Search

Ziel Läsionsbezogene Überprüfung der diagnostischen Wertigkeit eines individuellen Algorithmus künstlicher Intelligenz (KI) in der Dignitätsbewertung von mammografisch detektierten und histologisch abgeklärten Mikroverkalkungen. Material und Methoden Die retrospektive Studie umfasste 634 Frauen mit abgeschlossener invasiver Abklärungsdiagnostik aufgrund von Mikroverkalkungen einer Mammografie-Screening-Einheit (Juli 2012 – Juni 2018). Das KI-System berechnete für jede Läsion einen Score zwischen 0 und 98. Scores > 0 wurden als KI-positiv betrachtet. Die KI-Performance wurde läsionen-spezifisch auf Basis des positiven prädiktiven Werts der umgesetzten invasiven Abklärungsdiagnostik (PPV3), der Rate falsch negativer und richtig negativer KI-Bewertungen evaluiert. Ergebnisse Der PPV3 stieg über die Befundstufen an (Befunder: 4a: 21,2 %, 4b: 57,7 %, 5: 100 %, gesamt 30,3 %; KI: 4a: 20,8 %, 4b: 57,8 %, 5: 100 %, gesamt: 30,7 %). Die Rate falsch negativer KI-Bewertungen lag bei 7,2 % (95 %-CI: 4,3 %, 11,4 %), die Rate richtig negativer KI-Bewertungen bei 9,1 % (95 %-CI: 6,6 %, 11,9 %). Diese Raten waren mit 12,5 % bzw. 10,4 % in der Befundstufe 4a am größten. Im Median war der KI-Score für benigne Läsionen am geringsten (61, Interquartilsabstand [IQR]: 45–74) und für invasive Mammakarzinome am höchsten (81, IQR: 64–86). Mediane Scores für das duktale Carcinoma in situ waren: 74 beim geringen (IQR: 63–84), 70 (IQR: 52–79) beim intermediären und 74 (IQR: 66–83) beim hohen Kernmalignitätsgrad. Schlussfolgerung Bei niedrigster Schwelle führt die Mikrokalk-bezogene KI-Bewertung zu einem zur menschlichen Bewertung vergleichbaren Anstieg des PPV3 über die Befundstufen. Der größte KI-bezogene Verlust an Brustkrebsdetektionen liegt bei geringstgradig suspekten Mikroverkalkungen vor mit einer vergleichbaren Einsparung falsch positiver invasiver Abklärungen. Eine Score-bezogene Stratifizierung maligner Läsionen lässt sich nicht ableiten. Kernaussagen: Zitierweise

Two dimensional (2D) full-field digital mammography is the current standard of breast cancer screening. Digital breast tomosynthesis generates pseudo-three dimensional datasets of the breast from which synthesised 2D (s2D) mammograms can be reconstructed. This innovative approach reduces the likelihood of overlapping breast tissues that can conceal features of malignancy. We aimed to compare digital breast tomosynthesis plus s2D mammography with digital screening mammography for the detection of invasive breast cancer.TOSYMA was a randomised, open-label, superiority trial done at 17 screening units in two federal states of Germany. Eligible participants were women aged 50-69 years who had been invited to participate in a population-wide, quality-controlled mammography screening programme. Women were randomly assigned (1:1) to digital breast tomosynthesis plus s2D mammography or digital mammography alone using block randomisation (block size of 32), stratified by site. The primary endpoints were the detection rate of invasive breast cancer and invasive interval cancer rate at 24 months, analysed in the modified full analysis set, which included all randomly assigned participants who underwent either type of screening examination. Ten examinations, corresponding to a second study participation, were excluded. Analyses were done according to the intention-to-treat principle. Interval cancer rates will be reported in the follow-up study. Safety was assessed in the as-treated population, which included all participants who were randomly assigned. This trial is registered with ClinicalTrials.gov, NCT03377036, and is closed to accrual.Between July 5, 2018, and Dec 30, 2020, 99 689 women were randomly assigned to digital breast tomosynthesis plus s2D mammography (n=49 804) or digital mammography (n=49 830). Invasive breast cancers were detected in 354 of 49 715 women with evaluable primary endpoint data in the digital breast tomosynthesis plus s2D group (detection rate 7·1 cases per 1000 women screened) and in 240 of 49 762 women in the digital mammography group (4·8 cases per 1000 women screened; odds ratio 1·48 [95% CI 1·25-1·75]; p0·0001). Adverse events and device deficiencies were rare (six adverse events in each group; 23 device deficiencies in the digital breast tomosynthesis plus s2D group vs five device deficiencies in the digital mammography group) and no serious adverse events were reported.The results from this study indicate that the detection rate for invasive breast cancer was significantly higher with digital breast tomosynthesis plus s2D mammography than digital mammography alone. Evaluation of interval cancer rates in the follow-up study will further help to investigate incremental long-term benefits of digital breast tomosynthesis screening.Deutsche Forschungsgemeinschaft (German Research Foundation).

