High-resolution nerve ultrasound and corneal confocal microscopy in taxane-induced polyneuropathy.

BACKGROUND AND PURPOSE: The role of high-resolution nerve ultrasound (HRUS) and corneal confocal microscopy (CCM) in the early detection of taxane-induced polyneuropathy (TIPN) is unclear. The present prospective longitudinal controlled observational pilot study estimates the role of HRUS and CCM in the early diagnosis of TIPN in breast cancer patients. METHODS: Fifteen breast cancer patients receiving paclitaxel and 15 healthy age matched controls were included. Visits before and 3 weeks, 8 weeks and 6 months after treatment included clinical examination, the total neuropathy score, nerve conduction studies (NCS), monocular CCM including corneal nerve fibre length, density and branching and HRUS of bilateral median, ulnar, radial, tibial, peroneal and sural nerves. Patients were compared between different visits and to healthy controls. RESULTS: Total neuropathy score increased from 2.2 at baseline to 5.8 (p < 0.001) at week 8. NCS showed a decreased sensory amplitude in the sural, radial, ulnar and median nerve after 6 months (p < 0.001). HRUS revealed a significant increase of cross-sectional area in the sural nerve (p = 0.004), the median nerve (p = 0.003) at the carpal tunnel and the ulnar nerve in the forearm (p = 0.006) after 6 months. CCM showed no changes at different visits. CONCLUSIONS: Corneal confocal microscopy and HRUS do not detect early signs of TIPN during the paclitaxel treatment period. HRUS and NCS might detect congruent signs of an axonal, predominantly sensory polyneuropathy after 6 months. The clinical examination remains the most sensitive tool in the early detection of TIPN in breast cancer patients.

Use and effectiveness of remdesivir for the treatment of patients with covid-19 using data from the Lean European Open Survey on SARS-CoV-2 infected patients (LEOSS): a multicentre cohort study.

OBJECTIVES: The use of remdesivir (RDV) as the first drug approved for coronavirus disease 2019 (COVID-19) remains controversial. Based on the Lean European Open Survey on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infected patients (LEOSS), we aim to contribute timing-focused complementary real-world insights to its evaluation. METHODS: SARS-CoV-2 infected patients between January 2020 and December 2021 treated with RDV were matched 1:1 to controls considering sociodemographics, comorbidities and clinical status. Multiple imputations were used to account for missing data. Effects on fatal outcome were estimated using uni- and multivariable Cox regression models. RESULTS: We included 9,687 patients. For those starting RDV administration in the complicated phase, Cox regression for fatal outcome showed an adjusted hazard ratio (aHR) of 0.59 (95%CI 0.41-0.83). Positive trends could be obtained for further scenarios: an aHR of 0.51 (95%CI 0.16-1.68) when RDV was initiated in uncomplicated and of 0.76 (95% CI 0.55-1.04) in a critical phase of disease. Patients receiving RDV with concomitant steroids exhibited a further reduction in aHR in both, the complicated (aHR 0.50, 95%CI 0.29-0.88) and critical phase (aHR 0.63, 95%CI 0.39-1.02). CONCLUSION: Our study results elucidate that RDV use, in particular when initiated in the complicated phase and accompanied by steroids is associated with improved mortality. However, given the limitations of non-randomized trials in estimating the magnitude of the benefit of an intervention, further randomized trials focusing on the timing of therapy initiation seem warranted.

Arterial thrombosis in Philadelphia-negative myeloproliferative neoplasms predicts second cancer: a case-control study.

Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P = .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P = .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P = .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.gov as NCT03745378.

Bleeding complications in bcr-abl-negative myeloproliferative neoplasms (MPN): A retrospective single-center study of 829 MPN patients.

