Raising concerns on questionable ethics approvals - a case study of 456 trials from the Institut Hospitalo-Universitaire Méditerranée Infection.

BACKGROUND: The practice of clinical research is strictly regulated by law. During submission and review processes, compliance of such research with the laws enforced in the country where it was conducted is not always correctly filled in by the authors or verified by the editors. Here, we report a case of a single institution for which one may find hundreds of publications with seemingly relevant ethical concerns, along with 10 months of follow-up through contacts with the editors of these articles. We thus argue for a stricter control of ethical authorization by scientific editors and we call on publishers to cooperate to this end. METHODS: We present an investigation of the ethics and legal aspects of 456 studies published by the IHU-MI (Institut Hospitalo-Universitaire Méditerranée Infection) in Marseille, France. RESULTS: We identified a wide range of issues with the stated research authorization and ethics of the published studies with respect to the Institutional Review Board and the approval presented. Among the studies investigated, 248 were conducted with the same ethics approval number, even though the subjects, samples, and countries of investigation were different. Thirty-nine (39) did not even contain a reference to the ethics approval number while they present research on human beings. We thus contacted the journals that published these articles and provide their responses to our concerns. It should be noted that, since our investigation and reporting to journals, PLOS has issued expressions of concerns for several publications we analyze here. CONCLUSION: This case presents an investigation of the veracity of ethical approval, and more than 10 months of follow-up by independent researchers. We call for stricter control and cooperation in handling of these cases, including editorial requirement to upload ethical approval documents, guidelines from COPE to address such ethical concerns, and transparent editorial policies and timelines to answer such concerns. All supplementary materials are available.

Breakthrough infections due to SARS-CoV-2 Delta variant: relation to humoral and cellular vaccine responses.

Introduction: COVID-19 vaccines are expected to provide effective protection. However, emerging strains can cause breakthrough infection in vaccinated individuals. The immune response of vaccinated individuals who have experienced breakthrough infection is still poorly understood. Methods: Here, we studied the humoral and cellular immune responses of fully vaccinated individuals who subsequently experienced breakthrough infection due to the Delta variant of SARS-CoV-2 and correlated them with the severity of the disease. Results: In this study, an effective humoral response alone was not sufficient to induce effective immune protection against severe breakthrough infection, which also required effective cell-mediated immunity to SARS-CoV-2. Patients who did not require oxygen had significantly higher specific (p=0.021) and nonspecific (p=0.004) cellular responses to SARS-CoV-2 at the onset of infection than those who progressed to a severe form. Discussion: Knowing both humoral and cellular immune response could allow to adapt preventive strategy, by better selecting patients who would benefit from additional vaccine boosters. Trial registration numbers: https://clinicaltrials.gov, identifier NCT04355351; https://clinicaltrials.gov, identifier NCT04429594.

Does Bariatric Surgery Reduce the Risk of Colorectal Cancer in Individuals with Morbid Obesity? A Systematic Review and Meta-Analysis.

Bariatric surgery has shown to be effective in producing sustained weight loss and the resolution of obesity related medical problems. Recent research focused on the role of obesity and adipose tissue in tumorigenesis, finding a strong crosslink through different mechanisms and highlighting an increase in cancer incidence in individuals with obesity. The aim of this meta-analysis is to find if bariatric surgery reduces the incidence of colorectal cancer in patients with obesity. We performed a meta-analysis including 18 studies (PROSPERO ID: CRD4202235931). Bariatric surgery was found to be significantly protective toward colorectal cancer incidence in individuals with obesity (HR: 0.81, p = 0.0142). The protective effect persisted when considering women (RR: 0.54, p = 0.0014) and men (RR: 0.74, p = 0.2798) separately, although this was not significant for the latter. No difference was found when comparing Roux-en-Y gastric bypass and sleeve gastrectomy. Bariatric surgery reduces the incidence of colorectal cancer in individuals with obesity independently from gender and surgical procedure. Prospective large cohort studies are needed to confirm these findings.

Scientific Integrity Requires Publishing Rebuttals and Retracting Problematic Papers.

