Clinical Importance Research Articles

Pelvic floor symptoms according to the severity of second-degree perineal tears within 12 months post-partum: Alongitudinal prospective cohort study.

Second-degree perineal tears following vaginal birth are common and presumed to be of little clinical importance. However, the extent of damage to the perineal body varies widely, and there is reason to believe that larger second-degree tears may be associated with more pelvic floor symptoms, compared to lesser form. Therefore, the aim of this study was to assess differences in pelvic floor symptoms according to the severity of second-degree perineal tears up to 12 months post-partum, stratified by parity. This was a prospective cohort study conducted at Akershus University Hospital, a tertiary referral hospital in Norway. The study sample consisted of 409 primiparas and 394 multiparas with vaginal births. Perineal tears were classified using the classification system recommended by the Royal College of Obstetricians and Gynecologists. Further, second-degree tears were subclassified as 2A, 2B, or 2C, depending on the percentage of damage to the perineal body. Episiotomies were analyzed as a separate group. Pelvic floor symptoms were assessed using the Karolinska Symptoms After Perineal Tear Inventory (KAPTAIN). A linear mixed model was estimated to assess the trend in pelvic floor symptom scores according to perineal tear category and stratified by parity. The primary and secondary outcome measures were the mean sum scores of the KAPTAIN-Inventory, measured in pregnancy (at 18 weeks of gestation), at 3-and 12 months post-partum, and the reported impact of genital discomfort on quality of life measured in pregnancy and at 12 months post-partum. There were no significant differences in pelvic floor symptom scores over time, or at any timepoint, between no tear, first-degree tear, or second-degree tear subcategories, for primi-, and multiparas. Pelvic floor symptoms increased from pregnancy to 3 months post-partum and remained higher at 12 months post-partum compared to pregnancy in all perineal tear categories. Compared to primiparas, multiparas reported a significantly higher impact of genital discomfort on quality of life in pregnancy and at 12 months post-partum. There were no statistically significant differences in pelvic floor symptoms according to the severity of second-degree perineal tears.

A hierarchical kidney outcome using win statistics in patients with heart failure from the DAPA-HF and DELIVER trials.

Win statistics offer a new approach to the analysis of outcomes in clinical trials, allowing the combination of time-to-event and longitudinal measurements and taking into account the clinical importance of the components of composite outcomes, as well as their relative timing. We examined this approach in a post hoc analysis of two trials that compared dapagliflozin to placebo in patients with heart failure and reduced ejection fraction (DAPA-HF) and mildly reduced or preserved ejection fraction (DELIVER). The effect of dapagliflozin on a hierarchical composite kidney outcome was assessed, including the following: (1) all-cause mortality; (2) end-stage kidney disease; (3) a decline in estimated glomerular filtration rate (eGFR) of ≥57%; (4) a decline in eGFR of ≥50%; (5) a decline in eGFR of ≥40%; and (6) participant-level eGFR slope. For this outcome, the win ratio was 1.10 (95% confidence interval (CI) = 1.06-1.15) in the combined dataset, 1.08 (95% CI = 1.01-1.16) in the DAPA-HF trial and 1.12 (95% CI = 1.05-1.18) in the DELIVER trial; that is, dapagliflozin was superior to placebo in both trials. The benefits of treatment were consistent in participants with and without baseline kidney disease, and with and without type 2 diabetes. In heart failure trials, win statistics may provide the statistical power to evaluate the effect of treatments on kidney as well as cardiovascular outcomes.

Ancestry of the major long-range regulatory site of the α-globin genes in the Portuguese population with the common 3.7 kb α-thalassemia deletion

