Reconstructing tumor history in breast cancer: signatures of mutational processes and response to neoadjuvant chemotherapy⋆.

BACKGROUND: Different endogenous and exogenous mutational processes act over the evolutionary history of a malignant tumor, driven by abnormal DNA editing, mutagens or age-related DNA alterations, among others, to generate the specific mutational landscape of each individual tumor. The signatures of these mutational processes can be identified in large genomic datasets. We investigated the hypothesis that genomic patterns of mutational signatures are associated with the clinical behavior of breast cancer, in particular chemotherapy response and survival, with a particular focus on therapy-resistant disease. PATIENTS AND METHODS: Whole exome sequencing was carried out in 405 pretherapeutic samples from the prospective neoadjuvant multicenter GeparSepto study. We analyzed 11 mutational signatures including biological processes such as APOBEC-mutagenesis, homologous recombination deficiency (HRD), mismatch repair deficiency and also age-related or tobacco-induced alterations. RESULTS: Different subgroups of breast carcinomas were defined mainly by differences in HRD-related and APOBEC-related mutational signatures and significant differences between hormone-receptor (HR)-negative and HR-positive tumors as well as correlations with age, Ki-67 and immunological parameters were observed. We could identify mutational processes that were linked to increased pathological complete response rates to neoadjuvant chemotherapy with high significance. In univariate analyses for HR-positive tumors signatures, S3 (HRD, P < 0.001) and S13 (APOBEC, P = 0.001) as well as exonic mutation rate (P = 0.002) were significantly correlated with increased pathological complete response rates. The signatures S3 (HRD, P = 0.006) and S4 (tobacco, P = 0.011) were prognostic for reduced disease-free survival of patients with chemotherapy-resistant tumors. CONCLUSION: The results of this investigation suggest that the clinical behavior of a tumor, in particular, response to neoadjuvant chemotherapy and disease-free survival of therapy-resistant tumors, could be predicted by the composition of mutational signatures as an indicator of the individual genomic history of a tumor. After additional validations, mutational signatures might be used to identify tumors with an increased response rate to neoadjuvant chemotherapy and to define therapy-resistant subgroups for future therapeutic interventions.

Digital Control of a Superconducting Qubit Using a Josephson Pulse Generator at 3 K.

Scaling of quantum computers to fault-tolerant levels relies critically on the integration of energy-efficient, stable, and reproducible qubit control and readout electronics. In comparison to traditional semiconductor-control electronics (TSCE) located at room temperature, the signals generated by rf sources based on Josephson-junctions (JJs) benefit from small device sizes, low power dissipation, intrinsic calibration, superior reproducibility, and insensitivity to ambient fluctuations. Previous experiments to colocate qubits and JJ-based control electronics have resulted in quasiparticle poisoning of the qubit, degrading the coherence and lifetime of the qubit. In this paper, we digitally control a 0.01-K transmon qubit with pulses from a Josephson pulse generator (JPG) located at the 3-K stage of a dilution refrigerator. We directly compare the qubit lifetime T 1, the coherence time T 2 * , and the thermal occupation P th when the qubit is controlled by the JPG circuit versus the TSCE setup. We find agreement to within the daily fluctuations of ±0.5 µs and ±2 µs for T 1 and T 2 * , respectively, and agreement to within the 1% error for P th. Additionally, we perform randomized benchmarking to measure an average JPG gate error of 2.1 × 10-2. In combination with a small device size (< 25 mm2) and low on-chip power dissipation (≪100 µW), these results are an important step toward demonstrating the viability of using JJ-based control electronics located at temperature stages higher than the mixing-chamber stage in highly scaled superconducting quantum information systems.

Proposal of a new classification system for complete mesocolic excison in right-sided colon cancer.

BACKGROUND: Although complete mesocolic excision has been performed for 10 years there remains no published prospective data. The lack of a classification which includes completeness of mesocolic tissue removal as well as plane of surgery contributes to the problem of comparing studies. The aim of the present study was to develop such a classification for right hemicolectomy. METHODS: In a prospective, non-randomized trial we collected specimens of right hemicolectomies from 38 German hospitals between February 2012 and October 2016. The degree of radicality of resection was reported. Photographs were taken of the specimens. After screening the images it became apparent that the specimens could be divided into four main groups according to the degree of missing mesocolic tissue, and three subgroups reflecting the plane of surgery. RESULTS: Of 1373 patients 1097 images were available. Grading was possible in 1077 (98.2%). Distribution was Type 0 (best) 38.6%, Type I 43.3%, Type II 8.5%, Type III (poorest) 7.8%. Surgery was considered to be in a suboptimal plane of surgery in 15.2% overall, highest in Type III (37%) and lowest in Type 0 (7.8%, p < 0.001). CONCLUSIONS: The proposed classification may be a relevant tool for the further investigation of CME for right colon cancer because it allows us to differentiate the aspects of lymphadenectomy and the preservation of the integrity of the mesocolon.

