Phase I, randomized, observer-blind, placebo-controlled studies to evaluate the safety, reactogenicity and immunogenicity of an investigational non-typeable Haemophilus influenzae (NTHi) protein vaccine in adults

Background: Non-typeable Haemophilus influenzae (NTHi) is a major cause of various respiratory diseases. The development of an effective vaccine against NTHi mandates new approaches beyond conjugated vaccines as this opportunistic bacterium is non-encapsulated. Here we report on the safety, reactogenicity and immunogenicity of a multi-component investigational vaccine based on three conserved surface proteins from NTHi (proteins D [PD],E [PE] and Pilin A [PilA]) in two observer-blind phase I studies. Methods: In the first study (NCT01657526), 48 healthy 18-40 year-olds received two vaccine formulations (10 or 30 mu g of each antigen [PD and a fusion protein PE-PilA]) or saline placebo at months 0 and 2. In the second study (NCT01678677), 270 50-70 year-olds, current or former smokers, received eight vaccine formulations (10 or 30 mu g antigen/dose non-adjuvanted or adjuvanted with alum, AS01(E) or ASO4(c)) or saline placebo at months 0,2 and 6 (plain and alum-adjuvanted groups) and at months 0 and 2 (AS-adjuvanted groups). Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days post-vaccination, respectively; potential immune-mediated diseases (pIMDs) and serious AEs (SAEs) throughout the studies. Humoral and antigen-specific T-cell immunity (in study 2 only) responses were assessed up to 12 months post-vaccination. Results: Observed reactogenicity was highest in the AS-adjuvanted groups but no safety concerns were identified with any of the NTHi vaccine formulations. One fatal SAE (cardiac arrest) not considered related to vaccination, and one pIMD (non-serious psoriasis) in the Placebo group, were reported post-dose 3 in Study 2. All formulations generated a robust antibody response while the AS01-adjuvanted formulations produced the highest humoral and cellular immune responses. Conclusion: This study confirms that the NTHi vaccine formulations had an acceptable reactogenicity and safety profile and were immunogenic in adults. These results justify further clinical development of this NTHi vaccine candidate

Patterns of care over 10 years in young breast cancer patients in the Netherlands, a nationwide population-based study

INTRODUCTION: Each year, around 600 young (<40 years) breast cancer (BC) patients are registered in the national NABON Breast Cancer Audit (NBCA). The aim of this study is to compare patient and treatment characteristics of young and older age BC patients over time with a focus on outcome of quality indicators (QIs). Furthermore, we analysed whether de-escalation trends of treatment can be recognized to the same degree in both patient groups. MATERIAL AND METHODS: From October 2011 to October 2020 all patients treated for stage I-III invasive BC were included. Tumour characteristics, treatment variables and outcome of QIs of two age categories young (<40 years) and older patient (≥40 years) were analysed. RESULTS: In total 114,700 patients were included: 4.6% young patients and 95.4% older patients. Young patients more often presented with a palpable mass, higher stage, and triple-negative BC. Overall, young patients more often started with neoadjuvant systemic treatment (NST) (54.3% vs. 18.6%) and a greater proportion of the young patients retained their breast contour after surgery (73.5% vs. 69.3%). De-escalation trends such as decrease in axillary lymph node dissections and in the use of boost were observed. The omission of radiation treatment after breast conserving surgery was only observed in older patients. CONCLUSION: Although this study shows that young women more often present with unfavourable tumours, therapeutic procedures are performed with a higher adherence to the QIs than for older patients and young women do benefit from some de-escalation trends to the same extend as older patients

Resection Ratios and Tumor Eccentricity in Breast-Conserving Surgery Specimens for Surgical Accuracy Assessment

