Incidence and Resolution of Eribulin-Induced Peripheral Neuropathy (IRENE) in Locally Advanced or Metastatic Breast Cancer: Prospective Cohort Study.

BACKGROUND: Eribulin, a halichondrin-class microtubule dynamics inhibitor, is a preferred treatment option for patients with advanced breast cancer who have been pretreated with an anthracycline and a taxane. Peripheral neuropathy (PN) is a common side effect of chemotherapies for breast cancer and other tumors. The Incidence and Resolution of Eribulin-Induced Peripheral Neuropathy (IRENE) noninterventional postauthorization safety study assessed the incidence and severity of PN in patients with breast cancer treated with eribulin. PATIENTS AND METHODS: IRENE is an ongoing observational, single-arm, prospective, multicenter, cohort study. Adult patients (≥18 years of age) with locally advanced or metastatic breast cancer and disease progression after 1-2 prior chemotherapeutic regimen(s) for advanced disease were treated with eribulin. Patients with eribulin-induced PN (new-onset PN or worsening of preexisting PN) were monitored until death or resolution of PN. Primary endpoints included the incidence, severity, and time to resolution of eribulin-induced PN. Secondary endpoints included time to disease progression and safety. RESULTS: In this interim analysis (data cutoff date: July 1, 2019), 67 (32.4%) patients experienced any grade eribulin-induced PN, and 12 (5.8%) patients experienced grade ≥3 eribulin-induced PN. Median time to resolution of eribulin-induced PN was not reached. Median time to disease progression was 4.6 months (95% CI, 4.0-6.5). Treatment-emergent adverse events (TEAEs) occurred in 195 (93.8%) patients and serious TEAEs occurred in 107 (51.4%) patients. CONCLUSION: The rates of any grade and grade ≥3 eribulin-induced PN observed in this real-world study were consistent with those observed in phase III randomized clinical trials. No new safety findings were observed.

A new technique to study nutrient flow in host-parasite systems by carbon stable isotope analysis of amino acids and glucose.

Stable isotope analysis of individual compounds is emerging as a powerful tool to study nutrient origin and conversion in host-parasite systems. We measured the carbon isotope composition of amino acids and glucose in the cestode Schistocephalus solidus and in liver and muscle tissues of its second intermediate host, the three-spined stickleback (Gasterosteus aculeatus), over the course of 90 days in a controlled infection experiment. Similar linear regressions of δ13C values over time and low trophic fractionation of essential amino acids indicate that the parasite assimilates nutrients from sources closely connected to the liver metabolism of its host. Biosynthesis of glucose in the parasite might occur from the glucogenic precursors alanine, asparagine and glutamine and with an isotope fractionation of - 2 to - 3 ‰ from enzymatic reactions, while trophic fractionation of glycine, serine and threonine could be interpreted as extensive nutrient conversion to fuel parasitic growth through one-carbon metabolism. Trophic fractionation of amino acids between sticklebacks and their diets was slightly increased in infected compared to uninfected individuals, which could be caused by increased (immune-) metabolic activities due to parasitic infection. Our results show that compound-specific stable isotope analysis has unique opportunities to study host and parasite physiology.

Insights into amino acid fractionation and incorporation by compound-specific carbon isotope analysis of three-spined sticklebacks.

Interpretation of stable isotope data is of upmost importance in ecology to build sound models for the study of animal diets, migration patterns and physiology. However, our understanding of stable isotope fractionation and incorporation into consumer tissues is still limited. We therefore measured the δ13C values of individual amino acids over time from muscle and liver tissue of three-spined sticklebacks (Gasterosteus aculeatus) on a high protein diet. The δ13C values of amino acids in the liver quickly responded to small shifts of under ± 2.0‰ in dietary stable isotope compositions on 30-day intervals. We found on average no trophic fractionation in pooled essential (muscle, liver) and non-essential (muscle) amino acids. Negative Δδ13C values of - 0.7 ± 1.3‰ were observed for pooled non-essential (liver) amino acids and might indicate biosynthesis from small amounts of dietary lipids. Trophic fractionation of individual amino acids is reported and discussed, including unusual Δδ13C values of over + 4.9 ± 1.4‰ for histidine. Arginine and lysine showed the lowest trophic fractionation on individual sampling days and might be useful proxies for dietary sources on short time scales. We suggest further investigations using isotopically enriched materials to facilitate the correct interpretation of ecological field data.

