A Sub-Group of Kidney-Transplant Recipients with Highly Aggressive Squamous Cell Carcinoma Expressing Phosphorylated Serine392p53.

Cutaneous squamous cell carcinomas in kidney-transplant recipients are frequent, with an increasing incidence linked to long immunosuppression durations and exposure to ultraviolet radiation. p53 is at the cornerstone of ultraviolet-induced DNA damage, but the role of p53 post-translational modifications in this context is not yet deciphered. Here, we investigated the phosphorylation status of p53 at Serine 392 in 25 cutaneous squamous cell carcinomas in kidney-transplant recipients, compared with 22 non-transplanted patients. Cutaneous squamous cell carcinomas in transplanted patients occurred after a median period of 19 years of immunosuppression, with a median number of 15 cutaneous squamous cell carcinomas and more aggressive histological and clinical characteristics. There was no significant difference between Ki67, p53, and pSer392p53 expression in the two groups. Using principal component analysis, we identified a cluster of exclusively transplanted patients with a median of 23 years of immunosuppression duration, significantly more aggressive biological characteristics, and higher pSer392p53 expression. pSer392p53 was expressed in the whole tumor, suggesting an early carcinogenic event in the course of prolonged immunosuppression. This high, diffuse pSer392p53 expression, corresponding to a high level of DNA damage, might be useful to identify aggressive cutaneous squamous cell carcinomas in kidney-transplant recipients to treat them more aggressively.

HER2 Amplification Level Predicts Pathological Complete Response in the Neoadjuvant Setting of HER2-Overexpressing Breast Cancer: A Meta-Analysis and Systematic Review.

Anti-HER2 therapies have dramatically improved the prognosis of human epidermal growth factor receptor 2 (HER2)-overexpressing cancers. However, the correlation between the HER2 copy number and the response rate to anti-HER2 remains unclear. Here, following the PRISMA method, we performed a meta-analysis in the neoadjuvant setting in breast cancer to study the association between the HER2 amplification level and the pathological complete response (pCR) to anti-HER2 therapies. Nine articles (four clinical trials, five observational studies) were retrieved after full-text screening, involving 11,238 women with locally advanced breast cancer in the neoadjuvant setting. The median HER2/CEP17 ratio cut-off value was 5.0 ± 5.0 (min-max = 1.0-14.0). For the overall population, the median pCR rate was 48% using the random effect model. The studies were categorized in quartiles as follows: ≤2 (Class 1); 2.1 to 5.0 (Class 2); 5.1 to 7.0 (Class 3); and >7.0 (Class 4). After grouping, the pCR rates were 33%, 49%, 57%, and 79%, respectively. When we excluded the study by Greenwell et al., which accounted for 90% of the patients, using the same quartiles, we still observed an increasing rate of pCR as the HER2/CEP17 ratio increased. This is the first meta-analysis demonstrating the relationship between the HER2 amplification level and the percentage of pCR in the neoadjuvant setting among women with HER2-overexpressing breast cancer, with potential therapeutic applications.

[Reversibility of frailty in elderly patients thanks to a multicomponent training programme]. / Réversibilité de la fragilité chez des patients âgés grâce à un programme d'entraînement multicomposante.

A retrospective study was conducted to evaluate the effects of a multi-component training program with strength machines on physical performance and reversibility of frailty in elderly people. At the end of the program, a significant increase in physical performance was observed and there was a significant decrease in frailty.

A Teleconsultation Device, Consult Station, for Remote Primary Care: Multisite Prospective Cohort Study.

BACKGROUND: Telemedicine technology is a growing field, especially in the context of the COVID-19 pandemic. Consult Station (Health for Development) is the first telemedicine device enabling completely remote medical consultations, including the concurrent collection of clinical parameters and videos. OBJECTIVE: Our aim was to collect data on the multisite urban and suburban implementation of the Consult Station for primary care and assess its contribution to health care pathways in areas with a low density of medical services. METHODS: In a proof-of-concept multisite prospective cohort study, 2134 consecutive patients had teleconsultations. Consultation characteristics were analyzed from both the patient and practitioner perspective. RESULTS: In this study, the main users of Consult Station were younger women consulting for low-severity seasonal infections. Interestingly, hypertension, diabetes, and preventive medical consultations were almost absent, while they accounted for almost 50% of consultations with a general practitioner (GP). We showed that for all regions where the Consult Station was implemented, the number of consultations increased as GP density decreased. The study of practitioner characteristics showed GPs from metropolitan areas are motivated to work with this device remotely, with a high level of technology acceptability. CONCLUSIONS: The multisite implementation of Consult Station booths is suitable for primary care and could also address the challenge of "medical deserts." In addition, further studies should be performed to evaluate the possible contribution of Consult Station booths to limiting work absenteeism.

