Normal Lactate Dehydrogenase Research Articles

Long-Term Survival in Patients With Advanced Melanoma

Long-term survival data from clinical trials show that survival curves of patients with advanced melanoma treated with immune checkpoint inhibitors (ICIs) gradually reach a plateau, suggesting that patients have a chance of achieving long-term survival. To investigate long-term survival in patients with advanced melanoma treated with ICIs outside clinical trials. Cohort study using prospectively collected data from the nationwide Dutch Melanoma Treatment Registry, including patients in the Netherlands with advanced melanoma treated with first-line ICIs from 2012 to 2019. Data were analyzed from January to September 2023. Patients were treated with first-line ipilimumab-nivolumab, antibodies that target programmed cell death (anti-PD-1), or ipilimumab. Progression-free survival (PFS) and melanoma-specific survival were analyzed, and a Cox proportional hazards model was used to investigate factors associated with PFS after reaching partial response (PR) or complete response (CR). A total of 2490 patients treated with first-line ICIs were included (median [IQR] age, 65.0 [55.3-73.0] years; 1561 male patients [62.7%]). Most patients had an Eastern Cooperative Oncology Group Performance Status of 1 or lower (2202 patients [88.5%]) and normal lactate dehydrogenase levels (1715 patients [68.9%]). PFS for all patients was 23.4% (95% CI, 21.7%-25.2%) after 3 years and 19.7% (95% CI, 18.0%-21.4%) after 5 years. Overall survival for all patients was 44.0% (95% CI, 42.1%-46.1%) after 3 years and 35.9% (95% CI, 33.9%-38.0%) after 5 years. Patients with metastases in 3 or more organ sites had a significantly higher hazard of progression after reaching PR or CR (adjusted hazard ratio, 1.37; 95% CI, 1.11-1.69). This cohort study of patients with advanced melanoma treated with ICIs in clinical practice showed that their survival reached a plateau, comparable with patients participating in clinical trials. These findings can be used in daily clinical practice to guide long-term surveillance strategies and inform both physicians and patients regarding long-term treatment outcomes.

Development and Optimization of a Lactate Dehydrogenase Assay Adapted to 3D Cell Cultures

In recent years, 3D cell culture systems have emerged as sophisticated in vitro models, providing valuable insights into human physiology and diseases. The transition from traditional 2D to advanced 3D cultures has introduced novel obstacles, complicating the characterization and analysis of these models. While the lactate dehydrogenase (LDH) activity assay has long been a standard readout for viability and cytotoxicity assessments in 2D cultures, its applicability in long-term 3D cultures is hindered by inappropriate normalization and low LDH stability over time. In response to these challenges, we propose an optimization of LDH assays, including a crucial normalization step based on total protein quantification and a storage method using an LDH preservation buffer. We applied it to compare unexposed cerebral organoids with organoids exposed to a toxic dose of valproic acid, and showed efficient normalization of cellular viability as well as enhanced LDH stability within the buffer. Importantly, normalized LDH activity results obtained were independent of organoid dimension and cell density. This refined LDH assay, tailored to address 3D culture constraints, allows for the transposition of this routine test from 2D to 3D cultures.

Camrelizumab plus apatinib and temozolomide as first-line therapy for advanced acral melanoma: 2-year survival results from CAP 03.

9547 Background: Acral melanoma is the predominant subtype in Asia, which presents with aggressive biological behavior. First-line immunotherapy yields modest efficacy in advanced acral melanoma, suggesting the need of combination therapy. Our CAP 03 study investigated the combination of anti-PD-1 antibody plus antiangiogenic agent and chemotherapy for the first-line treatment of advanced acral melanoma, and the primary analysis has been published on JAMA Oncology in June 2023 (objective response rate [ORR], 64%; median progression-free survival [PFS], 18.4 months). Here we updated the efficacy results with a median follow-up of 30.3 months (95% CI, 28.9-32.5; reverse Kaplan-Meier method) at data cutoff date on January 8, 2024. Methods: In this single-center phase 2 trial (NCT04397770), patients with pathologically confirmed unresectable stage III or IV acral melanoma and without prior systemic therapy for advanced disease were recruited. Patients received first-line intravenous camrelizumab (200 mg once every 2 weeks) plus oral apatinib (250 mg once a day) and intravenous temozolomide (200 mg/m2 once a day on days 1-5 every 4 weeks) until disease progression or intolerable toxicity. The primary endpoint was ORR per Response Evaluation Criteria In Solid Tumors, version 1.1. Imaging assessment was performed after 4 weeks, then every 8 weeks until one year, and every 3 months thereafter. Overall survival (OS) was followed every 3 months. Results: Between May 2020 and August 2021, a total of 50 patients were enrolled. The confirmed ORR was 66.0% (33 of 50; 95% CI, 51.2%-78.8%). The median PFS was 21.2 months (95% CI, 10.1-27.1). The median OS was not reached, and the 1-year and 2-year OS rates were 88.0% (95% CI, 75.2%-94.4%) and 64.8% (95% CI, 49.5%-76.5%), respectively. Further analyses indicated comparable PFS benefit in subgroups by age (<65 years vs ≥65 years), sex (male vs female), Eastern Cooperative Oncology Group performance status (0 vs 1), NRAS status (variant vs wild-type), stage, lactic dehydrogenase (LDH) level, and PD-L1 combined positive score (<5 vs ≥5). Regarding OS, similar trends were observed in these subgroups, except that patients with normal LDH had better median OS than those with elevated LDH (not reached vs 22.6 months, log-rank nominal P=0.033). Conclusions: This first-line triplet combination shows encouraging survival benefits in patients with advanced acral melanoma, regardless of NRAS status or PD-L1 expression level. Follow-up is still ongoing to obtain mature OS data. Clinical trial information: NCT04397770 .

