PET/CT radiomics for prediction of hyperprogression in metastatic melanoma patients treated with immune checkpoint inhibitors.

Purpose: This study evaluated pretreatment 2[18F]fluoro-2-deoxy-D-glucose (FDG)-PET/CT-based radiomic signatures for prediction of hyperprogression in metastatic melanoma patients treated with immune checkpoint inhibition (ICI). Material and method: Fifty-six consecutive metastatic melanoma patients treated with ICI and available imaging were included in the study and 330 metastatic lesions were individually, fully segmented on pre-treatment CT and FDG-PET imaging. Lesion hyperprogression (HPL) was defined as lesion progression according to RECIST 1.1 and doubling of tumor growth rate. Patient hyperprogression (PD-HPD) was defined as progressive disease (PD) according to RECIST 1.1 and presence of at least one HPL. Patient survival was evaluated with Kaplan-Meier curves. Mortality risk of PD-HPD status was assessed by estimation of hazard ratio (HR). Furthermore, we assessed with Fisher test and Mann-Whitney U test if demographic or treatment parameters were different between PD-HPD and the remaining patients. Pre-treatment PET/CT-based radiomic signatures were used to build models predicting HPL at three months after start of treatment. The models were internally validated with nested cross-validation. The performance metric was the area under receiver operating characteristic curve (AUC). Results: PD-HPD patients constituted 57.1% of all PD patients. PD-HPD was negatively related to patient overall survival with HR=8.52 (95%CI 3.47-20.94). Sixty-nine lesions (20.9%) were identified as progressing at 3 months. Twenty-nine of these lesions were classified as hyperprogressive, thereby showing a HPL rate of 8.8%. CT-based, PET-based, and PET/CT-based models predicting HPL at three months after the start of treatment achieved testing AUC of 0.703 +/- 0.054, 0.516 +/- 0.061, and 0.704 +/- 0.070, respectively. The best performing models relied mostly on CT-based histogram features. Conclusions: FDG-PET/CT-based radiomic signatures yield potential for pretreatment prediction of lesion hyperprogression, which may contribute to reducing the risk of delayed treatment adaptation in metastatic melanoma patients treated with ICI.

Long-term outcomes of operable stage III NSCLC in the pre-immunotherapy era: results from a pooled analysis of the SAKK 16/96, SAKK 16/00, SAKK 16/01, and SAKK 16/08 trials.

BACKGROUND: Chemoradiotherapy with durvalumab consolidation has yielded excellent results in stage III non-small-cell lung cancer (NSCLC). Therefore, it is essential to identify patients who might benefit from a surgical approach. MATERIAL AND METHODS: Data from 437 patients with operable stage III NSCLC enrolled in four consecutive Swiss Group for Clinical Cancer Research (SAKK) trials (16/96, 16/00, 16/01, 16/08) were pooled and outcomes were analyzed in 431 eligible patients. All patients were treated with three cycles of induction chemotherapy (cisplatin/docetaxel), followed in some patients by neoadjuvant radiotherapy (44 Gy, 22 fractions) (16/00, 16/01, 16/08) and cetuximab (16/08). RESULTS: With a median follow-up time of 9.3 years (range 8.5-10.3 years), 5- and 10-year overall survival (OS) rates were 37% and 25%, respectively. Overall, 342 patients (79%) underwent tumor resection, with a complete resection (R0) rate of 80%. Patients (n = 272, 63%) with R0 had significantly longer OS compared to patients who had surgery but incomplete resection (64.8 versus 19.2 months, P < 0.001). OS for patients who achieved pathological complete remission (pCR) (n = 66, 15%) was significantly better compared to resected patients without pCR (86.5 versus 37.0 months, P = 0.003). For patients with pCR, the 5- and 10-year event-free survival and OS rates were 45.7% [95% confidence interval (CI) 32.8% to 57.7%] and 28.1% (95% CI 15.2% to 42.6%), and 58.2% (95% CI 45.2% to 69.2%) and 45.0% (95% CI 31.5% to 57.6%), respectively. CONCLUSION: We report favorable long-term outcomes in patients with operable stage III NSCLC treated with neoadjuvant chemotherapy with cisplatin and docetaxel ± neoadjuvant sequential radiotherapy from four prospective SAKK trials. Almost two-third of the patients underwent complete resection after neoadjuvant therapy. We confirm R0 resection and pCR as important predictors of outcome.

Synthesis of oligosaccharides with prebiotic potential by crude enzyme preparation from Bifidobacterium.

