Bronchoscopy with and without needle-based confocal laser endomicroscopy for peripheral lung nodule diagnosis: protocol for a multicentre randomised controlled trial (CLEVER trial).

INTRODUCTION: Despite many technological advances, the diagnostic yield of bronchoscopic peripheral lung nodule analysis remains limited due to frequent mispositioning. Needle-based confocal laser endomicroscopy (nCLE) enables real-time microscopic feedback on needle positioning, potentially improving the sampling location and diagnostic yield. Previous studies have defined and validated nCLE criteria for malignancy, airway and lung parenchyma. Larger studies demonstrating the effect of nCLE on diagnostic yield are lacking. We aim to investigate if nCLE-imaging integrated with conventional bronchoscopy results in a higher diagnostic yield compared with conventional bronchoscopy without nCLE. METHODS AND ANALYSIS: This is a parallel-group randomised controlled trial. Recruitment is performed at pulmonology outpatient clinics in universities and general hospitals in six different European countries and one hospital in the USA. Consecutive patients with a for malignancy suspected peripheral lung nodule (10-30 mm) with an indication for diagnostic bronchoscopy will be screened, and 208 patients will be included. Web-based randomisation (1:1) between the two procedures will be performed. The primary outcome is diagnostic yield. Secondary outcomes include diagnostic sensitivity for malignancy, needle repositionings, procedure and fluoroscopy duration, and complications. Pathologists will be blinded to procedure type; patients and endoscopists will not. ETHICS AND DISSEMINATION: Primary approval by the Ethics Committee of the Amsterdam University Medical Center. Dissemination involves publication in a peer-reviewed journal. SUPPORT: Financial and material support from Mauna Kea Technologies. TRIAL REGISTRATION NUMBER: NCT06079970.

Towards a Standardization of Learning Curve Assessment in Minimally Invasive Liver Surgery.

OBJECTIVE: The aim was to analyze the learning curves of minimal invasive liver surgery(MILS) and propose a standardized reporting. SUMMARY BACKGROUND DATA: MILS offers benefits compared to open resections. For a safe introduction along the learning curve, formal training is recommended. However, definitions of learning curves and methods to assess it lack standardization. METHODS: A systematic review of PubMed, Web of Science, and CENTRAL databases identified studies on learning curves in MILS. The primary outcome was the number needed to overcome the learning curve. Secondary outcomes included endpoints defining learning curves, and characterization of different learning phases(competency, proficiency and mastery). RESULTS: 60 articles with 12'241 patients and 102 learning curve analyses were included. The laparoscopic and robotic approach was evaluated in 71 and 18 analyses and both approaches combined in 13 analyses. Sixty-one analyses (60%) based the learning curve on statistical calculations. The most often used parameters to define learning curves were operative time (n=64), blood loss (n=54), conversion (n=42) and postoperative complications (n=38). Overall competency, proficiency and mastery were reached after 34 (IQR 19-56), 50 (IQR 24-74), 58 (IQR 24-100) procedures respectively. Intraoperative parameters improved earlier (operative time: competency to proficiency to mastery: -13%, 2%; blood loss: competency to proficiency to mastery: -33%, 0%; conversion rate (competency to proficiency to mastery; -21%, -29%), whereas postoperative complications improved later (competency to proficiency to mastery: -25%, -41%). CONCLUSIONS: This review summarizes the highest evidence on learning curves in MILS taking into account different definitions and confounding factors. A standardized three-phase reporting of learning phases (competency, proficiency, mastery) is proposed and should be followed.

Prevalence and risk factors for HPV seropositivity and anogenital DNA positivity among men who have sex with men: a repeated cross-sectional study.

