Genetic and immunological biomarkers predict metastatic disease recurrence in stage III colon cancer.

BACKGROUND: Even though the post-operative outcome varies greatly among patients with nodal positive colon cancer (UICC stage III), personalized prediction of systemic disease recurrence is currently insufficient. We investigated in a retrospective setting whether genetic and immunological biomarkers can be applied for stratification of distant metastasis occurrence risk. METHODS: Eighty four patients with complete resection (R0) of stage III colon cancer from two clinical centres were analysed for genetic biomarkers: microsatellite instability, oncogenic mutations in KRAS exon2 and BRAF exon15, expression of osteopontin and the metastasis-associated genes SASH1 and MACC1. Tumor-infiltrating CD3 and CD8 positive T-cells were quantified by immunocytochemistry. Results were correlated with outcome and response to 5-FU based adjuvant chemotherapy, using Cox's proportional hazard models and integrative two-step cluster analysis. RESULTS: Distant metastasis risk was significantly correlated with oncogenic KRAS mutations (p = 0.015), expression of SASH1 (p = 0.016), and the density of CD8-positive T-cells (p = 0.007) in Kaplan-Meier analysis. Upon multivariate Cox-regression analysis, KRAS mutation (p = 0.008) and density of CD8-positive TILs (p = 0.009) were retained as prognostic parameters for metachronous distant metastasis. Integrative two-step cluster analysis was used to combine all genetic markers, allowing stratification of patient subgroups. Post-operative distant metastasis risk ranged from 31% (low-risk) to 41% (intermediate), and 57% (high-risk) (p = 0.032). Increased expression of osteopontin (p = 0.019) and low density of CD8-positive T-cells (p = 0.043) were significantly associated with unfavourable response to 5-FU. CONCLUSIONS: Integrative biomarker analysis allows stratification of stage III colon cancer patients for the risk of metastatic disease recurrence and may indicate response to 5-FU. Thus, biomarker analysis might facilitate the use of adjuvant therapy for high risk patients.

Should every patient with pancreatic cancer receive perioperative/neoadjuvant therapy?

Pancreatic ductal adenocarcinoma is a highly aggressive disease, and medical as well as surgical therapeutic options are limited. This article reviews stage dependent treatment options, with a special focus on the current controversy of perioperative treatment regimens in initially borderline resectable or locally advanced patients. Neoadjuvant treatment can potentially increase the rate of complete tumor resection and may be more effective than adjuvant systemic therapy. Further, in the case of disease progression during or after neoadjuvant therapy, patients can be spared extensive surgery. Today, common therapeutic regimens include gemcitabine/nab-paclitaxel and FOLFIRINOX, as well as chemoradiation. However, because of the paucity of evidence from randomized trials, most guidelines do not recommend neoadjuvant therapy in resectable tumors, and for borderline or locally advanced tumors only within clinical trials. Importantly, every patient should be discussed in multidisciplinary tumor boards.

Non-contaminating camouflage: multifunctional skin microornamentation in the West African Gaboon viper (Bitis rhinoceros).

The West African Gaboon viper (Bitis rhinoceros) has an extraordinary coloration of pale brown and velvety black markings. The velvety black appearance is caused by a unique hierarchical surface structures which was not found on the pale brown scales. In the present study we examined the wettability of the vipers scales by measuring contact angles of water droplets. Velvet black scale surfaces had high static contact angles beyond 160° and low roll-off angles below 20° indicating an outstanding superhydrophobicity. Our calculations showed that the Cassie-Baxter model describes well wettability effects for these surfaces. Self-cleaning capabilities were determined by contaminating the scales with particles and fogging them until droplets formed. Black scales were clean after fogging, while pale scales stayed contaminated. Black scales feature multifunctional structures providing not only water-repellent but also self-cleaning properties. The pattern of nanoridges can be used as a model for surface-active technical surfaces.

Vortex formation with a snapping shrimp claw.

Snapping shrimp use one oversized claw to generate a cavitating high speed water jet for hunting, defence and communication. This work is an experimental investigation about the jet generation. Snapping shrimp (Alpheus-bellulus) were investigated by using an enlarged transparent model reproducing the closure of the snapper claw. Flow inside the model was studied using both High-Speed Particle Image Velocimetry (HS-PIV) and flow visualization. During claw closure a channel-like cavity was formed between the plunger and the socket featuring a nozzle-type contour at the orifice. Closing the mechanism led to the formation of a leading vortex ring with a dimensionless formation number of approximate ΔT*≈4. This indicates that the claw might work at maximum efficiency, i.e. maximum vortex strength was achieved by a minimum of fluid volume ejected. The subsequent vortex cavitation with the formation of an axial reentrant jet is a reasonable explanation for the large penetration depth of the water jet. That snapping shrimp can reach with their claw-induced flow. Within such a cavitation process, an axial reentrant jet is generated in the hollow cylindrical core of the cavitated vortex that pushes the front further downstream and whose length can exceed the initial jet penetration depth by several times.

