Phase I trial of the DLL3/CD3 bispecific T-cell engager BI 764532 in DLL3-positive small-cell lung cancer and neuroendocrine carcinomas.

Poorly differentiated neuroendocrine carcinomas such as small-cell lung cancer (SCLC) have poor survival and high relapse rates. DLL3 is found on these carcinomas and has become a target of increasing interest in recent years. The bispecific DLL3/CD3 T-cell engager BI 764532 has been shown to induce complete tumor regression in a human T cell-engrafted mouse model.

Left Internal Mammary Artery-to-Pulmonary Vein Fistula: A Rare Cause of Unstable Angina.

The incidence of acquired left internal mammary artery-to-pulmonary vein fistulas has been increasing in the last few decades. This has been attributed to the increase in coronary artery bypass surgery (CABG). The most commonly reported symptoms are angina and dyspnea.

[Cardiac arrest in obstructive sleep apnea syndrome: treatment options. Case series].

Clinical data of seven patients with severe obstructive sleep apnea, in whom episodes of asystole were recorded at night, is analyzed. In five of seven cases against the background of initiated CPAP therapy (all patients were compliant with the therapy), episodes of asystole were eliminated, and only two cases required the installation of a pacemaker. Conclusions are drawn about the possibility of asystole developing in the background of obstructive respiratory episodes during sleep in patients with severe OSAS and the preventive effect of CPAP therapy.

Clinical Determinants of Myocardial Injury, Detectable and Serial Troponin Levels among Patients with Hypertensive Crisis.

Introduction There is a high prevalence of hypertensive crisis with myocardial injury, as evidenced by elevation in cardiac troponin levels. The risk factors predisposing patients to developing a myocardial injury, detectable troponin, and increase in serial troponin in this population are not known. Methods A retrospective study was designed to include all patients, presenting to the emergency room, diagnosed with hypertensive crisis, using International Classification of Diseases, 10 revision, Clinical Modification (ICD-10-CM) codes between 2016-2018 (n=467).

Nintedanib for the treatment of patients with refractory metastatic colorectal cancer (LUME-Colon 1): a phase III, international, randomized, placebo-controlled study.

Background: Angiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies.

A multicentre, open-label, phase-I/randomised phase-II study to evaluate safety, pharmacokinetics, and efficacy of nintedanib vs. sorafenib in European patients with advanced hepatocellular carcinoma.

Background: This multicentre, open-label, phase-I/randomised phase-II trial evaluated safety, pharmacokinetics, maximum-tolerated-dose (MTD) per dose-limiting toxicities (DLTs), and efficacy of nintedanib vs. sorafenib in European patients with unresectable advanced hepatocellular carcinoma (aHCC).

Methods: Phase I: Patients were stratified into two groups per baseline aminotransferase/alanine aminotransferase and Child-Pugh score; MTD was determined.

Rationale and Design for the LUME-Colon 1 Study: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Nintedanib Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in Patients With Advanced Colorectal Cancer Refractory to Standard Treatment.

Background: Clinical studies of antivascular endothelial growth factor (anti-VEGF) agents have demonstrated that angiogenesis is critical to colorectal cancer (CRC) tumor growth and metastasis. Nintedanib is a triple angiokinase inhibitor of VEGF, platelet-derived growth factor, and fibroblast growth factor signaling. Nintedanib, combined with docetaxel, has been approved in the European Union for the treatment of patients with non-small-cell lung cancer with adenocarcinoma tumor histologic type after first-line chemotherapy.

A phase I/II, open-label, randomised study of nintedanib plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 in first-line metastatic colorectal cancer patients.

Background: This randomised, open-label, phase I/II study evaluated the efficacy and safety of nintedanib, an oral, triple angiokinase inhibitor, combined with chemotherapy, relative to bevacizumab plus chemotherapy as first-line therapy in patients with metastatic colorectal cancer (mCRC).

Patients And Methods: Patients with histologically confirmed mCRC (adenocarcinoma), an Eastern Cooperative Oncology Group performance status ≤ 2 and adequate organ function were included. Patients were randomised 2:1 to receive nintedanib 150 mg or 200 mg b.