Efficacy and toxicity of KIT targeted therapy in elderly patients with melanoma.

e23269 Background: Most cases of malignant melanoma are cutaneous, with ≈50% having a BRAF driver mutation that predicts response to MAPK pathway inhibitors. A small minority of melanoma cases harbor an activating KIT mutation, most notably in mucosal and acral melanomas (15-20%) and occasionally in those arising from chronic sun-damaged skin (2-3%). Only about a third of KIT mutated melanomas respond to targeted therapy with Imatinib, yet data is scarce and limited, especially in older patients. We sought to characterize the efficacy and toxicity of Imatinib in KIT-mutated melanoma patients over 65. Methods: We identified electronic medical records of patients over 65 that were treated with Imatinib for KIT mutated melanoma at our institution over the years 2017-2023. Data was retrospectively collected including demographics, disease characteristics, response patterns and toxicity. Results: 10 patients were identified, 50% were males. The median age at treatment initiation was 75 years (71-100). 3 patients had cutaneous primary, 3 had Vulvar/vaginal primary, 3 had acral primary and 1 had anal canal primary. All patients had normal Lactate dehydrogenase at treatment initiation and ECOG performance status was 0-2 (median 0). 9 patients received Imatinib for stage IV disease with an overall response rate (ORR) of 55% (44% partial response, 11% complete response). Median duration of response was 4 months. Responses were seen in acral melanoma (67%), vulvar/vaginal melanoma (67%) and cutaneous melanoma (33%). Median Progression free survival was 4.3 months (1.8-44), median overall survival from treatment initiation was 22.6 months (4-64). 6 patients were treated as 2nd line with an ORR of 67% and 3 were treated as 3rd line with an ORR of 33%. There was one patient with M1d disease who did not respond to treatment either systematically or intracranially. 6 patients had Exon 11 mutations (V560D/G/E, N564S and L576P) of which 4 responded (67%). 2 had Exon 17 mutations (N822C/K) of which 1 responded (50%) and the 2 others had an Exon 14 (F681I) and Exon 13 (K642E) mutation that did not respond to treatment at all. Toxicity was moderate with 90% of patients experiencing any grade AE, yet only 1 experienced toxicity requiring dose interruption with two Grade 3 toxicities - Pneumonitis and decreased neutrophil count, leading to temporary treatment interruption, dose reduction and a course of corticosteroids. The rest of the patients experienced only Grade 1-2 toxicity. 4 patients needed dose reductions, there were no treatment discontinuations due to toxicity. Conclusions: Treatment with Imatinib for elderly KIT mutated melanoma patients is safe and well tolerated with no treatment discontinuations recorded. The response rate is encouraging yet seems to vary according to the KIT mutation present as previously reported. The duration of response is usually short-lived and alternative/combination treatments are still needed for this patient population.

Association between Serum Lactate Dehydrogenase Level and 30-day Mortality in Patients with Intracranial Hemorrhage with Acute Leukemia in the Induction Phase: A Cohort Study.

Objectives This study aimed to identify the association between lactate dehydrogenase (LDH) levels and 30-day mortality in patients with intracranial hemorrhage (ICH) with acute leukemia during the induction phase. Methods This cohort study included patients with acute leukemia with ICH during induction. We evaluated serum LDH levels upon admission. Multivariable Cox regression analyzed the LDH 30-day mortality association. Interaction and stratified analyses based on factors like age, sex, albumin, white blood cell count, hemoglobin level, and platelet count were conducted. Results We selected 91 patients diagnosed with acute leukemia and ICH. The overall 30-day mortality rate was 61.5%, with 56 of the 91 patients succumbing. Among those with LDH levels ≥ 570 U/L, the mortality rate was 74.4% (32 out of 43), which was higher than the 50% mortality rate of the LDH < 570 U/L group (24 out of 48) ( p = 0.017). In our multivariate regression models, the hazard ratios and their corresponding 95% confidence intervals for Log2 and twice the upper limit of normal LDH were 1.27 (1.01, 1.58) and 2.2 (1.05, 4.58), respectively. Interaction analysis revealed no significant interactive effect on the relationship between LDH levels and 30-day mortality. Conclusions Serum LDH level was associated with 30-day mortality, especially in patients with LDH ≥ 570 U/L.

Expression of CD30 in Patients with Diffuse Large B-Cell Lymphoma and Clinical Significance

To investigate the expression and clinical significance of CD30 in patients with diffuse large B-cell lymphoma (DLBCL). A retrospective analysis was conducted on 124 cases of primary DLBCL diagnosed at Changzhou Second People's Hospital Affiliated with Nanjing Medical University from January 2018 to July 2020. The expression of CD30 in patients with DLBCL was detected by immunohistochemical method, and the clinicopathological characteristics were analyzed and compared between CD30+ and CD30- groups. Kaplan-Meier analysis was used for survival analysis. The relationship between CD30 expression and clinical features and prognosis were analyzed. Among the 124 patients with DLBCL, 19 patients expressed CD30, and the positive rate is 15.32%. The clinico-pathological characteristics of CD30+ in patients with DLBCL were characterized by low age, more common in males, fewer extranodal lesions, lower international prognostic index (IPI), GCB type being more common in Hans subtype, and achieving better therapeutic effects (P < 0.05). However, there were no significant statistical differences in B-symptoms (P =0.323), Ann Arbor staging (P =0.197), Eastern Cooperative Oncology Group (ECOG) score (P =0.479), lactate dehydrogenase (LDH) (P =0.477), and the involvement of bone marrow (P =0.222). There were significant differences in OS and PFS between the CD30+ and CD30- groups (χ2=5.653, P =0.017; χ2＝4.109，P =0.043), the CD30+ group had a better prognosis than that of the CD30- group. The results of subgroup analysis showed that the CD30+ group in the IPI score=1-2, LDH elevated group had a better prognosis (P < 0.05). In the subgroups of Ann Arbor staging III-IV (P =0.055) and non GCB type (P =0.053), the CD30+ group had a good prognosis trend, but the difference was not statistically significant. The results of univariate analysis showed that the good prognosis of DLBCL patients was closely related to CD30+ expression, no B-symptoms, early Ann Arbor staging, low ECOG score, normal LDH, low IPI score, fewer extranodal involvement, and obtaining the best therapeutic effect as CR (all P <0.05). COX multivariate regression analysis showed that the presence of B-symptoms and achieving the best therapeutic effect as Non-CR were independent risk factors affecting the prognosis of DLBCL patients (P < 0.05). The CD30+ expression in DLBCL patients indicates a good prognosis and has certain diagnostic value in evaluating the prognosis of DLBCL patients.

