Functional Engagement of the PD-1/PD-L1 Complex But Not PD-L1 Expression Is Highly Predictive of Patient Response to Immunotherapy in Non-Small-Cell Lung Cancer.

PURPOSE: In many cancers, the expression of immunomodulatory ligands leads to immunoevasion, as exemplified by the interaction of PD-L1 with PD-1 on tumor-infiltrating lymphocytes. Profound advances in cancer treatments have come with the advent of immunotherapies directed at blocking these immuno-suppressive ligand-receptor interactions. However, although there has been success in the use of these immune checkpoint interventions, correct patient stratification for these therapies has been challenging. MATERIALS AND METHODS: To address this issue of patient stratification, we have quantified the intercellular PD-1/PD-L1 interaction in formalin-fixed paraffin-embedded tumor samples from patients with non-small cell lung carcinoma, using a high-throughput automated quantitative imaging platform (quantitative functional proteomics [QF-Pro]). RESULTS: The multisite blinded analysis across a cohort of 188 immune checkpoint inhibitor-treated patients demonstrated the intra- and intertumoral heterogeneity of PD-1/PD-L1 immune checkpoint engagement and notably showed no correlation between the extent of PD-1/PD-L1 interaction and PD-L1 expression. Importantly, PD-L1 expression scores used clinically to stratify patients correlated poorly with overall survival; by contrast, patients showing a high PD-1/PD-L1 interaction had significantly better responses to anti-PD-1/PD-L1 treatments, as evidenced by increased overall survival. This relationship was particularly strong in the setting of first-line treatments. CONCLUSION: The functional readout of PD-1/PD-L1 interaction as a predictive biomarker for the stratification of patients with non-small-cell lung carcinoma, combined with PD-L1 expression, should significantly improve the response rates to immunotherapy. This would both capture patients excluded from checkpoint immunotherapy (high PD-1/PD-L1 interaction but low PD-L1 expression, 24% of patients) and additionally avoid treating patients who despite their high PD-L1 expression do not respond and suffer from side effects.

Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19: an update from the Dutch Oncology COVID-19 Consortium.

AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. METHODS: The Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. RESULTS: Between 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. CONCLUSION: There was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic.

Peripheral trauma and movement disorders: a systematic review of reported cases.

OBJECTIVE: To perform a systematic review of cases reported in the literature in which a peripheral trauma preceded the onset of a movement disorder (MD). METHODS: Two reviewers independently searched Medline and EMBASE. Data regarding patient characteristics, type of MD and type of injury were collected, as well as information on the spread of MD, predisposing factors, psychological characteristics, presence of nerve lesions and treatment. RESULTS: 133 publications presenting findings on 713 patients with peripherally induced movement disorders (PIMDs) were included. MDs were more frequent in women. The most commonly reported PIMD was fixed dystonia, which was often associated with pain and sensory abnormalities of the affected body part. In 26% of patients, a nerve injury was identified. More than one-third of patients had complex regional pain syndrome; these patients were younger, had a shorter interval before developing MDs and more often showed spread of MD to other body parts. Nearly 15% were diagnosed with a psychogenic movement disorder (PMD). PMD was associated with higher frequencies of fixed dystonia and tremor. In general, response to various treatments, including botulinum toxin administrations, was disappointing. CONCLUSIONS: While there is overlap in clinical characteristics between PIMDs and PMDs, the current review indicates that there are many well documented organic cases of PIMDs. This suggests that MDs, such as dystonia, tremor, myoclonus and tics, may under certain circumstances (e.g., nerve lesions or genetic predisposition) be triggered by peripheral trauma. Potential mechanisms that may explain the underlying pathophysiology are addressed.

Association between head circumference and body size.

BACKGROUND/AIMS: Studies on the association between head circumference (HC) and height or weight have shown variable results. METHODS: Using data from the Dutch nationwide survey performed in 1997 (n = 14,500), we calculated correlations for different ages, and fitted a regression model for the estimation of HC. HC versus height charts were created for different age groups. Data from children from other ethnic groups and children with various growth disorders were plotted on the charts and compared with reference data. RESULTS: Correlations between HC and height or weight showed similar patterns: highest at birth, followed by a rapid decline to a stable level and a peak in adolescence. On charts containing the regression line ±2 standard deviations for subjects aged 0-2 months and 2 months to 21 years, Turkish and Moroccan children, as well as children with idiopathic short stature and small for gestational age, had a normal HC for height, whereas children with an insulin-like growth factor 1 receptor defect or Sotos syndrome showed trends towards a smaller or larger HC for height, respectively. CONCLUSION: HC correlates strongly with height and weight. The charts of HC for height may serve as an additional tool to interpret HC in short or tall children.

Thermal hypesthesia in patients with complex regional pain syndrome related dystonia.

The quantitative thermal test showed cold and warmth hypesthesia without increased heat pain sensitivity in the affected limbs of complex regional pain syndrome (CRPS) patients with tonic dystonia (n = 44) in comparison with healthy controls with a similar age and sex distribution (n = 35). The degrees of cold and warmth hypesthesia were strongly correlated. We conclude that dysfunction in small nerve fiber (i.e., C and Aδ) processing is present in patients with CRPS-related dystonia.

Peripheral trauma and movement disorders.

The question whether peripheral trauma can cause movement disorders has since long been a subject of debate. In this review we present the pro's and con's of arguments that have been presented in the literature and discuss their plausibility. Additionally, recent developments on the potential mechanisms that underlie dystonia in complex regional pain syndrome are used to illustrate how the relation between peripheral trauma and movement disorders may evolve.