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Differences between molecular subtypes with regard to initial tumor control irrespective of chemotherapeutic regimen (p-value 0.033). Y-axis is representing total patient count.

Frequency distributions of IHC-derived subtypes of PDAC and unclassifiable cases (purple) in all cohorts investigated in this study.

Kaplan-Meier curves for survival differences between investigated chemotherapeutic regimens after stratification for molecular subtype of PDAC. P-values calculated by log rank test.

a)+b) Bar graphs of the distribution of histopathological grade in IHC-derived subtypes of PDAC (p-value a:0.102 b:0.986) c) Bar graph of in depth analysis of histomorphological growth patterns (PR2 cohort) and molecular subtype. Y-axis depicts total number of cases. Combined/heterogeneous growth patterns depicted with "_". CD=classic ductal.

Cohort characteristics

Association of clinical patient characteristics with molecular subtypes

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis and poor therapeutic response to current chemotherapy regimens in unselected patient populations. Recently, it has been shown that PDAC may be stratified into functionally and therapeutically relevant molecular subgroups and that some of these subtypes can be recapitulated by IHC for KRT81 [quasi-mesenchymal (QM)/squamous/basal-like] and HNF1A (non-QM, overlap with exocrine/ADEX subtype).Experimental Design: We validated the different outcome of the HNF1A/KRT81 PDAC subtypes in two independent cohorts of surgically treated patients and examined the treatment response to chemotherapy in a third cohort of unresectable patients. The first two cohorts included 262 and 130 patients, respectively, and the third independent cohort comprised advanced-stage PDAC patients who were treated with either FOLFIRINOX (64 patients) or gemcitabine (61 patients).Results: In both cohorts with resected PDAC, the HNF1A-positive subtype showed the best, the KRT81-positive subtype the worst, and the double-negative subtype an intermediate survival (P < 0.013 and P < 0.009, respectively). In the chemotherapy cohort, the survival difference between the double-negative and the HNF1A-positive subtype was lost, whereas the dismal prognosis of KRT81-positive PDAC patients was retained (P < 0.021). Patients with a KRT81-positive subtype did not benefit from FOLFIRINOX therapy, whereas those with HNF1A-positive tumors responded better compared with gemcitabine-based treatment (P < 0.038).Conclusions: IHC stratification recapitulating molecular subtypes of PDAC using HNF1A and KRT81 is associated with significantly different outcomes and responses to chemotherapy. These results may pave the way toward future pretherapeutic biomarker-based stratification of PDAC patients. Clin Cancer Res; 24(2); 351–9. ©2017 AACR.

Crosstab of association of TMA-derived molecular subtypes with whole tissue slide derived subtyping.

a+b) Bar graphs of the frequencies of application of adjuvant chemotherapy in primary resected cohorts (p-value a: 0.637, b: 0.548). Y-axis depicts total number of cases. c-f) Kaplan-Meier analysis of survival effects of IHC derived subtypes after stratification for adjuvant therapy. X-axis represents survival time (in days). P-values calculated by log rank test. Ticks indicating censored cases.

Introduction: Colorectal cancer (CRC) is a disease of older patients, but evidence-based guidelines for chemotherapy in older patients are scarce. Geriatric assessment (GA) evaluates a patient’s functional status (FS) and helps in decision-making when choosing chemotherapy for older patients. However, the change of FS during chemotherapy is rarely studied as GA is mostly performed once instead of sequentially. Methods: We performed a subgroup analysis of a prospective, multicenter study EpiReal 75. Patients aged ≥75 years with gastrointestinal malignancy prior to initiation of chemotherapy or receiving palliative chemotherapy were screened. We defined geriatric core assessments including the Eastern Cooperative Oncology Group score, Barthel’s activities of daily living (ADL) scale, Lawton’s instrumental activities of daily living (IADL) scale, and G-8 questionnaire, which were performed at baseline and repeated every 3 months. Quality of life (QoL) assessed by QLQ-C30 questionnaire was also re-evaluated every 3 months. We defined any deterioration in any of the geriatric parameters as unstable in the corresponding function. Results: 28 patients with CRC were enrolled between April 2014 and December 2018. 20 patients were evaluable for statistical analysis with a mean age of 78.5 years (range, 75–88). Most patients received chemotherapy in palliative setting. During 3 months of chemotherapy, 25% of patients became more dependent as measured by ADL or IADL. During a median follow-up of 15 months, patients with unstable ADL or IADL had a significantly shorter overall survival (OS) than those with stable ADL or IADL (plogrank = 0.0055 and 0.0253, respectively), without a significant difference in progression-free survival (PFS). Also, unstable IADL correlated with a deterioration in aspects of QoL such as role functioning and emotional functioning (p = 0.0189 and 0.0239, respectively). 20% of patients experienced treatment-related grade 3 adverse events (AEs), no grade 4–5 AEs occurred. Conclusion: Sequential GA revealed changes in FS in older patients with CRC receiving chemotherapy. A deterioration of FS during chemotherapy did not influence PFS but had a negative impact on OS and QoL. It is therefore important to maintain FS in older patients with cancer, and regular performance of geriatric core assessments should be encouraged in the clinical practice.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Recently, the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib has been approved for maintenance therapy after successful platinum-based chemotherapy in patients with germline mutations in BRCA1 and BRCA2. Approval was based on the POLO study that has shown a significant improvement in progression-free survival for patients with metastatic PDAC after at least 4 months of platinum-based chemotherapy. Hopefully, this first biomarker-directed targeted therapy for a relevant subgroup of pancreatic cancer patients is only the beginning of an era of personalized therapy for pancreatic cancer. The potential role for PARPi in improving survival in patients with pancreatic cancer containing somatic tumor mutations has yet to be established. Multiple studies investigating whether PARPi therapy might benefit a larger group of pancreatic cancer patients with homologous recombination repair deficiency and whether combinations with chemotherapy, immunotherapy, or small molecules can improve efficacy are currently underway. We here review the molecular basis for PARPi therapy in PDAC patients and recent developments in clinical studies.

