99mTc Hynic-rh-Annexin V scintigraphy for in vivo imaging of apoptosis in patients with head and neck cancer treated with chemoradiotherapy

PURPOSE: The purpose of this study was to determine the value of (99m)Tc Hynic-rh-Annexin-V-Scintigraphy (TAVS), a non-invasive in vivo technique to demonstrate apoptosis in patients with head and neck squamous cell carcinoma. METHODS: TAVS were performed before and within 48 h after the first course of cisplatin-based chemoradiation. Radiation dose given to the tumour at the time of post-treatment TAVS was 6-8 Gy. Single-photon emission tomography data were co-registered to planning CT scan. Complete sets of these data were available for 13 patients. The radiation dose at post-treatment TAVS was calculated for several regions of interest (ROI): primary tumour, involved lymph nodes and salivary glands. Annexin uptake was determined in each ROI, and the difference between post-treatment and baseline TAVS represented the absolute Annexin uptake: Delta uptake (DeltaU). RESULTS: In 24 of 26 parotid glands, treatment-induced Annexin uptake was observed. Mean DeltaU was significantly correlated with the mean radiation dose given to the parotid glands (r = 0.59, p = 0.002): Glands that received higher doses showed more Annexin uptake. DeltaU in primary tumour and pathological lymph nodes showed large inter-patient differences. A high correlation was observed on an inter-patient level (r = 0.71, p = 0.006) between the maximum DeltaU in primary tumour and in the lymph nodes. CONCLUSIONS: Within the dose range of 0-8 Gy, Annexin-V-scintigraphy showed a radiation-dose-dependent uptake in parotid glands, indicative of early apoptosis during treatment. The inter-individual spread in Annexin uptake in primary tumours could not be related to differences in dose or tumour volume, but the Annexin uptake in tumour and lymph nodes were closely correlated. This effect might represent a tumour-specific apoptotic respons

Trends in treatment and overall survival among patients with proximal esophageal cancer

BACKGROUND: The management of proximal esophageal cancer differs from that of tumors located in the mid and lower part of the esophagus due to the close vicinity of vital structures. Non-surgical treatment options like radiotherapy and definitive chemoradiation (CRT) have been implemented. The trends in (non-)surgical treatment and its impact on overall survival (OS) in patients with proximal esophageal cancer are unclear, related to its rare disease status. To optimize treatment strategies and counseling of patients with proximal esophageal cancer, it is therefore essential to gain more insight through real-life studies. AIM: To establish trends in treatment and OS in patients with proximal esophageal cancer. METHODS: In this population-based study, patients with proximal esophageal cancer diagnosed between 1989 and 2014 were identified in the Netherlands Cancer Registry. The proximal esophagus consists of the cervical esophagus and the upper thoracic section, extending to 24 cm from the incisors. Trends in radiotherapy, chemotherapy, and surgery, and OS were assessed. Analyses were stratified by presence of distant metastasis. Multivariable Cox proportional hazards regression analyses was performed to assess the effect of period of diagnosis on OS, adjusted for patient, tumor, and treatment characteristics. RESULTS: In total, 2783 patients were included. Over the study period, the use of radiotherapy, resection, and CRT in non-metastatic disease changed from 53%, 23%, and 1% in 1989-1994 to 21%, 9%, and 49% in 2010-2014, respectively. In metastatic disease, the use of chemotherapy and radiotherapy increased over time. Median OS of the total population increased from 7.3 mo [95% confidence interval (CI): 6.4-8.1] in 1989-1994 to 9.5 mo (95%CI: 8.1-10.8) in 2010-2014 (logrank P < 0.001). In non-metastatic disease, 5-year OS rates improved from 5% (95%CI: 3%-7%) in 1989-1994 to 13% (95%CI: 9%-17%) in 2010-2014 (logrank P < 0.001). Multivariable regression analysis demonstrated a significant treatment effect over time on survival. In metastatic disease, median OS was 3.8 mo (95%CI: 2.5-5.1) in 1989-1994, and 5.1 mo (95%CI: 4.3-5.9) in 2010-2014 (logrank P = 0.26). CONCLUSION: OS significantly improved in non-metastatic proximal esophageal cancer, likely to be associated with an increased use of CRT. Patterns in metastatic disease did not change significantly over time

A national study to assess outcomes of definitive chemoradiation regimens in proximal esophageal cancer

