Search

Abstract Background 90% of glioblastomas (GBM) relapse within two years of diagnosis. In contrast to the initial setting, there is no standard management for recurrent disease and options include hypofractionated stereotactic re-irradiation (re-mHSRT). The aims of this study were to investigate re-mHSRT practice in Swiss neuro-oncology centres. Methods A survey of 18 questions regarding re-irradiation for GBM was created and distributed electronically (SurveyMonkey, USA) to 11 radiation oncologists in Switzerland specialising in brain tumours. We evaluated the clinical outcomes of a multicentre series of patients treated with an established re-mHSRT schedule to benchmark these against the literature and investigated the radiological patterns of relapse after re-mHSRT. Results 8 of 11 (73%) radiation oncologists responded to the survey and re-irradiation practice was heterogeneous. The 10 × 3.5 Gy schedule (RTOG 1205, BRIOChe trials) was used by 5/8 respondents and 47/50 patients with recurrent GBM treated with re-mHSRT with this schedule in daily practice were included in the analysis. The median time to re-mHSRT following completion of adjuvant RT was 23.3 (7-224) months. The median PTV at re-mHSRT was 22.0 cm3 (0.9–190). Combined CTV + PTV margins ranged from 0 to 10 mm and median prescription isodose was 80% (67–100). 14/47 (30%) patients received temozolomide and four (8.5%) continued bevacizumab concomitantly. On multivariable analysis, concomitant systemic therapy predicted for progression-free survival (PFS), HR 2.87 (95% CI 1-03-7.96), p = 0.042. Median PFS following re-mHSRT was 6.6 (0.2–92.5) months and 26/47 patients (55%) received subsequent systemic therapy. The median overall survival (OS) following recurrence was 11.8 months (1.5–92.5), similar to the 10.8 months in the literature with the same schedule. The six-month OS rate was 37/47 (79%), which compares well with the 73% reported in a meta-analysis of 50 publications employing various schedules. In a subgroup analysis of 36/47 (79%) patients with MR follow-up after re-mHSRT, 8/36 (22%) had no radiological evidence of tumour progression at a median follow-up of 9.4 months. 21/28 (75%) radiological relapses were in-field, two were marginal and five were out of field. Conclusions Re-mHSRT with 10 × 3.5 Gy can achieve local control in selected patients with recurrent GBM.

Abstract Advanced triple negative breast cancer (TNBC) is an aggressive, but initially chemo-sensitive disease. The prognosis is poor and more than three quarters of patients experience progression 12 months after the initiation of conventional first-line chemotherapy. Approximately two thirds of TNBC express epidermal growth factor receptor 1 (EGFR). We have developed an anti-EGFR targeted nanocontainer drug by inserting anti-EGFR antibody fragments into the membrane of pegylated liposomes (anti-EGFR-ILs-dox). The payload consists of doxorubicin, a standard drug for TNBC. In a first-in-human phase I trial in 26 patients with various advanced solid malignancies, anti-EGFR-ILs-dox has shown little toxicity and encouraging efficacy. In this single-arm phase II trial, we assessed the efficacy of anti-EGFR-ILs-dox as first-line therapy in patients with advanced, EGFR + TNBC. The primary endpoint was progression-free survival at 12 months (PFS12m). Secondary endpoints included overall response rate (ORR), duration of response (DOR), time to progression (TTP), overall survival (OS) and adverse events (AEs). 48 patients received anti-EGFR-ILs-dox 50 mg/m2 iv, on day one of a 28 days-cycle until progression. The Kaplan–Meier estimate for PFS12m was 13% (one-sided 90% CI 7%, 95% CI [5%, 25%]), median PFS was 3.5 months (95% CI 1.9, 5.4). The trial has not reached its primary endpoint. There were no new toxicity signals. Based on these results, anti-EGFR-ILs-dox should not be further developed for TNBC. It remains an open question whether anti-EGFR-ILs-dox would offer more opportunities in other EGFR-expressing malignancies, where targeting this receptor has already shown anticancer effects. Trial registration: This trial was registered at clinicaltrials.gov: NCT02833766. Registered 14/07/2016.

