Decrease in treatment intensity predicts worse outcome in patients with locally advanced head and neck squamous cell carcinoma undergoing radiochemotherapy.

PURPOSE: Radiochemotherapy (RCT) is an effective standard therapy for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Nonetheless, toxicity is common, with patients often requiring dose modifications. METHODS: To investigate associations of RCT toxicities according to CTCAE version 5.0 and subsequent therapy modifications with short- and long-term treatment outcomes, we studied all 193 patients with HNSCC who received RCT (70 Gy + platinum agent) at an academic center between 03/2010 and 04/2018. RESULTS: During RCT, 77 (41%, 95% CI 34-49) patients developed at least one ≥ grade 3 toxicity, including seven grade 4 and 3 fatal grade 5 toxicities. The most frequent any-grade toxicities were xerostomia (n = 187), stomatitis (n = 181), dermatitis (n = 174), and leucopenia (n = 98). Eleven patients (6%) had their radiotherapy schedule modified (mean radiotherapy dose reduction = 12 Gy), and 120 patients (64%) had chemotherapy modifications (permanent discontinuation: n = 67, pause: n = 34, dose reduction: n = 7, change to other chemotherapy: n = 10). Objective response rates to RCT were 55% and 88% in patients with and without radiotherapy modifications (p = 0.003), and 84% and 88% in patients with and without chemotherapy modifications (p = 0.468), respectively. Five-year progression-free survival estimates were 20% and 50% in patients with and without radiotherapy modifications (p = < 0.001), and 53% and 40% in patients with and without chemotherapy modifications (p = 0.88), respectively. CONCLUSIONS: Reductions of radiotherapy dose were associated with impaired long-term outcomes, whereas reductions in chemotherapy intensity were not. This suggests that toxicities during RCT should be primarily managed by modifying chemotherapy rather than radiotherapy.

Critical evaluation of platelet size as a prognostic biomarker in colorectal cancer across multiple treatment settings: a retrospective cohort study.

PURPOSE: The role of mean platelet volume (MPV) as a predictor of outcomes in various cancer entities including colorectal cancer (CRC) has already been analyzed. However, data on the prognostic and predictive value of MPV in CRC over multiple lines of systemic therapy are missing. METHODS: In this retrospective single-center cohort study, 690 patients with UICC stage II, III or IV CRC receiving adjuvant and/or palliative chemotherapy were included. Primary endpoints in the adjuvant, palliative and best supportive care (BSC) setting were 3-year recurrence-free survival (RFS), 6-months progression-free survival (PFS), and 6-months overall survival (OS), respectively. Kaplan-Meier estimators, log-rank tests, and uni- and multivariable Cox models were used to analyze RFS, PFS and OS. A cut-off defining patients with low MPV was chosen empirically at the 25th percentile of the MPV distribution in the respective treatment setting. RESULTS: Three-year RFS was 76%. Median 6-month PFS estimates in 1st, 2nd and 3rd line therapy were 59, 37 and 27%, respectively. Median 6-month OS in BSC was 31%. Small platelets as indicated by low MPV did not predict for shorter RFS. In the first 3 palliative treatment lines a consistent association between low MPV and decreased 6-month PFS was not observed. In the BSC setting, patients with low MPV had numerically but not significantly shorter OS. Higher MPV levels did not consistently predict for ORR or DCR across the first 3 palliative treatment lines. CONCLUSION: Small platelets are not predicting CRC outcomes, and thus are hardly useful for influencing clinical decision making.

Combination of isocitrate dehydrogenase 1 (IDH1) mutation and podoplanin expression in brain tumors identifies patients at high or low risk of venous thromboembolism.