OBJECTIVES: This study aimed to assess associations of potential risk factors with human papillomavirus (HPV) seropositivity among men who have sex with men (MSM) and compare these to risk factors for anal and penile (HPV) deoxyribonucleic acid (DNA)-positivity in the same study population. METHODS: Seropositivity and anal and penile HPV DNA-positivity were determined for seven high-risk HPV genotypes for MSM aged 16-24 years participating in Papillomavirus Surveillance among STI clinic Youngsters in the Netherlands (PASSYON) 2009-2021. Logistic regression models were conducted to assess risk factors for seropositivity, anal and penile HPV DNA-positivity. RESULTS: Overall, 1019 MSM were included. HPV-16 and -18 were most common for serology, and anal and penile HPV DNA-positivity. Although no clear similarities were observed for most risk factors for HPV seropositivity and anal or penile DNA positivity, receptive anal intercourse (RAI) was the strongest associated risk factor for both seropositivity ('RAI ever' adjusted odds ratio [aOR] 3.50, 95% confidence interval [CI] 1.56-7.88; 'RAI previous 6 months' aOR 2.17, 95% CI 1.44-3.26) and anal DNA-positivity ('RAI previous 6 months' aOR 1.67, 95% CI 1.09-2.56). CONCLUSIONS: Our study is suggestive of site-specific immune response after HPV infection; RAI might lead to anal HPV infections and consequently to seroconversion. Finally, as the two genotypes that are most oncogenic and preventable by all HPV vaccines were most common, our results underline the importance of gender-neutral vaccination.

A Dutch paediatric palliative care guideline: a systematic review and evidence-based recommendations for symptom treatment.

BACKGROUND: Children with life-threatening and life-limiting conditions can experience high levels of suffering due to multiple distressing symptoms that result in poor quality of life and increase risk of long-term distress in their family members. High quality symptom treatment is needed for all these children and their families, even more so at the end-of-life. In this paper, we provide evidence-based recommendations for symptom treatment in paediatric palliative patients to optimize care. METHODS: A multidisciplinary panel of 56 experts in paediatric palliative care and nine (bereaved) parents was established to develop recommendations on symptom treatment in paediatric palliative care including anxiety and depression, delirium, dyspnoea, haematological symptoms, coughing, skin complaints, nausea and vomiting, neurological symptoms, pain, death rattle, fatigue, paediatric palliative sedation and forgoing hydration and nutrition. Recommendations were based on evidence from a systematic literature search, additional literature sources (such as guidelines), clinical expertise, and patient and family values. We used the GRADE methodology for appraisal of evidence. Parents were included in the guideline panel to ensure the representation of patient and family values. RESULTS: We included a total of 18 studies that reported on the effects of specific (non) pharmacological interventions to treat symptoms in paediatric palliative care. A few of these interventions showed significant improvement in symptom relief. This evidence could only (partly) answer eight out of 27 clinical questions. We included 29 guidelines and two textbooks as additional literature to deal with lack of evidence. In total, we formulated 221 recommendations on symptom treatment in paediatric palliative care based on evidence, additional literature, clinical expertise, and patient and family values. CONCLUSION: Even though available evidence on symptom-related paediatric palliative care interventions has increased, there still is a paucity of evidence in paediatric palliative care. We urge for international multidisciplinary multi-institutional collaboration to perform high-quality research and contribute to the optimization of symptom relief in palliative care for all children worldwide.

Lung transplant airway complications treated with biodegradable airway stents: The Dutch multi-center experience.

INTRODUCTION: Treatment of post lung-transplant airway complications is challenging, and treatment with conventional airway stents is associated with adverse events. More recently, biodegradable airway stents (BDS) have been introduced and may be used to reduce these adverse events. In this study we explore the feasibility of treatment with BDS post lung transplant. METHODS: All patients treated with BDS in The Netherlands were included in this retrospective multicenter study. Feasibility, life span of the stent, occurrence of adverse events, and evolution of lung function were evaluated. RESULTS: Twelve patients (six malacia and six stenosis) received a total of 57 BDS, ranging from 1 to 10 BDS per patient. Six patients had been pretreated with conventional airway stents. Median stent life span was 112 days (range 66-202). No adverse events occurred during stent placement. In 5 out of 57 stent placements, a single additional bronchoscopy was necessary because of mucus accumulation (n = 4) or excessive granulation tissue (n = 1). All stent naïve patients became airway stent independent after treatment; all patients pretreated with conventional airway stents were still airway stent dependent at the end of follow up. CONCLUSION: Treatment with BDS is safe and feasible. Adverse events were mild and easily treatable. All patients with initial treatment with BDS were airway stent independent at the end of follow up with a median treatment of 4 BDS.

Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex.

A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.

Palliative care for children: methodology for the development of a national clinical practice guideline.

BACKGROUND: Provision of paediatric palliative care for children with life-threatening or life-limiting conditions and their families is often complex. Guidelines can support professionals to deliver high quality care. Stakeholders expressed the need to update the first Dutch paediatric palliative care guideline with new scientific literature and new topics. This paper provides an overview of the methodology that is used for the revision of the Dutch paediatric palliative care guideline and a brief presentation of the identified evidence. METHODS: The revised paediatric palliative care guideline was developed with a multidisciplinary guideline panel of 72 experts in paediatric palliative care and nine (bereaved) parents of children with life-threatening or life-limiting conditions. The guideline covered multiple topics related to (refractory) symptom treatment, advance care planning and shared-decision making, organisation of care, psychosocial care, and loss and bereavement. We established six main working groups that formulated 38 clinical questions for which we identified evidence by updating two existing systematic literature searches. The GRADE (CERQual) methodology was used for appraisal of evidence. Furthermore, we searched for additional literature such as existing guidelines and textbooks to deal with lack of evidence. RESULTS: The two systematic literature searches yielded a total of 29 RCTs or systematic reviews of RCTs on paediatric palliative care interventions and 22 qualitative studies on barriers and facilitators of advance care planning and shared decision-making. We identified evidence for 14 out of 38 clinical questions. Furthermore, we were able to select additional literature (29 guidelines, two textbooks, and 10 systematic reviews) to deal with lack of evidence. CONCLUSIONS: The revised Dutch paediatric palliative care guideline addresses many topics. However, there is limited evidence to base recommendations upon. Our methodology will combine the existing evidence in scientific literature, additional literature, expert knowledge, and perspectives of patients and their families to provide recommendations.

In-depth analysis of immunohistochemistry concordance in biopsy-resection pairs of bronchial carcinoids.

Primary diagnosis of bronchial carcinoids (BC) is always made on biopsies and additional immunohistochemistry (IHC) is often necessary. In the present study we investigated the concordance of common diagnostic (synaptophysin, chromogranin, CD56 and INSM-1) and potential prognostic (OTP, CD44, Rb and p16) IHC markers between the preoperative biopsies and resections of in total 64 BCs, 26 typical (41 %) and 38 atypical (59 %) carcinoid tumors. Synaptophysin and chromogranin had 100 % concordance in all resected carcinoids and paired diagnostic biopsies. Synaptophysin was not affected by variable expression in biopsies compared to chromogranin, CD56 and INSM-1. Notably, INSM-1 IHC was false negative in 8 % of biopsies. Of the novel and potential prognostic markers, only CD44 showed 100 % concordance between biopsies and resections, while OTP showed two (4 %) false negative results in paired biopsies. While Rb IHC was false negative in 8 % of biopsies, no strong and diffuse pattern of p16 expression was observed. In this study, most false negative IHC results (85 %, 22/26) were observed in small flexible biopsies. Taken together, our data suggest excellent concordance of synaptophysin and CD44 on the preoperative biopsy samples, while other neuroendocrine markers, Rb and OTP should be interpreted with caution, especially in small biopsies.

Splenic rupture or infarction associated with Epstein-Barr virus infectious mononucleosis: a systematic literature review.