Construction of a hybrid clamped cell for high-pressure neutron-diffraction experiments with a large diamond window.

A hybrid pressure cell was fabricated from commercially available copper-beryllium and custom-made Ni-Cr-Al Russian alloy, tailored for usage as a reaction vessel supplying a volume of about 400 mm3. In order to directly (in situ) monitor pressure and chemical reactions within the chamber, a large diamond window suitable for spectroscopic sample analysis was implemented. The performance of the hybrid cell was validated from high-pressure neutron-diffraction measurements on carbon dioxide.

[Transanal total mesorectal excision-a critical appraisal]. / Transanale totale mesorektale Exzision ­ eine kritische Standortbestimmung.

INTRODUCTION: Total mesorectal excision (TME) is the international standard for rectal cancer surgery. In addition to laparoscopic TME (lapTME), transanal TME (taTME) was developed in recent years to reduce the rate of incomplete TME, conversion to open surgery and postoperative functional impairment. Despite limited evidence, this technique is becoming increasingly more popular and is already routinely used by many hospitals for rectal cancer in varying tumor level locations. The aim of this review was to evaluate the taTME compared to anterior rectal resection with lapTME as the standard of care in rectal cancer surgery based on currently available evidence. METHOD: The databases PubMed and Medline were systematically searched for publications on transanal total mesorectal excision (taTME) and transanal minimally invasive surgery (TAMIS). Relevant studies were selected and further research based on the reference lists was undertaken. RESULTS: A total of 16 studies analyzing 3782 patients were identified. The taTME does not lead to a higher rate of complete TME-resected specimens compared to the standard procedure. So far, superiority could not be demonstrated for complication rates or for functional or oncological results. Serious complications secondary to dissection in incorrect planes were observed. The anastomotic level generally seems to be closer to the sphincter after taTME versus anterior lapTME. CONCLUSION: Considering current evidence, taTME failed to show superiority compared to conventional anterior lapTME. Although taTME has some potential advantages, it carries substantial risks. If performed outside of clinical trials, it should therefore only be used in carefully selected patients with a high possibility of conversion, following adequate patient informed consent and after intense and systematic training of the surgeon.

Johnson Noise Thermometry.

Johnson noise thermometers infer thermodynamic temperature from measurements of the thermally-induced current fluctuations that occur in all electrical conductors. This paper reviews the status of Johnson noise thermometry and its prospects for both metrological measurements and for practical applications in industry. The review begins with a brief description of the foundations and principles of Johnson noise thermometry before outlining the many different techniques and technological breakthroughs that have enabled the application of JNT to high-accuracy, cryogenic, and industrial thermometry. Finally, the future of noise thermometry is considered. As the only purely electronic approach to thermodynamic temperature measurement, Johnson noise thermometry has appeal for metrological applications at temperatures ranging from below 1 µK up to 800 K. With the rapid advances in digital technologies, there are also expectations that noise thermometry will become a practical option for some industrial applications reaching temperatures above 2000 K.

The Boltzmann project.

The International Committee for Weights and Measures (CIPM), at its meeting in October 2017, followed the recommendation of the Consultative Committee for Units (CCU) on the redefinition of the kilogram, ampere, kelvin and mole. For the redefinition of the kelvin, the Boltzmann constant will be fixed with the numerical value 1.380 649 × 10-23 J K-1. The relative standard uncertainty to be transferred to the thermodynamic temperature value of the triple point of water will be 3.7 × 10-7, corresponding to an uncertainty in temperature of 0.10 mK, sufficiently low for all practical purposes. With the redefinition of the kelvin, the broad research activities of the temperature community on the determination of the Boltzmann constant have been very successfully completed. In the following, a review of the determinations of the Boltzmann constant k, important for the new definition of the kelvin and performed in the last decade, is given.

[Quality indicators for colon cancer surgery : Evidence-based development of a set of indicators for the outcome quality]. / Qualitätsindikatoren für die onkologische Kolonchirurgie : Evidenzbasierte Entwicklung eines Indikatorensets für die Ergebnisqualität.

