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SummaryColorectal cancer (CRC) is one of the most frequent malignancies. While adjuvant fluoropyrimidine-based chemotherapy has been established as standard of care for patients with stage III disease, its value and role are still uncertain for stage II disease. This review discusses the usefulness of adjuvant therapy in both stages and highlights the use of liquid biopsy via circulating tumor DNA (ctDNA) for the assessment of minimal residual disease which will shape the therapy decision for adjuvant treatment in future.

Abstract: BTC is a rare and aggressive cancer disease, bearing an overall dismal prognosis with only finite therapy options. Only combination chemotherapy regimens achieve disease control, which is often only short-lived since the tumor tissue exhibits high resistance to chemotherapy. The emergence of immune checkpoint inhibitors in recent years has significantly improved the survival of cancer patients and thus, has been integrated into the therapeutic management of several solid tumors, including melanoma, colorectal carcinoma (CRC), hepatocellular carcinoma (HCC), triple- negative breast cancer (TNBC), and non-small-cell lung cancer (NSCLC). Investigation of the tumor biology of BTC and results of preliminary studies have shown that BTC may also be amenable to immunomodulation. In this review, we seek to give a comprehensive overview of the role, potential, and clinical significance of ICPI in the management of BTC.

With the growth of the number of old buildings in urban cities, there is an imperative demand for retrofitting those buildings to minimize their energy consumption and maximize their sustainability. This article seeks to provide a multi-criteria assessment of different retrofitting scenarios in the Malaysian context, focusing replacement of windows. Four different criteria assessed operation energy usage, global warming potential (GWP) emission, embodied energy, and the cost of each alternative. Life cycle analysis is used for each scenario using the Energy Plus software program to estimate the energy demand. The preliminary result showed that a louvered window is unsuitable for operational energy usage compared to other options. In embodied energy and GWP, double-glazing shows an optimal choice by 532 MJ kg/m

Summary Background Advanced therapy-refractory parotid gland carcinomas have a poor prognosis with limited therapy options. We used molecular profiling to offer molecular guided therapies to patients with advanced metastatic parotid gland malignancies. Methods In this retrospective analysis we describe the molecular profiling of ten patients diagnosed with therapy-refractory metastatic parotid gland malignancies. Results We identified seven genetic aberrations in five patients: two mutations in CDKN2A and one mutation in APC, ATM, TP53, SMARCB1 and FGFR1, respectively. No mutations were detected in five patients. The IHC demonstrated frequent expressions of EGFR and p‑mTOR, as well as PTEN in eight patients. For four fifths (n = 8) of the patients, a targeted therapy was suggested. Eventually, three patients received the targeted therapy recommendation and one patient achieved stable disease for 14 months. Conclusion A total of eight therapy recommendations were provided. Based on our observations, molecular-guided therapies may be a feasible treatment approach for this rare disease entity.

Background Therapeutic options are limited for advanced, metastatic biliary tract cancer. The pivotal NAPOLI-1 trial demonstrated the superior clinical benefit of nanoliposomal irinotecan (Nal-IRI) in gemcitabine-pretreated patients with metastatic pancreatic ductal adenocarcinoma; however, the antitumor activity of Nal-IRI in biliary tract cancer is unknown. This is the first report describing the efficacy of Nal-IRI in biliary tract cancer. Methods In this multicenter retrospective cohort analysis, we identified patients with metastatic biliary tract adenocarcinoma who were treated with Nal-IRI in combination with 5-fluorouracil and folinic acid following tumor progression under standard therapy at one of the study centers between May 2016 and January 2019. We assessed disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results There were 14 patients; the median age at the time of diagnosis and the median age at the initiation of Nal-IRI were 59.3 and 60.0 years, respectively. Nal-IRI in combination with 5-fluorouracil and folinic acid was administered as second-, third-, fourth-, and fifth-line treatment in 6 (43%), 5 (36%), 2 (14%), and 1 (7%) patient with metastatic disease, respectively. The objective DCR with Nal-IRI was 50% (7/14 patients). Six patients (43%) had partial response, and one patient (7%) had stable disease. Progressive disease was observed in seven patients. The median PFS and median OS following Nal-IRI initiation were 10.6 and 24.1 months, respectively. Conclusions This retrospective analysis provides the first evidence that Nal-IRI might exhibit a clinical meaningful antitumor activity in metastatic biliary tract cancer.

