Assessment of the current and emerging criteria for the histopathological classification of lung neuroendocrine tumours in the lungNENomics project.

BACKGROUND: Six thoracic pathologists reviewed 259 lung neuroendocrine tumours (LNETs) from the lungNENomics project, with 171 of them having associated survival data. This cohort presents a unique opportunity to assess the strengths and limitations of current World Health Organization (WHO) classification criteria and to evaluate the utility of emerging markers. PATIENTS AND METHODS: Patients were diagnosed based on the 2021 WHO criteria, with atypical carcinoids (ACs) defined by the presence of focal necrosis and/or 2-10 mitoses per 2 mm2. We investigated two markers of tumour proliferation: the Ki-67 index and phospho-histone H3 (PHH3) protein expression, quantified by pathologists and automatically via deep learning. Additionally, an unsupervised deep learning algorithm was trained to uncover previously unnoticed morphological features with diagnostic value. RESULTS: The accuracy in distinguishing typical from ACs is hampered by interobserver variability in mitotic counting and the limitations of morphological criteria in identifying aggressive cases. Our study reveals that different Ki-67 cut-offs can categorise LNETs similarly to current WHO criteria. Counting mitoses in PHH3+ areas does not improve diagnosis, while providing a similar prognostic value to the current criteria. With the advantage of being time efficient, automated assessment of these markers leads to similar conclusions. Lastly, state-of-the-art deep learning modelling does not uncover undisclosed morphological features with diagnostic value. CONCLUSIONS: This study suggests that the mitotic criteria can be complemented by manual or automated assessment of Ki-67 or PHH3 protein expression, but these markers do not significantly improve the prognostic value of the current classification, as the AC group remains highly unspecific for aggressive cases. Therefore, we may have exhausted the potential of morphological features in classifying and prognosticating LNETs. Our study suggests that it might be time to shift the research focus towards investigating molecular markers that could contribute to a more clinically relevant morpho-molecular classification.

High-precision stereotactic irradiation for focal drug-resistant epilepsy versus standard treatment: a randomized waitlist-controlled trial (the PRECISION trial).

INTRODUCTION: The standard treatment for patients with focal drug-resistant epilepsy (DRE) who are not eligible for open brain surgery is the continuation of anti-seizure medication (ASM) and neuromodulation. This treatment does not cure epilepsy but only decreases severity. The PRECISION trial offers a non-invasive, possibly curative intervention for these patients, which consist of a single stereotactic radiotherapy (SRT) treatment. Previous studies have shown promising results of SRT in this patient population. Nevertheless, this intervention is not yet available and reimbursed in the Netherlands. We hypothesize that: SRT is a superior treatment option compared to palliative standard of care, for patients with focal DRE, not eligible for open surgery, resulting in a higher reduction of seizure frequency (with 50% of the patients reaching a 75% seizure frequency reduction at 2 years follow-up). METHODS: In this waitlist-controlled phase 3 clinical trial, participants are randomly assigned in a 1:1 ratio to either receive SRT as the intervention, while the standard treatments consist of ASM continuation and neuromodulation. After 2-year follow-up, patients randomized for the standard treatment (waitlist-control group) are offered SRT. Patients aged ≥ 18 years with focal DRE and a pretreatment defined epileptogenic zone (EZ) not eligible for open surgery will be included. The intervention is a LINAC-based single fraction (24 Gy) SRT treatment. The target volume is defined as the epileptogenic zone (EZ) on all (non) invasive examinations. The seizure frequency will be monitored on a daily basis using an electronic diary and an automatic seizure detection system during the night. Potential side effects are evaluated using advanced MRI, cognitive evaluation, Common Toxicity Criteria, and patient-reported outcome questionnaires. In addition, the cost-effectiveness of the SRT treatment will be evaluated. DISCUSSION: This is the first randomized trial comparing SRT with standard of care in patients with DRE, non-eligible for open surgery. The primary objective is to determine whether SRT significantly reduces the seizure frequency 2 years after treatment. The results of this trial can influence the current clinical practice and medical cost reimbursement in the Netherlands for patients with focal DRE who are not eligible for open surgery, providing a non-invasive curative treatment option. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT05182437. Registered on September 27, 2021.

