Publications by authors named "Paul Hofman"

650 Publications

Small but Challenging Conjunctival Melanoma: New Insights, Paradigms and Future Perspectives.

Cancers (Basel) 2021 Nov 14;13(22). Epub 2021 Nov 14.

Ophthalmology Department, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, 06000 Nice, France.

Although its incidence has increased over the last decades, conjunctival melanoma (CM) remains a rare but challenging periocular malignancy. While there is currently no recognized standard of care, "no-touch" surgical excision followed by adjuvant treatments is usually recommended. Despite its small size, managing CM is challenging for clinicians. The first challenge is the high risk of tumour local recurrence that occurs in about one third of the patients. The management of locally advanced CM (≥T2) or multiple recurrences may require mutilating surgeries such as orbital exenteration (OE). The second challenge is the metastatic spread of CM that occurs in about one quarter of patients, regardless of whether complete surgical excision is performed or not. This highlights the infiltrative and highly aggressive behaviour of CM. Recently, attention has been directed towards the use of eye-sparing strategies to avoid OE. Initially, wide conservative surgeries followed by customized brachytherapy or radiotherapy have appeared as viable strategies. Nowadays, new biological insights into CM have revealed similarities with cutaneous melanoma. These new findings have allowed clinicians to reconsider the management of locally advanced CM with "medical" eye-sparing treatment as well as the management of metastatic spread. The aim of this review was to summarize the current and future perspectives of treatment for CM based on recent biological findings.
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http://dx.doi.org/10.3390/cancers13225691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616295PMC
November 2021

COVID-19 vaccination and cancer immunotherapy: should they stick together?

Br J Cancer 2021 Nov 19. Epub 2021 Nov 19.

Université Côte d'Azur, Centre Antoine Lacassagne, EA7497, Nice, France.

The combination of COVID-19 vaccination with immunotherapy by checkpoint inhibitors in cancer patients could intensify immunological stimulation with potential reciprocal benefits. Here, we examine more closely the possible adverse events that can arise in each treatment modality. Our conclusion is that caution should be exercised when combining both treatments.
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http://dx.doi.org/10.1038/s41416-021-01618-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603902PMC
November 2021

Safety and cross-variant immunogenicity of a three-dose COVID-19 mRNA vaccine regimen in kidney transplant recipients.

EBioMedicine 2021 Nov 8;73:103679. Epub 2021 Nov 8.

Department of Nephrology, Dialysis and Transplantation, Pasteur 2 Hospital, Nice University Hospital, 30 voie Romaine, 06300, Nice, France; Laboratory of Molecular Physio Medicine, University Côte d'Azur, CNRS, 28 Avenue de Valombrose, 06107, Nice, France; Clinical Research Unit Côte d'Azur (UR2CA), University Côte d'Azur, 28 Avenue de Valombrose, 06107, Nice, France. Electronic address:

Background: The immunogenicity of a two-dose mRNA COVID-19 vaccine regimen is low in kidney transplant (KT) recipients. Here, we provide a thorough assessment of the immunogenicity of a three-dose COVID-19 vaccine regimen in this population.

Methods: We performed a prospective longitudinal study in sixty-one KT recipients given three doses of the BNT162b2 COVID-19 vaccine. We performed semi-structured pharmacovigilance interviews and monitored donor-specific antibodies and kidney function. We compared levels of anti-spike IgG, pseudo-neutralization activity against vaccine homologous and heterologous variants, frequency of spike-specific interferon (IFN)-γ-secreting cells, and antigen-induced cytokine production 28 days after the second and third doses.

Findings: Reactions to vaccine were mild. One patient developed donor-specific anti-HLA antibodies after the second dose which could be explained by non-adherence to immunosuppressive therapy. Spike-specific IgG seroconversion raised from 44·3% (n=27) after the second dose to 62·3% (n=38) after the third dose (p<0·05). The mean level of spike-specific IgG increased from 1620 (SD, 3460) to 8772 (SD, 16733) AU/ml (p<0·0001). Serum neutralizing activity increased after the third dose for all variants of concern tested including the Delta variant (p<0·0001). The frequency of spike-specific IFN-γ-secreting cells increased from 19·9 (SD, 56·0) to 64·0 (SD, 76·8) cells/million PBMCs after the third dose (p<0·0001). A significant increase in IFN-γ responses was also observed in patients who remained seronegative after three doses (p<0·0001).

Interpretation: A third dose of the BNT162b2 vaccine increases both cross-variant neutralizing antibody and cellular responses in KT recipients with an acceptable tolerability profile.

Funding: Nice University Hospital, University Cote d'Azur.
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http://dx.doi.org/10.1016/j.ebiom.2021.103679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573385PMC
November 2021

Evaluation of Sample Pooling for SARS-CoV-2 Detection in Nasopharyngeal Swab and Saliva Samples with the Idylla SARS-CoV-2 Test.

Microbiol Spectr 2021 Nov 10:e0099621. Epub 2021 Nov 10.

Laboratory of Clinical and Experimental Pathology, Centre Hospitalier Universitaire de Nice, FHU OncoAge, Université Côte d'Azur, Nice, France.

