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Objectives: Nephron-sparing surgery (NSS) exposes the kidney to ischemia–reperfusion injury. Blood loss and hypotension are also associated with kidney injury. We aimed to test the hypothesis that, during NSS, both ischemia duration and blood loss significantly affect postoperative renal function and that their effects interact. Methods: Consecutive patients undergoing NSS were enrolled. The primary endpoint was renal function expressed as the absolute delta between preoperative and postoperative peak creatinine. We developed a generalized linear model with the ischemia duration and absolute hemoglobin difference as independent variables, their interaction term, and the RENAL score. The model was than expanded to include a history of hypertension (as a proxy for hypotension susceptibility) and related interaction terms. Further, we described the perioperative and mid-term oncological outcomes. Results: A total of 478 patients underwent NSS, and 209 (43.7%) required ischemia for a mean of 10.9 min (SD 8). Both the ischemia duration (partial eta 0.842, p = 0.006) and hemoglobin difference (partial eta 0.933, p = 0.029) significantly affected postoperative renal function, albeit without evidence of a significant interaction (p = 0.525). The RENAL score also significantly influenced postoperative renal function (p = 0.023). After the addition of a previous history of hypertension, the effects persisted, with a significant interaction between blood loss and a history of hypertension (p = 0.02). Conclusions: Ischemia duration and blood loss had a similar impact on postoperative renal function, albeit without potentiating each other. While the surgical technique and ischemia minimization remain crucial to postoperative kidney function, increased awareness of conscious hemodynamic management appears warranted.

The IMMUNED trial previously showed significant improvements in recurrence-free survival for adjuvant nivolumab plus ipilimumab as well as for adjuvant nivolumab alone in patients with stage IV melanoma with no evidence of disease after resection or radiotherapy. Here, we report the final analysis, including overall survival data.IMMUNED was an investigator-sponsored, double-blind, placebo-controlled, three-arm, phase 2 trial conducted in 20 academic medical centres in Germany. Eligible patients were aged 18-80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Patients were randomly assigned (1:1:1) to either nivolumab plus ipilimumab (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks), nivolumab monotherapy (nivolumab 3 mg/kg every 2 weeks), or matching placebo, for up to 1 year. The primary endpoint was recurrence-free survival in the intention-to-treat population. Secondary endpoints were time-to-recurrence, overall survival, progression-free survival or recurrence-free survival 2 (in patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence), and safety endpoints. This trial is registered on ClinicalTrials.gov (NCT02523313), and is complete.Between Sept 2, 2015, and Nov 20, 2018, 175 patients were enrolled in the study, and 167 were randomly assigned to receive either nivolumab plus ipilimumab (n=56), nivolumab plus ipilimumab-matching placebo (n=59), or double placebo control (n=52). At a median follow-up of 49·2 months (IQR 34·9-58·1), 4-year recurrence-free survival was 64·2% (95% CI 49·2-75·9) in the nivolumab plus ipilimumab group, 31·4% (19·7-43·8) in the nivolumab alone group, and 15·0% (6·7-26·6) in the placebo group. The hazard ratio (HR) for recurrence for the nivolumab plus ipilimumab group versus placebo was 0·25 (97·5% CI 0·13-0·48; p0·0001), and for the nivolumab group versus placebo was 0·60 (0·36-1·00; p=0·024). Median overall survival was not reached in any treatment group. The HR for overall survival was significantly in favour of the nivolumab plus ipilimumab group versus placebo (HR 0·41; 95% CI 0·17-0·99; p=0·040), but not for the nivolumab group versus placebo (HR 0·75; 0·36-1·56; p=0·44). 4-year overall survival was 83·8% (95% CI 68·8-91·9) in the nivolumab plus ipilimumab group, 72·6% (57·4-83·2) in the nivolumab alone group, and 63·1% (46·9-75·6) in the placebo group. The median progression-free survival or recurrence-free survival 2 of patients in the placebo group who crossed over to nivolumab monotherapy after experiencing disease recurrence was not reached (95% CI 21·2 months to not reached). Rates of grade 3-4 treatment-related adverse events remained largely unchanged compared with our previous report, occurring in 71% (95% CI 57-82) of the nivolumab plus ipilimumab group, and 29% (95% CI 17-42) of patients receiving nivolumab alone. There were no treatment-related deaths.Both active regimens continued to show significantly improved recurrence-free survival compared with placebo in patients with stage IV melanoma with no evidence of disease who were at high risk of recurrence. Overall survival was significantly improved for patients receiving nivolumab plus ipilimumab compared with placebo. Use of subsequent anti-PD-1-based therapy was high in patients in the placebo group after recurrence and most likely impacted the overall survival comparison of nivolumab alone versus placebo. The recurrence-free and overall survival benefit of nivolumab plus ipilimumab over placebo reinforces the change of practice already initiated for the treatment of patients with stage IV melanoma with no evidence of disease.Bristol-Myers Squibb.

