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Objective This study aims to evaluate the effect of resident peer-to-peer education on knowledge of appropriate urinary catheter (UC) placement in the emergency department (ED) and to determine if this translates into further reduction in UC utilisation. Background Instituting guidelines for appropriate UC placement reduces UC utilisation in the ED. No study has explored if resident education in a teaching hospital would further reduce UC utilisation. Methods An educational intervention implemented in February 2009 consisted of a lecture, distribution of pocket cards and a peer-administered weekly review of institutional UC guidelines. A 12-question multiple-choice test was given to residents prelecture and postlecture, and the 12-question test was repeated 3 months later. Retrospective chart review was performed to evaluate UC utilisation before, immediately after and 3 months after the educational intervention. Results 30 residents completed all three tests. Significant differences were found between the mean test score pre-education and the mean test score immediately after education (9.43±1.17 vs 10.87±1.46, p<0.001) and between the mean test score pre-education and the mean test score 3 months posteducation (9.43±1.17 vs 10.43±1.28, p<0.001). There was no significant difference in UC utilisation or in the proportion of indicated UCs placed by residents within the three study periods. Conclusions Resident peer-to-peer education was associated with improvement of knowledge but did not result in decreased UC utilisation. A more active approach must be taken and other factors need to be further explored to reduce unnecessary placement of UC by residents in the ED. [ABSTRACT FROM AUTHOR]

Purpose: We conducted a phase I study to determine the recommended dose of selenomethionine (SLM) in combination with irinotecan that consistently results in a protective plasma selenium (Se) concentrations > 15 microM after 1 week of SLM loading.Experimental Design: A 3-3 standard escalation design was followed. SLM was given orally twice daily (BID) for one week (loading) followed by continuous once daily (QD) dosing (maintenance). Seven dose levels of selenomethionine were investigated. Irinotecan was given intravenously at a fixed standard weekly dose, starting on the first day of maintenance SLM.Results: Thirty-one patients were treated on study. Dose limiting diarrhea complicated by sepsis was noted in one of six patients at each of the dose-levels 1 and 7. Dose-levels > or = 5 (4,800 mcg/dose loading maintenance) resulted in day 8 Se concentrations >15 microM while dose-level 7 (7,200 mcg/dose loading and maintenance) resulted in day 8 Se concentrations > 20 muM. No significant variations in SN-38 or biliary index were noted between weeks 1 and 4 of treatment. Despite achieving target Se concentrations, gastrointestinal and bone marrow toxicities were common and irinotecan dose modification was prevalent. Objective responses were seen in two patients and nine patients had disease control for 6 months or longer.Conclusions: Selenomethionine can be escalated safely to 7,200 mcg BID x 1 week followed by 7,200 mcg QD in combination with a standard dose of irinotecan. No major protection against irinotecan toxicity was established; however, interesting clinical benefits were noted-supporting the investigation of this combination in future efficacy trials. [ABSTRACT FROM AUTHOR]

Neoadjuvant chemoradiation is now considered the clear preferable adjuvant standard of care in the management of stage II/III rectal cancer. Neoadjuvant fluorouracil (5-FU) plus radiation results in a decrease in local relapse rates and a favorable toxicity profile in comparison with postoperative adjuvant 5-FU plus radiation therapy. Recent nonrandomized comparative studies have shown that capecitabine (Xeloda) plus radiation result in downstaging and pathologic complete responses equivalent to those of 5-FU plus radiation, making this combination an acceptable alternative neoadjuvant treatment. The addition of oxaliplatin (Eloxatin) or irinotecan (Camptosar) to 5-FU or capecitabine concurrently with radiation therapy appears to result in more favorable pathologic responses in phase I/II trials. These combinations should be investigated further in larger phase III studies before they are endorsed in the routine neoadjuvant treatment of rectal cancer. This article will review the progress of chemoradiation over the past 2 decades, current standards of care, and investigational treatments in the neoadjuvant treatment of rectal cancer. [ABSTRACT FROM AUTHOR]

Carcinoembryonic antigen (CEA) monitoring in patients with stage I-IV colorectal cancer has been, and remains, a controversial issue in oncology practice. Recommendations vary from bimonthly monitoring to no monitoring in the surveillance setting (for stage I-III disease). In the metastatic setting, there are no clear guidelines for CEA follow-up, although continued monitoring in such patients is common in the oncology community. This manuscript reviews the accuracy of CEA testing, its value as a prognostic indicator, and its role in surveillance and response assessment. The limitations of the test in the adjuvant and metastatic settings are illustrated through several case reports from the Colorectal Oncology Clinic at Roswell Park Cancer Institute. Guidelines for CEA monitoring are provided, based on a detailed literature review and institutional experience. [ABSTRACT FROM AUTHOR]

Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1-confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10-26%), and DCR was 61% (62/101; 95% CI, 51-71%). Median DOR was not reached (NR; 95% CI, 5.7 months-NR), and median PFS was 3.5 months (95% CI, 2.7-4.1 months), at a median follow-up of 10.3 months (range, 0.5-42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 ., (© 2024. The Author(s).)

We performed a systematic literature review to identify and summarize data from studies reporting clinical efficacy and safety outcomes for trifluridine/tipiracil (FTD/TPI) combined with other antineoplastic agents in advanced cancers, including metastatic colorectal cancer (mCRC). We conducted a systematic search on May 29, 2021, for studies reporting one or more efficacy or safety outcome with FTD/TPI-containing combinations. Our search yielded 1378 publications, with 38 records meeting selection criteria: 35 studies of FTD/TPI-containing combinations in mCRC (31 studies second line or later) and 3 studies in other tumor types. FTD/TPI plus bevacizumab was extensively studied, including 19 studies in chemorefractory mCRC. Median overall survival ranged 8.6-14.4 months and median progression-free survival 3.7-6.8 months with FTD/TPI plus bevacizumab in refractory mCRC. Based on one randomized and several retrospective studies, FTD/TPI plus bevacizumab was associated with improved outcomes compared with FTD/TPI monotherapy. FTD/TPI combinations with chemotherapy or other targeted agents were reported in small early-phase studies; preliminary data indicated higher antitumor activity for certain combinations. Overall, no safety concerns existed with FTD/TPI combinations; most common grade ≥ 3 adverse event was neutropenia, ranging 5%-100% across all studies. In studies comparing FTD/TPI combinations with monotherapy, grade ≥ 3 neutropenia appeared more frequently with combinations (29%-67%) vs. monotherapy (5%-41%). Discontinuation rates due to adverse events ranged 0%-11% for FTD/TPI plus bevacizumab and 0%-17% with other combinations. This systematic review supports feasibility and safety of FTD/TPI plus bevacizumab in refractory mCRC. Data on non-bevacizumab FTD/TPI combinations remain preliminary and need further validation., (© The Author(s) 2024. Published by Oxford University Press.)

