The use of segmented regression in analysing interrupted time series studies : an example in pre-hospital ambulance care

Peer reviewedPublisher PD

EUS-FNA Biopsies to Guide Precision Medicine in Pancreatic Cancer: Results of a Pilot Study to Identify KRAS Wild-Type Tumours for Targeted Therapy

Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death and lacks effective treatment options. Diagnostic endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsies represent an appealing source of material for molecular analysis to inform targeted therapy, as they are often the only available tissue for patients presenting with PDAC irrespective of disease stage. However, EUS-FNA biopsies are typically not used to screen for precision medicine studies due to concerns about low tissue yield and quality. Epidermal growth factor receptor (EGFR) inhibition has shown promise in clinical trials of unselected patients with advanced pancreatic cancer, but has not been prospectively tested in KRAS wild-type patients. Here, we examine the clinical utility of EUS-FNA biopsies for molecular screening of KRAS wild-type PDAC patients for targeted anti-EGFR therapy to assess the feasibility of this approach. Patients and Methods: Fresh frozen EUS-FNA or surgical biopsies from PDAC patient tumours were used to screen for KRAS mutations. Eligible patients with recurrent, locally advanced, or metastatic KRAS wild-type status who had received at least one prior line of chemotherapy were enrolled in a pilot study (ACTRN12617000540314) and treated with panitumumab at 6mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was 4-month progression-free survival (PFS). Results: 275 patient biopsies were screened for KRAS mutations, which were detected in 88.3% of patient samples. 8 eligible KRAS wild-type patients were enrolled onto the interventional study between November 2017 and December 2020 and treated with panitumumab. 4-month PFS was 14.3% with no objective tumour responses observed. The only grade 3/4 treatment related toxicity observed was hypomagnesaemia. Conclusions: This study demonstrates proof-of-principle feasibility to molecularly screen patients with pancreatic cancer for targeted therapies, and confirms diagnostic EUS-FNA biopsies as a reliable source of tumour material for molecular analysis. Single agent panitumumab was safe and tolerable but led to no objective tumour responses in this population

Effects of technetium on marine micro-organisms

Eleven bacterial species have been isolated from the upper layer of intertidal sediments collected along the Belgian coast (Coxyde). Three of them (no. 1, 4 and 11) have been chosen for their halophilous character. One species has been identified as Flavobacterium halmephilum, the other two are being investigated. Effects of technetium (99Tc) have been studied on a mixed bacterial population isolated from sediments, as well as on the three halophilic species.At the concentrations utilized in this work (up to 100 microg ml-1), 99Tc has no evident effects on bacterial growth. Uptake of technetium (99Tc and/or 95mTc) has been investigated in the mixed bacterial population, in the three halophilic bacteria (including Flavobacterium halmephilum) and in the benthic ciliate Uronema marinum. It has been found that technetium is taken up by all these micro-organisms. However, the transfer factor (TF) in bacteria may vary considerably (from 0.5 to 200), but the cause of this variability is not known and deserves further study.The ciliate Uronema marinum, which feeds on living marine bacteria, was found to take up 95mTc added to the culture medium. However, the TF in this ciliate is rather low (from 1.4 to 5.5). Because it feeds on bacteria, Uronema marinum is supposed to take up technetium from water (direct contamination) as well as from contaminated bacteria (indirect contamination). Experiments with 95mTc-labeled bacterial cells might be useful, as they could indicate which form of contamination (direct or indirect) is prevailing

Gastrointestinal perforation in metastatic colorectal cancer patients with peritoneal metastases receiving bevacizumab