In patients with bcr-abl-negative myeloproliferative neoplasms (MPN), concerns are often raised about the use of anticoagulants because of an increased bleeding risk. However, there are few MPN studies focusing on bleeding. To investigate bleeding complications in MPN, we report our retrospective, single-center study of 829 patients with a median follow-up of 5.5 years (range: 0.1-35.6). A first bleeding event occurred in 143 of 829 patients (17.2%), corresponding to an incidence rate of 2.29% per patient/year. During the follow-up period, one out of 829 patients (0.1%) died due to bleeding. Regarding anticoagulation, most bleeding occurred in patients on antiplatelet therapies (60.1%), followed by patients on anticoagulation therapies (20.3%) and patients not on anticoagulation (19.6%). In multivariate analysis, administration of antiplatelet (HR 2.31 [1.43, 3.71]) and anticoagulation therapies (HR 4.06 [2.32, 7.09]), but not age, gender or mutation status, was associated with an increased bleeding risk. Comparing the "probability of bleeding-free survival" between the MPN subtypes, no significant difference was observed (p = 0.91, log-rank test). Our retrospective study shows that antiplatelet and anticoagulation therapies significantly increase the risk of bleeding in MPN patients without affecting mortality. However, there is no reason to refrain from guideline-conform primary or secondary anticoagulation in MPN patients.

Prediction of COVID-19 deterioration in high-risk patients at diagnosis: an early warning score for advanced COVID-19 developed by machine learning.

PURPOSE: While more advanced COVID-19 necessitates medical interventions and hospitalization, patients with mild COVID-19 do not require this. Identifying patients at risk of progressing to advanced COVID-19 might guide treatment decisions, particularly for better prioritizing patients in need for hospitalization. METHODS: We developed a machine learning-based predictor for deriving a clinical score identifying patients with asymptomatic/mild COVID-19 at risk of progressing to advanced COVID-19. Clinical data from SARS-CoV-2 positive patients from the multicenter Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS) were used for discovery (2020-03-16 to 2020-07-14) and validation (data from 2020-07-15 to 2021-02-16). RESULTS: The LEOSS dataset contains 473 baseline patient parameters measured at the first patient contact. After training the predictor model on a training dataset comprising 1233 patients, 20 of the 473 parameters were selected for the predictor model. From the predictor model, we delineated a composite predictive score (SACOV-19, Score for the prediction of an Advanced stage of COVID-19) with eleven variables. In the validation cohort (n = 2264 patients), we observed good prediction performance with an area under the curve (AUC) of 0.73 ± 0.01. Besides temperature, age, body mass index and smoking habit, variables indicating pulmonary involvement (respiration rate, oxygen saturation, dyspnea), inflammation (CRP, LDH, lymphocyte counts), and acute kidney injury at diagnosis were identified. For better interpretability, the predictor was translated into a web interface. CONCLUSION: We present a machine learning-based predictor model and a clinical score for identifying patients at risk of developing advanced COVID-19.

[Modern Multimodal Concepts for Advanced and Metastatic Esophageal Cancer]. / Moderne multimodale Konzepte für fortgeschrittene und metastasierte Ösophaguskarzinome.

Modern Multimodal Concepts for Advanced and Metastatic Esophageal Cancer Abstract. In case of locally advanced esophageal carcinoma, the clear recommendation for multimodal therapy has been established in the guidelines. This also applies to systemic therapy in the palliative, metastatic situation. Against the background of increasing experience with multimodal concepts and a parallel trend towards more and more personalized tumor therapy, therapy options that go beyond this are increasingly being used. The most recent chapter here is the successful use of antibodies and immune checkpoint inhibitors in the adjuvant, additive or palliative setting. Salvage concepts and the salvage operation are also used. These are efficient options to be able to react surgically from a situation of clinical remission and close observation in case of tumor recurrence. The limited radical surgical procedures with reconstruction according to "Merendino" and the "double tract procedure" with limited resection of the distal esophagus and proximal stomach via abdominal approach are options for high-risk patients or very elderly patients. They show great advantages with regard to the operational stress and - especially the "double tract procedure" - with regard to the quality of life. The oligometastatic situation is also the subject of ongoing studies. Under strict clinical observation, it may make sense not to exclude patients with very limited metastases from a curative concept. Numerous cases of long-term survival encourage this. In the palliative setting, in addition to classic chemotherapy and best supportive care, immunotherapy is also playing an increasingly important role, and here, too, a conversion to a curative concept is possible if the response is good. Palliative esophageal resections in the case of disseminated metastases, infiltration of vertebral bodies, aorta or trachea or main bronchi must be strictly avoided and must unfortunately be described as incurable.

