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Supplementary Figure 3: Gating strategy for a representative sample

Supplementary Tables S1-S2

Purpose:Patients with cancer display reduced humoral responses after double-dose COVID-19 vaccination, whereas their cellular response is more comparable with that in healthy individuals. Recent studies demonstrated that a third vaccination dose boosts these immune responses, both in healthy people and patients with cancer. Because of the availability of many different COVID-19 vaccines, many people have been boosted with a different vaccine from the one used for double-dose vaccination. Data on such alternative vaccination schedules are scarce. This prospective study compares a third dose of BNT162b2 after double-dose BNT162b2 (homologous) versus ChAdOx1 (heterologous) vaccination in patients with cancer.Experimental Design:A total of 442 subjects (315 patients and 127 healthy) received a third dose of BNT162b2 (230 homologous vs. 212 heterologous). Vaccine-induced adverse events (AE) were captured up to 7 days after vaccination. Humoral immunity was assessed by SARS-CoV-2 anti-S1 IgG antibody levels and SARS-CoV-2 50% neutralization titers (NT50) against Wuhan and BA.1 Omicron strains. Cellular immunity was examined by analyzing CD4+ and CD8+ T-cell responses against SARS-CoV-2–specific S1 and S2 peptides.Results:Local AEs were more common after heterologous boosting. SARS-CoV-2 anti-S1 IgG antibody levels did not differ significantly between homologous and heterologous boosted subjects [GMT 1,755.90 BAU/mL (95% CI, 1,276.95–2,414.48) vs. 1,495.82 BAU/mL (95% CI, 1,131.48–1,977.46)]. However, homologous-boosted subjects show significantly higher NT50 values against BA.1 Omicron. Subjects receiving heterologous boosting demonstrated increased spike-specific CD8+ T cells, including higher IFNγ and TNFα levels.Conclusions:In patients with cancer who received double-dose ChAdOx1, a third heterologous dose of BNT162b2 was able to close the gap in antibody response.

BACKGROUND: and purpose: Phenazopyridine (PAP) is an over-the-counter drug widely used to provide symptomatic relief of bladder pain in conditions such as cystitis or bladder pain syndrome (BPS). Whereas the analgesic effect of PAP has been attributed to a local effect on the mucosa of the lower urinary tract (LUT), the molecular targets of PAP remain unknown. We investigated the effect of PAP on pain-related Transient Receptor Potential (TRP) channels expressed in sensory neurons that innervate the bladder wall. EXPERIMENTAL APPROACH: The effects of PAP on the relevant TRP channels (TRPV1, TRPA1, TRPM8, TRPM3) expressed in HEK293 or CHO cells was investigated using Fura-2-based calcium measurements and whole-cell patch-clamp recordings. Activity of PAP on TRPM8 was further analysed using Fura-2-based calcium imaging on sensory neurons isolated from lumbosacral dorsal root ganglia (DRG) of mice. KEY RESULTS: PAP rapidly and reversibly inhibits responses of TRPM8 expressed in HEK293 cells to cold and menthol, with IC50 values between 2 and 10 μM. It acts by shifting the voltage dependence of channel activation towards positive potentials, opposite to the effect of menthol. PAP also inhibits TRPM8-mediated, menthol-evoked calcium responses in lumbosacral DRG neurons. At a concentration of 10 μM, PAP did not significantly affect TRPA1, TRPV1, or TRPM3. CONCLUSION AND IMPLICATIONS: PAP inhibits TRPM8 in a concentration range consistent with PAP levels in the urine of treated patients. Since TRPM8 is expressed in bladder afferent neurons and upregulated in patients with painful bladder disorders, TRPM8 inhibition may underlie the analgesic activity of PAP. ispartof: European Journal Of Pharmacology vol:942 ispartof: location:Netherlands status: Published online

Purpose: Patients with cancer display reduced humoral responses after double-dose COVID-19 vaccination, whereas their cellular response is more comparable with that in healthy individuals. Recent studies demonstrated that a third vaccination dose boosts these immune responses, both in healthy people and patients with cancer. Because of the availability of many different COVID-19 vaccines, many people have been boosted with a different vaccine from the one used for double-dose vaccination. Data on such alternative vaccination schedules are scarce. This prospective study compares a third dose of BNT162b2 after double-dose BNT162b2 (homologous) versus ChAdOx1 (heterologous) vaccination in patients with cancer. Experimental Design: A total of 442 subjects (315 patients and 127 healthy) received a third dose of BNT162b2 (230 homologous vs. 212 heterologous). Vaccine-induced adverse events (AE) were captured up to 7 days after vaccination. Humoral immunity was assessed by SARS-CoV-2 anti-S1 IgG antibody levels and SARS-CoV-2 50% neutralization titers (NT50) against Wuhan and BA.1 Omicron strains. Cellular immunity was examined by analyzing CD4+ and CD8+ T-cell responses against SARS-CoV-2–specific S1 and S2 peptides. Results: Local AEs were more common after heterologous boosting. SARS-CoV-2 anti-S1 IgG antibody levels did not differ significantly between homologous and heterologous boosted subjects [GMT 1,755.90 BAU/mL (95% CI, 1,276.95–2,414.48) vs. 1,495.82 BAU/mL (95% CI, 1,131.48–1,977.46)]. However, homologous-boosted subjects show significantly higher NT50 values against BA.1 Omicron. Subjects receiving heterologous boosting demonstrated increased spike-specific CD8+ T cells, including higher IFNγ and TNFα levels. Conclusions: In patients with cancer who received double-dose ChAdOx1, a third heterologous dose of BNT162b2 was able to close the gap in antibody response.

