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Introduction: Up to 90% of patients undergo inadequate resection for incidentally diagnosed T1b-T3 gallbladder cancer (GBC). We evaluated whether adjuvant therapies (ATs) are associated with prolonged overall survival (OS) for patients undergoing inadequate resection of T1b-T3 GBC., Methods: Patients who underwent inadequate resection, defined as simple cholecystectomy, for T1b-T3, Nx-N2, and M0 GBC were identified from the National Cancer Database (2004-2016). Patient characteristics, variables associated with AT use, and OS were described using the chi-square test, multivariable logistical regression, Kaplan-Meier, and Cox proportional hazard models., Results: Of 1386 patients who met inclusion criteria, most received no AT (64%), 20% received chemotherapy (CT), and 16% received chemoradiotherapy (CRT). Patients who received no AT were generally older (51% ≥ 75 y) and had no comorbidities (65% Charlson Comorbidity Index 0). Among those who received AT, CRT rather than CT, tended to be employed for patients who were older (≥75 y) or had more comorbidities (Charlson Comorbidity Index ≥1). Patients with advanced disease (T3, positive lymph nodes, or positive margins) were more likely to receive CRT. For T1b-T3 GBC, any AT was associated with prolonged median OS compared to no AT (22 months versus 15 mo, P < 0.01). Relative to no AT, CT (hazard ratio 0.76, 95% confidence interval 0.67-0.92) and CRT (0.59, 95% confidence interval 0.49-0.72) were associated with decreased risk of death., Conclusions: AT was associated with prolonged OS for patients with inadequately resected T1b-T3 GBC. CRT may have a role in treatment for patients with high-risk disease following inadequate resection of T1b-T3 GBC., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cow-calf contact has been suggested as an alternative to the common practice of early separation of dairy cow and calf. Increasing cow-calf contact poses challenges by reducing the machine milk yield and increasing separation stress. Part-time cow-calf contact may prove more feasible than full-time contact for farmers but may affect the maternal behavior of the cows. Gradually reducing the daily contact could gradually wean the calf off milk, preparing it for separation. This study aims to investigate (1) how cows' maternal behaviors toward their own calf are affected by part-time contact, and (2) whether calves' suckling behavior is reduced by reducing daily cow contact. Fifty-six dairy cows and their calves were assigned to either full-time (23 h/d) or part-time (10 h/d) cow-calf contact for 7 wk (main rearing period). This was followed by 2 wk of either reduced contact (50% in wk 8, then 25% of original contact time in wk 9) or unchanged contact. First, the maternal behavior of full- and part-time cows was observed for 24 h in the third week of the main rearing period. Part-time cows spent less time nursing and grooming their own calf than full-time cows did. However, the amount of nursing in the inverse parallel position and the probability of a cow nursing a calf other than her own did not differ between the 2 treatments. Second, calf suckling behavior was observed for 24 h in both weeks of the reduced contact period. Averaged across both observations, total suckling time (i.e., time spent suckling any cow) was lower in part-time calves that experienced reduced contact compared with part-time calves with unchanged contact. In wk 9, time spent suckling only the dam was lower for full-time calves with reduced contact compared with part-time calves with unchanged contact. In conclusion, although we found a lower nursing and grooming time in part-time cows compared with full-time, we found no difference between treatments with regard to nursing in the inverse parallel position and nursing a calf other than the cow's own. The effect of gradually reducing cow-calf contact on calves' suckling time requires more research., (© 2024, The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

When weaning offspring, female mammals limit nursing opportunities. This study aimed to investigate whether imposing a gradual reduction in daily contact time, by separating cows from their calves as an attempt to stimulate weaning, reduced dairy cows' motivation to nurse their calves. For seven weeks, 84 Holstein-Friesian cow-calf pairs were housed with either full-time (23 h contact/d), part-time (10 h contact/d), or no contact. In the following two weeks, half of full- and part-time pairs were subjected to reduced contact (50% of initial contact in week 8, 25% of initial contact in week 9), while the other half continued with unchanged contact. In weeks 8 and 9, cows' motivation to obtain full contact to and opportunity to nurse their calves was measured using weighted push gates using a novel maximum price paid method providing an alternative choice to the cows to reduce frustration. Cows with reduced calf contact were more motivated than cows with unchanged contact; however, cows used the alternative choice less than expected. The results show that cows' motivation for full calf contact and opportunity to nurse increases when daily calf contact is reduced, illustrating that dairy cows are motivated to continue nursing their 9- to 10-week-old calves., (© 2024. The Author(s).)

Purpose: The ACOSOG Z0011 (Z11) trial assessed the benefit of axillary dissection (ALND) for breast cancer patients with sentinel lymph node (SLN) metastases; however, Z11 excluded patients with ≥ 3 positive SLNs. We analyzed trends in ALND omission in patients with ≥ 3 positive SLNs., Methods: Women with ≥ 3 positive SLNs who underwent breast-conserving surgery (BCS) or mastectomy between 2018 and 2020 in the National Cancer Database were included using SLN codes initiated in 2018. Patients with stage IV disease, recurrent breast cancer, and who underwent neoadjuvant chemotherapy were excluded. A multivariable logistic regression model was utilized to determine the proportion who received ALND and factors associated with ALND omission. A subgroup analysis was performed among patients who met the remainder of the Z11 inclusion criteria (BCS, T1/T2 breast cancer)., Results: We identified 3654 patients with ≥ 3 positive SLNs. ALND was omitted in 37% of patients, and omission significantly increased from 2018 to 2020 (29% vs. 41%, p < 0.0001). Older age, lower grade tumors, no radiation, non-academic facility, BCS, more SLNs examined and fewer positive SLNs were significantly associated with ALND omission. 942 patients with ≥ 3 positive SLNs met the remainder of the Z11 inclusion criteria. ALND was omitted in 49% of these patients, and omission increased from 2018 to 2020 (44% vs. 49%, p = 0.22)., Conclusion: Approximately one-third of patients with ≥ 3 positive SLNs do not undergo ALND; omission of ALND increased from 2018 to 2020. Studies assessing oncologic outcomes of patients with ≥ 3 positive SLNs who do and do not receive ALND are required., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

