Minimum P-value Approach Research Articles

Prognostic Impact of a Decrease in Serum Carbohydrate Antigen 19-9 Levels After Preoperative Therapy for 4 Months or More for Borderline Resectable Pancreatic Cancer Abutting Major Arteries.

Background: This study aimed to identify the prognostic factors after pancreatectomy for borderline resectable pancreatic cancer abutting major arteries (BR-A).Methods: We retrospectively investigated relationship between preoperative and intraoperative variables and overall survival (OS) through univariate and multivariate analyses. The cut-off points of preoperative therapy duration and response rates of serum carbohydrate antigen 19-9 (CA19-9) levels after preoperative therapy were determined through a minimum P-value approach using the log-rank test for OS. Overall survival was compared among patients stratified according to the independent prognostic factors and the presence or absence of pancreatectomy.Results: After pretreatment, 17 patients underwent pancreatectomy and four patients continued chemotherapy without surgery. Multivariate analysis in 17 resected BR-A patients demonstrated decreased serum CA19-9 levels and preoperative therapy duration of ≥4 months were the independent prognostic factors [hazard ratio (HR) 0.01; P = 0.002, HR 0.13; P = 0.02]. Patients who underwent surgery with decreased serum CA19-9 levels after preoperative therapy of ≥4 months had a significantly better prognosis than those without one or both of independent prognostic factors and those who did not undergo surgery (median survival time: not estimated, 23.3 months, 10.5 months, and 10.8 months; P = 0.02, P = 0.004, and P = 0.001, respectively). Furthermore, the prognosis did not significantly differ between the patients who underwent surgery without meeting either one or both criteria and those without surgery.Conclusions: Preoperative therapy duration of ≥4 months and decreased serum CA19-9 levels are independent prognostic factors among BR-A patients.

Predictive factors of actual 5-y recurrence-free survival after upfront surgery for resectable pancreatic cancer: Exploration of patients who did not require neoadjuvant treatment.

The present study investigated the prognostic factors associated with actual 5-y recurrence-free survival (RFS) after upfront surgery for resectable pancreatic cancer (R-PC) in patients who were deemed not to require neoadjuvant treatment. Between 2007 and 2016, 316 patients who underwent pancreatectomy for radiologically R-PC were retrospectively reviewed to evaluate the predictors of actual 5-y RFS. Predictors were identified using logistic regression analysis of preoperative evaluable factors. The cutoff values for continuous variables were determined based on a minimum p-value approach (model 1) or the value that maximized the rate of 5-y RFS survivors (model 2). Fifty-one patients (16.1%) achieved a 5-y RFS. A tumor size ≤23 mm, the absence of serosal invasion on computed tomography (CT), and Neutrophil-to-Lymphocyte Ratio <1.0, were significantly associated with the 5-y RFS in model 1. A Prognostic Nutritional Index ≥58 and the absence of serosal invasion and extrapancreatic nerve plexus invasion on CT were significantly associated with 5-y RFS in model 2. Only six (11.8%, model 1) and four (7.8%, model 2) patients had all three prognostic factors, and their 5-y RFS rates were 83.3% and 100%, respectively. A modest number of patients who underwent upfront surgery achieved 5-y RFS, but only ~10% of them could be identified preoperatively. Based on these results, almost all R-PC patients are forced to undergo neoadjuvant treatment in daily practice.

Expression of the receptor tyrosine kinase AXL and clinical outcomes to cabozantinib and everolimus in patients with metastatic renal cell carcinoma enrolled in the METEOR trial.

4543 Background: High expression of the receptor tyrosine kinase AXL has been associated with resistance to targeted agents and anti-PD-1 therapy in multiple tumor types, including metastatic clear cell Renal Cell Carcinoma (mccRCC). Cabozantinib (cabo), a multitargeted tyrosine kinase inhibitor (TKI) active against VEGFR, MET, and AXL, is approved for the treatment of mccRCC, but no predictive biomarkers are available. Here, we analyzed tumor samples from the METEOR trial to assess whether AXL expression predicts improved clinical outcomes with cabo relative to everolimus (evero, mTOR inhibitor) in patients (pts) with mccRCC. Methods: Double immunohistochemistry staining for AXL and CD45/CD163 (immune cell/ macrophage markers) was performed on 278 pretreatment tumor tissues from the METEOR trial (cabo=147; evero=131). Image analysis algorithms were used to assess the % of AXL+ tumor cells (TC), % of AXL+ immune cells (IC), and combined % of AXL+ TC and IC (TC/IC). Optimal cutoffs, based on the minimum p-value approach, were determined at the 17th, 30th, and 22nd percentile for TC, IC, and TC/IC, respectively. The association with progression-free survival (PFS) was assessed using Cox regression adjusted for IMDC risk groups, the presence of bone metastases, and the number of previous VEGFR TKI treatments. The association with objective response rate (ORR) (cabo arm only due to low response rate in evero arm) was reported descriptively. Results: We observed a strong correlation between % AXL+ TC and % AXL+ IC (Spearman correlation coefficient 0.85; p-value &lt;0.001). In the evero arm, high % AXL+ TC and high % AXL+ TC/IC were significantly associated with shorter PFS (median 1.9 vs. 4.1 months and 1.9 vs 4.2 months, respectively); a similar trend was observed for % AXL+ IC. In the cabo arm, % AXL+ TC, % AXL+ IC, and % AXL+ TC/IC were not associated with PFS or ORR (Table). The magnitude of increase in PFS for pts receiving cabo versus evero was larger in pts with high % AXL+ TC compared to pts with low % AXL+ TC (HR: 0.30 vs. 0.51, p-interaction=0.18) and in pts with high % AXL+ TC/IC compared to pts with low % AXL+ TC/IC (HR: 0.30 vs 0.53, p-interaction=0.12). Conclusions: Our finding that the improvement in outcome with cabo relative to evero is more evident in pts with high levels of AXL expression supports that the antitumor activity of cabo in mccRCC is mediated, in part, by AXL inhibition. Our work identifies AXL expression as a potential predictive biomarker for cabo-based therapies in mccRCC. [Table: see text]