Background: Coronavirus disease (COVID-19) is interfering heavily with the screening, diagnosis and treatment of cancer patients. Better knowledge of the seroprevalence and immune response after Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in this population is important to manage them safely during the pandemic. Methods: 922 cancer patients, 100 non-cancer patients and 94 health care workers (HCW) attending the Multidisciplinary Oncology Unit of Antwerp University Hospital from 24th of March 2020 till 31st of May 2020, and the Oncology Unit of AZ Maria Middelares Hospital, Ghent, from 13th of April 2020 till 31st of May 2020 participated in the study. The Alinity (A; Abbott) and Liaison (D; DiaSorin) commercially available assays were used to measure SARS-CoV-2 IgG, while total SARS-CoV-2 Ig was measured by Elecsys (R; Roche). Results: In the overall study population IgG/total SARS-CoV-2 antibodies were found in respectively 32/998 (3.2%), 68/1020 (6.7%), 37/1010 (3.7%) and of individuals using the A, D or R test. Forty-six out of 618 (7.4%) persons had a positive SARS-CoV-2 polymerase chain reaction (RT-PCR) test. Seroprevalence in cancer patients (A:2.2%, D:6.2%, R:3.0%), did not significantly differ from that in non-cancer patients (A:1.1%, D:5.6%, R:0.0%), but was lower than the HCW (A:13%, D:12%, R:12%; respectively Fisher’s exact test p Z 0.00001, p Z 0.046, p Z 0.0004). A positive SARS-CoV-2 RT-PCR was found in 6.8% of the cancer patients, 2.3% of the non-cancer patients and 28.1% of the HCW (Fisher’s exact test p Z 0.0004). Correlation between absolute values of the different Ig tests was poor in the cancer population. Dichotomising a positive versus negative test result, the A and R test correlated well (kappa 0.82 p McNemar test Z 0.344), while A and D and R and D did not (respectively kappa 0.49 and 0.57; result significantly different p McNemar test Z 75%) and median absolute antibody levels (A: 7.0 versus 4.7; D 74.0 versus 26.6, R: 16.34 versus 7.32; all >P Mann Whitney U test Z 0.28) in cancer patients and HCW with a positive RT-PCR at least 7 days earlier did not show any differences. However, none (N Z 0/4) of the patients with hematological tumours had seroconversion and absolute antibody levels remained much lower compared to patients with solid tumours (R: 0.1 versus 37.6, p 0.003; D 4.1 versus 158, p 0.008) or HCW (all p < 0.0001). Conclusion: HCW were at high risk of being infected by SARS-CoV-2 during the first wave of the pandemic. Seroprevalence in cancer patients was low in the study period. Although Ig immune response in cancer patients with solid tumours does not differ from healthy volunteers, patients with hematological tumours have a very poor humoral immune response. This has to be taken into account in future vaccination programmes in this population. SARS-CoV-2 antibody tests have divergent results and seem to have little added value in the management of cancer patients.

Patients with advanced lung cancer and depressive/anxiety symptoms experience worse quality of life (QoL) We examined whether and how coping strategy influenced QoL in these patients. A multicenter cross-sectional study of 125 patients with advanced lung cancer was conducted. Patients using positive reframing as coping strategy, experience less anxiety and depressive symptoms leading to a better QoL. Introduction: Patients with advanced lung cancer experience high physical symptom burden with substantial psychological distress. Depressive and anxiety symptoms are common and associated with worse quality of life (QoL). Early palliative care (EPC) addresses the complex supportive care needs improving QoL and mood. The mechanisms of EPC are uncertain. We examined whether and how coping strategy, a primary component of EPC, influenced QoL in these patients. Materials and Methods: We conducted a multicenter cross-sectional study of patients with advanced lung cancer. A total of 125 patients completed assessments of QoL (QLQ-C15-PAL), depressive and anxiety symptoms (HADS), and coping (brief COPE questionnaire). The data were analyzed by descriptive statistics. To determine whether and how coping strategy influences QoL, correlations and logistic regressions were performed. Results: Positive refraining correlates significantly with global QoL (r 0.25, P

ispartof: CLINICAL KIDNEY JOURNAL vol:16 issue:4 pages:760-761 ispartof: location:England status: published

Medical writing and editorial assistance were provided by Tim Ibbotson, PhD, of ApotheCom (Yardley, PA, USA) and funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Statistical analysis was done by Herbert Thijs, Sofie Van Waes, and Filip Deforce (DICE). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. The authors thanks to Hermine Leroi for the operational support and assistance during this project. The authors thank Katrien Willaert for the initiation of the study and its study design.

