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Introduction: Immune checkpoint inhibitors (ICIs) have substantially advanced the treatment of patients with malignant melanoma. However, improving therapeutic efficacy requires identifying drug combinations that elicit durable responses without inducing intolerable toxicity. Within that context, selinexor emerges as a possible combination option that has been shown in preclinical studies to enhance the efficacy of ICI therapy. Methods: In this phase 1b study, we investigated selinexor in combination with pembrolizumab in 25 patients with advanced non-uveal melanoma. Patients received selinexor at a dosage of 60 mg taken orally twice weekly, and pembrolizumab intravenously at a dosage of 200 mg every 3 weeks. Results: Despite the high incidence of adverse events (96%), most treatment-related toxicities were manageable with supportive care and dose reductions. The most common adverse events of any grade were nausea (n = 20; 80%), decreased white blood cell count (n = 15; 60%), vomiting (n = 14; 56%), anemia (n = 12; 48%), fatigue (n = 12; 48%), and decreased platelet count (n = 12; 48%). The 10 patients with treatment-naïve evaluable disease had an objective response rate (ORR) of 70% (n = 7, including three patients with complete response), which was significantly higher than that of the 14 patients with prior anti–programmed cell death protein 1 (anti-PD-1) therapy, whose ORR was 7% (n = 1; p = 0.002). Stable disease was observed in two patients (20%) with treatment-naïve disease and seven patients (50%) with prior anti-PD-1 therapy. Conclusion: Selinexor combined with pembrolizumab showed promising antitumor activity in patients with treatment-naïve metastatic melanoma. The toxicity profile of the combination was consistent with that reported for individual agents, with no additional safety concerns.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols have improved treatment outcomes and have standardized patient care. OBJECTIVES: Identify the benefit of introducing the ERAS protocol for feeding after gastrostomy insertion with or without Nissen fundoplication, the effects on the time of reaching the full feeds the length of stay single-center experience, and complications associated with early feeding protocols. DESIGN: Retrospective cohort study SETTING: Tertiary hospital METHODS: The study review included cases performed between 2015 and 2021 by four surgeons, and cases performed in 2022 by all surgeons using ERAS feeding protocol (P) in a tertiary hospital. MAIN OUTCOME MEASURES: Comparison the mean and mode of the length of stay (LOS) and the time until the patient reached full feed (TFF). SAMPLE SIZE: 224 patients; 181 by the four surgeons and 43 cases by the ERAS protocol group. RESULTS: The difference in the ERAS protocol from the four surgeons in TFF and LOS was statistically significant (P

Cleidocranial dysplasia (CCD) is a rare genetic skeletal syndrome. The most common features are open fontanelles, hypertelorism, mid-face retrusion, hypoplasia, or aplasia of the clavicles leading to excessive shoulder mobility, dental abnormalities such as supernumerary, and impacted teeth. This case report describes a 31-year-old male with CCD with several unusual symptoms like generalized joint hypermobility, skin laxity, and smooth skin, which leads to set a diagnosis of hypermobile Ehlers-Danlos syndrome (hEDS). To our knowledge, this is the first case report in the literature that describes a patient with these 2 distinct syndromes CCD and hEDS.

Background Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past.Patients and methods We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion Torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3).Results Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs.Conclusion The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs.

This paper presents the results of the blind test competition carried out within the scope of the European project SERA.ta "Seismic Response of Masonry Cross Vaults: Shaking table tests and numerical validations". The purpose of the competition was to predict the results of a set of tests carried out on an unstrengthened full-scale cross vault with mortar joints and solid bricks (then strengthened with textile reinforced mortar) subjected to a horizontal dynamic excitation. The paper offers an overview of the modelling approaches utilised, along with their corresponding predictions and post dictions. The findings are assessed based on both the damage mechanisms and predicted values for displacements and accelerations in both directions. The results are then compared with the experimental findings. Modelling approaches utilizing the Finite Element Method (FEM) yielded the most accurate predictions regarding displacements and crack patterns. Conversely, a submission employing a Discrete Element model provided the most accurate prediction of damage mechanisms. Nonetheless, the significant discrepancies in predicted displacements and accelerations underscore the necessity for continued efforts to establish consensus on appropriate modelling assumptions for masonry vaults. [ABSTRACT FROM AUTHOR]

