CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells.

A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982).

A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase.

Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4(CRBN) E3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism. Crystallographic studies of the CRBN-DDB1-CC-885-GSPT1 complex reveal that GSPT1 binds to cereblon through a surface turn containing a glycine residue at a key position, interacting with both CC-885 and a 'hotspot' on the cereblon surface. Although GSPT1 possesses no obvious structural, sequence or functional homology to previously known cereblon substrates, mutational analysis and modelling indicate that the cereblon substrate Ikaros uses a similar structural feature to bind cereblon, suggesting a common motif for substrate recruitment. These findings define a structural degron underlying cereblon 'neosubstrate' selectivity, and identify an anti-tumour target rendered druggable by cereblon modulation.

Complementary Control over Habits and Behavioral Vigor by Phasic Activity in the Dorsolateral Striatum.

Despite clear evidence linking the basal ganglia to the control of outcome insensitivity (i.e., habit) and behavioral vigor (i.e., its behavioral speed/fluidity), it remains unclear whether or how these functions relate to one another. Here, using male Long-Evans rats in response-based and cue-based maze-running tasks, we demonstrate that phasic dorsolateral striatum (DLS) activity occurring at the onset of a learned behavior regulates how vigorous and habitual it is. In a response-based task, brief optogenetic excitation at the onset of runs decreased run duration and the occurrence of deliberative behaviors, whereas midrun stimulation carried little effect. Outcome devaluation showed these runs to be habitual. DLS inhibition at run start did not produce robust effects on behavior until after outcome devaluation. At that time, when the DLS was plausibly most critically required for performance (i.e., habitual), inhibition reduced performance vigor measures and caused a dramatic loss of habitual responding (i.e., animals quit the task). In a second cue-based "beacon" task requiring behavior initiation at the start of the run and again in the middle of the run, DLS excitation at both time points could improve the vigor of runs. Postdevaluation testing showed behavior on the beacon task to be habitual as well. This pattern of results suggests that one role for phasic DLS activity at behavior initiation is to promote the execution of the behavior in a vigorous and habitual fashion by a diverse set of measures.SIGNIFICANCE STATEMENT Our research expands the literature twofold. First, we find that features of a habitual behavior that are typically studied separately (i.e., maze response performance, deliberation movements, running vigor, and outcome insensitivity) are quite closely linked together. Second, efforts have been made to understand "what" the dorsolateral striatum (DLS) does for habitual behavior, and our research provides a key set of results showing "when" it is important (i.e., at behavior initiation). By showing such dramatic control over habits by DLS activity in a phasic time window, plausible real-world applications could involve more informed DLS perturbations to curb intractably problematic habits.

Speed cells in the medial entorhinal cortex.

Grid cells in the medial entorhinal cortex have spatial firing fields that repeat periodically in a hexagonal pattern. When animals move, activity is translated between grid cells in accordance with the animal's displacement in the environment. For this translation to occur, grid cells must have continuous access to information about instantaneous running speed. However, a powerful entorhinal speed signal has not been identified. Here we show that running speed is represented in the firing rate of a ubiquitous but functionally dedicated population of entorhinal neurons distinct from other cell populations of the local circuit, such as grid, head-direction and border cells. These 'speed cells' are characterized by a context-invariant positive, linear response to running speed, and share with grid cells a prospective bias of ∼50-80 ms. Our observations point to speed cells as a key component of the dynamic representation of self-location in the medial entorhinal cortex.

Gamma Oscillations in the Rat Ventral Striatum Originate in the Piriform Cortex.

Local field potentials (LFPs) recorded from the human and rodent ventral striatum (vStr) exhibit prominent, behaviorally relevant gamma-band oscillations. These oscillations are related to local spiking activity and transiently synchronize with anatomically related areas, suggesting a possible role in organizing vStr activity. However, the origin of vStr gamma is unknown. We recorded vStr gamma oscillations across a 1.4 mm2 grid spanned by 64 recording electrodes as male rats rested and foraged for rewards, revealing a highly consistent power gradient originating in the adjacent piriform cortex. Phase differences across the vStr were consistently small (<15°) and current source density analysis further confirmed the absence of local sink-source pairs in the vStr. Reversible occlusions of the ipsilateral (but not contralateral) nostril, known to abolish gamma oscillations in the piriform cortex, strongly reduced vStr gamma power and the occurrence of transient gamma-band events. These results imply that local circuitry is not a major contributor to gamma oscillations in the vStr LFP and that piriform cortex is an important driver of gamma-band oscillations in the vStr and associated limbic areas.SIGNIFICANCE STATEMENT The ventral striatum (vStr) is an area of anatomical convergence in circuits underlying motivated behavior, but it remains unclear how its inputs from different sources interact. A major proposal about how neural circuits may switch dynamically between convergent inputs is through temporal organization reflected in local field potential (LFP) oscillations. Our results show that, in the rat, the mechanisms controlling gamma-band oscillations in the vStr LFP are primarily located in the in the adjacent piriform cortex rather than in the vStr itself, providing a novel interpretation of previous rodent work on gamma oscillations in the vStr and related circuits and an important consideration for future work seeking to use oscillations in these areas as biomarkers for behavioral and neurological disorders.

Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial.

BACKGROUND: The tAnGo trial was designed to investigate the potential role of gemcitabine when added to anthracycline and taxane-containing adjuvant chemotherapy for early breast cancer. When this study was developed, gemcitabine had shown significant activity in metastatic breast cancer, and there was evidence of a favourable interaction with paclitaxel. METHODS: tAnGo was an international, open-label, randomised, phase 3 superiority trial that enrolled women aged 18 years or older with newly diagnosed, early-stage breast cancer who had a definite indication for chemotherapy, any nodal status, any hormone receptor status, Eastern Cooperative Oncology Group performance status of 0-1, and adequate bone marrow, hepatic, and renal function. Women were recruited from 127 clinical centres and hospitals in the UK and Ireland, and randomly assigned (1:1) to one of two treatment regimens: epirubicin, cyclophosphamide, and paclitaxel (four cycles of 90 mg/m2 intravenously administered epirubicin and 600 mg/m2 intravenously administered cyclophosphamide on day 1 every 3 weeks, followed by four cycles of 175 mg/m2 paclitaxel as a 3 h infusion on day 1 every 3 weeks) or epirubicin, cyclophosphamide, and paclitaxel plus gemcitabine (the same chemotherapy regimen as the other group, with the addition of 1250 mg/m2 gemcitabine to the paclitaxel cycles, administered intravenously as a 0·5 h infusion on days 1 and 8 every 3 weeks). Patients were randomly assigned by a central computerised deterministic minimisation procedure, with stratification by country, age, radiotherapy intent, nodal status, and oestrogen receptor and HER-2 status. The primary endpoint was disease-free survival and the trial aimed to detect 5% differences in 5-year disease-free survival between the treatment groups. Recruitment completed in 2004 and this is the final, intention-to-treat analysis. This trial is registered with EudraCT (2004-002927-41), ISRCTN (51146252), and ClinicalTrials.gov (NCT00039546). FINDINGS: Between Aug 22, 2001, and Nov 26, 2004, 3152 patients were enrolled and randomly assigned to epirubicin, cyclophosphamide, paclitaxel, and gemcitabine (gemcitabine group; n=1576) or to epirubicin, cyclophosphamide, and paclitaxel (control group; n=1576). 11 patients (six in the gemcitabine group and five in the control group) were ineligible because of pre-existing metastases and were therefore excluded from the analysis. At this protocol-specified final analysis (median follow-up 10 years [IQR 10-10]), 1087 disease-free survival events and 914 deaths had occurred. Disease-free survival did not differ significantly between the treatment groups at 10 years (65% [63-68] in the gemcitabine group vs 65% [62-67] in the control group), and median disease-free survival was not reached (adjusted hazard ratio 0·97 [95% CI 0·86-1·10], p=0·64). Toxicity, dose intensity, and a detailed safety substudy showed both regimens to be safe, deliverable, and tolerable. Grade 3 and 4 toxicities were reported at expected levels in both groups. The most common were neutropenia (527 [34%] of 1565 patients in the gemcitabine group vs 412 [26%] of 1567 in the control group), myalgia and arthralgia (207 [13%] vs 186 [12%]), fatigue (207 [13%] vs 152 [10%]), infection (202 [13%] vs 141 [9%]), vomiting (143 [9%] vs 108 [7%]), and nausea (132 [8%] vs 102 [7%]). INTERPRETATION: The addition of gemcitabine to anthracycline and taxane-based adjuvant chemotherapy at this dose and schedule confers no therapeutic advantage in terms of disease-free survival in early breast cancer, although it can cause increased toxicity. Therefore, gemcitabine has not been added to standard adjuvant chemotherapy in breast cancer for any subgroup. FUNDING: Cancer Research UK core funding for Clinical Trials Unit at the University of Birmingham, Eli Lilly, Bristol-Myers Squibb, and Pfizer.

Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.

BACKGROUND: Olaparib (AZD2281) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that has shown antitumor activity in patients with high-grade serous ovarian cancer with or without BRCA1 or BRCA2 germline mutations. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2 study to evaluate maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum-based regimens and had had a partial or complete response to their most recent platinum-based regimen. Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. The primary end point was progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines. RESULTS: Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Progression-free survival was significantly longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P=0.75). CONCLUSIONS: Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.).

3D printing: a useful tool for safe clinical practice in children with complex vasculature.

BACKGROUND: 3D printing has been used in different medical contexts, although it is underutilised in paediatrics. We present the first use of 3D printing in the management of three paediatric patients with complex renovascular disease. METHODS: Patient-specific 3D models were produced from conventional 2D imaging and manufactured using 3D polyjet printing technology. All three patients had different underlying pathologies, but all underwent multiple endovascular interventions (renal artery balloon angioplasty) prior to 3D printing and subsequent vascular surgery. The models were verified by an expert radiologist and then presented to the multidisciplinary team to aid with surgical planning. RESULTS: Following evaluation of the 3D-printed models, all patients underwent successful uni/bilateral renal auto-transplants and aortic bypass surgery. The 3D models allowed more detailed preoperative discussions and more focused planning of surgical approach, therefore enhancing safer surgical planning. It influenced clinical decision-making and shortened general anaesthetic time. The families and the patients reported that they had a significantly improved understanding of the patient's condition and had more confidence in understanding proposed surgical intervention, thereby contributing to obtaining good-quality informed consent. CONCLUSION: 3D printing has a great potential to improve both surgical safety and decision-making as well as patient understanding in the field of paediatrics and may be considered in wider surgical areas.

SF3B1 mutations provide genetic vulnerability to copper ionophores in human acute myeloid leukemia.

In a phenotypical screen of 56 acute myeloid leukemia (AML) patient samples and using a library of 10,000 compounds, we identified a hit with increased sensitivity toward SF3B1-mutated and adverse risk AMLs. Through structure-activity relationship studies, this hit was optimized into a potent, specific, and nongenotoxic molecule called UM4118. We demonstrated that UM4118 acts as a copper ionophore that initiates a mitochondrial-based noncanonical form of cell death known as cuproptosis. CRISPR-Cas9 loss-of-function screen further revealed that iron-sulfur cluster (ISC) deficiency enhances copper-mediated cell death. Specifically, we found that loss of the mitochondrial ISC transporter ABCB7 is synthetic lethal to UM4118. ABCB7 is misspliced and down-regulated in SF3B1-mutated leukemia, creating a vulnerability to copper ionophores. Accordingly, ABCB7 overexpression partially rescued SF3B1-mutated cells to copper overload. Together, our work provides mechanistic insights that link ISC deficiency to cuproptosis, as exemplified by the high sensitivity of SF3B1-mutated AMLs. We thus propose SF3B1 mutations as a biomarker for future copper ionophore-based therapies.

Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer.

INTRODUCTION: This Phase I study evaluated the safety, tolerability and efficacy of olaparib, a potent oral poly(ADPribose) polymerase (PARP) inhibitor, in combination with paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). METHODS: Eligible patients who had received ≤1 prior cytotoxic regimen for mTNBC were treated with olaparib 200 mg bid continuously plus weekly paclitaxel 90 mg/m2 for three weeks per four-week cycle. Dose modifications in a large proportion of patients due to neutropenia resulted in enrollment of a second cohort of patients who, if they experienced grade ≥2 neutropenia in cycle 1, received granulocyte-colony stimulating factor, which was continued prophylactically in subsequent cycles. All patients had measurable disease; tumor responses were evaluated according to RECIST (version 1.0). RESULTS: Nineteen patients (cohort 1, n = 9; cohort 2, n = 10) received treatment; 15 had received prior taxane chemotherapy. The most frequent adverse events were diarrhea (n = 12, 63%), nausea (n = 11, 58%) and neutropenia (n = 11, 58%). Seven neutropenia events were reported in cohort 1 (four grade ≥3) and four in cohort 2 (two grade ≥3, including one event of febrile neutropenia). The median (range) dose intensity of paclitaxel was 57% (26 to 100%) in cohort 1 and 73% (29 to 100%) in cohort 2. Seven patients (37%) had a confirmed partial response; one patient remains on olaparib monotherapy without progression. CONCLUSIONS: The combination of olaparib and weekly paclitaxel was complicated by a significant clinical interaction, with higher-than-expected rates of neutropenia despite secondary prophylaxis. Given the encouraging response rate, alternative scheduling and dosing strategies should be considered (funded by AstraZeneca; ClinicalTrials.gov, NCT00707707).

Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a phase I multicentre trial in patients scheduled for elective breast cancer surgery.

Olaparib (AZD2281) is an oral poly(ADP-ribose) polymerase (PARP) inhibitor with antitumour activity in cancer patients with BRCA1/2 germline mutations and in patients with homologous recombination deficiency. In this dose-finding study, patients were randomized to olaparib 10, 30, 100, 200 or 400 mg (capsule formulation) twice daily for the 4-5 days preceding breast cancer surgery. The primary objective was to identify an effective biological dose of olaparib for future trials. Secondary endpoints included evaluation of PARP-1 inhibition dose/exposure-response, and safety. Olaparib plasma pharmacokinetics (PK) and the pharmacodynamics (PD) in tumour and peripheral blood mononuclear cells (PBMCs) were evaluated. Population PK/PD modelling was performed on pooled data from this study and a previously reported study. Sixty patients were randomized (n = 12, each dose). Dose-dependent increases in exposure to olaparib were observed, but at ~50 % lower plasma exposure levels than seen in advanced disease studies. The mean maximal extent of PARP inhibition in PBMCs and tumour tissue was 50.6 % and 70.0 %, respectively, and was similar to inhibitory levels reported previously. No PARP inhibition-dose relationship was observed. Due to the unexpectedly low olaparib exposure, we were unable to determine an effective biological dose. Common adverse events included procedural pain (n = 31 patients), nausea, asthenia, malaise and increased blood creatinine (n = 6, each); these were of mild-to-moderate intensity, and all were manageable. Despite low olaparib exposure, PARP inhibition was consistent with previous reports. Reasons for the inter-study differences in exposure are unclear. The tolerability profile of olaparib was consistent with previous studies.

Concurrent short-term use of prednisolone with cyclosporine A accelerates pruritus reduction and improvement in clinical scoring in dogs with atopic dermatitis.

BACKGROUND: A randomized, unmasked, multicenter study was conducted to evaluate the rate of pruritus reduction and improvement in clinical scoring by cyclosporine A (5 mg/kg orally, once daily for 28 days) either alone (n = 25 dogs) or with concurrent prednisolone (1 mg/kg once daily for 7 days, followed by alternate dosing for 14 days; n = 23 dogs) for the treatment of atopic dermatitis in dogs. Dogs were included in the study after exclusion of other causes of pruritic dermatitis, and were assessed by dermatologists on days 0, 14 ± 1 and 28 ± 2. Assessments included: general physical examination, CADESI-03 lesion scoring, overall clinical response, evaluation of adverse events (AEs), body weight and clinical pathology (hematology, clinical chemistry and urinalysis). Owner assessments, including pruritus (visual analogue scale, VAS) and overall assessment of response were conducted every 3-4 days, either during visits to the clinic or at home. Owners reported AEs to the investigator throughout the study. RESULTS: By day 28 ± 2 both treatment groups resulted in a significant improvement of the atopic dermatitis. Both investigators and owners agreed that concurrent therapy resulted in a quicker improvement of the dogs 'overall' skin condition and of pruritus (significant reduction of pruritus by day 3-4, 72.8% improvement by day 14 ± 1), when compared to cyclosporine A alone (significant reduction of pruritus by day 7-8, 24.7% improvement by day 14 ± 1). CADESI-03 scores significantly improved in both groups by day 14 ± 1 onwards, and there were no significant differences in the scores between treatment groups at any time points. A total of 56 AEs (cyclosporine A alone = 34; concurrent therapy = 22) were reported in 33 dogs. No dogs died or stopped treatment due to an AE. The most commonly reported AEs in the cyclosporine A group were associated with the digestive tract, whilst systemic disorders were reported more frequently observed following concurrent therapy. Evaluation of body weight change and clinical pathology indices showed no overall clinically significant abnormalities. CONCLUSIONS: In dogs with atopic dermatitis, a short initiating course of prednisolone expedited the efficacy of cyclosporine A in resolving pruritus and associated clinical signs. The observed adverse events were consistent with those expected for the individual veterinary medicinal products.

Linking temporal coordination of hippocampal activity to memory function.