Essentials Risk stratification for venous thromboembolism (VTE) in patients with brain tumors is challenging. Patients with IDH1 wildtype and high podoplanin expression have a 6-month VTE risk of 18.2%. Patients with IDH1 mutation and no podoplanin expression have a 6-month VTE risk of 0%. IDH1 mutation and podoplanin overexpression in primary brain tumors appear to be exclusive. SUMMARY: Background Venous thromboembolism (VTE) is a frequent complication in primary brain tumor patients. Independent studies revealed that podoplanin expression in brain tumors is associated with increased VTE risk, whereas the isocitrate dehydrogenase 1 (IDH1) mutation is associated with very low VTE risk. Objectives To investigate the interrelation between intratumoral podoplanin expression and IDH1 mutation, and their mutual impact on VTE development. Patients/Methods In a prospective cohort study, intratumoral IDH1 R132H mutation and podoplanin were determined in brain tumor specimens (mainly glioma) by immunohistochemistry. The primary endpoint of the study was symptomatic VTE during a 2-year follow-up. Results All brain tumors that expressed podoplanin to a medium-high extent showed also an IDH1 wild-type status. A score based on IDH1 status and podoplanin expression levels allowed prediction of the risk of VTE. Patients with wild-type IDH1 brain tumors and high podoplanin expression had a significantly increased VTE risk compared with those with mutant IDH1 tumors and no podoplanin expression (6-month risk 18.2% vs. 0%). Conclusions IDH1 mutation and podoplanin overexpression seem to be exclusive. Although brain tumor patients with IDH1 mutation are at very low risk of VTE, the risk of VTE in patients with IDH1 wild-type tumors is strongly linked to podoplanin expression levels.

Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients.

Essentials Neutrophil extracellular traps (NETs) might play a role in cancer-related coagulopathy. We determined NET biomarkers and followed cancer patients for venous thromboembolism (VTE). We found a constant association with VTE for citrullinated histone H3. Biomarkers of NET formation could reflect a novel pathomechanism of cancer-related VTE. SUMMARY: Background Neutrophil extracellular traps (NETs) are decondensed chromatin fibers that might play a role in the prothrombotic state of cancer patients. Objectives To investigate whether the levels of citrullinated histone H3 (H3Cit), a biomarker for NET formation, cell-free DNA (cfDNA) and nucleosomes predict venous thromboembolism (VTE) in cancer patients. Patients/Methods Nine-hundred and forty-six patients with newly diagnosed cancer or progression after remission were enrolled in this prospective observational cohort study. H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients were followed for 2 years. VTE occurred in 89 patients; the cumulative 3-month, 6-month, 12-month and 24-month incidence rates of VTE were 3.7%, 6.0%, 8.1%, and 10.0%, respectively. Results Patients with elevated H3Cit levels (> 75th percentile of its distribution, n = 236) experienced a higher cumulative incidence of VTE (2-year risk of 14.5%) than patients with levels below this cut-off (2-year risk of 8.5%, n = 710). In a competing-risk regression analysis, a 100 ng mL-1 increase in H3Cit level was associated with a 13% relative increase in VTE risk (subdistribution hazard ratio [SHR] 1.13, 95% confidence interval [CI] 1.04-1.22). This association remained after adjustment for high VTE risk and very high VTE risk tumor sites, D-dimer level, and soluble P-selectin level (SHR 1.13, 95% CI 1.04-1.22). The association of elevated nucleosome and cfDNA levels with VTE risk was time-dependent, with associations with a higher risk of VTE only during the first 3-6 months. Conclusion These data suggest that biomarkers of NET formation are associated with the occurrence of VTE in cancer patients, indicating a role of NETs in the pathogenesis of cancer-associated thrombosis.

Long-term cardiovascular complications in stage I seminoma patients

Purpose. The cure rate of stage I seminoma patients is close to 100% and so the recent focus of clinical research has shifted onto the prevention of treatment-related complications. We assessed long-term cardiovascular complications and identified risk factors for cardiovascular events (CVEs) in stage I seminoma patients. Methods. This retrospective cohort study included 406 consecutive stage I seminoma patients. Primary endpoint was CVE rate. Results. During a median follow-up of 8.6 years, we observed 23 CVEs in 406 patients [10-year CVE risk 5.6% (95% CI 3.2 to 8.8)]. In univariable competing risk analysis, higher age, positive smoking status, history of diabetes and hypertension were significantly associated with the occurrence of CVE. In multi-state analysis, new onset of diabetes, hypertension and hyperlipidemia during follow-up predicted for an excessively increased CVE risk. In multivariable analysis adjusting for age and smoking, the development of hypertension and hyperlipidemia after tumor-specific treatment prevailed as risk factors for CVE. Regarding adjuvant treatment modalities, patients receiving adjuvant radiotherapy had a significantly higher probability of CVE than patients receiving adjuvant carboplatin [16% vs. 0%; risk difference (RD) = 16%, 95% CI 6 to 25%, p = 0.001]. This difference prevailed after adjusting for age, follow-up-time, diabetes, hypertension and smoking (RD = 11%, 95% CI 1 to 20%, p = 0.025). Conclusion. We identified a panel of baseline risk factors and dynamically, occurring predictors of CVE in stage I seminoma patients. This information may be used for targeting comorbidity management in these patients. The observed association of adjuvant radiotherapy with higher CVE risk warrants further investigation (AU)

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Long-term cardiovascular complications in stage I seminoma patients.

