GDF-15 in solid vs non-solid treatment-naïve malignancies.

AIM: GDF-15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF-15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF-15 to other cardiac biomarkers and the general association of GDF-15 on prognosis in an unselected cohort of treatment-naïve cancer patients. METHODS: We prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF-15 concentrations were determined alongside other cardiac and routine laboratory markers. All-cause mortality was defined as primary endpoint. RESULTS: GDF-15 levels were 338 ng/L (IQR:205-534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF-15 [435 ng/L (IQR:279-614) vs 266 ng/L (IQR:175-427), P < .001]. GDF-15 correlated positively with inflammatory status reflected by CRP, SAA and IL-6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NT-proBNP, hsTnT, MR-proADM and CT-proET-1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF-15 was significantly associated with all-cause mortality after multivariate adjustment [adj.HR for ln(GDF-15) 1.78, 95%CI:1.47-2.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF-15 with outcome in myelodysplastic and myeloproliferative disease. CONCLUSIONS: Elevated plasma GDF-15 is associated with progressing disease severity and poor prognosis in solid tumours of treatment-naïve cancer patients. GDF-15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF-15 represents a promising target for our pathophysiologic understanding in cardio-oncology linking conditions of both cardiac and neoplastic disease.

Public perception of cancer care in Poland and Austria.

BACKGROUND: We compared the public perception of cancer care in Poland and Austria. Both countries are members of the European Union (EU) but reflect two extremes in health-related per capita spending. Recently, the EUROCARE-5 study reported on very discrepant cancer outcomes between the two countries. METHODS: A one-time survey was conducted to compare the public perception of cancer treatment in Poland and Austria. In total, 3,649 subjects, representing the general population, cancer patients, and cancer patients' family members, were surveyed. RESULTS: In both countries, cancer was considered the most challenging problem of the health care system, and health care was indicated as the most important issue influencing political election decisions. Polish compared with Austrian cancer patients gave a significantly lower positive assessment of overall cancer treatment efficacy and detection methods. Cancer cure rates estimated by Polish and Austrian citizens were 29% and 44%, respectively. The majority of all citizens interviewed thought that cancer patients should have access to all available registered cancer drugs. However, only 18% of Poles versus 62% of Austrians agreed with the notion that the available cancer treatment in their countries is of a standard comparable to that of other EU countries. Consequently, 24% of Poles and 7% of Austrians identified financial status, age, gender, and residence as factors influencing the availability of cancer treatments. CONCLUSION: In both countries, cancer is considered the most challenging problem of the health care system, and health care issues may strongly influence decisions for political elections. Vast differences in the two populations' perceptions of cancer care reflect actual cancer outcomes and the national per capita spending on health-related issues.

Primary radiotherapy or postoperative radiotherapy in patients with head and neck cancer: Comparative analysis of inflammation-based prognostic scoring systems.

INTRODUCTION: Inflammation-based scoring systems have potential value in evaluating the prognosis of cancer patients; however, detailed comparative analyses in well-characterized head and neck cancer patient collectives are missing. METHODS: We analyzed overall survival (OS) in locally advanced head and neck cancer patients who were treated with curative intent by primary radiotherapy (RT) alone, by RT in combination with cetuximab (RIT) or with cisplatin (RCHT), and by primary surgery followed by postoperative radiotherapy (PORT). The primary RT collective (N = 170) was analyzed separately from the surgery plus RT group (N = 148). OS was estimated using the Kaplan-Meyer method. Cox proportional-hazard regression models were applied to compare the risk of death among patients stratified according to risk factors and the inflammation-based Glasgow Prognostic Score (GPS), the modified GPS (mGPS), the neutrophil-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), and the prognostic index (PI). RESULTS: A prognostic relevance of the scoring systems for OS was observed in the primarily irradiated, but not in the PORT collective. OS was 35.5, 18.8, and 15.4 months, respectively, according to GPS 0, 1, and 2. OS according to mGPS 0-2 was identical. The PLR scoring system was not of prognostic relevance, while OS was 27.3 months in the NLR 0 group and 17.3 months in the NLR 1 group. OS was 35.5 months in PI 0, 16.1 months in PI 1, and 22.6 months in PI 2. CONCLUSION: GPS/mGPS scoring systems are able to discriminate between three risk groups in primarily, but not postoperatively irradiated locally advanced head and neck cancer patients.

