Regional Variation in Deescalated Therapy in Older Adults With Early-Stage Breast Cancer.

Importance: Although trial data support the omission of axillary surgery and radiation therapy (RT) in women aged 70 years or older with T1N0 hormone receptor-positive (HR+) breast cancer, potential overtreatment in older adults with frailty persists. Objective: To determine how much geospatial variation in locoregional therapy may be attributed to region vs patient factors. Design, Setting, and Participants: This retrospective cross-sectional study included women aged 70 years or older who were diagnosed with HR+/ERBB2-negative (ERBB2-) breast cancer from January 1, 2013, to December 31, 2017. Data came from Surveillance, Epidemiology, and End Results-Medicare. Hierarchical multivariable modeling was used to evaluate the variance in deescalated care attributable to 4 domains, ie, (1) random, (2) region (health service area [HSA]), (3) patient factors, and (4) unexplained. Patient factors included age, frailty (validated claims-based measure), Charlson Comorbidity Index (CCI), and socioeconomic status (Yost index). Analyses were performed from January to October 2023. Exposure: HSA. Main Outcomes and Measures: Deescalated care, defined as omission of axillary surgery, RT, or both. Standard therapy was defined as lumpectomy, axillary surgery, and RT or mastectomy with axillary surgery. Multivariable logistic regression was used to identify factors associated with deescalated care receipt. Results: Of 9173 patients (mean [SD] age, 76.5 [5.2] years), 2363 (25.8%) were aged 80 years or older, 705 (7.7%) had frailty, and 419 (4.6%) had a CCI of 2 or greater. While 4499 (49.1%) underwent standard therapy, 4674 (50.9%) underwent deescalated therapy (1193 [13.0%] of the population omitted axillary surgery and 4342 [55.5%] of patients undergoing lumpectomy omitted RT). Of the total variance, random variation explained 27.3%, region/HSA explained 35.3%, patient factors explained 2.8%, and 34.5% was unexplained. In adjusted models, frailty and increased age were associated with a higher likelihood of undergoing deescalated therapy (frailty: odds ratio [OR], 1.70; 95% CI, 1.43-2.02; age, by 1-year increment: OR, 1.10; 95% CI, 1.09-1.11), but CCI was not. Patients in rural areas compared with those in urban areas (OR, 0.82; 95% CI, 0.68-0.99) and Asian and Pacific Islander patients compared with non-Hispanic White patients (OR, 0.68; 95% CI, 0.54-0.85) had a lower likelihood of undergoing deescalated therapy. Conclusions and Relevance: In this retrospective cross-sectional study of women aged 70 years or older diagnosed with T1N0 HR+/ERBB2- breast cancer, region/HSA contributed more to the variation in deescalated therapy use than patient factors. Unexplained variation may be attributed to unmeasured characteristics, such as multidisciplinary environment and patient preference. Decision support efforts to address overtreatment should target regions with low rates of evidence-based deescalation.

Magnesium-enriched deep-sea water inhibits NLRP3 inflammasome activation and dampens inflammation.

The NLRP3 inflammasome is an essential component of the innate immune system, but excessive activation can lead to inflammatory diseases. Ion fluxes across the plasma membrane or from intracellular stores are known to regulate NLRP3 inflammasome activation. Deep-sea water (DSW) contains high concentrations of many mineral ions, which could potentially influence NLRP3 inflammasome activation. However, the impact of DSW on NLRP3 inflammasome activation has not been investigated. Here, we demonstrated that DSW with water hardness levels up to 500 mg/L did not affect cell viability or the expression of NLRP3 inflammasome components in macrophages derived from THP-1 cells. However, the DSW significantly inhibited IL-1ß secretion and caspase-1 activation in response to NLRP3 activators such as nigericin, ATP, or monosodium urate (MSU) crystals. Mechanically, it was discovered that the presence of 5 mM magnesium ions (Mg2+), equivalent to the Mg2+ concentration found in the DSW with a water hardness of 500 mg/L, inhibits NLRP3 inflammasome activation. This indicates that Mg2+ contributes to the mechanism by which DSW mitigates NLRP3 inflammasome activation. Moreover, DSW administration effectively lessens MSU-triggered peritonitis in mice, a commonly used model for examining the impacts of NLRP3 inflammasome activation. These results show that DSW enriched with Mg2+ could potentially be beneficial in modulating NLRP3 inflammasome-associated diseases.

