Citations

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have become the first-line treatment of unresectable hepatocellular carcinoma (HCC). The prognostic value of immune-related adverse events (irAEs) in these patients remains controversial. We aimed to investigate the association between irAEs and clinical outcomes in patients with HCC treated with ICIs. METHODS: We searched the PubMed, Scopus, Web of Science, and Central Register of Controlled Trials databases for articles published from inception to June 2024, using keywords including ICI, HCC, and irAEs. Statistical analysis was performed with a random effects model. RESULTS: Of 3,028 studies, 24 (4,127 patients) met the criteria for inclusion. Atezolizumab plus bevacizumab was the most common treatment regimen (n = 10 studies). IrAEs were associated with an increased objective response rate (pooled relative ratio: 1.73; 95% confidence interval [CI]: 1.36–2.21, I 2 = 41%), a higher disease control rate (pooled relative ratio: 1.45; 95% CI: 1.21–1.74, I 2 = 74%), and longer progression-free survival (pooled hazard ratio [HR]: 0.66; 95% CI: 0.52–0.84, I 2 = 71%). There was a trend toward longer overall survival for patients with irAEs compared with those without (pooled HR: 0.84; 95% CI: 0.63–1.12, I 2 = 73%). Subgroup analysis indicated a survival benefit for patients with grade 1–2 irAEs (pooled HR: 0.50; 95% CI: 0.36–0.67, I 2 = 0%) and for those with endocrine irAEs (pooled HR: 0.63; 95% CI: 0.48–0.83, I 2 = 12%). DISCUSSION: The development of irAEs is associated with favorable clinical outcomes in HCC, including improved progression-free survival and higher objective response rate. Overall survival benefit was noted in patients with mild irAEs but not those with severe irAEs.

Background: Procalcitonin (PCT) is recognized as an inflammatory biomarker, often elevated in COVID-19 pneumonia alongside other biomarkers. Understanding its association with severe outcomes and comparing its predictive ability with other biomarkers is crucial for clinical management. Objectives: This retrospective multicenter observational study aimed to investigate the association between PCT levels and adverse outcomes in hospitalized COVID-19 patients. Additionally, it sought to compare the predictive performance of various biomarkers. Design: The study analyzed data from the Society of Critical Care Medicine (SCCM) Viral Infection and Respiratory Illness Universal Study (VIRUS) registry, comprising COVID-19 patients hospitalized across multiple Mayo Clinic sites between March 2020 and June 2022. Methods: A total of 7851 adult COVID-19 patients were included. Patients were categorized into 6 groups based on the worst WHO ordinal scale. Multivariate models were constructed using peak biomarker levels within 72 hours of admission, adjusted for confounders. Results: Elevated PCT levels were independently associated with increased odds of adverse outcomes, including ICU admission (adjusted odds ratio [aOR] 1.32, 95%CI 1.27-1.38), IMV requirement (aOR 1.35, 95%CI: 1.28-1.42), and in-hospital mortality (aOR 1.30, 95%CI: 1.22-1.37). A 3.48-fold increase in IMV requirement and 3.55 times increase in in-hospital mortality were noted with peak PCT ⩾ 0.25 ng/ml. Similar associations were observed with other biomarkers like NLR (AUC 0.730), CRP, IL-6, LDH (AUC 0.800), and D-dimer (AUC 0.719). Models incorporating NLR, LDH, D-dimer, and PCT demonstrated the highest predictive accuracy, with a combined model exhibiting an area under the curve (AUC) of 0.826 (95%CI 0.803-0.849). Conclusions: Higher PCT levels were significantly linked to worse outcomes in COVID-19 patients, emphasizing its potential as a prognostic marker. Biomarker-based predictive models, particularly those including PCT, showed promising utility for risk assessment and clinical decision-making. Further prospective studies are warranted to validate these findings on a larger scale.

Histamine appears to be intimately involved with skeletal muscle responses during and following exercise. Blocking histamine’s actions during endurance exercise training by taking common over-the-counter antihistamines resulted in diminished gains in fitness. These results indicate that exercise-induced histamine release is important in generating many of the positive adaptations to exercise training.

