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Fig S2. Technical validation using NuGEN's Ovation System. The scatter plot shows the fold change consistency of genes differentially expressed using WG-DASL and NuGEN methods. Only 6 out of the 509 DE genes were found discordant, confirming the WG-DASL patterns. Data are plotted as log2 fold change (FC) expression long/short PFS; positive log2(FC) values stand for genes up-regulated in long-PFS cases, while negative values stand for up-regulation in short-PFS cases. Statistical significance was tested through Monte Carlo test (1000 interactions) yielding p-value

Fig S1. Volcano plot for the 17,378 genes detected by microarray analysis. The x-axis is the fold-change, and the y-axis is log10 p value. A total of 509 probes (blue dots) were differentially expressed in long-PFS patients (14) compared with short-PFS patients (26), imposing a FDR < 15%. Probability of finding by chance 509 significant DE genes between the classes: p = 0.016.

FigS3: Biasogram representing the influence of tissue origin on outcome. Y axes indicate the outcome vector (long- versus short- PFS), while B indicates the nuisance variable (tissue origin; primary versus recurrence/metastatic). The colorgram represents a bivariate histogram of all the 17,378 detected genes; the green circles indicate the genes present in our signature.

Purpose: To identify the tumor portrait of the minority of head and neck squamous cell carcinoma (HNSCC) patients with recurrent–metastatic (RM) disease who upon treatment with platinum-based chemotherapy plus cetuximab present a long-lasting response.Experimental Design: The gene expression of pretreatment samples from 40 HNSCC-RM patients, divided in two groups [14 long-progression-free survival (PFS) and 26 short-PFS (median = 19 and 3 months, respectively)], was associated with PFS and was challenged against a dataset from metastatic colon cancer patients treated with cetuximab. For biologic analysis, we performed functional and subtype association using gene set enrichment analysis, associated biology across all currently available HNSCC signatures, and inferred drug sensitivity using data from the Cancer Genomic Project.Results: The identified genomic profile exhibited a significant predictive value that was essentially confirmed in the single publicly available dataset of cetuximab-treated patients. The main divergence between long- and short-PFS groups was based on developmental/differentiation status. The long-PFS patients are characterized by basal subtype traits such as strong EGFR signaling phenotype and hypoxic differentiation, further validated by the significantly higher association with the hypoxia metagene. The short-PFS patients presented a strong activation of RAS signaling confirmed in an in vitro model of two isogenic HNSCC cell lines sensitive or resistant to cetuximab. The predicted drug sensitivity for all four EGFR inhibitors was higher in long- versus short-PFS patients (P range: Conclusions: Our data uncover the biology behind response to platinum-based chemotherapy plus cetuximab in RM-HNSCC cancer and may have translational implications improving treatment selection. Clin Cancer Res; 22(15); 3961–70. ©2016 AACR.See related commentary by Chau and Hammerman, p. 3710

Fig S4. Ability of existing gene signatures to predict outcome following cetuximab treatment. Five available prognostic gene-expression based signatures were taken into account: i) the hypoxia metagene (Winter, 2007); ii) the 13-gene OSCC signature (Lohavanichbutr, 2013); iii) the RSI-index (Eschrich, 2009); iv) the 42-gene Chung's high risk signature (Chung, 2006); v) the 172-gene signature (De Cecco, 2014). A score was assessed for each sample entering into our study following the model developed by the authors and compared among long- and short PFS cases. The boxplots depicts the data in the two groups. Green: long-PFS; Red: short-PFS.

Supplementary Table S2 Gene sets associated to long- and short-PFS patients

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent type of non-melanoma skin cancer. Its incidence has been rising in recent years, with the highest rate reported in Switzerland compared to other countries in Europe. While the majority of cSCC cases are low-grade tumors with an excellent prognosis following surgical excision, a minority of cSCC lesions (approximately 5% of patients) progress to locally advanced cSCC (lacSCC) or distant metastatic disease (mcSCC), both of which have an unfavorable prognosis. Recent evidence from studies with checkpoint immunotherapy has changed the systemic treatment landscape for lacSCC and mcSCC patients. While both programmed death-1 (PD-1) receptor inhibitors cemiplimab and pembrolizumab are approved by the FDA, cemiplimab is the only approved systemic therapy for the treatment of nonresectable advanced cSCC in the EU and was recently also approved in Switzerland. Based on the latest evidence from randomized clinical trials, national consensus recommendations for the systemic treatment of advanced cSCC have been defined. For classification and optimal management of patients with lacSCC or mcSCC, an interdisciplinary tumor board discussion should be mandatory. Difficult-to-treat advanced cSCC patients should be referred to and treated by specialized centers. These Swiss recommendations provide guidance for the management of patients aged ≥18 years with lacSCC or mcSCC, specifically systemic therapy with a PD-1 inhibitor in the first-line setting. These up-to-date recommendations will also help Swiss physicians in their decision-making and address treatment variability in Swiss clinical practice. Keywords: cSCC, locally advanced, metastatic, systemic treatment, immunotherapy, cemiplimab

Head and neck cancer (HNC) can have a devastating impact on patient's lives as both disease and treatment may affect the ability to speak, swallow and breathe. These conditions limit the oral intake of food and drugs, reduce social functioning and impact on patient's quality of life. Up to 80% of patients suffering from HNC have pain due to the spread of the primary tumor, because of consequences of surgery, or by developing oral mucositis, dysphagia or neuropathy as toxic side effects of radiotherapy, chemotherapy or both. All healthcare professionals caring for HNC patients should assess palliative and supportive care needs in initial treatment planning and throughout the disease, with awareness when specialist palliative care expertise is needed. This paper focuses on assessment, characterizations and clinical management of pain in advanced HNC patients undergoing surgery, chemotherapy and radiotherapy, also underlining the importance of symptom assessment in HNC survivors and the need of clinical research in this field.

