Goniotomy Viable Option for Glaucoma Patients with Previous Surgical Failure

A recent study has shed light on the promising role of goniotomy (GT) as a potential solution for individuals facing glaucoma recurrence after prior unsuccessful surgeries. The study was published in The Journal Of Glaucoma by Lin and colleagues. This innovative approach, evaluated through a prospective multicenter study, offers hope for improved outcomes and better management for this challenging condition.

Researchers conducted a comprehensive investigation on patients who underwent GT following one or multiple previous surgeries for glaucoma. The study aimed to assess the efficacy and safety of GT over 12 months, focusing on several critical outcome measures, including intraocular pressure (IOP) changes, visual acuity improvements, medication usage, and occurrence of adverse events.

  • Their findings, based on 38 eyes of 34 patients, revealed encouraging results. A significant proportion of eyes achieved success post-GT: complete success was observed in 42.1% of the eyes, meeting the criteria of a postoperative IOP within 6–18 mmHg with a 20% reduction from baseline, without the need for ocular hypotensive medications.

  • Additionally, 78.9% of the eyes attained qualified success, aligning with the criteria but allowing for postoperative medication use. Prior to the procedure, patients exhibited high baseline IOP levels, with a mean of 29.4±6.9 mmHg, which significantly decreased to 16.7±3.6 mmHg (a remarkable 43.2% reduction; P<0.001) by the 12-month mark post-surgery.

  • The median number of glaucoma medications used also saw a substantial decrease, from a preoperative median of 3.0 to 2.0 at month 12 (P<0.001).

  • While demonstrating promise, the study did note some associated complications post-GT, with common occurrences including hyphema (13.2%), IOP spike (7.9%), and corneal edema (5.2%). Notably, older age emerged as a contributing factor to surgical success.

This study’s conclusions strongly support the efficacy and safety of GT as a viable intervention for individuals facing recurrent glaucoma despite prior unsuccessful surgeries. The findings hold promise for patients seeking alternatives in managing this challenging condition

The insights gained from this research could significantly impact clinical practice, offering a potential solution for those with a history of unsuccessful glaucoma surgeries. The study encourages further exploration and adoption of GT, providing renewed hope for better outcomes in managing this complex ophthalmologic condition.

Reference:

Lin, F., Nie, X., Shi, J., Song, Y., Lv, A., Li, X., Lu, P., Zhang, H., Jin, L., Tang, G., Fan, S., Weinreb, R. N., & Zhang, X. Safety and efficacy of goniotomy following failed surgery for glaucoma. Journal of Glaucoma,2023;32(11):942–947. https://doi.org/10.1097/ijg.0000000000002301

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Treatment with cyclobenzaprine sublingual tablets may reduce pain in fibromyalgia patients

Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a biopharmaceutical company with marketed products and a pipeline of development candidates, today announced that the Phase 3 RESILIENT study evaluating TNX-102 SL (cyclobenzaprine HCl sublingual tablets) met its pre-specified primary endpoint in the second of two positive Phase 3 clinical trials, significantly reducing daily pain compared to placebo (p=0.00005) in participants with fibromyalgia (Table 1). Statistically significant and clinically meaningful results were also seen in all key secondary endpoints related to improving sleep quality, reducing fatigue, and improving overall fibromyalgia symptoms and function. Additionally, as it relates to improving daily pain, treatment with TNX-102 SL showed a robust and clinically meaningful analgesic effect size of 0.38, with rapid onset of action, separating from placebo for each week of the study. TNX-102 SL was well tolerated with an adverse event profile comparable to prior studies, and no new safety signals were observed. Tonix plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the second half of 2024 for TNX-102 SL for the management of fibromyalgia. An estimated 6 million to 12 million U.S. adults are living with fibromyalgia, the majority of whom are women.

TNX-102 SL is a tablet formulation containing 2.8 mg cyclobenzaprine HCl and is a novel, centrally-acting, non-opioid analgesic, designed to be taken once daily at bedtime for the management of fibromyalgia. RESILIENT was a 14-week randomized, double-blind, placebo-controlled trial of TNX-102 SL 5.6 mg, in which 457 participants with fibromyalgia were randomized in a 1:1 ratio to TNX-102 SL or placebo across 33 sites in the U.S. All participants received one 2.8 mg tablet of TNX-102 SL (2.8 mg) or placebo for the first 2 weeks, which was increased to two 2.8 mg tablets of TNX-102 SL (5.6 mg) or placebo for the remaining 12 weeks.