Improved survival in HPV/p16-positive oropharyngeal cancer patients treated with postoperative radiotherapy.

INTRODUCTION: In the literature, HPV infection and/or p16 positivity have been consistently demonstrated to correlate with improved response rates in oropharyngeal squamous cell carcinoma (OPSCC) patients treated with primary radiotherapy (RT) alone and in combination with chemotherapy. However, the exact role of HPV/p16 positivity in patients treated with postoperative RT is still unclear. METHODS: We analyzed tumor samples for HPV-DNA and p16 expression and correlated these variables with treatment outcome in a series of 63 consecutively treated oropharyngeal cancer patients (95% stage III/IV). HPV and p16 analysis were performed using validated test systems. Survival was estimated by the Kaplan-Meier method. Cox proportional hazard regression models were applied to compare the risk of death among patients stratified according to risk factors. RESULTS: Expression of p16 or high-risk HPV-DNA was detected in 60.3% and 39.6% of the tumors, respectively. p16 expression [overall survival (OS) at 2 years: 91%] as well as HPV infection (OS at 2 years: 95%) was associated with improved OS. Mean survival in p16-positive patients was 112 months compared to 64.6 months in case of p16 negativity. All HPV-positive tumors stained positive for p16. In a multivariable analysis, p16 positivity was associated with improved OS and with disease-free survival. CONCLUSION: p16 expression and HPV infection are strongly associated with the outcome of postoperatively irradiated OPSCC patients. HPV and p16 double-negative OPSCC patients should be regarded as a distinct "very high-risk patient group" that may benefit from intensified or novel treatment combinations.

Baseline carcinoembryonic antigen (CEA) serum levels predict bevacizumab-based treatment response in metastatic colorectal cancer.

Carcinoembryonic antigen (CEA) affects tumorigenesis by enhancing tumor cell survival and by inducing tumor angiogenesis. This study aimed to evaluate baseline CEA serum levels to predict bevacizumab-based therapy effect and survival in patients with metastatic colorectal cancer (mCRC). Two hundred and ninety eight mCRC patients receiving chemotherapy plus either bevacizumab or cetuximab were analyzed in a retrospective study. Disease control (DC), progression-free survival (PFS), and overall survival were assessed and related to pretreatment CEA serum levels. Patients with baseline CEA serum levels below the statistical median of 26.8 ng/mL (group I) were compared with patients with higher CEA levels (group II). The cetuximab-based treatment cohort was analyzed for specificity assessment of CEA to predict the anti-vascular endothelial growth factor effect in mCRC. Baseline CEA serum levels inversely correlated with therapeutic response in patients receiving bevacizumab-based treatment (disease control rate, 84% vs 60%), inversely correlated with median PFS leading to a median PFS benefit of 2.1 months for patients in group I when compared with group II, as well as inversely correlated with median overall survival (37.5 months vs 21.4 months). In an independent cohort of 129 patients treated with cetuximab-based therapy, no association of therapeutic response or PFS with CEA serum levels was found. As expected, baseline CEA levels were prognostic for mCRC. These data give first evidence that baseline serum CEA levels might constitute an important predictor for the efficacy of first-line bevacizumab-based therapy in patients with mCRC.

Response to GEMOX plus erlotinib in pancreatic cancer is associated with ERCC1 overexpression.

