Pulmonary vein reconnection and repeat ablation characteristics following cryoballoon-compared to radiofrequency-based pulmonary vein isolation.

BACKGROUND: Despite advances in efficacy and safety of pulmonary vein isolation (PVI), atrial fibrillation (AF) recurrence after PVI remains common. PV-reconnection is the main finding during repeat PVI procedures performed to treat recurrent AF. OBJECTIVE: To analyze pulmonary vein (PV) reconnection patterns during repeat ablation procedures in a large cohort of consecutive patients undergoing radio frequency or cryoballoon-based PVI. METHODS: Retrospective analysis of PV-reconnection patterns and analysis of re-ablation strategies in consecutive index RF- and CB-based PVI and their respective re-ablation procedures during concomitant usage of both energy sources at a single high-volume center in Germany. RESULTS: A total of 610 first (06/2015-10/2022) and 133 s (01/2016-11/2022) repeat ablation procedures after 363 (60%) RF- and 247 (40%) CB-based index PVIs between 01/2015 and 12/2021 were analyzed. PV-reconnection was found in 509/610 (83%) patients at first and 74/133 (56%) patients at second repeat procedure. 465 of 968 (48%) initially via CB isolated PVs were reconnected at first re-ablation but 796 of 1422 initially RF-isolated PV (56%) were reconnected (OR: 0.73 [95% CI: 0.62-0.86]; p < .001). This was driven by fewer reconnections of the left PVs (LSPV: OR: 0.60 [95% CI: 0.42-0.86]; p = .005 and LSPV: 0.67 [0.47-0.95]; p = .026). PV-reconnection was more likely after longer, RF-based index PVI and in older females. Repeat procedures were shorter after CB-compared to after RF-PVI. CONCLUSIONS: Reconnection remains the most common reason for repeat AF ablation procedures after PVI. Our data suggest to preferentially use of the cryoballoon during index PVI, especially in older women.

Randomized controlled trial of a group intervention combining self-hypnosis and self-care: secondary results on self-esteem, emotional distress and regulation, and mindfulness in post-treatment cancer patients.

PURPOSE: Cancer patients often report low self-esteem and high emotional distress. Two factors seem particularly linked to these symptoms: emotion regulation strategies and mindfulness. The interest of hypnosis and self-care to relieve these symptoms is not well documented. Our randomized controlled trial aimed at assessing the effect of a group intervention combining self-hypnosis and self-care on self-esteem, emotional distress, emotion regulation, and mindfulness abilities of post-treatment cancer patients, as well as investigating the links between these variables. METHODS: One hundred and four patients who had suffered from cancer were randomized into the intervention group (N = 52) and the wait-list control group (N = 52). They had to answer questionnaires before (T1) and after the intervention (T2). Nine men were excluded from the analyses, leading to a final sample of 95 women with cancer. Group-by-time changes were assessed with MANOVA, and associations with self-esteem and emotional distress were investigated with hierarchical linear regression models. RESULTS: Participants in the intervention group (mean age = 51.65; SD = 12.54) reported better self-esteem, lower emotional distress, a decreased use of maladaptive emotion regulation strategies, and more mindfulness abilities after the intervention, compared to the WLCG. This increase in mindfulness explained 33% of the improvement of self-esteem and 41.6% of the decrease of emotional distress in the intervention group. Self-esteem and emotional distress also predicted each other. CONCLUSION: Our study showed the efficacy of our hypnosis-based intervention to improve all the investigated variables. Mindfulness predicted the improvement of self-esteem and emotional distress. The primary impact of our intervention on mindfulness abilities seems to explain, at least in part, its efficacy. Registration: ClinicalTrials.gov (NCT03144154). Retrospectively registered on the 1st of May, 2017.

[Short version of the 2nd edition of the German-Austrian S3 guidelines "Cardiogenic shock complicating myocardial infarction-Diagnosis, monitoring and treatment"]. / Kurzversion der 2. Auflage der deutsch-österreichischen S3-Leitlinie "Infarkt-bedingter Kardiogener Schock ­ Diagnose, Monitoring und Therapie".