Extracorporeal bullet trajectory determination from scanned phantoms with bullet defects.

Shots with two different calibres (0.32 Auto and 9 mm Luger) were fired through phantoms that simulated human torsos, mounted on undercarriages with witness panels. The perforated phantoms were scanned with computed tomography (Siemens) using 80 kV and 140 kV and a slice thickness of 1 mm. The intracorporeal trajectories in the phantoms were compared to the known extracorporeal trajectories, derived from the perforations in witness panels. The discrepancy between the intracorporeal and extracorporeal trajectories, denoted as the absolute angle, was calculated for the trajectories before (front) and after (rear) the phantoms. Mean absolute angles at the front were lower than at the rear (2.27° vs. 4.54°) and the difference was statistically significant (p < 0.001). The results of the study imply that the line between the entrance and the exit wound in a scanned victim can be extended to the extracorporeal bullet trajectory leading towards the entrance wound. The absolute angles presented in this study give an impression of the expected errors with the two calibres. This can be helpful in shooting investigations to assess the position of the shooter from entrance and exit wounds in a scanned victim.

Real-world EGFR testing practices for non-small-cell lung cancer by thoracic pathology laboratories across Europe.

BACKGROUND: Testing for epidermal growth factor receptor (EGFR) mutations is an essential recommendation in guidelines for metastatic non-squamous non-small-cell lung cancer, and is considered mandatory in European countries. However, in practice, challenges are often faced when carrying out routine biomarker testing, including access to testing, inadequate tissue samples and long turnaround times (TATs). MATERIALS AND METHODS: To evaluate the real-world EGFR testing practices of European pathology laboratories, an online survey was set up and validated by the Pulmonary Pathology Working Group of the European Society of Pathology and distributed to 64 expert testing laboratories. The retrospective survey focussed on laboratory organisation and daily EGFR testing practice of pathologists and molecular biologists between 2018 and 2021. RESULTS: TATs varied greatly both between and within countries. These discrepancies may be partly due to reflex testing practices, as 20.8% of laboratories carried out EGFR testing only at the request of the clinician. Many laboratories across Europe still favour single-test sequencing as a primary method of EGFR mutation identification; 32.7% indicated that they only used targeted techniques and 45.1% used single-gene testing followed by next-generation sequencing (NGS), depending on the case. Reported testing rates were consistent over time with no significant decrease in the number of EGFR tests carried out in 2020, despite the increased pressure faced by testing facilities during the COVID-19 pandemic. ISO 15189 accreditation was reported by 42.0% of molecular biology laboratories for single-test sequencing, and by 42.3% for NGS. 92.5% of laboratories indicated they regularly participate in an external quality assessment scheme. CONCLUSIONS: These results highlight the strong heterogeneity of EGFR testing that still occurs within thoracic pathology and molecular biology laboratories across Europe. Even among expert testing facilities there is variability in testing capabilities, TAT, reflex testing practice and laboratory accreditation, stressing the need to harmonise reimbursement technologies and decision-making algorithms in Europe.

Post-mortem radiology in fetal and neonatal death: the diagnostic value of post-mortem MRI versus autopsy regarding non-cardiac thoracic and abdominal abnormalities.

