Neoadjuvant Chemotherapy and Radiation Improves Recurrence-free and Overall Survival in Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: The objective of this study is to analyze the outcomes of patients with resectable/borderline resectable PDAC who receive total neoadjuvant therapy vs upfront surgery. METHODS AND ANALYSIS: Patients who were treated at a single institution from 2006 to 2021 were included. The primary outcome was overall survival (OS). Secondary outcomes included disease free survival (DFS), rates of lymph node positivity, and R0 resection. All survival analyses were performed with intention-to-treat. RESULTS: 26 patients received neoadjuvant chemotherapy and radiation (TNT), 28 received neoadjuvant chemotherapy only (NAC), and 168 received upfront surgery. Demographics were comparable across all three groups. Patients who received TNT or NAC had longer OS and DFS compared to the surgery first patients (P < .01). Patients who received TNT had a lymph node positivity rate of 0% at time of surgery compared to 5.3% and 13.3% in the NAC and surgery-first groups, respectively (P < .01). The rate of R0 resection did not differ between groups (P = .17). CONCLUSION: Patients with resectable/borderline resectable PDAC who receive neoadjuvant therapy have longer OS and RFS relative to those who receive upfront surgery.

Emission lines due to ionizing radiation from a compact object in the remnant of Supernova 1987A.

The nearby Supernova 1987A was accompanied by a burst of neutrino emission, which indicates that a compact object (a neutron star or black hole) was formed in the explosion. There has been no direct observation of this compact object. In this work, we observe the supernova remnant with JWST spectroscopy, finding narrow infrared emission lines of argon and sulfur. The line emission is spatially unresolved and blueshifted in velocity relative to the supernova rest frame. We interpret the lines as gas illuminated by a source of ionizing photons located close to the center of the expanding ejecta. Photoionization models show that the line ratios are consistent with ionization by a cooling neutron star or a pulsar wind nebula. The velocity shift could be evidence for a neutron star natal kick.

Timing of mastectomy and the effect on the likelihood of outpatient surgery and cost savings in breast cancer patients.

BACKGROUND: Same-day discharge after mastectomy has potential patient- and hospital-level benefits; however, few data are available regarding factors affecting the likelihood of same-day discharge in order to address barriers. We sought to evaluate factors contributing to same-day discharge, focusing on the timing of mastectomy during the operative day. METHODS: We conducted a single-institution retrospective review of patients who underwent mastectomies for malignancy over a 3-y time frame. Clinicopathologic variables were collected along with a binary variable for mastectomy start time (morning versus afternoon). Our primary endpoint was rate of same-day discharge. A multivariable logistic regression model was constructed from significant univariate variables to determine independent predictors of same-day discharge. A secondary endpoint was a cost-utility analysis for morning versus afternoon start time, using hospital cost data. RESULTS: There were 451 patients included in the analysis. Factors associated with same-day discharge rate included the American Society of Anesthesiologists score, use of a preoperative regional anesthesia block, type of mastectomy performed, individual surgeon variation, and a morning start for the mastectomy. On multivariable analysis, morning start was a strong independent predictor of same-day discharge (odd ratio = 2.83; 95% CI, 1.75-4.60). The cost-utility analysis favored a morning start, with average cost savings of $550 per patient. CONCLUSION: Despite patient- and surgeon-specific variations, simple scheduling policies can improve same-day discharge rates after mastectomy, leading to improved hospital bed use and cost reduction.

Can we let our patients sleep in the hospital? A randomized controlled trial of a pragmatic sleep protocol in surgical oncology patients.

BACKGROUND: Postoperative inpatients experience increased stress due to pain and poor restorative sleep than non-surgical inpatients. OBJECTIVES AND METHODS: A total of 101 patients, undergoing major oncologic surgery, were randomized to a postoperative sleep protocol (n = 50) or standard postoperative care (n = 51), between August 2020 and November 2021. The primary endpoint of the study was postoperative sleep time after major oncologic surgery. Sleep time and steps were measured using a Fitbit Charge 4®. RESULTS: There was no statistically significant difference found in postoperative sleep time between the sleep protocol and standard group (median sleep time of 427 min vs. 402 min; p = 0.852, respectively). Major complication rates were similar in both groups (7.4% vs. 8.9%). Multivariate analysis found sex and Charlson Comorbidity Index to be significant factors affecting postoperative sleep time and step count. Postoperative delirium was only observed in the standard group, although this did not reach statistical significance. There were no in hospital mortalities. CONCLUSION: The use of a sleep protocol was found to be safe in our study population. There was no statistical difference in postoperative sleep time or major complications. Institution of a more humane sleep protocol for postoperative inpatients should be considered.