BACKGROUND: The present guidelines ( http://leitlinien.net ) focus exclusively on cardiogenic shock due to myocardial infarction (infarction-related cardiogenic shock, ICS). The cardiological/cardiac surgical and the intensive care medicine strategies dealt with in these guidelines are essential to the successful treatment and survival of patients with ICS; however, both European and American guidelines on myocardial infarction and heart failure and also position papers on cardiogenic shock focused mainly on cardiological aspects. METHODS: Evidence on the diagnosis, monitoring and treatment of ICS was collected and recommendations compiled in a nominal group process by delegates of the German Cardiac Society (DGK), the German Society for Medical Intensive Care Medicine and Emergency Medicine (DGIIN), the German Society for Thoracic and Cardiovascular Surgery (DGTHG), the German Society for Anaesthesiology and Intensive Care Medicine (DGAI), the Austrian Society for Internal and General Intensive Care Medicine (ÖGIAIM), the Austrian Cardiology Society (ÖKG), the German Society for Prevention and Rehabilitation of Cardiovascular Diseases (DGPR) and the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI), under the auspices of the Working Group of the Association of Medical Scientific Societies in Germany (AWMF). If only poor evidence on ICS was available, general study results on intensive care patients were inspected and presented in order to enable analogue conclusions. RESULTS: A total of 95 recommendations, including 2 statements were compiled and based on these 7 algorithms with defined instructions on the course of treatment.

Presence of a 34-gene signature is a favorable prognostic marker in squamous non-small cell lung carcinoma.

BACKGROUND: The tumor immune microenvironment is a heterogeneous entity. Gene expression analysis allows us to perform comprehensive immunoprofiling and may assist in dissecting the different components of the immune infiltrate. As gene expression analysis also provides information regarding tumor cells, differences in interactions between the immune system and specific tumor characteristics can also be explored. This study aims to gain further insights in the composition of the tumor immune infiltrate and to correlate these components to histology and overall survival in non-small cell lung cancer (NSCLC). METHODS: Archival tissues from 530 early stage, resected NSCLC patients with annotated tumor and patient characteristics were analyzed using the NanoString nCounter Analysis system. RESULTS: Unsupervised clustering of the samples was mainly driven by the overall level of inflammation, which was not correlated with survival in this patient set. Adenocarcinoma (AD) showed a significantly higher degree of immune infiltration compared to squamous cell carcinoma (SCC). A 34-gene signature, which did not correlate with the overall level of immune infiltration, was identified and showed an OS benefit in SCC. Strikingly, this benefit was not observed in AD. This difference in OS in SCC specifically was confirmed in two independent NSCLC cohorts. The highest correlation between expression of the 34-gene signature and specific immune cell populations was observed for NK cells, but although a plausible mechanism for NK cell intervention in tumor growth could be established in SCC over AD, this could not be translated back to immunohistochemistry, which showed that NK cell infiltration is scarce irrespective of histology. CONCLUSIONS: These findings suggest that the ability of immune cell infiltration and the interaction between tumor and immune cells may be different between AD and SCC histology and that a subgroup of SCC tumors seems more susceptible to Natural Killer cell recognition and killing, whereas this may not occur in AD tumors. A highly sensitive technique like NanoString was able to detect this subgroup based on a 34-gene signature, but further research will be needed to assist in explaining the biological rationale of such low-level expression signatures.

[Therapeutic management of nonvalvular atrial fibrillation]. / Therapeutisches Management des nichtvalvulären Vorhofflimmerns.

Atrial fibrillation (AF) is the most frequent persistent cardiac arrhythmia and is associated with an increased mortality. Therefore, an effective differential treatment of patients is mandatory. After a risk stratification oral anticoagulation (OAC) should be initiated depending on the individual stroke risk of each patient. Alternatively, in the presence of contraindications for OAC and an increased risk for bleeding and/or stroke, the implantation of a left atrial appendage closure device can be considered. Symptomatic patients should undergo a rhythm control strategy if possible. Based on the risk-benefit considerations, catheter ablation (CA) of AF plays an increasingly important role in establishing long-term medicinal rhythm control. A pulmonary vein isolation can lead to freedom from AF for 1 year in 70-80% of patients with paroxysmal AF (and approximately 50% in persistent AF). So far, a survival advantage of CA could only be shown in patients with heart failure, so that in most cases this is only a symptomatic treatment for improvement in the quality of life.

Variation in red cell transfusion decisions in the intensive care unit - a nationwide survey in the Netherlands.