Importance: Guidelines recommend withholding antibiotics in asymptomatic bacteriuria (ASB), including among patients with altered mental status (AMS) and no systemic signs of infection. However, ASB treatment remains common., Objectives: To determine prevalence and factors associated with bacteremia from a presumed urinary source in inpatients with ASB with or without AMS and estimate antibiotics avoided if a 2% risk of bacteremia were used as a threshold to prompt empiric antibiotic treatment of ASB., Design, Setting, and Participants: This cohort study assessed patients hospitalized to nonintensive care with ASB (no immune compromise or concomitant infections) in 68 Michigan hospitals from July 1, 2017, to June 30, 2022. Data were analyzed from August 2022 to January 2023., Main Outcomes and Measures: The primary outcome was prevalence of bacteremia from a presumed urinary source (ie, positive blood culture with matching organisms within 3 days of urine culture). To determine factors associated with bacteremia, we used multivariable logistic regression models. We estimated each patient's risk of bacteremia and determined what percentage of patients empirically treated with antibiotics had less than 2% estimated risk of bacteremia., Results: Of 11 590 hospitalized patients with ASB (median [IQR] age, 78.2 [67.7-86.6] years; 8595 female patients [74.2%]; 2235 African American or Black patients [19.3%], 184 Hispanic patients [1.6%], and 8897 White patients [76.8%]), 8364 (72.2%) received antimicrobial treatment for UTI, and 161 (1.4%) had bacteremia from a presumed urinary source. Only 17 of 2126 patients with AMS but no systemic signs of infection (0.7%) developed bacteremia. On multivariable analysis, male sex (adjusted odds ratio [aOR], 1.45; 95% CI, 1.02-2.05), hypotension (aOR, 1.86; 95% CI, 1.18-2.93), 2 or more systemic inflammatory response criteria (aOR, 1.72; 95% CI, 1.21-2.46), urinary retention (aOR, 1.87; 95% CI, 1.18-2.96), fatigue (aOR, 1.53; 95% CI, 1.08-2.17), log of serum leukocytosis (aOR, 3.38; 95% CI, 2.48-4.61), and pyuria (aOR, 3.31; 95% CI, 2.10-5.21) were associated with bacteremia. No single factor was associated with more than 2% risk of bacteremia. If 2% or higher risk of bacteremia were used as a cutoff for empiric antibiotics, antibiotic exposure would have been avoided in 78.4% (6323 of 8064) of empirically treated patients with low risk of bacteremia., Conclusions and Relevance: In patients with ASB, bacteremia from a presumed urinary source was rare, occurring in less than 1% of patients with AMS. A personalized, risk-based approach to empiric therapy could decrease unnecessary ASB treatment.

The coronavirus disease 2019 (COVID-19) pandemic has demonstrated the importance of stewardship of viral diagnostic tests to aid infection prevention efforts in healthcare facilities. We highlight diagnostic stewardship lessons learned during the COVID-19 pandemic and discuss how diagnostic stewardship principles can inform management and mitigation of future emerging pathogens in acute-care settings. Diagnostic stewardship during the COVID-19 pandemic evolved as information regarding transmission (eg, routes, timing, and efficiency of transmission) became available. Diagnostic testing approaches varied depending on the availability of tests and when supplies and resources became available. Diagnostic stewardship lessons learned from the COVID-19 pandemic include the importance of prioritizing robust infection prevention mitigation controls above universal admission testing and considering preprocedure testing, contact tracing, and surveillance in the healthcare facility in certain scenarios. In the future, optimal diagnostic stewardship approaches should be tailored to specific pathogen virulence, transmissibility, and transmission routes, as well as disease severity, availability of effective treatments and vaccines, and timing of infectiousness relative to symptoms. This document is part of a series of papers developed by the Society of Healthcare Epidemiology of America on diagnostic stewardship in infection prevention and antibiotic stewardship. 1 .

Background: KRAS G12C is a mutation that occurs in approximately 3 to 4% of patients with metastatic colorectal cancer. Monotherapy with KRAS G12C inhibitors has yielded only modest efficacy. Combining the KRAS G12C inhibitor sotorasib with panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, may be an effective strategy., Methods: In this phase 3, multicenter, open-label, randomized trial, we assigned patients with chemorefractory metastatic colorectal cancer with mutated KRAS G12C who had not received previous treatment with a KRAS G12C inhibitor to receive sotorasib at a dose of 960 mg once daily plus panitumumab (53 patients), sotorasib at a dose of 240 mg once daily plus panitumumab (53 patients), or the investigator's choice of trifluridine-tipiracil or regorafenib (standard care; 54 patients). The primary end point was progression-free survival as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Key secondary end points were overall survival and objective response., Results: After a median follow-up of 7.8 months (range, 0.1 to 13.9), the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 6.3) and 3.9 months (95% CI, 3.7 to 5.8) in the 960-mg sotorasib-panitumumab and 240-mg sotorasib-panitumumab groups, respectively, as compared with 2.2 months (95% CI, 1.9 to 3.9) in the standard-care group. The hazard ratio for disease progression or death in the 960-mg sotorasib-panitumumab group as compared with the standard-care group was 0.49 (95% CI, 0.30 to 0.80; P = 0.006), and the hazard ratio in the 240-mg sotorasib-panitumumab group was 0.58 (95% CI, 0.36 to 0.93; P = 0.03). Overall survival data are maturing. The objective response was 26.4% (95% CI, 15.3 to 40.3), 5.7% (95% CI, 1.2 to 15.7), and 0% (95% CI, 0.0 to 6.6) in the 960-mg sotorasib-panitumumab, 240-mg sotorasib-panitumumab, and standard-care groups, respectively. Treatment-related adverse events of grade 3 or higher occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with sotorasib-panitumumab., Conclusions: In this phase 3 trial of a KRAS G12C inhibitor plus an EGFR inhibitor in patients with chemorefractory metastatic colorectal cancer, both doses of sotorasib in combination with panitumumab resulted in longer progression-free survival than standard treatment. Toxic effects were as expected for either agent alone and resulted in few discontinuations of treatment. (Funded by Amgen; CodeBreaK 300 ClinicalTrials.gov number, NCT05198934.)., (Copyright © 2023 Massachusetts Medical Society.)

