Women are Underrepresented in Non-small Cell Lung Cancer Clinical Trials: A Systematic Review.

PURPOSE: To perform a systematic review of clinical trials examining non-small cell lung cancer (NSCLC) to better understand the equity afforded to women in the study of lung cancer. METHODS: An electronic search was conducted for all NSCLC clinical trials published between 2010 and 2020 with included words "carcinoma, non-small cell, lung" and "non-small cell lung cancer." Studies from PubMed, Cochrane, and SCOPUS were included and were uploaded into Covidence to assist with systematic review. All articles were screened by two separate individuals and reviewed for location, study type, cancer stage, field of study of the research team, and percentage of females included. Student's t-test was used to compare the means of males and females. RESULTS: Across the 269 studies that met inclusion criteria, fewer females than males were enrolled (38.7% vs. 61.1%; p < 0.0001). Compared with studies from 2010 to 2015, those from 2016 to 2020 had greater representation of females (36.7% vs. 41.4%, p = 0.0091, respectively). Both nonsurgical and surgical studies enrolled fewer female than male patients (38.1% vs. 61.7%, p < 0.0001; 43.1% vs. 57.2%, p = 0.0002, respectively). Clinical trials from the USA had the least difference between sexes with an average of 46.7% females enrolled. Less females compared with males were enrolled in early-stage NSCLC (37.6% female vs. 62.6% male, p < 0.0001) and late-stage NSCLC trials (37.6% female vs. 62.0% male, p < 0.0001). CONCLUSIONS: Despite recent improvement, there continues to be significant underrepresentation of females compared with males in NSCLC clinical trials.

The association of spinal deformity with dural ectasia in neurofibromatosis type 1.

Objective: To establish the prevalence of dural ectasia in patients with complex neurofibromatosis type-1 (NF-1) and its association with spinal deformities that manifest alongside.Methods: Analysis of the neuroradiological notes from 24 months of multidisciplinary team meetings for patients with complex NF-1 (equating to 378 patients). Review of the MRI scans of all patients with dural ectasia with each scan graded using a novel grading system.Results: A total of 38 of the 378 patients were found to have dural ectasia (10.05%). The median age of these 38 patients was 36 years ranging from 18 to 64. The male: female ratio was 16:22. In all, 90.9% of patients with a 'major' form of dural ectasia had a concurrent spinal deformity present compared to 18.18% of patients with a minor form.Conclusions: The more severe the dural ectasia, the greater the likelihood a concurrent deformity with NF-1. The vertebral bodies and pedicles are more commonly involved than the posterior elements.

Between a rux and a hard place: evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation.

Ruxolitinib is a JAK1/2 inhibitor that is effective in managing symptoms and splenomegaly related to myelofibrosis (MF). Unfortunately, many patients must discontinue ruxolitinib, at which time treatment options are not well defined. In this study, we investigated salvage treatment options and clinical outcomes among MF patients who received and discontinued ruxolitinib outside the context of a clinical trial. Among 145 patients who received ruxolitinib, 23 died while on treatment, 58 remained on treatment at time of analysis, leaving 64 people available for analysis. Development of cytopenias was the most common reason for discontinuation (38%) after median treatment time of 3.8 months (mo). The majority of patients received some form of salvage therapy after ruxolitinib discontinuation (n = 42; 66%), with allogeneic hematopoietic stem cell transplant (alloHSCT) (n = 17), being most commonly employed. Lenalidomide, thalidomide, hydroxyurea, interferon, and danazol were used with similar frequency. The response rate to salvage treatment was 26% (8 responses) and responses were most often seen with lenalidomide or thalidomide. Improved outcomes were observed in patients who underwent alloHSCT or received salvage therapy compared to those who did not receive additional therapy. Median overall survival (OS) after ruxolitinib discontinuation was 13 months. These findings show that salvage therapy can provide clinical responses after ruxolitinib discontinuation; however, these responses are rare and outcomes in this patient population are poor. This represents an area of unmet clinical need in MF.