Oligosaccharides especially prebiotics take high attention in the development of foods because of their physiological properties in human health. They are generally synthetized enzymatically via transferases or hydrolases from mold or bacteria. The fact is that such oligosaccharides synthetized by probiotic bacteria, should be utilized by these microorganisms. This study focused on the production of oligosaccharides with prebiotic potential by crude enzyme preparation from bifidobacteria. Both monosubstrates and bisubstrates systems together with TLC and HPLC techniques, were applied. The crude enzyme preparation has different hydrolase activities such as α-glucosidase (2U/mL), ß-glucosidase (0.3 U/mL), α-galactosidase (1.2 U/mL), ß-galactosidase (0.4 U/mL), ß-fructosidase (11.5 U/mL). Additionally, it also has transglycosylation activities on lactose, lactulose, maltose and sucrose substrates. Two or three types of oligosaccharides were detected. The glycosyltransferase activity peaked at 45 °C, pH 6.6 and 30 g/100 mL substrate concentration. Significant high amount of oligosaccharides were formed in the case of lactose:sucrose combination than others. Both glucooligosaccharides and galactooligosaccharides are detected in the reaction mixtures of bisubstrate. When the lactose is present, the galactosyltransferation is predominated. One-one new types of oligosaccharides were detected in the reaction mixture of bioconversion. Among newly synthetized oligosaccharides, the fraction namely OS4 was utilized by probiotic bifidobacteria only. In conclusion, new types of galacto- and glucooligosaccharides with high prebiotic potentials were synthetized by the crude enzyme from probiotic Bifidobacterium strains.

Perceptions of mental health and help-seeking behavior in an urban community in Vietnam: an explorative study.

This explorative study assesses perceptions of mental health and help-seeking behavior among adults in Vietnam. Methods included questionnaires (200) and focus group discussions (eight). Respondents were often unable to name specific mental illnesses. Frequently mentioned symptoms of mental illness were talking nonsense, talking/laughing alone and wandering. Pressure/stress and studying/thinking too much were often identified causes. Most respondents showed a preference for medical treatment options, often in combination with family care. The results show that perceptions of mental health and help-seeking behaviour are influenced by a lack of knowledge and a mix of traditional and modern views.

Loss of the ClpXP Protease Leads to Decreased Resistance to Cell-Envelope Targeting Antimicrobials in Bacillus anthracis Sterne.

The ClpX ATPase is critical for resistance to cell envelope targeting antibiotics in Bacillus anthracis, however, it is unclear whether this is due to its function as an independent chaperone or as part of the ClpXP protease. In this study, we demonstrate that antibiotic resistance is due to formation of the ClpXP protease through construction of a ClpX complementation plasmid that is unable to interact with ClpP. Additionally, we genetically disrupted both clpP genes, clpP1 and clpP2, found in B. anthracis Sterne and find that the loss of either increases susceptibility to cell envelope targeting antimicrobials, although neither has as strong of a phenotype as loss of clpX and neither clpP gene is essential for virulence in a G. mellonella model of infection. Lastly, we looked at changes to cell envelope morphology that could contribute to increased antibiotic sensitivity. We find no difference in cell charge or cell lysis, although we do see increased hydrophobicity in the ΔclpX strain, decreased cellular density and slightly thinner cells walls. We also see significant cell division defects in ΔclpX, although only when cells are grown in the mammalian cell culture medium, RPMI. We conclude that the intrinsic resistance of B. anthracis to cell wall active antimicrobials is dependent on formation of the ClpXP protease and that this could be due, at least in part, to the role of ClpX in regulating cell envelope morphology.

FDG PET versus CT radiomics to predict outcome in malignant pleural mesothelioma patients.

BACKGROUND: Careful selection of malignant pleural mesothelioma (MPM) patients for curative treatment is of highest importance, as the multimodal treatment regimen is challenging for patients and harbors a high risk of substantial toxicity. Radiomics-a quantitative method for image analysis-has shown its prognostic ability in different tumor entities and could therefore play an important role in optimizing patient selection for radical cancer treatment. So far, radiomics as a prognostic tool in MPM was not investigated. MATERIALS AND METHODS: This study is based on 72 MPM patients treated with surgery in a curative intent at our institution between 2009 and 2017. Pre-treatment Fluorine-18 fluorodeoxyglucose (FDG) PET and CT scans were used for radiomics outcome modeling. After extraction of 1404 CT and 1410 FDG PET features from each image, a preselection by principal component analysis was performed to include only robust, non-redundant features for the cox regression to predict the progression-free survival (PFS) and the overall survival (OS). Results were validated on a separate cohort. Additionally, SUVmax and SUVmean, and volume were tested for their prognostic ability for PFS and OS. RESULTS: For the PFS a concordance index (c-index) of 0.67 (95% CI 0.52-0.82) and 0.66 (95% CI 0.57-0.78) for the training cohort (n = 36) and internal validation cohort (n = 36), respectively, were obtained for the PET radiomics model. The PFS advantage of the low-risk group translated also into an OS advantage. On CT images, no radiomics model could be trained. SUV max and SUV mean were also not prognostic in terms of PFS and OS. CONCLUSION: We were able to build a successful FDG PET radiomics model for the prediction of PFS in MPM. Radiomics could serve as a tool to aid clinical decision support systems for treatment of MPM in future.

Benchmarking Monte-Carlo dose calculation for MLC CyberKnife treatments.