BackgroundThe α-Major Regulatory Element (α-MRE), also known as HS-40, is located upstream of the α-globin gene cluster and has a crucial role in the long-range regulation of the α-globin gene expression. This enhancer is polymorphic and several haplotypes were identified in different populations, with haplotype D almost exclusively found in African populations. The purpose of this research was to identify the HS-40 haplotype associated with the 3.7 kb α-thalassemia deletion (-α3.7del) in the Portuguese population, and determine its ancestry and influence on patients’ hematological phenotype.Methods and resultsWe selected 111 Portuguese individuals previously analyzed by Gap-PCR to detect the presence of the -α3.7del: 50 without the -α3.7del, 34 heterozygous and 27 homozygous for the -α3.7del. The HS-40 region was amplified by PCR followed by Sanger sequencing. Four HS-40 haplotypes were found (A to D). The distribution of HS-40 haplotypes and genotypes are significantly different between individuals with and without the -α3.7del, being haplotype D and genotype AD the most prevalent in patients with this deletion in homozygosity. Furthermore, multiple correspondence analysis revealed that individuals without the -α3.7del are grouped with other European populations, while samples with the -α3.7del are separated from these and found more closely related to the African population.ConclusionThis study revealed for the first time an association of the HS-40 haplotype D with the -α3.7del in the Portuguese population, and its likely African ancestry. These results may have clinical importance as in vitro analysis of haplotype D showed a decrease in its enhancer activity on α-globin gene.

Low-density lipoprotein cholesterol response to statins according to comorbidities and co-medications: a population-based study.

The response of low-density lipoprotein cholesterol (LDL-C) to statin therapy is variable, and may be affected by the presence of co-morbid conditions or the use of concomitant medications. Systematic variation in the response to statins based on these factors could affect the selection of the statin treatment regimen in population subgroups. We investigated whether common comorbidities and co-medications had clinically important effects on statin responses in individual patients. This register-based cohort study included 89,006 simvastatin or atorvastatin initiators with measurements of pre-statin and on-statin LDL-C levels, in Denmark, 2008-2018. We defined statin response as the percentage reduction in LDL-C, and used linear regression to estimate percentage reduction differences (PRD) according to 175 chronic comorbidities and 99 co-medications. We evaluated both the statistical significance (p-values corrected for multiple testing) and the clinical importance (PRD of 5 percentage points or more) of the observed associations. Concomitant use of oral blood-glucose lowering drugs, which included metformin in 96% of treated individuals, was associated with a greater response to statin therapy that was both statistically significant and clinically important, with a PRD of 5.18 (95% confidence interval: 4.79 to 5.57). No other comorbidity or co-medication reached the prespecified thresholds for a significant, clinically important effect on statin response. Overall, comorbidities and co-medications had little effect on statin response, and altogether explained only 1.7% of the total observed population variance. Most of the studied comorbidities and co-medications did not have a clinically important effect on statin response, suggesting no need to modify treatment regimens. However, use of metformin was associated with a significantly enhanced LDL-C response to statins, suggesting that lower statin doses may be effective in patients taking metformin.

Clinicopathological characteristics of mucinous carcinoma of the breast.

Objective: To highlight clinicopathological differences between Pure Mucinous Carcinoma (PMC) and Mixed Mucinous Carcinoma (MMC) of the breast. Study Design: Descriptive Retrospective study. Setting: Private Lab in Faisalabad, Pakistan. Period: January 2017 to December 2022. Methods: FNAC smears diagnosed with Mucinous Carcinoma fulfilling the inclusion and exclusion criteria were carefully examined for features such as cellularity, extracellular mucin (ECM), nuclear pleomorphism, plasmacytoid cells, macrophages, and myxovascular fragments (MVFs). The diagnosis was confirmed by histopathology and were characterized in to PMC and MMC. Immunohistochemistry slides were evaluated according to established protocols. Statistical analysis was performed using SPSS (p < 0.05). Results: The study analyzed 16 FNAC cytological samples with subsequent histopathological confirmation. These cases were derived from a pool of 712 female breast carcinoma cytology cases over a five-year duration. The predominant age group was 40 to 50 years, with the left breast and upper outer quadrant being the most common site. Distinct cytological characteristics, particularly the significant presence of extracellular mucin in PMC, were observed. Tumor grade and lymph node involvement emerged as crucial prognostic factors. MMC exhibited a high Ki-67 index, indicating increased cellular proliferation. Conclusion: Pure mucinous carcinomas (PMCs) are uncommon breast tumors with distinguished cytologic features. It is clinically and genetically distinct from mixed mucinous carcinoma (MMC) and other types of breast cancer. An important prognostic factor is lymph node involvement, and PMCs often have a low proliferation rate and a more favorable long-term prognosis. Therefore, the identification of PMC through FNAC holds significant diagnostic and clinical importance.

Initial screening for neuronal autoantibodies and their putative impact on survival in patients with small-cell lung cancer.