This study aims to evaluate several defined specimen parameters that would allow to determine the surgical accuracy of breast-conserving surgeries (BCS) in a representative population of patients. These specimen parameters could be used to compare surgical accuracy when using novel technologies for intra-operative BCS guidance in the future. Different specimen parameters were determined among 100 BCS patients, including the ratio of specimen volume to tumor volume (resection ratio) with different optimal margin widths (0 mm, 1 mm, 2 mm, and 10 mm). Furthermore, the tumor eccentricity [maximum tumor-margin distance − minimum tumor-margin distance] and the relative tumor eccentricity [tumor eccentricity ÷ pathological tumor diameter] were determined. Different patient subgroups were compared using Wilcoxon rank sum tests. When using a surgical margin width of 0 mm, 1 mm, 2 mm, and 10 mm, on average, 19.16 (IQR 44.36), 9.94 (IQR 18.09), 6.06 (IQR 9.69) and 1.35 (IQR 1.78) times the ideal resection volume was excised, respectively. The median tumor eccentricity among the entire patient population was 11.29 mm (SD = 3.99) and the median relative tumor eccentricity was 0.66 (SD = 2.22). Resection ratios based on different optimal margin widths (0 mm, 1 mm, 2 mm, and 10 mm) and the (relative) tumor eccentricity could be valuable outcome measures to evaluate the surgical accuracy of novel technologies for intra-operative BCS guidance.</p

Associations of hospital volume and hospital competition with short-term, middle-term and long-term patient outcomes after breast cancer surgery:a retrospective population-based study

OBJECTIVES: For oncological care, there is a clear tendency towards centralisation and collaboration aimed at improving patient outcomes. However, in market-based healthcare systems, this trend is related to the potential trade-off between hospital volume and hospital competition. We analyse the association between hospital volume, competition from neighbouring hospitals and outcomes for patients who underwent surgery for invasive breast cancer (IBC). OUTCOME MEASURES: Surgical margins, 90 days re-excision, overall survival. DESIGN, SETTING, PARTICIPANTS: In this population-based study, we use data from the Netherlands Cancer Registry. Our study sample consists of 136 958 patients who underwent surgery for IBC between 2004 and 2014 in the Netherlands. RESULTS: Our findings show that treatment types as well as patient and tumour characteristics explain most of the variation in all outcomes. After adjusting for confounding variables and intrahospital correlation in multivariate logistic regressions, hospital volume and competition from neighbouring hospitals did not show significant associations with surgical margins and re-excision rates. For patients who underwent surgery in hospitals annually performing 250 surgeries or more, multilevel Cox proportional hazard models show that survival was somewhat higher (HR 0.94). Survival in hospitals with four or more (potential) competitors within 30 km was slightly higher (HR 0.97). However, this effect did not hold after changing this proxy for hospital competition. CONCLUSIONS: Based on the selection of patient outcomes, hospital volume and regional competition appear to play only a limited role in the explanation of variation in IBC outcomes across Dutch hospitals. Further research into hospital variation for high-volume tumours like the one studied here is recommended to (i) use consistently measured quality indicators that better reflect multidisciplinary clinical practice and patient and provider decision-making, (ii) include more sophisticated measures for hospital competition and (iii) assess the entire process of care within the hospital, as well as care provided by other providers in cancer networks

From Multiple Quality Indicators of Breast Cancer Care Toward Hospital Variation of a Summary Measure

Objectives: To improve quality in breast cancer care, large numbers of quality indicators are collected per hospital, but benchmarking remains complex. We aimed to assess the validity of indicators, develop a textbook outcome summary measure, and compare case-mix adjusted hospital performance. Methods: From a nationwide population-based registry, all 79 690 nonmetastatic breast cancer patients surgically treated between 2011 and 2016 in 91 hospitals in The Netherlands were included. Twenty-one indicators were calculated and their construct validity tested by Spearman's rho. Between-hospital variation was expressed by interquartile range (IQR), and all valid indicators were included in the summary measure. Standardized scores (observed/expected based on case mix) were calculated as above (>100) or below (<100) expected. The textbook outcome was presented as a continuous and all-or-none score. Results: The size of between-hospital variation varied between indicators. Sixteen (76%) of 21 quality indicators showed construct validity, and 13 were included in the summary measure after excluding redundant indicators that showed collinearity with others owing to strong construct validity. The median all-or-none textbook outcome score was 49% (IQR 42%-54%) before and 49% (IQR 48%-51%) after case-mix adjustment. From the total of 91 hospitals, 3 hospitals were positive (3%) and 9 (10%) were negative outlier

Therapeutic applications of radioactive sources: From image-guided brachytherapyto radio-guided surgical resection

