First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity

<p>Abstract</p> <p>Background</p> <p>IMP321 is a recombinant soluble LAG-3Ig fusion protein that binds to MHC class II with high avidity and mediates APC and then antigen-experienced memory CD8⁺T cell activation. We report clinical and biological results of a phase I/II in patients with metastatic breast carcinoma (MBC) receiving first-line paclitaxel weekly, 3 weeks out of 4.</p> <p>Methods</p> <p>MBC patients were administered one dose of IMP321 s.c. every two weeks for a total of 24 weeks (12 injections). The repeated single doses were administered the day after chemotherapy at D2 and D16 of the 28-day cycles of paclitaxel (80 mg/m²at D1, D8 and D15, for 6 cycles). Blood samples were taken 13 days after the sixth and the twelfth IMP321 injections to determine sustained APC, NK and memory CD8 T cell responses.</p> <p>Results</p> <p>Thirty MBC patients received IMP321 in three cohorts (doses: 0.25, 1.25 and 6.25 mg). IMP321 induced both a sustained increase in the number and activation of APC (monocytes and dendritic cells) and an increase in the percentage of NK and long-lived cytotoxic effector-memory CD8 T cells. Clinical benefit was observed for 90% of patients with only 3 progressors at 6 months. Also, the objective tumor response rate of 50% compared favorably to the 25% rate reported in the historical control group.</p> <p>Conclusions</p> <p>The absence of toxicity and the demonstration of activity strongly support the future development of this agent for clinical use in combined first-line regimens.</p> <p>Trial registration</p> <p>ClinicalTrials.gov NCT00349934</p

Maternal and fetal cardiometabolic recovery following ultrasound-guided high-intensity focused ultrasound placental vascular occlusion.

High-intensity focused ultrasound (HIFU) is a non-invasive method of selective placental vascular occlusion, providing a potential therapy for conditions such as twin-twin transfusion syndrome. In order to translate this technique into human studies, evidence of prolonged fetal recovery and maintenance of a healthy fetal physiology following exposure to HIFU is essential. At 116 ± 2 days gestation, 12 pregnant ewes were assigned to control ( n = 6) or HIFU vascular occlusion ( n = 6) groups and anaesthetized. Placental blood vessels were identified using colour Doppler ultrasound; HIFU-mediated vascular occlusion was performed through intact maternal skin (1.66 MHz, 5 s duration, in situ ISPTA 1.8-3.9 kW cm-2). Unidentifiable colour Doppler signals in targeted vessels following HIFU exposure denoted successful occlusion. Ewes and fetuses were then surgically instrumented with vascular catheters and transonic flow probes and recovered from anaesthesia. A custom-made wireless data acquisition system, which records continuous maternal and fetal cardiovascular data, and daily blood sampling were used to assess wellbeing for 20 days, followed by post-mortem examination. Based on a comparison of pre- and post-treatment colour Doppler imaging, 100% (36/36) of placental vessels were occluded following HIFU, and occlusion persisted for 20 days. All fetuses survived. No differences in maternal or fetal blood pressure, heart rate, heart rate variability, metabolic status or oxygenation were observed between treatment groups. There was evidence of normal fetal maturation and no evidence of chronic fetal stress. There were no maternal injuries and no placental vascular haemorrhage. There was both a uterine and fetal burn, which did not result in any obstetric or fetal complications. This study demonstrates normal long-term recovery of fetal sheep from exposure to HIFU-mediated placental vascular occlusion and underlines the potential of HIFU as a potential non-invasive therapy in human pregnancy

Altered Cardiovascular Defense to Hypotensive Stress in the Chronically Hypoxic Fetus.

The hypoxic fetus is at greater risk of cardiovascular demise during a challenge, but the reasons behind this are unknown. Clinically, progress has been hampered by the inability to study the human fetus non-invasively for long period of gestation. Using experimental animals, there has also been an inability to induce gestational hypoxia while recording fetal cardiovascular function as the hypoxic pregnancy is occurring. We use novel technology in sheep pregnancy that combines induction of controlled chronic hypoxia with simultaneous, wireless recording of blood pressure and blood flow signals from the fetus. Here, we investigated the cardiovascular defense of the hypoxic fetus to superimposed acute hypotension. Pregnant ewes carrying singleton fetuses surgically prepared with catheters and flow probes were randomly exposed to normoxia or chronic hypoxia from 121±1 days of gestation (term ≈145 days). After 10 days of exposure, fetuses were subjected to acute hypotension via fetal nitroprusside intravenous infusion. Underlying in vivo mechanisms were explored by (1) analyzing fetal cardiac and peripheral vasomotor baroreflex function; (2) measuring the fetal plasma catecholamines; and (3) establishing fetal femoral vasoconstrictor responses to the α1-adrenergic agonist phenylephrine. Relative to controls, chronically hypoxic fetal sheep had reversed cardiac and impaired vasomotor baroreflex function, despite similar noradrenaline and greater adrenaline increments in plasma during hypotension. Chronic hypoxia markedly diminished the fetal vasopressor responses to phenylephrine. Therefore, we show that the chronically hypoxic fetus displays markedly different cardiovascular responses to acute hypotension, providing in vivo evidence of mechanisms linking its greater susceptibility to superimposed stress.The British Heart Foundatio