Utility and costs of surveillance imaging for low- and very low-risk gastrointestinal stromal tumors.

BACKGROUND: There is limited evidence on the optimal surveillance approach in patients with low- and very low-risk gastrointestinal stromal tumors, resulting in inconsistent and arbitrary approaches to surveillance in this population. In this study, we reviewed our institutional approach to surveillance in patients with low- and very low-risk gastrointestinal stromal tumors and the costs associated with detecting recurrence. METHODS: We retrospectively reviewed consecutive adult patients treated for low- and very low-risk gastrointestinal stromal tumors at our institution from 2010 to 2019. Data collected included patient and tumor characteristics, surgical management, and postoperative follow-up. Surveillance-related expenses were calculated using estimates of average costs obtained from our institution. A cost analysis was performed to evaluate estimated yearly costs based on the surveillance strategy used. RESULTS: There were 60 patients included. The mean age at diagnosis was 63.9 (±12.5) years. The primary tumor was typically in the stomach (73%; n = 44). Computed tomography scan of the abdomen and pelvis with intravenous contrast was the most common surveillance modality (total = 226 scans). No recurrences were identified. Median follow-up duration was 49.0 (interquartile range = 19.5-61.5) months. The mean number of surveillance images per patient was 4 (±2.6). Surveillance imaging was obtained more frequently than just annually in 83% (n = 50) of patients, with an estimated yearly cost of $2,840.77 (interquartile range = $2,273.62-$3,895.92) and no detection of recurrence. CONCLUSION: In this study population, patients with low- and very low-risk gastrointestinal stromal tumors underwent frequent imaging studies for surveillance with little yield and at substantial cost. Further multi-institutional studies on practice patterns and outcomes of surveillance are warranted to better inform standardized surveillance recommendations.

Outflows from the youngest stars are mostly molecular.

The formation of stars and planets is accompanied not only by the build-up of matter, namely accretion, but also by its expulsion in the form of highly supersonic jets that can stretch for several parsecs1,2. As accretion and jet activity are correlated and because young stars acquire most of their mass rapidly early on, the most powerful jets are associated with the youngest protostars3. This period, however, coincides with the time when the protostar and its surroundings are hidden behind many magnitudes of visual extinction. Millimetre interferometers can probe this stage but only for the coolest components3. No information is provided on the hottest (greater than 1,000 K) constituents of the jet, that is, the atomic, ionized and high-temperature molecular gases that are thought to make up the jet's backbone. Detecting such a spine relies on observing in the infrared that can penetrate through the shroud of dust. Here we report near-infrared observations of Herbig-Haro 211 from the James Webb Space Telescope, an outflow from an analogue of our Sun when it was, at most, a few times 104 years old. These observations reveal copious emission from hot molecules, explaining the origin of the 'green fuzzies'4-7 discovered nearly two decades ago by the Spitzer Space Telescope8. This outflow is found to be propagating slowly in comparison to its more evolved counterparts and, surprisingly, almost no trace of atomic or ionized emission is seen, suggesting its spine is almost purely molecular.

Water in the terrestrial planet-forming zone of the PDS 70 disk.

Terrestrial and sub-Neptune planets are expected to form in the inner (less than 10 AU) regions of protoplanetary disks1. Water plays a key role in their formation2-4, although it is yet unclear whether water molecules are formed in situ or transported from the outer disk5,6. So far Spitzer Space Telescope observations have only provided water luminosity upper limits for dust-depleted inner disks7, similar to PDS 70, the first system with direct confirmation of protoplanet presence8,9. Here we report JWST observations of PDS 70, a benchmark target to search for water in a disk hosting a large (approximately 54 AU) planet-carved gap separating an inner and outer disk10,11. Our findings show water in the inner disk of PDS 70. This implies that potential terrestrial planets forming therein have access to a water reservoir. The column densities of water vapour suggest in-situ formation via a reaction sequence involving O, H2 and/or OH, and survival through water self-shielding5. This is also supported by the presence of CO2 emission, another molecule sensitive to ultraviolet photodissociation. Dust shielding, and replenishment of both gas and small dust from the outer disk, may also play a role in sustaining the water reservoir12. Our observations also reveal a strong variability of the mid-infrared spectral energy distribution, pointing to a change of inner disk geometry.

Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma.

BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

Apixaban for Extended Thromboprophylaxis After Oncologic Resection: Outcomes and Cost Analysis.

BACKGROUND: Patients undergoing oncologic resection are at risk of developing venous thromboembolism (VTE), and this can lead to increased morbidity and hospital costs. Low-molecular weight heparin (LMWH) is recommended as extended thromboprophylaxis (ETP) in high-risk patients and has been shown to reduce rates of VTE. METHODS: This is a retrospective review of consecutive patients undergoing resection for oncologic indications at a single institution from May 2016 to May 2019. This study evaluated the use of apixaban as ETP at discharge. The primary outcomes were deep vein thrombosis (DVT), pulmonary embolism (PE), or mesenteric/portal venous thromboembolism at 30, 60, and 90 days postoperatively. RESULTS: A total of 600 patients were included; 449 patients received no ETP, and 151 patients received apixaban. PE occurred in 1.1, 1.6, and 2.3% of patients without ETP and 0, 0, and .7% of patients in the apixaban group (at 30, 60, and 90 days; P = .338, P = .201, and P = .306, respectively). DVT occurred in 1.8, 2.1, and 2.8% of patients without ETP and 0, 0, and 1.4% in the apixaban group (P = .211, P = .121, and P = .535, respectively). The total cost, including ETP and readmission for VTE, per patient was US $5.51 more in the apixaban group. CONCLUSION: Apixaban therapy for ETP did not produce a statistically significant reduction in VTE events in our patients. Future studies should include more patients in a prospective multicenter trial.

Surgeon Burnout and Usage of Personal Communication Devices: Examining the Technology "Empowerment/Enslavement Paradox".

INTRODUCTION: Access to patients' electronic medical records (EMRs) on personal communication devices (PCDs) is beneficial but can negatively impact surgeons. In a recent op-ed, Cohen et al. explored this technology "empowerment/enslavement paradox" and its potential effect on surgeon burnout. We examined if there is a relationship between accessing EMRs on PCDs and surgeon burnout. METHODS: This was a cohort study with retrospective and prospective arms. Trainees and attendings with a background in general surgery completed the Maslach Burnout Index for Medical Personnel, a validated survey scored on three areas of burnout (emotional exhaustion, depersonalization, and low personal accomplishment). Data on login frequency to EMRs on PCDs over the previous 6 mo were obtained. Pearson correlation coefficients were calculated to determine if burnout and login frequency were associated. RESULTS: There were 52 participants included. Residents were 61.5% (n = 32) of participants. The mean login frequency over 6 mo was 431.0 ± 323.9. The mean scores (out of 6) for emotional exhaustion, depersonalization, and personal accomplishment were 2.3 ± 1.1, 1.9 ± 1.2, and 4.9 ± 0.8, respectively. There was no correlation between burnout and logins. Residents had higher median depersonalization scores (2.3 versus 1.2, P = 0.03) and total logins (417.5 versus 210.0, P < 0.001) than attendings. Participants who overestimated logins had higher median emotional exhaustion and depersonalization scores than those who underestimated (2.6 versus 1.4, P = 0.03, and 2.4 versus 0.8, P = 0.003, respectively). CONCLUSIONS: Using EMRs on PCDs is common, but frequency of logins did not correlate with burnout scores in this study. However, perception of increased workload may contribute to experiencing burnout.

Contemporary approaches to the axilla in breast cancer.

Over the past decade, axillary management in breast cancer has fundamentally shifted. The former notion that any degree of axillary nodal involvement warrants axillary lymph node dissection (ALND) has been challenged. Following publication of the ACOSOG Z0011 trial, national trends demonstrated significant reductions in ALND performance. Axillary radiotherapy in lieu of ALND is a consideration for select patients with a positive sentinel lymph node, while ongoing studies are investigating the role of adjuvant regional radiotherapy in women with positive nodes prior to neoadjuvant chemotherapy. Efforts toward de-escalation of axillary surgery continue to evolve, as do the indications for sentinel node biopsy omission in select subsets of patients. This review highlights the recent advances and neoteric approaches to local therapy of the axilla in breast cancer.

Timing and necessity of staging imaging in clinical stage II cutaneous melanoma: Cost-effectiveness and clinical decision analysis.

