Publications by authors named "Michael Mark"

83 Publications

Binimetinib, pemetrexed and cisplatin, followed by maintenance of binimetinib and pemetrexed in patients with advanced non-small cell lung cancer (NSCLC) and KRAS mutations. The phase 1B SAKK 19/16 trial.

Lung Cancer 2021 Apr 25;156:91-99. Epub 2021 Apr 25.

University of Berne, Hochschulstrasse 6, 3012 Bern, Switzerland; Department of Oncology/Hematology, Cantonal Hospital St.Gallen, Rorschacher Strasse 95, 9007 St.Gallen, Switzerland. Electronic address:

Background: KRAS mutations are found in 20-25 % of non-squamous non-small cell lung cancer (NSCLC) and therapies targeting the RAS/MEK/ERK pathway are in development. We performed a multicenter open-label phase 1B trial to determine the recommended phase 2 dose and early antitumor activity of the MEK-inhibitor binimetinib combined with cisplatin and pemetrexed.

Methods: Eligible patients (pts) had stage III-IV NSCLC unsuitable for curative treatment, KRAS exon 2 or 3 (codon 12, 13 or 61) mutations, no prior systemic therapy. Pts were enrolled into part 1: 3 + 3 design with dose escalation in 2 dose levels (DL) of binimetinib and part 2: expansion cohort at the maximum tolerated dose (MTD). Pts received 4 cycles of cisplatin 75 mg/m, pemetrexed 500 mg/mand binimetinib 30 (DL1)/45 mg (DL2) orally twice a day (bid) d1-14 q3w followed by pemetrexed and binimetinib until progressive disease (PD) or unacceptable toxicity.

Results: From May 2017 to Dec 2019, 18 pts (13 dose escalation, 5 expansion cohort) were enrolled. Median age was 60 (48-73, range). KRAS mutations were 87.5 % at codon 12. No DLT occurred in the dose escalation cohort. Median number of cycles was 2 (1-17, range). Treatment discontinuation was mainly due to PD (33 %) or pts/physicians' decision (27 %). Together with the expansion cohort, 16 pts were evaluable for safety. Most frequent treatment-related grade 3 AEs were lung infection (25 %), fatigue (19 %), anemia (19 %). Overall response rate among 9 evaluable pts receiving binimetinib at MTD (45 mg bid) was 33 % (7-70 %, 95 % CI). Median progression-free survival was 5.7 months (1.1-14.0, 95 % CI) and overall survival 6.5 months (1.8-NR, 95 % CI).

Conclusions: Pts treated with combination of cisplatin, pemetrexed and binimetinib presented no unexpected toxicity. No early signal of increased antitumor activity of binimetinib added to chemotherapy was observed in our pts population.
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http://dx.doi.org/10.1016/j.lungcan.2021.04.002DOI Listing
April 2021

Urinary dipeptidyl peptidase-4 protein is increased by linagliptin and is a potential predictive marker of urine albumin-to-creatinine ratio reduction in patients with type 2 diabetes.

Diabetes Obes Metab 2021 Apr 21. Epub 2021 Apr 21.

Boehringer Ingelheim International GmbH, Ingelheim, Germany.

Results of a post hoc analysis of urinary dipeptidyl peptidase-4 (DPP-4) protein as a predictor of urine albumin-to-creatinine ratio (UACR) response to linagliptin treatment based on MARLINA-T2D trial data are described. MARLINA was a 24-week, phase 3b, multinational, placebo-controlled clinical trial, in which patients with type 2 diabetes (T2D), HbA1c 6.5%-10.0% and UACR 30-3000 mg/g (n = 360) were treated with linagliptin or placebo. After 24 weeks of treatment, linagliptin significantly inhibited urinary DPP-4 activity and increased urinary DPP-4 protein. Furthermore, medium urinary DPP-4 protein levels (between 5.5 and 7.5 natural logarithmic [ln] μg/g creatinine) at baseline allowed for prediction of improved UACR in linagliptin-treated individuals. In patients with lower or higher levels of urinary DPP-4 protein at baseline, no association between linagliptin treatment and improved UACR was present. This might suggest a varying degree of importance of DPP-4 as a pathophysiological factor in T2D-associated kidney disease. In summary, urinary DPP-4 might be a useful predictive biomarker for UACR improvement by linagliptin.
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http://dx.doi.org/10.1111/dom.14407DOI Listing
April 2021

Challenges in tackling energy expenditure as obesity therapy: From preclinical models to clinical application.

Mol Metab 2021 Apr 18;51:101237. Epub 2021 Apr 18.

Cardio Metabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. Electronic address:

Background: A chronic imbalance of energy intake and energy expenditure results in excess fat storage. The obesity often caused by this overweight is detrimental to the health of millions of people. Understanding both sides of the energy balance equation and their counter-regulatory mechanisms is critical to the development of effective therapies to treat this epidemic.

Scope Of Review: Behaviors surrounding ingestion have been reviewed extensively. This review focuses more specifically on energy expenditure regarding bodyweight control, with a particular emphasis on the organs and attractive metabolic processes known to reduce bodyweight. Moreover, previous and current attempts at anti-obesity strategies focusing on energy expenditure are highlighted. Precise measurements of energy expenditure, which consist of cellular, animal, and human models, as well as measurements of their translatability, are required to provide the most effective therapies.

Major Conclusions: A precise understanding of the components surrounding energy expenditure, including tailored approaches based on genetic, biomarker, or physical characteristics, must be integrated into future anti-obesity treatments. Further comprehensive investigations are required to define suitable treatments, especially because the complex nature of the human perspective remains poorly understood.
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http://dx.doi.org/10.1016/j.molmet.2021.101237DOI Listing
April 2021

Patterns of care and economic consequences of using bone-targeted agents for castration-sensitive prostate cancer patients with bone metastases to prevent skeletal-related events in Switzerland - the SAKK 95/16 prostate study.

Swiss Med Wkly 2021 Mar 1;151:w20464. Epub 2021 Mar 1.

Department of Haematology/Oncology, Kantonsspital Graubünden, Chur, Switzerland.

Background: International guidelines state that bone-targeted agents such as denosumab or zoledronic acid at doses used for bone metastasis are not indicated for patients with metastatic castration-sensitive prostate cancer (mCSPC) with bone metastases. Whereas denosumab has never been studied in this patient population, zoledronic acid has been shown to be ineffective in decreasing the risk for skeletal-related events. This study estimates the prevalence and economic consequences of real-world use of bone-targeted agents for mCSPC patients in Switzerland.

