Reviews on Recent Clinical Trials - Volume 18, Issue 3, 2023

The implementation of the new European Clinical Trial Regulation on 31 January 2022, is a major step to promote clinical research in Europe. The French National Agency for Medicines and Health Products Safety (ANSM) proposes to share some key aspects of the preparation for the application of the Regulation initiated in 2017 and to discuss shared indicators that should be considered to monitor clinical trials opportunities on a territory with regards to access to innovation for patients and attractiveness for sponsors. New criteria based on the time from the first request for authorisation to the first inclusion could be of particular interest to appraise the implementation of the European Clinical Trial Regulation.

Background: Neoadjuvant chemoradiotherapy (nCRT) decreases the risk of local recurrence after surgery in patients with locally advanced rectal cancer (LARC) and metformin is constantly gaining scientific interest due to its potentially radiosensitizing effect. Objective: This review article aims to better clarify the role of metformin as a radiosensitizer in patients with LARC undergoing neoadjuvant concurrent chemoradiotherapy. Methods: We used the PubMed database to retrieve journal articles and the inclusion criteria were all human studies that illustrated the effective role of metformin in the neoadjuvant setting of locally advanced rectal cancer. Results: Our search resulted in 17 citations, of which 10 eventually fulfilled the inclusion criteria of our study. Promising results (improved tumor and nodal regression as well as higher pathologic complete response rate) have been occasionally documented with metformin use in some of the included studies. However, regarding survival and all-cause mortality, no significant difference has been found. Conclusion: Metformin might constitute a highly promising radiosensitizer in neoadjuvant LARC treatment attracting much scientific interest. Due to the lack of studies with high evidence, further advanced research is required to enhance the existing knowledge about its potential value in this field.

The battle against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) associated coronavirus disease 2019 (COVID-19) is continued worldwide by administering firsttime emergency authorized novel mRNA-based and conventional vector-antigen-based anti- COVID-19 vaccines to prevent further transmission of the virus as well as to reduce the severe respiratory complications of the infection in infected individuals. However; the emergence of numerous SARS-CoV-2 variants is of concern, and the identification of certain breakthrough and reinfection cases in vaccinated individuals as well as new cases soaring in some low-to-middle income countries (LMICs) and even in some resource-replete nations have raised concerns that only vaccine jabs would not be sufficient to control and vanquishing the pandemic. Lack of screening for asymptomatic COVID-19-infected subjects and inefficient management of diagnosed COVID-19 infections also pose some concerns and the need to fill the gaps among policies and strategies to reduce the pandemic in hospitals, healthcare services, and the general community. For this purpose, the development and deployment of rapid screening and diagnostic procedures are prerequisites in premises with high infection rates as well as to screen mass unaffected COVID-19 populations. Novel methods of variant identification and genome surveillance studies would be an asset to minimize virus transmission and infection severity. The proposition of this pragmatic review explores current paradigms for the screening of SARS-CoV-2 variants, identification, and diagnosis of COVID-19 infection, and insights into the late-stage development of new methods to better understand virus super spread variants and genome surveillance studies to predict pandemic trajectories.

Background: The increased prevalence of irritable bowel syndrome (IBS) among medical and nursing students is a global challenge. Unfortunately, data on the Italian medical and nurse student population are scarce. Therefore, this study was designed to assess the prevalence of IBS in this setting and to evaluate the demographic, university, Mediterranean diet adherence, and anxiety factors associated with its increased presence. Objective: To assess the prevalence of IBS, anxiety levels, and adherence to the Mediterranean diet in medical and nursing university students. Methods: An anonymous online questionnaire was sent to participants. Several demographic and educational variables were assayed, and the presence of symptoms associated with the definition of IBS (according to Rome IV criteria). In addition, anxiety levels and adherence to the Mediterranean diet were also assessed. Results: Of 161 students, 21.11% met the Rome IV criteria for IBS. Some subgroups, the out-ofcourse students or no scholarship recipients, were found to have a higher percentage of IBS (p < 0.05). Being out-of-course was shown to be associated with an increased and unreported risk of presenting IBS (OR: 8.403, p < 0.001). Levels of anxiety and adherence to the Mediterranean diet were significantly worse in the IBS group (p < 0.01). Adherence to the Mediterranean diet was associated with a reduced risk of presenting IBS in our setting (OR 0.258, p = 0.002). Conclusion: Our sample of Italian medical and nursing students recorded a non-negligible percentage of IBS. Therefore, screening and awareness campaigns could be suggested.