The European journal of cancer : EJC 173, 307-316 (2022). doi:10.1016/j.ejca.2022.07.002, Published by Elsevier, Amsterdam [u.a.]

Background: Circular urethral compression with an artificial sphincter allows control of voiding, even in patients with severe stress urinary incontinence, but it heightens the risk of urethral atrophy and erosion. This study of one of the largest populations of patients treated with radiotherapy investigates the additive effect of the post-radiogenic stricture of the membranous urethra/bladder neck on AMS 800 artificial urinary sphincter outcomes. Methods: In a retrospective multicenter cohort study, we analyzed patients fitted with an AMS 800, comparing those who had received radiotherapy with patients presenting a devastated bladder outlet (stricture of the membranous urethra/bladder neck). We determined the correlation between these groups of patients using both univariate and stepwise adjusted multivariate regression. The revision-free interval was estimated by a Kaplan–Meier plot and compared by applying the log-rank test. A p value below 0.05 was considered statistically significant. Results: Of the 123 irradiated patients we identified, 62 (50.4%) had undergone at least one prior desobstruction for bladder-neck/urethra stenosis. After a mean follow-up of 21 months, the latter tended to achieve social continence less frequently (25.7% vs. 35%; p = 0.08). Revision was required significantly more often for this group (43.1% vs. 26.3%; p = 0.05) due to urethral erosion in 18 of 25 cases. A stenosis recurred in five cases; desobstruction was performed in two cases, leading to erosion in both. Multivariate analysis revealed a significantly higher risk of revision when recurrent stenosis necessitated at least two prior desobstructions (HR 2.8; p = 0.003). Conclusions: A devastated bladder outlet is associated with a lower proportion of men with social continence and a significantly higher need for revision compared with irradiated patients without a history of urethral stenosis. Alternative surgical procedures should be discussed beforehand, especially in cases of recurrent urethral stenosis.

Background: Convolutional neural network (CNN)-based melanoma classifiers face several challenges that limit their usefulness in clinical practice. Objective: To investigate the impact of multiple real-world dermoscopic views of a single lesion of interest on a CNN-based melanoma classifier. Methods: This study evaluated 656 suspected melanoma lesions. Classifier performance was measured using area under the receiver operating characteristic curve (AUROC), expected calibration error (ECE) and maximum confidence change (MCC) for (I) a single-view scenario, (II) a multiview scenario using multiple artificially modified images per lesion and (III) a multiview scenario with multiple real-world images per lesion. Results: The multiview approach with real-world images significantly increased the AUROC from 0.905 (95% CI, 0.879-0.929) in the single-view approach to 0.930 (95% CI, 0.909-0.951). ECE and MCC also improved significantly from 0.131 (95% CI, 0.105-0.159) to 0.072 (95% CI: 0.052-0.093) and from 0.149 (95% CI, 0.125-0.171) to 0.115 (95% CI: 0.099-0.131), respectively. Comparing multiview real-world to artificially modified images showed comparable diagnostic accuracy and uncertainty estimation, but significantly worse robustness for the latter. Conclusion: Using multiple real-world images is an inexpensive method to positively impact the performance of a CNN-based melanoma classifier.

Abstract: Brain tissue is known to have elevated citrate levels, necessary to regulate ion chelation, neuron excitability, and are also necessary for the supply of necessary energy substrates to neurons. Importantly, citrate also acts as a central substrate in cancer metabolism. Recent studies have shown that extracellular citrate levels in the brain undergo significant changes during tumor development and may play a dual role in tumor progression, as well as cancer cell aggressiveness. In the present article, we review available literature describing changes of citrate levels in brain tissue, blood, and cerebrospinal fluid, as well as intracellular alterations during tumor development before and after metastatic progression. Based on the available literature and our recent findings, we hypothesize that changes in extracellular citrate levels may be related to the increased consumption of this metabolite by cancer cells. Interestingly, cancerassociated cells, including reactive astrocytes, might be a source of citrate. Extracellular citrate uptake mechanisms, as well as potential citrate synthesis and release by surrounding stroma, could provide novel targets for anti-cancer treatments of primary brain tumors and brain metastases.