Opportunities to improve the diagnosis and treatment of primary hyperparathyroidism: retrospective cohort study.

Background: Although primary hyperparathyroidism (PHPT) is readily diagnosed biochemically and can be cured with low-risk surgery, it is often underrecognized and undertreated. Our objectives were to characterize, within our health system, how often patients with hypercalcemia were evaluated for PHPT and how often patients with PHPT underwent definitive treatment with parathyroidectomy. Methods: Ambulatory patients aged 18 years or older seen at our health system between January 2018 and June 2023 with chronic hypercalcemia were identified from the medical record. After excluding causes of secondary hyperparathyroidism, the proportion of patients with parathyroid hormone (PTH) tests was calculated. Among patients with biochemical evidence of PHPT, the proportion of patients who underwent parathyroidectomy was calculated. Multivariable logistic regression was used to identify factors associated with an evaluation for PHPT and, separately, with parathyroidectomy. Results: Of 7,675 patients with chronic hypercalcemia, 3,323 (43.3%) had a PTH test obtained within 6 months. An age between 40-49 vs. <30 years [(odds ratio (OR) =3.2; 95% confidence interval (CI): 1.8-5.6; P<0.001], a serum calcium level between 11.6-12.0 vs. <11.0 mg/dL (OR =3.9; 95% CI: 3.2-4.7; P<0.001), and osteoporosis (OR =3.1; 95% CI: 2.7-3.5; P<0.001) were associated with an evaluation for PHPT. Among those with PTH levels, 1,327 (39.9%) had PHPT but only 916 (69.0%) were recognized. Three hundred and forty-five (26.0%) patients with PHPT underwent parathyroidectomy. An increasing number of surgical indications was associated with parathyroidectomy (P<0.001), though overall rates remained less than 40%. Among indications for surgery, including age and serum total calcium level, only osteoporosis was associated with parathyroidectomy (OR =2.0; 95% CI: 1.4-2.8; P<0.001). Conclusions: In this study, more than half of patients with chronic hypercalcemia were not evaluated for PHPT. Among patients with biochemical evidence of PHPT, one-third were unrecognized and only one-in-four received curative treatment. Opportunities to improve the management of PHPT exist within our large integrated health system.

Identifying Barriers to Timely Follow-up After Elevated PSA Screening: A Retrospective Analysis of a Large Healthcare System.

OBJECTIVE: To examine elevated PSA follow-up within our system and identify areas for improvement in the timely diagnosis of prostate cancer. METHODS: We queried the Mass General Brigham's Enterprise Data Warehouse from 2018-2021, identifying patients with elevated PSA and documented time to follow-up. Timely follow-up was defined as having a urologist appointment, prostate biopsy, or prostate magnetic resonance imaging within 6 months from diagnosis. We stratified the location of elevated PSA diagnosis to academic medical centers versus community sites. Univariable and multivariable analyses were performed to identify factors impacting follow-up. RESULTS: We included 28,346 patients, with 50.30%, 15.02%, and 34.69% receiving timely, untimely, and no follow-up during the study period, respectively. In multivariable analysis, patients seen at academic medical centers were more likely to receive follow-up care (OR=1.39, 95%CI 1.30-1.48). In a sensitivity analysis including 2 of our largest community hospitals as part of academic medical facilities, those following up at our main sites showed even higher odds of timely follow-up (OR=1.61, 95%CI 1.51-1.73). CONCLUSION: Our study observed variations in follow-up rate between our academic medical centers and community sites. This finding highlights the need for efforts to improve consistency and timeliness of prostate cancer follow-up care across all facilities. By addressing interfacility disparities, we can facilitate the delivery of timely care to all patients.

Cordycepin Augments the Efficacy of Anti-PD1 against Colon Cancer.

