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Background: the tight and reciprocal interaction between cancer and hemostasis has stimulated investigations on the possible role of hemostatic biomarkers in predicting specific cancer outcomes, such as disease progression (DP) and overall survival (OS). In a prospective cohort of newly diagnosed metastatic gastrointestinal (GI) cancer patients from the HYPERCAN study, we aimed to assess whether the hemostatic biomarker levels measured before starting any anticancer therapy may specifically predict for 6-months DP (6m-DP) and for 1-year OS (1y OS). Methods: plasma samples were collected and tested for thrombin generation (TG) as global hemostatic assay, and for D-dimer, fibrinogen, and prothrombin fragment 1 + 2 as hypercoagulation biomarkers. DP and mortality were monitored during follow-up. Results: A prospective cohort of 462 colorectal and 164 gastric cancer patients was available for analysis. After 6 months, DP occurred in 148 patients, providing a cumulative incidence of 24.8% (21.4–28.4). D-dimer and TG endogenous thrombin potential (ETP) were identified as independent risk factors for 6m-DP by multivariate Fine–Gray proportional hazard regression model corrected for age, cancer site, and >1 metastatic site. After 1 year, we observed an OS of 75.7% (71.9–79.0). Multivariate Cox regression analysis corrected for age, site of cancer, and performance status identified D-dimer and ETP as independent risk factors for 1y OS. Patients with one or both hemostatic parameters above the dichotomizing threshold were at higher risk for both 6m-DP and 1-year mortality. Conclusion.: in newly diagnosed metastatic GI cancer patients, pretreatment ETP and D-dimer appear promising candidate biomarkers for predicting 6m-DP and 1y OS. In this setting, for the first time, the role of TG as a prognostic biomarker emerges in a large prospective cohort.

The aim of this systematic review is to undertake a critical appraisal of the evidence in the published literature concerning the conversion factors between kerma-area product (P KA) and effective/organ dose (DCED_PKA, DCHT_PKA) for cardiac interventional fluoroscopy procedures performed in adults and paediatric patients and to propose reference conversion factors to help standardize dose calculations. A search strategy utilizing MeSH headings in three databases identified 59 (adult) and 37 (paediatric) papers deemed eligible for the review. Exclusion criteria were adopted to select data only from publications which established DCED_PKA in patients using the ICRP 103 tissue weighting factors. A time restriction from January 2007 was introduced in the search to capture the evolving trends of utilization of fluoroscopy-guided intervention technologies only in recent years. The suggested DCED_PKA and DCHT_PKA were synthesized by calculating the weighted averages of the values reported by the authors with weights corresponding to the study sample size. Eighteen studies for both adult (9) and paediatric (9) patients matching the search terms fulfilled the inclusion criteria. The suggested value for DCED_PKA in adult patients amounts to 0.24 mSv Gy−1cm−2. The suggested values for DCHT_PKA ranged from a minimum of 0.15 mSv Gy−1cm−2 for the female breast to a maximum of 0.97 mSv Gy−1cm−2 for the lungs. The suggested values for DCED_PKA in paediatric patients ranged from 3.45 mSv Gy−1cm−2 for the new-born to 0.49 mSv Gy−1cm−2 in the 15 years age class. The suggested values for DCHT_PKA ranged from a minimum of 0.33 mSv Gy−1cm−2 for bone marrow in the 15 years age class to a maximum of 11.49 mSv Gy−1cm−2 for the heart in the new-born. To conclude, values of DCED_PKA/DCHT_PKA were provided for calculating effective/organ doses in cardiac interventional procedures. They can be useful for standardizing dose calculations, hence for comparison of the radiation detriment from different imaging procedures and in the framework of epidemiologic studies.