Oscillations in neural activity are widespread throughout the brain and can be observed at the population level through the local field potential. These rhythmic patterns are associated with cycles of excitability and are thought to coordinate networks of neurons, in turn facilitating effective communication both within local circuits and across brain regions. In the hippocampus, theta rhythms (4-12 Hz) could contribute to several key physiological mechanisms including long-range synchrony, plasticity, and at the behavioral scale, support memory encoding and retrieval. While neurons in the hippocampus appear to be temporally coordinated by theta oscillations, they also tend to fire in sequences that are developmentally preconfigured. Although loss of theta rhythmicity impairs memory, these sequences of spatiotemporal representations persist in conditions of altered hippocampal oscillations. The focus of this review is to disentangle the relative contribution of hippocampal oscillations from single-neuron activity in learning and memory. We first review cellular, anatomical, and physiological mechanisms underlying the generation and maintenance of hippocampal rhythms and how they contribute to memory function. We propose candidate hypotheses for how septohippocampal oscillations could support memory function while not contributing directly to hippocampal sequences. In particular, we explore how theta rhythms could coordinate the integration of upstream signals in the hippocampus to form future decisions, the relevance of such integration to downstream regions, as well as setting the stage for behavioral timescale synaptic plasticity. Finally, we leverage stimulation-based treatment in Alzheimer's disease conditions as an opportunity to assess the sufficiency of hippocampal oscillations for memory function.

Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.

BACKGROUND: The inhibition of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a potential synthetic lethal therapeutic strategy for the treatment of cancers with specific DNA-repair defects, including those arising in carriers of a BRCA1 or BRCA2 mutation. We conducted a clinical evaluation in humans of olaparib (AZD2281), a novel, potent, orally active PARP inhibitor. METHODS: This was a phase 1 trial that included the analysis of pharmacokinetic and pharmacodynamic characteristics of olaparib. Selection was aimed at having a study population enriched in carriers of a BRCA1 or BRCA2 mutation. RESULTS: We enrolled and treated 60 patients; 22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA-associated cancer but declined to undergo mutational testing. The olaparib dose and schedule were increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice daily (grade 3 mood alteration and fatigue) and two of five patients receiving 600 mg twice daily (grade 4 thrombocytopenia and grade 3 somnolence). This led us to enroll another cohort, consisting only of carriers of a BRCA1 or BRCA2 mutation, to receive olaparib at a dose of 200 mg twice daily. Other adverse effects included mild gastrointestinal symptoms. There was no obvious increase in adverse effects seen in the mutation carriers. Pharmacokinetic data indicated rapid absorption and elimination; pharmacodynamic studies confirmed PARP inhibition in surrogate samples (of peripheral-blood mononuclear cells and plucked eyebrow-hair follicles) and tumor tissue. Objective antitumor activity was reported only in mutation carriers, all of whom had ovarian, breast, or prostate cancer and had received multiple treatment regimens. CONCLUSIONS: Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCA2 mutation. (ClinicalTrials.gov number, NCT00516373.)

Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study.

BACKGROUND: The aim of this phase I study was to determine the safety and tolerability and to establish the maximum tolerated dose (MTD) of orally administered olaparib (AZD2281) in combination with topotecan in patients with advanced solid tumors. PATIENTS AND METHODS: Patients aged ≥ 18 years with histologically or cytologically diagnosed advanced solid tumors for whom no suitable effective therapy exists were included. Patients in four cohorts received topotecan (0.5 mg/m(2)/day × 3 days or 1.0 mg/m(2)/day × 3 days) intravenously in combination with oral olaparib 50, 100 or 200 mg bid for six cycles. The primary objectives were to determine the safety and tolerability and to establish the MTD of olaparib in combination with topotecan. RESULTS: Twenty-one patients were enrolled and 19 received treatment. Dose-limiting toxicities were neutropenia and thrombocytopenia. The MTD was established as topotecan 1.0 mg/m(2)/day × 3 days plus olaparib 100 mg bid. The most common adverse events (AEs) included fatigue and gastrointestinal events. There was an olaparib and topotecan dose-related increase in neutropenia which was dose limiting. CONCLUSIONS: Further development of olaparib and topotecan in combination was not explored due to dose-limiting hematological AEs and the resulting sub-therapeutic MTD.

Achilles tendinoscopy and plantaris tendon release and division in the treatment of non-insertional Achilles tendinopathy.