BACKGROUND: Quality assessment in surgery is gaining in importance. Although sporadic recommendations for quality indicators (QI) in oncological colon surgery can be found in the literature, these are usually not systematically derived from a solid evidence base. Moreover, reference ranges for QI are unknown. OBJECTIVE: The aim of this initiative was the development of evidence-based QI for oncological colon resections by an expert panel invited by the German Society of General and Visceral Surgery (DGAV). Reference ranges from the literature and reference values from the Study, Documentation, and Quality Center (StuDoQ)|Colon Cancer Register were compared in order to deduce recommendations which are tailored to the German healthcare system. RESULTS: Based on the most recent scientific evidence and agreed by expert consensus, five QI for oncological colon surgery were defined and evaluated according to the QUALIFY tool. Mortality, MTL30 (mortality, transfer to another acute care hospital, or length of stay ≥30 days), anastomotic leakage requiring reintervention, surgical site infections necessitating reopening of the wound and ≥12 lymph nodes in the specimen qualified as QI owing to their relevance, scientific nature, and practicability. Based on the results of the systematic literature search and the statistical analysis of the StuDoQ|Colon Cancer Register, preliminary reference values are proposed for each QI. CONCLUSION: The presented set of QI seems appropriate for quality assessment of oncological colon surgery in the context of the German healthcare system. The validity of the QI and the reference values must be reviewed within the framework of their implementation. The StuDoQ|Colon Cancer Register provides a suitable infrastructure for collecting clinical data for quality assessment and risk adjustment.

A Boltzmann Constant Determination Based on Johnson Noise Thermometry.

A value for the Boltzmann constant was measured electronically using an improved version of the Johnson Noise Thermometry (JNT) system at the National Institute of Standards and Technology (NIST), USA. This system is different from prior ones, including those from the 2011 determination at NIST and both 2015 and 2017 determinations at the National Institute of Metrology (NIM), China. As in all three previous determinations, the main contribution to the combined uncertainty is the statistical uncertainty in the noise measurement, which is mitigated by accumulating and integrating many weeks of cross-correlated measured data. The second major uncertainty contribution also still results from variations in the frequency response of the ratio of the measured spectral noise of the two noise sources, the sense resistor at the triple-point of water and the superconducting quantum voltage noise source. In this paper, we briefly describe the major differences between our JNT system and previous systems, in particular the input circuit and approach we used to match the frequency responses of the two noise sources. After analyzing and integrating 49 days of accumulated data, we determined a value: k = 1.380 642 9(69)×10-23 J/K with a relative standard uncertainty of 5.0×10-6 and relative offset -4.05×10-6 from the CODATA 2014 recommended value.

[Obstacles and facilitators of conducting studies - the perspective of colorectal cancer centers' coordinators]. / Hemmende und fördernde Faktoren bei der Durchführung von Studien - Die Sicht von Darmkrebszentrumskoordinatorinnen und -koordinatoren.

INTRODUCTION: Clinical trials and health services research are crucial pillars for improving patient care. This paper examines factors inhibiting and promoting the study activity and the knowledge and use of trial registries (e. g. DRKS, StudyBox) as an opportunity to learn about existing studies. MATERIAL AND METHODS: The coordinators of 274 cancer center sites certified according to the requirements of the German Cancer Society were surveyed using a standardized online questionnaire. Data were analyzed using descriptive and bivariate statistics to identify associations with characteristics of the sites (e. g. patient volume, ownership, teaching status). RESULTS: 176 sites participated in the survey (64.2 %). The central obstacle to study participa-tion from the centers' view is the low number of existing studies. General knowledge of the population about studies was considered low. Trial registries are known to almost all respondents, but are rarely used. DISCUSSION: The results of the survey suggest that comprehensive measures are needed to sustainably increase the study activity. These include, for example, better information about studies, for example through appropriate databases, and (industry-independent) research funding. One possible way to sensitize patients for studies could be the comprehensive education of the population about the purpose of studies.

[LSD score. A new classification system for peristomal skin lesions]. / LSD-Score. Ein neues Klassifikationssystem für peristomale Hautläsionen.