Methods: To estimate the frequency of bone-targeted agent administration and skeletal-related events, data from a non-interventional, cross-sectional survey involving oncologists across Switzerland (SAKK 95/16) was combined with data from the Swiss National Institute for Cancer Epidemiology and Registration (NICER). Economic parameters were calculated from the perspective of the healthcare system over the median time to prostate-specific antigen (PSA) progression for the extrapolated patient group, using data from NICER. The cost calculation covered costs for bone-targeted agents, their administration and skeletal-related events. The time to PSA progression (33.2 months), as well as the probability and cost of skeletal-related events were derived from the literature.

Results: The survey was answered by 86 physicians treating 417 patients, of whom 106 (25.4%) had prostate cancer, with 36 (34.0%) of these mCSPC. The majority of mCSPC patients (52.8%, n = 19) received bone-targeted agents monthly. Denosumab was the treatment of choice in 84.2% of patients (n = 16). Extrapolation using data from NICER indicated that 568 mCSPC patients may be treated with bone-targeted agents at doses used for bone metastasis  every year in Switzerland, leading to estimated total costs of more than CHF 8.3 million over 33.2 months. Because of its more frequent prescription and higher price, it appears that almost 93% of the total costs can be attributed to denosumab. For both denosumab and zoledronic acid, the most expensive components were the cost of administration and the drug cost, making up more than 90% of the total costs, with the rest being costs of skeletal-related events.

Conclusions: This study found that the administration of bone-targeted agents in doses used for bone-metastatic diseases to prevent skeletal-related events is frequent in the setting of mCSPC and results in significant costs for the healthcare system.
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http://dx.doi.org/10.4414/smw.2021.20464DOI Listing
March 2021

Quality of life and pain in patients with metastatic bone disease from solid tumors treated with bone-targeted agents- a real-world cross-sectional study from Switzerland (SAKK 95/16).

BMC Cancer 2021 Feb 19;21(1):182. Epub 2021 Feb 19.

Kantonsspital Graubünden, Chur, Switzerland.

Background: Bone-targeted agents (BTAs) are widely used in the management of patients with bone metastases from solid tumors. Knowledge of the impact of their routine care use on patient-reported pain and bone pain-related quality of life (QoL) is limited.

Methods: This real world, cross-sectional study enrolled patients over a 3-month period through oncologists across Switzerland. Patients were ≥ 18 years, had solid tumors and at least one bone metastasis, and received routine care for bone metastases. Physicians provided data on BTA-related practices, risk of bone complications and BTA regimen. Patients completed questionnaires about pain (BPI-SF), general and bone pain-related QoL (FACT-G, FACT-BP) and treatment satisfaction (FACIT-TS-G).

Results: Eighteen sites recruited 417 patients. Based on the FACT-BP, 42% of the patients indicated not having bone pain. According to the BPI-SF, 28% reported no, 43% mild, 14% moderate, and 15% severe pain, respectively. Patients not treated with a BTA had better overall QoL (FACT-G: p = 0.031) and bone pain-related QoL (FACT-BP, p = 0.007) than those treated with a BTA. All pain and other QoL scales did not differ between groups. Patients perceived at 'low risk of bone complications' by their physician not receiving a BTA reported less pain and better QoL than those considered at 'low risk' but receiving BTA treatment or those considered at 'high risk' regardless of BTA treatment. Overall satisfaction with the treatment was good; almost 50% of patients reporting that they were completely satisfied.

Conclusions: Overall, pain and QoL did not differ according to BTA treatment or physicians' risk perception. Patient with low risks not receiving BTA treatment reported least pain and highest QoL scores. These results may suggest that treating physicians assess bone complication risk appropriately and treat patients accordingly, but they need to be confirmed by objective determination of longitudinal skeletal complication risk.
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http://dx.doi.org/10.1186/s12885-021-07903-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893880PMC
February 2021

[Commercial soda lime ingestion during a dive].

Anaesthesist 2021 04 16;70(4):327-332. Epub 2021 Feb 16.

Zentrale Notaufnahme, Universitätsklinikum Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Deutschland.

Breathing lime is used in closed circuit and semi-closed circuit rebreathers (CCR/SCR) for technical diving. Similar to the use in anesthesia systems, the lime usually contains hydroxycarbamide, which can react to caustic soda under the influence of water. The ingestion of components of the soda lime can lead to burns of the esophageal mucosa with the formation of colliquation necrosis and the danger of esophageal perforation. Early endoscopy is essential in this case to assess the consequences of ingestion.
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http://dx.doi.org/10.1007/s00101-021-00920-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026445PMC
April 2021

The potential use of lactate blockers for the prevention of COVID-19 worst outcome, insights from exercise immunology.

Med Hypotheses 2021 Mar 28;148:110520. Epub 2021 Jan 28.

Research Accessibility Team, Student and Internship Research Program, Faculty of Medicine, Cairo University, Egypt.

Following the decline in Physical Activity (PA) due to COVID-19 restrictions in the form of government mandated lockdowns and closures of public spaces, the modulatory effect of physical exercise on immunity is being heavily revisited. In an attempt to comprehend the wide discrepancy in patient response to COVID-19 and the factors that potentially modulate it, we summarize the findings relating PA to inflammation and immunity. A distinction is drawn between moderate intensity and high intensity physical exercise based on the high lactate production observed in the latter. We hypothesize that, the lactate production associated with high intensity anaerobic exercise is implicated in the modulation of several components of the innate and adaptive immunity. In this review, we also summarize these immunomodulatory effects of lactate. These include increasing serum IL-6 levels, the main mediator of cytokine storms, as well as affecting NK cells, Macrophages, Dendritic cells and cytotoxic T-lymphocytes. The implications of high lactate levels in athletic performance are highlighted where athletes should undergo endurance training to increase VO2 max and minimize lactate production. Tumor models of hypoxia were also reported where lactate levels are elevated leading to increased invasiveness and angiogenesis. Accordingly, the novel lactate blocking strategy employed in cancer treatment is evaluated for its potential benefit in COVID-19 in addition to the readily available beta-blockers as an antagonist to lactate. Finally, we suggest the diagnostic/prognostic purpose of the elevated lactate levels that can be determined through sweat lactate testing. It is the detrimental effect of lactate on immunity and its presence in sweat that qualify it to be used as a potential non-invasive marker of poor COVID-19 outcome.
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http://dx.doi.org/10.1016/j.mehy.2021.110520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840393PMC
March 2021

SAKK 19/17: safety analysis of first-line durvalumab in patients with PD-L1 positive, advanced nonsmall cell lung cancer and a performance status of 2.

Cancer Immunol Immunother 2021 May 1;70(5):1255-1262. Epub 2020 Nov 1.

Department of Medical Oncology, Kantonsspital St. Gallen, St Gallen, Switzerland.