Due to increased demand for testing, as well as restricted supply chain resources, testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to face many hurdles. Pooling several samples has been proposed as an alternative approach to address these issues. We investigated the feasibility of pooling nasopharyngeal swab (NPS) or saliva samples for SARS-CoV-2 testing with a commercial assay (Idylla SARS-CoV-2 test; Biocartis). We evaluated the 10-pool and 20-pool approaches for 149 subjects, with 30 positive samples and 119 negative samples. The 10-pool approach had sensitivity of 78.95% (95% confidence interval [CI], 54.43% to 93.95%) and specificity of 100% (95% CI, 71.51% to 100%), whereas the 20-pool approach had sensitivity of 55.56% (95% CI, 21.20% to 86.30%) and specificity of 100% (95% CI, 25% to 100%). No significant difference was observed between the results obtained with pooled NPS and saliva samples. Given the rapidity, full automation, and practical advantages of the Idylla SARS-CoV-2 assay, pooling of 10 samples has the potential to significantly increase testing capacity for both NPS and saliva samples, with good sensitivity. To control outbreaks of coronavirus disease 2019 (COVID-19) and to avoid reagent shortages, testing strategies must be adapted and maintained for the foreseeable future. We analyzed the feasibility of pooling NPS and saliva samples for SARS-CoV-2 testing with the Idylla SARS-CoV-2 test, and we found that sensitivity was dependent on the pool size. The SARS-CoV-2 testing capacity with both NPS and saliva samples could be significantly expanded by pooling 10 samples; however, pooling 20 samples resulted in lower sensitivity.
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http://dx.doi.org/10.1128/Spectrum.00996-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579845PMC
November 2021

Can screening for low vitamin D levels prevent bone health complications in paediatric oncology patients?

Cancer Rep (Hoboken) 2021 Oct 26:e1534. Epub 2021 Oct 26.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Background: No international standards include vitamin D levels at diagnosis or during treatment. It is included in the Children's Oncology Group long-term follow-up guidelines. However, bone health complications (like osteopenia and atraumatic fractures) can occur at diagnosis or during treatment as well.

Cases: In this small case series, we illustrate the complexity of bone health complications among our broad paediatric oncology population. If the vitamin D level is low we supplement the patient with one standard oral dose (150 000 units for 1-2 year olds, 300 000 units for 2-5 year olds and 600 000 units for >5 year olds). We do not adjust depending on diagnosis.

Conclusion: Because of the potentially negative outcomes on short, medium and long term, we recommend checking vitamin D levels on diagnosis for all newly diagnosed patients. It is a simple, low cost test and one dose of oral supplementation can easily treat the deficiency.
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http://dx.doi.org/10.1002/cnr2.1534DOI Listing
October 2021

The associations between maternal BMI and gestational weight gain and health outcomes in offspring at age 1 and 7 years.

Sci Rep 2021 Oct 21;11(1):20865. Epub 2021 Oct 21.

Liggins Institute, University of Auckland, Auckland, New Zealand.

In secondary analyses of a randomised controlled trial of exercise during pregnancy, we examined associations between mid-pregnancy maternal body mass index (BMI) and excessive gestational weight gain (GWG) with offspring health. Follow-up data were available on 57 mother-child pairs at 1-year and 52 pairs at 7-year follow-ups. Clinical assessments included body composition and fasting blood tests. At age 1 year, increased maternal BMI in mid-gestation was associated with greater weight standard deviation scores (SDS) in the offspring (p = 0.035), with no observed associations for excessive GWG. At age 7 years, greater maternal BMI was associated with increased weight SDS (p < 0.001), BMI SDS (p = 0.005), and total body fat percentage (p = 0.037) in their children. Irrespective of maternal BMI, children born to mothers with excessive GWG had greater abdominal adiposity (p = 0.043) and less favourable lipid profile (lower HDL-C and higher triglycerides). At 7 years, maternal BMI and excessive GWG had compounded adverse associations with offspring adiposity. Compared to offspring of mothers with overweight/obesity plus excessive GWG, children of normal-weight mothers with adequate and excessive GWG were 0.97 and 0.64 SDS lighter (p = 0.002 and p = 0.014, respectively), and 0.98 and 0.63 SDS leaner (p = 0.001 and p = 0.014, respectively). Both greater maternal BMI in mid-pregnancy and excessive GWG were independently associated with increased adiposity in offspring at 7 years.
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http://dx.doi.org/10.1038/s41598-021-99869-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531053PMC
October 2021

Automated Analysis of Proliferating Cells Spatial Organisation Predicts Prognosis in Lung Neuroendocrine Neoplasms.

Cancers (Basel) 2021 Sep 29;13(19). Epub 2021 Sep 29.

Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.

Lung neuroendocrine neoplasms (lung NENs) are categorised by morphology, defining a classification sometimes unable to reflect ultimate clinical outcome. Subjectivity and poor reproducibility characterise diagnosis and prognosis assessment of all NENs. Here, we propose a machine learning framework for tumour prognosis assessment based on a quantitative, automated and repeatable evaluation of the spatial distribution of cells immunohistochemically positive for the proliferation marker Ki-67, performed on the entire extent of high-resolution whole slide images. Combining features from the fields of graph theory, fractality analysis, stochastic geometry and information theory, we describe the topology of replicating cells and predict prognosis in a histology-independent way. We demonstrate how our approach outperforms the well-recognised prognostic role of Ki-67 Labelling Index on a multi-centre dataset comprising the most controversial lung NENs. Moreover, we show that our system identifies arrangement patterns in the cells positive for Ki-67 that appear independently of tumour subtyping. Strikingly, the subset of these features whose presence is also independent of the value of the Labelling Index and the density of Ki-67-positive cells prove to be especially relevant in discerning prognostic classes. These findings disclose a possible path for the future of grading and classification of NENs.
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http://dx.doi.org/10.3390/cancers13194875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508355PMC
September 2021

Genomic and evolutionary classification of lung cancer in never smokers.