Abstract Background Preexisting diabetes (PDM) increases the risk of maternal and perinatal mortality and morbidity. Reduction of maternal hyperglycemia prior to and during pregnancy can reduce these risks. Despite compelling evidence that preconception care (PCC), which includes achieving strict glycemic goals, reduces the risk of congenital malformations and other adverse pregnancy outcomes, only a minority of individuals receive PCC. Suboptimal pregnancy outcomes demonstrated in real-world data highlight the need to further optimize prenatal glycemia. New evolving technology shows promise in helping to achieve that goal. Dysglycemia is not the only driver of poor pregnancy outcomes in PDM. The increasing impact of obesity on pregnancy outcomes underscores the importance of optimal nutrition and management of insulin sensitizing medications during prenatal care for PDM. Objective To provide recommendations for the care of individuals with PDM that lead to a reduction in maternal and neonatal adverse outcomes. Methods The Guideline Development Panel (GDP) composed of a multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 10 clinically relevant questions related to the care of individuals with diabetes before, during and after pregnancy. The GDP prioritized randomized controlled trials (RCTs) evaluating the effects of different interventions (eg, PCC, nutrition, treatment options, delivery) during the reproductive life cycle of individuals with diabetes, including type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Systematic reviews queried electronic databases for publications related to these 10 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and develop recommendations. The approach incorporated perspectives from 2 patient representatives and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. Results In individuals with diabetes mellitus who have the possibility of becoming pregnant, we suggest asking a screening question about pregnancy intention at every reproductive, diabetes, and primary care visit. Screening for pregnancy intent is also suggested at urgent care/emergency room visits when clinically appropriate (2 | ⊕OOO). This was suggested based on indirect evidence demonstrating a strong association between PCC and both reduced glycated hemoglobin (HbA1c) at the first prenatal visit and congenital malformations. In individuals with diabetes mellitus who have the possibility of becoming pregnant, we suggest use of contraception when pregnancy is not desired (2 | ⊕⊕OO). This was suggested based on indirect evidence in women with diabetes, where PCC—including contraception as a key component—showed a clinically significant association with improvements in first-trimester HbA1c and the rate of congenital malformations, together with indirect evidence from the general population regarding the reduction of unplanned pregnancies and pregnancy terminations with the use of contraception. In individuals with T2DM, we suggest discontinuation of glucagon-like peptide-1 receptor agonist (GLP-1RA) before conception rather than discontinuation between the start of pregnancy and the end of the first trimester (2 | ⊕OOO). This was suggested based on limited data on risk of exposure to GLP-1RA receptor agonists during pregnancy. In pregnant individuals with T2DM already on insulin, we suggest against routine addition of metformin (2 | ⊕OOO). This was suggested based on the GDP judgment that the benefit of adding metformin to insulin to achieve decrease in rates of large for gestational age infants did not outweigh the potential harm of increasing the risk of small for gestational age infants or adverse childhood outcomes related to changes in body composition. In individuals with PDM, we suggest either a carbohydrate-restricted diet (<175 g/day) or usual diet (>175 g/day) during pregnancy (2 | ⊕OOO). This was suggested based on the GDP judgment that the available evidence was limited and very indirect, resulting in significant uncertainty about the net benefits or harms. As such, the evidence was insufficient to support a recommendation either for or against a carbohydrate intake cutoff of 175 g/day. In pregnant individuals with T2DM, we suggest either the use of a continuous glucose monitor (CGM) or self-monitoring of blood glucose (SMBG) (2 | ⊕OOO). There is lack of direct evidence supporting superiority of CGM use over SMBG for T2DM during pregnancy. There is indirect evidence supporting improved glucometrics with the use of CGM for individuals with T2DM outside of pregnancy, substantial improvements in neonatal outcomes for individuals with T1DM using CGM during pregnancy and the potential for decreasing adverse pregnancy outcomes with improved glucometrics in individuals with T2DM. In individuals with PDM using a CGM, we suggest against the use of a single 24-hour CGM target <140 mg/dL (7.8 mmol/L) in place of standard-of-care pregnancy glucose targets of fasting <95 mg/dL (5.3 mmol/L), 1-hour postprandial <140 mg/dL (7.8 mmol/L), and 2-hour postprandial < 120 mg/dL (6.7 mmol/L) (2 | ⊕OOO). This was suggested based on indirect evidence that associated adverse pregnancy outcomes with a fasting glucose > 126 mg/dL (7 mmol/L). In individuals with T1DM who are pregnant, we suggest the use of a hybrid closed-loop pump (pump adjusting automatically based on CGM) rather than an insulin pump with CGM (without an algorithm) or multiple daily insulin injections with CGM (2 | ⊕OOO). This was suggested based on a meta-analysis of RCTs which demonstrated improvement in glucometrics with increased time in range (MD +3.81%; CI −4.24 to 11.86) and reduced time below range (MD −0.88%; 95% CI: −2.04 to 0.27) with the use of hybrid closed-loop pump technology. In individuals with PDM, we suggest early delivery based on risk assessment rather than expectant management (2 | ⊕OOO). This was suggested based on indirect evidence that risks may outweigh benefits of expectant management beyond 38 weeks gestation and that risk assessment criteria may be useful to inform ideal delivery timing. In individuals with PDM (including those with pregnancy loss or termination), we suggest postpartum endocrine care (diabetes management), in addition to usual obstetric care (2 | ⊕OOO). As the postpartum period frequently overlaps with preconception, this was suggested based on indirect evidence demonstrating a strong association between PCC and both reduced HbA1c at the first prenatal visit and congenital malformations. Conclusion The data supporting these recommendations were of very low to low certainty, highlighting the urgent need for research designed to provide high certainty evidence to support the care of individuals with diabetes before, during, and after pregnancy. Investment in implementation science for PCC is crucial to prevent significant mortality and morbidity for individuals with PDM and their children. RCTs to further define glycemic targets in pregnancy and refinement of emerging technology to achieve those targets can lead to significant reduction of harm and in the burden of diabetes care. Data on optimal nutrition and obesity management in pregnancy are lacking. More research on timing of delivery in women with PDM is also needed.