This work presents the numerical simulations of shaking table tests of a full-scale masonry cross vault. The boundary conditions simulate the presence of a continuous lateral wall and of a colonnade-between-naves condition. The seismic action is applied along the longitudinal direction of the specimen, with increasing amplitude. The model used for the simulations allows for the elastic finite element modelling of masonry units and the discrete element modelling of the interfaces between them. A tension cut-off governs the interface: no tensile stress can be transmitted once this strength is exceeded. The shear response is defined by cohesion and friction: once the former is exceeded the interface reacts according to Coulomb's behaviour. The simulations are related to the blind predictions, according to the scheduled tests, and the post-dictions, according to the actual testing sequence. The prediction model overestimates displacements and does not catch the actual crack distribution. Therefore, a post-simulation model was implemented, revising the masonry elastic modulus as well as the stiffness and boundary conditions of the supporting piers. Simulations are improved both in terms of displacement predictions and damage mechanism. Finally, the sensitivity to finite-element size, damping ratio and block discretisation was explored. [ABSTRACT FROM AUTHOR]

Introduction: Immune checkpoint inhibitors (ICIs) have substantially advanced the treatment of patients with malignant melanoma. However, improving therapeutic efficacy requires identifying drug combinations that elicit durable responses without inducing intolerable toxicity. Within that context, selinexor emerges as a possible combination option that has been shown in preclinical studies to enhance the efficacy of ICI therapy. Methods: In this phase 1b study, we investigated selinexor in combination with pembrolizumab in 25 patients with advanced non-uveal melanoma. Patients received selinexor at a dosage of 60 mg taken orally twice weekly, and pembrolizumab intravenously at a dosage of 200 mg every 3 weeks. Results: Despite the high incidence of adverse events (96%), most treatment-related toxicities were manageable with supportive care and dose reductions. The most common adverse events of any grade were nausea (n = 20; 80%), decreased white blood cell count (n = 15; 60%), vomiting (n = 14; 56%), anemia (n = 12; 48%), fatigue (n = 12; 48%), and decreased platelet count (n = 12; 48%). The 10 patients with treatment naïve evaluable disease had an objective response rate (ORR) of 70% (n = 7, including three patients with complete response), which was significantly higher than that of the 14 patients with prior anti-programmed cell death protein 1 (anti-PD-1) therapy, whose ORR was 7% (n = 1; p = 0.002). Stable disease was observed in two patients (20%) with treatment-naïve disease and seven patients (50%) with prior anti-PD-1 therapy. Conclusion: Selinexor combined with pembrolizumab showed promising antitumor activity in patients with treatment-naïve metastatic melanoma. The toxicity profile of the combination was consistent with that reported for individual agents, with no additional safety concerns. [ABSTRACT FROM AUTHOR]

Abstract Background/purpose Surgical management of high-type anorectal malformations (ARM) has evolved over the years with the widespread of the laparoscopic approach over the last two decades. This study aims to compare the outcome of patients with high anorectal malformation (ARM) managed with laparoscopic-assisted anorectal pull-through (LAARP) vs. the open posterior sagittal anorectoplasty (PSARP) at a single Institution. Methods A retrospective chart review of pediatric patients, who were managed for high-type ARM at our institution, was performed for the period 2000–2015. Nine were excluded because of a lack of important data. Demographic data, surgical approach, associated anomalies, and complications were collected. Functional outcome was measured using the modified clinical scoring for the defecation function of the Japanese study group of anorectal anomalies. Comparison between groups was done using the T test for continuous variables and the Fisher-exact test for proportions. P

The current paper presents the assessment of the infusion of sustainability principles into university curricula at two Jordanian universities. The peer review process of revising the curricula infusing sustainability principles is also discussed. The research methodology involved quantitative methods to assess the revised courses. The results revealed the following: the most relevant ESD themes in the revised curricula were "human connections to the physical and natural world", and "ethics/values". The most relevant ESD topics were: "sustainable production/consumption" and "health promotion". The most infused ESD pillars (competencies) were: "learning to know" and "learning to do". The most relevant ESD principles were: "practiced locally" and "responds through applied learning". The findings offered a rich scenario of the strategies applied by the university professors in revising the curricula, providing evidence of a mental attitude to adopt ESD strategies, as well as a goal-oriented approach in curriculum planning. The paper also discusses the implications of the study results for syllabus revision and development, as well as the refinement of the teaching methods that focus on infusing sustainability into university curricula.

Needle fracture during dental local anesthetic injections is a rare but significant, potentially serious complication. Various approaches for the location and removal of broken needles have been described; however, there are several difficulties and concerns related to the potential complications and critical anatomic challenges peculiar to the head and neck region. In this case, we describe the diagnostic approaches utilized in locating a broken needle that migrated in the pterygomandibular space following gag reflex, and sudden head movement of a middle-aged male patient. A meticulous diagnostic approach was employed to locate the needle utilizing CBCT scan, CT scan with contrast, and C-arm X-ray machine. The needle was successfully retrieved using an angled hemostat inserted through an oral incision, guided by a C-arm X-ray machine and ENT endoscopic instruments. While careful planning could prevent many complications that may arise during oral surgical procedures, inadvertent events leading to serious complications should be addressed using the appropriate and timely diagnostic techniques pre-and intra-operatively.

