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Background: Several studies showed that pathologic complete response (pCR) is a surrogate for disease free survival (DFS) and overall survival (OS). Combinations of trastuzumab and anthracyclines in HER2-positive breast cancer are highly active but associated with a high incidence of cardiotoxicity. The risk of cardiac damage can be significantly reduced through liposomal encapsulation of anthracyclines. This phase I/II study was initiated to evaluate the combination of non-pegylated liposomal doxorubicin (NPLD), paclitaxel and lapatinib as primary treatment for patients with early stage, HER2-positive primary breast cancer. Patients and Methods: Patients with newly diagnosed HER2-positive (IHC 3+ or FISH+) early stage (T1c N1-2 or T2 N0-2) breast cancer were treated with NPLD (60mg/m²; day 1), paclitaxel (175mg/m², day 1) and lapatinib (750-1500 mg orally daily) in 3-week intervals for up to 6 cycles. The primary endpoints were dose-limiting toxicities (DLT) and pathological complete response (pCR). Secondary endpoints include safety, incidence of cardiac events, and clinical response. Exploratory endpoints include molecular markers for sensitivity or resistance to chemotherapy and/or lapatinib evaluated. Results: A total of 84 patients have been included. No dose-limiting toxicity were observed and the maximum tolerated doses were NPLD 60mg/m², paclitaxel 175mg/m² and lapatinib 1500mg. Recommended phase 2 doses (P2D) were NPLD 60mg/m², paclitaxel 175mg/m² and lapatinib 1250mg. The treatment was generally well tolerated and associated with toxicities that were consistent with the known side-effects of the individual agents. No cardiac event has been observed to date. Preliminary efficacy data confirm a pCR breast rate of 41.7% and pCR rate in breast and lymph nodes of 37.5%, in 32 evaluable patients treated at ≥ P2D. Conclusions: The combination of NPLD, paclitaxel and lapatinib is well tolerated and has high antitumor activity in patients with HER2-positive primary breast cancer. Updated results of all 84 patients will be presented. [ABSTRACT FROM AUTHOR]

