Significantly longer time to deterioration of quality of life due to CANKADO PRO-React eHealth support in HR+ HER2- metastatic breast cancer patients receiving palbociclib and endocrine therapy: primary outcome analysis of the multicenter randomized AGO-B WSG PreCycle trial.

BACKGROUND: The multicenter, randomized, phase IV, intergroup AGO-B WSG PreCycle trial (NCT03220178) evaluated the impact of CANKADO-based electronic patient-reported outcome (ePRO) assessment on quality of life (QoL) in hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer (MBC) patients receiving palbociclib and an aromatase inhibitor or palbociclib + fulvestrant. CANKADO PRO-React, a European Union-registered medical device, is an interactive autonomous application reacting to patient self-reported observations. PATIENTS AND METHODS: Between 2017 and 2021, 499 patients (median age 59 years) from 71 centers were randomized (2 : 1, stratified by therapy line) between an active version of CANKADO PRO-React (CANKADO-active arm) and a version with limited functionality (CANKADO-inform arm). A total of 412 patients (271 CANKADO-active; 141 CANKADO-inform) were available for analysis of the primary endpoint, time to deterioration (TTD) of QoL [10-point drop on the Functional Assessment of Cancer Therapy-General (FACT-G) score], using an Aalen-Johansen estimator for cumulative incidence function of TTD DQoL (QoL deterioration) with 95% pointwise confidence intervals (CIs). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and DQoL. RESULTS: In all patients [intention-to-treat (ITT)-ePRO], cumulative incidence of DQoL was significantly more favorable (lower) in the CANKADO-active arm (hazard ratio 0.698, 95% CI 0.506-0.963). Among first-line patients (n = 295), the corresponding hazard ratio was 0.716 (0.484-1.060; P = 0.09), and in second-line patients (n = 117) it was 0.661 (0.374-1.168; P = 0.2). Absolute patient numbers declined in later visits; FACT-G completion rates were 80% and higher until about visit 30. Mean FACT-G scores showed a steady decline from baseline and an offset in favor of CANKADO-active. No significant differences in clinical outcome were observed between arms: median PFS (ITT population) was 21.4 (95% CI 19.4-23.7) (CANKADO-active) and 18.7 (15.1-23.5) months (CANKADO-inform); median OS was not reached (CANKADO-active) and 42.6 months (CANKADO-inform). CONCLUSIONS: PreCycle is the first multicenter randomized eHealth trial demonstrating a significant benefit for MBC patients receiving oral tumor therapy when using an interactive autonomous patient empowerment application.

A phase II, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy and safety of VT-1161 oral tablets in the treatment of patients with distal and lateral subungual onychomycosis of the toenail.

BACKGROUND: Onychomycosis is a fungal disease that affects the fingernails and toenails and is predominantly caused by dermatophytes. VT-1161 is a novel inhibitor of fungal CYP51 through the inhibition of lanosterol demethylase, and has demonstrated potent activity against Trichophyton rubrum and Trichophyton mentagrophytes. OBJECTIVES: To evaluate the safety and efficacy of four dosing regimens of orally administered VT-1161 compared with placebo in patients with moderate-to-severe distal and lateral subungual onychomycosis of the toenail. METHODS: This was a phase II, randomized, double-blind, placebo-controlled, multicentre study (ClinicalTrials.gov identifier NCT02267356). Patients aged 18-70 years (n = 259) who had 25-75% mycotic involvement were randomized to five treatment groups. They received 300 mg VT-1161 as a 2-week daily dose, followed by a once-weekly dose for either 10 or 22 weeks, or 600 mg VT-1161 as a 2-week daily dose, followed by a once-weekly dose for either 10 or 22 weeks. All treatments were followed by a nontreatment period of 36 weeks. A matching placebo arm was included. RESULTS: In the intent-to-treat population, at week 48 the complete cure rates were 0% in the placebo group and ranged from 32% to 42% in the VT-1161 treatment groups (P < 0·001 vs. placebo). VT-1161 was well tolerated, with no evidence of an adverse effect on liver function or QT intervals. CONCLUSIONS: VT-1161 treatment led to high nail clearance rates and a favourable safety profile. VT-1161 exhibits characteristics that appear promising for the treatment of this chronic and difficult-to-treat condition and warrants further evaluation in larger studies.

Impact of guideline-based use of uPA/PAI-1 on patient outcome in intermediate-risk early breast cancer.