Correction: A Teleconsultation Device, Consult Station, for Remote Primary Care: Multisite Prospective Cohort Study.

[This corrects the article DOI: 10.2196/33507.].

After laparoscopic liver resection for colorectal liver metastases, age does not influence morbi-mortality.

BACKGROUND: Hepatectomy remains the only curative option in patients presenting with colorectal liver metastases (CLM). Although laparoscopic approach has improved postoperative morbidity and mortality rates, its suitability for patients of all age groups has yet to be confirmed. The aim of this study was to analyze postoperative outcomes following laparoscopic liver resection (LLR) in different age groups of patients presenting with CLM. METHODS: All patients who underwent LLR for CLM from 2008 to 2017 were reviewed. Patients were divided into four age groups: < 55, 55-65 years, 65-75 and > 75 years. Baseline and intraoperative characteristics as well as postoperative morbidity and mortality were compared between all four groups. RESULTS: Overall, 335 patients were included with 34 (10%), 113 (34%), 136 (41%) and 52 (15%) in < 55, 55-65, 65-75 and > 75 years subgroups. Baseline characteristics were similar between all four groups except for elevated pressure, dyslipidemia and ASA score which were higher in older patients. Regarding surgical procedures, major hepatectomy, uni- or bisegmentectomy and wedge resection were performed in 122 (36%), 87 (26%) and 126 (38%) patients, respectively, with no significant differences between age groups. Overall, 90-day postoperative mortality rate was nil and postoperative morbidity was similar between all four groups except for biliary fistula occurrence, which was higher in < 55 years patients (p = 0.006). CONCLUSION: Short-term postoperative outcome following LLR for CLM does not seem to be affected by age. Curative laparoscopic treatment should therefore be considered whenever possible, regardless of patient age.

[Risk assessment in medical geriatric oncology]. / Évaluation des risques en oncogériatrie médicale.

The assessment of risks in medical geriatric oncology requires close collaboration between oncologists and geriatricians. Vulnerability, death and severe chemotoxicity during cancer treatment represent the main risks to be assessed before making a decision regarding treatment in elderly patients with cancer. A comprehensive geriatric assessment and predictive scores enable a multidimensional assessment of the elderly cancer patient to be carried out.

[Assessment of walking problems in the elderly person]. / Évaluation des troubles de la marche chez la personne âgée.

Walking problems represent a major public health issue in the geriatric population due to their frequency and the dramatic consequences they cause. They also mark a starting point of the physical frailty of elderly people. Their early detection should result in adapted functional rehabilitation in order to reduce the associated complications. Overview of walking problems in the elderly and the clinical means for assessing them.

[Training and action research in a short-stay geriatric oncology unit]. / Recherche-action et formation dans une unité de court séjour oncogériatrique.

A participative action research project was undertaken in a geriatric oncology hospital unit. It resulted in the training of paramedical staff regarding the specific care to be provided to elderly people with cancer.

Anti-Angiogenic Tyrosine Kinase Inhibitor-Related Toxicities Among Cancer Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Targeting of angiogenesis has become a major therapeutic approach for the treatment of various advanced cancers. There are many unresolved questions on the toxicity of anti-angiogenic tyrosine kinase inhibitors (TKIs). OBJECTIVE: We performed a meta-analysis to assess the toxicity prevalence of the different anti-angiogenic TKIs among cancer patients and in subpopulations of interest including patients with renal cell carcinoma. PATIENTS AND METHODS: We searched the MEDLINE and Cochrane Library databases to November 2023. Clinical trials were eligible if they set out to report the grade ≥3 toxicities related to one of the seven currently approved anti-angiogenic TKIs as monotherapies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method was applied with PROSPERO (CRD42023411946). RESULTS: The 421 eligible studies included a total of 56,895 cancer patients treated with anti-angiogenic TKI monotherapy. Twenty-four different cancer types were identified, mainly renal cell carcinoma (41.9% of the patients). The anti-angiogenic TKI was sorafenib (34.5% of the patients), sunitinib (30.5%), regorafenib (10.7%), pazopanib (9.4%), cabozantinib (7.7%), axitinib (4.3%), and lenvatinib (2.9%). The pooled prevalence of grade 3 and 4 toxicities was 56.1% (95% confidence interval 53.5-58.6), with marked between-study heterogeneity (I2 = 96.8%). Toxicity profiles varied considerably depending on the type of TKI, the cancer type, and the specific patient characteristics. In particular, Asian patients and elderly people had higher prevalences of severe toxicities, with pazopanib being the best-tolerated drug. For patients treated with sunitinib, particularly those with metastatic RCC, there was no significant difference in terms of toxicity according to the regimen schedule. CONCLUSIONS: This meta-analysis highlights the toxicity profiles of anti-angiogenic TKI monotherapies, and thus enables high-level recommendations for the choice of anti-angiogenic TKIs on the basis of the patient's age, ethnicity, comorbidities, and comedications, for personalized treatment.

