Randomised, open-label, phase II study of Gemcitabine with and without IMM-101 for advanced pancreatic cancer

Background: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. Methods: Patients were randomised (2 : 1) to IMM-101 (10 mg ml−l intradermally)+GEM (1000 mg m−2 intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected. Results: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44–1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33–0.87, P=0.01). Conclusions: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study

Attrition between lines of therapy and real-world outcomes of patients with HER2-positive metastatic breast cancer in Europe: a cohort study leveraging electronic medical records

PurposeTo characterize real-world attrition rates across first-line (1L) to third-line (3L) therapies in patients with HER2-positive (HER2 +) metastatic breast cancer (mBC) receiving routine care in seven hospital systems across Europe (France, Germany, Italy, Spain, and the UK).MethodsThis retrospective, observational, multi-country, cohort study collected electronic medical record data from women aged ≥ 18 years diagnosed with HER2 + mBC from 2017–2021. The primary endpoint was attrition rate (the proportion of patients receiving a line of therapy [LOT] with no further evidence of subsequent LOTs). Key additional endpoints included treatment patterns, real-world time to treatment discontinuation (TTD), and time to next treatment (TTNT).Results29.6% (95% confidence interval [CI] 25.0–34.6) and 34.2% (95% CI 27.5–41.5) of treated patients with HER2 + mBC had no further evidence of treatment beyond 1L and second-line (2L) therapy, respectively. Attrition was primarily owing to death, move to end-of-life palliative care, loss to follow up, and “other” reasons. Treatment patterns were generally aligned with clinical guidelines. Decreases in TTD (12.1 months [95% CI 10.4–14.5] for 1L, 8.9 months [95% CI 7.3–11.9] for 2L, 6.4 months [95% CI 5.2–8.9] for 3L) and TTNT (15.4 months [95% CI 13.6–20.6] for 1L, 13.5 months [95% CI 10.8–19.4] for 2L) were observed with each subsequent LOT.ConclusionResults unveil a large proportion of patients who do not benefit from state-of-the-art subsequent LOT, and suggest diminishing effectiveness with each subsequent LOT

The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study

Abstract Background: Development of noninvasive molecular assays to improve disease diagnosis and patient monitoring is a critical need. In renal transplantation, acute rejection (AR) increases the risk for chronic graft injury and failure. Noninvasive diagnostic assays to improve current late and nonspecific diagnosis of rejection are needed. We sought to develop a test using a simple blood gene expression assay to detect patients at high risk for AR. Methods and Findings: We developed a novel correlation-based algorithm by step-wise analysis of gene expression data in 558 blood samples from 436 renal transplant patients collected across eight transplant centers in the US, Mexico, and Spain between 5 February 2005 and 15 December 2012 in the Assessment of Acute Rejection in Renal Transplantation (AART)study. Gene expression was assessed by quantitative real-time PCR (QPCR) in one center. A 17-gene set the Kidney Solid Organ Response Test (kSORT) was selected in 143 samples for AR classification using discriminant analysis (area under the receiver operating characteristic curve [AUC] = 0.94; 95% CI 0.91-0.98), validated in 124 independent samples (AUC = 0.95; 95% CI 0.88-1.0) and evaluated for AR prediction in 191 serial samples, where it predicted AR up to 3 mo prior to detection by the current gold standard (biopsy). A novel reference-based algorithm (using 13 12-gene models) was developed in 100 independent samples to provide a numerical AR risk score, to classify patients as high risk versus low risk for AR. kSORT was able to detect AR in blood independent of age, time post-transplantation, and sample source without additional data normalization; AUC = 0.93 (95% CI 0.86-0.99). Further validation of kSORT is planned in prospective clinical observational and interventional trials. Conclusions: The kSORT blood QPCR assay is a noninvasive tool to detect high risk of AR of renal transplants

Ybp2 Associates with the Central Kinetochore of Saccharomyces cerevisiae and Mediates Proper Mitotic Progression

The spindle checkpoint ensures the accurate segregation of chromosomes by monitoring the status of kinetochore attachment to microtubules. Simultaneous mutations in one of several kinetochore and cohesion genes and a spindle checkpoint gene cause a synthetic-lethal or synthetic-sick phenotype. A synthetic genetic array (SGA) analysis using a mad2Δ query mutant strain of yeast identified YBP2, a gene whose product shares sequence similarity with the product of YBP1, which is required for H2O2-induced oxidation of the transcription factor Yap1. ybp2Δ was sensitive to benomyl and accumulated at the mitotic stage of the cell cycle. Ybp2 physically associates with proteins of the COMA complex (Ctf19, Okp1, Mcm21, and Ame1) and 3 components of the Ndc80 complex (Ndc80, Nuf2, and Spc25 but not Spc24) in the central kinetochore and with Cse4 (the centromeric histone and CENP-A homolog). Chromatin-immunoprecipitation analyses revealed that Ybp2 associates specifically with CEN DNA. Furthermore, ybp2Δ showed synthetic-sick interactions with mutants of the genes that encode the COMA complex components. Ybp2 seems to be part of a macromolecular kinetochore complex and appears to contribute to the proper associations among the central kinetochore subcomplexes and the kinetochore-specific nucleosome

