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.

Takotsubo syndrome occurring in systemic diseases: A French multicenter retrospective case-control study and literature review.

OBJECTIVE: Describe the characteristics of patients presenting with TTS during the course of a broad spectrum of systemic diseases, in comparison to classic TTS. METHODS: French multicenter retrospective case-control study completed by a literature review. RESULTS: 19 new cases were included in the study. The literature review identified 25 previously published cases. Among the 44 patients, 41 were females, with a median age of 67 years. The main underlying systemic diseases were systemic lupus erythematosus for seven, rheumatoid arthritis for six and primary Sjögren's syndrome for five. A TTS trigger was found in 34 cases, including a systemic disease flare-up in 28. The flare-up was treated in 15 cases, mainly with corticosteroids. One patient died during the episode, unrelated to the TTS. With a median follow-up of 24 months, all patients had recovered a normal LVEF, one had presented a recurrence of TTS, and none had died of a cardiac cause. Finally, the 19 new patients were compared with 19 classic TTS. The disease characteristics were extremely similar, with no significant difference in terms of clinical, electrocardiographic, biological and echocardiographic presentation. CONCLUSION: A broad spectrum of systemic diseases may rarely be accompanied by TTS, particularly during disease flare-ups. Although uncommon, TTS should be borne in mind in the presence of any cardiac symptomatology during the course of a systemic disease. Compared with classic TTS, their clinical, biological and echographic presentation is unremarkable. The prognosis for TTS appears to be good, with the consistent recovery of LVEF and no cardiac-related deaths.

A massive open online course to teach undergraduate medical students in oncology: keys of success.

Massive Open Online Courses (MOOCs) are gaining popularity in education while classroom lectures are being deserted, especially after COVID-19 pandemic. Their added value in teaching undergraduate medical students remains to be confirmed. This study evaluated a MOOC devoted to undergraduate medical students in a blended oncology-teaching university program. It was the first to target undergraduate medical students in oncology at its beginning. Students were asked to participate in a survey before and after MOOC to explore interactions between their characteristics and final grades, 65% of the participating students belonged to the rich class. 70% of the students completed the MOOC. Grades distributions were similar before and after MOOC implementation, so MOOC doesn't alter overall results. In addition, there was a positive effect of the MOOC on median grades on the immediate test. The univariate and multivariate analysis showed that socioeconomic status and student's willingness to participate interacted significantly with final results. Particularly, students' motivation and satisfaction were associated with better results; Almost 70% of students asked for blended learning. E-learning is reliable to teach oncology to undergraduate medical students. The success is directly linked to students' willingness to participate, and can be improved using blended methods including tutorials.

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

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

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.

Lung ultrasound is a reliable diagnostic technique to predict abnormal CT chest scan and to detect oxygen requirements in COVID-19 pneumonia.

COVID-19 pneumonia can be severe, with an unpredictable evolution and high mortality prevalence in older patients. The diagnosis is usually performed by RT-PCR or CT chest scan. Lung ultrasonography (LUS) has been proposed as an alternative method to monitor patients with COVID-19 pneumonia. To assess the diagnostic performance of LUS, we performed LUS using a portable device and adapting a protocol already used in Acute Respiratory Syndrome. We used the score obtained with the index we created to assess for LUS diagnostic performance as compared to lung CT chest scan and to predict for oxygen requirements. Daily bedside LUS was easy to perform and microbiologically safe. LUS was 89% sensitive and 100% specific in predicting CT chest scan abnormalities, and 95% sensitive and 67% specific in detecting oxygen requirements. This is the first report on the diagnostic performance of LUS as compared to CT chest scan for the diagnosis of COVID-19 pneumonia and assessments of oxygen requirements by LUS. LUS could help in the orientation of dyspneic patients to intensive care. It could also be proposed when there is limited access to CT scan in the context of a pandemic crisis, or to implement clinical lung examinations for outpatient follow-up.

ADL-dependency, D-Dimers, LDH and absence of anticoagulation are independently associated with one-month mortality in older inpatients with Covid-19.