BRAF and MEK kinase inhibitors can be highly effective in treating BRAF-mutant melanomas, but their safety and activity in patients with active/symptomatic brain metastases are unclear. We sought to shed light on this open clinical question. We conducted a multicenter retrospective study on real-life patients with melanoma and active brain metastases treated with combination BRAF/MEK inhibitors. A total of 65 patients were included (38 men and 27 women; median age: 49 years). Of them, 53 patients received dabrafenib/trametinib, 10 received vemurafenib/cobimetinib, one received encorafenib/binimetinib, and one received vemurafenib/trametinib. We did not observe any unexpected treatment-related safety signals in our cohort. Overall, 17 patients continued on therapy through the cutoff date. After initiation of therapy, steroid dose could be decreased in 22 of 33 patients (11 tapered off entirely), anticonvulsants were stopped in four of 21, and narcotics were stopped in four of 12. Median progression-free survival from the start of therapy was 5.3 months (95% confidence interval: 3.6-6.1), and median overall survival was 9.5 months (95% confidence interval: 7.7-13.5). A total of 20 patients were surviving at the cutoff date. Univariate analysis of age, sex, ulceration status, thickness, stage, location, or lactate dehydrogenase did not reveal significant predictors of progression-free survival or overall survival within our cohort, but multivariate analysis suggested that older age, lower risk location of original lesion, and nodular melanoma are poor prognostic indicators. Combination therapy with BRAF/MEK inhibitors is a viable treatment option for patients with BRAF-mutant melanoma and brain metastases, but further studies should help to define the optimal treatment approach in this population.

Background Until recently, no second-line treatment for recurrent and/or metastatic head and neck squamous cell cancer (r/mHNSCC) was able to improve overall survival (OS). Nivolumab has become a promising treatment for r/mHNSCC. The CheckMate-141 trial showed that nivolumab improves OS compared to investigator’s choice (IC) (cetuximab, methotrexate, docetaxel). Treatment with immune checkpoint inhibitors is however expensive. The aim of this analysis was to assess the cost-effectiveness of nivolumab as second-line treatment for r/mHNSCC in Switzerland. Methods Based on the CheckMate-141 trial, we constructed a Markov model comparing nivolumab to IC, including follow-up data up to 24 months. We assessed costs for treatments from the perspective of the Swiss health system with a 60 months’ time horizon. PD-L1 and p16 testing were considered in scenarios. Incremental cost-effectiveness ratios (ICER) were compared to an informal willingness-to-pay of CHF (Swiss Francs) 100,000 per QALY gained. Results For the base case we estimated an incremental effectiveness of 0.35 QALYs and incremental costs of CHF 35,562 with nivolumab, resulting in an ICER of CHF 102,957 per QALY gained. Most influential drivers for the ICER were the price of nivolumab and the progressive disease state utility weights. In 45.5% of probabilistic sensitivity analysis simulations nivolumab was estimated below 100,000 CHF/QALY. Reducing the price of nivolumab according to a consented payback by 4.75%, resulted in an ICER of CHF 98,325/QALY gained. Conclusions At current prices nivolumab has an ICER of around CHF 100,000 per QALY gained in the second line treatment of r/mHNSCC patients in Switzerland.

The European School of Oncology (ESO) embarked on an online educational project, starting with live sessions in 2008 (e-ESO). Our scholars and young oncologists identified the need to be offered independent high-level online education with contributions from experts around the world, free of charge and available at any moment. We report on various types of e-sessions, such as grand-rounds, highlights, debates, clinical cases and other sessions. Our audience has grown over the last decade, reaching 11,123 users who have viewed a total of 77,041 sessions since the beginning of 2008. Moreover, our activities on social media platforms have enhanced our visibility, reaching more physicians around the globe. Due to the recent events surrounding the COVID-19 pandemic, online education has proven to be of great value in offering long-distance teaching. We have analyzed the growth of our audience and its attendance over the last 12 years.