Ki-67: level of evidence and methodological considerations for its role in the clinical management of breast cancer: analytical and critical review

Clinicians can use biomarkers to guide therapeutic decisions in estrogen receptor positive (ER+) breast cancer. One such biomarker is cellular proliferation as evaluated by Ki-67. This biomarker has been extensively studied and is easily assayed by histopathologists but it is not currently accepted as a standard. This review focuses on its prognostic and predictive value, and on methodological considerations for its measurement and the cut-points used for treatment decision. Data describing study design, patients’ characteristics, methods used and results were extracted from papers published between January 1990 and July 2010. In addition, the studies were assessed using the REMARK tool. Ki-67 is an independent prognostic factor for disease-free survival (HR 1.05–1.72) in multivariate analyses studies using samples from randomized clinical trials with secondary central analysis of the biomarker. The level of evidence (LOE) was judged to be I-B with the recently revised definition of Simon. However, standardization of the techniques and scoring methods are needed for the integration of this biomarker in everyday practice. Ki-67 was not found to be predictive for long-term follow-up after chemotherapy. Nevertheless, high KI-67 was found to be associated with immediate pathological complete response in the neoadjuvant setting, with an LOE of II-B. The REMARK score improved over time (with a range of 6–13/20 vs. 10–18/20, before and after 2005, respectively). KI-67 could be considered as a prognostic biomarker for therapeutic decision. It is assessed with a simple assay that could be standardized. However, international guidelines are needed for routine clinical use

Pathogenic variants in the human m(6)A reader YTHDC2 are associated with primary ovarian insufficiency

Primary ovarian insufficiency (POI) affects 1% of women and carries significant medical and psychosocial sequelae. Approximately 10% of POI has a defined genetic cause, with most implicated genes relating to biological processes involved in early fetal ovary development and function. Recently, Ythdc2, an RNA helicase and N6-methyladenosine reader, has emerged as a regulator of meiosis in mice. Here, we describe homozygous pathogenic variants in YTHDC2 in 3 women with early-onset POI from 2 families: C. 2567C>G, p.P856R in the helicase-associated (HA2) domain and c.1129G>T, p.E377*. We demonstrated that YTHDC2 is expressed in the developing human fetal ovary and is upregulated in meiotic germ cells, together with related meiosisassociated factors. The p.P856R variant resulted in a less flexible protein that likely disrupted downstream conformational kinetics of the HA2 domain, whereas the p.E377*variant truncated the helicase core. Taken together, our results reveal that YTHDC2 is a key regulator of meiosis in humans and pathogenic variants within this gene are associated with POI

Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors

Background: Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. Methods: In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. Findings: 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59–1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69–0·88; approximately 370 mL) in the 10-week group (p&lt;0·0001 for both). In women, compared with the 16-week group, it increased by 0·84 units (95% CI 0·76–0·91; approximately 395 mL) in the 12-week group and by 0·46 units (0·39–0·53; approximately 215 mL) in the 14-week group (p&lt;0·0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men [for all listed symptoms]), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p&lt;0·0001 for each) than those observed in the standard frequency groups. Interpretation: Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency. Funding: NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation

Encephalopathy associated with autoimmune thyroid disease in patients with Graves' disease: clinical manifestations, follow-up, and outcomes