PURPOSE: The cure rate of stage I seminoma patients is close to 100% and so the recent focus of clinical research has shifted onto the prevention of treatment-related complications. We assessed long-term cardiovascular complications and identified risk factors for cardiovascular events (CVEs) in stage I seminoma patients. METHODS: This retrospective cohort study included 406 consecutive stage I seminoma patients. Primary endpoint was CVE rate. RESULTS: During a median follow-up of 8.6 years, we observed 23 CVEs in 406 patients [10-year CVE risk 5.6% (95% CI 3.2 to 8.8)]. In univariable competing risk analysis, higher age, positive smoking status, history of diabetes and hypertension were significantly associated with the occurrence of CVE. In multi-state analysis, new onset of diabetes, hypertension and hyperlipidemia during follow-up predicted for an excessively increased CVE risk. In multivariable analysis adjusting for age and smoking, the development of hypertension and hyperlipidemia after tumor-specific treatment prevailed as risk factors for CVE. Regarding adjuvant treatment modalities, patients receiving adjuvant radiotherapy had a significantly higher probability of CVE than patients receiving adjuvant carboplatin [16% vs. 0%; risk difference (RD) = 16%, 95% CI 6 to 25%, p = 0.001]. This difference prevailed after adjusting for age, follow-up-time, diabetes, hypertension and smoking (RD = 11%, 95% CI 1 to 20%, p = 0.025). CONCLUSION: We identified a panel of baseline risk factors and dynamically, occurring predictors of CVE in stage I seminoma patients. This information may be used for targeting comorbidity management in these patients. The observed association of adjuvant radiotherapy with higher CVE risk warrants further investigation.

OC-16 - Neutrophil extracellular traps and tissue factor-bearing microvesicles: a liaison dangereuse causing overt DIC in cancer patients?

INTRODUCTION: Overt disseminated intravascular coagulation (DIC) is a systemic process characterized by excessive coagulation activation and fibrinolysis that may occur in cancer patients. The underlying pathomechanisms are still poorly understood. Recent experimental studies found an important role for the interaction between procoagulant neutrophil extracellular traps (NETs) and tissue factor (TF) in the pathogenesis of thrombosis. AIM: To investigate whether NETs and TF-bearing microvesicles (MVs) play a central role in cancer-related overt DIC. MATERIALS AND METHODS: Twenty-eight cancer patients with overt DIC (ISTH score ≥5, 14 females, median age: 62 years [range: 21-80], 13 with solid tumors, 15 with acute leukemia) and 28 matched healthy controls were included. NET formation parameters (plasma DNA and nucleosomes), MVassociated TF activity, and routine coagulation parameters were determined at study inclusion. In 11 patients with acute myeloid leukemia (AML), follow-up measurements were also performed. RESULTS: Plasma DNA, nucleosomes, and MV-TF activity were highly elevated in patients with cancer-related DIC compared to healthy individuals (all p-values<0.001). Strong correlations were found between plasma DNA and nucleosomes (Spearman correlation-coefficient: r=0.68), nucleosomes and MV-TF activity (r=0.62), and DNA and MV-TF activity (r=0.57). In multivariate regression, altered routine coagulation parameters were highly associated with NET parameters and MV-TF activity. In detail, a doubling in plasma DNA was associated with a 7.6% decrease in fibrinogen (p=0.012), a 15.3% decrease in platelet count (p=0.002), a 3.9% decrease in prothrombin time (p=0.014), and a 41.0% increase in D-dimer (p<0.001). A 10% increase in nucleosomes was associated with a 3.1% decrease in fibrinogen (p<0.001), a 5.0% decrease in platelet count (p<0.001), a 1.0% decrease in prothrombin time (p<0.009), and a 112.7% increase in D-dimer (p<0.001). A 10% increase in MV-TF activity was associated with a 4.9% decrease in fibrinogen (p<0.001), a 7.1% decrease in platelet count (p<0.001), a 1.3% decrease in prothrombin time (p<0.001), and a 15.5% increase in D-dimer (p<0.001). After initiation of chemotherapy in AML patients, NET parameters and MV-TF activity decreased significantly (nucleosomes: 3.3-fold decrease and normalization after 1 week; DNA: 1.2-fold decrease after 1 week and 1.5-fold decrease after 1 month; MV-TF activity: 10-fold decease after 1 week and normalization after 1 month) (Figure 1), and routine coagulation parameters improved. CONCLUSIONS: Our results add to experimental studies that have investigated the interaction between NETs and TF. Taken together, evidence indicates the presence of a liaison dangereuse between NETs and TF-bearing MVs, which could be the underlying cause of cancer-related overt DIC.