Background The folate receptor alpha (FRα) is an interesting target for imaging and therapy of different cancers. We present the first in-human radiation dosimetry and radiation safety results acquired within a prospective, multicentric trial (NCT03242993) evaluating the 18F-AzaFol (3′-aza-2′-[18F]fluorofolic acid) as the first clinically assessed PET tracer targeting the FRα. Material and methods Six eligible patients presented a histologically confirmed adenocarcinoma of the lung with measurable lesions (≥ 10 mm according to RECIST 1.1). TOF-PET images were acquired at 3, 11, 18, 30, 40, 50, and 60 min after the intravenous injection of 327 MBq (range 299–399 MBq) of 18F-AzaFol to establish dosimetry. Organ absorbed doses (AD), tumor AD, and patient effective doses (E) were assessed using the OLINDA/EXM v.2.0 software and compared with pre-clinical results. Results No serious related adverse events were observed. The highest AD were in the liver, the kidneys, the urinary bladder, and the spleen (51.9, 45.8, 39.1, and 35.4 μGy/MBq, respectively). Estimated patient and gender-averaged E were 18.0 ± 2.6 and 19.7 ± 1.4 μSv/MBq, respectively. E in-human exceeded the value of 14.0 μSv/MBq extrapolated from pre-clinical data. Average tumor AD was 34.8 μGy/MBq (range 13.6–60.5 μGy/MBq). Conclusions 18F-Azafol is a PET agent with favorable dosimetric properties and a reasonable radiation dose burden for patients which merits further evaluation to assess its performance., EJNMMI Resarch, 10 (1), ISSN:2191-219X

Background The folate receptor alpha (FRα) is an interesting target for imaging and therapy of different cancers. We present the first in-human radiation dosimetry and radiation safety results acquired within a prospective, multicentric trial (NCT03242993) evaluating the 18F-AzaFol (3′-aza-2′-[18F]fluorofolic acid) as the first clinically assessed PET tracer targeting the FRα. Material and methods Six eligible patients presented a histologically confirmed adenocarcinoma of the lung with measurable lesions (≥ 10 mm according to RECIST 1.1). TOF-PET images were acquired at 3, 11, 18, 30, 40, 50, and 60 min after the intravenous injection of 327 MBq (range 299–399 MBq) of 18F-AzaFol to establish dosimetry. Organ absorbed doses (AD), tumor AD, and patient effective doses (E) were assessed using the OLINDA/EXM v.2.0 software and compared with pre-clinical results. Results No serious related adverse events were observed. The highest AD were in the liver, the kidneys, the urinary bladder, and the spleen (51.9, 45.8, 39.1, and 35.4 μGy/MBq, respectively). Estimated patient and gender-averaged E were 18.0 ± 2.6 and 19.7 ± 1.4 μSv/MBq, respectively. E in-human exceeded the value of 14.0 μSv/MBq extrapolated from pre-clinical data. Average tumor AD was 34.8 μGy/MBq (range 13.6–60.5 μGy/MBq). Conclusions 18F-Azafol is a PET agent with favorable dosimetric properties and a reasonable radiation dose burden for patients which merits further evaluation to assess its performance. Trial registration ClinicalTrial.gov, NCT03242993, posted on August 8, 2017

SARS-CoV-2 pandemic and COVID-19 diffusion have recently become an international public health emergency. Cancer patients, as a frail population, are particularly exposed to the risk related to infections. The clinical decision-making process and the organizational workflow of radiotherapy department should be revised in the light of the critical situation. We herein provide practical suggestions derived from the available literature and discussed during an online session held within the e-learning educational program of the European School of Oncology on March 31st 2020.

To compare safety and effectiveness of prolonged (>28 days) versus short duration (≤28 days) use of nasogastric tube for enteral nutrition and weight loss prevention during curative radiotherapy with or without concurrent chemotherapy or cetuximab for head and neck cancer patients. We performed a retrospective study and database review of all patients at our center, treated with radiotherapy for head and neck cancer receiving enteral nutrition by nasogastric tube. Type of treatment, weight and body mass index changes, and related complications (gastroesophageal reflux, pneumonia, ulcer, feeding tube obstruction, or dislocation) were documented. Comparison between patients with prolonged (>28 days, group A) and short duration (≤28 days, group B) of EN through nasogastric tube was performed. Data expressed as mean ± SD or median (min; max) values as appropriate, and analyzed by ANOVA repeated measures and Kaplan-Meier estimates. We identified 114 patients who fulfilled the inclusion criteria. Among them, 10% were treated with radiotherapy alone, while 90% received concurrent chemotherapy or cetuximab. Ninety-four patients (82%, group A) had a nasogastric tube in place for a period >28 days and 20 (18%, group B) for ≤28 days during treatment. Patients were mainly men (86 patients, 75%), with a median age of 61 years (range 49-73) and advanced stage IV disease in most cases (87 patients, 76%) without differences between both groups (p = 0.53, 0.47, and 0.30, respectively). Treatment discontinuation did not occur within both groups. Fifty-six patients (49%) developed complications, without a significant difference between both groups (P = 0.23). Body weight and BMI changes did not differ during EN (-0.8 ± 4.5 and -0.3 ± 1.6), the oncological treatment (-5.3 ± 4.0 and -1.8 ± 1.4), or 6 months after the end of treatment (-0.6 ± 4.4 and -0.2 ± 1.5). Our findings suggest that prolonged enteral nutrition by nasogastric tube is safe and effective in preventing weight loss during curative radiotherapy or radio-chemotherapy for head and neck cancer.

