Search

Background The association of early changes in the immune infiltrate during neoadjuvant chemotherapy (NACT) with pathological complete response (pCR) in triple-negative breast cancer (TNBC) remains unexplored.Methods Multiplexed immunohistochemistry was performed in matched tumor biopsies obtained at baseline and after 3 weeks of NACT from 66 patients from the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer - Triple Negative Breast Cancer (WSG-ADAPT-TN) trial. Association between CD4, CD8, CD73, T cells, PD1-positive CD4 and CD8 cells, and PDL1 levels in stroma and/or tumor at baseline, week 3 and 3-week change with pCR was evaluated with univariable logistic regression.Results Compared with no change in immune cell composition and functional markers, transition from ‘cold’ to ‘hot’ (below-median and above-median marker level at baseline, respectively) suggested higher pCR rates for PD1-positive CD4 (tumor: OR=1.55, 95% CI 0.45 to 5.42; stroma: OR=2.65, 95% CI 0.65 to 10.71) and PD1-positive CD8 infiltrates (tumor: OR=1.77, 95% CI 0.60 to 5.20; stroma: OR=1.25, 95% CI 0.41 to 3.84; tumor+stroma: OR=1.62, 95% CI 0.51 to 5.12). No pCR was observed after ‘hot-to-cold’ transition in PD1-positive CD8 cells. pCR rates appeared lower after hot-to-cold transitions in T cells (tumor: OR=0.26, 95% CI 0.03 to 2.34; stroma: OR=0.35, 95% CI 0.04 to 3.25; tumor+stroma: OR=0.00, 95% CI 0.00 to 1.04) and PD1-positive CD4 cells (tumor: OR=0.60, 95% CI 0.11 to 3.35; stroma: OR=0.22, 95% CI 0.03 to 1.92; tumor+stroma: OR=0.32, 95% CI 0.04 to 2.94). Higher pCR rates collated with ‘altered’ distribution (levels below-median and above-median in tumor and stroma, respectively) of T cell (OR=3.50, 95% CI 0.84 to 14.56) and PD1-positive CD4 cells (OR=4.50, 95% CI 1.01 to 20.14).Conclusion Our exploratory findings indicate that comprehensive analysis of early immune infiltrate dynamics complements currently investigated predictive markers for pCR and may have a potential to improve guidance for individualized de-escalation/escalation strategies in TNBC.

OBJECTIVE: This study aimed to prospectively investigate associations of working night shifts with weight gain in the Nightingale Study, a large cohort of female nurses. METHODS: This study included 36 273 registered nurses, who completed questionnaires in 2011 and 2017. Cumulative number of nights, mean number of nights/month and consecutive number of nights/month in 2007–2011 were assessed. We used Poisson regression to estimate multivariable-adjusted incidence rate ratios (IRR) of >5% weight gain from 2011 to 2017 among all participants and assess risk of development of overweight/obesity (BMI≥25 kg/m^2) among women with healthy baseline body mass index. The reference group consisted of women who never worked nights. RESULTS: Overall, working night shifts in 2007–2011 was associated with >5% weight gain [IRR 1.07, 95% confidence interval (CI) 1.01–1.13]. Associations differed by menopausal status in 2011, with an increased risk of gaining >5% weight limited to postmenopausal women who worked nights (IRR 1.23, 95% CI 1.10–1.38). Postmenopausal women had an increased risk of >5% weight gain when they worked on average ≥4 nights/month (4–5: IRR 1.29, 95% CI 1.09–1.52, ≥6: IRR 1.27, 95% CI 1.11–1.47) or ≥4 consecutive nights/month (IRR 1.37, 95% CI 1.19–1.58), compared to postmenopausal women who never worked nights. For postmenopausal women with healthy weight at baseline, night shift work was associated with an increased risk of overweight/obesity at follow-up (IRR 1.24, 95% CI 1.03–1.50). CONCLUSIONS: Working night shifts was associated with a slightly increased risk of weight gain and overweight/obesity development among women who were postmenopausal at study inclusion. Our findings emphasize the importance of health promotion to maintain a healthy weight among (postmenopausal) night workers.