Introduction: The safety of first-line (1L) durvalumab in patients with advanced nonsmall-cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (PS2) is unknown. This is an interim unplanned safety analysis of the study SAKK 19/17 for patients with metastatic NSCLC with programmed death-ligand 1 (PD-L1) expression in ≥ 25% of tumor cells and an ECOG PS2 treated with 1L durvalumab. This safety analysis was triggered by the SAKK data and safety monitoring board due to a high mortality rate observed after the recruitment of the first 21 patients.

Methods: This single-arm phase II study recruited patients with metastatic NSCLC with PD-L1 in ≥ 25% and ECOG PS2. Patients received durvalumab 1500 mg every four weeks. The trial aims to recruit 48 patients in total. This report includes safety analyses only. Adverse events (AEs) were assessed using National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) Version 5.0. Efficacy data including the primary endpoint overall survival at 6 months and secondary endpoints (objective response rate, progression-free survival, and quality of life) will be reported at a later time point.

Results: The data from 21 patients were available at this interim safety analysis. Among these, 13 deaths (13/21; 62%) were reported, including one treatment-related fatal colonic perforation at 9 months after treatment initiation (1/13; 8%). Twelve deaths were not treatment-related (12/13; 92%), and mostly attributed to tumor progression (10/13; 77%). Of note, seven deaths (7/13; 54%) occurred during the first 5 weeks (range 0.6-4.7 weeks) after treatment initiation. Four (4/7; 57%) were respiratory failures attributed to tumor progression. One of these patients (25%) had pre-existing COPD, and three (75%) had baseline dyspnea grade 2-3 related to the tumor. Grade ≥ 3 treatment-related AEs (TRAEs) included colonic perforation (grade 5), abdominal pain, and colitis (grade 3 each) in one patient, and fatigue (grade 3) in another. Other Grade ≥ 3 AEs unrelated to treatment were all of pulmonary origin: lung infections (19%), dyspnea (24%), cough (5%), and bronchial obstruction (5%).

Conclusions: 1L durvalumab in patients with ECOG PS2 and metastatic NSCLC with PD-L1 expression ≥ 25% resulted in an unexpectedly high number of fatal early events due to rapid tumor progression. We recommend to avoid treatment with 1 L durvalumab of patients who are highly symptomatic from the tumor, particularly those with respiratory symptoms. The study is continuing its accrual after an amendment excluding these patients.
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http://dx.doi.org/10.1007/s00262-020-02757-8DOI Listing
May 2021

SGLT2 is not expressed in pancreatic α- and β-cells, and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans.

Mol Metab 2020 12 5;42:101071. Epub 2020 Sep 5.

Pole of Endocrinology, Diabetes, and Nutrition (EDIN), Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain (UCLouvain), 1200, Brussels, Belgium. Electronic address:

Objective: Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i), or gliflozins, are anti-diabetic drugs that lower glycemia by promoting glucosuria, but they also stimulate endogenous glucose and ketone body production. The likely causes of these metabolic responses are increased blood glucagon levels, and decreased blood insulin levels, but the mechanisms involved are hotly debated. This study verified whether or not SGLT2i affect glucagon and insulin secretion by a direct action on islet cells in three species, using multiple approaches.

Methods: We tested the in vivo effects of two selective SGLT2i (dapagliflozin, empagliflozin) and a SGLT1/2i (sotagliflozin) on various biological parameters (glucosuria, glycemia, glucagonemia, insulinemia) in mice. mRNA expression of SGLT2 and other glucose transporters was assessed in rat, mouse, and human FACS-purified α- and β-cells, and by analysis of two human islet cell transcriptomic datasets. Immunodetection of SGLT2 in pancreatic tissues was performed with a validated antibody. The effects of dapagliflozin, empagliflozin, and sotagliflozin on glucagon and insulin secretion were assessed using isolated rat, mouse and human islets and the in situ perfused mouse pancreas. Finally, we tested the long-term effect of SGLT2i on glucagon gene expression.

Results: SGLT2 inhibition in mice increased the plasma glucagon/insulin ratio in the fasted state, an effect correlated with a decline in glycemia. Gene expression analyses and immunodetections showed no SGLT2 mRNA or protein expression in rodent and human islet cells, but moderate SGLT1 mRNA expression in human α-cells. However, functional experiments on rat, mouse, and human (29 donors) islets and the in situ perfused mouse pancreas did not identify any direct effect of dapagliflozin, empagliflozin or sotagliflozin on glucagon and insulin secretion. SGLT2i did not affect glucagon gene expression in rat and human islets.

Conclusions: The data indicate that the SGLT2i-induced increase of the plasma glucagon/insulin ratio in vivo does not result from a direct action of the gliflozins on islet cells.
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http://dx.doi.org/10.1016/j.molmet.2020.101071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554656PMC
December 2020

[Lactate in emergency medicine].

Anaesthesist 2020 11;69(11):826-834

Zentrale Notaufnahme, Universitätsklinikum Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Deutschland.

The basis of all metabolic processes in the human body is the production and metabolism of carriers of energy. Lactate is the end-product of anaerobic glycolysis. Lactate can serve as a substrate for gluconeogenesis and as an oxidation substrate. Hyperlactatemia can be detected as the result of a multitude of acute events (e.g. shock, sepsis, cardiac arrest, trauma, seizure, ischemia, diabetic ketoacidosis, thiamine deficiency, liver failure and intoxication). Hyperlactatemia can be associated with increased mortality, therefore in emergency medicine the search for the cause of hyperlactatemia is just as important as an effective causal treatment. Repetitive measurements of lactate are components of several treatment algorithms as observation of the dynamic development of blood lactate concentrations can help to make a better assessment of the acute medical condition of the patient and to evaluate the effectiveness of the measures undertaken.
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http://dx.doi.org/10.1007/s00101-020-00819-1DOI Listing
November 2020

SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition.

Cell Metab 2020 09 28;32(3):404-419.e6. Epub 2020 Jul 28.

Department of Medicine, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan. Electronic address:

SGLT2 inhibitors offer strong renoprotection in subjects with diabetic kidney disease (DKD). But the mechanism for such protection is not clear. Here, we report that in damaged proximal tubules of high-fat diet-fed ApoE-knockout mice, a model of non-proteinuric DKD, ATP production shifted from lipolysis to ketolysis dependent due to hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). We further found that empagliflozin raised endogenous ketone body (KB) levels, and thus its use or treatment with 1,3-butanediol, a KB precursor, prevented decreases in renal ATP levels and organ damage in the mice. The renoprotective effect of empagliflozin was abolished by gene deletion of Hmgcs2, a rate-limiting enzyme of ketogenesis. Furthermore, KBs attenuated mTORC1-associated podocyte damage and proteinuria in diabetic db/db mice. Our findings show that SGLT2 inhibition-associated renoprotection is mediated by an elevation of KBs that in turn corrects mTORC1 hyperactivation that occurs in non-proteinuric and proteinuric DKD.
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http://dx.doi.org/10.1016/j.cmet.2020.06.020DOI Listing
September 2020

A Randomized Open-Label Phase III Trial Evaluating the Addition of Denosumab to Standard First-Line Treatment in Advanced NSCLC: The European Thoracic Oncology Platform (ETOP) and European Organisation for Research and Treatment of Cancer (EORTC) SPLENDOUR Trial.