In December 2020, Tonix reported positive results from the first Phase 3 RELIEF study of TNX-102 SL 5.6 mg for the management of fibromyalgia. The RELIEF study met its pre-specified primary endpoint, significantly reducing daily pain compared to placebo (p=0.010) in participants with fibromyalgia, and showing activity in key secondary endpoints.

“We believe that the positive results of RESILIENT and RELIEF show that fibromyalgia can be successfully treated by TNX-102 SL 5.6 mg and may provide the opportunity for Tonix to have the first FDA-approved drug for fibromyalgia in more than a decade,” said Seth Lederman, M.D., President and Chief Executive Officer of Tonix Pharmaceuticals. “We are now an important step closer to bringing a new, first-line treatment to fibromyalgia patients that offers broad symptom relief and favorable tolerability for chronic use and adherence. We believe that we are well positioned to submit an NDA to the FDA under the 505(b)(2) regulatory approval pathway in the second half of 2024, and are on track to supply the U.S. market upon FDA approval.”

Abbreviations: FIQ-R = Fibromyalgia Impact Questionnaire – Revised; NRS = Numeric Rating Scale; PROMIS = Patient-Reported Outcomes Measurement Information System

*Statistically significant; to control for overall type 1 error, a pre-specified, serial gatekeeping procedure was utilized.

1Analysis by mixed model repeated measures with multiple imputation unless otherwise indicated.

2Primary endpoint analysis for FDA approvals of Cymbalta® and Lyrica® in fibromyalgia.

3Pearson’s chi-squared test responder analysis, with missing data considered non-responders

“These data are terrific news for patients with fibromyalgia,” said Daniel J. Clauw, M.D., Professor of Anesthesiology, Medicine and Psychiatry at the University of Michigan. “Despite approved medications, there remains a need for new treatment options to better address the quality of life impacts many fibromyalgia patients experience on a chronic basis. TNX-102 SL is a non-opioid, centrally-acting analgesic, the active ingredient of which has a known, favorable safety profile from decades of use. The fact that cyclobenzaprine was also beneficial in many other key symptom domains, including sleep quality, sleep disturbance and fatigue, will be appreciated by fibromyalgia patients that struggle with not just pain but multiple other symptoms.”

“These positive data from RESILIENT and previously with RELIEF, with remarkable separation from placebo on pain, sleep, and fatigue, add support to TNX-102 SL’s proposed mechanism of improving sleep quality to improve the syndromal effects of fibromyalgia,” commented Gregory Sullivan, M.D., Chief Medical Officer of Tonix Pharmaceuticals. “The sublingual formulation of TNX-102 SL, which uses our proprietary Protectic® and Angstro® technologies, is integral to our treatment paradigm. These technologies enable transmucosal delivery of cyclobenzaprine with distinctive pharmacokinetic properties that include rapid absorption after dosing and bypass of first-pass hepatic metabolism. I would like to thank the RESILIENT study participants and their families and caregivers, as well as the investigators and their hard-working staff who all made this a highly successful trial.”

Summary of Topline Results of the RESILIENT Study

The RESILIENT study achieved statistical significance on the pre-specified primary efficacy endpoint: change from baseline in the weekly average of daily diary pain severity numerical rating scale (NRS) scores for TNX-102 SL 5.6 mg (LS mean [SE]: -1.8 [0.12] units) versus placebo (-1.2 [0.12] units), analyzed by mixed model repeated measures with multiple imputation (LS mean [SE] difference: -0.7 [0.16] units, p=0.00005, Table 1). In addition, all pre-specified sensitivity analyses of the primary endpoint were statistically significant (p<0.001). Figure 1 shows reduction in pain across all weeks of the 14-week study, with nominal p<0.01 for every week. Note the rapid onset of action with separation from placebo at Week 1 was sustained throughout all weeks of dosing.