Neuroinflammation in Parkinson's disease: role in neurodegeneration and tissue repair.

Neuroinflammation in Parkinson's disease [PD] is a process that occurs alongside the loss of dopaminergic neurons, and is associated with alterations to many cell types, most notably microglia. This review examines the key evidence contributing to our understanding of the role of inflammation-mediated degeneration of the dopaminergic (DA) nigrostriatal pathway in PD. It will consider the potential role inflammation plays in tissue repair within the brain, inflammation linked gene products that are associated with sporadic Parkinsonian phenotypes (alpha-synuclein, Parkin and Nurr 1), and developing anti-inflammatory drug treatments in PD. With growing evidence supporting the key role of neuroinflammation in PD pathogenesis, new molecular targets are being found that could potentially prevent or delay nigrostriatal DA neuron loss. Hence, this creates the opportunity for disease modifying treatment, to currently what is an incurable disease.

Pericardioesophageal fistulae after left atrial ablation: a case series.

Pericardioesophageal fistula is an uncommon, yet serious complication that can occur after left atrial ablation for cardiac arrhythmias. Timing of this complication is variable; however, it has been reported to occur from a week to over a month post-ablation. The incidence of this complication after ablation is <0.05%; however with increasing rates of left atrial ablations, early recognition is imperative. Nonspecific symptoms, including chest pain, dysphagia, and fever, can indicate the presence of a fistula within the first month after ablation. Early drainage with subsequent definitive treatment is key to limiting morbidity. Here we report four cases of pericardioesophageal fistula all occurring ~1 month post-ablation, with two patients surviving after prompt diagnosis and surgical treatment. Successful treatment in these two cases was achieved with fistula takedown and intercostal muscle flap interposition and esophageal stenting.

Secondary Repair of Jersey Finger: A Novel Method of Tendon Length Estimation via Measurement of Adjacent Landmarks.

Jersey finger describes the rupture of the flexor digitorum profundus (FDP) tendon at its insertion into the distal phalanx. In the absence of an evidence-based approach to tensioning during secondary repair, we aimed to devise a novel method to determine the required tendon length pre/intraoperatively. We measured anatomical landmarks, associated with the FDP tendon, on dissected cadavers, to assess whether these can be used to estimate tendon segment lengths. Eight cadaveric hands were dissected. Three measurements from the distal lumbrical origin to (1) FDP insertion, (2) the distal end of A1 (Annular 1 pulley), and (3) the proximal end of A1 were recorded for digits II-V. Relative ratios for measurement 1 were consistent for all digits, compared to digit III. Linear regression analysis confirmed a strong correlation for measurement 1 between digit II (R2 =0.97) and digit IV(R2 =0.97) compared to digit III across all specimens. Digit III distal lumbrical origin to FDP insertion measurements could facilitate the estimation of the required graft length for digit II or IV during secondary repair. This is a level IV study, providing proof of concept for a novel method of tendon tensioning.

Wide-Awake Hand Trauma Surgery: Designing Strategies to Optimise Patient Experience.

INTRODUCTION: The regional hand trauma service in Greater Manchester, United Kingdom, underwent significant reorganisation early in the COVID-19 pandemic, with a shift from predominantly general anaesthesia (GA) procedures to the adoption of a Wide-Awake Local Anaesthetic No Tourniquet (WALANT) technique. We implemented strategies targeted towards optimising patient experience, largely applicable to most healthcare settings. METHODS: Four domains were explored: (i) compliance in timing to nationally agreed treatment guidelines, (ii) the role of patient information leaflets, (iii) the introduction of a post-operative analgesia protocol, and (iv) broadly evaluating the environmental impact following the implementation of a same-day 'see and treat' service. RESULTS: Following reorganisation to a predominantly WALANT service, we observed an increase in compliance with nationally agreed standards for the treatment of common hand injuries. Patient education and peri-operative counselling reduced anxiety, whereas post-operative pain was better managed with the introduction of an analgesic protocol. Using a travel carbon calculator, it can be inferred that there are significant reductions in carbon emissions generated when patients are evaluated and treated on the same day as their clinical presentation. CONCLUSIONS: It is widely acknowledged that WALANT benefits patients and the healthcare system. We contemplated whether further incremental changes in clinical practice could further improve patient experience. Given our findings, we advocate a multi-modal approach with a greater focus on patient outcomes (trials are currently underway, e.g., WAFER) supplemented by universally accepted validated patient-reported outcome measures (PROMs).

