Crevasse accidents in the Swiss Alps Epidemiology and mortality of 405 victims of crevasse accidents from 2010 to 2020.

INTRODUCTION: The clinical spectrum of injuries in crevasse accidents can range from benign to life-threatening, even including death. To date, little is known about incidence and causes. METHODS: We retrospectively analyzed mountain rescue missions that included crevasse accidents and took place in Switzerland from 2010 to 2020. Demographic and epidemiological data were collected. Injury severity was graded according to the National Advisory Committee for Aeronautics (NACA) score. Winter season was defined as December to May, and summer season as June to November. RESULTS: A total of 321 victims of crevasse falls were included in the study. The median age of victims was 41.2 years (interqauartile range [IQR] 31.3 to 51.6), with 82% (n=260) being male and 59% (n=186) foreigners. The typical altitude range at which rescue missions were performed was between 3000 and 3499m (44% of all cases). The median depth of the fall was 15 meters (IQR 8 to 20) during the winter season compared to 8 meters (IQR 5 to 10) during the summer, p<0.001. Overall mortality was 6.5%. The NACA score was ≥4 for 9.4% (n=30) of the victims. 55% (n=177) had a NACA score of 0 or 1. There was a significant positive correlation between the depth of fall and the injury severity (Pearson`s correlation r=0.35, 95%- confidence interval: 0.18 to 0.51), p<0.001. CONCLUSION: More than half of victims fallen into a crevasse are uninjured or sustain mild injury. Life-threathening injuries were found in about 10% of victims and the crevasse fall was fatal in 6.5% of cases. Injury severity positively correlates with the depth of fall, which is higher during winter season.

Sensitive and robust liquid biopsy-based detection of PIK3CA mutations in hormone-receptor-positive metastatic breast cancer patients.

BACKGROUND: The benefit of alpelisib in hormone-receptor-positive (HR+) metastatic breast cancer patients provided clinical evidence for the increasing importance of PIK3CA testing. We performed a comparison of liquid biopsy and tissue-based detection of PIK3CA mutations. MATERIALS AND METHODS: PIK3CA hotspot mutation analysis using a high-resolution SiMSen-Seq assay was performed in plasma from 93/99 eligible patients with HR+/HER2- breast cancer. Additionally, mFAST-SeqS was used to estimate the tumour fractions in plasma samples. In 72/93 patients, matched tissue was available and analysed using a customised Ion Torrent panel. RESULTS: PIK3CA mutations were detected in 48.6% of tissue samples and 47.3% of plasma samples, with identical PIK3CA mutation detected in 24/72 (33.3%) patients both in tissue and plasma. In 10 (13.9%) patients, mutations were only found in plasma, and in 6 (8.3%) patients, PIK3CA mutations found in tissue were not detectable in ctDNA. In 49/93 plasma samples without detectable PIK3CA mutations, 22 (44.9%) samples had elevated tumour fractions, implying true negative results. CONCLUSION: SiMSen-Seq-based detection of PIK3CA mutations in plasma shows advantageous concordance with the tissue analyses. A combination with an untargeted approach for detecting ctDNA fractions may confirm a negative PIK3CA result and enhance the performance of the SiMSen-Seq test.

The value of MRI compared to conventional radiography in analysing morphologic changes in the spine in axial spondyloarthritis.