BACKGROUND: The mainstay of treatment for non-insertional Achilles tendinopathy is non-operative, however a proportion of patients will fail conservative measures. We describe the results of Achilles tendinoscopy with plantaris tendon release in patients who have failed first line conservative treatment for at least 6 months. METHODS: A consecutive series of 11 patients with a minimum of 2 years follow up. RESULTS: The mean AOFAS scores significantly improved from 68 pre-op to 92 post op (p=0.0002) as did the AOS scores for both pain (28% pre-op to 8% post op (p=0.0004)) and disability (38% pre-op to 10% post op (p=0.0005). The mean SF-36 scores also improved but were not statistically significant (pre-op 76, post op 87 (p=0.059). There were no complications. 8 of the 11 patients were satisfied, the other 3 somewhat satisfied. CONCLUSIONS: The results of Achilles tendinoscopy and division of the plantaris tendon are encouraging but further studies are required to compare it to other treatments. It is minimally invasive and low risk so should not affect the ability to perform a formal open procedure if unsuccessful.

Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.

BACKGROUND: Olaparib (AZD2281) is a small-molecule, potent oral poly(ADP-ribose) polymerase (PARP) inhibitor. We aimed to assess the safety and tolerability of this drug in patients without BRCA1 or BRCA2 mutations with advanced triple-negative breast cancer or high-grade serous and/or undifferentiated ovarian cancer. METHODS: In this phase 2, multicentre, open-label, non-randomised study, women with advanced high-grade serous and/or undifferentiated ovarian carcinoma or triple-negative breast cancer were enrolled and received olaparib 400 mg twice a day. Patients were stratified according to whether they had a BRCA1 or BRCA2 mutation or not. The primary endpoint was objective response rate by Response Evaluation Criteria In Solid Tumors (RECIST). All patients who received treatment were included in the analysis of toxic effects, and patients who had measurable lesions at baseline were included in the primary efficacy analysis. This trial is registered at ClinicalTrials.gov, number NCT00679783. FINDINGS: 91 patients were enrolled (65 with ovarian cancer and 26 breast cancer) and 90 were treated between July 8, 2008, and Sept 24, 2009. In the ovarian cancer cohorts, 64 patients received treatment. 63 patients had target lesions and therefore were evaluable for objective response as per RECIST. In these patients, confirmed objective responses were seen in seven (41%; 95% CI 22-64) of 17 patients with BRCA1 or BRCA2 mutations and 11 (24%; 14-38) of 46 without mutations. No confirmed objective responses were reported in patients with breast cancer. The most common adverse events were fatigue (45 [70%] of patients with ovarian cancer, 13 [50%] of patients with breast cancer), nausea (42 [66%] and 16 [62%]), vomiting (25 [39%] and nine [35%]), and decreased appetite (23 [36%] and seven [27%]). INTERPRETATION: Our study suggests that olaparib is a promising treatment for women with ovarian cancer and further assessment of the drug in clinical trials is needed. FUNDING: AstraZeneca.

Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori-induced inflammation-driven gastric carcinogenesis.

Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. Here, we demonstrate that H. pylori augmented gastric injury in INS-GAS mice under iron-deficient conditions. Mechanistically, these phenotypes were not driven by alterations in the gastric microbiota; however, discovery-based and targeted metabolomics revealed that bile acids were significantly altered in H. pylori-infected mice with iron deficiency, with significant upregulation of deoxycholic acid (DCA), a carcinogenic bile acid. The severity of gastric injury was further augmented when H. pylori-infected mice were treated with DCA, and, in vitro, DCA increased translocation of the H. pylori oncoprotein CagA into host cells. Conversely, bile acid sequestration attenuated H. pylori-induced injury under conditions of iron deficiency. To translate these findings to human populations, we evaluated the association between bile acid sequestrant use and gastric cancer risk in a large human cohort. Among 416,885 individuals, a significant dose-dependent reduction in risk was associated with cumulative bile acid sequestrant use. Further, expression of the bile acid receptor transmembrane G protein-coupled bile acid receptor 5 (TGR5) paralleled the severity of carcinogenic lesions in humans. These data demonstrate that increased H. pylori-induced injury within the context of iron deficiency is tightly linked to altered bile acid metabolism, which may promote gastric carcinogenesis.

Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.

BACKGROUND: Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer. METHODS: Women (aged >or=18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234. FINDINGS: Patients had been given a median of three previous chemotherapy regimens (range 1-5 in cohort 1, and 2-4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25-59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11-41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]). INTERPRETATION: The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations. FUNDING: AstraZeneca.