AIM: To compare the diagnostic value and accuracy of post-mortem magnetic resonance imaging (PMMRI) and autopsy for non-cardiac thoracic and abdominal abnormalities in fetal death. MATERIALS AND METHODS: This single-institution retrospective study included all consecutive cases of fetal and perinatal death between January 2015 and December 2021 for which PMMRI followed by autopsy was conducted. These cases comprised fetuses at >18 weeks of gestation and preterm and term neonates who lived for <24 h. All PMMRI and autopsy reports were re-assessed and scored for seven non-cardiac thoracic and 52 abdominal abnormalities, and concordance between autopsy and PMMRI findings was determined as the primary outcome. RESULTS: Eighty cases were included in this study. Fetal loss was caused by termination of pregnancy in 80% of cases. Further, the mean gestational age was 166 days (23 weeks and 5 days, range 126-283 days). The concordance between PMMRI and autopsy for non-cardiac thoracic and abdominal abnormalities was 83.1% (95% confidence interval [CI] 71.3-83.3) and 76.3% (95% CI 65.8-84.2%), respectively, with a substantial and moderate strength of agreement (Cohen's kappa = 0.63 and 0.51 respectively). CONCLUSION: PMMRI exhibited good overall diagnostic value for non-cardiac thoracic and abdominal abnormalities, specifically large structural abnormalities. PMMRI may offer parents and physicians a valuable addition to autopsy for the detection of non-cardiac thoracic and abdominal abnormalities, or even an alternative option when parents do not consent to autopsy.

Prognostic impact of tumour budding in squamous cell carcinoma of the lung: a systematic review and meta-analysis.

Tumour budding is an established prognostic factor in various solid tumours, including colorectal cancers and oral squamous cell carcinomas. However, its role is unclear and needs to be defined for squamous cell carcinoma of the lung (LSCC). Hence, we conducted a systematic review and meta-analysis investigating the prognostic role of tumour budding in LSCC. PubMed, Embase and Scopus were searched for peer-reviewed literature investigating the association between tumour budding and survival outcomes or clinicopathological variables in LSCC. The primary outcomes were pooled estimates for overall and recurrence-free survival with hazard ratio (HR) as the effect measure. The association between tumour budding and clinicopathological parameters was also investigated. Of 243 studies, nine were included, comprising 2546 patients. An increased risk of death [HR = 1.76, 95% confidence interval (CI) = 1.50-2.05, P < 0.00001] and recurrence (HR = 1.37, 95% CI = 1.12-1.68, P = 0.003) was evident in patients with high-grade tumour budding. Sensitivity and subgroup analyses revealed consistent results. Pathological stage II, lymph node metastasis, lymphovascular and pleural invasion were associated with high-grade tumour budding. Tumour budding is a new and promising prognostic factor in patients with LSCC. However, pervasive heterogeneity and publication bias reduces the credibility of these findings and the applicability of tumour budding in clinical practice. Future studies are required to standardise reporting on tumour budding in LSCC.

The search for a unifying diagnosis involving neurological, endocrine and immune dysfunction: a case report of a novel presentation of DAVID syndrome.

BACKGROUND: We report a novel presentation of deficit in anterior pituitary function with variable immune deficiency (DAVID) syndrome in a healthy young girl presenting in Addisonian crisis with raised intracranial pressure. Nearly all cases of DAVID syndrome described in the literature have presented with recurrent infections and variable immunodeficiency. Pseudotumour cerebri has not been reported in DAVID syndrome to date. CASE PRESENTATION: A four-year-old girl represented to hospital with vomiting, confusion and diplopia after ten days of tiredness, neck and abdominal pain, and headache. Her cranial nerve examination demonstrated a right abducens nerve palsy and papilloedema, and she was found to have ketotic hypoglycaemia and hypocortisolaemia secondary to adrenocorticotrophic hormone (ACTH) deficiency. Her neuroimaging was consistent with pseudotumour cerebri, and her lumbar puncture opening pressure confirmed raised intracranial pressure (30-40 cmH2O). Cerebrospinal fluid analysis was normal. The patient's symptoms improved with hydrocortisone replacement and acetazolamide, but the raised intracranial pressure recurred after acetazolamide was discontinued. She was subsequently found to have panhypogammaglobulinaemia, and DAVID syndrome was diagnosed. Genetic testing demonstrated a truncating mutation in the NFKB2 gene c.2557C > T, p.(Arg853*). CONCLUSIONS: This case demonstrates pseudotumour cerebri as a novel neurological presentation of DAVID syndrome, highlights the rare association between adrenal insufficiency and intracranial hypertension, and shows the challenges in diagnosing isolated ACTH deficiency. We emphasise that cortisol should be checked in pre-pubertal children with pseudotumour cerebri and a diagnosis of DAVID syndrome considered in those presenting with low cortisol and neurological symptoms.