There is growing interest in managing cow and calf together for a prolonged period, but concerns remain about how best to wean and separate the cow and calf to minimize stress. One approach is to progressively reduce suckling opportunity over time, as in nature. There is also interest in part-time contact (suckling for part of the day) to improve milk yield for the farmer and potentially reduce stress at weaning and separation. The primary objective of this study was to compare the behavioral responses of dairy cows to gradual or abrupt weaning and separation, when managed either full or part time with their calves; a secondary focus was the vocal responses of calves under these management conditions. In a 3 × 2 factorial design (n = 14/ treatment), dairy cows and their calves (n = 84 in 7 blocks of 12 cow-calf pairs) were assigned to one of 3 dam-contact treatments at birth: (1) full-time contact between the dam and calf, apart from milking times (total 23 h/d) (2) part-time contact between the dam and calf, between morning and afternoon milking only (total 10 h/d); (3) no contact, where the dam and calf were separated after leaving the maternity pen and had no further contact. At wk 8, one of 2 weaning treatments was assigned: (1) gradual weaning by reduced contact time (50%, then 25% of original dam-contact time in wk 8 and 9, respectively), or gradually reduced milk allowance for no-contact calves (50%, then 25% of estimated 12-L milk intake in wk 8 and 9, respectively) until complete milk removal and dam-calf separation at wk 10; (2) abrupt weaning where milk removal occurred simultaneously with dam-calf separation at wk 10, or only milk removal for no-contact calves. Overall, part-time contact did not reduce weaning and separation distress for cows or calves for either weaning method. Part-time cows showed reduced behavioral responses to separation (greater lying time and less searching behavior), especially on the day of and 24 h after separation, but they showed a similarly strong vocal response to separation as full-time cows. Part-time calves made substantially more high-pitched vocalizations than full-time calves at 24 h after separation. Furthermore, gradual weaning by reducing contact time did not seem to better prepare cows or calves for complete milk removal and separation; most behavioral and vocal responses occurred on the day of separation for gradual-weaning cows and calves, but 24 h later, the reverse occurred for abrupt-weaning cows and there was no difference between gradual- and abrupt-weaning calves. Our results suggest that part-time contact and gradual-weaning conditions likely resulted in hunger and expectation for reunion, which together may have exaggerated behavioral responses at separation. Temporary daily separations may not have increased independence of cow and calf, and the gradual-weaning method here may not have reduced milk intake by calves. These elements are important criteria to facilitate the weaning process, so future work should explore ways to gradually reduce milk intake and promote social independence of cow and calf to minimize weaning distress., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Medical students rotating through emergency departments as part of their clinical education are typically evaluated using an on-shift evaluation tool. The National Clinical Assessment Tool for Medical Students in the Emergency Department (NCAT-EM) is the current standard of evaluation for medical students in the emergency department, regardless of level of training. This study aims to evaluate whether the NCAT-EM can detect differences in skill levels between third-year medical students (MS3s) and fourth-year medical students (MS4s) rotating at a level 1 trauma center and teaching institution. These authors hypothesized that MS4s should outperform MS3s across all assessment domains given their additional training. A total of 930 performance evaluations were gathered for MS3 and MS4 rotating between May 2022 and June 2023. There were 321 evaluations of MS3s and 609 evaluations of MS4s. Across the six assessment domains, MS4s had statistically significant higher performances in two domains - namely emergency recognition and management (fully entrustable: 37.4% vs. 23.8% (p = 0.03)) and communication (fully entrustable: 46.2% vs. 33.6% (p = 0.03)). These findings indicate that the use of the NCAT-EM at this institution reliably differentiated between MS3s and MS4s in these two assessment domains. There were trends suggesting MS4s outperform MS3s in the other four domains, which did not rise to the level of statistical significance, but are consistent with prior validation studies of the NCAT., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Kumar et al.)

The surgical management of primary and secondary liver tumors is constantly evolving. Patient selection, particularly with regard to determining resectability, is vital to the success of programs directed toward invasive treatments of liver tumors. Particular attention should be paid toward determining whether patients are best served with surgical resection or ablative therapies. A multidisciplinary approach is necessary to provide optimal care to patients with liver malignancy., Competing Interests: Conflict of Interest The authors declare no conflicts of interest relevant to the material presented herein., (Thieme. All rights reserved.)

A positive mood in humans tends to broaden attentional scope while negative mood narrows it. A similar effect may be present in non-human animals; therefore, attentional scope may be a novel method to assess emotional states in livestock. In this proof-of-concept exploratory study, we examined the attentional scope of dairy cows housed with their calves either full-time, part-time (during daytime only), or with no calf contact (enrolled n  = 10 each). Housing conditions were previously verified to induce differences in positive and negative emotional state, where part-time was considered more negative. Cows were trained to approach or avoid hierarchical images on a screen that were consistent in local and global elements (i.e., 13 small circles or crosses arranged in an overall circle or cross). After discrimination learning (>80% correct, over two consecutive days), 14 cows proceeded to test ( n  = 6 each full-and part-time; n  = 2 no-contact, not analyzed). Test images showed inconsistent combinations of global and local elements (i.e., the overall global shape differs from the smaller local elements, such as a global circle composed of smaller local crosses and vice versa). Over two test days, approach responses to global and local images (each presented four times) were recorded. All cows were more likely to approach the local than the global image, especially part-time cows who never approached the global image; this may reflect a narrowed attentional scope in these cows. Full-time cows approached images more often than part-time cows, but overall response rates to global and local images were low, making specific conclusions regarding attentional scope difficult. Different housing conditions have potential to affect attentional scope, and possibly emotional state, of dairy cows, but statistical comparison to no-contact treatment was not possible. Cortisol concentration did not affect responses to images; thus arousal due to treatment or test conditions could not explain test performance. Further work with refined methodology and a larger sample size is required to validate the reliability of attentional scope as an assessment method of emotional state in cattle. Beyond this, the attentional scope test revealed how cattle may process, learn and respond to different visual hierarchical images, which further our understanding of cognitive and visual processes in cattle., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Neave, Rault, Bateson, Jensen and Jensen.)