Predicting Prognosis of Breast Cancer Patients with Brain Metastases in the BMBC Registry-Comparison of Three Different GPA Prognostic Scores.

Several scores have been developed in order to estimate the prognosis of patients with brain metastases (BM) by objective criteria. The aim of this analysis was to validate all three published graded-prognostic-assessment (GPA)-scores in a subcohort of 882 breast cancer (BC) patients with BM in the Brain Metastases in the German Breast Cancer (BMBC) registry. The median age at diagnosis of BM was 57 years. All in all, 22.3% of patients (n = 197) had triple-negative, 33.4% (n = 295) luminal A like, 25.1% (n = 221) luminal B/HER2-enriched like and 19.2% (n = 169) HER2 positive like BC. Age ≥60 years, evidence of extracranial metastases (ECM), higher number of BM, triple-negative subtype and low Karnofsky-Performance-Status (KPS) were all associated with worse overall survival (OS) in univariate analysis (p < 0.001 each). All three GPA-scores were associated with OS. The breast-GPA showed the highest probability of classifying patients with survival above 12 months in the best prognostic group (specificity 68.7% compared with 48.1% for the updated breast-GPA and 21.8% for the original GPA). Sensitivities for predicting 3 months survival were very low for all scores. In this analysis, all GPA-scores showed only moderate diagnostic accuracy in predicting the OS of BC patients with BM.

Characteristics and Clinical Outcome of Breast Cancer Patients with Asymptomatic Brain Metastases.

Background: Brain metastases (BM) have become a major challenge in patients with metastatic breast cancer. Methods: The aim of this analysis was to characterize patients with asymptomatic BM (n = 580) in the overall cohort of 2589 patients with BM from our Brain Metastases in Breast Cancer Network Germany (BMBC) registry. Results: Compared to symptomatic patients, asymptomatic patients were slightly younger at diagnosis (median age: 55.5 vs. 57.0 years, p = 0.01), had a better performance status at diagnosis (Karnofsky index 80-100%: 68.4% vs. 57%, p < 0.001), a lower number of BM (>1 BM: 56% vs. 70%, p = 0.027), and a slightly smaller diameter of BM (median: 1.5 vs. 2.2 cm, p < 0.001). Asymptomatic patients were more likely to have extracranial metastases (86.7% vs. 81.5%, p = 0.003) but were less likely to have leptomeningeal metastasis (6.3% vs. 10.9%, p < 0.001). Asymptomatic patients underwent less intensive BM therapy but had a longer median overall survival (statistically significant for a cohort of HER2-positive patients) compared to symptomatic patients (10.4 vs. 6.9 months, p < 0.001). Conclusions: These analyses show a trend that asymptomatic patients have less severe metastatic brain disease and despite less intensive local BM therapy still have a better outcome (statistically significant for a cohort of HER2-positive patients) than patients who present with symptomatic BM, although a lead time bias of the earlier diagnosis cannot be ruled out. Our analysis is of clinical relevance in the context of potential trials examining the benefit of early detection and treatment of BM.

Resumption of Trastuzumab in Patients With Disease Recurrence After (Neo-) Adjuvant Anti-HER2-therapy in Patients With HER2-positive Breast Cancer.

BACKGROUND/AIM: HER2-positive breast cancers eventually relapse in about one third of patients. Is anti-HER2-directed therapy with Herceptin® (trastuzumab) effective in re-treatment? Between 2008 and 2018, 216 patients with recurrent HER2-positive breast cancer (BC) were re-treated with Herceptin (HER) during first-line therapy. This study assessed the effectiveness and tolerability of re-treatment with HER. PATIENTS AND METHODS: After approval from Ethical committee, the NIS was conducted according to German Drug Act. Re-treatment with HER was documented at routine visits starting with a basic observational period of maximum 12 months and a follow-up period of maximum additional four years. RESULTS: HER2-positive BC relapsed after a median of 36.5 months (mos). Patients were re-treated with HER +/- chemotherapy +/- endocrine therapy. HER-containing regimens resulted in median progression-free survival (mPFS) of 12.7 (95%CI=10.5-14.8) mos and overall survival (OS-2) of 31.6 mos (95%CI=28.8-38.4) since recurrence diagnosis. Differentiation of recurrence types (local, visceral, non-visceral) unfolded worst prognosis for patients with visceral metastases. Cardiac monitoring within this non-interventional study (NIS) did not result in new safety concerns. CONCLUSION: Re-therapy with HER in the first-line setting of advanced HER2-positive breast cancer is effective and without unexpected or intensified adverse events.