BACKGROUND: Vendor-independent Monte Carlo (MC) dose calculation (IDC) for patient-specific quality assurance of multi-leaf collimator (MLC) based CyberKnife treatments is used to benchmark and validate the commercial MC dose calculation engine for MLC based treatments built into the CyberKnife treatment planning system (Precision MC). METHODS: The benchmark included dose profiles in water in 15 mm depth and depth dose curves of rectangular MLC shaped fields ranging from 7.6 mm × 7.7 mm to 115.0 mm × 100.1 mm, which were compared between IDC, Precision MC and measurements in terms of dose difference and distance to agreement. Dose distributions of three phantom cases and seven clinical lung cases were calculated using both IDC and Precision MC. The lung PTVs ranged from 14 cm3 to 93 cm3. Quantitative comparison of these dose distributions was performed using dose-volume parameters and 3D gamma analysis with 2% global dose difference and 1 mm distance criteria and a global 10% dose threshold. Time to calculate dose distributions was recorded and efficiency was assessed. RESULTS: Absolute dose profiles in 15 mm depth in water showed agreement between Precision MC and IDC within 3.1% or 1 mm. Depth dose curves agreed within 2.3% / 1 mm. For the phantom and clinical lung cases, mean PTV doses differed from - 1.0 to + 2.3% between IDC and Precision MC and gamma passing rates were > =98.1% for all multiple beam treatment plans. For the lung cases, lung V20 agreed within ±1.5%. Calculation times ranged from 2.2 min (for 39 cm3 PTV at 1.0 × 1.0 × 2.5 mm3 native CT resolution) to 8.1 min (93 cm3 at 1.1 × 1.1 × 1.0 mm3), at 2% uncertainty for Precision MC for the 7 examined lung cases and 4-6 h for IDC, which, however, is not optimized for efficiency but used as a gold standard for accuracy. CONCLUSIONS: Both accuracy and efficiency of Precision MC in the context of MLC based planning for the CyberKnife M6 system were benchmarked against MC based IDC framework. Precision MC is used in clinical practice at our institute.

Independent Monte-Carlo dose calculation for MLC based CyberKnife radiotherapy.

This work aims to develop, implement and validate a Monte Carlo (MC)-based independent dose calculation (IDC) framework to perform patient-specific quality assurance (QA) for multi-leaf collimator (MLC)-based CyberKnife® (Accuray Inc., Sunnyvale, CA) treatment plans. The IDC framework uses an XML-format treatment plan as exported from the treatment planning system (TPS) and DICOM format patient CT data, an MC beam model using phase spaces, CyberKnife MLC beam modifier transport using the EGS++ class library, a beam sampling and coordinate transformation engine and dose scoring using DOSXYZnrc. The framework is validated against dose profiles and depth dose curves of single beams with varying field sizes in a water tank in units of cGy/Monitor Unit and against a 2D dose distribution of a full prostate treatment plan measured with Gafchromic EBT3 (Ashland Advanced Materials, Bridgewater, NJ) film in a homogeneous water-equivalent slab phantom. The film measurement is compared to IDC results by gamma analysis using 2% (global)/2 mm criteria. Further, the dose distribution of the clinical treatment plan in the patient CT is compared to TPS calculation by gamma analysis using the same criteria. Dose profiles from IDC calculation in a homogeneous water phantom agree within 2.3% of the global max dose or 1 mm distance to agreement to measurements for all except the smallest field size. Comparing the film measurement to calculated dose, 99.9% of all voxels pass gamma analysis, comparing dose calculated by the IDC framework to TPS calculated dose for the clinical prostate plan shows 99.0% passing rate. IDC calculated dose is found to be up to 5.6% lower than dose calculated by the TPS in this case near metal fiducial markers. An MC-based modular IDC framework was successfully developed, implemented and validated against measurements and is now available to perform patient-specific QA by IDC.

Phorbasin A: a novel diterpene from a southern australian marine sponge, Phorbas species.

A southern Australian Phorbas species has yielded a novel diterpene, phorbasin A (1), possessing an unprecedented carbon skeleton. The structure for phorbasin A was determined by detailed spectroscopic analysis.

Seabather's eruption.

Seabather's eruption is an unusual rash that develops in individuals who have been swimming in the ocean. We report the case of a 25-year-old woman who had the rash in a typical bathing suit distribution. Several species of cnidarian larvae have been implicated in causing the disease. Symptomatic treatment is the mainstay of therapy for this self-limited rash. Preventive measures allow patients to avoid the disease altogether.

Onnamide F: a new nematocide from a southern Australian marine sponge, Trachycladus laevispirulifer.

A southern Australian marine sponge, Trachycladus laevispirulifer, has yielded a potent new nematocide with antifungal activity which has been identified as onnamide F (1). The structure for 1 was assigned by detailed spectroscopic analysis and chemical conversion to the methyl ester 2. Onnamide F contains a common structural motif previously described in a number of natural products exhibiting interesting pharmacological activities, including the insect chemical defense agent pederin (3), and the sponge metabolites the onnamides, mycalamides, and theopederins.