Lesion-related evaluation of the diagnostic performance of an individual artificial intelligence (AI) system to assess mamographically detected and histologically proven calcifications. This retrospective study included 634 women of one screening unit (July 2012 - June 2018) who completed the invasive assessment of calcifications. For each leasion, the AI-system calculated a score between 0 and 98. Lesions scored 0 were classified as AI-positive. The performance of the system was evaluated based on its positive predictive value of invasive assessment (PPV3), the false-negative rate and the true-negative rate. The PPV3 increased across the categories (readers: 4a: 21.2 %, 4b: 57.7 %, 5: 100 %, overall 30.3 %; AI: 4a: 20.8 %, 4b: 57.8 %, 5: 100 %, overall: 30.7 %). The AI system yielded a false-negative rate of 7.2 % (95 %-CI: 4.3 %: 11.4 %) and a true-negative rate of 9.1 % (95 %-CI: 6.6 %; 11.9 %). These rates were highest in category 4a, 12.5 % and 10.4 % retrospectively. The lowest median AI score was observed for benign lesions (61, interquartile range (IQR): 45-74). Invasive cancers yielded the highest median AI score (81, IQR: 64-86). Median AI scores for ductal carcinoma in situ were: 74 (IQR: 63-84) for low grade, 70 (IQR: 52-79) for intermediate grade and 74 (IQR: 66-83) for high grade. At the lowest threshold, the AI system yielded calcification-related PPV3 values that increased across categories, similar as seen in human evaluation. The strongest loss in AI-based breast cancer detection was observed for invasively assessed calcifications with the lowest suspicion of malignancy, yet with a comparable decrease in the false-positive rate. An AI-score based stratification of malignant lesions could not be determined. · The AI-based PPV3 for calcifications is comparable to human assessment.. · AI showed a lower detection performance of screen-positive and screen-negative lesions in category 4a.. · Histological subgroups could not be discriminated by AI scores..· Weigel S, Brehl AK, Heindel W et al. Artificial Intelligence for Indication of Invasive Assessment of Calcifications in Mammography Screening. Fortschr Röntgenstr 2023; 195: 38 - 46.ZIEL: Läsionsbezogene Überprüfung der diagnostischen Wertigkeit eines individuellen Algorithmus künstlicher Intelligenz (KI) in der Dignitätsbewertung von mammografisch detektierten und histologisch abgeklärten Mikroverkalkungen. Die retrospektive Studie umfasste 634 Frauen mit abgeschlossener invasiver Abklärungsdiagnostik aufgrund von Mikroverkalkungen einer Mammografie-Screening-Einheit (Juli 2012 – Juni 2018). Das KI-System berechnete für jede Läsion einen Score zwischen 0 und 98. Scores 0 wurden als KI-positiv betrachtet. Die KI-Performance wurde läsionen-spezifisch auf Basis des positiven prädiktiven Werts der umgesetzten invasiven Abklärungsdiagnostik (PPV3), der Rate falsch negativer und richtig negativer KI-Bewertungen evaluiert. Der PPV3 stieg über die Befundstufen an (Befunder: 4a: 21,2 %, 4b: 57,7 %, 5: 100 %, gesamt 30,3 %; KI: 4a: 20,8 %, 4b: 57,8 %, 5: 100 %, gesamt: 30,7 %). Die Rate falsch negativer KI-Bewertungen lag bei 7,2 % (95 %-CI: 4,3 %, 11,4 %), die Rate richtig negativer KI-Bewertungen bei 9,1 % (95 %-CI: 6,6 %, 11,9 %). Diese Raten waren mit 12,5 % bzw. 10,4 % in der Befundstufe 4a am größten. Im Median war der KI-Score für benigne Läsionen am geringsten (61, Interquartilsabstand [IQR]: 45–74) und für invasive Mammakarzinome am höchsten (81, IQR: 64–86). Mediane Scores für das duktale Carcinoma in situ waren: 74 beim geringen (IQR: 63–84), 70 (IQR: 52–79) beim intermediären und 74 (IQR: 66–83) beim hohen Kernmalignitätsgrad. Bei niedrigster Schwelle führt die Mikrokalk-bezogene KI-Bewertung zu einem zur menschlichen Bewertung vergleichbaren Anstieg des PPV3 über die Befundstufen. Der größte KI-bezogene Verlust an Brustkrebsdetektionen liegt bei geringstgradig suspekten Mikroverkalkungen vor mit einer vergleichbaren Einsparung falsch positiver invasiver Abklärungen. Eine Score-bezogene Stratifizierung maligner Läsionen lässt sich nicht ableiten. · Der PPV3 der Mikrokalkabklärung ist unter KI-Bewertung vergleichbar zur menschlichen Bewertung.. · Die Befundstufe 4a unterliegt der ausgeprägtesten KI-induzierten Minderung Screening-positiver sowie Screening-negativer Läsionen.. · Die Score-Werte diskriminieren keine Subgruppen histologischer Läsionen..· Weigel S, Brehl AK, Heindel W et al. Artificial Intelligence for Indication of Invasive Assessment of Calcifications in Mammography Screening. Fortschr Röntgenstr 2023; 195: 38 – 46.