J Thorac Oncol 2020 10 18;15(10):1647-1656. Epub 2020 Jun 18.

Spanish lung cancer group (Grupo Español de Cancer de Pulmón (GECP)), Barcelona, Spain; Department of Medical Oncology, Hospital Puerta de Hierro-Majadahonda, Madrid, Spain.

Introduction: Receptor activator of NF-kB ligand stimulates NF-kB-dependent cell signaling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumors suggested significant overall survival (OS) advantage for patients with lung cancer with denosumab (p = 0.01). The randomized open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improved OS in advanced NSCLC.

Methods: Patients with stage IV NSCLC were randomized in a 1:1 ratio to either chemotherapy with or without denosumab (120 mg every 3-4 wks), stratified by the presence of bone metastases (at diagnosis), Eastern Cooperative Oncology Group performance status, histology, and region. To detect an OS increase from 9 to 11.25 months (hazard ratio [HR] = 0.80), 847 OS events were required. The trial closed prematurely owing to decreasing accrual rate.

Results: A total of 514 patients were randomized, with 509 receiving one or more doses of the assigned treatment (chemotherapy: 252, chemotherapy-denosumab: 257). The median age was 66.1 years, 71% were men, and 59% were former smokers. Bone metastases were identified in 275 patients (53%). Median OS (95% confidence interval [CI]) was 8.7 (7.6-11.0) months in the control arm versus 8.2 (7.5-10.4) months in the chemotherapy-denosumab arm (HR = 0.96; 95% CI: 0.78-1.19; one-sided p = 0.36). For patients with bone metastasis, HR was 1.02 (95% CI: 0.77-1.35), whereas for those without, HR was 0.90 (95% CI: 0.66-1.23). Adverse events grade 3 or greater were observed in 40.9%, 5.2%, 8.7% versus 45.5%, 10.9%, 10.5% of patients. Conditional power for OS benefit was less than or equal to 10%.

Conclusions: Denosumab was well-tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the intention-to-treat population and the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in patients with NSCLC without bone metastases.
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http://dx.doi.org/10.1016/j.jtho.2020.06.011DOI Listing
October 2020

Robust identification of controlled Hawkes processes.

Phys Rev E 2020 Apr;101(4-1):043305

École Polytechnique Fédérale de Lausanne, Station 5, CH-1015 Lausanne, Switzerland.

The identification of Hawkes-like processes can pose significant challenges. Despite substantial amounts of data, standard estimation methods show significant bias or fail to converge. To overcome these issues, we propose an alternative approach based on an expectation-maximization algorithm, which instrumentalizes the internal branching structure of the process, thus improving convergence behavior. Furthermore, we show that our method provides a tight lower bound for maximum-likelihood estimates. The approach is discussed in the context of a practical application, namely the collection of outstanding unsecured consumer debt.
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http://dx.doi.org/10.1103/PhysRevE.101.043305DOI Listing
April 2020

Impact of Early Prophylactic Cranial Irradiation With Hippocampal Avoidance on Neurocognitive Function in Patients With Limited Disease Small Cell Lung Cancer. A Multicenter Phase 2 Trial (SAKK 15/12).

Int J Radiat Oncol Biol Phys 2020 06 4;107(2):279-287. Epub 2020 Mar 4.

Quality of Life Office SAKK Coordinating Center and International Breast Cancer Study Group (IBCSG) Coordinating Center, Bern, Switzerland.

Purpose: Our purpose was to evaluate neurocognitive function (NCF) and clinical outcomes after early hippocampal avoidance (HA) prophylactic cranial irradiation (PCI) in limited disease (LD) small cell lung cancer (SCLC).

Methods And Materials: In a phase 2 trial, patients with LD SCLC received HA-PCI concomitant with the second cycle of chemotherapy and thoracic radiation therapy. All patients underwent objective NCF testing at baseline, 6 weeks, and 6 and 12 months after HA-PCI. NCF tests included Hopkins Verbal Learning Test Revised, Controlled Oral Word Association, and Trail Making Tests A and B. The primary endpoint was NCF decline at 6 months after HA-PCI. We assumed ≤30% of patients with no NCF decline to be unpromising. Secondary endpoints included brain metastases-free survival (BMFS), overall survival (OS), and safety of the concomitant treatment.

Results: Among the 44 patients enrolled in the trial, 38 had evaluable NCF assessment at 6 months after HA-PCI. The proportion of evaluable patients showing no NCF decline at 6 and 12 months was 34.2% (90% confidence interval [CI], 21.6-48.8) and 48.5% (95% CI, 30.8-66.5), respectively. Median follow-up was 13.2 months (95% CI, 12.6-14.1). At 12 months, BMFS was 84.2% and OS was 87.7% (95% CI, 73.0-94.7). Four patients died of SCLC, 1 of respiratory failure, 1 of hemorrhage, and 1 for unknown reason. The most frequently reported grade ≥3 acute adverse events were anemia (21.4%), febrile neutropenia (19.1%), and fatigue (14.3%).

Conclusions: The proportion of patients showing no NCF decline 6 and 12 months after early HA-PCI does not appear to be better than, but rather similar to, that observed in patients receiving sequential PCI without HA. Early HA-PCI in LD SCLC is feasible, with observation of promising BMFS and OS in this selected population.
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http://dx.doi.org/10.1016/j.ijrobp.2020.02.029DOI Listing
June 2020

Linagliptin and telmisartan induced effects on renal and urinary exosomal miRNA expression in rats with 5/6 nephrectomy.

Sci Rep 2020 02 25;10(1):3373. Epub 2020 Feb 25.

Boehringer Ingelheim Pharma GmbH & Co. KG, Cardiometabolic Diseases Research, Biberach, Germany.