BACKGROUND: Imaging of morphologic changes in the vertebral spine in axial spondyloarthritis (SpA) is routinely performed with conventional radiography limited by superposition in the thoracic segments and radiation exposure. The objective was to assess the reliability of MRI compared to conventional radiography in depicting morphologic vertebral lesions in patients with axial SpA. Forty patients diagnosed with axial SpA were included in this cross-sectional study. Patients underwent MRI of the whole spine with T1-weighted and TIRM sequences in the sagittal plane and conventional radiography of the cervical and lumbar spine in lateral projections. Morphologic changes (syndesmophytes and erosions) in the anterior vertebral endplates on MRI and conventional radiography were independently evaluated by two radiologists. Inter-modality and interobserver agreement were calculated using Cohen's Kappa. RESULTS: Inter-modality agreement was low for cervical and lumbar syndesmophytes and erosions (κ ≤ 0.2 ± 0.07-0.1). Interobserver agreement on conventional radiography was highest for cervical and lumbar anterior syndesmophytes/bridging (κ = 0.92 ± 0.02-0.03). Syndesmophytes in thoracic anterior vertebral units were the most frequent MRI finding with a high interobserver agreement (κ = 0.83 ± 0.05). CONCLUSIONS: In imaging morphologic changes in the spine in patients with axial SpA, MRI was shown to be not an equivalent substitute but a complementary imaging modality to conventional radiography. Conventional radiography seems superior to depict morphologic cervical and lumbar vertebral changes compared to MRI, whereas MRI may visualise morphologic lesions in the thoracic spine.

Patterns of Recurrence after Neoadjuvant Therapy in Early Breast Cancer, according to the Residual Cancer Burden Index and Reductions in Neoadjuvant Treatment Intensity.

BACKGROUND: The prognostic performance of the residual cancer burden (RCB) score is a promising tool for breast cancer patients undergoing neoadjuvant therapy. We independently evaluated the prognostic value of RCB scores in an extended validation cohort. Additionally, we analyzed the association between chemotherapy dose reduction and RCB scores. METHODS: In this extended validation study, 367 breast cancer patients with available RCB scores were followed up for recurrence-free survival (RFS), distant disease-free survival (DDFS), and overall survival (OS). We also computed standardized cumulative doses of anthracyclines and taxanes (A/Ts) to investigate a potential interaction between neoadjuvant chemotherapy dose reduction and RCB scores. RESULTS: Higher RCB scores were consistently associated with adverse clinical outcomes across different molecular subtypes (HR for RFS = 1.60, 95% CI 1.33-1.93, p < 0.0001; HR for DDFS = 1.70, 95% CI 1.39-2.05, p < 0.0001; HR for OS = 1.67, 95% CI 1.34-2.08, p < 0.0001). The adverse impact prevailed throughout 5 years of follow-up, with a peak for relapse risk between 1-2 years after surgery. Clinical outcomes of patients with RCB class 1 did not differ substantially at 5 years compared to RCB class 0. A total of 180 patients (49.1%) underwent dose reduction of neoadjuvant A/T chemotherapy. We observed a statistically significant interaction between dose reduction and higher RCB scores (interaction p-value = 0.042). CONCLUSION: Our results confirm RCB score as a prognostic marker for RFS, DDFS, and OS independent of the molecular subtype. Importantly, we show that lower doses of cumulative neoadjuvant A/T were associated with higher RCB scores in patients who required a dose reduction.

Safety and Clinical Evaluation of Dual Inhibition with Pertuzumab and Trastuzumab Biosimilar SB3 in HER2-Positive Breast Cancer Patients.

BACKGROUND: The addition of trastuzumab to standard chemotherapy has improved survival in patients with HER2-positive breast cancer in neoadjuvant, adjuvant, and metastatic settings. In higher tumor stages, the addition of pertuzumab is now a standard of care and associated with a favorable toxicity profile. We evaluated the safety and efficacy of the trastuzumab biosimilar SB3 in combination with pertuzumab in HER2-positive breast cancer patients. METHODS: Seventy-eight patients with HER2-positive breast cancer treated at the Division of Oncology at the Medical University of Graz were included. Summary measures are reported as medians (25th to 75th percentile) for continuous variables and as absolute frequencies (%) for count data. RESULTS: Thirty-five patients received a median of 4 (3-7) cycles of trastuzumab biosimilar SB3 plus pertuzumab. All patients had a normal baseline left ventricular ejection fraction (LVEF; >50%) prior to the initiation of SB3 plus pertuzumab treatment with a median LVEF of 60% (60-65). Twenty-one patients had a median absolute LVEF decline of 1% (-5 to 0). Two patients (5.7%) had a LVEF reduction ≤50%, but none ≥10%. There were no unexpected adverse events. Twenty-two of 35 patients (63%) were treated with trastuzumab biosimilar SB3 and pertuzumab in the neoadjuvant setting and 11 patients (50%) achieved a pathological complete response. The safety and the efficacy in this setting was comparable to the trastuzumab plus pertuzumab combination in neoadjuvantly treated matched samples. CONCLUSION: In this series of HER2-positive breast cancer patients, the combination of SB3 plus pertuzumab was consistent with the known safety and efficacy profile of trastuzumab and pertuzumab combination.