Background Demographic changes are leading to an increase in geriatric urolithiasis patients aged ≥70 yr. Published data regarding their management remain sparse. In particular, for the subgroup of patients aged ≥80 yr there is a lack of evidence supporting the hypothesis that stone-removing treatment is effective, safe, and beneficial. Objective To examine the efficiency and safety of stone-removing treatment in geriatric urolithiasis patients aged ≥80 yr compared to their younger geriatric counterparts aged 70–79 yr against the background of their respective life expectancy. Design, setting, and participants Data for the study cohort were extracted from an institutional review board–approved retrospective database with 325 patients aged ≥70 yr (70–79 yr: n = 241; ≥80 yr: n = 84) consecutively admitted to hospital because of symptomatic urolithiasis from 2013 to 2018. Outcome measurements and statistical analysis Baseline characteristics, outcome and follow-up data, and survival were compared using Wilcoxon-Mann-Whitney U tests, χ2 tests, Kaplan-Meier estimation, log-rank tests, and Cox regression. Results and limitations At baseline, the incidence of infected hydronephrosis was greater among patients aged ≥80 yr (p 0.05). Survival analysis for the two groups demonstrated a 2-yr overall survival (OS) rate of 0.91 (95% confidence interval [CI] 0.75–1) for patients aged ≥80 yr and 0.97 (95% CI 0.88–1), for those aged 70–79 yr (p Conclusions Stone-removing treatment for patients aged ≥80 yr proved to be as effective and safe as for patients in their seventies. Although characterized by shorter remaining life expectancy, excellent 2-yr OS for patients aged ≥80 yr supports the hypothesis of equal benefit from stone-removing treatment when compared to septuagenarians. Patient summary There is a lack of evidence supporting the benefit of urinary stone-removing treatment for patients older than 80 yr. Our study included geriatric patients older than 70 yr with symptomatic urinary stone disease for which urinary drainage or stone removal is indicated. We compared treatment outcomes and survival between two age groups: patients aged 70–79 yr and those aged 80 yr or older. We found equivalent outcomes for the two groups and excellent 2-yr overall survival of 91% for those older than 80 yr. The study strengthens the evidence that active stone-removing therapy is safe and beneficial for these patients.

To investigate the efficacy and safety of multi-tract percutaneous nephrolithotomy (PNL) against the benchmark of the single-tract approach.A retrospective analysis of 391 consecutive PNL procedures was conducted in our tertiary referral center between April 2016 and March 2020. Clinical outcome parameters such as stone-free rate, operation time, postoperative complications according to Clavien-Dindo, length of hospital stay and time to ipsilateral recurrence resulting in active treatment were assessed.Multi-tract PNL and single-tract PNL were performed in 37 (9%) and 354 (91%) cases respectively. At baseline, compared to single-tract PNL, multi-tract PNL cases were characterized by significantly larger stone burden (2.62 vs 0.97 cmIn this retrospective single-center analysis, a multi-tract PNL has been proved to be an efficient and safe expansion of single-tract PNL for large stone burden and complex kidney stone disease. Future prospective research should focus on the procedure's potential effectiveness in reducing the number of interventions until stone-free status in patients with massive stone disease.

Die Einführung von Antikörpern gegen die immunregulatorischen Oberflächenmoleküle, programmed cell death protein 1 (PD-1) und cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), hat die Behandlung von Tumorerkrankungen revolutioniert. Diese sogenannten Immuncheckpoint-Inhibitoren verfügen über ein enormes therapeutisches Potenzial und werden zur Behandlung vieler verschiedener Tumorentitäten eingesetzt. Häufig treten bei Patienten, die mit Checkpoint-Inhibitoren behandelt werden, immunvermittelte Nebenwirkungen auf, die die klinische Anwendung limitieren. Trotz umfassender Bemühungen, die Ätiologie immunvermittelter Komplikationen zu verstehen, sind die zugrundeliegenden zellulären Mechanismen nach wie vor weitgehend ungeklärt. Unserer Arbeitsgruppe ist es gelungen, Patienten mit metastasiertem Melanom zu identifizieren, die eine erhöhtes Risiko haben, eine immunvermittelte Hepatitis zu entwickeln. Diese Gruppe von Patienten zeichnet sich durch eine erhöhte Anzahl von CD4