Objective Platinum-based chemotherapy plus the anti-EGFR monoclonal antibody (mAb) cetuximab is used to treat recurrent/metastatic (RM) head-neck squamous cell carcinoma (HNSCC). Recently, we defined Cluster3 gene-expression signature as a potential predictor of favorable progression-free survival (PFS) in cetuximab-treated RM-HNSCC patients and predictor of partial metabolic FDG-PET response in an afatinib window-of-opportunity trial. Another anti-EGFR-mAb (panitumumab) was used as the treatment agent in RM-HNSCC patients in the phase II PANI01trial. PANI01 tumor samples were analyzed using functional genomics to explore response predictors to anti-EGFR therapy. Materials and methods Whole-gene expression and real-time PCR analyses were applied to pre-treatment samples from 25 PANI01 patients. Three gene signatures (Cluster3 score, RAS onco-signature, microenvironment score) and seven selected miRNAs were separately analyzed for association with panitumumab efficacy. Results Cluster3 expression levels had a profile with a significant bimodal separation of samples (P = 3.08 E−13). Higher RAS activation, microenvironment score, and miRNA expression were associated with low-Cluster3 patients. The same biomarkers were separately associated with PFS. Patients with high-Cluster3 had significantly longer PFS than patients with low-Cluster3 (median PFS: 174 versus 51 days; log-rank P = 0.0021). ROC analysis demonstrated accuracy in predicting PFS (AUC = 0.877). Conclusions Despite differences in clinical settings and anti-EGFR inhibitors used for treatment, response prediction by the Cluster3 signature and selected miRNAs was essentially the same. Translation into a useful clinical assay requires validation in a broader setting.

BACKGROUND/AIM Recurrent/metastatic head and neck squamous cell cancer (r/mHNSCC) patients often need a percutaneous endoscopic gastrostomy feeding tube (PEG). Among known prognostic factors, PEG could be prognostic as well. PATIENTS AND METHODS We retrospectively analyzed r/mHNSCC patients referred for systemic treatment. Kaplan-Meier and multivariate cox regression models were applied to assess prognostic impact of PEG. RESULTS One hunderd and ten patients were identified, 42 had a PEG at treatment start. Median survival from start of 1st-line systemic treatment was 8 months (95%CI=6.5-12.0 months), 4.5 months (95%CI=2.5-7.0 months) for patients with PEG and 11.5 months (95%CI=7.5-14.5 months) without PEG (adjusted HR=1.98, p=0.011). Similarly, survival from first recurrence of distant metastases was lower in patients with PEG as compared to patients without (7.5 vs. 15.5 months, adjusted HR=2.60, p

javax.xml.bind.JAXBElement@5a6991ed Differentiated thyroid cancer (DTC) accounts for approximately 95% of thyroid carcinomas. In the metastatic RAI-refractory disease, chemotherapy has very limited efficacy and is associated with substantial toxicity. With increasing knowledge of the molecular pathogenesis of DTC, novel targeted therapies have been developed. Lenvatinib is a tyrosine kinase inhibitor (TKI) with promising clinical activity based on the randomized phase III SELECT trial. In Switzerland, a Named Patient Program (NPP) was installed to bridge the time gap to Swissmedic approval. Here, we report the results from the Swiss Lenvatinib NPP including patients with metastatic RAI-refractory DTC. javax.xml.bind.JAXBElement@7407c55a Main inclusion criteria for the Swiss NPP were RAI-refractory DTC, documented disease progression, Eastern Cooperative Oncology Group (ECOG) performance status 0-3. The number of previous therapies was not limited. The Swiss Lenvatinib NPP was initiated in June 2014 and was closed in October 2015 with the approval of the drug. javax.xml.bind.JAXBElement@1c5cb2cc Between June 2014 and October 2015, 13 patients with a median age of 72 years have been enrolled. Most patients (69%) had at least one prior systemic therapy, mainly sorafenib. 31% of patients showed a PR and 31% SD. Median progression free survival was 7.2 months and the median overall survival was 22.7 months. Dose reduction due to adverse events was necessary in 7 patients (53%). At the time of analysis 6 patients (47%) were still on treatment with a median time on treatment of 9.98 months. javax.xml.bind.JAXBElement@713fc2d4 Our results show that lenvatinib has reasonable clinical activity in unselected patients with RAI-refractory thyroid cancer with nearly two-third of patients showing clinical benefit. The toxicity profile of lenvatinib is manageable.

In solid organ transplant recipients (sOTRs), 5 years after transplantation cancer is a relevant cause of death. We aimed to report cancer incidence in the Swiss Transplant Cohort Study (STCS) between 2008 and 2014 and conducted a prospective cohort study of kidney, heart, lung, pancreas and liver transplant recipients enrolled into the STCS by retrospective analysis of collected data. The STCS provided data on 2758 solid organ transplants. In total, 134 cases of cancer were observed (30 liver, 21 prostate, 18 lung, 13 kidney, 52 other cancers). Standardised incidence ratios (SIRs) were highest for liver cancer, kidney cancer, thyroid cancer, gastric cancer, bladder cancer, cancer of the oral cavity and the pharynx and for lung cancer. Cancer occurrence differed according to the transplanted organ. Cancers were mainly diagnosed at World Health Organisation (WHO) stages I and IV. Treatment received was mainly surgery and, in some cases, included also radiation and/or chemotherapy. Bladder, kidney, liver, lung and prostate cancer were detected at a younger age compared with the general population. Cumulative hazards for death were increased for transplant recipients with cancer. Solid organ transplant recipients show an organ specific increase of cancer compared with the general Swiss population. Clinical trial registration number: NCT02333279.

