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Summary: Background: Due to the continuing lack of sensitive and specific diagnostic tools, clinical data on opportunistic invasive fungal infections (IFIs) remain difficult to assess and postmortem data are indispensable to monitor trends in frequency and disease patterns. Methods: Following-up on our previous report covering the period between 1978 and 1992, all protocols of postmortems performed between 1993 and 2005 at the University Hospital of Frankfurt/Main were retrospectively screened for the presence of IFIs. Results: The analysis of 2707 consecutive autopsies identified 221 patients with IFIs (mean age, 52 years; range, 10 days–94 years). The prevalence of IFIs at autopsy steadily increased over the analyzed time periods (from 6.6% in 1993–1996 to 10.4% in 2001–2005), continuing the trend that was observed at our institution before. The increasing prevalence of IFIs was mainly due to an increase in Candida infections; rates of infections caused by Aspergillus, Cryptococcus, Zygomycetes and Pneumocystis remained constant. However, Aspergillus remained the leading pathogen. Patients with hematologic malignancies had the highest frequency of IFIs at postmortem. Candida most commonly affected the gastrointestinal tract, whereas Aspergillus most commonly affected the lung. Conclusions: The results of this analysis show continuing and relevant changes in the epidemiology of IFIs over time. Despite the expanding antifungal armamentarium, IFIs infections remain an important cause of morbidity and mortality in severely ill hospitalized patients. [ABSTRACT FROM AUTHOR]

Background: The GAIN-2 trial was designed to identify a superior intense dose-dense (idd) strategy for high-risk patients with early breast cancer. Here, we report an interim analysis, at which the predefined futility boundary was crossed., Patients and Methods: GAIN-2 was an open-label, randomised, multicentre phase III trial. Two thousand eight hundred and eighty seven patients were randomised 1:1 between three courses each of idd epirubicin (E) 150 mg/m 2 , nab-paclitaxel (nP) 330 mg/m 2 and cyclophosphamide (C) 2000 mg/m 2 (iddEnPC) versus four cycles of leucocyte nadir-based tailored and dose-dense EC (dtEC) followed by four cycles of tailored and dose-dense docetaxel (dtD) (dtEC-dtD)., Results: The duration of median follow-up was 45.8 (range 0.0-88.3) months. Trial objectives included invasive disease-free survival (iDFS) as the primary end-point. A total of 593 patients received the treatment as neoadjuvant chemotherapy. At the time of futility interim analysis, 414 events for iDFS were reported. Overall, there was no difference in iDFS between iddEnPC and dtEC-dtD with 4-year iDFS rates of 84.3% (95% confidence interval (CI) 82.0-86.4%). Among all predefined subgroups, hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-), lobular cancer and ≤50 years subgroups predicted for better iDFS in the dtEC-dtD arm. Overall, 88.1% of patients completed all treatment in both arms. Haematological toxicity grade 3/4 and grade 3/4 non-haematological adverse events were significantly higher with iddEnPC (iddEnPC 50.8% vs dtEC-dtD 45.1%, P = 0.002), especially arthralgia and peripheral sensory neuropathy. Two treatment-related deaths occurred during dtEC-dtD, corresponding to a low mortality rate of 0.07%., Conclusions: iDFS is equal in both regimens, but tailoring dose-dense chemotherapy improved outcomes in HR+/HER2-, lobular cancer and patients ≤50 years., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AS reports grants from Celgene, grants from Roche, grants from AbbVie, personal fees from Roche, personal fees from AstraZeneca, personal fees from Celgene, personal fees from Roche, personal fees from Roche, personal fees from Celgene, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Novartis, personal fees from MSD, personal fees from Tesaro, personal fees from Lilly, personal fees from Pfizer, other from Roche, outside the submitted work; CD reports personal fees from Novartis, Roche, MSD Oncology, Daiichi Sankyo, grants from Myriad Genetics, other from Sividon Diagnostics/Myriad, outside the submitted work and has a patent EP18209672 pending, a patent EP20150702464 pending and a patent Software (VMscope digital pathology) pending. CJ reports honoraria from Roche, Celgene, Novartis, Genomic Health and Amgen; compensation for consulting and advisory role from Roche, Novartis and Pfizer; travel expenses from Roche, Astra Zeneca and Genomic Health; CS reports compensation for consulting and advisory role from Olympus, Hologic; and travel expenses from imed, MedConcept, Medtronic, Diaglog Service, Mentor, mylan, GBG and Pfizer; ES reports honoraria from Roche, Astra Zeneca, Novartis, Pfizer, ESAI, Tesaro and MSD; compensation for consulting and advisory role from Roche and Tesaro; and travel expenses from Roche and Pfizer; FM reports personal fees from Roche, AstraZeneca, Pfizer, Tesaro, Novartis, Amgen, PharmaMar, GenomicHealth, CureVac, EISAI, Celgene, Clovis, Janssen-Cilag, Immunomedics, GSK, MSD, Seagen and Lilly outside the submitted work; JH reports grants and personal fees from Novartis, personal fees from Lilly, personal fees and other from Pfizer, personal fees and other from Roche, personal fees from Abbvie, personal fees from Astra Zeneca, personal fees from Eisai, other from Daichii, grants, personal fees and other from Celgene, personal fees from MSD, grants and personal fees from Hexal, outside the submitted work; JUB reports personal fees from AMGEN, personal fees from ASTRA Zeneca, personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, personal