Gain and Gut Microbiota Modifications Are Side Effects of Long-Term Doxycycline and Hydroxychloroquine Treatment".

UNIQUE MICROBIOME SIGNATURES RELATED TO CANCER SURVIVORSHIP AND COGNITIVE DECLINE IN OLDER ADULTS

Abstract Significant scientific advancements have resulted in new and effective therapies for patients with cancer. Although this leads to an increased cancer survivor population, there are several long-term side effects of cancer treatments, including a high risk of developing dementia. Emerging evidence shows that the gut microbiota significantly contributes to brain health and dementia pathology; however, its role in cancer treatment-related side effects, specifically in older adults, is not well known. Here, we used 110 participants from our MiaGB (Microbiome in aging Gut and Brain) consortium aged 60 years and older and analyzed their gut microbiome (using whole genome sequencing) with cognitive function (using Montreal Cognitive Assessment (MoCA) and MiniCog). We observed an 8% increase in cognitive impairment (CI) in cancer survivors compared to non-cancer participants (46% vs 38%, respectively). When only comparing cognitively healthy versus CI, the abundance of Escherichia coli was significantly higher in the CI group, while Streptococcus thermophilus was higher in the cognitively healthy group. Additionally, the abundances of Dorea sp. CAG 317, Ruminococcus gnavus, Roseburia faecis, and Eggerthella lenta were significantly increased in the gut of cancer survivors compared to non-cancer participants. Specifically, the abundance of Dorea sp. CAG 317 was increased in cancer survivors with CI. These findings suggest that unique microbiome signatures induced by cancer treatments may impair cognitive function. Furthermore, understanding the associations between the microbiota and cognitive function in cancer survivors will aid the development of therapeutics to combat cancer treatment-related side effects, which are a growing public health concern.

Role of raloxifene in the management of postmenopausal osteoporosis of rheumatoid arthritis patients

Abstract Objective Due to the severe side effects of long-term treatment using hormone replacement therapy, Raloxifene (RLX) is introduced with beneficial effects on rheumatoid arthritis (RA) for postmenopausal women. This review was conducted to collect data from the available literature on RLX for the management of postmenopausal women suffering from RA. Method All studies published up to 2019 were searched in four databases, including Google Scholar, PubMed, Scopus, and Medline. All articles were searched using several keywords, including “Raloxifene” or “Evista” in combination with “Rheumatoid Arthritis” or “Autoimmunity”. Finally, six studies were selected for the review analysis of this study. In all studies, 60 mg/day RLX was administered for postmenopausal subjects. The majority of the studies showed that the use of RLX was effective in postmenopausal women who underwent corticosteroid therapy. No severe complications were reported after RLX therapy in patients with RA. Result Based on the obtained results, RLX is a selective estrogen receptor modulator that its short-term anti-arthritic effects are proven in the treatment of postmenopausal osteoporosis. It was well tolerated without serious adverse events. Conclusion It seems that RLX is a promising treatment candidate in postmenopausal RA due to its anti-arthritic and anti-osteoporotic effects and based on the outcomes of experimental postmenopausal arthritis in animal and human studies.

Chemotherapy-Induced Peripheral Neuropathy: Diagnosis, Agents, General Clinical Presentation, and Treatments.

This review aims to discuss pathophysiology, diagnosis, clinical presentation, and treatment of chemotherapy-induced peripheral neuropathy. Agent-specific presentation and pathophysiology is also being discussed. As new systemic oncological treatments continue to be developed, the number of cancer survivors continues to grow. Survivors are living longer with the long-term side effects of oncological treatments. We reviewed the pathophysiology of agent-specific chemotherapy-induced peripheral neuropathy and the updates in its treatment and preventative tools. Chemotherapy-induced peripheral neuropathy is a debilitating long-term side effect that often impairs cancer survivors' function and quality of life. The increasing life expectancy of cancer survivors has resulted in increased prevalence of this condition. Understanding its intricacies can provide physicians with better treatment tools and research opportunities to develop or identify new therapeutic agents.

Extended Adjuvant Endocrine Therapy in Early Breast Cancer Patients-Review and Perspectives.