Longitudinal tumor fraction trajectories predict risk of progression in metastatic HR+ breast cancer patients undergoing CDK4/6 treatment.

Despite improved clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitor treatment has limited the success of this treatment in HR+ HER2- metastatic breast cancer patients. Biomarkers are urgently needed, and longitudinal biomarker measurements may harbor more dynamic predictive and prognostic information compared to single time point measurements. The aim of this study was to explore the longitudinal evolution of circulating tumor fractions within cell-free DNA assessed by an untargeted sequencing approach during CDK4/6 therapy and to quantify the potential association between longitudinal z-score measurements and clinical outcome by using joint models. Forty-nine HR+ HER2- metastatic breast cancer patients were enrolled, and z-score levels were measured at baseline and during 132 follow-up visits (median number of measurements per patient = 3, 25th -75th percentile: 3-5, range: 1-8). We observed higher baseline z-score levels (estimated difference 0.57, 95% CI: 0.147-0.983, P-value = 0.008) and a constant increase of z-score levels over follow-up time (overall P-value for difference in log z-score over time = 0.024) in patients who developed progressive disease. Importantly, the joint model revealed that elevated z-score trajectories were significantly associated with higher progression risk (HR of log z-score at any time of follow-up = 3.3, 95% CI, 1.44-7.55, P = 0.005). In contrast, single z-score measurement at CDK4/6 inhibitor treatment start did not predict risk of progression. In this prospective study, we demonstrate proof-of-concept that longitudinal z-score trajectories rather than single time point measurements may harbor important dynamic information on the development of disease progression in HR+ HER2- breast cancer patients undergoing CDK4/6 inhibitor treatment.

The Lipase/Amylase Ratio (LAR) in Peripheral Blood Might Represent a Novel Prognostic Marker in Patients with Surgically Resectable Pancreatic Cancer.

Pancreatic enzymes might play a pivotal role in the pathophysiology and prognosis of pancreatic cancer. The aim of this study is to investigate the lipase/amylase ratio (LAR), representing a marker previously used in the differentiation of pancreatitis, as a potential prognostic marker in pancreatic cancer. Data from 157 surgically treated patients with ductal pancreatic adenocarcinoma and 351 patients with metastatic disease were evaluated retrospectively. Cancer-specific survival (CSS) was considered the endpoint of the study. After applying Kaplan-Meier curve analysis, uni- and multivariate Cox regression models were calculated to evaluate the prognostic relevance of LAR. An elevated LAR at diagnosis of localized pancreatic cancer was significantly associated with higher CA19-9 levels (p < 0.05). In univariate analysis, we observed an increased LAR as a significant factor for lower CSS in localized pancreatic cancer patients (HR = 1.63; 95% CI = 1.12-2.36; p = 0.01), but not in metastatic patients (HR = 1.12; 95% CI = 0.87-1.43; p = 0.363). In multivariate analysis, including age, gender, tumor stage, Karnofsky Performance Status, tumor grade, administration of chemotherapy and the LAR, an increased LAR was confirmed to represent an independent prognostic factor regarding CSS (HR = 1.81; 95% CI = 1.17-2.77; p = 0.007) in localized pancreatic cancer patients. In conclusion, our study identified the LAR as an independent prognostic factor in surgically treated pancreatic cancer patients.

External validation of the prognostic relevance of the advanced lung cancer inflammation index (ALI) in pancreatic cancer patients.