[Chemotherapy and Radio-Chemotherapy of Locally Advanced Esophageal Cancer]. / Chemotherapie und Radio-/Chemotherapie des lokal fortgeschrittenen Ösophaguskarzinoms.

Chemotherapy and Radio-Chemotherapy of Locally Advanced Esophageal Cancer Abstract. Surgical resection alone of locally advanced esophageal carcinoma leads to long-term survival in only about 30% of cases. The multimodal strategy for locally advanced tumors, especially neoadjuvant radiochemotherapy and chemotherapy, has significantly improved the long-term prognosis. Multimodal therapy concepts have been developed which improve overall survival. Therapy planning must be performed pretherapeutically in an interdisciplinary tumor board, preferably at a high-volume center. For squamous cell carcinomas, neoadjuvant radio/chemotherapy followed by resection or definitive radio/chemotherapy are currently the therapies of choice. For adenocarcinomas, neoadjuvant radio/chemotherapy followed by resection or perioperative chemotherapy are considered equivalent therapeutic standards. After neoadjuvant radiochemotherapy, adjuvant immunotherapy is currently recommended in case of only incomplete histopathological response.

Development and validation of a simplified risk score for the prediction of critical COVID-19 illness in newly diagnosed patients.

Scores to identify patients at high risk of progression of coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may become instrumental for clinical decision-making and patient management. We used patient data from the multicentre Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) and applied variable selection to develop a simplified scoring system to identify patients at increased risk of critical illness or death. A total of 1946 patients who tested positive for SARS-CoV-2 were included in the initial analysis and assigned to derivation and validation cohorts (n = 1297 and n = 649, respectively). Stability selection from over 100 baseline predictors for the combined endpoint of progression to the critical phase or COVID-19-related death enabled the development of a simplified score consisting of five predictors: C-reactive protein (CRP), age, clinical disease phase (uncomplicated vs. complicated), serum urea, and D-dimer (abbreviated as CAPS-D score). This score yielded an area under the curve (AUC) of 0.81 (95% confidence interval [CI]: 0.77-0.85) in the validation cohort for predicting the combined endpoint within 7 days of diagnosis and 0.81 (95% CI: 0.77-0.85) during full follow-up. We used an additional prospective cohort of 682 patients, diagnosed largely after the "first wave" of the pandemic to validate the predictive accuracy of the score and observed similar results (AUC for the event within 7 days: 0.83 [95% CI: 0.78-0.87]; for full follow-up: 0.82 [95% CI: 0.78-0.86]). An easily applicable score to calculate the risk of COVID-19 progression to critical illness or death was thus established and validated.

Direct oral anticoagulants (DOAC) for prevention of recurrent arterial or venous thromboembolic events (ATE/VTE) in myeloproliferative neoplasms.

In patients with BCR-ABL-negative myeloproliferative neoplasms (MPN), arterial or venous thromboembolic events (ATE/VTE) are a major burden. In order to control these complications, vitamin K antagonists (VKA) are widely used. There is no robust evidence supporting the use of direct oral anticoagulants (DOAC) in MPN patients. We therefore compared the efficacy and safety of both anticoagulants in 71 cases from a cohort of 782 MPN patients. Seventy-one of 782 MPN patients (9.1%) had ATE/VTE with nine ATE (12.7%) and 62 VTE (87.3%). Forty-five of 71 ATE/VTE (63.4%) were treated with VKA and 26 (36.6%) with DOAC. The duration of anticoagulation therapy (p = 0.984), the number of patients receiving additional aspirin (p = 1.0), and the proportion of patients receiving cytoreductive therapy (p = 0.807) did not differ significantly between the VKA and DOAC groups. During anticoagulation therapy, significantly more relapses occurred under VKA (n = 16) compared to DOAC treatment (n = 0, p = 0.0003). However, during the entire observation period of median 3.2 years (0.1-20.4), ATE/VTE relapse-free survival (p = 0.2) did not differ significantly between the two anticoagulants. For all bleeding events (p = 0.516) or major bleeding (p = 1.0), no significant differences were observed between VKA and DOAC. In our experience, the use of DOAC was as effective and safe as VKA, possibly even potentially beneficial with a lower number of recurrences and no increased risk for bleedings. However, further and larger studies are required before DOAC can be routinely used in MPN patients.