Background Prognosis of metastatic non-small cell lung cancer significantly improved with the availability of checkpoint inhibitors (anti-PD-1/PD-L1). Unfortunately, reliable biomarkers to predict treatment benefit are lacking. Patients and methods We prospectively collected clinical and laboratory data of 56 non-small cell lung cancer patients treated with a checkpoint inhibitor. The aim was to identify baseline parameters correlating with worse outcome and to create a risk score that enabled to stratify patients into different risk groups. As inflammation is known to promote tumor growth, we focused on inflammation markers in the blood. Disease control (DC) was defined as complete response, partial response, and stable disease on CT scan according to RECIST 1.1. Results Half of the patients achieved DC. Four parameters differed significantly between the DC group and the no disease control group: Eastern Cooperative Oncology Group performance status (P=0.009), number of organs with metastases (P=0.001), lactate dehydrogenase (P=0.029), and ferritin (P=0.005). A risk score defined as the number of these parameters (0= no risk factor) exceeding a threshold (Eastern Cooperative Oncology Group performance status ≥2, number of organs with metastases ≥4, lactate dehydrogenase ≥262U/L, and ferritin ≥241 µg/L) was associated with overall survival and progression-free survival. Overall survival at 6 and 12 months is as follows: Scores 0–1: 95% and 95%; Score 2: 67% and ≤33%; Scores 3–4: 15% and 0%. Progression-free survival at 6 and 12 months is as follows: Scores 0–1: 81% and 50%; Score 2: 25% and ≤25%; Scores 3–4: 0% and 0%. Conclusion We propose an easy-to-apply risk score categorizing patients into different risk groups before treatment start with a PD-1/PD-L1 antibody.

Until recently, standard treatment for advanced melanoma comprised basically dacarbazine and interleukin-2, leading to low response rates and significant toxicity. These days, new treatments such as immunotherapy (anti-CTLA4 and anti-PD1 antibodies) and targeted therapy with BRAF/MEK-inhibitor combinations for patients harboring a BRAF mutation are available. In BRAF wild-type patients harboring an NRAS mutation, not fit for immunotherapy treatment options are still dismal. We describe an 84-year-old patient with widespread metastatic melanoma. He presented in July 2015 with a cerebral hemorrhage under anticoagulation for atrial fibrillation. Computed tomography revealed extensive metastatic disease (liver, lung, bones, lymph nodes, heart, and brain). Molecular testing was negative for BRAF but showed the presence of an NRAS mutation in exon 3 (pQ61K [c.181C>A]). The patient received as first-line treatment two cycles of cobimetinib showing a good partial remission and manageable side effects.

Background: Delay of systemic treatment in recurrent/metastatic head and neck squamous cell cancer (r/mHNSCC) has never been assessed. Whether time span to start systemic treatment affects survival and whether referral to a medical oncologist is important has not been explored. Methods: We analyzed our head and neck database to assess the prognostic impact of time between diagnosis of r/mHNSCC and start of systemic treatment (time to treatment [TTT]). Secondarily, we assessed the prognostic impact of time to referral to a medical oncologist (referral time). For this purpose, we used pairwise correlation analysis and multivariate Cox regression analysis as statistical tests. Results: A total of 110 patients with r/mHNSCC were evaluable for analysis. TTT correlated significantly with OS from r/mHNSCC diagnosis ( R = 0.43, p < 0.0001). A nonsignificant, positive correlation was found between referral time and OS ( R = 0.17, p = 0.10). Conclusions: Results of this retrospective analysis suggest that longer TTT is not associated with worse prognosis. Referral time seems not to have an impact on prognosis.

BACKGROUND Novel systemic therapies have improved the prognosis of metastatic non-small cell lung cancer (NSCLC), but costs of some of these drugs are a matter of ongoing debate. More recently, local therapies (LT) such as radiotherapy and surgery have been suggested as additional treatment in oligometastatic NSCLC demonstrating an improved progression-free survival (PFS) in a phase II trial compared to maintenance chemotherapy (MC) alone. The aim of this analysis was to assess the cost-effectiveness of local therapies in oligometastatic NSCLC. METHODS We constructed a Markov model comparing the cost-effectiveness of LT versus MC for oligometastatic NSCLC from the Swiss healthcare payer's perspective. Treatment specifications and PFS were based on the phase II trial (NCT01725165). Overall survival (OS) was inferred from a recent phase III trial. Utilities were taken from published data. Primary outcome was the incremental cost-effectiveness-ratio (ICER, costs in Swiss Francs (CHF) per quality-adjusted life-year (QALY) gained). RESULTS PFS in the model was 3.8 months for MC and 11.4 months for LT (compared to 3.9 months and 11.9 months in the trial). OS in the model was 15.5 months in both arms. LT was cost-effective with a gain of 0.24 QALYs at an additional cost of CHF 9641, resulting in an ICER of CHF 40,972/QALY gained. Probabilistic sensitivity analyses demonstrated that LT was dominant or cost-effective at a willingness-to-pay threshold of CHF 100,000 per QALY in 61.7% of the simulations. CONCLUSIONS LT may be cost-effective for selected patients with oligometastatic NSCLC responding to first-line systemic therapy.