Radiomic parenchymal phenotypes on mammograms were used to predict breast cancer risk among both Black and White women, notably for false-negative findings and symptomatic interval cancer.

Abstract Rationale Amikacin liposome inhalation suspension (ALIS), as part of a combination antibacterial regimen, is currently the only FDA-approved treatment for patients with refractory Mycobacterium avium complex lung disease (rMACLD). MAC is the most common cause of nontuberculous mycobacterial lung disease (NTMLD). A real-world evidence study demonstrated significant decreases in hospitalizations from baseline over a 12-month follow-up period following ALIS initiation; however, study conclusions were limited by the absence of a comparator arm. In this study, we compared healthcare resource utilization in US patients who initiated ALIS versus non-ALIS antibiotic treatment for possible rMACLD. Methods This was a retrospective claims analysis using the Merative™ MarketScan® databases between 2016 and 2021. As no diagnosis codes for MACLD exist in claims, we defined 2 cohorts of patients receiving treatment for possible rMACLD as follows: 1) patients who initiated ≥28 days of continuous treatment with ALIS; and 2) patients who initiated ≥28 days of continuous treatment with ≥1 non-ALIS antibiotic used to treat rMACLD (i.e., parenteral aminoglycoside, clofazimine, fluoroquinolones, linezolid, tedizolid, or bedaquiline) ≥6 months after initiating treatment used for MACLD (i.e., with a combination of ≥2 antibiotics from a macrolide, ethambutol, and a rifamycin). The date of initiating treatment with ALIS or non-ALIS antibiotic for rMACLD was referred to as the index date. Other inclusion criteria: ≥1 diagnosis code for NTMLD anytime pre-index, ≥6 months continuous eligibility pre-index, and ≥12 months continuous eligibility post-index. Hospitalizations (all-cause, respiratory-related, NTMLD-related) and emergency room (ER) visits at 0-6 and 7-12 month post-index periods were compared with baseline (6 month pre-index period) per treatment arm. Results A total of 116 patients comprised the ALIS cohort and 63 patients the non-ALIS cohort. In the ALIS cohort, statistically significant reductions from baseline in all-cause, respiratory-related, and NTMLD-related hospitalizations were observed during the 7-12 month post-index period (Table). In contrast, the non-ALIS cohort did not show significant reductions from baseline in hospitalizations at follow-up. No statistically significant changes from baseline in ER visits were observed in either group. Conclusions Patients treated with ALIS for rMACLD had statistically significant reductions in hospitalizations from baseline during the 7-12 month post-index period, whereas no statistically significant improvements in hospitalizations were observed in the non-ALIS antibiotics group.

