Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer

AIM: Because the tyrosine kinases c-MET and vascular endothelial growth factor receptors (VEGFR) are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in patients with recurrent/metastatic (R/M) SGC. PATIENTS AND METHODS: A single-centre phase II study was conducted. Patients with immunohistochemical c-MET-positive R/M SGC were included in three cohorts: adenoid cystic carcinoma (ACC); salivary duct carcinoma (SDC) and other miscellaneous SGCs. No prior systemic treatments were required. Patients started cabozantinib 60 mg once daily. The primary outcome was the objective response rate (ORR). Secondary outcomes included survival, safety and quality of life. Per Simon-two-stage design, depending on efficacy, a maximum of 43 patients would be included. RESULTS: In total, 25 patients were included until premature closure owing to severe toxicity. Six patients (24%) had grade 3-5 wound complications, occurring at a median of 7.1 months on cabozantinib treatment (range 2.1-12.6). Remarkably, four of these six patients developed this complication in the area prior exposed to high-dose radiotherapy. Other grade ≥3 adverse events in >1 patient were hypertension (20%), diarrhoea (8%) and dehydration (8%). Twenty-one patients were evaluable for response; 1/15 ACC (ORR: 7%); 1/4 SDC and 0/2 patients with other miscellaneous SGC responded. Median progression-free survival was 9.4 months (95% confidence interval [CI] 7.4-11.4 months), 7.2 months (95%CI 0.0-15.1) and 6.9 months (95%CI 0.0-15.1), respectively. CONCLUSION: This study showed too many severe cabozantinib-associated wound complications in patients with SGC, especially in prior irradiated areas. Therefore, the study closed prematurely. The efficacy in the limited number of evaluable patients was low to moderate. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov: NCT03729297

MUC5B levels in submandibular gland saliva of patients treated with radiotherapy for head-and-neck cancer: A pilot study

<p>Abstract</p> <p>Background</p> <p>The salivary mucin MUC5B, present in (sero)mucous secretions including submandibular gland (SMG) saliva, plays an important role in the lubrication of the oral mucosa and is thought to be related to the feeling of dry mouth. We investigated if MUC5B levels in SMG saliva could distinguish between the presence or absence of severe dry mouth complaints 12 months after radiotherapy (RT) for head-and-neck cancer (HNC).</p> <p>Findings</p> <p>Twenty-nine HNC patients with a residual stimulated SMG secretion rate of ≥0.2 ml/10 min at 12 months after RT were analyzed. MUC5B (in U; normalized to 1) and total protein levels (mg/ml) were measured in SMG saliva at baseline and 12 months after RT using ELISA and BCA protein assay, respectively. Overall, median MUC5B levels decreased after RT from 0.12 to 0.03 U (<it>p</it> = 0.47). Patients were dichotomized into none/mild xerostomia (n = 12) and severe xerostomia (n = 17) based on a questionnaire completed at 12 months. SMG and whole saliva flow rates decreased after RT but were comparable in both groups. The median MUC5B level was higher in patients with no or mild xerostomia compared to patients with severe xerostomia (0.14 vs 0.01 U, <it>p</it> = 0.22). Half of the patients with severe xerostomia had no detectable MUC5B at 12 months after RT. No differences in total protein levels were observed.</p> <p>Conclusions</p> <p>Qualitative saliva parameters like MUC5B need further investigation in RT-induced xerostomia. This pilot study showed a trend towards lower MUC5B levels in the SMG saliva of patients with severe xerostomia 12 months after RT for HNC.</p

Sex and Gender-Related Differences in COVID-19 Diagnoses and SARS-CoV-2 Testing Practices During the First Wave of the Pandemic:The Dutch Lifelines COVID-19 Cohort Study

Background: Although sex differences are described in Coronavirus Disease 2019 (COVID-19) diagnoses and testing, many studies neglect possible gender-related influences. Additionally, research is often performed in clinical populations, while most COVID-19 patients are not hospitalized. Therefore, we investigated associations between sex and gender-related variables, and COVID-19 diagnoses and testing practices in a large general population cohort during the first wave of the pandemic when testing capacity was limited. Methods: We used data from the Lifelines COVID-19 Cohort (N = 74,722; 60.8% female). We applied bivariate and multiple logistic regression analyses. The outcomes were a COVID-19 diagnosis (confirmed by SARS-CoV-2 PCR testing or physician's clinical diagnosis) and PCR testing. Independent variables included among others participants' sex, age, somatic comorbidities, occupation, and smoking status. Sex-by-comorbidity and sex-by-occupation interaction terms were included to investigate sex differences in associations between the presence of comorbidities or an occupation with COVID-19 diagnoses or testing practices. Results: In bivariate analyses female sex was significantly associated with COVID-19 diagnoses and testing, but significance did not persist in multiple logistic regression analyses. However, a gender-related variable, being a health care worker, was significantly associated with COVID-19 diagnoses (OR = 1.68; 95%CI = 1.30-2.17) and testing (OR = 12.5; 95%CI = 8.55-18.3). Female health care workers were less often diagnosed and tested than male health care workers (ORinteraction = 0.54; 95%CI = 0.32-0.92, ORinteraction = 0.53; 95%CI = 0.29-0.97, respectively). Conclusions: We found no sex differences in COVID-19 diagnoses and testing in the general population. Among health care workers, a male preponderance in COVID-19 diagnoses and testing was observed. This could be explained by more pronounced COVID-19 symptoms in males or by gender inequities