Recommendations for a practical implementation of circulating tumor DNA mutation testing in metastatic non-small-cell lung cancer.

BACKGROUND: Liquid biopsy (LB) is a rapidly evolving diagnostic tool for precision oncology that has recently found its way into routine practice as an adjunct to tissue biopsy (TB). The concept of LB refers to any tumor-derived material, such as circulating tumor DNA (ctDNA) or circulating tumor cells that are detectable in blood. An LB is not limited to the blood and may include other fluids such as cerebrospinal fluid, pleural effusion, and urine, among others. PATIENTS AND METHODS: The objective of this paper, devised by international experts from various disciplines, is to review current challenges as well as state-of-the-art applications of ctDNA mutation testing in metastatic non-small-cell lung cancer (NSCLC). We consider pragmatic scenarios for the use of ctDNA from blood plasma to identify actionable targets for therapy selection in NSCLCs. RESULTS: Clinical scenarios where ctDNA mutation testing may be implemented in clinical practice include complementary tissue and LB testing to provide the full picture of patients' actual predictive profiles to identify resistance mechanism (i.e. secondary mutations), and ctDNA mutation testing to assist when a patient has a discordant clinical history and is suspected of showing intertumor or intratumor heterogeneity. ctDNA mutation testing may provide interesting insights into possible targets that may have been missed on the TB. Complementary ctDNA LB testing also provides an option if the tumor location is hard to biopsy or if an insufficient sample was taken. These clinical use cases highlight practical scenarios where ctDNA LB may be considered as a complementary tool to TB analysis. CONCLUSIONS: Proper implementation of ctDNA LB testing in routine clinical practice is envisioned in the near future. As the clinical evidence of utility expands, the use of LB alongside tissue sample analysis may occur in the patient cases detailed here.

Proximal Region of Carotid Atherosclerotic Plaque Shows More Intraplaque Hemorrhage: The Plaque at Risk Study.

BACKGROUND AND PURPOSE: Intraplaque hemorrhage contributes to lipid core enlargement and plaque progression, leading to plaque destabilization and stroke. The mechanisms that contribute to the development of intraplaque hemorrhage are not completely understood. A higher incidence of intraplaque hemorrhage and thin/ruptured fibrous cap (upstream of the maximum stenosis in patients with severe [≥70%] carotid stenosis) has been reported. We aimed to noninvasively study the distribution of intraplaque hemorrhage and a thin/ruptured fibrous cap in patients with mild-to-moderate carotid stenosis. MATERIALS AND METHODS: Eighty-eight symptomatic patients with stroke (<70% carotid stenosis included in the Plaque at Risk study) demonstrated intraplaque hemorrhage on MR imaging in the carotid artery plaque ipsilateral to the side of TIA/stroke. The intraplaque hemorrhage area percentage was calculated. A thin/ruptured fibrous cap was scored by comparing pre- and postcontrast black-blood TSE images. Differences in mean intraplaque hemorrhage percentages between the proximal and distal regions were compared using a paired-samples t test. The McNemar test was used to reveal differences in proportions of a thin/ruptured fibrous cap. RESULTS: We found significantly larger areas of intraplaque hemorrhage in the proximal part of the plaque at 2, 4, and 6 mm from the maximal luminal narrowing, respectively: 14.4% versus 9.6% (P = .04), 14.7% versus 5.4% (P < .001), and 11.1% versus 2.2% (P = .001). Additionally, we found an increased proximal prevalence of a thin/ruptured fibrous cap on MR imaging at 2, 4, 6, and 8 mm from the MR imaging section with the maximal luminal narrowing, respectively: 33.7% versus 18.1%, P = .007; 36.1% versus 7.2%, P < .001; 33.7% versus 2.4%, P = .001; and 30.1% versus 3.6%, P = .022. CONCLUSIONS: We demonstrated that intraplaque hemorrhage and a thin/ruptured fibrous cap are more prevalent on the proximal side of the plaque compared with the distal side in patients with mild-to-moderate carotid stenosis.

