Anesthetic Oxygen Use and Sex Are Critical Factors in the FLASH Sparing Effect.

Purpose: Ultra High Dose-Rate (UHDR) radiation has been reported to spare normal tissue, compared with Conventional Dose-Rate (CDR) radiation. However, important work remains to be done to improve the reproducibility of the FLASH effect. A better understanding of the biologic factors that modulate the FLASH effect may shed light on the mechanism of FLASH sparing. Here, we evaluated whether sex and/or the use of 100% oxygen as a carrier gas during irradiation contribute to the variability of the FLASH effect. Methods and Materials: C57BL/6 mice (24 male, 24 female) were anesthetized using isoflurane mixed with either room air or 100% oxygen. Subsequently, the mice received 27 Gy of either 9 MeV electron UHDR or CDR to a 1.6 cm2 diameter area of the right leg skin using the Mobetron linear accelerator. The primary postradiation endpoint was time to full thickness skin ulceration. In a separate cohort of mice (4 male, 4 female), skin oxygenation was measured using PdG4 Oxyphor under identical anesthesia conditions. Results: Neither supplemental oxygen nor sex affected time to ulceration in CDR irradiated mice. In the UHDR group, skin damage occured earlier in male and female mice that received 100% oxygen compared room air and female mice ulcerated sooner than male mice. However, there was no significant difference in time to ulceration between male and female UHDR mice that received room air. Oxygen measurements showed that tissue oxygenation was significantly higher when using 100% oxygen as the anesthesia carrier gas than when using room air, and female mice showed higher levels of tissue oxygenation than male mice under 100% oxygen. Conclusions: The skin FLASH sparing effect is significantly reduced when using oxygen during anesthesia rather than room air. FLASH sparing was also reduced in female mice compared to male mice. Both tissue oxygenation and sex are likely sources of variability in UHDR studies. These results suggest an oxygen-based mechanism for FLASH, as well as a key role for sex in the FLASH skin sparing effect.

The importance of non-technical skills in robot-assisted surgery in gynaecology.

Robot-assisted surgery (RAS) in gynaecology has undergone exponential growth in recent decades, with utility in treating both benign and malignant gynaecological conditions. The technological complexities and amended theatre dynamics that RAS demands mean that effective non-technical skills (NTS) are vitally important to overcome these unique challenges. However, NTS have been neglected in RAS-training programmes with focus placed instead on the exclusive acquisition of technical skills (TS). NTS include teamwork, communication, leadership, situational awareness, decision-making and stress management. Communication is the most frequently cited NTS impacted during RAS, as the physical limitations imposed by the robotic hardware make communication exchange difficult. The full immersion that RAS enables can contribute to situational awareness deficits. However, RAS can complement communication and teamwork when multidisciplinary (MDT) surgeries (such as complex endometriosis excisions) are undertaken; dual-console capabilities facilitate the involvement of specialties such as general surgery and urology. The development of NTS in RAS cannot be achieved with in-situ experience alone, and current training is poorly standardised. RAS-training programmes and curricula for gynaecology do exist, however the integration of NTS remain limited. Simulation is a viable tool to facilitate enhanced-NTS integration, yet cost implications form a barrier to its wider implementation. However, given that RAS will continue to occupy a greater proportion of the gynaecological caseload, integration of NTS within gynaecological RAS training curricula is necessary. Patients undergoing gynaecological RAS would benefit from the improved safety standards and enhanced surgical outcomes that would result.

Simulation-based training for intraoperative posterior capsule rupture management: an analysis of nontechnical skills development and the relationship between technical and nontechnical skills.