A Fab of trastuzumab to treat HER2 overexpressing breast cancer brain metastases.

Despite major therapeutic advances for two decades, including the most recently approved anti-HER2 drugs, brain metastatic localizations remain the major cause of death for women with metastatic HER2 breast cancer. The main reason is the limited drug passage of the blood-brain barrier after intravenous injection and the significant efflux of drugs, including monoclocal antibodies, after administration into the cerebrospinal fluid. We hypothesized that this efflux was linked to the presence of a FcRn receptor in the blood-brain barrier. To overcome this efflux, we engineered two Fab fragments of trastuzumab, an anti-HER2 monoclonal antibody, and did a thorough preclinical development for therapeutic translational purpose. We demonstrated the safety and equal efficacy of the Fabs with trastuzumab in vitro, and in vivo using a patient-derived xenograft model of HER2 overexpressing breast cancer. For the pharmacokinetic studies of intra-cerebrospinal fluid administration, we implemented original rat models with catheter implanted into the cisterna magna. After intraventricular administration in rats, we demonstrated that the brain-to-blood efflux of Fab was up to 10 times lower than for trastuzumab, associated with a two-fold higher brain penetration compared to trastuzumab. This Fab, capable of significantly reducing brain-to-blood efflux and enhancing brain penetration after intra-cerebrospinal fluid injection, could thus be a new and original effective drug in the treatment of HER2 breast cancer brain metastases, which will be demonstrated by a phase I clinical trial dedicated to women in resort situations.

PROM2 overexpression induces metastatic potential through epithelial-to-mesenchymal transition and ferroptosis resistance in human cancers.

INTRODUCTION: Despite considerable therapeutic advances in the last 20 years, metastatic cancers remain a major cause of death. We previously identified prominin-2 (PROM2) as a biomarker predictive of distant metastases and decreased survival, thus providing a promising bio-target. In this translational study, we set out to decipher the biological roles of PROM2 during the metastatic process and resistance to cell death, in particular for metastatic melanoma. METHODS AND RESULTS: Methods and results: We demonstrated that PROM2 overexpression was closely linked to an increased metastatic potential through the increase of epithelial-to-mesenchymal transition (EMT) marker expression and ferroptosis resistance. This was also found in renal cell carcinoma and triple negative breast cancer patient-derived xenograft models. Using an oligonucleotide anti-sense anti-PROM2, we efficaciously decreased PROM2 expression and prevented metastases in melanoma xenografts. We also demonstrated that PROM2 was implicated in an aggravation loop, contributing to increase the metastatic burden both in murine metastatic models and in patients with metastatic melanoma. The metastatic burden is closely linked to PROM2 expression through the expression of EMT markers and ferroptosis cell death resistance in a deterioration loop. CONCLUSION: Our results open the way for further studies using PROM2 as a bio-target in resort situations in human metastatic melanoma and also in other cancer types.

Ultrasound assessment is linked to histological vein wall thickness in chronic venous disease.

OBJECTIVES: Few studies compared both ultrasound and histological approaches for the same series of patients with chronic venous disease (CVD). We aimed to assess the diagnostic performances of duplex ultrasound assessment (US) of Vein Wall Thickness (VWT) among patients with CVD. METHODS: 38 adults with primary varicose veins having undergone Great Saphenous Vein thermal ablation with phlebectomy, and agreeing to biopsy of the Posterior Accessory Great Saphenous Vein (PASV) were consecutively included in a two-center prospective study. VWT assessment of the PASV was performed using both US, and microscope examination. High values for microscope-assessed VWT were defined at > 0.5 mm. RESULTS: The mean age was 53.0 ± 13.1 years, 71% were women. Maximization of US performances was obtained with a threshold of 0.6 mm: Sensitivity (Se) = 92.9%, Specificity (Sp) = 91.7%, positive (86.7%) and negative predictive value (NPV) (95.7%), positive (11.1) and negative likelihood ratio (NLR) (0.07). CONCLUSIONS: US assessment of VWT could be a non-invasive tool for diagnosis and follow-up in CVD, and an interesting in vivo parameter complementing diameter and reflux measures, with a view to optimizing treatment. It could help to determine i) the energy level necessary in case of endovenous laser ablation, and ii) the sclerosing agent concentration in case of chemical ablation.