Jak inhibitors are potent anti-inflammatory drugs that have the potential to dampen the hyperactive inflammatory response associated with severe COVID-19. We reviewed the clinical outcomes of 218 patients with COVID-19 hospitalized for severe pneumonia and treated with ruxolitinib through a compassionate use program. Data on the duration of treatment, outcomes at 4, 7, 14, and 28 days, oxygen support requirements, clinical status, and laboratory parameters were retrospectively collected. Overall, according to the physician evaluation, 66.5% of patients showed improvement at follow-up, of these, 83.5% showed improvement by day 7. Oxygen support status also showed improvement, and by day 7, 21.6% of patients were on ambient air, compared with 1.4% at baseline, which increased to 48.2% by day 28. Significant decreases in C-reactive protein and increases in the lymphocyte total count were already observed by day 4, which seemed to correlate with a positive outcome. At the end of the observation period, 87.2% of patients were alive. No unexpected safety findings were observed, and grade 3/4 adverse events were reported in 6.9% of patients.

Introduction Arterial graft physiology influences the long‐term outcome of coronary artery bypass grafting (CABG). We studied factors that can affect the overall resistance to flow using internal mammary artery grafting to the left anterior descending artery. Methods This was a prospective, nonrandomized observational study of 100 consecutive patients who underwent elective on‐pump isolated or combined valve surgery and CABG. Coronary stenoses were assessed using conventional and quantitative coronary angiography assessment. The flow and pulsatility index (PI) of the grafts were assessed by transit‐time flowmetry during cardioplegic arrest and at the end of the operation. Fractional polynomials were used to explore linearity, followed by multivariable regression analysis. Results Univariate analysis demonstrated higher flows at the end of the operation in patients who had higher flows with the cross‐clamp on (P

In cancer patients, hypercoagulability is a common finding. It has been associated with an increased risk of venous thromboembolism, but also to tumor proliferation and progression. In this prospective study of a large cohort of breast cancer patients, we aimed to evaluate whether pre-chemotherapy abnormalities in hemostatic biomarkers levels: (i) are associated with breast cancer-specific clinico-pathological features; and (ii) can predict for disease recurrence. D-dimer, fibrinogen, prothrombin fragment 1+2, and FVIIa/antithrombin levels were measured in 701 early-stage resected breast cancer patients candidate to adjuvant chemotherapy and prospectively enrolled in the HYPERCAN study. Significant prognostic parameters for disease recurrence were identified by Cox regression multivariate analysis and used for generating a risk assessment model. Pre-chemotherapy D-dimer, fibrinogen, and pro-thrombin fragment 1+2 levels were significantly associated with tumor size and lymph node metastasis. After 3.4 years of follow up, 71 patients experienced a recurrence. Cox multivariate analysis identified prothrombin fragment 1+2, tumor size, and Luminal B HER2-negative or triple negative molecular subtypes as independent risk factors for disease recurrence. Based on these variables, we generated a risk assessment model that significantly differentiated patients at low- and high-risk of recurrence (cumulative incidence: 6.2 vs. 20.7%; Hazard Ratio=3.5; P

OBJECTIVES We evaluated graft patency by computed tomography and explored the determinants of intraoperative mean graft flow (MGF) and its contribution to predict early graft occlusion. METHODS One hundred and forty-eight patients under a single surgeon were prospectively enrolled. Arterial and endoscopically harvested venous conduits were used. Intraoperative graft characteristics and flows were collected. Graft patency was blindly evaluated by a follow-up computed tomography at 11.4 weeks (median). RESULTS Graft occlusion rate was 5.2% (n = 22 of 422; 8% venous and 3% arterial). Thirteen were performed on non-significant proximal stenosis while 9 on occluded or >70% stenosed arteries. Arterial and venous graft MGF were lower in females (Parterial = 0.010, Pvenous = 0.009), with median differences of 10 and 13.5 ml/min, respectively. Arterial and venous MGF were associated positively with target vessel diameter ≥1.75 mm (Parterial = 0.025; Pvenous = 0.002) and negatively with pulsatility index (Parterial < 0.001; Pvenous < 0.001). MGF was an independent predictor of graft occlusion, adjusting for EuroSCORE-II, pulsatility index, graft size and graft type (arterial/venous). An MGF cut-off of 26.5 ml/min for arterial (sensitivity 83.3%, specificity 80%) and 36.5 ml/min for venous grafts (sensitivity 75%, specificity 62%) performed well in predicting early graft occlusion. CONCLUSIONS We demonstrate that MGF absolute values are influenced by coronary size, gender and graft type. Intraoperative MGF of >26.5 ml/min for arterial and >36.5 ml/min for venous grafts is the most reliable independent predictor of early graft patency. Modern-era coronary artery bypass graft is associated with low early graft failure rates when transit time flow measurement is used to provide effective intraoperative quality assurance.