Background: Screening options for pancreatic ductal adenocarcinoma (PDAC) are limited. New-onset type 2 diabetes (NoD) is associated with subsequent diagnosis of PDAC in observational studies and may afford an opportunity for PDAC screening. We evaluated this association using a large administrative database., Methods: Patients were identified using claims data from the OptumLabs® Data Warehouse. Adult patients with NoD diagnosis were matched 1:3 with patients without NoD using age, sex and chronic obstructive pulmonary disease (COPD) status. The event of PDAC diagnosis was compared between cohorts using the Kaplan-Meier method. Factors associated with PDAC diagnosis were evaluated with Cox's proportional hazards modeling., Results: We identified 640 421 patients with NoD and included 1 921 263 controls. At 3 years, significantly more PDAC events were identified in the NoD group vs control group (579 vs 505; P < 0.001). When controlling for patient factors, NoD was significantly associated with elevated risk of PDAC (HR 3.474, 95% CI 3.082-3.920, P < 0.001). Other factors significantly associated with PDAC diagnosis were increasing age, increasing age among Black patients, and COPD diagnosis (P ≤ 0.05)., Conclusions: NoD was independently associated with subsequent diagnosis of PDAC within 3 years. Future studies should evaluate the feasibility and benefit of PDAC screening in patients with NoD., (© The Author(s) 2022. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In the RESTORE-IMI 2 trial, imipenem/cilastatin/relebactam (IMI/REL) was noninferior to piperacillin/tazobactam in treating hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. This post hoc analysis was conducted to determine independent predictors of efficacy outcomes in the RESTORE-IMI 2 trial, to assist in treatment decision making., Methods: A stepwise multivariable regression analysis was conducted to identify variables that were independently associated with day 28 all-cause mortality (ACM), favorable clinical response at early follow-up (EFU), and favorable microbiologic response at end of treatment (EOT). The analysis accounted for the number of baseline infecting pathogens and in vitro susceptibility to randomized treatment., Results: Vasopressor use, renal impairment, bacteremia at baseline, and Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II scores ≥15 were associated with a greater risk of day 28 ACM. A favorable clinical response at EFU was associated with normal renal function, an APACHE II score <15, no vasopressor use, and no bacteremia at baseline. At EOT, a favorable microbiologic response was associated with IMI/REL treatment, normal renal function, no vasopressor use, nonventilated pneumonia at baseline, intensive care unit admission at randomization, monomicrobial infections at baseline, and absence of Acinetobacter calcoaceticus-baumannii complex at baseline. These factors remained significant after accounting for polymicrobial infection and in vitro susceptibility to assigned treatment., Conclusions: This analysis, which accounted for baseline pathogen susceptibility, validated well-recognized patient- and disease-related factors as independent predictors of clinical outcomes. These results lend further support to the noninferiority of IMI/REL to piperacillin/tazobactam and suggests that pathogen eradication may be more likely with IMI/REL., Clinical Trials Registration: NCT02493764., Competing Interests: Potential conflicts of interest. L. F. C., J. D., M. C. L., A. P., C. A. D., M. W., and E. H. J. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, New Jersey, who may own stock and/or hold stock options in the Merck & Co, Inc, Rahway, New Jersey. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Metal hydrides are an interesting group of chemical compounds, able to store hydrogen in a reversible, compact and safe manner. Among them, A 2 B 7 -type intermetallic alloys based on La-Mg-Ni have attracted particular attention due to their high electrochemical hydrogen storage capacity (∼400 mAh/g) and extended cycle life. However, the presence of Mg makes their synthesis via conventional metallurgical routes challenging. Replacing Mg with Y is a viable approach. Herein, we present a systematic study for a series of compounds with a nominal composition of La 2- x Y x Ni 6.50 Mn 0.33 Al 0.17 , x = 0.33, 0.67, 1.00, 1.33, 1.67, focusing on the relationship between the material structural properties and hydrogen sorption performances. The results show that while the hydrogen-induced phase amorphization occurs in the Y-poor samples (x < 1.00) already during the first hydrogen absorption, a higher Y content helps to maintain the material crystallinity during the hydrogenation cycles and increases its H-storage capacity (1.37 wt.% for x = 1.00 vs. 1.60 wt.% for x = 1.67 at 50 °C). Thermal conductivity experiments on the studied compositions indicate the importance of thermal transfer between powder individual particles and/or a measuring instrument.

Background: Patients with estrogen receptor (ER)-positive, HER2-negative breast cancer (BC), and high-risk 21-gene recurrence score (RS) results benefit from chemotherapy. We evaluated chemotherapy refusal and survival in healthy older women with high-RS, ER-positive BC., Methods: Retrospective review of the National Cancer Database (2010-2017) identified women ≥ 65 years of age, with ER-positive, HER2-negative, high-RS (≥ 26) BC. Patients with Charlson Comorbidity Index ≥ 1, stage III/IV disease, or incomplete data were excluded. Women were compared by chemotherapy receipt or refusal using the Cochrane-Armitage test, multivariable logistical regression modeling, the Kaplan-Meier method, and Cox's proportional hazards modeling., Results: 6827 women met study criteria: 5449 (80%) received chemotherapy and 1378 (20%) refused. Compared to women who received chemotherapy, women who refused were older (71 vs 69 years), were diagnosed more recently (2014-2017, 67% vs 61%), and received radiation less frequently (67% vs 71%) (p ≤ 0.05). Refusal was associated with decreased 5-year OS for women 65-74 (92% vs 95%) and 75-79 (85% vs 92%) (p ≤ 0.05), but not for women ≥ 80 years old (84% vs 91%; p = 0.07). On multivariable analysis, hazard of death increased with refusal overall (HR 1.12, 95% CI 1.04-1.2); but, when stratified by age, was not increased for women ≥ 80 years (HR 1.10, 95% CI 0.80-1.51)., Conclusions: Among healthy women with high-RS, ER-positive BC, chemotherapy refusal was associated with decreased OS for women ages 65-79, but did not impact the OS of women ≥ 80 years old. Genomic testing may have limited utility in this population, warranting prudent shared decision-making and further study., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Conflicts of interest None disclosed.

Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinson's disease (PD). Iron-loaded microglia are frequently found in affected brain regions, but how iron accumulation influences microglia physiology and contributes to neurodegeneration is poorly understood. Here we show that human induced pluripotent stem cell-derived microglia grown in a tri-culture system are highly responsive to iron and susceptible to ferroptosis, an iron-dependent form of cell death. Furthermore, iron overload causes a marked shift in the microglial transcriptional state that overlaps with a transcriptomic signature found in PD postmortem brain microglia. Our data also show that this microglial response contributes to neurodegeneration, as removal of microglia from the tri-culture system substantially delayed iron-induced neurotoxicity. To elucidate the mechanisms regulating iron response in microglia, we performed a genome-wide CRISPR screen and identified novel regulators of ferroptosis, including the vesicle trafficking gene SEC24B. These data suggest a critical role for microglia iron overload and ferroptosis in neurodegeneration., (© 2022. The Author(s).)

Background: Ceftolozane/tazobactam, a combination antibacterial agent comprising an anti-pseudomonal cephalosporin and β-lactamase inhibitor, is approved for the treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) in adults. Participants in the ASPECT-NP trial received ceftolozane/tazobactam (3 g [2 g ceftolozane/1 g tazobactam] every 8 h) or meropenem (1 g every 8 h). Participants failing prior antibacterial therapy for the current HABP/VABP episode at study entry had lower 28-day all-cause mortality (ACM) rates with ceftolozane/tazobactam versus meropenem treatment. Here, we report a post hoc analysis examining this result., Methods: The phase 3, randomized, controlled, double-blind, multicenter, noninferiority trial compared ceftolozane/tazobactam versus meropenem for treatment of adults with ventilated HABP/VABP; eligibility included those failing prior antibacterial therapy for the current HABP/VABP episode at study entry. The primary and key secondary endpoints were 28-day ACM and clinical response at test of cure (TOC), respectively. Participants who were failing prior therapy were a prospectively defined subgroup; however, subgroup analyses were not designed for noninferiority testing. The 95% CIs for treatment differences were calculated as unstratified Newcombe CIs. Post hoc analyses were performed using multivariable logistic regression analysis to determine the impact of baseline characteristics and treatment on clinical outcomes in the subgroup who were failing prior antibacterial therapy., Results: In the ASPECT-NP trial, 12.8% of participants (93/726; ceftolozane/tazobactam, n = 53; meropenem, n = 40) were failing prior antibacterial therapy at study entry. In this subgroup, 28-day ACM was higher in participants who received meropenem versus ceftolozane/tazobactam (18/40 [45.0%] vs 12/53 [22.6%]; percentage difference [95% CI]: 22.4% [3.1 to 40.1]). Rates of clinical response at TOC were 26/53 [49.1%] for ceftolozane/tazobactam versus 15/40 [37.5%] for meropenem (percentage difference [95% CI]: 11.6% [- 8.6 to 30.2]). Multivariable regression analysis determined concomitant vasopressor use and treatment with meropenem were significant factors associated with risk of 28-day ACM. Adjusting for vasopressor use, the risk of dying after treatment with ceftolozane/tazobactam was approximately one-fourth the risk of dying after treatment with meropenem., Conclusions: This post hoc analysis further supports the previously demonstrated lower ACM rate for ceftolozane/tazobactam versus meropenem among participants who were failing prior therapy, despite the lack of significant differences in clinical cure rates., Clinicaltrials: gov registration NCT02070757 . Registered February 25, 2014, clinicaltrials.gov/ct2/show/NCT02070757 ., (© 2022. The Author(s).)