Colon cancer has a poor clinical response to anti-PD1 therapy. This study aimed to evaluate the effect of cordycepin on the efficacy of anti-PD1 treatment in colon cancer. The viability of CT26 mouse colon carcinoma cells, cell-cycle progression, morphology, and the expression of mRNA and protein were assessed. A syngeneic animal model was established by implanting CT26 cells into BALB/c mice for in vivo experiments. Multi-parameter flow cytometry was used to analyze the splenic cell lineages and tumor microenvironment (TME). The in vitro data revealed that cordycepin, but not adenosine, inhibited CT26 cell viability. The protein, but not mRNA, expression levels of A2AR and A2BR were suppressed by cordycepin but not by adenosine in CT26 cells. The combination of cordycepin, but not adenosine, with anti-PD1 exhibited a greater tumor-inhibitory effect than anti-PD1 alone as well as inhibited the expression of A2AR and A2BR in splenic macrophages. In the TME, the combination of cordycepin and anti-PD1 increased the number of CD3+ T cells and neutrophils and decreased the number of natural killer (NK) cells. Overall, cordycepin augmented the antitumor effects of anti-PD1 against mouse colon carcinoma cells and inhibited the expression of the adenosine receptors A2AR and A2BR in splenic macrophages and intratumoral NK cells.

A Self-Cascade Penetrating Brain Tumor Immunotherapy Mediated by Near-Infrared II Cell Membrane-Disrupting Nanoflakes via Detained Dendritic Cells.

Immunotherapy can potentially suppress the highly aggressive glioblastoma (GBM) by promoting T lymphocyte infiltration. Nevertheless, the immune privilege phenomenon, coupled with the generally low immunogenicity of vaccines, frequently hampers the presence of lymphocytes within brain tumors, particularly in brain tumors. In this study, the membrane-disrupted polymer-wrapped CuS nanoflakes that can penetrate delivery to deep brain tumors via releasing the cell-cell interactions, facilitating the near-infrared II (NIR II) photothermal therapy, and detaining dendritic cells for a self-cascading immunotherapy are developed. By convection-enhanced delivery, membrane-disrupted amphiphilic polymer micelles (poly(methoxypoly(ethylene glycol)-benzoic imine-octadecane, mPEG-b-C18) with CuS nanoflakes enhances tumor permeability and resides in deep brain tumors. Under low-power NIR II irradiation (0.8 W/cm2), the intense heat generated by well-distributed CuS nanoflakes actuates the thermolytic efficacy, facilitating cell apoptosis and the subsequent antigen release. Then, the positively charged polymer after hydrolysis of the benzoic-imine bond serves as an antigen depot, detaining autologous tumor-associated antigens and presenting them to dendritic cells, ensuring sustained immune stimulation. This self-cascading penetrative immunotherapy amplifies the immune response to postoperative brain tumors but also enhances survival outcomes through effective brain immunotherapy.

Potential Overtreatment of DCIS in Patients with Limited Life Expectancy.

INTRODUCTION: As the benefits of intensive locoregional therapy for ductal carcinoma in situ (DCIS) are realized over time in older adults, life expectancy may help to guide treatment decisions. We examined whether life expectancy was associated with extent of locoregional therapy in this population. PATIENTS AND METHODS: Women ≥ 70 years old with < 5 cm of DCIS diagnosed 2010-2015 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset and categorized by a life expectancy ≤ 5 or > 5 years, defined by a validated claims-based measure. Differences in locoregional therapy (mastectomy + axillary surgery, mastectomy-only, lumpectomy + radiation therapy (RT) + axillary surgery, lumpectomy + RT, lumpectomy-only, and no treatment) by life expectancy were assessed using Pearson chi-squared tests. Generalized linear mixed models were used to identify factors associated with receipt of lumpectomy-only. RESULTS: Of 5346 women (median age of 75 years, range 70-97 years), 927 (17.3%) had a life expectancy ≤ 5 years. Of the 4041 patients who underwent lumpectomy, 710 (13.3%) underwent axillary surgery. More patients with life expectancy ≤ 5 years underwent lumpectomy-only (39.4% versus 27%), mastectomy-only (8.1% versus 5.3%), or no treatment (5.8% versus 3.2%; p < 0.001). On multivariable analysis, women with life expectancy ≤ 5 years had a significantly greater likelihood of undergoing lumpectomy-only [OR 1.90, 95% CI (1.63-2.22)]. CONCLUSIONS: Life expectancy is associated with lower-intensity locoregional therapy for older women with DCIS, yet a large proportion of patients with a life expectancy ≤ 5 years received RT and axillary surgery, highlighting potential overtreatment and opportunities to de-escalate locoregional therapy in older adults.

