Recommendations for the use of next-generation sequencing (NGS) for patients with advanced cancer in 2024: a report from the ESMO Precision Medicine Working Group.

BACKGROUND: Advancements in the field of precision medicine have prompted the European Society for Medical Oncology (ESMO) Precision Medicine Working Group to update the recommendations for the use of tumour next-generation sequencing (NGS) for patients with advanced cancers in routine practice. METHODS: The group discussed the clinical impact of tumour NGS in guiding treatment decision using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) considering cost-effectiveness and accessibility. RESULTS: As for 2020 recommendations, ESMO recommends running tumour NGS in advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, and ovarian cancer. Moreover, it is recommended to carry out tumour NGS in clinical research centres and under specific circumstances discussed with patients. In this updated report, the consensus within the group has led to an expansion of the recommendations to encompass patients with advanced breast cancer and rare tumours such as gastrointestinal stromal tumours, sarcoma, thyroid cancer, and cancer of unknown primary. Finally, ESMO recommends carrying out tumour NGS to detect tumour-agnostic alterations in patients with metastatic cancers where access to matched therapies is available. CONCLUSION: Tumour NGS is increasingly expanding its scope and application within oncology with the aim of enhancing the efficacy of precision medicine for patients with cancer.

ESMO study on the availability and accessibility of biomolecular technologies in oncology in Europe.

BACKGROUND: Access to biomolecular technologies has become an essential requirement to ensure optimal and timely treatment of patients with cancer. This study sought to provide a comprehensive overview of the availability and accessibility of biomolecular technologies to patients, the status of their use and prescription, barriers to access, and potential economic issues related to cost and reimbursement. MATERIALS AND METHODS: A total of 201 field reporters from 48 European countries submitted data through an electronic survey tool between July and December 2021. The survey methodology mirrored that from previous ESMO studies addressing the availability and accessibility of antineoplastic medicines, in Europe and worldwide. The preliminary data were posted on the ESMO website for open peer-review, and amendments were incorporated into the final report. RESULTS: Overall, basic single-gene techniques are widely available, whereas access to advanced biomolecular technologies, including large next-generation sequencing panels and complete genomic profiles, is highly heterogeneous. In most countries, advanced biomolecular technologies remain largely inaccessible in clinical practice, are limited to clinical trials or basic research, and associated with progressively increasing cost as the technique becomes more advanced. Differences also exist regarding national sequencing initiatives or molecular tumour boards. The most important barriers to multiple versus single-gene sequencing techniques are the reimbursement of the test (59% versus 24%), and the availability of a suitable medicine, either through reimbursement of treatment (48% versus 30%), off-label treatment (52% versus 35%), or clinical trial enrolment (53% versus 39%). CONCLUSIONS: Cost and availability of both treatment and test are the two main factors limiting patients' access to advanced biomolecular technologies and as a consequence to innovative anticancer strategies. In the era of precision medicine, tackling the accessibility to biomolecular technologies is a key step to reduce inequalities to transformative cancer care.

Oncology phase I trial design and conduct: time for a change - MDICT Guidelines 2022.

In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.

Clinical utility of circulating tumor DNA sequencing with a large panel: a National Center for Precision Medicine (PRISM) study.

BACKGROUND: Circulating tumor DNA (ctDNA) sequencing is a promising approach for tailoring therapy in patients with cancer. We report hereby the results from a prospective study where we investigated the impact of comprehensive molecular profiling of ctDNA in patients with advanced solid tumors. PATIENTS AND METHODS: Genomic analysis was performed using the FoundationOne Liquid CDx Assay [324 genes, tumor mutational burden (TMB), microsatellite instability status]. Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB). Actionable targets were classified by ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) tier leading to molecular-based treatment suggestions wherever it was possible. RESULTS: Between December 2020 and November 2021, 1772 patients with metastatic solid tumors underwent molecular profiling. Median time to assay results was 12 days. Results were contributive for 1658 patients (94%). At least one actionable target was detected in 1059 patients (64%) with a total of 1825 actionable alterations including alteration of the DNA damage repair response pathway (n = 336, 18%), high TMB (>16 mutations/Mb; n = 243, 13%), PIK3CA mutations (n = 150, 8%), ERBB family pathway alterations (n = 127, 7%), PTEN alterations (n = 95, 5%), FGFR alterations (n = 67, 4%) and MET activations (n = 13, 0.7%). The MTB recommended a matched therapy for 597 patients (56%) with a total of 819 therapeutic orientations: clinical trials (n = 639, 78%), off-label/compassionate use (n = 81, 10%), approved drug (n = 51, 6%), and early access program (n = 48, 6%). In total, 122 patients (21%) were treated. Among the assessable patients (n = 107), 4 (4%) had complete response, 35 (33%) had partial response, 27 (25%) had stable disease, and 41 (38%) a progressive disease as best response. The median progression-free survival and median overall survival were 4.7 months (95% confidence interval 2.7-6.7 months) and 8.3 months (95% confidence interval 4.7-11.9 months) respectively. CONCLUSIONS: ctDNA sequencing with a large panel is an efficient approach to match patients with advanced cancer with targeted therapies.

Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group.

Next-generation sequencing (NGS) allows sequencing of a high number of nucleotides in a short time frame at an affordable cost. While this technology has been widely implemented, there are no recommendations from scientific societies about its use in oncology practice. The European Society for Medical Oncology (ESMO) is proposing three levels of recommendations for the use of NGS. Based on the current evidence, ESMO recommends routine use of NGS on tumour samples in advanced non-squamous non-small-cell lung cancer (NSCLC), prostate cancers, ovarian cancers and cholangiocarcinoma. In these tumours, large multigene panels could be used if they add acceptable extra cost compared with small panels. In colon cancers, NGS could be an alternative to PCR. In addition, based on the KN158 trial and considering that patients with endometrial and small-cell lung cancers should have broad access to anti-programmed cell death 1 (anti-PD1) antibodies, it is recommended to test tumour mutational burden (TMB) in cervical cancers, well- and moderately-differentiated neuroendocrine tumours, salivary cancers, thyroid cancers and vulvar cancers, as TMB-high predicted response to pembrolizumab in these cancers. Outside the indications of multigene panels, and considering that the use of large panels of genes could lead to few clinically meaningful responders, ESMO acknowledges that a patient and a doctor could decide together to order a large panel of genes, pending no extra cost for the public health care system and if the patient is informed about the low likelihood of benefit. ESMO recommends that the use of off-label drugs matched to genomics is done only if an access programme and a procedure of decision has been developed at the national or regional level. Finally, ESMO recommends that clinical research centres develop multigene sequencing as a tool to screen patients eligible for clinical trials and to accelerate drug development, and prospectively capture the data that could further inform how to optimise the use of this technology.

Patients' selection and trial matching in early-phase oncology clinical trials.

BACKGROUND: Early-phase clinical trials (EPCT) represent an important part of innovations in medical oncology and a valuable therapeutic option for patients with metastatic cancers, particularly in the era of precision medicine. Nevertheless, adult patients' participation in oncology clinical trials is low, ranging from 2% to 8% worldwide, with unequal access, and up to 40% risk of early discontinuation in EPCT, mostly due to cancer-related complications. DESIGN: We review the tools and initiatives to increase patients' orientation and access to early phase cancer clinical trials, and to limit early discontinuation. RESULTS: New approaches to optimize the early-phase clinical trial referring process in oncology include automatic trial matching, tools to facilitate the estimation of patients' prognostic and/or to better predict patients' eligibility to clinical trials. Classical and innovative approaches should be associated to double patient recruitment, improve clinical trial enrollment experience and reduce early discontinuation rates. CONCLUSIONS: Whereas EPCT are essential for patients to access the latest medical innovations in oncology, offering the appropriate trial when it is relevant for patients should increase by organizational and technological innovations. The oncologic community will need to closely monitor their performance, portability and simplicity for implementation in daily clinical practice.

Geolocalization of water-waves origin within water distribution networks using time reversal of first event detection.

Drinking water distribution networks in urban areas are daily subject to fast propagating pressure waves resulting from routine operations. These water-hammer waves lead to structural aging and facility damages, the origin of which is not easy to find but are sometimes of high managerial interest. In this contribution, we demonstrate that using a reasonable number of high-frequency pressure detectors distributed within the network combined with a proper post-processing method permits a close geolocalization of the damaging wave origin. The method is first tested and validated on a real water distribution network having approximately 26000 pipes, whereas considering a known, prescribed waveorigin, so that the sensitivity to sensor number (sensor spatial density), sensor location and signal-to-noise ratio on the geolocalization robustness are analyzed in detail. It is then applied and illustrated over real sensor recordings the result of which are validated on the field from history matching. This paper thus presents the first field-scale geolocalization of water-hammer events origin test as well conditions for which, given sensor density and signal-to-noise ratio, the geolocalization success is to be expected.