Introduction Endothelial damage and hypercoagulability are major players behind the hemostatic derangement of SARS-CoV-2 infection.Aim In this prospective study we assessed endothelial and inflammatory biomarkers in a cohort of COVID-19 patients, aiming to identify predictive factors of in-hospital mortality.Methods COVID-19 patients hospitalized in intensive care (ICU) and non-ICU units at 2 Bergamo (Italy) hospitals from March 23 to May 30, 2020, were enrolled. Markers of endothelium activation including von-Willebrand factor (vWF), soluble thrombomodulin (sTM), and fibrinolytic proteins (t-PA and PAI-1) were measured. Additionally, D-dimer, Fibrinogen, FVIII, nucleosomes, C reactive protein (CRP) and procalcitonin were assessed.Results Sixty-three (45 ICU, and 18 non-ICU) patients, with a median age of 62 years were analyzed. Increased plasma levels of D-dimer, FVIII, fibrinogen, nucleosomes, CRP, and procalcitonin were observed in the whole cohort. Extremely elevated vWF levels characterized all patients (highest values in ICU-subjects). After a median time of 30 days, death occurred in 13 (21%) patients. By multivariable analysis, vWF-activity, neutrophil-count and PaO2/FiO2 were significantly associated with death. Using these variables, a linear score with 3-risk groups was generated that provided a cumulative incidence of death of 0% in the low-, 32% in the intermediate-, and 78% in the high-risk group.Conclusions COVID-19-induced hemostatic abnormalities are exacerbated by the severity of the disease and strongly correlate with the inflammatory status, underlying the link between coagulation, endothelial activation, and inflammation. Our study provides evidence for a role of vWF, together with neutrophils and PaO2/FiO2, as a significant predictor of in-hospital mortality by SARSCoV-2 infection.

Physica status solidi / Rapid research letters 2100409 (2021). doi:10.1002/pssr.202100409, Published by Wiley-VCH, Weinheim

Introduction On February 20, 2020, a severe case of pneumonia due to SARS-CoV-2 was diagnosed in northern Italy (Lombardy). Some studies have identified obesity as a risk factor for severe disease in patients with COVID-19. The purpose of this study was to investigate the incidence of SARS-CoV-2 infection and its severity in patients who have undergone bariatric surgery. Material and Methods During the lockdown period (until May 2020), we contacted operated patients by phone and social networks (e.g., Facebook) to maintain constant contact with them; in addition, we gave the patients a dedicated phone number at which to call us for emergencies. We produced telemedicine and educational videos for obese and bariatric patients, and we submitted a questionnaire to patients who had undergone bariatric surgery in the past. Results A total of 2145 patients (313 male; 1832 female) replied to the questionnaire. Mean presurgical BMI: 44.5 ± 6.8 kg/m2. Mean age: 44.0 ± 10.0 year. Mean BMI after surgery: 29.3 ± 5.5 kg/m2 (p

