A signal-seeking Phase 2 study of olaparib and durvalumab in advanced solid cancers with homologous recombination repair gene alterations

Purpose: To determine the safety and efficacy of PARP plus PD-L1 inhibition (olaparib + durvalumab, O + D) in patients with advanced solid, predominantly rare cancers harbouring homologous recombination repair (HRR) defects. Patients and methods: In total, 48 patients were treated with O + D, 16 with BRCA1/2 alterations (group 1) and 32 with other select HRR alterations (group 2). Overall, 32 (66%) patients had rare or less common cancers. The primary objective of this single-arm Phase II trial was a progression-free survival rate at 6 months (PFS6). Post hoc exploratory analyses were conducted on archival tumour tissue and serial bloods. Results: The PFS6 rate was 35% and 38% with durable objective tumour responses (OTR) in 3(19%) and 3(9%) in groups 1 and 2, respectively. Rare cancers achieving an OTR included cholangiocarcinoma, perivascular epithelioid cell (PEComa), neuroendocrine, gallbladder and endometrial cancer. O + D was safe, with five serious adverse events related to the study drug(s) in 3 (6%) patients. A higher proportion of CD38 high B cells in the blood and higher CD40 expression in tumour was prognostic of survival. Conclusions: O + D demonstrated no new toxicity concerns and yielded a clinically meaningful PFS6 rate and durable OTRs across several cancers with HRR defects, including rare cancers

ElectrochemicalN-demethylation of tropane alkaloids

A practical, efficient, and selective electrochemicalN-demethylation method of tropane alkaloids to their nortropane derivatives is described. Nortropanes, such as noratropine and norscopolamine, are important intermediates for the semi-synthesis of the medicines ipratropium or oxitropium bromide, respectively. Synthesis was performed in a simple home-made electrochemical batch cell using a porous glassy carbon electrode. The reaction proceeds at room temperature in one step in a mixture of ethanol or methanol and water. The method avoids hazardous oxidizing agents such as H(2)O(2)orm-chloroperbenzoic acid (m-CPBA), toxic solvents such as chloroform, as well as metal-based catalysts. Various key parameters were investigated in electrochemical batch or flow cells, and the optimized conditions were used in batch and flow-cells at gram scale to synthesize noratropine in high yield and purity using a convenient liquid-liquid extraction method without any need for chromatographic purification. Mechanistic studies showed that the electrochemicalN-demethylation proceeds by the formation of an iminium intermediate which is converted by water as the nucleophile. The optimized method was further applied to scopolamine, cocaine, benzatropine, homatropine and tropacocaine, showing that this is a generic way ofN-demethylating tropane alkaloids to synthesize valuable precursors for pharmaceutical products

Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.Experimentele farmacotherapi

Track A Basic Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138319/1/jia218438.pd

Maximizing health outcomes from government investment in surgical interventions

Prema Thavaneswaran and Guy J. Madder

Consumer perspectives in surgical research and audit

Objectives: The aim was to learn about perspectives of consumers contributing to the work of the Division of Research, Audit and Academic Surgery of the Royal Australasian College of Surgeons. The research arm of the Division has worked with consumers since it was formed in 1998. Methods: Nine consumers who worked with the Division over the past 5 years completed (1) a written survey focused on their background and past experience, and (2) a semi-structured phone interview focused on their motivations for becoming involved in this work; their role; the evolution of the role of consumers in healthcare research; and what health information for consumers should contain. Results: Participants came from various backgrounds and had different motivations for being involved. A common theme was concern about uncertainties in surgery and the need to provide consumers with information about potential benefits and risks of a procedure. Participants believed that a consumer presence was vital in research on surgical procedures, and that the content and wording of consumer information must be chosen carefully in order for the public to use it in a meaningful way. They also acknowledged the changing role of the consumer, who was rapidly becoming a partner in the doctor–patient relationship. Conclusions: In surgical research and audit, the consumer perspective is unique and informed by a wealth of experience. The findings of this study may be of interest to other health technology assessment and associated agencies seeking to involve consumers within their own research process.Eleanor Ahern, Prema Thavaneswaran, Wendy Babidge, Guy J. Madder

