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With the increasing use of genomic profiling for diagnosis and therapy guidance in many tumor types, precision oncology is rapidly reshaping cancer care. However, the current trajectory of drug development in oncology results in a paradox: if patients cannot access advanced diagnostics, we may be developing drugs that will reach few patients. In this Perspective, we outline the major challenges to the implementation of precision oncology and discuss critical steps toward resolving these, including facilitation of equal access to genomics tests, ensuring that clinical studies provide robust evidence for new drugs and technologies, enabling physicians to interpret genomics data, and empowering patients toward shared decision-making. A multi-stakeholder approach to evidence generation, value assessment, and healthcare delivery is necessary to translate advances in precision oncology into benefits for patients with cancer globally. Precision medicine is reshaping cancer care, but the benefits are not accessible to all patients. This Perspective outlines the major challenges to the implementation of precision oncology and discusses critical steps toward resolving these.

Among the ‘most wanted’ targets in cancer therapy is the oncogene MYC, which coordinates key transcriptional programs in tumor development and maintenance. It has, however, long been considered undruggable. OMO-103 is a MYC inhibitor consisting of a 91-amino acid miniprotein. Here we present results from a phase 1 study of OMO-103 in advanced solid tumors, established to examine safety and tolerability as primary outcomes and pharmacokinetics, recommended phase 2 dose and preliminary signs of activity as secondary ones. A classical 3 + 3 design was used for dose escalation of weekly intravenous, single-agent OMO-103 administration in 21-day cycles, encompassing six dose levels (DLs). A total of 22 patients were enrolled, with treatment maintained until disease progression. The most common adverse events were grade 1 infusion-related reactions, occurring in ten patients. One dose-limiting toxicity occurred at DL5. Pharmacokinetics showed nonlinearity, with tissue saturation signs at DL5 and a terminal half-life in serum of 40 h. Of the 19 patients evaluable for response, 12 reached the predefined 9-week time point for assessment of drug antitumor activity, eight of those showing stable disease by computed tomography. One patient defined as stable disease by response evaluation criteria in solid tumors showed a 49% reduction in total tumor volume at best response. Transcriptomic analysis supported target engagement in tumor biopsies. In addition, we identified soluble factors that are potential pharmacodynamic and predictive response markers. Based on all these data, the recommended phase 2 dose was determined as DL5 (6.48 mg kg −1 ). ClinicalTrials.gov identifier: NCT04808362 . In this first-in-human phase 1 dose-escalation trial of OMO-103, a MYC inhibitor, in patients with solid tumors, treatment was safe and showed preliminary clinical activity along with demonstrated target engagement and identification of potential pharmacodynamic markers.

The current COVID-19 pandemic challenges oncologists to profoundly re-organize oncological care in order to dramatically reduce hospital visits and admissions and therapy-induced immune-related complications without compromising cancer outcomes. Since COVID-19 is a novel disease, guidance by scientific evidence is often unavailable, and impactful decisions are inevitably made on the basis of expert opinions. Here we report how the seven comprehensive cancer centers of Cancer Core Europe have organized their healthcare systems at an unprecedented scale and pace to make their operations ‘pandemic proof’. We identify and discuss many commonalities, but also important local differences, and pinpoint critical research priorities to enable evidence-based remodeling of cancer care during the COVID-19 pandemic. Also, we discuss how the current situation offers a unique window of opportunity for assessing the effects of de-escalating anticancer regimens, which may fast-forward the development of more-refined and less-toxic treatments. By sharing our joint experiences, we offer a roadmap for proceeding and aim to mobilize the global research community to generate the data that are critically needed to offer the best possible care to patients. The Cancer Core Europe centers share their experience on caring for patients with cancer during the COVID-19 pandemic ― a time of challenges and opportunities for cancer health professionals, researchers and patients alike.

Little is known about conversion disorder in childhood. To document clinical incidence, features, management and 12-month outcome of non-transient conversion disorder in under 16-year-olds in the U.K. and Ireland. Surveillance through the British Paediatric Surveillance Unit and Child and Adolescent Psychiatry Surveillance System. In total, 204 cases (age range 7-15 years) were reported, giving a 12-month incidence of 1.30/100 000 (95% CI 1.11-1.52). The most common symptoms were motor weakness and abnormal movements. Presentation with multiple symptoms was the norm. Antecedent stressors were reported for 80.8%, most commonly bullying in school. Most children required in-patient admission with frequent medical investigations. Follow-up at 12 months was available for 147 children, when all conversion disorder symptoms were reported as improved. Most families (91%) accepted a non-medical explanation of the symptoms either fully or partially. Childhood conversion disorder represents an infrequent but significant clinical burden in the UK and Ireland.

