Tyrosine-kinase inhibitors (TKIs) have become the standard treatment for patients with advanced gastrointestinal stromal tumor (GIST); however, secondary mutations can still drive disease progression. Studies have shown that ripretinib, a novel switch-control TKI, inhibits various primary and secondary drug-resistant mutations. There is a paucity of data on the effectiveness and safety of ripretinib in a real-world setting. This prospective, large-scale, real-world registry study aimed to evaluate the effectiveness and safety of ripretinib as a fourth-line treatment in Chinese patients with advanced GIST.
Methods
Patients ≥ 18 years of age having recurrent/metastatic GIST were enrolled. Key endpoints were median progression-free survival (mPFS), median overall survival (mOS), and adverse events (AEs) incidence. Univariate and multivariate analyses were conducted to identify various parameters associated with PFS.
Results
A total of 240 patients were enrolled. After a median follow-up period of 6.5 months, the mPFS [95% confidence interval (CI)] was 7.70 (6.60, 8.60) months and the mOS was not reached. Multivariate analysis revealed association of Eastern Cooperative Oncology Group (ECOG) performance status score with PFS and superior benefits for non-gastric was observed as compared to gastric GISTs [hazard ratio (HR) 0.58, 95% CI (0.39–0.86)]. Disease control rate and tumor shrinkage (any magnitude) was 73% and 43%, respectively. Ripretinib was also effective in the subgroup of patients with different gene mutations. The toxicities were tolerable, and most reported AEs were alopecia (17.1%) and hand-foot syndrome (15.4%).
Conclusion
Ripretinib demonstrated effectiveness and a tolerable safety profile, making it a viable option as a fourth- or later-line treatment in Chinese patients with advanced GISTs, especially for non-gastric GISTs.
Xinhua Zhang, Peng Zhang, and Haibo Qiu are co-first authors.
Key Summary Points
Why carry out this study?
Ripretinib has demonstrated a favorable safety profile and promising efficacy in patients with advanced gastrointestinal stromal tumors (GIST).
However, there is a paucity of real-world evidence on ripretinib in Chinese patients with GIST. Hence, we conducted this study by collecting and analyzing real-world data from Chinese patients with advanced GIST.
What was learned from this study?
The results showed a clinically meaningful benefit and a tolerable safety profile of ripretinib as a fourth- or later-line treatment in Chinese patients with advanced GISTs, especially for non-gastric GISTs.
In addition, ripretinib was effective in the subgroup of patients with different gene mutations.
Introduction
Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract, with the most common site being stomach (60–65%) followed by the small intestine (20–25%) [1, 2]. GISTs mostly occur among middle-aged individuals between 60 and 65 years and a minority of children and young adults [3], with a slightly higher incidence in males [2]. They account for around 20% of soft tissue sarcomas [4], with an incidence of 10–15 cases per million worldwide, with the highest incidence rate being reported from China (Hong Kong and Shanghai areas) [5]. Most GISTs harbor oncogenic mutations in the receptor tyrosine kinase (KIT; 65–80%) or in the related platelet-derived growth factor receptor α (PDGFRA; 5–10%), which controls the tyrosine kinase receptors and causes constitutional activation, leading to tumor growth of cells [6, 7]. Approximately 8% of GISTs have a PDGFRA gain-of-function mutation involving the substitution of aspartic acid for valine at codon 842 in exon 18 (D842V) [8]. Until 2001, the only available treatment for GISTs was surgery, which had many challenges as complete resection was not possible in approximately half of the patients, with a median survival ranging from only 10–23 months [9].
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With the discovery that the mutational activation of KIT and PDGFRA genes stimulated the growth of these cancer cells, the treatment armamentarium of GIST has expanded. The advent of a tyrosine kinase inhibitor (TKI), imatinib, have shown to improve the survival of patients with GIST, and has been indicated in both the adjuvant and neoadjuvant settings [10, 11]. The National Comprehensive Cancer Network and the European Society for Medical Oncology guidelines also recommend the treatment with TKI for GIST [12, 13]. Although adenosine triphosphate (ATP)-competitive TKIs (imatinib, sunitinib, regorafenib, and avapritinib) have improved the outcome of patients with GIST, secondary TKI-specific inactivating mutations in the ATP-binding domain or activation loop of KIT/PDGFRA are likely to arise, resulting in tumor progression [14, 15]. Moreover, the PDGFRA D842V mutation causes primary resistance to imatinib and other TKIs [3]. Hence, there is an unmet medical need for effective treatments against a broad range of KIT/PDGFRA mutations in advanced GIST.