Prostate magnetic resonance imaging utilization and its relationship with advanced prostate cancer detection.

BACKGROUND: The rise in advanced prostate cancer has coincided with increased use of Magnetic Resonance Imaging (MRI), leading to the hypothesis that this increase in surveillance registries is an artifact of more sensitive imaging tools. We assessed the association between regional variation in prostate MRI and advanced prostate cancer diagnoses. METHODS: We utilized SEER-Medicare data (2004-2015), including men > 65 diagnosed with localized prostate cancer. The predictor variable was the utilization of prostate MRI in each hospital referral region (HRR, representing regional healthcare markets). We compared the proportion of disease recorded as locally advanced or of regional risk group (cT3, cT4, and cN1) which would plausibly have been detected by prostate MRI. We conducted adjusted multivariable analysis and performed correlation analysis with Spearman rank coefficient at the level of the HRR. Sensitivity analysis for years 2011 to 2015 was conducted. RESULTS: Of 98,921 men diagnosed, 4.01% had locally advanced or regional disease. The median prostate MRI utilization rate was 4.58% (IQR [3.03%, 8.12%]). Adjusted multivariable analysis revealed no statistically significant correlation between MRI utilization and proportion of advanced prostate cancer (aOR = 1.01, 95% CI, [0.99,1.03]) in each region. The correlation between MRI usage and advanced diagnosis was not significant (Spearman Ρ = 0.09, P = 0.4). Sensitivity analysis conducted between 2011 and 2015 showed similar results (aOR = 1.008, 95% CI, [0.989, 1.027]; Spearman Ρ = 0.16, P = 0.1). CONCLUSIONS: During our study period, HRR-level utilization of MRI was not associated with higher incidences of advanced prostate cancer. This suggests the rising advanced prostate cancer diagnoses observed in this period are unlikely an artifact of greater sensitivity of modern imaging tests, but potentially due to other factors such as changes in screening or risk factors. With increased utilization and evolving techniques in recent years, the association between MRI and advanced prostate cancer detection warrants continued monitoring.

Effectiveness of fentanyl buccal soluble film in cancer patients with inadequate breakthrough pain control.

BACKGROUND: Clinical evidence for the rapidity and effectiveness of fentanyl buccal soluble film (FBSF) in reducing pain intensity of breakthrough cancer pain (BTcP) remains inadequate. This study aimed to evaluate the efficacy of FBSF proportional to the around-the-clock (ATC) opioid regimens in rapidly relieving the intensity of BTcP episodes by determining the percentage of patients requiring further dose titration. METHODS: The study procedure included a dose-finding period followed by a 14-day observation period. Pain intensity was recorded with a Numeric Rating Scale (NRS) at onset and 5, 10, 15, and 30 min after FBSF self-administration. Meaningful pain relief was defined as the final NRS score ≤ 3. Satisfaction survey was conducted for each patient after treatment using the Global Satisfaction Scale. RESULTS: A total of 63 BTcP episodes occurred in 30 cancer patients. Only one patient required rescue medication at first BTcP episode and then achieved meaningful pain relief after titrating FBSF by 200 µg. Most BTcP episodes relieved within 10 min. Of 63 BTcP episodes, 30 (47.6%), 46 (73.0%), and 53 (84.1%) relieved within 5, 10, and 15 min after FBSF administration. Only grade 1/2 adverse events were reported, including somnolence, malaise, and dizziness. Of the 63 BTcP episodes, 82.6% were rated as excellent/good satisfaction with FBSF. CONCLUSION: FBSF can be administrated "on demand" by cancer patients at the onset of BTcP, providing rapid analgesia by achieving meaningful pain relief within 10 min. TRIAL REGISTRATION: This study was retrospectively registered 24 December, 2021 at Clinicaltrial.gov (NCT05209906): https://clinicaltrials.gov/study/NCT05209906 .