Nat Genet 2021 09 6;53(9):1348-1359. Epub 2021 Sep 6.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS.
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http://dx.doi.org/10.1038/s41588-021-00920-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432745PMC
September 2021

New technologies for improved relevance in miRNA research.

Trends Genet 2021 Dec 30;37(12):1060-1063. Epub 2021 Aug 30.

Université Côte d'Azur, Institute of Research on Cancer and Ageing of Nice (IRCAN), Centre Antoine Lacassagne, CNRS, INSERM, Nice, France; FHU-OncoAge, Nice, France. Electronic address:

After a number of years of research in the field of miRNA, the robustness and biological relevance of many published articles is increasingly being questioned. We propose the use of new RNA-seq approaches, genome editing technologies, and updated public databases to improve the quality, reliability, and relevance of published data.
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http://dx.doi.org/10.1016/j.tig.2021.08.006DOI Listing
December 2021

Status Assessment for Better Care of Early Stage Non-Small Cell Lung Carcinoma: What Is Changing in the Daily Practice of Pathologists?

Authors:
Paul Hofman

Cells 2021 08 21;10(8). Epub 2021 Aug 21.

Laboratory of Clinical and Experimental Pathology, CHU Nice, FHU OncoAge, Pasteur Hospital, Université Côte d'Azur, 06108 Nice, France.

The recent emergence of novel neoadjuvant and/or adjuvant therapies for early stage (I-IIIA) non-small cell lung carcinoma (NSCLC), mainly tyrosine kinase inhibitors (TKIs) targeting mutations and immunotherapy or chemo-immunotherapy, has suddenly required the evaluation of biomarkers predictive of the efficacy of different treatments in these patients. Currently, the choice of one or another of these treatments mainly depends on the results of immunohistochemistry for PD-L1 and of the status of and . This new development has led to the setup of different analyses for clinical and molecular pathology laboratories, which have had to rapidly integrate a number of new challenges into daily practice and to establish new organization for decision making. This review outlines the impact of the management of biological samples in laboratories and discusses perspectives for pathologists within the framework of TKIs in early stage NSCLC.
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http://dx.doi.org/10.3390/cells10082157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392580PMC
August 2021

Perspectives and Issues in the Assessment of Deficiency in the Management of Lung Cancer Patients.

Cells 2021 07 29;10(8). Epub 2021 Jul 29.

Laboratory of Clinical and Experimental Pathology, Hospital-Integrated Biobank (BB-0033-00025), Nice Hospital University, FHU OncoAge, Université Côte d' Azur, 06000 Nice, France.

Lung cancers are ranked third among the cancer incidence in France in the year 2020, with adenocarcinomas being the commonest sub-type out of ~85% of non-small cell lung carcinomas. The constant evolution of molecular genotyping, which is used for the management of lung adenocarcinomas, has led to the current focus on tumor suppressor genes, specifically the loss of function mutation in the gene. -deficient adenocarcinomas are preponderant in younger aged male smokers with a predominant solid morphology. The importance of identifying -deficient adenocarcinomas has gained interest for lung cancer management due to its aggressive behavior at diagnosis with vascular invasion and metastasis to the pleura seen upon presentation in most cases. These patients have poor clinical outcome with short overall survival rates, regardless of the stage of disease. The detection of deficiency is possible in most pathology labs with the advent of sensitive and specific immunohistochemical antibodies. The gene mutations can be detected together with other established lung cancer molecular markers based on the current next generation sequencing panels. Sequencing will also allow the identification of associated gene mutations, notably , , and which have an impact on the overall survival and progression-free survival of the patients. Predictive data on the treatment with anti-PD-L1 are currently uncertain in this high tumor mutational burden cancer, which warrants more groundwork. Identification of target drugs is also still in pre-clinical testing. Thus, it is paramount to identify the -deficient adenocarcinoma, as it carries worse repercussions on patient survival, despite having an exceptionally low prevalence. Herein, we discuss the pathophysiology of , the clinicopathological consequences, and different detection methods, highlighting the perspectives and challenges in the assessment of deficiency for the management of non-small cell lung cancer patients. This is imperative, as the contemporary shift on identifying biomarkers associated with tumor suppressor genes such as are trending; hence, awareness of pathologists and clinicians is needed for the -dNSCLC entity with close follow-up on new management strategies to overcome the poor possibilities of survival in such patients.
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http://dx.doi.org/10.3390/cells10081920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394288PMC
July 2021

Reference standards for gene fusion molecular assays on cytological samples: an international validation study.

J Clin Pathol 2021 Aug 24. Epub 2021 Aug 24.

Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium.

Aims: Gene fusions assays are key for personalised treatments of advanced human cancers. Their implementation on cytological material requires a preliminary validation that may make use of cell line slides mimicking cytological samples. In this international multi-institutional study, gene fusion reference standards were developed and validated.

Methods: Cell lines harbouring (13)(20) and (4)(32) gene fusions were adopted to prepare reference standards. Eight laboratories (five adopting amplicon-based and three hybridisation-based platforms) received, at different dilution points two sets of slides (slide A 50.0%, slide B 25.0%, slide C 12.5% and slide D wild type) stained by Papanicolaou (Pap) and May Grunwald Giemsa (MGG). Analysis was carried out on a total of 64 slides.