The success of cancer immunotherapy is limited by resistance to immune checkpoint blockade. We therefore conducted a genetic screen to identify genes that mediated resistance against CTLs in anti–PD-L1 treatment–refractory human tumors. Using PD-L1–positive multiple myeloma cells cocultured with tumor-reactive bone marrow–infiltrating CTL as a model, we identified calcium/calmodulin-dependent protein kinase 1D (CAMK1D) as a key modulator of tumor-intrinsic immune resistance. CAMK1D was coexpressed with PD-L1 in anti–PD-L1/PD-1 treatment–refractory cancer types and correlated with poor prognosis in these tumors. CAMK1D was activated by CTL through Fas-receptor stimulation, which led to CAMK1D binding to and phosphorylating caspase-3, -6, and -7, inhibiting their activation and function. Consistently, CAMK1D mediated immune resistance of murine colorectal cancer cells in vivo. The pharmacologic inhibition of CAMK1D, on the other hand, restored the sensitivity toward Fas-ligand treatment in multiple myeloma and uveal melanoma cells in vitro. Thus, rapid inhibition of the terminal apoptotic cascade by CAMK1D expressed in anti–PD-L1–refractory tumors via T-cell recognition may have contributed to tumor immune resistance.

siRNA library

Supplementary Table 2

Supplementary Figures 1-7

Purpose: The death ligand tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-R) are involved in immune surveillance and tumor development. Here, we studied a possible association between the expression of TRAIL/TRAIL-Rs and the prognosis in patients with renal cell carcinomas (RCC).Experimental Design: A tissue microarray containing RCC tumor tissue samples and corresponding normal tissue samples from 838 patients was generated. Expression of TRAIL and TRAIL-Rs was examined by immunohistochemistry and the effect of TRAIL and TRAIL-R expression on disease-specific survival was assessed.Results: High TRAIL-R2 expression levels were associated with high-grade RCCs (P < 0.001) and correlated negatively with disease-specific survival (P = 0.01). Similarly, high TRAIL expression was associated with a shorter disease-specific survival (P = 0.01). In contrast, low TRAIL-R4 expression was associated with high-stage RCCs (P < 0.001) as well as with the incidence of distant metastasis (P = 0.03) and correlated negatively with disease-specific survival (P = 0.02). In patients without distant metastasis, multivariate Cox regression analyses revealed that TRAIL-R2 and TRAIL are independent prognostic factors for cancer-specific survival (in addition to tumor extent, regional lymph node metastasis, grade of malignancy, and type of surgery).Conclusion: High TRAIL-R2, high TRAIL, and low TRAIL-R4 expression levels are associated with a worse disease-specific survival in patients with RCCs. Therefore, the assessment of TRAIL/TRAIL-R expression offers valuable prognostic information that could be used to select patients for adjuvant therapy studies. Moreover, our findings are of relevance for a potential experimental therapeutic administration of TRAIL-R agonists in patients with RCCs.

Supplementary Data from Prognostic Value of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (TRAIL) and TRAIL Receptors in Renal Cell Cancer

We prove new lower bounds on the growth of robust quantum circuit complexity -- the minimal number of gates $C_{\delta}(U)$ to approximate a unitary $U$ up to an error of $\delta$ in operator norm distance. More precisely we show two bounds for random quantum circuits with local gates drawn from a subgroup of $SU(4)$. First, for $\delta=\Theta(2^{-n})$, we prove a linear growth rate: $C_{\delta}\geq d/\mathrm{poly}(n)$ for random quantum circuits on $n$ qubits with $d\leq 2^{n/2}$ gates. Second, for $ \delta=\Omega(1)$, we prove a square-root growth of complexity: $C_{\delta}\geq \sqrt{d}/\mathrm{poly}(n)$ for all $d\leq 2^{n/2}$. Finally, we provide a simple conjecture regarding the Fourier support of randomly drawn Boolean functions that would imply linear growth for constant $\delta$. While these results follow from bounds on the moments of random quantum circuits, we do not make use of existing results on the generation of unitary $t$-designs. Instead, we bound the moments of an auxiliary random walk on the diagonal unitaries acting on phase states. In particular, our proof is comparably short and self-contained., Comment: 13 pages, 1 figure, v2: modified main theorem due to a gap in v1