Background Pancreatoblastoma is a rare malignancy that occurs predominantly in children. Less than 50 adult cases, including 17 patients with metastatic disease, have been published to date. Recent outcome data from children with advanced-stage disease suggest an intensive multimodal treatment approach; however, little is known about the most beneficial therapy in adults. Molecular characterization of pancreatoblastoma is limited to a small number of pediatric cases and revealed few recurrent genetic events without immediate clinical relevance. Methods Patients were treated between 2013 and 2018 at a high-volume German university cancer center. Molecular analyses included whole genome, exome, transcriptome, and fusion gene panel sequencing. Molecularly guided treatment recommendations were discussed within a dedicated molecular tumor board (MTB) embedded in a precision oncology program (NCT MASTER). Results We identified four adult patients with metastatic pancreatoblastoma. In three patients, local approaches were combined with systemic treatment. Oxaliplatin-containing protocols showed an acceptable tumor control as well as an adequate toxicity profile. Overall survival was 15, 17, 18 and 24 months, respectively. Three tumors harbored genetic alterations involving the FGFR pathway that included an oncogenic FGFR2 fusion. Conclusion Oxaliplatin-containing chemotherapy seems to be a reasonable approach in adult patients with advanced pancreatoblastoma, whereas the benefit of intensified treatment including local ablative techniques or surgical resection remains unclear. Our finding of FGFR alterations in three of four cases indicates a potential role of FGFR signaling in adult pancreatoblastoma whose clinical significance warrants further study.

PD-1/PD-L1 inhibitors do not show activity in mismatch repair proficient (MMRp) colorectal cancer. Inhibition of C-C motif chemokine receptor 5 (CCR5) leads to an antitumoral activation of macrophages, affecting immune cell infiltrates. PICCASSO is a phase I trial exploring safety and efficacy of pembrolizumab and maraviroc in refractory MMRp CRC.Twenty patients received pembrolizumab and maraviroc (core period, eight cycles), followed by pembrolizumab monotherapy. Primary endpoint was the feasibility rate (patients without treatment-related grade ≥3 immune-related adverse events, treatment-related grade ≥4 adverse events, or any toxicity-related premature withdrawal of treatment). Secondary endpoints included safety/toxicity, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Optional biopsies of liver metastases were performed for analyses of the micromilieu.The feasibility rate was 94.7% [90% CI 77.4-99.7%], with one grade 4 hyperglycemia and no additional ≥ grade 3 treatment-related toxicities. ORR according to RECIST was 5.3%. Median PFS according to RECIST was 2.10 months [95%CI 1.68-2.30], median OS 9.83 months [95% CI, 5.59-20.02]. Disease control rate of poststudy salvage treatment was70%. Translational analyses showed an increase of antitumoral chemokines during treatment; eotaxin, a chemokine involved in chemotaxis, was identified as a biomarker linked to OS.Therapy with pembrolizumab and maraviroc was feasible and showed a beneficial toxicity pattern. Clinical activity in MMRp CRC patients was limited with prolonged disease stabilizations observed in single patients. Efficacy of poststudy salvage treatment and OS was higher than expected in this heavily pretreated population. THIS TRIAL IS REGISTERED AT CLINICALTRIALS.GOV: NCT03274804.

Patients with cancer frequently receive immune-checkpoint inhibitors (ICIs), which may modulate immune responses to COVID-19 vaccines. Recently, cytokine release syndrome (CRS) was observed in a patient with cancer who received BTN162b2 vaccination under ICI treatment. Here, we analyzed adverse events and serum cytokines in patients with 23 different tumors undergoing (n = 64) or not undergoing (n = 26) COVID-19 vaccination under ICI therapy in a prospectively planned German single-center cohort study (n = 220). We did not observe clinically relevant CRS (≥grade 2) after vaccination (95% CI 0-5.6%; Common Terminology of Adverse Events v.5.0) in this small cohort. Within 4 weeks after vaccination, serious adverse events occurred in eight patients (12.5% 95% CI 5.6-23%): six patients were hospitalized due to events common under cancer therapy including immune related adverse events and two patients died due to conditions present before vaccination. Despite absence of CRS symptoms, a set of pairwise-correlated CRS-associated cytokines, including CXCL8 and interleukin-6 was1.5-fold upregulated in 40% (95% CI 23.9-57.9%) of patients after vaccination. Hence, elevated cytokine levels are common and not sufficient to establish CRS diagnosis.