Introduction Advanced gynecologic cancers have a poor prognosis and constitute a major challenge for adequate treatment strategies. By analyzing and targeting molecular alterations, molecular guided treatments may be a viable option for the treatment of advanced gynecologic cancers. Patients and Methods In this single‐center, real‐world retrospective analysis of our platform for precision cancer medicine (PCM), we describe the molecular profiling of 72 patients diagnosed with different types of advanced gynecologic malignancies. Tumor samples of the patients were examined by next‐generation sequencing panel and immunohistochemistry (IHC). Results In total, we identified 209 genetic aberrations in 72 patients. The ten most frequent alterations were TP53 (n = 42, 20%), KRAS (n = 14, 6.6%), PIK3CA (n = 11, 5.2%), PIK3R1 (n = 9, 4.3%), ATR (n = 8, 3.8%), PTEN (n = 8, 3.8%), BRCA1 (n = 6, 2.8%), NF1 (n = 4, 1.9%), NOTCH1 (n = 4, 1.9%), and POLE (n = 4, 1.9%), which account for more than half of all molecular alterations (52.6%). In 21 (29.1%) patients only one mutation could be detected, and 44 (61.1%) patients had more than one mutation. No molecular alterations were detected in seven (9.7%) patients. IHC detected expression of phosphorylated mammalian target of rapamycin and epidermal growth factor receptor in 58 (80.6%) and 53 (73.6%) patients, respectively. In over two thirds (n = 49, 68.1%), a targeted therapy was suggested, based on the identified genetic aberrations. The most frequently recommended specific treatment was the combination of everolimus with exemestane (n = 18, 25 %). Conclusion Based on our observations, it seems that PCM might be a feasible approach for advanced gynecologic cancers with limited treatment options. Implications for Practice Nowadays molecular profiling of advanced gynecologic malignancies is feasible in the clinical routine. A molecular portrait should be done for every patient with an advanced therapy‐refractory gynecologic malignancy to offer molecular‐based treatment concepts., To determine the feasibility of precision cancer medicine (PCM) in gynecologic cancers, this retrospective study analyzed patients with advanced gynecologic cancers enrolled and profiled in a PCM platform, MONDTI, focusing on the technical feasibility to map the molecular profiles of advanced, pretreated, and mainly relapsed gynecologic cancers and to subsequently target the detected molecular alterations

Immunotherapy with check-point inhibitors serves as a promising treatment strategy in patients with upper gastrointestinal (GI) tumors. Human epidermal growth factor receptor 2 (HER2) is the only identified therapeutic target in upper GI tumors, whose potential interaction with programmed death-ligand 1 (PD-L1) is unknown. The aim of this study was the investigation of PD-L1 and HER2 in upper GI tumors. We retrospectively identified patients with HER2 positive gastroesophageal cancers and matched them with a HER2 negative group. We investigated the tumor specimens for HER2 status and PD-L1 expression, with the following assessments being performed: i) staining of tumor cells in terms of tumor proportion score (TPS), ii) staining for tumor-associated immune cells (TAIs), iii) interface pattern and iv) combined positive score (CPS). Both HER2 positive and negative group consisted of 59 patients. Expression of PD-L1 in TAIs and interface pattern were associated with a favorable outcome (p = 0.02, HR = 0.8; p = 0.04, HR = 0.39; respectively) in patients with localized disease, whereas TPS was associated with an unfavorable outcome in patients with advanced tumor (p = 0.02, HR = 1.4). These effects were HER2 independent. PD-L1 expression in its different assessment is equally observed in HER2 positive and negative patients. Future studies will show whether dual inhibition of HER2 and PD-L1 improves survival of this selected patient population. Electronic supplementary material The online version of this article (10.1007/s12253-020-00814-2) contains supplementary material, which is available to authorized users.