BACKGROUND: Epstein-Barr virus (EBV), also known as human herpesvirus 4, is one of the most common pathogenic viruses in humans. EBV mononucleosis always involves the spleen and as such it predisposes to splenic rupture, often without a trauma, and splenic infarction. Nowadays the goal of management is to preserve the spleen, thereby eliminating the risk of post-splenectomy infections. METHODS: To characterise these complications and their management, we performed a systematic review (PROSPERO CRD42022370268) following PRISMA guidelines in three databases: Excerpta Medica, the United States National Library of Medicine, and Web of Science. Articles listed in Google Scholar were also considered. Eligible articles were those describing splenic rupture or infarction in subjects with Epstein-Barr virus mononucleosis. RESULTS: In the literature, we found 171 articles published since 1970, documenting 186 cases with splenic rupture and 29 with infarction. Both conditions predominantly occurred in males, 60% and 70% respectively. Splenic rupture was preceded by a trauma in 17 (9.1%) cases. Approximately 80% (n = 139) of cases occurred within three weeks of the onset of mononucleosis symptoms. A correlation was found between the World Society of Emergency Surgery splenic rupture score, which was retrospectively calculated, and surgical management: splenectomy in 84% (n = 44) of cases with a severe score and in 58% (n = 70) of cases with a moderate or minor score (p = 0.001). The mortality rate of splenic rupture was 4.8% (n = 9). In splenic infarction, an underlying haematological condition was observed in 21% (n = 6) of cases. The treatment of splenic infarction was always conservative without any fatal outcomes. CONCLUSIONS: Similarly to traumatic splenic rupture, splenic preservation is increasingly common in the management of mononucleosis-associated cases as well. This complication is still occasionally fatal. Splenic infarction often occurs in subjects with a pre-existing haematological condition.

Global Type-Specific Genital Human Papillomavirus Prevalence in Men, by Sexual Orientation: A Systematic Review and Meta-Analysis.

BACKGROUND: Knowledge on genital type-specific human papillomavirus (HPV) prevalence among men is important for prevention of HPV-related cancers and other diseases. Men who have sex with men (MSM) have higher anal prevalence than men who have sex with women only (MSW) but for genital HPV this is unclear. We performed a systematic review and meta-analysis of type-specific genital HPV prevalence among men, by sexual orientation. METHODS: MEDLINE and Embase were used for searching publications reporting on male genital HPV prevalence with data from November 2011 onwards. A random-effects meta-analysis was conducted estimating pooled type-specific and grouped external genital and urethral HPV prevalence. Subgroup analyses were conducted for sexual orientation. RESULTS: Twenty-nine studies were eligible. Of those, 13 studies reported prevalence among MSM, 5 among MSW, and 13 studies did not stratify by sexual orientation. The most common genotypes were HPV-6 and HPV-16 for both anatomical locations, although heterogeneity was high. HPV prevalence was similar among studies reporting on MSW, MSM, and men with unknown sexual orientation. CONCLUSIONS: Genital HPV is common among men, with HPV-6 and HPV-16 being the most common genotypes. Type-specific HPV genital prevalence appears to be similar among MSM and MSW, which contrasts with earlier findings on anal HPV.

A Multimodal Biomarker Predicts Dissemination of Bronchial Carcinoid.

Background: Curatively treated bronchial carcinoid tumors have a relatively low metastatic potential. Gradation into typical (TC) and atypical carcinoid (AC) is limited in terms of prognostic value, resulting in yearly follow-up of all patients. We examined the additional prognostic value of novel immunohistochemical (IHC) markers to current gradation of carcinoids. Methods: A retrospective single-institution cohort study was performed on 171 patients with pathologically diagnosed bronchial carcinoid (median follow-up: 66 months). The risk of developing distant metastases based on histopathological characteristics (Ki-67, p16, Rb, OTP, CD44, and tumor diameter) was evaluated using multivariate regression analysis and the Kaplan−Meier method. Results: Of 171 patients, seven (4%) had disseminated disease at presentation, and 164 (96%) received curative-intent treatment with either endobronchial treatment (EBT) (n = 61, 36%) or surgery (n = 103, 60%). Among the 164 patients, 13 developed metastases at follow-up of 81 months (IQR 45−162). Univariate analysis showed that Ki-67, mitotic index, OTP, CD44, and tumor diameter were associated with development of distant metastases. Multivariate analysis showed that mitotic count, Ki-67, and OTP were independent risk factors for development of distant metastases. Using a 5% cutoff for Ki-67, Kaplan−Meier analysis showed that the risk of distant metastasis development was significantly associated with the number of risk predictors (AC, Ki-67 ≥ 5%, and loss of OTP or CD44) (p < 0.0001). Six out of seven patients (86%) with all three positive risk factors developed distant metastasis. Conclusions: Mitotic count, proliferation index, and OTP IHC were independent predictors of dissemination at follow-up. In addition to the widely used carcinoid classification, a comprehensive analysis of histopathological variables including Ki-67, OTP, and CD44 could assist in the determination of distant metastasis risks of bronchial carcinoids.