Safety and efficacy of immunotherapy according to the age threshold of 80 years.

BACKGROUND: To compare safety and efficacy of ICIs among patients<80 and those ≥80 years of age. METHODS: A single-center retrospective observational cohort study comparing patients<80 and ≥80 years of age matched for cancer site (lung vs others) and participation in a clinical trial. PRIMARY ENDPOINT: grade ≥2 toxicity during the first three months of ICI therapy. The two groups were compared using univariate and multivariate regression. RESULTS: Two hundred and ten consecutive patients were recruited, with the following characteristics: mean age: 66.5±16.8, 20% aged ≥80 years, 75% male, 97% ECOG-PS ≤ 2, 78% G8-index ≤ 14/17, 80% lung or kidney cancer, and 97% metastatic cancer. The grade ≥2 toxicity rate during the first three months of ICI therapy was 68%. Patients aged ≥80 years of age had a more significant (P<0.05) proportion of grade ≥2 non-hematological toxicities (64% vs 45%) than those aged<80 years: rash (14% vs 4%), arthralgia (7.1% vs 0.6%), colitis (4.7% vs 0.6%), cytolysis (7.1% vs 1.2%), gastrointestinal bleeding (2.4% vs 0%), onycholysis (2.4% vs 0%), oral mucositis (2.4% vs 0%), psoriasis (2.4% vs 0%), or other skin toxicities (25% vs 3%). Efficacy among patients ≥80 and<80 years of age was comparable. CONCLUSIONS: Although non-hematological toxicities affected 20% more patients aged ≥80 years, hematological toxicities and efficacy were comparable between patients aged ≥80 and<80 years with advanced cancer and treated with ICIs.

Genomics of Breast Cancer Brain Metastases: A Meta-Analysis and Therapeutic Implications.

Breast cancer brain metastases are a challenging daily practice, and the biological link between gene mutations and metastatic spread to the brain remains to be determined. Here, we performed a meta-analysis on genomic data obtained from primary tumors, extracerebral metastases and brain metastases, to identify gene alterations associated with metastatic processes in the brain. Articles with relevant findings were selected using Medline via PubMed, from January 1999 up to February 2022. A critical review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement (PRISMA). Fifty-seven publications were selected for this meta-analysis, including 37,218 patients in all, 11,906 primary tumor samples, 5541 extracerebral metastasis samples, and 1485 brain metastasis samples. We report the overall and sub-group prevalence of gene mutations, including comparisons between primary tumors, extracerebral metastases and brain metastases. In particular, we identified six genes with a higher mutation prevalence in brain metastases than in extracerebral metastases, with a potential role in metastatic processes in the brain: ESR1, ERBB2, EGFR, PTEN, BRCA2 and NOTCH1. We discuss here the therapeutic implications. Our results underline the added value of obtaining biopsies from brain metastases to fully explore their biology, in order to develop personalized treatments.

Pre-Therapeutic Sarcopenia among Cancer Patients: An Up-to-Date Meta-Analysis of Prevalence and Predictive Value during Cancer Treatment.

This study will address the prevalence of pre-therapeutic sarcopenia (PS) and its clinical impact during cancer treatment among adult cancer patients ≥ 18 years of age. A meta-analysis (MA) with random-effect models was performed via a MEDLINE systematic review, according to the PRISMA statement, focusing on articles published before February 2022 that reported observational studies and clinical trials on the prevalence of PS and the following outcomes: overall survival (OS), progression-free survival (PFS), post-operative complications (POC), toxicities (TOX), and nosocomial infections (NI). A total of 65,936 patients (mean age: 45.7-85 y) with various cancer sites and extensions and various treatment modes were included. Mainly defined by CT scan-based loss of muscle mass only, the pooled prevalence of PS was 38.0%. The pooled relative risks were 1.97, 1.76, 2.70, 1.47, and 1.76 for OS, PFS, POC, TOX, and NI, respectively (moderate-to-high heterogeneity, I2: 58-85%). Consensus-based algorithm definitions of sarcopenia, integrating low muscle mass and low levels of muscular strength and/or physical performance, lowered the prevalence (22%) and heterogeneity (I2 < 50%). They also increased the predictive values with RRs ranging from 2.31 (OS) to 3.52 (POC). PS among cancer patients is prevalent and strongly associated with poor outcomes during cancer treatment, especially when considering a consensus-based algorithm approach.