Predictors of Immunotherapy Efficacy in Metastatic Non-Small Cell Lung Cancer: Lung Immune Prognostic Index and Immune-Related Toxicity.

Immune checkpoint inhibitors (ICIs) have been proposed as the standard first-line and subsequent treatment for metastatic non-small cell lung cancer (NSCLC). This study analyzed whether patients with good lung immune prognostic index (LIPI) have a better response to ICIs and the relationship between immune-related adverse events (irAEs) and response in clinical practice. This was an observational, retrospective, single-center study. Patients with stage IV NSCLC between 2016 and 2021 were included in the study. Toxicity was assessed according to The Common Terminology Criteria for Adverse Events. Response assessment was performed according to RECIST 2.0 and immuno-related criteria. Descriptive and survival analyses were conducted. Degree of toxicity and response to treatment (based on treatment and histology) were assessed. LIPI and response were assessed. LIPI included dNLR (absolute neutrophil count/(white blood cell count - absolute neutrophil count)) ≥ 3 and lactate dehydrogenase (LDH) greater than the upper limit of normal. Patients were stratified into good (G), intermediate (I), and poor (P) prognostic groups. A total of 168 patients were included (130 men and 38 women, mean age 64.3 years). ICI use in the first- or second-line treatment was 65% and 35%, respectively. Fifteen (9%) patients showed complete response (CR), 50 (30%) showed partial response (PR), 39 (22%) had stable disease (SD), 45 (28%) had progressive disease (PD), and 19 (11%) were not evaluated (NE). Patients with good prognostic LIPI (dNLR < 3 and normal LDH levels) showed a better response. Progression-free survival (PFS) was 19 months in G, 6 months in I, and 2 months in P. Overall survival (OS) was 27 months in G, 8 months in I, and 3 months in P. One hundred fourteen patients died (56% G, 76% I, 93% P). Patients with adenocarcinoma were 116 (77 with irAEs G1-4 (13 CR, 31 PR, 21 SD, eight PD, and four NE)), and without were 39 (three PR, six SD, 21 PD, and nine NE). Fifty-two patients had squamous carcinoma (27 with irAEs G1-4 (two CR, 12 PR, nine SD, and four PD)), and 25 did not (four PR, three SD, 12 PD, and six NE)). IrAEs appearance was observed in longer PFS (19 vs. 2 months) and OS (27 vs. 4 months; P < 0.0001). LIPI was a positive predictor of response to ICI. The presence of irAEs is associated with a better immune response. In contrast, the absence of toxicity predicted a worse prognosis.

Abstract 3680: Prognostic value of serum biomarkers in pancreatic adenocarcinoma: Results from a Swiss single center cohort analysis

Abstract Introduction: Inflammatory and nutritional biomarkers, such as neutrophil to lymphocyte ratio (NLR), C-Reactive Protein (CRP), lactate dehydrogenase (LDH) and albumin, are valuable prognostic indicators, refining stratification strategies in oncological patients. This study aims to delineate the impact of these markers on overall survival in patients with pancreatic adenocarcinoma, in order to aid in clinical risk stratification. Methods: We conducted a retrospective analysis on patients with adenocarcinoma of the pancreas, treated at the Cantonal Hospital Baselland (January 2018 - February 2022). Clinical data, including diagnosis, treatment, and blood markers, were extracted from electronic records. The analysis incorporated the computation of median values for each blood marker, followed by survival analysis and determination of Cox proportional hazard ratios with a 95% confidence interval. Results: Our cohort included 43 patients, 53% women, 44% men, median age 73 years (IQR 14.75) with adenocarcinoma of the pancreas. Most patients (56%) had advanced distant disease and 25% of these did not receive any oncological therapy. At least one cycle of chemotherapy was administered in 85% of patients. NLR&amp;lt;4 was reported in 63% of cases, normal albumin levels in 72%, normal LDH levels in 79%, and normal CRP levels in 47%. In the multivariate Cox regression analysis, there was a significant higher risk for death with metastatic disease (HR 6.216 CI 2.00-19.28, p=0.002), age ≥75 (HR 4.88, CI 1.65-14.39, p=0.004) and CRP&amp;gt;10 (HR 3.38, CI 1.18-9.66, p=0.023) and lower risk with addition of chemotherapy (HR 0.076, CI 0.02-0.29, p&amp;lt;0.001). NLR, LDH and albumin levels did not significantly correlate with higher HR for death. At a median follow-up period of 8.5 months (IQR 14), the median overall survival was 9 months (IQR 14.5) with a worsening prognostic for increased CRP (p=0.00027), NLR&amp;gt;4 (p=0.051), albumin &amp;lt;35g/l (p=0.0024), LDH &amp;gt;250 U/l (p=0.037). Better survival rates were seen in patients receiving chemotherapy 75% vs 20 for those without chemotherapy (p&amp;lt;0.0001) and in those with local disease 80% vs 60% for metastatic disease p=0.034). Age ≥75 years carried a significant poorer prognostic (p=0.0017), while gender was not relevant. However, due to small sample size, age adjusted survival was not carried out and age was considered not relevant for the survival analysis. Conclusion: Beyond the expected factors like stage of disease and therapy, an increased CRP appears to carry significant correlation with hazard ratio for death among patients with adenocarcinoma of the pancreas. In our cohort, abnormal CRP, NLR, albumin and LDH levels demonstrated significant association with shorter survival period, underscoring the potential utility of these biomarkers in prognostic stratification and their incorporation into routine oncological assessments. Citation Format: Elena D. Chiru, Marie Knufike, Martina Sonderegger-Stalder, Raphael Mosimann, Antonia Sgries, Robert Rosenberg, Emanuel Burri, Sandra Mitrovic, Michèle Voegeli, Kristen Mertz, Alessandra Angelini, Marcus Vetter. Prognostic value of serum biomarkers in pancreatic adenocarcinoma: Results from a Swiss single center cohort analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3680.