In ride-sharing systems, platform providers aim to distribute the drivers in the city to meet current and potential future demand and to avoid service cancellations. Ensuring such distribution is particularly challenging in the case of a crowdsourced fleet, as drivers are not centrally controlled but are free to decide where to reposition when idle. Thus, providers look for alternative ways to ensure a vehicle distribution that benefits users, drivers, and the provider. We propose an intuitive mean to improve idle ride-sharing vehicles’ repositioning: repositioning heatmaps. These heatmaps highlight driver-specific earning opportunities approximated based on the expected future demand, current and expected future fleet distribution, and the location of the specific driver. Based on the heatmaps, drivers make decentralized yet better-informed repositioning decisions. As our heatmap policy changes the driver distribution in the future, we propose an adaptive learning algorithm for designing our heatmaps in large-scale ride-sharing systems. We simulate the system and generate heatmaps based on the previously learned policy in every iteration. We then update the policy based on the simulation’s outcome and use it in the next iteration. We test our heatmap design in a comprehensive case study on New York ride-sharing data. We show that carefully designed heatmaps reduce service cancellations and therefore, revenue loss for the platform and drivers significantly while leading to a better service level for the users and to a fairer treatment of drivers. History: This paper has been accepted for the Transportation Science Special Issue on Machine Learning Methods and Applications in Large-Scale Route Planning Problems. Funding: This research is funded by the German Research Foundation (Deutsche Forschungsgemeinschaft) [Grant 494812908]. M. W. Ulmer’s work is funded by the German Research Foundation Emmy Noether Programme [Grant 444657906]. Supplemental Material: The online appendix is available at https://doi.org/10.1287/trsc.2023.1202 .

(1) Background: Keratinocyte cancer (KC) is associated with exposure to ultraviolet (UV) radiation. However, data are controversial as to whether chronic UV exposure or high intermittent UV exposure are key drivers of carcinogenesis in cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC). Prolonged sun exposure of the skin causes photo-aging, which is associated with actinic elastosis, a condition characterized by the degeneration of elastin in the upper dermis, which is assessable via conventional histology. In this study, we aimed to compare the degree of actinic elastosis in different types of KC with regard to various patient characteristics. (2) Methods: We defined a semiquantitative score for the degree of actinic elastosis ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration). The extent was measured histometrically by two independent dermatohistopathologists in the immediate vicinity of 353 KC. The scores were merged and matched with tumor types (cSCC and BCC with subtypes), and clinical variables such as body site, sex and age. (3) Results: As expected, the degree of actinic elastosis correlated with age. However, it was significantly higher in cSCC compared to BCC irrespective of age, sex, body site and tumor subtypes. (4): Conclusions: Lifetime sun exposure may be estimated via routine histology using this scoring technique for actinic elastosis as a surrogate marker. cSCCs are more strongly associated with chronic UV exposure than BCCs, even in sun-exposed localizations such as the face.

Due to their ability to solve complex problems, deep neural networks (DNNs) are becoming increasingly popular in medical applications. However, decision-making by such algorithms is essentially a black-box process that renders it difficult for physicians to judge whether the decisions are reliable. The use of explainable artificial intelligence (XAI) is often suggested as a solution to this problem. We investigate how XAI is used for skin cancer detection: how is it used during the development of new DNNs? What kinds of visualisations are commonly used? Are there systematic evaluations of XAI with dermatologists or dermatopathologists?Google Scholar, PubMed, IEEE Explore, Science Direct and Scopus were searched for peer-reviewed studies published between January 2017 and October 2021 applying XAI to dermatological images: the search terms histopathological image, whole-slide image, clinical image, dermoscopic image, skin, dermatology, explainable, interpretable and XAI were used in various combinations. Only studies concerned with skin cancer were included.37 publications fulfilled our inclusion criteria. Most studies (19/37) simply applied existing XAI methods to their classifier to interpret its decision-making. Some studies (4/37) proposed new XAI methods or improved upon existing techniques. 14/37 studies addressed specific questions such as bias detection and impact of XAI on man-machine-interactions. However, only three of them evaluated the performance and confidence of humans using CAD systems with XAI.XAI is commonly applied during the development of DNNs for skin cancer detection. However, a systematic and rigorous evaluation of its usefulness in this scenario is lacking.

In dem Artikel von J. Singer „Dosismanagement – Neue Aufgaben für MTRA“ in der Radiopraxis 02/2021 1 wurden die Grundlagen, der Aufbau und Nutzen eines Dosismanagementsystems (DMS) ausführlich dargestellt. In diesem Artikel soll es nun um die wichtigsten Schritte bei der Implementierung sowie um die praktischen Aspekte der Nutzung eines DMS gehen.