Introduction: On the basis of the landmark trial KEYNOTE-189 (KN-189), pembrolizumab plus chemotherapy has become the standard-of-care first-line treatment for patients with advanced nonsquamous NSCLC without oncogenic driver alterations.KN-189 included a selected patient population and lacks external validity. In clinical practice, many patients do not meet the inclusion criteria of KN-189, although they are treated accordingly. It is unknown whether these patients benefit equally as the trial population. Methods: We retrospectively analyzed all patients with advanced nonsquamous NSCLC without targetable oncogenic alterations who received the KN-189 treatment regimen between April 2018 and May 2021 at the University Hospital Basel, Switzerland. Patients were grouped into those who retrospectively met the inclusion criteria of KN-189 (group A) and those who did not (group B). Outcome parameters included progression-free survival (PFS), overall survival (OS), and objective response rate. Multivariate subgroup analyses were performed. Results: We identified 75 patients, including 29 patients in group A and 46 patients in group B. Median PFS was 9.2 and 4.6 months in group A and B, respectively (p = 0.12). Median OS was 16.5 and 6.5 months in group A and B, respectively (p = 0.11). Objective response rate was 59% in group A and 33% in group B (p = 0.03). Eastern Cooperative Oncology Group performance status greater than or equal to 2 and active infections were significantly associated with shorter PFS and OS. Conclusions: We report real-world data for patients treated according to the KN-189 regimen with inferior outcomes in patients who did not meet the KN-189 inclusion criteria. Better treatment options for this vulnerable patient population are needed.

Introduction: This paper aims to investigate consumer knowledge, attitude, risk perceptions and environmental assessment of food safety and their direct effects on food poisoning preventive behaviour. Consumers play a crucial role in ensuring the safety of the food they consume, particularly when it comes to cooked food that is sold to them. Therefore, understanding consumers' knowledge, attitude, risk perceptions, and food safety environmental assessment is crucial in influencing their behaviour to prevent food poisoning. Materials and methods: We conducted a cross-sectional survey among 430 consumers aged 18 years and above around Ampang areas in Selangor using a validated Knowledge, Attitude, Practice, Perception and Environment (KAP2E) questionnaire. The questionnaires were self-administered among consumers and information on sociodemographic, food poisoning knowledge, attitude, risk perceptions and food safety environmental assessment were gathered. We used PLS-SEM to establish the relationship between the constructs under investigation. Results: The evaluation of the structural model indicates that knowledge, attitude, risk perceptions, and food safety environmental assessment account for 22.1% of preventive food poisoning preventive behaviour. Attitude was the strongest predictor (β= 0.381, p< 0.05) among other constructs. This study confirmed that food poisoning knowledge have positive impact on consumer's attitude (R² = 0.053).Conclusion: The present study highlights the importance of incorporating consumer risk perceptions and food safety environmental assessment into food safety education. By enhancing consumers' knowledge and attitude towards food poisoning prevention, we can ensure the effectiveness of these educational efforts. [ABSTRACT FROM AUTHOR]

Over the last 2 decades, permafrost degradation has been observed to be a major driver of enhanced rock slope instability and associated hazards in high mountains. While the thermal regime of permafrost degradation in high mountains has been addressed in several modelling approaches, no mechanical models that thoroughly explain rock slope destabilisation controls in degrading permafrost have been developed. Meanwhile, recent laboratory studies have shown that degrading permafrost affects both, rock and ice mechanical strength parameters as well as the strength of rock–ice interfaces. This study presents a first general approach for a temperature-dependent numerical stability model that simulates the mechanical response of a warming and thawing permafrost rock slope. The proposed procedure is exemplified using a rockslide at the permafrost-affected Zugspitze summit crest. Laboratory tests on frozen and unfrozen rock joint and intact rock properties provide material parameters for discontinuum models developed with the Universal Distinct Element Code (UDEC). Geophysical and geotechnical field surveys reveal information on permafrost distribution and the fracture network. This model can demonstrate how warming decreases rock slope stability to a critical level and why thawing initiates failure. A generalised sensitivity analysis of the model with a simplified geometry and warming trajectory below 0 ∘C shows that progressive warming close to the melting point initiates instability above a critical slope angle of 50–62∘, depending on the orientation of the fracture network. The increase in displacements intensifies for warming steps closer to 0 ∘C. The simplified and generalised model can be applied to permafrost rock slopes (i) which warm above −4 ∘C, (ii) with ice-filled joints, (iii) with fractured limestone or probably most of the rock types relevant for permafrost rock slope failure, and (iv) with a wide range of slope angles (30–70∘) and orientations of the fracture network (consisting of three joint sets). Here, we present a benchmark model capable of assessing the future destabilisation of degrading permafrost rock slopes.