Ripretinib, a switch-control kinase inhibitor, is designed to inhibit both KIT and PDGFRA kinase signaling by binding to both the switch pocket and the activation loop, preventing downstream signaling and cell proliferation [16]. It demonstrated a favorable safety profile and promising efficacy in patients with advanced GIST previously treated with imatinib across all lines of therapy [17, 18]. Moreover, in a phase 3 study (n = 129), ripretinib significantly improved survival outcomes in patients with late-line GIST compared with placebo ([median overall survival (mOS) 18.2 vs. 6.3 months, hazard ratio (HR 0.42); median progression-free survival (mPFS) 6.3 vs. 1.0 months, HR 0.15], and an enhanced patients' quality of life (QoL) as well as a favorable safety [19]. Multiple phase 3 trials have demonstrated tolerable safety profile of ripretinib, with most side effects being of low grade and manageable in nature. The most common AEs reported were alopecia (49–63% in women), myalgia (28%), nausea (26%), fatigue (26%), hand-foot syndrome (21%), and diarrhea (20%) [20]. Furthermore, the analysis of European individual case safety reports showed a lower reporting probability of AEs with ripretinib than other TKIs, indicating a good safety profile of ripretinib [21].
Recently, the Chinese 4L bridging study (n = 39) showed a good clinical efficacy and safety of ripretinib in Chinese patients, with a mPFS of 7.2 months and an objective response rate (ORR) of 18.4% [22]. Based on these studies, ripretinib was approved in China on March 2021. The efficacy and safety of ripretinib used in late-line setting was also demonstrated (response rate: 25%, clinical benefit rate: 60%) in Taiwan and Hong Kong patients (n = 20) after a median follow-up of 10.4 months in a real-world study [23]. Given the small sample size of patients in the bridging and the real-world study, as well as the short marketing time of ripretinib, further exploration on the long-term efficacy and safety of ripretinib, as well as the dominant gene mutation type of ripretinib in Chinese GIST patients, is required. Hence, we planned to further explore the effectiveness of ripretinib and predictors of effectiveness by collecting and analyzing real-world data from Chinese patients with advanced GIST treated with ripretinib.
Methods
Study Design
This was a prospective, large-scale, real-world registry study based on the Patient Assistance Program (PAP) involving patients with histologically confirmed recurrent/metastatic GIST (ClinicalTrials.gov identifier: NCT05697107). The study was conducted in accordance with the ethical standards of the Declaration of Helsinki and approved by the ethics committee of Peking University Cancer Hospital (2022YJZ117). The study end points included mPFS (defined as the time from the start of ripretinib to the first documentation of progression as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 GIST-Specific Standard [24], or death from any cause), mOS (defined as the time from the start of ripretinib therapy to death from any cause), disease control rate [DCR, defined as the proportion of patients with a complete response or partial response or a stable disease lasting for at least 12 weeks], changes in patient self-reported QoL based on changes in European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3L) scale, and the incidence of adverse events (AEs) which were coded by the Medical Dictionary for Regulatory Activities (MedDRA) version 24.0.
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Patient Population
Patients with recurrent/metastatic GIST who had received ≥ 3 prior lines of TKIs were enrolled. Written informed consent was obtained from all the patients before enrollment. The inclusion criteria of the study were male and female patients aged ≥ 18 years, histologically confirmed GIST, had adequate organ function and bone marrow reserve, and received ripretinib therapy from March 2021 and March 2022. Patients who received < 1 cycle (28 days/cycle) of ripretinib treatment were not included in the study due to PAP restriction.
Procedures and Data Collection
The baseline information was collected, including gender, age, primary tumor initiation site, metastatic site, number of previous treatment lines, previous targeted therapy, KIT and PDGFRA pathogenic variant classification, maximum lesion size, Eastern Cooperative Oncology Group (ECOG) score, etc. The mutation profile was obtained from patients' medical records or from the PAP Medical Confirmation Form. The PAP Medical Confirmation Form (Supplementary Material Table 1) was used to confirm the diagnosis, site, and size of the tumor. In addition, information on previous lines of therapies and the ripretinib dosage was collected. Along with these, the information on past pathol, to assess QoL, EQ-5D-3L questionnaires were collected at baseline. To assess the effectiveness and safety of ripretinib at follow-up, a PAP Follow-up Form (Supplementary Material Table 2) was used. The CT/MRI examination report after medication (every 2 months) and the health utility data generated through the Chinese population-specific EQ-5D-3L scoring system[25] were also collected during the follow-up. QoL in terms of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression were collected at baseline and post-treatment with ripretinib.