Abstract Background Concomitant high‐dose cisplatin with radiotherapy is commonly used for treating head and neck squamous cell carcinoma (HNSCC). Cisplatin, often used with radiotherapy, is known for causing irreversible sensorineural hearing loss, with individual variability suggesting a genetic component. This study aims to enhance the predictive ability of the clinical prediction model for cisplatin‐induced hearing loss (CIHL) in HNSCC patients, as outlined in Theunissen et al., by incorporating significant genetic variants. Methods Conducted at the Netherlands Cancer Institute, this retrospective study included 74 patients treated between 1997 and 2011. Thirty‐one SNPs that were previously associated with CIHL or other cisplatin‐induced toxicities were identified and incorporated into the model. The primary outcome measured was the change in decibels at posttreatment 1‐2‐4 kHz hearing levels per additional minor allele of these SNPs, evaluated using linear mixed‐effects regression models. The model's predictive accuracy was determined by the area under the curve (AUC) using 10‐fold cross‐validation. Results The rs2289669 SNP in the SLC47A1/MATE1 gene was linked to a significant 2.67 dB increase in hearing loss per allele (95% CI 0.49–4.86, p = 0.017). Incorporating rs2289669 improved the model's AUC from 0.78 to 0.83, a borderline significant improvement (p = 0.073). Conclusions This study underscores the importance of the rs2289669 SNP in CIHL and demonstrates the potential of combining genetic and clinical data for enhanced predictive models in personalized treatment strategies.

Abstract Background Due to the abundant usage of chemotherapy in young triple-negative breast cancer (TNBC) patients, the unbiased prognostic value of BRCA1-related biomarkers in this population remains unclear. In addition, whether BRCA1-related biomarkers modify the well-established prognostic value of stromal tumor-infiltrating lymphocytes (sTILs) is unknown. This study aimed to compare the outcomes of young, node-negative, chemotherapy-naïve TNBC patients according to BRCA1 status, taking sTILs into account. Methods We included 485 Dutch women diagnosed with node-negative TNBC under age 40 between 1989 and 2000. During this period, these women were considered low-risk and did not receive chemotherapy. BRCA1 status, including pathogenic germline BRCA1 mutation (gBRCA1m), somatic BRCA1 mutation (sBRCA1m), and tumor BRCA1 promoter methylation (BRCA1-PM), was assessed using DNA from formalin-fixed paraffin-embedded tissue. sTILs were assessed according to the international guideline. Patients’ outcomes were compared using Cox regression and competing risk models. Results Among the 399 patients with BRCA1 status, 26.3% had a gBRCA1m, 5.3% had a sBRCA1m, 36.6% had tumor BRCA1-PM, and 31.8% had BRCA1-non-altered tumors. Compared to BRCA1-non-alteration, gBRCA1m was associated with worse overall survival (OS) from the fourth year after diagnosis (adjusted HR, 2.11; 95% CI, 1.18–3.75), and this association attenuated after adjustment for second primary tumors. Every 10% sTIL increment was associated with 16% higher OS (adjusted HR, 0.84; 95% CI, 0.78–0.90) in gBRCA1m, sBRCA1m, or BRCA1-non-altered patients and 31% higher OS in tumor BRCA1-PM patients. Among the 66 patients with tumor BRCA1-PM and ≥ 50% sTILs, we observed excellent 15-year OS (97.0%; 95% CI, 92.9–100%). Conversely, among the 61 patients with gBRCA1m and