BACKGROUND: To assess factors associated with one-month mortality among older inpatients with Covid-19. RESULTS: The mean age was 78 ± 7.8 years, 55.5% were men, CT scan lung damage was observed in 76% of the patients (mild 23%, moderate 38%, extensive 22%, and severe 7%). The mortality rate was 26%. Dependency/Activities of Daily Living (ADL) score ≤ 5/6, D-Dimers, LDH, and no anticoagulation by reference for curative were independently associated with one-month mortality. A score derived from the multivariate model showed good calibration and very good discrimination (Harrell's C index [95%CI] = 0.83 [0.79-0.87]). CONCLUSION: ADL-dependency, high serum levels of D-Dimers and LDH and the absence of anticoagulation were independently associated with one-month mortality among older inpatients with Covid-19. METHODS: 108 consecutive older inpatients aged 65 and over with Covid-19 confirmed by RT-PCR and/or typical CT chest scan were prospectively included in a French single-centre cohort study from March to April 2020. A systematic geriatric assessment was performed. Covariates were lymphocyte count, serum levels of albumin, C-Reactive Protein, D-Dimers and Lactate Dehydrogenase (LDH), anticoagulation level, and exposure to the hydroxychloroquine and azithromycin combined therapy. Cox uni- and multivariate proportional-hazard regressions were performed to identify predictors of one-month mortality.

A Constitutional Activating MET Mutation Makes the Genetic Link between Malignancies and Chronic Inflammatory Diseases.

PURPOSE: The genesis of all cancers results from an accumulation of mutations, constitutional and/or acquired when induced by external mutagenic factors. High-speed technologies for genome sequencing have completely changed the study of disease genetics, but with limited knowledge of the functional value of most genetic changes. EXPERIMENTAL DESIGN: Here, we proposed an innovative individual approach by studying tissue samples from a young woman with an unusual association of breast cancer, polycythemia vera, and rheumatoid arthritis. We performed genomic analyses for copy number variations and point mutations on laser-microdissected tumor cells from the breast cancer, and on CD34+ cells sorted from bone marrow aspiration, to identify gene abnormalities common to these two types of cell populations. RESULTS: Using ONCOSCAN technology, we identified a constitutional pR988C, c2962C>T mutation of MET. Using CRISPR-Cas9 technology, we established pR988C MET-mutated transgenic mice, which reproduced the autoimmune diseases and myeloproliferation found in our index-case; one of the transgenic mice spontaneously developed a skin squamous cell carcinoma. We also showed that additional mutagenic factors were required to induce cancers, including skin squamous cell carcinoma and thyroid cancer. Using an anti-MET drug, cabozantinib, we demonstrated for the first time the functional role of this mutation in the maintenance of myeloproliferation and rheumatoid arthritis, and in cancer genesis. CONCLUSIONS: Our study opens a considerable field of application in the domain of constitutional genetics, to establish genetic links between cancers and other very different severe diseases.

Systemic inflammatory and autoimmune manifestations associated with myelodysplastic syndromes and chronic myelomonocytic leukaemia: a French multicentre retrospective study.

OBJECTIVE: We describe myelodysplastic syndrome (MDS)-associated systemic inflammatory and autoimmune diseases (SIADs), their treatments and outcomes and the impact of SIADs on overall survival in a French multicentre retrospective study. METHODS: In this study, 123 patients with MDS and SIADs were analysed. RESULTS: Mean age was 70 years (s.d. 13) and the male:female ratio was 2. The SIADs were systemic vasculitis in 39 (32%) cases, CTD in 31 (25%) cases, inflammatory arthritis in 28 (23%) cases, a neutrophilic disorder in 12 (10%) cases and unclassified in 13 cases (11%). The SIADs fulfilled the usual classification criteria in 75 (66%) cases, while complete criteria were not reached in 21 (19%) cases. A significant association was shown between chronic myelomonocytic leukaemia (CMML) and systemic vasculitis (P = 0.0024). One hundred and eighteen (96%) SIAD patients were treated (91% with steroids), with an 83% response to first-line treatment, including 80% for steroids alone. A second-line treatment for SIADs was required for steroid dependence or relapse in 48% of cases. The effect of MDS treatment on SIADs could be assessed in 11 patients treated with azacytidine and SIAD response was achieved in 9/11 (80%) and 6/11 (55%) patients at 3 and 6 months, respectively. Compared with 665 MDS/CMML patients without SIADs, MDS/CMML patients with SIADs were younger (P < 0.01), male (P = 0.03), less often had refractory anaemia with ring sideroblasts (P < 0.01), more often had a poor karyotype (16% vs 11%, P = 0.04) and less frequently belonged to low and intermediate-1 International Prognostic Scoring System categories, but no survival difference was seen between patients with MDS-associated SIADs and without SIADs (P = 0.5). CONCLUSION: The spectrum of SIADs associated to MDS is heterogeneous, steroid sensitive, but often steroid dependent.

