Quantitative Evaluation of Large Language Models to Streamline Radiology Report Impressions: A Multimodal Retrospective Analysis.

Background The complex medical terminology of radiology reports may cause confusion or anxiety for patients, especially given increased access to electronic health records. Large language models (LLMs) can potentially simplify radiology report readability. Purpose To compare the performance of four publicly available LLMs (ChatGPT-3.5 and ChatGPT-4, Bard [now known as Gemini], and Bing) in producing simplified radiology report impressions. Materials and Methods In this retrospective comparative analysis of the four LLMs (accessed July 23 to July 26, 2023), the Medical Information Mart for Intensive Care (MIMIC)-IV database was used to gather 750 anonymized radiology report impressions covering a range of imaging modalities (MRI, CT, US, radiography, mammography) and anatomic regions. Three distinct prompts were employed to assess the LLMs' ability to simplify report impressions. The first prompt (prompt 1) was "Simplify this radiology report." The second prompt (prompt 2) was "I am a patient. Simplify this radiology report." The last prompt (prompt 3) was "Simplify this radiology report at the 7th grade level." Each prompt was followed by the radiology report impression and was queried once. The primary outcome was simplification as assessed by readability score. Readability was assessed using the average of four established readability indexes. The nonparametric Wilcoxon signed-rank test was applied to compare reading grade levels across LLM output. Results All four LLMs simplified radiology report impressions across all prompts tested (P < .001). Within prompts, differences were found between LLMs. Providing the context of being a patient or requesting simplification at the seventh-grade level reduced the reading grade level of output for all models and prompts (except prompt 1 to prompt 2 for ChatGPT-4) (P < .001). Conclusion Although the success of each LLM varied depending on the specific prompt wording, all four models simplified radiology report impressions across all modalities and prompts tested. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Rahsepar in this issue.

Immunotherapy Initiation at the End of Life in Patients With Metastatic Cancer in the US.

Importance: While immunotherapy is being used in an expanding range of clinical scenarios, the incidence of immunotherapy initiation at the end of life (EOL) is unknown. Objective: To describe patient characteristics, practice patterns, and risk factors concerning EOL-initiated (EOL-I) immunotherapy over time. Design, Setting, and Participants: Retrospective cohort study using a US national clinical database of patients with metastatic melanoma, non-small cell lung cancer (NSCLC), or kidney cell carcinoma (KCC) diagnosed after US Food and Drug Administration approval of immune checkpoint inhibitors for the treatment of each disease through December 2019. Mean follow-up was 13.7 months. Data analysis was performed from December 2022 to May 2023. Exposures: Age, sex, race and ethnicity, insurance, location, facility type, hospital volume, Charlson-Deyo Comorbidity Index, and location of metastases. Main Outcomes and Measures: Main outcomes were EOL-I immunotherapy, defined as immunotherapy initiated within 1 month of death, and characteristics of the cohort receiving EOL-I immunotherapy and factors associated with its use. Results: Overall, data for 242 371 patients were analyzed. The study included 20 415 patients with stage IV melanoma, 197 331 patients with stage IV NSCLC, and 24 625 patients with stage IV KCC. Mean (SD) age was 67.9 (11.4) years, 42.5% were older than 70 years, 56.0% were male, and 29.3% received immunotherapy. The percentage of patients who received EOL-I immunotherapy increased over time for all cancers. More than 1 in 14 immunotherapy treatments in 2019 were initiated within 1 month of death. Risk-adjusted patients with 3 or more organs involved in metastatic disease were 3.8-fold more likely (95% CI, 3.1-4.7; P < .001) to die within 1 month of immunotherapy initiation than those with lymph node involvement only. Treatment at an academic or high-volume center rather than a nonacademic or very low-volume center was associated with a 31% (odds ratio, 0.69; 95% CI, 0.65-0.74; P < .001) and 30% (odds ratio, 0.70; 95% CI, 0.65-0.76; P < .001) decrease in odds of death within a month of initiating immunotherapy, respectively. Conclusions and Relevance: Findings of this cohort study show that the initiation of immunotherapy at the EOL is increasing over time. Patients with higher metastatic burden and who were treated at nonacademic or low-volume facilities had higher odds of receiving EOL-I immunotherapy. Tracking EOL-I immunotherapy can offer insights into national prescribing patterns and serve as a harbinger for shifts in the clinical approach to patients with advanced cancer.

Analysis of Radiation Therapy Quality Assurance in NRG Oncology RTOG 0848.

PURPOSE: NRG/Radiation Therapy Oncology Group 0848 is a 2-step randomized trial to evaluate the benefit of the addition of concurrent fluoropyrimidine and radiation therapy (RT) after adjuvant chemotherapy (second step) for patients with resected pancreatic head adenocarcinoma. Real-time quality assurance (QA) was performed on each patient who underwent RT. This analysis aims to evaluate adherence to protocol-specified contouring and treatment planning and to report the types and frequencies of deviations requiring revisions. METHODS AND MATERIALS: In addition to a web-based contouring atlas, the protocol outlined step-by-step instructions for generating the clinical treatment volume through the creation of specific regions of interest. The planning target volume was a uniform 0.5 cm clinical treatment volume expansion. One of 2 radiation oncology study chairs independently reviewed each plan. Plans with unacceptable deviations were returned for revision and resubmitted until approved. Treatment started after final approval of the RT plan. RESULTS: From 2014 to 2018, 354 patients were enrolled in the second randomization. Of these, 160 patients received RT and were included in the QA analysis. Resubmissions were more common for patients planned with 3-dimensional conformal RT (43%) than with intensity modulated RT (31%). In total, at least 1 resubmission of the treatment plan was required for 33% of patients. Among patients requiring resubmission, most only needed 1 resubmission (87%). The most common reasons for resubmission were unacceptable deviations with respect to the preoperative gross target volume (60.7%) and the pancreaticojejunostomy (47.5%). CONCLUSION: One-third of patients required resubmission to meet protocol compliance criteria, demonstrating the continued need for expending resources on real-time, pretreatment QA in trials evaluating the use of RT, particularly for pancreas cancer. Rigorous QA is critically important for clinical trials involving RT to ensure that the true effect of RT is assessed. Moreover, RT QA serves as an educational process through providing feedback from specialists to practicing radiation oncologists on best practices.

Phase I study to assess the effect of adavosertib (AZD1775) on the pharmacokinetics of substrates of CYP1A2, CYP2C19, and CYP3A in patients with advanced solid tumors.

PURPOSE: Adavosertib may alter exposure to substrates of the cytochrome P450 (CYP) family of enzymes. This study assessed its effect on the pharmacokinetics of a cocktail of probe substrates for CYP3A (midazolam), CYP2C19 (omeprazole), and CYP1A2 (caffeine). METHODS: Period 1: patients with locally advanced or metastatic solid tumors received 'cocktail': caffeine 200 mg, omeprazole 20 mg, and midazolam 2 mg (single dose); period 2: after 7- to 14-day washout, patients received adavosertib 225 mg twice daily on days 1-3 (five doses), with cocktail on day 3. After cocktail alone or in combination with adavosertib administration, 24-h pharmacokinetic sampling occurred for probe substrates and their respective metabolites paraxanthine, 5-hydroxyomeprazole (5-HO), and 1'-hydroxymidazolam (1'-HM). Safety was assessed throughout. RESULTS: Of 33 patients (median age 60.0 years, range 41-83) receiving cocktail, 30 received adavosertib. Adavosertib co-administration increased caffeine, omeprazole, and midazolam exposure by 49%, 80%, and 55% (AUC0-12), respectively; AUC0-t increased by 61%, 98%, and 55%. Maximum plasma drug concentration (Cmax) increased by 4%, 46%, and 39%. Adavosertib co-administration increased 5-HO and 1'-HM exposure by 43% and 54% (AUC0-12) and 49% and 58% (AUC0-t), respectively; paraxanthine exposure was unchanged. Adavosertib co-administration decreased Cmax for paraxanthine and 5-HO by 19% and 7%; Cmax increased by 33% for 1'-HM. After receiving adavosertib, 19 (63%) patients had treatment-related adverse events (six [20%] grade ≥ 3). CONCLUSION: Adavosertib (225 mg bid) is a weak inhibitor of CYP1A2, CYP2C19, and CYP3A. CLINICALTRIALS: GOV: NCT03333824.

Adavosertib (AZD1775) does not prolong the QTc interval in patients with advanced solid tumors: a phase I open-label study.

PURPOSE: Adavosertib is a small-molecule, ATP-competitive inhibitor of Wee1 kinase. Molecularly targeted oncology agents have the potential to increase the risk of cardiovascular events, including prolongation of QT interval and associated cardiac arrhythmias. This study investigated the effect of adavosertib on the QTc interval in patients with advanced solid tumors. METHODS: Eligible patients were ≥ 18 years of age with advanced solid tumors for which no standard therapy existed. Patients received adavosertib 225 mg twice daily on days 1-2 at 12-h intervals and once on day 3. Patients underwent digital 12-lead electrocardiogram and pharmacokinetic assessments pre-administration and time-matched assessments during the drug administration period. The relationship between maximum plasma drug concentration (Cmax) and baseline-adjusted corrected QT interval by Fridericia (QTcF) was estimated using a prespecified linear mixed-effects model. RESULTS: Twenty-one patients received adavosertib. Concentration-QT modeling of ΔQTcF and the upper limit of the 90% confidence interval corresponding to the geometric mean of Cmax observed on days 1 and 3 were below the threshold for regulatory concern (not > 10 ms). No significant relationship between ΔQTcF (vs baseline) and adavosertib concentration was identified (P = 0.27). Pharmacokinetics and the adverse event (AE) profile were consistent with previous studies at this dose. Eleven (52.4%) patients experienced 17 treatment-related AEs in total, including diarrhea and nausea (both reported in six [28.6%] patients), vomiting (reported in two [9.5%] patients), anemia, decreased appetite, and constipation (all reported in one [4.8%] patient). CONCLUSION: Adavosertib does not have a clinically important effect on QTc prolongation. CLINICALTRIALS: GOV: NCT03333824.

Distribution and Disparities of Industry Payments to Radiologists (2016-2020).

BACKGROUND: The frequency, magnitude, and distribution of industry payments to radiologists are not well understood. RATIONALE AND OBJECTIVES: The aim of this study was to analyze the distribution of industry payments to physicians working in diagnostic radiology, interventional radiology, and radiation oncology, study the categories of payments and determine their correlation. MATERIALS AND METHODS: The Open Payments Database from the Centers for Medicare & Medicaid Services was accessed and analyzed for the period from January 1, 2016 to December 31, 2020. Payments were grouped into six categories: consulting fees, education, gifts, research, speaker fees, and royalties/ownership. The total amount and types of industry payments going to the top 5% group were determined overall and for each category of payment. RESULTS: From 2016 to 2020, a total of 513 020 payments, amounting to $370 782 608, were made to 28 739 radiologists suggesting that approximately 70% of the 41 000 radiologists in the US received at least one industry payment during the 5-year period. The median payment value was $27 (IQR: $15-$120) and the median number of payments per physician over the 5-year period was 4 (IQR: 1-13). Gifts were the most frequent payment type made (76.4%), but accounted for only 4.8% of payment value. The median total value of payments earned by members of the top 5% group over the 5-year period was $58 878 (IQR: $29 686-$162 425) ($11 776 per year) compared to $172 (IQR: $49-877) ($34 per year) in the bottom 95% group. Members of the top 5% group received a median of 67 (IQR: 26-147) individual payments (13 payments per year) while members of the bottom 95% group received a median of 3 (IQR: 1-11) (0.6 payments per year). CONCLUSION: Between 2016 and 2020, industry payments to radiologists were highly concentrated both in terms of number/frequency and value of payments.

Clinical Implementation of a Combined Artificial Intelligence and Natural Language Processing Quality Assurance Program for Pulmonary Nodule Detection in the Emergency Department Setting.

OBJECTIVE: This quality assurance study assessed the implementation of a combined artificial intelligence (AI) and natural language processing (NLP) program for pulmonary nodule detection in the emergency department setting. The program was designed to function outside of normal reading workflows to minimize radiologist interruption. MATERIALS AND METHODS: In all, 19,246 CT examinations including at least some portion of the lung anatomy performed in the emergent setting from October 1, 2021, to June 1, 2022, were processed by the combined AI-NLP program. The program used an AI algorithm trained on 6-mm to 30-mm pulmonary nodules to analyze CT images and an NLP to analyze radiological reports. Cases flagged as negative for pulmonary nodules by the NLP but positive by the AI algorithm were classified as suspected discrepancies. Discrepancies result in secondary review of examinations for possible addenda. RESULTS: Out of 19,246 CT examinations, 50 examinations (0.26%) resulted in secondary review, and 34 of 50 (68%) reviews resulted in addenda. Of the 34 addenda, 20 patients received instruction for new follow-up imaging. Median time to addendum was 11 hours. The majority of reviews and addenda resulted from missed pulmonary nodules on CT examinations of the abdomen and pelvis. CONCLUSION: A background quality assurance process using AI and NLP helped improve the detection of pulmonary nodules and resulted in increased numbers of patients receiving appropriate follow-up imaging recommendations. This was achieved without disrupting in-shift radiologist workflow or causing significant delays in patient follow for the diagnosed pulmonary nodule.

Reduced expression of perineuronal nets in the normotopic somatosensory cortex of the tish rat.

The tish (telencephalic internal structural heterotopia) rat is a naturally occurring and unique model of a malformation of cortical development (MCD) arising from a sponeantous mutation in the Eml1 gene. Tish rats are characterized by a macroscopic bilateral heterotopic dysplastic cortex (HDCx) and an overlaying, intact normotopic neocortex (NNCx). These two cortices are functional and have been reported to innervate and establish connections with subcortical regions including the thalamus, resulting in a dual-cortical representation. Additionally, impaired GABAergic neurotransmission and early-onset spike wave discharge bursts have been reported in developing tish rats. Perineuronal nets (PNNs) are specialized extraceullar matrix structures that predominately surround and stabilize parvalbumin-positive (PV+) GABAergic interneurons and are essential components of the neural landscape. Here, we report a significant reduction in the average number of WFA+-PNNs in the normotopic somatosensory cortex (NSSCx) of the tish rat at two developmental time points, P16 and P35, corresponding to a decrease in the number of PV+ interneurons ensheathed by a PNN in the NSSCx. Compared with control animals, PNN expression was partially, but significantly restored following treatment with insulin-like growth factor 1 (IGF-1). These data suggest that the 'dual cortical representation' in the setting of an MCD reduces the cortical activation necessary for proper PNN expression likely contributing to the impairments in GABAergic neurotransmission and network excitability previously identified in the tish rat.

Cost-effectiveness of chimeric antigen receptor T-cell therapy in adults with relapsed or refractory follicular lymphoma.

Follicular lymphoma (FL) is traditionally considered treatable but incurable. In March 2021, the US Food and Drug Administration approved the use of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory (R/R) FL after ≥2 lines of therapy. Priced at $373 000, CAR T-cell therapy is potentially curative, and its cost-effectiveness compared with other modern R/R FL treatment strategies is unknown. We developed a Markov model to assess the cost-effectiveness of third-line CAR T-cell vs standard of care (SOC) therapies in adults with R/R FL. We estimated progression rates for patients receiving CAR T-cell and SOC therapies from the ZUMA-5 trial and the LEO CReWE study, respectively. We calculated costs, discounted life years, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) of CAR T-cell vs SOC therapies with a willingness-to-pay threshold of $150 000 per QALY. Our analysis was conducted from a US payer's perspective over a lifetime horizon. In our base-case model, the cost of the CAR T-cell strategy was $731 682 compared with $458 490 for SOC therapies. However, CAR T-cell therapy was associated with incremental clinical benefit of 1.50 QALYs, resulting in an ICER of $182 127 per QALY. Our model was most sensitive to the utilities associated with CAR T-cell therapy remission and third-line SOC therapies and to the total upfront CAR T-cell therapy cost. Under current pricing, CAR T-cell therapy is unlikely to be cost-effective in unselected patients with FL in the third-line setting. Both randomized clinical trials and longer term clinical follow-up can help clarify the benefits of CAR T-cell therapy and optimal sequencing in patients with FL.

Digital Full-Mouth Reconstruction: From Diagnostics to Final Full Zirconia Restorations.

BACKGROUND: This clinical report describes the use of digital technology for full-mouth rehabilitation using fixed implant-supported full-contour zirconia prostheses. CASE PRESENTATION: A 61-year-old female patient presented with existing acrylic overdentures retained by mini implants; her chief concern was to improve esthetics and function through the use of fixed prostheses. Digital tools comprising CAD/CAM, 3D printing, guided implant surgery, and 2D smile design were utilized from the planning stage to final restorations combined with analog components in an efficient manner to address the patient's chief concern. Existing mini implants were used to help position surgical guides and provisional restorations. Final restorations were fabricated using a monolithic multilayered full-contour zirconia dental material, which provided excellent physical and esthetic properties. CONCLUSION: Digital technology is an essential component of modern dentistry to achieve predictable outcomes for the treatment of complex cases in an efficient manner.

Oral administration of TRAIL-inducing small molecule ONC201/TIC10 prevents intestinal polyposis in the Apc min/+ mouse model.

Colorectal cancer (CRC) incidence is rising globally. Hence, preventing this disease is a high priority. With this aim, we determined the CRC prevention potential of the TRAIL-inducing small molecule ONC201/TIC10 using a preclinical model representing high-risk familial adenomatous polyposis (FAP) patients, Apc min/+ mice. Prior to the efficacy study, optimal and non-toxic doses of ONC201 were determined by testing five different doses of ONC201 (0-100 mg/kg body weight (BW); twice weekly by oral gavage) in C57BL/6J mice (n=6/group) for 6 weeks. BW gain, organ weights and histopathology, blood profiling, and the plasma liver enzyme profile suggested no toxicities of ONC201 at doses up to 100 mg/kg BW. For efficacy determination, beginning at six weeks of age, groups of Apc min/+ male and female mice (n≥20) treated with colon carcinogen azoxymethane (AOM) (AOM-Apc min/+) were administered ONC201 (0, 25, and 50 mg/kg BW) as above up to 20 weeks of age. At termination, efficacy was determined by comparing the incidence and multiplicity of intestinal tumors between vehicle- and drug-treated groups. ONC201 showed a strong suppressive effect against the development of both large and small intestinal tumors in male and female mice. Apc min/+ mice treated with ONC201 (50 mg/kg BW) showed >50% less colonic tumor incidence (P<0.0002) than controls. Colonic tumor multiplicity was also significantly reduced by 68% in male mice (0.44 ± 0.11 in treated vs. 1.4 ± 0.14 in controls; P<0.0001) and by 75% in female mice (0.30 ± 0.10 in treated vs. 1.19 ± 0.19 in controls; P<0.0003) with ONC201 treatment (50 mg/kg BW). Small intestinal polyps were reduced by 68% in male mice (11.40 ± 1.19 in treated vs. 36.08 ± 2.62 in controls; P<0.0001) and female mice (9.65 ± 1.15 in treated vs. 29.24 ± 2.51 in controls; P<0.0001). Molecular analysis of the tumors suggested an increase in TRAIL, DR5, cleaved caspases 3/7/8, Fas-associated death domain protein (FADD), and p21 (WAF1) in response to drug treatment. Serum analysis indicated a decrease in pro-inflammatory serum biomarkers, such as IL1ß, IL6, TNFα, G-CSF, and GM-CSF, in the ONC201-treated mice compared with controls. Our data demonstrated excellent chemopreventive potential of orally administered ONC201 against intestinal tumorigenesis in the AOM-Apc min/+ mouse model.

Personalized Model to Predict Keratoconus Progression From Demographic, Topographic, and Genetic Data.

PURPOSE: To generate a prognostic model to predict keratoconus progression to corneal crosslinking (CXL). DESIGN: Retrospective cohort study. METHODS: We recruited 5025 patients (9341 eyes) with early keratoconus between January 2011 and November 2020. Genetic data from 926 patients were available. We investigated both keratometry or CXL as end points for progression and used the Royston-Parmar method on the proportional hazards scale to generate a prognostic model. We calculated hazard ratios (HRs) for each significant covariate, with explained variation and discrimination, and performed internal-external cross validation by geographic regions. RESULTS: After exclusions, model fitting comprised 8701 eyes, of which 3232 underwent CXL. For early keratoconus, CXL provided a more robust prognostic model than keratometric progression. The final model explained 33% of the variation in time to event: age HR (95% CI) 0.9 (0.90-0.91), maximum anterior keratometry 1.08 (1.07-1.09), and minimum corneal thickness 0.95 (0.93-0.96) as significant covariates. Single-nucleotide polymorphisms (SNPs) associated with keratoconus (n=28) did not significantly contribute to the model. The predicted time-to-event curves closely followed the observed curves during internal-external validation. Differences in discrimination between geographic regions was low, suggesting the model maintained its predictive ability. CONCLUSIONS: A prognostic model to predict keratoconus progression could aid patient empowerment, triage, and service provision. Age at presentation is the most significant predictor of progression risk. Candidate SNPs associated with keratoconus do not contribute to progression risk.

Perioperative magnetic resonance imaging in breast cancer care: Distinct adoption trajectories among physician patient-sharing networks.

BACKGROUND: Despite no proven benefit in clinical outcomes, perioperative magnetic resonance imaging (MRI) was rapidly adopted into breast cancer care in the 2000's, offering a prime opportunity for assessing factors influencing overutilization of unproven technology. OBJECTIVES: To examine variation among physician patient-sharing networks in their trajectory of adopting perioperative MRI for breast cancer surgery and compare the characteristics of patients, providers, and mastectomy use in physician networks that had different adoption trajectories. METHODS AND FINDINGS: Using the Surveillance, Epidemiology, and End Results-Medicare database in 2004-2009, we identified 147 physician patient-sharing networks (caring for 26,886 patients with stage I-III breast cancer). After adjusting for patient clinical risk factors, we calculated risk-adjusted rate of perioperative MRI use for each physician network in 2004-2005, 2006-2007, and 2008-2009, respectively. Based on the risk-adjusted rate, we identified three distinct trajectories of adopting perioperative MRI among physician networks: 1) low adoption (risk-adjusted rate of perioperative MRI increased from 2.8% in 2004-2005 to 14.8% in 2008-2009), 2) medium adoption (8.8% to 45.1%), and 3) high adoption (33.0% to 71.7%). Physician networks in the higher adoption trajectory tended to have a larger proportion of cancer specialists, more patients with high income, and fewer patients who were Black. After adjusting for patients' clinical risk factors, the proportion of patients undergoing mastectomy decreased from 41.1% in 2004-2005 to 38.5% in 2008-2009 among those in physician networks with low MRI adoption, but increased from 27.0% to 31.4% among those in physician networks with high MRI adoption (p = 0.03 for the interaction term between trajectory group and time). CONCLUSIONS: Physician patient-sharing networks varied in their trajectory of adopting perioperative MRI. These distinct trajectories were associated with the composition of patients and providers in the networks, and had important implications for patterns of mastectomy use.

Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): a multicentre, randomised, phase 3 trial.

BACKGROUND: Trastuzumab is a monoclonal antibody against HER2 (also known as ERBB2). The primary objective of the NRG Oncology/RTOG-1010 trial was to establish whether trastuzumab improves disease-free survival when combined with trimodality treatment (paclitaxel plus carboplatin and radiotherapy, followed by surgery) for patients with untreated HER2-overexpressing oesophageal adenocarcinoma. METHODS: NRG Oncology/RTOG-1010 was an open label, randomised, phase 3 trial for which patients were accrued from 111 NRG-affiliated institutions in the USA. Eligible patients were adults (aged ≥18 years) with newly diagnosed pathologically confirmed oesophageal adenocarcinoma, American Joint Committee on Cancer 7th edition T1N1-2 or T2-3N0-2 stage disease, and a Zubrod performance status of 0-2. Patients were stratified by adenopathy (no vs yes [coeliac absent] vs yes [coeliac present ≤2 cm]) and randomly assigned (1:1) to receive weekly intravenous paclitaxel (50 mg/m2 intravenously over 1 h) and carboplatin (area under the curve 2, intravenously over 30-60 min) for 6 weeks with radiotherapy 50·4 Gy in 28 fractions (chemoradiotherapy) followed by surgery, with or without intravenous trastuzumab (4 mg/kg in week one, 2 mg/kg per week for 5 weeks during chemoradiotherapy, 6 mg/kg once presurgery, and 6 mg/kg every 3 weeks for 13 treatments starting 21-56 days after surgery). The primary endpoint, disease-free survival, was defined as the time from randomisation to death or first of locoregional disease persistence or recurrence, distant metastases, or second primary malignancy. Analyses were done by modified intention to treat. This study is registered with Clinicaltrials.gov, NCT01196390; it is now closed and in follow-up. FINDINGS: 606 patients were entered for HER2 assessment from Dec 30, 2010 to Nov 10, 2015, and 203 eligible patients who were HER2-positive were enrolled and randomly assigned to chemoradiotherapy plus trastuzumab (n=102) or chemoradiotherapy alone (n=101). Median duration of follow-up was 2·8 years (IQR 1·4-5·7). Median disease-free survival was 19·6 months (95% CI 13·5-26·2) with chemoradiotherapy plus trastuzumab compared with 14·2 months (10·5-23·0) for chemoradiotherapy alone (hazard ratio 0·99 [95% CI 0·71-1·39], log-rank p=0·97). Grade 3 treatment-related adverse events occurred in 41 (43%) of 95 patients in the chemoradiotherapy plus trastuzumab group versus 52 (54%) of 96 in the chemoradiotherapy group and grade 4 events occurred in 20 (21%) versus 21 (22%). The most common grade 3 or worse treatment-related adverse events for both groups were haematological (53 [56%] of 95 patients in the chemoradiotherapy plus trastuzumab group vs 55 [57%] of 96 patients in the chemotherapy group) or gastrointestinal disorders (28 [29%] vs 20 [21 %]). 34 (36%) of 95 patients in the chemoradiotherapy plus trastuzumab group and 27 (28%) of 96 patients in the chemoradiotherapy only group had treatment-related serious adverse events. There were eight treatment-related deaths: five (5%) of 95 patients in the chemoradiotherapy plus trastuzumab group (bronchopleural fistula, oesophageal anastomotic leak, lung infection, sudden death, and death not otherwise specified), and three (3%) of 96 in the chemoradiotherapy group (two multiorgan failure and one sepsis). INTERPRETATION: The addition of trastuzumab to neoadjuvant chemoradiotherapy for HER2-overexpressing oesophageal cancer was not effective. Trastuzumab did not lead to increased toxicities, suggesting that future studies combining it with or using other agents targeting HER2 in oesophageal cancer are warranted. FUNDING: National Cancer Institute and Genentech.