Small-cell lung cancer (SCLC) may be associated with neuronal autoantibodies and paraneoplastic neurological syndromes. It has been suggested that neuronal autoantibodies, especially antineuronal nuclear antibody type 1 (Hu) autoantibodies, are associated with longer survival of patients with SCLC. The objective of this study was to determine the frequency and distribution of neuronal autoantibodies at the time of diagnosis of SCLC patients and assess survival rates in relation to autoimmunity. In this retrospective study, serum from 40 patients with biopsy-proven SCLC at the time of diagnosis was studied prior to treatment. The sera originated from a cancer registry at the Oncology Department, Vejle Hospital from 2007 to 2010. The sera were analyzed blindly to clinical status for the presence of neuronal autoantibodies. Medical records were reviewed for neurological symptoms. Neuronal autoantibodies were detected in 22/40 (55%) of the SCLC patients. A broad range of neurological symptoms was recorded in 28/40 (70%) patients, of which 14/28 (50%) were positive for neuronal autoantibodies. The most frequently detected autoantibodies were Hu (7/40, 17.5%) followed by GAD65 (6/22, 15.0%). Striational and P/Q- or N-type voltage-gated calcium channel antibodies were less common, with each found in five patients (12.5%). Eight patients (20%) had coexisting autoantibodies. Autoantibody-positivity was not associated with survival. Neuronal autoantibodies were at time of diagnosis found in approximately half of the treatment-naïve SCLC patients. Neither autoantibody positivity at diagnosis nor neurological manifestations correlated with survival and their clinical importance requires further studies in larger, prospective cohorts.

The impact of maxillary dimensions on determining surgical approach of fungal ball in the maxillary sinus

Endoscopic middle meatal antrostomy (MMA) is commonly used for maxillary sinus (MS) fungal ball removal. For challenging cases involving anterior or inferior recess, an additional inferior meatal approach (IMA) might be needed. We analyzed the differences in MS dimensions on CT scans according to the surgical approach to suggest preoperative variables that could facilitate an additional IMA. CT scans of 281 adult patients who underwent ESS for the MS fungal ball (139 MMA, 62 MMA & IMA) were evaluated for comparative analysis of 8 MS measurements based on the surgical approach. Complete removal was achieved in all cases. Age and sex didn't differ significantly (p > 0.05). The maximum distances between the anterior–posterior walls, the inferior ostium border to the lateral recess, and the ostium to the inferior wall of the MS were statistically greater in the MMA & IMA group compared to the MMA group (p = 0.003, p = 0.005, and p = 0.010, respectively), especially among females. This study underscores the clinical importance of specific measurements—anterior to posterior wall, medial wall to lateral recess, and ostium to inferior wall of the maxillary sinus—for guiding optimal surgical approaches in MS lesions.

Clinical Importance of the First Trimester Uterine Artery Doppler Measurements in Patients with Hyperemesis Gravidarum

Clinical Importance of the First Trimester Uterine Artery Doppler Measurements in Patients with Hyperemesis Gravidarum

Estrogen Signals through ERβ in Breast Cancer; What We Have Learned since the Discovery of the Receptor

Estrogen receptor (ER) β (ERβ) is the second ER subtype that mediates the effects of estrogen in target tissues along with ERα that represents a validated biomarker and target for endocrine therapy in breast cancer. ERα was the only known ER subtype until 1996 when the discovery of ERβ opened a new chapter in endocrinology and prompted a thorough reevaluation of the estrogen signaling paradigm. Unlike the oncogenic ERα, ERβ has been proposed to function as a tumor suppressor in breast cancer, and extensive research is underway to uncover the full spectrum of ERβ activities and elucidate its mechanism of action. Recent studies have relied on new transgenic models to capture effects in normal and malignant breast that were not previously detected. They have also benefited from the development of highly specific synthetic ligands that are used to demonstrate distinct mechanisms of gene regulation in cancer. As a result, significant new information about the biology and clinical importance of ERβ is now available, which is the focus of discussion in the present article.

The influence of trinucleotide repeats in the androgen receptor gene on androgen-related traits and diseases.