Background: Metastatic basal cell carcinoma is rare and the prognosis is poor, with a lack of established treatment options for patients progressing on or after treatment with inhibitors of the hedgehog signaling pathway. Case Report: A man with pulmonary metastases of a basal cell carcinoma progressing after treatment with sonidegib and vismodegib was started on treatment with the anti-PD-1 antibody pembrolizumab. Upon treatment, rapid clinical improvement occurred, and after 5 cycles, the computed tomography scan showed near-complete remission of all tumor lesions. The tumor cells showed the absence of PD-L1 expression. Discussion: We report the first case of a patient with metastatic basal cell carcinoma experiencing an exceptional response to treatment with pembrolizumab in the absence of PD-L1 expression on the tumor cells. Immune checkpoint inhibition seems a promising treatment strategy for metastatic basal cell carcinoma. Our case suggests that the lack of PD-L1 expression does not rule out potential benefit from checkpoint inhibitor treatment.

Prediction of benefit from combined chemotherapy and the antiepidermal growth factor receptor cetuximab is a not yet solved question in head and neck squamous cell carcinoma (HNSCC). In a selected series of 14 long progression-free survival (PFS) and 26 short PFS patients by whole gene and microRNA expression analysis, we developed a model potentially predictive of cetuximab sensitivity. To better decipher the “omics” profile of our patients, we detected transcript fusions by RNA-seq through a Pan-Cancer panel targeting 1385 cancer genes. Twenty-seven different fusion transcripts, involving mRNA and long noncoding RNA (lncRNA), were identified. The majority of fusions (81%) were intrachromosomal, and 24 patients (60%) harbor at least one of them. The presence/absence of fusions and the presence of more than one fusion were not related to outcome, while the lncRNA-containing fusions resulted enriched in long PFS patients (P=0.0027). The CD274-PDCD1LG2 fusion was present in 7/14 short PFS patients harboring fusions and was absent in long PFS patients (P=0.0188). Among the short PFS patients, those harboring this fusion had the worst outcome (P=0.0172) and increased K-RAS activation (P=0.00147). The associations between HNSCC patient’s outcome following cetuximab treatment and lncRNA-containing fusions or the CD274-PDCD1LG2 fusion deserve validation in prospective clinical trials.

Objectives Second-line chemotherapy in recurrent and/or metastatic head and neck cancer (r/mHNSCC) patients showed dismal results with limited tumor response and reduced life expectancy. Outside of clinical trials, data on efficacy of second line treatment after first line anti-EGFR-AB combination therapy are not available. Material and methods Data regarding r/mHNSCC consecutive pts treated with cetuximab and platinum from 2009 to 2014 at our center were retrospectively collected. The analyses of response, Progression-Free Survival (PFS) and Overall Survival (OS), each evaluated starting from first and second-line treatment, were performed. Survival curves were estimated with the Kaplan-Meier method and compared using the log-rank test. Results We identified 117 patients treated with first-line platinum and cetuximab-based therapy. Sixty-four (55%) patients did not receive second-line treatment due to worsening in performance status, 2 were not assessable for response thus 51 patients were included for analysis. Fifty-six percent were smokers/former smokers and 78% were male. Primary tumor sites were oropharynx (39%), oral cavity (31%), larynx/hypopharynx (24%) and others (6%). Regimens used in second-line were mostly monotherapies. Twenty-one % of the patients were treated within a clinical trial. Response rate (PR, CR) was 6% with 45% showing SD as best response. Median PFS was 2.2 months (95%CI:1.5–2.8 months) and OS 6.1 months (95%CI:3.7–7.2 months). Conclusions Within our single center experience only half of the patients with r/mHNSCC were able to receive second-line treatment. Response rate was unsatisfactory, but median OS seems higher than previously reported in an anti-EGFR-AB naive population (Leon 2005).

Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage and has a dismal prognosis. Nearly 10 years after the approval of cetuximab, anti-PD1/PD-L1 checkpoint inhibitors are the first drugs that have shown any survival benefit for the treatment on platinum-refractory recurrent/metastatic (R/M) HNSCC. Furthermore, checkpoint inhibitors are better tolerated than chemotherapy. The state of the art in the treatment of R/M HNSCC is changing, thanks to improved results for checkpoint inhibitors. Results for these treatments are also awaited in curative settings and for locally advanced HNSCC. Unfortunately, the response rate of immunotherapy is low. Therefore, the identification of predictive biomarkers of response and resistance to anti-PD1/PD-L1 is a key point for better selecting patients that would benefit the most from immunotherapy. Furthermore, the combination of checkpoint inhibitors with various agents is being currently evaluated to improve the response rate, prolong response duration, and even increase the chances for a cure. In this review, we summarize the most important results regarding immune targeting agents for HNSCC, predictive biomarkers for resistance to immune therapies, and future perspectives.