Data Analysis
The statistical analysis of this study is of a descriptive nature. Categorical variables were presented as frequency and percentage, while continuous variables with normally distributed data as mean ± SD, and median (minimum, maximum) or 25th and 75th quantile for data which were not distributed normally. The mPFS, mOS, and other time-dependent variables were determined using the Kaplan–Meier method, with medians and corresponding 2-sided 95% confidence interval (CI) values reported and analyzed using the log-rank test. A stratified Cox proportional hazard model was used to analyze the independent factors [age (< 65 years old vs. ≥ 65 years old), gender (male/female), ECOG performance (0 vs. ≥ 1), maximum lesion diameter (≤ 10 cm vs. > 10 cm), number of previous treatment lines (≤ 3 vs. ≥ 4), tumor primary site (gastric site vs. non-gastric), exon 13/14 mutation (yes/no), and exon 17/18 mutation (yes/no)] associated with PFS. The statistical analysis was performed using SAS® version 9.4 (SAS Institute, Cary, NC, USA). A P value of ≤ 0.05 was considered statistically significant. The average health utility of pre-progression (progression-free, PF) and post-progressive (progressive disease, PD) states was calculated using SPSS software version 26.0.
Results
Patient Characteristics
A total of 240 patients with GIST receiving ripretinib enrolled in the study (Fig. 1). The median age of the patients was 58.1 years (range 21.6–90.7), and the majority of them were male (66.6%). Overall, 37.5% of patients had ECOG performance status (PS) score ≥ 2 and 33.3% of them had a lesion diameter of > 10 cm. The most common primary tumor site was small intestine (58.7%) followed by stomach (25%), and 94.5% of the tumors were metastatic in nature. KIT 11 was the most common primary mutation (49.6%) presented by the patients (Table 1).
aPatient may have multiple metastatic sites at the same time; as long as there is a certain metastatic site, it will be counted in a certain classification. Patients may be included in different metastatic site classifications at the same time, so the combined proportion of each type of patients is > 100%
bPatient may have multiple mutations at the same time; as long as a certain mutation is met, it will be counted in a certain mutation classification. Patients may be counted concurrently into different mutation categories, so the proportion of each type of patients combined is > 100%
×
Response and Survival
After a median follow-up period of 6.5 months, the mPFS (95% CI) was 7.7 (6.6, 8.6) months (Fig. 2). The DCR was 73%, and tumor shrinkage of any magnitude occurred in 43% of patients (Supplementary Material Table 3). The mOS was not reached [NR, 12.3, not evaluable (NE)] (Fig. 3).
Fig. 2
The mPFS of patients with ≥ 3 previous treatment lines. CI confidence interval, mPFS median progression-free survival
Fig. 3
The mOS of patients with ≥ 3 previous treatment lines. CI confidence interval, mOS median overall survival, NE not evaluable, NR not reached
×
×
In the subgroup of patients with different gene mutations, patients with KIT 11 mutation had a mPFS (95% CI) of 7.9 (6.6, NE) months, and those with KIT 9 mutation showed a mPFS (95% CI) of 6.1 (3.2, 8.6) months. In patients with any KIT 13/14 mutation and any KIT 17/18 mutation, the mPFS were 7.1 (4.9, NE) months and 6.8 (4.9, 8.1) months, respectively. In addition, ripretinib showed clinical benefit in wild-type [mPFS (95% CI): 6.3 (1.5, NE)] and also genotype unknown [mPFS (95% CI): 8.2 (5.7, 9.6)] groups (Table 2; Fig. 4).