The purpose of this study was to evaluate the influence of guideline-based prospective use of uPA/PAI-1 on clinical outcome in an intermediate-risk cohort of breast cancer patients. We analyzed 381 consecutive primary breast cancer patients (2003-2011) at the breast center Ostbayern meeting the following criteria: M0/N0/estrogen receptor (ER)+/G2. Clinical-pathological data, uPA/PAI-1, and follow-up data were collected. Decisions for adjuvant chemotherapy were made upon consideration of prospectively measured uPA/PAI-1. Observed disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier estimates. Using guideline-based analysis of uPA/PAI-1, treatment with adjuvant chemotherapy was avoided in 86.5 % of patients with low uPA/PAI-1, i.e., 38.8 % of the total patient collective. Median follow-up was 52.5 months. Five-year relapse-free survival in intermediate-risk patients (N0, G2) without chemotherapy was 99 %. Five-year overall survival including all causes of death was 95 %. By using uPA/PAI-1, adjuvant chemotherapy can be avoided in a major part of patients with intermediate-risk breast cancer. Nevertheless, DFS and OS of these patients at 5 years remain excellent. The potential, but hardly measurable, benefit of adjuvant chemotherapy has to be set in contrast with its associated side effects and increased morbidity. Patients with high uPA/PAI-1 show benefit from chemotherapy. In this subgroup, a very good OS was observed as well. These findings strongly support the use of uPA/PAI-1 together with clinic-pathological parameters as an evidence-based, clinically relevant and inexpensive decision tool in the routine of a breast center.

Surgical management of ipsilateral breast tumor recurrence.

PURPOSE: Approximately 10-15% of breast cancer patients treated by breast conserving surgery (BCS) and adjuvant radiotherapy (RT) will develop ipsilateral breast tumor recurrence (IBTR). International guidelines suggest total mastectomy as treatment of choice for IBTR following lumpectomy and RT. Nevertheless, there is evidence that second BCS might be equally sufficient. PATIENTS AND METHODS: Patients with IBTR diagnosed between 1990 and 2014 after BCS and RT were included (n = 170). 34.1% women underwent secondary BCS, whereas 65.9% were treated by mastectomy. We determined predictive factors for time to local progression (TTP), disease free survival (DFS), and overall survival (OS) comparing these two groups. RESULTS: Median follow-up after primary IBTR was 49 months (59 months for patients still alive at time of analysis). Five-year IBTR-free rate after secondary BCS was 77.6% (SD ± 6.1%) and 75.0% (SD ± 4.5%) for patients after mastectomy. Five-year DFS was 57.3% (SD ± 8.2%), and 61.9% (SD ± 5.5%), five-year OS was 84.7% (SD ± 5.8%), and 72.6% (SD ± 5.1%), respectively. Prior adjuvant systemic therapy, muscular invasion, and skin infiltration were independent significant risk factors for a shorter TTP. Additionally, lymphovascular infiltration (LVI) in the IBTR increased the risk for a shorter DFS. LVI, muscular invasion, and skin infiltration were identified as independent significant risk factors for a shorter OS. CONCLUSION: No significant difference in local control, DFS, and OS was seen between IBTR patients treated either by secondary BCS or mastectomy. Our data suggest that secondary BCS for IBTR patients after initial BCS and RT is feasible in selected patients.

Prevention of retinal capillary basement membrane thickening in diabetic dogs by a non-steroidal anti-inflammatory drug.

AIMS/HYPOTHESIS: To investigate the effect of treatment with the non-steroidal anti-inflammatory drug Sulindac on the early vascular pathology of diabetic retinopathy in the dog, and it's effect on recognised biochemical indices of hyperglycaemia-related pathophysiology. METHODS: Experimental diabetes (streptozotocin/alloxan) was induced in 22 male beagle dogs and 12 of the animals were assigned at random to receive oral Sulindac (10 mg/kg daily). Age- and sex-matched control animals were maintained as non-diabetic controls. After 4 years, several morphological parameters were quantified in the retinal microvasculature of each animal group using an established stereological method. Also, the following diabetes-associated biochemical parameters were analysed: accumulation of advanced glycation end products (AGEs), red blood cell polyol levels and antioxidant status. RESULTS: Diabetes increased red blood cell sorbitol levels when compared to non-diabetic controls (p< or =0.05), however, there was no difference in sorbitol levels between the untreated and the treated diabetic animals. No significant differences were found in red blood cell myoinositol levels between the three groups of animals. Pentosidine and other AGEs were increased two- to three-fold in the diabetic animals (p< or =0.001) although treatment with Sulindac did not affect their accumulation in diabetic skin collagen or alter diabetes-induced rises in plasma malondialdehyde. Retinal capillary basement membrane volume was significantly increased in the untreated diabetic dogs compared to non-diabetic controls or Sulindac-treated diabetic animals (p< or =0.0001). CONCLUSION/INTERPRETATION: This study has confirmed the beneficial effect of a non-steroidal anti-inflammatory drug on the early vascular pathology of diabetic retinopathy. However the treatment benefit was not dependent on inhibition of polyol pathway activity, advanced glycation, or oxidative stress.

