Not Available Research Articles

Assessing the prognostic role of panimmune inflammation in high-grade gliomas.

High-grade gliomas are aggressive brain tumors with poor prognoses. Understanding the factors that influence their progression is crucial for improving treatment outcomes. This study investigates the prognostic significance of panimmune inflammation in patients diagnosed with high-grade gliomas. Data from 89 high-grade glioma patients were analysed retrospectively. The Panimmune inflammation Value (PIV) of each patient meeting the eligibility criteria was calculated on the basis of platelet, monocyte, neutrophil, and lymphocyte counts obtained from peripheral blood samples taken on the first day of treatment. PIV is calculated using the following formula: PIV = T × M × N ÷ L. A receiver operating characteristic (ROC) analysis was employed to identify the optimal cut-off value for PIV about progression-free survival (PFS) and overall survival (OS) outcomes. The primary and secondary endpoints were the differences in OS and PFS between the PIV groups. The Kaplan‒Meier method was used for survival analyses. The ROC analysis indicated that the optimal PIV threshold was 545.5, which exhibited a significant interaction with PFS and OS outcomes. Patients were subsequently divided into two groups based on their PIV levels: a low PIV (L-PIV) group comprising 45 patients and a high PIV (H-PIV) group comprising 44 patients. A comparative analysis of survival rates indicated that patients with elevated PIV had a shorter median PFS of 4.0months compared to 8.0months in the low PIV group (P = 0.797), as well as a reduced median OS of 19.0months versus not available (NA) in the low PIV group (P = 0.215). Our study results did not reveal a statistically significant association between H-PIV measurements and reduced PFS or OS. However, PIV effectively stratified newly diagnosed high-grade glioma patients into two distinct groups with significantly different PFS and OS outcomes.

Proteomic analysis of breast cancer based on immune subtypes

BackgroundImmunotherapy is applied to breast cancer to resolve the limitations of survival gain in existing treatment modalities. With immunotherapy, a tumor can be classified into immune-inflamed, excluded and desert based on the distribution of immune cells. We assessed the clinicopathological features, each subtype’s prognostic value and differentially expressed proteins between immune subtypes.MethodsImmune subtyping and proteomic analysis were performed on 56 breast cancer cases with neoadjuvant chemotherapy. The immune subtyping was based on the level of tumor-infiltrating lymphocytes (TILs) and Klintrup criteria. If the level of TILs was ≥ 10%, it was classified as immune-inflamed type without consideration of the Klintrup criteria. In cases of 1–9% TIL, Klintrup criteria 1–3 were classified as the immune-excluded subtype and Klintrup criteria not available (NA) was classified as NA. Cases of 1% TILs and Klintrup 0 were classified as the immune-desert subtype. Mass spectrometry was used to identify differentially expressed proteins in formalin-fixed paraffin-embedded biopsy tissues.ResultsOf the 56 cases, 31 (55%) were immune-inflamed, 21 (38%) were immune-excluded, 2 (4%) were immune-desert and 2 (4%) were NA. Welch’s t-test revealed two differentially expressed proteins between immune-inflamed and immune-excluded/desert subtypes. Coronin-1A was upregulated in immune-inflamed tumors (adjusted p = 0.008) and α-1-antitrypsin was upregulated in immune-excluded/desert tumors (adjusted p = 0.008). Titin was upregulated in pathologic complete response (pCR) than non-pCR among immune-inflamed tumors (adjusted p = 0.036).ConclusionsCoronin-1A and α-1-antitrypsin were upregulated in immune-inflamed and immune-excluded/desert subtypes, respectively. Titin's elevated expression in pCR within the immune-inflamed subtype may indicate a favorable prognosis. Further studies involving large representative cohorts are necessary to validate these findings.

PATH-10. SURGICALLY RESECTED RECURRENT DIFFUSE GLIOMAS: HISTOMOLECULAR SPECTRUM

Abstract Histological treatment-related changes (TRC) may mimic radiological progression in diffuse-gliomas on follow-up after complete therapy. If scans suggest recurrence, patients undergo re-surgery& re-RT, if recurrence is histologically confirmed. We evaluated 1) baseline characteristics of surgically-resected gliomas re-operated for clinicoradiological suspected recurrence; 2) compared histological changes from initial surgery. All adult-type diffuse-gliomas (n=122) re-operated following complete therapy, with available initial& subsequent slides reviewed, classified as per current WHO classification. Clinico-pathological features noted. RESULTS: Baseline median age:36years (IQR:29-44years), M:F=2.21, tumor-bed recurrence in majority (116/122). Of 92 astrocytomas, 47 were IDH-mutant (grade-2:18, grade-3:14, grade-4:15); 31 were IDH-WT (histological grade-2:4, grade-3:5, grade-4:22), IDH not-available (NA) in 14. Among IDH-mutant, 26 were MGMT-methylated (MGMT-M), 11 unmethylated (MGMT-UM). In IDH-WT 4 were MGMT-M, 23 MGMT-UM. Of 30 oligodendrogliomas, 21 were grade-2, 9 grade-3. All grade-2 gliomas (25astrocytoma, 21oligodendroglioma) showed high-grade transformation at re-surgery, with 40% astrocytoma upgrading to grade-3; 60% to grade-4. Six grade-3 astrocytoma recurred at same grade, while 18 as grade-4. Of 43 grade-4, on re-surgery 11 showed predominantly TRC ( >30%) with quiescent residual tumor (4 IDH-mutant, 5 IDH-WT, 2NA), while 32 showed recurrence (10 IDH-mutant, 18 IDH-WT, 4NA), of which 11 had scant (<5%) to focal (6-30%) TRC along-with actively proliferating tumor. Only 2 oligodendrogliomas showed TRC. Median disease-free interval (DFI) between both surgeries was significantly higher for oligodendroglioma (6.76years) than astrocytoma (3.59years, p-value< 0.001); for grade-2 (5.37years)& grade-3 astrocytoma (5.19years) than grade-4 (2.85years, p-value< 0.001); grade-2 versus grade-3 oligodendroglioma (7.02years versus 4.91years, p-value 0.041), &for MGMT-M versus MGMT-UM (5.17 versus 3.02years, p-value< 0.01). Significantly, median DFI was lower for grade-4 astrocytoma with TRC than without (2.34 versus 3.27years, p-value 0.015). CONCLUSIONS: Pseudo-progression gets confused with progression more commonly in high-grade gliomas than low-grade gliomas, and is associated with surgery closer to therapy completion. Careful histological assessment thus may help guide management.