Background The use of computed tomography (CT) for coronavirus disease 2019 (COVID-19) diagnosis in an area of northern Italy with a high incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may have identified more patients with this disease than RT-PCR in the very early onset of the COVID-19 pandemic. Methods We retrospectively reviewed 148 chest CT scans of oncological patients who were referred to the Radiological Unit of Policlinico S. Marco from 1 February 2020 to 30 April 2020, during the COVID-19 outbreak in Bergamo area. In parallel, we analyzed RT-PCR tests of these 148 patients. Results Among 32 patients with a diagnosis of COVID-19, 17 patients were asymptomatic or had mild symptoms (53.1%), while 15 developed severe disease (46.8%). The incidence of SARS-CoV-2 infection was 22.9%, the mortality rate was 18.8%. We did not find any correlation between disease severity and age, sex, smoking, or cardiovascular comorbidities. Remarkably, patients who were on treatment for cancer developed a milder disease than patients who were not on treatment. Conclusions The acceptance of CT-defined diagnoses in COVID-19 high-incidence areas like Bergamo region highlighted a larger oncological population affected by COVID-19 than RT-PCR, in particular, asymptomatic and mildly symptomatic patients, because only symptomatic patients underwent nasopharyngeal swabbing at the onset of the COVID-19 pandemic. We observed that patients actively treated for their cancer had a milder disease, in agreement with previous studies that suggested a protective role of immunosuppression. Admittedly, the sample of patients in our study was heterogeneous regarding the oncological disease, their prognosis, and the type of treatment, therefore, other studies are needed to confirm our data.

To estimate the number of patients who receive a cumulative effective dose (CED) of ≥ 100 mSv from computed tomography (CT) in a single day or episode of care. We examined 28,870 patients who underwent 49,834 CT examinations in a tertiary care centre in Italy in 2.5 years. Radiation exposures were retrieved from the hospital’s automatic exposure monitoring system. Two cohorts were identified as those who received a CED of ≥ 100 mSv in a single day and within a month starting from the first examination. Organ doses were estimated for the first cohort. Among the 1765 (6.1%) patients who received CED ≥ 100 mSv in the observation period, 427 received a CED of ≥ 100 mSv within a month (and 70 patients in a single day). This group represented 1.5% of all patients who underwent CT exams and 24% of those who received CED ≥ 100 mSv in the observation period. The clinical indication for referral included cancer in 132 patients (31%) and non-oncological indications in 295 patients (69%). In 68/70 patients with CED > 100 mSv in a single day, at least one organ/tissue received a dose of ≥ 100 mGy. The finding of a sizeable percentage of patients undergoing CT exams and receiving CED ≥ 100 mSv in a single episode of care points toward the need of imaging appropriateness criteria, to revise the routine protocols, to replace older machines, and to provide to the radiologist the patient’s prior radiation history to facilitate an appropriate decision-making process. • Patients can receive effective doses greater than 100 mSv in a single CT or in multiple CT examinations performed in a single episode of care in 1.5% of patients in a 2.5-year period. • In this study, the clinical indication for CT referral was non-oncological in 69% of patients. • The patient’s prior radiation history should be provided to the referring physicians and the radiological medical practitioner to facilitate an appropriate decision-making process.

Background Hemophagocytic syndrome (HPS) is a severe hyperinflammatory disease, whose diagnosis is based on the HLH-2004 criteria. In secondary forms of HLH (sHLH), the primary goal is treating the triggering factors such as COVID-19 (Coronavirus disease 2019). The link between the cytokine storm related to COVID-19 and development of sHLH has already been reported since the onset of pandemic, but little is known about clinical manifestations of HLH which develop after the patient’s recovery from mild symptomatic or asymptomatic Sars-CoV-2 infection. Case presentation We describe the case of a woman diagnosed with sHLH related to previous Sars-CoV-2 infection and successfully treated with steroids, colchicine, etoposide and ruxolitinib. Conclusions Our report suggests that HLH-like syndrome might be secondary to Sars-CoV-2 infection, even if the patient utterly recovered from the mildly symptomatic viral infection. In addition, we underline the treatment with low dose ruxolitinib plus etoposide as a potential choice for Sars-CoV-2 infection related HLH.

