Viscoelastic testing reveals normalization of the coagulation profile 12 weeks after severe COVID-19

COVID 19 is associated with a hypercoagulable state and frequent thromboembolic complications. For how long this acquired abnormality lasts potentially requiring preventive measures, such as anticoagulation remains to be delineated. We used viscoelastic rotational thrombelastometry (ROTEM) in a single center cohort of 13 critical ill patients and performed follow up examinations three months after discharge from ICU. We found clear signs of a hypercoagulable state due to severe hypofibrinolysis and a high rate of thromboembolic complications during the phase of acute illness. Three month follow up revealed normalization of the initial coagulation abnormality and no evidence of venous thrombosis in all thirteen patients. In our cohort the coagulation profile was completely normalized three months after COVID-19. Based on these findings, discontinuation of anticoagulation can be discussed in patients with complete venous reperfusion

Sodium Thiosulfate Reduces Acute Kidney Injury in Patients Undergoing Cytoreductive Surgery Plus Hyperthermic Intraperitoneal Chemotherapy with Cisplatin: A Single-Center Observational Study

Background: Cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) represents a multimodal treatment concept for patients with peritoneal surface malignancies. The use of intraperitoneal cisplatin (CDDP) is associated with a risk of acute kidney injury (AKI). The aim of this study is to evaluate the protective effect of perioperative sodium thiosulfate (STS) administration on kidney function in patients undergoing CRS and CDDP-based HIPEC. Patients and Methods: We retrospectively analyzed clinical data of all patients who underwent CRS and CDDP-based HIPEC at our hospital between March 2017 and August 2020. Patients were stratified according to the use of sodium thiosulfate (STS vs. no STS). We compared kidney function and clinical outcome parameters between both groups and determined risk factors for postoperative AKI on univariate and multivariate analysis. AKI was classified according to acute kidney injury network (AKIN) criteria. Results: Of 238 patients who underwent CRS and CDDP-based HIPEC, 46 patients received STS and 192 patients did not. There were no significant differences in baseline characteristics. In patients who received STS, a lower incidence (6.5% vs. 30.7%; p = 0.001) and severity of AKI (p = 0.009) were observed. On multivariate analysis, the use of STS (OR 0.089, p = 0.001) remained an independent kidney-protective factor, while arterial hypertension (OR 5.283, p < 0.001) and elevated preoperative urea serum level (OR 5.278, p = 0.032) were predictors for postoperative AKI. Conclusions: The present data suggest that STS protects patients from AKI caused by CRS and CDDP-based HIPEC. Further prospective studies are needed to validate the benefit of STS among kidney-protective strategies

Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer

Background: Initial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches. Methods: FIRE-8 (NCT05007132) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m(2) body surface area (BSA), orally twice daily on days 1-5 and 8-12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled. Discussion: To the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy

Dynamics in treatment response and disease progression of metastatic colorectal cancer (mCRC) patients with focus on BRAF status and primary tumor location: analysis of untreated RAS-wild-type mCRC patients receiving FOLFOXIRI either with or without panitumumab in the VOLFI trial (AIO KRK0109)

Purpose: In mCRC, disease dynamics may play a critical role in the understanding of long-term outcome. We evaluated depth of response (DpR), time to DpR, and post-DpR survival as relevant endpoints. Methods: We analyzed DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), early tumor shrinkage (≥ 20% reduction in tumor diameter at first reassessment), time to DpR (study randomization to DpR-image), post-DpR progression-free survival (pPFS = DpR-image to tumor progression or death), and post-DpR overall survival (pOS = DpR-image to death) with special focus on BRAF status in 66 patients and primary tumor site in 86 patients treated within the VOLFI-trial, respectively. Results: BRAF wild-type (BRAF-WT) compared to BRAF mutant (BRAF-MT) patients had greater DpR (− 57.6% vs. − 40.8%, p = 0.013) with a comparable time to DpR [4.0 (95% CI 3.1–4.4) vs. 3.9 (95% CI 2.5–5.5) months; p = 0.8852]. pPFS was 6.5 (95% CI 4.9–8.0) versus 2.6 (95% CI 1.2–4.0) months in favor of BRAF-WT patients (HR 0.24 (95% CI 0.11–0.53); p < 0.001). This transferred into a significant difference in pOS [33.6 (95% CI 26.0–41.3) vs. 5.4 (95% CI 5.0–5.9) months; HR 0.27 (95% CI 0.13–0.55); p < 0.001]. Similar observations were made for patients stratified for primary tumor site. Conclusions: BRAF-MT patients derive a less profound treatment response compared to BRAF-WT patients. The difference in outcome according to BRAF status is evident after achievement of DpR with BRAF-MT patients hardly deriving any further disease control beyond DpR. Our observations hint towards an aggressive tumor evolution in BRAF-MT tumors, which may already be molecularly detectable at the time of DpR

Optimization of systemic treatment in gastrointestinal tumors focusing on metastatic colorectal cancer

Die vorliegende Habilitationsschrift umfasst die Darstellung der geleisteten wissenschaftlichen Arbeit im Kontext des gegenwärtigen Forschungsstandes. Im Anschluss an eine Darlegung der aktuellen Behandlungsstandards für PatientInnen mit metastasiertem kolorektalen Karzinom wird zu der Systemtherapieoptimierung auf Basis patientInnen- und tumorspezifischer Faktoren Stellung bezogen und die eigenen Forschungsergebnisse in die aktuelle Literatur eingeordnet

Cisplatin plus Ifosfamide with/without Etoposide as salvage treatment in heavily pretreated patients with metastatic breast bancer

Einleitung: Das Mammakarzinom stellt mit etwa 25% aller malignen Primärtumoren das häufigste Malignom des weiblichen Geschlechtes dar. Trotz neuer Behandlungsoptionen und einer Zunahme der zielgerichteten und individualisierten Therapiemöglichkeiten haben Patientinnen mit metastasiertem Mammakarzinom (MBC) eine limitierte Prognose. Für Patientinnen mit progredienter metastasierter Erkrankung, die eine schnelle Remissionsinduktion erfordert, stellt die Chemotherapie weiterhin die effektivste Behandlung dar. Insbesondere in späteren Therapielinien existieren für diese Patientinnen mangels prospektiver Studien keine Therapiestandards. Cisplatin, Ifosfamid und Etoposid sind wirksame Substanzen in der Behandlung des Mammakarzinoms. Ihre Kombination ist aus der Therapie der Keimzelltumoren bekannt und gut etabliert. Die Wirksamkeit und Toxizität von Platin- und Ifosfamid-basierten Chemotherapien als Salvagebehandlung des MBC wurden bisher nicht ausreichend evaluiert. Methodik: Alle MBC-Patientinnen, die sich an der Medizinischen Klinik für Hämatologie, Onkologie und Tumorimmunologie des Campus Charité Mitte einer Behandlung mit Cisplatin und Ifosfamid mit (PEI) oder ohne Etoposid (PI) zwischen April 2005 und April 2014 unterzogen, wurden retrospektiv hinsichtlich objektiver Ansprechrate (OR), progressionsfreien Überlebens (PFS), Gesamtüberlebens (OS) und therapieassoziierter Toxizitäten evaluiert. Ergebnisse: Es wurden insgesamt 20 Patientinnen mit im Median vier zytostatischen Vortherapien identifiziert, von denen 18 bezüglich der OR ausgewertet werden konnten. Die Behandlung mit PEI beziehungsweise PI resultierte in einer kompletten Remission, neun partiellen Remissionen und zwei Krankheitsstabilisierungen. Das mediane PFS betrug vier (Range 0-18) Monate und das mediane OS von Therapiebeginn belief sich auf 8,5 (Range 0-50) Monate. Die Therapie mit PEI beziehungsweise PI verursachte bei 80% der Patientinnen Grad 3/4-Toxizitäten (überwiegend hämatologisch). Schlussfolgerung: PEI/PI stellt eine effektive Salvagetherapie für MBC- Patientinnen dar, deren Anwendung jedoch aufgrund der schwerwiegenden Toxizität nicht generell empfohlen werden kann. Der Vergleich mit den Ergebnissen aus Platinmonotherapie-Studien legt den Schluss nahe, dass PEI oder PI bei Patientinnen mit tripel-negativem Mammakarzinom besonders effektiv ist. Eine weiterführende Untersuchung dieser Chemotherapie in prospektiven klinischen Studien erscheint gerechtfertigt.Background: Breast cancer is the most common cancer in women worldwide representing approximately 25% of all malignant tumors in females. Despite new treatment options and the increase of targeted and individualized therapies, patients with metastatic breast cancer (MBC) still have a limited prognosis. Chemotherapy remains the backbone of effective treatment in case of progressive metastatic disease requiring the induction of a rapid remission. In spite of effective treatment options in first- and second-line therapy of MBC, the best possible therapy thereafter remains controversial. Cisplatin, etoposide, and ifosfamide are each effective in breast cancer. Their combination is effective and well established in germ cell cancer treatment, whereas the efficacy and toxicity of platinum- and ifosfamide-based chemotherapy as salvage treatment in MBC has not yet been evaluated sufficiently. Methods: Patients with MBC treated with cisplatin plus ifosfamide with (PEI) or without (PI) etoposide in the Department of Hematology, Oncology and Tumor Immunology at the Charité - University Medicine Berlin, Campus Mitte between 04/2005 and 04/2014 were retrospectively analyzed with special attention to the objective response (OR), progression-free survival (PFS), overall survival (OS) and treatment-related toxicities. Results: A total of 20 patients (median four prior chemotherapies) treated with PEI or PI were identified, of whom 18 were evaluable for OR. Treatment with PEI/PI resulted in one complete remission, nine partial remissions and two cases of stable disease. The median PFS was 4 (range 0-18) months and median OS from therapy initiation was 8.5 (range 0-50) months. PEI/PI therapy caused grade 3/4 toxicities (mainly hematological) in 80% of patients. Conclusion: PEI/PI is an effective salvage treatment for patients with MBC but cannot be recommended generally due to toxicity. However, comparison with platinum monotherapy trials suggests that PEI/PI might be a more effective treatment in triple-negative breast cancer. Prospective clinical trials should be performed to further evaluate the clinical value of this chemotherapy