In antisynthetase syndrome, ACPA are associated with severe and erosive arthritis: an overlapping rheumatoid arthritis and antisynthetase syndrome.

Anticitrullinated peptide/protein antibodies (ACPA), which are highly specific for rheumatoid arthritis (RA), may be found in some patients with other systemic autoimmune diseases. The clinical significance of ACPA in patients with antisynthetase syndrome (ASS), a systemic disease characterized by the association of myositis, interstitial lung disease, polyarthralgia, and/or polyarthritis, has not yet been evaluated with regard to phenotype, prognosis, and response to treatment. ACPA-positive ASS patients were first identified among a French multicenter registry of patients with ASS. Additionally, all French rheumatology and internal medicine practitioners registered on the Club Rhumatismes et Inflammation web site were asked to report their observations of ASS patients with ACPA. The 17 collected patients were retrospectively studied using a standardized questionnaire and compared with 34 unselected ACPA-negative ASS patients in a case-control study. All ACPA-positive ASS patients suffered from arthritis versus 41% in the control group (P < 0.0001). The number of swollen joints was significantly higher (7.0 ±â€Š5.0 vs 2.9 ±â€Š3.9, P < 0.005), with a distribution resembling that of RA. Radiographic damages were also more frequent in ACPA-positive ASS patients (87% vs 11%, P < 0.0001). Aside from a significantly higher transfer factor for carbon monoxide in ACPA-ASS patients, lung, muscle, and skin involvements had similar incidences, patterns, and severity in both groups. Although Nonbiologic treatments were similarly used in both groups, ACPA-positive patients received biologics more frequently (59% vs 12%, P < 0.0008), mostly due to refractory arthritis (n = 9). Eight patients received anti-Cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) with good efficacy and tolerance, whereas 2 of the 5 patients treated with antitumor necrosis factor drugs had worsened myositis and/or interstitial lung disease. After a >7-year mean follow-up, extra-articular outcomes and survival were not different. ACPA-positive ASS patients showed an overlapping RA-ASS syndrome, were at high risk of refractory erosive arthritis, and might experience ASS flare when treated with antitumor necrosis factor drugs. In contrast, other biologics such as anti-CD20 mAb were effective in this context, without worsening systemic involvements.

Inflammatory arthritis in patients with myelodysplastic syndromes: a multicenter retrospective study and literature review of 68 cases.

We describe the characteristics and outcome of inflammatory arthritis in patients with myelodysplastic syndrome (MDS) in a French multicenter retrospective study. Twenty-two patients with MDS (median age, 77.5 yr [interquartile range, 69-81]; 10 women) were included. Inflammatory arthritis presented as polyarthritis in 17 cases (77%) and with symmetric involvement in 15 cases (68%). At diagnosis, the median disease activity score 28 based on C-reactive protein (DAS28-CRP) was 4.5 [2-6.5]. Two patients had anti-citrullinated protein antibodies (ACPAs), and 1 had radiologic erosions. The median time between the diagnoses of arthritis and MDS was 10 months [6-42], with a median articular symptom duration of 3 months [2-8]. The diagnosis of both diseases was concomitant in 6 cases (27%); arthritis preceded MDS in 12 cases (55%), and occurred after MDS in 4 (18%). While the number of swollen and tender joints significantly decreased during follow-up, as did the median DAS28-CRP (from 4.3 [3.8-4.6] at baseline to 2.9 [1.75-3.3]; p < 0.05), CRP remained elevated (CRP >20 mg/L) in 8 patients (42%). Nevertheless, radiographic progression and new ACPA positivity were not observed during a median follow-up of 29 months [9-76]. While most of the patients were treated with steroids (n = 16) for arthritis, additional treatment was administered in only 4 patients (hydroxychloroquine, n = 2; sulfasalazine [Salazopyrin] and etanercept, n = 1, respectively). Eleven patients died during follow-up from acute myeloid leukemia (n = 5); infections (n = 3); or cerebral bleeding, cardiorespiratory failure, or undetermined cause (n = 1, respectively). Inflammatory arthritis associated with MDS can have various presentations and is often seronegative and nonerosive. Steroids alone are the most common treatment in MDS-associated arthritis, but that treatment is insufficient to control arthritis. Steroid-sparing strategies need to be identified.

