Treatment of Intrahepatic Cholangiocarcinoma—A Multidisciplinary Approach

Intrahepatic cholangiocarcinoma (iCC) is distinguished as an entity from perihilar and distal cholangiocarcinoma and gallbladder carcinoma. Recently, molecular profiling and histopathological features have allowed further classification. Due to the frequent delay in diagnosis, the prognosis for iCC remains poor despite major technical advances and multimodal therapeutic approaches. Liver resection represents the therapeutic backbone and only curative treatment option, with the functional residual capacity of the liver and oncologic radicality being deciding factors for postoperative and long-term oncological outcome. Furthermore, in selected cases and depending on national guidelines, liver transplantation may be a therapeutic option. Given the often advanced tumor stage at diagnosis or the potential for postoperative recurrence, locoregional therapies have become increasingly important. These strategies range from radiofrequency ablation to transarterial chemoembolization to selective internal radiation therapy and can be used in combination with liver resection. In addition, adjuvant and neoadjuvant chemotherapies as well as targeted therapies and immunotherapies based on molecular profiles can be applied. This review discusses multimodal treatment strategies for iCC and their differential use

Safety of intermittent Pringle maneuver during minimally invasive liver resection in patients with hepatocellular carcinoma with and without cirrhosis

Purpose: The aim of this study was to analyze the impact of minimally invasive intermittent Pringle maneuver (IPM) on postoperative outcomes in patients with hepatocellular carcinoma (HCC) and liver cirrhosis. Methods: In this retrospective cohort study, we evaluated the safety of IPM in patients with HCC who underwent minimally invasive liver resection during five years at our center. Factors influencing the use of IPM were examined in univariate and multivariate regression analysis. Cases with use of IPM (IPM) and those without use of IPM (no IPM) were then compared regarding intraoperative and postoperative outcomes after propensity score matching (PSM) for surgical difficulty. Results: One hundred fifty-one patients underwent liver resection for HCC at our center and met inclusion criteria. Of these, 73 patients (48%) received IPM with a median duration of 18 min (5-78). One hundred patients (66%) had confirmed liver cirrhosis. In multivariate analysis, patients with large tumors (>= 3 cm) and difficult tumor locations (segments VII or VIII) were more likely to undergo IPM (OR 1.176, p = 0.043, and OR 3.243, p = 0.001, respectively). After PSM, there were no differences in intraoperative blood transfusion or postoperative complication rates between the IPM and no IPM groups. Neither did we observe any differences in the subgroup analysis for cirrhotic patients. Postoperative serum liver function tests were not affected by the use of IPM. Conclusions: Based on our findings, we conclude that the use of IPM in minimally invasive liver resection is safe and feasible for patients with HCC, including those with compensated liver cirrhosis

Recurrence of Hepatocellular Carcinoma After Liver Transplantation is Associated with Episodes of Acute Rejections.

Purpose The impact of acute rejection (AR) after liver transplantation (LT) for hepatocellular carcinoma (HCC) on patient outcome is uncertain. This aim of this study is to investigate whether AR is associated with HCC relapse and overall survival. Patients and Methods Patients undergoing LT for HCC between 2001 and 2015 were retrospectively analyzed with regard to histopathological proven AR within the median time until recurrence. Cox's regression analysis was conducted revealing risk factors for HCC recurrence. Results HCC recurred in 47 of 252 analyzed patients with a median time to recurrence of 20 months. Patients with AR (28.6%) had a significantly higher frequency of recurrence compared to patients without AR (13.0%, p=0.002). Multiple Cox regression analyses identified AR within 20 months to be an independent risk factor for HCC recurrence both as dichotomized (HR=2.91, 95%CI: 1.30-6.53; p=0.009) and as a continuous variable (HR=1.81, 95%CI: 1.28-2.54; p=0.001). HCC recurrence and AR were associated with higher grades of liver fibrosis one year after LT, when compared to patients without AR (p=0.019). Conclusion Our results demonstrate an association of AR with HCC recurrence after LT with implications for intervals of monitoring in tumor surveillance. Graft fibrosis and immune mechanisms are potentially related and causal interactions are worth further investigation