Introduction Advanced therapy-refractory biliary tract cancer (BTC) has poor prognosis and constitutes a major challenge for adequate treatment strategies. By mapping the molecular profiles of advanced BTC patients, precision cancer medicine may provide targeted therapies for these patients. Objective In this analysis, we aimed to show the potential of PCM in metastatic BTC. Methods In this single-center, real-world retrospective analysis of our PCM platform, we describe the molecular profiling of 30 patients diagnosed with different types of metastatic BTC. Tumor samples of the patients were examined using a 161-gene next-generation sequencing panel, immunohistochemistry (IHC), and fluorescence in situ hybridization for chromosomal translocations. Results In total, we identified 35 molecular aberrations in 30 patients. The predominant mutations were KRAS (n = 8), TP53 (n = 7), IDH2 (n = 4), and IDH1 (n = 3) that accounted for the majority of all molecular alterations (62.86%). BRAF mutations were observed in two patients. Less frequent alterations were noted in ARID1A, CTNNB1, ESR1, FBXW7, FGFR2, MET, NOTCH2, PIK3CA, PTCH1, SMAD4, and SRC1, each in one case. FGFR fusion gene was detected in one patient. No mutations were detected in eight patients. IHC revealed EGFR and p-mTOR expression in 28 patients. Applying these results to our patients, targeted therapy was recommended for 60% of the patients (n = 18). One patient achieved stable disease. Conclusions PCM is a feasible treatment approach and may provide molecular-guided therapy recommendations for metastatic BTC.

BACKGROUND/AIM A standard treatment recommendation for advanced stage gastroesophageal cancer is still missing. PATIENTS AND METHODS We retrospectively analyzed clinical data of patients with inoperable locally advanced or metastatic gastroesophageal cancer treated between 2001 and 2017 at the Vienna General Hospital, Austria. RESULTS Administration of systemic therapy was positively associated with overall survival (OS) (469 days vs. 185 days; p

Brain tumours that are refractory to treatment have a poor prognosis and constitute a major challenge in offering effective treatment strategies. By targeting molecular alterations, precision cancer medicine may be a viable option for the treatment of brain tumours. In this retrospective analysis of our PCM platform, we describe the molecular profiling of primary brain tumours from 50 patients. Tumour samples of the patients were examined by a 161-gene next-generation sequencing panel, immunohistochemistry, and fluorescence in situ hybridization (FISH). We identified 103 molecular aberrations in 36 (72%) of the 50 patients. The predominant mutations were TP53 (14.6%), IDH1 (9.7%) and PIK3CA (6.8%). No mutations were detected in 14 (28%) of the 50 patients. IHC demonstrated frequent overexpression of EGFR and mTOR, in 38 (76%) and 35 (70%) patients, respectively. Overexpression of PDGFRa and PDGFRb were less common and detected in 16 and four patients, respectively. For 35 patients a targeted therapy was recommended. In our database, the majority of patients displayed mutations, against which targeted therapy could be offered. Based on our observations, PCM may be a feasible novel treatment approach in neuro-oncology.

In this report, we present the medical history of a 30-year-old male patient with HER2- and PD-L1-negative metastasized adenocarcinoma of the gastric cardia, who received three cycles of pembrolizumab (200 mg every 2 weeks) after the failure of the first-line (1L) treatment with docetaxel, cisplatin, 5‑fluorouracil (DCF). A restaging computed tomography (CT) scan for the chest and abdomen revealed an apparent progressive disease; therefore, the treatment was terminated. Five months after the termination of the treatment, a new CT scan demonstrated a spontaneous treatment response although no treatment was given during this time period, indicating pseudo-progression of the tumor in the first restaging after three cycles of pembrolizumab. This finding is apparently due to the long-term sustainable immunological effects of pembrolizumab. The current report will present this rare case in more detail and summarize the closed and ongoing clinical trials of immunotherapy drugs in gastroesophageal cancer.