Epidemiology of primary Sjögren's syndrome in a French multiracial/multiethnic area.

OBJECTIVE: To describe the epidemiology of primary Sjögren's syndrome (SS) in a multiracial/multiethnic population. METHODS: A cross-sectional study with 5 case-retrieval sources identified adults with primary SS living in the Greater Paris area (population 1,172,482 adults) in 2007. Diagnoses were verified by the American-European Consensus Group (AECG) criteria and study-specific enlarged criteria based on the presence of ≥3 of 4 AECG items among subjective oral or ocular dryness, anti-SSA/SSB positivity, and positive minor salivary gland biopsy results. Prevalence estimates were standardized to those for the world population and a 5-source capture-recapture analysis (CRA) was used. Racial/ethnic differences in primary SS features were evaluated. RESULTS: In all, 133 subjects met the AECG criteria and 203 met the enlarged criteria. The 2007 prevalence of primary SS was 1.02 cases per 10,000 adults (95% confidence interval [95% CI] 0.85-1.22) for the AECG criteria and 1.52 cases per 10,000 adults (95% CI 1.30-1.76) for the enlarged criteria. The CRA indicated completeness of case findings of ∼90%. Compared to subjects with European backgrounds, those with non-European backgrounds had 2.1-2.3 times higher primary SS prevalence and were younger (P < 0.0001) and were more likely to have polyclonal hypergammaglobulinemia (P < 0.0001) and anti-SSA/SSB antibodies (P = 0.0005 and P < 0.0001 for the AECG and enlarged criteria, respectively). CONCLUSION: The figure of 1.02­1.52 cases per 10,000 adults we found and estimates from the few other population-based census surveys support that the prevalence of diagnosed primary SS is between 1 and 9 cases per 10,000 (0.01-0.09%) [corrected] in the general population. Non-European race/ethnicity may be associated with increased primary SS risk and a distinct disease profile.

Mechanisms in endocrinology. Role of emotional stress in the pathophysiology of Graves' disease.

The role of stress in the pathophysiology of Graves' disease is suggested by several clinical observations, by recent advances in immunology and by better understanding of autoimmune diseases which provides new insights into potential effects of stress hormones on T helper cell imbalance involved in the pathogenesis of autoimmune diseases. Stress management should therefore be an important part of the treatment of Graves' disease, as stress reduction may improve the effect of therapy. However, this field still requires interventional data to support stress management in the treatment of Graves' disease.

Rheumatoid arthritis: from autoimmunity to synovitis and joint destruction.

Rheumatoid arthritis is an autoimmune disease characterized by the production of two known antibodies - rheumatoid factor and anti-citrullinated peptide antibody (ACPA) - against common autoantigens that are widely expressed within and outside the joints. The interactions between genes and environment are crucial in all stages of the disease, involving namely genes from major histocompatibility complex locus, and antigens such as tobacco or microbes (e.g. Porphyromonas gingivalis). T and B cells are activated as soon as the earliest phases of the disease, rheumatoid arthritis appearing as a Th1 and Th17 disease. Inflammatory cytokines have a considerable importance in the hierarchy of the processes involved in RA. The joint destruction seen in RA is caused not only by cytokine imbalances, but also by specific effects of the Wnt system and osteoprotegerin on osteoclasts and by matrix production dysregulation responsible for cartilage damage. Both innate and adaptative immunity demonstrated their respective cornerstone position in rheumatoid arthritis, since targeted treatments has been efficiently developed against TNF-α, IL-6 receptor, IL-1ß, CD20 B cells and T-cell/Dendritic cell interactions.