The next-generation internet (6G) requires highly functional devices that e.g. realize frequencies in the THz range for higher data rates and lower latencies. Those requirements exceed the physical limits of established CMOS technologies based on silicon (Si). Hence, there is demand for other semiconductor materials with superior electronic and optical properties that complement Si. One of the key candidates is the III-V compound semiconductor, indium phosphide (InP). Due to its high electron mobility and direct band gap, InP-based devices allow access to frequencies >100 GHz and operate at the optical fibre compatible wavelength of 1.55 μm.1 With the perspective of leveraging the advantages of Si-based CMOS technology and III-V semiconductors, hetero-integration of III-V materials on Si is of great interest. However, existing integration approaches entail certain disadvantages: (i) High dislocation densities due to the lattice mismatch of InP and Si for integration via hetero-epitaxial growth;2 (ii) limited integration density and the requirement of accurate alignment for flip-chip integration; and (iii) high process-related losses of Si and III-V materials as well as thermal stress and low thermal conductivity of adhesive layers degrading device performance for wafer/die bonding technologies.3 Another promising approach for III-V-on-Si integration is micro-transfer-printing (μTP) that involves pick-up and transfer of µm-small chips from a source substrate to a target substrate with high alignment accuracy by using an elastomeric stamp. Advantages of μTP are high integration densities and efficient material use. The technique was already implemented for III-V-on-Si photonic integrated circuits by transfer of epitaxial III-V layers.4 However, using sacrificial III-V interlayers for release and adhesives for bonding still leads to transfer issues and low operation temperature for the devices, respectively. We pursue a new approach to hetero-integration of III-V on Si that aims at the transfer of single-crystalline InP coupons onto Si via μTP. This will be achieved by obtaining crystalline coupons with a thickness of d ≤ 10 µm and two polished surfaces that attain low roughness, needed i.a. for µTP. If the high structural quality of the single-crystalline InP source material can be maintained, this process will provide high quality templates for subsequent epitaxial growth. Towards this goal, we developed a sophisticated micro-preparation process in cooperation with the Leibniz Institute for High Performance Microelectronics IHP.5 Starting from 4-inch single crystals with homogeneous, low dislocation density of 2×103 cm- 2 grown at IKZ,6 thinned InP dies were obtained by sawing, grinding and employing an optimized two-step chemical mechanical polishing (CMP). In order to produce µm-sized transfer-printable coupons, the InP dies were micro structured by means of photolithography assisted patterning and wet (under-)etching (Fig. 1). The coupons can then be picked up with a stamp and transferred to the target wafer. Main innovation of this process is the resin which serves as low stress fixing layer for CMP as well as sacrificial layer for later release. The optimized CMP process with abrasive-free final polishing yielded InP platelets of the desired thickness below 10 μm with low thickness deviation < 1 µm and excellent surface roughness of S q ≈ 0.3 nm (Fig. 2a,b,d). This value even meets the requirements for adhesive-free bonding (S q ≤ 2 nm) and subsequent epitaxial growth (S q ≤ 0.5 nm). X-ray rocking curve mapping provides accurate spatial maps of lattice deformations in the material that may be a consequence of the mechanical processing. Rocking curve widths mappings of the 004 reflection of a (001) sample before and after thinning are homogeneous and below 25 arcsec in the majority of the sample area. Overall no signs of systematic crystal quality deterioration in the product platelets compared to bulk samples have been detected. In summary, the feasibility of μm-thin InP platelet fabrication was demonstrated. Final platelets meet the prerequisites of low and uniform thickness, high planarity, low roughness and little crystal quality deterioration. Furthermore, first InP platelets could successfully be patterned to 100–400 µm-sized coupons using optical lithography and wet etching (Fig. 2c). This opens a path to take the next steps towards hetero-integration on Si by means of µTP with high potential for adhesive-free bonding. References [1] J. C. Rode, et al. IEEE Trans. Electron Devices 2015, 62, 2779–2785. [2] Q. Li, K. M. Lau Prog. Cryst. Growth Charact. Mater. 2017, 63, 105–120. [3] X. Guo, et al. J. Semicond. 2019, 40, 101304. [4] J. Zhang, et al. APL Photonics 2019, 4, 110803. [5] IKZ-IHP Patent filed - DE 10 2022 100 661.1. [6] K. Giziewicz, et al. 51st Annual Meeting of the German Association of Crystal Growth, 2021, Berlin. Figure 1