INTRODUCTION: There are no data about the efficacy of gemcitabine in combination with oxaliplatin (GEMOX) and erlotinib for the treatment of metastatic pancreatic cancer (mPC). Thus, we performed this retrospective analysis in mPC patients to investigate the activity and safety of GEMOX plus erlotinib and correlated the benefit with ERCC1 expression, a potential biomarker for treatment response. PATIENTS AND METHODS: Patients with untreated mPC receiving off-protocol GEMOX plus erlotinib were included. Data collection included baseline demographic, response and toxicity data as well as PFS and OS. Additionally, immunohistochemistry was performed to stain for ERCC1 expression. RESULTS: A total of 51 patients were included. The median age was 62 years and the median ECOG performance score was 1 (range, 0-1). Objective response or disease stabilization was achieved in 54% of the patients. The median PFS was 4·4 months (95% CI 4·4-5·4) and median OS was 8·5 months (95% CI 6·1-10·9). The 27 patients, who benefited from this regimen, had a median PFS of 6·7, a median OS of 11·2 months and an overexpression of ERCC1 (histoscore 10, P ≤ 0·05) compared to nonresponders (histoscore 7·2). Myelosuppression was the most frequent side effect. The most common severe nonhematological toxicities were diarrhoea and skin toxicity in six (12%) patients each. CONCLUSIONS: These data suggest that the combination of GEMOX plus erlotinib is safe and active in about half of the patients. Patients, who had a higher ERCC1 staining pattern, benefited most from this therapy. Prospective biomarker studies are warranted to confirm these findings.

Significance of p16 expression in head and neck cancer patients treated with radiotherapy and cetuximab.

BACKGROUND: HPV-infection, p16 positivity, and EGFR expression have been correlated with favorable responses of head and neck cancer patients treated with radiotherapy (RT) with or without chemotherapy. However, a possible correlation of HPV/p16 and EGFR status on the effect of RT in combination with cetuximab has not been sufficiently investigated. MATERIALS AND METHODS: We analyzed tumor samples for p16 and EGFR expression and correlated these variables with treatment outcome. Cox-proportional-hazard regression models were applied to compare the risk of death among patients stratified according to risk factors. Survival was estimated by the Kaplan-Meier method. Results were compared with an institutional historical control group treated without cetuximab and with published data. RESULTS: Expression of p16 was predominantly found in oropharyngeal squamous cell cancer patients (OPSCC; 36.6% positivity; 92% of all cases), while EGFR was expressed at high levels in all tumor subsites (82%). p16 expression was associated with improved overall survival in irradiated OPSCC patients (2-year overall survival of 80% in p16-positive vs. 33% overall survival in p16-negative patients). In a multivariable analysis covering all tumor sites, nodal stage (> N2a vs. ≤ N2a) and tumor site (OPSSC vs. non-OPSCC) had an impact on overall survival. CONCLUSION: Our results show that p16 positivity is associated with a favorable outcome in OPSCC patients treated with RT and cetuximab.

Postoperative failure of platelet recovery is an independent risk factor for poor survival in patients with oral and oropharyngeal cancer.

OBJECTIVE: The aim of this study was to evaluate the postoperative platelet count changes in patients with oral and oropharyngeal squamous cell carcinoma undergoing preoperative chemoradiotherapy in order to test the hypothesis that the failure of platelets to recover to normal range within 7 days after surgery represents a significant risk factor for poor survival. MATERIALS AND METHODS: A cohort of 102 patients with primary locally advanced oral and oropharyngeal squamous cell carcinoma undergoing neoadjuvant chemoradiotherapy and surgery was retrospectively analyzed. For each patient, platelet counts were evaluated prior to neoadjuvant treatment, prior to surgery and throughout postoperative days 1 to 7. The Kaplan-Meier method and Cox regression models were used to assess the impact of platelet count changes on survival. RESULTS: Overall survival rate at 5 years was 28% for patients whose platelets did not recover by day 7, with 52% for patients whose platelets remained within a normal level or recovered to this by day 7 (p = 0.005). In multivariate analysis, failure of platelet recovery by day 7 was independently associated with shorter overall survival (p = 0.03). CONCLUSIONS: We demonstrated that the failure of platelets to recover to normal range by the seventh postoperative day is an independent adverse prognostic factor in patients with oral and oropharyngeal cancer undergoing neoadjuvant treatment and surgery. CLINICAL RELEVANCE: Our results indicate that physicians should pay closer attention to monitoring the postoperative platelet count course, as it may predict the clinical outcome of patients with oral and oropharyngeal cancer.

Long COVID symptoms in hospital employees after post-vaccination SARS-CoV-2 infection in Austria: A study on self-reported incidence and associated factors.