BACKGROUND: Preoperative imaging in clinical stage II melanoma is not indicated per National Comprehensive Cancer Network (NCCN) guidelines but remains common in clinical practice. METHODS: Patients presenting with cutaneous clinical stage II melanoma from 2007 to 2019 were retrospectively reviewed. A clinical decision analysis with cost data was designed to understand ideal practice patterns in managing stage II melanoma, with pre-versus selective post-operative imaging as the initial decision node. RESULTS: There were 277 subjects included, and 143 underwent preoperative imaging (49.5%). This changed management (i.e. no surgery) in one patient (0.4%). Overall, 16 patients had additional findings on imaging (5.8%). Upfront surgery with selective postoperative imaging was a more cost-effective strategy than routine performance of preoperative imaging, with savings of $1677 per patient. CONCLUSION: Preoperative imaging is a low yield, costly approach for patients with clinical stage II melanoma with minimal impact on the decision to proceed with surgical management.

Starting a minimally invasive inguinal lymphadenectomy program: Initial learning experience and outcomes.

BACKGROUND: There is promising data on minimally invasive inguinal lymphadenectomy indicating decreased wound complications compared with the standard open approach. We examined our institutional experience with starting a minimally invasive inguinal lymphadenectomy program. METHODS: This is a retrospective case series of consecutive patients undergoing videoscopic minimally invasive inguinal lymphadenectomy from August 2017 to March 2022 by a single surgeon. Patients meeting criteria for inguinal lymphadenectomy were considered for minimally invasive inguinal lymphadenectomy unless there was skin involvement by tumor or bulky disease. Data collected included patient characteristics, primary cancer, surgery, and postoperative complications. RESULTS: There were 26 patients included. The mean age was 60.6 ± 16.2 years. Most patients were female (n = 17, 65.4%), and the primary diagnosis was melanoma (n = 21, 19.2%). In 6 cases (23.1%), minimally invasive inguinal lymphadenectomy was combined with deep pelvic node dissection, but most patients did not have a concurrent procedure (n = 15, 57.7%). The median operative time was 119.0 minutes (range, 89.0-160.0), or 130.5 minutes (range, 89.0-345.0) when including concurrent procedures. The mean number of nodes retrieved was 9.8 ± 3.7, with a positive node identified in 19 patients (73.1%) during minimally invasive inguinal lymphadenectomy. There were 12 (46.2%) patients experiencing at least one postoperative complication within 30 days of surgery, the most common being infection (n = 4, 15.4%). One patient required reoperation for infected hematoma washout. Postoperative intervention for seroma was undertaken in 3 patients (11.5%). CONCLUSION: Minimally invasive inguinal lymphadenectomy is a safe approach to inguinal lymph node dissection, in terms of node retrieval and postoperative complications, and can feasibly be adopted into practice with minimal learning curve.

Pancreatic Cancer: A Review of Current Treatment and Novel Therapies.

Pancreatic cancer is one of the leading causes for cancer-related deaths in the United States. Majority of patients present with unresectable or metastatic disease. For those that present with localized disease, a multidisciplinary approach is necessary to maximize survival and optimize outcomes. The quality and safety of surgery for pancreatic cancer have improved in recent years with increasing adoption of minimally invasive techniques and surgical adjuncts. Systemic chemotherapy has also evolved to impact survival. It is now increasingly being utilized in the neoadjuvant setting, often with concomitant radiation. Increased utilization of genomic testing in metastatic pancreatic cancer has led to better understanding of their biology, thereby allowing clinicians to consider potential targeted therapies. Similarly, targeted agents such as PARP inhibitors and immune checkpoint- inhibitors have emerged with promising results. In summary, pancreatic cancer remains a disease with poor long-term survival. However, recent developments have led to improved outcomes and have changed practice in the past decade. This review summarizes current practices in pancreatic cancer treatment and the milestones that brought us to where we are today, along with emerging therapies.

Eye-Tracking Technology to Determine Procedural Proficiency in Ultrasound-Guided Regional Anesthesia.