Analysis of Adverse Events Following Phenobarbital Administration for Pediatric Patients Categorized by One-Year Age Increments Using the U.S. Food and Drug Administration Adverse Event Reporting System.

Background Organ and body development greatly varies in pediatric patients from year to year. Therefore, the incidence of each adverse event following phenobarbital (PB) administration would vary with age. However, in clinical trials, increasing the sample size of pediatric patients in each age group has been challenging. Therefore, previous studies were conducted by dividing pediatric patients into three or four age groups based on the development stage. Although these results were useful in clinical settings, information on adverse events that occurred at one-year age increments in pediatric patients could further enhance treatment and care. Objectives This study investigated in one-year age increments the occurrence tendency of each adverse event following PB administration in pediatric patients. Methods This study used data obtained from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Two inclusion criteria were set: (1) treatment with PB between January 2004 and June 2023 and (2) age 0-15 years. Using the cutoff value obtained using the Wilcoxon-Mann-Whitney test by the minimum p-value approach, this study explored changes in the occurrence tendency of each adverse event in one-year age increments. At the minimum p-value of <0.05, the age corresponding to this p-value was determined as the cutoff value. Conversely, at the minimum p-value of ≥0.05, the cutoff value was considered nonexistent. Results This study investigated all types of adverse events and explored the cutoff value for each adverse event. We identified 34, 16, 15, nine, five, five, eight, three, and eight types of adverse events for the cutoff values of ≤3/>3, ≤4/>4, ≤5/>5, ≤6/>6, ≤7/>7, ≤8/>8, ≤9/>9, ≤10/>10, and ≤11/>11 years, respectively. Conclusions This study demonstrated that adverse events requiring attention in pediatric patients varied with age. The findings help in the improvement of treatment and care in the pediatric clinical settings.

Combined morphologic-metabolic biomarkers from [18F]FDG-PET/CT stratify prognostic groups in low-risk NSCLC.

The aim of this study was to derive prognostic parameters from 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG-PET/CT) in patients with low-risk NSCLC and determine their prognostic value. 81 (21 female, mean age 66 a) therapy-naive patients that underwent [18F]FDG-PET/CT before histologic confirmation of NSCLC with stadium I and II between 2008-2016 were included. A mean follow-up time of 58 months (13-176), overall and progression free survival (OS, PFS) were registered. A volume of interest for the primary tumor was defined on PET and CT images. Parameters SUVmax, PET-solidity, PET-circularity, and CT-volume were analyzed. To evaluate the prognostic value of each parameter for OS, a minimum p-value approach was used to define cutoff values, survival analysis, and log-rank tests were performed, including subgroup analysis for combinations of parameters. Mean OS was 58±28 months. Poor OS was associated with a tumor CT-volume >14.3 cm3 (p=0.02, HR=7.0, CI 2.7-17.7), higher SUVmax values >12.2 (p=0.003; HR=3.0, CI 1.3-6.7) and PET-solidity >0.919 (p=0.004; HR=3.0, CI 1.0-8.9). Combined parameter analysis revealed worse prognosis in larger volume/high SUVmax tumors compared to larger volume/lower SUVmax (p=0.028; HR=2.5, CI 1.1-5.5), high PET-solidity/low volume (p=0.01; HR=2.4, CI 0.8-6.6) and low SUVmax/high PET-solidity (p=0.02, HR=4.0, CI 0.8-19.0). Even in this group of low-risk NSCLC patients, we identified a subgroup with a significantly worse prognosis by combining morphologic-metabolic biomarkers from [18F]FDG-PET/CT. The combination of SUVmax and CT-volume performed best. Based on these preliminary data, future prospective studies to validate this combined morphologic-metabolic imaging biomarker for potential therapeutic decisions seem promising.

The Prognostic Role of Preoperative Hematological and Inflammatory Indices in Canine Appendicular Osteosarcoma.