Background: Proximal esophageal cancer (EC) is commonly treated with definitive chemoradiation (CRT). The radiation dose and type of chemotherapy backbone are still under debate. The objective of this study was to compare the treatment outcomes of contemporary CRT regimens. Material and Methods: In this retrospective observational cohort study, we included patients with locally advanced squamous cell cancer of the proximal esophagus, from 11 centers in the Netherlands, treated with definitive CRT between 2004 and 2014. Each center had a preferential CRT regimen, based on cisplatin (Cis) or carboplatin-paclitaxel (CP) combined with low (≤50.4 Gy) or high (>50.4 Gy) dose radiotherapy (RT). Differences in overall survival (OS) between CRT regimens were assessed using a fully adjusted Cox proportional hazards and propensity score (PS) weighted model. Safety profiles were compared using a multilevel logistic regression model. Results: Two hundred patients were included. Fifty-four, 39, 95, and 12 patients were treated with Cis-low-dose RT, Cis-high-dose RT, CP-low-dose RT, and CP-high-dose RT, respectively. Median follow-up was 62.6 months (95% CI: 47.9–77.2 months). Median OS (21.9 months; 95% CI: 16.9–27.0 months) was comparable between treatment groups (logrank p = .88), confirmed in the fully adjusted and PS weighted model (p > .05). Grades 3–5 acute adverse events were less frequent in patients treated with CP-low-dose RT versus Cis-high-dose RT (OR 3.78; 95% CI: 1.31–10.87; p = .01). The occurrence of grades 3–5 late toxicities was not different between treatment groups. Conclusion: Our study was unable to demonstrate a difference in OS between the CRT regimens, probably related to the relatively small sample size. Based on the superior safety profile, carboplatin and paclitaxel-based CRT regimens are preferred in patients with locally advanced proximal EC

Distinct inflammatory signatures of upper and lower body adipose tissue and adipocytes in women with normal weight or obesity

IntroductionUpper and lower body fat accumulation poses an opposing obesity-related cardiometabolic disease risk. Depot-differences in subcutaneous adipose tissue (SAT) function may underlie these associations. We aimed to investigate the inflammatory signatures of abdominal (ABD) and femoral (FEM) SAT in postmenopausal women with normal weight or obesity.MethodsWe included 23 postmenopausal women with normal weight (n = 13) or obesity (n = 10). In vivo secretion of adipokines from ABD and FEM SAT was measured using the arterio-venous balance technique. Adipokine gene expression and adipocyte morphology were examined in ABD and FEM SAT. Furthermore, adipokine expression and secretion were investigated in vitro using differentiated human primary ABD and FEM subcutaneous adipocytes derived from the study participants.ResultsPlasma leptin and plasminogen activator inhibitor (PAI)-1 concentrations were higher, and ABD and FEM adipocytes were larger in women with obesity than normal weight. No differences in adipocyte size and blood flow were apparent between ABD and FEM SAT. We found significant release of leptin and monocyte chemoattractant protein (MCP)-1 from ABD and FEM SAT, with higher fractional release of MCP-1 from ABD than FEM SAT. Gene expression of leptin, PAI-1, and tumor necrosis factor-α was lower in ABD than FEM SAT and higher in women with obesity than normal weight. In ABD adipocytes, interleukin-6, PAI-1, and leptin gene expression were higher, while adiponectin and dipeptidyl-peptidase-4 gene expression were lower than in FEM adipocytes. Finally, ABD adipocytes secreted less MCP-1 compared to FEM adipocytes.DiscussionThese findings demonstrate that upper and lower body SAT and adipocytes are characterized by distinct inflammatory signatures in postmenopausal women, which seem independent of adipocyte size

Patterns of recurrence following definitive chemoradiation for patients with proximal esophageal cancer

Introduction: The aim of this retrospective study was to determine the patterns of recurrence and overall survival (OS) in patients achieving clinical complete response after treatment with definitive chemoradiation (CRT) for proximal esophageal cancer. Materials and methods: Patients with proximal esophageal cancer treated with CRT between 2004 and 2014 in 11 centers in the Netherlands were included. OS and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Cumulative incidence of first recurrence (locoregional or distant) and locoregional recurrence (LRR) were assessed using competing risk analyses. Results: In 197 of the 200 identified patients, response was evaluated, 133 (68%) showed a complete response. In complete responders, median OS, three-year OS, and PFS were 45.0 months (95% CI 34.8-61.5 months), 58% (95% CI 48-66), and 49% (95% CI 40-57), respectively. Three- and five-year risk of recurrence were respectively 40% (95% CI 31-48), and 45% (95% CI 36-54). Three- and five-year risk of LRR were 26% (95% CI 19-33), and 30% (95% CI 22-38). Eight of 32 patients with an isolated LRR underwent salvage surgery, with a median OS of 32.0 months (95% CI 6.8-not reached). Conclusion: In patients with a complete response after definitive CRT for proximal esophageal cancer, most recurrences were locoregional and developed within the first three years after CRT. These findings suggest to shorten locoregional follow-up from five to three years. (C) 2021 The Authors. Published by Elsevier Ltd

No evidence for cardiac dysfunction in Kif6 mutant mice.