Ruxolitinib-treated polycythemia vera patients and their risk of secondary malignancies.

Recently, there has been increased concern about a risk of secondary malignancies (SM) occurring in myelofibrosis (MF) patients receiving ruxolitinib (RUX). In polycythemia vera (PV), on the other hand, only limited data on the risk of SM under RUX treatment are available. To investigate the association between RUX therapy in PV and SM, we conducted a retrospective, single-center study that included 289 PV patients. RUX was administered to 32.9% (95/289) of patients for a median treatment duration of 48.0 months (range 1.0-101.6). Within a median follow-up of 97 months (1.0-395.0) after PV diagnosis, 24 SM occurred. Comparing the number of PV patients with RUX-associated SM (n = 10, 41.7%) with the 14 (58.3%) patients who developed SM without RUX, no significant difference (p = 0.34, chi square test) was found. No increased incidences of melanoma, lymphoma, or solid "non-skin" malignancies were observed with RUX (p = 0.31, p = 0.60, and p = 0.63, respectively, chi square test). However, significantly more NMSC occurred in association with RUX treatment (p = 0.03, chi-squared test). The "SM-free survival" was not significantly different by log rank test for all 289 patients (p = 0.65), for the patients (n = 208; 72%) receiving cytoreductive therapy (p = 0.48) or for different therapy sequences (p = 0.074). In multivariate analysis, advanced age at PV diagnosis (HR 1.062 [95% CI 1.028, 1.098]) but not administration of RUX (HR 1.068 [95% CI 0.468, 2.463]) was associated with an increased risk for SM (p = 0.005). According to this retrospective analysis, no increased risk of SM due to RUX treatment could be substantiated for PV.

The management, outcome, and postpartum disease course of 41 pregnancies in 20 women with polycythemia vera.

OBJECTIVES: Pregnancies in women with polycythemia vera (PV) are associated with an increased risk of PV-related maternal complications and often result in miscarriage. Recommendations for the management of PV pregnancies are mainly based on studies with a small number of patients. A correlation between pregnancy outcome and postpartum course has been reported for essential thrombocythemia, but corresponding data for PV are lacking so far. METHODS: In 41 PV pregnancies, the pregnancy outcome, the use of PV-specific therapies (ie, acetylsalicylic acid, low-molecular weight heparin and/or interferon-alpha), and the postpartum PV course were investigated. RESULTS: A live birth rate of 51.2% (21/41 pregnancies) was observed. 43.9% of pregnancies ended in spontaneous abortion and 4.9% in stillbirth. A significantly increased live birth rate occurred in pregnancies with PV-specific therapies compared to standard antenatal care (69.0% vs. 8.3%; P < .0019). The use of PV-specific therapy significantly increased the number of maternal hemorrhages (P = .021) without increasing the risk of fetal complications. During the median postpartum follow-up period of 1.2 years (range 0.1-13.7), complicated postpartum PV occurred significantly more often after miscarriages (P = .035). CONCLUSIONS: According to our analysis, PV-specific therapy improved the live birth rate. Significantly more complicated postpartum PV courses were observed after miscarriages.

Clinical course and predictive risk factors for fatal outcome of SARS-CoV-2 infection in patients with chronic kidney disease.