Background: After the MERINO trial with piperacillin/tazobactam, the efficacy of β-lactam/tazobactam combinations in serious infections involving extended-spectrum β-lactamase (ESBL)-producing pathogens merits special evaluation., Objectives: To further confirm the efficacy of ceftolozane/tazobactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) involving ESBL-positive and/or AmpC-producing Enterobacterales., Methods: Retrospective subgroup analysis of the ASPECT-NP trial comparing ceftolozane/tazobactam with meropenem for treating HABP/VABP in mechanically ventilated adults (ClinicalTrials.gov NCT02070757). ESBLs were identified using whole genome sequencing. Chromosomal AmpC production was quantified employing a high-sensitivity mRNA transcription assay., Results: Overall, 61/726 (8.4%) participants had all baseline lower respiratory tract (LRT) isolates susceptible to both study treatments and ≥1 baseline ESBL-positive/AmpC-overproducing Enterobacterales isolate. In this subgroup (ceftolozane/tazobactam n = 30, meropenem n = 31), baseline characteristics were generally comparable between treatment arms. The most frequent ESBL-positive and/or AmpC-overproducing Enterobacterales isolates (ceftolozane/tazobactam n = 31, meropenem n = 35) overall were Klebsiella pneumoniae (50.0%), Escherichia coli (22.7%), and Proteus mirabilis (7.6%). The most prevalent ESBLs were CTX-M-15 (75.8%), other CTX-M (19.7%), and SHV (4.5%); 10.6% of isolates overproduced chromosomal AmpC. Overall, 28 day all-cause mortality was 6.7% (2/30) with ceftolozane/tazobactam and 32.3% (10/31) with meropenem (25.6% difference, 95% CI: 5.54 to 43.84). Clinical cure rate at test-of-cure, 7-14 days after end of therapy, was 73.3% (22/30) with ceftolozane/tazobactam and 61.3% (19/31) with meropenem (12.0% difference, 95% CI: -11.21 to +33.51). Per-isolate microbiological response at test-of-cure was 64.5% (20/31) with ceftolozane/tazobactam and 74.3% (26/35) with meropenem (-9.8% difference, 95% CI: -30.80 to +12.00)., Conclusions: These data confirm ceftolozane/tazobactam as an effective treatment option for HABP/VABP involving ceftolozane/tazobactam-susceptible ESBL-positive and/or AmpC-producing Enterobacterales., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: In the ASPECT-NP trial, ceftolozane/tazobactam was non-inferior to meropenem for treating nosocomial pneumonia; efficacy outcomes by causative pathogen were to be evaluated., Methods: Mechanically ventilated participants with hospital-acquired/ventilator-associated bacterial pneumonia were randomized to 3 g ceftolozane/tazobactam (2 g ceftolozane/1 g tazobactam) q8h or 1 g meropenem q8h. Lower respiratory tract (LRT) cultures were obtained ≤36 h before first dose; pathogen identification and susceptibility were confirmed at a central laboratory. Prospective secondary per-pathogen endpoints included 28 day all-cause mortality (ACM), and clinical and microbiological response at test of cure (7-14 days after the end of therapy) in the microbiological ITT (mITT) population., Results: The mITT population comprised 511 participants (264 ceftolozane/tazobactam, 247 meropenem). Baseline LRT pathogens included Klebsiella pneumoniae (34.6%), Pseudomonas aeruginosa (25.0%) and Escherichia coli (18.2%). Among baseline Enterobacterales isolates, 171/456 (37.5%) were ESBL positive. For Gram-negative baseline LRT pathogens, susceptibility rates were 87.0% for ceftolozane/tazobactam and 93.3% for meropenem. For Gram-negative pathogens, 28 day ACM [52/259 (20.1%) and 62/240 (25.8%)], clinical cure rates [157/259 (60.6%) and 137/240 (57.1%)] and microbiological eradication rates [189/259 (73.0%) and 163/240 (67.9%)] were comparable with ceftolozane/tazobactam and meropenem, respectively. Per-pathogen microbiological eradication for Enterobacterales [145/195 (74.4%) and 129/185 (69.7%); 95% CI: -4.37 to 13.58], ESBL-producing Enterobacterales [56/84 (66.7%) and 52/73 (71.2%); 95% CI: -18.56 to 9.93] and P. aeruginosa [47/63 (74.6%) and 41/65 (63.1%); 95% CI: -4.51 to 19.38], respectively, were also comparable., Conclusions: In mechanically ventilated participants with nosocomial pneumonia owing to Gram-negative pathogens, ceftolozane/tazobactam was comparable with meropenem for per-pathogen 28 day ACM and clinical and microbiological response., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: It is unclear whether the addition of chemoradiation (CRT) to adjuvant chemotherapy (CT) following upfront resection of pancreatic ductal adenocarcinoma (PDAC) provides any benefit. While some studies have suggested a benefit to combined modality therapy (CMT) (adjuvant CT plus CRT), it is not clear if this benefit was related to increased CT usage in patients who received CMT. We sought to clarify the use of CMT in patients who underwent upfront resection of PDAC., Methods: Patients with non-metastatic PDAC were retrospectively identified from the linked SEER-Medicare database. Those who underwent upfront resection were identified and divided into two cohorts - patients who received adjuvant CT and patients who received adjuvant CMT. Cohorts were compared. Univariate analysis described patient characteristics. Kaplan-Meier and multivariable Cox proportional hazards modeling were used to estimate overall survival (OS)., Results: 3555 patients were identified; 856 (24%) received CT and 573 (16%) received CMT. The median number of CT doses was 11 for both groups. Patients who received CMT were younger, diagnosed in the earlier time frame, and had fewer comorbidities. The median OS was 21 months and 18 months for those treated with CMT and CT ( P < .0001), respectively, but when stratified by nodal status, the association with improved OS in the CMT cohort was only observed in node-positive patients. On multivariable analysis, receipt of CMT and removal of >15 lymph nodes decreased the risk of death ( P < .05)., Discussion: Receipt of CMT following upfront resection for PDAC was associated with improved survival, which was confined to node-positive patients. The role of adjuvant CMT in PDAC with nodal metastases warrants further study.