Recently, an article by Seneff et al. entitled "Innate immunosuppression by SARS-CoV-2 mRNA vaccinations: The role of G-quadruplexes, exosomes, and MicroRNAs" was published in Food and Chemical Toxicology (FCT). Here, we describe why this article, which contains unsubstantiated claims and misunderstandings such as "billions of lives are potentially at risk" with COVID-19 mRNA vaccines, is problematic and should be retracted. We report here our request to the editor of FCT to have our rebuttal published, unfortunately rejected after three rounds of reviewing. Fighting the spread of false information requires enormous effort while receiving little or no credit for this necessary work, which often even ends up being threatened. This need for more scientific integrity is at the heart of our advocacy, and we call for large support, especially from editors and publishers, to fight more effectively against deadly disinformation.

Low baseline IFN-γ response could predict hospitalization in COVID-19 patients.

The SARS-CoV-2 infection has spread rapidly around the world causing millions of deaths. Several treatments can reduce mortality and hospitalization. However, their efficacy depends on the choice of the molecule and the precise timing of its administration to ensure viral clearance and avoid a deleterious inflammatory response. Here, we investigated IFN-γ, assessed by a functional immunoassay, as a predictive biomarker for the risk of hospitalization at an early stage of infection or within one month prior to infection. Individuals with IFN-γ levels below 15 IU/mL were 6.57-times more likely to be hospitalized than those with higher values (p<0.001). As confirmed by multivariable analysis, low IFN-γ levels, age >65 years, and no vaccination were independently associated with hospitalization. In addition, we found a significant inverse correlation between low IFN-γ response and high level of IL-6 in plasma (Spearman's rho=-0.38, p=0.003). Early analysis of the IFN-γ response in a contact or recently infected subject with SARS-CoV-2 could predict hospitalization and thus help the clinician to choose the appropriate treatment avoiding severe forms of infection and hospitalization.

Humoral and cellular responses after a third dose of SARS-CoV-2 BNT162b2 vaccine in patients with lymphoid malignancies.

Patients with hematological malignancies have impaired immune response after two doses of BNT162b2 (Pfizer/BioNTech) vaccine against SARS-CoV-2. Here, in this observational study (registration number HDH F20210324145532), we measure SARS-CoV-2 anti-Spike antibodies, neutralizing antibodies and T-cell responses after immune stimulation with a third dose (D3) of the same vaccine in patients with chronic lymphocytic leukemia (n = 13), B cell non-Hodgkin lymphoma (n = 14), and multiple myeloma (n = 16)). No unexpected novel side effects are reported. Among 25 patients with positive anti-S titers before D3, 23 (92%) patients increase their anti-S and neutralizing antibody titer after D3. All 18 (42%) initially seronegative patients remain negative. D3 increases the median IFN-γ secretion in the whole cohort and induces IFN-γ secretion in a fraction of seronegative patients. Our data thus support the use of a third vaccine dose amongst patients with lymphoid malignancies, even though some of them will still have vaccine failure.

Third dose of anti-SARS-CoV-2 vaccine for patients with cancer: Should humoral responses be monitored? A position article.

Taking into account higher risk of severe coronavirus disease 2019 or death among patients with cancer, as well as impaired immunogenicity after anti-SARS-CoV-2 vaccines, in addition to waning immunity, booster dosing appears mandatory in this patient population. This review sought to provide reasonable evidence so as to assist oncologists in their daily practice, helping them decide when an anti-SARS-Cov2 antibody (Ab) dosage should be scheduled after a full two-dose vaccination and, if necessary, propose an early third dose (D3). Such D3 could apply to non-responder patients with anti-Spike (S) Abs titres <40 binding Ab unit (BAU)/mL. For lowresponder patients with anti-S Ab titres between 40 BAU/mL and 100/260 BAU/mL (suggested area of uncertainty), an early D3 may similarly be proposed. Nevertheless, this D3 could be administered in a less urgent manner, taking into account associated comorbidities and regional epidemic incidence rates. This latter strategy may comprise a monthly dosage of anti-S titres so as to better assess the kinetics of waning immunity. For responder patients with anti-S titres above 260 BAU/mL, we suggest to follow the recommendations outlined for the general population. Given this context, patients with anti-S titres above 1000 BAU/mL should be given the possibility to undergo anti-S titre control after three months, designed to assess rapid humoral waning immunity. We strongly recommend that patients with cancer be included into observational serological monitoring studies or clinical trials that are dedicated to severe immunocompromised patients without any humoral seroconversion after D3.