Oncogenic alterations in RET have been identified in multiple tumour types, including 1–2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC. ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0–2 (later limited to 0–1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1·1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis. Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50–71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50–86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were no treatment-related deaths in this population. Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC. Blueprint Medicines.

Cancer response to immunotherapy depends on the infiltration of CD8 + T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8 + T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8 + T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival. LIF is a pleiotropic cytokine that promotes an immunosuppressive microenvironment and has critical functions in embryonic development. Here, the authors show that LIF regulates CD8 +  T cell tumor infiltration in cancer by repressing CXCL19 and promoting the presence of protumoral macrophages and thatLIF inhibition, via neutralizing antibodies, promotes T cell infiltration and synergizes with immune checkpoint inhbitors resulting in tumor regression and immunological memory.

ObjectiveTo determine if an age-appropriate intervention is more effective than treatment as usual (TAU) in reducing post-traumatic stress disorder (PTSD) symptoms in parents/guardians of children discharged from paediatric intensive care unit (PICU).DesignA two-arm, parallel-group, single-centre randomised controlled trial.SettingPICU, St Mary’s Hospital, London, UK.PatientsChildren admitted to the PICU between July 2021 and September 2022, with a length of stay >24 hours, and a corrected gestational age of >36 weeks at the time of PICU admission, up to <16 years of age. Parents/guardians were required to be >18 years old. We predefined subgroups of children as those <4 years and those ≥4 years.InterventionAn age-appropriate educational booklet given at PICU discharge and a targeted telephone call at 6 weeks posthospital discharge.Main outcome(s) and measure(s)Parental PTSD symptoms 6 months after PICU discharge, measured by the Impact of Events Scale-Revised (IES-R).Results679 children were admitted to PICU, 212 were eligible for enrolment, 81 declined and 131 were included, of which 126 completed the study. 64 were randomised to TAU and 62 to intervention. 6-month questionnaires were returned by 60 families (36 from TAU group and 24 from intervention group (p=0.049)). There was no significant difference in IES-R scores between the TAU and intervention groups overall (IES-R score 37 vs 17 (p=0.132)). The ≥4-year intervention group had lower IES-R scores compared with TAU (13 in intervention vs 42 in TAU (p=0.008)). There was no difference in the <4-year group or in any secondary outcome.ConclusionsThis intervention was effective in reducing PTSD symptoms in parents of children ≥4 years after PICU discharge.Trial registration numberNCT04635449.

Early detection of immunotherapy-induced tumor response is of major benefit for patients but can be complicated by therapy-induced pseudoprogression. A consensus guideline-iRECIST- was developed as a modification of Response Evaluation Criteria in Solid Tumours (RECIST version 1.1). Here we describe which next steps are required to test its validity and how novel approaches for response criteria might be developed and included.

Cancer treatment has made significant strides towards the promise of personalized medicine. Recent scientific advances have shown that there are numerous genetic deregulations that are common in multiple cancer types, raising the possibility of developing drugs targeting those deregulations irrespective of the tumour type. Precision Cancer Medicine (PCM) was born out of accumulated evidence matching targeted agents with these tumour molecular deregulations. At the same time, the therapeutic armamentarium is rapidly increasing and the number of new drugs (including immune‐oncology agents) entering drug development continues to rise. These factors, added to strong collaboration with regulatory agencies, which have approved novel agents based on data obtained from phase 1/2 trials, have led to unprecedented evolution in the design of early‐stage clinical trials. Currently, we have seen rapid phase 1 dose‐escalation trials followed by remarkably large expansion cohorts, and are witnessing the emergence of new trials, such as adaptive studies with basket and umbrella designs aimed at optimizing the biomarker–drug co‐development process. Alongside the growing complexity of these clinical trials, new frameworks for stronger and faster collaboration between all stakeholders in drug development, including academic institutions and frameworks, clinicians, pharma companies and regulatory agencies, have been established. In this review article, we describe the main challenges and opportunities that these new trial designs may provide for a more efficient drug development process, which may ultimately help ensure that PCM becomes a reality for patients. New clinical trial designs are helping optimize early drug development. An umbrella trial is a master protocol for which the patient's eligibility is defined by the presence of a tumour type that is substratified according to specific molecular alterations matched to different anticancer therapies. Basket trials include patients with different tumour types with a common molecular alteration who are treated with the same matched therapy.