Dipeptidyl peptidase 4 inhibitors and angiotensin II receptor blockers attenuate chronic kidney disease progression in experimental diabetic and non-diabetic nephropathy in a blood pressure and glucose independent manner, but the exact molecular mechanisms remain unclear. MicroRNAs (miRNAs) are short, non-coding RNA species that are important post-transcriptional regulators of gene expression and play an important role in the pathogenesis of nephropathy. miRNAs are present in urine in a remarkably stable form, packaged in extracellular vesicles. Here, we investigated linagliptin and telmisartan induced effects on renal and urinary exosomal miRNA expression in 5/6 nephrectomized rats. In the present study, renal miRNA profiling was conducted using the Nanostring nCounter technology and mRNA profiling using RNA sequencing from the following groups of rats: sham operated plus placebo; 5/6 nephrectomy plus placebo; 5/6 nephrectomy plus telmisartan; and 5/6 nephrectomy plus linagliptin. TaqMan Array miRNA Cards were used to evaluate which of the deregulated miRNAs in the kidney are present in urinary exosomes. In kidneys from 5/6 nephrectomized rats, the expression of 13 miRNAs was significantly increased (>1.5-fold, P < 0.05), whereas the expression of 7 miRNAs was significantly decreased (>1.5-fold, P < 0.05). Most of the deregulated miRNA species are implicated in endothelial-to-mesenchymal transition and inflammatory processes. Both telmisartan and linagliptin suppressed the induction of pro-fibrotic miRNAs, such as miR-199a-3p, and restored levels of anti-fibrotic miR-29c. In conclusion, the linagliptin and telmisartan-induced restorative effects on miR-29c expression were reflected in urinary exosomes, suggesting that miRNA profiling of urinary exosomes might be used as a biomarker for CKD progression and monitoring of treatment effects.
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http://dx.doi.org/10.1038/s41598-020-60336-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042229PMC
February 2020

Patterns of care for patients with metastatic bone disease in solid tumors: A cross-sectional study from Switzerland (SAKK 95/16).

J Bone Oncol 2020 Apr 16;21:100273. Epub 2019 Dec 16.

Department of Hematology/Oncology, Kantonsspital Graubünden, Loestrasse 170, 7000 Chur, Switzerland.

Background: Bone-targeted agents (BTAs) are widely used in the management of patients with bone metastases from solid tumors, but knowledge of their routine care use and the therapeutic implications remains limited. This non-interventional study aimed to characterize real-world BTA patterns of care in Switzerland.

Materials And Methods: Non-interventional, cross-sectional study involving oncologists from across Switzerland who completed a Treating Physician questionnaire, providing data on their clinical setting and BTA-related practices, and a Patient Characteristics and Treatment questionnaire, providing data on their patients' disease status, risk of bone complications, BTA regimen and related outcomes. Eligible patients were aged ≥ 18 years, with solid tumors and at least one bone metastasis and were receiving routine management at the participating physician's center over the 3-month study period.

Results: A total of 86 oncologists recruited 417 patients from across 18 centers in Switzerland (80% public hospitals; 20% private clinics). The majority of physicians (70.9%) reported prescribing BTAs in line with international guidelines; denosumab was the treatment of choice in 78.5% of patients. BTAs were widely administered (94.2%) according to a 3-4-weekly dosing regimen; 33.7% of physicians reported extending intervals to 12 weeks after an initial 2 years of treatment. Physicians appeared to use clinical judgement, as well as formal risk assessment, to guide treatment for symptomatic skeletal events. No association was seen between either BTA use, or risk of complications, and incidence of skeletal complications. Only 4.3% of patients were reported to be experiencing severe bone pain at the time of the study.

Conclusions: This cross-sectional, non-interventional study found high implementation of guideline-recommended BTA prescribing, good pain control and low incidence of skeletal-related events. Long-term BTA randomized controlled trials have the potential to further optimize routine care outcomes for patients.
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http://dx.doi.org/10.1016/j.jbo.2019.100273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965709PMC
April 2020

Excited State Torsional Processes in Chalcogenopyrylium Monomethine Dyes.

J Phys Chem A 2019 Oct 8;123(41):8807-8822. Epub 2019 Oct 8.

Department of Chemistry , University of Rochester , Rochester , New York 14627 United States.

Chalcogenopyrylium monomethine (CGPM) dyes represent a class of environmentally activated singlet oxygen generators with applications in photodynamic therapy (PDT) and photoassisted chemotherapy (PACT). Upon binding to genomic material, the dyes are presumed to rigidify, allowing for intersystem crossing to outcompete excited state deactivation by internal conversion. This results in large triplet yields and hence large singlet oxygen yields. To understand the nature of the internal conversion process that controls the activity of the dyes, femtosecond transient absorption experiments were performed on a series of S-, Se-, and Te-substituted CGPM dyes. For S- and Se-substituted species in methanol, rapid internal conversion from the singlet excited state, S, occurs in ∼5 ps, deactivating the optically active excited state. The internal conversion produces a distorted ground-state species that returns to its equilibrium structure in ∼20 ps. For Te-substituted species, the internal conversion competes with rapid intersystem crossing to the lowest triplet state, T, which occurs with a ∼ 100 ps time constant in methanol. In more viscous methanol/glycerol mixtures, the internal conversion to the ground state slows by 2 orders of magnitude, occurring in 500-600 ps. For Se- and Te-substituted species in viscous environments, the slower internal conversion rate allows a larger triplet yield. Using femtosecond stimulated Raman spectroscopy (FSRS) and time-dependent density functional theory (TD-DFT), the internal conversion is determined to occur by twisting of the pyrylium rings about the monomethine bridge. Evolution from the distorted ground state occurs by twisting back to the S equilibrium structure. The environmentally dependent photoactivity of CGPM dyes is discussed in the context of PDT and PACT applications.
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http://dx.doi.org/10.1021/acs.jpca.9b07268DOI Listing
October 2019

A Phase 1 study of BAL101553, a novel tumor checkpoint controller targeting microtubules, administered as 48-h infusion in adult patients with advanced solid tumors.

Invest New Drugs 2020 08 30;38(4):1067-1076. Epub 2019 Aug 30.

Department of Medical Oncology, Cantonal Hospital Graubünden, Chur, Switzerland.

Purpose BAL101553, the prodrug of the microtubule-destabilizer BAL27862, previously showed signs of antitumor activity when administered as a 2-h infusion, but its use was limited by vascular toxicity. We investigated an alternative dosing strategy aimed at improving the safety profile of BAL101553. Methods This multicenter, open-label, Phase 1 dose-escalation study used a 3 + 3 design to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and antitumor activity of BAL101553 administered as a 48-h IV infusion on Days 1, 8, and 15 of a 28-day cycle. Patients received oral BAL101553 on Days 15-21 of cycle 2 to assess oral bioavailability. Results BAL101553 was well tolerated at doses up to ≤70 mg/m. Three grade 3 DLTs occurred: hypotension (70 mg/m), hyponatremia and neutropenia (both 90 mg/m). The MTD for 48-h IV BAL101553 was 70 mg/m. At this dose level, the AUC for BAL27862 was 8580 ng.h/mL and the C was 144 ng/mL. No apparent dose-related effects on blood pressure were observed with 48-h BAL101553 IV infusion. BAL27862 oral bioavailability was >80%. Conclusions Continuous 48-h IV BAL101553 infusion achieved higher exposure of the BAL27862 active metabolite than a 2-h infusion at the RP2D and did not cause vascular toxicity. Clinicaltrials.gov registration: NCT02895360.
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http://dx.doi.org/10.1007/s10637-019-00850-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340672PMC
August 2020

Impact of Addition of Metformin to Abiraterone in Metastatic Castration-Resistant Prostate Cancer Patients With Disease Progressing While Receiving Abiraterone Treatment (MetAb-Pro): Phase 2 Pilot Study.

