KRAS mutational status has been shown to be a predictive biomarker of resistance to anti-EGFR monoclonal antibody (mAb) therapy in patients with metastatic colorectal cancer. We report the spectrum ...of KRAS mutation in 1506 patients with colorectal cancer and the identification and characterization of rare insertion mutations within the functional domain of KRAS. KRAS mutations are found in 44.5% (670/1506) of the patients. Two cases are found to harbor double mutations involving both codons 12 and 13. The frequencies of KRAS mutations at its codons 12, 13, 61, and 146 are 75.1%, 19.3%, 2.5%, and 2.7%, respectively. The most abundant mutation of codon 12 is G12D, followed by G12V and G12C while G13D is the predominant mutation in codon 13. Mutations in other codons are rare. The KRAS mutation rate is significantly higher in women (48%, 296/617) than in men (42.1%, 374/889, P = 0.023). Tumors on the right colon have a higher frequency of KRAS mutations than those on the left (57.3% vs. 40.4%, P < 0.0001). Two in-frame insertion mutations affect the phosphate-binding loop (codon 10-16) of KRAS are identified. One of them has never been reported before. Compared with wild-type protein, the insertion variants enhance the cellular accumulation of active RAS (RAS-GTP) and constitutively activate the downstream signaling pathway. NIH3T3 cells transfected with the insertion variants show enhanced anchorage-independent growth and in vivo tumorigenicity. Potentially these mutations contribute to primary resistance to anti-EGFR mAb therapy but the clinical implication requires further validation.
Structural variation (SV) is a major cause of genetic disorders. In this paper, we show that low-depth (specifically, 4×) whole-genome sequencing using a single Oxford Nanopore MinION flow cell ...suffices to support sensitive detection of SV, particularly pathogenic SV for supporting clinical diagnosis. When using 4× ONT WGS data, existing SV calling software often fails to detect pathogenic SV, especially in the form of long deletion, terminal deletion, duplication, and unbalanced translocation. Our new SV calling software SENSV can achieve high sensitivity for all types of SV and a breakpoint precision typically ± 100 bp; both features are important for clinical concerns. The improvement achieved by SENSV stems from several new algorithms. We evaluated SENSV and other software using both real and simulated data. The former was based on 24 patient samples, each diagnosed with a genetic disorder. SENSV found the pathogenic SV in 22 out of 24 cases (all heterozygous, size from hundreds of kbp to a few Mbp), reporting breakpoints within 100 bp of the true answers. On the other hand, no existing software can detect the pathogenic SV in more than 10 out of 24 cases, even when the breakpoint requirement is relaxed to ± 2000 bp.
To evaluate efficacy and toxicity of cetuximab plus carboplatin in recurrent or metastatic nasopharyngeal carcinoma (NPC) resistant to platinum treatment.
A multicenter, open-label, single-arm, phase ...II study in patients with epidermal growth factor receptor-expressing NPC who progressed on or within 12 months after termination of platinum-based chemotherapy for recurrent or metastatic disease. Cetuximab was administered at an initial dose of 400 mg/m2 followed by weekly doses of 250 mg/m2. Carboplatin area under the curve 5 was administered every 3 weeks up to a maximum of eight cycles.
Sixty patients were enrolled (46 males, 14 females; median age, 44.5 years; range, 23 to 64 years), and all patients were included in the intent-to-treat and safety analyses. Of the 59 patients assessable for efficacy, there were seven partial responses (11.7%), 29 patients (48.3%) with stable disease, and 23 patients (38.3%) with progressive disease, giving an overall response rate of 11.7% (95% CI, 4.8% to 22.6%). The median time to progression was 81 days in all patients and was longest in the group of patients with a confirmed response (173 days). The median overall survival time was 233 days in all patients. Six patients (10%) experienced serious treatment-related adverse events. Grade 3 or 4 toxicities occurred in 31 patients (51.7%); of these patients, only 19 (31.7%) were considered to have toxicity related to cetuximab.
Cetuximab in combination with carboplatin demonstrates clinical activity and an acceptable safety profile in heavily pretreated patients with recurrent or metastatic NPC who had previously experienced treatment failure with platinum-based therapy.
Abstract
Background
Many patients with metastatic breast cancer experience cancer- and treatment-related side effects that impair activities of daily living and negatively affect the quality of life. ...There is a need for interventions that improve quality of life by alleviating fatigue and other side effects during palliative cancer treatment. Beneficial effects of exercise have been observed in the curative setting, but, to date, comparable evidence in patients with metastatic breast cancer is lacking. The aim of this study is to assess the effects of a structured and individualized 9-month exercise intervention in patients with metastatic breast cancer on quality of life, fatigue, and other cancer- and treatment-related side effects.