Diagnosis of atypical carcinoid can be made on biopsies > 4 mm2 and is accurate.

In the 2021 WHO thoracic tumors, gradation of lung carcinoids in biopsies is discouraged. We hypothesized that atypical carcinoid (AC) could be reliably diagnosed in larger preoperative biopsies. Biopsy-resection paired specimens of carcinoid patients were included, and definitive diagnosis was based on the resection specimen according to the WHO 2021 classification. A total of 64 biopsy-resection pairs (26 typical carcinoid (TC) (41%) and 38 AC (59%)) were analyzed. In 35 patients (55%), tumor classification between the biopsy and resection specimen was concordant (26 TC, 9 AC). The discordance in the remaining 29 biopsies (45%, 29 TC, 0 AC) was caused by misclassification of AC as TC. In biopsies measuring < 4 mm2, 15/15 AC (100%) were misclassified compared to 14/23 AC (61%) of biopsies ≥ 4 mm2. Categorical concordance of Ki-67 in biopsy-resection pairs at threshold of 5% was 68%. Ki-67 in the biopsy was not of additional value to discriminate between TC and AC, irrespective of the biopsy size. Atypical carcinoid is frequently missed in small bronchial biopsies (< 4 mm2). If the carcinoid classification is clinically relevant, a cumulative biopsy size of at least 4 mm2 should be considered. Our study provides strong arguments to make the diagnosis of AC in case of sufficient mitosis for AC on a biopsy and keep the diagnosis "carcinoid NOS" for carcinoids with ≤ 1 mitosis per 2 mm2. Ki-67 has a good concordance but was not discriminative for definitive diagnosis.

The effect of tumor size and metastatic extent on the efficacy of first line pembrolizumab monotherapy in patients with high PD-L1 expressing advanced NSCLC tumors.

BACKGROUND: Tumor size and metastatic extent may influence tumor response to immunotherapy in non-small cell lung cancer (NSCLC). The aim of this study was to examine the relationship between both baseline sum of longest diameters (bSLD) and number of metastatic organs (NMO) and the tumor response to pembrolizumab. Secondly, we aimed to analyze the association of baseline SLD and NMO with progression-free survival (PFS) and overall survival (OS). METHODS: This retrospective study included patients with high PD-L1 expressing tumors (≥50%) and a good performance score (ECOG ≤ 2) that received first-line pembrolizumab monotherapy. Tumor response was calculated as the 'SLD-change score' and 'early treatment discontinuation' within 3 months on therapy (ETD). The relationship of both bSLD (based on RECIST v1.1) and NMO with tumor response and survival outcome (PFS, OS) was evaluated. RESULTS: No significant differences in SLD-change score could be found using bSLD (OR = 1.010, 95%CI = 0.999-1.021), or using NMO at baseline (OR = 1.608, 95%CI = 0.943-2.743). A bSLD cut-off value of 90 mm was found to be most distinctive for ETD. This cut-off value showed a significant difference for PFS (HR = 2.28, 95%CI = 1.12-4.64, p = 0.023) and OS (HR = 2.99, 95%CI = 1.41-6.34, p = 0.004). NMO also showed a difference for PFS and OS, however, not statistically significant. CONCLUSIONS: Tumor size and metastatic extent could not discriminate for tumor response, however, a bSLD of 90 mm could differentiate for PFS and OS.