Background The acknowledgment of computed tomography (CT) defined diagnosis in high prevalence northern Italy may identify more patients with Coronavirus Disease-2019 (COVID 19) infection, than RT-PCR alone. Methods We retrospectively reviewed 148 chest CT scans of oncological patients who were referred to the Radiological Unit of Policlinico S. Marco from 1st of February 2020 to 30th of April 2020, during the Covid-19 outbreak in Bergamo area. Therefore, we analyzed RT-PCR tests of these 148 patients. Results Among 32 patients with diagnosis of COVID-19 infection: 17 patients were asymptomatic or had mild symptoms (53.1%), while 15 developed severe disease (46.8%). The incidence of COVID-19 infection is 22.9%, the mortality rate is 18.8%. Severe COVID-19 disease is associated with higher median age. We did not find any correlation between disease severity and sex, smoke or cardiovascular comorbidities. Remarkably, patients who were on treatment developed milder disease than cancer patients who were not on treatment. Conclusions The acceptance of CT-defined diagnosis in high prevalence area like Bergamo highlighted a larger number of COVID-19 oncological population than RT-PCR alone, in particular asymptomatic and mild symptomatic patients. We observed that actively treated patients had milder disease, according to previous studies that suggested a protective role of immunosuppression.

Histerosalpingography (HSG) remains the dominant diagnostic tool for investigation of infertility in women. Conversion factors used to estimate effective (E) and organ doses (HT) from air Kerma area product (KAP) are needed to estimate patient doses in HSG, performed with state-of-the-art fluoroscopic X-ray systems with digital detectors. In this study, estimates of E and HT for six critical organs/tissues, were derived on an individual basis in 120 HSG procedures and in 1410 irradiation events, performed on two X-ray systems from information available through the radiation dose structured report using Monte Carlo methods. Mean values of E and Hovaries were1.0 ± 0.9 mSv and 5.6 ± 5.4 mGy. E/KAP conversion factors of 0.13; 0.18; 0.28 and 0.35 mSv Gy−1cm−2 were established for irradiation events with a Cu filtration of 0.0; 0.1; 0.4 and 0.9 mm. A high agreement was obtained between E estimated through Monte Carlo methods and E/KAP conversion factors accounting separately for the different modes of fluoroscopy and the radiography component of HSG, with a systematic error of 0 mSv and lower/upper limits of agreement of −0.6 and 0.5 mSv. On the contrary, the use of a single coefficient of conversion did not provide accurate estimates of E, showing a bias of −0.4 mSv and lower and upper limits of agreement of −1.9 and 1.2 mSv. An algorithm for the estimation of effective and organ doses from KAP has been established in HSG procedures depending on the Cu filtration in the X-ray irradiation events.

Conversion factors used to estimate effective (E) and organ doses (HT) from air Kerma area product (KAP) are required to estimate population doses in percutaneous transhepatic biliary drainage (PTBD) and trans arterial chemoembolization (TACE) interventional procedures. In this study, E and HT for ten critical organs/tissues, were derived in 64 PTBD and 48 TACE procedures and in 14,540 irradiation events from dosimetric, technical and geometrical information included in the radiation dose structured report using the PCXMC Monte Carlo model, and the ICRP 103 organ weighting factors. Conversion factors of: 0.13; 0.19; 0.26 and 0.32 mSv Gy−1 cm−2 were established for irradiation events characterized by a Cu filtration of 0.0; 0.1; 0.4 and 0.9 mm, respectively. While a single coefficient of conversion is not able to provide estimates of E with enough accuracy, a high agreement is obtained between E estimated through Monte Carlo methods and E estimated through E/KAP conversion factors accounting separately for the different modes of fluoroscopy and the fluorography component of the procedures. An algorithm for the estimation of effective and organ doses from KAP has been established in biliary procedures which considers the Cu filtration in the X-ray irradiation events. A similar algorithm could be easily extended to other interventional procedures and incorporated in radiation dose monitoring systems to provide dosimetric estimates automatically with enough accuracy to assess population doses.

We enrolled 62 consecutive patients with advanced stage cancers and venous thromboembolism (VTE), prospectively followed until 1 year. All patients received 6 month low-molecular-weight heparin (LMWH) therapy. We evaluated thrombin generation (TG) and D-dimer levels at different time points, to determine whether they were sensitive to LMWH and explore a possible association with VTE recurrence, bleeding, and overall survival. During LMWH, levels of TG and D-dimer significantly dropped. No VTE recurrences occurred, one patient had cancer-related intestinal hemorrhage. LMWH treatment was effective in controlling patient hypercoagulation. No VTE recurrences were detected. High D-dimer concentration was an independent predictor of poor survival.

