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Breast (Edinburgh, Scotland) Jun 2024The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump...
BACKGROUND
The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump inhibitors (PPI). Herein, we report the effect of PPI on palbociclib capsule activity and safety in the PARSIFAL study.
METHODS
First-line endocrine-sensitive, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) patients received palbociclib capsules plus fulvestrant or letrozole. The primary endpoint was progression-free survival (PFS). This post-hoc analysis compared PPI use. Patients were PPI-naïve (N-PPI) if not on PPI during the study, and either early (E-PPI) or long-term PPI (LT-PPI) if on PPI at study entry or for at least ≥⅔ of treatment, respectively. PPI groups were not mutually exclusive.
RESULTS
Among 486 patients, 66.9 % were N-PPI, 13.2 % E-PPI, 18.7 % LT-PPI, and 11.5 % of the PPI users were defined as neither. Median PFS (mPFS) was 29.6 months in the study population, 28.7 months in N-PPI, 23.0 months in E-PPI (Hazard Ratio [HR] 1.5; 95%Confidence Interval [CI] 1.1-2.2; p = 0.024), and 23.0 months in LT-PPI (HR 1.4; 95%CI 1.0-1.9; p = 0.035). By landmark analysis, PPI use was associated with poorer mPFS at 3 and 12 months. Grade ≥3 hematological adverse events occurred in 71.7 % of N-PPI, 57.8 % of E-PPI (p = 0.021), and 54.9 % of LT-PPI (p = 0.003). Dose reductions and dosing delays due to hematological toxicity occurred in 70.8 % of N-PPI, 56.3 % of E-PPI (p = 0.018), and 52.7 % of LT-PPI (p = 0.002).
CONCLUSIONS
PPI use may reduce palbociclib capsule toxicity, dose modifications, and clinical activity in HR+/HER2- ABC.
PubMed: 38880077
DOI: 10.1016/j.breast.2024.103761 -
Medicine Jun 2024Approximately 10% to 40% of patients with gastroesophageal reflux disease (GERD) exhibit poor response to proton pump inhibitors (PPIs), indicating refractory GERD... (Randomized Controlled Trial)
Randomized Controlled Trial
Approximately 10% to 40% of patients with gastroesophageal reflux disease (GERD) exhibit poor response to proton pump inhibitors (PPIs), indicating refractory GERD (RGERD). Banxia Houpu Decoction is a traditional Chinese medicine formula used for treating GERD, particularly for atypical symptoms. This study aimed to investigate the improvement of different symptoms in RGERD patients treated with Banxia Houpu Decoction and identify relevant factors influencing its efficacy. From November 2021 to November 2022, a total of 89 RGERD patients voluntarily participated in this clinical study at our hospital. They were randomly assigned to 2 treatment groups: the Banxia Houpu Decoction group and the Western medicine group. The former received standard-dose Banxia Houpu Decoction, while the latter had a switch in PPI type with double-dose maintenance and the addition of magnesium aluminum carbonate as an acid suppressant. The improvement of different symptoms was compared between the 2 groups. Clinical data, including age, gender, gastric mucosal status, and esophagitis severity, were collected. Univariate analysis was performed to explore factors influencing the therapeutic effect of Banxia Houpu Decoction. Both treatment groups showed significant improvement in Frequency Scale for the Symptoms of GERD (FSSG) scores. The Banxia Houpu Decoction group exhibited the most significant efficacy in relieving throat burning sensation (P = .003) and frequent hiccups (P = .003). It also demonstrated improvement in swallowing difficulty (P = .048) and postprandial abdominal distension (P = .041), surpassing the Western medicine group. The Western medicine group had the most significant improvement in heartburn sensation (P = .008) and showed significant improvement in gastric burning sensation (P = .022), surpassing Banxia Houpu Decoction. Age (P = .025) and gastroesophageal flap valve (GEFV) grade (P = .014) were identified as factors influencing the efficacy of Banxia Houpu Decoction. Banxia Houpu Decoction exhibits superior efficacy compared to double-dose PPI combined with acid suppressants in relieving symptoms such as throat burning sensation, swallowing difficulty, and frequent hiccups. It shows significant efficacy in patients under 60 years of age and with GEFV grades I-II.