BACKGROUND AND OBJECTIVES: Most guidelines recommend a restrictive transfusion trigger of 7 g/dl. It is unclear whether this resulted in more uniform transfusion practices. The primary objective was to uncover the extent of variation in transfusion decisions within four scenarios of critically ill patients among critical care physicians in the Netherlands. MATERIALS AND METHODS: An online survey comprising four different hypothetical clinical scenarios was sent to all members of the Dutch Society of Intensive Care. The scenarios represented patients with acute myocardial infarction (Hb 8·5 g/dl), abdominal sepsis (Hb 7·1 g/dl), traumatic brain injury (TBI) (Hb 7·9 g/dl) and post-surgical complications (Hb 7·3 g/dl). The questions explored the decision whether or not to transfuse and a ranking of clinical characteristics playing the most important role in the transfusion decision. RESULTS: A total of 224 members (22%) participated in the study of whom 188 (84%) completed all questions. The percentages of respondents that decided to transfuse ranged from 25·9% in the scenario with TBI to 81·6% in the scenario with post-surgical complications. Most controversy was seen in the scenario with sepsis for which 43·2% decided to transfuse, whereas 56·8% decided not to. Haemoglobin level, diagnosis and haemodynamics were most important for the transfusion decision in all scenarios. CONCLUSIONS: Physicians decided differently on red-blood-cell transfusion given the clinical scenarios and weighed clinical characteristics differently in their transfusion decisions. These findings suggest there still is substantial variation in critical care transfusion practice.

[Subtrochanteric pathological fracture on bisphosphonates]. / Le cas clinique du mois. Fracture pathologique sous-trochantérienne sur prise de bisphosphonates.

Bisphosphonates have frequently shown their efficacy in the treatment of osteoporosis, including ibandronate and alendronate. But more and more mention is made in the literature of patients taking a long-term bisphosphonate and undergoing an atypical fracture associated with this therapy. These complications are most often femoral fractures in the proximal part of the femoral diaphysis. We report the case of a 73-year-old patient who had a subtrochanteric pathological fracture after a prolonged intake of alendronate followed by ibandronate.

Les bisphosphonates ont fréquemment démontré leur efficacité dans le traitement de l'ostéoporose, notamment l'ibandronate et l'alendronate. Mais, de plus en plus, il est fait mention dans la littérature de cas de patients traités par un bisphosphonate au long cours et présentant une fracture atypique qui y serait liée. Il s'agit, le plus souvent, de fractures fémorales dans la partie proximale de la diaphyse. Nous rapportons ici le cas d'une patiente de 73 ans ayant subi une fracture pathologique sous-trochantérienne après une prise prolongée d'alendronate suivie d'une prise d'ibandronate.

Molecular Tumor Boards: current practice and future needs.

BACKGROUND: Due to rapid technical advances, steeply declining sequencing costs, and the ever-increasing number of targeted therapies, it can be expected that extensive tumor sequencing such as whole-exome and whole-genome sequencing will soon be applied in standard care. Clinicians will thus be confronted with increasingly complex genetic information and multiple test-platforms to choose from. General medical training, meanwhile, can hardly keep up with the pace of innovation. Consequently, there is a rapidly growing gap between clinical knowledge and genetic potential in cancer care. Multidisciplinary Molecular Tumor Boards (MTBs) have been suggested as a means to address this disparity, but shared experiences are scarce in literature and no quality requirements or guidelines have been published to date. METHODS: Based on literature review, a survey among hospitals in The Netherlands, and our own experience with the establishment of a nationally operating MTB, this article evaluates current knowledge and unmet needs and lays out a strategy for successful MTB implementation. RESULTS: Having access to an MTB can improve and increase the application of genetics-guided cancer care. In our survey, however, <50% of hospitals and only 5% of nonacademic hospitals had access to an MTB. In addition, current MTBs vary widely in terms of composition, tasks, tools, and workflow. This may not only lead to variation in quality of care but also hinders data sharing and thus creation of an effective learning community. CONCLUSIONS: This article acknowledges a leading role for MTBs to govern (extensive) tumor sequencing into daily practice and proposes three basic necessities for successful MTB implementation: (i) global harmonization in cancer sequencing practices and procedures, (ii) minimal member and operational requirements, and (iii) an appropriate unsolicited findings policy. Meeting these prerequisites would not only optimize MTB functioning but also improve general interpretation and application of genomics-guided cancer care.

Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study.

BACKGROUND: The phase 3 CAIRO3 study showed that capecitabine plus bevacizumab (CAP-B) maintenance treatment after six cycles capecitabine, oxaliplatin, and bevacizumab (CAPOX-B) in metastatic colorectal cancer (mCRC) patients is effective, without compromising quality of life. In this post hoc analysis with updated follow-up and data regarding sidedness, we defined subgroups according to RAS/BRAF mutation status and mismatch repair (MMR) status, and investigated their influence on treatment efficacy. PATIENTS AND METHODS: A total of 558 patients with previously untreated mCRC and stable disease or better after six cycles CAPOX-B induction treatment were randomised to either CAP-B maintenance treatment (n = 279) or observation (n = 279). Upon first progression, patients were to receive CAPOX-B reintroduction until second progression (PFS2, primary end point). We centrally assessed RAS/BRAF mutation status and MMR status, or used local results if central assessment was not possible. Intention-to-treat stratified Cox models adjusted for baseline covariables were used to examine whether treatment efficacy was modified by RAS/BRAF mutation status. RESULTS: RAS, BRAF mutations, and MMR deficiency were detected in 240/420 (58%), 36/381 (9%), and 4/279 (1%) patients, respectively. At a median follow-up of 87 months (IQR 69-97), all mutational subgroups showed significant improvement from maintenance treatment for the primary end point PFS2 [RAS/BRAF wild-type: hazard ratio (HR) 0.57 (95% CI 0.39-0.84); RAS-mutant: HR 0.74 (0.55-0.98); V600EBRAF-mutant: HR 0.28 (0.12-0.64)] and secondary end points, except for the RAS-mutant subgroup regarding overall survival. Adjustment for sidedness instead of primary tumour location yielded comparable results. Although right-sided tumours were associated with inferior prognosis, both patients with right- and left-sided tumours showed significant benefit from maintenance treatment. CONCLUSIONS: CAP-B maintenance treatment after six cycles CAPOX-B is effective in first-line treatment of mCRC across all mutational subgroups. The benefit of maintenance treatment was most pronounced in patients with RAS/BRAF wild-type and V600EBRAF-mutant tumours. CLINICALTRIALS.GOV NUMBER: NCT00442637.

The time to progression ratio: a new individualized volumetric parameter for the early detection of clinical benefit of targeted therapies.

BACKGROUND: Early signs of efficacy are critical in drug development. Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to determine the efficacy of anti-cancer therapy in clinical trials. RECIST, however, emphasizes the value of tumor shrinkage, while many targeted agents induce prolonged tumor growth arrest. This limits its use for the detection of treatment efficacy for these more cytostatic regimens. Therefore, we designed an individualized variant of a time to progression (TTP) end point based on prospective volumetric measurements and an intra-patient control, the TTP ratio. PATIENTS AND METHODS: Patients with any metastatic malignancy, without regular treatment options, were treated with the mTOR inhibitor everolimus. Treatment response was determined using both RECIST and the TTP ratio. The TTP ratio was defined as the volumetric pretreatment TTP divided by the volumetric on-treatment TTP. A patient was classified as a responder if the TTP ratio was <0.7. Consistency and reproducibility of volumetric measurements were determined. RESULTS: Seventy-three patients were included of whom 59 started treatment. A TTP ratio could be established in 73% (n = 43) of the treated patients. The inter-observer agreement for volumetric progression was 0.78 (95% confidence interval 0.70-0.87) (Krippendorff's α-coefficient). According to RECIST, 35 patients (59%) had stable disease (SD) and 1 patient demonstrated a partial response (PR), whereas only 21 patients (36%) met the prespecified criteria for treatment efficacy according to the TTP ratio. Treatment response according to both the TTP ratio and RECIST (SD + PR) correlated with overall survival (OS) [P(log-rank) < 0.001]. The TTP ratio, however, was also able to differentiate which patients had a better OS within the RECIST SD group [P(log-rank) = 0.0496]. CONCLUSION: The TTP ratio had a high inter-observer agreement, correlated with OS and identified which patients within the RECIST SD group had a longer OS. CLINICALTRIALSGOV IDENTIFIER: NCT01566279.

A retrospective review of 345 patients with lumbar TDR in two years follow-up over 10 years of practice in one Belgian clinical center : Results.