A 35-gene mutation profile predicts the therapeutic outcome of patients with esophageal squamous cell carcinoma receiving neo-adjuvant chemoradiation.

Esophageal cancer is a common malignancy worldwide with a poor prognosis without radical resection. Neoadjuvant concurrent chemoradiotherapy (NACRT) followed by esophagectomy is widely used for treating locally advanced esophageal cancer in the thorax. The study aimed to assess mutation profiles and their correlation with therapeutic outcomes in patients diagnosed with locally advanced thoracic esophageal squamous cell carcinoma (ESCC). A retrospective analysis was conducted on 62 patients with ESCC who underwent NACRT. All patients received concurrent chemoradiotherapy (CCRT) utilizing intensity-modulated radiation therapy alongside concurrent chemotherapy with a cisplatin-based regimen. A 35-gene next-generation sequencing (NGS) panel detecting 402 genetic variants was used, which has been proven predictive in ESCC patients who received definitive chemoradiation. The 35-gene mutation profiles were analyzed in pre-treatment biopsies. The results reveled there were variants correlated with pathological complete remission or partial response, overall survival, and progression-free survival. A combination of p.Pro1319Ser and p.Arg2159Gly mutations in the MUC17 gene demonstrated an adverse impact on pathological response (OR [95% CI] = 7.00 (3.07-15.94), P < 0.001). Additionally, the variants located in the MUC17, MUC4, and MYH4 genes exhibited notably effects on tumor recurrence or mortality. Patients harboring either the MUC17 p.Thr2702Val or MUC4 p.Thr3355Ser mutation displayed a more than four-fold increased risk for disease recurrence or mortality. We concluded that specific mutations correlated to the pathological complete response in ESCC receiving neoadjuvant chemoradiation can be identified through the utilization of 35-gene expression profiles. Further investigation into the pathophysiological roles of MUC17 and MUC4 mutations in ESCC is warranted.

A Randomized Crossover Trial Evaluating the Impact of Cultural Dexterity Training on Surgical Residents' Knowledge, Cross-Cultural Care, Skills, and Beliefs: The Provider Awareness and Cultural Dexterity Training for Surgeons (PACTS) Trial.

OBJECTIVES: This trial examines the impact of the Provider Awareness and Cultural dexterity Toolkit for Surgeons (PACTS) curriculum on surgical residents' knowledge, cross-cultural care, skills, and beliefs. BACKGROUND: Cross-cultural training of providers may reduce health care outcome disparities, but its effectiveness in surgical trainees is unknown. METHODS: PACTS focuses on developing skills needed for building trust, working with patients with limited English proficiency, optimizing informed consent, and managing pain. The PACTS trial was a randomized crossover trial of 8 academic general surgery programs in the United States: The Early group ("Early") received PACTS between periods 1 and 2, while the Delayed group ("Delayed") received PACTS between periods 2 and 3. Residents were assessed preintervention and postintervention on Knowledge, Cross-Cultural Care, Self-Assessed Skills, and Beliefs. χ 2 and Fisher exact tests were conducted to evaluate within-intervention and between-intervention group differences. RESULTS: Of 406 residents enrolled, 315 were exposed to the complete PACTS curriculum. Early residents' Cross-Cultural Care (79.6%-88.2%, P <0.0001), Self-Assessed Skills (74.5%--85.0%, P <0.0001), and Beliefs (89.6%-92.4%, P =0.0028) improved after PACTS; knowledge scores (71.3%-74.3%, P =0.0661) were unchanged. Delayed resident scores pre-PACTS to post-PACTS showed minimal improvements in all domains. When comparing the 2 groups in period 2, Early residents had modest improvement in all 4 assessment areas, with a statistically significant increase in Beliefs (92.4% vs 89.9%, P =0.0199). CONCLUSIONS: The PACTS curriculum is a comprehensive tool that improved surgical residents' knowledge, preparedness, skills, and beliefs, which will help with caring for diverse patient populations.