Preserved Myocardial Deformation after Successful Coarctation Repair: A CMR Feature-Tracking Study

Contains fulltext : 190059.pdf (publisher's version ) (Open Access

Diagnosis, imaging and clinical management of aortic coarctation

Coarctation of the aorta (CoA) is a well-known congenital heart disease (CHD), which is often associated with several other cardiac and vascular anomalies, such as bicuspid aortic valve (BAV), ventricular septal defect, patent ductus arteriosus and aortic arch hypoplasia. Despite echocardiographic screening, prenatal diagnosis of CoA remains difficult. Most patients with CoA present in infancy with absent, delayed or reduced femoral pulses, a supine arm-leg blood pressure gradient (>20 mm Hg), or a murmur due to rapid blood flow across the CoA or associated lesions (BAV). Transthoracic echocardiography is the primary imaging modality for suspected CoA. However, cardiac magnetic resonance imaging is the preferred advanced imaging modality for non-invasive diagnosis and follow-up of CoA. Adequate and timely diagnosis of CoA is crucial for good prognosis, as early treatment is associated with lower risks of long-term morbidity and mortality. Numerous surgical and transcatheter treatment strategies have been reported for CoA. Surgical resection is the treatment of choice in neonates, infants and young children. In older children (>25 kg) and adults, transcatheter treatment is the treatment of choice. In the current era, patients with CoA continue to have a reduced life expectancy and an increased risk of cardiovascular sequelae later in life, despite adequate relief of the aortic stenosis. Intensive and adequate follow-up of the left ventricular function, valvular function, blood pressure and the anatomy of the heart and the aorta are, therefore, critical in the management of CoA. This review provides an overview of the current state-of-the-art clinical diagnosis, diagnostic imaging algorithms, treatment and follow-up of patients with CoA

Diagnosis, imaging and clinical management of aortic coarctation

Coarctation of the aorta (CoA) is a well-known congenital heart disease (CHD), which is often associated with several other cardiac and vascular anomalies, such as bicuspid aortic valve (BAV), ventricular septal defect, patent ductus arteriosus and aortic arch hypoplasia. Despite echocardiographic screening, prenatal diagnosis of CoA remains difficult. Most patients with CoA present in infancy with absent, delayed or reduced femoral pulses, a supine arm-leg blood pressure gradient (>20 mm Hg), or a murmur due to rapid blood flow across the CoA or associated lesions (BAV). Transthoracic echocardiography is the primary imaging modality for suspected CoA. However, cardiac magnetic resonance imaging is the preferred advanced imaging modality for non-invasive diagnosis and follow-up of CoA. Adequate and timely diagnosis of CoA is crucial for good prognosis, as early treatment is associated with lower risks of long-term morbidity and mortality. Numerous surgical and transcatheter treatment strategies have been reported for CoA. Surgical resection is the treatment of choice in neonates, infants and young children. In older children (>25 kg) and adults, transcatheter treatment is the treatment of choice. In the current era, patients with CoA continue to have a reduced life expectancy and an increased risk of cardiovascular sequelae later in life, despite adequate relief of the aortic stenosis. Intensive and adequate follow-up of the left ventricular function, valvular function, blood pressure and the anatomy of the heart and the aorta are, therefore, critical in the management of CoA. This review provides an overview of the current state-of-the-art clinical diagnosis, diagnostic imaging algorithms, treatment and follow-up of patients with CoA

Arterioventricular interaction after coarctation repair

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Arterioventricular interaction after coarctation repair