Thrombocytopenia is a recognized complication following aortic valve replacement (AVR). While post-operative thrombotic thrombocytopenic purpura (TTP) is less common than heparin-induced thrombocytopenia (HIT), it is associated with high mortality and morbidity and prompt diagnosis and treatment is vital. In this case report, we describe the first reported case of TTP after AVR using the trifecta bio-prosthesis. We recommend that patients with severe and progressive thrombocytopenia following biological AVR should have early screening for both HIT and TTP, to shorten the decision-making process and provide the appropriate therapy. Cardiol Res. 2018;9(6):392-394 doi: https://doi.org/10.14740/cr780w

Background: Cancer patients present with a hypercoagulable state often associated with poor disease prognosis. Objectives: This study aims to evaluate whether thrombin generation (TG), a global coagulation test, may be a useful tool to improve the identification of patients at high risk of early disease recurrence (i.e. E-DR within 2 years) after breast cancer surgery. Patients/methods: A cohort of 522 newly diagnosed patients with surgically resected high-risk breast cancer were enrolled in the ongoing prospective HYPERCAN study. TG potential was measured in plasma samples collected before starting systemic chemotherapy. Significant predictive hemostatic and clinic-pathological parameters were identified in the derivation cohort by Cox-regression analysis. A risk prognostic score for E-DR was generated in the derivation and tested in the validation cohort. Results: After a median observation period of 3.4 years, DR occurred in 51 patients, 28 of whom were E-DR. E-DR subjects presented with the highest TG values as compared to both late-DR (from 2 to 5 years) and no relapse subjects (p

Purpose Cetuximab and panitumumab are monoclonal antibody inhibitors that bind the epidermal growth factor receptor (EGFR) currently used in the treatment of metastatic colorectal cancer. The main adverse event related to EGFR inhibitors (EGFR-Is) is cutaneous toxicity, which can cause dosage reduction and interruption of treatment. State-of-the-art management of skin toxicity associated with EGFR-Is therapy involves the topical administration of corticosteroids and oral antibiotics, but is not completely effective in the management of toxicity. Subcutaneous desensitization with increasing concentrations of monoclonal antibodies can induce a tolerance to drug administration and reduce cutaneous adverse effects. To our knowledge, this is the first case in which a reduction or a disappearance of skin toxicity caused by EGFR-Is through subcutaneous desensitization has been achieved. Case Report We present cases of 2 Caucasian patients with adenocarcinoma of the colon treated with EGFR-Is who developed severe cutaneous toxicity. A 73-year-old man presented grade 4 skin toxicity of the face and grade 3 skin toxicity of the trunk during treatment with cetuximab. A 68-year-old woman developed G2 rash on the face after the first administration of cetuximab. These patients underwent subcutaneous desensitization with increasing concentrations of EGFR-Is. After this procedure, patients restarted therapy at the optimal dosage with reduction or disappearance of skin toxicity. Conclusions These cases suggest that by giving rising doses of antibody it is possible to obtain desensitization able to prevent severe cutaneous adverse events in patients treated with EGFR-Is.