Trinucleotide repeats in the androgen receptor have been proposed to influence testosterone signaling in men, but the clinical relevance of these trinucleotide repeats remains controversial. To examine how androgen receptor trinucleotide repeat lengths affect androgen-related traits and disease risks and whether they influence the clinical importance of circulating testosterone levels. We quantified CAG and GGC repeat lengths in the androgen receptor (AR) gene of European-ancestry male participants in UK Biobank from whole-genome and whole-exome sequence data using ExpansionHunter, and tested associations with androgen-related traits and diseases. We also examined whether the associations between testosterone levels and these outcomes were affected by adjustment for the repeat lengths. We successfully quantified the repeat lengths from whole-genome and/or whole-exome sequence data in 181,217 males. Both repeat lengths were shown to be positively associated with circulating total testosterone level and bone mineral density, whereas CAG repeat length was negatively associated with male-pattern baldness, but their effects were relatively small and were not associated with most of the other outcomes. Circulating total testosterone level was associated with various outcomes, but this relationship was not affected by adjustment for the repeat lengths. In this large-scale study, we found that longer CAG and GGC repeats in the AR gene influence androgen resistance, elevate circulating testosterone level via a feedback loop and play a role in some androgen-targeted tissues. Generally, however, circulating testosterone level is a more important determinant of androgen action in males than repeat lengths.

Abstract PO3-19-12: Evaluating the impact of ePRO-based follow-up system (Pink Ribbon Diary) on quality of life and treatment adherence in patients with breast cancer receiving CDK4/6 inhibitors: a single center, randomized controlled study (JPRO-B)

Abstract Background: Treatment-related toxicities (TRT) may decrease patient’s quality of life (QOL) and may result in a decrease of adherence to the therapy. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), such as palbociclib (PAL) and abemaciclib (ABM) improved patients’ outcomes with estrogen receptor-positive (ER+) HER2 negative (HER2-) advanced breast cancer (ABC), however, majority of patients who undergo CDK4/6i therapy experience ≥ Grade 2 TRTs, such as hematological abnormalities, gastrointestinal disorders or general fatigue. While prompt management of those TRTs is mandatory to prevent patients from discontinuing the therapy, real-time monitoring of TRTs has been warranted. Recently, efforts have been made to monitor symptoms using electronic patient-reported outcome (ePRO) to detect side effects as early as possible and to provide timely support. However, the efficacy of ePRO in daily clinical practice for those receiving CDK4/6is is still unclear. In addition, the researches in the field of ePRO to date have only focused on drugs administered intravenously in hospitals, where patients’ adherence has no clinical importance. Study design and eligibility criteria: This randomized, open-label, controlled phase 2 trial is designed to assess the efficacy of a new proprietary ePRO system, the Pink Ribbon Diary (PRD), compared with placebo (usual care without the ePRO system) in breast cancer patients with ER+HER2-ABC receiving oral CDK4/6i-based therapy aged ≥ 20 years. All eligible patients who complete training on how to use ePRO system are randomly allocated to either arm A using ePRO system or arm B receiving usual care (1:1). Participants in the arm A are required to record medication taken and physical condition every day for 3 months, and report adverse events using PRO-CTCAETM once a week. Patients in the arm B are also asked to answer to questions concerning adverse events using PRO-CTCAETM at monthly hospital visit for 3 months. All participants are asked to respond to the EORTC QLQ-C30 at their monthly visit and a questionnaire survey on adherence before the study and after completion of the study. Participants in the arm A and healthcare providers, will answer the questionnaire about the feeling of using the PRD. Primary endpoint is the change in global health status/QOL (EORTC QLQ-C30) at 3 months from baseline. Secondary endpoints are RDI (relative dose intensity), other domains of EORTC QLQ-C30, number of days missed medication, PDC (proportion of days covered), survey of medication compliance awareness using MMAS-8 (Morisky Medication Adherence Scale), questionnaire on use of PRD, and comparison between two groups of occurrence of adverse events and incidence of missed medication. Study objective: To assess the clinical efficacy of PRD in patients with ER+HER2-ABC undergoing CDK4/6i-based therapy. Statistical methods: For analysis of QOL, the primary endpoint, the differences in global health status/QOL (EORTC QLQ-C30) before and after the study will be compared between the two groups using the t-test. Present accrual and target accrual: The study was approved by institutional review board in December 2022, and is open for enrollment. The target sample size is 70. The study is on-going and 22 patients have been accrued to date. Trial registration numbers: Japan Registry of Clinical Trials (jRCT) jRCT1030220626 (https://jrct.niph.go.jp/re/reports/detail/30182). Citation Format: Rie Ozeki, Hideo Shimizu, Kotaro Iijima, Misato Okazaki, Junichiro Watanabe, Mitsue Saito. Evaluating the impact of ePRO-based follow-up system (Pink Ribbon Diary) on quality of life and treatment adherence in patients with breast cancer receiving CDK4/6 inhibitors: a single center, randomized controlled study (JPRO-B) [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 PO3-19-12.