BACKGROUND: The advanced lung cancer inflammation index (ALI) was first introduced for prognosis prediction in lung cancer patients and since then evaluated in several other malignancies. However, in pancreatic cancer (PC) the ALI and its prognostic utility were only investigated in a comparably small and specific cohort of locally advanced PC patients treated with chemoradiotherapy. METHODS: In our single-center cohort study, we included 429 patients with histologically verified PC who were treated between 2003 and 2015 at our academic institution. The ALI was defined as body mass index (BMI; kg/m2 ) × serum albumin levels (g/dL)/neutrophil-lymphocyte ratio (NLR) and we defined the optimal cutoff for biomarker dichotomization by ROC-analysis. Kaplan-Meier method as well as uni- and multivariate Cox regression Hazard proportional models were implemented to assess the prognostic potential of ALI in PC patients. We considered cancer-specific survival (CSS) as the primary endpoint of the study. RESULTS: The ALI showed a significant negative correlation with CA19-9 levels and C-reactive protein levels whereas we found an association with localized tumor stage and better performance status (P < .05 for all mentioned variables). As opposed to patients with a high ALI, decreased ALI was significantly associated with shorter CSS (HR = 0.606, 95% CI: 0.471-0.779, P = .001). Multivariate analysis demonstrated tumor grade, tumor stage, chemotherapy, C-reactive protein levels, and CA19-9 levels to independently predict for CSS (all P < .05). In contrast the ALI failed to independently predict for CSS in the performed multivariate models (HR = 0.878, 95% CI: 0.643-1.198, P = .411). CONCLUSION: In this large cohort of PC patients, the ALI did not complement existing clinicopathological factors for outcome determination.

Decreased Activity of Circulating Butyrylcholinesterase in Blood Is an Independent Prognostic Marker in Pancreatic Cancer Patients.

Introduction: The activity of butyrylcholinesterase (BChE) in blood reflects liver function and has recently been associated with systemic inflammatory response and tumor cachexia. As these conditions have been previously linked with pancreatic cancer (PC), the purpose of the present study was to evaluate the prognostic impact of plasma BChE in PC. Methods: Data from 574 consecutive PC patients, treated between 2004 and 2018 at a single academic center, was evaluated. The primary endpoint was cancer-specific survival (CSS), analyzed by Kaplan-Meier curve, and both univariate and multivariate Cox proportional models. Results: BChE activity negatively correlated with other liver parameters (bilirubin, gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and C-reactive protein (CRP)), and positively correlated with albumin levels, respectively (p < 0.01). In univariate analysis, a low plasma BChE activity was a factor of poor CSS (hazard ratio: 1.4, 95% confidence interval: 1.129-1.754, p = 0.002). In multivariate analysis, tumor stage, tumor grade, administration of chemotherapy, bilirubin levels and a low BChE activity (hazard ratio: 1.42, 95% confidence interval: 1.10-1.82; p = 0.006) were identified as independent prognostic factors. Conclusion: Decreased activity of BChE in blood plasma predicts shorter survival time in PC patients. Therefore, BChE might be helpful in additional stratification of patients into different prognostic risk groups.

Biomarkers in Her2- Positive Disease.

BACKGROUND: Breast cancer is a heterogeneous disease with well-known characteristics such as hormone receptor (HR) status and human epidermal growth factor (Her)2 status. Although Her2 represents an established treatment target, the development of resistance mechanisms during treatment, cardiotoxicity, and a worse response to standard therapies lead to worse outcomes. SUMMARY: Therefore, we investigated various biomarkers in breast cancer such as Her2 mutations, Her2 heterogeneity, HR, PIK3CA, PTEN, programmed death receptor ligand 1 (PD-L1), tumor-infiltrating lymphocytes (TIL), micro RNA (miRNA), and BRCA mutations with regard to their clinical impact in Her2-positive disease. HR status and Her2 status, such as the presence of PIK3CA mutations, already play a role in treatment decision-making processes, whereas other biomarkers like PD-L1 status or TIL represent promising future markers. The influence of BRCA mutations in Her2-positive disease, Her2 mutations, and the impact of miRNA is vague to date. Antibody-drug conjugates (ADC) such as T-DM have been established as important treatment strategies, especially in Her2-positive disease. KEY MESSAGE: However, up-to-date biomarkers appropriate for clinical practice are missing. Further studies are needed.