Background: Abnormalities of laboratory coagulation tests are common in cancer patients, underlying a subclinical hypercoagulable state. Due to the reciprocal interaction between coagulation and cancer, the biomarkers of hemostatic system activation are under evaluation as a tool for predicting cancer outcomes, disease progression, and mortality. Aim: In this analysis of a prospective cohort of patients with newly diagnosed metastatic gastro-intestinal (GI) cancer, we wanted to evaluate whether the pre-chemotherapy abnormalities of hemostatic biomarkers may predict for early-disease progression (E-DP), i.e. within 6 months from cancer diagnosis, and for 1-year overall survival (1-year OS). Methods: The study cohort included 304 newly diagnosed metastatic GI cancer patients, candidate to chemotherapy associated or not with immunotherapy, enrolled from March 2012 to March 2019 in the HYPERCAN study (ClinicalTrials.gov, ID# NCT02622815), an ongoing Italian prospective, multicenter, observational study; 191 healthy subjects acted as a control group. At diagnosis, before starting any curative chemotherapy, plasma samples were collected and tested for the following hypercoagulation biomarkers: D-dimer and fibrinogen by an automated coagulometer analyzer (ACL TOP500, Werfen Group), and prothrombin fragment 1+2 (F1+2) by ELISA (Siemens). In addition, thrombin generation (TG) potential was evaluated by Calibrated Automated Thrombogram (CAT) assay at 5 pM tissue factor and endogenous thrombin potential (TG ETP) and TG peak were analyzed. Clinical data [i.e. age, sex, BMI, ECOG Performance Status (ECOG-PS), relevant comorbidies] and the hemochromocytometric parameters were recorded at enrollment, whereas E-DP was clinically monitored every 3 chemotherapy cycles and during follow-up. Results: A cohort of 304 (205M/99F) metastatic GI cancer patients (206 colorectal and 98 gastric cancers) with a median age of 66 years (min-max: 29-85) was available for analysis. At enrollment, patients presented with a hypercoagulable state, as shown by significantly higher (p1 (HR=3.858), and chemotherapy plus immunotherapy treatment (HR=2.274). Conclusion: Our results show that, in newly diagnosed metastatic gastrointestinal cancer patients, before the start of antitumor treatment, a procoagulant state exists. Among the different hemostatic parameters evaluated, D-dimer and TG ETP appear as candidate biomarkers to predict for 6-month DP and 1-year OS. In particular, in this setting, the role of TG as a prognostic biomarker emerges for the first time in a large prospective cohort of GI cancer patients. Project funded by "5xMILLE" n. 12237 grant from the "Italian Association for Cancer Research (AIRC)" Disclosures Santoro: Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy; Arqule, Sanofi: Consultancy; Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD: Speakers Bureau; Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD: Speakers Bureau; Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, MSD: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy, Speakers Bureau; Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy.

INTRODUCTION The occurrence of a hypercoagulable state in hospitalized COVID-19 patients is supported by studies conducted with routine coagulation tests, including plasma D-dimer and fibrinogen, and platelet count. AIM In this study we performed an extensive characterization of the hemostatic alterations by both global and specific assays in a cohort of 78 patients hospitalized for COVID-19. The aims were to: 1) clarify mechanisms underlying the coagulopathy, and 2) identify predictive factors of disease severity and thrombotic events (i.e. deep vein thrombosis [DVT], pulmonary embolism [PE] or arterial thromboembolism [ATE]). METHODS COVID-19 patients admitted to the Hospital Papa Giovanni XXIII in Bergamo, Italy, from March 23 to May 30, 2020, were enrolled prospectively, providing informed consent. As a global assay, thromboelastometry (ROTEM) was performed in whole blood by EXTEM, INTEM, and FIBTEM tests. Specific assays included plasma levels of intrinsic and extrinsic pathway coagulation factors, von Willebrand factor (vWF) antigen and activity, anticoagulant proteins (i.e. protein C [PC], free-protein S [PS], and antithrombin [AT]), fibrinolytic proteins (i.e. tissue plasminogen activator [t-PA], and inhibitor [PAI-1]), and hypercoagulation biomarkers (i.e. prothrombin fragment 1+2 [F1+2], and D-dimer). In addition, biomarkers of immunoinflammation (i.e. neutrophil extracellular traps [NETs], CRP and procalcitonin) were measured. Occurrence of thrombotic events and death were monitored during follow up. RESULTS 78 patients (56M/22F), median age 62.7 years (25-87), were analyzed. According to disease severity, 45 were ICU, and 33 non-ICU patients. Sixty-three of them were on thromboprophylaxis. Global hemostasis analysis by ROTEM showed a prothrombotic profile in patients compared to controls, with a significantly shorter clot formation time (CFT), and increased maximum clot firmness (MCF), which were significantly greater in the ICU vs non-ICU patients. The occurrence of an 'in vivo' hypercoagulable state was confirmed by increased plasma levels of F1+2 and D-dimer, with the highest values of D-dimer in the ICU subjects. Hypercoagulability, rather than factors' consumption, was also shown by the findings of significantly higher plasma procoagulant factors V, VIII, IX and fibrinogen in ICU compared to non-ICU patients (p After a median time of 8.8 days, 19 (24%) patients experienced thrombosis (3 DVT, 8 PE, 8 ATE). Thirteen (17%) patients from total population died after a median time of 33 days of hospitalization. Baseline D-dimer and t-PA levels were significantly higher in patients developing VTE, while baseline FVIII, vWF and D-dimer levels were greater in subjects who died during follow-up. By Cox analysis, high D-dimer and younger age were significantly associated with mortality. CONCLUSIONS Our study provides for the first time an extensive overview of the hypercoagulable state induced by SARSCoV-2 infection, demonstrating alterations in all of the different hemostatic compartments analyzed. The viral infection-induced hemostatic abnormalities are exacerbated by the severity of the disease and strongly correlate with the proinflammatory status, demonstrating the link between coagulation and inflammation. This link is further supported by the clear correlation found between NETosis and markers of endothelial and blood clotting activation. Finally, these data add evidence to the role of D-dimer as a significant predictor of intra-hospital mortality. Disclosures No relevant conflicts of interest to declare.