15 years of patient-reported outcomes in clinical trials leading to GU cancer drug approvals: a systematic review on the quality of data reporting and analysis.

Background: Standardized, high-quality PRO data reporting is crucial for patient centered care in the field of oncology, especially in clinical trials that establish standard of care. This study evaluated PRO endpoint design, conduct and reporting methods in FDA approved drugs for GU malignancies. Methods: A systematic review of the FDA archives identified GU cancer drug approvals from Feb 2007 to July 2022. ClinicalTrials.gov and PubMed were used to retrieve relevant data. PRO data was screened, and analytic tools, interpretation methods in the published papers and study protocols were reviewed. Compliance with PRO reporting standards were assessed using PRO Endpoint Analysis Score (PROEAS), a 24-point scoring scale from Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium (SISAQOL). Findings: We assessed 40 trial protocols with 27,011 participants, resulting in 14 renal cell cancer (RCC), 16 prostate cancer (PC), and 10 urothelial cancer (UC) approvals. PRO data was published for 27 trials, with 23 PRO publications (85%) focusing solely on PRO data, while 4 (15%) included PRO data in the original paper. Median time between primary clinical and secondary paper with PRO data was 10.5 months (range: 9-25 months). PROs were not planned as primary endpoints for any study but 14 (52%) reported them as secondary, 10 (37%) as exploratory outcomes, and 3 (11%) lacked any clarity on PRO data as endpoint. Mean PROEAS score of all GU cancers was 11.10 (range: 6-15), RCC (11.86, range: 6-15), UC (11.50, range: 9-14), and PC (10.56, range: 6-15). None met all the SISAQOL recommendations. Interpretation: Low overall PROEAS score and delays in PRO data publication in GU cancer drug trials conducted in the past decade emphasize the need for improvement in quality of design and conduct of PRO endpoint in future trials and accelerated publication of PRO endpoints, using standardized analysis, and prespecified hypothesis driven endpoint. These improvements are essential for facilitating interpretation and application of PRO study findings to define patient care. Funding: None.

'Hubble-bubble leads to trouble'--waterpipe smoking and oral health.

UNLABELLED: Waterpipes are used to smoke tobacco by more than 100 million people worldwide. Use is not restricted to any single racial, ethnic, or cultural group, and dentists are almost certain to encounter waterpipe users amongst their patients. This article describes what the practice involves and seeks to inform members of the dental team of the significantly detrimental impacts of waterpipe smoking on both general and oral health and how'hubble-bubble really can lead to trouble'. Advising patients on ceasing waterpipe use is also discussed. CLINICAL RELEVANCE: This paper explains what smoking a waterpipe involves, the associated misconceptions of safety amongst users and the dangers to health.

Cost Effectiveness of Treatment Sequences in Advanced Renal Cell Carcinoma.