Real-world (RW) testing patterns of serum lactate dehydrogenase (LDH) and its prognostic value among patients (pts) with metastatic colorectal cancer (mCRC).

46 Background: LDH is a potential prognostic biomarker of outcomes for pts with mCRC. This retrospective, observational cohort study describes RW LDH testing patterns and assesses LDH as a prognostic factor for overall survival (OS) in pts receiving chemotherapy (CT) for mCRC in the USA. Methods: Pts with mCRC, ≥18 years (yrs) of age, who initiated first line (1L) CT (index date) between January 1, 2016, and November 30, 2022, were identified in the nationwide de-identified Flatiron Electronic Health Record-derived database. Practice patterns for LDH testing are described. Pts were categorized into normal vs abnormal LDH baseline (≤3 months prior to/at index date) value based on the lab reference range. Prognostic relationship between normal vs abnormal LDH baseline value and OS was assessed using Kaplan-Meier and multivariate Cox proportional-hazards model. Results: Of 15,329 eligible pts, 57% were male, 49% were ≥65 yrs of age and 66% had ECOG performance status 0–1; 59% had stage IV disease at initial diagnosis; 29% had a KRAS mutation (at any time ≤30 days post-index; 35% not tested). Median time from mCRC diagnosis to index was 35 days. Most common 1L regimens were FOLFOX ± bevacizumab (48%), FOLFIRI ± bevacizumab (15%), and capecitabine (13%). Median follow up from index date was 15.6 months (mos); 60% died. LDH testing was performed in 2,547 pts (17%) during baseline and 3,379 pts (22%) post-index. Among those with ≥1 LDH test during each line of therapy (LOT), median number of LDH tests per pt was 4–6 and median time from line initiation to first LDH test was 7–10 days across the first five LOTs (Table). Among LDH tested pts during follow-up (n=3,379), 21% and 40% had abnormal and normal LDH values at baseline, respectively (39% missing). Demographic characteristics of abnormal vs normal LDH pts were similar; abnormal LDH pts were more likely to be ≥65 years (52% vs 49%), African American or Black (12% vs 7%), and reside in the Northeast (30% vs 21%). Median OS (95% CI) in pts with normal vs abnormal baseline LDH was 29.9 (28.3, 31.7) mos vs 16.8 (14.8, 18.2) mos. In multivariate Cox proportional-hazards model, pts with abnormal baseline LDH values had higher risk of death (HR 1.91, p&lt;0.0001) after adjustment for pt demographic and clinical characteristics. Conclusions: In RW clinical practice in the USA, only one-fifth of mCRC pts receiving CT undergo LDH testing even though LDH value has been found to be a prognostic factor of OS. Efforts to increase LDH testing may help guide treatment decisions in this setting. [Table: see text]

Efficacy and safety of anti-PD-1 inhibitor versus anti-PD-L1 inhibitor in first-line treatment of extensive-stage small cell lung cancer: a multicenter retrospective study

BackgroundImmunotherapy targeting PD-1/PD-L1 has revolutionized the treatment of extensive-stage small cell lung cancer (ES-SCLC). However, clinical trials suggest differential efficacy of anti-PD-1 agents and anti-PD-L1 agents in first-line treatment of ES-SCLC. This retrospective multicenter study aimed to compare the efficacy and safety of anti-PD-1 agents versus anti-PD-L1 agents in first-line treatment of ES-SCLC in real-world practice.MethodsPatients with pathologically or cytologically confirmed ES-SCLC treated with platinum plus etoposide combined with anti-PD-1 or PD-L1 agents as first-line treatment in different centers of PLA General Hospital between January 2017 and October 2021 were included for this study. Survival outcomes and safety were compared between patients receiving anti-PD-1 and PD-L1 agents.ResultsOf the total 154 included patients, 68 received anti-PD-1 agents plus chemotherapy (PD-1 group), and 86 received anti-PD-L1 agents plus chemotherapy (PD-L1 group). Progression-free survival (PFS) and overall survival (OS) in the entire cohort were 7.6 months (95% confidence interval [CI]: 6.5–8.2 months) and 17.4 months (95% CI: 15.3–19.3 months), respectively. Median PFS and OS were comparable between the PD-1 group and PD-L1 group (PFS: 7.6 months vs. 8.3 months, HR = 1.13, 95% CI: 0.79–1.62, p = 0.415; OS: 26.9 months vs. 25.6 months, HR = 0.96, 95% CI: 0.63–1.47, p = 0.859. The objective response rate and disease control rate were comparable between the two groups: 79.4% vs. 79.1% and 92.6% vs. 94.2%, respectively. The 6-month, 12-month, and 18-month PFS and OS rates were slightly higher in the PD-L1 group than in the PD-1 group, while the 24-month PFS rate was slightly higher in the PD-1 group than in the PD-L1 group. Stratified analysis showed that locoregional thoracic radiotherapy and normal lactate dehydrogenase level were independent predictors of better OS in ES-SCLC patients treated with first-line chemotherapy plus ICI. Adverse events were not significantly different between the two groups.ConclusionsAnti-PD-1 agents and anti-PD-L1 agents combined with chemotherapy as first-line treatment for ES-SCLC are comparably effective and well tolerated.