Abbreviations: LS = least squares; NRS = numerical rating scale; SE = standard error

The statistically significant improvement in pain is further substantiated when diary pain was analyzed by another standard statistical approach, a 30 percent responder analysis, with 45.9% on active and 27.1% on placebo having a 30 percent or greater reduction in pain (Pearson Chi-Squared Test; difference in proportions [95% CI]: 18.8% [10.1%, 27.4%]; nominal p<0.001).

TNX-102 SL showed statistical significance (p≤0.001) on all six pre-specified key secondary efficacy outcome measures (Table 1).

Consistent with the proposed mechanism that TNX-102 SL acts in fibromyalgia through improving sleep quality, TNX-102 SL showed statistically significant improvement of sleep by two main measures. For the daily diary sleep quality ratings, improvement in sleep quality for TNX-102 SL (-1.8 [0.12] units) was significantly greater than that of placebo (-1.2 [0.12] units; LS mean [SE] difference from placebo: -0.6 [0.17] units; p<0.001). For the PROMIS Sleep Disturbance instrument, TNX-102 SL also demonstrated significantly greater improvement over placebo on T-scores (LS mean [SE] difference from placebo: -4.2 [0.79] units; p<0.001). Fatigue is another cardinal symptom of fibromyalgia and has a major impact on quality of life. TNX-102 SL showed significant improvement over placebo on the PROMIS Fatigue instrument T-scores (-3.0 [0.77] units; p<0.001).

The Fibromyalgia Impact Questionnaire – Revised (FIQ-R) is a 21-item self-rated instrument that assesses level of function, overall impact, and symptoms due to fibromyalgia, and the symptoms and function domains were key secondary endpoints in RESILENT. At Week 14 on the FIQ-R Symptoms domain, there was significantly greater improvement with TNX-102 SL than with placebo (LS mean [SE] difference from placebo: -7.7 [1.62], p<0.001). Similarly, TNX-102 SL resulted in greater improvement on FIQ-R Function (LS mean [SE] difference from placebo: -5.4 [1.66], p=0.001). Although not a key secondary efficacy endpoint, TNX-102 SL also separated from placebo on the FIQ-R Impact domain (nominal p=0.001). These results, along with the robust effects on improving sleep and fatigue, suggests broad symptomatic coverage of the syndrome of fibromyalgia.

Safety Results of the Phase 3 RESILIENT Study

In the RESILIENT study, TNX-102 SL was well tolerated and consistent with prior trials, with no new safety signals observed. Among participants randomized to the TNX-102 SL and placebo arms, 81.0% and 79.2%, respectively, completed the 14-week dosing period. As expected based on prior TNX-102 SL studies, administration site reactions were the most commonly reported adverse events and were higher in the TNX-102 SL treatment group (Table 2). Hypoaesthesia oral and paraesthesia oral, or tongue and mouth numbness or tingling, product taste abnormal (typically a bitter aftertaste upon dosing), and tongue discomfort were local effects nearly always temporally related to dose administration and transiently expressed (<60 minutes) in most occurrences. The only treatment-emergent adverse events that occurred at a rate of 3.0% or greater in either arm were these four oral adverse events, along with COVID-19, somnolence, and headache (Table 2). Adverse events resulted in premature study discontinuation in 6.1% of those who received TNX-102 SL compared with 3.5% of placebo recipients. There were a total of seven serious adverse events in five patients, five of which were experienced by three patients in the placebo arm, and two of which were in the TNX-102 SL arm. Of the two in the TNX-102 SL arm, one was renal cancer, deemed unrelated to study drug, and the other was acute pancreatitis with onset 14 days after dosing was completed and reported as possibly related to study drug.

The Changes in Sexual Functioning Questionnaire short form (CSFQ-14) served as a safety measure for assessing potential adverse effects on sexual functioning. In females, the total score on the CSFQ-14 at Week 14 improved (indicating better sexual functioning) in the TNX-102 SL group compared with placebo (nominal p=0.010 by analysis of covariance). This potentially indicates an important tolerability advantage over pharmacotherapeutics which potently inhibit reuptake of serotonin. The low percentage of males in the safety population (<5%) did not allow meaningful analysis of the CSFQ-14 data.