Background Digital breast tomosynthesis (DBT) plus synthesized mammography (SM) reduces the diagnostic pitfalls of tissue superimposition, which is a limitation of digital mammography (DM). Purpose To compare the invasive breast cancer detection rate (iCDR) of DBT plus SM versus DM screening for different breast density categories. Materials and Methods An exploratory subanalysis of the TOmosynthesis plus SYnthesized MAmmography (TOSYMA) study, a randomized, controlled, multicenter, parallel-group trial recruited within the German mammography screening program from July 2018 to December 2020. Women aged 50-69 years were randomly assigned (1:1) to DBT plus SM or DM screening examination. Breast density categories A-D were visually assessed according to the Breast Imaging Reporting and Data System Atlas. Exploratory analyses were performed of the iCDR in both study arms and stratified by breast density, and odds ratios and 95% CIs were determined. Results A total of 49 762 women allocated to DBT plus SM and 49 796 allocated to DM (median age, 57 years [IQR, 53-62 years]) were included. In the DM arm, the iCDR was 3.6 per 1000 screening examinations in category A (almost entirely fatty) (16 of 4475 screenings), 4.3 in category B (102 of 23 534 screenings), 6.1 in category C (116 of 19 051 screenings), and 2.3 in category D (extremely dense breasts) (six of 2629 screenings). The iCDR in the DBT plus SM arm was 2.7 per 1000 screening examinations in category A (12 of 4439 screenings), 6.9 in category B (154 of 22 328 screenings), 8.3 in category C (156 of 18 772 screenings), and 8.1 in category D (32 of 3940 screenings). The odds ratio for DM versus DBT plus SM in category D was 3.8 (95% CI: 1.5, 11.1). The invasive cancers detected with DBT plus SM were most often grade 2 tumors; in category C, it was 58% (91 of 156 invasive cancers), and in category D, it was 47% (15 of 32 invasive cancers). Conclusion The TOmosynthesis plus SYnthesized MAmmography trial revealed higher invasive cancer detection rates with digital breast tomosynthesis plus synthesized mammography than digital mammography in dense breasts, relatively and absolutely most marked among women with extremely dense breasts. ClinicalTrials.gov registration no.: NCT03377036 © RSNA, 2022

We have previously shown that remote ischemic preconditioning reduces acute kidney injury (acute kidney injury) in high-risk patients undergoing cardiopulmonary bypass and that the protective effect is confined to patients who exhibit an increased urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 in response to remote ischemic preconditioning. The purpose of this study was to determine the optimal intensity of remote ischemic preconditioning to induce required [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] changes and further explore mechanisms of remote ischemic preconditioning.Observational and randomized controlled, double-blind clinical trial.University Hospital of Muenster, Germany.High-risk patients undergoing cardiac surgery as defined by the Cleveland Clinic Foundation Score.In the interventional part, patients were randomized to receive either one of four different remote ischemic preconditioning doses (3 × 5 min, 3 × 7 min, 3 × 10 min remote ischemic preconditioning, or 3 × 5 min remote ischemic preconditioning + 2 × 10 min remote ischemic preconditioning in nonresponders) or sham-remote ischemic preconditioning (control).The primary endpoint of the interventional part was change in urinary [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] between pre- and postintervention. To examine secondary objectives including acute kidney injury incidence, we included an observational cohort. A total of 180 patients were included in the trial (n = 80 observational and n = 100 randomized controlled part [20 patients/group]). The mean age was 69.3 years (10.5 yr), 119 were men (66.1%). Absolute changes in [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] were significantly higher in all remote ischemic preconditioning groups when compared with controls (p0.01). Although we did not observe a dose-response relationship on absolute changes in [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] across the four different remote ischemic preconditioning groups, in the 15 patients failing to respond to the lowest dose, nine (60%) responded to a subsequent treatment at a higher intensity. Compared with controls, fewer patients receiving remote ischemic preconditioning developed acute kidney injury within 72 hours after surgery as defined by both Kidney Disease: Improving Global Outcomes criteria (30/80 [37.5%] vs 61/100 [61.0%]; p = 0.003).All doses of remote ischemic preconditioning significantly increased [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] and significantly decreased acute kidney injury compared with controls. High-dose remote ischemic preconditioning could stimulate [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] increases in patients refractory to low-dose remote ischemic preconditioning.

The one-sample log-rank test allows to compare the survival of a single sample with a prefixed reference survival curve. It naturally applies in single-arm phase IIa trials with time-to-event endpoint. Several authors have described that the original one-sample log-rank test is conservative when sample size is small and have proposed strategies to correct the conservativeness. Here, we propose an alternative approach to improve the one-sample log-rank test. Our new one-sample log-rank statistic is based on the unique transformation of the underlying counting process martingale such that the moments of the limiting normal distribution have no shared parameters. Simulation results show that the new one-sample log-rank test gives type I error rate and power close to the nominal levels also when sample size is small, while relevantly reducing the required sample size to achieve the desired power as compared to current approaches to design studies to compare the survival outcome of a sample with a reference.