Aminoguanidine inhibits albuminuria, but not the formation of advanced glycation end-products in skin collagen of diabetic rats.

Aminoguanidine, an inhibitor of advanced glycation reactions in vitro, inhibits the development of diabetic complications in animal models of diabetes, suggesting that it acts by inhibition of advanced glycation reactions in vivo. However, effects of aminoguanidine on the formation of specific advanced glycation end-products (AGEs) in vivo have not been rigorously examined. Therefore, we studied the effects of aminoguanidine on the formation of pentosidine and N(epsilon)-(carboxymethyl)lysine (CML), measured by analytical chemical methods, in collagen of streptozotocin-diabetic Lewis rats at doses which ameliorated urinary albumin excretion, an index of diabetic nephropathy. At 12 weeks, diabetic animals had fivefold higher blood glucose, threefold higher glycated hemoglobin and fivefold higher collagen glycation, compared to metabolically healthy controls; pentosidine and CML in skin collagen were increased by approximately 30 and 150%, respectively. Administration of aminoguanidine, 50 mg/kg by daily intraperitoneal injection, significantly inhibited the development of albuminuria (approximately 60%, P < 0.01) in diabetic rats, without an effect on blood glucose or glycation of hemoglobin or collagen. Surprisingly, aminoguanidine failed to inhibit the increase in pentosidine and CML in diabetic rat skin collagen. Similar results were obtained in an independent experiment in which aminoguanidine was administered in drinking water at a dose of 0.5 g/l. We conclude that the therapeutic benefits of aminoguanidine on albuminuria may not be the result of inhibition of AGE formation.

Chemical modification of proteins by methylglyoxal.

Methylglyoxal is formed in vivo by spontaneous decomposition of triose phosphate intermediates in aerobic glycolysis. It may also be formed during oxidative degradation of both carbohydrates (pentoses and ascorbate) and lipids (arachidonate). In addition to reaction with arginine residues to form imidazolone adducts, methylglyoxal reacts with lysine residues in protein to form N(epsilon)-(carboxyethyl)lysine (CEL) and the imidazolium crosslink, methylglyoxal-lysine dimer (MOLD). Like the glycoxidation products, N(epsilon)-(carboxymethyl)lysine (CML) and glyoxal-lysine dimer (GOLD) which are formed on reaction of glyoxal with protein, CEL and MOLD increase in lens proteins and skin collagen with age. CML and CEL also increase in skin collagen in diabetes, while all four compounds increase in plasma proteins in uremia. Overall, CML, CEL, GOLD and MOLD are quantitatively the major biomarkers of the Maillard reaction in tissue proteins. GOLD and MOLD, in particular, are present at 10-50 fold higher concentrations than the fluorescent crosslink, pentosidine. Together, these dicarbonyl-derived advanced glycation endproducts (AGEs) represent the major chemical modifications that accumulate in tissue proteins with age and in chronic diseases such as diabetes and atherosclerosis.

Role of the Maillard reaction in aging of tissue proteins. Advanced glycation end product-dependent increase in imidazolium cross-links in human lens proteins.

Dicarbonyl compounds such as glyoxal and methylglyoxal are reactive dicarbonyl intermediates in the nonenzymatic browning and cross-linking of proteins during the Maillard reaction. We describe here the quantification of glyoxal and methylglyoxal-derived imidazolium cross-links in tissue proteins. The imidazolium salt cross-links, glyoxal-lysine dimer (GOLD) and methylglyoxal-lysine dimer (MOLD), were measured by liquid chromatography/mass spectrometry and were present in lens protein at concentrations of 0. 02-0.2 and 0.1-0.8 mmol/mol of lysine, respectively. The lens concentrations of GOLD and MOLD correlated significantly with one another and also increased with lens age. GOLD and MOLD were present at significantly higher concentrations than the fluorescent cross-links pentosidine and dityrosine, identifying them as major Maillard reaction cross-links in lens proteins. Like the N-carboxy-alkyllysines Nepsilon-(carboxymethyl)lysine and Nepsilon-(carboxyethyl)lysine, these cross-links were also detected at lower concentrations in human skin collagen and increased with age in collagen. The presence of GOLD and MOLD in tissue proteins implicates methylglyoxal and glyoxal, either free or protein-bound, as important precursors of protein cross-links formed during Maillard reactions in vivo during aging and in disease.