Seventy percent of all breast cancer subtypes are hormone receptor-positive. Adjuvant endocrine therapy in these patients plays a key role. Despite the traditional duration of a 5-year intake, the risk of relapse remains elevated in a substantial proportion of patients. Several trials report that the risk of late recurrence is reduced by the extension of adjuvant endocrine therapy beyond 5 years. However, the optimal duration of endocrine therapy is still a matter of debate. The newer data only show a marginal benefit resulting from extension beyond 7 to 10 years. Furthermore, extension may be associated with more side effects. Thus, the adequate selection of patients qualifying for an extended adjuvant therapy is of importance. Tools/genomic tests, which include the characteristics of the patient and the tumor, may help to better identify patients with a risk of a late relapse. Taken together, the magnitude of benefit for extended adjuvant endocrine therapy is based on the precise estimation of the risk of relapse after 5 years. This must be balanced against the long-term side effects of endocrine treatment and the competing risks. For patients with an intermediate risk, 7 years appears to be the optimal duration, and in those with high-risk features, endocrine therapy up to 10 years may be considered.

Estimating transition intensity rate on interval-censored data using semi-parametric with EM algorithm approach

Phase IV clinical trials are designed to monitor long-term side effects of medical treatment. For instance, childhood cancer survivors treated with chest radiation and/or anthracycline are often at risk of developing cardiotoxicity during their adulthood. Often the primary focus of a study could be on estimating the cumulative incidence of a particular outcome of interest such as cardiotoxicity. However, it is challenging to evaluate patients continuously and usually, this information is collected through cross-sectional surveys by following patients longitudinally. This leads to interval-censored data since the exact time of the onset of the toxicity is unknown. Rai et al. computed the transition intensity rate using a parametric model and estimated parameters using maximum likelihood approach in an illness-death model. However, such approach may not be suitable if the underlying parametric assumptions do not hold. This manuscript proposes a semi-parametric model, with a logit relationship for the treatment intensities in two groups, to estimate the transition intensity rates within the context of an illness-death model. The estimation of the parameters is done using an EM algorithm with profile likelihood. Results from the simulation studies suggest that the proposed approach is easy to implement and yields comparable results to the parametric model.

Understanding the health-related quality of life and treatment-related side-effects in patients who have been in remission from testicular cancer for 12–24 months

IntroductionDespite the excellent long-term prognosis after treatment for testicular cancer (TCa), therapy-related side effects can be persistent and severe. The aim of this study was to determine the nature and prevalence of post-treatment symptoms and their impact on health-related quality of life (HRQoL) in TCa patients 12 to 24 months after treatment.Materials and methodsCross-sectional, single-center study. All patients who were aged 18 and over, had completed TCa treatment 12–24 months previously and had no evidence of disease recurrence were considered eligible. Participants were stratified into four groups: 1) orchidectomy only; 2) orchidectomy and single dose adjuvant carboplatin; 3) multi-agent induction chemotherapy (CBOP-BEP, BEPx3 or x4, or Epx4 regimens); and 4) post-chemo retroperitoneal lymph node dissection (PC-RPLND). Eligible patients were asked to complete the EQ-5D-5L questionnaire and the EORTC QLQ-TC26 questionnaire. We performed a thematic analysis of free-text commentary to evaluate the sensitivity of PROMs used across the treatment groups. Descriptive results were reported. For categorical variables, numbers and percentages were used, and for continuous variables median and IQR values were used.ResultsThe EQ-5D-5L questionnaire showed that patients treated with orchidectomy only and orchidectomy and adjuvant carboplatin experienced only minor physical medium- to long-term side-effects. In contrast, more intensive treatment regimens, such as multi-agent chemotherapy or PC-RPLND, were associated with a higher burden of medium- to long-term side-effects. Similar results were obtained with the EORTC QLQ-TC26 questionnaire.ConclusionsThis study reports the medium- to long-term HRQoL and side effects of TCa treatments, using both EQ-5D-5L and EORTC QLQ-TC26 questionnaires, and identifies possibly “unasked” questions from a patient perspective in relation to supportive care needs following TCa treatment. This information will help clinicians to better understand the consequences of treatment and in turn provide better patient counseling before treatment.