The article discusses the results of the validation and psychometric parameters of the Polish-language version of the Fear of Being Single Scale (FBSS), originally developed by Spielmann and colleagues (2013 (See CR26)). The study participants included 175 Polish respondents aged 18 to 67 (M = 27.19, SD = 8.63). The findings confirmed the one-dimensional structure of the Polish FBSS, convergent, discriminant and concurrent validity, reliability of the Polish FBSS, and its high test-retest reliability over a lag of six months. The obtained results make it possible to assess the Polish FBSS as a reliable and valid measure of fear of being single in a Polish non-clinical sample of adults., Author(s): Katarzyna Adamczyk [sup.1] , Radoslaw Trepanowski [sup.1] , Agata Celejewska [sup.1] , Joanna Kosinska [sup.1] , Anita Mamot [sup.1] , Martyna Palczewska [sup.1] , Klaudia Rodziejczak [sup.1] Author Affiliations: [...]

Introduction: Driven by the current unsatisfactory outcomes for patients with locally advanced pancreatic cancer (LAPC), a biologically intensified clinical protocol was developed to explore the feasibility and efficacy of FOLFORINOX chemotherapy followed by deep hyperthermia concomitant with chemoradiation and subsequent FOLFORINOX chemotherapy in patients with LAPC. Methods: Nine patients with LAPC were treated according to the HEATPAC Phase II trial protocol which consists of 4 cycles of FOLFORINOX chemotherapy followed by gemcitabine-based chemoradiation to 56 Gy combined with weekly deep hyperthermia and then a further 8 cycles of FOLFORINOX chemotherapy. Results: One grade three related toxicity was reported and two tumours became resectable. The median overall survival was 24 months and 1 year overall survival was 100%. Conclusions: Intensification of chemoradiation with deep hyperthermia was feasible in nine consecutive patients with LAPC.

A temperature- and stress-dependent failure criterion for ice-filled rock (limestone) joints was proposed in 2018 as an essential tool to assess and model the stability of degrading permafrost rock slopes. To test the applicability to other rock types, we conducted laboratory tests with mica schist and gneiss, which provide the maximum expected deviation of lithological effects on the shear strength due to strong negative surface charges affecting the rock–ice interface. Retesting 120 samples at temperatures from −10 to −0.5 ∘C and normal stress of 100 to 400 kPa, we show that even for controversial rocks the failure criterion stays unaltered, suggesting that the failure criterion is transferable to mostly all rock types.

Abstract Background The impact of HER2-targeted therapy alone followed by the addition of chemotherapy at disease progression (PD) versus upfront combination was investigated by the SAKK 22/99 trial. The aim of this exploratory analysis of the SAKK 22/99 trial was to characterize the specific subset of patients deriving long-term benefit from trastuzumab monotherapy alone and to identify potential predictive factors of long-term response. Methods This is an unplanned post-hoc analysis of patients randomized to Arm A (trastuzumab monotherapy). Patients were divided in two groups: patients with durable clinical benefit from trastuzumab monotherapy and short-term responders without durable clinical benefit from trastuzumab monotherapy Univariate and multivariate analyses of clinical characteristics correlating with response duration was performed. Results Eighty six patients were randomized in arm A, 24 patients (28%) were long-term responders and 62 (72%) were short-term responders with a 5y-overall survival (OS) of 54% (95% CI 31–72) and of 18% (95%CI 10–30), respectively. Absence of ER expression, absence of PgR expression and presence of visceral disease emerged as possible negative predictive factors for durable clinical benefit. Conclusion Durable clinical benefit can be achieved with trastuzumab monotherapy in a subgroup of HER2-positive patients with advanced disease and it is predictive for longer OS. Further investigations of predictive biomarkers are necessary to better characterize this subgroup of patients and develop further de-escalating strategies. Trial registration NCT00004935; first posted 27.01.2003, retrospectively registered.