Background Neoadjuvant chemotherapy (neoCTx) followed by hepatic resection is the treatment of choice for patients with colorectal cancer liver metastasis (CLM). Treatment response is generally assessed using radiologic imaging after several cycles of chemotherapy. However, earlier assessment of response would be desirable since nonresponders could be switched early to an alternative chemotherapy regimen. Recent evidence suggests that circulating free methylated tumor DNA is a highly sensitive biomarker and may more accurately reflect tumor burden and treatment response than conventional markers for CRC. Patients and methods Thirty-four patients with CLM who received neoCTx prior to intended hepatic resection were included in this prospective nonrandomized study. Peripheral blood plasma was collected at baseline and before each cycle of neoCTx and was then analyzed for aberrant methylation of 48 CRC-associated genes. Methylation marker levels were correlated with baseline tumor volume and treatment response and compared with the standard tumor markers CEA and CA 19-9. Results The methylation markers SEPT9, DCC, BOLL, and SFRP2 were present in all patients at baseline and displayed a stronger correlation with tumor volume than CEA and CA 19-9. Serial measurement of these methylation markers allowed for discrimination between operated and nonoperated patients already after 1 cycle of neoCTx with high sensitivity and specificity. The early dynamic changes of SEPT9 and DCC also seemed to correlate with pathohistological response. Conclusion Our data suggest that serial measurements of CRC-associated methylation markers could be a particularly valuable tool for early response assessment in patients receiving neoCTx for CLM.

In this paper, the crack propagation behavior in flat and stiffened plates with central-cracked is studied based on the theory of linear elastic fracture mechanics and 3D finite-element method. The magnitude and distribution of the stress intensity factor in a 3D stiffened plates are affected by the out-of-plane bending and loading modes. Initially, for validating this method, the behavior of crack propagation in a central-cracked flat plate (unstiffened), followed by the propagation behavior and the crack arrest effects on stiffened plates by stiffeners, as well as the out-of-plane bending effect on the geometry correction function distribution are studied; However, the results are compared with the results of the referenced article. In order to analyze the effect of stiffeners in preventing crack expansion, stiffeners with variable thickness and height were used. It should also be noted that the crack propagation behavior in the stiffened plate is analyzed in two methods. In the first analysis, after the crack tip reaches to the stiffeners, they have not fracture and the crack only expands in the stiffened plate (in the stiffened plate type 1 and 2). In the second analysis, with the crack growth in the stiffened plate and the crack tip reaching to the stiffeners, Also they fractured and cracks in the stiffened plate and stiffeners are propagated (only in the stiffened plate type 2). In both analyses, the magnitudes ​​of the geometry correction function in the middle-plane, the crack arrest effect by the stiffeners (Δβs), and the out-of-plane bending effect (Δβ) were obtained. Then, the changes in these magnitudes ​​were investigated. It was observed that the stiffeners thickness had a negligible effect on the distribution of the geometry correction function and, in general, the stiffeners had a significant role in preventing the crack growth compared to the flat plate, and the more the crack tip is closer to the adjoining stiffeners; the stiffeners effect in the crack arrest will increases. Furthermore, with attention to the geometry correction function that is studied for different crack sizes, it was determined that the geometry correction function and stress intensity coefficient with increasing the length of the crack in the plate, increase.

Introduction: Colon cancer (CC) is one of the most frequent malignant diseases. Adjuvant chemotherapy is of utmost importance in the management of localized disease. With the emergence of precision medicine, treatment approaches are becoming increasingly personalized and complex. This review contributes to a broader understanding of the role and relevance of personalized adjuvant treatment strategies in colon carcinoma, and summarizes the current status in this disease entity. Methods: We searched the websites ClinicalTrials.gov, PubMed, and ASCO (American Society of Medical Oncology) Meeting Library for clinical trials and retrospective analyses in the field of adjuvant treatment of CC with special attention to personalized approaches. Results: Various factors, including gender, age, sidedness, stage, dMMR/MSI-H, mutations, molecular profile, CMS, immunoscore, minimal residual disease, type of adjuvant therapy, therapy duration, and the patient’s wish play an important role in the adjuvant setting of CC and should be considered in treatment decision making. Conclusion: Future molecular profiling ideally assessed and monitored by liquid biopsy might personalize decision making even more in the adjuvant setting of CC patients. Further research and clinical trials are needed to clarify relevant questions and to highlight important clinical aspects.