Low back pain is one of the most common symptom with high cost for the public health. When conservative treatment fails, patients are heading to surgical treatment. Instead of lumbar arthrodesis, we can offer an alternative that will keep the intervertebral mobility : Total disc replacement (TDR) by prosthesis. Many studies have published good results rate over 80%, since first implantation in 1984. Believing in keeping the mobility, we promote TDR since 2002. This retrospective study review 345 patients with two years follow-up. The outcomes show 81% of good and really good results, according to gain of improvement on VAS and ODI scores. We report 6.88% of complications for the abdominal approach and 4.57% for the device, without harmful complication. Same results are obtained in case of postdiscectomy syndrome.

Impact of preoperative evaluation of tumour grade by core needle biopsy on clinical risk assessment and patient selection for adjuvant systemic treatment in breast cancer.

BACKGROUND: Histological characteristics are important when making a decision on adjuvant systemic treatment in breast cancer. Preoperative assessments of core needle biopsy (CNB) specimens are becoming increasingly relevant as novel minimally invasive ablative techniques are introduced, because a surgical specimen is no longer obtained with these methods. The clinical impact of potential underestimation of tumour grade on preoperative CNB on clinical decision-making was evaluated. METHODS: Histological tumour grade was reassessed on CNB and resection specimens from consecutive invasive ductal carcinomas diagnosed between 2010 and 2013. For each patient, the indication for systemic therapy was assessed, based on either CNB or surgical excision, in combination with clinical characteristics and imaging findings. The clinical impact of discordance between tumour grade on CNB versus the resection specimen was assessed. RESULTS: The analysis included 213 invasive ductal carcinomas in 199 patients. Discordance in tumour grade between CNB and the resection specimen was observed in 64 (30.0 per cent) of 213 tumours (κ = 0.53, 95 per cent c.i. 0.43 to 0.63). A decision on adjuvant treatment based on CNB would have resulted in overtreatment in seven (3.5 per cent) and undertreatment in three (1.5 per cent) of 199 patients. In the undertreated patients, incorrect omission of adjuvant systemic treatment would have increased the predicted 10-year mortality rate by 2.6-5.2 per cent and 10-year recurrence rate by 8.2-15.3 per cent based on the online risk assessment tool Adjuvant! CONCLUSION: The substantial discordance in tumour grading between CNB and resection specimens from breast cancer affects the indication for adjuvant therapy in only a small minority of patients with invasive ductal carcinoma. Assessment of tumour grade by CNB is feasible and accurate for the planning of postoperative treatment.

[Pre-interventional, peri-interventional and post-interventional anticoagulation in the setting of catheter ablation for atrial fibrillation : current practice and practical approach]. / Prä-, peri- und postinterventionelle Antikoagulation im Rahmen der Vorhofflimmerablation : Aktueller Stand und praktisches Vorgehen.

In addition to treatment with drugs to control the rate and rhythm, the method of catheter ablation is a cornerstone in the treatment of atrial fibrillation. Another crucial part in treating patients with atrial fibrillation is an adequate oral anticoagulation. Apart from the vitamin K antagonists (VKA) phenprocoumon and warfarin, the direct oral anticoagulants (DOAC) apixaban, dabigatran and rivaroxaban have been approved for oral anticoagulation of patients with atrial fibrillation. As a result there are different potential treatment possibilities for pre-interventional, peri-interventional and post-interventional anticoagulation in the setting of catheter ablation for atrial fibrillation. Due to increasing clinical experience with DOAC and the increasing number of atrial fibrillation ablations worldwide, peri-interventional treatment strategies are continuously changing. Therefore, the current article discusses current standards and gives practical guidance.

Clinicopathological Factors as Predictors for Establishment of Patient Derived Head and Neck Squamous Cell Carcinoma Organoids.