Ovarian Real-World International Consortium (ORWIC): A multicentre, real-world analysis of epithelial ovarian cancer treatment and outcomes

IntroductionMuch drug development and published analysis for epithelial ovarian cancer (EOC) focuses on early-line treatment. Full sequences of treatment from diagnosis to death and the impact of later lines of therapy are rarely studied. We describe the establishment of an international network of cancer centers configured to compare real-world treatment pathways in UK, Portugal, Germany, South Korea, France and Romania (the Ovarian Real-World International Consortium; ORWIC).Methods3344 patients diagnosed with EOC (2012-2018) were analysed using a common data model and hub and spoke programming approach applied to existing electronic medical records. Consistent definition of line of therapy between sites and an efficient approach to analysis within the limitations of local information governance was achieved.ResultsMedian age of participants was 53-67 years old and 5-29% were ECOG >1. Between 62% and 84% of patients were diagnosed with late-stage disease (FIGO III-IV). Sites treating younger and fitter patients had higher rates of debulking surgery for those diagnosed at late stage than sites with older, more frail patients. At least 21% of patients treated with systemic anti-cancer therapy (SACT) had recurrent disease following second-line therapy (2L); up to 11 lines of SACT treatment were recorded for some patients. Platinum-based SACT was consistently used across sites at 1L, but choices at 2L varied, with hormone therapies commonly used in the UK and Portugal. The use (and type) of maintenance therapy following 1L also varied. Beyond 2L, there was little consensus between sites on treatment choice: trial compounds and unspecified combinations of other agents were common.DiscussionSpecific treatment sequences are reported up to 4L and the establishment of this network facilitates future analysis of comparative outcomes per line of treatment with the aim of optimizing available options for patients with recurrent EOC. In particular, this real-world network can be used to assess the growing use of PARP inhibitors. The real-world optimization of advanced line treatment will be especially important for patients not usually eligible for involvement with clinical trials. The resources to enable this analysis to be implemented elsewhere are supplied and the network will seek to grow in coverage of further sites

Peer mentoring : models and outcomes at QUT

Students entering university study often experience feelings of isolation and disconnection, both academically and socially. At Queensland University of Technology, like many universities, there is a commitment to the student experience, in relation to welfare, satisfaction, retention, and success. The first year experience is a priority for many universities. Kift and Nelson (2005) described the unique needs of students-in-transition: social, academic, and administrative support. Efforts to facilitate the transition to university for first-year students include transition programs targeted for specific faculties’ requirements (McInnis et al., 2000); academically oriented peer support programs (McInnis et al., 2000); reciprocal peer tutoring (Rittschof & Griffin, 2001); online support (O’Reagan et al., 2004); and mentoring programs (Drew et al., 2000). Peer mentors may be a valuable resource for institutions to use in increasing persistence rates and enhancing the first year experience (Kahn & Nauta, 2001). Some of the benefits for first-year students include preventing the negative effects of stress (Jacobi, 1991, cited in Glaser et al., 2006); enhancing the sense of belonging and identity with the university, school or faculty (Evans & Peel, 1999, cited in Glaser et al., 2006); early access to information about resources on campus (Clark & Crome, 2004, cited in Glaser et al., 2006); academic success (Rodger & Tremblay, 2003, cited in Glaser et al., 2006); social connections (Pope & Van Dyke, 1999, cited in Glaser et al., 2006); skill development (Treston, 1999, cited in Glaser et al., 2006); and improved retention (Jacobi, 1991, cited in Glaser et al., 2006). In implementing a mentoring program, research indicates several factors critical to the success of the mentoring relationship including: organisational support; clarifying goals and roles; matching mentor and mentees; training mentors; sufficient resources; and monitoring and evaluation (Lloyd & Bristol, 2006). The structure of mentoring programs may vary depending on the target faculty or discipline. Key characteristics associated with effective programs, correspond with characteristics that are critical to the success of mentoring programs. These include: the characteristics of the mentor; the size of the mentoring group; the sustainability of the program; the presence of a coordinator; ongoing monitoring and evaluation; and a multidimensional approach (Rolfe-Flett, 2000)

Aring, Charles D. -- 1985-90 -- Correspondence, Individual -- letter, 1989-12-01

Letter from Cheeseman, Mary Sue to Sabin, Albert B. dated 1989-12-01.Sabin Collection Fair Use Policy</a