Results: Four (50.0%) out of eight laboratories reported results on all slides and dilution points. While 12 (37.5%) out of 32 MGG slides were inadequate, 27 (84.4%) out of 32 Pap slides produced libraries adequate for variant calling. The laboratories using hybridisation-based platforms showed the highest rate of inadequate results (13/24 slides, 54.2%). Conversely, only 10.0% (4/40 slides) of inadequate results were reported by laboratories adopting amplicon-based platforms.

Conclusions: Reference standards in cytological format yield better results when Pap staining and processed by amplicon-based assays. Further investigation is required to optimise these standards for MGG stained cells and for hybridisation-based approaches.
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http://dx.doi.org/10.1136/jclinpath-2021-207825DOI Listing
August 2021

Five-year follow-up of a family-based multidisciplinary program for children with obesity.

Obesity (Silver Spring) 2021 09 9;29(9):1458-1468. Epub 2021 Aug 9.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Objective: This study aimed to determine 5-year outcomes from a 12-month, family-based, multidisciplinary lifestyle intervention program for children.

Methods: This study was the 5-year follow-up of a randomized clinical trial comparing a low-intensity control group (home-based assessments) with a high-intensity intervention group (assessments plus weekly sessions) in New Zealand. Participants were aged 5 to 16 years with BMI ≥ 98th centile or > 91st centile with weight-related comorbidities. The primary outcome was BMI standard deviation score (BMISDS). Secondary outcomes included various health markers.

Results: Of the 199 children included in the study at baseline (47% who identified as Māori, 53% who identified as female, 28% in the most deprived quintile, mean age = 10.7 years, mean BMISDS = 3.12), 86 completed a 5-year assessment (43%). BMISDS reduction at 12 months was not retained (control = 0.00 [95% CI: -0.22 to 0.21] and intervention = 0.17 [95% CI: -0.01 to 0.34]; p = 0.221) but was greater in participants aged <10 years versus >10 years at baseline (-0.15 [95% CI: -0.33 to 0.03] vs. 0.21 [95% CI: 0.03 to 0.40]; p = 0.008). BMISDS trajectory favored participants with high attendance (p = 0.013). There were persistent improvements in water intake and health-related quality of life in both groups as well as reduced sweet drink intake in the intervention group.

Conclusions: This intervention, with high engagement from those most affected by obesity, did not achieve long-term efficacy of the primary outcome. Attendance and age remain important considerations for future interventions to achieve long-term BMISDS reduction.
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http://dx.doi.org/10.1002/oby.23225DOI Listing
September 2021

Detection of ALK fusion transcripts in plasma of non-small cell lung cancer patients using a novel RT-PCR based assay.

Ann Transl Med 2021 Jun;9(11):922

University Côte d'Azur, Nice, France.

Background: Detection of genomic rearrangements, like anaplastic lymphoma kinase () fusions, is a pivotal requirement in non-small cell lung cancer (NSCLC) for the initiation of a targeted treatment. While tissue testing remains the gold standard, detection of these alterations using liquid biopsies is an unmet need. To enable the detection of rearrangements from circulating-free RNA (cfRNA) from NSCLC patients, we have evaluated a novel reverse transcription PCR (RT-PCR) based assay.

Methods: Sixty-six patients with advanced stage NSCLC were included in the study. ALK status was determined by immunohistochemistry (IHC) and/or FISH on tissue sections. For the detection of rearrangements from 2ml plasma collected in EDTA or Streck BCT DNA tubes, cfRNA was extracted using a prototype cfRNA sample preparation method and tested by a novel multiplex ALK/RET RT-PCR assay (Roche).

Results: Of the forty-two patients with an rearrangement, 30 (71%) were included at baseline. In 10 of the baseline patients, an rearrangement was detected by RT-PCR [baseline sensitivity 33.33% (95% CI: 17.29-52.81%)]. All 24 negative ALK IHC/FISH-negative patients were negative using the RT-PCR based assay (specificity =100%).

Conclusions: The prototype Roche ALK/RET RT-PCR assay was able to detect fusion transcripts in the plasma of NSCLC patients at baseline as well as at disease progression with limited sensitivity but high specificity. Consequently, this assay could potentially be considered to select patients for an ALK-targeting therapy when tissue samples are lacking.
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http://dx.doi.org/10.21037/atm-20-7900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263889PMC
June 2021

A rapid near-patient RT-PCR test for suspected COVID-19: a study of the diagnostic accuracy.

Ann Transl Med 2021 Jun;9(11):921

Institute of Research on Cancer and Aging (IRCAN), Université Côte d'Azur, CNRS, INSERM, Nice, France.

Background: Management of large numbers of reverse transcriptase-polymerase chain reactions (RT-PCR) for diagnosis of coronavirus 2019 disease (COVID-19) requires robust infrastructures, located in dedicated premises with a high standard of biosafety procedures, and well-trained personnel. The handling of a "run-of-river sample" to obtain rapid reporting of results is challenging.

Methods: We studied the clinical performance of the Idylla™ SARS-CoV-2 Test (index test) on a platform capable of fully automated nucleic acid testing including extraction, amplification, and detection in a single-use cartridge to establish the diagnosis of COVID-19. The study was conducted on a prospective cohort of 112 volunteers with recent symptoms and an unknown SARS-CoV-2 status who came to free screening centers of the Nice metropolitan area. All subjects underwent bilateral nasopharyngeal sampling. One sample was processed using the index test, the other using the standard of care RT-PCR. Samples were treated blind.