The Impact of the Availability of Immunotherapy on Patterns of Care in Stage III NSCLC: A Dutch Multicenter Analysis.

INTRODUCTION: Treatment patterns in stage III NSCLC can vary considerably between countries. The PACIFIC trial reported improvements in progression-free and overall survival with adjuvant durvalumab after concurrent chemoradiotherapy (CCRT). We studied treatment decision-making by three Dutch regional thoracic multidisciplinary tumor boards between 2015 and 2019, to identify changes in practice when adjuvant durvalumab became available. METHODS: Details of patients presenting with stage III NSCLC were retrospectively collected. Both CCRT and multimodality schemes incorporating planned surgery were defined as being radical-intent treatment (RIT). RESULTS: Of 855 eligible patients, most (95%) were discussed at a thoracic multidisciplinary tumor board, which recommended a RIT in 63% (n = 510). Only 52% (n = 424) of the patients finally received a RIT. Predictors for not recommending RIT were age greater than or equal to 70 years, WHO performance score greater than or equal to 2, Charlson comorbidity index greater than or equal to 2 (excluding age), forced expiratory volume in 1 second less than 80% of predicted value, N3 disease, and period of diagnosis. Between 2015 to 2017 and 2018 to 2019, the proportion of patients undergoing CCRT increased from 34% to 42% (p = 0.02) and use of sequential chemoradiotherapy declined (21%-16%, p = 0.05). Rates of early toxicity and 1-year mortality were comparable for both periods. After 2018, 57% of the patients who underwent CCRT (90 of 159) received adjuvant durvalumab. CONCLUSIONS: After publication of the PACIFIC trial, a significant increase was observed in the use of CCRT for patients with stage III NSCLC with rates of early toxicity and mortality being unchanged. Since 2018, 57% of the patients undergoing CCRT went on to receive adjuvant durvalumab. Nevertheless, approximately half of the patients were still considered unfit for a RIT.

Late Central Airway Toxicity after High-Dose Radiotherapy: Clinical Outcomes and a Proposed Bronchoscopic Classification.

The study's purpose was to identify the bronchoscopic patterns of central airway toxicity following high-dose radiotherapy or chemoradiotherapy, and to look at the consequences of these findings. Our institutional bronchoscopy database was accessed to identify main patterns of airway toxicity observed in a seven-year period. A total of 70 patients were identified with central airway toxicity, and the findings of bronchoscopy were used to derive a classification system. Patient characteristics, time from radiotherapy to toxicity, follow-up and survival were retrospectively analyzed. Results: The main bronchoscopic patterns of airway toxicity were vascular changes (telangiectasia, loss of vascularity, necrosis) and stenosis of the lumen (moderate, severe). Indications for bronchoscopy were airway symptoms (n = 28), assessment post-CRT/surgery (n = 12), (suspected) recurrence (n = 21) or assessment of radiological findings (n = 9). Stenosis was revealed by bronchoscopy at a median time of 10.0 months (IQR: 4-23.5) after radiotherapy and subsequent follow-up after identification was 23 months (IQR: 1.5-55). The corresponding findings for vascular changes were 29 months (IQR: 10.5-48.5), and follow-up after identification was nine months (IQR: 2.5-19.5). There was a statistically significant difference in survival rates between patients with necrosis and telangiectasia (p = 0.002) and loss of vascularity (p = 0.001). Eight out of 10 deceased patients with telangiectasia died of other causes and 4/8 patients with necrosis died of other causes. We identified two main patterns of central airway toxicity visualized with bronchoscopy after high-dose radiotherapy or chemoradiotherapy, and propose a bronchoscopic classification system based on these findings. Preliminary analysis suggests that the pattern and severity of radiation damage might be of prognostic value. Prospective data are required to confirm our findings.