About the Phase 3 RESILIENT Study

The RESILIENT study is a double-blind, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of TNX-102 SL (cyclobenzaprine HCl sublingual tablets) in the management of fibromyalgia. The two-arm trial randomized 457 participants in the U.S. across 33 sites. The first two weeks of treatment consist of a run-in period in which participants start on TNX-102 SL 2.8 mg (1 tablet) or placebo. Thereafter, all participants increase their dose to TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) or two placebo tablets for the remaining 12 weeks. The primary endpoint is the daily diary pain severity score change (TNX-102 SL 5.6 mg vs. placebo) from baseline to Week 14 (using the weekly averages of the daily numerical rating scale scores), analyzed by mixed model repeated measures with multiple imputation.

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Low carbohydrate intake from plant based foods and whole grains good for weight management: JAMA

USA: A recent study published in JAMA Network Open has revealed the importance of diet quality within low-carbohydrate diet (LCD) patterns for long-term weight management.

The researchers stated, “Only LCDs that emphasized high-quality fat, protein and carbohydrates from whole grains and other plant-based foods were associated with less weight gain, while a lower-quality LCD was associated with the opposite result.”

The cohort study used data from three large prospective cohort studies among 123 332 individuals. It revealed that LCDs that stressed om high-quality proteins, carbohydrates, and fats from whole grains and other healthy plant-based foods were significantly linked with slower weight gain in the long term. In contrast, LCDs emphasizing animal-sourced fats and protein or refined carbohydrates were associated with faster weight gain.

Low-carbohydrate diets have gained popularity due to their promising nature for promoting weight loss and improving metabolic health. In clinical trials, LCDs, such as ketogenic diets have resulted in favorable short-term weight changes. However, there is no clarity on the association of these diets with long-term weight management. In addition, continued adherence to diets extremely low in carbohydrates may be unsustainable.

Against the above background, Binkai Liu, Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, and colleagues aimed to prospectively examine associations between changes in LCD indices and weight change among US adults in a prospective cohort study.

The study included initially healthy participants at baseline from the Health Professionals Follow-up Study (HPFS; 1986-2018), Nurses’ Health Study (NHS; 1986-2010), and Nurses’ Health Study II (NHSII; 1991-2015).

Five LCD indices were investigated: (1) a total LCD (TLCD) that emphasized overall low carbohydrate intake; (2) an animal-based LCD (ALCD) that emphasized protein and fat from animal sources; (3) a vegetable-based LCD (VLCD) emphasizing on plan-source of fat and protein; (4) a healthy LCD (HLCD) emphasizing less refined carbs, more healthy fat, and plant protein; and (5) an unhealthy LCD (ULCD) emphasizing more animal protein, less healthful carbs, and unhealthy fat.

The main outcome was 4-year changes in self-reported body weight. The study included a total of 123 332 participants (mean age, 45.0 years; 83.8% female).

The study led to the following findings:

  • The median carbohydrate intake (as a percentage of energy) of the highest quintiles of TLCD score at baseline ranged from 38.3% in HPFS to 40.9% in NHSII.
  • Mean weight gain over 4-year intervals among participants varied from 0.8 kg in the HPFS to 1.8 kg in the NHSII.
  • After adjusting for demographics and baseline and concomitant changes of selected lifestyle factors, each 1-SD increase in TLCD score was associated with 0.06 kg more weight gain over the 4-year periods.
  • Participants gained 0.13 kg per each 1-SD increase in ALCD score and 0.39 kg per each 1-SD change in ULCD score.
  • Each 1-SD increase in VLCD score was associated with 0.03 kg less weight gain, and each 1-SD increase in HLCD score was associated with 0.36 kg less weight gain.
  • The associations were more pronounced among obese individuals (per 1-SD increase in HLCD score: BMI ≥30, 0.88 kg less weight gain; BMI <25, 0.23 kg less weight gain).

“The study findings argue against the sole focus of macronutrient quantity for weight management and suggest the important role of nutrient quality in maintaining a healthy body weight,” the researchers wrote.

“Future studies are needed to validate these findings in more diverse populations and elucidate the mechanisms underlying these associations,” they concluded.

Reference:

Liu B, Hu Y, Rai SK, Wang M, Hu FB, Sun Q. Low-Carbohydrate Diet Macronutrient Quality and Weight Change. JAMA Netw Open. 2023;6(12):e2349552. doi:10.1001/jamanetworkopen.2023.49552

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High-risk PE patients have high mortality rates among patients with hemodynamic collapse

In a recent study from the Pulmonary Embolism Response Team (PERT) Consortium Registry found the contemporary care patterns and outcomes for high-risk pulmonary embolism (PE) patients. The findings of the study were published in the Journal of the American College of Cardiology.