Objectives To compare two prostaglandin analogs and two application intervals between mifepristone and the prostaglandin analog administration on the time to abortion in second trimester termination of pregnancy. Other endpoints were live birth rate and fetal lifetime after expulsion. Methods Retrospective data of 373 abortions performed were evaluated. Four medical induction subgroups and two feticide subgroups were considered. The definition criteria of the subgroups were the choice of administered prostaglandin analog (misoprostol vs. sulprostone) and the time interval between mifepristone and prostaglandin analog administration (48 vs. 24 h). The outcome parameters were the time to complete uterine evacuation (TCUE), the live birth rate and duration of fetal life. Results In the misoprostol subgroups, the median TCUE was 1.6 h longer in the 24-h group than in the 48-h group (p=0.950). In the sulprostone subgroups, the median TCUE was 1.9 h shorter in the 24-h group than in the 48-h group (p=0.950). The median TCUE was shorter for sulprostone than for misoprostol in all six subgroups (p Conclusions Both application intervals and prostaglandin analogs are similarly effective. The therapy regime should be adapted to the personal preferences of the woman, the situational and clinical conditions.

Objectives To evaluate if artificial intelligence (AI) can discriminate recalled benign from recalled malignant mammographic screening abnormalities to improve screening performance. Methods A total of 2257 full-field digital mammography screening examinations, obtained 2011–2013, of women aged 50–69 years which were recalled for further assessment of 295 malignant out of 305 truly malignant lesions and 2289 benign lesions after independent double-reading with arbitration, were included in this retrospective study. A deep learning AI system was used to obtain a score (0–95) for each recalled lesion, representing the likelihood of breast cancer. The sensitivity on the lesion level and the proportion of women without false-positive ratings (non-FPR) resulting under AI were estimated as a function of the classification cutoff and compared to that of human readers. Results Using a cutoff of 1, AI decreased the proportion of women with false-positives from 89.9 to 62.0%, non-FPR 11.1% vs. 38.0% (difference 26.9%, 95% confidence interval 25.1–28.8%; p < .001), preventing 30.1% of reader-induced false-positive recalls, while reducing sensitivity from 96.7 to 91.1% (5.6%, 3.1–8.0%) as compared to human reading. The positive predictive value of recall (PPV-1) increased from 12.8 to 16.5% (3.7%, 3.5–4.0%). In women with mass-related lesions (n = 900), the non-FPR was 14.2% for humans vs. 36.7% for AI (22.4%, 19.8–25.3%) at a sensitivity of 98.5% vs. 97.1% (1.5%, 0–3.5%). Conclusion The application of AI during consensus conference might especially help readers to reduce false-positive recalls of masses at the expense of a small sensitivity reduction. Prospective studies are needed to further evaluate the screening benefit of AI in practice. Key Points • Integrating the use of artificial intelligence in the arbitration process reduces benign recalls and increases the positive predictive value of recall at the expense of some sensitivity loss. • Application of the artificial intelligence system to aid the decision to recall a woman seems particularly beneficial for masses, where the system reaches comparable sensitivity to that of the readers, but with considerably reduced false-positives. • About one-fourth of all recalled malignant lesions are not automatically marked by the system such that their evaluation (AI score) must be retrieved manually by the reader. A thorough reading of screening mammograms by readers to identify suspicious lesions therefore remains mandatory.

BACKGROUND Precise risk stratification models are necessary to determine patient selection for deintensifying treatment trials in human papilloma virus (HPV)-associated oropharyngeal squamous cell cancer (HPV+ OPSCC). METHODS We examined 526 cases with OPSCC treated at our department between 2002 and 2017. Every patient was classified after the 7th and 8th edition UICC staging manual. For HPV+ OPSCC, we calculated a simple risk score with four risk groups based on multivariable Cox regression analysis of clinical and lifestyle parameters (UICC 8th edition stage, tobacco/alcohol abuse, age, gender). RESULTS Two hundred and thirty-nine patients with OPSCC (45.4%) showed a positive histological HPV status. In comparison to UICC 8th edition stages, our proposed risk model showed a tendency for better stratification between risk strata I/III, I/IV, and II/IV (each p

Minimal extrathyroidal extension (mETE) of papillary thyroid microcarcinoma (PTMC) is no longer considered in the new eighth edition of the staging manual of the American Joint Committee on Cancer and the International Union Against Cancer. Therefore, PTMC with mETE previously staged as pT3 will now be staged as pT1a and most likely not receive adjuvant radioiodine therapy. However, it remains unclear whether mETE is associated with higher aggressiveness in PTMC. Therefore, the aim of this study was to investigate whether mETE is associated with a higher risk of lymph node metastases (LNMs) or distant metastases. Methods: In total, 721 patients with PTMC presenting at our department for postoperative counseling from May 1983 to August 2012 were included in this retrospective analysis (median follow-up time, 9.30 y). The impact of mETE on the presence of LNMs at thyroidectomy and relapse through LNMs and distant metastases was assessed by logistic regression and Fine–Gray model analyses. Results: mETE was present in 10.7% (n = 77) of patients and was an independent risk factor for LNMs at thyroidectomy, with an adjusted odds ratio of 4.33 (95% CI, 2.02–9.60; P < 0.001) in multivariable analysis. Patients with mETE had significantly more relapses through LNMs (over 5 y: 13.1% vs. 1.25%; P < 0.001) and distant metastases (over 5 y: 7.8% vs. 1.1%; P < 0.001) than did patients without mETE. mETE was an independent risk factor for relapse through LNMs and distant metastases in multivariable analysis (hazard ratio of 7.78 and 95% CI of 2.87–21.16 for LNMs [P < 0.001]; hazard ratio of 4.09 and 95% CI of 1.25–13.36 for distant metastases [P = 0.020]). Conclusion: mETE is a statistically significant and independent risk factor for relapse through LNMs and distant metastases in PTMC. Therefore, future studies should evaluate whether patients with mETE and PTMC might benefit from intensified surveillance and therapy.