Clin Genitourin Cancer 2019 04 2;17(2):e323-e328. Epub 2019 Jan 2.

Kantonsspital Graubünden, Chur, Switzerland.

Background: There is evidence linking metformin to improved prostate cancer-related outcomes.

Patients And Methods: Twenty-five men with metastatic castration-resistant prostate cancer and prostate-specific antigen (PSA) progression while receiving treatment with abiraterone from 3 Swiss centers were included in this single-arm phase 2 trial between November 2013 and September 2016. Metformin was added to abiraterone continuously at 1000 mg twice daily in uninterrupted 4-week cycles. The primary end point was the absence of disease progression at 12 weeks (PFS12). The Fleming single-stage design was applied. With a 5% significance level and 80% power, 25 patients were required to test PFS12 ≤ 15% (H0) compared to ≥ 35% (H1). Secondary end points included toxicity and safety issues. The study was registered at ClinicalTrials.gov (NCT01677897).

Results: The primary end point PFS12 was 12% (3 of 25 patients) (95% confidence interval, 3-31). Most patients had PSA progression, almost half had radiographic progression, but only 1 patient had symptomatic progression. Eleven (44%) of 25 patients had grade 1 and 2 patients each grade 2 (8%) or grade 3 (8%) gastrointestinal toxicity (nausea, diarrhea, loss of appetite). One patient discontinued treatment at week 5 because of intolerable grade 3 diarrhea.

Conclusion: The addition of metformin to abiraterone for patients with metastatic castration-resistant prostate cancer and PSA progression while receiving abiraterone therapy does not affect further progression and has no meaningful clinical benefit. A higher-than-expected gastrointestinal toxicity attributed to metformin was observed.
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http://dx.doi.org/10.1016/j.clgc.2018.12.009DOI Listing
April 2019

Multimodal Treatment in Operable Stage III NSCLC: A Pooled Analysis on Long-Term Results of Three SAKK trials (SAKK 16/96, 16/00, and 16/01).

J Thorac Oncol 2019 01 26;14(1):115-123. Epub 2018 Sep 26.

Department of Medical Oncology, Cantonal Hospital of Winterthur, Winterthur, Switzerland.

Introduction: Long-term data on outcomes of operable stage III NSCLC are scarce.

Methods: Individual patient data from 368 patients enrolled in one phase III and two phase II trials were pooled and outcomes after applying the eighth (denoted with an asterisk [*]) versus the sixth TNM staging edition were compared. Patients were treated with either preoperative radiotherapy following 3 cycles of induction chemotherapy (trimodal) or neoadjuvant chemotherapy alone (bimodal).

Results: With the sixth version, the 5- and 10-year survival rates were 38% and 28% for stage IIIA, respectively, and 36% and 24% for stage IIIB, respectively. Factors associated with improved 5-year overall survival were younger age, R0 resection, and pathologic complete remission (pCR) (p = 0.043, p < 0.001 and p = 0.009). With the eighth TNM staging version, 162 patients were moved from stage IIIA to IIIB*. The 5- and 10-year survival rates were 41% and 29% for stage IIIA*, respectively, and 35% and 27% for stage IIIB* patients, respectively. There was no difference in the bi- versus trimodal group with regard to median overall survival (28 months [95% confidence interval (CI): 21-39 months] and 37 months [95% CI: 24-51 months], p = 0.9) and event-free survival (12 months [95% CI: 9-15 months] versus 13 months [95% CI: 10-22 months], p = 0.71).

Conclusions: We showed favorable 10-year survival rates of 29% and 27% in stage IIIA* and IIIB*, respectively. Younger age, R0 resection, and pathologic complete response were associated with improved long-term survival. Outcomes using the sixth versus eighth edition of the TNM classification were similar in operable stage III NSCLC.
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http://dx.doi.org/10.1016/j.jtho.2018.09.011DOI Listing
January 2019

Differences in kidney-specific DPP-4 inhibition by linagliptin and sitagliptin.

Diabetes Res Clin Pract 2018 Sep 18;143:199-203. Epub 2018 Jul 18.

Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. Electronic address:

The two dipeptidyl peptidase (DPP)-4 inhibitors, linagliptin and sitagliptin, were shown to exert different binding kinetics in vitro. Twenty-four hours after oral dosing particularly in vivo inhibition of renal-specific DPP-4 activity was more sustained in Sprague Dawley rats after exposure to linagliptin than it was after sitagliptin.
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http://dx.doi.org/10.1016/j.diabres.2018.07.009DOI Listing
September 2018

Panchromatic Sensitization with Zn Porphyrin-Based Photosensitizers for Light-Driven Hydrogen Production.

ChemSusChem 2018 Aug 25;11(15):2517-2528. Epub 2018 Jul 25.

College of Chemistry, Fuzhou University, Fuzhou, Fujian, 350108, P. R. China.

Three molecular photosensitizers (PSs) with carboxylic acid anchors for attachment to platinized titanium dioxide nanoparticles were studied for light-driven hydrogen production from a fully aqueous medium with ascorbic acid (AA) as the sacrificial electron donor. Two zinc(II) porphyrin (ZnP)-based PSs were used to examine the effect of panchromatic sensitization on the photocatalytic H generation. A dyad molecular design was used to construct a difluoro boron-dipyrromethene (bodipy)-conjugated ZnP PS (ZnP-dyad), whereas the other one featured an electron-donating diarylamino moiety (YD2-o-C8). To probe the use of the ZnP scaffold in this particular energy conversion process, an organic PS without the ZnP moiety (Bodipy-dye) was also synthesized for comparison. Ultrafast transient absorption spectroscopy was adopted to map out the energy transfer processes occurring in the dyad and to establish the bodipy-based antenna effect. In particular, the systems with YD2-o-C8 and ZnP-dyad achieved a remarkable initial activity for the production of H with an initial turnover frequency (TOF ) higher than 300 h under white light irradiation. The use of ZnP PSs in dye-sensitized photocatalysis for the H evolution reaction in this study indicated the importance of the panchromatic sensitization capability for the development of light absorbing PSs.
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http://dx.doi.org/10.1002/cssc.201801255DOI Listing
August 2018

Rhodamine-Platinum Diimine Dithiolate Complex Dyads as Efficient and Robust Photosensitizers for Light-Driven Aqueous Proton Reduction to Hydrogen.

J Am Chem Soc 2018 02 8;140(7):2575-2586. Epub 2018 Feb 8.