Patients with microsatellite stable (MSS) colorectal cancer with liver metastases are resistant to immune checkpoint inhibitor (ICI) therapy, while about one-third of patients with colorectal cancer without liver metastases, particularly those with lung-only metastases, respond to ICI. We analyzed primary colorectal cancer tumors and major metastatic sites (liver, lung, peritoneal) using multiplex immunofluorescence and whole-slide spatial analyses to identify variations in immune contexture and regional localization within the tumor microenvironment. While levels of T and B cells within peritumoral regions were similar, their levels were significantly lower within the tumor core of liver and peritoneal metastases compared with lung metastases. In contrast, antigen-presenting cells (APC) and APC-T cell interactions were more abundant in all regions of lung metastases. We also identified an abundance of lymphoid aggregates throughout lung metastases, but these were present only within peritumoral regions of liver and peritoneal metastases. Larger lymphoid aggregates consistent with features of tertiary lymphoid structures were observed within or adjacent to primary tumors, but not metastatic lesions. Our findings were validated using NanoString GeoMx DSP, which further showed that liver metastases had higher expression of immune-suppressive markers, while lung metastases showed higher proinflammatory activity and T-cell activation markers. Peritoneal metastases demonstrated higher expression of cancer-associated fibroblast-related proteins and upregulated PD-1/PD-L1 signaling molecules. Our results demonstrate that functional status and spatial distribution of immune cells vary significantly across different metastatic sites. These findings suggest that metastatic site-dependent immune contexture may underlie discordant responses to ICI therapy in patients with MSS colorectal cancer., Significance: Our results demonstrate that functional status and spatial distribution of immune cells vary significantly across different metastatic sites in MSS colorectal cancer. These findings suggest that metastatic site-dependent immune contexture may underlie discordant responses to ICI therapy in patients with MSS colorectal cancer., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Background: In the phase III TAGS trial, trifluridine/tipiracil showed survival benefit versus placebo in patients with metastatic gastric/gastroesophageal junction cancer and ≥ 2 prior chemotherapies. This post hoc exploratory analysis assessed the impact of prior therapy type on outcomes., Methods: Based on prior treatment, patients in TAGS (N = 507) were categorized into overlapping subgroups: ramucirumab ± other agents (n = 169), no ramucirumab (n = 338), paclitaxel but no ramucirumab (n = 136), ramucirumab + paclitaxel sequentially or in combination (n = 154), neither paclitaxel nor ramucirumab (n = 202), irinotecan (n = 281), and no irinotecan (n = 226). Overall and progression-free survival, time to Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2, and safety were assessed., Results: Baseline characteristics and prior therapy patterns were generally well balanced between trifluridine/tipiracil and placebo arms across subgroups. Trifluridine/tipiracil was associated with survival benefits versus placebo regardless of prior treatment: across subgroups, median overall survival was 4.6-6.1 versus 3.0-3.8 months (hazard ratios, 0.47-0.88), median progression-free survival was 1.9-2.3 versus 1.7-1.8 months (hazard ratios, 0.49-0.67), and median time to ECOG PS ≥ 2 was 4.0-4.7 versus 1.9-2.5 months (hazard ratios, 0.56-0.88). Among trifluridine/tipiracil-randomized patients, median overall and progression-free survival trended longer in those who had not received ramucirumab, paclitaxel and ramucirumab, or irinotecan (6.0-6.1 and 2.1-2.3 months, respectively) than in those who previously received these agents (4.6-5.7 and 1.9 months). The trifluridine/tipiracil safety profile was consistent across subgroups, with similar overall incidences of grade ≥ 3 adverse events. Minor variations in hematologic toxicities were noted., Conclusions: In TAGS, third- or later-line trifluridine/tipiracil treatment demonstrated overall and progression-free survival and functioning benefits versus placebo and a consistent safety profile in patients with metastatic gastric/gastroesophageal junction cancer, regardless of prior treatment type., Clinical Trials Registration: clinicaltrials.gov NCT02500043., (© 2023. The Author(s).)

Objective: To determine the proportion of hospitals that implemented 6 leading practices in their antimicrobial stewardship programs (ASPs). Design: Cross-sectional observational survey., Setting: Acute-care hospitals., Participants: ASP leaders., Methods: Advance letters and electronic questionnaires were initiated February 2020. Primary outcomes were percentage of hospitals that (1) implemented facility-specific treatment guidelines (FSTG); (2) performed interactive prospective audit and feedback (PAF) either face-to-face or by telephone; (3) optimized diagnostic testing; (4) measured antibiotic utilization; (5) measured C. difficile infection (CDI); and (6) measured adherence to FSTGs., Results: Of 948 hospitals invited, 288 (30.4%) completed the questionnaire. Among them, 82 (28.5%) had <99 beds, 162 (56.3%) had 100-399 beds, and 44 (15.2%) had ≥400+ beds. Also, 230 (79.9%) were healthcare system members. Moreover, 161 hospitals (54.8%) reported implementing FSTGs; 214 (72.4%) performed interactive PAF; 105 (34.9%) implemented procedures to optimize diagnostic testing; 235 (79.8%) measured antibiotic utilization; 258 (88.2%) measured CDI; and 110 (37.1%) measured FSTG adherence. Small hospitals performed less interactive PAF (61.0%; P = .0018). Small and nonsystem hospitals were less likely to optimize diagnostic testing: 25.2% (P = .030) and 21.0% (P = .0077), respectively. Small hospitals were less likely to measure antibiotic utilization (67.8%; P = .0010) and CDI (80.3%; P = .0038). Nonsystem hospitals were less likely to implement FSTGs (34.3%; P < .001)., Conclusions: Significant variation exists in the adoption of ASP leading practices. A minority of hospitals have taken action to optimize diagnostic testing and measure adherence to FSTGs. Additional efforts are needed to expand adoption of leading practices across all acute-care hospitals with the greatest need in smaller hospitals.

Purpose: To develop recommendations for treatment of patients with metastatic colorectal cancer (mCRC)., Methods: ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice., Results: Five systematic reviews and 10 randomized controlled trials met the systematic review inclusion criteria., Recommendations: Doublet chemotherapy should be offered, or triplet therapy may be offered to patients with previously untreated, initially unresectable mCRC, on the basis of included studies of chemotherapy in combination with anti-vascular endothelial growth factor antibodies. In the first-line setting, pembrolizumab is recommended for patients with mCRC and microsatellite instability-high or deficient mismatch repair tumors; chemotherapy and anti-epidermal growth factor receptor therapy is recommended for microsatellite stable or proficient mismatch repair left-sided treatment-naive RAS wild-type mCRC; chemotherapy and anti-vascular endothelial growth factor therapy is recommended for microsatellite stable or proficient mismatch repair RAS wild-type right-sided mCRC. Encorafenib plus cetuximab is recommended for patients with previously treated BRAF V600E-mutant mCRC that has progressed after at least one previous line of therapy. Cytoreductive surgery plus systemic chemotherapy may be recommended for selected patients with colorectal peritoneal metastases; however, the addition of hyperthermic intraperitoneal chemotherapy is not recommended. Stereotactic body radiation therapy may be recommended following systemic therapy for patients with oligometastases of the liver who are not considered candidates for resection. Selective internal radiation therapy is not routinely recommended for patients with unilobar or bilobar metastases of the liver. Perioperative chemotherapy or surgery alone should be offered to patients with mCRC who are candidates for potentially curative resection of liver metastases. Multidisciplinary team management and shared decision making are recommended. Qualifying statements with further details related to implementation of guideline recommendations are also included.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Coronavirus disease 2019 (COVID-19) vaccination rates of a large health system reflected their respective service areas but varied by work role. Nurse vaccination rates were higher (56.9%) and rates among nursing support personnel were lower (38.6%) than those of their communities (51.7%; P < .001). Physician vaccination rates were highest (71.6%) and were not associated with community vaccination levels.