Background: Thermal ablation is an effective treatment for patients with metastatic colon and rectal cancer and allows surgeons to offer curative intent therapy to patients who are otherwise not candidates for resection. We aimed to report outcomes of a single institution experience using microwave ablation (MWA) with or without resection to treat five or more liver metastases., Methods: In this retrospective cohort study, the University of Minnesota Division of Surgical Oncology liver surgery database was queried to identify all patients who underwent thermal ablation of five or more colorectal liver metastases (CRLM) between 2012-2018. We reviewed patient, disease, and tumor characteristics and measured local, intrahepatic, and extrahepatic recurrence (EHR) rates. We also calculated median overall survival (OS) and disease-free survival (DFS)., Results: Ten patients identified had five or more (range, 5-18) tumors ablated with or without combined liver and bowel resection. Median age was 50, and most patients were male (70%) and Caucasian (90%). Four patients received ablation alone (5-12 lesions), while six had combined resection and ablation (5-18 lesions). Ablation was performed laparoscopically in six patients, and four had ablations without resection. All patients received pre- and post-operative chemotherapy. A median of 7 tumors were ablated per patient. Median follow-up was 2.3 years. Among 75 tumors ablated, ablation site recurrence (ASR) (within 1 cm of ablation site) was seen in three with a per-lesion recurrence rate of 4%. Intrahepatic recurrence (IHR) occurred in 6 (60%) patients and EHR in 1 (10%). Five patients underwent retreatment of IHR during follow-up. Median OS was 3 years and DFS was 7.1 months. At the time of last follow up, 6 patients were disease-free., Conclusions: Thermal ablation can provide acceptable DFS and OS, even with high volume metastatic colorectal cancers. Future efforts should be focused on defining selection criteria for those most likely to benefit from this aggressive approach., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/jgo-21-203). CJL reports that he receives grant from Masonic Cancer center for investigation of oncolytic viruses for colorectal cancer therapy. EHJ reports that he is a consultant and receives honoraria from Johnson & Johnson to teach national and international programs to educate surgeons about the use of microwave ablation. The other authors have no conflicts of interest to declare., (2021 Journal of Gastrointestinal Oncology. All rights reserved.)

Background: Acute and persistent pain after surgery is well described. However, no large-scale studies on immediate postoperative pain in the operating room (OR) exist, hindering potential areas of research to improve clinical outcomes. Thus, we aimed to describe the occurrence and severity of immediate postoperative pain in a large, unselected cohort., Methods: This was a prospective cohort study, encompassing all procedures in 31 public hospitals in the Danish Realm, during a 5-day period including the weekend. Data on procedures and anesthesia were collected and the main outcome was occurrence of moderate or severe pain in the OR. Secondary outcomes included pain, sedation and nausea in the OR or during the first 15 min in the postanesthesia care unit (PACU) including relevant risk factors. Descriptive and logistic regression statistics were used., Results: A total of 3675 procedures were included for analysis (87% inclusion rate). Moderate or severe pain occurred in 7.4% (95% CI 6.5% to 8.3%) of cases in the OR immediately after awakening, rising to 20.2% in the OR and/or PACU. Large intraprocedure and interprocedure variations occurred (0.0%-37.5%), and in 20% of cases with epidural-general anesthesia patients experienced moderate or severe pain. Independent risk factors were female sex, younger age, preoperative pain, daily opioid use and major surgical procedures., Conclusion: Moderate or severe pain in the immediate postoperative phase occurred in 20% of all cases with procedure and anesthesiological technique variations, suggesting a need for identification of relevant procedure-specific risk factors and development of preventive treatments., Trial Registration Number: RoPR ID 43191., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in patients with previously treated, advanced NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% and ≥1%. We report 5-year efficacy and safety follow-up for the KEYNOTE-010 study., Methods: Patients were randomized to pembrolizumab 2 mg/kg or 10 mg/kg once every 3 weeks or docetaxel 75 mg/m 2 once every 3 weeks for up to 35 cycles (2 y). Patients who completed pembrolizumab treatment and subsequently had recurrence could receive second-course pembrolizumab for up to 17 cycles (1 y). Pembrolizumab doses were pooled in this analysis., Results: A total of 1034 patients were randomized (pembrolizumab, n = 691; docetaxel, n = 343). Median study follow-up was 67.4 months (range: 60.0‒77.9). The hazard ratio (95% confidence interval) for OS was 0.55 (0.44‒0.69) for patients with PD-L1 TPS ≥50% and 0.70 (0.61‒0.80) with PD-L1 TPS ≥1%. The 5-year OS rates for pembrolizumab versus docetaxel were 25.0% versus 8.2% in patients with PD-L1 TPS ≥50% and 15.6% versus 6.5% with PD-L1 TPS ≥1%. Among 79 patients who completed 35 cycles/2 years of pembrolizumab, the OS rate 3 years after completion (∼5 y from randomization) was 83.0%. A total of 21 patients received second-course pembrolizumab; 11 (52.4%) had an objective response after starting the second course and 15 (71.4%) were alive at data cutoff. Exploratory biomarker analysis revealed that higher tissue tumor mutational burden (≥175 mutations per exome) was associated with improved outcomes with pembrolizumab., Conclusions: Pembrolizumab continued to provide long-term benefit than docetaxel in patients with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1%. Our findings confirm pembrolizumab as a standard-of-care treatment in the second-line or later setting., (Copyright © 2021. Published by Elsevier Inc.)

Background: Ceftolozane/tazobactam is approved for treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) at double the dose approved for other infection sites. Among nosocomial pneumonia subtypes, ventilated HABP (vHABP) is associated with the lowest survival. In the ASPECT-NP randomized, controlled trial, participants with vHABP treated with ceftolozane/tazobactam had lower 28-day all-cause mortality (ACM) than those receiving meropenem. We conducted a series of post hoc analyses to explore the clinical significance of this finding., Methods: ASPECT-NP was a multinational, phase 3, noninferiority trial comparing ceftolozane/tazobactam with meropenem for treating vHABP and VABP; study design, efficacy, and safety results have been reported previously. The primary endpoint was 28-day ACM. The key secondary endpoint was clinical response at test-of-cure. Participants with vHABP were a prospectively defined subgroup, but subgroup analyses were not powered for noninferiority testing. We compared baseline and treatment factors, efficacy, and safety between ceftolozane/tazobactam and meropenem in participants with vHABP. We also conducted a retrospective multivariable logistic regression analysis in this subgroup to determine the impact of treatment arm on mortality when adjusted for significant prognostic factors., Results: Overall, 99 participants in the ceftolozane/tazobactam and 108 in the meropenem arm had vHABP. 28-day ACM was 24.2% and 37.0%, respectively, in the intention-to-treat population (95% confidence interval [CI] for difference: 0.2, 24.8) and 18.2% and 36.6%, respectively, in the microbiologic intention-to-treat population (95% CI 2.5, 32.5). Clinical cure rates in the intention-to-treat population were 50.5% and 44.4%, respectively (95% CI - 7.4, 19.3). Baseline clinical, baseline microbiologic, and treatment factors were comparable between treatment arms. Multivariable regression identified concomitant vasopressor use and baseline bacteremia as significantly impacting ACM in ASPECT-NP; adjusting for these two factors, the odds of dying by day 28 were 2.3-fold greater when participants received meropenem instead of ceftolozane/tazobactam., Conclusions: There were no underlying differences between treatment arms expected to have biased the observed survival advantage with ceftolozane/tazobactam in the vHABP subgroup. After adjusting for clinically relevant factors found to impact ACM significantly in this trial, the mortality risk in participants with vHABP was over twice as high when treated with meropenem compared with ceftolozane/tazobactam., Trial Registration: clinicaltrials.gov, NCT02070757. Registered 25 February, 2014, clinicaltrials.gov/ct2/show/NCT02070757., (© 2021. The Author(s).)