Application of Soft-Clustering Analysis Using Expectation Maximization Algorithms on Gaussian Mixture Model

Research on soft-clustering has not been explored much compared to hard-clustering. Soft-clustering algorithms are important in solving complex clustering problems. One of the soft-clustering methods is the Gaussian Mixture Model (GMM). GMM is a clustering method to classify data points into different clusters based on the Gaussian distribution. This study aims to determine the number of clusters formed by using the GMM method. The data used in this study is synthetic data on water quality indicators obtained from the Kaggle website. The stages of the GMM method are: imputing the Not Available (NA) value (if there is an NA value), checking the data distribution, conducting a normality test, and standardizing the data. The next step is to estimate the parameters with the Expectation Maximization (EM) algorithm. The best number of clusters is based on the biggest value of the Bayesian Information Creation (BIC). The results showed that the best number of clusters from synthetic data on water quality indicators was 3 clusters. Cluster 1 consisted of 1110 observations with low-quality category, cluster 2 consisted of 499 observations with medium quality category, and cluster 3 consisted of 1667 observations with high-quality category or acceptable. The results of this study recommend that the GMM method can be grouped correctly when the variables used are generally normally distributed. This method can be applied to real data, both in which the variables are normally distributed or which have a mixture of Gaussian and non-Gaussian.

PREVENTION CAN BE THE BEST TOOL FOR ADULT T-CELL LEUKEMIA. UPDATED T-CELL BRAZIL PROJECT

T-cell Brazil project started in April 2017 an ambispective study focusing to collecting epidemiological and clinical data from the most frequent subtypes of PTCL, among them the ATL. As of July 2022 T-cell Brazil database contained 81 (16%) ATL out of 520 registered cases. Our goals are to describe demographic and clinical features, analyze the overall and progression-free survival (OS and PFS), and try to identify factors that could influence outcome. Brazilian Registry using REDcap Platform by Vanderbilt realized descriptive and bivariate analyses, then it was applied Kaplan-Meier method and log-rank test to obtain survival estimates, and besides that, it was used the Cox Regression to identify any factor that could influence the OS and PFS. The median age was 52 years (24-91); 32 (39%) male; the majority of clinical subtypes were 52% lymphoma type; 81% received chemotherapy. The best response assessment after first-line treatment was: progression or no response in 31%; 26% complete response; 21% partial response, 21% not available (NA) due to death or on treatment; 34% of patients were alive and the 24-month OS and PFS was 33% and 21%, respectively. As predictors for PFS and OS were B symptom and elevated LDH values. This study, even recognizing a limited sample size, highlights the poor prognosis associated with ATL, mainly acute and lymphoma type, with high mortality rates. Hence, apparently, a good shot, it would be one of the bases for the prevention of ATL to establish a disease entity of “chronic active HTLV-1 infection” that defines high-risk carriers for ATL development, and then, enables preventive intervention.

Prognostic significance of lung metastasis-related finding in lenvatinib treatment for differentiated thyroid cancer.

This study aimed to analyze the clinical course of patients with differentiated thyroid cancer (DTC) who were treated by lenvatinib and investigate the specific criteria for the initiation of lenvatinib in lung metastasis. A total of 111 patients with DTC treated by lenvatinib were included in the study. Patients were divided into two groups based on the target lesion for the initiation of lenvatinib: lung metastasis group and other metastases group. In the univariate analysis, the tumor size for the lung metastasis (p = 0.002) and the factor of lung metastasis group (p < 0.001) were significantly associated with overall survival (OS). Multivariate analysis revealed that the factor of lung metastasis group [hazard ratio, 0.408; 95% confidence interval (CI), 0.206-0.810; p = 0.010] was the only independent prognostic factor of OS. Of the 53 patients in the lung metastasis group, 12 (23%) had lung metastasis-related finding such as pleural effusion (n = 12), hemoptysis (n = 2), and dyspnea (n = 1) at the initiation of lenvatinib treatment. The median OS in patients with or without lung metastasis-related findings were 41.0 [95% CI, 10.4-not available (NA)] months and 62.9 (95% CI, 53.0-NA) months, respectively (p = 0.022). Patients with lung metastasis-related finding at the initiation of lenvatinib treatment had a poorer prognosis among the lung metastasis group. It is important to consider not only the tumor size but also the presence of lung metastasis-related findings when initiating lenvatinib treatment for DTC patients with lung metastasis.

