Update in Immunotherapy for Advanced Non-Small Cell Lung Cancer: Optimizing Treatment Sequencing and Identifying the Best Choices.

The introduction of immunotherapy has brought about a paradigm shift in the management of advanced non-small cell lung cancer (NSCLC). It has not only significantly improved the prognosis of patients but has also become a cornerstone of treatment, particularly in those without oncogenic driver mutations. Immune checkpoint inhibitors (ICIs) play a crucial role in the treatment of lung cancer and can be classified into two main groups: Anti-cytotoxic T lymphocyte antigen-4 (Anti-CTLA-4) and anti-T-cell receptor programmed cell death-1 or its ligand (Anti-PD-1 and Anti-PD-L1). Certainly, the landscape of approved first line immunotherapeutic approaches has expanded to encompass monotherapy, immunotherapy-exclusive protocols, and combinations with chemotherapy. The complexity of decision-making in this realm arises due to the absence of direct prospective comparisons. However, a thorough analysis of the long-term efficacy and safety data derived from pivotal clinical trials can offer valuable insights into optimizing treatment for different patient subsets. Moreover, ongoing research is investigating emerging biomarkers and innovative therapeutic strategies that could potentially refine the current treatment approach even further. In this comprehensive review, our aim is to highlight the latest advances in immunotherapy for advanced NSCLC, including the mechanisms of action, efficacy, safety profiles, and clinical significance of ICI.

Systematic Review of Platelet-Rich Plasma for Low Back Pain.

BACKGROUND: Low back pain (LBP) has a high economic burden and is strongly related to the degenerative process of the spine, especially in the intervertebral disc and of the facet joints. Numerous treatment modalities have been proposed for the management of LBP, and the use of platelet-rich plasma (PRP) has emerged as an innovative therapeutic option for degenerative disease of the spine. The present study aims to evaluate the efficacy of PRP injections in managing low back pain. METHODS: We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, a registered at PROSPERO Systematic Reviews Platform, under number CRD42021268491. The PubMed, Web of Science, and Scopus databases were searched to identify relevant articles, along with hand searching to identify gray literature articles, with no language restrictions. Randomized clinical trials (RCTs), nonrandomized trials (NRTs), and case series (CSs) with more than 10 patients were considered eligible. The quality assessment and the risk of bias of the randomized clinical trials were evaluated using the RoB II tool. An evaluation of the description of the preparation methods was performed using an adapted version of the MIBO checklist. RESULTS: An electronic database search resulted in 2324 articles, and after the exclusion of noneligible articles, 13 RCTs and 27 NRTs or CSs were analyzed. Of the 13 RCTs, 11 found favorable results in comparison to the control group in pain and disability, one showed no superiority to the control group, and one was discontinued because of the lack of therapeutic effect at eight-week evaluation. Description of the PRP preparation techniques were found in almost all papers. The overall risk of bias was considered high in 2 papers and low in 11. An adapted MIBO checklist showed a 72.7% compliance rate in the selected areas. CONCLUSIONS: In this systematic review, we analyzed articles from English, Spanish and Russian language, from large databases and grey literature. PRP was in general an effective and safe treatment for degenerative LPB. Positive results were found in almost studies, a small number of adverse events were related, the risk of bias of the RCTs was low. Based on the evaluation of the included studies, we graded as level II the quality of the evidence supporting the use of PRP in LBP. Large-scale, multicenter RCTs are still needed to confirm these findings.

Maxilla Reconstruction with Xenograft Blocks to Allow Implant Rehabilitation: A Case Report.

Reducing patient morbidity is one of the challenging goals of proper surgical techniques. The rehabilitation success begins with a good surgical plan. Scientifically proven biomaterials are excellent options to overcome the lack of autologous bone for maxillary reconstructions. This case report presents a clinical case of maxillary reconstruction combining guided bone regeneration with xenograft blocks and maxillary sinus elevation. This technique achieved maxillary rehabilitation with a fixed implant-supported prosthesis of a challenging case. The clinical case has an 18-month follow-up with no major complications and excellent clinical and radiographic results.

Outcomes of a QST Protocol in Healthy Subjects and Chronic Pain Patients: A Controlled Clinical Trial.