Vascular effects, efficacy and safety of nintedanib in patients with advanced, refractory colorectal cancer: a prospective phase I subanalysis.

Background: Nintedanib is a potent, oral angiokinase inhibitor that targets VEGF, PDGF and FGF signalling, as well as RET and Flt3. The maximum tolerated dose of nintedanib was evaluated in a phase I study of treatment-refractory patients with advanced solid tumours. In this preplanned subanalysis, the effect of nintedanib on the tumour vasculature, along with efficacy and safety, was assessed in 30 patients with colorectal cancer (CRC).

Tumor stroma engraftment of gene-modified mesenchymal stem cells as anti-tumor therapy against ovarian cancer.

Background Aims: Many ovarian cancers originate from ovarian surface epithelium, where they develop from cysts intermixed with stroma. The stromal layer is critical to the progression and survival of the neoplasm and consequently is recruited into the tumor microenvironment.

Methods: Using both syngeneic mouse tumors (ID8-R) and human xenograft (OVCAR3, SKOV3) tumor models, we first confirmed that intraperitoneally injected circulating mesenchymal stem cells (MSCs) could target, preferentially engraft and differentiate into α-smooth muscle actin-positive myofibroblasts, suggesting their role as "reactive stroma" in ovarian carcinoma development and confirming their potential as a targeted delivery vehicle for the intratumoral production of interferon-β (IFN-β).

Outcomes of primary percutaneous intervention of the unprotected left main coronary artery stenosis in myocardial infarction.

Objective: The aim of our study was to examine the 30-day and 1-year survival rate for patients undergoing percutaneous coronary artery intervention (PCI) of unprotected left main (ULM) stenosis by the presence (acute myocardial infarction [AMI] group) or absence (non-AMI group) of AMI at the time of hospital admission.

Methods: We retrospectively reviewed 64 patients undergoing PCI of ULM stenosis at our regional heart institute between 2000 and 2008. Patients had no history of coronary artery bypass grafting.

Quality improvement in an anticoagulation clinic: development of a new treatment protocol.

We sought to improve patient outcomes and efficiency in our anticoagulation clinic through development of a new protocol for managing heart valve patients with subtherapeutic international normalized ratio (INR) tests. The new protocol standardized use of 1 anticoagulation agent while warfarin was retitrated, timelines for INR retesting, and target INR levels depending on the type of valve implanted. The new protocol provided significant improvements in patient care; however, outcomes for clinic operating efficiency were mixed.

Acetaminophen combinations protect against iron-induced cardiac damage in gerbils.

This study tested if acetaminophen, N-methyl-D-glucamine dithiocarbamate (NMGDTC), deferoxamine, and combinations of these agents reduce excess iron content, prevent iron-induced pathology, reduce cardiac arrhythmias, and reduce mortality in iron-overloaded gerbils. Eight groups of 16 gerbils received iron dextran injections (ferric hydroxide dextran complex, 120 mg/kg, ip) or saline solution (controls) twice/wk for 8 wk. The 8 groups were treated every Monday, Wednesday, and Friday with one of the following: saline control, acetaminophen, 150 mg/kg, ip), acetaminophen (150 mg/kg, po), deferoxamine, 83 mg/kg, ip), NMGDTC (200 mg/kg, ip), or combinations of acetaminophen (75 mg/kg) with deferoxamine (42 mg/kg, each ip, separately) or acetaminophen (75 mg/kg) with NMGDTC (100 mg/kg, each ip, separately).

Reduction of nontarget infection and systemic toxicity by targeted delivery of conditionally replicating viruses transported in mesenchymal stem cells.

The fiber-modified adenoviral vector Delta-24-RGD (D24RGD) offers vast therapeutic potential. Direct injection of D24RGD has been used to successfully target ovarian tumors in mice. However, systemic toxicity, especially in the liver, profoundly limits the efficacy of direct viral vector delivery.

Mesenchymal stem cells in cancer: tumor-associated fibroblasts and cell-based delivery vehicles.