Objectives Acinar cell carcinoma of the pancreas (pACC) forms a rare subgroup of pancreatic tumors. We report on our institutional experience with systemic first- and further-line therapy in patients with metastatic pACC and embed our findings in a review of the literature. Methods Patients with stage IV pACC who started systemic treatment between 2008 and 2019 at our institution were identified via our institutional database. Clinical data were extracted from the patients' electronic data records. Survival times were calculated by the Kaplan-Meier method. Results Six patients received a fluoropyrimidine- and oxaliplatin-containing first-line treatment, and 4 patients were started on gemcitabine-based protocols. Median progression-free survival was 4.8 months [95% confidence interval (CI), 3.3 to not available (n.a.)], and median overall survival was 15.3 months (95% CI, 10.1 to n.a.). Residual survival for second-line treatment was 2.1 months (95% CI, 1.3 to n.a.), although 1 patient experienced almost complete remission under targeted therapy. Conclusions The most encouraging and deep responses result from poly-chemotherapy with leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), which seems to be the appropriate choice in fit patients. Gemcitabine monotherapy seems without substantial activity in pACC. Whenever possible, patients with pACC should be screened for targetable mutations.

Background: Checkpoint inhibitors are a standard of care in the treatment of advanced renal cell carcinoma (RCC) and urothelial carcinoma (UC). Patients with these tumors often suffer from concomitant chronic kidney disease (CKD). Limited data are available on the efficacy and toxicity of checkpoint inhibitors in patients with CKD. Methods: We retrospectively analyzed 126 patients who received checkpoint inhibitors for RCC (n = 85) or UC (n = 41) and analyzed the frequency of treatment- and immune-related adverse events (AEs). We performed a multivariate analysis to determine progression-free survival (PFS) and overall survival (OS). Results: A total of 38.9% of patients had CKD. Frequencies of general AEs (49.0% in CKD vs. 48.1%, p &gt, 0.99999) and immune-related AEs (28.6 vs. 24.7%, p ≥ 0.9999) did not significantly differ between the groups. There was no difference in PFS for patients with RCC or UC and CKD or without CKD (RCC: 6.81 vs. 7.54 months, HR 1.000 (95%CI 0.548-01.822), p = 0.999, UC:2.33 vs. 3.67 months, HR 01.492 (95%CI 0.686-3.247), p = 0.431). CKD appeared to be a potential effect modifier for OS in both RCC and UC (RCC: NR vs. 23.9 months, HR 0.502 (95%CI 0.219-1.152), p = 0.104, UC:18.84 vs. 15.42 months, HR 0.656 (95%CI 0.296-1.454), p = 0.299). Conclusions: Checkpoint inhibitor treatment in our cohort of patients with CKD was as safe and efficient as in the cohort of patients without CKD.

A microporous layer (MPL) is typically added to the gas diffusion layer of polymer electrolyte fuel cells (PEFCs) to promote cell performance and water management. The transport mechanism of the water through the MPL is, however, not well understood due to its small pores (20-500 nm). Here, we demonstrate that polychromatic X-ray tomographic microscopy (XTM) can be used to determine the porosity and the spatial distribution of water in nanoporous materials and can quantitatively map the liquid water saturation of MPLs. The presented technique requires no a priori knowledge of the composition of the MPL and has a field of view on the millimeter scale, which is orders of magnitude larger than conventional electron microscopy techniques for nanoscale materials. The available field of view is compatible with existing operando cells for X-ray tomography, paving the way for the analysis of water transport in MPLs during operation.

Perioperative systemic treatment is standard of care for Caucasian patients with locally advanced, resectable gastric adenocarcinoma. The prognostic relevance of the microsatellite instability (MSI) status in patients undergoing neoadjuvant chemotherapy followed by resection is unclear. We analyzed the association of the MSI status with histological regression and clinical outcome in patients undergoing neoadjuvant systemic treatment. Tumor tissue from patients undergoing neoadjuvant chemotherapy followed by resection for gastric or gastroesophageal-junction adenocarcinoma was analyzed for MSI status using a mononucleotide marker panel encompassing the markers BAT25, BAT26, and CAT25. Histological regression, relapse-free survival and overall survival were calculated and correlated with MSI status. We identified the MSI-H phenotype in 9 (8.9%) out of 101 analyzed tumors. Though a poor histological response was observed in eight out of nine MSI-H patients, overall survival was significantly better for patients with MSI-H compared to MSS tumors (median overall survival not reached vs. 38.6 months, log-rank test p = 0.014). Among MSI-H patients, an unexpected long-term survival after relapse was observed. Our data indicate that the MSI-H phenotype is a favorable prognostic marker in gastric cancer patients undergoing neoadjuvant treatment. The benefit of perioperative cytotoxic treatment in patients with MSI-H gastric cancer, however, remains questionable. Future trials should stratify patients according to their MSI status, and novel treatment modalities focusing on MSI-H tumors should be considered.