PB1993: MULTIPLE MYELOMA BRAZILIAN REGISTER- HOW ABOUT THE TRANSPLANT ELIGIBLE PATIENTS?

Background: The Brazilian Multiple Myeloma Group (GBRAM) developed an electronic database platform with the intention of prospectively registering the multiple myeloma (MM) cases diagnosed in the Brazilian healthcare system and analyzing the disease characteristics, treatments patterns and the outcomes. Aims: Describe characteristics, treatment and outcomes from MM transplant eligible patients belonging to GBRAM prospective database plataform. Methods: This is a prospective, multicenter data-based platform. This analysis was focused on the MM transplant eligible patients (TE). The MM patients diagnosed after January 1, 2018 have been included. The eligibility criteria were: intent-to-treat (ITT) MM patients, aged over 18 years and under care in any healthcare system (private and public). All clinical and laboratory data, prognostic profiling, treatment patterns and responses, adverse events and survival were compiled. The data were analyzed with the NCSS® 2020 software. This project is registered in the Brazilian study platform (CAAE-05340918.3.1001.8098). Results: A total of 915 patients were registered with transplant intent-to-treat. The median age was 59 (25 - 80) years and 475 (51.9%) were male. A total of 413 (45.1%) of the patients were nonwhite. According to the (ECOG) rating at diagnosis: 0 = 217 (32.9%), 1 = 222 (33.7%), 2 = 110 (17.6%), 3 = 71 (10.85%) and 4 = 39 (5.9%). The ISS 1, 2, and 3 were 209 (25.7%), 228 (28.1%) and 303 (37.2%), respectively, and 72 (8.9%) not available (NA). The respective isotypes were: 466 (52.5%) IgG, 168 (18.9%) IgA, 158 (17.8%) free-light chain, 15(1.7%) non-secretor and 68 (7.7%) NA. Stratifying the intent-to-treat TE patients according to healthcare system, 178 (19.5%) and 737 (80.5%) were from the private and public systems, respectively. Among the patients who underwent the transplant, 89 (66.4%) belonged to the private system and 154 (32.6%), the public. The induction chemotherapy treatments in the public system were: 366 (59%) based on thalidomide, 226 (36.5%) based on bortezomib and 21 (3.4%) based on daratumumab. In the private system the induction treatments were: 7 (4.2%) based on thalidomide, 135 (75.8%) based on bortezomib and 31 (18.8%) based on daratumumab. After a median follow-up of 18.4 months, the complete response (RC) rate post transplant was 13.5% for the public and 28.7% for the private system, respectively (p < 0.01). Summary/Conclusion: This prospective register enrolled patients diagnosed since January 2018 and is of a nationwide scope. Our register, in addition to identifying the epidemiological characteristics of the Brazilian multiple myeloma patients, demonstrates the treatment standards at the public and private institutions. Patients eligible for transplant have greater access to the procedure at private institutions than at public ones (p < 0.001), as well as to better chemotherapy induction protocols. The complete remission (CR) rate following transplant was greater in the private system than in the public and, with a longer follow-up, it will be possible to demonstrate the impact of the treatments on the survival in patients eligible for transplant.

Feasibility of Applying Novel FDP Threshold Criteria to DIC Diagnostic Scoring Systems in Japanese Women with Placental Abruption

<i>Objectiv</i>e: The diagnosis of disseminated intravascular coagulation (DIC) in obstetrics characterized by marked elevation of fibrin/fibrinogen degradation products (FDP) requires specific FDP criteria, however, no reference values are currently available. We previously reported the FDP criteria reflecting the degree of coagulation activity, determined by the quantitative relation between the distributions of FDP and fibrinogen. We aimed to evaluate the feasibility of applying the novel FDP criteria to four existing DIC diagnostic scoring systems, in a retrospective study of Japanese women with placental abruption. <i>Materials and Methods</i>: The study population was 68 pregnant women who had been diagnosed with placental abruption at Okayama Medical Center (Japan) between January 2008 and December 2020. DIC was clinically determined using the following four categories: plasma fibrinogen level < 100 mg/dl, hemorrhage amount at delivery ≥ 2000 g, blood product (red blood cells and fresh frozen plasma) transfusion, and renal dysfunction. Based on our previous report on the artificial intelligence analysis of the FDP distribution function, FDP criteria for the normal upper limit, moderate increase, and marked increase were defined as 20, 32, and 80 μg/ml, respectively. We applied the FDP criteria to compare four current and revised DIC diagnostic scoring systems: Japanese Ministry of Health and Welfare (JMHW), Japanese Association for Acute Medicine (JAAM), International Society on Thrombosis and Haemostasis (ISTH), and pregnancy-modified ISTH (PM-ISTH) DIC score. We used the Kruskal-Wallis test, Wilcoxon rank-sum test, and proportion test for statistical analysis. <i>Results</i>: Clinical DIC was observed in nine cases. Sensitivity was 1.00 in all DIC scoring systems. The current/revised sensitivity of the JMHW, JAAM, ISTH, and PM-ISTH systems was 1.00/1.00, 1.00/1.00, not available (NA)/1.00, and 1.00/NA, respectively. The current/revised specificity of the JMHW, JAAM, ISTH, and PM-ISTH systems was 0.864/0.864, 0.678/0.797, NA/0.864, and 0.424/NA, respectively. The specificity of the revised JMHW and revised ISTH systems was higher than for the current JAAM (<I>P </I>< 0.05) and current PM-ISTH (<I>P </I>< 0.0001) systems. The specificity of the revised JAAM improved from 0.678 to 0.797. <i>Conclusion</i>: Our novel proposed FDP criteria are potentially useful for diagnosis of DIC in placental abruption.