Hematological indices play a prognostic role in human osteosarcoma (OSA), but data are limited in dogs. The aim of this retrospective multicentric cohort study was to investigate the prognostic significance of pre-operative hematological/inflammatory indices in a cohort of client-owned dogs with appendicular OSA receiving standardized treatment. Cut-offs associated with progression-free survival (PFS) for pre-operative hematological values/ratios were established using the minimal p-value approach. Historical prognostic factors were also assessed. Statistical analyses were performed for the whole population and after the exclusion of sighthounds. Fifty-nine dogs were included (13 were sighthounds). Multivariable analysis revealed that a low neutrophil count (<4.37 × 109/L, HR0.28, CI 95% 0.13-0.61, p = 0.001), a high red blood cell count (≥7.91, HR3.5, CI 95% 1.56-7.9, p = 0.002), and a proximal humerus location (HR3.0, CI 95% 1.48-6.1, p = 0.002) were associated with shorter PFS. In the sighthound-only population, only OSA location was significantly associated with PFS in univariable analysis. When sighthounds were excluded, a low neutrophil count, a low monocyte count, and a proximal humerus location were associated with shorter PFS, in multivariable analysis. Neutrophil count and possibly monocyte and red blood cell counts can be useful prognostic markers in canine OSA treated with amputation and adjuvant carboplatin. However, not all indices are appropriate in sighthounds.

Association between age at menarche and risk of myopia in the United States: NHANES 1999-2008.

We evaluate the effect of menarche on myopia in women in the United States (US). A cross-sectional survey and examination were conducted using data from the 1999-2008 US National Health and Nutrition Examination Survey (NHANES), and 8,706 women aged ≥20 years (95% confidence interval [CI], 44.23 to 45.37) were enrolled. Characteristics were compared between nonmyopic and myopic participants. Univariable and multivariable logistic regression analysis was performed to evaluate the risk factors for myopia. A minimum p-value approach was used to estimate the cut-off point for age at menarche. The prevalence of myopia was 32.96%. Mean spherical equivalent (SE) were -0.81 diopters (95% CI, -0.89 to -0.73) and the mean age of menarche was 12.67 years (95% CI, 12.62 to 12.72). In the crude logistic regression model, age (odd ratio [OR] 0.98), height (OR, 1.02), astigmatism (OR, 1.57) (all p < 0.0001), age at menarche (OR, 0.95; p = 0.0005), white ethnicity, being born in the US, higher level of education, and higher annual household income (all p trend <0.0001) were significantly associated with myopia. 1-year increments in age at menarche was associated with a 4% decrease in the risk of myopia after adjusting for age, height, body mass index (BMI), ethnicity, and astigmatism (OR, 0.96; 95% CI, 0.93 to 0.99, p = 0.0288). The cut-off value for age at menarche was 15 years by the maximum chi-square test (p < 0.0001). Age at menarche may attribute to myopia progression, along with other environmental and individual risk factors.

Plasma phosphocreatine (PC) as a predictive biomarker for immune checkpoint inhibition in patients with refractory metastatic colorectal cancer (mCRC): Analysis of the CCTG CO.26 trial.

183 Background: In response to energetic stress, colorectal cancer cells secrete creatine kinase brain-type (CKB). CKB converts creatine and ATP from the extracellular matrix to PC, which is imported intracellularly to sustain survival and metastatic spread. In addition, PC modulates immune cell functions and may play a role in mediating responses to immune checkpoint inhibition. CO.26 was a phase II trial (NCT02870920) that randomized patients (pts) with refractory mCRC to durvalumab plus tremelimumab (D+T) versus best supportive care (BSC). In an exploratory, post-hoc analysis, we investigated the role of plasma PC as a predictive biomarker for response to D+T. Methods: PC concentrations were determined from pre-treatment blood samples with HPLC-tandem mass spectrometer. A minimum p-value approach was used to select an optimum cut-off value which dichotomized patients into low (&lt; 95.6 ng/ml) versus high (≥ 95.6 ng/ml) groups predictive for benefit. Cox proportional hazard models were used to analyze predictive impacts of PC on progression free survival (PFS) and overall survival (OS). Results: Of 180 pts enrolled, pre-treatment blood samples were available for 162 pts (N =115 for D+T; 47 BSC). Pre-treatment PC was low in 15% (N=24) and high in 85% (N=138). There were no differences in baseline characteristics between pts included in this analysis and the total study pts, or PC low and high pts. D+T improved OS significantly in PC low pts (median OS 4.7 months vs 2.3 months; Hazard Ratio (HR) 0.32, 95% confidence interval (CI): 0.11 – 0.95, p = 0.03). There was no improvement in PC high pts with D+T (median OS 6.8 vs 5.2 months; HR 0.80, 95% CI: 0.55 – 1.17, p = 0.24. Interaction p &lt; 0.0001). Plasma PC values had no impact on PFS and rates of disease control. Conclusions: Pts with low plasma PC derived more benefit from immune checkpoint inhibition with D+T in pts with refractory mCRC. Further prospective validation studies are needed. Predictive analysis for OS with pre-treatment PC levels dichotomized by minimum p approach. [Table: see text]