This research comprised a total of 5,790 patients by meticulously categorizing the individuals who present with intermediate-risk PE, high-risk PE, and catastrophic PE and involved cases with hemodynamic collapse.

1,442 out of the total patients in the study presented with high-risk PE showed that advanced therapies were more frequently employed in this subgroup compared to those with intermediate-risk PE. But, the ground reality unveiled a high in-hospital mortality rates (20.6%) and a higher incidence of major bleeding (10.5%) in PE patients with high-risk. The factors like the use of vasopressor, extracorporeal membrane oxygenation utilization, clot-in-transit identification and malignancy emerged as major important contributors to the in-hospital mortality.

Also, catastrophic PE patients constituted to 13.7% of high-risk PE cases and they faced even graver outcomes with significantly higher in-hospital mortality rates (42.1%). The extracorporeal membrane oxygenation and systemic thrombolysis were more commonly utilized in the cases of catastrophic PE.

This study highlights the urgent need for enhanced strategies in managing high-risk PE patients. With mortality rates reaching alarming levels specially in the catastrophic cases. This findings of this study call for a reevaluation of the current practices and the development of interventions that are more effective to improve outcomes in patients.

Reference:

Kobayashi, T., Pugliese, S., Sethi, S. S., Parikh, S. A., Goldberg, J., Alkhafan, F., Vitarello, C., Rosenfield, K., Lookstein, R., Keeling, B., Klein, A., Gibson, C. M., Glassmoyer, L., Khandhar, S., Secemsky, E., & Giri, J. (2024). Contemporary Management and Outcomes of Patients With High-Risk Pulmonary Embolism. In Journal of the American College of Cardiology (Vol. 83, Issue 1, pp. 35–43). Elsevier BV. https://doi.org/10.1016/j.jacc.2023.10.026

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Radical Cystectomy Improves Survival compared to Trimodal Therapy in Bladder Cancer

A comprehensive meta-analysis compared the treatment modalities for muscle-invasive bladder cancer (MIBC) by using either radical cystectomy (RC) or trimodal therapy (TMT). The findings were published in the Frontiers in Surgery.

This meticulous study explored the academic databases such as Scopus, PubMed, Cochrane, EMBASE, and others from 1966 to December 2023. This yielded data from 14 studies by encompassing 54,816 bladder cancer patients. Out of these, a total of 6,228 underwent trimodal therapy, while 48,588 opted for radical cystectomy.

The results unveiled a significant difference in survival rates with the RC group exhibiting higher overall survival than the TMT group (pooled hazard ratio [HR] = 1.23, 95% CI: 1.18–1.28, P < 0.001). Cancer-specific survival was significantly prolonged in the RC group (pooled HR = 1.47, 95% CI: 1.29–1.67, P < 0.001). Also, the patients in the TMT group faced an increased risk of all-cause mortality compared to their RC counterparts (pooled HR: 1.30, P < 0.001).

The meta-analysis suggests a clear advantage of radical cystectomy in terms of overall survival for the patients of muscle-invasive bladder cancer. The data strongly indicate that cancer-specific survival is also significantly prolonged in addition to better overall survival rates in individuals who opt for radical cystectomy when compared to trimodal therapy.

Also, the outcomes of this study conclude that the patients undergoing trimodal therapy face a higher risk of all-cause mortality by emphasizing the potential superiority of radical cystectomy as a treatment option for muscle-invasive bladder cancer. These findings contribute valuable insights to the ongoing discourse on optimizing therapeutic approaches for this challenging form of cancer.

Source:

Al-Qudimat, A. R., Singh, K., Ojha, L. K., Moustafa, D. A., Elaarag, M., Al-Zoubi, R. M., & Aboumarzouk, O. M. (2023). Comparing trimodal therapy with radical cystectomy in muscle-invasive bladder cancer: an updated meta-analysis. In Frontiers in Surgery (Vol. 10). Frontiers Media SA. https://doi.org/10.3389/fsurg.2023.1276746

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Benzodiazepine use during pregnancy tied to a 69 per cent increased risk of miscarriage: JAMA

Taiwan: A nationwide case-time-control study showed an increased miscarriage risk associated with benzodiazepine use during pregnancy after accounting for measurable confounders, and findings were unlikely to be due to unmeasured confounding.