PURPOSE: Post acute sequelae of SARS-CoV-2 infection are defined by persistence or re-occurrence of symptoms six to 12 weeks after SARS-CoV-2 infections. METHODS: Twice vaccinated hospital employees after mild to moderate post-vaccination SARS-CoV-2 infection completed a questionnaire on the incidence of general, respiratory, neuropsychiatric, dermatological and gastrointestinal symptoms, experienced during their acute infection and eight weeks after recovery. Post acute sequelae of SARS-CoV-2 infection were analysed in relation to socio-demographic-, health-, virus- and acute infection-related characteristics. RESULTS: 73 participants, 25 women and 48 men with a mean age of 40.9 years, with a post-vaccination SARS-CoV-2 infection completed the survey. Out of these 93 % reported at least one symptom at time of initial SARS-CoV-2 infection, 31.5 %, predominantly women, reported post acute sequelae at least eight weeks after the acute infection stage. Fatigue, dysgeusia and dysosmia, headache or difficulty concentrating and shortness of breath during acute infection, BMI> 25 and pre-existing pulmonary disorders were associated with post acute sequelae of SARS-CoV-2 infection. Participants with initially more than five symptoms were four times more likely to report post acute sequelae. CONCLUSION: It is suggested that the multiplicity of symptoms during acute SARS-CoV-2 infections increases the risk for post acute symptoms.

Postvaccination infections among staff of a tertiary care hospital after vaccination with severe acute respiratory syndrome coronavirus 2 vector and mRNA-based vaccines.

OBJECTIVES: The identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen or RNA in respiratory specimens ≥14 days after administration of all recommended doses of authorized coronavirus disease 2019 (COVID-19) vaccines is defined as breakthrough infection. In the present investigation, mRNA and vector-based SARS-CoV-2 vaccines were analysed with respect to postvaccination infections in vaccinated hospital employees. METHODS: A total of 8553 staff members were vaccinated with BNT162b2 (47%) or ChAdOx1-S (53%) between January and May 2021. In a retrospective observational cohort study, incidence of SARS-CoV-2 postvaccination infections was analysed in relation to demographic data, viral load, virus variants, vaccine brand and vaccination status at time of positive PCR test (fully vaccinated: ≥14 days since second dose; partially vaccinated: >21 days since first, but <14 days after second dose; insufficiently vaccinated: <22 days since first dose). RESULTS: Within the follow-up period, ending on 31 July 2021, person-time at risk-adjusted monthly rates for SARS-CoV-2 postvaccination infections were 0.18% (BNT162b2) and 0.57% (ChAdOx1-S) for insufficiently vaccinated, 0.34% (BNT162b2) and 0.32% (ChAdOx1-S) for partially vaccinated and 0.06% (BNT162b2) and 0.04% (ChAdOx1-S) for fully vaccinated participants. The two vaccine types did not differ with respect to hazard ratios for any of the respective postvaccination infection types. No cases of COVID-19-related hospitalizations or deaths were reported. Genotyping of positive PCR specimens revealed 42 variants of concern: B.1.1.7 (Alpha variant; n = 34); B.1.351 (Beta variant; n = 2), B.1.617.2 (Delta variant; n = 6). CONCLUSIONS: BNT162b2 and ChAdOx1-S are both effective in preventing breakthrough infections; however, it seems important, that all recommended vaccine doses are administered.

The cancer survival index-A prognostic score integrating psychosocial and biological factors in patients diagnosed with cancer or haematologic malignancies.