Background: Colorectal liver metastases (CRLM) are the most common extra-lymphatic metastases in colorectal cancers, however, only 15-20% of these patients are candidates for resection. We reviewed our institutional experience with 135 surgical ablations for unresectable CRLM., Methods: Retrospective review of surgically ablated CRLM from 2009 to 2018. Patient-specific variables were obtained from the medical record. Kaplan-Meier modeling was performed for survival analyses., Results: We ablated 135 CRLM in 36 patients over 40 procedures. Median age was 52 years and 58% of patients were male. All patients received systemic chemotherapy. The ablation procedure was completed laparoscopically in 68% of procedures. Median number of ablated lesions per patient was 2 (range 1-15). Median maximum diameter of ablated lesions was 1.9 cm (range 0.5-12.2). Median follow up of the study was 28 months. In this time, median disease-free survival was not reached. Of the 135 lesions ablated, the per-lesion recurrence rate was 6/135 (4.4%). Median overall survival was 81 months., Conclusions: Surgical ablation of CRLM can provide excellent local control and long-term survival outcomes in patients who may otherwise not be candidates for other liver-directed therapies., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Breast cancer is one of the most common causes of cancer mortality for all women, including American Indian and Alaska Native (AI/AN) women. The use of the 21-gene recurrence score (RS) appears to be predictive of the benefit of chemotherapy for women with estrogen receptor (ER)-positive breast cancer. The objective of the current study was to compare RS testing between AI/AN and non-Hispanic White (NHW) women with breast cancer., Methods: The Surveillance, Epidemiology, and End Results program was used to identify women with ER-positive breast cancer from 2004 through 2015. Multivariable logistic regression was used to evaluate factors associated with RS use, with high-risk RS, and with chemotherapy use among those with a high-risk RS., Results: A total of 363,387 NHW patients and 1951 AI/AN patients with ER-positive breast cancer were identified. AI/AN women were found to be less likely to undergo RS testing and, when tested, were more likely to have a high-risk RS. In the multivariable logistic regression analysis, AI/AN women were found to be significantly more likely to have a high-risk RS (odds ratio,1.28; 95% confidence interval, 1.01-1.66). Among untested women, chemotherapy use was higher for AI/AN women; however, the use of chemotherapy was not found to be significantly different between the groups with a high-risk RS. Using Cox proportional hazards models, AI/AN race was found to be significantly associated with worse overall survival., Conclusions: AI/AN women were less likely to undergo RS testing compared with NHW women and were more likely to have a high-risk RS. Reversing the disparity in genomic expression assay testing is critical to ensure guideline-based breast cancer treatment and improve survival rates for AI/AN women with breast cancer., (© 2020 American Cancer Society.)

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by motor neuron (MN) death. Lipid dysregulation manifests during disease; however, it is unclear whether lipid homeostasis is adversely affected in the in the spinal cord gray matter (GM), and if so, whether it is because of an aberrant increase in lipid synthesis. Moreover, it is unknown whether lipid dysregulation contributes to MN death. Here, we show that cholesterol ester (CE) and triacylglycerol levels are elevated several-fold in the spinal cord GM of male sporadic ALS patients. Interestingly, HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, was reduced in the spinal cord GM of ALS patients. Increased cytosolic phospholipase A2 activity and lyso-phosphatidylcholine (Lyso-PC) levels in ALS patients suggest that CE accumulation was driven by acyl group transfer from PC to cholesterol. Notably, Lyso-PC, a byproduct of CE synthesis, was toxic to human MNs in vitro Elevations in CE, triacylglycerol, and Lyso-PC were also found in the spinal cord of SOD1 G93A mice, a model of ALS. Similar to ALS patients, a compensatory downregulation of cholesterol synthesis occurred in the spinal cord of SOD1 G93A mice; levels of sterol regulatory element binding protein 2, a transcriptional regulator of cholesterol synthesis, progressively declined. Remarkably, overexpressing sterol regulatory element binding protein 2 in the spinal cord of normal mice to model CE accumulation led to ALS-like lipid pathology, MN death, astrogliosis, paralysis, and reduced survival. Thus, spinal cord lipid dysregulation in ALS likely contributes to neurodegeneration and developing therapies to restore lipid homeostasis may lead to a treatment for ALS. SIGNIFICANCE STATEMENT Neurons that control muscular function progressively degenerate in patients with amyotrophic lateral sclerosis (ALS). Lipid dysregulation is a feature of ALS; however, it is unclear whether disrupted lipid homeostasis (i.e., lipid cacostasis) occurs proximal to degenerating neurons in the spinal cord, what causes it, and whether it contributes to neurodegeneration. Here we show that lipid cacostasis occurs in the spinal cord gray matter of ALS patients. Lipid accumulation was not associated with an aberrant increase in synthesis or reduced hydrolysis, as enzymatic and transcriptional regulators of lipid synthesis were downregulated during disease. Last, we demonstrated that genetic induction of lipid cacostasis in the CNS of normal mice was associated with ALS-like lipid pathology, astrogliosis, neurodegeneration, and clinical features of ALS., (Copyright © 2020 the authors.)

Background: Intrahepatic cholangiocarcinoma (ICC) is rare with limited evidence-based guidelines. This retrospective study evaluates the use of chemotherapy in patients with resected ICC., Methods: The Surveillance Epidemiology and End Results (SEER) program database was used to identify patients with resected ICC. Patients were stratified by date of diagnosis (2000-2004, 2005-2009, 2010-2014), T, and N stage. Multivariable logistic regression models identified predictors of chemotherapy use. Kaplan-Meier and Cox proportional hazard models were used to identify survival trends., Results: One thousand and two hundred twenty-three patients met inclusion criteria. Chemotherapy utilization increased over time (33% to 41%, P≤0.05). Chemotherapy use increased in lymph node (LN) positive patients [32% to 60% in 2010-2014; (P≤0.05) and T3/T4 disease (40% to 60% in 2010-2014; P≤0.01], but not in patients with LN negative or T1/T2 disease. LN positivity was associated with utilization of chemotherapy in 2005-2009 and 2010-2014. Overall survival increased from 32 to 41 months (P≤0.05). In LN positive patients, chemotherapy was associated with a decreased hazard ratio of death (P≤0.05) and T3/T4 disease was associated with an increased hazard ratio of death (P≤0.05)., Conclusions: Adjuvant chemotherapy use in ICC has increased. More LN positive or patients with T3/T4 tumors are receiving chemotherapy, which may explain the improvement in overall survival., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/hbsn.2019.06.12). The authors have no conflicts of interest to declare., (2020 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Background: Lymph node-positive biliary tract cancers have poor overall survival. Surgical resection followed by systemic chemotherapy is the mainstay of treatment. We sought to assess the delivery of multimodality therapy in the United States., Methods: The Surveillance, Epidemiology, and End Results program database was used to identify patients with node-positive biliary tract cancers without distant metastases from 2000 to 2014. Patients were stratified by disease subtype (gallbladder cancer, intrahepatic, extrahepatic, or hilar cholangiocarcinoma) and treatment received (surgery alone, chemotherapy alone, or surgery + chemotherapy). Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard modeling., Results: A total of 3226 patients with node-positive biliary tract cancers were identified. Of 2837 patients who underwent surgical resection, 1386 (49%) received no systemic chemotherapy following surgery, while 1451 (51%) received surgery + chemotherapy. A total of 389 patients (12%) received chemotherapy alone. Median overall survival was longer for patients who underwent surgery + chemotherapy (19 months, p < 0.0001). There was no difference in survival for those who received surgery alone versus chemotherapy alone (10 months for both, p = NS). Receipt of surgery + chemotherapy was independently associated with survival on Cox proportional hazard ratio modeling compared to surgery alone (HR for mortality 1.71, 95% CI 1.56-1.87, p < 0.0001) or chemotherapy alone (HR 1.68, 95% CI 1.46-1.92, p < 0.0001). These trends were consistent across all disease subtypes., Discussion: Optimal survival for node-positive biliary tract cancers depends on multimodality therapy. Following surgery, a substantial proportion of patients do not receive guideline recommended adjuvant therapy., (Copyright © 2020. Published by Elsevier Ltd.)