Assessment of various efficacy outcomes using ERIVANCE-like criteria in patients with locally advanced basal cell carcinoma receiving sonidegib: results from a preplanned sensitivity analysis

BackgroundThe BOLT study for sonidegib, a Hedgehog pathway inhibitor (HHI) approved for patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy, used modified Response Evaluation Criteria in Solid Tumors (mRECIST) for laBCC tumor evaluation. The ERIVANCE study for vismodegib, another HHI, used a composite RECIST endpoint of ≥30% reduction in externally visible tumor or radiographic dimension, or complete ulceration resolution. This preplanned sensitivity BOLT analysis evaluated efficacy outcomes using ERIVANCE-like criteria in patients with laBCC who received sonidegib 200 mg once daily.MethodsThis phase 2, double-blind study randomized patients 1:2 to sonidegib 200:800 mg daily, respectively. Key endpoints included objective response rate (ORR), duration of response (DOR), complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). laBCC tumors were assessed by both mRECIST and ERIVANCE-like criteria. Per mRECIST, an overall response of CR was based on negative histology; photographic assessment of CR, PR (scar/fibrosis only), SD (scar/fibrosis only), or not available (NA); and a magnetic resonance imaging response of CR or NA. An overall response of CR was primarily based on negative histology using ERIVANCE-like criteria.ResultsPer mRECIST criteria, ORR (95% confidence interval [CI]) by central and investigator review for patients with laBCC (n = 66) was 56.1% (43.3–68.3%) and 71.2% (58.7–81.7%), respectively. CR per central review was achieved in 3 (4.5%) patients and PR, SD, and PD occurred in 34 (51.5%), 23 (34.8%), and 1 (1.5%) patient, respectively. Median (95% CI) DOR was 26.1 months (not estimable [NE]).Using ERIVANCE-like criteria, efficacy outcomes per central and investigator review were higher, with an ORR (95% CI) of 60.6% (47.8–72.4%) and 74.2% (62.0–84.2%), respectively. CR per central review was reached in 14 (21.2%) patients and PR, SD, and PD occurred in 26 (39.4%), 20 (30.3%), and 1 (1.5%) patient, respectively. DOR was unchanged with a median (95% CI) of 26.1 months (NE).ConclusionsOverall, applying ERIVANCE-like criteria to patients with laBCC receiving sonidegib 200 mg daily yielded higher response rates vs mRECIST criteria.Trial registrationBOLT registration: ClinicalTrials.gov (NCT01327053) on March 30, 2011.

Ambulatory Care Pharmacist Perception of Formulary Medication Shortage: Tertiary Center Experience.

Background: Medication shortage is a serious issue affecting public health and patient care. It causes a major burden on the medical team of a healthcare organization in the delivery of quality care. Objectives: This study aims to assess the perception of ambulatory care pharmacist about formulary medication shortage as well as to assess the rate of medication shortage and explore the highest classes of the not-available (NA) medication. Methods: A cross-sectional survey was performed to assess pharmacist perception regarding medication shortage. The data for NA medication was collected from the hospital health information system "HIS" (Best care) to investigate the type and classes of medication shortage. Results: The overall survey response rate was 92.7%. The majority (61%) of participants encountered 5 to 15 labels of NA medication per day, 43% of participants encountered unpleasant behavior from patients usually due to NA medication and the main reason of patient dissatisfaction was the negative effect of NA medication on their course of therapy. Ninety-seven percent of participants agreed that medication shortage adds extra pressure/workload and 66% agreed that medication shortage increases the chance of medication error. A total of 113 medication shortage was recorded between January and March 2020. The 2 drug classes, which showed maximum shortage, were gastrointestinal and cardiovascular medications. The most prevalent type of medication shortage was for drugs administered by oral route (91.2%). Conclusions: The study provides insights into the frequency, management, and problems confronted due to medication shortage from the pharmacist perception. The study findings highlight the classes and type of medication shortage in the hospital which needs intervention to enhance patient care. The findings of the study would help the higher administration to implement an effective strategy to mitigate the shortage of medication, improve patient satisfaction, and to reduce pharmacist workload.

Patency period of a metallic ureteral stent and its determinants in patients with malignant ureteral obstruction: a prospective review

BackgroundMalignant ureteral obstruction caused by extrinsic compression of a primary malignant tumour or by metastatic disease is an indicator of poor prognosis with a median life expectancy of about one year. We examined clinical outcomes following Resonance Metallic Ureteral Stent (Cook Medical, Bloomington, IN) placement in patients with malignant ureteral obstruction.MethodsThis was a prospective study of patients with malignant ureteral obstruction who underwent Resonance Metallic Ureteral Stent placement from April 2016 to March 2021. We registered 21 patients (27 collecting systems) with malignant ureteral obstruction and observed them prospectively. The patients first underwent polymer ureteral stent placement followed by replacement with a metallic ureteral stent one month later. Primary outcome was the metallic ureteral stent patency period based on both serum creatinine and the level of hydronephrosis; secondary outcomes were factors affecting patency period and stent-related complications such as symptoms of obstruction (flank pain), bladder irritation, haematuria, and urinary tract infection (presence or absence of fever).ResultsThe study comprised 21 patients (six men, 15 women) with a mean age of 72 years. The median stent patency period in days was not available (NA) (95% CI 210–NA) due to the inability to extract this value from the Kaplan–Meier curve because the event rate did not reach 50%, and the one-year patency rate was 59.2% (95% CI 23.2–82.9). A normal serum creatinine (0.65 to 1.07 mg/dL for men and 0.46 to 0.79 mg/dL for women) one week after polymer ureteral stent placement was a significant factor affecting the long-term metallic ureteral stent patency period. There were no major complications.ConclusionThe Resonance Metallic Ureteral Stent was effective and safe for patients with malignant ureteral obstruction. A normal serum creatinine level one week after placement of a polymer ureteral stent may predict a longer patency period of metallic ureteral stents in patients with malignant ureteral obstruction.

Beyond BRCA Status: Clinical Biomarkers May Predict Therapeutic Effects of Olaparib in Platinum-Sensitive Ovarian Cancer Recurrence

The purpose of this study was to investigate the predictors of the effect of olaparib on platinum-sensitive recurrent ovarian cancer with unknown germline BRCA mutations. We retrospectively examined 20 patients with platinum-sensitive ovarian cancer who were treated at the Nippon Medical School Chiba Hokusoh Hospital, Japan, from 2018 to 2020. We found that the median progression-free survival was 11.4 months (95% Confidence interval (CI): 3.8–Not Available (NA)) in the group with NLPN score [recurrent neutrophil-lymphocyte ratio (rNLR) × number of previous regimens] >7.51, and median progression-free survival was not reached in the group with NLPN score <7.51 (95% CI: 21.8–NA) (p = 0.0185). There was a clear correlation between the degree of dose reduction of olaparib and recurrence (p = 0.00249). Our results show that NLPN scores lower than 7.51 are associated with a favorable outcome of olaparib treatment for platinum-sensitive recurrent ovarian cancer. In cases with a high rNLR, it may be necessary to start olaparib treatment as early as possible to obtain low NLPN scores. Our results imply that the effectiveness of olaparib can be determined after recurrence and before platinum treatment begins. As newer drugs for ovarian cancer are developed, the measurement of biomarker levels at the start of treatment for recurrent ovarian cancer, as shown in our study, may provide strong support for cancer treatment protocols.

Derivation and validation of a lipid-covered prognostic model for mature T-cell lymphomas

BackgroundMature T-cell lymphomas (MTCLs), a group of diseases with high aggressiveness and vulnerable prognosis, lack for the accurate prognostic stratification systems at present. Novel prognostic markers and models are urgently demanded. Aberrant lipid metabolism is closely related to the tumor progression but its prognostic significance in MTCLs remains unexplored. This study aims to investigate the relationship between dysregulated lipid metabolism and survival prognosis of MTCLs and establish a novel and well-performed prognostic scoring system for MTCL patients.MethodsA total of 173 treatment-naive patients were enrolled in this study. Univariate and multivariate Cox regression analysis were performed to assess the prognostic significance of serum lipid profiles and screen out independent prognostic factors, which constituted a novel prognostic model for MTCLs. The performance of the novel model was assessed in the training and validation cohort, respectively, by examining its calibration, discrimination and clinical utility.ResultsAmong the 173 included patients, 115 patients (01/2006–12/2016) constituted the training cohort and 58 patients (01/2017–06/2020) formed the validation cohort. Univariate analysis revealed declined total cholesterol (TC, P = 0.000), high-density lipoprotein cholesterol (HDL-C, P = 0.000) and increased triglycerides (TG, P = 0.000) correlated to inferior survival outcomes. Multivariate analysis revealed extranodal involved sites ≥ 2 (hazard ratio [HR]: 2.439; P = 0.036), β2-MG ≥ 3 mg/L (HR: 4.165; P = 0.003) and TC < 3.58 mmol/L (HR: 3.338; P = 0.000) were independent predictors. Subsequently, a novel prognostic model, EnBC score, was constructed with these three factors. Harrell’s C-index of the model in the training and validation cohort was 0.840 (95% CI 0.810–0.870) and 0.882 (95% CI 0.822–0.942), respectively, with well-fitted calibration curves. The model divided patients into four risk groups with distinct OS [median OS: not available (NA) vs. NA vs. 14.0 vs. 4.0 months, P < 0.0001] and PFS (median PFS: 84.0 vs. 19.0 vs. 8.0 vs. 1.5 months, P < 0.0001). Time-dependent receiver operating characteristic curve and decision curve analysis further revealed that EnBC score provided higher diagnostic capacity and clinical benefit, compared with International Prognostic Index (IPI).ConclusionFirstly, abnormal serum lipid metabolism was demonstrated significantly related to the survival of MTCL patients. Furthermore, a lipid-covered prognostic scoring system was established and performed well in stratifying patients with MTCLs.