Methods
The EFFECT study is a multinational, randomized controlled trial including 350 patients with metastatic breast cancer. Participants are randomly allocated (1:1) to an exercise or control group. The exercise group participates in a 9-month multimodal exercise program, starting with a 6-month period where participants exercise twice a week under the supervision of an exercise professional. After completing this 6-month period, one supervised session is replaced by one unsupervised session for 3 months. In addition, participants are instructed to be physically active for ≥30 min/day on all remaining days of the week, while being supported by an activity tracker and exercise app. Participants allocated to the control group receive standard medical care, general written physical activity advice, and an activity tracker, but no structured exercise program. The primary outcomes are quality of life (EORTC QLQ-C30, summary score) and fatigue (EORTC QLQ-FA12), assessed at baseline, 3, 6 (primary endpoint), and 9 months post-baseline. Secondary outcomes include physical fitness, physical performance, physical activity, anxiety, depression, pain, sleep problems, anthropometric data, body composition, and blood markers. Exploratory outcomes include quality of working life, muscle thickness, urinary incontinence, disease progression, and survival. Additionally, the cost-effectiveness of the exercise program is assessed. Adherence and safety are monitored throughout the intervention period.
Discussion
This large randomized controlled trial will provide evidence regarding the (cost-) effectiveness of exercise during treatment of metastatic breast cancer. If proven (cost-)effective, exercise should be offered to patients with metastatic breast cancer as part of standard care.
Trial registration
ClinicalTrials.gov
NCT04120298
. Registered on October 9, 2019.
Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels ...of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.
BackgroundThe Saudi Community pharmacy sector has been changing towards patient-centred care rather than depending solely on dispensing medications. Accordingly, pharmacies can now provide many ...services that they previously could not offer. The aims of this study were to identify all pharmacy services provided in a community setting and to assess public awareness and utilization of and satisfaction with these services.MethodsThis was a cross-sectional study in which the authors first purposively visited community pharmacies to identify the services offered. Pharmacists were asked about pharmacy services currently provided to community. Fieldnotes were used to document pharmacists' responses. After identifying pharmacy services, a questionnaire was desgined and reviewed by experts in the field, piloted and approved by the Ethics Committee at King Faisal University, then disseminated via Google Forms. The satisfaction level with pharmacy services was assessed using a five-point Likert scale. Data were collected from 24 January 2023 to 2 March 2023.ResultsEighteen community pharmacies offering 17 different services were visited across Alahsa Governorate. The number of participants who completed the questionnaire was 350. Of those (232 66.3%) were female, and the majority of the sample (80.5%) were younger than 40 years old. The majority of the participants were unaware of pharmacy services. Out of 17 services, six received a score of 50% or higher regarding participant awareness. The most utilized services were the medication dispensing service "Wasfaty" (250 71.4%), medication counselling provided by pharmacists (232 66.3%) and minor ailment service (231 66%). The overall satisfaction score for pharmacy services was 87.2%.ConclusionThe majority of the participants were unaware of the full range of available pharmacy services. There is a potential for community pharmacists to fill the capacity gap in the healthcare system since, overall, the participants rated the pharmacies' clinical services as satisfactory. Commissioners of pharmacy services may consider extending the scope of community pharmacies to include services that best utilize the expertise of clinical pharmacists.
In this article, high dense glasses based heavy metal former and modifier have been synthesized. The glass system with composition formula of (60-x)TeO2–10GeO2 -20ZnO–10BaO - xBi2O3 (where x = 2.5, ...5, 7.5, and 10 mol. %). The glasses have been produced using the usual melt, quenching, and annealing process. Many physical features were investigated. To confirm the amorphous nature of theses glasses, we examined the samples with X-ray diffraction in the range of between 10° and 80°. Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) transmission spectrum for the current glass samples within the range of 400–1500 cm−1 has been recorded to study the behavior of the obtained glasses that is mixed between tellurium and germanium glass phase. To study the transparency and cut-off wavelength and other optical properties, Ultraviolet–Visible spectrometer (UV–Vis) was utilized between 200 and 800 nm. Radiation shielding ability of the (60-x) TeO2–10GeO2-20ZnO–10BaO-xBi2O3 glasses was examined. Monte Carlo simulation method was applied to estimate the shielding parameters for gamma photons with various energies varied in rang from 0.015 to 15 MeV.
•High dens glasses based heavy metal former and formers has been synthesized.•Radiation shielding characteristics of synthesized glasses have been investigated.•FTIR was employed to study the functional groups of all elements.•Optical absorption was used to investigate the cut-off wavelength and optical band gap.
Background and purpose
This prospective study aimed to investigate adaptive magnetic resonance (MR)-guided stereotactic body radiation therapy (MRgSBRT) with rectal spacer for localized prostate ...cancer (PC) and report 1-year clinical outcomes.