Aim of the Study: Evaluation of the impact of a de-escaleted chemotherapy regimen consisting of capecitabine (Cap) on invasive disease-free survival (iDFS) in patients ≥65 years with node-positive/high-risk node-negative early breast cancer (BC) receiving ibandronate (Ib)., Methods: ICE (Ib with or without Cap in Elderly patients with early breast cancer) was a multicentre phase 3 clinical trial with a 2020 update of long-term follow-up for overall survival enroling node-positive/high-risk node-negative patients ≥65 years with early BC. Patients were randomised to Cap 2000 mg/m² day 1-14 q3w for 6 cycles plus Ib (50 mg p.o. daily or alternatively 6 mg intravenous q4w) or Ib alone for 2 years. Endocrine therapy was recommended for hormone receptor (HR)-positive patients. The primary endpoint was iDFS analysed using Cox proportional hazards regression and log-rank analysis., Results: 1358 (96.4%) of 1409 randomised patients started treatment. 564 (83.4%) completed 6 cycles of Cap. 513 (77.7%) and 516 (78.8%) completed Ib in the Cap+Ib and Ib alone arm, respectively. Median age was 71 (range 64-88) years, 1099 (81%) were HR-positive, 705 (51.9%) node-negative. At a median follow-up of 61.3 months, 5-year iDFS was 78.8% for Cap+Ib versus 75.0% for Ib alone (p = 0.80). Effects were independent of age, nodal, and HR status. The addition of Cap caused significantly higher skin and gastrointestinal toxicity., Conclusions: The adjuvant combination of Cap+Ib did not show significantly better iDFS than Ib alone in node-positive/high-risk node-negative older BC patients, of whom HR-positive patients were also treated with endocrine therapy., Trial Registration: Study in elderly patients with early breast cancer (ICE), NCT00196859, https://clinicaltrials.gov/ct2/show/NCT00196859?term=NCT00196859., Competing Interests: Declaration of Competing Interest M. Schmidt reports personal fees from AstraZeneca, personal fees from BioNTech, personal fees from Daiichi Sankyo, personal fees from Eisai, peronal fees from Lilly, personal fees from MSD, personal fees from Novartis, personal fees from Pfizer, personal fees from Pierre-Fabre, personal fees from Roche, and personal fees from SeaGen outside the submitted work; in addition, M. Schmidt has a patent for EP 2390370 B1: A method for predicting the response of a tumour in a patient suffering from or at risk of developing recurrent gynaecologic cancer towards a chemotherapeutic agent issued and a patent for EP 2951317 B1: A method for predicting the benefit from inclusion of a taxane in a chemotherapy regimen in patients with breast cancer issued. S. Loibl reports grants or contracts paid to institute from Abbvie, AstraZeneca, DSI, Celgene, Gilead, Novartis, Pfizer, Roche, Molecular H; in addition, S. Loibl has royalties or licences for Digital Ki67 Evaluator from VM Scope GmbH that were paid to institute; in addition, S. Loibl receives honorary for lectures paid to the institute from AstraZeneca, DSI, Gilead, Novartis, Pfizer, and Roche; non-financial for Medical Writing from DSI, Gilead, Novartis, Pfizer, Roche, and Seagen; in addition, S. Loibl has patent for EP14153692.0, EP21152186.9, EP15702464.7 and EP19808852.8, all patents via institute; in addition, S. Loibl declares participation on a Data Safety Monitoring Board or Advisory Board from Abbvie, Amgen, AstraZeneca, BMS, Celgene, DSI, Eirgenix, Eisai Europe, GSK, Gilead, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Relay Therapeutics, Roche, Sanofi, and Seagen, all paid to institute. C. Jakisch reports consulting fees from Novartis, Roche, Celgene, Pfizer, Lilly, and Exact Sciences; in addition, C. Jakisch declares support for attending meetings and/or travel from Novartis, Roche, Celgene, Pfizer, Lilly, and Exact Sciences. J. Huober reports grants or contracts paid to institute from Celgene, Novartis, Hexal, and Lilly; in addition, J. Huober declares consulting fees from Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene, Eisai, Abbvie, Seagen, and Gilead; in addition, J. Huober receives payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene, Eisai, Abbvie, Seagen, and Gilead; in addition, J. Huober reports support for attending meetings and/or travel from Roche, Pfizer, Novartis, Celgene, Daiichi, and Gilead. M. Untch reports support for the present manuscript from GBG, financial and drug support from AstraZeneca, and financial and drug support from Roche; in addition, M. Untch receives consulting fees to the institution from AstraZeneca, Roche, Pfizer, Novartis, Sanofi Aventis, Daiichi Sankyo, Pierre Fabre, Gilead, Seagen, Amgen, Lilly, and MSD; in addition, M. Untch reports payment for lectures to the institution from AstraZeneca, Roche, Pfizer, Novartis, Sanofi Aventis, Daiichi Sankyo, Pierre Fabre, Gilead, Seagen, Amgen, Lilly, and MSD; in addition, M. Untch declares support for attending meetings and/or travel within the bounds of speakers or expert agreement. V. Nekljudova declares to be GBG Forschungs GmbH employee. GBG Forschungs GmbH received funding for research grants from Abbvie, AstraZeneca, BMS, Daiichi-Sankyo, Gilead, Novartis, Pfizer and Roche (paid to the institution); other (non-financial/medical writing) from Daiichi-Sankyo, Gilead, Novartis, Pfizer, Roche and Seagen (paid to the institution). GBG Forschungs GmbH has following royalties/patents: EP14153692.0, EP21152186.9, EP15702464.7, EP19808852.8 and VM Scope GmbH. A. Belau, H. Graf, M. Hofmann, M. Just, J. Krocker, U. Nitz, I. Runnebaum, and E. Stickeler report no disclosures. No other potential conflict of interest relevant to this article was reported., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: We provide a scoping review of Digital Health Interventions (DHIs) that mitigate COVID-19 misinformation and disinformation seeding and spread., Materials and Methods: We applied our search protocol to PubMed, PsychINFO, and Web of Science to screen 1666 articles. The 17 articles included in this paper are experimental and interventional studies that developed and tested public consumer-facing DHIs. We examined these DHIs to understand digital features, incorporation of theory, the role of healthcare professionals, end-user experience, and implementation issues., Results: The majority of studies (n = 11) used social media in DHIs, but there was a lack of platform-agnostic generalizability. Only half of the studies (n = 9) specified a theory, framework, or model to guide DHIs. Nine studies involve healthcare professionals as design or implementation contributors. Only one DHI was evaluated for user perceptions and acceptance., Discussion: The translation of advances in online social computing to interventions is sparse. The limited application of behavioral theory and cognitive models of reasoning has resulted in suboptimal targeting of psychosocial variables and individual factors that may drive resistance to misinformation. This affects large-scale implementation and community outreach efforts. DHIs optimized through community-engaged participatory methods that enable understanding of unique needs of vulnerable communities are urgently needed., Conclusions: We recommend community engagement and theory-guided engineering of equitable DHIs. It is important to consider the problem of misinformation and disinformation through a multilevel lens that illuminates personal, clinical, cultural, and social pathways to mitigate the negative consequences of misinformation and disinformation on human health and wellness., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In trauma patients, shock-induced endotheliopathy (SHINE) is associated with a poor prognosis. We have previously identified four metabolic phenotypes in a small cohort of trauma patients (N = 20) and displayed the intracellular metabolic profile of the endothelial cell by integrating quantified plasma metabolomic profiles into a genome-scale metabolic model (iEC-GEM). A retrospective observational study of 99 trauma patients admitted to a Level 1 Trauma Center. Mass spectrometry was conducted on admission samples of plasma metabolites. Quantified metabolites were analyzed by computational network analysis of the iEC-GEM. Four plasma metabolic phenotypes (A-D) were identified, of which phenotype D was associated with an increased injury severity score ( p < 0.001); 90% (91.6%) of the patients who died within 72 h possessed this phenotype. The inferred EC metabolic patterns were found to be different between phenotype A and D. Phenotype D was unable to maintain adequate redox homeostasis. We confirm that trauma patients presented four metabolic phenotypes at admission. Phenotype D was associated with increased mortality. Different EC metabolic patterns were identified between phenotypes A and D, and the inability to maintain adequate redox balance may be linked to the high mortality., Competing Interests: The authors declare no conflict of interest.