Gliomas are intrinsic brain tumours, which are classified by the World Health Organization (WHO) into different grades of malignancy, with glioblastoma being the most frequent and most malignant subtype (WHO grade IV). Mutations in the isocitrate dehydrogenase (IDH) 1 or 2 genes are frequent in lower (WHO II/III) grade tumours but typically absent in classical glioblastoma. IDH mutations are associated with a better prognosis compared with IDH wild-type tumours of the same WHO grade. Following detection of a tumour mass by imaging, maximum safe surgery as feasible is commonly performed to reduce mass effect and to obtain tissue allowing histopathological diagnosis and molecular assessment. Radiotherapy has been the mainstay in the treatment of diffuse gliomas for several decades. It provides improved local control, but is not curative. Furthermore, several randomised trials have shown that the addition of alkylating chemotherapy, either temozolomide or nitrosourea-based regimens, to radiotherapy results in prolonged survival. Tumour-treating fields (TTFields) have emerged as an additional treatment option in combination with maintenance temozolomide treatment for patients with newly diagnosed glioblastoma. Treatment at recurrence is less standardised and depends on the patient’s performance status, symptom burden and prior treatments. Bevacizumab prolongs progression-free survival in newly diagnosed and recurrent glioblastoma, but does not impact overall survival. However, in Switzerland and some other countries, it is still considered a valuable treatment option to reduce clinical symptom burden. Given the generally poor outcome for these patients, various novel treatment approaches are currently being explored within clinical trials including immunotherapeutic strategies such as immune checkpoint inhibition and the brain-penetrant proteasome inhibitor marizomib.

Instability and failure of high mountain rock slopes have significantly increased since the 1990s coincident with climatic warming and are expected to rise further. Most of the observed failures in permafrost-affected rock walls are likely triggered by the mechanical destabilisation of warming bedrock permafrost including ice-filled joints. The failure of ice-filled rock joints has only been observed in a small number of experiments, often using concrete as a rock analogue. Here, we present a systematic study of the brittle shear failure of ice and rock–ice interfaces, simulating the accelerating phase of rock slope failure. For this, we performed 141 shearing experiments with rock–ice–rock sandwich' samples at constant strain rates (10−3 s−1) provoking ice fracturing, under normal stress conditions ranging from 100 to 800 kPa, representing 4–30 m of rock overburden, and at temperatures from −10 to −0.5 °C, typical for recent observed rock slope failures in alpine permafrost. To create close to natural but reproducible conditions, limestone sample surfaces were ground to international rock mechanical standard roughness. Acoustic emission (AE) was successfully applied to describe the fracturing behaviour, anticipating rock–ice failure as all failures are predated by an AE hit increase with peaks immediately prior to failure. We demonstrate that both the warming and unloading (i.e. reduced overburden) of ice-filled rock joints lead to a significant drop in shear resistance. With a temperature increase from −10 to −0.5 °C, the shear stress at failure reduces by 64 %–78 % for normal stresses of 100–400 kPa. At a given temperature, the shear resistance of rock–ice interfaces decreases with decreasing normal stress. This can lead to a self-enforced rock slope failure propagation: as soon as a first slab has detached, further slabs become unstable through progressive thermal propagation and possibly even faster by unloading. Here, we introduce a new Mohr–Coulomb failure criterion for ice-filled rock joints that is valid for joint surfaces, which we assume similar for all rock types, and which applies to temperatures from −8 to −0.5 °C and normal stresses from 100 to 400 kPa. It contains temperature-dependent friction and cohesion, which decrease by 12 % °C−1 and 10 % °C−1 respectively due to warming and it applies to temperature and stress conditions of more than 90 % of the recently documented accelerating failure phases in permafrost rock walls.

The present study sought to determine the effectiveness of newly developed low calorie chocolate using modified fat through enzymatic interesterification process as cocoa butter substitute of male Sprague Dawley rats (n = 35) compared to cocoa butter as control. Body weight gains did not differ significantly (p>0.05) in all the test groups fed with chocolates which were using different types of fats. Triacylglycerol and cholesterol test showed no significant difference (p>0.05) for all treatment samples. in this study, a pancreatic lipase hydrolysis was performed to determine the fatty acid composition of the sn-2 position of the structure lipids.