Objective: Weight loss is common in patients with malignant tumors and it can adversely affect quality of life and survival. The aim of the present study was to investigate the effects of a nutritional intervention in cancer patients in an outpatient setting. Methods: Cancer outpatients (N ¼ 58) who were classified as undernourished or at high risk for undernutrition by the Nutritional Risk Screening 2002 tool were randomized into two groups. One group (n ¼ 30) received standardized individual nutritional therapy, including counseling by a dietitian, food fortification, and oral nutritional supplements if required. The second group (n ¼ 28) received standard care. The nutritional intervention lasted 3 mo. Dietary intake (3-d dietary record), nutritional status (body weight), physical functioning (performance status, hand-grip strength) and quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0) were assessed at baseline and after 6 wk and 3 mo. An additional follow-up assessment was carried out 3 mo post-intervention. Results: Nutritional intervention led to a significantly higher average energy and protein intake in the nutritional therapy group (þ379 kcal; 95% confidence interval [CI], 117–642; P ¼ 0.007, respectively; þ10.4 g; 95% CI, 2.3–18.5; P ¼ 0.016). However, the increased dietary intake was not associated with improvements in nutritional status, physical functioning, or quality of life. Conclusions: Individual nutritional counseling significantly and positively influenced energy and protein intake, but did not improve nutritional or physical outcome or quality of life. These results indicate that nutritional therapy alone is of limited efficacy in cancer patients whose nutritional status has already deteriorated.

Skeletal-related events represent a substantial burden for patients with advanced cancer. Randomized, controlled studies suggested superiority of denosumab over zoledronic acid in the prevention of skeletal-related events in metastatic cancer patients, with a favorable safety profile. Experts gathered at the 2012 Skeletal Care Academy in Istanbul to bring forward practical recommendations, based on current evidence, for the use of denosumab in patients with bone metastases of lung cancer. Based on current evidence, use of denosumab in lung cancer patients with confirmed bone metastases is recommended. It is important to note that clinical judgment should take into consideration the patient’s general performance status, overall prognosis, and live expectancy. Currently, the adverse event profile reported for denosumab includes hypocalcemia and infrequent occurrence of osteonecrosis of the jaw. Therefore, routine calcium and vitamin D supplementation, along with dental examination prior to denosumab initiation are recommended. There is no evidence for renal function impairment due to denosumab administration. At present, there is no rationale to discourage concomitant use of denosumab and surgery or radiotherapy.

Immunotherapy leads to significantly prolonged survival of patients with metastatic melanoma. Autoimmune side effects including colitis, dermatitis, and endocrine abnormalities are common in patients treated with ipilimumab [anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4)]. Antibodies such as pembrolizumab that interfere with the PD-1 (programmed cell death 1)/PD-L1 pathway show greater efficacy and less toxicity than ipilimumab. Here we report 2 cases of pembrolizumab-induced uveitis associated with complete or partial tumor response. We suggest that uveitis may serve as a surrogate marker for a tumor response to therapy with pembrolizumab.

Cutaneous melanoma is the most deadly cutaneous neoplasm. In order to guide treatment decisions and follow-up of melanoma patients, guidelines for the management of melanoma in Switzerland were inaugurated in 2001 and revised in 2006 and 2016. Recent data on surgical and medical treatments from randomised trials necessitated modification of the treatment and follow-up recommendations.

SUMMARY Pulmonary neuroendocrine tumors (pNETs) are normally included in trials comprising neuroendocrine tumors (NETs) of different organs of origin. Typical and atypical carcinoids are regarded as low-grade NETs and show low proliferation rates and minor responses with classic chemotherapy regimens. Somatostatin analogs were traditionally applied in patients with carcinoid syndrome and recently also demonstrated tumor response. Recently, novel agents such as sunitinib and everolimus showed improved survival in randomized studies. These trials contained only low numbers of pNETs. Another promising field of targeted therapy in low-grade NETs includes peptide receptor radionuclide therapy. High-grade pNETs include large-cell neuroendocrine carcinoma and small-cell lung cancer. We will discuss large-cell neuroendocrine carcinoma and will address small-cell lung cancer at the end of this review.

e18065Background: Previous studies suggested that cisplatin and cetuximab administered concurrently to radiotherapy (RT) improve only marginally the outcome of patients older than 65 years. Methods...

Purpose: This phase I infusion rate escalation trial was undertaken to evaluate the maximum applicable infusion rate for rituximab without steroid premedication in patients having received one previous rituximab infusion. Experimental Design: Cohorts of at least three patients were assigned to rituximab with or without concomitant chemotherapy. The initial infusion rate was 200 mg/h in the first cohort, and was increased by 100 mg/h in each subsequent cohort to a maximum of 700 mg/h. In each patient the infusion rate was increased by 100 mg/h every 30 minutes to the total dose (375 mg/m2). In the first six cohorts (21 patients), two well-tolerated rituximab administrations were required; in the 7th cohort (11 patients) one previously well-tolerated rituximab infusion was required. Patients did not receive steroid premedication and were monitored with electrocardiograms (ECG), echocardiograms, Holter ECGs, troponin, and brain natriuretic peptide (BNP). Results: Thirty-two patients were included and 128 cycles were done, 85 at a rate of 700 mg/h. Patients tolerated infusion rates without major side effects. There were no new clinically relevant ECG alterations. Troponin (< 0.1 ng/L) and mean cardiac ejection fraction (65%) remained in the reference range; BNP baseline level increased significantly 24 hours after rituximab administration (from 30.4 to 64.1 ng/L; P < 0.0001). Conclusions: Rituximab can be administered safely at 700 mg/h without steroid premedication in patients having received at least one rituximab dose in the previous 3 months.