Abstract The aim was to conduct a systematic review of literature and meta-analysis of randomized controlled trials (RCTs) comparing short-term outcomes of bipolar hemiarthroplasty (HA) through SuperPATH and bipolar HA through conventional approaches (CAs) in patients with femoral neck fractures. The following PICO question was formulated: In human participants with femoral neck fractures, are the short-term outcomes of SuperPATH HA better than the short-term outcomes of CAs HA? The following databases were searched until 25 August 2023: PubMed, CNKI, CENTRAL of The Cochrane Library, Clinical trials, and Google Scholar. Quality assessment of the RCTs was performed, according to the Cochrane’s Risk of Bias 2 tool and the recommendations of the GRADE system. Furthermore, we evaluated publication bias with funnel plots. Mean differences (MDs) with 95% confidence intervals (CIs) were calculated for continuous variables using the Hartung–Knapp–Sidik–Jonkman method and a random effects model. Nine RCTs with overall 762 patients were included in this meta-analysis. All 9 RCTs were rated with a moderate risk of bias. The quality of evidence of the outcome parameters was rated moderate to very low. The funnel plots were overall broadly symmetrical, possibly indicating low to moderate publication bias. SuperPATH had a longer operation time compared to CAs (MD = 21.79, 95% CI 12.57 to 31.02). SuperPATH decreased incision length (MD = − 4.50; 95% CI − 5.80 to − 3.20), intraoperative blood loss (MD = − 103.96, 95% CI − 150.27 to − 55.66), postoperative drainage volume (MD = − 137.30, 95% CI − 178.74 to − 95.86), time to mobilization (MD = − 3.86; 95% CI − 5.96 to − 1.76), pain VAS ≤ 1 week postoperatively (MD = − 1.81; 95% CI − 2.17 to − 1.45), and hospitalization time (MD = − 4.05; 95% CI − 4.96 to − 3.15). SuperPATH improved HHS ≤ 1 week postoperatively (MD = 11.10; 95% CI 1.65 to 20.54) and HHS 3 months postoperatively (MD = 6.33; 95% CI 3.97 to 8.69). There was no difference in pain VAS 1–3 months postoperatively (MD = − 0.08; 95% CI − 0.22 to 0.05) and HHS 6 months postoperatively (MD = 0.44; 95% CI − 0.11 to 1.00). This is the first meta-analysis comparing SuperPATH HA with CAs HA in patients with femoral neck fractures. SuperPATH HA was superior in the early short-term functional outcome (HHS) compared to CAs HA, reaching minimal clinically important differences. Furthermore, SuperPATH HA showed significantly better results in incision length, blood loss, time to mobilization, pain intensity (VAS), and hospitalization time than CAs HA.

Abstract Background Our aim was to determine the best operative procedure in human participants with a displaced or non-displaced femoral neck fracture comparing cannulated screw (CS) fixation, dynamic hip screw (DHS) fixation, hemiarthroplasty (HA), and total hip arthroplasty (THA) in terms of surgical and functional outcomes, reoperation and postoperative complications. Methods We searched PubMed, The Cochrane Library, Clinical trials, CINAHL, and Embase for randomized controlled trials (RCTs) or quasi-RCTs up to 31 July 2022. A frequentist network meta-analysis was performed to assess the comparative effects of the four operative procedures, using fixed-effects and random-effects models. Mean differences (MDs) with 95% confidence intervals (CIs) were estimated for continuous variables and odds ratios (ORs) with 95% CIs were estimated for binary variables. Results A total of 33 RCTs with 5703 patients were included in our network meta-analysis. CS fixation was best in terms of operation time (CS: MD = − 57.70, 95% CI − 72.78; − 42.62; DHS: MD = − 53.56, 95% CI − 76.17; − 30.95; HA: MD = − 20.90, 95% CI − 30.65; − 11.15; THA: MD = 1.00 reference) and intraoperative blood loss (CS: MD = − 3.67, 95% CI − 4.44; − 2.90; DHS: MD = − 3.20, 95% CI − 4.97; − 1.43; HA: MD = − 1.20, 95% CI − 1.73; − 0.67; THA: MD = 1.00 reference). In life quality and functional outcome, measured at different time points with EQ-5D and the Harris Hip Score (HHS), THA ranked first and HA second (e.g. EQ-5D 2 years postoperatively: CS: MD = − 0.20, 95% CI − 0.29; − 0.11; HA: MD = − 0.09, 95% CI − 0.17; − 0.02; THA: MD = 1.00 reference; HHS 2 years postoperatively: CS: MD = − 5.50, 95% CI − 9.98; − 1.03; DHS: MD = − 8.93, 95% CI − 15.08; − 2.78; HA: MD = − 3.65, 95% CI − 6.74; − 0.57; THA: MD = 1.00 reference). CS fixation had the highest reoperation risk, followed by DHS fixation, HA, and THA (CS: OR = 9.98, 95% CI 4.60; 21.63; DHS: OR = 5.07, 95% CI 2.15; 11.96; HA: OR = 1.60, 95% CI 0.89; 2.89; THA: OR = 1.00 reference). Conclusion In our cohort of patients with displaced and non-displaced femoral neck fractures, HHS, EQ-5D, and reoperation risk showed an advantage of THA and HA compared with CS and DHS fixation. Based on these findings, we recommend that hip arthroplasty should be preferred and internal fixation of femoral neck fractures should only be considered in individual cases. Level of evidence I: a systematic review of randomized controlled trials. Trial registration: PROSPERO on 10 August 2022 (CRD42022350293).