OBJECTIVE: We aimed to investigate whether (1) psychological and social indicators influence survival in patients diagnosed with cancer or haematologic malignancies when important biological aspects are controlled for, (2) psychological, social and biological indicators can be utilised to design one collated index for survival, usable in clinical practice to identify patients at risk of shorter survival and to improve personalised healthcare provision. METHODS: In this cross-sectional study, 2263 patients with cancer or haematologic malignancies participated. We analysed 15 biological, psychological and social indicators as risk factors for survival with a Cox proportional hazards model. Indicators significantly associated with survival were combined to compute models for the identification of patient groups with different risks of death. The training sample contained 1122 patients. Validation samples included the remaining 1141 patients, the total sample, as well as groups with different cancer entities. RESULTS: Five indicators were found to significantly impact survival: Cancer site (HR: 3.56), metastatic disease (HR: 1.88), symptoms of depression (HR: 1.34), female sex (HR: 0.73) and anaemia (HR: 0.48). Combining these indicators to a model, we developed the Cancer Survival Index, identifying three distinct groups of patients with estimated survival times of 47.2 months, 141 months and 198.2 months (p < 0.001). Post hoc analysis of the influence of depression on survival showed a mediating effect of the following four factors, related to both depression and survival: previous psychiatric conditions, employment status, metastatic disease and haemoglobin levels. CONCLUSIONS: Psychosocial and biological factors impact survival in various malignancies and can be utilised jointly to compute an index for estimating the survival of each patient individually-the Cancer Survival Index.

Incidence of dermatitis in head and neck cancer patients treated with primary radiotherapy and cetuximab.

PURPOSE: To retrospectively assess the incidence of radiation dermatitis in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) who received primary radiotherapy in combination with cetuximab in a curative intent. PATIENTS AND METHODS: A total of 112 consecutively treated patients who received cetuximab in combination with radiotherapy at the Departments of Radiotherapy at the Medical University in Vienna and the Hospital Hietzing (Vienna) were analyzed. Radiotherapy was administered either as conventional radiotherapy (70 Gy in 7 weeks) or using a concomitant boost protocol (72 Gy in 6 weeks). The incidence of dermatitis and mucositis within the radiation portals in 103 eligible patients was compared with a historical control group treated at the Medical University of Vienna as well as with published data. RESULTS: The incidence of grade 1/2, 3, and 4 dermatitis was 57%, 29%, and 1% in the radiotherapy plus cetuximab treated collective. The incidence of grade 1/2, 3, and 4 mucositis was 37%, 47%, and 4%, respectively. The incidence of grade 3 dermatitis during concurrent radiotherapy plus cetuximab was 29% in our patient collective. Only one case of grade 4 dermatitis was observed. CONCLUSION: These results do not statistically differ significantly from the incidence reported in the Bonner trial and indicate that cetuximab in combination with radiotherapy is well tolerated.

Inflammation-Based Scores as a Common Tool for Prognostic Assessment in Heart Failure or Cancer.

Background: Inflammation-based scores are widely tested in cancer and have been evaluated in cardiovascular diseases including heart failure. Objectives: We investigated the impact of established inflammation-based scores on disease severity and survival in patients with stable heart failure with reduced ejection fraction (HFrEF) paralleling results to an intra-institutional cohort of treatment naïve cancer patients. Methods: HFrEF and cancer patients were prospectively enrolled. The neutrophil-to-lymphocyte-ratio (NLR), the monocyte-to-lymphocyte-ratio (MLR), the platelet-to-lymphocyte-ratio (PLR), and the prognostic nutritional index (PNI) at index day were calculated. Association of scores with disease severity and impact on overall survival was determined. Interaction analysis was performed for the different populations. Results: Between 2011 and 2017, a total of 818 patients (443 HFrEF and 375 cancer patients) were enrolled. In HFrEF, there was a strong association between all scores and disease severity reflected by NT-proBNP and NYHA class (p ≤ 0.001 for all). In oncologic patients, association with tumor stage was significant for the PNI only (p = 0.035). In both disease entities, all scores were associated with all-cause mortality (p ≤ 0.014 for all scores). Kaplan-Meier analysis confirmed the discriminatory power of all scores in the HFrEF and the oncologic study population, respectively (log-rank p ≤ 0.026 for all scores). A significant interaction with disease (HFrEF vs. cancer) was observed for PNI (p interaction = 0.013) or PLR (p interaction = 0.005), respectively, with higher increase in risk per inflammatory score increment for HFrEF. Conclusion: In crude models, the inflammatory scores NLR, MLR, PLR, and PNI are associated with severity of disease in HFrEF and with survival in HFrEF similarly to cancer patients. For PNI and PLR, the association with increase in risk per increment was even stronger in HFrEF than in malignant disease.

High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS).