Trichotomization with two cutoff values using Kruskal-Wallis test by minimum P-value approach

Abstract In clinical trials, age is often converted to binary data by the cutoff value. However, when looking at a scatter plot for a group of patients whose age is larger than or equal to the cutoff value, age and outcome may not be related. If the group whose age is greater than or equal to the cutoff value is further divided into two groups, the older of the two groups may appear to be at lower risk. In this case, it may be necessary to further divide the group of patients whose age is greater than or equal to the cutoff value into two groups. This study provides a method for determining which of the two or three groups is the best split. The following two methods are used to divide the data. The existing method, the Wilcoxon-Mann-Whitney test by minimum P-value approach, divides data into two groups by one cutoff value. A new method, the Kruskal-Wallis test by minimum P-value approach, divides data into three groups by two cutoff values. Of the two tests, the one with the smaller P-value is used. Because this was a new decision procedure, it was tested using Monte Carlo simulations (MCSs) before application to the available COVID-19 data. The MCS results showed that this method performs well. In the COVID-19 data, it was optimal to divide into three groups by two cutoff values of 60 and 70 years old. By looking at COVID-19 data separated into three groups according to the two cutoff values, it was confirmed that each group had different features. We provided the R code that can be used to replicate the results of this manuscript. Another practical example can be performed by replacing x and y with appropriate ones.

Thermal ablation for small renal masses: Identifying the most appropriate tumor size cut-off for predicting perioperative and oncological outcomes.

To test TRIFECTA achievement [1) absence of CLAVIEN-DINDO ≥3 complications; 2) complete ablation; 3) absence of ≥30% decrease in eGFR] and local recurrence rates, according to tumor size, in patients treated with thermal ablation (TA: radiofrequency [RFA] and microwave ablation [MWA]) for small renal masses. Retrospective analysis (2008-2020) of 432 patients treated with TA (RFA: 162 vs. MWA: 270). Tumor size was evaluated as: 1) continuously coded variable (cm); 2) tumor size strata (0.1-2 vs. 2.1-3 vs. 3.1-4 vs. >4 cm). Multivariable logistic regression models and a minimum P-value approach were used for testing TRIFECTA achievement. Kaplan-Meier plots depicted local recurrence rates over time. Overall, 162 (37.5%) vs. 140 (32.4%) vs. 82 (19.0%) vs. 48 (11.1%) patients harboured, respectively, 0.1 to 2 vs. 2.1 to 3 vs. 3.1 to 4 vs. >4 cm tumors. In multivariable logistic regression models, increasing tumor size was associated with higher rates of no TRIFECTA achievement (OR:1.11; P< 0.001). Using a minimum P-value approach, an optimal tumor size cut-off of 3.2 cm was identified (P< 0.001). In multivariable logistic regression models, 3.1 to 4 cm tumors (OR:1.27; P< 0.001) and >4 cm tumors (OR:1.49; P< 0.001), but not 2.1 to 3 cm tumors (OR:1.05; P= 0.3) were associated with higher rates of no TRIFECTA achievement, relative to 0.1 to 2 cm tumors. The same results were observed in separate analyses of RFA vs. MWA patients. After a median (IQR) follow-up time of 22 (12-44) months, 8 (4.9%), 8 (5.7%), 11 (13.4%), and 5 (10.4%) local recurrences were observed in tumors sized 0.1 to 2 vs. 2.1 to 3 vs. 3.1 to 4 vs. >4 cm, respectively (P= 0.01). A tumor size cut-off value of ≤3 cm is associated with higher rates of TRIFECTA achievement and lower rates of local recurrence over time in patients treated with TA for small renal masses.

Cisplatin-based concurrent chemoradiotherapy improved the survival of locoregionally advanced nasopharyngeal carcinoma after induction chemotherapy by reducing early treatment failure

PurposeThe aims of this study focusing on Locoregionally advanced nasopharyngeal carcinoma (LANPC) were mainly two-fold: on the one hand, to establish a cut-off value to differentiate early and late failure based on prognosis after recurrence or metastasis; and on the other hand, to investigate the duration of concurrent cisplatin benefit over follow-up time. The results of our study have the potential to guide clinical practice and follow-up.MethodsIn total, 3123 patients with stage III-IVa NPC receiving Induction chemotherapy followed by concurrent cisplatin or not were analysed. The cut-off value of treatment failure was calculated using the minimum P-value approach. Random survival forest (RSF) model was to simulate the cumulative probabilities of treatment failure (locoregional recurrence and /or distant metastasis) over-time, as well as the monthly time-specific, event-occurring probabilities, for patients at different treatment groups.ResultsBased on subsequent prognosis, early locoregional failure (ELRF) should be defined as recurrence within 14 months (P = 1.47 × 10 − 3), and early distant failure (EDF) should be defined as recurrence within 20 months (P = 1.95 × 10 − 4). A cumulative cisplatin dose (CCD) > 200 mg/m2 independently reduced the risk of EDF (hazard ratio, 0.351; 95% confidence interval (CI), 0.169–0.732; P = 0.005). Better failure-free survival (FFS) and overall survival (OS) were observed in concurrent chemotherapy settings ([0 mg/m2 vs. 1-200 mg/m2 vs. >200 mg/m2]: FFS: 70.4% vs. 74.4% vs. 82.6%, all P < 0.03; OS: 79.5% vs. 83.8% vs. 90.8%, all P < 0.01). In the monthly analysis, treatment failure mainly occurred during the first 4 years, and the risk of distant failure in patients treated with concurrent chemotherapy never exceeded that of patients without concurrent chemotherapy.ConclusionLocoregional failure that developed within 14 months and/or distant failure within 20 months had poorer subsequent survival. Concurrent chemotherapy provides a significant FFS benefit, primarily by reducing EDF, translating into a long-term OS benefit.