PURPOSE: The ongoing pandemic caused by the novel severe acute respiratory coronavirus 2 (SARS-CoV-2) has stressed health systems worldwide. Patients with chronic kidney disease (CKD) seem to be more prone to a severe course of coronavirus disease (COVID-19) due to comorbidities and an altered immune system. The study's aim was to identify factors predicting mortality among SARS-CoV-2-infected patients with CKD. METHODS: We analyzed 2817 SARS-CoV-2-infected patients enrolled in the Lean European Open Survey on SARS-CoV-2-infected patients and identified 426 patients with pre-existing CKD. Group comparisons were performed via Chi-squared test. Using univariate and multivariable logistic regression, predictive factors for mortality were identified. RESULTS: Comparative analyses to patients without CKD revealed a higher mortality (140/426, 32.9% versus 354/2391, 14.8%). Higher age could be confirmed as a demographic predictor for mortality in CKD patients (> 85 years compared to 15-65 years, adjusted odds ratio (aOR) 6.49, 95% CI 1.27-33.20, p = 0.025). We further identified markedly elevated lactate dehydrogenase (> 2 × upper limit of normal, aOR 23.21, 95% CI 3.66-147.11, p < 0.001), thrombocytopenia (< 120,000/µl, aOR 11.66, 95% CI 2.49-54.70, p = 0.002), anemia (Hb < 10 g/dl, aOR 3.21, 95% CI 1.17-8.82, p = 0.024), and C-reactive protein (≥ 30 mg/l, aOR 3.44, 95% CI 1.13-10.45, p = 0.029) as predictors, while renal replacement therapy was not related to mortality (aOR 1.15, 95% CI 0.68-1.93, p = 0.611). CONCLUSION: The identified predictors include routinely measured and universally available parameters. Their assessment might facilitate risk stratification in this highly vulnerable cohort as early as at initial medical evaluation for SARS-CoV-2.

First results of the "Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS)".

PURPOSE: Knowledge regarding patients' clinical condition at severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is sparse. Data in the international, multicenter Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) cohort study may enhance the understanding of COVID-19. METHODS: Sociodemographic and clinical characteristics of SARS-CoV-2-infected patients, enrolled in the LEOSS cohort study between March 16, 2020, and May 14, 2020, were analyzed. Associations between baseline characteristics and clinical stages at diagnosis (uncomplicated vs. complicated) were assessed using logistic regression models. RESULTS: We included 2155 patients, 59.7% (1,287/2,155) were male; the most common age category was 66-85 years (39.6%; 500/2,155). The primary COVID-19 diagnosis was made in 35.0% (755/2,155) during complicated clinical stages. A significant univariate association between age; sex; body mass index; smoking; diabetes; cardiovascular, pulmonary, neurological, and kidney diseases; ACE inhibitor therapy; statin intake and an increased risk for complicated clinical stages of COVID-19 at diagnosis was found. Multivariable analysis revealed that advanced age [46-65 years: adjusted odds ratio (aOR): 1.73, 95% CI 1.25-2.42, p = 0.001; 66-85 years: aOR 1.93, 95% CI 1.36-2.74, p < 0.001; > 85 years: aOR 2.38, 95% CI 1.49-3.81, p < 0.001 vs. individuals aged 26-45 years], male sex (aOR 1.23, 95% CI 1.01-1.50, p = 0.040), cardiovascular disease (aOR 1.37, 95% CI 1.09-1.72, p = 0.007), and diabetes (aOR 1.33, 95% CI 1.04-1.69, p = 0.023) were associated with complicated stages of COVID-19 at diagnosis. CONCLUSION: The LEOSS cohort identified age, cardiovascular disease, diabetes and male sex as risk factors for complicated disease stages at SARS-CoV-2 diagnosis, thus confirming previous data. Further data regarding outcomes of the natural course of COVID-19 and the influence of treatment are required.

Second cancers in MPN: Survival analysis from an international study.