Cancer patients are at high risk for venous thromboembolism (VTE). Laboratory parameters with a predictive value for VTE could help stratify patients into high- or low-risk groups. The cell adhesion molecule P-selectin was recently identified as risk factor for VTE. To investigate soluble P-selectin (sP-selectin) in cancer patients as risk predictor for VTE, we performed a prospective cohort study of 687 cancer patients and followed them for a median (IQR) of 415 (221-722) days. Main tumor entities were malignancies of the breast (n = 125), lung (n = 86), gastrointestinal tract (n = 130), pancreas (n = 42), kidney (n = 19), prostate (n = 72), and brain (n = 80); 91 had hematologic malignancies; 42 had other tumors. VTE occurred in 44 (6.4%) patients. In multivariable analysis, elevated sP-selectin (cutoff level, 53.1 ng/mL, 75th percentile of study population) was a statistically significant risk factor for VTE after adjustment for age, sex, surgery, chemotherapy, and radiotherapy (hazard ratio = 2.6, 95% confidence interval, 1.4-4.9, P = .003). The cumulative probability of VTE after 6 months was 11.9% in patients with sP-selectin above and 3.7% in those below the 75th percentile (P = .002). High sP-selectin plasma levels independently predict VTE in cancer patients. Measurement of sP-selectin at diagnosis of cancer could help identify patients at increased risk for VTE.

Impact of New Chemotherapy Regimens on the Treatment Landscape and Survival of Locally Advanced and Metastatic Pancreatic Cancer Patients.

BACKGROUND: New chemotherapy regimens for the treatment of metastatic pancreatic cancer have changed the therapy paradigm. We aimed to assess their impact on the treatment landscape and clinical outcome at our academic institution. METHODS: In this single institutional posthoc registry analysis, we assessed characteristics and survival rates from all patients with locally advanced and metastatic pancreatic cancer who started a systemic treatment between 01/2011 and 12/2017. Survival analyses were performed by Kaplan-Meier and Cox proportional hazards model. RESULTS: A total of 301 patients started a systemic treatment in the observation period. In the first line treatment, we observed a shift from the four different main regimens (gemcitabine/nab-paclitaxel, modified FOLFIRINOX, gemcitabine/oxaliplatin +/- erlotinib or gemcitabine alone) to gemcitabine/nab-paclitaxel and modified FOLFIRINOX that add up to more than 80% of administered first line treatments in each of the time cohorts (2011-2013 vs. 2014-2017). The rate for first line modified FOLFIRINOX treatment was balanced between the two groups (19% and 15%). Median overall survival differed significantly between the two time cohorts (8.89 versus 11.9 months, p = 0.035). Survival rates for different first to second line treatment sequences (modified FOLFIRINOX to gemcitabine/nab-paclitaxel, gemcitabine/nab-paclitaxel to fluoropyrimidines plus nanoliposomal irinotecan, or gemcitabine/nab-paclitaxel to fluoropyrimidines plus oxaliplatin) were not significantly different and median overall survival ranged from 14.27 to 15.64 months. CONCLUSION: Our study provides real-world evidence for the effectiveness of the new chemotherapy regimens and underscores the importance of the choice of the front-line regimen when considering different sequencing strategies.

Increased resting heart rate and prognosis in treatment-naïve unselected cancer patients: results from a prospective observational study.