Assessing the Benefit-Risk Ratio of Approved Treatments for Bipolar Depression Using Likelihood to be Helped or Harmed (LHH) Analyses

Four medications are FDA approved for bipolar depression: lurasidone (LUR), cariprazine (CAR), quetiapine IR & XR (QUE), and olanzapine-fluoxetine combination (OFC). Indirect comparisons for efficacy using Number Needed to Treat (NNT) and for tolerability using Number Needed to Harm (NNH) can be useful clinical benchmarks to aid treatment decisions. Benefit and risk may also be examined using the Likelihood to be Helped or Harmed (LHH). In this post-hoc analysis, we examined the benefit-risk ratio of the four treatments using LHH. Individual and pooled monotherapy data from short-term clinical registration trials of patients with bipolar depression were assessed for LUR, CAR, pooled QUE (300 and 600 mg), and pooled OFC (considered as monotherapy for this study at fixed doses of 6/25, 6/50, 12/50 mg) data. NNT estimates were calculated using the proportions of MADRS responders (defined as ≥ 50% improvement at study endpoint) and MADRS remitters (defined as a score of ≤ 10 [for LUR and CAR] and ≤ 12 [for QUE and OFC]) at study endpoint. NNH data were calculated for the proportions of patients who discontinued due to an adverse event (AE) and for individual AEs commonly associated with each treatment. LHH was calculated as the ratio of NNH/NNT to determine the benefit-risk ratio. The NNT estimates for response vs. placebo were: 5 for both LUR 20-60 mg and 80-120 mg; 10 for both CAR 1.5 mg and 3.0 mg; 6 for QUE; and 4 for OFC. The NNTs for remission vs placebo were: 7 for LUR 20-60 mg and 9 for LUR 80-120 mg; 10 for CAR 1.5 mg and 13 for CAR 3.0 mg; 6 for QUE; and 5 for OFC. The NNH estimates for discontinuations due to AEs were: 642 for LUR 20-60 mg and -151 for LUR 80-120 mg; 298 for CAR 1.5 mg and 31 for CAR 3.0 mg; 10 for QUE; and -37 for OFC. NNH values that were negative were assigned a value of 1000 to permit LHH to be calculated. The LHHs for response vs discontinuation due to an AE were: 128.4 for LUR 20-60 mg and 200 for LUR 80-120 mg; 29.8 for CAR 1.5 mg and 3.1 for CAR 3.0 mg; 1.7 for QUE; and 250 for OFC. The LHHs for response vs akathisia were: 3.6 for LUR 20-60 mg and 2.4 for LUR 80-120 mg; 3.6 for CAR 1.5 mg and 1.3 for CAR 3.0 mg; 34 for QUE; and not available (NA) for OFC. The LHHs for response vs EPS were: 8 for LUR 20-60 mg and 3.2 for LUR 80-120 mg; 5 for CAR 1.5 mg and 2.5 for CAR 3.0 mg; NA for QUE; and NA for OFC. The LHH for response vs weight gain was 5.8 for LUR 20-60 mg and 1110 for LUR 80-120 mg; 5 for both doses of CAR; 2.7 for QUE; and 1.5 for OFC. LHH can illustrate the trade-offs regarding potential benefits versus potential harms. Across a variety of measures, the lower-dose groups for both LUR and CAR generally evidenced a better benefit-risk profile than the higher-dose groups. While quetiapine and OFC demonstrated robust efficacy, their reduced tolerability resulted in a more marginal benefit-risk ratio for some of the outcomes. Sunovion Pharmaceuticals Inc.

Feasibility and Safety of Endoluminal Radiofrequency Ablation as a Rescue Treatment for Bilateral Metal Stent Obstruction Due to Tumor Ingrowth in the Hilum: A Pilot Study.

Background. Radiofrequency ablation (RFA) is a palliative method known for its application in the endoscopic treatment of malignant bile duct obstruction. It may be a useful rescue method for metal stent malfunction caused by tumor ingrowth. This study aimed to examine the feasibility and safety of endoluminal RFA for occluded bilateral hilar metal stents due to tumor ingrowth in patients with malignant hilar bile duct obstruction. Methods: From March 2016 to June 2018, 11 patients with unresectable malignant hilar bile duct stricture with occluded bilateral hilar metal stents due to tumor ingrowth were enrolled. Endoluminal RFA was performed through a novel temperature-controlled catheter at a setting of 7 W power for 120 s with a target temperature of 80 °C via endoscopic retrograde cholangiopancreatography (ERCP). The patients’ demographics, clinical outcomes, and adverse events were investigated. Results: The median age was 64 (interquartile range, 54–72) years. All RFA procedures were successful. Clinical success was achieved in eight patients (72.7%). During the follow-up, eight patients (72.7%) showed stent dysfunction, and the median patency after RFA was 50 days (95% confidence interval (CI): 34–not available (NA)). All stent dysfunctions were successfully managed with ERCP. Ten patients died, and the median overall survival was 289 days (95% CI, 107–NA) from RFA to death. There was one case of mild abdominal pain after the procedure without serious adverse events. Conclusions: As a rescue therapy for occluded bilateral hilar metal stents due to tumor ingrowth, endoluminal RFA seemed to be safe and useful in selected patients.