Minimal extrathyroidal extension (mETE) of papillary thyroid microcarcinoma (PTMC) is no longer considered in the new eighth edition of the staging manual of the American Joint Committee on Cancer and the International Union Against Cancer. Therefore, PTMC with mETE previously staged as pT3 will now be staged as pT1a and most likely not receive adjuvant radioiodine therapy. However, it remains unclear whether mETE is associated with higher aggressiveness in PTMC. Therefore, the aim of this study was to investigate whether mETE is associated with a higher risk of lymph node metastases (LNMs) or distant metastases. Methods: In total, 721 patients with PTMC presenting at our department for postoperative counseling from May 1983 to August 2012 were included in this retrospective analysis (median follow-up time, 9.30 y). The impact of mETE on the presence of LNMs at thyroidectomy and relapse through LNMs and distant metastases was assessed by logistic regression and Fine-Gray model analyses. Results: mETE was present in 10.7% (n = 77) of patients and was an independent risk factor for LNMs at thyroidectomy, with an adjusted odds ratio of 4.33 (95% CI, 2.02-9.60; P < 0.001) in multivariable analysis. Patients with mETE had significantly more relapses through LNMs (over 5 y: 13.1% vs. 1.25%; P < 0.001) and distant metastases (over 5 y: 7.8% vs. 1.1%; P < 0.001) than did patients without mETE. mETE was an independent risk factor for relapse through LNMs and distant metastases in multivariable analysis (hazard ratio of 7.78 and 95% CI of 2.87-21.16 for LNMs [P < 0.001]; hazard ratio of 4.09 and 95% CI of 1.25-13.36 for distant metastases [P = 0.020]). Conclusion: mETE is a statistically significant and independent risk factor for relapse through LNMs and distant metastases in PTMC. Therefore, future studies should evaluate whether patients with mETE and PTMC might benefit from intensified surveillance and therapy.

Purpose Postoperative pancreatic fistula (POPF) with reported incidence rates up to 45% contributes substantially to overall morbidity. In this study, we conducted a retrospective evaluation of POPF along with its potential perioperative clinical risk factors and its effect on tumor recurrence. Methods Clinical data on patients who had received pancreatoduodenectomy (PD), distal pancreatectomy (DP), or duodenum-preserving pancreatic head resection (DPPHR) were prospectively collected between 2007 and 2016. A Picrosirius red staining score was developed to enable morphological classification of the resection margin of the pancreatic stump. The primary end point was the development of major complications. The secondary end points were overall and recurrence-free survival. Results 340 patients underwent pancreatic resection including 222 (65.3%) PD, 87 (25.6%) DP, and 31 (9.1%) DPPHR. Postoperative major complications were observed in 74 patients (21.8%). In multivariable logistic regression analysis, POPF correlated with body mass index (BMI) (p = 0.025), prolonged stay in hospital (p Conclusion Besides the known clinicopathological risk factors BMI and amylase in the drain fluid, the incidence of POPF correlates with high Picrosirius red staining score in the resection margins of the pancreatic stumps of curatively resected pancreatic ductal adenocarcinoma (PDAC). Furthermore, clinically relevant POPF seems to be a prognostic factor for tumor recurrence in PDAC.

Background: Cough is a key symptom in patients with cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). Objective: The study objectives were to test whether cough is related to parameters reflecting their disease severity and whether CF and PCD differ in cough frequency. Methods: In this prospective observational study, we used a microphone-based monitoring system (LEOSound® Monitor) to count the coughs in healthy subjects (HS) and in stable patients with CF and PCD (25 subjects per group) on 2 consecutive nights. Results: The median number of coughs/h in the HS, CF, and PCD groups was 0.0, 1.3, and 0.5 on the first night and 0.0, 2.3, and 0.2 on the second night, respectively. Patients with CF and PCD coughed more than HS (p < 0.001 and p = 0.009, respectively) and CF patients coughed more than PCD patients (p = 0.023). A multivariable mixed model analysis revealed forced expiratory volume in 1 s as an independent risk factor for increased cough frequency in patients. The reliability for repeated measurements was higher for cough epochs/h than for coughs/h (intraclass correlation coefficient: 0.75 and 0.49, respectively). Conclusions: Patients with CF cough more than patients with PCD. The cough frequency in CF and PCD is associated with parameters reflecting disease severity. Cough frequency is a possible endpoint in clinical trials and cough epochs/h may be more useful than coughs/h.