Abstract PO3-03-11: Receptor discordance after neoadjuvant chemotherapy with pembrolizumab in early-stage triple-negative breast cancer

Abstract Background: Discordance in hormone receptor (HR) and/or HER2 status between matched primary tumors and residual specimens following neoadjuvant therapy is a known phenomenon. In the neoadjuvant setting, systemic treatment is primarily informed by the HR and HER2 status from the diagnostic biopsy. Current guidelines recommend additional adjuvant capecitabine and/or pembrolizumab and/or olaparib for patients with triple-negative breast cancer (TNBC) after neoadjuvant systemic therapy if residual disease is present at the time of surgery. Discordance in biomarker status between the initial diagnosis and residual cancer may impact postoperative systemic therapy recommendations. This study aims to investigate the discordance rate in HR and HER2 status after neoadjuvant chemotherapy (NAC) plus pembrolizumab in early-stage TNBC. Furthermore, given the emerging data in support of novel antibody-drug conjugates (ADCs) for HER2-low breast cancer, the prevalence of HER2-low disease following standard-of-care neoadjuvant therapy may have critical clinical importance. Methods: We performed a single-institution, retrospective study of early-stage TNBC patients diagnosed between February 1st, 2020 and December 1st, 2022 who were treated with neoadjuvant chemotherapy and pembrolizumab. Patients who had not undergone definitive surgery were excluded. Demographic information, clinical and pathologic characteristics, and treatment data were collected from an institutional database. Pathologic complete response (pCR) was defined as ypT0/Tis and ypN0. HR and HER2 status before and after neoadjuvant therapy were collected. This study was approved by an Institutional Review Board. Results: Among the 94 patients included the median age was 55 years (IQR 47.0-61.8). The majority of patients had invasive ductal carcinomas (90.4%), were clinical T2 stage (68.1%), and node negative (55.3%). On the core tumor biopsy, estrogen receptor (ER) was < 1% in 90 (95.7%) patients and 1-10% in 4 (4.3%) of patients. Progesterone receptor (PR) was < 1% in 91 (96.8%) of patients and 1-10% in 3 (3.2%) of patients. HER2 was 0 by IHC in 49 (52.1%) patients, 1+ in 30 (31.9%) patients, 2+ in 11 (11.7%) patients, and not performed in 4 (4.3%) patients. A pCR (ypT0/Tis ypN0) was achieved in 60 (63.8%) of the 94 patients. In the 34 patients with residual disease, 29 patients had ER status evaluated at the time of surgery. Of these patients, 4 had tumors with ER < 1% at baseline but >5% at surgery. 28 patients with residual disease had PR evaluated at the time of surgery. Of these patients, all had tumors with PR < 1% at the time of surgery. 28 patients had residual tumors with HER2 status evaluated at the time of surgery (table). Of these patients, 18 (64.3%) tumor specimens were HER2-ultra-low, 9 (32.1%) were HER2-low-positive, and 1 (3.6%) was HER2-positive. Conclusion: Receptor discordance from the time of initial biopsy to residual disease can occur in patients with early-stage TNBC treated with NAC with pembro. As additional systemic therapy is indicated in patients who do not achieve pCR, accurate tumor marker status is critical. This study highlights the potential impact of reassessment of HR and HER2 status on the surgical tumor specimen. Clinical trials that tailor adjuvant therapy recommendations based on residual biomarker analyses may further improve outcomes for women with high risk TNBC. Table. Discordance in HER2 Status Between Primary Tumor and Residual Specimen Citation Format: Alexis LeVee, Megan Wong, Sarah Flores, Nora Ruel, Heather McArthur, James Waisman, Joanne Mortimer. Receptor discordance after neoadjuvant chemotherapy with pembrolizumab in early-stage triple-negative 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 PO3-03-11.