Materials and methods
Thirty-four consecutive patients with low- to high-risk localized PC that underwent 5-fraction adaptive MRgSBRT with rectal spacer were enrolled. The dosimetric comparison was performed on a risk- and age-matched cohort treated with MRgSBRT but without a spacer at a similar timepoint. Clinician-reported outcomes were based on Common Terminology Criteria for Adverse Events. Patient-reported outcomes were based on the Expanded Prostate Cancer Index Composite (EPIC) questionnaire at baseline, acute (1–3 months), subacute (4–12 months), and late (> 12 months) phases.
Results
The median follow-up was 390 days (range 28–823) and the median age was 70 years (range 58–82). One patient experienced rectal bleeding soon after spacer insertion that subsided before MRgSBRT. The median distance between the midline of the prostate midgland and the rectum after spacer insertion measured 7.8 mm (range 2.6–15.3), and the median length of the spacer was 45.9 mm (range 16.8–62.9) based on T2-weighted MR imaging. The use of spacer resulted in significant improvements in target coverage (V100% > 95% = 98.6% range 93.4–99.8 for spacer vs. 97.8% range 69.6–99.7 for non-spacer) and rectal sparing (V95% < 3 cc = 0.7 cc range 0–4.6 for spacer vs. 4.9 cc range 0–12.5 for non-spacer). Nine patients (26.5%) experienced grade 1 gastrointestinal toxicities, and no grade ≥ 2 toxicities were observed. During the 1-year follow-up period, EPIC scores for the bowel domain remained stable and were the highest among all other domains.
Conclusions
MRgSBRT with rectal spacer for localized PC showed exceptional tolerability with minimal gastrointestinal toxicities and satisfactory patient-reported outcomes. Improvements in dosimetry, rectal sparing, and target coverage were achieved with a rectal spacer. Randomized trials are warranted for further validation.
We aimed to investigate the roles of antegrade residual flow and leptomeningeal collateral flow in sustaining cerebral perfusion distal to an intracranial atherosclerotic stenosis (ICAS). Patients ...with apparently normal cerebral perfusion distal to a symptomatic middle cerebral artery (MCA)-M1 stenosis were enrolled. Computational fluid dynamics models were built based on CT angiography to obtain a translesional pressure ratio (PR) to gauge the residual antegrade flow. Leptomeningeal collaterals (LMCs) were scaled on CT angiography. Cerebral perfusion metrics were obtained in CT perfusion maps. Among 83 patients, linear regression analyses revealed that both translesional PR and LMC scale were independently associated with relative ipsilesional mean transit time (rMTT). Subgroup analyses showed that ipsilesional rMTT was significantly associated with translesional PR (p < 0.001) rather than LMC scale in those with a moderate (50–69%) MCA stenosis, which, however, was only significantly associated with LMC scale (p = 0.051) in those with a severe (70–99%) stenosis. Antegrade residual flow and leptomeningeal collateral flow have complementary effects in sustaining cerebral perfusion distal to an ICAS, while cerebral perfusion may rely more on the collateral circulation in those with a severe stenosis.
Background: Patient satisfaction is crucial for assessing healthcare quality and identifying strengths and weaknesses in healthcare organizations. In Saudi Arabia, the Ministry of Health (MOH) ...implemented the Patient Experience Measurement Program to enhance patient experience and healthcare quality. This study aimed to identify specific aspects of patient satisfaction with dental visits in Saudi Arabia to improve dental care quality and inform dental services development. Methods: The study used a standardized self-administered questionnaire (Health Links/Press Ganey) and analyzed surveys from patients who visited MOH-specialized dental clinics in Saudi Arabia during the first half of 2022. The dental section comprised 20 questions across five domains, with patients rating their experience on a 5-point Likert scale. Statistical analysis was performed using IBM SPSS Statistics 25. Results: A total of 964 patients were surveyed. The overall patient satisfaction with dental settings was 3.61 out of 5.0 (72.2%). The highest satisfaction score was for personal issues with the dental clinic domain (3.93/5; 78.6%), while the least satisfaction score was for access to the dental clinic domain (3.29/5; 65.8%). Among all items, the cleanliness of the facility showed the highest satisfaction score (4.11/5; 82.2%). The least satisfaction was for the ease of contacting the dental clinic (2.71/5; 54.2%). Conclusion: The study found high levels of satisfaction among Saudi patients with dental services provided through MOH facilities across various component domains. This highlights the crucial role of dentists in ensuring high-quality dental care and serves as an indication of the overall healthcare quality in MOH facilities. Keywords: patient experience, patient-centered care, patient satisfaction, dental care, Saudi Arabia, Press Ganey
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