Trabectedin plus pegylated liposomal doxorubicin (PLD) for patients with platinum-sensitive recurrent ovarian cancer: a prospective, observational, multicenter study.

PURPOSE: The OVA-YOND study is the first prospective, non-interventional trial designed to evaluate trabectedin (1.1 mg/m2) plus PLD (30 mg/m2) in patients with platinum-sensitive recurrent ovarian cancer (ROC), given according to the marketing authorization in real-life clinical practice across Germany. METHODS: Eligible patients were adults with platinum-sensitive ROC, pretreated with ≥ 1 platinum-containing regimen/s. The primary endpoint was to assess safety/tolerability of the combination. RESULTS: Seventy-seven patients with platinum-sensitive relapse from 31 sites were evaluated. Patients received a median of 6 cycles (range 1-21) with 39 patients (50.6%) receiving ≥ 6 cycles. Median treatment duration was 4.2 months (range 0.7-18.8), mostly on an outpatient basis (88.3% of patients). Most common grade 3/4 trabectedin-related adverse events (AEs) were leukopenia (18.2%), neutropenia (15.6%), thrombocytopenia (9.1%), alanine (7.8%) and aspartate aminotransferase (6.5%) increase, and nausea/vomiting (5.2% each). Neutropenia (18.2%), leukopenia (15.6%), thrombocytopenia (10.4%), and nausea/vomiting (5.2% each) were the most frequent grade 3/4 PLD-related AEs. No deaths attributed to drug-related AEs or unexpected AEs occurred. Five patients (6.5%) had a complete response and 19 patients (24.7%) achieved a partial response for an objective response rate of 31.2% with median response duration of 6.25 months. Sixteen patients (20.8%) had disease stabilization for a disease control rate of 51.9%. Median progression-free survival was 6.3 months and median overall survival was 16.4 months. CONCLUSION: Trabectedin plus PLD confer clinically meaningful benefit to pre-treated patients with platinum-sensitive ROC, being comparable to those previously observed in selected populations from clinical trials and with a manageable safety profile.

Radiological Patterns of Brain Metastases in Breast Cancer Patients: A Subproject of the German Brain Metastases in Breast Cancer (BMBC) Registry.

Evidence about distribution patterns of brain metastases with regard to breast cancer subtypes and its influence on the prognosis of patients is insufficient. Clinical data, cranial computed tomography (CT) and magnetic resonance imaging (MRI) scans of 300 breast cancer patients with brain metastases (BMs) were collected retrospectively in four centers participating in the Brain Metastases in Breast Cancer Registry (BMBC) in Germany. Patients with positive estrogen (ER), progesterone (PR), or human epidermal growth factor receptor 2 (HER2) statuses, had a significantly lower number of BMs at diagnosis. Concerning the treatment mode, HER2-positive patients treated with trastuzumab before the diagnosis of BMs showed a lower number of intracranial metastases (p < 0.001). Patients with a HER2-positive tumor-subtype developed cerebellar metastases more often compared with HER2-negative patients (59.8% vs. 44.5%, p = 0.021), whereas patients with triple-negative primary tumors had leptomeningeal disease more often (31.4% vs. 18.3%, p = 0.038). The localization of Brain metastases (BMs) was associated with prognosis: patients with leptomeningeal disease had shorter survival compared with patients without signs of leptomeningeal disease (median survival 3 vs. 5 months, p = 0.025). A shorter survival could also be observed in the patients with metastases in the occipital lobe (median survival 3 vs. 5 months, p = 0.012). Our findings suggest a different tumor cell homing to different brain regions depending on subtype and treatment.

In situ microscopy as a tool for the monitoring of filamentous bacteria: a case study in an industrial activated sludge system dominated by M. parvicella.