AIM To investigate the safety and efficacy of adding bevacizumab to first-line chemotherapy in metastatic colorectal cancer patients with peritoneal disease. METHODS We compared rates of gastrointestinal perforation in patients with metastatic colorectal cancer and peritoneal disease receiving first-line chemotherapy with and without bevacizumab in three distinct cohorts: (1) the AGITG MAX trial (Phase III randomised clinical trial comparing capecitabine vs capecitabine and bevacizumab vs capecitabine, bevacizumab and mitomycinC); (2) the prospective Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry (any first-line regimen ± bevacizumab); and (3) two cancer centres in New South Wales, Australia [Macarthur Cancer Therapy Centre and Liverpool Cancer Therapy Centre (NSWCC) from January 2005 to Decenber 2012, (any first-line regimen ± bevacizumab). For the AGITG MAX trial capecitabine was compared to the other two arms (capecitabine/bevacizumab and capecitabine/bevacizumab/mitomycinC). In the AGITG MAX trial and the TRACC registry rates of gastrointestinal perforation were also collected in patients who did not have peritoneal metastases. Secondary endpoints included progression-free survival, chemotherapy duration, and overall survival. Time-to-event outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS Eighty-four MAX, 179 TRACC and 69 NSWCC patients had peritoneal disease. There were no gastrointestinal perforations recorded in either the MAX subgroup or the NSWCC cohorts. Of the patients without peritoneal disease in the MAX trial, 4/300 (1.3%) in the bevacizumab arms had gastrointestinal perforations compared to 1/123 (0.8%) in the capecitabine alone arm. In the TRACC registry 3/126 (2.4%) patients who had received bevacizumab had a gastrointestinal perforation compared to 1/53 (1.9%) in the chemotherapy alone arm. In a further analysis of patients without peritoneal metastases in the TRACC registry, the rate of gastrointestinal perforations was 9/369 (2.4%) in the chemotherapy/bevacizumab group and 5/177 (2.8%) in the chemotherapy alone group. The addition of bevacizumab to chemotherapy was associated with improved progression-free survival in all three cohorts: MAX 6.9 m vs 4.9 m, HR = 0.64 (95%CI: 0.42-1.02); P = 0.063; TRACC 9.1 m vs 5.5 m, HR = 0.61 (95%CI: 0.37-0.86); P = 0.009; NSWCC 8.7 m vs 6.8 m, HR = 0.75 (95%CI: 0.43-1.32); P = 0.32. Chemotherapy duration was similar across the groups. CONCLUSION Patients with peritoneal disease do not appear to have an increased risk of gastrointestinal perforations when receiving first-line therapy with bevacizumab compared to systemic therapy alone

Irinotecan or FOLFIRI for 2nd line colorectal

Background Second-line treatment with irinotecan for advanced or metastatic colorectal cancer prolongs survival. It is uncertain whether irinotecan is better administered with 5- fluorouracil or alone in patients previously treated with a fluoropyrimidine. We compared toxicity (particularly diarrhoea), quality of life, and efficacy of combination chemotherapy and irinotecan in these patients. Methods In DaVINCI, a randomised phase II trial, patients with advanced colorectal cancer were randomly allocated to: combination therapy (FOLFIRI), irinotecan (180 mg/m2 IV over 90 min, day 1), 5-fluorouracil (400 mg/m2 IV bolus and 2400 mg/m2 by 46-hour infusion from day 1) and folinic acid (20 mg/m2 IV bolus, day 1), 2-weekly; or single-agent, irinotecan (350 mg/m2 IV over 90 min), 3-weekly. Toxicity was evaluated every treatment cycle; QOL and response 6 weekly. Analysis was by intention to treat. Results were also combined with those of other trials. Findings We randomised 44 patients to combination and 45 to single-agent. The most common toxicity was complete alopecia (single-agent 37%, combination 14%, P<0.02). Eight patients in the irinotecan arm and 4 in the combination arm had grade 3–4 diarrhoea (P=0.24). The treatment groups did not differ significantly in overall QOL changes, response rate, or progression free or overall survival. In a systematic review of 29 trials of second-line irinotecan-based treatment, single-agent irinotecan was associated with more diarrhoea and alopecia than the combination, but efficacy was similar. Interpretation Combination treatment compared with single-agent irinotecan appears to reduce the rateof complete alopecia and diarrhoea without compromising efficacy on clinical outcomes.Australasian Gastro-Intestinal Trials Grou

Prognostic nomogram for progression-free survival in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer on maintenance olaparib therapy following response to chemotherapy

Background: The impact of maintenance therapy with PARP inhibitors (PARPi) on progression-free survival (PFS) in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer (PSROC) varies widely. Individual prognostic factors do not reliably distinguish patients who progress early from those who have durable benefit. We developed and validated a prognostic nomogram to predict PFS in these patients. / Methods: The nomogram was developed using data from a training patient cohort with BRCA mutations and high-grade serous PSROC on the placebo arm of two maintenance therapy trials, Study 19 and SOLO2/ENGOT-ov21. We performed multivariable Cox regression analysis based on pre-treatment characteristics to develop a nomogram that predicts PFS. We assessed the discrimination and validation of the nomogram in independent validation patient cohorts treated with maintenance olaparib. / Results: The nomogram includes four PFS predictors: CA-125 at randomisation, platinum-free interval, presence of measurable disease and number of prior lines of platinum therapy. In the training (placebo) cohort (internal validation C-index 0.64), median PFS in the model-predicted good, intermediate and poor-risk groups was: 7.7 (95% CI 5.3–11.3), 5.4 (4.8–5.8) and 2.9 (2.8–4.4) months, respectively. In the validation (olaparib) cohort (C-index 0.71), median PFS in the model-predicted good, intermediate and poor-risk groups was: not reached, 16.6 (13.1–22.4) and 8.3 (7.1–10.8) months, respectively. The nomogram showed good calibration in the validation cohort (calibration plot). / Conclusions: This nomogram can be used to predict PFS and counsel patients with BRCA mutations and PSROC prior to maintenance olaparib and for stratification of patients in trials of maintenance therapies

Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial

© Cuzick et al. Open Access article distributed under the terms of CC BY.http://dx.doi.org/10.1016/S1470-2045(14)71171-

Impact of Stripe Shape on the Reflectivity of Monolithic High Contrast Gratings

Monolithic high contrast gratings (MHCGs) composed of a one-dimensional grating patterned in a monolithic layer provide up to 100% optical power reflectance and can be fabricated in almost any semiconductor and dielectric material used in modern optoelectronics. MHCGs enable monolithic integration, polarization selectivity, and versatile phase tuning. They can be from 10 to 20 times thinner than distributed Bragg reflectors. The subwavelength dimensions of MHCGs significantly reduce the possibility of ensuring the smoothness of the sidewalls of the MHCG stripes and make precise control of the shape of the MHCG stripe cross-section difficult during the etching process. The question is then whether it is more beneficial to improve the etching methods to obtain a perfect cross-section shape, as assumed by the design, or whether it is possible to find geometrical parameters that enable high optical power reflectance using the shape that a given etching method provides. Here, we present a numerical study supported by the experimental characterization of MHCGs fabricated in various materials using a variety of common surface nanometer-scale shaping methods. We demonstrate that MHCG stripes with an arbitrary cross-section shape can provide optical power reflectance of nearly 100%, which greatly relaxes their fabrication requirements. Moreover, we show that optical power reflectance exceeding 99% with a record spectral bandwidth of more than 20% can be achieved for quasi-Trapezoidal cross-sections of MHCGs. We also show that sidewall corrugations of the MHCG stripes have only a slight impact on MHCG optical power reflectance if the amplitude of the corrugation is less than 16% of the MHCG period. This level of stripe fabrication precision can be achieved using the most current surface etching methods. Our results are significant for the design and production of a variety of photonic devices employing MHCGs. The flexibility with regard to cross-section shape facilitates the reliable fabrication of highly reflective subwavelength grating mirrors. This in turn will enable the manufacture of monolithically integrated high-quality-factor optical micro-and nanocavity devices