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Immunotherapies have improved the prognosis of many cancer patients including patients with advanced melanoma. Immune checkpoint receptors including CTLA-4 and PD-1 have been established as main therapeutic targets for immunotherapy of melanoma. Although monotherapy is effective in melanoma patients, a dual therapy approach has been shown to be most effective. Dual checkpoint blockade, however, increases substantially the risk for immune-related adverse events (irAEs). In this study, we characterized peripheral immune cell subsets in patients with anti-PD-1 monotherapy and with dual immune receptors blockade targeting PD-1 and CTLA-4. We found differences in peripheral T cells between patients who developed severe immune-related side effects and patients with mild irAEs. We identified several mainly changes in CD8 T cell subsets in patients with severe irAE under dual PD-1 and CTLA-4 blockade. This work suggests that peripheral immune cell dynamics could be associated with severe immune-related side effects in patients receiving immune checkpoint inhibitors. These changes could be used as future biomarkers in early diagnosis of irAEs.

Several studies in patients undergoing chemotherapy for advanced pancreatic carcinoma have linked a decrease in the concentration of the tumour marker carbohydrate antigen (CA) 19-9 to lengthened survival. The aim of this study was to test the hypotheses that an early decrease in baseline serum CA 19-9 concentration (on day 42, after two cycles of chemotherapy) by at least 50% is associated with lengthened survival, and that a decrease in CA 19-9 concentration of at least 50% from the baseline concentration to the lowest value measured at any time during treatment (nadir) is of prognostic significance, enabling its use as a surrogate endpoint for survival. CA 19-9 serum concentration was measured at baseline and every 3 weeks thereafter in patients with histologically proven advanced pancreatic carcinoma enrolled in a randomised trial of gemcitabine versus gemcitabine plus capecitabine. Patients were excluded if baseline serum CA 19-9 concentration was below the upper limit of normal (ULN) in the laboratory or if this measurement was missing. Comparisons of survival between patients with and without a CA 19-9 response were corrected for the guarantee-time bias by the landmark method. The trial on which this study is based is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00030732. 247 of 319 randomised patients were assessable for analysis of baseline serum CA 19-9 concentration, and, of these, 175 patients were assessable for tumour-marker response to treatment. Median overall survival for patients with a baseline CA 19-9 concentration equal to or above the median value (ie, 59×ULN) was 5·8 months (95% CI 5·1–7·0), which was significantly shorter than that for patients with baseline concentrations below the median value (10·3 months [95% CI 8·6–12·8], p<0·0001). An early decrease in CA 19-9 concentration of at least 50% after two cycles of chemotherapy was not associated with a longer overall survival compared with patients who did not have a decrease of at least 50% (median 10·1 months [9·2–12·7] vs 8·6 months [6·9–11·2], p=0·53; hazard ratio for death 1·11 [0·81–1·52]). Furthermore, a decrease in CA 19-9 concentration of at least 50% reached at the CA 19-9 nadir concentration was not associated with a longer overall survival compared with those patients who did not have a decrease of at least 50% (median 7·8 months [6·5–10·1] vs 6·7 months [5·5–9·8], p=0·74; 0·95 [0·69–1·31]) after adjusting for the guarantee-time bias. Pretreatment serum CA 19-9 concentration is an independent prognostic factor for survival, but a decrease in concentration during chemotherapy is not significantly associated with lengthened survival compared with those who did not have a corresponding decrease. Our data suggest that CA 19-9 response during chemotherapy is not a valid surrogate endpoint for survival in clinical trials.

Background Being diagnosed with cancer causes major psychological distress, yet the majority of newly diagnosed cancer patients lack psychological support. Internet interventions overcome many barriers for seeking face-to-face support and allow for independence in time and place. We assess efficacy and feasibility of the first web-based stress management intervention (STREAM: STREss-Aktiv-Mindern) for newly diagnosed, German-speaking cancer patients. Methods/design In a prospective, wait-list controlled trial 120 newly diagnosed cancer patients will be included within 12 weeks of starting anti-cancer treatment and randomized between an immediate (intervention group) or delayed (control group) 8-week, web-based intervention. The intervention consists of eight modules with weekly written feedback by a psychologist (“minimal-contact”) based on well-established stress management manuals including downloadable audio-files and exercises. The aim of this study is to evaluate efficacy in terms of improvement in quality of life (FACT-F), as well as decrease in anxiety and depression (HADS), as compared to patients in the wait-list control group. A sample size of 120 patients allows demonstrating a clinically relevant difference of nine points in the FACT score after the intervention (T2) with a two-sided alpha of 0.05 and 80 % power. As this is the first online stress management intervention for German-speaking cancer patients, more descriptive outcomes are equally important to further refine the group of patients with the largest potential for benefit who then will be targeted more specifically in future trials. These descriptive endpoints include: patients’ characteristics (type of cancer, type of treatment, socio-demographic factors), dropout rate and dropout reasons, adherence and satisfaction with the program. Discussion New technologies open new opportunities: minimal-contact psychological interventions are becoming standard of care in several psychological disorders, where their efficacy is often comparable to face-to-face interventions. With our study we open this field to the population of newly diagnosed cancer patients. We will not only assess clinical efficacy but also further refine the target population who has the most potential to benefit. An internet-based minimal-contact stress management program might be an attractive, time- and cost-effective way to effectively deliver psychological support to newly diagnosed cancer patients and an opportunity to include those who currently are not reached by conventional support. Trial registration ClinicalTrials.gov NCT02289014 .

Background High rates of venous thromboembolic events (VTEs), mainly in advanced disease, are reported for patients with cancer of the upper gastrointestinal tract (stomach, pancreas) and for treatment with cisplatin. Methods Exploratory analysis of VTEs reported as adverse events and serious adverse events in a prospective, randomised, multicentre, multimodal phase III trial according to VTEs reported as adverse events and severe adverse events. Patients with resectable oesophageal cancer (T2N1–3, T3-4aNx) were randomized to 2 cycles of chemotherapy with docetaxel 75 mg/m 2 , cisplatin 75 mg/m 2 followed by chemo-radiotherapy (CRT) and subsequent surgery (control arm) or the same treatment with addition of cetuximab (investigational arm). Results VTEs occurred in 26 of 300 patients included in the trial, resulting in an incidence rate (IR) of 8.7% [95% CI 5.7–12.4%]. A total of 29 VTEs were reported:13 (45%) VTEs were grade 2, 13 (45%) grade 3 and three (10%) fatal grade 5 events. 72% (21/29) of all VTEs occurred preoperatively (IR 6.7%): 14% (4/29) during chemotherapy and 59% (17/29) during CRT. In multivariable logistic regression only adenocarcinoma (IR 11.1%, 21/189 patients) compared to squamous cell cancer (IR 4.5%, 5/111 patients) was significantly associated with VTE-risk during treatment, OR 2.9 [95%CI 1.0–8.4], p  = 0.046. Baseline Khorana risk score was 0 in 73% (19/26), 1–2 in 23% (6/26) and 3 in only 4% (1/26) of patients with VTEs. Conclusion A high incidence of VTEs during preoperative therapy of resectable oesophageal cancer is observed in this analysis, especially in patients with adenocarcinoma. The role of prophylactic anticoagulation during neoadjuvant therapy in resectable esophageal cancer should be further evaluated in prospective clinical trials. According to our data, which are in line with other analysis of VTE-risk in patients with oesophageal cancer patients treated with neoadjuvant cisplatin-based chemotherapy and CRT, prophylactic anticoagluation could be considered balanced against individual bleeding risks, especially in patients with adenocarcinoma. In addition to the established risk factors, oesophageal adenocarcinoma treated with neoadjuvant cisplatin-based therapy may be regarded as a high-risk situation for VTEs. Trial registration Registered at clinicaltrials.gov , NCT01107639 , on 21 April 2010,