Recently, IoT has been massively applied in different areas of human life. Meanwhile, in many of the IoT applications, e.g., the remote patient health-care monitoring systems, the reliability of communications, and the consumed energy in IoT devices, which are mostly battery-operated, are very challenging. Since IoT devices are typically operated in lossy environments, providing a reliable transmission for the packets imposes a noticeable amount of energy consumption. In addition, the runtime movement of the IoT devices in mobile networks further intensifies these issues. Therefore, the applied policies in the IPv6 RPL as the standard routing mechanism in IoT networks, play an important role in providing a reliable and energy-efficient packet delivery. Nevertheless, RPL is significantly suffering from low reliability in mobile applications due to existence of outdated parents in the limited neighbor table of the moving objects. Hence, in this study, we propose REFER; a mobility-aware version of RPL, which provides reliable and energy-efficient communication between IoT devices with utilizing a new neighbor placement policy based on a leasing time of the parents along with considering various node/link metrics for its path selections in mobile situations. Based on our evaluations, which have been conducted in different network configurations and under different mobility models, while REFER has enhanced the amount of energy consumption in the nodes, it is able to improve the reliability of the communications by at least 2.2x compared with its counterpart.

Background The clinical behaviour and outcome of young patients with gastroesophageal tumours (GET) is surmised to differ from older patients, yet data on the comparison of these two patient subgroups is scarce. This study focuses on the investigation of the clinical characteristics and survival outcome of younger-age people with GET, when compared to older patients. Methods Patients diagnosed with GET at the Medical University of Vienna between 2004 and 2016 were included in this study. Clinical parameters and the overall survival (OS) were compared between young (≤ 45 years) and elderly (≥ 65 years) patients. Results Among 796 patients, who were eligible for this analysis, fifty-eight patients (7%) were ≤ 45 years at the initial onset of the disease. These 58 young patients were then matched to elderly patients based on the gender, tumour stage, histology and tumour location. The number of metastatic lesions was significantly higher among young patients (p p = 0.028). Furthermore, young patients with extensive metastatic disease (2 or more metastatic site) had a significantly poorer OS than elderly patients (median 450 versus 646 days, p = 0.033). Conclusion These results indicate that young patients might be diagnosed very late, which might lead to the development of a more aggressive disease compared to older patients, but a relatively long OS when diagnosed and treated in a non-metastatic setting. Thus, screening methods for younger patients might be considerable to enhance the outcome of young patients with GET.

Background Monitoring of molecular response (MR) using quantitative polymerase chain reaction (PCR) for BCR-ABL1 is a pivotal tool for guiding tyrosine kinase inhibitor therapy and the long-term follow-up of patients with chronic myeloid leukemia (CML). Results of MR monitoring are standardized according to the International Scale (IS), and specific time-dependent molecular milestones for definition of optimal response and treatment failure have been included in treatment recommendations. The common practice to use peripheral blood (PB) instead of bone marrow (BM) aspirate to monitor the MR monitoring in CML has been questioned. Some studies described differences between BCR-ABL1 levels in paired PB and BM specimens. Methods We examined 631 paired PB and BM samples from 283 CML patients in a retrospective single-center study using an IS normalized quantitative reverse transcription (qRT)-PCR assay for quantification of BCR-ABL1 IS. Results A good overall concordance of BCR-ABL1 IS results was found, a systematic tendency towards higher BCR-ABL1 IS levels in PB was observed in samples of CML patients in a major MR. This difference was most pronounced in patients treated with imatinib for at least 1 year. Importantly, the difference resulted in a significantly lower rate of deep MR when BCR-ABL1 IS was assessed in the PB compared to BM aspirates. Conclusions In summary, our data suggest that the classification of deep MR in patients with CML is more stringent in PB than in BM. Our study supports the current practice to primarily use PB for long-term molecular follow-up monitoring in CML.