Current perspectives for SARS-CoV-2 vaccination efficacy improvement in patients with active treatment against cancer.

A higher risk of death from coronavirus disease 19 has been shown for patients with solid cancers or haematological malignancies (HM). Thanks to the accelerated development of anti-SARS-SoV-2 vaccines in less than a year since the start of the global pandemic, patients with cancer were quickly prioritised in early 2021 for vaccination, however dependent on the very unequal availability at the global level. Impaired immunogenicity of SARS-CoV-2 mRNA vaccines in immunocompromised patients was rapidly reported as early as April 2021, although the vaccination fortunately appears to be generally effective without increasing the spacing. Worryingly, the humoral response of the SARS-CoV-2 vaccination is, however, considered insufficient in patients followed for HM, in particular when they are on anti-CD20 treatment. Thus, improving vaccination coverage by strengthening immune stimulation should be evaluated in patients under active treatment against cancer. Here, we discuss three different approaches: a third dose of early vaccine (repeated immune stimulation), heterologous prime-boost vaccination (multimodal immune stimulation) and a double-dose strategy (maximisation of immune response). Dedicated therapeutic trials, currently almost non-existent, seem rapidly necessary.

Cognitive rehabilitation program to improve cognition of cancer patients treated with chemotherapy: A 3-arm randomized trial.

BACKGROUND: There is no treatment for cancer-related cognitive impairment, an important adverse effect that negatively impacts quality of life (QOL). We conducted a 3-arm randomized controlled trial to evaluate the impact of computer-assisted cognitive rehabilitation (CR) on cognition, QOL, anxiety, and depression among cancer patients treated with chemotherapy. METHODS: Patients who reported cognitive complaints during or after completing chemotherapy were randomly assigned to 1 of 3 12-week CR programs: computer-assisted CR with a neuropsychologist (experimental group A), home cognitive self-exercises (active control group B), or phone follow-up (active control group C). Subjective cognition was assessed by the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), objective cognition was assessed by neuropsychological tests, QOL was assessed by the FACT-General, and depression and anxiety were assessed by psychological tests. The primary endpoint was the proportion of patients with a 7-point improvement in the FACT-Cog perceived cognitive impairment (PCI) score. RESULTS: Among the 167 enrolled patients (median age, 51 years), group A had the highest proportion of patients with a 7-point PCI improvement (75%), followed by groups B (59%) and C (57%), but the difference was not statistically significant (P = .13). Compared with groups B and C, the mean difference in PCI score was significantly higher in group A (P = .02), with better perceived cognitive abilities (P < .01) and a significant improvement in working memory (P = .03). Group A reported higher QOL related to cognition (FACT-Cog QOL) (P = .01) and improvement in depression symptoms (P = .03). CONCLUSIONS: These results suggest a benefit of a computer-based CR program in the management of cancer-related cognitive impairment and complaints.

Prolonged efficacy of pembrolizumab in a patient presenting a multi-treated metastatic hepatocholangiocarcinoma.