The findings published in JAMA Psychiatry indicate that healthcare professionals should meticulously balance the risk-benefit ratio when considering benzodiazepine use for treating sleep and psychiatric disorders during pregnancy.

“The study of more than 3 million pregnancies found that benzodiazepine use was linked with a 69% increased risk of miscarriage,” the researchers reported. “The increased risk was present for both long-acting (OR 1.67) and short-acting (OR 1.66) benzodiazepines.”

Owing to the potential adverse effects of benzodiazepine on neonates, the use of this drug class during pregnancy has raised significant concerns. There are limited studies on the association between benzodiazepine use and the risk of miscarriage. To fill this knowledge gap, Lin-Chieh Meng, National Taiwan University, Taipei, Taiwan, and colleagues aimed to quantify the risk of miscarriage linked with benzodiazepine use during pregnancy after controlling for unmeasured confounders and exposure time trends.

The nationwide, population-based case-time-control study was conducted using Taiwan’s National Birth Certificate Application database and the National Health Insurance database. The pregnancies that resulted in miscarriage between 2004 and 2018 were included in the case group. They were 1:1 matched with exposure time-trend control individuals using disease risk score, considering prepregnancy comorbidities and demographic characteristics.

Discordant exposures to benzodiazepines during the risk period (1-28 days before miscarriage) and two reference periods (31-58 days and 181-208 days prior to the last menstrual period) were compared for each pregnancy.

Miscarriage was defined as any pregnancy loss that occurred between the first prenatal care visit (usually 8 weeks) and the 19th completed pregnancy week.

The researchers reported the following findings:

  • This study included 3 067 122 pregnancies among 1 957 601 women, 4.4% of which resulted in miscarriage. The mean age of the study population was 30.61 years.
  • Benzodiazepine use during pregnancy was associated with an increased risk of miscarriage (odds ratio [OR], 1.69), and consistent findings were observed across multiple sensitivity analyses considering different time windows and accounting for misclassification.
  • In subgroup analyses, an increased risk of miscarriage was associated with each commonly used individual benzodiazepine, ranging from case-time-control ORs of 1.39 for alprazolam to 2.52 for fludiazepam.

“The observation of an increased miscarriage risk associated with the use of benzodiazepines suggests that benzodiazepines should only be used after a thorough evaluation of the potential benefits and risks for both the mother and child,” the researchers concluded.

Reference:

Meng L, Lin C, Chuang H, Chen L, Hsiao F. Benzodiazepine Use During Pregnancy and Risk of Miscarriage. JAMA Psychiatry. Published online December 27, 2023. doi:10.1001/jamapsychiatry.2023.4912

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New PET tracer noninvasively identifies cancer gene mutation for more precise diagnosis and therapy

A novel PET imaging tracer has been proven to safely and effectively detect a common cancer gene mutation that is an important molecular marker for tumor-targeted therapy. By identifying this mutation early, physicians can tailor treatment plans for patients to achieve the best results. This research was published in the December issue of The Journal of Nuclear Medicine.

Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene that is present in approximately 20-70 percent of cancer cases. Patients with KRAS mutations usually respond poorly to standard therapies. As such, the National Comprehensive Cancer Network and other leading cancer research centers recommend assessing the mutation status in cancer patients to determine the most effective treatment.

“Currently, KRAS mutation screening relies on a biopsy combined with gene sequencing. However, biopsies have the potential for significant complications and their use is limited by the quality of the tissue sample. Thus, there is an urgent need for accurate yet noninvasive methods of evaluating the KRAS mutation status,” stated Jing Wang, MD, PhD, nuclear medicine physician at Xijing Hospital of Fourth Military Medical University in Xi’an, China.

In this first-in-humans study, researchers sought to develop a KRAS-targeted radiotracer and investigate its targeting potential in non-small cell lung cancer (NSCLC) and colorectal cancer.