OBJECTIVES: To analyse development of individual nontechnical skills (NTS) domains after undertaking a previously developed simulation-based training model and analyse the relationship between technical skills (TS) and NTS in ophthalmic surgery. METHODS: The simulation-based training model involved a cataract surgery case complicated by intraoperative posterior capsule rupture. Cataract surgeons underwent the simulation twice, separated by a training intervention. Two blinded independent experts assessed participants' NTS using HUFOES, NOn-Technical Skills for Surgeons (NOTSS), and the OSATS global rating scale for TS. Paired t-tests assessed differences in individual NTS domains, with p < 0.05 indicating significance. The Pearson Product Moment Correlation Coefficient was used to assess the correlation between scores from each scoring system. RESULTS: All NTS domains within HUFOES and NOTSS demonstrated statistically significant improvements secondary to the training intervention. Positive correlations were demonstrated between HUFOES and OSATS scores in the pre- and post-training simulations, r = 0.870 (p < 0.001) and r = 0.861 (p < 0.001), respectively. Positive correlations were also demonstrated between NOTSS and OSATS scores in pre- and post-training simulations, r = 0.849 (p < 0.001) and r = 0.757 (p = 0.001), respectively. Positive correlations were demonstrated between HUFOES and NOTSS scores; r = 0.979 (p < 0.001) (n = 17) and r = 0.959 (p < 0.001) for pre- and post-training simulations, respectively. CONCLUSION: All NTS domains contained within HUFOES and NOTSS demonstrated significant increases following the completion of the simulation-based training model. Positive correlations exist between an ophthalmic surgeon's TS and NTS. This is the first study to report these findings within ophthalmic surgery.

Robot Assisted Laparoscopic Surgery in Gynaecology: An Evolving Assistive Technology.

Laparoscopic surgery is extensively utilized to treat a range of gynaecological conditions and pathologies. The advantages of laparoscopic surgery include the minimalization of blood loss and scarring, improved recovery times, and shorter hospital admissions. However, robotic technologies have had an increasing presence within gynaecological laparoscopic surgery in recent decades. This literature review therefore aims to discuss laparoscopy from 3 perspectives. First, the evolution of laparoscopy is reviewed with a focus on its origins, its transition from a diagnostic to an operative tool, and its role in present-day gynaecology. Second, interventions for benign gynaecological conditions (including excision of benign ovarian tumours, total laparoscopic hysterectomy, and laparoscopic myomectomy) are reviewed. The laparoscopic management of malignant gynaecology (including ovarian cancer, endometrial cancer, and cervical cancer) is also discussed. Finally, whilst robot-assisted laparoscopic surgery is experiencing rapid technological advancement, it is pertinent to consider the extent of its benefits when compared to open or conventional laparoscopic approaches in gynaecological surgery.

Association of differential censoring with survival and suboptimal control arms among oncology clinical trials.

Differential censoring (DC), referring to censoring imbalance between treatment arms, may bias the interpretation of survival outcomes in clinical trials. In 146 phase 3 oncology trials with statistically significant time-to-event surrogate primary endpoints (PEPs), we evaluated the association between DC in the surrogate PEP, control arm adequacy, and the subsequent statistical significance of OS results. Twenty-four (16%) trials exhibited DC favoring the control arm (ConDC), while 15 (10%) exhibited experimental arm DC (ExpDC). Positive OS was more common in ConDC trials (63%) than trials without DC (37%) or with ExpDC (47%; odds ratio [OR] 2.64, 95% CI 1.10-7.20; P=.04). ConDC trials more frequently used suboptimal control arms (46%) compared to 20% without DC and 13% with ExpDC (OR 3.60, 95% CI 1.29-10.0; P=.007). The presence of ConDC in trials with surrogate PEPs, especially in those with OS conversion, may indicate an inadequate control arm and should be examined and explained.

Clinical value of random esophageal biopsies in patients with dysphagia and normal endoscopy who are treated with a proton pump inhibitor.

Rome IV recommended esophageal biopsies in patients with dysphagia and normal endoscopy to exclude mucosal disease. Thus far, studies evaluating the utility of this recommendation remain scarce. The aims of this study were to determine the value of random esophageal biopsies in heartburn patients with dysphagia and normal endoscopy and compare the yield of random esophageal biopsies between younger versus older patients. Data were collected from consecutive patients presenting with dysphagia, 18 years and older, who were on proton pump inhibitors and had normal upper endoscopy. Biopsy results of patients with and without heartburn were recorded. Logistic regression analysis was used to compare normal versus abnormal biopsy results in younger and older patients accounting for confounding variables. The number of abnormal biopsies was significantly higher than normal biopsies (68% and 32%, respectively, P = 0.0001). Among abnormal biopsy results, microscopic gastroesophageal reflux disease was significantly more common than all other findings (39%, P = 0.0495). There was no significant difference in biopsy results in patients with and without heartburn as well as younger versus older patients (P = 0.3384, P = 0.1010, and P = 0.8468, respectively). Our study demonstrated that most patients with dysphagia and normal upper endoscopy who are on proton pump inhibitor have some type of histologic mucosal abnormality, which can direct future management. Among abnormal biopsies, microscopic reflux was by far the most common finding in patients with or without a history of heartburn. While this supports the management strategy proposed by Rome IV, age did not drive esophageal biopsy results.