Nontherapeutic Male Circumcision: Tackling the Difficult Issues

© 2009 International Society for Sexual MedicineIntroductionMale circumcision is the most commonly performed surgical procedure in the world. Circumcision may be performed to treat an underlying pathological process ("therapeutic circumcision"). However there may be religious, cultural, and social indications.AimThis article addresses the religious, cultural, social, and ethical issues surrounding nontherapeutic male circumcision (NTMC).Main outcome measuresAny religious, social, cultural, or ethical issues relating to NTMC.MethodsBecause of the absence of high level evidence, a concise literature review was undertaken to identify articles published between January 1990 and February 2009 summarizing current knowledge on NTMC.ResultsThere are complex religious, cultural, social, and prophylactic incentives for NTMC. The procedure may have associated clinical and psychosocial adverse events and raises such ethical issues as bodily integrity and consent. Because of the strength of the incentives for NTMC, there may be important implications in denying patients the procedure. Several important issues must be considered when introducing mass circumcision as a preventative strategy for HIV/AIDS.ConclusionWhen assessing whether NTMC will benefit or harm a patient, clinicians must take his religious, cultural, and social circumstances into account. Males requiring mandatory religious or cultural NTMC are likely to suffer significant harm if they do not receive circumcision and should be considered separately to males in general.Caryn L. Perera, Franklin H.G. Bridgewater, Prema Thavaneswaran, Guy J. Madder

Postnatal ontogeny of glucose homeostasis and insulin action in sheep

Copyright © 2004 by the American Physiological Society.Glucose tolerance declines with maturation and aging in several species, but the time of onset and extent of changes in insulin sensitivity and insulin secretion and their contribution to changes in glucose tolerance are unclear. We therefore determined the effect of maturation on glucose tolerance, insulin secretion, and insulin sensitivity in a longitudinal study of male and female sheep from preweaning to adulthood, and whether these measures were related across age. Glucose tolerance was assessed by intravenous glucose tolerance test (IVGTT, 0.25 g glucose/kg), insulin secretion as the integrated insulin concentration during IVGTT, and insulin sensitivity by hyperinsulinemic-euglycemic clamp (2 mU insulin·kg–1·min–1). Glucose tolerance, relative insulin secretion, and insulin sensitivity each decreased with age (P < 0.001). The disposition index, the product of insulin sensitivity, and various measures of insulin secretion during fasting or IVGTT also decreased with age (P < 0.001). Glucose tolerance in young adult sheep was independently predicted by insulin sensitivity (P = 0.012) and by insulin secretion relative to integrated glucose during IVGTT (P = 0.005). Relative insulin secretion before weaning was correlated positively with that in the adult (P = 0.023), whereas glucose tolerance, insulin sensitivity, and disposition indexes in the adult did not correlate with those at earlier ages. We conclude that glucose tolerance declines between the first month of life and early adulthood in the sheep, reflecting decreasing insulin sensitivity and absence of compensatory insulin secretion. Nevertheless, the capacity for insulin secretion in the adult reflects that early in life, suggesting that it is determined genetically or by persistent influences of the perinatal environment.K. L. Gatford, M. J. De Blasio, P. Thavaneswaran, J. S. Robinson, I. C. McMillen, and J. A. Owen

Sex-specific effects of placental restriction on components of the metabolic syndrome in young adult sheep

Copyright © 2007 by the American Physiological Society.Prenatal and early postnatal life experiences, reflected by size at birth and postnatal catch-up growth, contribute to the risk of developing the metabolic syndrome in adulthood, but their relative importance is unclear. Therefore, we determined the effects of restricted placental and fetal growth on components of the metabolic syndrome in young adult sheep and the relationships of the latter to size at birth and early postnatal growth. Fasting plasma metabolites, glucose tolerance (by intravenous glucose tolerance test, IVGTT), insulin secretion and sensitivity, and resting blood pressure were measured in 22 control and 20 placentally restricted (PR) 1-yr-old sheep. In male sheep, PR increased the initial rise in glucose during an IVGTT and reduced diastolic blood pressure, and small size at birth independently predicted reduced adult size, glucose tolerance, and fasting plasma insulin and insulin disposition of glucose metabolism but increased insulin disposition of circulating FFAs. Also in males, high fractional growth rates in early postnatal life independently predicted impaired early glucose clearance during an IVGTT. In female animals, PR increased insulin sensitivity of glucose metabolism and reduced fasting plasma FFAs, and thinness at birth predicted increased adult size, fasting blood glucose, and pulse pressure. In conclusion, PR and small size at birth are associated with more components of the metabolic syndrome in adult male than in adult female sheep, with few independent effects of early postnatal growth. These sex differences in the onset and extent of adverse metabolic consequences after prenatal restraint in the sheep are consistent with observations in humans.J. A. Owens, P. Thavaneswaran, M. J. De Blasio, I. C. McMillen, J. S. Robinson, and K. L. Gatfor