An oncoprotein-targeted PET tracer, 18F-PFPMD, was created based on a recently FDA-approved KRASG12C inhibitor. The targeting specificity and imaging ability of the tracer were assessed through both in vitro and in vivo study. Further evaluation in healthy volunteers, non–small cell lung cancer (NSCLC) patients, and colorectal cancer (CRC) patients was also conducted.

18F-PFPMD was obtained with a high radiochemical yield, radiochemical purity, and stability and was proven to selectively bind to the KRASG12C protein in preclinical studies. The tracer was found to be safe for humans, clearing rapidly from the gallbladder and intestines. In NSCLC and colorectal cancer patients, 18F-PFPMD accumulation was significantly higher in tumors with the KRASG12C mutation as opposed to those without the mutation.

“This research reveals that 18F-PFPMD is a promising molecular imaging tool of significant clinical relevance,” said Wang. “Moving forward, the tracer could be useful to screen the KRASG12C mutation status, as well as for patient selection of KRASG12C targeted therapy. Moreover, it could be used for monitoring therapeutic response and drug resistance for cancer patients.”

Reference:

Xiang Li, Jiajun Ye, Jingyi Wang, Zhiyong Quan, Guiyu Li, Wenhui Ma, Mingru Zhang, Weidong Yang, Junling Wang, Taoqi Ma, Fei Kang and Jing Wang, First-in-Humans PET Imaging of KRASG12C Mutation Status in Non–Small Cell Lung and Colorectal Cancer Patients Using [18F]PFPMD, Journal of Nuclear Medicine, DOI: https://doi.org/10.2967/jnumed.123.265715.

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Running Could Ease Irritable Bowel Symptoms

Running Could Ease Irritable Bowel Symptoms suggests a new study published in the Neurogastroenterology & Motility.

Physical activity has been suggested to alleviate gastrointestinal (GI) symptoms in patients with irritable bowel syndrome (IBS); however, evidence is scarce. Running has become increasingly popular and may be beneficial for patients with IBS. To obtain more insight in the potential application of running as therapy, we aimed to explore the impact of running and its intensity on GI symptoms in patients with IBS.

Data from a large observational study in runners were used for this nested case–control study, which included 153 runners with IBS and 153 controls. All participants had completed a questionnaire on personal characteristics, running characteristics and GI symptoms. Regarding GI symptoms, the severity of nine symptoms was asked, both at rest and during and/or shortly (up to 3 h) after running. Each symptom could be scored on a scale from 0 (not bothersome) to 100 (very bothersome), resulting in a maximum total score of 900 points.

Key Results

The prevalence and total severity score of GI symptoms were higher in runners with IBS than in controls, both at rest and during running. Among runners with IBS, the median (25th–75th percentile) total severity score during/after running was significantly lower than at rest (118 [50–200] vs. 150 [90–217]), while in controls no significant difference between running and rest was observed. Analyses stratified for running intensity revealed that the beneficial effect in runners with IBS was present when their most intensive training session was moderately intensive or intensive but not very intensive.

Running, particularly on moderate intensity, could have a beneficial effect on GI symptoms in patients with IBS.

Reference:

Baart, AM, Mensink, M, Witteman, BJM. The impact of running on gastrointestinal symptoms in patients with irritable bowel syndrome. Neurogastroenterology & Motility. 2023; 00:e14707. doi:10.1111/nmo.14707

Keywords:

Baart, AM, Mensink, M, Witteman, BJM, moderate, intensity, could, beneficial, effect, GI, symptoms, patients, IBS.

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AI-aided home stethescope promising and straightforward in diagnosing asthma exacerbations

Asthma is a heterogeneous disease characterized by chronic airway inflammation and respiratory symptoms such as cough, wheezing, shortness of breath, and chest tightness. It is a major source of childhood health burden worldwide and affects 10-12% of children.

According to a study published in the Annals of Family Medicine, researchers have concluded that AI-aided home stethoscope offers reliable insights into asthma flare-ups, particularly for young children. Its implementation in healthcare may significantly improve the detection of asthma exacerbations and simplify remote patient monitoring.
New medical devices enable asthma patients to monitor their condition at home, offering a more comprehensive understanding of their disease than intermittent clinic visits. The question arises here: “Which devices and parameters excel in detecting exacerbations?”
In a 6-month observational study, 149 asthma patients (90 children, 59 adults) used three devices daily for the first two weeks, then weekly for 5.5 months, with increased frequency during exacerbations. They used an AI-aided home stethoscope, a peripheral capillary oxygen saturation meter, and a peak expiratory flow meter and filled out a health state survey. The resulting 6,029 examinations were evaluated by physicians for exacerbations. Machine learning models were trained for each registered parameter, and the area under the receiver operating characteristic curve (AUC) was calculated to assess their utility in detecting exacerbations.
The best single-parameter discriminators of exacerbations were wheeze intensity for young children (AUC 84%, rhonchi intensity for older children (AUC 81%), and survey answers for adults (AUC 92%). The greatest efficacy was observed for a combination of various parameters.
The current study demonstrates that an AI-aided home stethoscope can detect exacerbations by measuring wheezes, rhonchi, coarse, HR, RR, and I/E. PEF measurements are not necessary, and the stethoscope may simplify asthma diagnosis and monitoring for younger children.
Reference:
Andrzej Emeryk et al. Home Monitoring of Asthma Exacerbations in Children and Adults with Use of an AI-Aided Stethoscope. The Annals of Family Medicine Nov 2023, 21 (6) 517-525; DOI: 10.1370/afm.3039

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Semaglutide, both oral and subcutaneous, significantly reduces systolic BP in patients with type 2 diabetes: Study

China: A recent systematic review and meta-analysis showed a significant reduction in systolic blood pressure (SBP) with oral or subcutaneous semaglutide in patients with type 2 diabetes (T2D).

Across 29 randomized controlled trials (RCTs), semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), was shown to notably reduce both body weight loss and glycated haemoglobin A1c (HbA1c), but no significant impact on diastolic blood pressure.

“In type 2 diabetes, SBP reduced significantly in the semaglutide group compared with placebo or other active controls,” Wei Wu, Chun’an First People’s Hospital (Zhejiang Provincial People’s Hospital Chun’an Branch), Hangzhou, Zhejiang, China, and colleagues reported in the journal Endocrine.

Poor blood pressure control is common in T2D patients; hypertension occurs in about two-thirds of patients, making optimal BP lowering crucial for disease management. Semaglutide has glucose-lowering effects in a glucose-dependent manner and does not increase the risk of hypoglycemia. The agent has been shown to reduce weight, and HbA1c, and provide additional benefits, including kidney function improvement and BP regulation.

There is a lack of studies analyzing semaglutide’s impact on blood pressure as a primary outcome. Therefore, the researchers aimed to evaluate the BP-lowering ability of semaglutide in individuals with type-2 diabetes.

For this purpose, the researchers identified RCTs comparing subcutaneous or oral semaglutide with placebo or other antihyperglycemic agents (AHAs) in T2D patients using online databases. These screened studies included the outcomes of interest: diastolic BP and/or systolic BP. Pooled and sensitivity analyses were performed, and the risk of bias was evaluated. Weighted mean differences (WMD) were used to present the meta-analysis results. The final analysis included twenty-nine RCTs with 26985 participants.

The researchers reported the following findings:

  • The WMD change from baseline in systolic BP of semaglutide versus placebo or other AHAs was −2.31 mmHg, while that for diastolic BP was 0.09 mmHg.
  • It also reduced glycated haemoglobin A1c (HbA1c) by 0.75% and body weight loss by 2.80 kg.
  • The reduction in SBP was similar for subcutaneous and oral administration of semaglutide, with −2.36 and −2.50, respectively.

“Our analysis suggests that semaglutide, either subcutaneous or oral, can significantly lower SBP in T2D patients,” the researchers wrote. “For T2D patients with hypertension, semaglutide’s antihypertensive effect may be greater than 2.31 mmHg in this paper, but still there is a need to determine the real-world effect.”

“Future studies to uncover the underlying blood pressure-lowering mechanisms of semaglutide will benefit more individuals with diabetes by increasing the understanding of these associations,” they concluded.

Reference:

Wu, W., Tong, Hm., Li, Ys. et al. The effect of semaglutide on blood pressure in patients with type-2 diabetes: a systematic review and meta-analysis. Endocrine (2023). https://doi.org/10.1007/s12020-023-03636-9

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