3D flow in the venom channel of a spitting cobra: do the ridges in the fangs act as fluid guide vanes?

The spitting cobra Naja pallida can eject its venom towards an offender from a distance of up to two meters. The aim of this study was to understand the mechanisms responsible for the relatively large distance covered by the venom jet although the venom channel is only of micro-scale. Therefore, we analysed factors that influence secondary flow and pressure drop in the venom channel, which include the physical-chemical properties of venom liquid and the morphology of the venom channel. The cobra venom showed shear-reducing properties and the venom channel had paired ridges that span from the last third of the channel to its distal end, terminating laterally and in close proximity to the discharge orifice. To analyze the functional significance of these ridges we generated a numerical and an experimental model of the venom channel. Computational fluid dynamics (CFD) and Particle-Image Velocimetry (PIV) revealed that the paired interior ridges shape the flow structure upstream of the sharp 90° bend at the distal end. The occurrence of secondary flow structures resembling Dean-type vortical structures in the venom channel can be observed, which induce additional pressure loss. Comparing a venom channel featuring ridges with an identical channel featuring no ridges, one can observe a reduction of pressure loss of about 30%. Therefore it is concluded that the function of the ridges is similar to guide vanes used by engineers to reduce pressure loss in curved flow channels.

Integrative marker analysis allows risk assessment for metastasis in stage II colon cancer.

OBJECTIVES: Individualized risk assessment in patients with UICC stage II colon cancer based on a panel of molecular genetic alterations. BACKGROUND: Risk assessment in patients with colon cancer and localized disease (UICC stage II) is not sufficiently reliable. Development of metachronous metastasis is assumed to be governed largely by individual tumor genetics. METHODS: Fresh frozen tissue from 232 patients (T3-4, N0, M0) with complete tumor resection and a median follow-up of 97 months was analyzed for microsatellite stability, KRAS exon 2, and BRAF exon 15 mutations. Gene expression of the WNT-pathway surrogate marker osteopontin and the metastasis-associated genes SASH1 and MACC1 was determined for 179 patients. The results were correlated with metachronous distant metastasis risk (n = 22 patients). RESULTS: Mutations of KRAS were detected in 30% patients, mutations of BRAF in 15% patients, and microsatellite instability in 26% patients. Risk of recurrence was associated with KRAS mutation (P = 0.033), microsatellite stable tumors (P = 0.015), decreased expression of SASH1 (P = 0.049), and increased expression of MACC1 (P < 0.001). MACC1 was the only independent parameter for recurrence prediction (hazard ratio: 6.2; 95% confidence interval: 2.4-16; P < 0.001). Integrative 2-step cluster analysis allocated patients into 4 groups, according to their tumor genetics. KRAS mutation, BRAF wild type, microsatellite stability, and high MACC1 expression defined the group with the highest risk of recurrence (16%, 7 of 43), whereas BRAF wild type, microsatellite instability, and low MACC1 expression defined the group with the lowest risk (4%, 1 of 26). CONCLUSIONS: MACC1 expression predicts development of metastases, outperforming microsatellite stability status, as well as KRAS/BRAF mutation status.

Dry under water: comparative morphology and functional aspects of air-retaining insect surfaces.

Superhydrophobic surfaces prevent certain body parts of semiaquatic and aquatic insects from getting wet while submerged in water. The air layer on these surfaces can serve the insects as a physical gill. Using scanning electron microscopy, we investigated the morphology of air-retaining surfaces in five insect species with different levels of adaptation to aquatic habitats. We found surfaces with either large and sparse hairs (setae), small and dense hairs (microtrichia), or hierarchically structured surfaces with both types of hairs. The structural parameters and air-film persistence of these surfaces were compared. Air-film persistence varied between 2 days in the beetle Galerucella nymphaea possessing only sparse setae and more than 120 days in the bugs Notonecta glauca and Ilyocoris cimicoides possessing dense microtrichia (up to 6.6 × 10(6) microtrichia per millimeter square). From our results, we conclude that the density of the surface structures is the most important factor that affects the persistence of air films. Combinations of setae and microtrichia are not decisive for the overall persistence of the air film but might provide a thick air store for a short time and a thin but mechanically more stable air film for a long time. Thus, we assume that a dense cover of microtrichia acts as a "backup system" preventing wetting of the body surface in case the air-water interface is pressed toward the surface. Our findings might be beneficial for the development of biomimetic surfaces for long-term air retention and drag reduction under water. In addition, the biological functions of the different air retention capabilities are discussed.