One out of ten patients with Philadelphia-negative myeloproliferative neoplasms (MPN) develop a second cancer (SC): in such patients we aimed at assessing the survival impact of SC itself and of MPN-specific therapies. Data were therefore extracted from an international nested case-control study, recruiting 798 patients with SC diagnosed concurrently or after the MPN. Overall, 2995 person-years (PYs) were accumulated and mortality rate (MR) since SC diagnosis was 5.9 (5.1-6.9) deaths for every 100 PYs. A "poor prognosis" SC (stomach, esophagus, liver, pancreas, lung, ovary, head-and-neck or nervous system, osteosarcomas, multiple myeloma, aggressive lymphoma, acute leukemia) was reported in 26.3% of the patients and was the cause of death in 65% of them (MR 11.0/100 PYs). In contrast, patients with a "non-poor prognosis" SC (NPPSC) incurred a MR of 4.6/100 PYs: 31% of the deaths were attributed to SC and 15% to MPN evolution. At multivariable analysis, death after SC diagnosis was independently predicted (HR and 95% CI) by patient age greater than 70 years (2.68; 1.88-3.81), the SC prognostic group (2.57; 1.86-3.55), SC relapse (1.53; 10.6-2.21), MPN evolution (2.72; 1.84-4.02), anemia at SC diagnosis (2.32; 1.49-3.59), exposure to hydroxyurea (1.89; 1.26-2.85) and to ruxolitinib (3.63; 1.97-6.71). Aspirin was protective for patients with a NPPSC (0.60; 0.38-0.95). In conclusion, SC is a relevant cause of death competing with MPN evolution. Prospective data are awaited to confirm the role of cytoreductive and anti-platelet drugs in modulating patient survival after the occurrence of a SC.

High risk of recurrent venous thromboembolism in BCR-ABL-negative myeloproliferative neoplasms after termination of anticoagulation.

Venous thromboembolism (VTE) is a major burden in patients with BCR-ABL-negative myeloproliferative neoplasms (MPN). In addition to cytoreductive treatment anticoagulation is mandatory, but optimal duration of anticoagulation is a matter of debate. In our single center study, we retrospectively included 526 MPN patients. In total, 78 of 526 MPN patients (14.8%) had 99 MPN-associated VTE. Median age at first VTE was 52.5 years (range 23-81). During a study period of 3497 years, a VTE event rate of 1.7% per patient/year was detected. 38.4% (38/99) of all VTEs appeared before or at MPN diagnosis and 55.6% (55/99) occurred at "uncommon" sites like splanchnic or cerebral veins. MPN patients with VTEs were significantly more female (p = 0.028), JAK2 positive (p = 0.018), or had a polycythemia vera (p = 0.009). MPN patients without VTEs were more often CALR positive (p = 0.023). Total study period after first VTE was 336 years with 20 VTE recurrences accounting for a recurrence rate of 6% per patient/year. In 36 of 71 MPN patients with anticoagulation therapy after first VTE event (50.7%), prophylactic anticoagulation was terminated after a median time of 6 months (range 1-61); 13 of those 36 patients (36.1%) had a VTE recurrence after a median of 13 months (range 4-168). In contrast, only three of 35 (8.6%) patients with ongoing anticoagulation had a VTE recurrence (p = 0.0127). Thus, termination of prophylactic anticoagulation was associated with a significantly higher risk of VTE recurrence. Our data suggest that in MPN patients with VTE, a prolonged duration of anticoagulation may be beneficial.

Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer - the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group.

BACKGROUND: Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. METHODS: NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany. DISCUSSION: The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02047513, 08/13/2014.

COVID-19 in Patients with Active Cancer: Higher Inflammatory Activity Predicts Poor Outcome.