Recent evidence suggests that mesenchymal stem cells (MSC) selectively home to tumors, where they contribute to the formation of tumor-associated stroma. This effect can be opposed by genetically modifying MSC to produce high levels of anti-cancer agents that blunt tumor growth kinetics and inhibit the growth of tumors in situ. In this review article, we describe the biological properties of MSC within the tumor microenvironment and discuss the potential use of MSC and other bone marrow-derived cell populations as delivery vehicles for antitumor proteins.

Age-associated changes in hearts of male Fischer 344/Brown Norway F1 rats.

Aging is associated with left ventricular hypertrophy, dilatation, and fibrosis of the heart. The Fischer 344/Brown Norway F1 (F344/BNF1) rat is recommended for age-related studies by the National Institutes on Aging because this hybrid rat lives longer and has a lower rate of pathological conditions than inbred rats. However, little is known about age-associated changes in cardiac and aortic function and structure in this model.

Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas.

The poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor. Because it has been suggested that circulating bone marrow-derived stem cells can be recruited into solid organs in response to tissue stresses, we hypothesized that human bone marrow-derived mesenchymal stem cells (hMSC) may have a tropism for brain tumors and thus could be used as delivery vehicles for glioma therapy. To test this, we isolated hMSCs from bone marrow of normal volunteers, fluorescently labeled the cells, and injected them into the carotid artery of mice bearing human glioma intracranial xenografts (U87, U251, and LN229).

Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents.

Background: High concentrations of interferon beta (IFN-beta) inhibit malignant cell growth in vitro. However, the therapeutic utility of IFN-beta in vivo is limited by its excessive toxicity when administered systemically at high doses. Mesenchymal stem cells (MSC) can be used to target delivery of agents to tumor cells.

Effect of experimental hyperhomocysteinemia on cardiac structure and function in the rat.

Male Sprague-Dawley rats were subjected for 2 weeks to daily injections of homocysteine (Hcy), which increased plasma Hcy approximately 2-fold. Echocardiography indicated significant increases in left ventricular diastolic (13%) and systolic (31%) dimensions and decreases in posterior wall thickness (diastolic, -17%; systolic, -20%) in Hcy-treated animals. Slight changes were noted in the ejection fraction, systolic fractional shortening, and maximal aortic valvular blood flow velocity, but they were not statistically significant or were similar to those in vehicle controls.

Effect of fasting on vascular contractility in lean and obese Zucker rats.

We compared the effects of fasting (36 h) on blood pressure and aortic contractile responsiveness in lean and obese Zucker rats. Fasting of lean animals resulted in a significant loss in body weight (-9.1 +/- 0.

Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors.

Molecules that physiologically control cell proliferation are often produced locally in tissues and are rapidly destroyed when they enter circulation. This allows local effects while avoiding interference with other systems. Unfortunately, it also limits the therapeutic use of these molecules via systemic delivery.

Directional coronary atherectomy in acute myocardial infarction.

Catheter-based intervention with directional coronary atherectomy (DCA) involving the surgical removal of obstructive plaque has been extensively studied in patients exhibiting stable and unstable angina. However, since no studies to date have evaluated the effectiveness of stand alone DCA as a primary treatment in the acute myocardial infarction (MI) setting, we conducted a five-year retrospective study of the early clinical and in-hospital outcomes of patients who underwent DCA within the 72-hour interval following acute MI. Our study included data obtained from a total of 30 acute MI patients treated between 1993 and 1998.

Information theoretical approach to constitution and reduction of medical data.

In medical decision problems it is very important to use the most relevant piece of information for decision making. We focus on a special case of diagnostic decision making when we can measure many symptoms and signs and we have to make diagnostic conclusions. We can state the problem as follows.

Metabolism of a [18F]fluorine labeled progestin (21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone) in humans: a clue for future investigations.

Assessment of estrogen receptors and progesterone receptors (PR) with PET may allow the determination of the hormone responsiveness of tumors without the need for multiple biopsies, and the monitoring of the effect of hormonal therapy. In spite of the favourable characteristics of 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone ([18F]FENP) found in preclinical studies, the compound failed to reveal the presence of PR in breast carcinomas and meningiomas. In view of the clinical significance of the PR assay in human breast cancer, it is worthwhile to explore mechanisms that are potentially involved in the inadequacy of [18F]FENP to image PR with PET.