// Leonidas Apostolidis 1 , Cathleen Nientiedt 1 , Eva Caroline Winkler 1 , Anne Katrin Berger 1 , Clemens Kratochwil 2 , Annette Kaiser 3 , Anne-Sophie Becker 3 , Dirk Jager 1 , Markus Hohenfellner 4 , Clemens Huttenbrink 5 , Sascha Pahernik 5 , Florian A. Distler 5, * and Carsten Grullich 1, * 1 Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany 2 Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany 3 Institute of Pathology, Klinikum Nuremberg, Paracelsus Medical University, Nuremberg, Germany 4 Department of Urology, University Hospital Heidelberg, Heidelberg, Germany 5 Department of Urology, Klinikum Nuremberg, Paracelsus Medical University, Nuremberg, Germany * These authors have contributed equally to this work Correspondence to: Leonidas Apostolidis, email: leonidas.apostolidis@med.uni-heidelberg.de Keywords: neuroendocrine carcinoma; neuroendocrine tumor; carcinoid; prostate; chemotherapy Received: September 19, 2018 Accepted: December 10, 2018 Published: January 01, 2019 ABSTRACT Background: Neuroendocrine carcinomas of the prostate (NEPCs) are rare tumors with poor prognosis. While platinum and etoposide-based chemotherapy regimens (PE) are commonly applied in first-line for advanced disease, evidence for second-line therapy and beyond is very limited. Methods: Retrospective analysis of all patients with NEPCs including mixed differentiation with adenocarcinoma component and well differentiated neuroendocrine tumors (NETs, carcinoids) at two high-volume oncological centers between 12/2000 and 11/2017. Results: Of 46 identified patients 39.1 % had a prior diagnosis of prostatic adenocarcinoma only, 43.5 % had a mixed differentiation at NEPC diagnosis, 67.4 % developed visceral metastases, 10.9 % showed paraneoplastic syndromes. Overall survival (OS) from NEPC diagnosis was 15.5 months, and significantly shorter in patients with a prior prostatic adenocarcinoma (5.4 vs. 32.7 months, p=0.005). 34 patients received palliative first-line systemic therapy with a median progression-free survival (PFS) of 6.6 months, mostly PE. Overall response rate (ORR) for PE was 48.1 %. 19 patients received second-line therapy, mostly with poor responses. Active regimens were topotecan (1 PR, 3 PD), enzalutamide (1 SD), abiraterone (1 SD), FOLFIRI (1 SD), and ipilimumab+nivolumab (1 PR). One patient with prostatic carcinoid was sequentially treated with octreotide, peptide receptor radionuclide therapy and everolimus, and survived for over 9 years. Conclusions: EP in first-line shows notable ORR, however limited PFS. For second-line therapy, topotecan, FOLFIRI, enzalutamide, abiraterone and immune checkpoint blockade are treatment options. Prostatic carcinoids can be treated in analogy to well differentiated gastrointestinal NETs.

Background To assess the predictive value of early metabolic response (ΔSUV) after short-term treatment with first-line cetuximab in patients (pts) with RAS-wt metastatic colorectal cancer (mCRC). Methods In this prospective phase II study, RAS-wt mCRC pts received a single-agent cetuximab run-in therapy of 2 weeks. ΔSUV was assessed with FDG-PET/CT on days 0 and 14. Early clinical response (ECR) was evaluated with CT on day 56 after treatment with FOLFIRI-cetuximab. Primary endpoint was the predictive significance of ΔSUV for ECR. Secondary endpoints were PFS (progression free survival), OS and the influence of ΔSUV on survival. Results Forty pts were enroled and 33 pts were evaluable for the primary endpoint. The CT response rate was 57.6%. For responders, ΔSUV was significantly higher (p = 0.0092). A significant association of ΔSUV with ECR was found (p = 0.02). Median PFS was 11.7 months and median OS was 33.5 months with a 1-year survival rate of 87.9%. ΔSUV was found to significantly impact the hazard for OS (p = 0.045). Conclusions We demonstrate that cetuximab induces metabolic responses in mCRC pts. The study endpoint was met with the ΔSUV discriminating between responders and non-responders. However, these data should be validated in larger patient cohorts.