Value of ultra-high field MRI in patients with suspected focal epilepsy and negative 3 T MRI (EpiUltraStudy): protocol for a prospective, longitudinal therapeutic study.

PURPOSE: Resective epilepsy surgery is a well-established, evidence-based treatment option in patients with drug-resistant focal epilepsy. A major predictive factor of good surgical outcome is visualization and delineation of a potential epileptogenic lesion by MRI. However, frequently, these lesions are subtle and may escape detection by conventional MRI (≤ 3 T). METHODS: We present the EpiUltraStudy protocol to address the hypothesis that application of ultra-high field (UHF) MRI increases the rate of detection of structural lesions and functional brain aberrances in patients with drug-resistant focal epilepsy who are candidates for resective epilepsy surgery. Additionally, therapeutic gain will be addressed, testing whether increased lesion detection and tailored resections result in higher rates of seizure freedom 1 year after epilepsy surgery. Sixty patients enroll the study according to the following inclusion criteria: aged ≥ 12 years, diagnosed with drug-resistant focal epilepsy with a suspected epileptogenic focus, negative conventional 3 T MRI during pre-surgical work-up. RESULTS: All patients will be evaluated by 7 T MRI; ten patients will undergo an additional 9.4 T MRI exam. Images will be evaluated independently by two neuroradiologists and a neurologist or neurosurgeon. Clinical and UHF MRI will be discussed in the multidisciplinary epilepsy surgery conference. Demographic and epilepsy characteristics, along with postoperative seizure outcome and histopathological evaluation, will be recorded. CONCLUSION: This protocol was reviewed and approved by the local Institutional Review Board and complies with the Declaration of Helsinki and principles of Good Clinical Practice. Results will be submitted to international peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: www.trialregister.nl : NTR7536.

Ultra-high field magnetic resonance imaging in human epilepsy: A systematic review.

RATIONALE: Resective epilepsy surgery is an evidence-based curative treatment option for patients with drug-resistant focal epilepsy. The major preoperative predictor of a good surgical outcome is detection of an epileptogenic lesion by magnetic resonance imaging (MRI). Application of ultra-high field (UHF) MRI, i.e. field strengths ≥ 7 Tesla (T), may increase the sensitivity to detect such a lesion. METHODS: A keyword search strategy was submitted to Pubmed, EMBASE, Cochrane Database and clinicaltrials.gov to select studies on UHF MRI in patients with epilepsy. Follow-up study selection and data extraction were performed following PRISMA guidelines. We focused on I) diagnostic gain of UHF- over conventional MRI, II) concordance of MRI-detected lesion, seizure onset zone and surgical decision-making, and III) postoperative histopathological diagnosis and seizure outcome. RESULTS: Sixteen observational cohort studies, all using 7T MRI were included. Diagnostic gain of 7T over conventional MRI ranged from 8% to 67%, with a pooled gain of 31%. Novel techniques to visualize pathological processes in epilepsy and lesion detection are discussed. Seizure freedom was achieved in 73% of operated patients; no seizure outcome comparison was made between 7T MRI positive, 7T negative and 3T positive patients. 7T could influence surgical decision-making, with high concordance of lesion and seizure onset zone. Focal cortical dysplasia (54%), hippocampal sclerosis (12%) and gliosis (8.1%) were the most frequently diagnosed histopathological entities. SIGNIFICANCE: UHF MRI increases, yet variably, the sensitivity to detect an epileptogenic lesion, showing potential for use in clinical practice. It remains to be established whether this results in improved seizure outcome after surgical treatment. Prospective studies with larger cohorts of epilepsy patients, uniform scan and sequence protocols, and innovative post-processing technology are equally important as further increasing field strengths. Besides technical ameliorations, improved correlation of imaging features with clinical semiology, histopathology and clinical outcome has to be established.