Purpose: Endotheliopathy of trauma (EoT), as defined by circulating levels of syndecan-1 ≥ 40 ng/mL, has been reported to be associated with significantly increased transfusion requirements and a doubled 30-day mortality. Increased shedding of the glycocalyx points toward the endothelial cell membrane composition as important for the clinical outcome being the rationale for this study., Results: The plasma metabolome of 95 severely injured trauma patients was investigated by mass spectrometry, and patients with EoT vs. non-EoT were compared by partial least square-discriminant analysis, identifying succinic acid as the top metabolite to differentiate EoT and non-EoT patients (VIP score = 3). EoT and non-EoT patients' metabolic flux profile was inferred by integrating the corresponding plasma metabolome data into a genome-scale metabolic network reconstruction analysis and performing a functional study of the metabolic capabilities of each group. Model predictions showed a decrease in cholesterol metabolism secondary to impaired mevalonate synthesis in EoT compared to non-EoT patients. Intracellular task analysis indicated decreased synthesis of thromboxanA2 and leukotrienes, as well as a lower carnitine palmitoyltransferase I activity in EoT compared to non-EoT patients. Sensitivity analysis also showed a significantly high dependence of eicosanoid-associated metabolic tasks on alpha-linolenic acid as unique to EoT patients., Conclusions: Model-driven analysis of the endothelial cells' metabolism identified potential novel targets as impaired thromboxane A2 and leukotriene synthesis in EoT patients when compared to non-EoT patients. Reduced thromboxane A2 and leukotriene availability in the microvasculature impairs vasoconstriction ability and may thus contribute to shock in EoT patients. These findings are supported by extensive scientific literature; however, further investigations are required on these findings., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Purpose: Although dose-dense (dd) chemotherapy plays a fundamental role in the treatment of breast cancer (BC), a variety of trials have presented divergent survival results. Here, we present data of patients with more than 3 positive axillary lymph nodes (+aLN) receiving dd chemotherapy after a median follow-up period of 12.3 years., Methods: In the years 1996-2000, 231 patients with invasive BC, ≥pN2a and no evidence of distant metastases were recruited to receive treatment A, i.e. dd 3 × epirubicin (E, 90 mg/m 2 ) + paclitaxel (P, 175 mg/m 2 ) every 2 weeks (q2w) followed by 3 × cyclophosphamide (C)/methotrexate/5-fluorouracil (CMF, 600/40/600 mg/m 2 , q2w), or treatment B, i.e. 4 × E + C (C, 600 mg/m 2 ) q3w followed by 3 × CMF q3w., Results: 113 patients in arm A and 113 patients in arm B were analysed after an updated median follow-up of 12.3 years. The median age was 55 years, with a median number of 6 +aLN, 50.4% had a T2 and 79.2% hormone receptor-positive BC. The disease-free survival (DFS) rate was 53.1% in arm A and 42.5% in arm B (adjusted p = 0.027). The overall survival (OS) rate was 54.9% in arm A and 48.7% in arm B (adjusted p = 0.058). In the multivariable analysis, the tumour burden was a significant predictor for DFS and OS., Conclusion: The adjuvant use of dd chemotherapy led to a statistically significant improvement of DFS after a follow-up of 12.3 years.