Biological signatures of the International Prognostic Index in diffuse large B-cell lymphoma

AbstractDiffuse large B-cell lymphoma (DLBCL) is a highly aggressive subtype of lymphoma with clinical and biological heterogeneity. The International Prognostic Index (IPI) shows great prognostic capability in the era of rituximab, but the biological signatures of IPI remain to be discovered. In this study, we analyzed the clinical data in a large cohort of 2592 patients with newly diagnosed DLBCL. Among them, 1233 underwent DNA sequencing for oncogenic mutations, and 487 patients underwent RNA sequencing for lymphoma microenvironment (LME) alterations. Based on IPI scores, patients were categorized into 4 distinct groups, with 5-year overall survival of 41.6%, 55.3%, 71.7%, and 89.7%, respectively. MCD-like subtype was associated with age of >60 years, multiple extranodal involvement, elevated serum lactate dehydrogenase (LDH), and IPI scores ranging from 2 to 5, whereas ST2-like subtype showed an opposite trend. Patients with EZB-like MYC+ and TP53Mut subtypes exhibited poor clinical outcome independent of the IPI; integrating TP53Mut into IPI could better distinguish patients with dismal survival. The EZB-like MYC−, BN2-like, N1-like, and MCD-like subtypes had inferior prognosis in patients with IPI scores of ≥2, indicating necessity for enhanced treatment. Regarding LME categories, the germinal center–like LME was more prevalent in patients with normal LDH and IPI scores of 0 to 1. The mesenchymal LME served as an independent protective factor, whereas the germinal center–like, inflammatory, and depleted LME categories correlated with inferior prognosis for IPI scores of 2 to 5. In summary, our work explored the biological signatures of IPI, thus providing useful rationale for future optimization of the IPI-based treatment strategies with multi-omics information in DLBCL.

Serum Cell Division Cycle 42 before and after Programmed Death-1 Inhibitor Therapy in Advanced Melanoma Patients: Correlation with Tumor Features, Clinical Response, and Survival.

Cell division cycle 42 (CDC42) mediates immune escape in cancers. This study aimed to investigate linkages of CDC42 with tumor features, treatment response, and survival in advanced melanoma patients receiving programmed death-1 (PD-1) inhibitors. Pre-treatment and post-treatment (after 2 cycles) serum CDC42 of 35 advanced melanoma patients receiving PD-1 inhibitor was assessed by enzyme-linked immunosorbent assay. Patients with tumor-node-metastasis (TNM) stage IV (vs. III) (P = 0.050) and abnormal (vs. normal) lactate dehydrogenase (LDH) (P = 0.022) had higher pre-treatment CDC42. After 2-cycle therapy, CDC42 was declined (P < 0.001). Objective response and disease control rates were 34.3% and 62.9%, respectively. Additionally, pre-treatment and post-treatment CDC42 was reduced in patients with objective response and disease control than those without (all P < 0.050). Concerning survival, pre-treatment with CDC42 > 700 pg/mL was associated with shorter progression-free survival (PFS) (P = 0.013), but not overall survival (OS) (P = 0.060). Specifically, the 12-month PFS rate was 26.7% and 66.2%, and the 12-month OS rate was 61.1% and 82.5% in patients with pre-treatment with CDC42 > 700 pg/mL and ≤ 700 pg/mL, respectively. Post-treatment with CDC42 > 700 pg/mL was correlated with shortened PFS (P = 0.010) and OS (P = 0.006). The 12-month PFS rate was 12.5% and 62.0%, and the 12-month OS rate was 42.3% and 88.0% in patients with post-treatment with CDC42 > 700 pg/mL and ≤ 700 pg/mL, accordingly. Furthermore, post-treatment with CDC42 > 700 pg/mL was independently related to PFS [hazard ratio (HR): 2.704, P = 0.029 and OS (HR: 7.749, P = 0.005)]. Elevated CDC42 correlates with advanced TNM, abnormal LDH, worse clinical response, and dismal survival in advanced melanoma patients receiving PD-1 inhibitors.

Baseline metastatic growth rate is an independent prognostic marker in patients with advanced BRAF V600 mutated melanoma receiving targeted therapy

BackgroundTargeted therapy (TT) of BRAF V600 mutated unresectable melanoma with inhibitors of the MAPK pathway achieves response rates of up to 76%, but most patients develop secondary resistance. Albeit TT is strikingly efficacious during the first days of treatment, even in advanced cases, long-term survival is highly unlikely, especially in patients with unfavorable baseline characteristics like elevated lactate dehydrogenase (LDH). In patients treated with anti-PD-1 immune checkpoint inhibitors, elevated baseline metastatic growth rate (MGR) was the most important prognostic factor. Here, we aimed at investigating the prognostic impact of MGR in patients with unresectable melanoma receiving TT. MethodsClinical records of 242 patients with at least one measurable target lesion (TL) receiving TT at seven skin cancer centers were reviewed. Baseline MGR was determined measuring the largest TL at baseline and at one earlier timepoint. ResultsOverall survival (OS) and progression-free survival (PFS) were significantly impaired in patients with an MGR > 3.9 mm/month (median OS: 11.4 vs. 35.5 months, P < 0.0001; median PFS: 4.8 vs. 9.2 months, P < 0.0001). Multivariable analysis of OS and PFS revealed that the prognostic impact of elevated MGR was independent of LDH, presence of brain and liver metastases, tumor burden, and line of treatment. The prognostic significance of elevated MGR was highest in patients with normal LDH. ConclusionsBaseline MGR is an important independent prognostic marker for OS and PFS in melanoma patients treated with TT. Its implementation in clinical routine is easy and could facilitate the prognostic stratification.

Patient Characteristics Associated with Growth of Patient-Derived Tumor Implants in Mice (Patient-Derived Xenografts).