BACKGROUND AND PURPOSE: Transient receptor potential melastatin 3 (TRPM3) is a non-selective cation channel that plays a pivotal role in the peripheral nervous system as a transducer of painful heat signals. Alternative splicing gives rise to several TRPM3 variants. The functional consequences of these splice isoforms are poorly understood. Here, the pharmacological properties of TRPM3 variants arising from alternative splicing in the pore-forming region were compared. EXPERIMENTAL APPROACH: Calcium microfluorimetry and patch clamp recordings were used to compare the properties of heterologously expressed TRPM3α1 (long pore variant) and TRPM3α2-α6 (short pore variants). Furthermore, site-directed mutagenesis was done to investigate the influence of the length of the pore loop on the channel function. KEY RESULTS: All short pore loop TRPM3α variants (TRPM3α2-α6) were activated by the neurosteroid pregnenolone sulphate (PS) and by nifedipine, whereas the long pore loop variant TRPM3α1 was insensitive to either compound. In contrast, TRPM3α1 was robustly activated by clotrimazole, a compound that does not directly activate the short pore variants but potentiates their responses to PS. Clotrimazole-activated TRPM3α1 currents were largely insensitive to established TRPM3α2 antagonists and were only partially inhibited upon activation of the μ opioid receptor. Finally, by creating a set of mutant channels with pore loops of intermediate length, we showed that the length of the pore loop dictates differential channel activation by PS and clotrimazole. CONCLUSION AND IMPLICATIONS: Alternative splicing in the pore-forming region of TRPM3 defines the channel's pharmacological properties, which depend critically on the length of the pore-forming loop. LINKED ARTICLES: This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc. ispartof: BRITISH JOURNAL OF PHARMACOLOGY vol:179 issue:14 pages:3560-3575 ispartof: location:England status: published

Purpose of review Controversy exists regarding the optimal treatment of patients with stage IIIA-N2 nonsmall cell lung cancer because of its heterogeneity. Patients are at risk for both local and distant disease relapse after primary local treatment. However, there may be a window of opportunity for surgery, if mediastinal downstaging has been obtained after induction therapy. This manuscript reviews the outcome of patients treated by neo-adjuvant chemotherapy (NA-C) followed by surgery, compared with patients treated with either definitive sequential or concurrent chemoradiotherapy (cCRT), illustrated by a single-centre retrospective case series. Recent findings Of 53 eligible patients, 19 received NA-C and underwent surgical resection, whilst 20 and 14 received concurrent or sequential definitive CRT, respectively. A significant difference in progression-free survival favouring NA-C followed by surgery over both CRT modalities was found. However, this translated only in an overall survival benefit in comparison with sequential definitive CRT. A trend for better outcome was observed in selected surgical patients with single-level mediastinal involvement and complete resection. Summary Our case series results are consistent with the present standard of care of CRT, which restricts surgical resection to carefully selected patients. Immunotherapy will likely change the treatment paradigm.

Simple Summary SARS-CoV-2 infection has been associated with broad dysregulation of the circulating immune system and inflammation that could persist for a long period. Chronic inflammation has been shown to play a significant role in cancer development and progression. Here we showed that several immune-related factors were altered in cancer patients who had previously been exposed to the virus. Several of these immune factors observed to be elevated even after 3 months of infection are also tumour-promoting factors. The results of this study suggest that we need to pay more attention to cancer patients who have recovered from COVID-19 for any increased rate of cancer progression. Abstract Cytokines, chemokines, and (angiogenic) growth factors (CCGs) have been shown to play an intricate role in the progression of both solid and haematological malignancies. Recent studies have shown that SARS-CoV-2 infection leads to a worse outcome in cancer patients, especially in haematological malignancy patients. Here, we investigated how SARS-CoV-2 infection impacts the already altered CCG levels in solid or haematological malignancies, specifically, whether there is a protective effect or rather a potentially higher risk for major COVID-19 complications in cancer patients due to elevated CCGs linked to cancer progression. Serially analysing immune responses with 55 CCGs in cancer patients under active treatment with or without SARS-CoV-2 infection, we first showed that cancer patients without SARS-CoV-2 infection (n = 54) demonstrate elevated levels of 35 CCGs compared to the non-cancer, non-infected control group of health care workers (n = 42). Of the 35 CCGs, 19 were common to both the solid and haematological malignancy groups and comprised previously described cytokines such as IL-6, TNF-α, IL-1Ra, IL-17A, and VEGF, but also several less well described cytokines/chemokines such as Fractalkine, Tie-2, and T cell chemokine CTACK. Importantly, we show here that 7 CCGs are significantly altered in SARS-CoV-2 exposed cancer patients (n = 52). Of these, TNF-α, IFN-β, TSLP, and sVCAM-1, identified to be elevated in haematological cancers, are also known tumour-promoting factors. Longitudinal analysis conducted over 3 months showed persistence of several tumour-promoting CCGs in SARS-CoV-2 exposed cancer patients. These data demonstrate a need for increased vigilance for haematological malignancy patients as a part of long COVID follow-up.