A Predictive Scoring System for Therapy Failure in Persons with Chronic Myeloid Leukemia Receiving Initial a Second-Generation Tyrosine Kinase Inhibitor Therapy

Purposes Develop and validate a predictive scoring system for therapy failure in persons with chronic phase chronic myeloid leukemia (CML) receiving initial a second-generation tyrosine kinase inhibitor (2G-TKI). Methods Data from 329 consecutive subjects with CML receiving initial 2G-TKI therapy at one centre (Beijing, China) in a training dataset were interrogated to develop a predictive model which was then validated in 1,083 subjects from 65 other centers in China. Therapy-failure was defined using the 2020 ELN criteria including progression to accelerated or blast phases or CML-related death. Fine-Gray model was used for uni- and multi-variable analyses (UVA and MVA) to identify co-variates significantly-associated with therapy-failure. Akaike information criterion (AIC) was used to select prognostic co-variate and determine the best model. 1000 bootstrap re-samplings, Fine-Gray test, the minimal p-value approach, Bonferroni correction and kernel density estimator were used to determine optimal cut-offs to classify subjects into risk cohorts. Time-dependent receiver-operator characteristic curves (ROC) were used to estimate prediction accuracy and calibration plots used to determine concordance between predicted and observed cumulative incidences. Decision curve analysis (DCA) was used to calculate the net benefit using the model. Results In the training dataset, 279 subjects (85%) initially received nilotinib; and 50 (15%), dasatinib. Median 2G-TKI therapy-duration was 36 months (interquartile range [IQR], 24-68 months). 75 subjects (23%) had therapy-failure at a median of 9 months (IQR 3-12 months) after therapy start. In MVA, increasing splenomegaly and a higher percentage blood blasts were significantly-associated with the higher cumulative incidences of therapy-failure. We used these data to develop a predictive scoring system: "2G-TKI failure risk score= 0.6405×[(spleen size below the costal margin in cm + 0.2)/10] + 0.1348×(blood blasts + 0.2)" which divided subjects into low- (score ≤ 0.3021; n = 89; 31%), intermediate- (0.3021 < score < 1.4508; n = 155; 54%) and high-risk (score ≥ 1.4508; n = 43; 15%) cohorts with 5-year cumulative incidences of therapy-failure of 3% (95% Confidence Interval [CI], 0, 5%), 26% (20, 32%) and 72% (56, 88%; p-value for trend < 0.001; Figure 1A). Hazard ratios (HRs) for therapy-failure (low-risk cohort as reference) were 4.8 (1.7, 13.6; p = 0.002) and 16.5 (5.7, 47.6; p < 0.001; p for trend < 0.001) for the intermediate- and high-risk cohorts. In the external validation dataset, subjects were classified into the low- (n = 433; 40%), intermediate- (n = 583; 54%) and high-risk (n = 67; 6%) cohorts using our scoring system. 5-year cumulative incidences of therapy failure were 8% (3, 13%), 18% (12, 25%) and 44% (29, 60%; p for trend < 0.001; Figure 1B). HRs (low-risk cohort as reference) were 2.7 (1.9, 3.6; p < 0.001) and 10.6 (5.8, 15.4; p < 0.001; p for trend < 0.001) for the intermediate- and high-risk cohorts. In the training dataset cohort time-dependent AUROC curves for therapy-failure at 1-, 3-, and 5-years in the model were 0.73-0.82 and 0.68-0.75 in the validation dataset. Calibration plots for the 1-, 3- and 5-years cumulative incidences of therapy-failure indicated good concordance between predicted and observed outcomes. DCA curves indicated net benefit from using the predictive scoring system in clinical settings. Conclusions We developed and externally validated a therapy-failure scoring system in persons with chronic phase CML receiving initial 2G-TKI. The model had high AUROCs and performed well in calibration plots and DCAs. Our model may help physicians decide appropriateness of initial the 2G-TKI therapy including possible selection of appropriate haematopoietic cell transplant candidates. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Time to Surgery Does Not Affect Overall or Disease-Free Survival of Patients with Primary Resectable PDAC.