BACKGROUND: The treatment landscape for metastatic renal cell carcinoma (mRCC) has significantly evolved in recent years. Without direct comparator trials, factors such as cost effectiveness (CE) are important to guide decision-making. OBJECTIVE: To assess the CE of guideline-recommended approved first- and second-line treatment regimens. DESIGN, SETTING, AND PARTICIPANTS: A comprehensive Markov model was developed to analyze the CE of the five current National Comprehensive Cancer Network-recommended first-line therapies with appropriate second-line therapy for patient cohorts with International Metastatic RCC Database Consortium favorable and intermediate/poor risk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Life years, quality-adjusted life years (QALYs), and total accumulated costs were estimated using a willingness-to-pay threshold of $150 000 per QALY. One-way and probabilistic sensitivity analyses were performed. RESULTS AND LIMITATIONS: In patients with favorable risk, pembrolizumab + lenvatinib followed by cabozantinib added $32 935 in costs and yielded 0.28 QALYs, resulting in an incremental CE ratio (ICER) of $117 625 per QALY in comparison to pembrolizumab + axitinib followed by cabozantinib. In patients with intermediate/poor risk, nivolumab + ipilimumab followed by cabozantinib added $2252 in costs and yielded 0.60 QALYs compared to cabozantinib followed by nivolumab, yielding an ICER of $4184. Limitations include differences in median follow-up duration between treatments. CONCLUSIONS: Pembrolizumab + lenvatinib followed by cabozantinib, and pembrolizumab + axitinib followed by cabozantinib were cost-effective treatment sequences for patients with favorable-risk mRCC. Nivolumab +ipilimumab followed by cabozantinib was the most cost-effective treatment sequence for patients with intermediate-/poor-risk mRCC, dominating all preferred treatments. PATIENT SUMMARY: Because new treatments for kidney cancer have not been compared head to head, comparison of their cost and efficacy can help in making decisions about the best treatments to use first. Our model showed that patients with a favorable risk profile are most likely to benefit from pembrolizumab and lenvatinib or axitinib followed by cabozantinib, while patients with an intermediate or poor risk profile will probably benefit most from nivolumab and ipilimumab followed by cabozantinib.

Evaluation of Online Near-Peer Teaching for Penultimate-Year Objective Structured Clinical Examinations in the COVID-19 Era: Longitudinal Study.

BACKGROUND: The benefits of near-peer learning are well established in several aspects of undergraduate medical education including preparing students for Objective Structured Clinical Examinations (OSCEs). The COVID-19 pandemic has resulted in a paradigm shift to predominantly online teaching. OBJECTIVE: This study aims to demonstrate the feasibility and benefits of an exclusively online near-peer OSCE teaching program in a time of significant face-to-face and senior-led teaching shortage. METHODS: A teaching program was delivered to penultimate-year students by final-year students at Manchester Medical School. Program development involved compiling a list of salient topics and seeking senior faculty approval. Teachers and students were recruited on Facebook. In total, 22 sessions and 42 talks were attended by 72 students and taught by 13 teachers over a 3-month period. Data collection involved anonymous weekly questionnaires and 2 separate anonymous student and teacher postcourse questionnaires including both quantitative and qualitative components. RESULTS: On a scale of 1-10, students rated the quality of the program highly (mean 9.30, SD 1.15) and felt the sessions were highly useful in guiding their revision (mean 8.95, SD 0.94). There was a significant increase in perceived confidence ratings after delivery of the program (P<.001). Teachers felt the program helped them better understand and retain the subject material taught (mean 9.36, SD 0.81) and develop skills to become effective clinical teachers (mean 9.27, SD 0.79). CONCLUSIONS: This is the first study demonstrating the efficacy of a near-peer OSCE teaching program delivered exclusively online. This provides an exemplary framework for how similar programs should be encouraged given their efficacy and logistical viability in supplementing the undergraduate curriculum.

Recommencement of anticoagulation/antiplatelet therapy following non-operative management of a Chronic Subdural Hematoma - Is there an optimal time frame?