// Selma Ugurel 1, 2 , Carmen Loquai 3 , Patrick Terheyden 4 , Dirk Schadendorf 1, 5 , Erika Richtig 6 , Jochen Utikal 7, 8 , Ralf Gutzmer 9 , Knuth Rass 10 , Cord Sunderkotter 11 , Annette Stein 12 , Michael Fluck 13 , Martin Kaatz 14 , Uwe Trefzer 15 , Katharina Kahler 16 , Rudolf Stadler 17 , Carola Berking 18 , Christoph Holler 19 , Laura Kerschke 20, 21 , Lutz Edler 20 , Annette Kopp-Schneider 20 and Jurgen C. Becker 1, 2, 5, 6 1 Department of Dermatology, University Hospital of Essen, Essen, Germany 2 Department of Dermatology, University Hospital of Wurzburg, Wurzburg, Germany 3 Department of Dermatology, University Hospital of Mainz, Mainz, Germany 4 Department of Dermatology, University Hospital of Lubeck, Lubeck, Germany 5 Translational Skin Cancer Research, Deutsches Konsortium fur Translationale Krebsforschung (DKTK), Essen, Germany 6 Department of Dermatology, Medical University of Graz, Graz, Austria 7 Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany 8 Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany 9 Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany 10 Department of Dermatology, The Saarland University Hospital, Homburg/Saar, Germany 11 Department of Dermatology, University Hospital of Munster, Munster, Germany 12 Department of Dermatology, University Hospital of Dresden, Dresden, Germany 13 Department of Internal Medicine, Fachklinik Hornheide, Hornheide, Germany 14 Department of Dermatology, University Hospital of Jena, Jena, Germany 15 Department of Dermatology, University Hospital Charite, Berlin, Germany 16 Department of Dermatology, University Hospital of Kiel, Kiel, Germany 17 Department of Dermatology, Johannes Wesling Klinikum, Minden, Germany 18 Department of Dermatology, University Hospital of Munich, Munich, Germany 19 Department of Dermatology, Medical University of Vienna, Vienna, Austria 20 Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany 21 Institute of Biostatistics and Clinical Research, University of Munster, Munster, Germany Correspondence to: Selma Ugurel, email: selma.ugurel@uk-essen.de Keywords: melanoma, chemosensitivity, individualized chemotherapy, phase-3 trial Received: March 06, 2017 Accepted: May 10, 2017 Published: June 27, 2017 ABSTRACT Chemotherapy still plays an important role in metastatic melanoma, particularly for patients who are not suitable or have no access to highly efficacious new therapies. Pre-therapeutic chemosensitivity testing might be useful to identify optimal chemotherapy regimens for individual patients. This multicenter randomized phase-3 trial was aimed to test for superiority of chemosensitivity-directed combination chemotherapy compared to standard dacarbazine monochemotherapy, and to demonstrate the chemosensitivity test result as prognostic in metastatic melanoma. Chemo-naive patients with advanced melanoma were biopsied from metastatic lesions. Tumor cells were isolated and tested ex-vivo for sensitivity to chemotherapeutic agents using an ATP-based viability assay. Patients with evaluable test results were randomly assigned to receive either chemosensitivity-directed combination chemotherapy (paclitaxel+cisplatin, treosulfan+gemcitabine, treosulfan+cytarabine), or dacarbazine. The primary study endpoint was overall survival (OS). After inclusion of 287 patients and a median follow-up of 26 months, the per-protocol population (n=244) showed no difference in OS between chemosensitivity-directed therapy and dacarbazine (median 9.2 vs 9.0 months, HR=1.08, p=0.64). The disease control rate (CR+PR+SD) tended to be higher in patients treated with chemosensitivity-directed therapy (32.8% vs 23.0%, p=0.088); objective response rates (CR+PR) showed no difference between groups (10.7% vs 12.3%, p=0.90). Patients whose tumors were tested chemosensitive showed no better OS or response rate than patients with chemoresistant tumors. Severe toxicities (CTC grade 3-4) were significantly more frequently observed with chemosensitivity-directed combination chemotherapy than with dacarbazine (40.2% vs 12.3%, p

Purpose To evaluate the effect of topical mydriatic eye drops on optical coherence tomography angiography (OCTA) parameters in patients with age-related macular degeneration (AMD). Methods 27 eyes of 27 patients suffering from AMD were included in this cross-sectional study. Patients with ≥-4.5 diopters spherical equivalent, corneal opacities or dense cataract preventing high-quality imaging were excluded. Whole-en-face scans of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) in the central 3x3mm foveal region as well as whole-en-face and peripapillary scans of the radial peripapillary capillaries (RPC) were generated using OCTA (AngioVue®, Optovue). Imaging was first conducted with patients’ eyes in miosis, then in mydriasis after instillation of a dilating eye drop (0.5% tropicamide, 2.5% phenylephrine-HCl). Main outcome measures were flow density (FD), foveal avascular zone (FAZ), signal strength index (SSI) and motion artifact score (MAS). Results Our results reveal that in AMD patients there is no significant difference between FD measurements taken in miosis and those taken in mydriasis around the SCP (p = 0.198), DCP (p = 0.458), RPC whole-en-face (p = 0.275) and RPC peripapillary (p = 0.503). Measurements taken in these two states appear to be equivalent for assessment of FD (90%CI within ± 0.05). No significant difference was found either in the area of the FAZ (p = 0.338) or in the SSI (p = 0.371) before and after the instillation of tropicamide/phenylephrine. MAS was significantly lower after the application of mydriatic eye drops (p = 0.003). Conclusions Our findings reveal that neither measurements of FD nor measurements of the FAZ area changed significantly in AMD patients after the application of tropicamide/phenylephrine. Since MAS improved significantly in dilation, mydriatic examination is recommended. Nevertheless, a comparison of OCTA metrics from images taken with different pupil states (miosis versus mydriasis) is valid for clinical trials.