FK228 suppress the growth of human malignant pleural mesothelioma tumor independent to epithelioid or non-epithelioid histology.

Human malignant pleural mesothelioma (hMPM) is an aggressive, rare disease with a poor prognosis. Histologically, MPM is categorized into epithelioid, biphasic, and sarcomatoid subtypes, with the epithelioid subtype generally displaying a better response to treatment. Conversely, effective therapies for the non-epithelioid subtypes are limited. This study aimed to investigate the potential role of FK228, a histone deacetylase inhibitor, in the suppression of hMPM tumor growth. We conducted a comprehensive analysis of the histological and molecular characteristics of two MPM cell lines, CRL-5820 (epithelioid) and CRL-5946 (non-epithelioid). CRL-5946 cells and non-epithelioid patient-derived xenografted mice exhibited heightened growth rates compared to those with epithelioid MPM. Both CRL-5946 cells and non-epithelioid mice displayed a poor response to cisplatin. However, FK228 markedly inhibited the growth of both epithelioid and non-epithelioid tumor cells in vitro and in vivo. Cell cycle analysis revealed FK228-induced G1/S and mitotic arrest in MPM cells. Caspase inhibitor experiments demonstrated that FK228-triggered apoptosis occurred via a caspase-dependent pathway in CRL-5946 but not in CRL-5820 cells. Additionally, a cytokine array analysis showed that FK228 reduced the release of growth factors, including platelet-derived and vascular endothelial growth factors, specifically in CRL-5946 cells. These results indicate that FK228 exhibits therapeutic potential in MPM by inducing cytotoxicity and modulating the tumor microenvironment, potentially benefiting both epithelioid and non-epithelioid subtypes.

Comparison of modified Furlow palatoplasty using small double-opposing Z-plasty and conventional Furlow palatoplasty: A long-term outcome study.

BACKGROUND: The aim of palatoplasty is to create a functional palate to achieve normal speech, while minimizing post-operative complications. This study aimed to compare the long-term outcomes of modified Furlow palatoplasty using small double-opposing Z-plasty (small-DOZ) and conventional Furlow palatoplasty (conventional-DOZ) performed in a single center. METHODS: A retrospective review of consecutive patients who underwent Furlow palatoplasty between May 2007 and March 2014 was executed. Non-syndromic patients subjected to palatoplasty prior to 24 months of age and followed-up until at least 9 years of age were included. RESULTS: A total of 196 small-DOZ and 280 conventional-DOZ palatoplasty patients were included in this study. Overall, 14 patients (2.9%) developed oronasal fistula, and 40 patients (8.4%) received velopharyngeal insufficiency (VPI) surgery. In comparisons, oronasal fistula rate was significantly higher in conventional-DOZ (0.5% vs. 4.6%, p = 0.01), and the VPI prevalence was not significantly different (9.2% vs. 7.9%, p = 0.62). Patients who developed fistula had a significantly higher likelihood of developing VPI than patients without oronasal fistula (50.0% vs. 7.1%, respectively; p < 0.01), with an odds ratio of 13.0. CONCLUSION: Both modalities of palatoplasty yielded commendable velopharyngeal function in the long-term follow-up. The small-DOZ with reduced tension lowered the risk of oronasal fistula.

Achieve fairness without demographics for dermatological disease diagnosis.

In medical image diagnosis, fairness has become increasingly crucial. Without bias mitigation, deploying unfair AI would harm the interests of the underprivileged population and potentially tear society apart. Recent research addresses prediction biases in deep learning models concerning demographic groups (e.g., gender, age, and race) by utilizing demographic (sensitive attribute) information during training. However, many sensitive attributes naturally exist in dermatological disease images. If the trained model only targets fairness for a specific attribute, it remains unfair for other attributes. Moreover, training a model that can accommodate multiple sensitive attributes is impractical due to privacy concerns. To overcome this, we propose a method enabling fair predictions for sensitive attributes during the testing phase without using such information during training. Inspired by prior work highlighting the impact of feature entanglement on fairness, we enhance the model features by capturing the features related to the sensitive and target attributes and regularizing the feature entanglement between corresponding classes. This ensures that the model can only classify based on the features related to the target attribute without relying on features associated with sensitive attributes, thereby improving fairness and accuracy. Additionally, we use disease masks from the Segment Anything Model (SAM) to enhance the quality of the learned feature. Experimental results demonstrate that the proposed method can improve fairness in classification compared to state-of-the-art methods in two dermatological disease datasets.