Abstract PO4-05-06: Hormone receptor-positive HER2-low metastatic breast cancer (mBC): evolution of HER2 status after CDK4/6 inhibitor treatment

Abstract Background Trastuzumab deruxtecan (T-DXd) is approved for HER2-low but not HER2-0 mBC. Therefore, identifying HER2-low status is of great clinical importance. Prior studies have shown HER2-low status is dynamic between primary tumor and metastatic relapse and between primary tumor and post-neoadjuvant chemotherapy residual tumor, and expert recommendations are to reiterate biopsies throughout the course of the disease. However, there is no data on when to repeat these biopsies. We provide here the first data on the evolution of HER2-low status in hormone receptor-positive (HR+) mBC before and after endocrine therapy (ET) in association with CDK4/6 inhibitor (CDK4/6i). Methods: Patients with pre-CDK4/6i+ET tumor biopsy were identified from a single large academic center database. Patients with unknown HER2 status were excluded. Pathological, clinical, and demographic data were extracted from clinical files. HER2-low was defined as HER2 IHC 1+, or 2+ with non-amplified HER2 by ISH, and HER2-0 by IHC score of 0+. Pathology central review for all paired pre- and post-treatment biopsies was performed by three expert breast cancer pathologists. Results: 304 consecutive patients with HR+/HER2- mBC treated with CDK4/6i+ET and who had immediate pre-treatment biopsy were included. Of these, 117 (38%) were HER2-0, and 187 (62%) were HER2-low. Clinical and demographic data did not differ between both groups. Patients received CDK4/6i+ET as first-line treatment in 48% of cases. Among this cohort, 49 patients had paired biopsies immediately after CDK4/6i+ET treatment. The discordance rate between pre- and post-CDK4/6i+ET HER2-status was 51% with 64% of HER2-0 patients becoming HER2-low and 38% of HER2-low switching to HER2-0. Among the 49 patients with paired biopsies, 43 had available material to perform a central pathology review. Of these, 22 (51%) were HER2-0, and 21 (49%) were HER2-low. Central pathology review showed a concordance level of 82% with pathology records, resulting in a modification of HER2 status in 7 HER2-0 patients as HER2-low, leading to a total of 65% of patient’s eligibility to T-DXd. Post-CDK4/6i+ET biopsy identified a switch to HER2-low in 10 additional HER2-0 patients resulting in a total of 38/43 (88%) candidates to T-DXd. No case became HER2 3+ after treatment. Neither baseline HER2 status, nor change in HER2 status after treatment affected the clinical outcome on CDK4/6i+ET (objective response, progression-free survival, overall survival). Conclusion: HER2-low status is dynamic, and 64% of mBC HER2-0 patients switched to HER2-low after a line of CDK4/6i+ET treatment. Since such a switch would guide post-progression treatment with T-DXd in patients initially not candidate, these results suggest that biopsy should be repeated early in the course of mBC to assess eligibility for T-DXd therapy. Our central pathology review of pre-treatment biopsies reclassified 24% of HER-0 patients as HER2-low, suggesting that pathology review is a legitimate first step before repeating biopsy or in the case of difficulty to re-biopsy. In our series, 88% of patients had a biopsy sample classified as HER2-low after pathological review of pre-treatment slides, followed by post-CDK4/6i+ET rebiopsy of HER2-0 cases. Citation Format: Alexandre de Nonneville, Pascal Finetti, Laurys Boudin, Lucas Usclade, Lenaïg Mescam, Emeline Durieux, Agathe Boucraut, Frederic Viret, Emilie Mamessier, Anthony Gonçalves, François Bertucci. Hormone receptor-positive HER2-low metastatic breast cancer (mBC): evolution of HER2 status after CDK4/6 inhibitor treatment [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 PO4-05-06.