The present study demonstrates the application of in situ microscopy for monitoring the growth of filamentous bacteria which can induce disturbances in an industrial activated sludge process. An in situ microscope (ISM) is immersed directly into samples of activated sludge with Microthrix parvicella as dominating species. Without needing further preparatory steps, the automatic evaluation of the ISM-images generates two signals: the number of individual filaments per image (ISM-filament counting) and the total extended filament length (TEFL) per image (ISM-online TEFL). In this first version of the image-processing algorithm, closely spaced crossing filament-segments or filaments within bulk material are not detected. The signals show highly linear correlation both with the standard filament index and the TEFL. Correlations were further substantiated by comparison with real-time polymerase chain reaction (real-time PCR) measurements of M. parvicella and of the diluted sludge volume index. In this case study, in situ microscopy proved to be a suitable tool for straightforward online-monitoring of filamentous bacteria in activated sludge systems. With future adaptation of the system to different filament morphologies, including cross-linking filaments, bundles, and attached growth, the system will be applicable to other wastewater treatment plants.

Evaluating the influence of wastewater composition on the growth of Microthrix parvicella by GCxGC/qMS and real-time PCR.

This study underlines the significance of long chain fatty acid (LCFA) content in wastewater influents as an influencing factor promoting the growth of Candidatus 'Microthrix parvicella' (M. parvicella), the most common filamentous bacteria causing foam in activated sludge systems worldwide. Quantification of M. parvicella by real-time polymerase chain reaction (real-time PCR) and analysis of LCFAs by means of two-dimensional gas chromatography coupled with mass spectrometry (GCxGC/qMS), involving solid phase micro-extraction (SPME) to enhance sensitivity, were combined for the first time as a monitoring tool. The results indicate a highly significant correlation between the abundance of M. parvicella and the total LCFA loading (r = 0.96) and linolenic acid C18:3 (r = 0.98) in particular. Additionally, comparison of slope values for the direct correlations of all significant LCFAs found in the analyses showed that the influence of LCFAs on M. parvicella growth increases with an increasing degree of unsaturation of carbon chains. These findings suggest that by removing lipid compounds from the incoming waters, substrate availability would be limited for M. parvicella.

Driver behavior following an automatic steering intervention.

The study investigated driver behavior toward an automatic steering intervention of a collision mitigation system. Forty participants were tested in a driving simulator and confronted with an inevitable collision. They performed a naïve drive and afterwards a repeated exposure in which they were told to hold the steering wheel loosely. In a third drive they experienced a false alarm situation. Data on driving behavior, i.e. steering and braking behavior as well as subjective data was assessed in the scenarios. Results showed that most participants held on to the steering wheel strongly or counter-steered during the system intervention during the first encounter. Moreover, subjective data collected after the first drive showed that the majority of drivers was not aware of the system intervention. Data from the repeated drive in which participants were instructed to hold the steering wheel loosely, led to significantly more participants holding the steering wheel loosely and thus complying with the instruction. This study seems to imply that without knowledge and information of the system about an upcoming intervention, the most prevalent driving behavior is a strong reaction with the steering wheel similar to an automatic steering reflex which decreases the system's effectiveness. Results of the second drive show some potential for countermeasures, such as informing drivers shortly before a system intervention in order to prevent inhibiting reactions.

Capecitabine in the routine treatment of advanced breast cancer: results from a non-interventional observational study in 876 [corrected] patients.

BACKGROUND: This observational study evaluated patient characteristics, treatment schedule and setting, efficacy and tolerability of capecitabine in routine clinical practice in Germany. PATIENTS AND METHODS: Patients with advanced breast cancer pretreated with or ineligible for anthracycline-containing therapy were treated with capecitabine. Data were collected until disease progression or completion of 12 cycles (with long-term follow-up in progression-free patients). RESULTS: 846 of the 876 [corrected] patients enrolled between 2002 and 2007 were eligible. Capecitabine was administered as monotherapy in 64% (median starting dose 1,070 mg/m(2) bis in diem (b.i.d.)) and combination chemotherapy (typically with vinorelbine or docetaxel) in 36% (median starting dose 987 mg/m(2) b.i.d.). Capecitabine was given as first-line therapy in 35% of patients. Objective response rate was 41% and median progression-free survival was 7.5 months. Good performance status at baseline was a significant predictor of efficacy. The most common non-hematological toxicity was hand-foot syndrome (all grades: 54%; grade 3: 7%). Myelosuppression and alopecia were substantially less common with capecitabine monotherapy than with capecitabine combination regimens. CONCLUSIONS: Capecitabine, alone or in combination, is a feasible, effective treatment for breast cancer. Our findings in real-life clinical practice compare favorably with results from interventional studies, perhaps reflecting the longer treatment duration possible at more tolerable doses.