INTRODUCTION: Active malignancies have been identified as an independent risk factor for severity and mortality in COVID-19. However, direct comparisons between SARS-CoV-2-infected patients with active (acP) and non-active cancers (n-acP) remain scarce. PATIENTS AND METHODS: We retrospectively analyzed a cohort of cancer patients with PCR-confirmed SARS-CoV-2 infection, enrolled from March 16, 2020, to July 31, 2021. Data on demographics, cancer, and laboratory findings were collected. Descriptive and subsequent regression analyses were performed. Endpoints were "deterioration to severe COVID-19" and "infection-associated mortality." RESULTS: In total, 987 cancer patients (510 acP vs. 477 n-acP) were included in our analysis. The majority was >55 years old, more men than women were included. At detection of SARS-CoV-2, 65.5% of patients had mild/moderate symptoms, while deterioration to severe COVID-19 was slightly more common in acP (19 vs. 16%; p = 0.284). COVID-19-associated mortality was significantly higher in acP (24 vs. 17.5%, p < 0.001). In terms of laboratory tests, severe cytopenia and elevated levels of inflammatory markers were common findings in acP at baseline, particularly in those who developed a severe infection or died. Multivariate analysis revealed that ferritin (HR 14.24 [2.1-96], p = 0.006) and CRP (HR 2.85 [1.02-8.02], p = 0.046) were associated with severity and mortality. In n-acP, association was seen for ferritin only (HR 4.1 [1.51-11.17], p = 0.006). CONCLUSION: Comparing patients with active and non-active cancer, the former showed higher mortality rates. Also, inflammatory markers were significantly increased, assuming higher levels of inflammation may play a role in the adverse outcome of COVID-19 in aCP.

Sequential therapy of refractory metastatic pancreatic cancer with 5-FU/LV/irinotecan (FOLFIRI) vs. 5-FU/LV/oxaliplatin (OFF). The PANTHEON trial (AIO PAK 0116).

PURPOSE: In patients with metastatic pancreatic cancer, after failure of gemcitabine/nab-paclitaxel, this trial compares the efficacy of second-line therapy with FOLFIRI vs. OFF (1:1 randomisation) with cross-over to the vice-versa regimen as third-line therapy. PATIENTS AND METHODS: The primary endpoint was PFS (progression-free survival: time from randomization until progression or death) of second-line therapy. The trial aimed to demonstrate non-inferiority of FOLFIRI vs OFF (non-inferiority margin of a hazard ratio (HR) of 1.5, power of 80% and a significance level of 5%, 196 events needed). Secondary endpoints included overall survival (OS), progression-free survival of third-line therapy and safety. The trial is registered with EudraCT Nr. 2016-004640-11. RESULTS: The trial was terminated with 60 evaluable (37 with FOLFIRI, 23 with OFF) patients due to insufficient recruitment. PFS of second-line therapy was 2.4 (95% CI 2.3-2.6) months with FOLFIRI vs 2.4 (95% CI 2.2-2.7) months with OFF (HR: 0.80, 95% CI 0.45-1.42, P = 0.43). OS was comparable between the arms (HR: 0.95, 95% CI 0.54-1.66), P = 0.84). Only 4 out of 28 (14%) patients receiving third-line therapy achieved a disease control (partial remission or stable disease). Both second-line regimens were well tolerated without new or unexpected safety signals being observed. CONCLUSION: The exploratory analysis of this early terminated trial suggests that FOLFIRI and OFF have similar efficacy ant toxicity as second-line therapy of PDAC after failure of gemcitabine/nab-paclitaxel. Third-line therapy regardless of regimen does not provide satisfactory efficacy in this sequential treatment algorithm.

Prediction of resistance to bevacizumab plus FOLFOX in metastatic colorectal cancer-Results of the prospective multicenter PERMAD trial.

BACKGROUND: Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab. PATIENTS AND METHODS: 15 German and Austrian centers prospectively recruited 50 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM). RESULTS: Using random forests, we developed a predictive machine learning model that discriminated between the situations of "no progress within 100 days before radiological progress" and "progress within 100 days before radiological progress". We could further identify a combination of ten out of the 102 CAF markers, which fulfilled this task with 78.2% accuracy, 71.8% sensitivity, and 82.5% specificity. CONCLUSIONS: We identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress.