High Risk Of Disease Progression Research Articles

Immunological and Hematological Response in COVID-19.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently and rapidly emerged and developed into a global pandemic. Through the renin-angiotensin system, the virus may impact the lung circulation, but the expression on endothelium may conduct to its activation and further systemic damage. While precise mechanisms underlying these phenomena remain to be further clarified, the understanding of the disease, its clinical course, as well as its immunological and hematological implications is of paramount importance in this phase of the pandemic. This review summarizes the evidence gathered until 12 June; electronic databases were screened for pertinent reports on coronavirus and inflammatory and hematological changes. Search was conducted by two independent investigators; keywords used were "SARS-CoV-2," "COVID-19," "inflammation," "immunological," and "therapy." The viral infection is able to trigger an excessive immune response in predisposed individuals, which can result in a "cytokine storm" that presents an hyperinflammation state able to determine tissue damage and vascular damage. An explosive production of proinflammatory cytokines such as TNF-α IL-1β and others occurs, greatly exaggerating the generation of molecule-damaging reactive oxygen species. These changes are often followed by alterations in hematological parameters. Elucidating those changes in SARS-CoV-2-infected patients could help to understand the pathophysiology of disease and may provide early clues to diagnosis. Several studies have shown that hematological parameters are markers of disease severity and suggest that they mediate disease progression. According to the available literature, the primary hematological symptoms-associated COVID-19, and which distinguish patients with severe disease from patients with nonsevere disease, are lymphocytopenia, thrombocytopenia, and a significant increase in D-dimer levels. SARS-CoV-2 infection triggers a complex response altering inflammatory, hematological, and coagulation parameters. Measuring these alterations at certain time points may help identify patients at high risk of disease progression and monitor the disease severity.

Clinical characteristics and outcomes of COVID-19 infected diabetic patients admitted in ICUs of the southern region of Bangladesh

Background and aimsDiabetes mellitus is highly prevalent among critical cases of coronavirus disease 2019 (COVID-19) with poor outcomes. This study aimed to describe the clinical characteristics and outcomes of COVID-19 patients with diabetes, admitted in the intensive care unit (ICU) of the southern region of Bangladesh. MethodsEpidemiological, clinical, laboratory, treatments, complications, and clinical outcomes data were extracted from electronic medical records of 168 COVID-19 patients admitted into ICU of two COVID-19 dedicated hospitals of Chattogram, Bangladesh and compared between diabetes (n = 88) and non-diabetes (n = 80) groups. ResultsThe prevalence of diabetes was high among 51–70 years old patients. All the diabetic patients had at least one other comorbidity, with a significantly higher incidence of hypertension (53.4% vs 27.5%, P < 0.05). Prevalence of male patients (74/88; 84.1%) was slightly higher among diabetic patients than the non-diabetic patients (60/80; 75%). Even though not significant, Kaplan-Meier survival curve showed that COVID-19 patients with diabetes had a shorter overall survival time than those without diabetes. In subgroup analysis, diabetic patients were classified into insulin-requiring and non-insulin-requiring groups based on their requirement of insulin during the stay in ICU. COVID-19 infected diabetic patients requiring insulin have high risk of disease progression and shorter survival time than the non-insulin required group. ConclusionsDiabetes is an independent risk factor for the poor prognosis of COVID-19. More attention should be paid to the prevention and prompt treatment of diabetic patients, to maintain good glycaemic control especially those who require insulin therapy.

Should Chest X-ray Be Used in Diagnosing COVID-19?

While chest x-ray is readily available and may precede RT-PCR test, chest x-ray has low sensitivity early in the COVID-19 disease and shows non-specific lung abnormalities in COVID-19 patients. &#x0D; &#x0D; Chest x-ray is part of the initial diagnostic tool used on COVID-19 patients in some hospitals as it yields fast results compared with reverse transcription-polymerase chain reaction (RT-PCR).&#x0D; &#x0D; &#x0D; Chest Computed Tomography (CT) has been reported to be more sensitive than chest x-ray in determining the presence of COVID-19.&#x0D; &#x0D; &#x0D; Chest x-ray findings in confirmed COVID-19 patients show:&#x0D; &#x0D;  Normal lung findings early in the illness and in mildly symptomatic patients&#x0D; Typical ground-glass opacities and consolidation in the lung periphery&#x0D; Lung abnormalities are non-specific and may likewise be present in other infections and coronavirus-types of pneumonia&#x0D; &#x0D; The American College of Radiology (ACR), Center for Disease Control and Prevention (CDC), Canadian Association of Radiologists (CAR), Canadian Society of Thoracic Radiology (CSTR), and British Society of Thoracic Imaging do not recommend the use of chest x-ray to diagnose COVID-19. The Fleisher Society, composed of radiologists and pulmonologists in ten countries, does not recommend a chest x-ray for patients suspected of mild COVID-19. A chest x-ray is recommended for patients with moderate to severe COVID-19 needing immediate triage and patients at high risk for disease progression. Despite presence of chest x-ray findings suggesting COVID-19, RT-PCR test remains the standard diagnostic procedure.&#x0D;

Elevated Serum Thymidine Kinase Levels Identify a Subgroup at High Risk of Disease Progression in Early, Nonsmoldering Chronic Lymphocytic Leukemia

AbstractChronic lymphocytic leukemia (CLL) shows a remarkably heterogeneous clinical outcome; survival ranges from several months in advanced stages to more than 10 years in early stages. The Binet and Rai staging systems distinguish three major prognostic subgroups, but do not accurately predict the individual risk of disease progression in early CLL (Binet stage A or Rai stage 0 to II). Because most newly diagnosed CLL patients present with early disease, it seems desirable to search for additional prognostic factors to identify early CLL patients at high risk of rapid progression. It has been shown that elevated serum thymidine kinase (s-TK) levels predict disease progression in CLL. Therefore, this study aimed to assess the prognostic value of s-TK in 122 previously untreated patients with Binet stage A CLL (mean age ± SD, 58.7 ± 8.5 years). In univariate analyses, 18 of the 22 parameters investigated predicted progression-free survival (PFS). In a stepwise multiple regression analysis, only three parameters provided independent prognostic information on PFS: s-TK greater than 7.1 U/L; presence of lymphadenopathy; and white blood cell (WBC) count greater than 75,000/μL. When added to the classification of smoldering versus nonsmoldering CLL, s-TK levels separated two groups within the group of nonsmoldering stage A patients: patients with s-TK values greater than 7.1 U/L had a median PFS of 8 months, whereas patients with s-TK values ≤ 7.1 U/L expected a much longer PFS (49 months; P < .001), similar to smoldering CLL (42 months). The results demonstrate that s-TK is a prognostic parameter that adds independent prognostic information to the definitions of smoldering and nonsmoldering CLL in Binet stage A.

First-generation vs second-generation tyrosine kinase inhibitors: which is best at diagnosis of chronic phase chronic myeloid leukemia?

In 2020, for the great majority of patients with chronic phase chronic myeloid leukemia (CML), life expectancy is unaffected by a diagnosis of CML because of the unparalleled efficacy of ABL-targeted tyrosine kinase inhibitors (TKIs) in halting disease progression. A wealth of choices exist for first-line treatment selection, including the first-generation TKI imatinib and the second-generation TKIs bosutinib, dasatinib, and nilotinib. How I select first-line therapy between first-generation and second-generation TKIs is discussed in the context of patient-specific CML disease risk, therapy-related risks, and treatment goals. Although rare, identifying patients with CML at higher risk for disease progression or resistance is important and influences first-line TKI selection. I review the impact of first-generation vs second-generation TKI selection on treatment response and outcomes; the ability to achieve, as well as the timing of, treatment-free remission; and the impact of specific TKIs on longer-term health.

Baseline Total Metabolic Tumor Volume and Total Lesion Glycolysis Measured on 18F-FDG PET-CT Predict Outcomes in T-Cell Lymphoblastic Lymphoma.

PurposeThere is no optimal prognostic model for T-cell lymphoblastic lymphoma (T-LBL). Here, we discussed the predictive value of total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) measured on 18F-fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) in T-LBL.Materials and MethodsThirty-seven treatment naïve T-LBL patients with PET-CT scans were enrolled. TMTV was obtained using the 41% maximum standardized uptake value (SUVmax) threshold method, and TLG was measured as metabolic tumor volume multiplied by the mean SUV. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier curves and compared by the log-rank test.ResultsThe optimal cutoff values for SUVmax, TMTV, and TLG were 12.7, 302 cm3, and 890, respectively. A high SUVmax, TMTV, and TLG indicated a shorten PFS and OS. On multivariable analysis, TMTV ≥ 302 cm3, and central nervous system (CNS) involvement predicted inferior PFS, while high SUVmax, TLG and CNS involvement were associated with worse OS. Subsequently, we generated a risk model comprising high SUVmax, TMTV or TLG and CNS involvement, which stratified the population into three risk groups, which had significantly different median PFS of not reached, 14 months, and 7 months for low-risk group, mediate-risk group, and high-risk group, respectively (p < 0.001). Median OS were not reached, 27 months, and 13 months, respectively (p < 0.001).ConclusionBaseline SUVmax, TMTV, and TLG measured on PET-CT are strong predictors of worse outcome in T-LBL. A risk model integrating these three parameters with CNS involvement identifies patients at high risk of disease progression.

PCN18 Matching-Adjusted Indirect Comparison (MAIC) of Entrectinib Versus Crizotinib in Patients with ROS1 NON-SMALL CELL LUNG Cancer (NSCLC): An Updated Analysis

Entrectinib is a central nervous system (CNS)-active potent inhibitor of TRK A/B/C and ROS1 and is licensed for the treatment of patients with ROS1-positive (ROS1+) NSCLC. The current study was undertaken to identify clinical studies conducted in patients with ROS1+ NSCLC and to estimate the relative efficacy and safety of entrectinib versus crizotinib. A systematic literature review conducted in March 2019 was updated in March 2020. Data available for evidence synthesis included a pooled analysis of three Phase I and Phase II clinical trials for entrectinib and one trial, PROFILE 1001, for crizotinib. A MAIC based on known prognostic and predictive factors, including CNS metastases, was used to compare treatments. As the percentage of patients with CNS metastases was not reported in PROFILE 1001, this parameter was varied in scenario analyses. Outcomes included objective response rate (ORR), overall survival (OS), progression free survival (PFS), and discontinuation due to adverse events (AEs). Results from the MAIC indicated a trend towards improved OS for entrectinib versus crizotinib in all three scenarios (hazard ratio (HR) ranging from 0.75 [95% confidence interval (CI) 0.46, 1.11] to 0.87 [95% CI 0.54, 1.27]). A numerical trend in favour of entrectinib was observed for discontinuation due to AEs (odds ratio (OR): 0.70 [95% CI 0.30, 1.10] to 0.70 [95% CI 0.30, 1.30]). There was no difference in ORR between treatments (OR: 0.90 [95% CI 0.60, 1.50] to 1.10 [95% CI 0.70, 1.60]). For PFS, there was a trend towards higher risk of disease progression for entrectinib versus crizotinib (HR: 1.23 [95% CI 0.89, 1.60] to 1.29 [95% CI 0.94, 1.68]). Entrectinib is an effective and well tolerated treatment for patients with ROS1+ NSCLC and data from the MAIC indicate a trend towards improved OS (but not PFS) and safety with entrectinib versus crizotinib.

Clinical features, prognosis, and influencing factors of contralateral prophylactic mastectomy in 58 patients with breast cancer.

BackgroundThe past two decades have witnessed the increasing application of contralateral prophylactic mastectomy (CPM) for women with breast cancer in the western countries. Over 30% of young patients choose to underwent CPM up to 2015. However, the adoption rate of CPM has not shown a remarkably increasing in Asian countries. In China, only a few centers have introduced CPM, and no relevant literature has been published. In this study, we look forward to identify the clinical features and prognostic factors of women who underwent CPM in our hospital, to inform decision-making processes for both doctors and patients.MethodsThe clinical data of 58 eligible patients were retrospectively analyzed. Intergroup comparisons were based on independent samples t-test and chi square test. The 5-year disease-free survival (DFS) and overall survival (OS) were obtained by using life tables, and factors affecting the survivals were analyzed by using the Kaplan-Meier method.ResultsThe mean age of these women was 40.14±11.17 years, with 30 patients (51.7%) being ≤40 years; 13 patients (22.4%) had a family history of breast cancer; and 49 (69.0%) had known risk factors for breast cancer. The median follow-up period was 66.77 months, the 5-year OS was 89% and the 5-year DFS was 74%. The average age of onset was 41.53 (±10.964) in the disease-free survival group and 34.18 (±10.4) years in the recurrence/metastasis group, and t-test revealed a significant difference in the average age between these two groups (P=0.049). Chi-square test showed that the disease progression rate significantly differed among the different age subgroups and among subjects with different body mass index (BMI) (all P≤0.05). Moreover, surgical procedure, family history of breast cancer, and some other factors showed no significant correlation with disease progression (all P>0.05). Kaplan-Meier survival analysis and log rank test further confirmed the above findings.ConclusionsThe majority of patients who choose CPM are young and with known risk factors for breast cancer. Part of the young patients (≤40 years of age) are at a higher risk of disease progression.

Distinct Atrophy Pattern of Hippocampal Subfields in Patients with Progressive and Stable Mild Cognitive Impairment: A Longitudinal MRI Study.

Predicting the prognosis of mild cognitive impairment (MCI) has outstanding clinical value, and the hippocampal volume is a reliable imaging biomarker of AD diagnosis. We aimed to longitudinally assess hippocampal sub-regional difference (volume and asymmetry) among progressive MCI (pMCI), stable MCI (sMCI) patients, and normal elderly. We identified 29 pMCI, 52 sMCI, and 102 normal controls (NC) from the ADNI database. All participants underwent neuropsychological assessment and 3T MRI scans three times. The time interval between consecutive MRI sessions was about 1 year. Volumes of hippocampal subfield were measured by Freesurfer. Based on the analysis of variance, repeated measures analyses, and receiver operating characteristic curves, we compared cross-sectional and longitudinal alteration sub-regional volume and asymmetry index. Compared to NC, both MCI groups showed significant atrophy in all subfields. At baseline, pMCI have a smaller volume than sMCI in the bilateral subiculum, molecular layer (ML), the molecular and granule cell layers of the dentate gyrus, cornu ammonis 4, and right tail. Furthermore, repeated measures analyses revealed that pMCI patients showed a faster volume loss than sMCI in bilateral subiculum and ML. After controlling for age, gender, and education, most results remained unchanged. However, none of the hippocampal sub-regional volumes performed better than the whole hippocampus in ROC analyses, and no asymmetric difference between pMCI and sMCI was found. The faster volume loss in subiculum and ML suggest a higher risk of disease progression in MCI patients. The hippocampal asymmetry may have smaller value in predicting the MCI prognosis.

Pathologic response to neoadjuvant therapy of high risk prostate cancer

Background. The role of pathological response, which develops as a result of systemic therapy for localized and locally advanced high risk prostate cancer, is not still fully understood. There are no clear indications for neoadjuvant therapy and no data on the relationship between neoadjuvant therapy and median of overall or progression free survival. According to increasing interest for neoadjuvant chemohormonal therapy followed by radical prostatectomy, we evaluated the features of pathological response and its effects on overall and progression free survival rates.Objective. Estimating residual disease and pathologic response to neoadjuvant therapy of high risk prostate cancer and its relationship with oncological results.Materials and methods. This was a prospective randomized study: patients with prostate cancer of high and very high-risk groups (prostate specific antigen levels &gt;20 ng/ml and/or Gleason score ≥8 and/or clinical stage ≥T2c) were treated with neoadjuvant chemohormonal therapy followed by radical prostatectomy (n = 36). The neoadjuvant course included the intravenous administration of docetaxel once every 21 days (75 mg/m2 up to 6 cycles) and the antagonist of the gonadotropin releasing hormone degarelix according to the standard scheme (6subcutaneous injections every 28 days). The prostate tissue was evaluated for the residual disease, features of pathological response according to the ABC system. Additionally, the expression of IHC markers (p53, bcl-2, p16, Ki-67, androgen receptors, c-MYC, ERG, PTEN) was evaluated on postoperative material using tissue microarray.Results. A totally of 480 H&amp;Epostoperative and 775 H&amp;E biopsy slides were analyzed. Group A included 10 (32.3 %) cases, group B — 16 (51.6 %), and group C — 5 (16.1 %). The variance analysis revealed a significant difference in the frequency of more localized forms of prostate cancer in group B (43.7 %) (p = 0.028). During assessment we did not found any relationship ABC system assignment and preoperative prostate specific antigen level, the presence of a positive surgical margin, the pathological stage of diseases or regional lymph nodes involvement. However, the values of relapse-free survival vary sharply between groups: the highest median of relapse-free survival was found in group B — 23.02 ± 12.61 months, patients of groups A/C could not achieve the level of median relapse-free survival — 11.7 ± 6.43 and 16.19 ± 16.54 months respectively.Conclusion. The effectiveness of neoadjuvant chemohormonal therapy for high risk prostate cancer can be assessed by the features of pathologic response through ABC system which has demonstrated own versatility and reproducibility in presented material. Neoadjuvant therapy with docetaxel and degarelix can improve the treatment outcomes of prostate cancer patients at high and very high risk of disease progression. The data on changes in the prostate tissue can be helpful in predicting the duration of the effect after chemohormonal therapy with subsequent surgery.

Identifying adolescent and young adult patients with sickle cell disease at highest risk of death.

Identifying adolescent and young adult patients with sickle cell disease at highest risk of death.

The Natural History of NPM1MUT Measurable Residual Disease (MRD) Positivity after Completion of Chemotherapy in Acute Myeloid Leukemia (AML)

The Natural History of NPM1MUT Measurable Residual Disease (MRD) Positivity after Completion of Chemotherapy in Acute Myeloid Leukemia (AML)

Emerging Role of Adoptive T Cell Therapy for EBV Induced Nasopharyngeal Carcinoma (NPC) - a Systematic Review

Introduction: Nasopharyngeal carcinoma (NPC) is defined as the cancer of squamous epithelium lining nasopharynx. The single most common culprit of undifferentiated NPC is the Epstein-Barr virus (EBV). Recurrent local-regional or metastatic NPC cannot be treated with repeated chemo-radiotherapy because of poor overall survival and profound effect of these therapies on quality of life. One safer approach is immunotherapy with autologous EBV specific cytotoxic T lymphocytes (EBV-CTLS) targeted to the EBV antigens EBNA1, latent membrane protein LMP1, and LMP2 expressed by most NPC tumors. This study aims to review the efficacy and toxicity of adoptive immunotherapy with EBV-CTLS in patients with EBV induced NPC. Methods: A systematic search of PubMed, Embase, Clinicaltrials.gov, and Web of Science was performed for adoptive immunotherapy in EBV induced NPC patients from inception to May 28, 2020. Out of 604 studies, 07 phase I and II clinical trials were selected for the systematic review. Results: A total of 134 patients (pts) were evaluated out of 157 pts. 56 had a locoregional disease, 63 had distant metastasis, 15 had both locoregional disease as well as distant metastasis, 8 were in remission and disease status was unknown in 5 pts. Li et al. (2015) in their phase I clinical trial on 20 NPC pts with ECOG performance status of &amp;lt;3 after chemoradiotherapy (CCRT) showed overall response rate (ORR) of 95% with complete response (CR) in 19 patients. One patient showed progressive disease (PD). Median progression-free survival (PFS) was observed to be 16 months. Eighteen (90%) pts showed disease-free survival of greater than 12 months after adoptive cell therapy (ACT). Grade (G) ≥3 adverse events (AEs) included leukopenia (5%) and neutropenia (5%). Phase I/II dose-escalation trial by Louis et al. (2010) on 23 pts showed ORR of 48.7% (20% CR, 13.3% undetermined complete response [Cru], 15.4% PR) among pts with active disease. Eight pts remained in remission while 10 had metastatic disease at the time of infusion. PD was 21.7%, Stable Disease (SD) 13%, and 3 pts (13%) had recurrent disease. The median time to progression was 1059 days with PFS of 65% and 52% at 1 and 2 years respectively while the (Overall Survival) OS was 87% and 70% at 1 year and 2 years respectively. There was a higher risk of disease progression (HR: 3.91, P= 0.015) and decreased overall survival (HR: 5.55, P=0.022) in metastatic disease as compared to locoregional disease. Huang J. et al (2017) conducted a phase I/ II trial in 21 pts with a mean waiting period of 71 days after chemotherapy. Two CTL infusions were given 2 weeks apart. Two pts (9.5%) maintained SD but all other pts (85%) showed PD after 8 weeks follow- up. One patient achieved CR (4.8%). Hence, ORR was 4.8% while median PFS and OS were of 2.2 months and 16.7 months respectively. In a phase II trial, 24 patients completed 6 EBV- CTL therapy cycles after receiving chemotherapy cycles of Gemcitabine and Carboplatin. ORR was observed to be 42.9% (CR 5.7%, PR 31.7%). SD was 20% while PD was 31.4%. Median OS was 29.9 months (95% CI 20.8-39.3) with 1, 2, and 3-year rates being 77.1%, 62.9%, and 37.1 % respectively. Median PFS was 7.6 months (95% CI 7.4-8.4). All G≥3 AE occurred during chemotherapy. (Chia et al, 2014) Secondino et al. (2011) conducted a phase I/II study in 11 NPC patients who also received chemotherapy consisting of cyclophosphamide and fludarabine. After a mean follow-up of 4 weeks, ORR was 27% (PR 18%, Minor Response [MR] 9%). PD was reported to be 45% and SD 27%. Median PFS at 6 months was 54% (6/11 pts). Only G≥3 AE reported was neutropenia (36%). Phase I/II trial by Comoli et al. (2005) evaluated 10 EBV-related stage IV NPC in progression after CCRT. After receiving two to twenty-three EBV-specific CTLs infusions, 2 patients showed PR (20%), 40% of pts maintained SD and all others showed evidence of PD (40%) at 1-2 months follow up. Median PFS was 6.5 months. Smith et al (2012) in their phase I trial on 14 patients with locoregional and metastatic NPC reported SD 71.4% and PD 28.6% of patients at a median follow up of 1 month. Median OS and PFS were 17.4 months and 4.5 months respectively. No G≥3 AEs were reported. Conclusion : Adoptive Immunotherapy with EBV-CTLS has shown impressive efficacy with improvement in median PFS and OS and a favorable safety profile. Key Words: Adoptive cell therapy, Cytotoxic T lymphocytes, nasopharyngeal carcinoma, Phase I/II clinical trials, Epstein-Barr virus. Disclosures Anwer: Celgene: Research Funding; AbbVie Pharmaceuticals: Research Funding; Incyte Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Astellas Pharma: Research Funding; Acetylon Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Millennium Pharmaceuticals: Research Funding.

Risk Profiling of Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients By Measuring Circulating Tumor DNA

Risk Profiling of Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients By Measuring Circulating Tumor DNA

Integrated analysis of concomitant medications and oncological outcomes from PD-1/PD-L1 checkpoint inhibitors in clinical practice.

BackgroundConcomitant medications, such as steroids, proton pump inhibitors (PPI) and antibiotics, might affect clinical outcomes with immune checkpoint inhibitors.MethodsWe conducted a multicenter observational retrospective study aimed at evaluating the impact of concomitant medications on clinical outcomes, by weighing their associations with baseline clinical characteristics (including performance status, burden of disease and body mass index) and the underlying causes for their prescription. This analysis included consecutive stage IV patients with cancer, who underwent treatment with single agent antiprogrammed death-1/programmed death ligand-1 (PD-1/PD-L1) with standard doses and schedules at the medical oncology departments of 20 Italian institutions. Each medication taken at the immunotherapy initiation was screened and collected into key categories as follows: corticosteroids, antibiotics, gastric acid suppressants (including proton pump inhibitors - PPIs), statins and other lipid-lowering agents, aspirin, anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors/Angiotensin II receptor blockers, calcium antagonists, β-blockers, metformin and other oral antidiabetics, opioids.ResultsFrom June 2014 to March 2020, 1012 patients were included in the analysis. Primary tumors were: non-small cell lung cancer (52.2%), melanoma (26%), renal cell carcinoma (18.3%) and others (3.6%). Baseline statins (HR 1.60 (95% CI 1.14 to 2.25), p=0.0064), aspirin (HR 1.47 (95% CI 1.04 to 2.08, p=0.0267) and β-blockers (HR 1.76 (95% CI 1.16 to 2.69), p=0.0080) were confirmed to be independently related to an increased objective response rate. Patients receiving cancer-related steroids (HR 1.72 (95% CI 1.43 to 2.07), p<0.0001), prophylactic systemic antibiotics (HR 1.85 (95% CI 1.23 to 2.78), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.09 to 1.53), p=0.0021), PPIs (HR 1.26 (95% CI 1.07 to 1.48), p=0.0050), anticoagulants (HR 1.43 (95% CI: 1.16 to 1.77), p=0.0007) and opioids (HR 1.71 (95% CI 1.28 to 2.28), p=0.0002) were confirmed to have a significantly higher risk of disease progression. Patients receiving cancer-related steroids (HR 2.16 (95% CI 1.76 to 2.65), p<0.0001), prophylactic systemic antibiotics (HR 1.93 (95% CI 1.25 to 2.98), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.06 to 1.57), p=0.0091), PPI (HR 1.26 (95% CI 1.04 to 1.52), p=0.0172), anticoagulants (HR 1.45 (95% CI 1.14 to 1.84), p=0.0024) and opioids (HR 1.53 (95% CI 1.11 to 2.11), p=0.0098) were confirmed to have a significantly higher risk of death.ConclusionWe confirmed the association between baseline steroids administered for cancer-related indication, systemic antibiotics, PPIs and worse clinical outcomes with PD-1/PD-L1 checkpoint inhibitors, which can be assumed to have immune-modulating detrimental effects.

CD71 mesangial IgA1 receptor and the progression of IgA nephropathy

The transferrin receptor (CD71) is known as a receptor for IgA1 on mesangial cells, but the role of CD71 in IgA nephropathy (IgAN) is unknown. We studied clinical implication of mesangial CD71 in 282 patients with biopsy-proven IgAN (2005-2018). The transcript and protein expression of glomerular CD71 was determined by real-time polymerase chain reaction and immunohistochemistry. Ten subjects with microscopic hematuria only and no evidence of histologic abnormalities on kidney biopsy were considered as controls. Human mesangial cells (HMCs) were treated with sera from IgAN patients and expression levels of CD71 and inflammatory cytokine markers were compared according to disease status. Disease progression was defined as a ≥30% decline in estimated glomerular filtration rate from the baseline value. During a mean follow up of 53.5 (18.3-75.9) months, 80 (28.4%) patients developed disease progression. The mRNA expression of CD71 was significantly higher in progressors than in nonprogressors (P = 0.001). Among the Oxford classification scores, patients with M1 had significantly higher CD71 expression levels than those with M0. In a multivariable Cox model, elevated transcript levels of CD71 were significantly associated with 4.32-fold higher risk of disease progression (P = 0.009). Furthermore, CD71 expression levels independently predicted the increase in proteinuria of ≥50% from the baseline (P = 0.03). Finally, HMCs treated with sera from IgAN patients with the higher Oxford score (M1E1S1T0) more increased the mRNA expression of CD71 and inflammatory markers than those with sera from negative score (M0E0S0T0). However, silencing CD71 significantly reduced expression levels of the inflammatory cytokine genes. Our results show that mesangial CD71 is significantly associated with disease progression and may play a biologic role in IgAN.

Risk of Metformin in Patients With Type 2 Diabetes With COVID-19: A Preliminary Retrospective Report.

The current outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection has spread across the world. No specific antiviral agents have been adequately evidenced for the treatment of coronavirus disease 2019 (COVID‐19). Although metformin has been recommended as a host‐directed therapy for COVID‐19, there are some opposite views. The effects of metformin on the disease severity of patients with COVID‐19 with diabetes during hospitalization remains unclear. This study aimed to determine the effect of metformin on disease severity. We enrolled 110 hospitalized patients with COVID‐19 with diabetes prescribed either metformin or non‐metformin hypoglycemic treatment for a case‐control study. The primary outcome was the occurrence of life‐threatening complications. There were no differences between the two groups in age, sex, comorbidities, and clinical severity at admission. Blood glucose and lactate dehydrogenase levels of the metformin group were higher than those of the non‐metformin group at admission. Other laboratory parameters at admission and treatments after admission were not different between the two groups. Strikingly, the percentage of patients who experienced life‐threatening complications was significantly higher in the metformin group (28.6% (16/56) vs. 7.4% (4/54), P = 0.004). Antidiabetic therapy with metformin was associated with a higher risk of disease progression in patients with COVID‐19 with diabetes during hospitalization (adjusted odds ratio = 3.964, 95% confidence interval 1.034–15.194, P = 0.045). This retrospective analysis suggested a potential safety signal for metformin, the use of which was associated with a higher risk of severe COVID‐19. We propose that metformin withdrawal in patients with COVID‐19 be considered to prevent disease progression.

S0984 Long-Term Efficacy and Safety of Obeticholic Acid in Patients With Primary Biliary Cholangitis: A Demographic Subgroup Analysis of 5-Year Results From the POISE Trial

INTRODUCTION: Primary biliary cholangitis (PBC) is a rare, progressive autoimmune liver disease that leads to fibrosis, cirrhosis, and liver transplantation. PBC primarily affects females, but male patients and those with earlier age at diagnosis are at high risk for disease progression. Obeticholic acid (OCA) is approved as second-line treatment of PBC in patients nonresponsive or intolerant to ursodeoxycholic acid. The efficacy and safety of 12-month OCA treatment in patients with PBC was previously demonstrated in the POISE trial.1 We report the long-term efficacy and safety of OCA for more than 5 years in demographic patient subgroups from the POISE trial. METHODS: POISE was a randomized, double-blind, placebo-controlled, 12-month, phase 3 trial evaluating the efficacy and safety of OCA 5–10 mg or 10 mg vs placebo in patients with PBC. This was followed by a 5-year open-label extension (OLE) study during which all patients received OCA. The current analysis evaluated efficacy and safety outcomes in patient subgroups based on sex (male vs female), median age at study entry (≤55 years vs > 55 years), and median age at diagnosis (≤47.5 years vs > 47.5 years). Assessments included changes from OCA baseline in clinical laboratory tests and adverse events (AEs). Paired t-tests assessed within group comparisons. RESULTS: A total of 193 patients were included in the OLE study (median exposure: 5.4 y). In the OLE analysis, significant decreases in mean alkaline phosphatase (ALP) values were observed from OCA baseline for each subgroup from month 3 through month 72 (Figure 1). Similar trends were observed for other key markers of cholestasis and hepatic damage in each subgroup (Table 1). AEs were consistent with previous OCA studies. Over the course of six years of study conduct, 69%–79% of patients reported a pruritus event. CONCLUSION: These findings provide additional information on OCA safety and efficacy in various demographic patient subgroups. Treatment with OCA resulted in improvements in ALP, ALT, AST, and GGT values in patients with PBC in all demographic subgroups assessed. In the OLE, improvements in ALP were achieved by 3 months after OCA treatment initiation and were sustained after 5 years; these are important findings given the progressive nature of the disease.Figure 1Table 1

The Prognostic Effect of Metastatic Lymph Node Ratio in Operated Gastric Cancer Patients

To assess the prognostic importance of metastatic lymph node ratio (MLNR) in operated gastric cancer patients. Observational study. Health Sciences University, Yildirim Beyazit Diskapi Training and Research Hospital, Department of General Surgery, Ankara, Turkey, between January 2014 and March 2019. Initially, record of a total of 171 patients, operated for gastric cancer, were retrieved. Inclusion criteria involved having gastric adenocarcinoma, undergoing curative-intent surgery, absence of neoadjuvant chemotherapy, dissection of ≥15 lymph nodes, negative surgical margins, and no mortality within the first 30 days after surgery. Thirty patients were excluded for various reasons. Thus, clinicopathological features and prognostic factors including MLNR on overall and disease-free survival (DFS) were evaluated for the remaining 141 patients. The median age of the 141 patients was 63 years (IQR: 54 - 72 years). The median MLNR was 0.18 (IQR: 0 - 0.47). The cut-off value with highest sensitivity and specificity was determined as 0.25 (area under the curve (AUC); 0.724, CI 95%; 0.639-0.808, p <0.001) in ROC curve analysis. Multivariable Cox regression analysis showed MLNR and perineural invasion (PNI) as independent prognostic factors. Patients with MLNR >0.25 had a 2.39-fold higher risk of disease progression, and 3.76-fold higher risk of shorter survival. The study contributed to the literature that MLNR is practical and useful as an independent prognostic factor predicting survival even better than tumor/node/metastasis (TNM) staging system. Key Words: Gastric cancer, Metastatic lymph node ratio, Prognostic factor, Surgery.

Development of a nomogram for the prediction of periodontal tooth loss using the staging and grading system: A long-term cohort study.

To develop and internally validate a nomogram built on a multivariate prediction model including parameters from the new classification of periodontal diseases, able to predict, at baseline, the occurrence of tooth loss due to periodontal reason (TLP). A total of 315 individuals diagnosed with periodontal disease and receiving a minimum of one annual supportive periodontal therapy visit were included in the study. Patients were staged and graded based upon baseline data. The population was divided into a development (254 patients) and a validation (61 patients) cohort to allow subsequent temporal validation of the model. According to the TLP at the 10-year follow-up, patients were categorized as "low tooth loss" (≤ 1 TLP) or "high tooth loss" (≥ 2 TLP). Bootstrap internal validation was performed on the whole data set to calculate an optimism-corrected estimate of performance. The generated nomogram showed a strong predictive capability (AUC=0.81) and good calibration with an intercept=0 and slope=1. These findings were confirmed by internal validation using bootstrapping (average bootstrap AUC=0.83). The clinical implementation of the present nomogram guides the prediction of patients with high risk of disease progression and subsequent tooth loss for personalized care.