Prostate Cancer Diagnosis and Characterization with Mass Spectrometry Imaging

Background: Prostate cancer (PCa), the most common cancer and second leading cause of cancer death in American men, presents the clinical challenge of distinguishing between indolent and aggressive tumors for proper treatment. PCa presents significant alterations in metabolic pathways that can potentially be measured using techniques like mass spectrometry (MS) or mass spectrometry imaging (MSI) and used to characterize PCa aggressiveness. MS quantifies metabolomic, proteomic, and lipidomic profiles of biological systems that can be further visualized for their spatial distributions through MSI. Methods: PubMed was queried for all publications relating to MS and MSI in human prostate cancer from April 2007 to April 2017. With the goal of reviewing the utility of MSI in diagnosis and prognostication of human PCa, MSI articles that reported investigations of PCa-specific metabolites or metabolites indicating PCa aggressiveness were selected for inclusion. Articles were included that covered MS and MSI principles, limitations, and applications in PCa. Results: We identified nine key studies on MSI in intact human prostate tissue specimens that determined metabolites which could either differentiate between benign and malignant prostate tissue or indicate prostate cancer aggressiveness. These MSI-detected biomarkers show promise in reliably identifying PCa and determining disease aggressiveness. Conclusions: MSI represents an innovative technique with the ability to interrogate cancer biomarkers in relation to tissue pathologies and investigate tumor aggressiveness. We propose MSI as a powerful adjuvant histopathology imaging tool for prostate tissue evaluations, where clinical translation of this ex vivo technique could make possible the use of MSI for personalized medicine in diagnosis and prognosis of prostate cancer. Moreover, the knowledge provided from this technique can majorly contribute to the understanding of molecular pathogenesis of PCa and other malignant diseases

Thromboembolic complications in critically ill COVID-19 patients are associated with impaired fibrinolysis

Background: There is emerging evidence for enhanced blood coagulation in coronavirus 2019 (COVID-19) patients, with thromboembolic complications contributing to morbidity and mortality. The mechanisms underlying this prothrombotic state remain enigmatic. Further data to guide anticoagulation strategies are urgently required. Methods: We used viscoelastic rotational thromboelastometry (ROTEM) in a single-center cohort of 40 critically ill COVID-19 patients. Results: Clear signs of a hypercoagulable state due to severe hypofibrinolysis were found. Maximum lysis, especially following stimulation of the extrinsic coagulation system, was inversely associated with an enhanced risk of thromboembolic complications. Combining values for maximum lysis with D-dimer concentrations revealed high sensitivity and specificity of thromboembolic risk prediction. Conclusions: The study identifies a reduction in fibrinolysis as an important mechanism in COVID-19-associated coagulopathy. The combination of ROTEM and D-dimer concentrations may prove valuable in identifying patients requiring higher intensity anticoagulation

Response and Disease Dynamics in Untreated Metastatic Colorectal Cancer With Bevacizumab-Based Sequential vs. Combination Chemotherapy—Analysis of the Phase 3 XELAVIRI Trial

Introduction: Early tumor shrinkage (ETS), depth of response (DpR), and time to DpR represent exploratory endpoints that may serve as early efficacy parameters and predictors of long-term outcome in metastatic colorectal cancer (mCRC). We analyzed these endpoints in mCRC patients treated with first-line bevacizumab-based sequential (initial fluoropyrimidines) versus combination (initial fluoropyrimidines plus irinotecan) chemotherapy within the phase 3 XELAVIRI trial. Methods: DpR (change from baseline to smallest tumor diameter), ETS (≥20% reduction in tumor diameter at first reassessment), and time to DpR (study randomization to DpR image) were analyzed. We evaluated progression-free survival and overall survival with ETS as stratification parameter according to treatment arm, molecular subgroup, and sex. Results: In 370 patients analyzed, a higher rate of ETS (60.9% vs. 43.5%; p = 0.001) and significantly greater DpR (-40.0% vs. -24.7%; p < 0.001) were observed in the initial combination therapy arm. The improvement was pronounced in RAS/BRAF wild-type tumors. ETS correlated with improved survival irrespective of treatment arm (PFS: p < 0.001; OS: p = 0.012) and molecular subgroup (PFS: p < 0.001; OS: p < 0.001). Male patients in contrast to female patients with ETS had survival benefit (PFS: p < 0.001, HR 0.532; OS: p < 0.001, HR 0.574 vs. PFS: p = 0.107; OS: p = 0.965). Conclusions: Initial irinotecan-based combination therapy with bevacizumab improved ETS and DpR in mCRC patients with a particularly high irinotecan sensitivity of RAS/BRAF wild-type tumors. ETS seems to be a suitable prognostic marker for fluoropyrimidine- and bevacizumab-based combinations in mCRC. This finding was rather driven by male patients, potentially indicating that ETS might be less predictive of long-term outcome in an elderly, female population

Mucin-1 Protein Is a Prognostic Marker for Pancreatic Ductal Adenocarcinoma: Results From the CONKO-001 Study

Background The Mucin-family protein, MUC1, impacts on carcinogenesis and tumor invasion. We evaluated the impact of MUC1 expression on outcome in a cohort of 158 patients with resected pancreatic ductal adenocarcinomas (PDAC) in the CONKO-001 study (adjuvant gemcitabine [gem] vs. observation [obs]). Methods The percentage of MUC1-positive tumor cells by immunohistochemistry (IHC) and the staining intensity were evaluated by two observers blinded to outcome. The numeric values of both parameters were multiplied, resulting in an immunoreactivity score (IRS) ranging from 0 to 12. The level of MUC1 expression was defined as follows: IRS 0-4 (low) vs IRS >4 (high). Outcomes in terms of disease-free (DFS) and overall survival (OS) were evaluated by Kaplan-Meier method, log-rank tests and Cox regressions. Results In total, tumors of 158 study patients were eligible for immunohistochemistry of MUC1. High cytoplasmic MUC1 expression was associated with impaired DFS and OS in the overall study population (hazard ratio (HR) for DFS: 0.49, 95% CI 0.31 to 0.78, p = .003; HR for OS: 0.46, 95% CI 0.29 to 0.73, p = .001). In the study arms, prognostic effects of MUC1 were also evident in the observation group (HR for DFS: 0.55; 95% CI 0.29 to 1.04, p = .062; HR for OS: 0.34, 95% CI 0.17 to 0.67, p = .001) and trending in the gem group (HR for DFS: 0.48, 95% CI 0.24 to 0.95, p = .041; HR for OS: 0.56, 95% CI 0.28 to1.11, p = .093). Conclusion Our data suggest that MUC1 expression is a powerful prognostic marker in patients with PDAC after curatively intended resection