Abstract Background Pancreatic cancer has a dismal prognosis with 5-year overall survival rate of around 5%. Although surgery is still the best option in operable cases, majority of the patients who present in locally advanced stages are deemed inoperable. Novel approaches are therefore needed for the management of around 80% of these inoperable locally advanced pancreatic cancers (LAPC). Hyperthermia (39–43 °C) is a potent radiosensitizer and further enhances the action of gemcitabine, also a known radiosensitizer. Thus through triple sensitization, a combination of hyperthermia, radiotherapy and gemcitabine could be expected to improve the therapeutic outcomes in LAPC. Methods This phase II randomized trial, HEATPAC in unresectable LAPC, explores the feasibility and efficacy of concurrent thermochemoradiotherapy (HTCTRT) over chemoradiotherapy (CTRT) alone with pre- and post-intervention FOLFIRINOX at standard dosage and schedule. Following 4 cycles of neoadjuvant FOLFIRINOX, patients with no metastasis and absence of gross peritoneal carcinomatosis would be randomized to either (a) control arm: concurrent CTRT with gemcitabine (400 mg/m2, weekly ×6) or (b) study arm: locoregional hyperthermia (weekly ×6 during radiotherapy) with concurrent CTRT (same as in control arm). All patients would receive simultaneous-integrated boost intensity-modulated radiation therapy to doses of 56Gy and 50.4Gy to the gross and clinical target volumes respectively delivered in 28 fractions over 5.5 weeks. Deep locoregional hyperthermia would be administered weekly and monitored with real-time intraduodenal multisensor thermometry probe. A temperature of 40–43 °C for 60 min would be aimed for each hyperthermia session. On completion of CTRT/HTCTRT, patients of both groups would receive an additional 8 cycles of FOLFIRINOX. Discussion The expected 1-year baseline overall survival with CTRT alone is considered as 40%. With HTCTRT, a survival advantage of +20% is expected. Considering α = 0.05 and β = 0.80 for sample size computation, a total of 86 patients would be equally randomized into the two treatment groups. This phase II study if found to be safe and effective, would form the basis of a future phase III randomized study. Trial registration The trial has been registered with the ClinicalTrials.gov ( NCT02439593 ). The study has been approved by the Ethical Commissions of Basel and Zurich and is open for patient recruitment.

Abstract Background/purpose Recently, the mutational background of diffuse large B cell lymphoma (DLBCL) has been revealed, identifying specific genetic events that drive lymphomagenesis. However, the prognostic value of these mutations remains to be determined. Prognostic biomarkers in DLBCL are urgently needed, since the current clinical parameter-based factors (e.g., International Prognostic Index (IPI)) are insufficient, particularly in identifying patients with poor prognosis who might benefit from alternative treatments. Methods We investigated the prognostic value of somatic mutations in DLBCL in a clinical trial (NCT00544219) patient cohort homogenously treated with six cycles of rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP), followed by two cycles of R (R-CHOP-14). The primary endpoint was event-free survival (EFS) at 2 years. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Targeted high-throughput sequencing (HTS) of tumor genomic DNA was performed on all exons or hotspots of 68 genes frequently mutated in B cell lymphomas. Mutational data was correlated with the endpoints to identify prognostic associations. Results Targeted HTS detected somatic mutations in 71/76 (93%) of investigated cases. The most frequently mutated genes were KMT2D, SOCS1, GNA13, and B2M. Survival analysis revealed that CREBBP- and EP300-mutated cases had significantly worse OS, PFS, and EFS. In addition, ATM mutations predicted worse outcomes for all three clinical endpoints in germinal center B cell-like DLBCL. In contrast, SOCS1 mutations were associated with better PFS. On multivariable analysis taken into account IPI and failure to achieve complete remission, CREBBP and EP300 mutations remained significant to predict worse OS, PFS, and EFS. Conclusion Targeted mutation analysis of a uniformly treated prospective clinical trial DLBCL cohort identifies tumor-based genetic prognostic markers that could be useful in the clinical management of such patients. Trial registration ClinicalTrials.gov NCT00544219