Neurological complications are common in COVID-19. Although SARS-CoV-2 has been detected in patients’ brain tissues, its entry routes and resulting consequences are not well understood. Here, we show a pronounced upregulation of interferon signaling pathways of the neurovascular unit in fatal COVID-19. By investigating the susceptibility of human induced pluripotent stem cell (hiPSC)-derived brain capillary endothelial-like cells (BCECs) to SARS-CoV-2 infection, we found that BCECs were infected and recapitulated transcriptional changes detected in vivo. While BCECs were not compromised in their paracellular tightness, we found SARS-CoV-2 in the basolateral compartment in transwell assays after apical infection, suggesting active replication and transcellular transport of virus across the blood-brain barrier (BBB) in vitro. Moreover, entry of SARS-CoV-2 into BCECs could be reduced by anti-spike-, anti-angiotensin-converting enzyme 2 (ACE2)-, and anti-neuropilin-1 (NRP1)-specific antibodies or the transmembrane protease serine subtype 2 (TMPRSS2) inhibitor nafamostat. Together, our data provide strong support for SARS-CoV-2 brain entry across the BBB resulting in increased interferon signaling., Graphical abstract, In this article, Pless and colleagues show upregulation of IFNγ signaling in the neurovascular unit of the brain in fatal COVID-19. They show that an hiPSC-derived brain capillary endothelial cell model can be infected with SARS-CoV-2, resulting in similar expression changes, viral replication, and release while endothelial cell integrity is maintained. Infection can be prevented by antibodies or protease inhibitors.

Prostate specific membrane antigen (PSMA) is an emerging diagnostic and therapeutic target in prostate cancer.

PURPOSE The combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma. METHODS Patients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 106 plaque-forming unit (PFU) followed by ≤ 4 × 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis. RESULTS Overall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm. CONCLUSION T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.

Recently, the dynamics of quantum systems that involve both unitary evolution and quantum measurements have attracted attention due to the exotic phenomenon of measurement-induced phase transitions. The latter refers to a sudden change in a property of a state of $n$ qubits, such as its entanglement entropy, depending on the rate at which individual qubits are measured. At the same time, quantum complexity emerged as a key quantity for the identification of complex behaviour in quantum many-body dynamics. In this work, we investigate the dynamics of the quantum state complexity in monitored random circuits, where $n$ qubits evolve according to a random unitary circuit and are individually measured with a fixed probability at each time step. We find that the evolution of the exact quantum state complexity undergoes a phase transition when changing the measurement rate. Below a critical measurement rate, the complexity grows at least linearly in time until saturating to a value $e^{\Omega(n)}$. Above, the complexity does not exceed $\operatorname{poly}(n)$. In our proof, we make use of percolation theory to find paths along which an exponentially long quantum computation can be run below the critical rate, and to identify events where the state complexity is reset to zero above the critical rate. We lower bound the exact state complexity in the former regime using recently developed techniques from algebraic geometry. Our results combine quantum complexity growth, phase transitions, and computation with measurements to help understand the behavior of monitored random circuits and to make progress towards determining the computational power of measurements in many-body systems., Comment: 18 pages, 3 figures

BackgroundDespite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy.MethodsPatients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC–V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS).ResultsOf 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwtpatients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmutpatients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmutpatients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmutpatients. In BRAFwtpatients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwtpatients. For BRAFmutpatients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK.ConclusionsIn BRAFmutpatients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwtpatients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1.

Many quantum information protocols require the implementation of random unitaries. Because it takes exponential resources to produce Haar-random unitaries drawn from the full $n$-qubit group, one often resorts to $t$-designs. Unitary $t$-designs mimic the Haar-measure up to $t$-th moments. It is known that Clifford operations can implement at most $3$-designs. In this work, we quantify the non-Clifford resources required to break this barrier. We find that it suffices to inject $O(t^{4}\log^{2}(t)\log(1/\varepsilon))$ many non-Clifford gates into a polynomial-depth random Clifford circuit to obtain an $\varepsilon$-approximate $t$-design. Strikingly, the number of non-Clifford gates required is independent of the system size -- asymptotically, the density of non-Clifford gates is allowed to tend to zero. We also derive novel bounds on the convergence time of random Clifford circuits to the $t$-th moment of the uniform distribution on the Clifford group. Our proofs exploit a recently developed variant of Schur-Weyl duality for the Clifford group, as well as bounds on restricted spectral gaps of averaging operators., v3: version published in Communications in Mathematical Physics, title changed; v2: improved presentation, added consequences of the main result and fixed typos; 46 pages, 1 figure