Technical note. The serum concentration of the advanced glycation end-product N epsilon-(carboxymethyl)lysine is increased in uremia.

Advanced glycation end products (AGEs) such as pentosidine and N epsilon-(carboxymethyl)lysine (CML) have been traditionally quantified by HPLC or gas chromatography--mass spectrometry (GC/MS). Enzyme-linked immunosorbent assays (ELISA) have been introduced as a convenient alternative to simplify the detection and measurement of AGEs in proteins and tissues, but some of these studies are limited by the lack of information on the structure of the epitopes recognized by antibodies to AGE-proteins. In this work we demonstrate that an antibody used in a previous study, reporting increased levels of AGEs in patients with diabetes or on continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD), recognizes CML as its major epitope. We also show that there is a significant correlation between the concentration of AGEs in serum measured by ELISA and a GC/MS assay for CML in serum proteins. Both analyses yielded comparable results, with patients on CAPD and HD having about threefold higher AGE- or CML-concentrations in their serum. Our data suggest that ELISA assays for CML should be useful for the clinical measurement of AGEs in serum proteins.

Carboxymethylethanolamine, a biomarker of phospholipid modification during the maillard reaction in vivo.

Nepsilon-(Carboxymethyl)lysine (CML) is a stable chemical modification of proteins formed from both carbohydrates and lipids during autoxidation reactions. We hypothesized that carboxymethyl lipids such as (carboxymethyl)phosphatidylethanolamine (carboxymethyl-PE) would also be formed in these reactions, and we therefore developed a gas chromatography-mass spectrometry assay for quantification of carboxymethylethanolamine (CME) following hydrolysis of phospholipids. In vitro, CME was formed during glycation of dioleoyl-PE under air and from linoleoylpalmitoyl-PE, but not from dioleoyl-PE, in the absence of glucose. In vivo, CME was detected in lipid extracts of red blood cell membranes, approximately 0.14 mmol of CME/mol of ethanolamine, from control and diabetic subjects, (n = 22, p >> 0.5). Levels of CML in erythrocyte membrane proteins were approximately 0.2 mmol/mol of lysine for both control and diabetic subjects (p >> 0.5). For this group of diabetic subjects there was no indication of increased oxidative modification of either lipid or protein components of red cell membranes. CME was also detected in fasting urine at 2-3 nmol/mg of creatinine in control and diabetic subjects (p = 0.085). CME inhibited detection of advanced glycation end product (AGE)-modified protein in a competitive enzyme-linked immunosorbent assay using an anti-AGE antibody previously shown to recognize CML, suggesting that carboxymethyl-PE may be a component of AGE lipids detected in AGE low density lipoprotein. Measurement of levels of CME in blood, tissues, and urine should be useful for assessing oxidative damage to membrane lipids during aging and in disease.

N-epsilon-(carboxyethyl)lysine, a product of the chemical modification of proteins by methylglyoxal, increases with age in human lens proteins.

Advanced glycation end-products and glycoxidation products, such as Nepsilon-(carboxymethyl)lysine (CML) and pentosidine, accumulate in long-lived tissue proteins with age and are implicated in the aging of tissue proteins and in the development of pathology in diabetes, atherosclerosis and other diseases. In this paper we describe a new advanced glycation end-product, Nepsilon-(carboxyethyl)lysine (CEL), which is formed during the reaction of methylglyoxal with lysine residues in model compounds and in the proteins RNase and collagen. CEL was also detected in human lens proteins at a concentration similar to that of CML, and increased with age in parallel with the concentration of CML. Although CEL was formed in highest yields during the reaction of methylglyoxal and triose phosphates with lysine and protein, it was also formed in reactions of pentoses, ascorbate and other sugars with lysine and RNase. We propose that levels of CML and CEL and their ratio to one another in tissue proteins and in urine will provide an index of glyoxal and methylglyoxal concentrations in tissues, alterations in glutathione homoeostasis and dicarbonyl metabolism in disease, and sources of advanced glycation end-products in tissue proteins in aging and disease.

Hirudisins. Hirudin-derived thrombin inhibitors with disintegrin activity.