Topics: Humans; Gastroesophageal Reflux; Male; Female; Middle Aged; Drugs, Chinese Herbal; Proton Pump Inhibitors; Adult; Treatment Outcome; Aged
PubMed: 38875370
DOI: 10.1097/MD.0000000000038045 -
BJR Open Jan 2024This article is an evaluation of the current trial processes within a national proton beam therapy (PBT) clinical trial service in the United Kingdom. The work within...
Clinical Trials Radiographers identifying priority challenges associated with implementing a national programme of clinical trials in the United Kingdom's first proton beam therapy centre.
OBJECTIVES
This article is an evaluation of the current trial processes within a national proton beam therapy (PBT) clinical trial service in the United Kingdom. The work within the article identifies priority challenges associated with the implementation of PBT trials with a view to improving patient trial processes.
METHODS
The nominal group technique (NGT) was used. Five Clinical Trials Radiographers were asked the target question "what are the major challenges when implementing PBT clinical trials and facilitating PBT trial-related activities?" Participants individually and silently listed their challenges to the target question. Following this, group discussion clarified and refined responses. Participants then individually selected five challenges that they deemed most pertinent to the target question, giving a weighted score (out of 10). Individual scores were combined to provide a ranked, weighted order of challenges. Further group discussion identified improvement strategies to the highest scored challenges.
RESULTS
After combining lists generated by participants, 59 challenges were identified. Group discussion eliminated 27 responses. Eighteen were merged, resulting in 14 challenges. The two challenges that ranked highest were: (i) lack of initial understanding of the responsibilities of teams and who the relevant stakeholders were, and (ii) that a national PBT service requires the provision of shared care across multi-disciplinary teams and sites. Improvement areas include the development of shared protocols, clarifying stakeholder responsibilities and improving communication between centres to streamline PBT trial processes.
CONCLUSIONS
This work has identified priority areas requiring development to improve the conduct of a national PBT clinical trials programme.
ADVANCES IN KNOWLEDGE
This is the first publication to evaluate current clinical trial processes for the United Kingdom's PBT service.
PubMed: 38873402
DOI: 10.1093/bjro/tzae012 -
Frontiers in Oncology 2024We tried to establish the normal tissue complication probability (NTCP) model of temporal lobe injury of recurrent nasopharyngeal carcinoma (NPC) patients after two...
PURPOSE
We tried to establish the normal tissue complication probability (NTCP) model of temporal lobe injury of recurrent nasopharyngeal carcinoma (NPC) patients after two courses of intensity modulated radiotherapy (IMRT) to provide more reliable dose-volume data reference to set the temporal lobe tolerance dose for recurrent NPC patients in the future.
METHODS AND MATERIALS
Recurrent NPC patients were randomly divided into training data set and validation data set in a ratio of 2:1, All the temporal lobes (TLs) were re-contoured as R/L structures and named separately in the MIM system. The dose distribution of the initial IMRT plan was deformed into the second course planning CT via MIM software to get the deformed dose. Equivalent dose of TLs in 2Gy fractions was calculated via linear quadratic model, using an α/β=3 for temporal lobes. NTCP model that correlated the irradiated volume of the temporal lobe and? the clinical variables were evaluated in a multivariate prediction model using AUC analysis.
RESULTS
From Jan. 2010 to Dec. 2020, 78 patients were enrolled into our study. Among which 26 (33.3%) developed TLI. The most important factors affecting TLI was the sum-dose d1.5cc of TL, while the possible clinical factors did not reach statistically significant differences in multivariate analysis. According to NTCP model, the TD5 and TD50 EQD2 dose of sum-dose d1.5cc were 65.26Gy (46.72-80.69Gy) and 125.25Gy (89.51-152.18Gy), respectively. For the accumulated EQD2 dose, the area under ROC shadow was 0.8702 (0.7577-0.9828) in model validation, p<0.001.
CONCLUSION
In this study, a NTCP model of temporal lobe injury after a second course of IMRT for recurrent nasopharyngeal carcinoma was established. TD5 and TD50 doses of temporal lobe injury after re-RT were obtained according to the model, and the model was verified by validation set data.