Clinical and molecular practice of European thoracic pathology laboratories during the COVID-19 pandemic. The past and the near future.

BACKGROUND: This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. MATERIALS AND METHODS: A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. RESULTS: Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. CONCLUSIONS: The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe.

A brief self-compassion intervention for adolescents with type 1 diabetes and disordered eating: a feasibility study.

AIM: To examine the feasibility and acceptability of a brief self-compassion intervention for adolescents with type 1 diabetes and disordered eating behaviour. METHODS: Twenty-seven adolescents with type 1 diabetes were recruited and randomized to receive the brief (two 2.5-h sessions) self-compassion intervention, either in the intervention group (n=11) or in a waitlist control group (n=8). The intervention was adapted from the standardized eight-session 'Making Friends with Yourself' programme, and sessions were delivered 1 week apart. Acceptability was assessed through qualitative questionnaires and feasibility was assessed based on session attendance and recruitment metrics. Possible changes to disordered eating behaviour, self-care behaviours, diabetes-related distress, self-compassion, stress and glycaemic control were also assessed. RESULTS: Nineteen participants completed the study, and they reported an increased sense of common humanity (acknowledging that we are not alone), mindfulness, and coping resources. In terms of feasibility, recruitment took longer than expected (8 months) and not all participants were able to attend both sessions (nine could only attend one of the two sessions). CONCLUSIONS: While self-compassion is a strong conceptual fit for the issues of type 1 diabetes and disordered eating behaviour in adolescence, and the intervention content appears acceptable, feasibility issues were such that brief self-compassion programmes will probably need to be adapted into digital interventions for future research. (Trial registration number: ANZCTR 12619000541101).

A pilot randomized controlled trial of a gratitude intervention for adolescents with Type 1 diabetes.

AIM: Cost-effective psychosocial interventions that can feasibly be implemented into busy clinical settings are needed to improve psychological and physical health outcomes in adolescents with Type 1 diabetes. We examined the efficacy of a gratitude journalling intervention to improve psychological well-being and glycaemic control in adolescents aged 10-16 years with Type 1 diabetes. METHODS: Eighty adolescents were randomized to the 8-week gratitude intervention (N = 40) or standard care (N = 40). Self-reported measures of stress, quality of life, self-care, depression and gratitude were assessed at baseline and 8 weeks after baseline. Glycaemic control (HbA1c ) was assessed at baseline and 12 weeks after baseline. A per-protocol analysis was conducted with the adolescents who completed all questionnaires (N = 60). Analysis of covariance (ANCOVA) was used to examine differences between treatment arms at follow-up adjusting for baseline scores. RESULTS: There was no evidence of any between-group differences in the psychological or behavioural measures at follow-up (all P-values > 0.05). Glycaemic control slightly increased in the control group while remaining stable in the gratitude group, with a between-group difference of 6.1 mmol/mol [95% confidence interval (CI) -2.6 to 14.7; 0.6%, 95% CI -0.2 to 1.3] at 12 weeks after baseline. After adjusting for baseline HbA1c , this between-group difference was significant (P = 0.048). CONCLUSIONS: This is the first randomized trial of a gratitude journalling intervention for adolescents with Type 1 diabetes. Gratitude journalling interventions represent a clinically usable approach. If and how it helps to stabilise glycaemic control in adolescents with Type 1 diabetes remains to be confirmed in future research.

Association of combined PD-L1 expression and tumour-infiltrating lymphocyte features with survival and treatment outcomes in patients with metastatic melanoma.