Large platelet size is associated with poor outcome in patients with metastatic pancreatic cancer.

Background Platelets are a major cellular component of blood and their interaction with cancer cells is well-established to influence cancer progression and metastases. The physical size of platelets may have a critical impact on the interaction with cancer cells. In this study, we explored the potential prognostic role of platelet size measured by the determination of the mean platetlet volume (MPV) in patients with pancreatic ductal adenocarcinoma (PDAC). Methods Data from 527 patients with PDAC diagnosed and treated between 2004 and 2015 at a single center were evaluated retrospectively. Associations between MPV and baseline covariates were assessed with Wilcoxon's rank-sum tests, χ2-tests, and Fisher's exact tests. Median follow-up was estimated with a reverse Kaplan-Meier estimator according to Schemper and Smith. Analysis of time-to-death was performed with Kaplan-Meier estimators, log-rank tests and uni- and multivariable Cox proportional hazards models. Results The median MPV was 10.5 femto liter (fL) [9.8-11.3], ranged from 5.9 to 17.7 fL. A large platelet volume was associated with high-grade G3/4 tumors (p=0.004) and worse overall survival (OS) in patients with metastatic disease in univariable analysis (hazard ratio [HR] per fL increase in MPV=1.13 [95% CI: 1.04-1.23, p=0.005]). In multivariable analysis of metatatic PDAC patients, the adverse association between large platelets and a higher risk-of-death prevailed (adjusted HR per doubling of MPV=2.00; 95% CI: 1.10-3.62, p=0.02). Conclusions Large platelets represent a negative prognostic factor and add an independent prognostic information to well-established factors in PDAC patients. MPV should be considered for future individual risk assessment in patients with stage IV PDAC.

One-year clinical outcome after ablation with a novel multipolar irrigated ablation catheter for treatment of atrial fibrillation: potential implications for clinical use.

AIMS: Pulmonary vein isolation (PVI) is an established therapy for atrial fibrillation (AF). However, PVI remains a time-consuming procedure. A novel multipolar irrigated radiofrequency (RF) ablation catheter (nMARQ™) is aiming to improve PVI. We investigated the influence on procedural parameters and assessed clinical outcomes after PVI using this novel catheter. METHODS AND RESULTS: Fifty-eight consecutive patients with paroxysmal AF were equally allocated (n = 29/group) to PVI treatment with (i) the novel multipolar ablation catheter (nMARQ™) and (ii) a standard single-tip ablation catheter (SAC). Study endpoints included procedure time, fluoroscopy time, radiation dose, RF time, number of energy applications, and clinical outcome defined as freedom from AF after a single procedure. Successful PVI was confirmed by a separate circular, multipolar mapping catheter in all patients treated with the nMARQ™. Pulmonary vein isolation was achieved in 100% in the SAC group. In the nMARQ™ group, PVI was suggested in all patients. However, confirmatory mapping revealed persistent pulmonary vein (PV) conduction in 19 out of 29 nMARQ™ patients. These patients underwent further ablation, which still failed to achieve PVI in 5 of the 29 nMARQ™ patients, mainly due to significant temperature rise in the oesophagus and device-related limitations reaching the right inferior PV. Mean fluoroscopy time (31 ± 12 vs. 23 ± 10 min, P < 0.05) and (132 ± 37 vs. 109 ± 30 min, P < 0.05) were longer in nMARQ™ vs. SAC patients. Radiofrequency time was shorter in nMARQ™ vs. SAC group (21 ± 9 vs. 35 ± 12 min, P < 0.001). Radiation dose and the number of energy applications did not differ between both groups. Clinical outcome analysis revealed no significant differences (nMARQ™: 72 vs. SAC: 72%) after a mean follow-up of 373 ± 278 days. CONCLUSION: The use of the nMARQ™ catheter is associated with important device-related limitations to achieve successful PVI. However, clinical outcomes were equivalent in nMARQ™- and SAC-treated patients.