PURPOSE: To determine the diurnal variations in peripapillary and macular flow density (FD), as measured using optical coherence tomography angiography (OCTA) and to elaborate on the relationship between diurnal FD, circulatory parameters and intraocular pressure (IOP) variations in primary open-angle glaucoma (POAG). METHODS: Forty eyes of 40 POAG patients were drawn into this cross-sectional study. The retinal microvasculature of the macula (superficial and deep layers) and optic nerve [radial peripapillary capillary (RPC)] was examined by OCTA (AngioVue® , Optovue). Optical coherence tomography angiography (OCTA) measurements were conducted at 08:00, 11:00, 15:00 and 20:00 over the course of two consecutive days. Intraocular pressure (IOP) and circulatory parameters were assessed accordingly. Diurnal variations in FD were analysed using linear mixed models. RESULTS: While superficial macular FD and RPC FD revealed not to be affected by diurnal variations (p = 0.492, p = 0.319), FD in the deep layer of the macula increased throughout the day (p < 0.001). Superficial macular FD was influenced significantly by mean arterial pressure (MAP) (p = 0.006) and heart rate (HR) (p = 0.033), whereas FD in the RPC layer was significantly affected by HR (p = 0.010). No statistically significant effect of IOP fluctuations on FD was observed. CONCLUSION: This study shows diurnal fluctuations of deep macular FD measured by OCTA and outlines the relationship between FD and hemodynamic parameters (MAP/HR) in POAG patients.

Background The aim of this study was to compare the adrenal gland size of fetuses of women with gestational diabetes mellitus (GDM) with that of healthy control fetuses. Methods This prospective cross-sectional study included measurements of the adrenal gland size of 62 GDM fetuses (GDM group) and 370 normal controls (control group) between the 19th and 41st week of gestation. A standardized transversal plane was used to measure the total width and the medulla width. The cortex width and an adrenal gland ratio (total width/medulla width) were calculated from these data. Adrenal gland size measurements were adjusted to the week of gestation and compared between the two groups in a multivariable linear regression analysis. A variance decomposition metric was used to compare the relative importance of predictors of the different adrenal gland size measurements. Results For all the investigated parameters of the adrenal gland size, increased values were found in the case of GDM (P Conclusion The fetal adrenal gland is enlarged in pregnancy complicated by GDM. The width of the cortex seems to be particularly affected.

Background and aims: Various attempts have been made to support recovery following optic neuritis (ON), but the respective trials have mostly been negative. The aim of this study was to determine whether disease-modifying treatment (DMT) following ON as first manifestation of relapsing-remitting multiple sclerosis influences long-term outcomes. Methods: A total of 79 patients with ON were identified and evaluated at relapse, DMT induction, and 12 months following treatment induction with either glatiramer acetate (GLAT), interferon-beta (IFN), or teriflunomide (TRF). Low-contrast letter acuity (LCLA) and full-field visual-evoked potentials (FF-VEP) were compared between treatment groups using multivariable regression models. The impact of TRF treatment induction compared with IFN or GLAT following relapses outside the optic nerves was evaluated in an independent cohort of 122 patients. Magnetic resonance imaging (MRI) outcomes and rates of confirmed improvement of relapse-related disability were evaluated. Results: TRF-treated patients exhibited higher LCLA and lower relative P100 latencies normalized to the fellow-eye. Findings were significant following covariate-adjustment by multivariable analyses. Cranial MRI lesion load as well as disability progression rates were not significantly different between groups. The cohort of patients following relapses other than ON showed no differences in confirmed improvement of disability. Conclusion: TRF treatment is associated with favorable outcomes regarding functional optic nerve recovery following ON in early multiple sclerosis.

Data on vitamin D status of patients with inherited ichthyosis in Europe is scarce and unspecific concerning the genetic subtype. This study determined serum levels of 25-hydroxyvitamin D3 (25(OH)D3) in 87 patients with ichthyosis; 69 patients were additionally analysed for parathyroid hormone. Vitamin D deficiency was pronounced in keratinopathic ichthyosis (n = 17; median 25(OH)D3: 10.5 ng/ml), harlequin ichthyosis (n = 2;7.0 ng/ml) and rare syndromic subtypes (n = 3; 7.0 ng/ml). Vitamin D levels were reduced in TG1-proficient lamellar ichthyosis (n = 15; 8.9 ng/ml), TG1-deficient lamellar ichthyosis (n = 12; 11.7 ng/ml), congenital ichthyosiform erythroderma (n = 13; 12.4 ng/ml), Netherton syndrome (n = 7; 10.7 ng/ml) and X-linked ichthyosis (n = 8; 13.9 ng/ml). In ichthyosis vulgaris 25(OH)D3 levels were higher (n = 10; 19.7 ng/ml). Parathyroid hormone was elevated in 12 patients. Low 25(OH)D3 levels were associated with high severity of scaling (p = 0.03) implicating scaling as a risk factor for vitamin D deficiency. Thus, this study supports our recent guidelines for ichthyoses, which recommend screening for and substituting of vitamin D deficiency., This study was supported by the Selbsthilfe Ichthyose e.V., the Medical Faculty of the University of Münster (OJI120817 & OJ111409) and of the German Research Foundation (DFG OJ 53/3-1). It is part of the medical thesis of Mi-Ran Kim. The work was supported by the Selbsthilfe Ichthyose e.V., the Medical Faculty of the University of Muenster (OJI120817 & OJ111409) and by the German Research Foundation (DFG OJ 53/3-1). Furthermore, we cooperated with members of the European Reference Network (ERN, subgroup ERN-skin). The cohort of this paper was also part of a project funded by the programme “Innovative Medizinische Forschung” (IMF); project number: SÜ212007.