Background: In the ARTIST trial, chemoradiation did not improve disease-free survival (DFS) in gastric cancer patients treated with curative-intent surgery and adjuvant chemotherapy. Subgroup analysis suggested chemoradiation improved DFS in patients with lymph node (LN) metastases, but the role of adjuvant chemoradiation remains uncertain. This study sought to determine the role of adjuvant chemoradiation using population-based methods., Methods: Surveillance, Epidemiology and End Results-Medicare linked data from 2004 to 2013 was used to identify patients aged 66 and older with LN-positive gastric adenocarcinoma. Multivariable logistic regression evaluated factors associated with receipt of chemoradiation. The Kaplan-Meier method and Cox proportional hazards modeling were used to evaluate overall survival (OS)., Results: A total of 2409 patients with LN-positive gastric adenocarcinoma who underwent upfront surgical resection were identified; 309 (13%) received adjuvant chemotherapy and 407 (17%) received adjuvant chemotherapy and chemoradiation. Among all patients, median OS was 15 months. Median OS was 20 months for patients who received chemotherapy alone and 27 months for patients who received chemotherapy and chemoradiation (p < 0.05). Recent diagnosis, older age, tumor stage T3 or T4, and Charleston Comorbidity Index were associated with an increased hazard ratio for death (p < 0.05). Receipt of chemoradiation was associated with a decreased hazard ratio for death (p < 0.05)., Conclusions: In patients with LN-positive gastric adenocarcinoma, the addition of chemoradiation to adjuvant chemotherapy after upfront surgical resection was associated with improved survival irrespective of the extent of lymphadenectomy. These data suggest chemoradiation should be considered in patients with LN-positive gastric adenocarcinoma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Renal impairment is not a consistently cited risk factor for recurrent Clostridioides difficile infection (rCDI). We examined the association between renal impairment and rCDI and the effect of bezlotoxumab, an anti-toxin B monoclonal antibody, in reducing rCDI in participants with renal impairment., Methods: We pooled data from 2 randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials conducted in participants receiving bezlotoxumab or placebo infusion during oral antibacterial drug treatment for CDI. We assessed the association between renal impairment and rCDI in placebo-treated participants and evaluated the effect of bezlotoxumab vs placebo in reducing rCDI among participants with renal impairment, defined as an estimated glomerular filtration rate <90 mL/min., Results: The proportion of placebo-treated participants experiencing rCDI within 12 weeks was higher in those with renal impairment (n = 919) vs those without renal impairment (n = 612; 36.6% and 27.7%, respectively; difference, 8.9%; 95% CI, 1.3% to 16.3%). Renal impairment was significantly associated with a higher rate of recurrence in placebo-treated participants lacking commonly recognized risk factors for rCDI (renal impairment as only risk factor, 28.8%; vs normal renal function and no risk factors, 12.5%; difference, 16.3%; 95% CI, 3.4% to 28.8%). Among all participants with renal impairment, the rate of rCDI was 19.5% among bezlotoxumab-treated vs 36.6% among placebo-treated participants (difference, -17.1%; 95% CI, -23.4% to -10.6%)., Conclusions: This post hoc analysis adds to the literature suggesting an association of renal impairment as an independent risk factor for rCDI and provides preliminary evidence that patients with renal impairment who suffer with CDI may benefit from adjunctive treatment with bezlotoxumab., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The utility of neoadjuvant treatment for resectable pancreas cancer is yet to be determined, but has commonly included chemoradiation. We evaluated outcomes in patients with radiographically resectable pancreatic adenocarcinoma treated with neoadjuvant chemotherapy without chemoradiation., Methods: A retrospective review of patients in our institutional pancreatic cancer registry was performed, which identified 36 patients who received neoadjuvant chemotherapy alone for resectable pancreatic adenocarcinoma between 2012 and 2016., Results: Median age at diagnosis was 66.3 years. Chemotherapy regimens included gemcitabine (n=17), gemcitabine/nab-paclitaxel (n=8), or 5-FU/leucovorin/irinotecan/oxaliplatin (FOLFIRINOX) (n=11). Surgical resection was performed in 69% of patients (n=25), with an R0 resection rate of 92% (n=23 patients). During chemotherapy, distant disease became apparent in 19% of patients (n=7), while no patients had evidence of local progression. Resection rates were similar between chemotherapy regimens (single agent =59%, multiple agent =79%). Median overall survival for all patients who received neoadjuvant chemotherapy was 30.3 and 34.4 months for those who underwent surgical resection. There was no difference in median survival for patients treated with gemcitabine (31.3 months) or multi-agent chemotherapy (29.7 months)., Conclusions: A short course of neoadjuvant chemotherapy without chemoradiation may improve patient selection prior to surgical resection for pancreas cancer. Further, local disease progression did not limit surgical resection in this small series., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/hbsn.2019.04.17). The authors have no conflicts of interest to declare., (2020 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Background and Objectives: Thermal ablation can be used as a bridge to transplant or with curative intent for hepatocellular carcinoma (HCC). We report our experience with laparoscopic ablation of HCC in patients deemed inaccessible by the percutaneous approach., Methods: We performed a retrospective review of surgical ablations from 2009 to 2017. Patient demographics, disease and treatment characteristics, and outcomes were abstracted from the medical record. Kaplan-Meier modeling was performed for survival and recurrence., Results: Thirty-three patients were included with a median age of 62 (interquartile range [IQR], 57-67). Most patients were male (76%) and Caucasian (70%). Ninety-seven percent had underlying cirrhosis. Median model for end stage liver disease-sodium was 9.5 (IQR, 8-12). The median maximal diameter of ablated lesions was 2.6 cm (IQR, 1.8-3.0). Thirty-nine lesions were ablated; 97% were completed laparoscopically. The median maximal diameter of the ablation zone was 4.8 cm (IQR, 3.8-5.7) with a median difference of ablation zone to the tumor of 2.0 cm (IQR, 1.5-2.75). Twelve patients received additional treatment. Median disease-free survival was 66.7 months and median follow-up 42.9 months. Disease recurrence occurred in 13 patients (39%)-systemic recurrence in 6%, intrahepatic recurrence in 27% and local recurrence in 6%., Conclusion: Laparoscopic thermal ablation of HCC is safe and provides good oncologic outcomes for otherwise inaccessible tumors., (© 2020 Wiley Periodicals, Inc.)