Results: Most of the participants (70%) were sampled within 4 days of symptom onset. Forty-five (40.2%) were positive for COVID-19. No clinical symptoms were distinguished between SARS-CoV-2 RT-PCR positive and negative subjects except anosmia and dysgeusia. Positive and negative agreement between the index and the standard of care test was 100%.

Conclusions: The Idylla™ SARS-CoV-2 Test is very sensitive, specific, rapid and easy to use in a near-patient RT-PCR approach to distinguish between symptomatic SARS-CoV-2 positive and negative patients in selected settings.
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http://dx.doi.org/10.21037/atm-21-690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263856PMC
June 2021

To inhibit or to boost the ATP/P2RX7 pathway to fight cancer-that is the question.

Purinergic Signal 2021 Aug 4. Epub 2021 Aug 4.

Université Côte D'Azur, CNRS, INSERM, IRCAN, 06108, Nice, France.

Despite new biological insights and recent therapeutic advances, many tumors remain at baseline during treatments. Therefore, there is an urgent need to find new therapeutic strategies to improve the care of patients with solid tumors. P2RX7 receptor (P2XR7), an ATP-gated ion channel characterized by its ability to form large pore within the cell membrane, is described by most of the investigators as a "chef d'orchestre" of the antitumor immune response. The purpose of this review is to detail the recent information concerning different cellular mechanisms linking P2RX7 to hallmarks of cancer and to discuss different progresses in elucidating how activation of the ATP/P2RX7/NLRP3/IL-18 pathway is a very promising approach to fight cancer progression by increasing antitumor immune responses.
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http://dx.doi.org/10.1007/s11302-021-09811-9DOI Listing
August 2021

Health system barriers to accessing care for children with weight issues in New Zealand: An interview-based study.

J Health Serv Res Policy 2021 10 20;26(4):234-241. Epub 2021 Jul 20.

Department of Paediatrics: Child and Youth Health, University of Auckland, New Zealand.

Objective: To identify barriers created and maintained by the health system affecting engagement in a family-based multidisciplinary healthy lifestyle programme for children and adolescents in New Zealand.

Methods: We conducted 64 semi-structured interviews with participants of the programme (n = 71) with varying levels of engagement, including those who declined contact after their referral. Half the interviews were with families with Māori children, allowing for appropriate representation. Interviews were analysed using thematic analysis.

Results: Five health system factors affecting engagement were identified: the national policy environment, funding constraints, lack of coordination between services, difficulty navigating the health system, and the cost of primary health care.

Conclusions: Engaging with a health system that creates and maintains substantial barriers to accessing services is difficult, affecting programme engagement, even where service-level barriers have been minimised. Lack of access remains a crucial barrier to improved health outcomes for children and their families experiencing childhood obesity in New Zealand. There is a need for comprehensive approaches that are accompanied by a clear implementation strategy and coordinated across sectors.
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http://dx.doi.org/10.1177/13558196211016011DOI Listing
October 2021

Weekly Lonapegsomatropin in Treatment-Naïve Children With Growth Hormone Deficiency: The Phase 3 heiGHt Trial.

J Clin Endocrinol Metab 2021 10;106(11):3184-3195

Ascendis Pharma, A/S, Hellerup, Denmark.

Context: For children with growth hormone deficiency (GHD), treatment burden with daily somatropin injections [human growth hormone (hGH)] is high, which may lead to poor adherence and suboptimal overall treatment outcomes. Lonapegsomatropin (TransCon hGH) is an investigational long-acting, once-weekly prodrug for the treatment of GHD.

Objective: The objective of this study was to evaluate the efficacy and safety of once-weekly lonapegsomatropin vs daily somatropin.

Design: The heiGHt trial was a randomized, open-label, active-controlled, 52-week Phase 3 trial (NCT02781727).

Setting: This trial took place at 73 sites across 15 countries.

Patients: This trial enrolled and dosed 161 treatment-naïve, prepubertal patients with GHD.

Interventions: Patients were randomized 2:1 to receive lonapegsomatropin 0.24 mg hGH/kg/week or an equivalent weekly dose of somatropin delivered daily.

Main Outcome Measure: The primary end point was annualized height velocity (AHV) at week 52. Secondary efficacy end points included change from baseline in height SD scores (SDS).

Results: Least squares (LS) mean (SE) AHV at 52 weeks was 11.2 (0.2) cm/year for lonapegsomatropin vs 10.3 (0.3) cm/year for daily somatropin (P = 0.009), with lonapegsomatropin demonstrating both noninferiority and superiority over daily somatropin. LS mean (SE) height SDS increased from baseline to week 52 by 1.10 (0.04) vs 0.96 (0.05) in the weekly lonapegsomatropin vs daily somatropin groups (P = 0.01). Bone age/chronological age ratio, adverse events, tolerability, and immunogenicity were similar between groups.

Conclusions: The trial met its primary objective of noninferiority in AHV and further showed superiority of lonapegsomatropin compared to daily somatropin, with similar safety, in treatment-naïve children with GHD.
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http://dx.doi.org/10.1210/clinem/dgab529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530727PMC
October 2021

New Targeted Therapies and Immunotherapies for Locally Advanced Periocular Malignant Tumours: Towards a New 'Eye-Sparing' Paradigm?

Cancers (Basel) 2021 Jun 5;13(11). Epub 2021 Jun 5.

Department of Ophthalmology, University Hospital of Nice, Cote d'Azur University, 06000 Nice, France.