Plasma clot properties in patients with a mild-to-moderate bleeding tendency of unknown cause.

In a large proportion of patients with mild bleeding disorders (MBDs) no diagnosis can be established by routine coagulation tests. We investigated whether alterations in plasma clot properties account for MBDs of unknown cause. Ninety-five patients with MBDs of unknown origin and 98 age- and sex-matched healthy controls were investigated. Furthermore, data of 25 patients with a deficiency of factor VIII were analyzed. Plasma clot characteristics in the absence and presence of recombinant tissue plasminogen activator (rtPA) represented by the lag phase, rate of protofibril formation (Vmax), fibrin structure (ΔAbs), time to peak (TTP), half lysis time (t50 and area under the curve (AUC) were measured in turbidometric clot formation and lysis assays. In the fibrinolysis assay, Vmax was lower in patients than in healthy controls. No differences in the other parameters of clot formation and lysis were detected between the groups. There was no clear association of plasma clot properties with the clinical severity of bleeding in patients with MBDs. Patients with known decreased factor VIII levels also showed a lower Vmax. Fibrinogen levels were positively associated with each of the assessed parameters in both groups, with the strongest association with ΔAbs, indicating altered fibrin structure. Factor VIII activity correlated with altered clot characteristics similar to fibrinogen, especially in patients, with the strongest positive correlation to Vmax. This cohort of patients with MBDs of unknown origin showed a lower rate of fibrin formation in the fibrinolysis assay, but otherwise similar plasma clot properties compared to healthy controls.

Estimating risk of venous thromboembolism in patients with cancer in the presence of competing mortality.

BACKGROUND: In studies on cancer-associated venous thromboembolism (VTE), patients not only are at risk for VTE but also may die from their underlying malignancy. OBJECTIVES: In this competing-risk (CR) scenario, we systematically compared the performance of standard (Kaplan-Meier estimator [1-KM]), log-rank test, and Cox model) and specific CR methods for time-to-VTE analysis. PATIENTS AND METHODS: Cancer patients (1542) were prospectively followed for a median of 24 months. VTE occurred in 112 (7.3%) patients, and 572 (37.1%) patients died. RESULTS: In comparison with the CR method, 1-KM slightly overestimated the cumulative incidence of VTE (cumulative VTE incidence at 12 and 24 months [1-KM vs. CR]: 7.22% vs. 6.74%, and 8.40% vs. 7.54%, respectively). Greater bias was revealed in tumor entities with high early mortality (e.g., pancreatic cancer, n = 99, 24-month cumulative VTE incidence: 28.37% vs. 19.30%). Comparing the (subdistribution) hazard of VTE between patients with low and high baseline D-dimer, the Cox model yielded a higher estimate than the corresponding CR model (hazard vs. subdistribution hazard ratio [95% CI] 2.85 [1.92-4.21] vs. 2.47 [1.67-3.65]). For this comparison, the log-rank test yielded a higher test statistic and smaller P-value than Gray's test (χ(2) on 1 degree of freedom: 29.88 vs. 21.34). CONCLUSION: In patients with cancer who are at risk for VTE and death, standard and CR methods for time-to-VTE analysis can generate differing results. For 1-KM, the magnitude of bias is a direct function of competing mortality. Consequently, bias tends to be negligible in cancer patient populations with low mortality but can be considerable in populations at high risk of death.

Single-stage revision for the infected total knee replacement: results from a single centre.