Purpose: In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in previously treated, programmed death-ligand 1 (PD-L1)‒expressing advanced non‒small-cell lung cancer (NSCLC) in patients with a tumor proportion score (TPS) ≥ 50% and ≥ 1%. We report KEYNOTE-010 long-term outcomes, including after 35 cycles/2 years or second-course pembrolizumab., Methods: Of 1,033 patients randomly assigned (intention to treat), 690 received up to 35 cycles/2 years of pembrolizumab 2 mg/kg (n = 344) or 10 mg/kg (n = 346) every 3 weeks, and 343 received docetaxel 75 mg/m 2 every 3 weeks. Eligible patients with disease progression after 35 cycles/2 years of pembrolizumab could receive second-course treatment (up to 17 cycles). Pembrolizumab doses were pooled because no between-dose difference was observed at primary analysis., Results: Pembrolizumab continued to improve OS over docetaxel in the PD-L1 TPS ≥ 50% and ≥ 1% groups (hazard ratio [HR], 0.53; 95% CI, 0.42 to 0.66; P < .00001; and HR, 0.69; 95% CI, 0.60 to 0.80; P < .00001, respectively) after a 42.6-month (range, 35.2-53.2 months) median follow-up. Estimated 36-month OS rates were 34.5% versus 12.7% and 22.9% versus 11.0%, respectively. Grade 3-5 treatment-related adverse events occurred in 16% versus 37% of patients, respectively. Seventy-nine of 690 patients completed 35 cycles/2 years of pembrolizumab; 12-month OS and progression-free survival rates after completing treatment were 98.7% (95% CI, 91.1% to 99.8%) and 72.5% (95% CI, 59.9% to 81.8%), respectively. Seventy-five patients (95%) had objective response (RECIST v1.1, blinded independent central review) and 48 (64%) had ongoing response. Grade 3-5 treatment-related adverse events occurred in 17.7% of patients. Fourteen patients received second-course pembrolizumab: 5 completed 17 cycles, 6 (43%) had partial response, and 5 (36%) had stable disease., Conclusion: Pembrolizumab provided long-term OS benefit over docetaxel, with manageable safety, durable responses among patients receiving 2 years of treatment, and disease control with second-course treatment, further supporting pembrolizumab for previously treated, PD-L1‒expressing advanced NSCLC.

We used data from the Surveillance, Epidemiology, and End Results Program to examine trends in breast cancer treatment and survival among a large sample of American Indian and Alaska Native women diagnosed from 2000-2015. Kaplan-Meier and Cox proportional hazard models were used to estimate survival. Alaska Natives were more likely to undergo mastectomy (48% compared with 39% of American Indians and 36% of non-Hispanic Whites) and were less likely to receive breast reconstruction following mastectomy (9% compared with 17% of American Indians and 28% of non-Hispanic Whites). Alaska Natives had both lower overall (HR: 1.40 95% CI: 1.19-1.65) and breast-cancer specific (HR: 1.29, 95% CI: 1.03, 1.63) survival compared with non-Hispanic Whites. Survival differences across the three racial groups varied significantly by age. Efforts to improve survival among American Indian and Alaska Native populations will need to address barriers to access among these vulnerable populations.

In the original article, Schelomo Marmor's last name is misspelled. It is correct as reflected here.

Background: Multiple trials have demonstrated a survival benefit for adjuvant chemotherapy after resection of pancreatic adenocarcinoma. This study aimed to identify the rate for completion of adjuvant chemotherapy, factors associated with completion, and its impact on survival after surgical resection., Methods: The Surveillance Epidemiology and End Results Medicare-linked data was used to identify patients who underwent upfront resection for pancreatic adenocarcinoma from 2004 to 2013. Billing codes were used to quantify receipt and completion of chemotherapy. Factors associated with completion of chemotherapy were identified using multivariable regression. Kaplan-Meier and Cox proportional-hazards modeling were used to examine survival., Results: The inclusion criteria were met by 2440 patients. Of these patients, 65% received no adjuvant chemotherapy, 28% received incomplete therapy, and 7% completed chemotherapy. The factors associated with chemotherapy completion were nodal metastases and treatment at a National Cancer Institute-designated cancer center (p ≤ 0.05). Comorbidities decreased the odds of completion (p ≤ 0.05). The median overall survival (OS) was 14 months for the patients who received no adjuvant chemotherapy, 17 months for those who received incomplete adjuvant chemotherapy, and 22 months for those who completed adjuvant chemotherapy (p ≤ 0.05). More recent diagnosis, comorbidities, T stage, nodal metastases, and no adjuvant chemotherapy were associated with an increased hazard ratio for death (p ≤ 0.05). Evaluation of 15 or more nodes and completion of chemotherapy decreased the hazard ratio for death (p ≤ 0.05)., Conclusions: Only 7% of the Medicare patients who underwent upfront resection for pancreatic cancer completed adjuvant chemotherapy, yet completion of adjuvant chemotherapy was associated with improved OS. Completion of adjuvant chemotherapy should be the goal after upfront resection, but neoadjuvant chemotherapy may ensure that patients receive systemic chemotherapy.

Purpose: Previous studies have reported increased rates of contralateral prophylactic mastectomy (CPM) in the United States among women with unilateral breast cancer. These trends have primarily focused on younger breast cancer patients. Given the growing aging population in the United States, we sought to determine whether CPM use is also increasing in elderly patients., Methods: This population-based study identified patients in the surveillance epidemiology and end results (SEER) data. We determined the rate of CPM as a proportion of all surgically treated patients and as a proportion of all mastectomies. We compared the unadjusted CPM rates over the study period using the Cochrane-Armitage test for trend. We used a logistic regression model to test for the factors associated with CPM utilization., Results: We identified 261,281 patients ≥ 65 years who underwent surgical treatment for breast cancer. For all patients treated with surgery for invasive breast cancer, the use of CPM increased from 1 in 2004 to 3% in 2014 (200% increase). Among mastectomy patients, the use of CPM increased from 3 in 2004 to 7% in 2014 (133% increase). Young age, non-Hispanic white race, lobular histology, higher grade, increased stage, negative lymph node status, and recent year of diagnosis were significantly associated with increased CPM rates., Conclusions: For elderly patients the use of CPM has continued to increase in the United States. These observations warrant concern in light of increasing evidence that CPM does not improve oncological outcomes and is associated with increased morbidity in older patients.