Patterns Of Care And Outcomes Analysis For Adult Patients With Newly Diagnosed Medulloblastoma: A 30-Year Single Institution Experience

Medulloblastoma in the adult population is a rare disease with limited data regarding patient prognosis and appropriate course of treatment. A recent NCDB analysis correlated adjuvant chemoradiation to improved overall survival (OS). We performed a study of adult (age ≥18 years old) medulloblastoma patients to better understand outcomes and prognostic factors. An IRB approved chart review of adult medulloblastoma patients treated at our institution with 6-month minimum follow-up was conducted. We collected patient, disease, and treatment characteristics and outcomes including OS, progression-free survival (PFS), local control (LC), and freedom from distant metastasis (FDM). Uni- and multivariable survival analyses were performed using Cox regression model. OS was estimated using Kaplan-Meier (KM) test methods. Statistical analysis was performed with JMP version 15.0 software with statistical significance established for p-values < 0.05. Thirty-two patients were treated (1992-2018) with postoperative radiotherapy (RT) including tumor bed/posterior fossa (median dose: 3600 cGy/20 fractions) and craniospinal irradiation (median dose: 2340 cGy/13 fractions) either alone (n = 10; 31%) or with adjuvant chemotherapy (aCTH: n = 22; 69%); of whom only 40% were known to complete the full aCTH course. Male patients demonstrated worse OS, PFS, FDM, and LC compared to their female counterparts. Univariable analysis showed sex, tumor location (lateral vs central), and completion of aCTH course to be significantly associated with OS; p<0.05. On multivariable analysis, however, only aCTH completion demonstrated a trend for better OS; HR = 0.15 (95% CI: 0.02-1.27, p = 0.08). KM survival analysis revealed superior 5-year OS and PFS in patients who completed aCTH compared to those who received RT alone or did not complete aCTH: 88.9% vs 68.6% vs 40%, p = 0.03 and 83.3% vs 59.3% vs 42%, p = 0.04, respectively. Our series demonstrates that completion of aCTH provides a significant OS and PFS advantage for adult medulloblastoma patients. Prospective studies are needed to develop optimal treatment approaches for these patients who have the potential for long term survival.Abstract 3734; TableVariableN (%)Age (median, interquartile range (IQR))29 (22-33)SexFemale: 13 (41) Male: 19 (59)Histologic subtypeClassic: 6 (19) Desmoplastic/nodular: 6 (19) Large cell/Anaplastic: 4 (12) Not available (NA):16 (50)Risk groupAverage: 19 (59) High: 6 (19) NA: 7 (22)LateralityLateral: 16 (50) Central: 16 (50)Extent of resectionGross total resection (GTR): 24 (75) Non-GTR: 8 (25)Craniospinal irradiation dose (Gray (Gy))23.4 Gy: 10 (31) 36 Gy: 17 (53) NA: 5 (16)Adjuvant chemotherapy (aCTH)None: 10 (31) A9961 CCNU: 12 (38) A9961 cyclophosphamide: 1 (3) ACNS0331: 5 (16) Other/NA: 4 (12)Treatment outcomes (months(mo), median, IQR)Local control duration: 39 (13-141) Freedom from distant metastasis duration: 47 (19-141) Overall survival duration: 54 (26-141) Open table in a new tab

Alterations in driver genes are predictive of survival in patients with resected pancreatic ductal adenocarcinoma.

KRAS, TP53, CDKN2A, and SMAD4 are established driver genes in pancreatic ductal adenocarcinoma (PDAC). This study was aimed at determining whether the mutational status of driver genes and those involved in DNA repair pathways are associated with clinical outcomes for individuals who undergo resection. Eligible individuals were those who underwent resection of PDAC and consented to targeted sequencing of their primary tumor via Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). Genomic alterations were determined on the basis of MSK-IMPACT results from formalin-fixed, paraffin-embedded samples. Associations between genomic alterations and clinical outcomes were assessed. Targeted sequencing was performed on 283 primary tumors resected between 2004 and 2017. The median follow-up was 23 months among survivors. Alterations in KRAS and TP53 were associated with worse overall survival (OS) in comparison to wild type (median for KRAS, 38.8 months [95% CI, 33.0-45.5 months] vs 91.0 months [95% CI, 34.8 months to not available (NA)]; P=.043; median for TP53, 37.4 months [95% CI, 32.1-42.8 months] vs 65.0 months [95% CI, 33.0 months to NA]; P=.035). KRAS G12D mutations were associated with worse OS (median, 31.6 months [95% CI, 25.3-45.5 months] vs 39.2 months [95% CI, 37.4-75.2 months]; P=.012). TP53 truncating mutations (median, 39.6 months [95% CI, 32.4-75.2 months] vs 33.9 months [95% CI, 24.0-39.0 months]; P=.020) and those associated with loss of heterozygosity (median, 26.6 months [95% CI, 21.6-44.2 months] vs 39.2 months [95% CI, 34.5-49.1 months]; P=.048) had decreased OS. TP53 alterations were independently associated with OS in a multivariate analysis (hazard ratio, 1.54; 95% CI, 1.01-2.33; P=.042). Individuals with germline alterations in homologous recombination deficiency (HRD) genes had improved OS in comparison with those without them (median, not reached vs 37.0 months; 95% CI, 33.0-49.8 months; P=.035). In patients with resected PDAC, genomic alterations in KRAS and TP53 are associated with worse outcomes, whereas alterations in HRD genes are associated with a favorable prognosis. Further studies are needed to better define these alterations as biomarkers in resected PDAC.