BACKGROUND: Peristomal skin lesions are frequent complications of ostomy; however, there is no generally accepted nomenclature and classification system. OBJECTIVE: An interdisciplinary German expert panel (GESS) composed of ten members, developed an innovative semiquantitative classification system for peristomal skin lesions for further stratification of ostomy therapy. This score is based on criteria which can be assessed by stomal therapists and treating physicians. RESULTS: The new peristomal skin lesion score grades three categories: lesion (L), status of ostomy (S) and disease (D). The L category describes the integrity of the skin as normal (L0), lesion with sustained integrity of skin (L1), integrity destroyed (L2) and local infection (L3). The S category rates the complexity of ostomy therapy as normal (S0), increased (S1) and high but not sufficiently effective (S2). The additional letters for categorization O. R. P. H. E. US describe anatomical pathologies of the stoma itself: ostomy stenosis (O), retraction (R), prolapse (P), hernia (H), edema (E) and unfavorable site (US). A systemic disorder is either absent (D0), irrelevant (D1) or relevant (D2). The LSD score is the basis for a management algorithm. CONCLUSION: The LSD score is comprehensive, standardized and holistic. Its straightforward use by health professionals can improve the consistency of the description of skin lesions and enhance the quality of ostomy therapy.

Identifying Francisella tularensis genes required for growth in host cells.

Francisella tularensis is a highly virulent Gram-negative intracellular pathogen capable of infecting a vast diversity of hosts, ranging from amoebae to humans. A hallmark of F. tularensis virulence is its ability to quickly grow to high densities within a diverse set of host cells, including, but not limited to, macrophages and epithelial cells. We developed a luminescence reporter system to facilitate a large-scale transposon mutagenesis screen to identify genes required for growth in macrophage and epithelial cell lines. We screened 7,454 individual mutants, 269 of which exhibited reduced intracellular growth. Transposon insertions in the 269 growth-defective strains mapped to 68 different genes. FTT_0924, a gene of unknown function but highly conserved among Francisella species, was identified in this screen to be defective for intracellular growth within both macrophage and epithelial cell lines. FTT_0924 was required for full Schu S4 virulence in a murine pulmonary infection model. The ΔFTT_0924 mutant bacterial membrane is permeable when replicating in hypotonic solution and within macrophages, resulting in strongly reduced viability. The permeability and reduced viability were rescued when the mutant was grown in a hypertonic solution, indicating that FTT_0924 is required for resisting osmotic stress. The ΔFTT_0924 mutant was also significantly more sensitive to ß-lactam antibiotics than Schu S4. Taken together, the data strongly suggest that FTT_0924 is required for maintaining peptidoglycan integrity and virulence.

Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome.

BACKGROUND: Glioblastoma (GBM) is the most common malignant brain cancer occurring in adults, and is associated with dismal outcome and few therapeutic options. GBM has been shown to predominantly disrupt three core pathways through somatic aberrations, rendering it ideal for precision medicine approaches. METHODS: We describe a 35-year-old female patient with recurrent GBM following surgical removal of the primary tumour, adjuvant treatment with temozolomide and a 3-year disease-free period. Rapid whole-genome sequencing (WGS) of three separate tumour regions at recurrence was carried out and interpreted relative to WGS of two regions of the primary tumour. RESULTS: We found extensive mutational and copy-number heterogeneity within the primary tumour. We identified a TP53 mutation and two focal amplifications involving PDGFRA, KIT and CDK4, on chromosomes 4 and 12. A clonal IDH1 R132H mutation in the primary, a known GBM driver event, was detectable at only very low frequency in the recurrent tumour. After sub-clonal diversification, evidence was found for a whole-genome doubling event and a translocation between the amplified regions of PDGFRA, KIT and CDK4, encoded within a double-minute chromosome also incorporating miR26a-2. The WGS analysis uncovered progressive evolution of the double-minute chromosome converging on the KIT/PDGFRA/PI3K/mTOR axis, superseding the IDH1 mutation in dominance in a mutually exclusive manner at recurrence, consequently the patient was treated with imatinib. Despite rapid sequencing and cancer genome-guided therapy against amplified oncogenes, the disease progressed, and the patient died shortly after. CONCLUSION: This case sheds light on the dynamic evolution of a GBM tumour, defining the origins of the lethal sub-clone, the macro-evolutionary genomic events dominating the disease at recurrence and the loss of a clonal driver. Even in the era of rapid WGS analysis, cases such as this illustrate the significant hurdles for precision medicine success.

[Complete Mesocolic Excision for Right-Sided Colon Cancer - The Role of Central Lymph Nodes]. / Die komplette mesokolische Exzision beim rechtsseitigen Kolonkarzinom - welche Rolle spielen die zentralen Lymphknoten?