Fifty years of evolution in infection prevention and control programs have involved significant accomplishments related to clinical practices, methodologies, and technology. However, regulatory mandates, and resource and research limitations, coupled with emerging infection threats such as the COVID-19 pandemic, present considerable challenges for infection preventionists. This article provides guidance and recommendations in 14 key areas. These interventions should be considered for implementation by United States health care facilities in the near future., (Copyright © 2022 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Urine cultures are nonspecific and often lead to misdiagnosis of urinary tract infection and unnecessary antibiotics. Diagnostic stewardship is a set of procedures that modifies test ordering, processing, and reporting in order to optimize diagnosis and downstream treatment. In this study, we aimed to develop expert guidance on best practices for urine culture diagnostic stewardship., Methods: A RAND-modified Delphi approach with a multidisciplinary expert panel was used to ascertain diagnostic stewardship best practices. Clinical questions to guide recommendations were grouped into three thematic areas (ordering, processing, reporting) in practice settings of emergency department, inpatient, ambulatory, and long-term care. Fifteen experts ranked recommendations on a 9-point Likert scale. Recommendations on which the panel did not reach agreement were discussed during a virtual meeting, then a second round of ranking by email was completed. After secondary review of results and panel discussion, a series of guidance statements was developed., Results: One hundred and sixty-five questions were reviewed. The panel reaching agreement on 104, leading to 18 overarching guidance statements. The following strategies were recommended to optimize ordering urine cultures: requiring documentation of symptoms, sending alerts to discourage ordering in the absence of symptoms, and cancelling repeat cultures. For urine culture processing, conditional urine cultures and urine white blood cell count as criteria were supported. For urine culture reporting, appropriate practices included nudges to discourage treatment under specific conditions and selective reporting of antibiotics to guide therapy decisions., Conclusions: These 18 guidance statements can optimize use of urine cultures for better patient outcomes., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Importance: Infection with SARS-CoV-2, which causes COVID-19, is associated with adverse maternal outcomes. While it is known that severity of COVID-19 varies by viral strain, the extent to which this variation is reflected in adverse maternal outcomes, including nonpulmonary maternal outcomes, is not well characterized., Objective: To evaluate the associations of SARS-CoV-2 infection with severe maternal morbidities (SMM) in pregnant patients delivering during 4 pandemic periods characterized by predominant viral strains., Design, Setting, and Participants: This retrospective cohort study included patients delivering in a multicenter, geographically diverse US health system between March 2020 and January 2022. Individuals with SARS-CoV-2 infection were propensity-matched with as many as 4 individuals without evidence of infection based on demographic and clinical variables during 4 time periods based on the dominant strain of SARS-CoV-2: March to December 2020 (wild type); January to June 2021 (Alpha [B.1.1.7]); July to November 2021 (Delta [B.1.617.2]); and December 2021 to January 2022 (Omicron [B.1.1.529]). Data were analyzed from October 2021 to June 2022., Exposures: Positive SARS-CoV-2 nucleic acid amplification test result during the delivery encounter., Main Outcomes and Measures: The primary outcome was any SMM event, as defined by the US Centers for Disease Control and Prevention, during hospitalization for delivery. Secondary outcomes were number of SMM, respiratory SMM, nonrespiratory SMM, and nontransfusion SMM events., Results: Over all time periods, there were 3129 patients with SARS-CoV-2, with a median (IQR) age of 29.1 (24.6-33.2) years. They were propensity matched with a total of 12 504 patients without SARS-CoV-2, with a median (IQR) age of 29.2 (24.7-33.2) years. Patients with SARS-CoV-2 infection had significantly higher rates of SMM events than those without in all time periods, except during Omicron. While the risk of any SMM associated with SARS-CoV-2 infection was increased for the wild-type strain (odds ratio [OR], 2.74 [95% CI, 1.85-4.03]) and Alpha variant (OR, 2.57 [95% CI, 1.69-4.01]), the risk during the Delta period was higher (OR, 7.69 [95% CI, 5.19-11.54]; P for trend < .001). The findings were similar for respiratory complications, nonrespiratory complications, and nontransfusion outcomes. For example, the risk of nonrespiratory SMM events for patients with vs without SARS-CoV-2 infection were similar for the wild-type strain (OR, 2.16 [95% CI, 1.40-3.27]) and Alpha variant (OR, 1.96 [95% CI, 1.20-3.12]), highest for the Delta variant (OR, 4.65 [95% CI, 2.97-7.29]), and not significantly higher in the Omicron period (OR, 1.21 [95% CI, 0.67-2.08]; P for trend < .001)., Conclusions and Relevance: This cohort study found that the SARS-CoV-2 Delta variant was associated with higher rates of SMM events compared with other strains. Given the potential of new strains, these findings underscore the importance of preventive measures.

Background: Little is known about the influence of hepatic artery infusion pump (HAIP) therapy in the setting of chemotherapy resistant hepatic disease in the era of modern systemic therapies., Methods: Patients who underwent HAIP therapy for chemotherapy resistant and unresectable colorectal liver metastases (CRLM) were reviewed retrospectively., Results: A total of 25 patients met inclusion criteria. 52% had isolated CRLM and 92% had five or more metastatic lesions. Partial response was noted in 40% of patients. Median hepatic progression-free survival (PFS) was 7 months in those with extrahepatic disease versus 6 months in those with isolated CRLM at the time of HAIP placement (p = 0.75). Median overall survival was 8 months in patients with extrahepatic disease and 14 months in patients with isolated CRLM (p = 0.06)., Conclusions: Our findings are comparable to published data and augment the literature which supports HAIP use in chemotherapy-resistant, liver-predominant metastatic colorectal cancer patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Macrophages are essential in eliciting antibody-dependent cellular phagocytosis (ADCP) of cancer cells. However, a satisfactory anticancer efficacy of ADCP is contingent on early antibody administration, and resistance develops along with cancer progression. Here, we investigate the mechanisms underlying ADCP and demonstrate an effective combinatorial strategy to potentiate its efficacy. We identified paclitaxel as a universal adjuvant that efficiently potentiated ADCP by a variety of anticancer antibodies in multiple cancers. Rather than eliciting cytotoxicity on cancer cells, paclitaxel polarized macrophages toward a state with enhanced phagocytic ability. Paclitaxel-treated macrophages down-regulated cell surface CSF1R whose expression was negatively correlated with patient survival in multiple malignancies. The suppression of CSF1R in macrophages enhanced ADCP of cancer cells, suggesting a role of CSF1R in regulating macrophage phagocytic ability. Together, these findings define a potent strategy for using conventional anticancer drugs to stimulate macrophage phagocytosis and promote the therapeutic efficacy of clinical anticancer antibodies.