Mitochondrial DNA mutations in Medulloblastoma

To date, several studies on genomic events underlying medulloblastoma (MB) biology have expanded our understanding of this tumour entity and led to its division into four groups—WNT, SHH, group 3 (G3) and group 4 (G4). However, there is little information about the relevance of pathogenic mitochondrial DNA (mtDNA) mutations and their consequences across these. In this report, we describe the case of a female patient with MB and a mitochondriopathy, followed by a study of mtDNA variants in MB groups. After being diagnosed with G4 MB, the index patient was treated in line with the HIT 2000 protocol with no indications of relapse after five years. Long-term side effects of treatment were complemented by additional neurological symptoms and elevated lactate levels ten years later, resulting in suspected mitochondrial disease. This was confirmed by identifying a mutation in the MT-TS1 gene which appeared homoplasmic in patient tissue and heteroplasmic in the patient’s mother. Motivated by this case, we explored mtDNA mutations across 444 patients from ICGC and HIT cohorts. While there was no statistically significant enrichment of mutations in one MB group, both cohorts encompassed a small group of patients harbouring potentially deleterious mtDNA variants. The case presented here highlights the possible similarities between sequelae caused by MB treatment and neurological symptoms of mitochondrial dysfunction, which may apply to patients across all MB groups. In the context of the current advances in characterising and interpreting mtDNA aberrations, recognising affected patients could enhance our future knowledge regarding the mutations’ impact on carcinogenesis and cancer treatment.

The Price of Success-The Long-Term Outcomes of Children with Craniopharyngioma-Two Institutions' Experience.

An analysis of patients below 21 years old treated due to craniopharyngioma in the years 1979-2022 was performed with the aim of evaluating the long-term outcome and treatment side-effects. The standard statistical tests were used, and 56 patients with a median age of 11 years were evaluated. Surgery was the primary treatment in 55 patients; however, in only 29 it was the only neurosurgical intervention. Eighteen children were treated with radiotherapy (RTH) in primary treatment. The most common neurosurgical side effects observed were visual and endocrine deficits and obesity, which were diagnosed in 27 (49%), 50 (91%), and 25 (52%) patients, respectively. Complications after RTH were diagnosed in 14 cases (32%). During the median follow-up of 8.4 years (range: 0.4-39.8 years), six patients died and the 5- and 10-year overall survival was 97% and 93%, respectively. Five-year progression-free survival for gross total resection, resection with adjuvant RTH, and non-radical resection alone was 83%, 68%, and 23%, respectively (p = 0.0006). Surgery combined with RTH provides comparable results to gross tumor resection in terms of oncologic outcome in craniopharyngioma patients. Adjuvant irradiation applied in primary or salvage treatment improves disease control. The rate of complications is high irrespective of improved surgical and radiotherapeutic management.

Long-Term Use of Amoxicillin Is Associated with Changes in Gene Expression and DNA Methylation in Patients with Low Back Pain and Modic Changes.

Long-term antibiotics are prescribed for a variety of medical conditions, recently including low back pain with Modic changes. The molecular impact of such treatment is unknown. We conducted longitudinal transcriptome and epigenome analyses in patients (n = 100) receiving amoxicillin treatment or placebo for 100 days in the Antibiotics in Modic Changes (AIM) study. Gene expression and DNA methylation were investigated at a genome-wide level at screening, after 100 days of treatment, and at one-year follow-up. We identified intra-individual longitudinal changes in gene expression and DNA methylation in patients receiving amoxicillin, while few changes were observed in patients receiving placebo. After 100 days of amoxicillin treatment, 28 genes were significantly differentially expressed, including the downregulation of 19 immunoglobulin genes. At one-year follow-up, the expression levels were still not completely restored. The significant changes in DNA methylation (n = 4548 CpGs) were mainly increased methylation levels between 100 days and one-year follow-up. Hence, the effects on gene expression occurred predominantly during treatment, while the effects on DNA methylation occurred after treatment. In conclusion, unrecognized side effects of long-term amoxicillin treatment were revealed, as alterations were observed in both gene expression and DNA methylation that lasted long after the end of treatment.

Kinetic and structural studies of Mycobacterium tuberculosis dihydroorotate dehydrogenase reveal new insights into class 2 DHODH inhibition

Tuberculosis (TB) is a leading cause of death worldwide. TB represents a serious public health threat, and it is characterized by high transmission rates, prevalence in impoverished regions, and high co-infection rates with HIV. Moreover, the serious side effects of long-term treatment that decrease patient adherence, and the emergence of multi-resistant strains of Mycobacterium tuberculosis, the causing agent of TBs, pose several challenges for its eradication. The search for a new TB treatment is necessary and urgent. Dihydroorotate dehydrogenase (DHODH) is responsible for the stereospecific oxidation of (S)-dihydroorotate (DHO) to orotate during the fourth and only redox step of the de novo pyrimidine nucleotide biosynthetic pathway. DHODH has been considered an attractive target against infectious diseases. As a first step towards exploiting DHODH as a drug target against TB, we performed a full kinetic characterization of both bacterial MtDHODH and its human ortholog (HsDHDOH) using both substrates coenzyme Q0 (Q0) and vitamin K3 (K3). MtDHODH follows a ping-pong mechanism of catalysis and shares similar catalytic parameters with the human enzyme. Serendipitously, Q0 was found to inhibit MtDHODH (KI (Q0) = 138 ± 31 μM). To the best of our knowledge, Q0 is the first non-orotate like dihydroorotate-competitive inhibitor for class 2 DHODHs ever described. Molecular dynamics simulations along with in silico solvent mapping allowed us to successfully probe protein flexibility and correlate it with the druggability of binding sites. Together, our results provide the starting point for the design of a new generation of potent and selective inhibitors against MtDHODH.