PubMed: 38873258
DOI: 10.3389/fonc.2024.1394111 -
Cureus May 2024() infections typically present with fever and gastrointestinal symptoms. This case report on enteritis documents atypical clinical, radiological, and endoscopic...
() infections typically present with fever and gastrointestinal symptoms. This case report on enteritis documents atypical clinical, radiological, and endoscopic findings raising diagnostic challenges. A 31-year-old male in the Kingdom of Saudi Arabia (KSA) presented with severe abdominal pain, vomiting, bloody diarrhea, and no fever. Initial diagnosis included amebiasis and other gastroenteritis infections. Despite treatment with ciprofloxacin and metronidazole, the patient's condition did not improve, and he kept having intractable abdominal pain and vomiting. Subsequent investigations, including abdominal ultrasound and esophagogastroduodenoscopy, revealed extensive and rapidly progressive intestinal inflammation with wall thickening and ascites. Stool culture eventually identified a multidrug-resistant strain of , sensitive only to ceftriaxone. Treatment with ceftriaxone and continuous infusion of proton pump inhibitor (PPI) led to significant improvement. The absence of fever in the context of bloody diarrhea, and the rapid development of ascites not improving with first-line treatment of gastroenteritis, led to the search for other diagnoses such as inflammatory bowel syndromes or tuberculosis. The presentation of diffuse intestinal wall thickening with intractable vomiting, bloody diarrhea, and progressively increasing ascites is not frequently encountered with . The case also underscores the growing concern of antibiotic-resistant strains. The patient's response to targeted antibiotic therapy emphasizes the importance of accurate microbial identification and susceptibility testing in managing infectious diseases. This case report illustrates an atypical presentation of enteritis with progressively increasing ascites and increased intestinal wall thickening. The uncommon complicated clinical picture led to challenges in diagnosis and management. It emphasizes the need for high clinical suspicion and comprehensive diagnostic approaches in atypical cases of common infections, especially in the context of increasing antibiotic resistance.
PubMed: 38868285
DOI: 10.7759/cureus.60217 -
Cell Communication and Signaling : CCS Jun 2024KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short...
BACKGROUND
KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions.
METHODS
Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model.
RESULTS
Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression.
CONCLUSIONS
We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Proto-Oncogene Proteins p21(ras); Cell Line, Tumor; Animals; Proto-Oncogene Proteins c-met; Mutation; Omeprazole; Mice; Pyridines; Pyrimidines; Xenograft Model Antitumor Assays; Mice, Nude; Pyrimidinones; Female; Triazines; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Piperazines; Piperidines; Pyridazines; Pyridones
PubMed: 38867255
DOI: 10.1186/s12964-024-01667-x -
Scientific Reports Jun 2024In the realm of radiation therapy, a conspicuous obstacle lies in the dearth of external observation concerning radiation beams aimed at the patient. While real-time...
In the realm of radiation therapy, a conspicuous obstacle lies in the dearth of external observation concerning radiation beams aimed at the patient. While real-time monitoring of such beams on the patient's surface during therapy holds promise, the imaging of particle beams has thus far proven to be a formidable task. Here, we show our discovery of polyester fabrics and cloths as auspicious scintillating materials, ideally suited for the visualization of radiation beams upon the patient's surface. The light output of polyester fabrics ranged from 10 to 20% of that observed in plastic scintillators. When exposed to spot scanning proton beams, clear beam spots emerged on the surface of the polyester cloths. The movement of these scanning beams was effectively captured using a CMOS camera in a light-shield-free with lights-off environment. The resulting images provided a means for evaluating spills of the proton beams. The inherent flexibility of polyester fabrics and clothing enhances their appeal for applications in the intricate landscape of radiation therapy, promising a bright future for surface beam imaging endeavors.
PubMed: 38866842
DOI: 10.1038/s41598-024-62456-7 -
Cell Death Discovery Jun 2024Ionising radiation (IR) is widely used in cancer treatment, including for head and neck squamous cell carcinoma (HNSCC), where it induces significant DNA damage leading...