(1) Background: Delay in therapy for pancreatic ductal adenocarcinoma (PDAC) may contribute to a worse outcome. The aim of this study was to investigate the prognostic value of time from diagnosis to surgery in patients undergoing upfront surgery for primarily resectable pancreatic carcinoma. (2) Methods: This retrospective single-center study included 214 patients who underwent primary resection of PDAC from January 2000 to December 2018 at University Hospital Erlangen. Using a minimum p-value approach, patients were stratified according to time to surgery (TtS) into two groups: TtS ≤ 23 days and TtS > 23 days. Postoperative outcome and long-term survival were compared. (3) Results: Median TtS was 25 days. The best cut-off for TtS was determined as 23 days. There were no differences regarding postoperative outcome or overall survival (OS) and disease-free survival (DFS) (OS: 23.8 vs. 20.4 months, p = 0.210, respectively, and DFS: 15.8 vs. 13.6 months, p = 0.187). Multivariate analysis revealed age, lymph node metastasis, tumor differentiation and resection status as significant independent prognostic predictors for OS and DFS. (4) Conclusions: A delay of surgery > 23 days after first diagnosis does not affect overall or disease-free survival of patients with primary resectable PDAC. However, the psychological impact of a delay to patients waiting for surgery should not be underestimated.

Prognostic significance of pretreatment red blood cell distribution width in primary diffuse large B-cell lymphoma of the central nervous system for 3P medical approaches in multiple cohorts.

Predicting the clinical outcomes of primary diffuse large B-cell lymphoma of the central nervous system (PCNS-DLBCL) to methotrexate-based combination immunochemotherapy treatment in advance and therefore administering the tailored treatment to the individual is consistent with the principle of predictive, preventive, and personalized medicine (PPPM/3PM). The red blood cell distribution width (RDW) has been reported to be associated with the clinical outcomes of multiple cancer. However, its prognostic role in PCNS-DLBCL is yet to be evaluated. Therefore, we aimed to effectively stratify PCNS-DLBCL patients with different prognosis in advance and early identify the patients who were appropriate to methotrexate-based combination immunochemotherapy based on the pretreatment level of RDW and a clinical prognostic model. A prospective-retrospective, multi-cohort study was conducted from 2010 to 2020. We evaluated RDW in 179 patients (retrospective discovery cohorts of Huashan Center and Renji Center and prospective validation cohort of Cancer Center) with PCNS-DLBCL treated with methotrexate-based combination immunochemotherapy. A generalized additive model with locally estimated scatterplot smoothing was used to identify the relationship between pretreatment RDW levels and clinical outcomes. The high vs low risk of RDW combined with MSKCC score was determined by a minimal P-value approach. The clinical outcomes in different groups were then investigated. The pretreatment RDW showed a U-shaped relationship with the risk of overall survival (OS, P = 0.047). The low RDW (< 12.6) and high RDW (> 13.4) groups showed significantly worse OS (P < 0.05) and progression-free survival (PFS; P < 0.05) than the median group (13.4 > RDW > 12.6) in the discovery and validation cohort, respectively. RDW could predict the clinical outcomes successfully. In the discovery cohort, RDW achieved the area under the receiver operating characteristic curve (AUC) of 0.9206 in predicting the clinical outcomes, and the predictive value (AUC = 0.7177) of RDW was verified in the validation cohort. In addition, RDW combined with MSKCC predictive model can distinguish clinical outcomes with the AUC of 0.8348 for OS and 0.8125 for PFS. Compared with the RDW and MSKCC prognosis variables, the RDW combined with MSKCC scores better identified a subgroup of patients with favorable long-term survival in the validation cohort (P < 0.001). RDW combined MSKCC score remained to be independently associated with clinical outcomes by multivariable analysis. Based on the pretreatment RDW and MSKCC scores, a novel predictive tool was established to stratify PCNS-DLBCL patients with different prognosis effectively. The predictive model developed accordingly is promising to judge the response of PCNS-DLBCL to methotrexate-based combination immunochemotherapy treatment. Thus, hematologists and oncologists could tailor and adjust therapeutic modalities by monitoring RDW in a prospective rather than the reactive manner, which could save medical expenditures and is a key concept in 3PM. In brief, RDW combined with MSKCC model could serve as an important tool for predicting the response to different treatment and the clinical outcomes for PCNS-DLBCL, which could conform with the principles of predictive, preventive, and personalized medicine. The online version contains supplementary material available at 10.1007/s13167-022-00290-5.