Background: Human papillomavirus (HPV) is the most common sexually transmitted infection in the US.The first HPV vaccine was introduced in 2006. There are three different HPV vaccines that commonly target high-risk HPV types. Objective: This study compares HPV vaccine efficacy based on alternative endpoints with the most recently available cervical cancer incidence data from the Surveillance, Epidemiology and End Results (SEER) program and SEER*Stat statistical software. Methods: The incidence of cervical cancer, mined from the most recent April 2021 SEER data set, was stratified according to age and racial groups. Trend analysis reporting cervical cancer incidence percentage change (PC) and annual percentage change (APC) was calculated by SEER*Stat statistical software. Results: A total of 46,583 cases of cervical cancer were reported, with an average of about 3,580 incidents of cervical cancer per year, with an overall decrement of about 60 cases over the period of 12 years. The percentage change according to age and race groups varied between -15.9 among 40- 44 years old (yo) and +13.8 among 30-34 yo, and from -12 among non-Hispanic White women to +13 among Hispanic women. Statistically significant APC was observed for five of the nine age groups and four of the five racial groups. Conclusion: There seems to be little if any, correlation between cervical cancer incidence and the HPV vaccine program in the US. HPV vaccine efficacy based on alternative endpoints, such as nucleic acid testing and cytological, surgical, and seropositivity endpoints, is fair. Therefore, it is important to emphasize such alternative testing and surrogate endpoints.

Background: In older patients, prevention of acute respiratory tract infections (RTIs) is challenging. Experimental studies have consistently underlined an immune-potentiating effect of the bacterial lysates product OM85, on both cellular and humoral responses. Objective: This work aimed to assess the potential efficacy of OM-85 for RTIs’ prevention in older individuals. Methods: This explorative longitudinal study included 24 patients aged 65 years or older recruited in the GeroCovid Observational Study- home and outpatient care cohort. For the study purposes, we included 8 patients treated with OM-85 from December 2020 to June 2021 (group A), and a control group of 16 patients, matched for sex and age, who did not receive bacterial lysates (group B). RTIs were recorded from the participants’ medical documentation in an e-registry from March 2020 to December 2021. Results: In 2020, group A experienced a total of 8 RTIs, which affected 6 out of 8 patients (75%); group B reported 21 RTIs, with at least one event in 11 out of 16 patients (68.7%). In 2021, RTIs affected 2 out of 8 patients (25%) in group A (p < 0.02), and 13 out of 16 patients (81.2%) in group B (within this group, 5 patients had two RTIs). The RTIs' cumulative incidence over the observation period significantly differed between groups (66.7% in group A vs. 24.3% in group B; p < 0.002), as well as the decrease in RTIs frequency from 2020 to 2021. No patients in group A were affected by COVID-19 during the observation period, while among controls, two patients had SARS-CoV-2 infection, notwithstanding three doses of vaccine. Conclusion: This study suggests that bacterial lysates may provide clinical benefits for preventing RTIs. Additional research involving larger cohorts is required to verify the effectiveness of OM-85 in preventing RTIs in older adults.

Background: Pituitary neurosurgery executed via the transsphenoidal endonasal approach is commonly performed for pituitary adenomas. Reasons for prolonged hospital stay include postoperative headache and protracted nausea with or without vomiting. Bilateral superficial trigeminal nerve blocks of the supra-orbital V1 and infra-orbital V2 (SION) nerves performed intra-operatively as a regional anesthetic adjunct to general anesthesia were hypothesized to decrease 6 hours postoperative morphine PCA (patient-controlled analgesia) use by patients. Methods: Forty-nine patients, following induction of general anesthesia for their transsphenoidal surgery, were prospectively randomized in a double-blinded fashion to receive additional regional anesthesia as either a block (0.5% ropivacaine with epi 1:200,000) or placebo/sham (0.9% normal saline). The primary endpoint of the study was systemic morphine PCA opioid consumption by the two groups in the first 6-hours postoperatively. The secondary endpoints included (1) pain exposure experienced postoperatively, (2) incidence of postoperative nausea and vomiting, and (3) time to eligibility for PACU discharge. Results: Of the 49 patients that were enrolled, 3 patients were excluded due to protocol violations. Ultimately, there was no statistically significant difference between morphine PCA use in the 6 hours postoperatively between the block and placebo/sham groups. There was, however, a slight visual tendency in the block group for higher pain scores, morphine use p=0.046, and delayed PACU discharge. False discovery rate corrected comparisons at each time point and then revealed no statistically significant difference between the two groups. There were no differences between the two groups for secondary endpoints. Conclusion: It was found that a 6-hour postoperative headache after endoscopic trans-sphenoidal pituitary surgery likely has a more complicated mechanism involving more than the superficial trigeminovascular system and perhaps is neuro-modulated by other brain nuclei.