INTRODUCTION: Hepatocholangiocarcinoma (HCC-ICC) is a rare tumor presenting the histologic characteristics of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). As there is no consensus on it management, the therapeutic strategy rests on the specific treatments for HCC or ICC. Programmed cell death 1 (PD-1) inhibitors showed encouraging results in the second line treatment of HCC after sorafenib but it efficacy in HCC-ICC has never been reported. METHODS AND RESULTS: We present the case of a 72-year-old male patient treated for metastatic HCC-ICC due to a viral hepatitis C cirrhosis in progression after two lines of treatment. Tumor was characterized by a PDL-1 status of 85%. Patient received pembrolizumab at doses of 200 mg every 21 days by intravenous infusion. After one injection he was presented an immediate clinical benefit, a partial response was observed after two months of treatment and a complete response two months later. This response was maintained over time along with toxicity-free tumor control after 18 months treatment. CONCLUSION: To our knowledge, we reported for the first time the efficacy of a PD1 inhibitor treatment in a patient presenting metastatic HCC-ICC due to viral cirrhosis and overexpressing PDL-1 after failure of two lines of treatment.

Intrathecal liposomal cytarabine plus systemic therapy versus systemic chemotherapy alone for newly diagnosed leptomeningeal metastasis from breast cancer.

BACKGROUND: DEPOSEIN (NCT01645839) was a randomized open-label phase III study to explore the role of intrathecal chemotherapy in patients with newly diagnosed leptomeningeal metastasis (LM), a common manifestation of breast cancer. METHODS: Patients with newly diagnosed LM defined by tumor cells in the cerebrospinal fluid or combination of clinical and neuroimaging signs of LM were randomized to receive systemic therapy alone (control group) or systemic therapy plus intrathecal liposomal cytarabine (experimental group). Progression-free survival related to LM (LM-PFS) was the primary endpoint. RESULTS: Thirty-seven and 36 patients were assigned to the control and the experimental groups. Median number of liposomal cytarabine injections in the experimental group was 5 (range 1-20). Focal radiotherapy was performed in 6 (16%) and 3 (8%) patients in the control and experimental groups. In the intent-to-treat population, median LM-PFS was 2.2 months (95% CI: 1.3-3.1) in the control versus 3.8 months (95% CI: 2.3-6.8) in the experimental group (hazard ratio 0.61, 95% CI: 0.38-0.98) (P = 0.04). Seventy-one patients have died. Median overall survival was 4.0 months (95% CI: 2.2-6.3) in the control versus 7.3 months (95% CI: 3.9-9.6) in the experimental group (hazard ratio 0.85, 95% CI: 0.53-1.36) (P = 0.51). Serious adverse events were reported in 22 and 30 patients, respectively. Quality of life until progression did not differ between groups. CONCLUSION: The addition of intrathecal liposomal cytarabine to systemic treatment improves LM-related PFS. Confirmatory trials with optimized patient selection criteria and more active drugs may be required to demonstrate a survival benefit from intrathecal pharmacotherapy.

Correction to: 18F-DOPA PET/CT in brain tumors: impact on multidisciplinary brain tumor board decisions.

Jérôme Barriere was inadvertently missing in the original version of this article. He has participated to the study design, protocol writing and inclusion of a significant number of patients.

Gastric Metastasis Mimicking Linitis Plastica 20 Years after Primary Breast Cancer. A Case Report.

Breast cancer metastases to the gastrointestinal tract are rare, with a median time interval from the diagnosis of the primary tumor to metastasis up to 7 years. The stomach is the most frequent metastatic site and invasive lobular carcinoma is the type with the highest affinity to the digestive system. We report the case of an 84-year-old female patient, with a past medical history 20 years earlier of invasive lobular carcinoma of the breast, who presented for dyspepsia. Upper endoscopy revealed hypertrophic gastric folds compatible with primary linitis plastica. Histology showed proliferation of malignant poorly cohesive cells. Immunohistochemistry stain showed intense positivity of estrogen receptors and anti-GATA-binding protein 3 nuclear antibodies, and absence of the human epidermal growth factor receptor 2. These findings confirmed the diagnosis of a metachronous metastasis of the invasive lobular breast adenocarcinoma. Considering metastases from breast cancer is crucial when patients with any subtle gastric symptom and a past medical history of invasive lobular adenocarcinoma of the breast seek medical advice, even though more than 20 years after primary breast cancer. Immunohistochemistry is the key to final diagnosis as these lesions can endoscopically and histologically mimic primary linitis plastica.