The lithium–sulfur (Li–S) battery chemistry has attracted great interest in the last decade because of its outstanding theoretical gravimetric energy density compared to the state-of-the-art lithium-ion battery technology. However, practically achieved energy density is still far below the theoretical value, even in small laboratory-scale batteries. The problems seen in laboratory-scale batteries will inevitably increase during scale-up to large application-format cells, as the electrolyte to active material (AM) ratio will need to be reduced in these cells to achieve high gravimetric energy density on cell-level basis. Our study shows the unique possibility of X-ray fluorescence (XRF) mapping to visualize the spatial distribution of the AM inside operating Li–S batteries in all cell components [working electrode (WE), separator, and counter electrode (CE)]. Through a combination of operando XRF mapping and X-ray absorption spectroscopy, we show that unless self-discharge is efficiently prevented, the AM can completely dissolve and distribute throughout the cell stack within a time frame of 2 h, causing poor capacity retention. Using a polysulfide diffusion barrier between the WE and the CE, we successfully suppress these processes and thereby establish a tool for examining the sealed cathode electrode compartment, enabling sophisticated studies for future optimization of the WE processes.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis and poor therapeutic response to current chemotherapy regimens in unselected patient populations. Recently, it has been shown that PDAC may be stratified into functionally and therapeutically relevant molecular subgroups and that some of these subtypes can be recapitulated by IHC for KRT81 [quasi-mesenchymal (QM)/squamous/basal-like] and HNF1A (non-QM, overlap with exocrine/ADEX subtype). Experimental Design: We validated the different outcome of the HNF1A/KRT81 PDAC subtypes in two independent cohorts of surgically treated patients and examined the treatment response to chemotherapy in a third cohort of unresectable patients. The first two cohorts included 262 and 130 patients, respectively, and the third independent cohort comprised advanced-stage PDAC patients who were treated with either FOLFIRINOX (64 patients) or gemcitabine (61 patients). Results: In both cohorts with resected PDAC, the HNF1A-positive subtype showed the best, the KRT81-positive subtype the worst, and the double-negative subtype an intermediate survival (P < 0.013 and P < 0.009, respectively). In the chemotherapy cohort, the survival difference between the double-negative and the HNF1A-positive subtype was lost, whereas the dismal prognosis of KRT81-positive PDAC patients was retained (P < 0.021). Patients with a KRT81-positive subtype did not benefit from FOLFIRINOX therapy, whereas those with HNF1A-positive tumors responded better compared with gemcitabine-based treatment (P < 0.038). Conclusions: IHC stratification recapitulating molecular subtypes of PDAC using HNF1A and KRT81 is associated with significantly different outcomes and responses to chemotherapy. These results may pave the way toward future pretherapeutic biomarker-based stratification of PDAC patients. Clin Cancer Res; 24(2); 351–9. ©2017 AACR.

The underlying mechanism of lithium-sulfur batteries is still not fully established because it involves a series of both chemical and electrochemical reactions as well as the formation of soluble polysulfide intermediates. To improve the mechanistic understanding of lithium-sulfur batteries, this study investigates chemical reactions between the Li2S cathode and more oxidized sulfur species, such as S8 and polysulfides, during the electrochemical charge of the battery. By combining the electrochemistry with X-ray absorption spectroscopy, we show that chemical reactions and, in particular, the resulting accumulation of solution species in the electrolyte are essential to oxidize Li2S at a low overpotential. Additionally, by efficiently separating the anode and cathode compartments of a battery with a lithium ion-exchanged Nafion interlayer, we establish the adverse effect of the anode on the buildup of solution intermediates. In the absence of the interlayer, polysulfide intermediates can diffuse through the separator and react at the anode's surface, while the addition of the interlayer allows the intermediates to accumulate in the separator of the cathode compartment and facilitate the oxidation of Li2S.

Acute kidney injury (AKI) is a major complication in patients with cancer, associated with significant morbidity and mortality. Only two cases of kidney lymphangitic carcinomatosis associated with AKI have been reported, in gastric and colorectal adenocarcinoma. Here, we report on a 53-year-old man with pancreatic adenocarcinoma who developed AKI as a result of kidney lymphangitic carcinomatosis. The patient rapidly became anuric and required haemodialysis. Kidney lymphangitic carcinomatosis should be considered as a cause of AKI in patients with cancer and may become a more frequent clinical finding as patients with metastatic carcinoma survive for longer.

A microporous layer (MPL) is typically added to gas diffusion layers in polymer electrolyte fuel cells (PEFC) to enhance fuel cell performance and water management. The related transport mechanisms are not completely understood and therefore characterization is required. However accurate determination of MPL liquid water saturation has not yet been broadly addressed, except for preliminary work. We demonstrate that X-ray computed tomography (XCT) is suitable and efficient in characterizing MPL’s local liquid water saturation in an ex situ model experiment setup. Our image evaluation pipeline was first developed on porous polymeric membrane materials, validated by independent gravimetric measurements. Mercury intrusion porosimetry (MIP) on MPL further justifies the efficacy of the method. The pipeline has indicated an accuracy of ca. ±7% and a field of view of 6 mm, which suits differential cell investigations. The linear relationship of greyscale value (GSV) and linear attenuation coefficients is shown to hold even for a polychromatic radiation source. This methodology has the potential to accurately characterize the water saturation in MPLs under operando PEFC conditions.

