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Simple Summary: Lung cancer (LC) is the leading cause of cancer death worldwide. After smoking, one of the most prominent risk factors for LC development is radon (Rn) exposure. In our study we analysed and compared the genetic landscape of LC patients from a Rn exposed village with local matched non-exposed patients. Within the concordant genetic landscape, an increase in genetic MET proto-oncogene, receptor tyrosine kinase (MET) alteration in the Rn-exposed cohort was monitored, underlining the importance of routine MET testing and potential to enable a more effective treatment for this specific subgroup. Effective targeted treatment strategies resulted from molecular profiling of lung cancer with distinct prevalent mutation profiles in smokers and non-smokers. Although Rn is the second most important risk factor, data for Rn-dependent driver events are limited. Therefore, a Rn-exposed cohort of lung cancer patients was screened for oncogenic drivers and their survival and genetic profiles were compared with data of the average regional population. Genetic alterations were analysed in 20 Rn-exposed and 22 histologically matched non-Rn exposed LC patients using targeted Next generation sequencing (NGS) and Fluorescence In Situ Hybridization (FISH). Sufficient material and sample quality could be obtained in 14/27 non-exposed versus 17/22 Rn-exposed LC samples. Survival was analysed in comparison to a histologically and stage-matched regional non-exposed lung cancer cohort (n = 51) for hypothesis generating. Median overall survivals were 83.02 months in the Rn-exposed and 38.7 months in the non-exposed lung cancer cohort (p = 0.22). Genetic alterations of both patient cohorts were in high concordance, except for an increase in MET alterations and a decrease in TP53 mutations in the Rn-exposed patients in this small hypothesis generating study. [ABSTRACT FROM AUTHOR]

Simple Summary: With increasing long-term survivorship of head and neck cancer (HNC), the functional outcomes are gaining importance. Recently, a tool for the rapid clinical assessment of the functional status in HNC-patients based on observable clinical criteria, termed "HNC-Functional InTegrity (FIT) Scales, was validated. Here, the functional outcomes of 681 newly diagnosed HNC-patients were reported using the HNC-FIT Scales. A normal/near-normal outcome in all six functional domains was observed in 61% of patients, with individual scores of 79% for food intake, 89% for breathing, 84% for speech, 89% for pain, 92% for mood, and 88% for neck and shoulder mobility. Clinically relevant impairment in at least one functional domain was observed in 30% of patients, and 9% had loss of function in at least one functional domain. Thus, clinically relevant persistent functional deficits in at least one functional domain must be expected in 40% of HNC-patients. The treatment of these functional deficits is an essential task of oncologic follow-up. With the increase in long-term survivorship of head and neck cancer (HNC), the functional outcomes are gaining importance. We reported the functional outcomes of HNC patients using the HNC-Functional InTegrity (FIT) Scales, which is a validated tool for the rapid clinical assessment of functional status based on observable clinical criteria. Patients with newly diagnosed HNC treated at the Medical University of Innsbruck between 2008 and 2020 were consecutively included, and their status in the six functional domains of food-intake, breathing, speech, pain, mood, and neck and shoulder mobility was scored by the treating physician at oncological follow-up visits on a scale from 0 (loss of function) to 4 (full function). HNC-FIT scales were available for 681 HNC patients at a median of 35 months after diagnosis. The response status was complete remission in 79.5%, 18.1% had recurrent or persistent disease, and 2.4% had a second primary HNC. Normal or near-normal scores (3 and 4) were seen in 78.6% for food intake, 88.7% for breathing, 83.7% for speech, 89% for pain, 91.8% for mood, and 87.5% for neck and shoulder mobility. A normal or near-normal outcome in all six functional domains was observed in 61% of patients. Clinically relevant impairment (score 1–2) in at least one functional domain was observed in 30%, and 9% had loss of function (score 0) in at least one functional domain. The main factors associated with poor functional outcome in a multivariable analysis were recurrence or persistent disease, poor general health (ASA III and IV), and higher T stage. Particularly, laryngeal and hypopharyngeal tumors impaired breathing and speech function, and primary radiation therapy or concomitant systemic therapy and radiotherapy worsened food intake. Clinically relevant persistent functional deficits in at least one functional domain must be expected in 40% of the patients with HNC. The treatment of these functional deficits is an essential task of oncologic follow-up. [ABSTRACT FROM AUTHOR]