BACKGROUND: There is no consensus among clinicians regarding recommencement of antithrombotic agents following conservative management of a Chronic Subdural Hematoma (cSDH). Thus, the primary objective of this study was to determine the most commonly recommended interval and whether the data reveal a general consensus that should be adopted. METHODS: A retrospective analysis of Salford Royal Foundation Trust's Neurosurgical referral database for patients referred with a cSDH between March 2017 and March 2020 was carried out. Patients were sorted by whether they were on blood-thinning medications. RESULTS: Over the 3-year period, there were a total of 1220 referral and 1099 patients. 502 (41.14%) of these referrals and 479 (43.59%) patients were on one more blood thinning agent. Of these patients 221 (46.13%) conservative management, there was a clear male predominance (M: F ≈ 2.5:1) in this cohort. 2 weeks was the most commonly advised time-frame (n = 76, 36.36%) to withhold. Of the 234 referrals, there were 13 (5.88%) re-referrals in total. Crucially, there was no significant difference in reaccumulation rates between patients asked to withhold their blood thinners for 2 weeks versus those asked to stop for longer than 2 weeks (P = 0.57). CONCLUSION: For the majority of bleeds, there is no clear benefit from asking patients to withhold their anticoagulant/antiplatelet for longer than 2 weeks. In cases, where it is deemed appropriate to stop for longer than 2 weeks, clear instructions should be provided and documented along with reasons behind the decision.

Postoperative Air Leaks After Lung Surgery: Predictors, Intraoperative Techniques, and Postoperative Management.

Postoperative air leak is one of the most common complications after pulmonary resection and contributes to postoperative pain, complications, and increased hospital length of stay. Several risk factors, including both patient and surgical characteristics, increase the frequency of air leaks. Appropriate intraoperative tissue handling is the most important surgical technique to reduce air leaks. Digital drainage systems have improved the management of postoperative air leak via objective data, portability, and ease of use in the outpatient setting. Several treatment strategies have been used to address prolonged air leak, including pleurodesis, blood patch, placement of endobronchial valves, and reoperative surgery.

Diabetic retinopathy in newly diagnosed Type 2 diabetes mellitus: Prevalence and predictors of progression; a national primary network study.

AIMS: To determine, inreal-world primary care settings, the prevalence of, and risk factors for, retinopathy atType 2 diabetes mellitus diagnosis and report cumulative incidence and progression of retinopathy seven years after diabetes diagnosis. METHODS: Retrospective cohort analysis of people with newly diagnosed Type 2 diabetesrecorded bythe Royal College of General Practitioners Research and Surveillance Centre(between 2005 and 2009, n=11,399).Outcomes included; retinopathy prevalence atdiabetesdiagnosis (baseline) and cumulative incidence or progression of retinopathy at seven years. Retinopathy prevalence was compared with the United Kingdom Prospective Diabetes Study (UKPDS-1998). Factors influencing retinopathy incidence and progression were analysed using logistic regression. RESULTS: Baseline retinopathy prevalencewas 18% (n=2,048) versus 37% in UKPDS. At seven years, 11.6% (n=237) of those with baseline retinopathyhad progression of retinopathy. In those without baseline retinopathy, 46.4% (n=4,337/9,351) developed retinopathy by seven years. Retinopathy development (OR: 1.05 [95%CI: 1.02-1.07] per mmol/mol increase) and progression (OR: 1.05 [1.04-1.06]) at seven years was associated with higher HbA1catdiabetesdiagnosis. Obesity (OR: 0.88 [0.79-0.98]) and high socioeconomic status (OR: 0.63 [0.53-0.74]) were negatively associated with retinopathy development at seven years. CONCLUSIONS: Baseline retinopathy prevalence has declined since UKPDS. Additionally, HbA1c at diabetes diagnosis remains important for retinopathy development and progression.

FEEDBK: a novel approach for providing feedback.

BACKGROUND: High-quality feedback is fundamental to students' learning. We describe and evaluate FEEDBK, a novel feedback tool that encompasses the focus of learning, student self-evaluation (reflection), the encounter with the patient (professionalism), one task that the student should continue to do (reinforcement), one task that they could do better (improvement) and a key take-home message for self-directed learning. METHODS: Medical students received regular bedside teaching and feedback during a 9-week clinical placement at a teaching hospital. Teaching fellows gave feedback in their usual style during weeks 1-3 and then used the FEEDBK tool during weeks 4-9. Questionnaires and focus groups were used to evaluate the students' experience of feedback before and after the introduction of FEEDBK. RESULTS: FEEDBK significantly enhanced the feedback experience across six domains: identifying learning objectives, chance to reflect, feedback on communication skills/professionalism, specific suggestions for improvement, clear take-home message and personalised feedback. The analysis of the feedback from focus groups yielded four categories: (i) FEEDBK influenced the feedback process (delivering timely feedback); (ii) the nature of the feedback (enhancing both the quantity and the quality of the feedback received); (iii) the structure of the feedback; and (iv) the evolution of teaching and learning. DISCUSSION: FEEDBK may enhance both the quantity and the quality of feedback and has the potential to improve the quality of teaching. It provides teachers with a quick and easy-to-follow framework to signpost curriculum-aligned feedback.