In this work, we show that learning the output distributions of brickwork random quantum circuits is average-case hard in the statistical query model. This learning model is widely used as an abstract computational model for most generic learning algorithms. In particular, for brickwork random quantum circuits on $n$ qubits of depth $d$, we show three main results: - At super logarithmic circuit depth $d=\omega(\log(n))$, any learning algorithm requires super polynomially many queries to achieve a constant probability of success over the randomly drawn instance. - There exists a $d=O(n)$, such that any learning algorithm requires $\Omega(2^n)$ queries to achieve a $O(2^{-n})$ probability of success over the randomly drawn instance. - At infinite circuit depth $d\to\infty$, any learning algorithm requires $2^{2^{\Omega(n)}}$ many queries to achieve a $2^{-2^{\Omega(n)}}$ probability of success over the randomly drawn instance. As an auxiliary result of independent interest, we show that the output distribution of a brickwork random quantum circuit is constantly far from any fixed distribution in total variation distance with probability $1-O(2^{-n})$, which confirms a variant of a conjecture by Aaronson and Chen., Comment: 57 pages

Brain metastasis still encompass very grim prognosis and therefore understanding the underlying mechanisms is an urgent need toward developing better therapeutic strategies. We uncover the intricate interactions between recruited innate immune cells and resident astrocytes in the brain metastatic niche that facilitate metastasis of melanoma and breast cancer. We show that granulocyte-derived lipocalin-2 (LCN2) induces inflammatory activation of astrocytes, leading to myeloid cell recruitment to the brain. LCN2 is central to inducing neuroinflammation as its genetic targeting or bone-marrow transplantation from LCN2-/- mice was sufficient to attenuate neuroinflammation and inhibit brain metastasis. Moreover, high LCN2 levels in patient blood and brain metastases in multiple cancer types were strongly associated with disease progression and poor survival. Our findings uncover a previously unknown mechanism, establishing a central role for the reciprocal interactions between granulocytes and astrocytes in promoting brain metastasis and implicate LCN2 as a prognostic marker and potential therapeutic target.

ZusammenfassungAls eine Art Entsandter der Freirechtsbewegung und Vertreter der Jurisprudenz sprach Hermann Kantorowicz auf Einladung von Max Weber vor dem Ersten Soziologentag 1910 in Frankfurt a. M. Sein Vortrag war in mehreren Perspektiven bedeutsam. Zunächst musste Kantorowicz seine Thesen aus dem berühmten „Kampf um die Rechtswissenschaft“ von 1906 präzisieren, um zu einer klaren Bestimmung des Verhältnisses zwischen Rechtswissenschaft und Soziologie zu gelangen. Dies führte zu klaren Abgrenzungen zu anderen „Freirechtlern“, insbesondere zu Eugen Ehrlich und den in Frankfurt anwesenden Ernst Fuchs und Hans Wüstendörfer. Viel deutlicher arbeitete er auch die Grundlagen einer Methodologie der Rechtswissenschaft heraus, wofür er sich erstmals zu Heinrich Rickert bekannte. Schließlich wurde schon in Frankfurt deutlich, dass sich die Annäherung an die Empirie für Kantorowicz als Durchgangsstadium erweisen würde, da bereits hier die drängende Problematik einer Wertphilosophie durchschimmerte, die ihn in späteren Jahren immer stärker interessieren sollte. Obwohl der Vortrag bei Max Weber große Zustimmung fand, löste die Diskussion große Kontroversen aus, die mit zur baldigen Krise der Deutschen Gesellschaft für Soziologie beitrugen.

International audience

European journal of cancer 154, 227-234 (2021). doi:10.1016/j.ejca.2021.05.026, Published by Elsevier, Amsterdam [u.a.]