Background: The objective of this prospectively randomized phase II trial (Trial registration: EUCTR2004-004007-37-DE) was to compare the clinical response of primary breast cancer patients to neoadjuvant therapy with letrozole alone (LET) or letrozole and zoledronic acid (LET + ZOL)., Methods: Patients were randomly assigned to receive either LET 2.5 mg/day (n = 79) or the combination of LET 2.5 mg/day and a total of seven infusions of ZOL 4 mg every 4 weeks (n = 89) for 6 months. Primary endpoint was clinical response rate as assessed by mammogram readings. The study was terminated prematurely due to insufficient recruitment. We report here on an exploratory analysis of this data., Results: Central assessment of tumor sizes during the treatment period was available for 131 patients (66 LET, 65 LET + ZOL). Clinical responses (complete or partial) were seen in 54.5% (95% CI: 41.8-66.9) of the patients in the LET arm and 69.2% (95% CI: 56.6-80.1) of those in the LET + ZOL arm (P = 0.106). A multivariate model showed an OR of 1.72 (95% CI: 0.83-3.59) for the experimental arm., Conclusion: No increase in the clinical response rate was observed with the addition of ZOL to a neoadjuvant treatment regimen with LET. However a trend towards a better reponse in the LET + ZOL arm could be observed. This trend is consistent with previous studies that have investigated the addition of ZOL to chemotherapy, and it may support the evidence for a direct antitumor action of zoledronic acid.

To evaluate the feasibility and tolerability of dose-dense adjuvant chemotherapy for older patients with node-positive breast cancer, a retrospective subset analysis compared dose delays and dose reductions for women aged > or = 60 years with those of younger women. Patients were randomized to a dose-dense (DD, 14-day cycle) or conventional-schedule (CS, 21-day cycle) regimen. DD patients (n = 104; 25 aged > or = 60 years) received epirubicin 90 mg/m2 plus paclitaxel 175 mg/m2 (four cycles), then cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2 and fluorouracil 600 mg/m2 (CMF 600/40/600) (three cycles), plus filgrastim 5 microg/kg per day in every cycle. CS patients (n = 107; 27 aged > or = 60 years) received epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 (four cycles), then CMF 600/40/600 (three cycles), plus filgrastim if required. Delays were more common in older patients in both the DD and CS groups (DD, 17% versus 6%; CS, 11% versus 6%), as were Grades 3-4 leukopenia (26% versus 12%) and neutropenia (33% versus 25%). All older DD and 89% of older CS patients received all seven chemotherapy cycles, with 99% of cycles at full dose. This study demonstrates that a dose-dense regimen combining epirubicin and paclitaxel can be administered to patients > or = 60 years of age with a tolerable safety profile.

The primary objective was to determine the optimal doses for gemcitabine (prolonged infusion), liposomal doxorubicin (Myocet) and docetaxel as primary (neoadjuvant) chemotherapy for locally advanced breast cancer. Secondary objectives included evaluation of the safety and efficacy of the regimen. Patients (n=19) with histologically confirmed stage II or III breast cancer were treated with liposomal doxorubicin (50-60 mg/m2) and docetaxel (60-75 mg/m2) on day 1, and gemcitabine as 4-h infusion (350-400 mg/m2) on day 4. Treatment was repeated every 3 weeks for a maximum of 6 cycles. The maximum tolerated doses were gemcitabine 350 mg/m2, liposomal doxorubicin 60 mg/m2 and docetaxel 75 mg/m2. Dose-limiting toxicities were stomatitis, diarrhea and infection. The predominant hematologic toxicity was mild-to-moderate myelosuppression with grade 3/4 neutropenia in 20% of cycles. Non-hematologic toxicity was generally mild, with no grade 4 toxicities being observed. Predominant non-hematologic toxicity was stomatitis, which occurred in 95% of patients. Grade 3 toxicities were reported for stomatitis, nausea, diarrhea, infection and constipation. No cases of cardiac, renal, pulmonary or neurotoxicity were observed. The clinical response rate was 83% and histologically confirmed, clinically complete remissions occurred in two patients (11%). We conclude that the combination of gemcitabine (prolonged infusion), liposomal doxorubicin and docetaxel is safe and highly effective in patients with locally advanced breast cancer as defined by maximum tolerated doses. The evaluated schedule is suitable for phase II studies.