Background: Eye-tracking measures attention patterns, which may offer insight into evaluating procedural expertise. The purpose of this study was to determine the feasibility of using eye tracking to assess visual fixation patterns when performing an ultrasound-guided regional anesthesia procedure and to assess for differences between experienced, intermediate, and novice practitioners. Methods: Participants performed an ultrasound-guided sciatic nerve block 3 times on a fresh cadaver model while wearing eye-tracking glasses. Gaze fixation and dwell time on each location were compared between participants. Eye-gaze paths were used to derive a measure of entropy, or how often participants switched gaze fixations between locations. Results: Five attending anesthesiologists, 5 third-year anesthesiology residents with prior ultrasound-guided regional anesthesia experience, and 5 medical students completed the study. Individuals with more experience were more likely to successfully perform the sciatic nerve block (5/5 attendings, 5/5 residents, 0/5 students; P = .002) and performed the procedure faster (average: attendings 62.6 seconds, residents 106.4 seconds, students 134.4 seconds; P = .089). Participants were progressively faster with practice (Trial 1: 41.8 seconds, Trial 2: 29.2 seconds, Trial 3: 28.9 seconds; P = .012), and the average number of eye shifts per trial decreased from 10.8 to 6.5 to 6 (P = .010). Attending physicians spent significantly less time fixating on the ultrasound monitor compared to trainees (P = .035). Average visual entropy progressively decreased from Trial 1 to Trial 3 (P = .03) and with greater experience (P = .15). There was a strong correlation between entropy and time on task (r(16) = 0.826, P = .001). Conclusions: Experienced providers make fewer back-and-forth visual fixations, spend less time in the procedure, and demonstrate less entropy during ultrasound-guided regional anesthesia procedures. Mobile eye-tracking has the potential to provide additional objective measures of performance that may help not only determine procedural competence but also distinguish between levels of proficiency.

Kirsten rat sarcoma (KRAS) oncogene mutation predicts magnitude of response and outcomes in hepatic arterial infusion pump therapy of unresectable colorectal liver metastases.

Background: The Kirsten rat sarcoma (KRAS) mutation predicts negative outcomes following resection of colorectal liver metastases (CRLM) and adjuvant hepatic arterial infusion (HAI) pump chemotherapy. Less is known on the effects of KRAS mutation on tumor response in patients with unresectable CRLM undergoing HAI chemotherapy with floxuridine. Methods: This is a retrospective cohort study investigating the effects of KRAS mutation on tumor response in patients with unresectable CRLM treated with HAI chemotherapy. Primary endpoint was objective response rate (ORR), secondary endpoints included overall tumor response and conversion to resectability. Results: Twenty-five patients with unresectable liver metastases from colorectal cancer were treated with HAI chemotherapy between 2017-2019. Median number of liver lesions was 12 (range, 1-59) and almost all (n=24) had prior chemotherapy before starting HAI therapy. Median number of cycles administered via HAI pump was 6 (range, 3-12). Overall decrease in liver tumor burden was 63.5% (median; range, -257-100%) with an ORR of 20/25 (80%) and 10 (40%) patients converting to resectable status. Eleven (44%) patients had KRAS positive tumors. When compared to wild-type, KRAS positive tumors had less overall percent decrease (58% vs. 70%; P=0.04) and ORR (7/11 vs. 13/13; P=0.03). Fewer patients with KRAS positive tumors converted to resectable status during HAI therapy (2/11 vs. 8/13; P=0.05). At a median follow-up of 14.6 months (range, 4.0-36.6 months), overall survival is 45% among KRAS-positive and 77% for wild type patients. Conclusions: KRAS mutational status in patients with unresectable liver metastases from colorectal cancer predicts worse response to HAI chemotherapy compared to wild type.

A copper chaperone-mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons progressively and rapidly degenerate, eventually leading to death. The first protein found to contain ALS-associated mutations was copper/zinc superoxide dismutase 1 (SOD1), which is conformationally stable when it contains its metal ligands and has formed its native intramolecular disulfide. Mutations in SOD1 reduce protein folding stability via disruption of metal binding and/or disulfide formation, resulting in misfolding, aggregation, and ultimately cellular toxicity. A great deal of effort has focused on preventing the misfolding and aggregation of SOD1 as a potential therapy for ALS; however, the results have been mixed. Here, we utilize a small-molecule polytherapy of diacetylbis(N(4)-methylthiosemicarbazonato)copper(II) (CuATSM) and ebselen to mimic the metal delivery and disulfide bond promoting activity of the cellular chaperone of SOD1, the "copper chaperone for SOD1." Using microscopy with automated image analysis, we find that polytherapy using CuATSM and ebselen is highly effective and acts in synergy to reduce inclusion formation in a cell model of SOD1 aggregation for multiple ALS-associated mutants. Polytherapy reduces mutant SOD1-associated cell death, as measured by live-cell microscopy. Measuring dismutase activity via zymography and immunoblotting for disulfide formation showed that polytherapy promoted more effective maturation of transfected SOD1 variants beyond either compound alone. Our data suggest that a polytherapy of CuATSM and ebselen may merit more study as an effective method of treating SOD1-associated ALS.