The management of periocular skin malignant tumours is challenging. Surgery remains the mainstay of treatment for localised eyelid cancers. For more locally advanced cancers, especially those invading the orbit, orbital exenteration has long been considered the gold standard; however, it is a highly disfiguring and traumatic surgery. The last two decades have been marked by the emergence of a new paradigm shift towards the use of 'eye-sparing' strategies. In the early 2000s, the first step consisted of performing wide conservative eyelid and orbital excisions. Multiple flaps and grafts were needed, as well as adjuvant radiotherapy in selected cases. Although being incredibly attractive, several limitations such as the inability to treat the more posteriorly located orbital lesions, as well as unbearable diplopia, eye pain and even secondary eye loss were identified. Therefore, surgeons should distinguish 'eye-sparing' from 'sight-sparing' strategies. The second step emerged over the last decade and was based on the development of targeted therapies and immunotherapies. Their advantages include their potential ability to treat almost all tumours, regardless of their locations, without performing complex surgeries. However, several limitations have been reported, including their side effects, the appearance of primary or secondary resistances, their price and the lack of consensus on treatment regimen and exact duration. The aim of this article was to review the evolution of the management of locally advanced periocular malignant tumours over the last three decades and highlight the new paradigm shift towards the use of 'eye-sparing' strategies.
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http://dx.doi.org/10.3390/cancers13112822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201354PMC
June 2021

The cost of investigating weight-related comorbidities in children and adolescents in Aotearoa/New Zealand.

J Paediatr Child Health 2021 Jul 1. Epub 2021 Jul 1.

Department of Paediatrics: Child and Youth Health, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Aim: Expert recommendations for child/adolescent obesity include extensive investigation for weight-related comorbidities, based on body mass index (BMI) percentile cut-offs. This study aimed to estimate the cost of initial investigations for weight-related comorbidities in children/adolescents with obesity, according to international expert guidelines.

Methods: The annual mean cost of investigations for weight-related comorbidities in children/adolescents was calculated from a health-funder perspective using 2019 cost data obtained from three New Zealand District Health Boards. Prevalence data for child/adolescent obesity (aged 2-14 years) were obtained from the New Zealand Health Survey (2017/2018), and prevalence of weight-related comorbidities requiring further investigation were obtained from a previous New Zealand study of a cohort of children with obesity.

Results: The cost of initial laboratory screening for weight-related comorbidities per child was NZD 28.36. Based on national prevalence data from 2018/2019 for children with BMI greater than the 98th percentile (obesity cut-off), the total annual cost for initial laboratory screening for weight-related comorbidities in children/adolescents aged 2-14 years with obesity was estimated at NZD 2,665,840. The cost of further investigation in the presence of risk factors was estimated at NZD 2,972,934.

Conclusions: Investigating weight-related comorbidities in New Zealand according to international expert guidelines is resource-intensive. Ways to further determine who warrants investigation with an individualised approach are required.
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http://dx.doi.org/10.1111/jpc.15618DOI Listing
July 2021

PD-L1 regulation revisited: impact on immunotherapeutic strategies.

Trends Mol Med 2021 09 26;27(9):868-881. Epub 2021 Jun 26.

Université Côte d'Azur, IRCAN, CNRS, Inserm, Centre Antoine Lacassagne, FHU-OncoAge, Nice, France. Electronic address:

A particularly promising cancer treatment is the use of monoclonal antibodies (mAbs) against immune checkpoints (i.e., immune checkpoint inhibitors; ICIs). However, many patients experience relapse and severe adverse events. To overcome these negative issues and improve efficiency, current approaches rely on combinatorial treatments, including some modulating the expression of programmed cell death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoints directly. In this review, we examine the recently discovered pathways involved in PD-L1 expression and highlight the relevant druggable strategies that are being developed to both improve the response rate and avoid the onset of resistance. Altogether, these new strategies will pave the way for effective treatment combinations in future oncology clinical trials.
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http://dx.doi.org/10.1016/j.molmed.2021.06.005DOI Listing
September 2021

The Carcinogen Cadmium Activates Lysine 63 (K63)-Linked Ubiquitin-Dependent Signaling and Inhibits Selective Autophagy.

Cancers (Basel) 2021 May 20;13(10). Epub 2021 May 20.

Université Côte d'Azur, Institute of Research on Cancer and Aging in Nice (IRCAN), Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération Hospitalo-Universitaire (FHU) OncoAge, Centre Antoine Lacassagne, F-06189 Nice, France.

Signaling, proliferation, and inflammation are dependent on K63-linked ubiquitination-conjugation of a chain of ubiquitin molecules linked via lysine 63. However, very little information is currently available about how K63-linked ubiquitination is subverted in cancer. The present study provides, for the first time, evidence that cadmium (Cd), a widespread environmental carcinogen, is a potent activator of K63-linked ubiquitination, independently of oxidative damage, activation of ubiquitin ligase, or proteasome impairment. We show that Cd induces the formation of protein aggregates that sequester and inactivate cylindromatosis (CYLD) and selective autophagy, two tumor suppressors that deubiquitinate and degrade K63-ubiquitinated proteins, respectively. The aggregates are constituted of substrates of selective autophagy-SQSTM1, K63-ubiquitinated proteins, and mitochondria. These protein aggregates also cluster double-membrane remnants, which suggests an impairment in autophagosome maturation. However, failure to eliminate these selective cargos is not due to alterations in the general autophagy process, as degradation of long-lived proteins occurs normally. We propose that the simultaneous disruption of CYLD and selective autophagy by Cd feeds a vicious cycle that further amplifies K63-linked ubiquitination and downstream activation of the NF-κB pathway, processes that support cancer progression. These novel findings link together impairment of selective autophagy, K63-linked ubiquitination, and carcinogenesis.
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http://dx.doi.org/10.3390/cancers13102490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161291PMC
May 2021

Birth Weight- or Gestational Age-adjusted Second-tier LCMSMS Cutoffs Improve Newborn Screening for CAH in New Zealand.