Table 2
Effectiveness data in different gene mutation subgroups
Type
Patients (n)
PD, n (%)
Death, n (%)
Censoring, n (%)
mPFS, months (95% CI)
KIT 11
119
48 (40.3)
4 (3.3)
67 (56.3)
7.9 (6.6, NE)
KIT 9
38
22 (57.8)
1 (2.6)
15 (39.4)
6.1 (3.2, 8.6)
Wild Type
5
3 (60.0)
0 (0.0)
2 (40.0)
6.3 (1.5, NE)
Genotype unknown
60
26 (43.3)
4 (6.6)
30 (50.0)
8.2 (6.5, 9.6)
Any KIT 13 or KIT 14
30
12 (40.0)
2 (6.6)
16 (53.3)
7.1 (4.9, NE)
Any KIT 17 or KIT 18
68
38 (55.8)
1 (1.4)
29 (42.6)
6.8 (4.9, 8.1)
CI confidence interval, KIT tyrosine kinase, mPFS median progression-free survival, NE not evaluable
Fig. 4
The mPFS of patients in KIT mutation subgroups A KIT 11 mutation, B KIT 13/14 mutation, C KIT9 mutation, D KIT 17/18 mutation, E wild-type, F genotype unknown. CI confidence interval, KIT receptor tyrosine kinase, NE not evaluable, mPFS median progression-free survival
×
Univariate and multivariate analyses were conducted to evaluate the associations of various parameters with the mPFS in subgroups. In the multivariate analysis, ECOG PS score (0 and not ≥ 1) showed association with PFS. Furthermore, the analysis showed non-gastric GIST can benefit more from ripretinib treatment compared to gastric GIST [HR, 95%CI (0.6, 0.4–0.9)] (Fig. 5).
Fig. 5
Univariate and multivariate analyses for evaluating the association of various parameters with mPFS. CI confidence interval, ECOG PS Eastern Cooperative Oncology Group Performance Status, HR hazard ratio, mPFS median progression free survival
×
Safety
The AEs were tolerable in nature, and no unexpected toxicities were observed. In total, 89 (37.0%) AEs were observed, and the most common AEs were alopecia (17.1%) and hand-foot syndrome (15.4%; Table 3). No treatment-related deaths were observed in the study. Patients reported any AE leading to dose interruption, dose reduction, and treatment discontinuation were 1.7%. 6.3%, and 0.8%, respectively (Supplementary Material Table 4). The information on the type of AEs causing dose reduction is presented in Supplementary Material Table 5.
Table 3
Incidence of adverse events
Adverse event
n (%)
Total
89 (37.0)
Alopecia
41 (17.1)
Hand–foot syndrome
37 (15.4)
Fatigue
15 (6.3)
Hypertension
9 (3.8)
Diarrhea
8 (3.3)
Myalgia
7 (2.9)
Gingival bleeding
4 (1.7)
Constipation
3 (1.3)
Nausea
3 (1.3)
Vomiting
3 (1.3)
Hoarse voice
3 (1.3)
Lower extremity edema
2 (0.8)
Epistaxis
2 (0.8)
Stomach ache
2 (0.8)
Arthralgia
2 (0.8)
Muscle spasms
2 (0.8)
Mouth ulcers
2 (0.8)
Weight loss
2 (0.8)
Grey hair
2 (0.8)
Dizziness
2 (0.8)
Anorexia
2 (0.8)
Leukopenia
1 (0.4)
Fever
1 (0.4)
Abdominal discomfort
1 (0.4)
Difficulty breathing
1 (0.4)
Increased creatinine
1 (0.4)
Physical intolerance
1 (0.4)
Kidney damage
1 (0.4)
Limb pain
1 (0.4)
Muscle fatigue
1 (0.4)
Gastrointestinal reaction
1 (0.4)
Tachycardia
1 (0.4)
Heart discomfort
1 (0.4)
Elevated blood sugar
1 (0.4)
Gum pain
1 (0.4)
Eyelid rash
1 (0.4)
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Patients' Self-Reported Health Status Scores
Of the 156 patients with available QoL data, disease progression was observed in 54 (34.6%). The mean health utility values of PF and PD were 0.8 (95% CI 0.8–0.8) and 0.7 (95% CI 0.6–0.7), respectively, suggesting that the reduction in QoL of patients due to AEs following ripretinib treatment was low, thereby confirming that ripretinib was well tolerated. The change in numbers (percentage) of − 13 (− 15), − 2 (− 2), − 3 (− 3), − 6 (− 7), 3 (3) were observed for EQ-5D scale parameters, such as mobility, self-care, usual activities, pain/discomfort, and anxiety/depression (Supplementary Material Table 6). The average score of the visual analogue scale (VAS) reported by patients at baseline and at every 2 months follow-up showed that the patient's health status remained stable during the treatment, suggesting that ripretinib was well tolerated (Supplementary Material Table 7).