INTRODUCTION: Patient derived organoids (PDOs) are 3D in vitro models and have shown to better reflect patient and tumor heterogeneity than conventional 2D cell lines. To utilize PDOs in clinical settings and trials for biomarker discovery or drug response evaluation, it is valuable to determine the best way to optimize sample selection for maximum PDO establishment. In this study, we assess patient, tumor and tissue sampling factors and correlate them with successful PDO establishment in a well-documented cohort of patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Tumor and non-tumorous adjacent tissue samples were obtained from HNSCC patients during routine biopsy or resection procedures at the University Medical Center Utrecht. The tissue was subsequently processed to establish PDOs. The sample purity was determined as the presence of epithelial cells in the culture on the day of organoid isolation as visualized microscopically by the researcher. PDO establishment was recorded for all samples. Clinical data was obtained from the medical records and was correlated to PDO establishment and presence of epithelial cells. RESULTS: Organoids could be established in 133/250 (53.2%) primary tumor site tissues. HNSCC organoid establishment tended to be more successful if patients were younger than the median age of 68 years (74/123 (60.2%) vs. 59/127 (46.5%), p = 0.03). For a subset of samples, the presence of epithelial cells in the organoid culture on the day of organoid isolation was recorded in 112/149 (75.2%) of these samples. When cultures were selected for presence of epithelial cells, organoid establishment increased to 76.8% (86/112 samples). CONCLUSION: This study found a trend between age and successful organoid outgrowth in patients with HNSCC younger than 68 years and emphasizes the value of efficient sampling regarding PDO establishment.

Regional differences in predictive biomarker testing rates for patients with metastatic NSCLC in the Netherlands.

BACKGROUND: Predictive biomarker testing has a key role in the treatment decision-making for patients with non-small cell lung cancer (NSCLC) and is mandated by (inter)national guidelines. The aim of this study was to establish guideline-adherent biomarker testing rates in the Netherlands in 2019 and to examine associations of demographical, clinical, and environmental factors with guideline-adherent testing. METHODS: This study involved the integration of clinical data of the Netherlands Cancer Registry with pathology reports of the Dutch Nationwide Pathology Databank. Data extracted from these reports included sample type, diagnosis, and molecular testing status of predictive biomarkers. The study population comprised all patients diagnosed with metastatic non-squamous NSCLC in the Netherlands in 2019. RESULTS: In the cohort of 3877 patients with metastatic non-squamous NSCLC under investigation, overall molecular testing rates for non-fusion predictive biomarkers (EGFR, KRAS, BRAF, ERBB2, MET) ranged from 73.9 to 89.0 %, while molecular testing for fusion-drivers (ALK, ROS1, RET, NTRK) ranged from 12.6 % to 63.9 %. Guideline-adherent testing of EGFR, KRAS, and ALK was performed in 85.2 % of patients, with regional rates spanning from 76.0 % to 90.8 %. Demographical and clinical factors associated with guideline-adherent biomarker testing included lower age (OR = 1.05 per one year decrease; p < 0.001), female sex (OR = 1.36; p = 0.002), diagnosis of adenocarcinoma (OR = 2.48; p < 0.001), availability of histological tumor material (OR = 2.46; p < 0.001), and clinical stage of metastatic disease (p = 0.002). Other factors associated with guideline-adherent biomarker testing included diagnosis at academic center (OR = 1.87; p = 0.002) and patient's region of residence (p < 0∙001). CONCLUSION: Optimization of the chain-of-care of predictive biomarker testing in patients with NSCLC in the Netherlands is needed to provide adequate care for these patients.

Optimising primary molecular profiling in non-small cell lung cancer.

INTRODUCTION: Molecular profiling of NSCLC is essential for optimising treatment decisions, but often incomplete. We assessed the efficacy of protocolised molecular profiling in the current standard-of-care (SoC) in a prospective observational study in the Netherlands and measured the effect of providing standardised diagnostic procedures. We also explored the potential of plasma-based molecular profiling in the primary diagnostic setting. METHODS: This multi-centre prospective study was designed to explore the performance of current clinical practice during the run-in phase using local SoC tissue profiling procedures. The subsequent phase was designed to investigate the extent to which comprehensive molecular profiling (CMP) can be maximized by protocolising tumour profiling. Successful molecular profiling was defined as completion of at least EGFR and ALK testing. Additionally, PD-L1 tumour proportions scores were explored. Lastly, the additional value of centralised plasma-based testing for EGFR and KRAS mutations using droplet digital PCR was evaluated. RESULTS: Total accrual was 878 patients, 22.0% had squamous cell carcinoma and 78.0% had non-squamous NSCLC. Stage I-III was seen in 54.0%, stage IV in 46.0%. Profiling of EGFR and ALK was performed in 69.9% of 136 patients included in the run-in phase, significantly more than real-world data estimates of 55% (p<0.001). Protocolised molecular profiling increased the rate to 77.0% (p = 0.049). EGFR and ALK profiling rates increased from 77.9% to 82.1% in non-squamous NSCLC and from 43.8% to 57.5% in squamous NSCLC. Plasma-based testing was feasible in 98.4% and identified oncogenic driver mutations in 7.1% of patients for whom tissue profiling was unfeasible. CONCLUSION: This study shows a high success rate of tissue-based molecular profiling that was significantly improved by a protocolised approach. Tissue-based profiling remains unfeasible for a substantial proportion of patients. Combined analysis of tumour tissue and circulating tumour DNA is a promising approach to allow adequate molecular profiling of more patients.

Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer.

BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.

The need for longitudinal data on the value of fertility treatment for infertile patients' quality of life: A review and pilot study.

Infertility threatens the life goal of parenthood and, hence, quality of life (QoL) of (wo)men, but the fertility clinic trajectory might be burdensome. This review of longitudinal studies and pilot longitudinal study examines the impact of the pre-in vitro fertilization (IVF) fertility clinic trajectory on patient-reported outcome measures (PROMs) for emotional well-being, including QoL. A publication found that the diagnostic workup decreases men's infertility-specific distress while publications disagree whether it decreases (wo)men's anxious and depressive reactions. Intrauterine insemination (IUI) was found to increase (wo)men's depressive reactions. Publications on infertility-specific, health-related, and overall QoL were missing. The pilot indicated that (wo)men's overall QoL is not affected by the diagnostic workup but is decreased by the time of the third IUI. Longitudinal studies on the impact of starting the fertility clinic trajectory on PROMs are needed as they are essential for patient-centered clinical decision-making and patient-centered policy-level decision-making.

p-mTOR, p-ERK and PTEN Expression in Tumor Biopsies and Organoids as Predictive Biomarkers for Patients with HPV Negative Head and Neck Cancer.

BACKGROUND: Survival rates of head and neck squamous cell carcinoma (HNSCC) have only marginally improved in the last decades. Hence there is a need for predictive biomarkers for long-time survival that can help to guide treatment decisions and might lead to the development of new therapies. The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway is the most frequently altered pathway in HNSCC, genes are often mutated, amplificated and overexpressed causing aberrant signaling affecting cell growth and differentiation. Numerous genetic alterations of upstream and downstream factors have currently been clarified. However, their predictive value has yet to be established. Therefore we assess the predictive value of p-mTOR, p-ERK and PTEN expression. METHODS: Tissue microarrays (TMA's) of HPV-negative patients with oropharyngeal (n = 48), hypopharyngeal (n = 16) or laryngeal (n = 13) SCC, treated with primary chemoradiation (cisplatin/carboplatin/cetuximab and radiotherapy), were histologically stained for p-mTOR, PTEN and p-ERK. Expression was correlated to overall survival (OS), disease free survival (DFS) and locoregional control (LRC). Also p-mTOR was histologically stained in a separate cohort of HNSCC organoids (n = 8) and correlated to mTOR-inhibitor everolimus response. RESULTS: High p-mTOR expression correlated significantly with worse OS in multivariate analysis in the whole patient cohort [Hazar Ratio (HR) 1.06, 95%CI 1.01-1.11, p = 0.03] and in the cisplatin/carboplatin group with both worse OS (HR 1.09, 95%CI 1.02-1.16, p = 0.02) and DFS (HR 1.06, 95%CI 1.00-1.12, p = 0,04). p-ERK expression correlated significantly with DFS in univariate analysis in the whole patient cohort (HR 1.03, 95%CI 1.00-1.05, p = 0.04) and cisplatin/carboplatin group (HR 1.03, 95%CI 1.00-1.07, p = 0.04). PTEN-expression did not correlate with OS/DFS/LRC. Better organoid response to everolimus correlated significantly to higher p-mTOR expression (Rs = - 0.731, p = 0.04). CONCLUSIONS: High p-mTOR expression predicts and high p-ERK expression tends to predict worse treatment outcome in HPV negative HNSCC patients treated with chemoradiation, providing additional evidence that these markers are candidate prognostic biomarkers for survival in this patient population. Also this study shows that the use of HNSCC organoids for biomarker research has potential. The role of PTEN expression as prognostic biomarker remains unclear, as consistent evidence on its prognostic and predictive value is lacking.