In proteomics, liquid chromatography-tandem mass spectrometry (LC-MS/MS) is established for identifying peptides and proteins. Duplicated spectra, that is, multiple spectra of the same peptide, occur both in single MS/MS runs and in large spectral libraries. Clustering tandem mass spectra is used to find consensus spectra, with manifold applications. First, it speeds up database searches, as performed for instance by Mascot. Second, it helps to identify novel peptides across species. Third, it is used for quality control to detect wrongly annotated spectra. We compare different clustering algorithms based on the cosine distance between spectra. CAST, MS-Cluster, and PRIDE Cluster are popular algorithms to cluster tandem mass spectra. We add well-known algorithms for large data sets, hierarchical clustering, DBSCAN, and connected components of a graph, as well as the new method N-Cluster. All algorithms are evaluated on real data with varied parameter settings. Cluster results are compared with each other and with peptide annotations based on validation measures such as purity. Quality control, regarding the detection of wrongly (un)annotated spectra, is discussed for exemplary resulting clusters. N-Cluster proves to be highly competitive. All clustering results benefit from the so-called DISMS2 filter that integrates additional information, for example, on precursor mass.

Introduction Development of digital breast tomosynthesis (DBT) provides a technology that generates three-dimensional data sets, thus reducing the pitfalls of overlapping breast tissue. Observational studies suggest that the combination of two-dimensional (2D) digital mammography and DBT increases diagnostic accuracy. However, because of duplicate exposure, this comes at the cost of an augmented radiation dose. This undesired adverse impact can be avoided by using synthesised 2D images reconstructed from the DBT data (s2D). We designed a diagnostic superiority trial on a high level of evidence with the aim of providing a comparison of screening efficacy parameters resulting from DBT+s2D versus the current screening standard 2D full-field digital mammography (FFDM) in a multicentre and multivendor setting on the basis of the quality-controlled, population-based, biennial mammography screening programme in Germany. Methods and analysis 80 000 women in the eligible age 50–69 years attending the routine mammography screening programme and willing to participate in the TOSYMA trial will be assigned by 1:1 randomisation to either the intervention arm (DBT+s2D) or the control arm (FFDM) during a 12-month recruitment period in screening units of North Rhine-Westphalia and Lower Saxony. State cancer registries will provide the follow-up of interval cancers. Primary endpoints are the detection rate of invasive breast cancers at screening examination and the cumulative incidence of interval cancers in the 2 years after a negative examination. Secondary endpoints are the detection rate of ductal carcinoma in situ and of tumour size T1, the recall rate for assessment, the positive predictive value of recall and the cumulative 12-month incidence of interval cancers. An adaptive statistical design with one interim analysis provides the option to modify the design. Ethics and dissemination This protocol has been approved by the local medical ethical committee (2016-132-f-S). Results will be submitted to international peer-reviewed journals. Trial registration NCT03377036; Pre-results.

560 Background: Optimization of axillary staging in patients converting from cN+ to ycN0 through PST is needed. The aim of this analysis was to develop a nomogram predicting the probability of ypN+ after PST based on clinical/pathological parameters. Methods: Patients converting from cN+ to ycN0 through PST from a prospective study (SENTINA arm C) were included. Univariate/multivariate analyses were carried out for 14 clinical/pathological parameters to predict ypN+ using logistic regression models. Odds ratios and 95% confidence intervals were reported. Model performance was assessed by leave-one-out cross-validation (LOOCV at .5 cut-offs) and ROC analyses. Calculations were performed using the SAS Software (Version 9.4). Results: 553 patients were assessed. Stepwise backward variable selection based on a multivariate analysis of all significant parameters resulted in a model (5M, Table, N = 369 evaluable) including ER (3.81; 2.25-6.44), multifocality (2.22; 1.26-3.92), LVI (9.16; 4.68-17.90), detection of SLN after PST (.50; .26-.95) and ycT (1.03; 1.01-1.06). In LOOCV, this model had an area under the curve of .81. Multivariate analysis of parameters available preoperatively showed an association between ypN0/ypN+, ER and ycT. Full subset selection resulted in a model (2M, N = 414) containing only ER (4.36; 2.80, 6.81) and ycT (1.04; 1.02, 1.07). Conclusions: A prediction model including parameters evaluable before/after definitive surgery resulted in a nomogram with acceptable accuracy. Limitation to parameters evaluable before surgery (i.e. ER, ycT) showed reduced accuracy that was comparable/superior to accuracy of using individual parameters. Since tumor biology was the strongest parameter in our models, we hypothesize that modern tumor biologic parameters such as gene expression profiling might optimize prediction of axillary status after PST improving patient counseling. [Table: see text]