Discussion
The main objective of this study was to evaluate the effectiveness and safety of ripretinib as a fourth- or later-line therapy with a large sample size in a real world setting in Chinese patients with advanced GIST. This study demonstrated that ripretinib is effective in Chinese patients as ≥ 4th line therapy. We also found a favorable safety profile of ripretinib with no incidence of drug-related serious AEs or unexpected toxicities.
In a phase 1 study of dose escalation with a subsequent expansion phase at the recommended phase 2 dose consisting of 184 patients with advanced GIST, < 33% of the patients experienced a dose-limiting toxicity. The overall ORR was 11.3%, ranging from 7.2% (fourth-line therapy) to 19.4% (second-line therapy), and the mPFS was 5.6 months, ranging from 5.5 (fourth-line therapy) to 10.7 months (second-line therapy) [17]. This study provided a support for the evaluation of ripretinib in a phase 3 study (INVICTUS) that established the efficacy of ripretinib in patients with advanced GIST as a fourth-line or greater-line therapy. The mPFS was 6.3 months versus 1.0 month in the ripretinib group compared with the placebo group. The ORR was 11.8% and the mOS was 18.2 months in the patients receiving ripretinib, which was higher than those in patients receiving placebo (ORR: 0%; mOS: 6.3 months) [19]. The results of our study were in line with those of the INVICTUS trial in terms of the mPFS, which was 7.7 months. However, the mOS was NR. Ripretinib, through a dual mechanism of action, inhibits both KIT and PDGFRA kinase signaling, thus preventing the downstream signaling of survival and proliferation [16, 18]. Owing to this unique dual mechanism, the current study evaluated the effectiveness of ripretinib in subgroups of patients with different gene mutations for the first time in Chinese patients. Exon 11 of KIT is known as the most frequently mutated region which affects approximately two-thirds of GIST [26], and this study demonstrated the effectiveness of ripretinib in patients with KIT 11 mutation with a mPFS of 7.90 months.
In contrast to the INVICTUS study, which had a higher proportion of patients with gastric GIST (47%) than non-gastric GIST [18], the primary tumor site of the patients was small intestine (58.7%) in the current study. The Chinese bridging study also had a higher proportion of patients with tumor of small intestine (71.8%) than gastric GIST [22]. The primary location of the tumor is considered as an important prognostic risk factor, and there exists a common dogma that small intestinal (non-gastric) GISTs have worse prognosis than gastric GISTs, because of the higher risk of metastases and tumor-related death associated with non-gastric GISTs [13, 27]. Further, Miettinen et al. demonstrated that the risk of recurrence for a tumor of the same size and mitotic count was higher for non-gastric GIST than gastric GIST [28]. The results of the current study suggested that non-gastric GISTs have better prognosis with ripretinib than gastric GISTs. This observation may prove an important clinical implication for the management of the higher risk non-gastric GIST. In a study by Lin et al., pretreatment albumin level (P = 0.036) and disease control (P = 0.009) were identified as independent prognostic factors for PFS in patients treated with ripretinib [23]. However, the study did not evaluate the primary tumor site as one of the prognostic factors for PFS.
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The assessment of QoL and self-reported function in the INVICTUS study showed that ripretinib was associated with patient benefit in advanced GIST, with patient-reported outcome measures of role and physical function, VAS, overall health, and overall QoL remaining stable. The VAS scores improved an average 3.7 points from baseline with ripretinib, while there was an average decline of 8.9 with placebo [29]. The assessment of QoL in the real-world setting is valuable for late-line use in more fragile patients. In the current study, the average VAS score reported by patients at baseline and at every 2 months follow-up remained stable. Moreover, except for anxiety/depression, QoL assessment showed improvement in all the other parameters, such as mobility, self-care, usual activities, and pain/discomfort after ripretinib treatment.