Missing data in multiple correspondence analysis under the available data principle of the NIPALS algorithm

Multiple correspondence analysis (MCA) in the presence of missing data is usually performed by removing the records that have missing or not available (NA) data; sometimes, an entire row or column of a data matrix is removed, which is not ideal because relevant information on an individual or variable of the study is lost. In some cases, it is assumed that the missing data are a category of the qualitative variable, resulting in a greater variance dispersion in the new axes. Possible solutions to this problem can be the imputation of the missing data or using an algorithm suited to the presence of this type of data. This work is focused on performing the MCA method in the presence of missing data, without using imputation techniques, by using the available data principle of the nonlinear estimation by iterative partial least squares (NIPALS) algorithm [25].

Estrogen-related receptor γ is a novel target for Lower-Chlorinated Polychlorinated Biphenyls and their hydroxylated and sulfated metabolites

Airborne lower-chlorinated PCBs are vulnerable to metabolization to PCB sulfates through further sulfation of the hydroxylated metabolites (OH-PCBs). However, studies on the toxic effects and mechanisms of PCB sulfates are still very limited. Here, we investigated for the first time the potential endocrine disruption effects of PCB sulfates through estrogen-related receptor γ (ERRγ) in comparison with their OH-PCBs precursors and PCB parent compounds. The binding affinity of thirteen PCBs/OH-PCBs/PCB sulfates was measured by using fluorescence competitive binding assays based on fluorescence polarization (FP). All of the tested chemicals could bind to ERRγ with the Kd (dissociation constant) values ranging from not available (NA) to 3.2 μM 4′–OH–PCB 12 showed the highest binding affinity with Kd value of 3.2 μM, which was comparable to that of a synthetic ERRγ agonist GSK4716. The effects of the thirteen chemicals on the ERRγ transcriptional activity were determined by using the luciferase reporter gene assay. We found the PCBs/OH-PCBs/PCB sulfates acted as agonists for ERRγ, with the lowest observed effective concentration reaching 3 μM. The binding affinity and agonistic activity of PCBs towards ERRγ were both enhanced after hydroxylation, while further sulfation of OH-PCBs decreased the activity instead. Molecular docking simulation showed that OH-PCBs had lower binding energy than the corresponding PCBs and PCB sulfates, indicating that OH-PCBs had higher binding affinity theoretically. In addition, OH-PCBs could form hydrogen bonds with amino acids Glu316 and Arg247 while PCBs and PCB sulfates could not, which might be the main factor impacting the binding affinity and agonistic activity. Overall, ERRγ is a novel target for lower-chlorinated PCBs and their metabolites.

Abstract 4530: An independent validation of a screening test using mass spectrometry for detection of hepatocellular carcinoma

Abstract Background: Early detection is critical to improve outcome in hepatocellular carcinoma (HCC). Despite inadequate sensitivity (SS) and specificity (SP), abdominal ultrasound and alpha-fetoprotein (AFP) are considered methods of choice for HCC surveillance. As less than 30% of patients (pts) are diagnosed early enough for resection or transplantation, a test with improved SS and SP is needed. A test to detect HCC in a high-risk population from 10 uL serum, combining MALDI mass spectrometry and AFP data was developed using a dropout-regularized hierarchical machine learning approach designed to minimize overfitting in small development sets. It was previously validated in 293 high risk pts (158 HCC, 135 non-HCC) with SS/SP of 83%/84% in development and 81%/79% in validation across various etiologies and Child-Pugh classification [1]. Methods: The test was applied to an independent validation cohort of 156 pts (97 HCC, 59 non-HCC healthy controls), blinded to clinical data, the performance was assessed by SS, SP. Sub-group analyses were performed by grade and stage. Performance was compared with that of AFP by area under the curve (AUC), using the test output prior to the predefined thresholding which yields the final binary cancer/benign test result. Results: Table 1.HCC patient demographics in the independent validation setClinical characteristicsIndependent validationPatients with HCC (N=97)Median age (range), years62 (38 - 89)Median AFP (range), ng/mL4.0 (less than 1.5 - 10,000)Gender, male / female85% / 16%Hepatitis B / C / No virus / not available (NA)3% / 27% / 20% / 51%Grade I / II / III / NA17% / 22% / 12% / 50%Stage I / II / III / IV / NA12% / 14% / 33% / 26% / 14%Previous liver directed or systemic therapy yes/no44% / 54%ECOG PS 0 / 1 / 2 / 3 / NA13% / 20% / 11% / 5% / 51% In independent validation, AUC for the test output prior to thresholding was 0.979, significantly better than AFP AUC 0.915 (P&amp;lt;0.001). SS and SP were 88% and 100%. SS in grade I, II, and III was 75%, 76%, and 92% and in stage I, II, III, and IV was 75%, 86%, 94%, and 92%. Conclusion: Results in the independent cohort confirm performance of the test, with better SS and SP than AFP and historical ultrasound. The SS was also high in low grade and early stage disease, indicating the test’s potential to improve early detection of HCC when curative approaches are feasible. Data and samples from Data Bank and BioRepository, Roswell Park; funding by the NCI grant P30CA016056 [1] D Mahalingam et al. Hepatology 62(S1): 1135A (2015) Citation Format: Sunyoung S. Lee, Kristopher Attwood, Heinrich Roder, Senait Asmellash, Krista Meyer, Stylianos Kakolyris, Carlos Oliveira, Joanna Roder, Julia Grigorieva, Leonidas Chelis, Renuka Iyer, Devalingam Mahalingam. An independent validation of a screening test using mass spectrometry for detection of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4530.