BACKGROUND: Complete mesocolic excision (CME) and central vascular ligation (CVL) for right-sided colon cancer may be superior to standard hemicolectomy in terms of oncological results. This hypothesis is currently being investigated in a large multicentre trial conducted by the authors of this paper (Resektatstudie). Because CVL in right-sided hemicolectomy is technically rather demanding the incidence of central node involvement is of special interest. Therefore, during the single centre pilot phase of our multicentre trial we have analysed the incidence of central lymph node metastasis in CME specimens. PATIENTS: In 51 patients with right-sided colon adenocarcinoma (cT1-3, cM0) an open CME with CVL was performed. In the fresh specimen the central four centimetres of the ileocolic vessels that would have been presumably left in place during a standard hemicolectomy were marked with a suture. The lymph nodes in this segment were separately analysed. RESULTS: In the CME specimen the mean lymph node count was 52.6 (range: 27-171). 35.0 % (range: 13.1-65.6 %) of the nodes were located in the central 4 cm segment. The proportion of patients with positive nodes was 25.5 % (13/51). Of all nodes 1.97 % (53/2686) were metastatic. In 3/51 (5.8 %) patients the central nodes were involved. In one patient the central nodes were the only metastatic site. UICC stage was influenced in two of the three patients who had central involvement (stage migration: UICC IIB to IIIB, UICC IIIB to IIIC). CONCLUSION: CME with CVL in right-sided colon adenocarcinoma increases the probability of complete removal of the local lymph node drainage and thus local metastatic lymph nodes. Considering this result an improvement of long-term survival by the CME procedure seems conceivable but needs to be confirmed by the current multicentre trial.

[Certified stomach cancer centres as seen by their directors: results of a questionaire to key personnel]. / Zertifizierte Darmkrebszentren aus Sicht der Zentrumsleitungen: Ergebnisse einer Schlüsselpersonenbefragung.

Since 2003 the German Cancer Society (Deutsche Krebsgesellschaft, DKG) has been certifying specific organ cancer centers in Germany. After 8 years activity, there are now more than 600 certified cancer centres that, as required by the national cancer plan, enable "oncological management at an assured quality level" in Germany. Anmong them are more than 200 certified centres for stomach cancer, that treat about 25 % of all newly diagnosed cases of stomach cancer. In this article we have examined the question as to what changes the certification concept has caused in the centres.

Surveillance of Salmonella prevalence in animal feeds and characterization of the Salmonella isolates by serotyping and antimicrobial susceptibility.

This article presents the surveillance data from the Feed Contaminants Program (2002-2009) and Salmonella Assignment (2007-2009) of the U.S. Food and Drug Administration (FDA), which monitor the trend of Salmonella contamination in animal feeds. A total of 2,058 samples were collected from complete animal feeds, feed ingredients, pet foods, pet treats, and supplements for pets in 2002-2009. These samples were tested for the presence of Salmonella. Those that were positive for Salmonella underwent serotyping and testing for antimicrobial susceptibility. Of the 2,058 samples, 257 were positive for Salmonella (12.5%). The results indicate a significant overall Salmonella reduction (p≤0.05) in animal feeds from 18.2% (187 samples tested) in 2002 to 8.0% (584 samples tested) in 2009. Among these samples, feed ingredients and pet foods/treats had the most significant reduction (p≤0.05). Of the 45 Salmonella serotypes identified, Salmonella Senftenberg and Salmonella Montevideo were the top two common serotypes (8.9%). Of the 257 Salmonella isolates obtained, 54 isolates (21%) were resistant to at least one antimicrobial. The findings provide the animal feed industries with Salmonella prevalence information that can be used to address Salmonella contamination problems. Our findings can also be used to educate pet owners when handling pet foods and treats at home to prevent salmonellosis.

[Indications for laparoscopic pancreas operations: results of a consensus conference and the previous laparoscopic pancreas register]. / Indikation zur laparoskopischen Pankreasoperation: Ergebnisse einer Konsensuskonferenz und des bisherigen laparoskopischen Pankreasregisters.

Laparoscopic pancreatic surgery is not common practice in Germany and is only carried out in approximately 20 clinics but with an increasing trend. The reasons for this are manifold, such as the current selection of patients and both skills in laparoscopic and pancreatic surgery are necessary to perform this operation safely. In 2008 a registry called "Laparoscopic pancreatic surgery" was implemented to collect enough data in Germany to find out whether the resection is safe, feasible and beneficial for the patient.For further development of new laparoscopic techniques new data is needed. A group of experts performing laparoscopic pancreatic surgery in Germany supplied their data for the German registry for laparoscopic pancreatic resection and a consensus conference about the indications became necessary. This consensus conference discussed in particular the indications for laparoscopic pancreatic resection. A consensus was found by all members of the conference utilizing currently available evidence-based data.It was suggested that all data of laparoscopic pancreatic surgery should be evaluated in the German Registry. A consensus was made which diseases were either suitable for laparoscopic resection or not suitable or suitable in selected cases.