Background: patient-derived xenografts (PDXs) have defined the field of translational cancer research in recent years, becoming one of the most-used tools in early drug development. The process of establishing cancer models in mice has turned out to be challenging, since little research focuses on evaluating which factors impact engraftment success. We sought to determine the clinical, pathological, or molecular factors which may predict better engraftment rates in PDXs. Methods: between March 2017 and January 2021, tumor samples obtained from patients with primary or metastatic cancer were implanted into athymic nude mice. A full comprehensive evaluation of baseline factors associated with the patients and patients' tumors was performed, with the goal of potentially identifying predictive markers of engraftment. We focused on clinical (patient factors) pathological (patients' tumor samples) and molecular (patients' tumor samples) characteristics, analyzed either by immunohistochemistry (IHC) or next-generation sequencing (NGS), which were associated with the likelihood of final engraftment, as well as with tumor growth rates in xenografts. Results: a total of 585 tumor samples were collected and implanted. Twenty-one failed to engraft, due to lack of malignant cells. Of 564 tumor-positive samples, 187 (33.2%) grew at time of analysis. The study was able to find correlation and predictive value for engraftment for the following: the use of systemic antibiotics by the patient within 2 weeks of sampling (38.1% (72/189) antibiotics- group vs. 30.7% (115/375) no-antibiotics) (p = 0.048), and the administration of systemic steroids to the patients within 2 weeks of sampling (41.5% (34/48) steroids vs. 31.7% (153/329), no-steroids) (p = 0.049). Regarding patient's baseline tests, we found certain markers could help predict final engraftment success: for lactate dehydrogenase (LDH) levels, 34.1% (140/411) of tumors derived from patients with baseline blood LDH levels above the upper limit of normality (ULN) achieved growth, against 30.7% (47/153) with normal LDH (p = 0.047). Histological tumor characteristics, such as grade of differentiation, were also correlated. Grade 1: 25.4% (47/187), grade 2: 34.8% (65/187) and grade 3: 40.1% (75/187) tumors achieved successful growth (p = 0.043), suggesting the higher the grade, the higher the likelihood of success. Similarly, higher ki67 levels were also correlated with better engraftment rates: low (Ki67 < 15%): 8.9% (9/45) achieved growth vs. high (Ki67 ≥ 15%): 31% (35/113) (p: 0.002). Other markers of aggressiveness such as the presence of lymphovascular invasion in tumor sample of origin was also predictive: 42.2% (97/230) with lymphovascular vs. 26.9% (90/334) of samples with no invasion (p = 0.0001). From the molecular standpoint, mismatch-repair-deficient (MMRd) tumors showed better engraftment rates: 62.1% (18/29) achieved growth vs. 40.8% (75/184) of proficient tumors (p = 0.026). A total of 84 PDX were breast models, among which 57.9% (11/19) ER-negative models grew, vs. 15.4% (10/65) of ER-positive models (p = 0.0001), also consonant with ER-negative tumors being more aggressive. BRAFmut cancers are more likely to achieve engraftment during the development of PDX models. Lastly, tumor growth rates during first passages can help establish a cutoff point for the decision-making process during PDX development, since the higher the tumor grades, the higher the likelihood of success. Conclusions: tumors with higher grade and Ki67 protein expression, lymphovascular and/or perineural invasion, with dMMR and are negative for ER expression have a higher probability of achieving growth in the process of PDX development. The use of steroids and/or antibiotics in the patient prior to sampling can also impact the likelihood of success in PDX development. Lastly, establishing a cutoff point for tumor growth rates could guide the decision-making process during PDX development.

Exposure-Response Relationships between the Complement Factor B Inhibitor Iptacopan and Lactate Dehydrogenase (LDH) and Hemoglobin (Hb) in Patients (Pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Background: PNH is an ultrarare disease characterized by complement-mediated hemolysis and subsequent anemia, bone marrow failure and thrombosis. In pts not treated with complement inhibitors, intravascular hemolysis (IVH) results from unregulated progression of the complement system and membrane attack complex formation. IVH is controlled in pts treated with anti-C5 therapy, but extravascular hemolysis (EVH) may emerge and cause persistent anemia. High LDH levels are a marker of ongoing IVH, while anemia can result from both IVH and EVH. Iptacopan is the first oral proximal complement inhibitor targeting factor B to selectively inhibit the alternative pathway of the complement cascade. As shown in PNH Phase III trials (APPLY-PNH [NCT04558918] and APPOINT-PNH [NCT04820530]), iptacopan can achieve good control of hemolysis. Aim: To support the dose selection for iptacopan, this analysis characterizes the exposure-response relationships between iptacopan and efficacy measures (LDH and Hb) in pts with PNH. The effect of prior anti-C5 treatment status has also been evaluated. Methods: This analysis is based on data from 4 clinical trials enrolling pts with PNH.Final data were used from the completed Phase II trials X2201 (NCT03439839; pts with active hemolysis despite anti-C5 therapy received concomitant iptacopan) and X2204 (NCT03896152; anti-C5-naïve pts received iptacopan monotherapy), in which iptacopan was administered orally in doses ranging from 25 to 200 mg twice daily (bid). Data up to the cut-off dates of 26 September 2022 and 2 November 2022 were used from the Phase III trials, APPLY-PNH (pts previously treated with anti-C5) and APPOINT-PNH (pts not treated with complement inhibitors including anti-C5), respectively, in which oral iptacopan was administered at 200 mg bid. A longitudinal mixed-effects modeling approach was applied to LDH and Hb. To account for the delay between exposure and response, indirect response models were developed for LDH and Hb. The models were used to predict the long-term (6 months) LDH and Hb responses for various iptacopan bid dose levels and to estimate (using simulation) the proportion of pts achieving LDH ≤1.5 × upper limit of normal (ULN) and Hb ≥12 g/dL. Results: The modeling dataset contained 161 pts with PNH; 94 (58%) were female, and median (range) age was 45 (18-84) years. For modeling of LDH and Hb levels, 2812 and 2587 samples were used, respectively, as well as 1577 pharmacokinetic samples. In total, 53 (33%) pts had not received anti-C5 treatment. Of the remaining 108 pts, 16 (15%) received iptacopan as add-on therapy to anti-C5 (pts from X2201) and 92 (85%) had previously received anti-C5 (pts from APPLY-PNH). The indirect response models were considered biologically plausible and adequately described the data using a common EC 50 value to both anti-C5-naïve pts and pts currently receiving or who previously received anti-C5. The estimated concentration of iptacopan required to achieve 90% of the maximum response (EC 90) of LDH was 268 ng/mL (90% confidence interval [CI] 238, 302), irrespective of prior anti-C5 treatment status ( Figure). The estimated typical LDH value after iptacopan treatment at an exposure &amp;gt;EC 90 was 237 U/L (90% CI 224, 250) within the normal LDH range (&amp;lt;250 U/L). Iptacopan 200 mg bid was the dose at which the highest proportion of pts (86%) achieved LDH ≤1.5 × ULN. While baseline LDH levels differed between anti-C5-naïve pts and pts currently receiving or who previously received anti-C5, similar proportions of these pts achieved LDH ≤1.5 × ULN (84% and 88%, respectively). The estimated EC 90 of Hb ≥12 g/dL was 1968 ng/mL (90% CI 1661, 2333) ( Figure); 89% of all pts were expected to reach EC 90 exposure at iptacopan 200 mg bid. The estimated Hb value after treatment with iptacopan at an exposure &amp;gt;EC 90 was 12.7 g/dL (90% CI 12.4, 13.0). 70% of pts were expected to achieve Hb normalization (≥12 g/dL) with iptacopan 200 mg bid. Similar proportions of anti-C5-naïve pts and pts who were currently receiving or who previously received anti-C5 achieved Hb ≥12 g/dL (71% and 68%, respectively). Conclusions: Indirect response models were developed to describe the exposure-response relationships between iptacopan and efficacy measures (LDH and Hb) in pts with PNH. The analysis demonstrated that 200 mg bid is the dose of oral iptacopan that achieves LDH ≤1.5 × ULN and Hb normalization in the highest proportion of patients regardless of prior treatment status.

High serum lactate dehydrogenase as a predictor of cardiac insufficiency at follow-up in elderly patients with acute myocardial infarction

BackgroundImpairment of cardiac function progresses after acute myocardial infarction (AMI). Lactate dehydrogenase (LDH), a marker of cardiac injury and an enzyme in anaerobic glycolysis, is suggested as a risk factor for patient mortality in inflammatory diseases. MethodsIn this study, 448 older and 445 younger AMI patients were recruited and followed up. The effect of baseline serum LDH on post-infarction cardiac function was assessed at follow-up. ResultsElderly patients in the high baseline LDH group had a high risk of being diagnosed with cardiac insufficiency during follow-up (adjusted hazard ratio: 3.643, P = 0.007), and the follow-up left ventricular ejection fraction of the quartile subgroup tended to decrease with increasing in baseline serum LDH (adjusted odds ratio: 1.301, P = 0.001) for each 100 U/L increase. The LVDd and LVVd of elderly patients in the high LDH group were not significantly different from those of patients in the normal LDH group at baseline but were further increased in the high LDH group at follow-up. In younger patients, the effect of LDH on post-infarction cardiac structure and function was similar to that in older patients, but unlike older patients, Cox regression analysis showed that LDH was not the predominant influence. ConclusionLongitudinal changes in cardiac function were independently associated with high baseline serum LDH levels in patients with AMI. Baseline LDH levels are superior to other myocardial injury markers and may be a useful parameter in predicting future cardiac dysfunction after AMI, especially in the elderly.

Assessment of computed tomography for the diagnosis of exudative and transudative pleural effusion

Introduction: The basic computed tomography (CT) characteristics of pleural effusion (PE) were analyzed, and the association between demographic factors and prominent CT findings with different types of PE was assessed. The individual CT characteristics and Light’s criteria for exudative PE were also evaluated. In addition, a cutoff for attenuation values of CT scans for exudative PE was determined. Methods: A cross-sectional study among 92 participants with PE was carried out at Bir Hospital, Kathmandu, Nepal. The χ2 test, logistic regression analysis, and diagnostic statistics were calculated. The ethical clearance was obtained from the institutional review committee of Institutional review board of National Academy of Medical Sciences (NAMS), Bir Hospital (Ref. 876/076/77). Results: The study examined 92 cases of PE, with 78.3% occurring in males and the majority affecting individuals aged 55–74 years old. Results showed that on CT scans, pleural thickening [odds ratio (OR): 13.89, 95% CI: 4.96–38.86, P &lt; 0.05], pleural nodules (OR: 12.72, 95% CI: 2.64–61.18, P &lt; 0.05) and loculations (OR: 13.46, 95% CI: 4.03–44.89, P &lt; 0.05) were significantly associated with exudative PE. Of these, pleural nodules had the highest specificity (96.4%) and positive likelihood ratio (9), whereas pleural thickening had the highest sensitivity (70.3%). When using the criterion “pleural fluid Lactate Dehydrogenase concentration as positive if it was over two-thirds of the upper limit of normal serum Lactate Dehydrogenase,” the CT scan had a positive likelihood ratio of 22.52. The study also found that an attenuation value ≥9.70 HU could indicate an exudative PE (area under the curve: 0.80, 95% CI: 0.70–0.90, P &lt; 0.05). Conclusion: The CT characteristics, such as pleural thickening, pleural nodules, and loculations, were more likely to be present in exudative PE. In addition, the attenuation values of PE could also determine its nature as either exudate or transudate, with an attenuation value of &gt;9.70 HU indicating an exudative PE.

Predictive value of serum lactate dehydrogenase on prognosis of patients with paraquat poisoning

Objective: To investigate the predictive value of serum lactate dehydrogenase (LDH) in the prognosis of patients with paraquat (PQ) poisoning, and to provide evidence for early prognosis assessment. Methods: In February 2022, 50 patients with PQ poisoning who completed serum LDH detection admitted to the Department of Emergency Medicine, the First Affiliated Hospital of Wenzhou Medical University from January 2012 to December 2021 were selected as the observation group, and 50 healthy physical examination personnel were randomly selected as the control group. Patients with PQ poisoning were divided into survival group and death group according to the prognosis, and the differences of blood routine routine, liver and kidney function and other indicators in the first admission between the two groups were compared. Multivariate logisitic regression model was established, ROC curve was drawn, and the influencing factors of prognosis of patients with PQ poisoning were analyzed. Results: Compared with the control group, the white blood cell count (WBC), total bilirubin (TBil), alanine aminotransferase (ALT), aspartate aminotransferase (AST), LDH, glucose (GLU) and creatinine (Cr) in observation group were significantly increased, while albumin (ALB) and total cholesterol (TC) were significantly decreased (P<0.05). Univariate analysis showed that WBC, elevated LDH (>247 U/L), TBil, ALT, AST and Cr were significantly different between PQ poisoning survival group and death group (P<0.05). Multivariate logisitic regression analysis showed that elevated serum LDH was an independent risk factor for the prognosis of PQ poisoning patients (OR=9.95, 95%CI: 1.34-73.82, P=0.025). The area under the ROC curve of LDH was 0.811 (95%CI: 0.692-0.930). When the cut-off value was 340 U/L, the sensitivity was 0.889 and the specificity was 0.719. Log-rank test showed that there was a statistically significant difference in survival rate between the normal LDH group and the elevated LDH group (P=0.001) . Conclusion: Serum LDH has a good predictive value in evaluating the prognosis of patients with PQ poisoning. Elevated LDH is a risk factor for poor prognosis of patients with PQ poisoning.

The REWRITE Study – REal-WoRld effectIveness of TrifluridinE/tipiracil in Patients with Previously Treated Metastatic Colorectal Cancer

AimsIn the pivotal RECOURSE trial, trifluridine/tipiracil improved survival outcomes in refractory metastatic colorectal cancer (mCRC), while demonstrating an acceptable toxicity profile. Routine clinical practice evidence is important to support the ongoing value of recently approved medicines. Our objective was to assess the utilisation patterns and real-world effectiveness of trifluridine/tipiracil in previously treated mCRC patients. Materials and methodsThis was a retrospective observational study including consecutive patients who started trifluridine/tipiracil between 1 April 2018 and 30 September 2019 in the medical oncology departments of three major public hospitals in Portugal. The primary outcome measure was overall survival. Associations between overall survival and patient and tumour characteristics were assessed using multivariate Cox regression analyses. ResultsIn total, 111 patients were included in the study, with a mean age of 64 years. From these, 45.9% received two prior lines of treatment, 47.8% had three or more previous lines of treatment and 83.6% had Eastern Cooperative Oncology Group (ECOG) performance status 0–1 at baseline. The median duration of trifluridine/tipiracil treatment was 3.7 cycles (95% confidence interval 3.4–4.1). Most patients (80.4%) remained on their planned dose throughout the trifluridine/tipiracil treatment period, fulfilling 100% relative dose intensity. The median overall survival in the total study cohort was 7.9 months (95% confidence interval 6.4–9.8) and the median progression-free survival was 3.4 months (95% confidence interval 3.2–3.9). The median overall survival was significantly higher in patients with a normal serum lactate dehydrogenase (LDH) level (median overall survival 11.2 months for [135, 205] IU/l LDH [95% confidence interval 8.2–NR] and 13.6 months for [205, 251] IU/l LDH [95% confidence interval 8.2–NR]) and in better fitted (ECOG = 0–1) patients (median overall survival 8.0 months; 95% confidence interval 6.7–10.0). The median time to worsening performance status was 6.2 months (95% confidence interval 5.0–8.0). Treatment discontinuation due to adverse events was low (3.1%). ConclusionOur study confirms the effectiveness of trifluridine/tipiracil in real-life mCRC patients. Overall survival and progression-free survival outcomes are consistent with the efficacy profile reported in the earlier randomised RECOURSE clinical trial. Like other real-world studies, we found no additional safety concerns in the use of trifluridine/tipiracil.

CPC06 Congenital urticaria pigmentosa mistaken for nonaccidental injury

Abstract A male infant presented to his general practitioner for a routine 6-week check. His parents reported the presence of tan–brown lesions since birth. The marks were uniform in colour, were present on the trunk, scalp and face, and were not overlying bony prominences. There was concern that these lesions represented bruising as a manifestation of nonaccidental injury (NAI), and urgent paediatric review was arranged. He was admitted for investigation of potential NAI, and dermatology consultation was sought. On examination, scattered reddish brown-to-tan macules and papules were noted on the torso and limbs, not overlying bony prominences. Darier sign was negative, although some reactive cutis marmorata was appreciable on the trunk following rubbing of multiple lesions. A diagnosis of urticaria pigmentosa (UP), or cutaneous mastocytosis, was made clinically. Skin biopsies demonstrated an infiltrate of spindled and round mast cells and scattered eosinophils within the superficial and mid-dermis, with immunohistochemistry positive for CD117, consistent with UP. Blood tests during admission showed a normal complete blood count and coagulation screen (including von Willebrand factor), normal renal and liver function, normal lactate dehydrogenase, normal immunoglobulins and normal mast cell tryptase. Cranial ultrasound and liver ultrasound were normal. Mastocytosis is a spectrum of disease characterized by pathological accumulation of mast cells in tissues, including skin, bone marrow and the gastrointestinal tract. Cutaneous mastocytosis can be further classified as maculopapular cutaneous mastocytosis, also known as UP, diffuse cutaneous mastocytosis and localized cutaneous mastocytomas. With UP, children typically present in the first 2 years of life with multiple reddish-brown macules, papules and/or plaques distributed anywhere on the body, most commonly the trunk. In darkly pigmented skin, lesions may be hyperpigmented and erythema less appreciable. Darier sign, a transient urticarial response upon gentle rubbing of the skin, is classic and supportive of diagnosis, although it is not always demonstrable. UP has rarely been reported to be misdiagnosed as NAI. Other ‘bruising’ mimics include disorders of coagulation, Valsalva petechiae, vasculitis, acute haemorrhagic oedema, incontinentia pigmenti, phytophotodermatitis, coin rubbing, spooning, cupping, Mongolian spots, morphoea, neuroblastoma and ink stains, some of which may be unfamiliar to paediatricians or dermatologists. Dermatologists have a crucial role in recognizing cutaneous manifestations of NAI in children, which commonly includes bruising, particularly in infants who are not yet mobile. While consideration of NAI is important in all children presenting for medical care, this case highlights the importance of considering underlying dermatoses to avoid unwarranted distress and unnecessary investigations.