BACKGROUND: Recent advances obtained with immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1) protein have significantly improved the outcome of patients with metastatic melanoma. The PD-L1 expression in tumour cells as detected by immunohistochemistry is a predictive biomarker in some solid tumours, but appears insufficient as prognostic or predictive factor of response to ICIs in metastatic melanomas. OBJECTIVES: We investigated whether the presence and the features of pretreatment CD8+ tumour-infiltrating T lymphocytes (TILs) could be a complementary prognostic or predictive biomarker in patients with metastatic melanoma. METHODS: In this retrospective study, we evaluated the association of PD-L1 expression ≥5% of tumour cells combined with TIL features (CD8, CD28, Ki67) with the overall survival (OS) among 51 patients treated with ICIs and 54 patients treated with other treatment options (non-ICIs). RESULTS: PD-L1 positivity was observed in 33% and 39% of primary melanomas and matched metastases, respectively, with, however, poor concordance between the primary and the matched metastatic site (κ = 0.283). No significant association was noted between PD-L1 expression and CD8+ TIL profile analysed as single markers and OS or response to immunotherapy. Instead, their combined analysis in primary melanoma samples showed that the PD-L1-/CD8+ status was significantly associated with prolonged OS in the whole population (P = 0.04) and in the subgroup treated with non-ICIs (P = 0.009). Conversely, the PD-L1+/CD8+ status was a good prognostic factor in patients treated with ICIs (P = 0.022), whereas was significantly associated with poor prognosis in patients treated with non-ICIs (P = 0.014). While the expression of CD28 was not related to outcome, the Ki67 expression was significantly associated with poor OS in the subgroup CD8+ TIL+/PD-L1- (P = 0.02). CONCLUSIONS: The pretreatment combination of PD-L1 expression with the level of CD8+ TILs could better assess OS and predict therapeutic response of patients with metastatic melanoma treated by either immunotherapy or other treatment regimens.

[Therapeutic strategies in advanced ALK positive non-small cell lung cancer]. / Stratégies thérapeutiques dans le cancer bronchique non à petites cellules ALK positif de stade IV.

Anaplastic lymphoma kinase (ALK) rearrangement is a therapeutically targetable oncogenic driver found in 5% of patients with non-small-cell lung cancer (NSCLC). The objective of this paper is to synthesise current knowledge on ALK rearrangement and its impact on the management of advanced NSCLC. Several inhibitors of the tyrosine kinase of ALK (crizotinib, ceritinib, alectinib) have been approved as first line therapies in patients with advanced ALK positive NSCLC, which are associated with a better median progression-free survival than conventional chemotherapy. Unfortunately, the emergence of drug resistance leads to tumor progression. In patients with oligoprogressive disease if local ablative therapy can be effected, continuing with the same ALK tyrosine kinase inhibitor is one option. In patients with progression, clinicians may consider switching to another therapy. Rebiopsy of the tumor or liquid biopsy could be attempted to identify the mechanisms of resistance and to customize ALK-target therapy. The emergence of crizotinib drug resistance has prompted the development of next generation drugs including ceritinb, alectinib, brigatinib and lorlatinib. The ability to quickly develop targeted therapies against specific oncogenic drivers will require close co-operation between pathologists, pulmonologists and oncologists in the future to keep pace with drug discoveries and to define optimal therapeutic strategies.

Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

Post-mortem computed tomography in forensic investigations of lethal gunshot incidents: is there an added value?

The aim of this study is to assess the added value of post-mortem computed tomography (PMCT) in fatal shooting incidents compared with autopsy findings. For this study, the analysis was restricted to the following four features: location of the entrance and exit wounds, internal injuries, location of projectiles or metal fragments and course of the trajectories. These features were selected because they provide essential information on the cause and manner of death. All data were retrospectively collected from medical forensic examinations of fatal shooting incidents in the Netherlands that occurred in 2010-2014. Twenty-one fatal shooting victims were included in this study, with a total of 100 trajectories. For all 100 trajectories, the forensic radiologist and pathologist came to a consensus on which examination had the highest diagnostic value for each of the four features. PMCT provides superior information on the presence of metal fragments, internal injuries and the course of trajectories. PMCT provides limited information on the discrimination of entrance and exit wounds. In conclusion, PMCT provides additional relevant information in over 60% of forensic medical examinations of deceased victims of shooting incidents. We therefore recommend adding PMCT as a standard examination in these cases.