Perforation of the esophagus during dilatation is a rare complication that might cause mortality. We present the report of a 3-year-old girl who was diagnosed with B cell acute lymphoblastic leukemia at 17 months of age. She experienced a complicated clinical course after chemotherapy was initiated, which included mucositis and acute pericarditis. She later developed an acquired esophageal stricture and tracheoesophageal fistula, which were managed with resection and primary anastomosis when she was in remission. Postoperatively, the patient developed a leak, which was treated conservatively. She subsequently developed a stricture that was treated successfully. On the fourth dilatation attempt and after she was sent home, she presented with persistent vomiting and low-grade fever and became vitally unstable on the same day, after stabilization, upper gastroenterology contrast revealed contrast filling the pericardium. She was managed conservatively with close observation and serial echocardiograms and then discharged home on day 18 in good condition after complete resolution of the pericardial effusion.

Background: Polymorphism within the human T-cell receptor beta variable (TRBV) gene has been proposed as a risk factor for autoimmune disease and immune-related adverse events (IRAEs) during immunotherapy. Previous efforts to evaluate TRBV polymorphism by whole genome sequencing have been hampered by the repetitive nature of the T-cell receptor beta (TCRB) locus. We present a novel long-amplicon TCRB repertoire sequencing approach to enable TRBV haplotype analysis from peripheral blood. Methods: Peripheral blood leukocyte total RNA from 81 Caucasians was used for sequencing of TCRB chains via the Oncomine TCRB-LR assay (amplicon spanning CDR1, 2 and 3) and the Ion Gene Studio S5. VDJ rearrangements were annotated by comparison to the IMGT database, then mined to construct TRBV allele profiles for each individual including, where detected, novel alleles not present in the ImMunoGeneTics (IMGT) database. Finally, TRBV allele profiles were subjected to principal component analysis and k-means clustering to identify TRBV allele haplotypes. Results: Clustering analysis revealed the presence of six major sets of coincident TRBV alleles, which we term haplotype groups. Allelic diversity varied markedly across haplotype groups, with approximately one third of the cohort showing limited TRBV allelic diversity and few uncommon alleles compared to members of other groups. Analysis revealed 37 putatively novel TRBV alleles that are absent from the IMGT database. Conclusion: We demonstrate a straightforward and cost-efficient method for TRBV haplotype analysis from long-amplicon TCRB sequencing data.

Background: The use of oral antineoplastic agents has increased in cancer medicine. However, the convenience of oral medication carries the risk of nonadherence and dosing errors, which could jeopardize therapeutic benefits and patient safety. This is a quality improvement project to investigate reasons for nonadherence and medication errors in patients receiving oral investigational treatment at the Phase 1 Department at MD Anderson Cancer Center, Houston, Texas. Early-phase clinical trials have an enormous impact on drug development and patient safety, not much has been done to evaluate adherence in patients receiving investigational oral antineoplastic agents. Materials and Methods: We examined our clinic dynamic including the initial encounter, follow-up phone calls, medication administration, and patient adherence the following visit. Then we explored and classified the main possible reasons for nonadherence and medication error across the workflow. Results: When examining potential deficiencies in the clinic flow, which are actionable and carry high impact, we found the initial encounter had a significant room for improvement and errors happened when instructions provided were unclear, not correct, or contradicted with the prescription or the label. Furthermore, the follow-up calling was also an important step to monitor and improve compliance. However, it was not a consistent practice and lacked a standardized format. Lastly and although the multistep reconciliation process for oral medication is important to monitor compliance, it was complex, had multiple manual aspects, and added substantial burden on the research staff. Conclusion: In this project, our goal was to shed light on the possible causes of oral medication errors and nonadherence in clinical trials. We proposed feasible measures including educational, training, and adherence monitoring tools. We will continue to monitor and evaluate our data to see any positive or negative impact from our interventions.

Introduction: Endodontically Treated Teeth (ETT) are most likely to get fractured, if it is left unrestored compared with the vital teeth due to the loss of tooth structure and reduced modulus of elasticity. Aim: To gain insight into the rationale for choice of endodontic posts and the different endodontic post systems currently used by dental practitioners in western region of Saudi Arabia. Materials and Methods: For this survey-based study, a questionnaire was designed consisting of eight questions to assess the details of why, when and how general practitioners restore ETT and to determine contemporary use of endodontic post from 1st of November 2018 till the end of January 2019. This questionnaire was sent online to 250 private dental practitioners in western region of Saudi Arabia, out of which 202 participants responded. Data was entered in the excel sheet. Descriptive statistics like frequency and proportion was calculated for qualitative data. Results: This study included 202 participants with the mean age group of 25-50 years, out of which 108 (53.4%) male participants and 94 (46.5%) female participants. 120 (59%) of the study sample were general practitioners and 82 (41%) of them were specialists. A total of 60 (29.70) of the study sample were into general practice, reported restoring ETT with post and core followed by the crown, whereas, 30 (14.85%) of them did the crown without post, 15 (7.42%) of them completed restoration with composite and 15 (7.42%) of them did buildup with post and core. An 82 (40.59%) of the study sample who were specialists, reported restoring ETT with post and core build-up and then proceed with crowns. An 80 (39.60%) of the study sample were into general practice, reported using prefabricated fiber post whereas, 23 (11.38%) of them using cast post and 17 (8.41%) of them using prefabricated metal posts. 72 (35.64%) of the study sample were specialists reported using prefabricated fiber posts and 10 (4.95%) of them used cast metal post. Conclusion: Based on the results of the study, it can be concluded that majority of the participants practiced reinforcement of ETT by using fiber posts with resin cements followed by crowns.