THE SMALLEST WORTHWHILE EFFECT OF EXERCISE THERAPY FOR PEOPLE WITH CHRONIC LOW BACK PAIN: A DISCRETE CHOICE EXPERIMENT STUDY

INTRODUCTION Understanding the magnitude of treatment effect patients need to see to consider a treatment worthwhile is of clear clinical and research importance. Current measures of clinical importance, such as the minimum clinical important difference, are limited as they are not determined by patients, and do not reflect specific costs, risks or inconveniences of individual treatments, i.e. you could have the same MCID for surgery as for exercise. We aimed to identify the smallest worthwhile effect (SWE), a new measure of clinical importance, of exercise therapy for people with non-specific chronic low back pain (CLBP) using discrete choice experiment. METHODS The SWE was estimated as the lowest reduction in pain that participants would consider exercising worthwhile, compared to not exercising i.e., effects due to natural history and other components (e.g., regression to the mean). We recruited English-speaking adults in Australia with non-specific CLBP to our online survey via email from a registry of previous participants and advertisements on social media. We used discrete choice experiment to estimate the SWE of exercise compared to no exercise for pain intensity. We analysed the discrete choice experiment using a mixed logit model, and mitigated hypothetical bias through certainty calibration, with sensitivity analyses performed with different certainty calibration thresholds. RESULTS 213 participants completed the survey. Mean age (±SD) was 50.7±16.5, median (IQR) pain duration 10 years (5-20), and mean pain intensity (±SD) was 5.8±2.3 on a 0-10 numerical rating scale. For people with CLBP the SWE of exercise was a between-group reduction in pain of 20%, compared to no exercise. This means, for a baseline pain of 5, the SWE would be a 1/10 between-group reduction in pain. CONCLUSION This patient-informed threshold of clinical importance should guide the interpretation of findings from randomised trials and meta-analyses of exercise therapy compared to no exercise.

Three-dimensional architecture and moment arms of human rotator cuff muscles invivo: Interindividual, intermuscular, and intramuscular variations.

The human rotator cuff consists of four muscles, each with a complex, multipennate architecture. Despite the functional and clinical importance, the architecture of the human rotator cuff has yet to be clearly described in humans invivo. The purpose of this study was to investigate the intramuscular, intermuscular, and interindividual variations in architecture and moment arms of the human rotator cuff. Muscle volumes, fascicle lengths, physiological cross-sectional areas (PCSAs), pennation angles, and moment arms of all four rotator cuff muscles were measured from mDixon and diffusion tensor imaging (DTI) scans of the right shoulders of 20 young adults. In accordance with the most detailed dissections available to date, we found substantial intramuscular variation in fascicle length (coefficients of variation (CVs) ranged from 26% to 40%) and pennation angles (CVs ranged from 56% to 62%) in all rotator cuff muscles. We also found substantial intermuscular and interindividual variations in muscle volumes, but relatively consistent mean fascicle lengths, pennation angles, and moment arms (CVs for all ≤17%). Moreover, when expressed as a proportion of total rotator cuff muscle volume, the volumes of individual rotator cuff muscles were highly consistent between individuals and sexes (CVs ≤16%), suggesting that rotator cuff muscle volumes scale uniformly, at least in a younger population without musculoskeletal problems. Together, these data indicate limited interindividual and intermuscular variability in architecture, which may simplify scaling routines for musculoskeletal models. However, the substantial intramuscular variation in architecture questions the validity of previously reported mean architectural parameters to adequately describe rotator cuff function.

Uptown Squirrel Does Not Eat That.

This essay plays out a few ethics reasons we have to reconsider what's really being marketed to us in some free offers that distract us from questions of ethical, cultural, and clinical importance, for example. Possible points of focus for bioethics as a field are related to antimicrobial resistance and stewardship.

NIO-1, a novel inhibitor of OCT1, enhances the antitumor action of radiofrequency ablation against hepatocellular carcinoma.

Radiofrequency ablation (RFA) is an important treatment strategy for patients with advanced hepatocellular carcinoma (HCC). However, its therapeutic effect is unsatisfactory and recurrence often occurs after RFA treatment. The octamer-binding transcription factor OCT1 is a novel tumour-promoting factor and an ideal target for HCC therapy. This study aimed to expand the understanding of HCC regulation by OCT1. The expression levels of the target genes were examined using qPCR. The inhibitory effects of a novel inhibitor of OCT1 (NIO-1) on HCC cells and OCT1 activation were examined using Chromatin immunoprecipitation or cell survival assays. RFA was performed in a subcutaneous tumour model of nude mice. Patients with high OCT1 expression in the tumour tissue had a poor prognosis after RFA treatment (n = 81). The NIO-1 showed antitumor activity against HCC cells and downregulated the expression of the downstream genes of OCT1 in HCC cells, including those associated with cell proliferation (matrix metalloproteinase-3) and epithelial-mesenchymal transition-related factors (Snail, Twist, N-cadherin, and vimentin). In a subcutaneous murine model of HCC, NIO-1 enhanced the effect of RFA treatment on HCC tissues (n = 8 for NIO-1 and n=10 for NIO-1 + RFA). This study demonstrated the clinical importance of OCT1 expression in HCC for the first time. Our findings also revealed that NIO-1 aids RFA therapy by targeting OCT1.