3010 Background: Checkpoint inhibition using PD-1/PD-L1 inhibitors does not show clinically relevant activity in MSS/pMMR (Mismatch Repair Proficient) colorectal cancer. Previous work showed that inhibition of CCR5 (C-C chemokine receptor type 5) leads to a macrophage re-polarization towards M1 macrophages within the tumor microenvironment which directly affects immune cell infiltrates. The current phase I trial explores a combined modification of the innate immune system (by CCR 5 blockade) and the adaptive immune system (by PD-1 inhibition) in the treatment of MSS CRC. Methods: 20 patients with metastatic MSS/pMMR colorectal cancer with failure of fluoropyrimidines, oxaliplatin, irinotecan, VEGF antibodies and EGFR antibodies (in ras WT patients) received pembrolizumab 200 mg q21d and maraviroc 300 mg bid cont. for 8 cycles, followed by pembrolizumab monotherapy for a maximum of 24 additional cycles. Imaging was performed every nine weeks (RECIST and irRECIST criteria). Primary endpoint was the feasibility rate (rate of patients receiving the protocol treatment during the core treatment without special event: treatment-related Grade ≥ 3 immune-related abnormalities, treatment-related Grade ≥ 4 AEs or any toxicity-related premature withdrawal of treatment). Secondary endpoints included safety/toxicity, ORR, PFS and OS. Results: 20 patients were enrolled. The median number of applied cycles was 3.5 for pembrolizumab and 3.5 for maraviroc. Two patients completed the core treatment period with pembrolizumab and started maintenance treatment. The feasibility rate was 94.7% (90% CI 77.4 to 99.7%), with one patient experiencing a special event. Except this grade 4 event (hyperglycemia) no ≥ 3 treatment-related toxicities were observed. According to irRECIST criteria one patient showed a partial response and one a stable disease as best response, resulting in an irDCR of 10.5%. Median PFS according to irRECIST was 2 months (CI 95%, 2 to 3), median OS 9 months (CI 95%, 6 to 20). Conclusions: Therapy with pembrolizumab and maraviroc was feasible and showed a beneficial toxicity pattern. Clinical activity in MSS CRC patients was limited, however prolonged disease stabilizations were observed in single patients and overall survival was higher than expected in this heavily pretreated population. Clinical trial information: NCT03274804 .

Background Pancreatic cancer is mainly a disease of the elderly population, but clinical trials do not reflect this age distribution. Data on treatment strategies and outcome of older patients are limited. The aim of our study was to analyze safety and outcome in elderly patients with advanced pancreatic cancer treated with palliative chemotherapy at the outpatient clinic of the National Center for Tumor Diseases (NCT) at Heidelberg University Hospital. Materials and methods We retrospectively analyzed 53 patients ≥70 years using a prospectively maintained database. Requirements were (1) histologically proven diagnosis of ductal pancreatic adenocarcinoma, (2) age ≥70 at time of diagnosis of advanced disease, and (3) measurable advanced disease. Results The median age was 73 years. 81% of the patients received a gemcitabine-based first-line therapy. Median overall survival was 6.7 months. Survival differed significantly between patient groups with low (≤1) and high (≥2) Eastern Cooperative Oncology Group performance status (7.8 vs. 3.9 months, p = 0.002). 30.2% of the patients developed side effects resulting in dosage reductions. 39.6% of the patients received second-line treatment. Residual survival after disease progression was significantly longer for second-line treatment compared to best supportive care (151 vs. 39 days, p = 0.019). Conclusions Overall, our older patients did not have an inferior outcome compared to the reported trial populations that included younger patients. Thus, palliative chemotherapy should be considered independently from chronological age, but the performance status should be carefully noticed. Second-line therapy should be considered for patients in good performance status after first progression.

The paper deals with the synthesis and properties of thermoplastic silicone elastomers containing soft segments of dimethylsiloxane and hard urea segments. To determine structure-property relations, regarding to permeation properties, the chemical structure was varied. In this study, thermoplastic silicone elastomers, based on polydimethylsiloxane oligomers with amino groups and different diisocyanates, were synthesized. The polymers were characterized by nuclear magnetic resonance (NMR) and infrared (FTIR) spectroscopy. Thin membranes of thermoplastic silicone thermoplastic elastomers were prepared and investigated with respect to the permeation properties of organic solvents. Vials were filled with a mixture of an aromatic (toluene) and an aliphatic hydrocarbon (iso-octane) and were sealed with the polymer films. The weight loss of the vials was measured. The concentration of residual solvent mixture was detected by the relation of the peak area of the two solvents. This was investigated by the GC-MS-technique. A separation of the solvent mixture occurred. The synthesized thermoplastic silicone elastomers are highly permeable for organic solvents and have selective barrier properties. The barrier properties are influenced by chemical structure of the elastomers. Therefore, these siloxane polymers can be used as semipermeable membranes for separation of solvent mixtures i.e. in oil field applications.

Objectives Pancreatic cancer patients are at high risk for venous thromboembolic events (VTEs), and chemotherapy is a known additional risk factor. In this context, there is a controversial discussion whether prophylactic anticoagulation should be offered to all outpatients receiving chemotherapy. Methods In this retrospective study, we analyzed incidental and symptomatic VTEs in 150 pancreatic cancer patients receiving either gemcitabine-based chemotherapy or chemotherapy according to the FOLFIRINOX protocol. Results VTEs were identified in 25% of patients, but were not associated with an adverse survival. There was no significant difference in VTE incidence between patients treated with gemcitabine-based chemotherapy or the more intensive FOLFIRINOX protocol. A commonly used risk score to predict VTEs in cancer patients did not predict the occurrence of VTEs in our patients. The occurrence of VTEs was not associated with one of the recently described pancreatic cancer subtypes. Conclusion One quarter of pancreatic cancer patients treated with palliative chemotherapy develops symptomatic or incidental VTEs that cannot be predicted by type of chemotherapy, subtype of pancreatic cancer or a commonly used risk score. Further studies are necessary to identify patients at risk, and to better define which patients at risk should be treated with prophylactic anticoagulation.