<p>Abstract</p> <p>Background</p> <p>The encephalopathy associated with autoimmune thyroid disease (EAATD) is characterized by neurological/psychiatric symptoms, high levels of anti-thyroid antibodies, increased cerebrospinal fluid protein concentration, non-specific electroencephalogram abnormalities, and responsiveness to the corticosteroid treatment in patients with an autoimmune thyroid disease. Almost all EAATD patients are affected by Hashimoto's thyroiditis (HT), although fourteen EAATD patients with Graves' disease (GD) have been also reported.</p> <p>Methods</p> <p>We have recorded and analyzed the clinical, biological, radiological, and electrophysiological findings and the data on the therapeutic management of all GD patients with EAATD reported so far as well as the clinical outcomes in those followed-up in the long term.</p> <p>Results</p> <p>Twelve of the fourteen patients with EAATD and GD were women. The majority of GD patients with EAATD presented with mild hyperthyroidism at EAATD onset or shortly before it. Active anti-thyroid autoimmunity was detected in all cases. Most of the patients dramatically responded to corticosteroids. The long term clinical outcome was benign but EAATD can relapse, especially at the time of corticosteroid dose tapering or withdrawal. GD and HT patients with EAATD present with a similar clinical, biological, radiological, and electrophysiological picture and require an unaffected EAATD management.</p> <p>Conclusions</p> <p>GD and HT equally represent the possible background condition for the development of EAATD, which should be considered in the differential diagnosis of all patients with encephalopathy of unknown origin and an autoimmune thyroid disease, regardless of the nature of the underlying autoimmune thyroid disease.</p

Randomised controlled trial and economic evaluation of a targeted cancer awareness intervention for adults living in deprived areas of the UK

Background: Cancer outcomes are poor in socioeconomically deprived communities, with low symptom awareness contributing to prolonged help-seeking and advanced disease. Targeted cancer awareness interventions require evaluation. Methods: Randomised controlled trial involving adults aged 40+ recruited in community and healthcare settings in deprived areas of South Yorkshire and South-East Wales. Intervention: personalised behavioural advice facilitated by a trained lay advisor. Control: usual care. Follow-up at 2-weeks and 6-months post-randomisation. Primary outcome: total cancer symptom recognition score 2-weeks post-randomisation. Results: 234 participants were randomised. The difference in total symptom recognition at 2-weeks [adjusted mean difference (AMD) 0.6, 95% CI:-0.03, 1.17, p=0.06] was not statistically significant. Intervention participants reported increased symptom recognition (AMD 0.8, 95% CI:0.18, 1.37, p=0.01) and earlier intended presentation (AMD -2.0, 95% CI:-3.02, -0.91, p<0.001) at 6-months. “Lesser known” symptom recognition was higher in the intervention arm (2-weeks AMD 0.5, 95% CI:0.03, 0.97 and 6-months AMD 0.7, 95% CI:0.16, 1.17). Implementation cost per participant was £91.34, with no significant between-groups differences in healthcare resource use post-intervention. Conclusions: Improved symptom recognition and earlier anticipated presentation occurred at longer-term follow-up. The ABACus Health Check is a viable low-cost intervention to increase cancer awareness in socioeconomically deprived communities. Clinical Trial Registration: ISRCTN1687254

Improving cancer symptom awareness and help-seeking among adults living in socioeconomically deprived communities in the UK using a facilitated health check: A protocol for the Awareness and Beliefs About Cancer (ABACus) Randomised Control Trial

Background Cancer survival is lower in socioeconomically deprived communities, partly due to low awareness of symptoms, negative beliefs and delayed help-seeking. We developed an interactive health check questionnaire facilitated by trained lay advisors. It entails 29 questions about background, lifestyle and health with tailored behaviour change advice. Personalised results are printed using a traffic light (red/amber/green) system, highlighting areas where action should be taken. This is an individually randomised control trial to test effectiveness of the health check on symptom recognition. Methods A total 246 participants aged 40+ years will be recruited from community and healthcare settings in socioeconomically deprived areas of Yorkshire and South Wales. Participants will be randomised to receive the health check or standard care (1:1 ratio). Outcome measures include: adapted Awareness and Beliefs about Cancer (primary outcome), brief State Trait Anxiety Inventory, intentions and motivation to adopt recommended health behaviours (early symptom presentation, cancer screening and lifestyle behaviours), adapted Client Service Receipt Inventory, brief medical history/screening and demographic questionnaire at: baseline; 2-weeks; and 6-months post-randomisation. A purposive sample of intervention sessions will be audio-recorded (n = 24) and half will additionally be observed (n = 12). Semi-structured interviews will take place at 2-weeks (n = 30) and 6-months (n = 15–20) post-randomisation. The primary analysis will compare cancer symptom recognition scores between arms at 2-weeks. Secondary analysis will assess cancer beliefs, barriers/time to presentation, screening and lifestyle behaviours, anxiety and costs. A process evaluation will assess intervention fidelity, dose and contamination