Incidence, Management, and Outcomes of Intraoperative Catastrophes During Robotic Pulmonary Resection.

BACKGROUND: Intraoperative catastrophes during robotic anatomical pulmonary resections are potentially devastating events. The present study aimed to assess the incidence, management, and outcomes of these intraoperative catastrophes for patients with primary lung cancers. METHODS: This was a retrospective, multiinstitutional study that evaluated patients who underwent robotic anatomical pulmonary resections. Intraoperative catastrophes were defined as events necessitating emergency thoracotomy or requiring an additional unplanned major surgical procedure. Standardized data forms were collected from each institution, with questions on intraoperative management strategies of catastrophic events. RESULTS: Overall, 1810 patients underwent robotic anatomical pulmonary resections, including 1566 (86.5%) lobectomies. Thirty-five patients (1.9%) experienced an intraoperative catastrophe. These patients were found to have significantly higher clinical TNM stage (P = .031) and lower forced expiratory volume in 1 second (81% vs 90%; P = .004). A higher proportion of patients who had a catastrophic event underwent preoperative radiotherapy (8.6% vs 2.3%; P = .048), and the surgical procedures performed differed significantly compared with noncatastrophic patients. Patients in the catastrophic group had higher perioperative mortality (5.7% vs 0.5%; P = .018), longer operative duration (195 minutes vs 170 minutes; P = .020), and higher estimated blood loss (225 mL vs 50 mL; P < .001). The most common catastrophic event was intraoperative hemorrhage from the pulmonary artery, followed by injury to the airway, pulmonary vein, and liver. Detailed management strategies were discussed. CONCLUSIONS: The incidence of catastrophic events during robotic anatomical pulmonary resections was low, and the most common complication was pulmonary arterial injury. Awareness of potential intraoperative catastrophes and their management strategies are critical to improving clinical outcomes.

In Laparoscopic Myomectomy, Does a Caseload of 100 Patients During the Learning Curve Produce a Significant Improvement in Performance Measures?

PURPOSE: Laparoscopic myomectomy (LM) offers considerable advantages over open myomectomy; however, LM is technically complex and associated with a steep learning curve. Few studies have evaluated the effect of the learning curve, and the limitations of most of these studies were the number of women included and the multiplicity of surgeons undertaking the procedure. The aim of this study is to evaluate the effect of a caseload of 100 patients during the learning curve of a single experienced surgeon performing LM. METHODS: A prospective comparative analysis of 200 consecutive cases of LM was conducted between December 2004 and March 2013. Outcomes of the first 100 procedures (Group A) were compared with the later 100 (Group B). RESULTS: The mean age of the cohort was 39 years (24-54 years), with a mean BMI of 27 kg/m(2) (16-46). Both the groups were very similar with regard to the number, size and weight of myomas removed, the duration of surgery, and blood loss. More women were sent home within 24 h in the second group (27 vs 10.2 %, p = 0.002). Group A suffered significantly higher complication rates compared to Group B (11 vs 7, p < 0.05). The laparotomy conversion rate was 1.5 % (3 in Group A, none in Group B). CONCLUSIONS: After a caseload of 100 patients during the learning curve, there was no difference in outcomes apart from increased confidence to discharge patients after 24 h and reduced complication rates. Thus, mere numbers do not influence the number/size of fibroids removed, operating time, or blood loss but do influence complication rates and post-operative discharge times.