The advancement of immune-therapeutics in cancer treatment has proven to be promising in various malignant diseases. However, in castration resistant prostate cancer (mCRPC) major Phase III trials have been unexpectedly disappointing. To contribute to a broader understanding of the role and use of immune-therapeutics in mCRPC, we conducted a systematic review. We searched the websites ClinicalTrials.gov, PubMed and ASCO Meeting Library for clinical trials employing immune checkpoint inhibitors in mCRPC. This article not only describes the rationale of individual trials, but it also summarizes the current status of the field and sheds light on strategies for future success.

The water entry problem of spherical projectile is simulated numerically and experimentally in this study. An explicit dynamic analysis method is employed to model the fluid-structure interaction using a Coupled Eulerian-Lagrangian (CEL) formulation that is available in finite element code Abaqus. The comparison of the numerical simulation results including displacement and velocity variations of spherical projectile in water depth as a function of time, with the theoretical results, indicates a good match between these results and the precision and applicability of the numerical algorithm used. The results reveal that pinch-off time is a very weak function of projectile mass and impact velocity on free water surface; while the pinch-off depth significantly increases along with increased this parameters. Additionally, the projectile mass has a subtle effect on viscous dissipation energy, while increasing the impact velocity on free water surface leads to decrese in dissipation energy.

Attempts for identifying targeted therapy strategies in metastatic gastric and gastroesopheal junction cancer (upper-GI) revealed that the inhibition of human epidermal growth factor receptor-2 (HER2) by monoclonal antibody trastuzumab improves survival of these patients. Hence, adding trastuzumab to doublet chemotherapy has become the standard treatment in this setting. Although the patient survival is extended among clinical trials, the knowledge on the real-time setting is limited. With this retrospective, single center analysis of the patient data of the Medical University of Vienna, we sought to investigate the clinical characteristics and outcome of patients, who received trastuzumab-based chemotherapy for metastatic upper-GI tumor. All patients, who received trastzumab at least once were included to the analysis. Clinical and pathological data were recorded. This search revealed 33 patients. The demographic data was comparable with that of the previous clinical trials. Progression free survival (PFS) was 11 months, whereas overall survival (OS) was 21 months. OS was significantly associated with initially favorable response to treatment. Thirteen patients (39%) received trastuzumab as maintenance treatment with a median cycle number of 6. Toxicity profile was acceptable with only one patient detected to have cardiotoxicity. Taken together, trastuzumab based treatment induced a considerable PFS and OS in metastatic or advanced upper-GI tumors with acceptable toxicity profile. The maintenance therapy with trastuzumab was safe and effective in patients who had initially a favorable response to chemotherapy. The optimal duration of the maintenance therapy should be tested in future clinical trials.

Measurement of cell-free DNA (cfDNA) in plasma - the so called liquid biopsy - is a novel method for early detection of cancer. Necrotic cancer cells release various DNA fragments that can be detected in plasma or serum. The aim of our study was to investigate the concentration of circulating ALU115, LINE79 and LINE297 fragments in plasma from venous and arterial blood of colorectal cancer (CRC) patients before, during and 5 days after surgical intervention.Thirty patients (16 female, 14 male, median age 56 years), undergoing surgery for colorectal and appendix cancer, and 17 healthy volunteers were included in this study. Plasma samples were collected from patients and healthy individuals. Qualitative polymerase chain reaction (PCR) and quantitative real-time PCR analyses were conducted using specific primers for ALU115, LINE79 and LINE297.The concentration of ALU115 was significantly increased in plasma of CRC patients compared to the control group (p = 0.002). Interestingly, the concentration of LINE297 was significantly higher in healthy individuals than patients (p = 0.031). We did not find any difference regarding LINE79 between the two groups (p = 0.893). The total cfDNA concentration was slightly increased in plasma after the surgery (p 0.056), however, the difference was not significant. Interestingly, no correlation was detected between the peritoneal carcinosis index (PCI) and conventional tumor markers.According to our results, the concentration of ALU115 in cfDNA could be a potential biomarker for diagnosis of CRC. LINE79 or the conventional tumor markers CEA or CA19-9 do not seem useful for the detection of malignant tumors. Whether the amount of LINE297 in cfDNA represents a reliable biomarker for early diagnosis has yet to be confirmed.