Chronic pain is an important cause of disability with a high burden to society. Quantitative sensory testing (QST) is a noninvasive multimodal method used to discriminate the function of nerve fibers. The aim of this study is to propose a new, reproducible, and less time-consuming thermal QST protocol to help characterize and monitor pain. Additionally, this study also compared QST outcomes between healthy and chronic pain subjects. Forty healthy young/adult medical students and fifty adult/elderly chronic pain patients were evaluated in individual sessions including pain history, followed by QST assessments divided into three proposed tests: pain threshold, suprathreshold, and tonic pain. In the chronic pain group, a significantly higher pain threshold (hypoesthesia) and a higher pain sensibility (hyperalgesia) were demonstrated at threshold temperature when compared to healthy participants. The sensitivity to the suprathreshold and tonic stimulus did not prove to be significantly different between both groups. The main results demonstrated that the heat threshold QST tests can be helpful in evaluating hypoesthesia and that the sensitivity threshold temperature test can demonstrate hyperalgesia in individuals with chronic pain. In conclusion, this study demonstrates the importance of using tools such as QST as a complement to detect changes in several pain dimensions.

A Randomized Clinical Trial Comparing Implants Placed in Two Different Biomaterials Used for Maxillary Sinus Augmentation.

The objective of this study was to compare marginal bone loss, surgical and clinical complications, and dental implant survival rate in bilateral maxillary sinus augmented by autologous or porcine xenograft. A randomized controlled clinical trial using split-mouth design enrolled 12 consent adult patients (59.7 ± 8.7 years), who received bilateral maxillary sinus floor augmentation for oral rehabilitation with implant-supported prosthesis. Each patient received both the autologous bone from the mandible (control) or porcine xenograft (test) during the random bilateral sinus lift surgery. A total of 39 dental implants were placed in the posterior maxilla of the 12 patients after 6 months, being rehabilitated after the respective osseointegration period. Both graft materials demonstrated a high implant survival rate at 12 months: 95% for the xenograft side, only 1 implant without osseointegration, and 100% for the autologous side. Radiographic bone loss was low and similar for both groups: control group with a mean of 0.063 ± 0.126, and test group with a mean of 0.092 ± 0.163. No major surgical-related complications have occurred. Only one patient had several prosthetic complications due to fractures of prosthetic components. The maxillary sinus augmentation procedure, both with autologous bone and porcine xenograft materials, is an excellent clinical option procedure for the prosthetic rehabilitation of atrophic maxillae, with low marginal bone loss after one year follow-up, few clinical complications, and a high implant survival rate.

Perceptions of medical students towards the role of histology and embryology during curricular review.

BACKGROUND: The continuous changes in the medical education to prepare medical doctors for the future requires updates in medical curriculum. However, the perspectives of the medical students are not frequently considered during the revision of the medical curriculum. In parallel with the process of defining and adjusting the medical curriculum, a large survey was performed to inquire the perspectives of the medical students at the Faculty of Medicine of the University of Porto (FMUP), Portugal, about the role of Histology and of Embryology. METHODS: Medical students at FMUP (Portugal) completed a structured and anonymous online questionnaire about the subjects Histology and Embryology. The questionnaire was prepared using questions of previous surveys performed in Europe, including another Portuguese medical school, and additional questions that were specifically prepared to this study. The questions referred to teaching methods, clinical relevance, use of virtual (digital) microscopes and association of Histology and Embryology with other subjects of the medical curriculum. RESULTS: Four hundred and sixty-two students participated in the study. The students in clinical years were more likely to recognise the clinical relevance of Histology (p = 0.016) and Embryology (p < 0.001). Students agree that teaching of these subjects would benefit from a clinical orientation (89% for Histology; 90% for Embryology). Students highlighted that Histology is crucial to understand Biopathology and agree (75%) that an integration of Histology with Biopathology could be considered in the medical curriculum. Most students (55%) agree that slide microscopes are more useful than virtual microscopes. CONCLUSIONS: Our study contributes to the debate about the evolution of medical curriculum. Gathering the medical students' perceptions using large surveys such as that performed in the present study may be useful to adapt the methods of teaching which may increase the motivation of the students. In the case of Histology and Embryology at the FMUP (Portugal) providing more clinically oriented teaching may be useful to motivate the students. Students of clinical years have strong clinical perspectives of Histology and Embryology and their enrolment in teaching of Histology and Embryology can also contribute to increase motivation of younger students. Consulting and involving medical students in the development of the medical curriculum can be positive and students should be more responsible and engaged in building their own education.