Integration of clinical phenoms and metabolomics facilitates precision medicine for lung cancer

Lung cancer is a common malignancy that is frequently associated with systemic metabolic disorders. Early detection is pivotal to survival improvement. Although blood biomarkers have been used in its early diagnosis, missed diagnosis and misdiagnosis still exist due to the heterogeneity of lung cancer. Integration of multiple biomarkers or trans-omics results can improve the accuracy and reliability for lung cancer diagnosis. As metabolic reprogramming is a hallmark of lung cancer, metabolites, specifically lipids might be useful for lung cancer detection, yet systematic characterizations of metabolites in lung cancer are still incipient. The present study profiled the polar metabolome and lipidome in the plasma of lung cancer patients to construct an inclusive metabolomic atlas of lung cancer. A comprehensive analysis of lung cancer was also conducted combining metabolomics with clinical phenotypes. Furthermore, the differences in plasma lipid metabolites were compared and analyzed among different lung cancer subtypes. Alcohols, amides, and peptide metabolites were significantly increased in lung cancer, while carboxylic acids, hydrocarbons, and fatty acids were remarkably decreased. Lipid profiling revealed a significant increase in plasma levels of CER, PE, SM, and TAG in individuals with lung cancer as compared to those in healthy controls. Correlation analysis confirmed the association between a panel of metabolites and TAGs. Clinical trans-omics studies elucidated the complex correlations between lipidomic data and clinical phenotypes. The present study emphasized the clinical importance of lipidomics in lung cancer, which involves the correlation between metabolites and the expressions of other omics, ultimately influencing clinical phenotypes. This novel trans-omics network approach would facilitate the development of precision therapy for lung cancer.Graphical 1. Integrating multiple biomarkers or trans-omics results improves diagnostic accuracy and reliability in heterogeneous lung cancer.2. Metabolomics and lipidomics, along with clinical phenotypes, construct a comprehensive metabolic profile of lung cancer patients.3. TAG expression shows strong positive correlation with polar metabolites, potentially impacting clinical phenotypic changes in lung cancer patients.

Canine leishmaniasis in the Americas: etiology, distribution, and clinical and zoonotic importance.

Canine leishmaniasis is a widespread disease on the American continent, with cases reported from Uruguay to the USA and Canada. While numerous Leishmania spp. have been reported in dogs in this region, Leishmania infantum and Leishmania braziliensis are the most common etiological agents of canine leishmaniasis from a continental perspective. Nonetheless, other species may predominate locally in some countries. The participation of dogs in the transmission cycle of various Leishmania spp. has long been speculated, but evidence indicates that their role as reservoirs of species other than L. infantum is negligible. Various native wildlife (e.g., small rodents, marsupials, sloths, and monkeys) are, in fact, the primary hosts of Leishmania spp. in the Americas. In this review, an updated list of Leishmania spp. infecting dogs in the Americas is presented, along with their distribution and clinical and zoonotic importance.

Novel multiplex-PCR test for Escherichia coli detection.

Detection of E. coli from environmental or clinical samples is important due to the common occurrence of this species of bacteria in all human and animal environments. As commonly known, these bacteria strains can be commensal and pathogenic, causing numerous infections of clinical importance, including infections of the digestive system, urinary, respiratory, and even meninges, particularly dangerous for newborns. The developed multiplex polymerase chain reaction test, confirming the presence of E. coli in samples, can be used in many laboratories. The test provides new opportunities for quick and cheap analyses, detecting E. coli using only three pairs of primers (analysis of the presence of three genes) responsible for metabolism and distinguishing E. coli from other pathogens from the Enterobacteriaceae family. Compared to other tests previously described in the literature, our method is characterized by high specificity and sensitivity.