Abstract The prognostic value of cytonuclear grade in ductal carcinoma in situ (DCIS) is debated, partly due to high interobserver variability and the use of multiple guidelines. The aim of this study was to evaluate interobserver agreement in grading DCIS between Dutch, British, and American pathologists. Haematoxylin and eosin‐stained slides of 425 women with primary DCIS were independently reviewed by nine breast pathologists based in the Netherlands, the UK, and the USA. Chance‐corrected kappa (κma) for association between pathologists was calculated based on a generalised linear mixed model using the ordinal package in R. Overall κma for grade of DCIS (low, intermediate, or high) was estimated to be 0.50 (95% confidence interval [CI] 0.44–0.56), indicating a moderate association between pathologists. When the model was adjusted for national guidelines, the association for grade did not change (κma = 0.53; 95% CI 0.48–0.57); subgroup analysis for pathologists using the UK pathology guidelines only had significantly higher association (κma = 0.58; 95% CI 0.56–0.61). To assess if concordance of grading relates to the expression of the oestrogen receptor (ER) and HER2, archived immunohistochemistry was analysed on a subgroup (n = 106). This showed that non‐high grade according to the majority opinion was associated with ER positivity and HER2 negativity (100 and 89% of non‐high grade cases, respectively). In conclusion, DCIS grade showed only moderate association using whole slide images scored by nine breast pathologists. As therapeutic decisions and inclusion in ongoing clinical trials are guided by DCIS grade, there is a pressing need to reduce interobserver variability in grading. ER and HER2 might be supportive to prevent the accidental and unwanted inclusion of high‐grade DCIS in such trials.

The spread of resistance to antibiotics is a major health concern worldwide due to the increasing rate of isolation of multidrug resistant pathogens hampering the treatment of infections. The food chain has been recognized as one of the key routes of antibiotic resistant bacteria transmission between animals and humans. Considering that lactic acid bacteria (LAB) could act as a reservoir of transferable antibiotic resistance genes, LAB strains intended to be used as feed additives should be monitored for their safety. Sixty-five LAB strains which might be potentially used as probiotic feed additives or silage inoculants, were assessed for susceptibility to eight clinically relevant antimicrobials by a minimum inhibitory concentration determination. Among antimicrobial resistant strains, a prevalence of selected genes associated with the acquired resistance was investigated. Nineteen LAB strains displayed phenotypic resistance to one antibiotic, and 15 strains were resistant to more than one of the tested antibiotics. The resistance to aminoglycosides and tetracyclines were the most prevalent and were found in 37 and 26% of the studied strains, respectively. Phenotypic resistance to other antimicrobials was found in single strains. Determinants related to resistance phenotypes were detected in 15 strains as follows, the aph(3″)-IIIa gene in 9 strains, the lnu(A) gene in three strains, the str(A)-str(B), erm(B), msr(C), and tet(M) genes in two strains and the tet(K) gene in one strain. The nucleotide sequences of the detected genes revealed homology to the sequences of the transmissible resistance genes found in lactic acid bacteria as well as pathogenic bacteria. Our study highlights that LAB may be a reservoir of antimicrobial resistance determinants, thus, the first and key step in considering the usefulness of LAB strains as feed additives should be an assessment of their antibiotic resistance. This safety criterion should always precede more complex studies, such as an assessment of adaptability of a strain or its beneficial effect on a host. These results would help in the selection of the best LAB strains for use as feed additives. Importantly, presented data can be useful for revising the current microbiological cut-off values within the genus Lactobacillus and Pediococcus.