Relationship between Postoperative Pain and Sociocultural Level in Major Orthopedic Surgery.

Background: Total knee arthroplasty (TKA) and total hip arthroplasty (THA) are associated with moderate to severe postoperative pain (POP). POP is theoretically predictable and may be influenced by sociocultural differences. This study aimed to identify the relationship between POP and the sociocultural level of the patient undergoing THA or TKA. Methods: Prospective study, involving informed-consenting adults conducted through consulting patient's clinical processes, preoperative and postoperative questionnaires. Demographic and anthropometric data, type of surgery, ASA classification, sociocultural level of the patient, and POP were assessed. Results: 95 patients, all Caucasian and natural from the north of the Portugal, were included. Younger women undergoing TKA reported higher levels of POP. In females, the ASA 3 physical condition was also associated with higher mean pain intensity. Patients with preoperative chronic pain, without depression diagnosis, and unsatisfied with the current profession showed higher levels of reported POP. Retirees, with lower school degree, reported higher levels of minimal pain. Conclusions: Job satisfaction, type of surgery, body mass index, presence of chronic pain, and the absence of depression were identified as the main predictors of pain after THA or TKA.

Treatment Sequencing Strategies in Lung Cancer.

BACKGROUND: The advances in the lung cancer screening methods and therapeutics, together with awareness towards deleterious habits, such as smoking, is increasing the overall survival with better quality of life for the patients. However, lung cancer is still one of the most common and fatal neoplasm with a high incidence and consequently burden to public health worldwide. Thus, based on guidelines and recent phases II and III clinical trials studies, this manuscript summarizes the current treatment sequencing strategies in lung cancer. METHODS: A comprehensive search of related articles was performed focused on phases II and III clinical trials studies. RESULTS: The lung cancer management should take into consideration the tumor characteristics, histology, molecular pathology and be discussed in a multidisciplinary team. Lung cancer treatment options comprises surgery whenever possible, radiotherapy associate with/or chemotherapy and immunotherapy as monotherapy, or combined with chemotherapy and best palliative care. CONCLUSIONS: The screening predictability in more patients, smoking reduction, early diagnosis, better disease understanding and individualized, more effective and tolerable therapeutics are related to an increasing in overall survival and quality of life. In the near future improvement of personalized therapy in precision medicine is expected, enhancing new predictive biomarkers, optimal doses and optimal treatment sequencing as well as anti-cancer vaccines development.

Pain as the fifth vital sign-A comparison between public and private healthcare systems.

BACKGROUND: The assessment of pain as the fifth vital sign (P5VS) is of paramount importance since it leads to the management of undertreated pain, consequently reducing suffering, readmissions and emergency department visits after hospital discharge. OBJECTIVE: To evaluate the implementation of P5VS in public and private hospitals. METHODS: Data analysis on validated questionnaires was sent to all 171 Portuguese hospitals via an official letter. RESULTS: When compared to private hospitals, public hospitals presented a higher adherence to the process related to the P5VS. It has demonstrated superiority in the charts properly placed to record P5VS, in the number of emergency departments recording P5VS, in the regularity of audits, and in the existence of guidelines and staff training on pain assessment and management. CONCLUSION: The standardization of both evaluation and recording of pain intensity constitutes a measure of good clinical practice. Public hospitals demonstrated better commitment to these procedures that should be properly carried out in all health care institutions.

Advantages of Porcine Xenograft over Autograft in Sinus Lift: A Randomised Clinical Trial.

This study aimed to compare the performance of intra-oral autologous bone grafts versus porcine xenografts in a two-step lateral window sinus lift. This split-mouth randomised controlled trial sequentially enrolled 12 patients with a 6-month follow-up. For each patient, a simultaneous randomised bilateral maxillary sinus lift was performed and filled with autologous bone from the mandible (control) or a porcine xenograft (test). A bone biopsy sample was collected during the implant placement for histological and histomorphometric analysis. CT scans were performed at the beginning and at the end of the trial to assess radiological evolution. A comparison of initial and six-month CT scans indicated statistically significant increases in bone level for both materials (7.8 ± 2.4 mm for autologous and 8.7 ± 2.2 mm for xenograft, p < 0.05), and there were no significant differences between the performance of the two materials over time (p = 0.26). The histological analysis showed various stages of the remodelling process and no cells or other signs of inflammation or infection were visible in both groups. The porcine xenografts presented similar results for the studied variables when compared to autologous bone, being a reasonable alternative for a sinus lift.