Overview of radiotherapy-induced chronic pain in childhood cancer survivors: A narrative review.

Radiotherapy is an important aspect of oncological treatment in several childhood cancers. However, radiotherapy is known to have numerous side effects, including detrimental effects on growth, neurocognitive impairment, and the development of secondary malignancies. One less studied long-term side effect of pediatric radiotherapy treatment is chronic pain. While the short-term toxicities of radiotherapy resolve over a few weeks to months, the chronic pain caused by radiotherapy-induced tissue damage can significantly affect children's quality of life. As long-term childhood cancer survivors age into adulthood, they are typically followed up by a wide variety of doctors, not all of whom may be familiar with radiotherapy-induced chronic pain and its management. The aim of this review is to discuss the various common manifestations of radiotherapy-related pain in children, as well as ways to identify and manage these. Common radiotherapy-related side effects leading to chronic pain symptoms include radiation fibrosis, enteritis, dermatitis, lymphedema, neuropathic pain, and effects on bone development. The pathophysiology, evaluation and management of these are briefly summarized in this review. This is followed by an overview of radiotherapy techniques that allow greater sparing of normal tissue, minimizing future painful side effects. Finally, the assessment of pain in children is described, as well as strategies for management, and red flag symptoms that should prompt urgent specialist referral. In conclusion, a good understanding of the long-term side effects of radiotherapy treatment in children is essential for the various medical professionals that follow-up the child in the years after treatment. For young children, the evaluation of pain is in itself a challenge, and effects on growth, development, and learning are crucial. For older children, social and psychological factors become increasingly important. As radiation therapy techniques continue to advance, the spectrum and incidence of chronic pain syndromes may change over time.

Obacunone targets macrophage migration inhibitory factor (MIF) to impede osteoclastogenesis and alleviate ovariectomy-induced bone loss

IntroductionOsteoporosis is the most common bone disorder where the hyperactive osteoclasts represent the leading role during the pathogenesis. Targeting hyperactive osteoclasts is currently the primary therapeutic strategy. However, concerns about the long-term efficacy and side effects of current frontline treatments persist. Alternative therapeutic agents are still needed. ObjectivesObacunone (OB) is a small molecule with a broad spectrum of biological activities, particularly antioxidant and anti-inflammatory effects. This study aims to examine OB’s therapeutic potential on osteoporosis and explore the rudimentary mechanisms. MethodsOsteoclast formation and osteoclastic resorption assays were carried out to examine OB’s inhibitory effects in vitro, followed by the in-vivo studies of OB’s therapeutic effects on ovariectomy-induced osteoporotic preclinical model. To further study the underlying mechanisms, mRNA sequencing and analysis were used to investigate the changes of downstream pathways. The molecular targets of OB were predicted, and in-silico docking analysis was performed. Ligand-target binding was verified by surface plasmon resonance (SPR) assay and Western Blotting assay. ResultsThe results indicated that OB suppressed the formation of osteoclast and its resorptive function in vitro. Mechanistically, OB interacts with macrophage migration inhibitory factor (MIF) which attenuates receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL)-induced signaling pathways, including reactive oxygen species (ROS), NF-κB pathway, and mitogen-activated protein kinases (MAPKs). These effects eventually caused the diminished expression level of the master transcriptional factor of osteoclastogenesis, nuclear factor of activated T cells 1 (NFATc1), and its downstream osteoclast-specific proteins. Furthermore, our data revealed that OB alleviated estrogen deficiency-induced osteoporosis by targeting MIF and thus inhibiting hyperactive osteoclasts in vivo. ConclusionThese results together implicated that OB may represent as a therapeutic candidate for bone disorders caused by osteoclasts, such as osteoporosis.