Department of Chemistry, University of Rochester , Rochester, New York 14627, United States.

Three new dyads consisting of a rhodamine (RDM) dye linked covalently to a Pt diimine dithiolate (PtNS) charge transfer complex were synthesized and used as photosensitizers for the generation of H from aqueous protons. The three dyads differ only in the substituents on the rhodamine amino groups, and are denoted as Pt-RDM1, Pt-RDM2, and Pt-RDM3. In acetonitrile, the three dyads show a strong absorption in the visible region corresponding to the rhodamine π-π* absorption as well as a mixed metal-dithiolate-to-diimine charge transfer band characteristic of PtNS complexes. The shift of the rhodamine π-π* absorption maxima in going from Pt-RDM1 to Pt-RDM3 correlates well with the HOMO-LUMO energy gap measured in electrochemical experiments. Under white light irradiation, the dyads display both high and robust activity for H generation when attached to platinized TiO nanoparticles (Pt-TiO). After 40 h of irradiation, systems containing Pt-RDM1, Pt-RDM2, and Pt-RDM3 exhibit turnover numbers (TONs) of 33600, 42800, and 70700, respectively. Ultrafast transient absorption spectroscopy reveals that energy transfer from the rhodamine π-π* state to the singlet charge transfer (CT) state of the PtNS chromophore occurs within 1 ps for all three dyads. Another fast charge transfer process from the rhodamine π-π* state to a charge separated (CS) RDM-Pt state is also observed. Differences in the relative activity of systems using the RDM-PtNS dyads for H generation correlate well with the relative energies of the CS state and the PtNSCT state used for H production. These findings show how one can finely tune the excited state energy levels to direct excited state population to the photochemically productive states, and highlight the importance of judicious design of a photosensitizer dyad for light absorption and photoinduced electron transfer for the photogeneration of H from aqueous protons.
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http://dx.doi.org/10.1021/jacs.7b11581DOI Listing
February 2018

Vitamin D levels in Swiss breast cancer survivors.

Swiss Med Wkly 2018 16;148:w14576. Epub 2018 Jan 16.

Breast Centre St Gallen, St Gallen Cantonal Hospital, Switzerland.

Background: Cholecalciferol (vitamin D3) is widely supplemented in breast cancer survivors because of the role of vitamin D in multiple health outcomes.

Methods: We conducted an observational study in 332 women in Eastern Switzerland with early, i.e., nonmetastatic breast cancer. Tumour-, patient-related and sociodemographic variables were recorded. Cholecalciferol intake and serum 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were measured at the first visit (baseline) and during a follow-up visit in a median of 210 days (range 87-857) after the first visit. Patients presenting 25(OH)D deficiency were advised to take cholecalciferol supplementation.

Results: At baseline, 60 (18%) patients had 25(OH)D deficiency (≤50 nmol/l, ≤20 ng/l), and 70 (21%) had insufficiency (50-74 nmol/l, 20-29 ng/l). Out of 121 patients with ongoing cholecalciferol supplementation at baseline, 25(OH)D deficiency and insufficiency was observed in 9 (7%) and 16 (13%) patients, respectively, whereas out of 52 patients with no supplementation, 15 (29%) had deficiency and 19 (37%) had insufficiency. Only 85 (26%) patients had optimal 25(OH)D levels (75-100 nmol/l, 30-40 ng/l) at baseline. Seasonal variation was significant for 25(OH)D (p = 0.042) and 1,25(OH)2D (p = 0.001) levels. Living in a rural area was associated with a higher median 25(OH)D concentration as compared with living in an urban area (87 nmol/l, range 16-216 vs 72 nmol/l, range 17-162; p = 0.001). Regular sporting activity was positively associated with 25(OH)D (p = 0.045). Body mass index was inversely related to both 25(OH)D and 1,25(OH)2D (Spearman's rho = -0.24, p <0.001; rho = -0.23, p <0.001, respectively). The levels of 25(OH)D and 1,25(OH)2D were correlated (rho = 0.21, p <0.001). Age and bone mineral density had no significant correlation with the levels of 25(OH)D. Follow-up 25(OH)D was available for 230 patients, 44 (19%) of whom had 25(OH)D deficiency and 47 (21%) had insufficiency; 25 (41.6%) initially 25(OH)D-deficient patients attained sufficient 25(OH)D levels, whereas 33 (16.5%) patients with sufficient baseline 25(OH)D levels became deficient. Only 67 (30%) patients presented optimal 25(OH)D at the follow-up.

Conclusion: A remarkable fraction of the patients had serum 25(OH)D below (40%) or above (30%) optimal levels, and only around 30% of patients had optimal levels. Levels of 25(OH)D and 1,25(OH)2D increased on cholecalciferol supplementation, but the usual supplementation regimens were not adequate to bring 25(OH)D to the optimal range for a large proportion of patients.

Trial Registration Number: EKSG 08/082/2B.
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http://dx.doi.org/10.4414/smw.2018.14576DOI Listing
September 2018

Characterization of the properties of a selective, orally bioavailable autotaxin inhibitor in preclinical models of advanced stages of liver fibrosis.

Br J Pharmacol 2018 02 17;175(4):693-707. Epub 2018 Jan 17.

Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.

Background And Purpose: Autotaxin (ATX) is a secreted phospholipase which hydrolyses lysophosphatidylcholine to generate lysophosphatidic acid (LPA). The extracellular signalling molecule LPA exerts its biological actions through activation of six GPCRs expressed in various cell types including fibroblasts. Multiple preclinical studies using knockout animals, LPA receptor antagonists or ATX inhibitors have provided evidence for a potential role of the ATX/LPA axis in tissue fibrosis. Despite growing evidence for a correlation between ATX levels and the degree of fibrosis in chronic liver diseases, including viral hepatitis and hepatocellular carcinoma, the role of ATX in non-alcoholic steatohepatitis (NASH) remains unclear.

Experimental Approach: The relevance of ATX in the pathogenesis of liver fibrosis was investigated by oral administration of Ex_31, a selective ATX inhibitor, in a 10 week model of carbon tetrachloride-induced liver injury and in a 14 week model of choline-deficient amino acid-defined diet-induced liver injury in rats.

Key Results: Oral administration of Ex_31, a selective ATX inhibitor, at 15 mg·kg twice daily in therapeutic intervention mode resulted in efficient ATX inhibition and more than 95% reduction in plasma LPA levels in both studies. Treatment with Ex_31 had no effect on biomarkers of liver function, inflammation, or fibrosis and did not result in histological improvements in diseased animals.