AIMS: Cancer patients suffer from impaired cardiovascular function. Elevated resting heart rate (RHR) has been identified as a marker for increased long-term mortality in cancer patients prior to the receipt of anticancer treatment. We aimed to establish whether RHR is associated with survival in treatment-naïve cancer patients. METHODS AND RESULTS: This prospective study enrolled 548 unselected treatment-naïve cancer patients between 2011 and 2013. The median age of the cohort was 62 years; 40.9% were male and 32.7% had metastatic disease. Median RHR was 72 b.p.m. Most patients were in sinus rhythm (n = 507, 92.5%). Clinical heart failure was noted in 37 (6.8%) patients. RHR was not related to cancer stage (P = 0.504). Patients in the highest RHR tertile had higher levels of high-sensitivity troponin (P = 0.003) and N-terminal pro-B-type natriuretic peptide (P = 0.039). During a median follow-up of 25 months (interquartile range: 16-32 months; range: 0-40 months), 185 (33.8%) patients died from any cause [1-year-mortality: 17%, 95% confidence interval (CI) 13-20%]. In univariate survival analysis, RHR predicted all-cause mortality [crude hazard ratio (HR) for a 5 b.p.m. increase in RHR: 1.09, 95% CI 1.04-1.15; P < 0.001], and remained significantly associated with outcome after adjustment for age, gender, tumour entity, tumour stage, cardiac status and haemoglobin (adjusted HR for a 5 b.p.m. increase in RHR: 1.10, 95% CI 1.04-1.16; P < 0.001). There was no significant impact of metastatic/non-metastatic disease state on the predictive value of RHR (P = 0.433 for interaction). In subgroup analyses, the strongest associations for RHR with mortality were observed in lung (crude HR 1.14; P = 0.007) and gastrointestinal (crude HR 1.31; P < 0.001) cancer. CONCLUSIONS: Treatment-naïve cancer patients with higher RHRs display higher levels of cardiovascular biomarkers. RHR was independently associated with all-cause mortality, especially in lung and gastrointestinal cancers. Elevated RHR and cardiovascular biomarkers may represent early signs of incipient cardiac dysfunction.

Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis.

BACKGROUND: Few data are available on the safety and efficacy of sorafenib in patients with multifocal hepatocellular carcinoma (HCC) and advanced liver cirrhosis. METHODS: Between May 2006 and December 2007, we treated 59 patients (Child-Pugh class A/B/C, 26/23/10) with unresectable HCC with sorafenib (daily target dose, 400 mg twice daily). Data were collected retrospectively. Survival curves were calculated via the Kaplan-Meier method. RESULTS: One patient (Child-Pugh class B) had a partial response, 14 patients (Child-Pugh class A/B/C, 5/7/2) had stable disease, and 32 patients (Child-Pugh class A/B/C, 15/11/6) had progressive disease; 12 patients were not evaluable because they had no follow-up radiologic evaluation. In the intention-to-treat group, the median time to progression and overall survival (OS) time were 2.8 months (range, 1.4-6.5 months) and 6.5 months (range, 0.4-17.4 months), respectively. Well-preserved liver function and lower Barcelona Clinic Liver Cancer stage were associated with a longer OS time on univariate analysis. There were four severe gastrointestinal bleedings (grade 4-5; Child-Pugh class B/C, 2/2). Most drug-related side effects were low grade and manageable irrespective of liver function. CONCLUSIONS: Sorafenib is effective and safe in patients with multifocal HCC and Child-Pugh class A cirrhosis. Survival in Child-Pugh class B patients is significantly less than in Child-Pugh class A patients, warranting a prospective randomized trial with a placebo group. Child-Pugh class C patients have a limited life expectancy despite sorafenib treatment because of their severe underlying disease and derive little benefit from sorafenib treatment.

Limited value of CA 19-9 in predicting early treatment failure in patients with advanced pancreatic cancer.

OBJECTIVE: The role of CA 19-9 in monitoring treatment response in advanced pancreatic cancer remains uncertain. We assessed its value in predicting early failure of first-line chemotherapy. METHODS: Data of 84 patients with advanced pancreatic cancer who had received first-line chemotherapy were analyzed with regard to changes in CA 19-9 during the first 2 months of treatment. RESULTS: Median time to progression and overall survival in patients with a transient increase in CA 19-9 during month 1 (n = 15; 5.5 and 13 months) and in those with no increase during the 2 months (n = 52; 6.5 and 12 months) were comparable and slightly above the median values of the entire study population. The hazard ratios for disease progression for a 20% increase in CA 19-9 during the first and second month of therapy were 1.065 and 1.339 in the univariate- and 1.092 and 1.298 in the multiple Cox regression model, respectively. CA 19-9 did not influence survival. CONCLUSION: Our results suggest that early CA 19-9 measurements are weakly associated with disease progression rather than survival in patients with advanced pancreatic cancer receiving palliative chemotherapy. In view of a possible tumor marker flare, values after the first month of therapy must be interpreted with caution.