Peri-prosthetic infection is amongst the most common causes of failure following total knee replacement (TKR). In the presence of established infection, thorough joint debridement and removal of all components is necessary following which new components may be implanted. This can be performed in one or two stages; two-stage revision with placement of an interim antibiotic-loaded spacer is regarded by many to be the standard procedure for eradication of peri-prosthetic joint infection. We present our experience of a consecutive series of 50 single-stage revision TKRs for established deep infection performed between 1979 and 2010. There were 33 women and 17 men with a mean age at revision of 66.8 years (42 to 84) and a mean follow-up of 10.5 years (2 to 24). The mean time between the primary TKR and the revision procedure was 2.05 years (1 to 8). Only one patient required a further revision for recurrent infection, representing a success rate of 98%. Nine patients required further revision for aseptic loosening, according to microbiological testing of biopsies taken at the subsequent surgery. Three other patients developed a further septic episode but none required another revision. These results suggest that a single-stage revision can produce comparable results to a two-stage revision. Single-stage revision offers a reduction in costs as well as less morbidity and inconvenience for patients.

Serum integrin-linked kinase (sILK) concentration and survival in non-small cell lung cancer: a pilot study

BACKGROUND: Integrin-linked kinase (ILK) is an intracellular signaling protein critically involved in cellular growth and motility. In non-small cell lung cancer (NSCLC), increased ILK expression has been associated with decreased recurrence-free and overall survival. Recently, ILK has also been detected in the serum of NSCLC patients. OBJECTIVE: To assess the prognostic impact of preoperative serum ILK (sILK) concentration on overall survival in surgically amenable NSCLC. PATIENTS AND METHODS: Preoperative sILK was quantified by ELISA in 50 newly diagnosed NSCLC patients. After surgery, patients were followed-up for a median interval of 2.5 years. RESULTS: Serum ILK concentrations ranged from 0 to 2.44 ng/ml. Mean sILK was around 2.3 times higher in the 16 patients who died as compared to the 34 patients who survived (1.04 vs. 0.45 ng/ml, p = 0.001). In univariate time-to-event analysis, increased sILK was associated with adverse survival [Hazard ratio (HR): 4.03, 95 % CI: 2.00-8.13, p < 0.001]. This association prevailed after multivariable adjustment for several clinical, demographic, and laboratory parameters (HR: 3.85, 95 % CI: 1.53-9.72, p = 0.004). CONCLUSIONS: Serum ILK shows potential as a novel strong and independent prognostic marker for postoperative survival in surgically amenable NSCLC (AU)

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Serum integrin-linked kinase (sILK) concentration and survival in non-small cell lung cancer: a pilot study.

BACKGROUND: Integrin-linked kinase (ILK) is an intracellular signaling protein critically involved in cellular growth and motility. In non-small cell lung cancer (NSCLC), increased ILK expression has been associated with decreased recurrence-free and overall survival. Recently, ILK has also been detected in the serum of NSCLC patients. OBJECTIVE: To assess the prognostic impact of preoperative serum ILK (sILK) concentration on overall survival in surgically amenable NSCLC. PATIENTS AND METHODS: Preoperative sILK was quantified by ELISA in 50 newly diagnosed NSCLC patients. After surgery, patients were followed-up for a median interval of 2.5 years. RESULTS: Serum ILK concentrations ranged from 0 to 2.44 ng/ml. Mean sILK was around 2.3 times higher in the 16 patients who died as compared to the 34 patients who survived (1.04 vs. 0.45 ng/ml, p = 0.001). In univariate time-to-event analysis, increased sILK was associated with adverse survival [Hazard ratio (HR): 4.03, 95 % CI: 2.00-8.13, p < 0.001]. This association prevailed after multivariable adjustment for several clinical, demographic, and laboratory parameters (HR: 3.85, 95 % CI: 1.53-9.72, p = 0.004). CONCLUSIONS: Serum ILK shows potential as a novel strong and independent prognostic marker for postoperative survival in surgically amenable NSCLC.

Resistance to EGFR targeting therapies in lung cancer.

The treatment of advanced non-small cell lung cancer (NSCLC) by therapies targeting the epidermal growth factor receptor (EGFR) pathway represents one of the most important advances in thoracic oncology. Reversible EGFR tyrosine kinase inhibitors (TKIs), like gefitinib and erlotinib, are able to achieve dramatic responses in a subset of patients. However, most patients treated with TKIs eventually develop resistance against these drugs. Here we review the physiology and pathology of EGFR activation in NSCLC, the clinical experience with TKIs, the mechanisms of resistance against TKIs, and discuss various approaches to treat resistance against TKIs.