Background: The COVID-19 pandemic has had a considerable impact leading to increases in health care-associated infections, particularly bloodstream infections (BSI)., Methods: We evaluated the impact of COVID-19 in 69 US hospitals on BSIs before and during the pandemic. Events associated with 5 pathogens (Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Candida sp.) were stratified by community onset (CO) if ≤ 3 days from admission or hospital onset (HO) if > 3 days after admission. We compared pre-pandemic CO and HO rates with pandemic periods and the rates of BSI for those with and without COVID-19., Results: COVID-19 patients were less likely to be admitted with COBSI compared to others (10.85 vs 22.35 per 10,000 patient days; P < .0001). There was a significant increase between pre-pandemic and pandemic HOBSI rates (2.78 vs 3.56 per 10,000 patient days; P < .0001). Also, COVID-19 infected patients were 3.5 times more likely to develop HOBSI compared to those without COVID-19 infection (9.64 vs 2.74 per 10,000 patient-days; P < .0001)., Conclusions: The COVID-19 pandemic period was associated with substantial increases in HOBSI and largely attributed to COVID-19 infected patients. Future research should evaluate whether such measures would be beneficial to incorporate in evaluating infection prevention trends., (Copyright © 2022. Published by Elsevier Inc.)

Importance: Cotargeting vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 may produce anticancer activity in refractory metastatic colorectal cancer (mCRC). The clinical benefit of atezolizumab combined with chemotherapy and bevacizumab remains unclear for the treatment of mCRC., Objectives: To assess whether the addition of atezolizumab to capecitabine and bevacizumab therapy improves progression-free survival (PFS) among patients with refractory mCRC and to perform exploratory analyses among patients with microsatellite-stable (MSS) disease and liver metastasis., Design, Setting, and Participants: This double-blind phase 2 randomized clinical trial enrolled 133 patients between September 25, 2017, and June 28, 2018 (median duration of follow-up for PFS, 20.9 months), with data cutoff on May 4, 2020. The study was conducted at multiple centers through the Academic and Community Cancer Research United network. Adult patients with mCRC who experienced disease progression while receiving fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and anti-epidermal growth factor receptor antibody therapy (if the patient had a RAS wild-type tumor) were included., Interventions: Patients were randomized (2:1) to receive capecitabine (850 or 1000 mg/m2) twice daily on days 1 to 14 and bevacizumab (7.5 mg/kg) on day 1 plus either atezolizumab (1200 mg; investigational group) or placebo (placebo group) on day 1 of each 21-day cycle., Main Outcomes and Measures: The primary end point was PFS; 110 events were required to detect a hazard ratio (HR) of 0.65 with 80% power (1-sided α = .10). Secondary end points were objective response rate, overall survival (OS), and toxic effects., Results: Of 133 randomized patients, 128 individuals (median age, 58.0 years [IQR, 51.0-65.0 years]; 77 men [60.2%]) were assessed for efficacy (82 in the investigational group and 46 in the placebo group). Overall, 15 patients (11.7%) self-identified as African American or Black, 8 (6.3%) as Asian, 1 (0.8%) as Pacific Islander, 101 (78.9%) as White, 1 (0.8%) as multiple races (Asian, Native Hawaiian/Pacific Islander, and White), and 2 (1.6%) as unknown race or unsure of race. Microsatellite-stable disease was present in 110 patients (69 in the investigational group and 41 in the placebo group). Median PFS was 4.4 months (95% CI, 4.1-6.4 months) in the investigational group and 3.6 months (95% CI, 2.2-6.2 months) in the placebo group (1-sided log-rank P = .07, a statistically significant result; HR, 0.75; 95% CI, 0.52-1.09). Among patients with MSS and proficient mismatch repair, the HR for PFS was 0.66 (95% CI, 0.44-0.99). The most common grade 3 or higher treatment-related adverse events in the investigational vs placebo groups were hypertension (6 patients [7.0%] vs 2 patients [4.3%]), diarrhea (6 patients [7.0%] vs 2 patients [4.3%]), and hand-foot syndrome (6 patients [7.0%] vs 2 patients [4.3%]). One treatment-related death occurred in the investigational group. In the investigational group, the response rate was higher among patients without liver metastasis (3 of 13 individuals [23.1%]) vs with liver metastasis (4 of 69 individuals [5.8%]). The benefit of atezolizumab for PFS and OS was greater among patients without vs with liver metastasis (primary analysis of PFS: HR, 0.63 [95% CI, 0.27-1.47] vs 0.77 [95% CI, 0.51-1.17]; OS: HR, 0.33 [95% CI, 0.11-1.02] vs 1.14 [95% CI, 0.72-1.81])., Conclusions and Relevance: In this randomized clinical trial, the addition of atezolizumab to capecitabine and bevacizumab therapy provided limited (ie, not clinically meaningful) clinical benefit. Patients with MSS and proficient mismatch repair tumors and those without liver metastasis benefited more from dual inhibition of the vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 pathways., Trial Registration: ClinicalTrials.gov Identifier: NCT02873195.