A Word of Caution

Background: Minimally invasive liver surgery (MILS) has a high variance in the type of resection and complexity, which has been underestimated in learning curve studies in the past. The aim of this work was to evaluate complexity-adjusted learning curves over time for laparoscopic liver resection (LLR) and robotic liver resection (RLR). Methods: Cumulative sum analysis (CUSUM) and complexity adjustment were performed using the Iwate score for LLR and RLR (n = 647). Lowest point of smoothed data was used to capture the cutoff of the increase in complexity. Data were collected retrospectively at the Department of Surgery of the Charité-Universitätsmedizin Berlin. Results: A total of 132 RLR and 514 LLR were performed. According to the complexity-adjusted CUSUM analysis, the initial learning phase was reached after 117 for LLR and 93 procedures for RLR, respectively. With increasing experience, the rate of (extended) right hemihepatectomy multiplied from 8.4% to 18.9% for LLR (P = 0.031) and from 21.6% to 58.3% for RLR (P 0.05). The complexity-adjusted CUSUM analysis demonstrated for blood transfusion, conversion, and operative time an increase during the learning phase (T1), while a steady state was reached in the following (T2). Conclusions: The learning phase for MILS after adjusting for complexity is about 4 times longer than assumed in previous studies, which should urge caution

Clara Immerwahr: A Life in the Shadow of Fritz Haber

We examine the life of Clara Haber, nee Immerwahr (1870–1915), including her tragic suicide and its possible relation to the involvement of her husband, Fritz Haber, in chemical warfare. Clara earned a doctorate in chemistry from the University of Breslau, in 1900, as the first woman ever, and married the physical chemist Fritz Haber within a year of her graduation. With no employment available for female scientists, Clara freelanced as an instructor in the continued education of women, mainly housewives, while struggling not to become a housewife herself. Her duties as the designated head of a posh household hardly brought fulfillment to her life. The outbreak of WWI further exacerbated the situation, as Fritz Haber applied himself in extraordinary ways to aid the German war effort, which included his initiative to develop chemical weapons. The night that he celebrated the “success” of the first chlorine cloud attack and his promotion to the rank of captain, Clara committed suicide. However, we found little evidence to support express claims that Clara was an outspoken pacifist who took her life because of her disapproval of her husband’s engagement in chemical warfare. We examine the origin of this “myth of Clara Immerwahr” that took root in the 1990s from the perspective offered by the available scholarly sources, including those that have only recently come to light

Ultrafast measurements of mode-specific deformation potentials of Bi2_2Te3_3 and Bi2_2Se3_3

Quantifying electron-phonon interactions for the surface states of topological materials can provide key insights into surface-state transport, topological superconductivity, and potentially how to manipulate the surface state using a structural degree of freedom. We perform time-resolved x-ray diffraction (XRD) and angle-resolved photoemission (ARPES) measurements on Bi$_2$Te$_3$ and Bi$_2$Se$_3$, following the excitation of coherent A$_{1g}$ optical phonons. We extract and compare the deformation potentials coupling the surface electronic states to local A$_{1g}$-like displacements in these two materials using the experimentally determined atomic displacements from XRD and electron band shifts from ARPES.We find the coupling in Bi$_2$Te$_3$ and Bi$_2$Se$_3$ to be similar and in general in agreement with expectations from density functional theory. We establish a methodology that quantifies the mode-specific electron-phonon coupling experimentally, allowing detailed comparison to theory. Our results shed light on fundamental processes in topological insulators involving electron-phonon coupling

Gluino-Squark Production at the LHC: The Threshold

An analysis of the cross section for hadronic production of gluino-squark pairs close to threshold is presented. Within the framework of non-relativistic QCD a significant enhancement compared to fixed order perturbation theory is observed which originates from the characteristic remnants of the gluino-squark resonances below the nominal pair threshold. The analysis includes all colour configurations of S-wave gluino-squark pairs, i.e. triplet, sextet and 15 representation. Matching coefficients at leading order are separately evaluated for all colour configurations. The dominant QCD corrections, arising from initial- and final-state radiation are included. The non-relativistic dynamics of the gluino pair is solved by calculating the Green's function in Next-to-Leading Order (NLO). The results are applied to benchmark scenarios, based on Snowmass Points and Slopes (SPS). As a consequence of the large decay rate of at least one of the constituents squark or gluino annihilation decays of the bound state (\tilde{g}\tilde{q})\rightarrow gq, q\gamma, qZ or q'W^{\pm} are irrelevant. Thus the signatures of gluino-quark production below and above the nominal threshold are identical. Numerical results for the cross section at the Large Hadron Collider (LHC) at \sqrt{s}=7 TeV and 14 TeV are presented. The enhancement of the total cross section through final state interaction amounts to roughly 3%.Comment: 25 pages, 9 figures, Eq. 10 modified. Reference [30] added. Discussion of the expected quality of the approximation added before eq. 23. Some changes in notation. Typos correcte

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts