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Importance: Ampullary adenocarcinoma (AA) is characterized by clinical and genomic heterogeneity. A previously developed genomic classifier defined biologically distinct phenotypes with greater accuracy than standard histologic classification. External validation is needed before routine clinical use., Objective: To test external validity of the prognostic value of the hidden genome classifier of AA., Design, Setting, and Participants: This retrospective cohort study took place at 6 international academic institutions. Consecutive patients (n = 192) who underwent curative-intent resection of histologically confirmed AA were included. The data were analyzed from January 2005 through July 2020., Exposures: The multilevel meta-feature regression model previously trained on a prospectively sequenced cohort of 3411 patients (1001 pancreatic adenocarcinoma, 165 distal bile duct adenocarcinoma, and 2245 colorectal adenocarcinoma) was applied to AA sequencing data to quantify the relative proportions of parental cell of origin., Main Outcome and Measures: Genomic classification was correlated with immunohistologic subtype (intestinal [INT] or pancreatobiliary [PB]) and with overall survival (OS), using the log-rank test and Cox proportional hazard models., Results: Among 192 patients with AA (median age, 69.0 [IQR, 60.0-74.0] years and 134 were male [64%]), concordance between immunohistologic and genomic subtypes was 55%. Most INT subtype tumors were categorized into the colorectal genomic subtype (43 of 57 [72.9%]). Of the 114 PB subtype tumors, 29 had a pancreatic genomic profile (25.4%) and 24 had a distal bile duct genomic profile (21.1%). Whereas the standard immunohistologic subtypes were not associated with survival (log rank P = .26), predicted genomic probabilities were correlated with survival probability. Genomic scores with higher colorectal probability were associated with higher survival probability; higher pancreatic and distal bile duct probabilities were associated with lower survival probability., Conclusions and Relevance: The AA genomic classifier is reproducible with available molecular testing in a diverse international cohort of patients and improves stratification of the divergent clinical outcomes beyond standard immunohistologic classification. These data provide a molecular classification that may be incorporated into clinical trials for prospective validation.

KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRAS G12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRAS G12R tumors are associated with decreased distant recurrence and improved survival as compared to KRAS G12D . To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRAS G12D and increased nuclear factor κB (NF-κB) signaling in KRAS G12R tumors. Orthogonal studies of mouse Kras G12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology., Competing Interests: Declaration of interests E.M.O., research funding: Genentech/Roche, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute, NIH/NCI, Pertzye; consulting/DSMB: Boehringer Ingelheim, BioNTech, Ipsen, Merck, Novartis, AstraZeneca, BioSapien, Astellas, Thetis, Autem, Novocure, Neogene, BMS, Tempus, Fibrogen, Merus, Agios (spouse), Genentech-Roche (spouse), Eisai (spouse). G.M.C.:A full listing of G.M.C.’s interests can be found at http://arep.med.harvard.edu/gmc/tech/html. C.E.M., founder: Onegevity, Twin Orbit, and Cosmica Biosciences; consulting: Nanostring. L.E.D., research funding/consulting: Revolution Medicines; scientific advisory board: Mirimus. R.C., research funding: Sanofi; consulting/DSMB: Boston Scientific., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: Improved prognostic tools are needed for patients with locally recurrent extremity or truncal soft tissue sarcoma (STS)., Objective: To examine the association between average local recurrence (LR) growth rate and outcomes following resection of locally recurrent extremity or truncal STS., Design, Setting, and Participants: This retrospective cohort study used a prospectively maintained database from a single high-volume tertiary sarcoma referral center in the US to identify patients 16 years of age or older who underwent repeat resection of a locally recurrent extremity or truncal STS between July 1, 1982, and December 31, 2021. Patients with atypical lipomatous tumors, desmoid tumors, dermatofibrosarcoma protuberans, angiosarcomas, and prior or synchronous distant recurrence were excluded. Data were analyzed from November 1, 2022, to June 17, 2024., Exposure: Average LR growth rate, defined as the sum of recurrent tumor maximal diameters divided by the disease-free interval after index operation., Main Outcomes and Measures: The primary outcomes were cumulative incidences of disease-specific death (DSD), with death from other causes as a competing risk, and second LR, with death from any cause as a competing risk., Results: The study cohort included 253 patients (median [IQR] age, 64 [51-73] years; 140 [55.3%] male). The 5-year cumulative incidence of DSD after repeat resection was 29%. Multivariable analysis indicated that LR growth rate (hazard ratio [HR], 1.12 [95% CI, 1.08-1.18]; P < .001), younger age (HR, 0.98 [95% CI, 0.97-0.99]; P = .002), R1 or R2 margins (HR, 1.71 [95% CI, 1.03-2.84]; P = .04), high LR grade (HR, 2.90 [95% CI, 1.17-7.20]; P = .02), and multifocality (HR, 2.92 [95% CI, 1.70-5.00]; P < .001) were independently associated with higher incidence of DSD. Using the minimum P value method, the optimal cutoff for growth rate was found to be 0.68 cm/mo. Patients with values above this cutoff had higher 5-year incidences of DSD following repeat resection (63% vs 19%; permutation test P < .001) and higher amputation rates (19% vs 7%; P = .008). Only R1 margins were independently associated with higher incidence of second LR (HR, 1.81 [95% CI, 1.19-2.78]; P = .006)., Conclusions and Relevance: In this cohort study of patients undergoing resection of a locally recurrent extremity or truncal STS, LR growth rate was independently associated with DSD. These findings suggest that patients with growth rates higher than 0.68 cm/mo who undergo LR resection may have high disease-specific mortality and amputation rates and should be considered for perioperative systemic therapy.

The delta opioid receptor (δOR or DOR) is a G protein-coupled receptor (GPCR) showing a promising profile as a drug target for nociception and analgesia. Herein, we design and synthesize new fluorescent antagonist probes with high δOR selectivity that are ideally suited for single-molecule microscopy (SMM) applications in unmodified, untagged receptors. Using our new probes, we investigated wild-type δOR localization and mobility at low physiological receptor densities for the first time. Furthermore, we investigate the potential formation of δOR homodimers, as such a receptor organization might exhibit distinct pharmacological activity, potentially paving the way for innovative pharmacological therapies. Our findings indicate that the majority of δORs labeled with these probes exist as freely diffusing monomers on the cell surface in a simple cell model. This discovery advances our understanding of OR behavior and offers potential implications for future therapeutic research.

Background: Weekend surgical time is an underused asset. Concerns over a possible weekend effect (substandard care) may be a barrier., Methods: This study examined whether a weekend effect applies to elective colorectal surgery via a single-center retrospective analysis comparing outcomes between patients who underwent elective colorectal surgery on a weekend vs a weekday. Demographics, length of stay (LOS), operative and anesthesia time, the rate of reoperation within 30 days, and the rate of major complications were compared between patient groups., Results: Of the 2008 patients identified, 1721 (85.7%) underwent surgery on a weekday, and 287 (14.3%) underwent surgery on a weekend. The proportion of operations with an open approach was higher on weekends than weekdays (49.5% vs 41.8%, P = .017). Patients who underwent surgery on the weekend tended to have a shorter mean (SE) for LOS (4.2 [0.2] vs 6.1 [0.2], P < .001), anesthesia time (233.8 [6.5] vs 307.6 [3.3] minutes, P < .001), and operative time (225.4 [6.4] vs. 297.6 [3.3] minutes, P < .001). On multivariable analysis, patients who had an operation on a weekend had a 38% lower chance of having a prolonged LOS (>75th percentile of LOS) compared with those who had an operation on a weekday (adjusted odds ratio = 0.62; 95% CI 0.42-0.92). There were no differences in rates of complications or reoperation for patients undergoing surgery on a weekend compared with a weekday., Conclusion: At centers with experienced anesthesiologists, appropriately trained nursing staff, and expert surgeons, colorectal surgery performed on a weekend has similar safety outcomes as surgeries performed on a weekday., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To assess whether selective omission of operative drains after pancreaticoduodenectomy (PD) and distal pancreatectomy (DP) is associated with adverse perioperative outcomes., Background: The routine use of operative drains after pancreatectomy is widely practiced; however, prospective randomized clinical trials and retrospective analyses have shown mixed results., Methods: Patients who underwent PD or DP between November 2009 and May 2021 were reviewed and stratified by operative drain placement. Patient demographics, morbidity, the need for additional procedures, and mortality were compared between patients who did or did not develop a clinically relevant post-operative pancreatic fistula (CR-POPF)., Results: In total, 1,855 PD and 752 DP cases were analyzed. Among PD patients with a CR-POPF (N=259, 14%), 160 (62%) had an operative drain placed, of whom 141 (88%) required at least 1 additional procedure. Within this subgroup, grade ≥ 4 complications (7.5% vs. 11.1%, P=0.37), 90-day mortality (3.8% vs. 6.1%, P=0.54), length of stay (LOS) (median 12 vs. 13 d, P=0.19) and readmission rates (63.1% vs. 54.6%, P=0.19) were similar between drained and non-drained patients. Of note, drained PD patients without a CR-POPF had a longer hospital stay (8 vs. 7 d, respectively, P=0.004) and more thromboembolic events (2.4% vs. 1.1%, respectively, P=0.04) Among DP patients with a CR-POPF (n=129), 44 had an operative drain, with 37 (84%) requiring an additional procedure. Within this subgroup, grade ≥ 4 complications (4.6% vs. 5.9%, P>0.95), 90-day mortality (0%), LOS (median 7 d for both, P=0.88) and readmission rates (72.7% vs. 80%, P=0.38) were similar in drained and non-drained patients., Conclusion: This study confirms that selective omission of operative drains does not compromise perioperative outcomes, as initially reported in our prospective randomized trial., Competing Interests: Conflicts of Interest and Source of Funding: This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Myeloablative T cell depleted (CD34-selected) hematopoietic cell transplantation (HCT) is associated with less acute and chronic graft versus host disease (GVHD). We aimed to examine vaccine responses in relation to immune reconstitution and post HCT rituximab administration in this population. This single center retrospective study included 251 patients with hematological malignancies who received a first CD34-selected HCT between 2012 and 2015. Of 251 patients, 190 were alive 1 year after HCT. Among the entire population, 77 (30.7%) patients were vaccinated. After vaccine administration, 35/44 (80%), 30/75 (40%), 27/36 (75%), 33/65 (51%), 34/51 (51%), 22/28 (79%) and 20/34 (59%) of evaluable patients had protective antibody titers for haemophilus influenzae type B (Hib), Pneumococcus, Tetanus, Diphtheria, Pertussis, hepatitis A (HAV), and hepatitis B (HBV) respectively. Responders to the pneumococcal vaccine had a higher CD45RA T cell count than non responders, with 12/18 patients (66.7%) vs 11/32 (34.4%) p = 0.04. For pneumococcal vaccine, there was also a trend to higher total lymphocyte B cell count in responders vs non responders p = 0.06. Rituximab post HCT was given to 59/251 (23.5%) patients. No difference was found in immune reconstitution patterns for rituximab use between vaccine responders and not. Recipients of CD34-selected HCT may respond to vaccination, and T and B cell subsets could be useful to predict vaccine response., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: To evaluate whether patient-controlled epidural analgesia (PCEA) improves postoperative pain during ambulation following elective open hepatectomy., Background: Strategies to alleviate postoperative pain are a critical element of recovery after surgery. However, the optimal postoperative pain management strategy following open hepatectomy remains unclear., Methods: We conducted a prospective, nonblinded, randomized comparison of PCEA (intervention) versus intravenous patient-controlled analgesia (IV PCA; control) for postoperative pain following elective open hepatectomy. The primary end point was pain during ambulation on postoperative day (POD) 2. The study was powered to detect a clinically significant 2-point difference on the pain numeric rating scale (NRS). Secondary end points included pain at rest, morbidity, time to return of bowel function, and length of stay., Results: From 2015 to 2020, 231 patients were randomized (116 patients in the PCEA arm and 115 in the IV PCA arm). The incidence of epidural failure was 3% (n=4/116), with no epidural-related complications. Patients in the PCEA arm had a <2-point difference in NRS pain scores during ambulation on POD 2 vs. IV PCA (median 4.0 vs. 5.0, P <0.001). There was no difference in overall complications between the PCEA and IV PCA arms (33% vs. 40%, P =0.276). Secondary outcomes, including pain scores at rest, were similar between the study arms., Conclusions: PCEA was safe following open hepatectomy and was associated with a small difference in pain with activity on POD 2 that did not reach our pre-specified definition of clinical significance., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: We conducted research on CDK4/6 inhibitors (CDK4/6i) simultaneously in the preclinical and clinical spaces to gain a deeper understanding of how senescence influences tumor growth in humans., Patients and Methods: We coordinated a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies interrogating the molecular basis of geroconversion., Results: Thirty patients with progressing DDLS enrolled and were treated with 200 mg of abemaciclib twice daily. The median progression-free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI, 57.7%-90.1%). No new safety signals were identified. Concurrent preclinical work in liposarcoma cell lines identified ANGPTL4 as a necessary late regulator of geroconversion, the pathway from reversible cell-cycle exit to a stably arrested inflammation-provoking senescent cell. Using this insight, we were able to identify patients in which abemaciclib induced tumor cell senescence. Senescence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy. However, those individuals with both senescence and increased TILs were also more likely to acquire resistance later in therapy. These suggest that combining senolytics with abemaciclib in a subset of patients may improve the duration of response., Conclusions: Abemaciclib was well tolerated and showed promising activity in DDLS. The discovery of ANGPTL4 as a late regulator of geroconversion helped to define how CDK4/6i-induced cellular senescence modulates the immune tumor microenvironment and contributes to both positive and negative clinical outcomes. See related commentary by Weiss et al., p. 649., (©2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: Enucleation is a common treatment modality performed for pediatric retinoblastoma patients, and the resultant defects are reconstructed using an ocular prosthesis. The prostheses are modified or replaced periodically, as the child develops due to orbital growth and patient-error. The purpose of this report is to evaluate the replacement frequency of prostheses in the pediatric oncologic population., Methods: A retrospective review was completed by the two senior research investigators, of patients that had ocular prostheses fabricated following enucleation of their retinoblastoma from 2005 to 2019 (n = 90). Data collected from the medical records of the patient included the pathology, date of surgery, date of prosthesis delivery, and the replacement schedule of the ocular prosthesis., Results: During the 15-year study period, 78 enucleated observations (ocular prosthesis fabricated) were included for analysis. The median age of the patients at the time of delivery of their first ocular prosthesis was calculated to be 2.6 years (range 0.3-18 years). The median time to the first modification of the prosthesis was calculated to be 6 months. The time to modification of the ocular prosthesis was further stratified by age., Conclusion: Pediatric patients require modification of their ocular prostheses throughout their growth and development period. Ocular prostheses are reliable prostheses with predictable outcomes. This data is helpful to set an expectation among the patient, parent, and provider., (© 2023 by the American College of Prosthodontists.)

The association between immune-related AEs (irAE) and outcome in patients with sarcoma is not known. We retrospectively reviewed a cohort of patients with advanced sarcoma treated with immune checkpoint blockade (ICB)-based therapy. Association of irAEs with survival was assessed using a Cox regression model that incorporated irAE occurrence as a time-dependent covariate. Tumor samples with available RNA sequencing data were stratified by presence of an irAE to identify patterns of differential gene expression. A total of 131 patients were included. Forty-two (32%) had at least one irAE of any grade and 16 (12%) had at least one grade ≥ 3 irAE. The most common irAEs were hypothyroidism (8.3%), arthralgias (5.3%), pneumonitis (4.6%), allergic reaction (3.8%), and elevated transaminases (3.8%). Median progression-free survival (PFS) and overall survival (OS) from the time of study entry were 11.4 [95% confidence interval (CI), 10.7-15.0) and 74.6 weeks (CI, 44.9-89.7), respectively. On Cox analysis adjusting for clinical covariates that were significant in the univariate setting, the HR for an irAE (HR, 0.662; CI, 0.421-1.041) approached, but did not reach statistical significance for PFS (P = 0.074). Patients had a significantly lower HR for OS (HR, 0.443; CI, 0.246-0.798; P = 0.007) compared with those without or before an irAE. Gene expression profiling on baseline tumor samples found that patients who had an irAE had higher numbers of tumor-infiltrating dendritic cells, CD8+ T cells, and regulatory T cells as well as upregulation of immune and inflammatory pathways., Significance: irAE after ICB therapy was associated with an improved OS; it also approached statistical significance for improved PFS. Patients who had an irAE were more likely to have an inflamed tumor microenvironment at baseline., (© 2023 The Authors; Published by the American Association for Cancer Research.)

While COVID-19 catalyzed a shift to telemedicine, little is known about the persistence of remote cancer care in non-emergent times. We assessed telemedicine use at a high-volume academic cancer center in New York City and analyzed breast and prostate cancer visits pre-COVID-19, peak COVID-19, and post-peak. Descriptive statistics assessed visit mode (in person, telemedicine) and type (new, follow-up, other) by department/specialty, with Fisher's exact tests comparing peak/post-peak differences. The study included 602,233 visits, with telemedicine comprising 2% of visits pre-COVID-19, 50% peak COVID-19, and 30% post-peak. Notable variations emerged by department/specialty and visit type. Post-peak, most departments/specialties continued using telemedicine near or above peak levels, except medicine, neurology, and survivorship, where remote care fell. In psychiatry, social work, and nutrition, nearly all visits were conducted remotely during and after peak COVID-19, while surgery and nursing maintained low telemedicine usage. Post-peak, anesthesiology and neurology used telemedicine seldom for new visits but often for follow-ups, while nursing showed the opposite pattern. These trends suggest department- and visit-specific contexts where providers and patients choose telemedicine in non-emergent conditions. More research is needed to explore these findings and evaluate telemedicine's appropriateness and impact across the care continuum.

Purpose: Although delirium is known to negatively affect critically ill patients, little data exist on delirium in critically ill patients with cancer., Methods: We analyzed 915 critically ill patients with cancer between January and December 2018. Delirium screening was performed using the Confusion Assessment Method for the intensive care unit (ICU), performed twice daily. Confusion Assessment Method-ICU incorporates four features of delirium: acute fluctuations in mental status, inattention, disorganized thinking, and altered levels of consciousness. Multivariable analysis controlling for admitting service, pre-ICU hospital length of stay (LOS), metastatic disease, CNS involvement, Mortality Probability Model II score on ICU admission, mechanical ventilation, and others was performed to determine precipitating factors for delirium, ICU, and hospital mortality and LOS., Results: Delirium occurred in 40.5% (n = 317) of patients; 43.8% (n = 401) were female; the median age was 64.9 (interquartile range, 54.6-73.2) years; 70.8% (n = 647) were White, 9.3% (n = 85) were Black, and 8.9% (n = 81) were Asian. The most common cancer types were hematologic (25.7%, n = 244) and gastrointestinal (20.9%, n = 191). Delirium was independently associated with age (OR, 1.01; 95% CI, 1.00 to 1.02; P = .038), longer pre-ICU hospital LOS (OR, 1.04; 95% CI, 1.02 to 1.06; P < .001), not resuscitating on admission (OR, 2.18; 95% CI, 1.07 to 4.44; P = .032), CNS involvement (OR, 2.25; 95% CI, 1.20 to 4.20; P = .011), higher Mortality Probability Model II score (OR, 1.02; 95% CI, 1.01 to 1.02; P < .001), mechanical ventilation (OR, 2.67; 95% CI, 1.84 to 3.87; P < .001), and sepsis diagnosis (OR, 0.65; 95% CI, 0.43 to 0.99; P = .046). Delirium was also independently associated with higher ICU mortality (OR, 10.75; 95% CI, 5.91 to 19.55; P < .001), hospital mortality (OR, 5.84; 95% CI, 4.03 to 8.46; P < .001), and ICU LOS (estimate, 1.67; 95% CI, 1.54 to 1.81; P < .001)., Conclusion: Delirium significantly worsens outcome in critically ill patients with cancer. Delirium screening and management should be integrated into the care of this patient subgroup.

Competing Interests: None.

The γ-aminobutyric acid type B (GABA B ) receptor is a prototypical family C G protein-coupled receptor (GPCR) that plays a key role in the regulation of synaptic transmission. Although growing evidence suggests that GPCR signaling in neurons might be highly organized in time and space, limited information is available about the mechanisms controlling the nanoscale organization of GABA B receptors and other GPCRs on the neuronal plasma membrane. Using a combination of biochemical assays in vitro, single-particle tracking, and super-resolution microscopy, we provide evidence that the spatial organization and diffusion of GABA B receptors on the plasma membrane are governed by dynamic interactions with filamin A, which tethers the receptors to sub-cortical actin filaments. We further show that GABA B receptors are located together with filamin A in small nanodomains in hippocampal neurons. These interactions are mediated by the first intracellular loop of the GABA B1 subunit and modulate the kinetics of Gα i protein activation in response to GABA stimulation., (© 2023. The Author(s).)

Background: Patients with cancer who require cardiopulmonary resuscitation (CPR) historically have had low survival to hospital discharge; however, overall CPR outcomes and cancer survival have improved. Identifying patients with cancer who are unlikely to survive CPR could guide and improve end-of-life discussions prior to cardiac arrest., Methods: Demographics, clinical variables, and outcomes including immediate and hospital survival for patients with cancer aged ≥18 years who required in-hospital CPR from 2012 to 2015 were collected. Indicators capturing the overall declining clinical and oncologic trajectory (ie, no further therapeutic options for cancer, recommendation for hospice, or recommendation for do not resuscitate) prior to CPR were determined a priori and manually identified., Results: Of 854 patients with cancer who underwent CPR, the median age was 63 years and 43.6% were female; solid cancers accounted for 60.6% of diagnoses. A recursive partitioning model selected having any indicator of declining trajectory as the most predictive factor in hospital outcome. Of our study group, 249 (29%) patients were found to have at least one indicator identified prior to CPR and only 5 survived to discharge. Patients with an indicator were more likely to die in the hospital and none were alive at 6 months after discharge. These patients were younger (median age, 59 vs 64 years; P≤.001), had a higher incidence of metastatic disease (83.0% vs 62.9%; P<.001), and were more likely to undergo CPR in the ICU (55.8% vs 36.5%; P<.001) compared with those without an indicator. Of patients without an indicator, 145 (25%) were discharged alive and half received some form of cancer intervention after CPR., Conclusions: Providers can use easily identifiable indicators to ascertain which patients with cancer are at risk for death despite CPR and are unlikely to survive to discharge. These findings can guide discussions regarding utility of resuscitation and the lack of further cancer interventions even if CPR is successful.

Background: We aim to explore the factors related to job satisfaction among pain physicians and identify the reasons why individuals minimize or stop practicing outpatient pain medicine., Objectives/study Design: This is a survey-based study with the primary goal to identify factors determining job satisfaction and dissatisfaction among pain medicine fellowship graduates who continue to practice and those who are no longer practicing interventional pain. A secondary goal is to elucidate reasons for anesthesiologists trained in pain medicine to leave pain medicine, despite an additional year of training, and to work as general anesthesiologists., Methods: In this study, all 114 pain program directors listed on the Accreditation Council for Graduate Medical Education (ACGME) website, or their administrative assistants were directly contacted via email. All email addresses were obtained from the ACGME website. The survey opened in September 2021, with reminder emails sent before the closing of the survey in December 2021. A final reminder email was sent 4 weeks prior to the closing of the survey., Results: Of all the respondents, 79 (89.77%) were currently practicing pain medicine, and 9 (10.23%) were no longer practicing pain medicine., Limitations: Our study has a major limitation as we are unable to determine the response rate and are limited in the data points gathered., Conclusion: We hope this study will allow for pain medicine fellowship program directors to improve recruitment and retention of pain fellows in the field while addressing the pros and cons of future career aspirations with anesthesiology residents prior to fellowship selection. A larger, more thorough study with an exact response rate can compare the various outcomes based upon different types of settings, such as private practice, partnership, and academia, as well as geographical locations.

Purpose: Patient portal secure messages are not always authored by the patient account holder. Understanding who authored the message is particularly important in an oncology setting where symptom reporting is crucial to patient treatment. Natural language processing has the potential to detect messages not authored by the patient automatically., Methods: Patient portal secure messages from the Memorial Sloan Kettering Cancer Center were retrieved and manually annotated as a predicted unregistered proxy (ie, not written by the patient) or a presumed patient. After randomly splitting the annotated messages into training and test sets in a 70:30 ratio, a bag-of-words approach was used to extract features and then a Least Absolute Shrinkage and Selection Operator (LASSO) model was trained and used for classification., Results: Portal secure messages (n = 2,000) were randomly selected from unique patient accounts and manually annotated. We excluded 335 messages from the data set as the annotators could not determine if they were written by a patient or proxy. Using the remaining 1,665 messages, a LASSO model was developed that achieved an area under the curve of 0.932 and an area under the precision recall curve of 0.748. The sensitivity and specificity related to classifying true-positive cases (predicted unregistered proxy-authored messages) and true negatives (presumed patient-authored messages) were 0.681 and 0.960, respectively., Conclusion: Our work demonstrates the feasibility of using unstructured, heterogenous patient portal secure messages to determine portal secure message authorship. Identifying patient authorship in real time can improve patient portal account security and can be used to improve the quality of the information extracted from the patient portal, such as patient-reported outcomes.

Background: COVID-19 has been a devastating pandemic with little known of its neuropsychiatric complications. Delirium is one of the most common neuropsychiatric syndromes among hospitalized cancer patients with incidence ranging from 25% to 40% and rates of up to 85% in the terminally ill. Data on the incidence, risk factors, duration, and outcomes of delirium in critically ill cancer patients with COVID-19 are lacking., Objective: To report the incidence, risks and outcomes of critically ill cancer patients who developed COVID-19., Methods: This is a retrospective single-center study evaluating delirium frequency and outcomes in all critically ill cancer patients with COVID-19 admitted between March 1 and July 10, 2020. Delirium was assessed by Confusion Assessment Method for Intensive Care Unit, performed twice daily by trained intensive care unit (ICU) nursing staff. Patients were considered to have a delirium-positive day if Confusion Assessment Method for Intensive Care Unit was positive at least once per day., Results: A total of 70 patients were evaluated. Of those 70, 53 (75.7%) were found to be positive for delirium. Patients with delirium were significantly older than patients without delirium (median age 67.5 vs 60.3 y, P = 0.013). There were no significant differences in demographic characteristics, chronic medical conditions, neuropsychiatric history, cancer type, or application of prone positioning between the 2 groups. Delirium patients were less likely to receive cancer-directed therapies (58.5% vs 88.2%, P = 0.038) but more likely to receive antipsychotics (81.1% vs 41.2%, P = 0.004), dexmedetomidine (79.3% vs 11.8%, P < 0.001), steroids (84.9% vs 58.8%, P = 0.039), and vasopressors (90.6% vs 58.8%, P = 0.006). Delirium patients were more likely to be intubated (86.8% vs 41.2%, P < 0.001), and all tracheostomies (35.9%) occurred in patients with delirium. ICU length of stay (19 vs 8 d, P < 0.001) and hospital length of stay (37 vs 12 d, P < 0.001) were significantly longer in delirium patients, but there was no statistically significant difference in hospital mortality (43.4% vs 58.8%, P = 0.403) or ICU mortality (34.0% vs 58.8%, P = 0.090)., Conclusions: Delirium in critically ill cancer patients with COVID-19 was associated with less cancer-directed therapies and increased hospital and ICU length of stay. However, the presence of delirium was not associated with an increase in hospital or ICU mortality., (Copyright © 2022 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: Radiation-associated sarcomas (RAS) are rare but aggressive malignancies. We sought to characterize the histology-specific presentation and behavior of soft tissue RAS to improve individualized prognostication., Methods: A single-institutional prospectively maintained database was queried for all patients with primary, nonmetastatic RAS treated with surgical resection from 1982 to 2019. Patients presenting with the five most common RAS histologies were propensity-matched to those with sporadic tumors of the same histology. Incidence of disease-specific death (DSD) was modeled using cumulative incidence analyses., Results: Among 259 patients with RAS, the five most common histologies were malignant peripheral nerve sheath tumor (MPNST; n = 19), myxofibrosarcoma (n = 20), leiomyosarcoma (n = 24), undifferentiated pleomorphic sarcoma (UPS; n = 55), and angiosarcoma (AS; n = 62). DSD varied significantly by histology ( P = .002), with RAS MPNST and UPS having the highest DSD. In unadjusted analysis, RAS MPNST was associated with increased DSD compared with sporadic MPNST (75% v 38% 5-year DSD, P = .002), as was RAS UPS compared with sporadic UPS (49% v 28% 5-year DSD, P = .004). Unadjusted DSD was similar among patients with RAS AS, leiomyosarcoma, or myxofibrosarcoma and sporadic sarcoma of the same histology. After matching RAS to sporadic patients within each histology, DSD only differed between RAS and sporadic MPNST (83% v 46% 5-year DSD, P = .013). Patients with RAS AS presented in such a distinct manner to those with sporadic AS that a successful match was not possible., Conclusion: The aggressive presentation of RAS is histology-specific, and DSD is driven by RAS MPNST and UPS histologies. Despite the aggressive presentation, standard prognostic factors can be used to estimate risk of DSD among most RAS. In MPNST, radiation association should be considered to independently associate with markedly higher risk of DSD.

Understanding the molecular and phenotypic profile of colorectal cancer (CRC) in West Africa is vital to addressing the regions rising burden of disease. Tissue from unselected Nigerian patients was analyzed with a multigene, next-generation sequencing assay. The rate of microsatellite instability is significantly higher among Nigerian CRC patients (28.1%) than patients from The Cancer Genome Atlas (TCGA, 14.2%) and Memorial Sloan Kettering Cancer Center (MSKCC, 8.5%, P < 0.001). In microsatellite-stable cases, tumors from Nigerian patients are less likely to have APC mutations (39.1% vs. 76.0% MSKCC P < 0.001) and WNT pathway alterations (47.8% vs. 81.9% MSKCC, P < 0.001); whereas RAS pathway alteration is more prevalent (76.1% vs. 59.6%, P = 0.03). Nigerian CRC patients are also younger and more likely to present with rectal disease (50.8% vs. 33.7% MSKCC, P < 0.001). The findings suggest a unique biology of CRC in Nigeria, which emphasizes the need for regional data to guide diagnostic and treatment approaches for patients in West Africa., (© 2021. The Author(s).)

Purpose: The clinical behavior of ampullary adenocarcinoma varies widely. Targeted tumor sequencing may better define biologically distinct subtypes to improve diagnosis and management., Experimental Design: The hidden-genome algorithm, a multilevel meta-feature regression model, was trained on a prospectively sequenced cohort of 3,411 patients (1,001 pancreatic adenocarcinoma, 165 distal bile-duct adenocarcinoma, 2,245 colorectal adenocarcinoma) and subsequently applied to targeted panel DNA-sequencing data from ampullary adenocarcinomas. Genomic classification (i.e., colorectal vs. pancreatic) was correlated with standard histologic classification [i.e., intestinal (INT) vs. pancreatobiliary (PB)] and clinical outcome., Results: Colorectal genomic subtype prediction was primarily influenced by mutations in APC and PIK3CA , tumor mutational burden, and DNA mismatch repair (MMR)-deficiency signature. Pancreatic genomic-subtype prediction was dictated by KRAS gene alterations, particularly KRAS G12D, KRAS G12R, and KRAS G12V. Distal bile-duct adenocarcinoma genomic subtype was most influenced by copy-number gains in the MDM2 gene. Despite high (73%) concordance between immunomorphologic subtype and genomic category, there was significant genomic heterogeneity within both histologic subtypes. Genomic scores with higher colorectal probability were associated with greater survival compared with those with a higher pancreatic probability., Conclusions: The genomic classifier provides insight into the heterogeneity of ampullary adenocarcinoma and improves stratification, which is dictated by the proportion of colorectal and pancreatic genomic alterations. This approach is reproducible with available molecular testing and obviates subjective histologic interpretation., (©2021 American Association for Cancer Research.)

Background: The reversal agent sugammadex has been shown to be more efficacious at reversal from neuromuscular blockade (NMB) induced by the aminosteroid class of non-depolarizing muscle relaxants than the traditionally used medication neostigmine. However, whether these differences lead to significantly faster PACU discharge readiness remains unknown. Given the increased acquisition cost of sugammadex as compared to neostigmine we compared these two reversal agents in our surgical population to determine if its pharmacokinetic superiority warranted a change in current practice., Methods: We conducted a single-center randomized patient and assessor blinded clinical trial. A total of 201 patients presenting for surgery requiring NMB with an estimated duration of ≤ 6 hours were included in the intention-to-treat (ITT) analysis. The primary outcome was time from reversal agent administration to PACU discharge readiness, measured by either the institutional discharge scoring tool or bedside clinical assessment by a PACU physician or advanced practice provider. Secondary outcomes included subjective assessment of recovery by the patient (pain, visual changes, speaking difficulty, swallowing difficulty, PONV, anxiety) and a simple strength assessment., Results: Median time from reversal administration to PACU discharge readiness was 3.59 hours (IQR 2.49-5.09) in the neostigmine group and 3.62 hours (IQR 2.70-5.87) in the sugammadex group. Patients who received sugammadex had 8% longer reversal to PACU discharge times (exp(estimate) 1.08, 95% CI [0.87-1.34], p=0.499). Patients age 70 or older had 28% longer reversal to PACU discharge times (exp(estimate) of 1.28, 95% CI [0.91-1.80], P=0.158). In the a modified ITT analysis, sugammadex patients were estimated to be in PACU 13% longer than neostigmine arm patients (exp(estimate) 1.13, 95% CI [0.91-1.40], p=0.265) and patients older than or equal to 70 years 31% longer than patients less than 70 years old (exp(estimate) 1.31, 95% CI [0.93-1.84], p=0.121). Treatment arm was not associated with any of the secondary outcomes., Conclusion: There was no significant difference in time to readiness to discharge from PACU, and there were no subjective or objective clinically relevant differences in recovery from neuromuscular blockade between the groups. Findings of this study support continued use of either agent at the anesthesiologist's discretion., Competing Interests: Conflict of interest statement: Dr. Echeverry - none. Mrs. Polskin - none. Dr. Tollinche serves as a paid consultant and has an advisory role for Merck. He is a grant recipient through Merck Investigator Studies Program to fund a clinical trial at Memorial Sloan Kettering Cancer Center (NCT03808077). Mr. Seier - none. Dr. Tan - none. Dr. McCormick - none. Dr. Fischer - none. Dr. Grant - none.

Introduction: Neoadjuvant imatinib (Neo-IM) therapy may facilitate R0 resection in primary gastrointestinal stromal tumors (GISTs) that are large or in difficult anatomic locations. While response to preoperative tyrosine kinase inhibitors is associated with better outcome in metastatic GIST, little is known about prognostic factors after Neo-IM in primary GIST., Study Design: Patients with primary GIST with or without synchronous metastases who underwent Neo-IM were retrospectively analyzed from a prospective maintained institutional database for Response Evaluation Criteria in Solid Tumors (RECIST), tumor viability, and mitotic rate. Overall survival (OS) was estimated by Kaplan-Meier and compared by log-rank test. Cox proportionate hazard models were used for univariate and multivariate analysis., Results: One hundred and fifty patients were treated for a median of 7.1 months (range 0.2-160). By RECIST, partial response, stable disease, and progressive disease were seen in 40%, 51%, and 9%, respectively. By pathologic analysis, ≤ 50% of the tumor was viable in 72%, and the mitotic rate was ≤ 5/50HPF in 74%. On multivariate analysis, RECIST response and tumor viability were not associated with OS, while post-treatment high mitotic rate (hazard ratio (HR) for death 5.3, CI 2.3-12.4), R2 margins (HR 6.0, CI 2.3-15.5), and adjuvant imatinib (HR 0.4, CI 0.2-0.9) were (p < 0.05). Five-year OS was 81 vs. 38% for low vs. high mitotic rate; 81, 59, and 39% for R0, R1, and R2 margins; and 75 vs 61% for adjuvant vs. no adjuvant imatinib therapy (p < 0.05)., Conclusions: In primary GIST undergoing Neo-IM therapy, progression was uncommon, but substantial down-sizing occurred in the minority. High tumor mitotic rate and incomplete resection following Neo-IM were associated with poor outcome, while adjuvant imatinib was associated with prolonged survival., (© 2020. The Society for Surgery of the Alimentary Tract.)

Objective: We sought to define the prognostic significance of histologic subtype for extremity/truncal liposarcoma (LPS)., Background: LPS, the most common sarcoma, is comprised of 5 histologic subtypes. Despite their distinct behaviors, LPS outcomes are frequently reported as a single entity., Methods: We analyzed data on all patients from a single-institution prospective database treated from July 1982 to September 2017 for primary, nonmetastatic, extremity or truncal LPS of known subtype. Clinicopathologic variables were tested using competing risk analyses for association with disease-specific death (DSD), distant recurrence (DR), and local recurrence (LR)., Results: Among 1001 patients, median follow-up in survivors was 5.4 years. Tumor size and subtype were independently associated with DSD and DR. Size, subtype, and R1 resection were independently associated with LR. DR was most frequent among pleomorphic and round cell LPS; the former recurred early (43% by 3 years), and the latter over a longer period (23%, 3 years; 37%, 10 years). LR was most common in dedifferentiated LPS, in which it occurred early (24%, 3 years; 33%, 5 years), followed by pleomorphic LPS (18%, 3 years; 25%, 10 years)., Conclusions: Histologic subtype is the factor most strongly associated with DSD, DR, and LR in extremity/truncal LPS. Both risk and timing of adverse outcomes vary by subtype. These data may guide selective use of systemic therapy for patients with round cell and pleomorphic LPS, which carry a high risk of DR, and radiotherapy for LPS subtypes at high risk of LR when treated with surgery alone., Competing Interests: The authors report no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The therapeutic management of pancreatic neuroendocrine tumors (PanNETs) is based on pathological tumor grade assessment. A noninvasive imaging method to grade tumors would facilitate treatment selection. This study evaluated the ability of quantitative image analysis derived from computed tomography (CT) images to predict PanNET grade., Methods: Institutional database was queried for resected PanNET (2000-2017) with a preoperative arterial phase CT scan. Radiomic features were extracted from the primary tumor on the CT scan using quantitative image analysis, and qualitative radiographic descriptors were assessed by two radiologists. Significant features were identified by univariable analysis and used to build multivariable models to predict PanNET grade., Results: Overall, 150 patients were included. The performance of models based on qualitative radiographic descriptors varied between the two radiologists (reader 1: sensitivity, 33%; specificity, 66%; negative predictive value [NPV], 63%; and positive predictive value [PPV], 37%; reader 2: sensitivity, 45%; specificity, 70%; NPV, 72%; and PPV, 47%). The model based on radiomics had a better performance predicting the tumor grade with a sensitivity of 54%, a specificity of 80%, an NPV of 81%, and a PPV of 54%. The inclusion of radiomics in the radiographic descriptor models improved both the radiologists' performance., Conclusion: CT quantitative image analysis of PanNETs helps predict tumor grade from routinely acquired scans and should be investigated in future prospective studies., Competing Interests: David S. KlimstraStock and Other Ownership Interests: Paige.AI Diane L. ReidyHonoraria: NovartisConsulting or Advisory Role: Lexicon, Advanced Accelerator ApplicationsResearch Funding: Novartis, Ipsen, Merck Peter J. AllenConsulting or Advisory Role: SanofiResearch Funding: Novartis Richard K. G. DoHonoraria: ALK, GenentechConsulting or Advisory Role: DBV TechnologiesPatents, Royalties, Other Intellectual Property: UptoDate chapters on Food AllergyNo other potential conflicts of interest were reported.

Background: Plasmacytoid urothelial carcinoma (PUC) is a rare, aggressive histologic variant of urothelial cancer characterised by a diffuse growth pattern and CDH1 mutation. We studied the efficacy of preoperative platinum-based chemotherapy in nonmetastatic PUC and immune checkpoint inhibitors (ICIs) in advanced PUC., Methods: Cases of nonmetastatic PUC and advanced PUC treated with ICIs at our institution were identified. Outcomes were compared to those of a published cohort of patients with urothelial carcinoma not otherwise specified., Results: We identified 81 patients with nonmetastatic PUC. Of the patients with localised disease who underwent neoadjuvant chemotherapy, pathologic complete response and downstaging rates were 12 and 21%, respectively. Pathologic downstaging was not associated with significant improvement in clinical outcomes. Up to 18% of localised disease and 28% of locally advanced cases had unresectable disease at the time of surgery. ICI-treated advanced PUC (N = 21) had progression-free and overall survival of 4.5 and 10.5 months, respectively, and a 38% response rate. FGFR3 and DNA damage response gene alterations were observed in 3 and 15% of cases, respectively., Conclusions: PUC is associated with high disease burden and poor chemosensitivity. Increased awareness and recognition of this disease variant will allow for new treatment strategies.

Objectives: The objective of this study was to describe practice patterns of anesthetic management during pericardial window creation., Design: Retrospective observational cohort study., Setting: Single tertiary cancer center., Participants: A total of 150 patients treated for cancer between 2011 and 2015 were included in the study., Measurements and Main Results: The primary objective was to evaluate anesthetic management in pericardial window creation. Secondary outcomes were 30-day mortality and overall survival after pericardial window creation. Thirty-day mortality was 19.3%, and median survival was 5.84 months. Higher American Society of Anesthesiologists (ASA) physical status of patients was associated with preinduction arterial line placement (51% ASA 3 v 79% ASA 4; p = 0.002) and use of etomidate for anesthetic induction (34% ASA 3 v 60% ASA 4; p = 0.003). However, there was no association between anesthetic management and presence of tamponade in these patients. Cardiac aspirate volume (per 10 mL: odds ratio [OR], 1.02 [95% CI, 1.0-1.04]; p = 0.026) and intraoperative arrhythmia (atrial fibrillation: OR, 6.76 [95% CI, 1.2-37.49]; p = 0.029; sinus tachycardia: OR, 4.59 [95% CI, 1.25-16.90]; p = 0.022) were associated independently with increased 30-day mortality. High initial heart rate (per 10 beats per minute: hazard ratio [HR], 1.18 [95% CI, 1.05-1.33]; p = 0.005) in the operating room and intraoperative sinus tachycardia (HR, 1.86 [95% CI, 1.15-3.03]; p = 0.012) were associated independently with worse overall survival., Conclusion: Risk of death after pericardial window creation remains high in patients with cancer. Variations in anesthetic management did not affect survival in oncologic patients with pericardial effusions., (Copyright © 2020 Elsevier Inc. All rights reserved.)