A KIF6 variant in man has been reported to be associated with adverse cardiovascular outcomes after myocardial infarction. No clear biological or physiological data exist for Kif6. We sought to investigate the impact of a deleterious KIF6 mutation on cardiac function in mice. Kif6 mutant mice were generated and verified. Cardiac function was assessed by serial echocardiography at baseline, after ageing and after exercise. Lipid levels were also measured. No discernable adverse lipid or cardiac phenotype was detected in Kif6 mutant mice. These data suggest that dysfunction of Kif6 is linked to other more complex biological/biochemical parameters or is unlikely to be of material consequence in cardiac function

Cisplatin-DNA adduct formation in patients treated with cisplatin-based chemoradiation: lack of correlation between normal tissues and primary tumor

Contains fulltext : 69595.pdf (publisher's version ) (Closed access)PURPOSE: In this study, the formation of cisplatin-DNA adducts after concurrent cisplatin-radiation and the relationship between adduct-formation in primary tumor tissue and normal tissue were investigated. METHODS: Three intravenous cisplatin-regimens, given concurrently with radiation, were studied: daily low-dose (6 mg/m(2)) cisplatin, weekly 40 mg/m(2), three-weekly 100 mg/m(2). A (32)P-postlabeling technique was used to quantify adducts in normal tissue [white blood cells (WBC) and buccal cells] and tumor. RESULTS: Normal tissue samples for adduct determination were obtained from 63 patients and tumor biopsies from 23 of these patients. Linear relationships and high correlations were observed between the levels of two guanosine- and adenosine-guanosine-adducts in normal and tumor tissue. Adduct levels in tumors were two to five times higher than those in WBC (P<0.001). No significant correlations were found between adduct levels in normal tissues and primary tumor biopsies, nor between WBC and buccal cells. CONCLUSIONS: In concurrent chemoradiotherapy schedules, cisplatin adduct levels in tumors were significantly higher than in normal tissues (WBC). No evidence of a correlation was found between adduct levels in normal tissues and primary tumor biopsies. This lack of correlation may, to some extent, explain the inconsistencies in the literature regarding whether or not cisplatin-DNA adducts can be used as a predictive test in anticancer platinum therapy

The development of a decision aid for patients with operable oropharyngeal carcinoma in the Netherlands - A mixed methods study

OBJECTIVE: The aim of this project is to create an interactive online patient decision aid (PDA) for oropharyngeal cancer (OPSCC) patients, eligible for transoral (robotic) surgery with an ultimate goal to assist both physicians and patients in making treatment choices. MATERIALS AND METHODS: Following the International Patient Decision Aid Standards, a mixed-methods approach was employed. The study involved semi-structured in-depth interviews with patients and physicians, thinking-out-loud sessions, and study-specific questionnaires. Thematic coding and analysis were conducted on verbatim transcriptions of audio-recorded interviews. RESULTS: The PDA drafts were evaluated by twenty OPSCC survivors and twenty multidisciplinary specialists. Significant revisions were made after phase 1 to enhance readability and reduce text, whilst incorporating videos and graphics. Following all phases, both patients and specialists rated the PDA as comprehensible, feasible, and a valuable addition to regular counseling. CONCLUSION: This study showcases the development of a PDA for early stage oropharyngeal cancer patients considering surgery and radiotherapy options. The decision aid emphasizes the disparities in short- and long-term side effects between the two treatments. Patients and physicians found the decision aid to be understandable, user-friendly, and helpful for future patients. The PDA is available on https://beslissamen.nl/

Sexual Behaviour and HPV Infections in 18 to 29 Year Old Women in the Pre-Vaccine Era in the Netherlands

Contains fulltext : 71058.pdf ( ) (Open Access)BACKGROUND: Infection with Human Papillomavirus (HPV) is a necessary event in the multi-step process of cervical carcinogenesis. Little is known about the natural history of HPV infection among unscreened young adults. As prophylactic vaccines are being developed to prevent specifically HPV 16 and 18 infections, shifts in prevalence in the post vaccine era may be expected. This study provides a unique opportunity to gather baseline data before changes by nationwide vaccination occur. METHODS AND PRINCIPAL FINDINGS: This cross-sectional study is part of a large prospective epidemiologic study performed among 2065 unscreened women aged 18 to 29 years. Women returned a self-collected cervico-vaginal specimen and filled out a questionnaire. All HPV DNA-positive samples (by SPF(10) DEIA) were genotyped using the INNO-LiPA HPV genotyping assay. HPV point prevalence in this sample was 19%. Low and high risk HPV prevalence was 9.1% and 11.8%, respectively. A single HPV-type was detected in 14.9% of all women, while multiple types were found in 4.1%. HPV-types 16 (2.8%) and 18 (1.4%) were found concomitantly in only 3 women (0.1%). There was an increase in HPV prevalence till 22 years. Multivariate analysis showed that number of lifetime sexual partners was the most powerful predictor of HPV positivity, followed by type of relationship, frequency of sexual contact, age, and number of sexual partners over the past 6 months. CONCLUSIONS AND SIGNIFICANCE: This study shows that factors independently associated with HPV prevalence are mainly related to sexual behaviour. Combination of these results with the relative low prevalence of HPV 16 and/or 18 may be promising for expanding the future target group for catch up vaccination. Furthermore, these results provide a basis for research on possible future shifts in HPV genotype prevalence, and enable a better estimate of the effect of HPV 16-18 vaccination on cervical cancer incidence