Liquid biopsy in the era of immuno-oncology: is it ready for prime-time use for cancer patients?

The emergence of immunotherapy in oncology requires the discovery, validation and subsequent adoption of robust, sensitive and specific predictive and prognostic biomarkers for daily practice. Until now, anti-PD-L1 immunohistochemistry (IHC) on tissue sections has been the only validated companion diagnostic test for first-line immunotherapy for advanced and metastatic cancer, notably non-small-cell lung cancer (NSCLC). However, detection of this biomarker presents limitations that have stimulated the development of other biomarkers and other approaches. Within this context, the use of a liquid biopsy (LB) could provide an important complementary or alternative added value to PD-L1 IHC. In this review, we discuss how LBs have been used in the field of immuno-oncology (I-O) to predict response, relapse or adverse advents for patients undergoing immune-checkpoint inhibitor (ICI) therapy (anti-PD-1/PD-L1 and CTLA-4) and we highlight recent developments. Circulating tumor cells (CTCs), cell-free DNA (cfDNA), proteins and cytokines detected in plasma as well as circulating T-lymphocytes are discussed as potential sources for developing new I-O biomarkers. The quantification of cfDNA as a predictive biomarker, as well as its sequencing for the determination of tumor mutational burden, is already well advanced. Additionally, the quantification of PD-L1 from CTCs, bound on exosomes or free in plasma, as well as the determination of cytokines, are also being actively investigated with promising results having recently been published. Lastly, analysis of T-lymphocytes, especially by analyzing the T-cell receptor, has recently emerged as a valuable biomarker that might become relevant for the prediction of response to ICIs. While LBs have not yet been implemented in routine I-O clinical practice, recent promising data and rapidly advancing technologies indicate that this approach has the potential to soon personalize the clinical management of cancer patients receiving ICIs.

Is CT bulletproof? On the use of CT for characterization of bullets in forensic radiology.

PURPOSE: Forensic investigations could benefit from non-invasive in situ characterization of bullets. Therefore, the use of CT imaging was explored for the analysis of bullet geometry and composition. Bullet visualization with CT is challenging as the metal constituents suffer from excessive X-ray attenuation due to their high atomic number, density, and geometry. METHODS: A metal reference phantom was developed containing small discs of various common metals (aluminum, iron, stainless steel, copper, brass, tungsten, and lead). CT images were acquired with 70-150 kVp and 200-400 mAs and were reconstructed using an extended Hounsfield unit (HU) scale (- 10,240 to + 30,710). For each material, the mean CT number (HU) was measured to construct a metal database. Different bullets (n = 11) were scanned in a soft tissue-mimicking phantom. Bullet size and shape were measured, and composition was evaluated by comparison with the metal database. Also, the effect of bullet orientation within the CT scanner was evaluated. RESULTS: In the reference phantom, metals were classified into three groups according to their atomic number (Z): low (Z ≤ 13; HU < 3000), medium (Z = 25-30; HU = 13,000-20,000), and high (Z ≥ 74; HU > 30,000). External bullet contours could be accurately delineated. Internal interfaces between jacket and core could not be identified. Cross-sectional spatial profile plots of the CT number along bullets' short axis revealed beam hardening and photon starvation effects that depended on bullet size, shape, and orientation within the CT scanner. Therefore, the CT numbers of bullets were unreliable and could not be used for material characterization by comparison with the reference phantom. CONCLUSION: CT-based characterization of bullets was feasible in terms of size and shape but not composition.