Nanoliposomal Irinotecan With Fluorouracil and Leucovorin or Gemcitabine Plus Cisplatin in Advanced Cholangiocarcinoma: A Phase II Study of the AIO Hepatobiliary-YMO Cancer Groups (NIFE-AIO-YMO HEP-0315).

PURPOSE: First-line therapy options in advanced cholangiocarcinoma (CCA) are based on the ABC-02 trial regimen (gemcitabine/cisplatin [G/C]). The NIFE trial examined nanoliposomal irinotecan/fluorouracil/leucovorin (nal-IRI/FU/LV) as alternative first-line therapy in advanced CCA. METHODS: NIFE is a prospective, open-label, randomized, multicenter phase II study that aimed at detecting efficacy comparable with the standard treatment. Patients with advanced CCA were randomly assigned (1:1) to receive nal-IRI/FU/LV (arm A) or G/C (arm B). Stratification parameters were intrahepatic versus extrahepatic CCA, sex, and Eastern Cooperative Oncology Group (ECOG; 0/1). Arm A was designed as a Simon's optimal two-stage design and arm B served as a randomized control group. The primary goal was to exclude an inferior progression-free survival (PFS) at 4 months of only 40%, while assuming a rate of 60% on G/C population. RESULTS: Between 2018 and 2020, overall 91 patients were randomly assigned to receive nal-IRI/FU/LV (n = 49) or G/C (n = 42). The NIFE trial formally met its primary end point with a 4-month PFS rate of 51% in patients receiving nal-IRI/FU/LV. The median PFS was 6 months (2.4-9.6) in arm A and 6.9 months (2.5-7.9) in arm B. Median overall survival (OS) was 15.9 months (10.6-20.3) in arm A and 13.6 months (6.5-17.7) in arm B. The exploratory comparison of study arms suggested a numerical but statistically not significant advantage for nal-IRI/FU/LV (hazard ratio for PFS, 0.85 [95% CI, 0.53 to 1.38] and for OS, 0.94 [95% CI, 0.58 to 1.50]). Analysis for stratification parameters revealed no differences for sex and ECOG, but for tumor localization. The objective response rate was 24.5% with nal-IRI/FU/LV and 11.9% with G/C. No unexpected toxicities occurred. AEs related to nal-IRI/FU/LV were mainly GI and to G/C hematologic. CONCLUSION: Treatment of advanced CCA with nal-IRI/FU/LV demonstrated efficacy in first-line therapy without new safety findings and merits further validation.

Prediction of resistance to bevacizumab plus FOLFOX in metastatic colorectal cancer-Results of the prospective multicenter PERMAD trial.

BACKGROUND: Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab. PATIENTS AND METHODS: 15 German and Austrian centers prospectively recruited 50 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM). RESULTS: Using random forests, we developed a predictive machine learning model that discriminated between the situations of "no progress within 100 days before radiological progress" and "progress within 100 days before radiological progress". We could further identify a combination of ten out of the 102 CAF markers, which fulfilled this task with 78.2% accuracy, 71.8% sensitivity, and 82.5% specificity. CONCLUSIONS: We identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress.

Interlayer Bonding Capability of Additively Manufactured Polymer Structures under High Strain Rate Tensile and Shear Loading.

Additive manufacturing of polymers via material extrusion and its future applications are gaining interest. Supporting the evolution from prototype to serial applications, additional testing conditions are needed. The additively manufactured and anisotropic polymers often show a weak point in the interlayer contact area in the manufacturing direction. Different process parameters, such as layer height, play a key role for generating the interlayer contact area. Since the manufacturing productivity depends on the layer height as well, a special focus is placed on this process parameter. A small layer height has the objective of achieving better material performance, whereas a larger layer height is characterized by better economy. Therefore, the capability- and economy-oriented variation was investigated for strain rates between 2.5 and 250 s-1 under tensile and shear load conditions. The test series with dynamic loadings were designed monitoring future applications. The interlayer tensile tests were performed with a special specimen geometry, which enables a correction of the force measurement. By using a small specimen geometry with a force measurement directly on the specimen, the influence of travelling stress waves, which occur due to the impact at high strain rates, is reduced. The interlayer tensile tests indicate a strain rate dependency of additively manufactured polymers. The capability-oriented variation achieves a higher ultimate tensile and shear strength compared to the economy-oriented variation. The external and internal quality assessment indicates an increasing primary surface profile and void volume content for increasing the layer height.

Optimization and Quality Evaluation of the Interlayer Bonding Performance of Additively Manufactured Polymer Structures.

The application of additive manufacturing changes from prototypes to series production. In order to fulfill all requirements of series production, the process and the material characteristics must be known. The machine operator of additive manufacturing systems is both a component and a material producer. Nevertheless, there is no standardized procedure for the manufacturing or testing of such materials. This includes the high degree of anisotropy of additively manufactured polymers via material extrusion. The interlayer bonding performance between two layers in the manufacturing direction z is the obvious weakness that needs to be improved. By optimizing this interlayer contact zone, the overall performance of the additively manufactured polymer is increased. This was achieved by process modification with an infrared preheating system (IPS) to keep the temperature of the interlayer contact zone above the glass transition temperature during the manufacturing process. Combining destructive and non-destructive testing methods, the process modification IPS was determined and evaluated by a systematic approach for characterizing the interlayer bonding performance. Thereby, tensile tests under quasi-static and cyclic loading were carried out on short carbon fiber-reinforced polyamide (SCFRP). In addition, micro-computed tomography and microscopic investigations were used to determine the process quality. The IPS increases the ultimate interlayer tensile strength by approx. 15% and shows a tendency to significantly improved the fatigue properties. Simultaneously, the analysis of the micro-computed tomography data shows a homogenization of the void distribution by using the IPS.