Background: Hypertension is common in patients with coarctation of the aorta (CoA), even after successful repair. Increased aortic stiffness has been implicated in the pathology of CoA-associated hypertension. This study aimed to investigate aortic vascular function and its relationship with hypertension in well-repaired CoA-patients at long-term follow-up. Furthermore, we assessed the additive effect of hypertension to adverse arterioventricular coupling associated with increased aortic stiffness. Methods: Twenty-two CoA-patients (age 30 ± 10.6 years) with successful surgical repair (n = 12) or balloon angioplasty (BA) (n = 10) between 3 months and 16 years of age with a follow-up of >10 years and 22 healthy controls underwent cardiac magnetic resonance imaging (CMR), at mean follow-up of 29.3 years, to study aortic pulse wave velocity (PWV), aortic distensibility, global left ventricular (LV) function, LV dimensions, and LV myocardial deformation. Results: CoA-patients had significantly increased aortic arch PWV (5.6 ± 1.9 m/s vs. 4.5 ± 1.0 m/s, P =.02) and decreased distensibility (4.5 ± 1.8 × 10–3 mmHg−1 vs. 5.8 ± 1.8 × 10–3 mmHg−1, P =.04) compared to controls. Significant differences in aortic arch PWV were found between hypertensive patients, normotensive patients and controls (6.1 ± 1.8 m/s vs. 4.9 ± 1.9 m/s and 4.5 ± 1.0 m/s, respectively, P =.03). Aortic arch PWV and distensibility were correlated with systolic blood pressure (R = 0.37 and R = −0.37, respectively, P =.03 for both). Global LV function, LV mass, LV dimensions and myocardial deformation were similar in CoA-patients when compared to controls. Conclusions: Central aortic stiffness is significantly increased in well-repaired CoA-patients long-term after repair, and is associated with hypertension. Global LV function, myocardial deformation indices and LV dimensions are however preserved

18F-FDG-PET/CT-guided radiotherapy of cervical lymph nodes in head and neck squamous cell carcinoma

The use of positron emission tomography with fluor-18-fluorodeoxyglucose (FDG-PET) in clinical practice for patients with head and neck squamous cell carcinoma (HNSCC) has expanded rapidly, with implications for diagnostic staging, radiotherapy planning, adaptive radiotherapy, and post-therapy evaluation. The implementation of FDG-PET/CT in radiation treatment planning not only has consequences for target volume definition and dose prescription but is also associated with an increased overall survival in patients with HNSCC. FDG-PET/CT-guided gradient dose prescription provides a window of opportunity for treatment de-intensification of the neck in order to decrease treatment-related toxicity without compromising oncological outcome. Further, interim FDG-PET/CT during radiotherapy can be useful to assess metabolic tumor response and enables opportunities for adaptive treatment strategies. The goals are to increase treatment effectivity in poor responders and reduce unnecessary toxicity in patients with good early tumor response. Further prospective trials investigating adaptive radiotherapy based on interim PET-evaluation are needed, especially regarding human papilloma virus-negative HNSCC and patients treated with primary radiotherapy

Preserved Myocardial Deformation after Successful Coarctation Repair : A CMR Feature-Tracking Study

Arterial vasculopathy and residual aortic obstruction can lead to left ventricular (LV) dysfunction in patients with coarctation of the aorta (CoA) related to adverse ventriculo-arterial coupling. This study aimed to investigate potential differences in LV myocardial deformation indices between repaired CoA patients and healthy controls. Twenty-two CoA patients (age 30 ± 10.6 years) after surgical repair (n = 12) or balloon angioplasty (BA) (n = 10) without residual stenosis, between 3 months and 16 years of age with > 10 years follow-up were compared to 22 healthy age- and gender-matched controls (age 30 ± 3.8 years). Cardiac magnetic resonance feature tracking (CMR-FT) was used for LV longitudinal-, circumferential-, and rotational deformation indices. Global systolic LV function was preserved in CoA patients (LV ejection fraction 58 ± 4.8 vs. 60 ± 6.8%, p = 0.56) when compared to controls, with normal LV dimensions and mass (p > 0.05). Twelve CoA patients (55%) were hypertensive, of whom 4 were on anti-hypertensive medication. LV global longitudinal strain was preserved in the four-chamber (− 18 ± 4.4 vs. − 16 ± 4.7%, p = 0.06) and two-chamber (− 22 ± 5.1 vs. − 20 ± 6.0%, p = 0.22) orientations in CoA patients. Global circumferential strain was preserved at basal (− 29 ± 4.1 vs. − 28 ± 4.8%, p = 0.43), mid-ventricular (− 27 ± 4.2 vs. − 25 ± 3.0%, p = 0.09), and apical levels (− 35 ± 7.8 vs. − 32 ± 34.9%, p = 0.32). No differences were found in global torsion (2.4 ± 1.3° vs. 2.0 ± 1.4°/cm, p = 0.28), twist (14 ± 5.8° vs. 12 ± 6.3°, p = 0.34), and recoil rate (− 17 ± 9.7° vs. − 17 ± 7.1°/cm s, p = 0.97). Analysis of intra-observer variability demonstrated good reproducibility for all CMR deformation indices. Global and rotational myocardial deformation indices are preserved in CoA patients long-term after repair without residual stenosis, despite a high incidence of hypertension