Background: Sotorasib, a specific, irreversible KRAS G12C protein inhibitor, has shown monotherapy clinical activity in KRAS G12C -mutated solid tumours, including colorectal cancer, in the CodeBreaK100 phase 1 trial. We aimed to investigate the activity and safety of sotorasib in phase 2 of the trial., Methods: In this single-arm, phase 2 trial, adult patients with KRAS G12C -mutated advanced solid tumours were enrolled, from 59 medical centres in 11 countries, if they were aged 18 years or older, had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Only data for patients with colorectal cancer, enrolled at 33 medical centres in nine countries, are presented from this basket trial. To be enrolled, the patients had to have progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan treatment. These patients were administered 960 mg sotorasib orally once per day until disease progression, development of unacceptable side-effects, withdrawal of consent, or death. The primary endpoint was objective response (complete or partial response) as assessed by blinded independent central review. Response was evaluated in patients who received at least one dose of sotorasib and had at least one measurable lesion at baseline; safety was evaluated in patients who received at least one dose of sotorasib. This analysis is a prespecified analysis triggered by the phase 2 colorectal cancer cohort. This study is registered with ClinicalTrials.gov, NCT03600883, and is active but no longer recruiting., Findings: On March 1, 2021, at data cutoff, 62 patients with KRAS G12C -mutant colorectal cancer had been enrolled between Aug 14, 2019, and May 21, 2020, and had received at least one dose of sotorasib monotherapy. Objective response was observed in six (9·7%, 95% CI 3·6-19·9) of 62 patients, all with partial response. Treatment-related adverse events at grade 3 occurred in six (10%) patients, the most common of which was diarrhoea (two [3%] of 62 patients), and at grade 4 occurred in one (2%) patient (blood creatine phosphokinase increase); no fatal events were recorded. Serious treatment-related adverse events occurred in two (3%) patients (back pain and acute kidney injury)., Interpretation: Although the 9·7% overall response rate did not reach the benchmark, oral administration of sotorasib once per day showed modest anti-tumour activity and manageable safety in these heavily pretreated chemorefractory patients. Sotorasib is under evaluation in combination with other therapeutics to increase potential activity and overcome potential resistance mechanisms., Funding: Amgen., Competing Interests: Declaration of interests MGF reports honoraria from Amgen; consulting or advisory roles for Taiho, Bayer, Array, Pfizer, Seattle Genetics, GlaxoSmithKline, Zhuhai Biotech, Mirati, and Incyte; speakers' bureau for Guardant; and research funding (to the institution) from Verastem, Bristol Myers Squibb, Novartis, Amgen, and AstraZeneca. SK reports stock or ownership interests in Navire and Lutris; consulting or advisory roles to EMD Serono, Merck, Holy Stone Healthcare, Novartis, Lilly, Boehringer Ingelheim, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, Redx Pharma, Ispen, Daiichi Sankyo, Natera, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata, Jazz Pharmaceuticals, Roche, Navire, and Amgen; and research funding (to the institution) from Roche, EMD Serono, MedImmune, Novartis, Amgen, Lilly, and Daiichi Sankyo; and research funding (to self) from Merck, Navire, Holy Stone Healthcare, Boehringer Ingelheim, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, Redx Pharma, Ispen, Natera, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata, and Jazz Pharmaceuticals. YK reports speaker's bureau for Taiho, ONO, Bayer, and Sanofi; research grants (to the institution) from Daiichi-Sankyo; being the principal investigator for Taiho, Takeda, ONO, AbbVie, AstraZeneca, Boehringer Ingelheim, Incyte, Amgen, Chugai, GlaxoSmithKline, Genmab, and Astelas; and advisory roles for Takeda, Boehringer Ingelheim, and Taiho. TWK reports research funding (to the institution) from Roche, Sanofi, Aventis, AstraZeneca. JCK reports support to the University of Michigan from Roche, Boston Biomedical, Bristol-Myers Squibb, NSABP Foundation, AstraZeneca, Isofol Medical, Merck Sharp and Dohme, AbbVie, Hutchison Medipharma, Novartis, and Tempest. GSF reports royalties from Wolters Kluwer; advisory roles (payment to the institution) for Fujifilm, Silicon, Navire, and Turning Point; advisory roles (payment to GSF) for EMD Serono; travel expenses (for research related to the institution) for Bristol-Myers Squibb, EMD Serono, Fujifilm, Millennium, and Sarah Cannon Research Institute; speaker's honorarium, Total Health Conferencing, and Rocky Mountain Oncology Society (2020); research funding (to the institution) for 3-V Biosciences, Abbisko, AbbVie, ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, AstraZeneca, BeiGene, Bioatla, Bioinvent, Biothera, Bicycle, Celldex, Celgene, Ciclomed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, IGM Biosciences, Ignyta, ImmunoGen/MacroGenics, Incyte, Jacobio, Jounce, Kolltan, Loxo/Bayer, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, Navire, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, PureTech, RasCal, Regeneron, Rgenix, Ribon, Sapience, Silicon, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point Therapeutics, University of Texas MD Anderson Cancer Center, Vegenics, and Xencor. VH reports honoraria from Amgen, Baxalta, Boehringer Ingelheim, Celgene, Lilly, Merck, Roche, Sanofi, SERVIER, Sirtex Medical, and Taiho Pharmaceutical; consulting or advisory roles for Amgen, Baxalta, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Halozyme, Merck, Merck Sharpe and Dohme (MSD), Roche, Sanofi, SERVIER, and Sirtex Medical; research funding from Amgen (to the institution), Boehringer Ingelheim (to the institution), Celgene (to the institution), Merck (to the institution), Roche (to the institution), Shire (to the institution), and Sirtex Medical (to the institution); and travel and accommodation expenses from Amgen, Bristol Myers Squibb, Merck, MSD, Roche, SERVIER, Shire, and Sirtex Medical. KM reports grants from Solasia Pharma, Merck Serono, Daiichi Sankyo, Parexel International, Pfizer, and MSD; grants and consulting fees from Amgen; grants, consulting fees, and honorarium from ONO Pharmaceutical; grants and honorarium from Sanofi and Taiho; consulting fees from AstraZeneca; and honorarium from Chugai, Takeda, Eli Lilly, Bristol Myers Squibb, and Bayer, outside the submitted work. JHS reports consulting and advisory board membership for AbbVie, Amgen, AstraZeneca, Bayer, Genentech/Roche, Inivata, Mereo, SeaGen, Natera, Pfizer, and Viatris; and research funding from SeaGen, Sanofi, AstraZeneca, AStar D3, Daiichi-Sankyo, Genentech/Roche, Gossamer Bio, AbbVie, Exelixis, Amgen, and Nektar. DSH reports grants from Bayer, Lilly, Genentech, LOXO, Pfizer, Amgen, Mirati, Ignyta, Merck, Daichii-Sanko, Eisai, Adaptimmune, AbbVie, AstraZeneca, Bristol Myers Squibb, Genmab, Infinity, Kite, Kyowa, Medimmune, Molecular Template, Novartis, and Takeda; personal fees from Mirna and LOXO; and honoraria or stock options from Bayer, Baxter, Guidepoint Global, Oncoresponse, Janssen, and Molecular Match, outside the submitted work. CSD reports grants (to the institution for research) from Amgen, AstraZeneca, Agios, Bristol Myers Squibb, BeiGene, Exelixis, Genmab, Macrogenics, Zymeworks, Sanofi Aventis, MedImmune, Array BioPharma, and Lycera; and honoraria (personal for scientific advising or data safety monitoring board) from Bristol Myers Squibb, Merck, Bayer, BeiGene, Astellas, Exelixis, Eli Lilly, Taiho Oncology, and Zymeworks. GG reports research funding from Amgen, BMS, MSD, Merck, and Roche. HH, QT, JKP, and GN report Amgen employment and stock. TJP reports Servier speaker honorarium and being on the MSD advisory board. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The associated mortality with COVID-19 has improved compared with the early pandemic period. The effect of hospital COVID-19 patient prevalence on COVID-19 mortality has not been well studied., Methods: We analysed data for adults with confirmed SARS-CoV-2 infection admitted to 62 hospitals within a multistate health system over 12 months. Mortality was evaluated based on patient demographic and clinical risk factors, COVID-19 hospital prevalence and calendar time period of the admission, using a generalised linear mixed model with site of care as the random effect., Results: 38 104 patients with COVID-19 were hospitalised, and during their encounters, the prevalence of COVID-19 averaged 16% of the total hospitalised population. Between March-April 2020 and January-February 2021, COVID-19 mortality declined from 19% to 12% (p<0.001). In the adjusted multivariable analysis, mid and high COVID-19 inpatient prevalence were associated with a 25% and 41% increase in the odds (absolute contribution to probability of death of 2%-3%) of COVID-19 mortality compared with patients with COVID-19 in facilities with low prevalence (<10%), respectively (high prevalence >25%: adjusted OR (AOR) 1.41, 95% CI 1.23 to 1.61; mid-prevalence (10%-25%): AOR 1.25, 95% CI 1.13 to 1.38). Mid and high COVID-19 prevalence accounted for 76% of patient encounters., Conclusions: Although inpatient mortality for patients with COVID-19 has sharply declined compared with earlier in the pandemic, higher COVID-19 hospital prevalence remained a common risk factor for COVID-19 mortality. Hospital leaders need to reconsider how we provide support to care for patients in times of increased volume and complexity, such as those experienced during COVID-19 surges., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has had a considerable impact on US hospitalizations, affecting processes and patient population., Objective: To evaluate the impact of COVID-19 pandemic on central-line-associated bloodstream infections (CLABSIs) and catheter associated urinary tract infections (CAUTIs) in hospitals., Methods: We performed a retrospective study of CLABSIs and CAUTIs in 78 US 12 months before COVID-19 and 6 months during COVID-19 pandemic., Results: During the 2 study periods, there were 795,022 central-line days and 817,267 urinary catheter days. Compared to the period before the COVID-19 pandemic, CLABSI rates increased by 51.0% during the pandemic period from 0.56 to 0.85 per 1,000 line days (P < .001) and by 62.9% from 1.00 to 1.64 per 10,000 patient days (P < .001). Hospitals with monthly COVID-19 patients representing >10% of admissions had a National Health Safety Network (NHSN) device standardized infection ratio for CLABSI that was 2.38 times higher than hospitals with <5% prevalence during the pandemic period (P = .004). Coagulase-negative Staphylococcus CLABSIs increased by 130% from 0.07 to 0.17 events per 1,000 line days (P < .001), and Candida spp by 56.9% from 0.14 to 0.21 per 1,000 line days (P = .01). In contrast, no significant changes were identified for CAUTI (0.86 vs 0.77 per 1,000 catheter days; P = .19)., Conclusions: The COVID-19 pandemic was associated with substantial increases in CLABSIs but not CAUTIs. Our findings underscore the importance of hardwiring processes for optimal line care and regular feedback on performance to maintain a safe environment.