Conclusions And Implications: Our findings question the role of ATX in the pathogenesis of hepatic fibrosis and the potential of small molecule ATX inhibitors for the treatment of patients with NASH and advanced stages of liver fibrosis.
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http://dx.doi.org/10.1111/bph.14118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787030PMC
February 2018

Randomized Phase III Trial of Erlotinib versus Docetaxel in Patients with Advanced Squamous Cell Non-Small Cell Lung Cancer Failing First-Line Platinum-Based Doublet Chemotherapy Stratified by VeriStrat Good versus VeriStrat Poor. The European Thoracic Oncology Platform (ETOP) EMPHASIS-lung Trial.

J Thorac Oncol 2017 04 23;12(4):752-762. Epub 2016 Dec 23.

Wilhelmina Hospital, Assen, The Netherlands.

Introduction: Docetaxel and erlotinib are registered second-line treatments for wild-type EGFR NSCLC. Previous studies suggested a predictive value of the VeriStrat test in second-line therapy of NSCLC, classifying patients as either VeriStrat good or VeriStrat poor. EMPHASIS-lung aimed at exploring this predictive effect in patients with squamous cell NSCLC. The trial closed prematurely because of low accrual and results from other trials. Our analysis includes an exploratory combined analysis with results from the PROSE trial.

Methods: EMPHASIS-lung was a randomized phase III multicenter trial exploring the differential effect of second-line erlotinib versus docetaxel on progression-free survival (PFS) in VeriStrat good versus VeriStrat poor patients with squamous cell NSCLC.

Results: A total of 80 patients were randomized, with 72.5% categorized as VeriStrat good. Patient characteristics were balanced between VeriStrat status and treatment groups. The median PFS times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 4.1 and 1.6 months, respectively, versus 1.9 and 2.1 months, respectively, in the VeriStrat poor cohort. The median overall survival (OS) times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 7.8 and 8.4 months, respectively, and 4.4 and 5.2 months, respectively, in the VeriStrat poor cohort. An additional exploratory analysis was performed; in it, 47 patients from the squamous cell subgroup of PROSE were included in a combined analysis, contributing with 45 PFS and 41 OS events.

Conclusions: The final analysis of EMPHASIS-lung did not show a differential effect on PFS for erlotinib versus docetaxel stratified by VeriStrat status. Similarly, in the combined analysis, no significant treatment by VeriStrat status interaction was observed (interaction p = 0.24 for PFS and 0.45 for OS, stratified by study).
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http://dx.doi.org/10.1016/j.jtho.2016.12.017DOI Listing
April 2017

Clinical Outcome of ALK-Positive Non-Small Cell Lung Cancer (NSCLC) Patients with De Novo EGFR or KRAS Co-Mutations Receiving Tyrosine Kinase Inhibitors (TKIs).

J Thorac Oncol 2017 04 19;12(4):681-688. Epub 2016 Dec 19.

Department of Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.

Introduction: NSCLC with de novo anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangements and EGFR or KRAS mutations co-occur very rarely. Outcomes with tyrosine kinase inhibitors (TKIs) in these patients are poorly understood.

Methods: Outcomes of patients with metastatic NSCLC de novo co-alterations of ALK/EGFR or ALK/KRAS detected by fluorescence in situ hybridization (ALK) and sequencing (EGFR/KRAS) from six Swiss centers were analyzed.

Results: A total of 14 patients with adenocarcinoma were identified. Five patients had ALK/EGFR co-alterations and nine had ALK/KRAS co-alterations. Six of seven patients with ALK/KRAS co-alterations (86%) were primary refractory to crizotinib. One patient has had ongoing disease stabilization for 26 months. Of the patients with ALK/EGFR co-alterations, one immediately progressed after receiving crizotinib for 1.3 months and two had a partial response for 5.7 and 7.3 months, respectively. Three of four patients with ALK/EGFR co-alterations treated with an EGFR TKI achieved one or more responses in different lines of therapy: four patients had a partial response, three with afatinib and one with osimertinib. One patient achieved a complete remission with osimertinib, and one patient was primary refractory to erlotinib. Median PFS during treatment with a first EGFR TKI was 5.8 months (range 3.0-6.9 months).

Conclusions: De novo concurrent ALK/KRAS co-alterations were associated with resistance to ALK TKI treatment in seven out of eight patients. In patients with ALK/EGFR co-alterations, outcomes with ALK and EGFR TKIs seem inferior to what would be expected in patients with either alteration alone, but further studies are needed to clarify which patients with ALK/EGFR co-alterations may still benefit from the respective TKI.
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http://dx.doi.org/10.1016/j.jtho.2016.12.003DOI Listing
April 2017

Response to Comment on Ferrannini et al. Diabetes Care 2016;39:1108-1114. Comment on Mudaliar et al. Diabetes Care 2016;39:1115-1122.

Diabetes Care 2016 11;39(11):e196-e197

Cardiometabolic Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.

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http://dx.doi.org/10.2337/dci16-0027DOI Listing
November 2016

Response to Comment on Ferrannini et al. CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care 2016;39:1108-1114.

Diabetes Care 2016 12;39(12):e226

Cardiometabolic Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.

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http://dx.doi.org/10.2337/dci16-0033DOI Listing
December 2016

A comparative study of the photophysics of phenyl, thienyl, and chalcogen substituted rhodamine dyes.

Photochem Photobiol Sci 2016 Nov;15(11):1417-1432

Department of Chemistry, University of Rochester, Rochester, New York 14627, USA.

Although rhodamine dyes have been extensively studied for a variety of applications, many details of their photophysics are not yet fully understood, including the possible presence of a charge separated electronic state lying near the optically active excited singlet state and the role of twisting substituent groups in excited-state quenching. To address this, a large library of rhodamine dyes was studied in which the chalcogen is varied from O, to S and Se and the aryl group is either absent (in the pyronin series) or is a phenyl or thienyl substituent. Through an analysis of steady-state absorption spectroscopy, electrochemistry, X-ray crystallography, and quantum mechanical calculations, we show that the lowest unoccupied molecular orbital (LUMO) energy decreases in the O → S → Se series and when a phenyl or thienyl substituent is added. The reduction of the LUMO energy is larger for thienyl species in which the aromatic group has increased torsional flexibility. Excited state lifetimes and fluorescence quantum yields of these dyes in a high and low polarity solvent reveal dramatically different photophysics between chromophores with phenyl and thienyl substituents, due to a combination of torsional and inductive effects. In the pyronin and phenyl-substituted species, non-radiative decay can occur through an amine-to-xanthylium core charge separated state that is stabilized in a highly polar environment. In the thienyl derivatives, a lower energy excited state, which we term S', is accessed from Svia rotation of the aryl group and the excited state population rapidly equilibrates between S and S' in 6-30 ps. Preliminary photochemical hydrogen production data display the potential application of the thienyl derivatives for conversion of solar energy.
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http://dx.doi.org/10.1039/c6pp00233aDOI Listing
November 2016