New-Onset Atrial Fibrillation Is a Red Flag to Microvascular Free Tissue Transfer Failure in Head and Neck Cancer Patients.

BACKGROUND: Postoperative new-onset atrial fibrillation (AF) has been shown to be associated with increased surgical morbidity and mortality following cancer ablation surgery. However, evidence of new-onset AF's impact on surgical outcomes in head and neck cancer patients undergoing tumor ablation and microvascular free tissue transfer remains scarce. This study aims to evaluate the association between AF and surgical outcomes in these patients. METHODS: We enrolled head and neck cancer patients who underwent tumor ablation reconstructed with microvascular free tissue transfer from the National Health Insurance Research Database (NHIRD). Patients were grouped into the following: (1) without AF, (2) new-onset AF, and (3) preexisting AF. The groups were matched by propensity score based on age, gender, cancer stage, and comorbidities. The primary outcome was postoperative complications, whereas all-cause mortality was the secondary outcome. RESULTS: In total, 26,817 patients were included in this study. After matching, we identified 2,176 (79.24%) patients without AF, 285 (10.37%) with preexisting AF, and 285 (10.37%) with new-onset AF. Our results demonstrated that the free flap failure rate was twofold escalated in patients with new-onset AF (9.8%) compared to those without AF (5.4%) or preexisting AF (5.3%; p = 0.01). However, we did not identify significant differences among other postoperative complications across groups. Additionally, we found that the risk of all-cause mortality was significantly elevated in patients with preexisting AF (p < 0.001) compared to those without AF or new-onset AF. CONCLUSION: Our study demonstrated that new-onset AF is associated with an increased risk of flap failure and could serve as a predictor. On the other hand, all-cause mortality in patients with preexisting AF was significantly elevated. Close postoperative monitoring in patients with new-onset and preexisting AF is crucial to identify any potential adverse effects.

Cimetidine Attenuates Therapeutic Effect of Anti-PD-1 and Anti-PD-L1 and Modulates Tumor Microenvironment in Colon Cancer.

Histamine modulates immunity by binding to histamine receptor 2 (H2R). Cimetidine, an H2R antagonist that inhibits gastric acid secretion and treats gastrointestinal ulcers, interferes with histamine-mediated immunomodulation and may have anticancer activity. This study examined cimetidine's effect on the anticancer effect of anti-PD-L1 in colon cancer. The MTT assay, colony formation assay, and DNA histograms assessed cell viability, clonogenicity, and cell cycle distribution, respectively. Flow cytometry measured H2R and PD-L1 expression and estimated specific immune cell lineages. For the in vivo study, tumor cells were subcutaneously implanted into the right flank of BALB/c mice. Cimetidine had no significant effect on CT26 cell viability, clonogenicity, or cell cycle distribution. It also did not affect H2R and PD-L1 expression levels in CT26 cells. In vivo, anti-PD-1 and anti-PD-L1 suppressed CT26 tumor growth, whereas cimetidine showed mild antitumor activity. In the combined experiment, cimetidine significantly attenuated anti-PD-1 and anti-PD-L1' antitumor effects without major toxicity. In the tumor microenvironment, anti-PD-L1 increased CD3+ T, CD4+ T, and CD8+ T cells and M1 macrophages. Combined treatment with cimetidine reversed this. Cimetidine also reversed anti-PD-1 and anti-PD-L1's decrease in circulating and tumor-associated neutrophils. Cimetidine attenuated anti-PD-L1's antitumor effect and modulated the tumor microenvironment in colon cancer.