fees from SonoScape, from Sysmex, outside the submitted work; MR reports honoraria from MSD, Astra Zeneca, Lilly, Novartis and SOMATEX; compensation for consulting and advisory role from Roche, Novartis, MSD, Astra Zeneca and Lilly; and travel expenses from Pfizer, Novartis and Celgene; MU reports honoraria paid to his employer by Amgen, Astra Zeneca, Celgene, Daiji Sankyo, Eisai, Lilly, MSD, Mundipharma, Pfizer, Novartis, Roche, Sanofi Aventis and PUMA Biotechnology; compensation for consulting and advisory role to the employer from Amgen, Abbvie, Astra Zeneca, Celgene, Daiji Sankyo, Eisai, Lilly, MSD, Mundipharma, Novartis, Odonate, Pfizer, Roche, PUMA Biotechnology, Sanofi Aventis and Teva; SL reports grants and other from Roche during the conduct of the study; grants and other from Abbvie, grants and other from Amgen, grants and other from Celgene, grants and non-financial support from Immunomedics, grants and other from Novartis, grants and other from Pfizer, other from Seattle Genetics, other from PriME/Medscape, personal fees from Chugai, grants from Teva, grants from Vifor, grants and other from Daiichi-Sankyo, other from Lilly, other from Samsung, other from EirGenix, other from BMS, other from Puma, other from MSD and grants and other from AstraZeneca outside the submitted work; In addition, SL has a patent EP14153692.0 pending. TL reports honoraria from Lilly, Teva, Tesaro, Roche, Novartis, Pfizer, MSD, Amgen and Clovis; compensation for consulting and advisory role from Lilly, Roche, Tesaro, Amgen and MSD; travel expenses from Roche, Pfizer and Celgene; VM reports speaker honoraria from Amgen, Astra Zeneca, Celgene, Roche, TEVA and consultancy honoraria from Roche, Amgen, Tesaro and Myelo Therapeutics; WJ reports grants and personal fees from Sanofi-Aventis, Novartis, Lilly, Pfizer, Roche, Chugai and AstraZeneca during the conduct of the study; No other potential conflict of interest relevant to this article was reported., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: GeparOcto compared efficacy and safety of two chemotherapy regimens in high-risk early breast cancer (BC): sequential treatment with intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) and weekly treatment with paclitaxel plus non-pegylated liposomal doxorubicin (M, Myocet®) with additional carboplatin (PM(Cb)) in triple-negative BC (TNBC)., Patients and Methods: Patients with cT1c-cT4a-d and centrally assessed human epidermal growth factor receptor (HER)2-positive BC or TNBC were eligible, irrespective of nodal status, luminal B-like tumours only if pN+. Patients were randomised (stratified by BC subtype, Ki67, lymphocyte-predominant BC) to receive 18 weeks of E (150 mg/m 2 ) followed by P (225 mg/m 2 ) followed by C (2000 mg/m 2 ), each q2w for 3 cycles or weekly P (80 mg/m 2 ) plus M (20 mg/m 2 ) plus, in TNBC, Cb (area under curve (AUC) 1.5). HER2-positive BC patients additionally received trastuzumab (6 [loading dose 8]mg/kg q3w) and pertuzumab (420 [840]mg q3w) with all P and C cycles. Primary end-point was pathological complete response (pCR, ypT0/is ypN0), secondary end-points included other pCR definitions, pCR in stratified subpopulations, tolerability and compliance. This trial is registered with ClinicalTrials.gov number NCT02125344., Results: 945/961 randomised patients started treatment. The median age was 48 years; 7.6% had cT3-4, 46% cN+, 66% G3, 40% HER2-positive, 43% TNBC. pCR rate with iddEPC was 48.3%, with PM(Cb) 48.0%, respectively (PM(Cb) versus iddEPC odds ratio 0.99; 95% confidence interval 0.77-1.28, P = 0.979) with no significant differences observed in TNBC, HER2-positive, luminal B-like subtypes. 16.4% with iddEPC and 34.1% with PM(Cb) discontinued treatment (P < 0.001), mainly due to adverse events; two patients on PM(Cb) died., Conclusions: In high-risk early BC there is no difference in pCR rates following neoadjuvant treatment with iddEPC or weekly PM(Cb), respectively. iddEPC is one of the effective dose-dense regimens feasible in daily practice., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Human epidermal growth factor receptor 2 (HER2) is a central predictive biomarker in breast cancer. Inaccurate HER2 results in different laboratories could be as high as 20%. However, this statement is based on data generated more than 13 years ago and may not reflect the standards of modern diagnostic pathology. We compared central and local HER2 testing in a total of 1581 HER2-positive tumors from five clinical trials. We evaluated the clinical relevance for pathological complete response (pCR) and disease-free survival in a subgroup of 677 tumors, which received an anti-HER2 therapy. Over the period of 12 years, the discordance rate for HER2 decreased from 52.4 (GeparTrio) to 8.4% (GeparSepto). Discordance rates were significantly higher in hormone receptor (HR)-positive tumors (26.6%), compared to HR-negative tumors (16.3%, P<0.0001), which could be explained by a different distribution of HER2 mRNA levels in HR-positive and HR-negative tumors. pCR rates were significantly lower in discordant tumors (13.7%) compared to concordant tumors (32.2%, GeparQuattro and GeparQuinto, P<0.001). In survival analysis, tumors with discordant HER2 testing had a reduced overall survival (OS) in the HR-negative group (P=0.019) and a trend for improved OS in the HR-positive group (P=0.125). The performance of local HER2 testing was considerably improved over time and has reached a 92% concordance, which shows that quality initiatives in diagnostic pathology are working. Tumors with discordant HER2 testing had a reduced therapy response and different survival rates.