Can I Leave? Perspectives on Parental Leave and Parenthood in Medical Training Among Program Directors and Trainees in Oncologic Specialties.

Purpose: Peak fertility commonly occurs during medical training, and delaying parenthood can complicate pregnancies. Trainee parental leave policies are varied and lack transparency. Research on the impacts of parenthood on trainee education is limited. Methods: A Qualtrics-based survey was distributed via e-mail/social media to program directors (PDs) within oncologic specialties with a request to forward a parallel survey to trainees. Questions assessed awareness of parental leave policies, supportiveness of parenthood, and impacts on trainee education. Statistical analyses included descriptive frequencies and bivariable comparisons by key groups. Results: A total of 195 PDs and 286 trainees responded. Twelve percent and 29% of PDs were unsure of maternity/paternity leave options, respectively. PDs felt they were more supportive of trainee parenthood than trainees perceived they were. Thirty-nine percent of nonparent trainees (NPTs) would have children already if not in medicine, and >80% of women trainees were concerned about declining fertility. Perceived impacts of parenthood on trainee overall education and academic productivity were more negative for women trainees when rated by PDs and NPTs; however, men/women parents self-reported equal impacts. Leave burden was perceived as higher for women trainees. Conclusions: A significant portion of PDs lack awareness of parental leave policies, highlighting needs for increased transparency. Trainees' perception of PD support for parenthood is less than PD self-reported support. Alongside significant rates of delayed parenthood and fertility concerns, this poses a problem for trainees seeking to start a family, particularly women who are perceived more negatively. Further work is needed to create a supportive culture for trainee parenthood.

Disparities in outcomes and access to therapy options in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) disproportionately impacts racial and ethnic minorities and patients with lower socioeconomic status. These social determinants of health (SDH) lead to disparities in access to care and outcomes. We aim to understand the relationship between SDH and survival and locoregional treatment options in HCC. METHODS: Using the National Cancer Database, we evaluated survival and access locoregional treatments including non-transplant surgery, liver transplant (LT), and liver-directed radiation therapy (LDRT) in patients with HCC diagnosed between 2004 and 2017. Variables including clinical stage, age, sex, race, income, rurality, year of diagnosis, facility type (FT), Charlson-Deyo score (CD), and insurance were evaluated. Cox proportional hazards multivariable regression and dominance analyses were used for analyses. RESULTS: In total, 140 340 patients were included. Worse survival was seen with advanced stage, older age, Black race, rurality, public insurance, treatment at a nonacademic center, and lower income. The top predictors for survival included stage, age, and income. Completion of non-transplant surgery was best predicted by stage, FT, and insurance type, whereas LT was predicted by age, year of diagnosis, and CD score. LDRT utilization was most associated with year of diagnosis, FT, and CD score. CONCLUSION: For patients with HCC, survival was predicted primarily by stage, age, and income. The primary sociodemographic factors associated with access to surgical treatments, in addition to FT, were insurance and income, highlighting the financial burdens of health care. Work is needed to address disparities in access to care, including improved insurance access, addressing financial inequities and financial toxicities of treatments, and equalizing care opportunities in community centers.

Anesthetic oxygen use and sex are critical factors in the FLASH sparing effect.

Introduction: Ultra-high dose-rate (UHDR) radiation has been reported to spare normal tissue compared to conventional dose-rate (CDR) radiation. However, reproducibility of the FLASH effect remains challenging due to varying dose ranges, radiation beam structure, and in-vivo endpoints. A better understanding of these inconsistencies may shed light on the mechanism of FLASH sparing. Here, we evaluate whether sex and/or use of 100% oxygen as carrier gas during irradiation contribute to the variability of the FLASH effect. Methods: C57BL/6 mice (24 male, 24 female) were anesthetized using isoflurane mixed with either room air or 100% oxygen. Subsequently, the mice received 27 Gy of either 9 MeV electron UHDR or CDR to a 1.6 cm2 diameter area of the right leg skin using the Mobetron linear accelerator. The primary post-radiation endpoint was time to full thickness skin ulceration. In a separate cohort of mice (4 male, 4 female) skin oxygenation was measured using PdG4 Oxyphor under identical anesthesia conditions. Results: In the UHDR group, time to ulceration was significantly shorter in mice that received 100% oxygen compared to room air, and amongst them female mice ulcerated sooner compared to males. However, no significant difference was observed between male and female UHDR mice that received room air. Oxygen measurements showed significantly higher tissue oxygenation using 100% oxygen as the anesthesia carrier gas compared to room air, and female mice showed higher levels of tissue oxygenation compared to males under 100% oxygen. Conclusion: The FLASH sparing effect is significantly reduced using oxygen during anesthesia compared to room air. The FLASH sparing was significantly lower in female mice compared to males. Both tissue oxygenation and sex are likely sources of variability in UHDR studies. These results suggest an oxygen-based mechanism for FLASH, as well as a key role for sex in the FLASH skin sparing effect.

Retrospective evidence for pediatric benefit of U.S. assault weapons ban as rationale for implementing an even more effective ban.

BACKGROUND: With data available since 1981, firearm death rates in American children and adolescents can be evaluated for trends during the 13 years before, the decade of, and during 16 years since the United States (U.S.) 1994-2004 Federal Assault Weapons Ban (FAWB). METHODS: National and regional firearm mortality trends in the U.S. during 1981-2020 were assessed with joinpoint regression applied to Centers for Disease Control and Prevention data. RESULTS: After increasing exponentially before the FAWB, the national firearm death rate in 0-14 year-olds promptly reversed course and declined throughout the FAWB and then reversed again after the FAWB and resumed an exponential increase (all phases p<0.001). The reduction in firearm death rate occurred within 1-3 years of the start of the FAWB, in both sexes, in all four census regions of the U.S., and in all four major race/ethnicity subgroups, especially non-Hispanic blacks. No other form of violence in 0-14 year-olds had this temporal relationship with the FAWB. The firearm mortality reduction during the FAWB is strongly-highly correlated with the concomitant reduction in handgun manufacturing in 91 % of 24 sex, race/ethnicity and region subsets analyzed, These FAWB-related trends were also apparent in older adolescents and young adults and less so in older persons. CONCLUSIONS: Firearm death rates in 0-14 year-olds before, during, and after the FAWB, and no other type of injury, implicate the FAWB as having had a beneficial effect. Legislation to mitigate firearm mortality and injury inclusive of a FAWB should be especially beneficial to children and young adolescents, and regardless of sex, race/ethnicity or region in the U.S.

Inflammation and oxidative stress markers in type 2 diabetes patients with Advanced Carotid atherosclerosis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major global health issue and a significant risk factor for atherosclerosis. Atherosclerosis in T2DM patients has been associated with inflammation, insulin resistance, hyperglycemia, dyslipidemia, and oxidative stress. Identifying molecular features of atherosclerotic plaques in T2DM patients could provide valuable insights into the pathogenesis of the disease. METHODS: The MASCADI (Arachidonic Acid Metabolism in Carotid Stenosis Plaque in Diabetic Patients) study aimed to investigate the increase of 2-arachidonoyl-lysophatidylcholine (2-AA-LPC) in carotid plaques from T2DM and control patients and to explore its association with plaque vulnerability as well as with blood and intra-plaque biomarkers altered during diabetes. RESULTS: In a population of elderly, polymedicated patients with advanced stage of atherosclerosis, we found that T2DM patients had higher systemic inflammation markers, such as high-sensitivity C-reactive protein (hsCRP) and IL-1ß, higher levels of oxysterols, increased triglyceride levels, and decreased HDL levels as compared to control patients. Furthermore, 2-AA-LPC was significantly enriched in plaques from diabetic patients, suggesting its potential role in diabetic atherosclerosis. Interestingly, 2-AA-LPC was not associated with systemic markers related to diabetes, such as hsCRP, triglycerides, or HDL cholesterol. However, it was significantly correlated with the levels of inflammatory markers within the plaques such as lysophospholipids and 25-hydroxycholesterol, strengthening the link between local inflammation, arachidonic acid metabolism and diabetes. CONCLUSION: Our study is in line with a key role for inflammation in the pathogenesis of diabetic atherosclerosis and highlights the involvement of 2-AA-LPC. Further research is needed to better understand the local processes involved in the alteration of plaque composition in T2DM and to identify potential therapeutic targets. TRIAL REGISTRATION: The MASCADI was registered on ClinicalTrials.gov (clinical registration number: NCT03202823).