Ripretinib was well tolerated in this study with no unexpected AEs. The most common AEs observed were alopecia (17.1%) and hand-foot syndrome (15.4%). Three patients had treatment interruption because of alopecia. The reason for alopecia might be the differences present in the inhibition of target kinases, the effect exerted on associated downstream pathways, and the role played by targeted molecules in hair follicle biology [30‐32]. The incidence of alopecia observed in our study was comparatively lower than that observed in previous studies (49% in phase III study and 62% in a phase I study) [17, 18]. Moreover, compared to the previous studies, incidence of hand-foot syndrome was lower in the current study (21% in phase III study and 43.7% in a phase I study). Post-marketing data also showed a high probability of ripretinib to report skin and subcutaneous tissue disorders, especially for alopecia (odds ratio: 1.5; 95% CI 1.0–2.2) [21]. In the INVICTUS trial, patients were stratified by the known prognostic variables such as ECOG PS and the number of previous therapies [18]. The multivariate analysis of the current study showed that ECOG PS was associated with PFS. However, no such analysis was performed to determine the risk factors in the Chinese bridging study [22].
Recently, the efficacy (mPFS: 7.2 months; ORR: 18.4%) and safety (majority of treatment-related AEs were of grade ½) of ripretinib were demonstrated in a phase 2 study consisting of Chinese patients with advanced GIST. The study showed that the efficacy, safety, and pharmacokinetic profiles of ripretinib were consistent with those in the global patient population [22]. Although clinical trials are essential for determining the efficacy of treatment, real-world studies are becoming an absolute necessity that can help clinicians make informed decisions in improving patient care and QoL. We believe that this study will provide further insights into the effectiveness of ripretinib in the real-world clinical setting. Moreover, the probable benefit of ripretinib in non-gastric GIST having a higher degree of recurrence compared to gastric GIST will provide a better treatment option for these patient populations. To our knowledge, this is the first study with the largest real-world data of ripretinib to date that has shown effectiveness even in patients with different gene mutations. The current study supports the clinically meaningful benefit of ripretinib demonstrated by the INVICTUS study in a mutation subgroup of patients with GIST [33]. The INVICTUS study showed PFS benefit of ripretinib over placebo regardless of mutation status (HR 0.1, 95% CI 0.1–0.2) [33]. Similarly, in the current study, patients with KIT 11, KIT 9, KIT 13/14, and KIT 17/18 mutations, wild-type, and unknown genotype, all showed mPFS in the range of 6.1–8.2, demonstrating the beneficial effects of ripretinib in patients with different gene mutations in the real-world setting.
Our study may be limited by the nature of the design as an observational study, in comparison with randomized controlled trials, which can commonly provide stronger evidence in the effectiveness of therapies. A detailed evaluation of AEs with grading and serious AEs was not performed in the current study, thus limiting the conclusive evidence on safety outcomes. In addition, the study was only conducted in Chinese patients, and, hence, the results may not be generalizable to other geographic regions.
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Conclusions
Ripretinib showed a clinically meaningful benefit and a tolerable safety profile as a fourth- or later-line therapy in patients with advanced GIST in the real-world setting. In addition, ripretinib was effective in the subgroup of patients with different gene mutations. Furthermore, patients with advanced GIST of non-gastric origin are more likely to benefit from ripretinib treatment than those of gastric origin. The results of the study suggest that ripretinib is a favorable option with promising activity for treating patients with refractory advanced GIST.
Acknowledgements
We would like to thank the China Primary Health Care Foundation for providing the original database.
Funding
No funding or sponsorship was received for this study. The Rapid Service and Open Access Fees were funded by The China Primary Health Care Foundation.
Medical Writing, Editorial, and Other Assistance
We would like to thank Dr. Sunita Rana and Anwesha Mandal of Indegene Pvt Ltd, Bengaluru, India for providing the medical writing assistance as funded by the China Primary Health Care Foundation.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Author Contributions
Xinhua Zhang: Conceptualization, data curation, formal analysis, writing–review and editing. Peng Zhang, Haibo Qiu, Yong Fang, Heli Liu, Yongjian Zhou, Hao Xu, JiRen Yu, Jun Zhang, Ming Wang, Lin Shen: Data curation, formal analysis, writing–review and editing. Jian Li: Conceptualization, supervision, writing–review and editing.
Disclosures
Xinhua Zhang, Peng Zhang, Haibo Qiu, Yong Fang, Heli Liu, Yongjian Zhou, Hao Xu, JiRen Yu, Jun Zhang, Ming Wang, Lin Shen, and Jian Li have nothing to disclose.
Compliance with Ethics Guidelines
The study was conducted in accordance with the ethical standards of the Declaration of Helsinki and approved by the ethics committee of Peking University Cancer Hospital (2022YJZ117). A written informed consent was obtained from all the patients before enrollment.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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