It is well known nowadays that radioactivity can destroy the living cells it interacts with. it is therefore unsurprising that radioactive sources, such as iodine-125, were historically developed for treatment purposes within radiation oncology with the goal of damaging malignant cells. however, since then, new techniques have been invented that make creative use of the same radioactivity properties of these sources for medi- cal applications. here, we review two distinct kinds of therapeutic uses of radioactive sources with applications to prostate, cervical, and breast cancer: brachytherapy and radioactive seed localization. in brachytherapy (BT), the radioactive sources are used for internal radiation treatment. current approaches make use of real-time image guidance, for instance by means of magnetic resonance imaging, ultrasound, computed tomog- raphy, and sometimes positron emission tomography, depending on clinical availability and cancer type. Such image-guided BT for prostate and cervical cancer presents a promising alternative and/or addition to external beam radiation treatments or surgical resections. radioactive sources can also be used for radio-guided tumor localization during surgery, for which the example of iodine-125 seed use in breast cancer is given. radioactive seed localization (rSl) is increasingly popular as an alternative tumor localization technique during breast cancer surgery. Advantages of applying RSL include added flexibility in the clinical scheduling logistics, an increase in tumor localization accuracy, and higher patient satisfaction; safety measures do however have to be employed. We exemply the implementation of rSl in a clinic through our experi- ences at the netherlands cancer institute

Systematic review of targeted axillary dissection in node-positive breast cancer treated with neoadjuvant systemic therapy:variation in type of marker and timing of placement

Background: In node-positive (cN+) breast cancer treated with neoadjuvant systemic therapy, combining sentinel lymph node biopsy and targeted lymph node excision, that is targeted axillary dissection, increases accuracy. Targeted axillary dissection procedures differ in terms of the targeted lymph node excision technique. This systematic review aimed to provide an overview of targeted axillary dissection procedures regarding definitive marker type and timing of placement: before neoadjuvant systemic therapy (1-step procedure) or after neoadjuvant systemic therapy adjacent to a clip placed before the neoadjuvant therapy (2-step procedure). Methods: PubMed and Embase were searched, to 4 July 2023, for RCTs, cohort studies, and case-control studies with at least 25 patients. Studies of targeted lymph node excision only (without sentinel lymph node biopsy), or where intraoperative localization of the targeted lymph node was not attempted, were excluded. For qualitative synthesis, studies were grouped by definitive marker and timing of placement. The targeted lymph node identification rate was reported. Study quality was assessed using a National Institutes of Health quality assessment tool.Results: Of 277 unique records, 51 studies with a total of 4512 patients were included. Six definitive markers were identified: wire, 125I-labelled seed, 99mTc, (electro)magnetic/radiofrequency markers, black ink, and a clip. Fifteen studies evaluated one-step procedures, with the identification rate of the targeted lymph node at surgery varying from 8 of 13 to 47 of 47. Forty-one studies evaluated two-step procedures, with the identification rate of the clipped targeted lymph node on imaging after neoadjuvant systemic therapy varying from 49 to 100%, and the identification rate of the targeted lymph node at surgery from 17 of 24 to 100%. Most studies (40 of 51) were rated as being of fair quality.Conclusion: Various targeted axillary dissection procedures are used in clinical practice. Owing to study heterogeneity, the optimal targeted lymph node excision technique in terms of identification rate and feasibility could not be determined. Two-step procedures are at risk of not identifying the clipped targeted lymph node on imaging after neoadjuvant systemic therapy.</p

Margin assessment during breast conserving surgery using diffuse reflectance spectroscopy

Significance: During breast-conserving surgeries, it is essential to evaluate the resection margins (edges of breast specimen) to determine whether the tumor has been removed completely. In current surgical practice, there are no methods available to aid in accurate real-time margin evaluation.Aim: In this study, we investigated the diagnostic accuracy of diffuse reflectance spectroscopy (DRS) combined with tissue classification models in discriminating tumorous tissue from healthy tissue up to 2 mm in depth on the actual resection margin of in vivo breast tissue.Approach: We collected an extensive dataset of DRS measurements on ex vivo breast tissue and in vivo breast tissue, which we used to develop different classification models for tissue classification. Next, these models were used in vivo to evaluate the performance of DRS for tissue discrimination during breast conserving surgery. We investigated which training strategy yielded optimum results for the classification model with the highest performance.Results: We achieved a Matthews correlation coefficient of 0.76, a sensitivity of 96.7% (95% CI 95.6% to 98.2%), a specificity of 90.6% (95% CI 86.3% to 97.9%) and an area under the curve of 0.98 by training the optimum model on a combination of ex vivo and in vivo DRS data.Conclusions: DRS allows real-time margin assessment with a high sensitivity and specificity during breast-conserving surgeries.</p