Purpose: Trifluridine/tipiracil (FTD/TPI) is approved for advanced colorectal and gastric/gastroesophageal cancer; however, data in patients with renal impairment (RI) are limited. This phase I study evaluated FTD/TPI in patients with advanced solid tumors and varying degrees of RI to develop dosing guidance., Methods: Patients were enrolled into normal renal function (CrCl ≥ 90 mL/min), mild RI (CrCl 60-89 mL/min), or moderate RI (CrCl 30-59 mL/min) cohorts and administered the recommended FTD/TPI dose (35 mg/m 2 twice daily, days 1-5 and 8-12; 28-day cycle). Based on interim pharmacokinetics/safety data, patients with severe RI (CrCl 15-29 mL/min) were enrolled and received FTD/TPI 20 mg/m 2 twice daily., Results: Forty-three patients (normal renal function [n = 12]; mild RI [n = 12]; moderate RI [n = 11]; severe RI [n = 8]) were enrolled and treated. At steady state, compared to values in patients with normal renal function, FTD area under the curve (AUC) was not significantly different in patients with RI, but TPI AUC was significantly higher and increased with RI severity. FTD/TPI safety profile was consistent with prior experience, but grade ≥ 3 adverse events (AEs) were more frequent in the RI cohorts (83.3% [mild], 90.9% [moderate], 75.0% [severe], and normal [50.0%]). Hematologic AEs (anemia and neutropenia) were more frequent with RI. Overall, seven patients discontinued because of unrelated, nonhematologic AEs., Conclusion: FTD/TPI is safe and tolerable at the recommended 35 mg/m 2 dose in patients with mild/moderate RI and at the reduced 20 mg/m 2 dose in patients with severe RI., Trial Registration: NCT02301117, registration date: November 21, 2014., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The extensive use of the urinalysis for screening and monitoring in diverse clinical settings usually identifies abnormal urinalysis parameters in patients with no suspicion of urinary tract infection, which in turn triggers urine cultures, inappropriate antimicrobial use, and associated harms like Clostridioides difficile infection. We highlight how urinalysis is misused, and suggest deconstructing it to better align with evolving patterns of clinical use and the differential diagnosis being targeted. Reclassifying the urinalysis components into infectious and non-infectious panels and interpreting urinalysis results in the context of individual patient's pretest probability of disease is a novel approach to promote proper urine testing and antimicrobial stewardship, and achieve better outcomes.

Elevated expression of EZH2, the enzymatic subunit of polycomb repressive complex 2 (PRC2), often occurs in cancer. EZH2 expression results in the silencing of genes that suppress tumor formation and metastasis through trimethylation of histone H3 at lysine 27 (H3K27me3) at their promoters. However, inhibitors of EZH2 enzymatic activity have not shown the expected efficacy against cancer in clinical trials, suggesting a need for other strategies to address EZH2 overexpression. Here, we show that SUMOylation, a posttranslational modification characterized by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins, enhances EZH2 transcription. Either knockdown of the SUMO-activating enzyme SAE2 or pharmacologic inhibition of SUMOylation resulted in decreased levels of EZH2 mRNA and protein as well as reduced H3K27me3 levels. SUMOylation regulated EZH2 expression by enhancing binding of the E2F1 transcriptional activator to the EZH2 promoter. Inhibition of SUMOylation not only resulted in reduced EZH2 mRNA and protein levels but also increased expression of genes silenced by EZH2, such as E-cadherin, which suppresses epithelial-mesenchymal transition and metastasis. In more than 6,500 patient tumor samples across different cancer types, expression of UBA2 and EZH2 was positively correlated. Taken together, our findings suggest that inhibition of SUMOylation may serve as a potential strategy to address EZH2 overexpression and improve current cancer therapeutic approaches. SIGNIFICANCE: These findings provide important biological insights into the mechanism of EZH2 overexpression in cancers and suggest that inhibiting SUMOylation may improve current cancer therapeutic approaches., (©2020 American Association for Cancer Research.)