BACKGROUND: Comorbidity between ADHD and Bipolar Disorder (BD) is associated with greater severity of BD. The current study aims at investigating, in a specialized mood disorders clinic, the percentage of comorbid ADHD-BD subjects and assessing the impact of ADHD on the severity of BD. METHODS: Out of 539 mood disorders subjects, the medical records of 138 BD subjects were scrutinized in terms of their clinical and demographic characteristics, and their scores at the Adult ADHD Self-Report Scale (ASRS-v1.1) Symptom Checklist were logged. Those positively scoring at the ASRS-v1.1 underwent clinical assessment by a senior psychiatrist specialized in ADHD. Comorbid ADHD-BD subjects were then compared with BD sufferers without ADHD. RESULTS: Sixty-three (45.65%) of the participants were screened positive at the ASRS-v1.1. 49 were clinically assessed for the presence of ADHD. Only 27 (55%) received a diagnosis of ADHD. Comorbid ADHD-BD subjects were found to be younger at the onset of BD, showed higher numbers of depressive episodes, more anxiety and substance use disorders, more borderline personality traits and greater cyclothymic temperament. Comorbid BD-ADHD subjects reported more childhood emotional abuse. LIMITATIONS: Some subjects were unreachable and thus not clinically assessed for ADHD. CONCLUSIONS: More than 20% of BD subjects were suffering from ADHD. The comorbidity of the two disorders was associated with worse outcomes, possibly resulting from stressful early-life events. More than 40% of the subjects who scored positively at the ASRS-v1.1 did not suffer from ADHD, which suggests that this scale should be used with caution in BD subjects.

Lessons Learned Panitumumab shows activity in terms of disease control rate and preventing disease progression but not for tumor shrinkage in head and neck squamous cell cancer for second-line treatment. Epidermal growth factor receptor (EGFR) copy number gain, a property of tumor cells that theoretically could identify patients more likely to experience disease response, was common among patients having disease control. Our trial, given the lower toxicity with an every-2-week schedule, provides guidance for future trials, for example, in combinations of immune therapies and anti-EGFR-antibodies. Background The objective of this study was to investigate the efficacy and safety of panitumumab (anti-epidermal growth factor receptor [EGFR] antibody) given as a single agent in platinum-pretreated head and neck squamous cell cancer (HNSCC). Methods Patients with advanced HNSCC previously treated with platinum-containing therapy were included. Panitumumab was administered intravenously every 2 weeks at a dose of 6 mg/kg. Primary endpoint was overall response rate (ORR) according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1; secondary endpoints were progression-free survival (PFS) and safety. A Simon's two-step design was chosen; 4 partial remissions (PR) in the first 32 patients were required for continuing to step two. An exploratory biomarker analysis was performed. Results Thirty-three patients were enrolled. Two patients obtained a PR for an ORR of 6%, and 15 (45%) showed stable disease (SD) for at least 2 months, resulting in a 51% disease control rate. Median PFS was 2.6 months (95% confidence interval [CI]: 1.7–3.7), while median OS was 9.7 months (95% CI: 6.3–17.2). The most frequent adverse drug reactions were cutaneous rash (64%) and hypomagnesemia (55%). Overall, 30% of patients experienced grade 3/4 adverse events. No infusion-related reactions occurred. EGFR copy number gain (CNG) was more frequent in patients who benefitted from panitumumab. Two uncommon KRAS mutations (G48E, T50I) and 3 canonical PIK3CA mutations (all E545K) were detected. High-risk HPV16 was found in 10 patients and EGFR CNG in 13 treated patients. EGFR CNG seems to be more frequent in individuals with at least SD compared with patients with progressive disease (59% vs. 30%). PFS for patients with EGFR CNG was 4.6 months (95% CI: 1.0–9.2 months) and 1.9 months (95% CI: 1.0–3.2 months) for patients without CNG (p = .02). Conclusion Panitumumab monotherapy in pretreated HNSCC patients was well tolerated but moderately active. We observed a considerable disease control rate. Future strategies with this agent comprise right patient selection through the identification of reliable biomarkers and gene signatures predicting response and, considering good tolerability and convenience, combination strategies with novel agents and immune therapeutic agents.

We present the case of a patient with rapidly accelerated fibrosarcoma gene F (BRAF) mutated adenocarcinoma of the lung, responding to BRAF inhibitor dabrafenib after progressing on vemurafenib followed by docetaxel. The present case illustrates the potential benefit of successful rechallenge with a BRAF inhibitor, a well known phenomenon observed in other oncogenic driven molecular subtypes of non-small cell lung cancer (NSCLC) such as epidermal growth factor receptor mutation. Rechallenge with a BRAF inhibitor in BRAF mutated NSCLC should be considered, particularly in the absence of alternative therpateutic options.

Ein 77-jahriger Patient stellt sich wegen eines akut aufgetretenen, schmerzhaften Exanthems im Spital vor. Als Vorerkrankung ist ein hepatisch und ossar metastasiertes, medullares Schilddrusenkarzinom bekannt, weshalb er unter einer Therapie mit Sorafinib steht.