Purpose Catheter-related bloodstream infections (CRBSIs) are a common problem in cancer patients with long-term catheters. The effectiveness of taurolidine, a new antimicrobial solution, in the management of CRBSIs is still unknown. A retrospective analysis of patients with proven CRBSIs treated with a taurolidine block in combination with systemic antibiotic treatment was performed to define its role in the management of CRBSIs. Methods Twenty-four episodes of CRBSIs in 23 cancer patients with permanent use of the long-term catheter were treated with a taurolidine block for 3 consecutive days in combination with systemic antibiotic treatment. Results Treatment was successful in 16 of 24 events (67%). Explantation was performed in 8 cases (33%): in 3 patients due to a second positive blood culture, and in 1 patient due to recurrent fever after the conservative treatment. In 4 patients, the conservative approach was prematurely stopped due to persisting fever. Conclusion Taurolidine-based treatment may be a promising, noninvasive therapeutical approach in the management of long-term catheter-related bloodstream infections in cancer patients.

Die Moglichkeiten in der Behandlung solider Tumoren haben sich im Verlauf der letzten Jahre um das Spektrum der zielgerichteten Tumortherapien („targeted therapies“) erweitert. Sowohl monoklonale Antikorper als auch „small molecules“ werden im klinischen Alltag inzwischen haufig bei der Behandlung verschiedener solider Tumorentitaten eingesetzt. Um die optimale Durchfuhrbarkeit der gewahlten Therapie zu gewahrleisten, ist es fur den behandelnden Arzt notwendig, die potentiellen Nebenwirkungen der eingesetzten Substanzen zu kennen, um ggf. die erforderlichen therapeutischen Schritte einleiten zu konnen.

Die Monotherapie mit Gemcitabin bildete lange Zeit die Standardbehandlung fur Patienten mit fortgeschrittenem Adenokarzinom des Pankreas. In den letzten Jahren wurden aufgrund der nach wie vor auserst schlechten Prognose der Erkrankung vermehrte Anstrengungen unternommen, im Rahmen groser klinischer Studien effektivere Therapiestrategien zu etablieren. Leider blieben die Fortschritte trotz Erweiterung des therapeutischen Spektrums um die Gruppe der „targeted therapies“ bislang begrenzt. Eine geringe Verbesserung der Gesamtuberlebenszeit wurde durch die Kombination mit Erlotinib erreicht; die Kombination aus Gemcitabin und Capecitabin konnte in einer Phase-III-Studie einen signifikanten Uberlebensvorteil fur die Kombination zeigen. Der Stellenwert einer Zweitlinientherapie ist bislang nicht abschliesend geklart. Patienten mit lokal begrenzter Erkrankung profitieren nach Resektion des Primarius von einer 6-monatigen adjuvanten Therapie mit Gemcitabin.

Hepatic alveolar echinococcosis (AE) resembles intrahepatic cholangiocarcinoma (ICC) on radiological imaging. The purpose of this study was to identify criteria to discriminate AE from ICC with CT and MR Imaging.One hundred and sixteen imaging studies of 94 patients (CT n = 65; MRI n = 51) diagnosed with AE (n = 55) or ICC (n = 39) were retrospectively reviewed by two blinded radiologists for lesion features including enhancement pattern and matrix composition. A consensus read was conducted in cases of disagreement. Uni- and multivariate logistic regression with bootstrapping were used for analysis.Using CT, no or septal enhancement and calcification yielded the highest values of sensitivity/specificity (90.9%/90.6% and 81.8%/96.9%) for AE. Using MRI, no or septal enhancement and cystic components achieved the highest sensitivity/specificity (90.9%/100.0% and 84.8%/66.7%) for AE. Multivariate logistic regression identified the following strong independent predictors for AE: for MRI, no or septal enhancement (odds ratio [OR] 322.4; p0.001); for CT, no or septal enhancement and calcification (OR 35.9 and 42.5; p0.001 and p0.01, respectively). No or septal enhancement and calcification demonstrated the highest interreader agreement (90%).Enhancement characteristics and matrix calcifications offer the strongest discriminating potential between AE and ICC with a high sensitivity, specificity, and interreader agreement.

Single-agent Gemcitabine has been the standard treatment for advanced pancreatic adenocarcinoma in the past years. Due to the aggressive and often chemotherapy-refractory character of this malignancy, systemic treatment options still remain limited. Many combination therapies have been evaluated in clinical trials to improve survival over Gemcitabine alone, until recently without satisfying results. Based on the positive results of a recent randomized trial, the combination of Gemcitabine and Capecitabine might become a new standard as first-line treatment for advanced pancreatic cancer. The clinical advantage of Erlotinib as a novel targeted agent in combination with Gemcitabine seems to be only marginal. Due to the small number of studies, there is still no standard of care in second-line therapy, but Oxaliplatin seems to be an active treatment option in Gemcitabine refractory disease. This article will review the development of cytotoxic antitumoral treatment for advanced pancreatic adenocarcinoma (locally advanced, irresectable and/or metastatic disease) including monotherapies and newer approaches with combination therapies.