PD-L1 Expression on Tumor Cells Is Associated With a Poor Outcome in a Cohort of Caucasian Nasopharyngeal Carcinoma Patients.

Background: Nasopharyngeal carcinoma (NPC) is endemic in East Asia but rare in the western world. Programmed death ligand 1 (PD-L1) expression on NPC correlates with clinical outcomes. However, data for Caucasian NPC patients are missing. Thus, we performed this retrospective analysis for investigating the potential association of immune checkpoint protein expression with outcome parameters in Caucasian NPC patients. Methods: Fifty-five patients with NPC treated between 1993 and 2018 at the Medical University of Vienna were identified. After the exclusion of Asian patients, data on baseline demographic, tumor stage, overall survival (OS), and disease-free survival (DFS) of 30 patients were analyzed. Their tumor samples were stained and scored (low vs. high) for PD-L1, programmed death receptor 1 (PD-1), lymphocyte activating gene 3 (LAG3), and cluster of differentiation 8 (CD8) antibodies. Statistical analysis was performed with Kaplan-Meier plots and log-rank test. Estimated hazard ratios of dichotomized analysis were calculated, together with 95% confidence intervals and p-values of Wald tests. Results: PD-L1 expression was ≥50% in 6 (20%) patients, whereas 19 (63%) had ≥1% expression and 5 (17%) tumor samples were PD-L1-negative. While sex and age had no impact on DFS or OS, <50% PD-L1 expression on tumor cells (TC) was associated with a significantly longer OS (log rank test p = 0.037; HR 0.275; 95% CI 0.073-1.03). There was no influence on DFS (log rank test p = 0.34; HR 0.599; 95% CI 0.208-1.728). However, <10% PD-L1 expression on tumor infiltrating lymphocytes (TILs) was correlated with a worse DFS (log rank test p = 0.0057; HR 4.06; 95% CI 1.389-11.868). LAG3 expression or the number of TILs did not play any prognostic role in our population. Conclusion: The PD-L1 expression rate on Caucasians was comparable to that in Asian patients. Although these results have to be interpreted with caution due to the limited number of Caucasian patients available, our data suggest that ≥50% PD-L1 expression on TC is associated with a poor outcome, while ≥10% PD-L1 expression on TILs is correlated with improved DFS. A prospective biomarker analysis of a predefined Caucasian NPC subpopulation would be desirable in future trials.

The circulating form of neprilysin is not a general biomarker for overall survival in treatment-naïve cancer patients.

The transmembrane zink-metalloendopeptidase neprilysin (NEP) is implicated in cardiovascular disease but also tumor biology. The aim of the study was to investigate the relationship of circulating NEP (cNEP) levels with established cardiovascular biomarkers and its effect on overall survival in an unselected cohort of treatment-naïve cancer patients. 555 consecutive cancer patients prior anticancer therapy were enrolled prospectively. NEP levels were determined alongside routine laboratory parameters, established cardiac biomarkers, i.e. NT-proBNP, hsTnT, MR-proANP, MR-proADM, CT-proET-1 and Copeptin, and inflammatory parameters, i.e. CRP, IL-6 and SAA, in venous plasma samples. All-cause mortality was the primary endpoint. cNEP levels of 276 pg/ml (IQR: 0-5981) displayed a weak inverse correlation with age [r = -0.12, p = 0.023] and inflammatory status [r = -0.14, p = 0.007 CRP; r = -0.20, p < 0.001 IL-6 and r = -0.18, p < 0.001 SAA]. cNEP was comparable between different tumor entities and stages and not related to functional parameters of other organ systems as kidney, liver or especially the heart. Moreover, cNEP was not associated with overall survival in the total cohort [adj.HR for ln (cNEP) 1.00, 95% CI: 0.94-1.06, p = 0.887] but in myelodysplatic malignancies [adj.HR for ln (cNEP) 1.27, 95% CI: 1.01-1.61, p = 0.044]. In conclusion, cNEP lacks association with outcome but for myelodysplastic disease. cNEP shows no correlation with established cardiovascular biomarkers related to prognosis, thereby holding a limited potential as a biomarker in cardio-oncology.