Background: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRAS G12C ., Methods: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1., Results: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma., Conclusions: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.)., (Copyright © 2020 Massachusetts Medical Society.)

Objective: The COVID-19 pandemic requires to conscientiously weigh "timely surgical intervention" for colorectal cancer against efforts to conserve hospital resources and protect patients and health care providers., Summary Background Data: Professional societies provided ad-hoc guidance at the outset of the COVID-19 pandemic on deferral of surgical and perioperative interventions, but these lack specific parameters to determine the optimal timing of surgery., Methods: Using the GRADE system, published evidence was analyzed to generate weighted statements for stage, site, acuity of presentation, and hospital setting to specify when surgery should be pursued, the time and duration of oncologically acceptable delays, and when to utilize nonsurgical modalities to bridge the waiting period., Results: Colorectal cancer surgeries-prioritized as emergency, urgent with imminent emergency or oncologically urgent, or elective-were matched against the phases of the pandemic. Surgery in COVID-19-positive patients must be avoided. Emergent and imminent emergent cases should mostly proceed unless resources are exhausted. Standard practices allow for postponement of elective cases and deferral to nonsurgical modalities of stage II/III rectal and metastatic colorectal cancer. Oncologically urgent cases may be delayed for 6(-12) weeks without jeopardizing oncological outcomes. Outside established principles, administration of nonsurgical modalities is not justified and increases the vulnerability of patients., Conclusions: The COVID-19 pandemic has stressed already limited health care resources and forced rationing, triage, and prioritization of care in general, specifically of surgical interventions. Established guidelines allow for modifications of optimal timing and type of surgery for colorectal cancer during an unrelated pandemic.

KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours 1,2 . The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity 3-5 . Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRAS G12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRAS G12D tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.

Laboratory-identified bloodstream infections (LAB-ID BSIs) in recently discharged patients are likely to be classified as healthcare-associated community-onset (HCA-CO) infections, even though they may represent hospital-onset (HO) infections. A review of LAB-ID BSIs among patients discharged within 14 days revealed that 109 of 756 cases (14.4%) were HO infections. The BSI risk being misclassified as HCA CO may underestimate the hospital infection risk.

Background: The device standardized infection ratio (SIR) is used to compare unit and hospital performance for different publicly reported infections. Interventions to reduce unnecessary device use may select a higher-risk population, leading to a paradoxical increase in SIR for some high-performing facilities. The standardized utilization ratio (SUR) adjusts for device use for different units and facilities., Methods: We calculated the device SIR (calculated based on actual device days) and population SIR (defined as Σ observed events divided by Σ predicted events based on predicted device days), adjusting for the facility SUR for both central-line-associated bloodstream infections (CLABSIs) and catheter-associated urinary tract infections (CAUTIs) in 84 hospitals from a single system for calendar years 2016 and 2017., Results: The central-line SUR was 1.02 for 801,172 central-line days, with a device SIR of 0.76 and a population SIR of 0.78, a 1.6% relative increase. On the other hand, the urinary catheter SUR was 0.90 for 757,504 urinary catheter days, with a device SIR of 0.84 and a population SIR of 0.76, a 10.0% relative decrease. The cumulative attributable difference for CAUTI to a target SIR of 1 was -135.4 for the device SIR compared to -203.66 for the population SIR, a 50.8% increase in prevented events., Conclusion: Population SIR accounts for predicted device utilization; thus, it is an attractive metric with which to address overall risk of infection or harm to a patient population. It also reduces the risk of selection bias that may impact the device SIR with interventions to reduce device use.

Immune checkpoint inhibitors represent a newly established standard of care in patients with refractory metastatic colorectal cancer with mismatch repair deficiency and microsatellite instability. However, the use of immunotherapy is unclear in recipients of liver transplants with or without concurrent liver function abnormalities. Clinical trials investigating immunotherapy have mostly excluded liver transplant recipients and patients with abnormal liver function. This report presents the first case, to our knowledge, of a liver transplant patient with mismatch repair-deficient colon adenocarcinoma with liver metastases and concurrent abnormal liver function who safely responded to immunotherapy. We also review the literature on checkpoint inhibitor use in patients with other metastatic solid tumors after liver transplant and those with baseline liver function abnormalities. An increasing body of evidence supports the safety of checkpoint inhibition in patients with cancer and solid organ transplants, but further prospective studies are warranted. Use of immunotherapy in liver transplant recipients who have metastatic colorectal cancer with microsatellite instability is feasible but should be performed in a multidisciplinary team setting.

Catheter-associated urinary tract infection (CAUTI) has long been considered a preventable healthcare-associated infection. Many federal agencies, the Centers for Medicare and Medicaid Services (CMS), and public and private healthcare organizations have implemented strategies aimed at preventing CAUTIs. To monitor progress in CAUTI prevention, the National Healthcare Safety Network (NHSN) CAUTI metric has been adopted nationally as the primary outcome measure and has been refined over the past decades. However, this surveillance metric may underestimate infectious and noninfectious catheter harm. We suggest evolving to more inclusive performance metrics to better reflect quality improvement efforts underway in hospitals. The standardized device utilization ratio (SUR) provides a good surrogate for preventable catheter harm. On the other hand, a population-based metric that combines both standardized infection ratio (SIR) and SUR would address both infectious and noninfectious harm, while adjusting for population risk. Finally, electronically captured catheter-associated bacteriuria may contribute essential information on local testing stewardship.

We compared interventions to improve urinary catheter care and urine culturing in adult intensive care units of 2 teaching hospitals. Compared to hospital A, hospital B had lower catheter utilization, more compliance with appropriate indications and maintenance, but higher urine culture use and more positive urine cultures per 1,000 patient days.

To systematically improve the appropriateness of antibiotic prescribing, antimicrobial stewardship programs have been developed. There is a paucity of literature examining how pharmacists perform antimicrobial stewardship using a clinical decision support system in a hospital setting. The purpose of this qualitative study was to develop a model exploring how pharmacists perform antimicrobial stewardship to identify areas for programmatic improvement. Semistructured interviews were conducted across a health care system until saturation of themes was reached. Pharmacists identified that self-efficacy and time were vital for antimicrobial stewardship to be performed, while culture of the hospital and attitude facilitated the process of stewardship. Antimicrobial stewardship programs using clinical decision support tools should ensure pharmacists have adequate time to address rules, provide easy-to-use resources and training to support self-efficacy, and engage influential physicians to support a culture of collaboration.