[Endovascular treatment of aortic isthmus ruptures: medium term results]. / Traitement endovasculaire des ruptures de l'isthme aortique: résultats à moyen terme.

UNLABELLED: Despite an improvement in the surgical management of aortic isthmus ruptures, the observed morbidity and mortality rates remain high. The use of aortic endoprostheses could improve these results, but there are not yet many medium term studies on ruptures of the isthmus. Between January 2000 and December 2005, we treated endovascularly 9 patients (7 males and 2 females) presenting with a rupture of the aortic isthmus, acute in 8 of them and chronic in one case. The average age was 46 years. All of the patients presented with significant traumatic co-morbidity. Ten endoprostheses were used in these 9 patients, and no immediate conversion was necessary. Complete excision of the lesions lasted on average 112 +/- 27 min and there were no per-operative deaths. Hospital mortality was 22% (2 patients: multiple organ failure on day 3, and a CVA on day 10). The mean length of hospital stay was 16 +/- 20 days. The mean follow up of the 7 surviving patients was 38 +/- 17 months. No complications relating to the endoprostheses were reported. In all of the patients an almost complete disappearance of lesions on CT scan was noted: by 6 months for the acute ruptures and at 1 year for the chronic rupture. CONCLUSION: the medium term results of endovascular treatment of isthmus ruptures are good.

[Evaluation of the analytical performances of CRP Diasys reagent on Roche Hitachi 917]. / Evaluation des performances analytiques du réactif CRP Diasys sur Roche Hitachi 917.

C reactive protein, the most sensible acute phase protein of inflammation and the labororatory should perform CRP testing on a continous 24 hour basis. The measurement is mainly performed by immunoturbimetry and immunonephelemetry methods available on multiparametric biochemical analyzer. In this study, we evaluated the analytical performances, precision and exactitude, of the CRP Diasys reagent on Roche Hitachi 917. The results were compared to those obtained with a CRP latex immunoassay (Roche). The reagent showed high analytical characteristics and especially a significant precision in a large range of CRP levels including low levels between 1 and 3 mg/L. Although this reagent is not considered as a high-sensitive CRP reagent, the measurement quality obtained in the 1-3 mg/L range allows an utilization as a cardiovascular risk predictor.

[Chronic dissection of the aorta after coronary bypass surgery]. / Dissection aortique chronique après pontages coronaires. Une stratégie chirurgicale difficile.

Dissection of the aorta is a potential complication of all forms of cardiac surgery. It occurs after a variable interval. When observed in the long term, surgery may be complex with greater technical difficulties resulting in increased postoperative morbidity and mortality compared with other types of dissection. These difficulties are all the more marked when the initial surgery is coronary bypass grafting and when the grafts, especially internal mammary artery grafts, remain patent. A surgical strategy has to be elaborated to prevent certain per- and postoperative complications. The authors report the case of a patient who developed a chronic dissection of the aorta 9 months after coronary bypass surgery with patent internal mammary artery grafts. In this situation, a strategy associating anterograde cerebral perfusion before the sternotomy and endovascular control of the internal mammary grafts was proposed.

Cooperation between general practitioners and diabetologists and clinical audit improve the management of type 2 diabetic patients.

A programme was set up in the Essonne (France) between 1994 and 1998 to improve the quality of care for Type 2 diabetic patients. A consensus panel of general practitioners and diabetes specialists established guidelines based on the French St. Vincent recommendations. An audit involving 73 volunteer general practitioners (out of 965 in the Essonne) then evaluated compliance with these guidelines. Care and outcome were assessed in 505 (1995) and 604 (1996) Type 2 diabetic patients. The first audit cycle showed that defined standards were not met for several criteria and also revealed a lack of standardisation of HbA1c measurements and delayed intervention when blood glucose control was inadequate. Corrective measures were adopted: cooperative protocols for foot care, prevention of nephropathy and retinopathy, standardisation of HbA1c, and an educational programme at the primary health care level. The second audit cycle showed improvement in foot care (+33.6%), quality (+39.9%), prescription of HbA1c (+11.9%), and control of blood pressure (+11.9%) and blood lipids (+12.8%). The proportion of early interventions in case of inadequate glucose control increased significantly (+10.5%). However, some gaps persisted, mainly regarding screening for complications, diet counselling and patient education. This study shows that cooperation between general practitioners and diabetes specialists is feasible and effective in the context of a district-wide approach, and that it facilitates the adoption of international guidelines by local physicians. A project has been developed to provide structured diabetes care in general practice and better access to specialist services in order to improve the outcome of Type 2 diabetic patients.