We have developed a 2-stage protocol for BRCA1 and BRCA2 mutation screening from blood spot paper. Stage 1 screening was aimed to analyze patients at highest risk for the most common disease-associated sequence variants listed in the BIC database. Accordingly, stage1 testing implied detection of 18 disease- associated BRCA1 and 9 BRCA2 mutations by adapting the 5' nuclease assay to heterozygote screening. For stage 2 screening, we applied the conformation sensitive gel electrophoresis (CSGE) method by adapting this technique to automated heteroduplex analysis of BRCA1 and BRCA2 using fragment scanning on an ABI 377 sequencing device. Of the 120 patients with a family history of breast and ovarian cancer who took part in this study so far, 45 entered stage 1 testing. Disease-associated mutations were detected in 6 patients by stage 1 testing (13%). For these patients, the final result was available within 10 days. Mutation 300T-->G was found in 2 patients. One patient with mutation 3036delACAA in BRCA2 reported only 1 sister with a multifocal bilateral breast cancer. New disease-associated mutations were detected in 2 of the 114 patients who entered the stage 2 test (1.7%). Of particular interest was 1 patient who was diagnosed with a medullary breast carcinoma at age 39 and who had no family history of breast cancer. We conclude that pre-screening by 5' nuclease assay for the mutations most frequently seen in a given population represents a relatively effective first line of analysis. Subsequent detailed analysis by fluorescence conformation sensitive gel electrophoresis (F-CSGE) and fragment sequencing is a sensitive alternative to full nucleotide sequencing., (Copyright 2000 Wiley-Liss, Inc.)

Objective: Taxanes and anthracyclines represent the two most active groups of agents for the treatment of breast cancer. We evaluated this combination in patients with more than 3 positive lymph nodes in an adjuvant, dose-intensive, sequential therapy in comparison with the standard chemotherapy regimen epirubicin/cyclophosphamide in relation to toxicities., Material and Methods: Since 9/96 127 patients with 4-9/over 9 positive lymph nodes have been recruited from 21 participating centers in an ongoing trial. 67 patients were prospectively randomised for first-line chemotherapy to treatment group A (epirubicin 90 mg/m2-paclitaxel 175 mg/m2; 4 cycles bi-weekly, supported by G-CSF 5 micrograms/kg day 5-13 and 3 sequential cycles of CMF 600/40/600 mg/m2 at 2-weeks interval) and 60 patients to treatment group B (epirubicin 90 mg/m2-cyclophosphamide 600 mg/m2, 4 cycles tri-weekly, and 3 sequential cycles of CMF 600/40/600 mg/m2 at 3-weeks interval)., Results: Preliminary safety and toxicity data are evaluable for 679 cycles. Data about response rate and disease-free-survival and overall survival will be delivered later. For the hematological toxicity the main grade 3 and 4 adverse events for A vs. B were: leucopenia 9.8% vs. 8.4%, febrile neutropenia 1.6% vs. 0.8%--anemia (< 5.9 mmol/l), 0.4% vs. 0.2%--thrombopenia 0% vs. 0%. Non-hematological toxicity occurred more frequently in group A (grade 2, 3, 4):--neuropathy 4.4% vs. 0%,--nausea/emesis 27.8% vs. 19.3%,--fatigue 14.6% vs. 3.4% and mucositis 2.8% vs. 0.3%.

Besides the lungs, the liver is the second most common site of hematogenous metastases from carcinomata of the breast. Hepar lobatum carcinomatosum is the rarest form of metastatic liver disease. Reported in this article is a case of a 59-year-old woman with invasive duct carcinoma of the breast with metastasis to the axillar lymph nodes and liver, treated with ablatio mammae and combination of chemotherapy. The etiology of hepar lobatum is caused by multiple pathogenetic factors. Tumor-related multifocal obstruction of portal and hepatic venous vessels and effects of chemotherapy are discussed.

A report its given about one case of squamous cell cancer of female breast. The authors analyse the therapeutic management and prognostic factors of this disease.