Pituitary carcinoma is an aggressive tumor characterized by metastatic spread beyond the sellar region. Symptoms can be debilitating due to hormonal excess and survival is poor. Pituitary carcinomas recur despite conventional multimodality treatments. Given the recent advances in the use of immune checkpoint inhibitors (CPIs) to treat various solid cancers, there has been interest in exploring the role of immunotherapy for treating aggressive, refractory pituitary tumors. We treated 4 patients with pituitary carcinoma with pembrolizumab as part of a phase II clinical trial. Two patients (patients 1 and 2) with functioning corticotroph pituitary carcinomas (refractory to surgery, radiotherapy and chemotherapy) had partial radiographic (60% and 32% per Immune-Related Response Evaluation Criteria In Solid Tumors, respectively) and hormonal responses. Patient 1’s response continues 42 months after initiation of pembrolizumab and his tumor tissue obtained after treatment with temozolomide demonstrated a hypermutator phenotype with MSH2 and MSH6 gene mutations. Patient 2’s tumor after exposure to temozolomide was not sampled, but prior somatic mutational testing was negative. One patient with a non-functioning corticotroph tumor (patient 3) had a best response of stable disease for 4 months. One patient with a prolactin-secreting carcinoma (patient 4) had progressive disease. The latter 2 patients’ tumors did not demonstrate a hypermutator phenotype after treatment with temozolomide. Programmed death-ligand 1 staining was negative in all tumors. We report 2 cases of corticotroph pituitary carcinoma responsive to pembrolizumab after prior exposure to alkylating agents. The role of CPIs in treating patients with pituitary carcinoma, the relationship between tumor subtype and response to immunotherapy and mechanisms of hypermutation in this orphan disease require further study.Trial registration number: NCT02721732.

Background Patients with advanced rare cancers have poor prognosis and few treatment options. As immunotherapy is effective across multiple cancer types, we aimed to assess pembrolizumab (programmed cell death 1 (PD-1) inhibitor) in patients with advanced rare cancers.Methods In this open-label, phase 2 trial, patients with advanced rare cancers whose tumors had progressed on standard therapies, if available, within the previous 6 months were enrolled in nine tumor-specific cohorts and a 10th cohort for other rare histologies. Pembrolizumab 200 mg was administered intravenously every 21 days. The primary endpoint was non-progression rate (NPR) at 27 weeks; secondary endpoints were safety and tolerability, objective response rate (ORR), and clinical benefit rate (CBR).Results A total of 127 patients treated between August 15, 2016 and July 27, 2018 were included in this analysis. At the time of data cut-off, the NPR at 27 weeks was 28% (95% CI, 19% to 37%). A confirmed objective response (OR) was seen in 15 of 110 (14%) evaluable patients (complete response in one and partial response in 14). CBR, defined as the percentage of patients with an OR or stable disease ≥4 months, was 38% (n=42). Treatment was ongoing in 11 of 15 patients with OR at last follow-up. In the cohort with squamous cell carcinoma (SCC) of the skin, the NPR at 27 weeks was 36%, ORR 31%, and CBR 38%. In patients with adrenocortical carcinoma (ACC), NPR at 27 weeks was 31%, ORR 15%, and CBR 54%. In the patients with carcinoma of unknown primary (CUP), NPR at 27 weeks was 33%, ORR 23%, and CBR 54%. In the paraganglioma–pheochromocytoma cohort, NPR at 27 weeks was 43%, ORR 0%, and CBR 75%. Treatment-related adverse events (TRAEs) occurred in 66 of 127 (52%) patients, and 12 (9%) had grade ≥3 TRAEs. The most common TRAEs were fatigue (n=25) and rash (n=17). There were six deaths, all of which were unrelated to the study drug.Conclusions The favorable toxicity profile and antitumor activity seen in patients with SCC of skin, ACC, CUP, and paraganglioma–pheochromocytoma supports further evaluation of pembrolizumab in this patient population.Trial registration number NCT02721732