Background:Cancer is related to not only physical but also mental suffering. Notably, body image disturbances are highly relevant to cancer-related changes often persisting beyond recovery from cancer. Scalable and low-barrier interventions that can be blended with face-to-face psychotherapy for cancer survivors are highly warranted.Objective:The aim of the study is to investigate whether smartphone-based bodily interventions are more effective to improve the mood of patients with cancer than smartphone-based fairy tale interventions (control intervention).Methods:We recruited patients with cancer in 2 Swiss hospitals and conducted daily, fully automated smartphone-based interventions 6 times a week for 5 consecutive weeks, blended with weekly face-to-face group body psychotherapy. We applied 2 types of smartphone-based interventions using a within-subject design, randomly assigning patients daily to either bodily interventions or fairy tales. Each intervention type was presented 3 times a week. For this secondary analysis, 3-level mixed models were estimated with mood assessed by the 3 Multidimensional Mood Questionnaire subscales for good-bad mood, wakefulness, and calmness as key indicators. In addition, the effects on experience of presence, vitality, and burden assessed with visual analog scales were investigated.Results:Based on the data from s=732 interventions performed by 36 participants, good-bad mood improved (β=.27; 95% CI 0.062-0.483), and participants became calmer (β=.98; 95% CI 0.740-1.211) following smartphone-based interventions. Wakefulness did not significantly change from pre- to postsmartphone–based intervention (β=.17; 95% CI –0.081 to 0.412). This was true for both intervention types. There was no interaction effect of intervention type with change in good-bad mood (β=–.01; 95% CI –0.439 to 0.417), calmness (β=.22; 95% CI –0.228 to 0.728), or wakefulness (β=.14; 95% CI –0.354 to 0.644). Experience of presence (β=.34; 95% CI 0.271-0.417) and vitality (β=.35; 95% CI 0.268-0.426) increased from pre- to postsmartphone–based intervention, while experience of burden decreased (β=–0.40; 95% CI –0.481 to 0.311). Again, these effects were present for both intervention types. There were no significant interaction effects of intervention type with pre- to postintervention changes in experience of presence (β=.14; 95% CI –0.104 to 0.384), experience of vitality (β=.06; 95% CI –0.152 to 0.265), and experience of burden (β=–.16; 95% CI –0.358 to 0.017).Conclusions:Our results suggest that both smartphone-based audio-guided bodily interventions and fairy tales have the potential to improve the mood of cancer survivors.Trial Registration:ClinicalTrials.gov NCT03707548; https://clinicaltrials.gov/study/NCT03707548International Registered Report Identifier (IRRID):RR2-10.1186/s40359-019-0357-1

Background Disturbances in bodily well-being represent one key source of suffering and impairment related to cancer. There is growing evidence that body psychotherapy (BPT) is efficacious for the treatment of various mental disorders. However, with regard to cancer patients, evidence is scarce. The aims of this project are to evaluate whether bodily disturbances in post-treatment cancer patients can be improved by group BPT, and to estimate the efficacy of intermittent smartphone-triggered bodily interventions. Methods The project is a bi-center study with two participating centers in Switzerland, applying a pre-post convergent parallel design of a weekly group BPT using a waiting-period comparator, including a nested RCT during the group BPT phase. During the BPT phase, either a smartphone-triggered bodily intervention or a smartphone-triggered control intervention is provided at random over 5 consecutive weeks, on 6 days weekly. Patients who had received curatively intended treatment for any malignant neoplasm (treatment being completed ≥3 months) and are suffering from bodily disturbances are screened to assess eligibility. Sample size estimation is based on an a priori power analysis. We plan to include a total of N  = 88 subjects, aiming at at least 52 completers. Patients are surveyed three times (baseline assessment (T0), pre- (T1) and post-intervention assessment (T2)), and on a daily basis along BPT during five consecutive weeks. The primary outcome, bodily disturbances, is assessed using the ‘Body Image Scale‘(BIS). For the secondary outcomes standardized questionnaires are used to assess changes in experience of presence and vitality, mood, body mindfulness, somatic symptoms and somatic symptom disorder, quality of life, anxiety, and depression including suicidal tendency, vitality and mental health, as well as group cohesion. Using semi standardized interviews (at T0 and T2), we aim to explore the relation of BPT with bodily disturbances and body image in post-treatment cancer patients, as well as the acceptance and burden of the intervention. Discussion The proposed study has strong potential benefits for cancer patients, as it may pave the way for new therapeutic approaches to treat bodily disturbances, which persist despite curative tumor therapy. These may considerably improve patients’ biopsychosocial well-being and quality of life. Trial registration ClinicalTrials.gov NCT03707548 (registered 9 October 2018; retrospectively registered).