Abstract Rationale: Critical illness survivors often experience anxiety, depression, and post-traumatic stress disorder (PTSD) due to traumatic experiences, sedation, and delirium. Early interventions of psychological support may help mitigate mental health deficits post-ICU. Memory of the ICU stay may play a key role in addressing trauma and facilitating therapeutic engagement. Therefore, we sought to determine the relationship between ICU memory recollection, in-ICU delirium, and mental health outcomes at 1-month follow-up in a critical illness recovery center. Methods: We analyzed data collected at 1-month follow-up in a critical illness recovery center seeing adults who had ICU stays of >4 days with sepsis, respiratory failure, and/or delirium. Patients were asked, “Do you remember your experience in the ICU, and if so, can you describe your most impactful memories?” and we qualitatively coded responses for A) presence/absence of memories and B) type of memories described. We analyzed unadjusted associations between demographic, clinical, and mental health measures (anxiety, depression, and PTSD) and memory recollection using chi-square and Wilcoxon rank-sum tests. Results: Among 196 patients seen at 1-month follow-up, 96 (49%) reported memories of their ICU stay. Of these, 44 (46%) described support they received in the ICU (e.g., feeling “safe and watched” by ICU staff, spouse at bedside), 36 (38%) recalled delusions and/or hallucinations (e.g., being kidnapped), 35 (37%) remembered specific treatments (e.g., cardioversion), and 33 (34%) described symptoms (e.g., pain, constipation). Baseline characteristics and critical illness features are shown in the Table. Patients who reported no memories of their ICU stay were more frequently admitted with neurological diagnoses, whereas those who reported memories were more often admitted with trauma or burns (p<0.001). Those without memories had more delirium days than those reporting memories (p=0.02). Although PTSD and anxiety symptoms at 1-month follow-up were not associated with memories, patients who remembered their ICU stay had fewer depression symptoms (p=0.04). Conclusions: One month after their critical illness, half of survivors recalled their ICU experience, with memories ranging from supportive interactions to distressing experiences. In unadjusted analyses, memory recollection was associated with fewer depressive symptoms during follow-up, but a larger study is needed to determine whether this association persists after adjusting for potential confounders. Memories of the ICU may provide a therapeutic foundation for interventions targeting depression after critical illness, such as exposure therapy or ICU diaries, which may improve mental health outcomes in critical illness survivors.