Introduction: Health Care System - The kingdom of Belgium with its capital Brussels is located in Western Europe (Fig. 1) and has a population of 11,492,641 inhabitants (January 2020) for a surface of 30,689 km2. The country is a member of the European Union (EU) and federally organized with a Dutch-speaking majority in the northern Flemish region, a French-speaking region (Wallonia) in the south, and the Brussels capital region. Its population is mainly of Caucasian ethnicity, with 10% immigrants from different non-EU countries, mostly Africa and Middle East. [...]

Urinary tract infections (UTI) rank among the most common bacterial infections in humans and are routinely treated with empirical antibiotics. However, due to increasing microbial resistance, the efficacy of the most used antibiotics has declined. To find alternative treatment options, there is a great need for a better understanding of the UTI pathogenesis and the mechanisms that determine UTI susceptibility. In order to investigate this in an animal model, a reproducible, non-invasive assay to study the course of UTI is indispensable. For years, the gold standard for the enumeration of bacterial load has been the determination of Colony Forming Units (CFU) for a particular sample volume. This technique requires post-mortem organ homogenates and serial dilutions, limiting data output and reproducibility. As an alternative, bioluminescence imaging (BLI) is gaining popularity to determine the bacterial load. Labeling pathogens with a lux operon allow for the sensitive detection and quantification in a non-invasive manner, thereby enabling longitudinal follow-up. So far, the adoption of BLI in UTI research remains limited. This manuscript describes the practical implementation of BLI in a mouse urinary tract infection model. Here, a step-by-step guide for culturing bacteria, intravesical instillation and imaging is provided. The in vivo correlation with CFU is examined and a proof-of-concept is provided by comparing the bacterial load of untreated infected animals with antibiotic-treated animals. Furthermore, the advantages, limitations, and considerations specific to the implementation of BLI in an in vivo UTI model are discussed. The implementation of BLI in the UTI research field will greatly facilitate research on the pathogenesis of UTI and the discovery of new ways to prevent and treat UTI.

Background Palliative Care (PC) medicine is strongly emerging worldwide. Despite the effort to implement PC in the basic medical curriculum in Belgium, little time is spent on it during theoretical training. For two consecutive years, a survey was presented to all students from the second master’s year medicine from the University of Antwerp. The survey consisted of demographic questions, a knowledge test about PC and an evaluation about students’ self-confidence regarding communicative skills used in end-of-life conversations. First, to evaluate students’ self-confidence regarding end-of-life conversation and mapping out possible gaps in the palliative care training at our university. Second, to assess whether our classes are able to get students to adequately reflect on possible factors that may influence end-of-life conversation.Results Students feel that not enough time is spent on palliative care education. However, good scores were obtained regarding the theoretical knowledge about PC. Students feel confident about general communicative skills, but don’t feel confident about communicative skills specific to palliative care/advance care planning.Conclusion Specific course content can help improve students’ confidence in end-of-life conversation. No difference was seen between real-life teaching or online teaching. Regularly evaluating students’ confidence can help alter course content for the future.

Compounds extracted from the cannabis plant, including the psychoactive Δ9-tetrahydrocannabinol (THC) and related phytocannabinoids, evoke multiple diverse biological actions as ligands of the G protein-coupled cannabinoid receptors CB1 and CB2. In addition, there is increasing evidence that phytocannabinoids also have non-CB targets, including several ion channels of the transient receptor potential superfamily. We investigated the effects of six non-THC phytocannabinoids on the epithelial calcium channels TRPV5 and TRPV6, and found that one of them, Δ9-tetrahydrocannabivarin (THCV), exerted a strong and concentration-dependent inhibitory effect on mammalian TRPV5 and TRPV6 and on the single zebrafish orthologue drTRPV5/6. Moreover, THCV attenuated the drTRPV5/6-dependent ossification in zebrafish embryos in vivo. Oppositely, 11-hydroxy-THCV (THCV-OH), a product of THCV metabolism in mammals, stimulated drTRPV5/6-mediated Ca2+ uptake and ossification. These results identify the epithelial calcium channels TRPV5 and TRPV6 as novel targets of phytocannabinoids, and suggest that THCV-containing products may modulate TRPV5- and TRPV6-dependent epithelial calcium transport. ispartof: PHARMACOLOGICAL RESEARCH vol:136 pages:83-89 ispartof: location:Netherlands status: published