Objective Anti-angiogenic drugs cause a reduction in tumour density (Choi criteria) first and then in size [Response Evaluation Criteria In Solid Tumours (RECIST)]. The prognostic significance of changes in tumour density in metastatic renal cell carcinoma (mRCC) is unknown and was assessed in this study. Methods The prognostic significance of partial response (PR) as opposed to non-response [stable disease (SD) + progressive (PD)] to anti-angiogenic therapy was assessed in patients with mRCC separately for both criteria using the log-rank test and Cox regression models. Results Both criteria were applied to 35 patients. The response was identical for all eight patients with PR and most patients with PD (10/12) when using the RECIST and Choi criteria. Adding tumour density information, 14 patients with SD were re-categorised as having PR (7), SD (4), and PD (3). Patients with PR (Choi) were progression free significantly longer [hazard ratio (HR) 0.24; 95 % CI 0.10–0.57; P  = 0.001] and had better overall survival (HR 0.36; 95 % CI 0.15–0.89; P  = 0.026) compared to patients with SD or PD. The predictive value of PR according to RECIST was not statistically significant. Conclusions In mRCC, the Choi criteria separate prognostic groups better when compared with RECIST. This may allow early discrimination of patients benefiting from continued treatment. Key Points • CT is widely used to assess patients with metastatic renal cell carcinoma. • Various algorithms can be applied for tumour therapy control in patients with mRCC. • Follow-up should be based on evaluation of the tumour size and density. • RECIST is based only on tumour shrinkage and might lead to wrong conclusions.

Background Obesity is a risk factor for developing pancreatic cancer. We investigated the impact of obesity on survival in patients diagnosed with locally advanced or metastatic pancreatic cancer. Methods In a multicentre, retrospective study, we included all patients with advanced or metastatic pancreatic cancer treated at four Swiss hospitals between 1994 and 2004. We categorized patients into four body mass index (BMI) groups (<18.5, 18.5 – 25, ≥ 25 – 29, ≥30 kg/m 2 ) and used multivariable Cox regression to investigate the impact of BMI on survival. Missing data were handled using multiple imputations. Results 483 patients were included. Median age was 66 years (range 59–74), 47% were female, 82% had stage IV disease, 72% had an ECOG below 2, and 84% were treated with gemcitabine-based first-line chemotherapy. After a median follow-up of 8.5 months, 6 and 12-month survival probabilities of the whole cohort were 67% (95% CI 63% - 71%) and 37% (95% CI 33% - 42%), respectively. Unadjusted 12-month survival rates in each BMI group were: 48% (95% CI 33% - 62%), 42% (95% CI 36% - 48%), 30% (95% CI 22% - 38%), and 11% (95% CI 4% - 24%), respectively. In multivariable analysis, increasing BMI (HR 1.22, 95% CI 1.04 – 1.41, p = 0.012) and CA 19–9 (HR 1.07, 95% CI 1.02 – 1.11, p = 0.003) were significantly associated with worse survival prognosis. Patients with a good clinical performance status (ECOG < 2) had a better prognosis (HR 0.76, 95% CI 0.65 – 0.96, p = 0.019). Conclusions Obese patients diagnosed with advanced pancreatic cancers have a worse prognosis compared to non-obese patients. BMI should be considered for risk stratification in future clinical trials.