Selection and Prejudice: Addressing Clinical Trial Disparities With a Review of Current Shortcomings and Future Directions.

Growing evidence has demonstrated significant, persistent, and widespread disparities in cancer clinical trial enrollment across myriad disease sites and target populations. Although mechanisms underlying such disparities are complex and multifactorial, clinical trial eligibility criteria may serve as a key structural barrier to equitable and diverse trial enrollment. In this review, we provide an overview of the data describing historical and current disparities in cancer clinical trial enrollment and subsequently describe several patient-, institution-, and trial-related factors which appear to be key drivers of enrollment inequity, with specific discussion regarding the impact of eligibility criteria. We further describe the landscape of ongoing professional efforts aimed at eliminating clinical trial disparities through various medical, professional, and advocacy groups. The review concludes with a practical discussion of how modernization of eligibility criteria in clinical trials may decrease or eliminate trial disparities, including specific actionable recommendations aimed at improving the quality of future eligibility criteria.

Effects of UHDR and Conventional Irradiation on Behavioral and Cognitive Performance and the Percentage of Ly6G+ CD45+ Cells in the Hippocampus.

We assessed the effects of conventional and ultra-high dose rate (UHDR) electron irradiation on behavioral and cognitive performance one month following exposure and assessed whether these effects were associated with alterations in the number of immune cells in the hippocampus using flow cytometry. Two-month-old female and male C57BL/6J mice received whole-brain conventional or UHDR irradiation. UHDR mice were irradiated with 9 MeV electrons, delivered by the Linac-based/modified beam control. The mice were irradiated or sham-irradiated at Dartmouth, the following week shipped to OHSU, and behaviorally and cognitively tested between 27 and 41 days after exposure. Conventional- and UHDR-irradiated mice showed impaired novel object recognition. During fear learning, conventional- and UHDR-irradiated mice moved less during the inter-stimulus interval (ISI) and UHDR-irradiated mice also moved less during the baseline period (prior to the first tone). In irradiated mice, reduced activity levels were also seen in the home cage: conventional- and UHDR-irradiated mice moved less during the light period and UHDR-irradiated mice moved less during the dark period. Following behavioral and cognitive testing, infiltrating immune cells in the hippocampus were analyzed by flow cytometry. The percentage of Ly6G+ CD45+ cells in the hippocampus was lower in conventional- and UHDR-irradiated than sham-irradiated mice, suggesting that neutrophils might be particularly sensitive to radiation. The percentage of Ly6G+ CD45+ cells in the hippocampus was positively correlated with the time spent exploring the novel object in the object recognition test. Under the experimental conditions used, cognitive injury was comparable in conventional and UHDR mice. However, the percentage of CD45+ CD11b+ Ly6+ and CD45+ CD11b+ Ly6G- cells in the hippocampus cells in the hippocampus was altered in conventional- but not UHDR-irradiated mice and the reduced percentage of Ly6G+ CD45+ cells in the hippocampus might mediate some of the detrimental radiation-induced cognitive effects.