Background: The SARS-CoV-2 pandemic has a far-reaching impact on healthcare. Cancer patients in particular were regarded as vulnerable and oncology departments drastically modified their Care systems and established new priorities. We evaluated the impact of SARS-CoV-2 on the activity of a single cancer center; and we studied patients’ perspectives of the preventive institutional or governmental safety measures.Methods: We performed a retrospective analysis of (i) Volumes of Oncological activities (2020 versus 2019), (ii) patients’ perception rate of the preventive measures, (iii) patients’ SARS-Cov-2 infections, clinical signs thereof and (iv) new diagnoses made during the SARS-CoV-2 pandemic. Results: As compared with a similar timeframe in 2019 the overall activity in total numbers of outpatient chemotherapy administrations and specialist visits, based on weekly average of daily accesses was not statistically different; while inpatient admissions decreased for both medical oncology and thoracic oncology (18% (p=0.0018) and 44% (p85%). However, only 46.2% of responding patients regarded telemedicine, although widely deployed, as an efficient surrogate to a consultation. Thirty-three patients developed SARS-CoV-2, 27 were hospitalized and 11 died within this time frame. These infected patients were younger, current smokers and suffered more comorbidities.Conclusions: This retrospective cohort analysis demonstrates that continuation of active cancer therapy and specialist visits is feasible and safe after implementation of population-wide, institutional and department specific safety measures. Substantial decreases in diagnosis of solid tumors were recorded. To manage the backlog of belated diagnoses, while providing continued state-of-the-art cancer care during this prolonged health crisis, we need policy interventions to adapt the health care system and allow telemedicine to fulfill a more prominent role.

The Covid-19 pandemic could facilitate an end-of-life conversation The new “severe acute respiratory syndrome” coronavirus (SARS-CoV-2) is testing our health care system in several ways. The need for clear end-of-life conversation is, more than ever, emphasized. The potential overcrowding in health facilities creates an important ethical dilemma about which patient can occupy which hospital bed. Most caregivers understand the importance of good communication and documentation of end-of-life conversations, yet few will conduct those conversations. Often, the emphasis lies on obtaining a “do not resuscitate” code (DNR), rather than exploring the patient’s care goals and values. Early care planning (ECP) focuses on those care goals and values. On the one hand, the COVID-19 pandemic is a good starting point for initiating conversations about end-of-life. On the other hand, there are important practical limitations regarding the adequate execution of those conversations. The current pandemic teaches us that ECP should be a central part of our clinical practice. It is important that healthcare providers take responsibility for identifying and initiating those patients who would benefit from such conversations.

Simple Summary The tumor microenvironment (TME) is increasingly believed to be involved in therapy resistance and disease progression of different cancer types. Cancer-associated fibroblasts (CAFs) are prominent components and a central player in creating this TME. In particular, lung and pancreatic cancer, two solid tumor types associated with therapy resistance and poor long-term prognosis have clear evidence of CAFs. In order to provide a more holistic approach of therapy resistance, we highlight different mechanisms of CAF contribution to tumor progression and provide a comprehensive review on how CAFs affect their response to clinical therapy and prognosis, and present an overview of novel therapies and future perspectives involving CAF-targeting agents for both cancer types. Abstract Cancer arises from mutations accruing within cancer cells, but the tumor microenvironment (TME) is believed to be a major, often neglected, factor involved in therapy resistance and disease progression. Cancer-associated fibroblasts (CAFs) are prominent and key components of the TME in most types of solid tumors. Extensive research over the past decade revealed their ability to modulate cancer metastasis, angiogenesis, tumor mechanics, immunosuppression, and drug access through synthesis and remodeling of the extracellular matrix and production of growth factors. Thus, they are considered to impede the response to current clinical cancer therapies. Therefore, targeting CAFs to counteract these protumorigenic effects, and overcome the resistance to current therapeutic options, is an appealing and emerging strategy. In this review, we discuss how CAFs affect prognosis and response to clinical therapy and provide an overview of novel therapies involving CAF-targeting agents in lung and pancreatic cancer.

Background Telehealth modalities were introduced during the SARS-CoV-2 pandemic to assure continuation of cancer care and maintain social distance. Methods This is a retrospective cohort analysis of our telehealth expansion programme. We adapted two existing patient-reported outcome (PRO) telemonitoring tools that register and (self-)manage toxicities to therapy, while screening for SARS-CoV-2-related symptoms. Outpatients from a tertiary cancer centre were enrolled. The adapted PRO interface allowed for uniform registration of SARS-CoV-2-related symptoms and effective triage of patients at home where we also implemented systematic throat washings, when available. Results Three hundred and sixty patients registered to the telemonitoring systems from March 13 to May 15, 2020. Four prespecified SARS-CoV-2 alarms resulted in three patients with positive PCR testing. Other Covid-19 symptoms (fever 5× and cough 2×) led to pretreatment triage resulting in 1 seroconversion after initial negative testing. One of the 477 throat washings proved positive. Conclusions The rapid adoption of an amended PRO (self-)registrations and toxicity management system was feasible and coordinated screening for Covid-19. Continued clinical cancer care was maintained, with significant decreased waiting time. The systemic screening with throat washings offered no real improvement.

Morvan's syndrome (MoS) is a rare autoimmune disorder characterized by central nervous system involvement, autonomic dysfunction and peripheral nerve hyperexcitability. MoS is believed to be caused by autoantibodies targeting contactin-associated protein 2 (Caspr2), a subunit of the neuronal voltage-gated potassium channel (VGKC) complex, usually in association with thymoma, less commonly with other malignancies. This case highlights an exceptional case of severe sleep disturbances and behavioural changes due to MoS, in a patient who would present with and be treated successfully for a second relapse of thymoma 30 months later. Originally he suffered from ocular myasthenia, another autoimmune disorder, which led to diagnosis of his original thymoma and first relapse.

Background: Lung cancer causes impairment of health-related quality of life (QoL), but little is known about gender aspects in QoL and symptom burden of lung cancer patients. The aim of this study was to investigate gender differences in QoL as assessed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the updated lung cancer module. Methods: In a prospective, international, cross-cultural, multicenter study that was undertaken to update the lung cancer-specific module EORTC QLQ-LC13, patients filled in the core questionnaire EORTC QLQ-C30 and the updated lung cancer module. Gender differences were calculated for all QoL scores using ANCOVAs that controlled for known and suspected confounders. Comparisons with historic data were drawn. Results: A total of 200 patients (82 female and 118 male, median age 65 years) were recruited. With the exception of coughing (estimated marginal means: women 33.86 and men 43.52, P=0.022) and diarrhea (estimated marginal means: women 26.01 and men 17.93, P=0.038) there were no significant QoL gender differences. Fatigue was the most pronounced symptom in both, men and women, outpacing typical respiratory symptoms. Quite generally, our sample of lung cancer patients showed considerably worse QoL in all scores when compared to EORTC reference data (lung cancer and combined cancer diagnoses, mean differences up to 13.70 and 21.54 score points, respectively) and to a German norm reference sample (up to 35.37 score points). Conclusions: This study adds to the literature in showing that the typical QoL gender difference effect (women doing worse than men) may not be generalizable across all patient samples.

Highlights • Cancer patients with COVID-19 have a higher morbidity and mortality. • Particularly patients with ongoing or recent cancer treatment, metastatic solid tumors and hematological malignancies are at risk. • Underlying immunosuppression, elevated cytokine levels, altered expression of the angiotensin converting enzyme (ACE-2) and TMPRSS2, and a prothrombotic status in cancer patients may fuel the effects of a SARS-CoV-2 sepsis. • The gene expression level of ACE2 may be an indicator of the susceptibility to SARS-CoV-2 infection, while TMPRSS2 plays a supporting role. • Better knowledge of the mechanisms involved may be a tool to identify high risk patients and to prevent severe complications by targeting the involved pathways., The outbreak of the SARS-CoV-2 pandemic has overwhelmed health care systems in many countries. The clinical presentation of the SARS-CoV-2 varies between a subclinical or flu-like syndrome to that of severe pneumonia with multi-organ failure and death. Initial reports have suggested that cancer patients may have a higher susceptibility to get infected by the SARS-CoV-2 virus but current evidence remains poor as it is biased by important confounders. Patients with ongoing or recent cancer treatment for advanced active disease, metastatic solid tumors and hematological malignancies are at higher risk of developing severe COVID-19 respiratory disease that requires hospitalization and have a poorer disease outcome compared to individuals without cancer. However it is not clear whether these are independent risk factors, or mainly driven by male gender, age, obesity, performance status, uncontrolled diabetes, cardiovascular disease and various other medical conditions. These often have a greater influence on the probability to die due to SARS-CoV-2 then cancer. Delayed diagnosis and suboptimal cancer management due to the pandemic results in disease upstaging and has considerable impact cancer on specific death rates. Surgery during the peak of the pandemic seems to increase mortality, but there is no convincing evidence that adjuvant systemic cancer therapy and radiotherapy are contraindicated, implicating that cancer treatment can be provided safely after individual risk/benefit assessment and some adaptive measures. Underlying immunosuppression, elevated cytokine levels, altered expression of the angiotensin converting enzyme (ACE-2) and TMPRSS2, and a prothrombotic status may fuel the effects of a SARS-CoV-2 in some cancer patients, but have the potential to be used as biomarkers for severe disease and therapeutic targets. The rapidly expanding literature on COVID-19 should be interpreted with care as it is often hampered by methodological and statistical flaws.

Background The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13) assesses quality of life (QOL) in patients with lung cancer and was the first EORTC module developed for use in international clinical trials. Since its publication in 1994, major treatment advances with possible effects on QOL have occurred. These changes called for an update of the module and its international psychometric validation. We aimed to investigate the scale structure and psychometric properties of the updated lung cancer module, QLQ-LC29, in patients with lung cancer. Methods This international, observational field study was done in 19 hospitals across 12 countries. Patients aged older than 18 years with a confirmed diagnosis of lung cancer and no other previous primary tumour, and who were mentally fit with sufficient language skills to understand and complete the questionnaire were included. Patients were asked during a hospital visit to fill in the paper versions of the core questionnaire EORTC QLQ-C30 plus QLQ-LC29, and investigators selected half of these patients to complete the questionnaire again 2-4 weeks later. Our primary aim was to assess the scale structure and psychometric properties of EORTC QLQ-LC29. We analysed scale structure using confirmatory factor analysis; reliability using Cronbach's a value (internal consistency) and intra-class coefficient (test-retest reliability); sensitivity using independent t tests stratified by Karnofsky performance status; and responsiveness to change over time by ANOVA. This study is registered with ClinicalTrials.gov, NCT02745691. Findings Between April 12, 2016, and Sept 26, 2018, 523 patients with a confirmed diagnosis of either non-small-cell lung cancer (n=442) or small-cell lung cancer (n=81) were recruited. Confirmatory factor analysis provided a solution composed of five multi-item scales (coughing, shortness of breath, fear of progression, hair problems, and surgery-related symptoms) plus 15 single symptom or side-effect items: chi(2)=370.233, root mean square error of approximation=0.075, and comparative-fit index=0.901. Cronbach's alpha for internal consistencies of all multi-item scales were above the threshold of 0.70. Intra-class coefficients for test retest reliabilities ranged between 0.82 and 0.97. Three (shortness of breath, fear of progression, and hair problems) of the five multi-item scales showed responsiveness to change over time (p values

Our current thoracic oncology practice could/should be adapted to the COVID-19 pandemic by reducing time in hospital and patient contacts with healthcare workers, whilst maintaining quality of care. This letter offers expert advice on how to do so.https://bit.ly/2JR2IoT

Exhaustion of antigen-specific T-cells in order to escape immune destruction is frequently seen in chronic viral infection and different types of cancer. Blockade of overexpressed negative co-stimulatory pathways, a process known as immune checkpoint modulation, is a promising novel therapy that could improve the treatment of liver diseases with features of T cell exhaustion. We present a case of a 54-year-old hepatitis C virus (HCV) positive patient with an acute flare of hepatitis during nivolumab treatment for a stage IV lung carcinoma, an anti-programmed death-1 (PD-1) immunotherapy. Retrospective testing of HCV RNA documented infection more than 6 months ago. Nivolumab treatment was associated with an alanine aminotransferase (ALT) flare reaching a peak value of 663 U/L, along with bilirubin levels of 0.74 mg/dL and no signs of coagulopathy. The assumption of a nivolumab-associated autoimmune hepatitis led to the interruption of the immune checkpoint inhibitor treatment. However, a subsequent 1-log decrease of HCV RNA load was noticed, which raised the possibility of an immune reconstitution against the HCV-infected hepatocytes with cell lysis. Liver biopsy specimen demonstrated no evidence for autoimmune liver disease or fibrosis. Clinical evolution was favorable and serum transaminases returned to normal levels and HCV RNA load increased to baseline values following nivolumab cessation. The current case suggests an anti-HCV activity of anti-PD-1 treatment in the setting of concomitant HCV viremia and lung carcinoma.

COVID-19 is an infectious pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus with varying presentations ranging from asymptomatic, sensation of a mild cold or influenza to severe bilateral pneumonia and death.1 Patients with cancer and COVID-19 are at a significantly higher likelihood of poor disease outcomes.2 3 In the absence of a vaccine or adequate treatment of COVID-19 current measures to minimise the infectious risk of SARS-CoV-2 in a cancer patient population are focused on physical distancing and protective measures. As it is clear that a hospital is a high-risk setting to contract COVID-19, one of the strategies we can use to treat patients with cancer as safe as possible is to reduce hospital visits to a strict minimum. We previously reported on AMTRA …

Key points Mutagenesis at positively charged amino acids (arginines and lysines) (R1-R4) in the voltage-sensor domain (transmembrane segment (S) 4) of voltage-gated Na+ , K+ and Ca2+ channels can lead to an alternative ion permeation pathway distinct from the central pore. Recently, a non-canonical ion permeation pathway was described in TRPM3, a member of the transient receptor potential (TRP) superfamily. The non-canonical pore exists in the native TRPM3 channel and can be activated by co-stimulation of the endogenous agonist pregnenolone sulphate and the antifungal drug clotrimazole or by stimulation of the synthetic agonist CIM0216. Alignment of the voltage sensor of Shaker K+ channels with the entire TRPM3 sequence revealed the highest degree of similarity in the putative S4 region of TRPM3, and suggested that only one single gating charge arginine (R2) in the putative S4 region is conserved. Mutagenesis studies in the voltage-sensing domain of TRPM3 revealed several residues in the voltage sensor (S4) as well as in S1 and S3 that are crucial for the occurrence of the non-canonical inward currents. In conclusion, this study provides evidence for the involvement of the voltage-sensing domain of TRPM3 in the formation of an alternative ion permeation pathway. Abstract Transient receptor potential (TRP) channels are cationic channels involved in a broad array of functions, including homeostasis, motility and sensory functions. TRP channel subunits consist of six transmembrane segments (S1-S6), and form tetrameric channels with a central pore formed by the region encompassing S5 and S6. Recently, evidence was provided for the existence of an alternative ion permeation pathway in TRPM3, which allows large inward currents upon hyperpolarization independently of the central pore. However, very little knowledge is available concerning the localization of this alternative pathway in the native TRPM3 channel protein. Guided by sequence homology with Shaker K+ channels, in which mutations in S4 can create an analogous 'omega' pore, we performed site-directed mutagenesis studies and patch clamp experiments to identify amino acid residues involved in the formation of the non-canonical pore in TRPM3. Based on our results, we pinpoint four residues in S4 (W982, R985, D988 and G991) as crucial determinants of the properties of the alternative ion permeation pathway.

Lung cancer patients often experience potentially life-threatening medical urgencies and emergencies, which may be a direct or indirect result of the underlying malignancy. This pictorial review addresses the most common thoracic, neurological and musculoskeletal medical emergencies in lung cancer patients, including superior vena cava syndrome, pulmonary embolism, spontaneous pneumothorax, cardiac tamponade, massive haemoptysis, central airway obstruction, oesophagorespiratory fistula, malignant spinal cord compression, carcinomatous meningitis, cerebral herniation and pathological fracture. Emphasis is placed on imaging findings, the role of different imaging techniques and a brief discussion of epidemiology, pathophysiology and therapeutic options. Since early diagnosis is important for adequate patient management and prognosis, radiologists have a crucial role in recognising and communicating these urgencies and emergencies. • Multiplanar multidetector computed tomography is the imaging examination of choice for thoracic urgencies and emergencies. • Magnetic resonance imaging is the imaging modality of choice for investigating central nervous system emergencies. • Urgencies and emergencies can be the initial manifestation of lung cancer. • Radiologists have a crucial role in recognising and in communicating these urgencies/emergencies.

Lung cancer is often associated with a poor quality of life, as reflected by patient-reported outcome measures (PROMs). The aim of this paper is to describe and compare the PROMs that are available. In this manuscript, we review the impact of PROMs on the management of lung cancer. Quality of the study and risk of bias were assessed using the appraisal tools recommended by the Dutch Cochrane Center. Out of 51 studies included in this review, ten instruments were identified and categorized as either generic, cancer- or lung cancer-specific. PROMs are primarily applied in scientific research to compare the therapy outcomes and in drug development to support labeling claims. The interest for the routine use of PROMs in daily practice is growing, which has positive effects on the communication with the patient, mutual decision making and the monitoring and managing of the patient. Besides that, PROMs have an independent prognostic value for survival in lung cancer and economic evaluations can be conducted using their results. Electronic platforms simplify the implementation of PROMs in the daily clinic. The EORTC QLQ-C30 and its lung cancer-specific module QLQ-LC13 are the most frequently used instruments in lung cancer patients. PROMs have the potential to improve the quality of care with a proper implementation in the routine practice. PROMS are needed to value and understand the experience of the patient.

Background Implementation of early palliative care (EPC) into daily oncology practice remains difficult. One of the barriers preventing oncologists from starting EPC is open communication about the palliative setting. The aim of this study was to investigate the relevance of this communication barrier. Patients and Methods In this cross-sectional multicenter study, 106 patients with advanced thoracic cancer were issued a questionnaire to survey 3 dimensions of interest: illness understanding, observation of conversation regarding prognosis and end-of-life (EoL) care, and information preferences of the patients. Results Only 45% of subjects were aware that their treatment was not curative. When comparing presumed treatment goals between patients who were aware that their treatment could not cure them and patients likely to think that their treatment could cure them, 39% of the former chose quality of life versus 9% of the latter, whereas 36% of the former chose cure versus 13% of the latter (χ 2 = 17.7, P = .001). Seventy-five percent never had a conversation about EoL care. More than 50% found a discussion about prognosis and EoL care to be very important. Conclusion This study reveals the existence of a communication barrier and underlines the importance of sustained emphasis with regard to the palliative intent of the treatment. Patients who are aware that they could not be cured were more aware of the primary goal of their treatment, namely quality of life. Most patients did not discuss prognosis and EoL care despite their wish for such a communication.