Ionising radiation (IR) is widely used in cancer treatment, including for head and neck squamous cell carcinoma (HNSCC), where it induces significant DNA damage leading ultimately to tumour cell death. Among these lesions, DNA double strand breaks (DSBs) are the most threatening lesion to cell survival. The two main repair mechanisms that detect and repair DSBs are non-homologous end joining (NHEJ) and homologous recombination (HR). Among these pathways, the protein kinases ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related (ATR) and the DNA dependent protein kinase catalytic subunit (DNA-Pkcs) play key roles in the sensing of the DSB and subsequent coordination of the downstream repair events. Consequently, targeting these kinases with potent and specific inhibitors is considered an approach to enhance the radiosensitivity of tumour cells. Here, we have investigated the impact of inhibition of ATM, ATR and DNA-Pkcs on the survival and growth of six radioresistant HPV-negative HNSCC cell lines in combination with either X-ray irradiation or proton beam therapy, and confirmed the mechanistic pathway leading to cell radiosensitisation. Using inhibitors targeting ATM (AZD1390), ATR (AZD6738) and DNA-Pkcs (AZD7648), we observed that this led to significantly decreased clonogenic survival of HNSCC cell lines following both X-ray and proton irradiation. Radiosensitisation of HNSCC cells grown as 3D spheroids was also observed, particularly following ATM and DNA-Pkcs inhibition. We confirmed that the inhibitors in combination with X-rays and protons led to DSB persistence, and increased micronuclei formation. Cumulatively, our data suggest that targeting DSB repair, particularly via ATM and DNA-Pkcs inhibition, can exacerbate the impact of ionising radiation in sensitising HNSCC cell models.
PubMed: 38866739
DOI: 10.1038/s41420-024-02059-3 -
Clinical Medicine (London, England) Apr 2024: This article has been withdrawn: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/policies/article-withdrawal). This article has...
: This article has been withdrawn: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/policies/article-withdrawal). This article has been withdrawn at the request of the authors, editor and publisher. The publisher regrets that an error occurred which led to the premature publication of this paper. This error bears no reflection on the article or its authors. The publisher apologizes to the authors and the readers for this unfortunate error.
Topics: Humans; Proton Pump Inhibitors; Acute Coronary Syndrome; Platelet Aggregation Inhibitors; Dual Anti-Platelet Therapy; Male; Female; Middle Aged; Aged
PubMed: 38866466
DOI: 10.1016/j.clinme.2024.100143 -
BMJ Open Jun 2024The onset of cancer compels patients to grapple with existential questions. Enabling individuals with cancer, irrespective of the disease stage, to experience meaningful...
INTRODUCTION
The onset of cancer compels patients to grapple with existential questions. Enabling individuals with cancer, irrespective of the disease stage, to experience meaningful lives is of utmost importance in enhancing their overall quality of life. This study will synthesise qualitative research evidence to understand cancer patients' perceptions and perspectives regarding their meaning in life. Such insights ultimately contribute to enhancing the profound experience of meaning throughout the life course of cancer patients.
METHODS AND ANALYSIS
The English and Chinese databases we will search include the Cochrane Library, PubMed, MEDLINE, Web of Science, EMbase, CINAHL, PsycINFO, China National Knowledge Infrastructure, Wan Fang Data, Chinese Biomedical Literature Database and VIP Database for Chinese Technical Periodicals. Two independent reviewers will assess the quality of the included studies using the standard JBI Critical Appraisal Checklist for Qualitative Research and extract data using the standard JBI Data Extraction Tool for Qualitative Research. The JBI meta-aggregation approach will be employed to compare, analyse and summarise the original results. To enhance confidence in the synthesised results of the qualitative study, the final synthesised study results will be graded using the JBI ConQual approach.
ETHICS AND DISSEMINATION
External ethical approval is not necessary for this review since it involves a retrospective analysis of publicly available primary data through secondary analysis. The findings of the review will be disseminated by publishing them in a peer-reviewed journal.
PROSPERO REGISTRATION NUMBER
CRD42023447664.
Topics: Humans; Qualitative Research; Neoplasms; Quality of Life; Research Design; Meta-Analysis as Topic; Perception
PubMed: 38862219
DOI: 10.1136/bmjopen-2023-078357