Recombinant hirudin variants have been designed which inhibit alpha-thrombin by the hirudin mechanism and which in addition exhibit disintegrin activity. These proteins, called "hirudisins," have been engineered by replacing the Ser-Asp-Gly-Glu sequence at the tip of hirudin's finger-like structure (residues 32-35) by Arg-Gly-Asp-Ser (RGDS) to yield hirudisin and Lys-Gly-Asp-Ser (KGDS) to obtain hirudisin-1. Comparison of thrombin inhibition activities showed that hirudisin is 2-fold more potent (K(i) = 160 +/- 70 fM) than hirudisin-1 (K(i) = 370 +/- 44 fM) and recombinant (r)-hirudin (K(i) = 270 +/- 50 fM). alpha-Thrombin-stimulated platelet aggregation was effectively inhibited by r-hirudin, hirudisin, and hirudisin-1 with IC50 of 5.7 to 6.8 nM. Unlike r-hirudin, hirudisin inhibits ADP-induced platelet aggregation (IC50 = 65 microM) 3- to 5-fold stronger than the linear GRGDS- and RGDS-peptide. Direct interaction of hirudisin with purified glycoprotein IIb-IIIa demonstrated that antiplatelet aggregation activity is due to the integrin-directed RGD motif. Disintegrin activity of hirudisin relative to that of reduced and carboxymethylated hirudisin suggests that the conformational strain favors binding to integrins. On the basis of these results, hirudisins appear to be interesting molecules for the design of potential antithrombotic agents with antithrombin as well as antiplatelet aggregation activities.

[Proportion of schizophrenia in inpatient treatment morbidity of a defined catchment area]. / Anteil der Schizophrenie an der stationären Behandlungsmorbidität eines definierten Einzugsbereiches.

The results of a survey performed on a specific date and an analysis of the discharge files are used as a starting point to discuss the large proportion of schizophrenics among the patients receiving ward treatment at hospitals. Many of these are chronic, long-term patients whose chances of being discharged decrease with increasing duration of hospitalisation. In contrast, instances of hospitalisation of acute schizophrenia cases in the region concerned has decreased considerably during the past 20 years as a result of the more consistent use of psychopharmaceutics and improved dispensary treatment. These modern forms of therapy can only yield optimal results, however, if all those concerned with rehabilitation show a good portion of sociopsychiatric involvement and nonmedical institutions also help with the therapy scheme.

[(Studies on intragastric titration in man) ]. / Untersuchungen zur intragastralen Titration beim Menschen.

The method of intragastric titration uses food particles for stimulation of gastric acid secretion and is characterised by an excellent reproducibility. The food stimulated gastric acid secretion is influenced by the pH-value of the stimulus, whereas concentration of the peptone solution and volume of the test meal is less important. Postprandial gastrin release, however is altered by pH of the stimulus concentration and volume of the test meal. Intragastric titration represents an excellent method for measuring gastric acid secretion and should mainly be applied to clinical pathophysiological studies.

Somatostatin and gastrin release from canine stomach.

Somatostatin and gastrin release into the veins draining the stomach was studied in 27 anaesthetized dogs. Basal somatostatin-like immunoreactivity (SLI) in corpus veins (136 +/- 36 pg/ml) was significantly higher than in antrum veins (83 +/- 20 pg/ml; p less than 0.05) and the femoral artery (58 +/- 15 pg/ml; p less than 0.02). During peptone, pH 6.5, perfusion of the stomach, SLI concentration increased significantly in the corpus veins to approximately four times basal and in the antrum veins to three times basal, whereas SLI levels in the peripheral circulation remained constant. Peptone, pH 3.5, and sodium oleate did not stimulate gastric SLI. Gastric distension increased significantly SLI release from the corpus. In gel filtration studies 50%--70% of SLI from gastric vein plasma samples but greater than 90% from femoral artery samples eluted in the void volume of Sephadex G-25 columns. Gastrin secretion was stimulated significantly only by peptone, pH 6.5.

[Position of the delayed-action neuroleptic penfluridol (Longperidol/Janssen) in psychiatric therapy]. / Zur Stellung des Langzeit-Neuroleptikum Penfluridol (Longoperidol/Janssen) in der psychiatrischen Therapie

Longoperidol/Janssen, an orally administered neuroleptic with a five- to seven-day duration of effects, was clinically tested in six mental hospitals in the G.D.R. where the agent was administered to subjects of chronic to subacute schizophrenia. It was not possible for fully consistent results to be obtained in these tests. Workers at mental hospitals in Leipzig and Mühlhausen recommended that the drug should be imported, whereas those at the four other centers (Dresden, Halle, Jena, and Schwerin) did not consider the medication to be indispensable, although they were also able to observe the good effects of the agent.

[Alcohol-induced lesions of the nerve and muscle]. / Alkoholbedingte Schäden an Nerv und Muskel

A review is given on the most important neurologic sequelae after long lasting abuse of alcohol. The paper especially deals with the clinical features of neuropathic and myopathic disorders in alcoholics. Electromyography (including electroneurography) is considered to be a major diagnostic aid in these conditions.