J Clin Endocrinol Metab 2021 08;106(9):e3390-e3399

Clinical Research Unit, Liggins Institute, University of Auckland, Auckland, New Zealand.

Context: The positive predictive value of newborn screening for congenital adrenal hyperplasia (CAH) in New Zealand is approximately 10%. The use of a second tier liquid chromatography-tandem mass spectrometry bloodspot steroid profile test with birth weight- or gestational age-adjusted screening cutoffs may result in further screening improvements.

Methods: Three years of newborn screening data with additional second-tier steroid metabolites was evaluated (n = 167 672 births). Data from babies with a negative screening test and confirmed CAH cases were compared. First- and second-tier steroid measurements were correlated with both birth weight and gestational age. Analysis of variance was used to determine birth weight and gestational age groups. Screening cutoffs were determined and applied retrospectively to model screening performance.

Results: First-tier immunoassay data correlated better with gestational age than with birth weight, but there was no difference with second-tier steroid measurements. Four distinct birth weight and gestational age groups were established for 17-hydroxyprogesterone and a steroid ratio measurement. Application of 97.5th percentile second-tier birth weight- or gestational age-adjusted cutoffs would result in 10 positive tests over the period of the study with 8 true-positive screens and 2 false-positive tests. The positive predictive value of screening would be increased from 10.8% to 80%.

Conclusions: The use of either birth weight- or gestational age-adjusted cutoffs for second-tier screening tests can significantly reduce the false positive rate of newborn screening for CAH in New Zealand without loss in screening sensitivity.
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http://dx.doi.org/10.1210/clinem/dgab383DOI Listing
August 2021

Evidence of a plateau in the incidence of type 1 diabetes in children 0-4 years of age from a regional pediatric diabetes center; Auckland, New Zealand: 1977-2019.

Pediatr Diabetes 2021 09 4;22(6):854-860. Epub 2021 Jun 4.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Objective: To determine the incidence of new onset type 1 diabetes in children aged 0-14 years from 1977 to 2019 in Auckland, New Zealand.

Research Design And Methods: A cohort study of children with type 1 diabetes aged 0-14 years (n = 1688; 50.4% male) managed by the regional diabetes service between 1977 and 2019. Incidence rates were estimated using census data.

Results: The incidence of type 1 diabetes increased by 2.9%/year from 1977 to 2006 (95% confidence interval [CI] 2.13% - 3.48%). Although there was no significant change from 2006 to 2019 (-0.3%/year, 95% CI -1.62% - 1.08%), there was a dramatic fall from 1976 to 2018 in the proportion of New Zealand Europeans, from 69.9 to 33.9%. New Zealand Europeans had the highest incidence (23.3/100,000, 95% CI 20.6-26.1) compared to Māori (8.3/100,000, 95% CI 6.3-10.2), Pasifika (8.6/100,000, 95% CI 6.9-10.4) and other (6.4/100,000, 95% CI 4.7-8.0). All groups showed an overall increase in incidence over time, Māori 4.4%/year, Pasifika 3.7%, compared to New Zealand European 2.7%, and other 2.1%. Incidence increased consistently in 5-9 and 10-14 year olds (2.0% and 2.2%/year, respectively). By contrast, whereas 0-4 year olds showed an increase of 4.6%/year from 1977 to 2003 (p < 0.01), there was no change from 2003 to 2019 (p = 0.2).

Conclusion: There has been a plateau in the incidence of type 1 diabetes in children 0-4 years of age in the Auckland region since 2003, but not older children. The apparent plateau in the overall incidence of new onset type 1 diabetes in children 0-14 years since 2006 was mediated by substantial changes in the ethnic makeup of the Auckland region.
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http://dx.doi.org/10.1111/pedi.13236DOI Listing
September 2021

Targeting histone deacetylase enhances the therapeutic effect of Erastin-induced ferroptosis in -activating mutant lung adenocarcinoma.

Transl Lung Cancer Res 2021 Apr;10(4):1857-1872

Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

Background: Intrinsic or acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is common, thus strategies for the management of EGFR-TKIs resistance are urgently required. Ferroptosis is a recently discovered form of cell death that has been implicated in tumorigenesis and resistance treatment. Accumulating evidence suggests that ferroptosis can be therapeutically exploited for the treatment of solid tumors; however, whether ferroptosis can be targeted to treat mutant lung cancer and/or overcome the resistance to EGFR-TKIs is still unknown.

Methods: The effect of ferroptosis inducers on a panel of mutant lung cancer cell lines, including those with EGFR-TKI intrinsic and acquired (generated by long-term exposure to the third-generation EGFR-TKI osimertinib), was determined using cytotoxicity assays. Further, drug candidates to enhance the effect of ferroptosis inducers were screened through implementing WGCNA (weighted gene co-expression network analysis) and CMAP (connectivity map) analysis. Flow cytometry-based apoptosis and lipid hydroperoxides measurement were used to evaluate the cell fates after treatment.