DIPNECH: pragmatic approach, uncertainties, notable associations, and a proposal for an improved definition.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare, but increasingly recognized entity that primarily affects middle-aged and elderly women. It is characterized by abnormal proliferation of pulmonary neuroendocrine cells (PNECs) and is considered a preinvasive lesion for carcinoid tumorlets/tumors. Sometimes, DIPNECH is accompanied by constrictive bronchiolitis which usually manifests as chronic cough and/or dyspnea, along with airflow limitation on spirometry. The telltale imaging sign of DIPNECH is the presence of multiple noncalcified pulmonary nodules and mosaic attenuation on CT. However, these clinico-radiologic features of DIPNECH are characteristic but nonspecific; thus, histopathologic confirmation is usually necessary. DIPNECH has an indolent course and only rarely leads to respiratory failure or death; progression to overt neuroendocrine tumor (carcinoid) of the lung occurs in a minority of patients. Of available therapies, somatostatin analogs and mechanistic target of rapamycin inhibitors are the most promising. In this review, we provide an update regarding the diagnosis and management of DIPNECH and describe critical gaps in our understanding of this entity, including the central terms 'diffuse' and 'idiopathic.' We also summarize the inconsistencies in definitions employed by recent studies and discuss the pitfalls of the DIPNECH definitions proposed by the World Health Organization in 2021. In this context, we propose an objective and reproducible radio-pathologic case definition intended for implementation in the research realm and seeks to enhance homogeneity across cohorts. Furthermore, we discuss aspects of PNECs biology which suggest that PNEC hyperplasia may contribute to the pathogenesis of phenotypes of lung disease aside from constrictive bronchiolitis and carcinoid tumorlets/tumors. Finally, we steer attention to some of the most pressing and impactful research questions awaiting to be unraveled.

Alternative Splicing of RIOK3 Engages the Noncanonical NFκB Pathway during Rift Valley Fever Virus Infection.

Although the noncanonical NFκB pathway was originally identified as a cellular pathway contributing to lymphoid organogenesis, in the past 20 years, its involvement in innate immunity has become more appreciated. In particular, the noncanonical NFκB pathway has been found to be activated and even exploited by some RNA viruses during infection. Intriguingly, activation of this pathway has been shown to have a role in disrupting transcription of type 1 interferon (IFN), suggesting a rationale for why this response could be co-opted by some viruses. Rift Valley fever virus (RVFV) is a trisegmented ambisense RNA virus that poses a considerable threat to domestic livestock and human health. Previously, we showed the atypical kinase RIOK3 is important for mounting an IFN response to RVFV infection of human epithelial cells, and shortly following infection with RVFV (MP12 strain), RIOK3 mRNA is alternatively spliced to its X2 isoform that encodes a truncated RIOK3 protein. Alternative splicing of RIOK3 mRNA has an inhibitory effect on the IFN response but also stimulates an NFκB-mediated inflammatory response. Here, we demonstrate alternative splicing of RIOK3 mRNA is associated with activation of the noncanonical NFκB pathway and suggest this pathway is co-opted by RVFV (MP12) to enhance viral success during infection.

Postoperative neurological symptoms following arthroscopic shoulder surgery with interscalene block: an exploratory secondary analysis of pooled randomized controlled trial data.

OBJECTIVE: Postoperative neurological symptoms (PONS) are recognized complications of regional anesthesia and orthopedic surgery. We aimed to better characterize prevalence and potential risk factors in a homogeneous population of randomized, controlled trial participants. METHODS: Data were pooled from two randomized controlled trials of analgesia after interscalene block with perineural or intravenous adjuvants (NCT02426736, NCT03270033). Participants were at least 18 years of age and undergoing arthroscopic shoulder surgery at a single ambulatory surgical center. PONS were assessed by telephone follow-up at 14 days and 6 months postoperatively, and defined as patient report of numbness, weakness, or tingling in the surgical limb, alone or in combination, and regardless of severity or etiology. RESULTS: At 14 days, PONS occurred in 83 of 477 patients (17.4%). Among these 83 patients, 10 (12.0%) continued to have symptoms a half-year after surgery. In exploratory univariate analyses, no patient, surgical or anesthetic characteristics were significantly associated with 14-day PONS except for lower postoperative day 1 Quality of Recovery-15 questionnaire total score (OR 0.97 (95% CI, 0.96 to 0.99), p<0.01). This result was driven largely by the emotional domain question scores (OR 0.90 95% CI 0.85 to 0.96, p<0.001). Report of all three of numbness, weakness and tingling at 14 days vs other 14-day symptom combinations was associated with persistent PONS at 6 months (OR 11.5 95% CI 2.2 to 61.8, p<0.01). CONCLUSION: PONS are common after arthroscopic shoulder surgery performed with single injection ultrasound-guided interscalene blocks. No definitive mitigating risk factors were identified.

Incidence of Primary End Point Changes Among Active Cancer Phase 3 Randomized Clinical Trials.

Importance: Primary end point (PEP) changes to an active clinical trial raise questions regarding trial quality and the risk of outcome reporting bias. It is unknown how the frequency and transparency of the reported changes depend on reporting method and whether the PEP changes are associated with trial positivity (ie, the trial met the prespecified statistical threshold for PEP positivity). Objectives: To assess the frequency of reported PEP changes in oncology randomized clinical trials (RCTs) and whether these changes are associated with trial positivity. Design, Setting, and Participants: This cross-sectional study used publicly available data for complete oncology phase 3 RCTs registered in ClinicalTrials.gov from inception through February 2020. Main Outcomes and Measures: The main outcome was change between the initial PEP and the final reported PEP, assessed using 3 methods: (1) history of tracked changes on ClinicalTrials.gov, (2) self-reported changes noted in the article, and (3) changes reported within the protocol, including all available protocol documents. Logistic regression analyses were performed to evaluate whether PEP changes were associated with US Food and Drug Administration approval or trial positivity. Results: Of 755 included trials, 145 (19.2%) had PEP changes found by at least 1 of the 3 detection methods. Of the 145 trials with PEP changes, 102 (70.3%) did not have PEP changes disclosed within the manuscript. There was significant variability in rates of PEP detection by each method (χ2 = 72.1; P < .001). Across all methods, PEP changes were detected at higher rates when multiple versions of the protocol (47 of 148 [31.8%]) were available compared with 1 version (22 of 134 [16.4%]) or no protocol (76 of 473 [16.1%]) (χ2 = 18.7; P < .001). Multivariable analysis demonstrated that PEP changes were associated with trial positivity (odds ratio, 1.86; 95% CI, 1.25-2.82; P = .003). Conclusions and Relevance: This cross-sectional study revealed substantial rates of PEP changes among active RCTs; PEP changes were markedly underreported in published articles and mostly occurred after reported study completion dates. Significant discrepancies in the rate of detected PEP changes call into question the role of increased protocol transparency and completeness in identifying key changes occurring in active trials.

Phase 2 study of preoperative chemotherapy with nab-paclitaxel and gemcitabine followed by chemoradiation for borderline resectable or node-positive pancreatic ductal adenocarcinoma.

BACKGROUND: Neoadjuvant treatment with nab-paclitaxel and gemcitabine for potentially operable pancreatic adenocarcinoma has not been well studied in a prospective interventional trial and could down-stage tumors to achieve negative surgical margins. METHODS: A single-arm, open-label phase 2 trial (NCT02427841) enrolled patients with pancreatic adenocarcinoma deemed to be borderline resectable or clinically node-positive from March 17, 2016 to October 5, 2019. Patients received preoperative gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on Days 1, 8, 15, every 28 days for two cycles followed by chemoradiation with 50.4 Gy intensity-modulated radiation over 28 fractions with concurrent fluoropyrimidine chemotherapy. After definitive resection, patients received four additional cycles of gemcitabine and nab-paclitaxel. The primary endpoint was R0 resection rate. Other endpoints included treatment completion rate, resection rate, radiographic response rate, survival, and adverse events. RESULTS: Nineteen patients were enrolled, with the majority having head of pancreas primary tumors, both arterial and venous vasculature involvement, and clinically positive nodes on imaging. Among them, 11 (58%) underwent definitive resection and eight of 19 (42%) achieved R0 resection. Disease progression and functional decline were primary reasons for deferring surgical resection after neoadjuvant treatment. Pathologic near-complete response was observed in two of 11 (18%) resection specimens. Among the 19 patients, the 12-month progression-free survival was 58%, and 12-month overall survival was 79%. Common adverse events were alopecia, nausea, vomiting, fatigue, myalgia, peripheral neuropathy, rash, and neutropenia. CONCLUSION: Gemcitabine and nab-paclitaxel followed by long-course chemoradiation represents a feasible neoadjuvant treatment strategy for borderline resectable or node-positive pancreatic cancer.