Strategies to sensitize cancer cells to immunotherapy.

Recent years have seen the emergence of immunotherapy as a promising modality for treating a variety of cancers. However, the initial data have led to the ultimate reality that such a treatment does not work effectively in all cancers, nor does it universally result in long-lasting benefits, which can be partly attributed to the development of drug resistance- itself a major challenge. Worse, in some cases, immunotherapy can lead to accelerated tumor growth known as hyperprogression. Tumor sensitization is being pursued as a means to circumvent resistance to immunotherapy, and perhaps as a means to prevent hyperprogression. Such approaches aim to counteract features of immune resistance demonstrated by refractory tumors, paving the way for improved treatment effectiveness when standard immunotherapies such as immune checkpoint inhibitors are utilized. Sensitizing agents can be categorized by whether their target is a tumor-intrinsic or a tumor cell-extrinsic factor. Tumor-intrinsic sensitization strategies act directly on cancer cells, suppressing their anti-immune tendencies, whereas tumor cell-extrinsic sensitization strategies target the tumor microenvironment to more effectively mediate the desired therapeutic effects of immunotherapy.

A randomized intervention involving family to improve communication in breast cancer care.

We examined the effects of a communication intervention to engage family care partners on patient portal (MyChart) use, illness understanding, satisfaction with cancer care, and symptoms of anxiety in a single-blind randomized trial of patients in treatment for breast cancer. Patient-family dyads were recruited and randomly assigned a self-administered checklist to clarify the care partner role, establish a shared visit agenda, and facilitate MyChart access (n = 63) or usual care (n = 55). Interviews administered at baseline, 3, 9 (primary endpoint), and 12 months assessed anxiety (GAD-2), mean FAMCARE satisfaction, and complete illness understanding (4 of 4 items correct). Time-stamped electronic interactions measured MyChart use. By 9 months, more intervention than control care partners registered for MyChart (77.8 % vs 1.8%; p < 0.001) and logged into the patient's account (61.2% vs 0% of those registered; p < 0.001), but few sent messages to clinicians (6.1% vs 0%; p = 0.247). More intervention than control patients viewed clinical notes (60.3% vs 32.7%; p = 0.003). No pre-post group differences in patient or care partner symptoms of anxiety, satisfaction, or complete illness understanding were found. Intervention patients whose care partners logged into MyChart were more likely to have complete illness understanding at 9 months (changed 70.0% to 80.0% vs 69.7% to 54.6%; p = 0.03); symptoms of anxiety were numerically lower (16.7% to 6.7% vs 15.2% to 15.2%; p = 0.24) and satisfaction numerically higher (15.8-16.2 vs 18.0-17.4; p = 0.25). A brief, scalable communication intervention led to greater care partner MyChart use and increased illness understanding among patients with more engaged care partners (NCT03283553).

Urgent Care Centers Delay Emergent Surgical Care Based on Patient Insurance Status in The United States.

OBJECTIVE: Patients may call urgent care centers (UCCs) with urgent surgical conditions but may not be properly referred to a higher level of care. This study aims to characterize how UCCs manage Medicaid and privately insured patients who present with an emergent condition. METHODS: Using a standardized script, we called 1245 randomly selected UCCs in 50 states on 2 occasions. Investigators posed as either a Medicaid or a privately-insured patient with symptoms of an incarcerated inguinal hernia. Rates of direct emergency department (ED) referral were compared between insurance types. RESULTS: A total of 1223 (98.2%) UCCs accepted private insurance and 981 (78.8%) accepted Medicaid. At the 971 (78.0%) UCCs that accepted both insurance types, direct-to-ED referral rates for private and Medicaid patients were 27.9% and 33.8%, respectively. Medicaid patients were significantly more likely than private patients to be referred to the ED [odds ratio (OR) 1.32, 95% confidence interval (CI) 1.09-1.60]. Private patients who were triaged by a clinician compared to nonclinician staff were over 6 times more likely to be referred to the ED (OR 6.46, 95% CI 4.63-9.01). Medicaid patients were nearly 9 times more likely to have an ED referral when triaged by a clinician (OR 8.72, 95% CI 6.19-12.29). CONCLUSIONS: Only one-third of UCCs across the United States referred an apparent emergent surgical case to the ED, potentially delaying care. Medicaid patients were more likely to be referred directly to the ED versus privately insured patients. All patients triaged by clinicians were significantly more likely to be referred to the ED; however, the disparity between private and Medicaid patients remained.