Prevalence of morphological and structural changes in the stylohyoid chain.

BACKGROUND: Total or partial calcification of the stylohyoid chain, elongation of the stylohyoid process of the temporal bone and/or calcification of the stylohyoid ligament are usually incidental radiographic findings. The purpose of this study was to evaluate the prevalence of morphological and structural changes within the stylohyoid chain in 4413 digital panoramic radiographs. MATERIAL AND METHODS: The images were evaluated for the presence or absence of changes in the stylohyoid chain by a specialist in dentofacial radiology and the information collected comprised gender, age, side, right and left measurements and classification of the chain side elongated or calcified stylohyoid process, as well as type and pattern of right or left calcification. RESULTS: 275 (6.2%) subjects presented alterations, mostly bilateral, in the stylohyoid chain, being 186 females (67.6%) and 89 males (32.4%), with a higher proportion elongation. Partial calcification was more prevalent than total calcification. The right side was most affected and the frequency of events increased with age. CONCLUSIONS: The findings of the present study demonstrate that the commonest alterations in the stylohyoid chain are bilateral, mainly elongation, with a clear trend to increased prevalence with increasing age, presenting a low incidence. Noneless, the clinicians must be aware of these alterations in the routinely radiographic examination. Key words:Stylohyoid process, Stylohyoid ligament calcification, Stylohyoid chain, Eagle's syndrome.

MicroRNAs in Lung Cancer Oncogenesis and Tumor Suppression: How it Can Improve the Clinical Practice?

BACKGROUND: Lung cancer (LC) development is a process that depends on genetic mutations. The DNA methylation, an important epigenetic modification, is associated with the expression of non-coding RNAs, such as microRNAs. MicroRNAs are particularly essential for cell physiology, since they play a critical role in tumor suppressor gene activity. Furthermore, epigenetic disruptions are the primary event in cell modification, being related to tumorigenesis. In this context, microRNAs can be a useful tool in the LC suppression, consequently improving prognosis and predicting treatment. CONCLUSION: This manuscript reviews the main microRNAs involved in LC and its potential clinical applications to improve outcomes, such as survival and better quality of life.

The Role of MET Inhibitor Therapies in the Treatment of Advanced Non-Small Cell Lung Cancer.

Introduction: Non-small cell lung cancer (NSCLC) is the second most common cancer globally. The mesenchymal-epithelial transition (MET) proto-oncogene can be targeted in NSCLC patients. Methods: We performed a literature search on PubMed in December 2019 for studies on MET inhibitors and NSCLC. Phase II and III clinical trials published in English between 2014 and 2019 were selected. Results: Data on MET inhibitors (tivantinib, cabozantinib, and crizotinib) and anti-MET antibodies (emibetuzumab and onartuzumab) are reported in the text. Conclusion: Emibetuzumab could be used for NSCLC cases with high MET expression. Further, studies on onartuzumab failed to prove its efficacy, while the results of tivantinib trials were clinically but not statistically significant. Additionally, cabozantinib was effective, but adverse reactions were common, and crizotinib was generally well-tolerated.

What Will We Expect From Novel Therapies to Esophageal and Gastric Malignancies?

Esophageal cancer and gastric cancer are aggressive diseases for which treatment approaches are facing a new era. Some molecular pathways, such as VEGF, EGFR, fibroblast growth factor receptor, PIK3CA, and PARP-1, have been studied, and novel targeted drugs are presumed to be developed in the near future. From The Cancer Genome Atlas report, 80% of Epstein-Barr virus tumors and 42% of tumors with microsatellite instability have PIK3CA mutations, suggesting that this pathway could be reevaluated as a possible target for new systemic treatment of gastric cancer. Notably, higher PARP-1 expression can be found in gastric cancer, which might be related to more advanced disease and worse prognosis. In addition, PD-L1 expression, high microsatellite instability, and mismatch repair deficiency can be found in gastric cancer, thus suggesting that immunotherapy may also play a role in those patients. We discuss trends related to the potential of novel therapies for patients with esophageal and gastric cancers in the near future.