Abstract Introduction / Rationale Mucus plugs (MPs) on chest computed tomography (CT) are associated with increased respiratory symptoms, worse lung function, and elevated mortality and acute exacerbations among individuals with GOLD2-4 COPD. Whether mucus plug distribution in the upper versus lower lobes differentially impacts future acute exacerbations (AEs) has been incompletely explored. Methods Data from current and former tobacco users, ages 40-80, with ≥10 pack-years, at the enrollment visit in COPDGene were analyzed. MPs were visually-assessed on chest CTs using a sequential reading system; the MP score was calculated as the number of bronchopulmonary segments with plugs (range 0-18). Among subjects with MPs, the percent of lower lobe MPs (%LLMPs) was calculated as the number of bronchopulmonary segments in the right and left lower lobes divided by the total number of bronchopulmonary segments (range 0-100%). Moderate-to-severe AEs were assessed prospectively biannually for up to 15.5 years. Zero-inflated Poisson regression, adjusting for age, sex, BMI, race, smoking status, pack-years, FEV1% predicted, history of AEs (year prior to enrollment), and clinical center assessed the relationship between %LLMPs, total MPs, and prospective AEs; duration of follow-up was included as the offset. Subgroup analyses by lung function category (GOLD0, GOLD 1-4 COPD, and Preserved Ratio Impaired Spirometry, PRISm) were also performed using the same model. Results Among 10,198 tobacco-exposed individuals, 9,406 subjects (mean age 59.7±9.0, 53.4% male, 68% non-Hispanic white) had chest CT scans scored for MPs. The overall prevalence of MP>0 was 30.4%, with an average MP score of 0.78±1.88 and average %LLMP of 48%±39%. The prevalence of MPs varied by lung function category (20.1% GOLD0, 26.2% PRISm, 40.8% COPD) as did the mean MP score (0.28±0.93 GOLD0, 0.49±1.38 PRISm, 1.30±2.42 COPD) (Figure 1). The %LLMP also varied by lung function category (33%±39% GOLD0, 38%±37% PRISm, 57%±37% COPD). Among subjects with MPs>0 (n=2,857), higher %LLMP was associated with a significantly increased risk for future AEs (adjusted rate ratio (aRR) [95%CI]= 1.11[1.05-1.17]; Figure 1). Subgroup analyses by lung function category supported a significant association between increased %LLMP and future AEs in GOLD0 (aRR 1.45 [1.25-1.69]), but not in the COPD or PRISm subgroups (Figure 1). Conclusions A higher proportion of lower lobe mucus plugs is significantly associated with increased risk for future AEs among tobacco-exposed persons. Despite having the lowest burden of MPs, the highest risk for prospective AEs with increasing %LLMP was observed in the subgroup with normal spirometry (GOLD0).

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more. PURPOSE To develop a clinical practice guideline and recommendations for symptom management of patients with well-differentiated grade 1 to grade 3 metastatic gastroenteropancreatic neuroendocrine tumors. METHODS ASCO convened an Expert Panel to develop a clinical practice guideline by reviewing the literature for relevant guidelines, systematic reviews, randomized controlled trials (RCTs), and observational studies to develop recommendations for clinical practice. RESULTS The literature review identified eight guidelines, 19 systematic reviews, and three RCTs that informed the development of guideline recommendations. RECOMMENDATIONS Recommendations are included for carcinoid syndrome, carcinoid heart disease and carcinoid crisis, and functional pancreatic neuroendocrine tumor syndromes. Recommendations are provided for surgical management, liver-directed therapy, and systemic therapy options, as well as palliative care. Limited guidance is provided for sequencing of interventions. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

ABSTRACT Lung cancer is the leading cause of cancer-related deaths worldwide and, despite treatment advances, immune suppression remains an obstacle to effective therapy. Effector CD4 + T cells (CD4 + Teffs) are critical for antitumor immunity, but their function is often inhibited by regulatory T cells (Tregs), which accumulate in lung tumors and perform suppressive functions through multiple mechanisms. This suppression leads to tumor progression and poor patient outcomes. However, the mechanisms underlying Treg-mediated suppression are not fully understood. Here, we identify the extracellular ATP receptor P2RX7 as a key regulator of Treg function in lung tumors. Using a murine lung cancer model induced by Lewis lung carcinoma cells, we demonstrate that P2RX7 enhances the suppressive capacity of tumor-infiltrating Tregs, promoting tumor growth. In T cell-specific P2RX7-KO mice, reduced Treg infiltration was accompanied by increased CD4 + Teff accumulation and improved tumor control. Treg-specific P2RX7-KO mice exhibit reduced tumor growth, confirming a cell-intrinsic role of P2RX7 in Tregs. Suppression assays revealed that tumor-infiltrating WT Tregs have greater suppressive activity compared to P2RX7-KO Tregs, which failed to inhibit type 1 and Tfh-like responses. This was associated with increased tumor-specific IgG production by lung B cells in P2RX7-KO mice. We also observed that WT Tregs express higher levels of the immunosuppressive surface molecule CTLA-4 when compared to P2RX7-KO Tregs. In summary, we show that P2RX7 expression on Tregs is essential for their suppressive function in lung cancer, and targeting of P2RX7 may constitute a novel strategy to improve lung cancer treatment by alleviating Treg-mediated immune suppression.