Simple Summary Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies of the skin with poor survival outcomes in advanced stages of the disease. Recent clinical trials demonstrated the efficacy of checkpoint-inhibitors (CPI) therapy for advanced stage disease, but there is a lack of data from real-world cohorts and trial-ineligible patients. In this retrospective, real-world cohort study, we investigated the efficacy of first-line checkpoint-inhibitor treatment in 39 patients with advanced cSCC from eight different German cancer centers and stratified outcomes by the immune status of the patients. Our data demonstrate that patients receiving CPI achieved high response rates with durable remissions in about 20% of patients. CPI also evoked tumor responses in patients with active autoimmune diseases and lymphoproliferative disorders, although these responses were often short-lived, resulting in a significantly shorter overall survival. Notably, CPI therapy was safe with only 15% of patients discontinuing for toxicity. Abstract Cutaneous squamous cell carcinoma (cSCC) is a common malignancy of the skin and has an overall favorable outcome, except for patients with an advanced stage of the disease. The efficacy of checkpoint inhibitors (CPI) for advanced cSCC has been demonstrated in recent clinical studies, but data from real-world cohorts and trial-ineligible cSCC patients are limited. We retrospectively investigated patients with advanced cSCC who have been treated with CPI in a first-line setting at eight German skin cancer centers registered within the multicenter registry ADOReg. Clinical outcome parameters including response, progression-free (PFS) and overall survival (OS), time-to-next-treatment (TTNT), and toxicity were analyzed and have been stratified by the individual immune status. Among 39 evaluable patients, the tumor response rate (rwTRR) was 48.6%, the median PFS was 29.0 months, and the median OS was not reached. In addition, 9 patients showed an impaired immune status due to immunosuppressive medication or hematological diseases. Our data demonstrated that CPI also evoked tumor responses among immunocompromised patients (rwTRR: 48.1 vs. 50.0%), although these responses less often resulted in durable remissions. In line with this, the median PFS (11 vs. 40 months, p = 0.059), TTNT (12 months vs. NR, p = 0.016), and OS (29 months vs. NR, p < 0.001) were significantly shorter for this patient cohort. CPI therapy was well tolerated in both subcohorts with 15% discontinuing therapy due to toxicity. Our real-world data show that first-line CPI therapy produced strong and durable responses among patients with advanced cSCC. Immunocompromised patients were less likely to achieve long-term benefit from anti-PD1 treatment, despite similar tumor response rates.

Fragestellung: Friedrich von Esmarch gilt als Begründer der Musikermedizin. Clara Schumann begab sich 1875 voller Verzweiflung wegen eines chronifizierten, äußerst schmerzhaften myofaszialen Schmerzsyndroms in seine Behandlung. Nach dem Tod ihres Mannes Robert Schumann war sie gezwungen. [zum vollständigen Text gelangen Sie über die oben angegebene URL]

Immune checkpoint inhibitors have revolutionized treatment of advanced melanoma, but commonly cause serious immune-mediated complications. The clinical ambition of reserving more aggressive therapies for patients least likely to experience immune-related adverse events (irAE) has driven an extensive search for predictive biomarkers. Here, we externally validate the performance of 59 previously reported markers of irAE risk in a new cohort of 110 patients receiving Nivolumab (anti-PD1) and Ipilimumab (anti-CTLA-4) therapy. Alone or combined, the discriminatory value of these routine clinical parameters and flow cytometry biomarkers was poor. Unsupervised clustering of flow cytometry data returned four T cell subsets with higher discriminatory capacity for colitis than previously reported populations, but they cannot be considered as reliable classifiers. Although mechanisms predisposing some patients to particular irAEs have been described, we are presently unable to capture adequate information from pre-therapy flow cytometry and clinical data to reliably predict risk of irAE in most cases.

Combined cisplatin–gemcitabine (GC) application is standard for treating muscle-invasive bladder cancer. However, since rapid resistance to treatment often develops, many patients turn to supplements in the form of plant-based compounds. Sulforaphane (SFN), derived from cruciferous vegetables, is one such compound, and the present study was designed to investigate its influence on growth and proliferation in a panel of drug-sensitive bladder cancer cell lines, as well as their gemcitabine- and cisplatin-resistant counterparts. Chemo-sensitive and -resistant RT4, RT112, T24, and TCCSUP cell lines were exposed to SFN in different concentrations, and tumor growth, proliferation, and clone formation were evaluated, in addition to apoptosis and cell cycle progression. Means of action were investigated by assaying cell-cycle-regulating proteins and the mechanistic target of rapamycin (mTOR)/AKT signaling cascade. SFN significantly inhibited growth, proliferation, and clone formation in all four tumor cell lines. Cells were arrested in the G2/M and/or S phase, and alteration of the CDK–cyclin axis was closely associated with cell growth inhibition. The AKT/mTOR signaling pathway was deactivated in three of the cell lines. Acetylation of histone H3 was up-regulated. SFN, therefore, does exert tumor-suppressive properties in cisplatin- and gemcitabine-resistant bladder cancer cells and could be beneficial in optimizing bladder cancer therapy.