The importance of the posterior joint space for functional mandibular movements: A laboratory cross-sectional study.

BACKGROUND: The search for the ideal, healthy and reproducible position of the condyles is of utmost importance for dental diagnosis and treatment. Thus, the objective of this laboratory cross-sectional study was to verify the relationship between the posterior joint space and the mandibular lateral movements. MATERIAL AND METHODS: Dental casts from 15 women and 15 men with normal mastication, 28 natural teeth and no history of temporomandibular disorders or pain, were fabricated and mounted on a fully adjustable articulator. From the maximum intercuspal position, condylar displacement was evaluated and measured on the working and nonworking sides during mandibular lateral movement, both to the right and left sides. RESULTS: The correlation between the measures of interest was assessed with the Pearson correlation coefficient (α=.05). Condylar displacement on the working side and nonworking side condyle was 0.88±0.71 mm and 3.57±1.11 mm (right mandibular lateral movement); and 0.91±0.58 mm and 3.51±0.78mm (left mandibular lateral movement), respectively. No significant correlation in the condylar displacement between the working side condyles on the right and on the left sides was observed (r=.22; P=.248). The condylar poles of the articulator moved posteriorly, simulating the functional movements of the mandible during mastication. In all cases, condylar displacement during mandibular lateral movement both to the right and left occurred posteriorly on the working side condyle. CONCLUSIONS: The condylar poles of the articulator moved posteriorly simulating the functional movements of the mandible during mastication. Moreover, left and right working condyles may require slightly different spaces to function, suggesting minor anatomical asymmetries. Key words:Mastication, dental occlusion, prosthodontics.

Lung cancer: a brief review of epidemiology and screening.

The global burden of lung cancer has been increasing over the past years, and is still a major threat to public health worldwide, leading to disabilities and premature mortality. Despite multifactorial cause, smoking remains as the major etiological factor, followed by occupational exposure to carcinogens, genetic predisposition and other concomitant diseases. In order to reduce the individual and social burden due to the direct and indirect costs related to the lung cancer treatment, accurate methods of screening are needed. Among those, x-ray with cytological analysis of sputum was first proposed. Nowadays, more sensitive methods such as low-dose computed tomography are being used to improve the early detection. In the future, molecular biomarkers may complement low-dose computed tomography and improve the robustness of early lung cancer detection.

The applications of regenerative medicine in sinus lift procedures: A systematic review.

BACKGROUND: Findings in regenerative medicine applied to the sinus lift procedures. PURPOSE: Evaluate the effectiveness of regenerative medicine in sinus lift. MATERIALS AND METHODS: An extensive search for manuscripts were performed by using different combinations of keywords and MeSH terms (Pub-med; Embase; Scopus; Web of Science Core Collection; Medline; Current Contents Connect; Derwent Innovations Index; Scielo Citation Index; Cochrane library). The full text selected articles are written in English, Portuguese, Spanish, Italian, German, or French, and published until 28 of November 2016. Inclusion criteria were: implant osteointegration, radiographic, histologic, and/or histomorphometric analysis, clinical studies in humans using of regenerative medicine. This systematic review was performed by selecting only randomized controlled clinical trials and controlled clinical trials. RESULTS: Eighteen published studies (11 CT and 7 RCT) were considered eligible for inclusion in the present systematic review. These studies demonstrated considerable variation of biomaterial and cell technics used, study design, sinus lift technic, outcomes, follow-up, and results. CONCLUSION: Only few studies have demonstrated potential of regenerative medicine in sinus lift; further randomized clinical trials are needed to achieve more accurate results.

MicroRNAs in lung cancer.

Lung cancer (LC) is a serious public health problem responsible for the majority of cancer deaths and comorbidities in developed countries. Tobacco smoking is considered the main risk factor for LC; however, only a few smokers will be affected by this cancer. Current screening methods are focused on identifying the early stages of this malignancy. Thus, new data concerning the roles of microRNA alterations in inflammation, epithelial-mesenchymal transition and lung disease have increased hope about LC pathogenesis, diagnosis, treatment and prognosis. MicroRNA mechanisms include angiogenesis promotion, cell cycle regulation by modulating cellular proliferation and apoptosis, and migration and invasion inhibition. In this context, this manuscript reviews the current information about many important microRNAs as they relate to the initiation and progression of LC.