Results: Compared with EGFR-TKI-sensitive cells, those with intrinsic or acquired resistance to EGFR-TKI display high sensitivity to ferroptosis inducers. In addition, Vorinostat, a clinically used inhibitor targeting histone deacetylase, can robustly enhance the efficacy of ferroptosis inducers, leading to a dramatic increase of hydroperoxides in mutant lung cancer cells with intrinsic or acquired resistance to EGFR-TKI. Mechanistically, Vorinostat promotes ferroptosis via xCT downregulation.

Conclusions: Ferroptosis-inducing therapy shows promise in -activating mutant lung cancer cells that display intrinsic or acquired resistance to EGFR-TKI. Histone deacetylase inhibitor (HDACi) Vorinostat can further promote ferroptosis by inhibiting xCT expression.
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http://dx.doi.org/10.21037/tlcr-21-303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107764PMC
April 2021

Participants' and caregivers' experiences of a multidisciplinary programme for healthy lifestyle change in Aotearoa/New Zealand: a qualitative, focus group study.

BMJ Open 2021 05 11;11(5):e043516. Epub 2021 May 11.

Kōhatu-Centre for Hauora Māori, University of Otago, Dunedin, New Zealand.

Objective: Child and adolescent obesity continues to be a major health issue internationally. This study aims to understand the views and experiences of caregivers and participants in a child and adolescent multidisciplinary programme for healthy lifestyle change.

Design: Qualitative focus group study.

Setting: Community-based healthy lifestyle intervention programme in a mixed urban-rural region of Aotearoa/New Zealand.

Participants: Parents/caregivers (n=6) and children/adolescents (n=8) who participated in at least 6 months of an assessment and weekly session, family-based community intervention programme for children and adolescents affected by obesity.

Results: Findings covered participant experiences, healthy lifestyle changes due to participating in the programme, the delivery team, barriers to engagement and improvements. Across these domains, four key themes emerged from the focus groups for participants and their caregivers relating to their experience: knowledge-sharing, enabling a family to become self-determining in their process to achieve healthy lifestyle change; the importance of connectedness and a family-based programme; the sense of a collective journey and the importance of a nonjudgemental, respectful welcoming environment. Logistical challenges and recommendations for improvement were also identified.

Conclusions: Policymakers need to consider the experiences of participants alongside quantitative outcomes when informing multidisciplinary intervention programmes for children and adolescents affected by obesity. Australian New Zealand Clinical Trials Registry (ANZCTR):12611000862943; Post-results.
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http://dx.doi.org/10.1136/bmjopen-2020-043516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118004PMC
May 2021

Detection of EGFR Mutations From Plasma of NSCLC Patients Using an Automatic Cartridge-Based PCR System.

Front Pharmacol 2021 14;12:657743. Epub 2021 Apr 14.

Laboratory of Clinical and Experimental Pathology, Biobank BB-0033-00025, Centre Hospitalier Universitaire Nice, Nice, France.

The introduction of liquid biopsies for the detection of mutations in non-small cell lung cancer patients (NSCLC) has revolutionized the clinical care. However, liquid biopsies are technically challenging and require specifically trained personnel. To facilitate the implementation of liquid biopsies for the detection of mutations from plasma, we have assessed a fully automated cartridge-based qPCR test that allows the automatic detection of mutations directly from plasma. We have analyzed 54 NSCLC patients and compared the results of the cartridge-base device to an FDA-approved assay. Detection of EGFR mutations was comparable but slightly lower in the cartridge-based device for L858R mutations (14/15 detected, 93%) and exon 19 deletions (18/20 detected, 90%). Unfortunately, 8/54 (15%) tests failed but increasing the proteinase K volume helped to recover 3/4 (75%) unsuccessful samples. In summary, the fully automated cartridge-based device allowed the detection of EGFR mutations directly from plasma in NSCLC patients with promising accuracy. However, protocol adjustments are necessary to reduce a high test failure rate.
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http://dx.doi.org/10.3389/fphar.2021.657743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079969PMC
April 2021

Exploring the views of adolescents with type 1 diabetes on digital mental health interventions: What functionality and content do they want?

Diabet Med 2021 Nov 14;38(11):e14591. Epub 2021 May 14.

Department of Psychological Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Background: Adolescents with type 1 diabetes (T1D) experience higher rates of psychological disorders compared with their healthy peers. As poor psychological health has been associated with suboptimal glycaemic control and more frequent complications, there is an urgent need to develop more 'clinically usable' interventions. Digital mental health interventions offer unique advantages compared with in-person interventions; however, what adolescents with T1D want in terms of content and functionality is poorly understood. Accordingly, the current study conducted focus groups to examine the views of adolescents with T1D regarding digital mental health interventions.

Methods: Four focus groups were conducted, including 16 adolescents with T1D, ranging from 13 to 17 years in age (69% female). Transcripts were analysed using directed content analysis to examine (1) 'what adolescents dislike about existing digital mental health interventions?' and (2) 'what adolescents want in future digital mental health interventions?'.

Results: Findings provide a preliminary understanding of what adolescents dislike and also the type of content and functional features, which may be important to include in digital mental health programs for this population, such as a peer support feature (reported by 16 of 16), emotion and diabetes check-in feature (11 of 16) and diabetes-relevant content (12 of 16).

Conclusions: Early data suggest that digital mental health interventions should include a significant peer support element, diabetes-relevant content and examples, and check-in on their mental health and diabetes self-management regularly, while avoiding fixed responses or modules and non-age-appropriate content. Based on these findings, a digital intervention is currently being developed.
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http://dx.doi.org/10.1111/dme.14591DOI Listing
November 2021
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