Simple Summary: In preclinical studies, the epithelial-to-mesenchymal transition (EMT)-related transcription factor Slug indicated radio- and chemoresistance in head and neck squamous cell carcinoma (HNSCC). Here we show that Slug is a biomarker associated with treatment failure in HNSCC patients treated with primary radio- or radiochemotherapy, but not in patients undergoing upfront surgery and postoperative radio- or chemoradiotherapy. Slug may thus serve as a predictive biomarker to identify HNSCC patients who will benefit from upfront surgery. Slug status is an immunohistochemical (IHC) parameter that is easy to determine. If the predictive value observed here can be confirmed in validation studies with independent data, Slug immunohistochemistry may have significant clinical relevance in treatment planning for HNSCC patients. EMT promotes radio- and chemotherapy resistance in HNSCC in vitro. As EMT has been correlated to the transcription factor Slug in tumor specimens from HNSCC patients, we assessed whether Slug overexpression predicts radio- and chemotherapy resistance and favors upfront surgery in HNSCC patients. Slug expression was determined by IHC scoring in tumor specimens from patients with incident HNSCC. Patients were treated with either definitive radiotherapy or chemoradiotherapy (primary RT/CRT) or upfront surgery with or without postoperative RT or CRT (upfront surgery/PORT). Treatment failure rates and overall survival (OS) were compared between RT/CRT and upfront surgery/PORT in Slug-positive and Slug-negative patients. Slug IHC was positive in 91/354 HNSCC patients. Primary RT/CRT showed inferior response rates (univariate odds ratio (OR) for treatment failure, 3.6; 95% CI, 1.7 to 7.9; p = 0.001) and inferior 5-year OS (univariate, p < 0.001) in Slug-positive patients. The independent predictive value of Slug expression status was confirmed in a multivariable Cox model (p = 0.017). Slug-positive patients had a 3.3 times better chance of survival when treated with upfront surgery/PORT versus primary RT/CRT. For HNSCC patients, Slug IHC represents a novel and feasible predictive biomarker to support upfront surgery. [ABSTRACT FROM AUTHOR]

We conducted a systematic review for evidence of the clinical efficacy of cancer immunotherapies. We searched PubMed from inception to 14 February 2018 for meta-analyses of randomized controlled trials (RCTs) of cancer immunotherapies. Re-analyses were performed to estimate the summary effect size under random-effects, the 95% confidence interval (CI), heterogeneity, and the 95% prediction interval, and we determined the strength of the evidence. We examined publication bias and excess significance bias. 63 articles corresponding to 247 meta-analyses were eligible. Nine meta-analyses were classified to have convincing evidence, and 75 were classified as suggestive evidence. The clinical benefit of immunotherapy was supported by convincing evidence in the following settings: anti-PD-1/PD-L1 monoclonal antibody (mAb) therapy for treating advanced melanoma and non-small cell lung cancer (NSCLC), the combination of rituximab and chemotherapy for treating chronic lymphocytic leukemia and B-cell non-Hodgkin's lymphoma, adoptive cell immunotherapy for NSCLC, and the combination of interferon α and chemotherapy for metastatic melanoma. A further meta-analysis of 16 RCTs showed that anti-PD-1/PD-L1 mAb therapy had a benefit in patients with solid tumors (overall survival; hazard ratio = 0.73, 95% CI: 0.68–0.79; p < 0.001), supported by convincing evidence. In the future, rigorous approaches are needed when interpreting meta-analyses to gain better insight into the true efficacy of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Hyperprogressive disease (HPD) is a recently acknowledged pattern of rapid tumor progression after the initiation of immune checkpoint inhibitors. HPD has been observed across various types of tumors and has been associated with poor survival. We performed a meta-analysis to identify baseline (i.e., prior to programmed cell death 1 [PD-1, PDCD1] / programmed cell death 1 ligand 1 [PD-L1, CD274] inhibitor therapy) patient factors associated with risks of developing HPD during PD-1/PD-L1 inhibitor therapy. We searched eight databases until 6 June 2019. We calculated the summary odds ratio (OR) and its 95% confidence interval (CI) using the random-effects model and explored between-study heterogeneity and small-study effects. A total of nine articles was eligible (217 HPD cases, 1519 cancer patients) for meta-analysis. There was no standard definition of HPD, and the incidence of HPD ranged from 1 to 30%. We identified twenty-three baseline patient factors, of which five factors were statistically significantly associated with HPD. These were serum lactate dehydrogenase (LDH) above the upper normal limit (OR = 1.89, 95% CI = 1.02–3.49, p = 0.043), more than two metastatic sites (OR = 1.86, 1.34–2.57, p < 0.001), liver metastases (OR = 3.33, 2.07–5.34, p < 0.001), Royal Marsden Hospital prognostic score of 2 or above (OR = 3.33, 1.96–5.66, p < 0.001), and positive PD-L1 expression status that was inversely correlated with HPD (OR = 0.60, 0.36–0.99, p = 0.044). Between-study heterogeneity was low. Evidence of small-study effect was found in one association (PD-L1 expression). Subset analyses of patients with non-small cell lung cancer showed similar results. Future studies are warranted to identify underlying molecular mechanisms and to test their roles as predictive biomarkers of HPD. [ABSTRACT FROM AUTHOR]