Adjuvant FOLFOX+Nab-Paclitaxel (FOLFOX-A) for Pancreatic Cancer: A Brown University Oncology Research Group Phase II Study (BrUOG295).

OBJECTIVES: Multiple clinical trials have established a role for adjuvant chemotherapy for patients with pancreatic ductal adenocarcinoma. Adjuvant FOLFIRINOX increases survival as compared with gemcitabine but with increased toxicity. FOLFOX+nab-paclitaxel (FOLFOX-A) was developed by the Brown University Oncology Research Group (BrUOG) as an alternative to FOLFIRINOX. This phase II trial explored the feasibility and toxicity of adjuvant FOLFOX-A in patients who have completed resection for pancreatic ductal adenocarcinoma. PATIENTS AND METHODS: Patients with resected pancreatic ductal adenocarcinoma were eligible. The primary objective was to determine the feasibility of adjuvant FOLFOX-A. Patients experiencing grade 2 neuropathy received a 20% reduction of oxaliplatin. Secondary end points were disease-free survival, and overall survival. RESULTS: Between June 2014 and October 2018, 25 patients were enrolled following surgical resection. The median number of cycles completed was 9.5. Median disease-free survival was 19.7 months (95% confidence interval, 10.3 to not reached) and median overall survival was 53.5 months (95% confidence interval, 24.2 to not reached). The most common treatment-related grade 3 or greater adverse events were fatigue (58%), nausea (13%), and neutropenia (26%). Fourteen patients had grade 2 neuropathy (58%) and 1 patient (4%) had grade 3 neuropathy. Only 2 patients (8%) had grade 3 diarrhea. CONCLUSIONS: Adjuvant FOLFOX-A is a feasible multi-agent adjuvant treatment regimen and, with further validation, could be an alternative to FOLFIRINOX.

A deletion in Eml1 leads to bilateral subcortical heterotopia in the tish rat.

Children with malformations of cortical development (MCD) are at risk for epilepsy, developmental delays, behavioral disorders, and intellectual disabilities. For a subset of these children, antiseizure medications or epilepsy surgery may result in seizure freedom. However, there are limited options for treating or curing the other conditions, and epilepsy surgery is not an option in all cases of pharmacoresistant epilepsy. Understanding the genetic and neurobiological mechanisms underlying MCD is a necessary step in elucidating novel therapeutic targets. The tish (telencephalic internal structural heterotopia) rat is a unique model of MCD with spontaneous seizures, but the underlying genetic mutation(s) have remained unknown. DNA and RNA-sequencing revealed that a deletion encompassing a previously unannotated first exon markedly diminished Eml1 transcript and protein abundance in the tish brain. Developmental electrographic characterization of the tish rat revealed early-onset of spontaneous spike-wave discharge (SWD) bursts beginning at postnatal day (P) 17. A dihybrid cross demonstrated that the mutant Eml1 allele segregates with the observed dysplastic cortex and the early-onset SWD bursts in monogenic autosomal recessive frequencies. Our data link the development of the bilateral, heterotopic dysplastic cortex of the tish rat to a deletion in Eml1.

Outcomes of Liver Transplantation for Hepatocellular Carcinoma Beyond the University of California San Francisco Criteria: A Single-center Experience.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor. Currently, liver transplantation may be the optimal treatment for HCC in cirrhotic patients. Patient selection is currently based on tumor size. We developed a program to offer liver transplantation to selected patients with HCC outside of traditional criteria. METHODS: Retrospective review for patients transplanted with HCC between April 2008 and June 2017. Patients were grouped by tumor size according to Milan, University of California San Francisco (UCSF), and outside UCSF criteria. Patient demographics, laboratory values, and outcomes were compared. Patients radiographically outside Milan criteria were selected based on tumor control with locoregional therapy (LRT) and 9 months of stability from LRT. α-fetoprotein values were not exclusionary. RESULTS: Two hundred twenty HCC patients were transplanted, 138 inside Milan, 23 inside UCSF, and 59 beyond UCSF criteria. Patient survival was equivalent at 1, 3, or 5 years despite pathologic tumor size. Waiting time to transplantation was not significantly different at an average of 344 days. In patients outside UCSF, tumor recurrence was equivalent to Milan and UCSF criteria recipients who waited >9 months from LRT. Although tumor recurrence was more likely in outside of UCSF patients (3% versus 9% versus 15%; P = 0.02), recurrence-free survival only trended toward significance among the groups (P = 0.053). CONCLUSIONS: Selective patients outside of traditional size criteria can be effectively transplanted with equivalent survival to patients with smaller tumors, even when pathologic tumor burden is considered. Tumor stability over time can be used to help select patients for transplantation.