Threshold heterogeneity of perioperative hemoglobin drop for acute kidney injury after noncardiac surgery: a propensity score weighting analysis

BackgroundPerioperative hemoglobin drop after noncardiac surgery is associated with acute kidney injury (AKI). However, opinion on the tolerable difference in postoperative hemoglobin drop in patients with different preoperative hemoglobin levels does not reach a consensus. This study aimed to identify hemoglobin drop thresholds for AKI after noncardiac surgery stratified by preoperative hemoglobin levels.MethodThis was a single-center retrospective cohort study for elective noncardiac surgery from January 1, 2012, to December 31, 2018. The endpoint was the occurrence of AKI 7 days postoperatively in the hospital. The generalized additive model described the non-linear relationship between hemoglobin drop and AKI occurrence. The minimum P-value approach identified cut-off points of hemoglobin drop within postoperative 7 days for patients with or without preoperative anemia. Stratified by preoperative anemia, hemoglobin drop’s odds ratio as continuous, quintile and dichotomous variables by various cut-off points for postoperative AKI were calculated in multivariate logistic regression models before and after propensity score weighting (PSW).ResultsOf the 35,631 surgery, 5.9% (2105 cases) suffered postoperative AKI. Non-linearity was found between hemoglobin drop and postoperative AKI occurrence. The thresholds and corresponding odds ratio of perioperative hemoglobin drop for patients with and without preoperative anemia were 18 g/L (1.38 (95%CI 1.14 -1.62), P < .001; after PSW: 1.42 (95%CI 1.17 -1.74), P < .001) and 43 g/L (1.81 (95%CI 1.35—2.27), P < .001; after PSW: 2.88 (95%CI 1.85—4.50), P < .001) respectively. Overall thresholds and corresponding odds ratio were 43 g/L (1.82 (95%CI 1.42—2.21)), P < .001; after PSW: 3.29 (95%CI 2.00—5.40), P < .001). Sensitivity analysis showed similar results. Heterogeneity subgroup analysis showed that intraoperatively female patients undergoing intraperitoneal surgery without colloid infusion seemed to be more vulnerable to higher hemoglobin drop. Further analysis showed a possible linear relationship between preoperative hemoglobin and perioperative hemoglobin drop thresholds. Additionally, this study found that the creatinine level changed simultaneously with hemoglobin level within five postoperative days.ConclusionsHeterogeneity of hemoglobin drop endurability exists after noncardiac non-kidney surgery. More care and earlier intervention should be put on patients with preoperative anemia.

Apparently healthy adults with high serum gamma-glutamyl transferase levels are at increased risk of asthma development in the near future: a Korean nationwide cohort study.

Serum gamma-glutamyl transferase (GGT), an indicator of oxidative stress and/or a chronic inflammatory process, is associated with the levels of leukotrienes and other inflammatory mediators that play a critical role in the pathogenesis of asthma. This study aimed at investigating whether apparently healthy subjects with higher serum GGT levels at a national health check-up are at an increased risk of developing asthma in the near future. We analyzed 564,213 Korean adults, aged 20-80 years who underwent a national general health examination, including measurement of baseline serum GGT between 2003 and 2015, using data from a large-scale representative cohort of the Korean population. Data were analyzed using a Cox proportional hazards regression analysis. In total, 516,956 participants were included in the final analysis. During the mean follow-up period of 8 years (standard deviation, 4.0), 7,439 incident asthma events occurred. We then classified the male and female participants according to quartiles of blood GGT levels (males: ≤ 20, 21-30, 31-51, and ≥ 52 IU/L; females: ≤ 12, 13-16, 17-22, and ≥ 23 IU/L, respectively). The adjusted hazard ratio (aHR) for incident asthma was significantly greater for subjects in the highest GGT quartile than for those in the lowest GGT quartile (aHR, 1.47; 95% confidence intervals, 1.36-1.59). Further, there was a significant linear trend across quartiles with regard to asthma (ptrend<0.001). We estimated the optimal cut-off values (using the minimum p-value approach) as 35 IU/L for the total population, 35 IU/L for males, and 36 IU/L for females, respectively. Clinicians should be aware of the risk of incident asthma in healthy subjects with elevated GGT levels. Our findings advance our understanding of asthma pathogenesis.

The Prognostic Relevance of Preoperative CEA and CA19-9 for Ampulla of Vater Carcinoma.

Increased serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA19-9) are established prognostic factors in ampulla of Vater carcinoma (AC). We determined the best cut-off values of preoperative CEA and CA19-9 and compared the prognostic power of preoperative CEA with that of preoperative CA19-9 for overall survival (OS). A total of 116 consecutive patients without jaundice who underwent macroscopic curative resection for AC between January 2002 and August 2019 were enrolled. Using the minimum p-value approach based on the OS, the optimal CEA cut-off value was found to be 6.5 ng/ml; however, the cut-off value of CA19-9 could not be determined, as no significant p value was identified. The OS of the patients with CEA >6.5 ng/ml (n=5; 3-year OS, 20.0%) was significantly worse than that with CEA ≤6.5 ng/ml (n=111; 3-year OS, 76.6%; p<0.001). A Cox proportional hazards analysis for OS revealed CEA >6.5 ng/ml (hazard ratio=4.01, p=0.019) to be an independent prognostic factor. In patients with AC, although the CA19-9 optimal cut-off value could not be determined, CEA >6.5 ng/ml independently affected long-term survival after resection.

Clinico-bacterial and prognostic factors in patients with suspected blood stream infection and elevated serum procalcitonin levels.

ABSTRACTThis study determined prognostic factors by comparing clinico-bacterial factors based on significant elevated serum procalcitonin levels in patients with suspected bloodstream infection (BSI). We retrospectively analyzed the medical records of 1,052 patients (age ≥16 years) with fever (temperature ≥38°C) and serum procalcitonin levels of ≥2.0 ng/mL, and blood culture results. The optimal cutoff value of the significant elevation of procalcitonin was determined using the minimum P-value approach. Clinico-bacterial factors were analyzed per the procalcitonin levels, and significant independent factors for short-term survival were investigated in 445 patients with BSI. Patients with suspected BSI were aged, on average, 72.3 ± 15.1 years, and the incidence of positive blood culture was 42.3%; and the 14-day survival was 83.4%. Procalcitonin ≥100 ng/mL was the most significant predictor for survival. Multivariate analysis in patients with suspected BSI showed that estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 and procalcitonin ≥100 ng/mL were significant independent unfavorable prognostic factors. Microorganisms were similar between patients with procalcitonin level 2–99 ng/mL (n=359) and those with ≥100 ng/mL (n=86). Multivariate analysis in patients with BSI showed that eGFR <30 mL/min/1.73 m2, procalcitonin ≥100 ng/mL, and primary infectious foci were significant independent prognostic factors. Patients with foci in the gastrointestinal tract and respiratory system had unfavorable 14-day survival. In conclusions, eGFR <30 mL/min/1.73 m2 and procalcitonin ≥100 ng/mL were significant independent unfavorable prognostic factors for suspected BSI. Primary infectious foci (gastrointestinal tract and respiratory system) were associated with unfavorable short-term survival in patients with positive blood culture.

Association Between the Frailty Index and Clinical Outcomes after Coronary Artery Bypass Grafting.

BackgroundThis study investigated the predictive value of the frailty index calculated using laboratory data and vital signs (FI-L) in patients who underwent coronary artery bypass grafting (CABG).MethodsThis study included 508 patients (age 67.3±9.7 years, male 78.0%) who underwent CABG between 2018 and 2021. The FI-L, which estimates patients’ frailty based on laboratory data and vital signs, was calculated as the ratio of variables outside the normal range for 32 preoperative parameters. The primary endpoints were operative and medium-term all-cause mortality. The secondary endpoints were early postoperative complications and major adverse cardiac and cerebrovascular events (MACCEs).ResultsThe mean FI-L was 20.9%±10.9%. The early mortality rate was 1.6% (n=8). Postoperative complications were atrial fibrillation (n=148, 29.1%), respiratory complications (n=38, 7.5%), and acute kidney injury (n=15, 3.0%). The 1- and 3-year survival rates were 96.0% and 88.7%, and the 1- and 3-year cumulative incidence rates of MACCEs were 4.87% and 8.98%. In multivariable analyses, the FI-L showed statistically significant associations with medium-term all-cause mortality (hazard ratio [HR], 1.042; 95% confidence interval [CI], 1.010–1.076), MACCEs (subdistribution HR, 1.054; 95% CI, 1.030–1.078), atrial fibrillation (odds ratio [OR], 1.02; 95% CI, 1.002–1.039), acute kidney injury (OR, 1.06; 95% CI, 1.014–1.108), and re-operation for bleeding (OR, 1.09; 95% CI, 1.032–1.152). The minimal p-value approach showed that 32% was the best cutoff for the FI-L as a predictor of all-cause mortality post-CABG.ConclusionThe FI-L was a significant prognostic factor related to all-cause mortality and postoperative complications in patients who underwent CABG.

Predictive risk factors for early recurrence in patients with localized pancreatic ductal adenocarcinoma who underwent curative-intent resection after preoperative chemoradiotherapy.

BackgroundThe optimal surgical indication after preoperative chemoradiotherapy (CRT) remains a subject of debate for patients with pancreatic ductal adenocarcinoma (PDAC) because early recurrence often occurs even after curative-intent resection. The present study aimed to identify perioperative risk factors of early recurrence for patients with PDAC who underwent curative-intent resection after preoperative CRT.MethodsTwo hundred three patients with PDAC who underwent curative-intent resection after preoperative CRT from February 2005 to December 2018 were retrospectively analyzed. The optimal threshold for differentiating between early and late recurrence was determined by the minimum p-value approach. Multivariate regression analysis was performed to identify predictive factors for early recurrence.ResultsIn 130 patients who developed recurrence after resection, 52 who had an initial recurrence within 12 months were defined as the early recurrence group, and the remaining 78 were defined as the late recurrence group. The incidence of hepatic recurrence was significantly higher in the early recurrence group than in the late recurrence group (39.7 vs. 15.4%). The early recurrence group had significantly lower 3-year rates of post-recurrence and overall survival than the late recurrence group (4.0 and 10.7% vs. 9.8 and 59.0%, respectively). Serum level of CA19-9 before surgery ≥56.8 U/ml was identified as an independent risk factor for early recurrence (OR:3.07, 95%CI:1.65–5.73, p<0.001) and associated with a significantly higher cumulative incidence rate of hepatic recurrence and lower rates of recurrence-free and overall survival.ConclusionSerum level of CA19-9 before surgery after preoperative CRT was a strong predictive factor for early recurrence.