Background: Computed tomography angiography (CTA) of the supraaortic arteries is commonly used for acute stroke workup and may reveal apical pulmonary lesions (APL). Aim: To determine the prevalence, follow-up algorithms, and in-hospital outcomes of stroke patients with APL on CTA. Methods: We retrospectively included consecutive adult patients with ischemic stroke, transient ischemic attack, or intracerebral hemorrhage and available CTA at a tertiary hospital between January 2014 and May 2021. We reviewed all CTA reports for the presence of APL. APL were classified as malignancy suspicious or benign appearing based on radiological-morphological criteria. We performed regression analyses to investigate the impact of malignancy suspicious APL on different in-hospital outcome parameters. Results: Among 2715 patients, APL on CTA were found in 161 patients (5.9% [95%CI: 5.1–6.9]; 161/2715). Suspicion of malignancy was present in one third of patients with APL (36.0% [95%CI: 29.0–43.7]; 58/161), 42 of whom (72.4% [95%CI: 60.0–82.2]; 42/58) had no history of lung cancer or metastases. When performed, further investigations confirmed primary or secondary pulmonary malignancy in three-quarters (75.0% [95%CI: 50.5–89.8]; 12/16), with two patients (16.7% [95%CI: 4.7–44.8]; 2/12) receiving de novo oncologic therapy. In multivariable regression, the presence of radiologically malignancy suspicious APL was associated with higher NIHSS scores at 24 h (beta = 0.67, 95%CI: 0.28–1.06, p = 0.001) and all-cause in-hospital mortality (aOR = 3.83, 95%CI: 1.29–9.94, p = 0.01). Conclusions: One in seventeen patients shows APL on CTA, of which one-third is malignancy suspicious. Further work-up confirmed pulmonary malignancy in a substantial number of patients triggering potentially life-saving oncologic therapy.

IntroductionChemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and clinically meaningful side effect of cancer treatment. CIPN is induced by neurotoxic agents, causing severe sensory and/or motor deficits, resulting in disability and poor recovery, reducing patients’ quality of life and limiting medical therapy. To date, effective treatment options are lacking. Whole-body vibration (WBV) training can attenuate motor and sensory deficits. We are conducting a two-armed, multicentre, assessor-blinded, randomised controlled trial, to investigate the effects of WBV on relevant symptoms of CIPN and determine the training characteristics.Methods and analysisIn this ongoing study, 44 patients who have completed therapy in the past 3 months, with a neurologically confirmed CIPN are assessed before and after a 12-week intervention and follow-up. The intervention group receives WBV twice a week. Exercises are individually tailored according to the initially determined optimal neuromuscular response. The control group receives care as usual.Primary endpoint is the patient reported reduction of CIPN-related symptoms (Functional Assessment of Cancer Therapy/Gynaecology Oncology Group—Neurotoxicity). Secondary endpoints are compound muscle action potentials, distal motor latency, conduction velocity, F-waves from the tibial and peroneal nerve, antidromic sensory nerve conduction studies of the sural nerve, normalised electromyographic activity, peripheral deep sensitivity, proprioception, balance, pain, the feasibility of training settings, quality of life and the level of physical activity.Aim, ethics and disseminationThe study was approved by both responsible ethics committees. (1) Our results may contribute to a better understanding of the effects of WBV on motor and sensory functions and (2) may provide information whether WBV at the most effective setting, is feasible for neuropathic patients. (3) Our results may also contribute to improve supportive care in oncology, thereby enhancing quality of life and enabling the optimal medical therapy. All results will be published in international peer-reviewed journals as well as a manual for clinical practice.Trial registration number NCT03032718