Background. Hypercoagulability, a common finding in cancer patients, is associated with an increased risk of both thrombosis and tumor development. The HYPERCAN study (ClinicalTrials.gov, ID# NCT02622815) is an ongoing Italian prospective, multicenter, observational study, evaluating the predictive value of thrombotic markers for early cancer diagnosis in healthy subjects and for cancer prognosis and venous thromboembolism in patients with newly diagnosed malignant disease. In this analysis of a large cohort of patients with breast cancer, we evaluated whether pre-chemotherapy thrombotic biomarker levels: 1. are associated with breast cancer-specific clinicopathological features; and 2. may predict for disease recurrence (DR). Patients and Methods. D-dimer, fibrinogen, prothrombin fragment 1+2 (F1+2), and FVIIa/antithrombin complex (FVIIa/AT) levels were measured in 701 early-stage resected breast cancer patients, candidate to adjuvant chemotherapy and prospectively enrolled in the HYPERCAN study. Significant prognostic parameters for DR were identified by Cox-regression multivariate analysis and used for generating a risk assessment model. The study protocol is approved by the local Ethics Committee. Informed written consent is obtained from all study subjects. Results. Increased pre-chemotherapy D-dimer, fibrinogen, and F1+2 levels were significantly associated with a large tumor size (≥ 5 cm) and lymph node positivity. After 3.4 years follow-up, 71 patients experienced a DR. Comparison of the levels of the hypercoagulation variables of patients who experienced relapse versus patients who remained disease-free during follow-up showed that there were no statistical differences for all, but F1+2 biomarker levels, which were significantly higher in the group patients who relapsed [223 (115-618) vs 197 (115-385) pmol/l; p=0.024]. In addition, correlation analyses showed that pre-chemotherapy levels of fibrinogen were significantly and inversely associated with time to relapse (β = -0.317; p=0.012). Cox-multivariate analysis identified F1+2 (HR 2; 95% CI, 1.1-3.6; p=0.019), tumor size ≥ 5cm (HR 2.6; 95% CI, 1.4-4.6; p=0.001), and Luminal B HER2-neg or TN molecular subtypes (HR 3.9; 95% CI, 2.1-7.5; p Conclusion. Our prospective laboratory data from the HYPERCAN breast cancer subjects were essential for generating a scoring model for DR risk assessment. Future investigations addressing the role of plasma thrombotic biomarkers in breast cancer patients' management are warranted and may provide the rationale for development of new therapeutic strategies. Project funded by AIRC "5xMILLE Multiunit extension program" n. 12237 grant from the "Italian Association for Cancer Research (AIRC)". Disclosures Santoro: Bayer: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; BMS: Consultancy; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Lilly: Speakers Bureau; Celgene: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Roche: Speakers Bureau; Abb-Vie: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Arqule: Consultancy, Speakers Bureau; MSD: Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau.