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Expression of high levels of immune cells including neutrophils has been associated with detrimental outcome in several solid tumors and new strategies to decrease their presence and activity are currently under clinical development. Here, we review some of the relevant literature of the role of neutrophils in different stages of the oncogenic process including tumor initiation, growth, proliferation or metastatic spreading and also focus on how neutrophil counts or the neutrophil-to-lymphocyte ratio may be used as a prognostic and predictive biomarker. Strategies to avoid the deleterious effects of neutrophils in cancer and to reduce their activity are discussed. Examples for such strategies include inhibition of CXCR1 and CXCR2 to decrease migration of neutrophils to tumoral areas or the inhibition of granulocyte colony stimulating factor to decrease the amount of neutrophils which has shown efficacy in preclinical models.

Informative censoring occurs when progression-free survival is the primary end point of a randomized clinical trial and unequal patient dropout is observed between treatment arms owing to poorer tolerance of experimental treatment. Herein we discuss how informative censoring in the experimental arm before criteria for disease progression are met causes bias towards a positive result.

Aberrations in the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/AKT pathway are common in solid tumors. Numerous drugs have been developed to target different components of this pathway. However the prognostic value of these aberrations is unclear. PubMed was searched for studies evaluating the association between activation of the PI3K/mTOR/AKT pathway (defined as PI3K mutation [PIK3CA], lack of phosphatase and tensin homolog [PTEN] expression by immunohistochemistry or western-blot or increased expression/activation of downstream components of the pathway by immunohistochemistry) with overall survival (OS) in solid tumors. Published data were extracted and computed into odds ratios (OR) for death at 5 years. Data were pooled using the Mantel-Haenszel random-effect model. Analysis included 17 studies. Activation of the PI3K/mTOR/AKT pathway was associated with significantly worse 5-year survival (OR:2.12, 95% confidence intervals 1.42-3.16, p<0.001). Loss of PTEN expression and increased expression/activation of downstream components were associated with worse survival. No association between PIK3CA mutations and survival was observed. Differences between methods for assessing activation of the PI3K/mTOR/AKT pathway were statistically significant (p = 0.04). There was no difference in the effect of up-regulation of the pathway on survival between different cancer sites (p = 0.13). Activation of the PI3K/AKT/mTOR pathway, especially if measured by loss of PTEN expression or increased expression/activation of downstream components is associated with poor survival. PIK3CA mutational status is not associated with adverse outcome, challenging its value as a biomarker of patient outcome or as a stratification factor for patients treated with agents acting on the PI3K/AKT/mTOR pathway.

An increasing recognition of traditional, complementary and integrative medicines' (TCIM) contributions for public health has driven the development of international policy recommendations for its inclusion into national healthcare systems. While many countries have made advances in the incorporation of TCIM in academic medicine, there are globally only a handful that have a constitutional mandate in this context. The present cross-sectional study focused on one of these, namely Switzerland, some fifteen years after TCIM was included into the country's Federal Constitution. This research aimed to examine attitudes of the future medical workforce in regard to TCIM within the only European country in which TCIM is mandated by the constitution. More specifically, using an online survey tailored to the country's socio-political context, this study assessed attitudes, knowledge, and expectancies regarding TCIM among medical students across all Swiss universities that offer degrees in human medicine. Even though Swiss medical schools have consolidated and expanded their TCIM-related curricula compared to earlier assessments, with all of them now offering mandatory TCIM classes, most participants were unaware of this. Nonetheless, two-thirds of the N = 695 participants considered TCIM a valuable extension of conventional medicine that should have a place in medical education. Views diverged greatly between TCIM modalities. Further, we found significant differences as a function of gender and linguistic regions, although in the latter case effect sizes were modest. Knowing the views of medical students as the future generation of physicians, clinical scientists, and often also decision-makers in the context of policy-driven integration is crucial in understanding the future trajectory of TCIM into mainstream healthcare. Based on Switzerland's unique experience and history in this context this work contributes to the broader discourse on the role of TCIM in national healthcare systems.

Background The presence of a high neutrophil-to-lymphocyte ratio (NLR) has been associated with increased mortality in several malignancies. Here, we quantify the effect of NLR on survival in patients with breast cancer, and examine the effect of clinicopathologic factors on its prognostic value. Methods A systematic search of electronic databases was conducted to identify publications exploring the association of blood NLR (measured pre treatment) and overall survival (OS) and disease-free survival (DFS) among patients with breast cancer. Data from studies reporting a hazard ratio (HR) and 95% confidence interval (CI) or a P value were pooled in a meta-analysis. Pooled HRs were computed and weighted using generic inverse variance. Meta-regression was performed to evaluate the influence of clinicopathologic factors such as age, disease stage, tumor grade, nodal involvement, receptor status, and NLR cutoff on the HR for OS and DFS. All statistical tests were two-sided. Results Fifteen studies comprising a total of 8563 patients were included. The studies used different cutoff values to classify high NLR (range 1.9–5.0). The median cutoff value for high NLR used in these studies was 3.0 amongst 13 studies reporting a HR for OS, and 2.5 in 10 studies reporting DFS outcomes. NLR greater than the cutoff value was associated with worse OS (HR 2.56, 95% CI = 1.96–3.35; P  < 0.001) and DFS (HR 1.74, 95% CI = 1.47–2.07; P  < 0.001). This association was similar in studies including only early-stage disease and those comprising patients with both early-stage and metastatic disease. Estrogen receptor (ER) and HER-2 appeared to modify the effect of NLR on DFS, because NLR had greater prognostic value for DFS in ER-negative and HER2-negative breast cancer. No subgroup showed an influence on the association between NLR and OS. Conclusions High NLR is associated with an adverse OS and DFS in patients with breast cancer with a greater effect on disease-specific outcome in ER and HER2-negative disease. NLR is an easily accessible prognostic marker, and its addition to established risk prediction models warrants further investigation.

An increasing recognition of traditional, complementary and integrative medicines' (TCIM) contributions for public health has driven the development of international policy recommendations for its inclusion into national healthcare systems. While many countries have made advances in the incorporation of TCIM in academic medicine, there are globally only a handful that have a constitutional mandate in this context. The present cross-sectional study focused on one of these, namely Switzerland, some fifteen years after TCIM was included into the country's Federal Constitution. This research aimed to examine attitudes of the future medical workforce in regard to TCIM within the only European country in which TCIM is mandated by the constitution. More specifically, using an online survey tailored to the country's socio-political context, this study assessed attitudes, knowledge, and expectancies regarding TCIM among medical students across all Swiss universities that offer degrees in human medicine. Even though Swiss medical schools have consolidated and expanded their TCIM-related curricula compared to earlier assessments, with all of them now offering mandatory TCIM classes, most participants were unaware of this. Nonetheless, two-thirds of the N = 695 participants considered TCIM a valuable extension of conventional medicine that should have a place in medical education. Views diverged greatly between TCIM modalities. Further, we found significant differences as a function of gender and linguistic regions, although in the latter case effect sizes were modest. Knowing the views of medical students as the future generation of physicians, clinical scientists, and often also decision-makers in the context of policy-driven integration is crucial in understanding the future trajectory of TCIM into mainstream healthcare. Based on Switzerland's unique experience and history in this context this work contributes to the broader discourse on the role of TCIM in national healthcare systems.

Molecular therapies for cancers with targetable driver mutations and immunotherapies have revolutionized treatment of non-small cell lung cancer (NSCLC) during the last decade. International treatment guidelines began integrating targeted therapies in 2009 and immunotherapies in 2015. The aim of this study was to examine whether the benefits described for these new therapies in pivotal phase III trials have been translated to a real world patient population. Data from all consecutive patients diagnosed with stage IV NSCLC diagnosed at a community hospital in Switzerland between 2007 and 2018 were analyzed. Three groups of patients were compared, namely patients diagnosed before 2009 (group 1), between 2009 and 2015 (introduction of targeted therapies, group 2) and after 2015 (introduction of immunotherapies, group 3). The primary outcome was overall survival (OS). Time to treatment failure was a secondary outcome. Both endpoints were estimated using the Kaplan Meyer method and compared by log-rank test. 408 patients were included. Patient characteristics were similar in the three groups. Median OS in groups 1, 2, and 3 was 9.8 (95% CI, 6.2 to 13.4), 9.9 (95% CI, 7.6 to 12.1) and 8.6 (95% CI, 6.6 to 10.5) months, respectively (p = 0.5). Across groups patients treated with targeted- and immunotherapies had a significantly better outcome than those treated with chemotherapy or best supportive care (p<0.001). Nevertheless, OS remained unchanged between groups despite adequate molecular testing and integration of targeted- and immunotherapies. Over time, the patient population got more morbid with respect to tumor burden (p = 0.02) and co-morbidities (p = 0.02). While selected subgroups of patients may benefit from new therapies, outcome in this unselected population of patients with stage IV NSCLC treated in daily practice has not improved over the last decade.

It is unknown to what extent cancer drugs approved in Switzerland by the Swissmedic fulfil criteria of clinical benefit according to the European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS), the American Society of Clinical Oncology Value Framework version 2 (ASCO-VF) and the Swiss OLUtool v2 (OLUtool). An electronic search identified studies that led to marketing authorisations in Switzerland 2010-2019. Studies were evaluated according to ESMO-MCBS, ASCO-VF and OLUtool. Substantial benefit for ESMO-MCBS, was defined as a grade A or B for (neo)adjuvant intent and 4 or 5 for palliative intent. For ASCO-VF and OLUtool clinical benefit was defined as score ≥45 and A or B, respectively. Concordance between the frameworks was calculated with Cohen's Kappa (κ). Factors associated with clinical benefit were evaluated by logistic regression. In the study period, 48 drugs were approved for 92 evaluable indications, based on 100 studies. Ratings for ESMO-MCBS, ASCO-VF and OLUtool could be performed for 100, 86, and 97 studies, respectively. Overall, 39 (39%), 44 (51%), 45 (46%) of the studies showed substantial clinical benefit according to ESMO-MCBS v1.1, ASCO-VF, OLUtool criteria, respectively. There was fair concordance between ESMO-MCBS and ASCO-VF in the palliative setting (κ = 0.31, P = 0.004) and moderate concordance between ESMO-MCBS and OLUtool (κ = 0.41, P<0.001). There was no significant concordance between ASCO-VF and OLUtool (κ = 0.18, P = 0.12). Factors associated with substantial clinical benefit in multivariable analysis were HRQoL benefit reported as secondary outcome for ESMO-MCBS and the ASCO-VF and blinded studies for OLUtool. At the time of approval, only around half of the trials supporting marketing authorisation of recently approved cancer drugs in Switzerland meet the criteria for substantial clinical benefit when evaluated with ESMO-MCBS, ASCO-VF or OLUtool. There was at best only moderate concordance between the grading systems.

Appropriate safety evaluations of anticancer drugs are crucial to assess their benefit–risk ratio. Substantial evidence shows that clinicians under-report harm in clinical trials, and at least three factors contribute to this problem: assessment of harm by clinicians might not represent the experience of patients; harm might be detected within trials, but is not reported appropriately by investigators or reporting is influenced by sponsors; and short-term follow-up might not detect long-term and potentially serious toxicities. Additionally, because of the selection of patients with good functional status in clinical trials, study results might not apply to patients treated in everyday clinical practice. New approaches for the conduct, oversight, and reporting of clinical trials should include patient-reported assessment of side-effects. Effective pharmacovigilance programmes and large-scale observational studies are needed to improve understanding of the tolerability of anticancer drugs in a real world setting.

Well-designed randomised controlled trials (RCTs) can prevent bias in the comparison of treatments and provide a sound basis for changes in clinical practice. However, the design and reporting of many RCTs can render their results of little relevance to clinical practice. In this Personal View, we discuss the limitations of RCT data and suggest some ways to improve the clinical relevance of RCTs in the everyday management of patients with cancer. RCTs should ask questions of clinical rather than commercial interest, avoid non-validated surrogate endpoints in registration trials, and have entry criteria that allow inclusion of all patients who are fit to receive treatment. Furthermore, RCTs should be reported with complete accounting of frequency and management of toxicities, and with strict guidelines to ensure freedom from bias. Premature reporting of results should be avoided. The bar for clinical benefit should be raised for drug registration, which should require publication and review of mature data from RCTs, post-marketing health outcome studies, and value-based pricing.