Purpose: Many studies have shown that patients with non-central nervous system (CNS) cancer can have brain abnormalities, such as reduced gray matter volume and cerebral microbleeds. These abnormalities can sometimes be present even before start of treatment, suggesting a potential detrimental effect of non-CNS cancer itself on the brain. In these previous studies, psychological factors associated with a cancer diagnosis and selection bias may have influenced results. To overcome these limitations, we investigated brain structure with magnetic resonance imaging (MRI) prior to cancer diagnosis. Patients and methods: Between 2005 and 2014, 4,622 participants from the prospective population-based Rotterdam Study who were free of cancer, dementia, and stroke, underwent brain MRI and were subsequently followed for incident cancer until January 1st, 2015. We investigated the association between brain MRI measurements, including cerebral small vessel disease, volumes of global brain tissue, lobes, and subcortical structures, and global white matter microstructure, and the risk of non-CNS cancer using Cox proportional hazards models. Age was used as time scale. Models were corrected for e.g. sex, intracranial volume, educational level, body mass index, hypertension, diabetes mellitus, smoking status, alcohol use, and depression sum-score. Results: During a median (interquartile range) follow-up of 7.0 years (4.9–8.1), 353 participants were diagnosed with non-CNS cancer. Results indicated that persons who develop cancer do not have more brain abnormalities before clinical manifestation of the disease than persons who remain free of cancer. The largest effect estimates were found for the relation between presence of lacunar infarcts and the risk of cancer (hazard ratio [HR] 95% confidence interval [CI] = 1.39 [0.97–1.98]) and for total brain volume (HR [95%CI] per standard deviation increase in total brain volume = 0.76 [0.55–1.04]). Conclusion: We did not observe associations between small vessel disease, brain tissue volumes, and global white matter microstructure, and subsequent cancer risk in an unselected population. These findings deviate from previous studies indicating brain abnormalities among patients shortly after cancer diagnosis.

Abstract Background Sentinel lymph node biopsy (SLNB) after intratumoral injection of 99mTc labeled nanocolloid and imaging with scintigraphy and SPECT/CT in renal tumors is feasible. However, sentinel lymph node (SN) non-detection rate with scintigraphy and SPECT/CT is high. The aim of the study was to determine factors affecting non-visualization (NV) of SN imaging in renal tumors. Seventy-eight patients with cT1–3 renal tumors received intratumoral injection of 225 MBq 99mTc-labeled nanocolloid 1 day before (partial) nephrectomy. Radiotracer injection was followed by anterioposterior and lateral scintigraphy in combination with SPECT/CT 20 min and 2–4 h after. Surgical treatment of the tumor with sentinel lymph node biopsy by aid of γ-probe and-camera was performed the next day. Scintigraphy and SPECT/CT images were evaluated and patient, tumor, and procedure characteristics were collected for 73 eligible patients used in uni- and multivariable analysis of a potential association with NV. Results A total of 80 (mean 1.1, IQR 0–2, max 6) sentinel lymph nodes in 46 patients were detected with scintigraphy and SPECT/CT. Preoperative visualization rate and intraoperative detection rate was 63% [95% CI 50–73%] and 61% [95% CI 49–72%], respectively. In uni- and multivariable analysis, the only factor associated with non-visualization was age, showing higher odds of non-visualization with higher age. Conclusion Our study demonstrated that non-visualization of SNs in renal tumors is relatively high and is associated with patient age. Furthermore, kidneys and also its tumors are highly vascularized which may cause a wash-out effect that could be identified with decreased kidney-liver ratios. However, in our data, the effect was statistically inconclusive. Further studies are needed to improve visualization and standardize the procedure of SLNB in renal tumors. The percentage of NV limits the use of SLNB for research and clinical purposes in renal cancer.

The host’s immune system plays a pivotal role in many tumor types, including squamous cell carcinomas (SCCs). We aim to identify immunological prognosticators for lymph node metastases (LNM) and disease-specific survival (DSS) in penile SCC. For this retrospective observational cohort study, penile SCC patients (n = 213) treated in the Netherlands Cancer Institute, were selected if sufficient formalin-fixed, paraffin-embedded tumor material was available. Analysis included previously described high-risk human papilloma virus (hrHPV) status, immunohistochemical scores for classical and non-classical human leukocyte antigen (HLA) class I, programmed death ligand-1 (PD-L1) expression, and novel data on tumor-infiltrating macrophages and cytotoxic an regulatory T-cells. Clinicopathological characteristics and extended follow-up were also included. Regression analyses investigated relationships of the immune parameters with LNM and DSS. In the total cohort, diffuse PD-L1 tumor-cell expression, CD163+ macrophage infiltration, non-classical HLA class I upregulation, and low stromal CD8+ T-cell infiltration were all associated with LNM. In the multivariable model, only tumor PD-L1 expression remained a significant predictor for LNM (odds ratio (OR) 2.8, p = 0.05). hrHPV negativity and diffuse PD-L1 tumor-cell expression were significantly associated with poor DSS and remained so upon correction for clinical parameters [hazard ratio (HR) 9.7, p