LDH Levels Research Articles

Clinical features and prognostic factors of elderly patients with mantle cell lymphoma

Objective: To examine the clinical characteristics and prognostic factors of elderly patients with mantle cell lymphoma (MCL) and the impact of nutrition and underlying diseases on the prognosis of elderly patients with MCL. Methods: retrospectively analyzed 255 elderly patients with MCL from 11 medical centers, including Peking University Third Hospital between January 2000 and February 2021. We analyzed clinical data, such as age, gender, Mantle Cell Lymphoma International Prognostic Index score, and treatment options, and performed univariate and multivariate prognostic analysis. We performed a comprehensive geriatric assessment on elderly MCL patients with medical records that included retraceable underlying disease and albumin levels, and we investigated the impact of basic nutrition and underlying disorders on MCL prognosis in the elderly. Results: There were 255 senior individuals among the 795 MCL patients. Elderly MCL was more common in males (78.4%), with a median age of 69 yr (ages 65-88), and the majority (88.6%) were identified at a late stage. The 3-yr overall survival (OS) rate was 42.0%, with a 21.2% progression-free survival (PFS) rate. The overall response rate (ORR) was 77.3%, with a 33.3% total remission rate. Elderly patients were more likely than younger patients to have persistent underlying illnesses, such as hypertension. Multivariate analysis revealed that variables related with poor PFS included age of ≥80 (P=0.021), Ann Arbor stage Ⅲ-Ⅳ (P=0.003), high LDH level (P=0.003), involvement of bone marrow (P=0.014). Age of ≥80 (P=0.001) and a high LDH level (P=0.003) were risk factors for OS. The complete geriatric assessment revealed that renal deficiency was associated with poorer OS (P=0.047) . Conclusions: Elderly MCL patients had greater comorbidities. Age, LDH, renal function, bone marrow involvement, and Ann Arbor stage are all independent risk factors for MCL in the elderly.

Risk factors of severe course and fatality in children hospitalized for COVID-19 – two centers cohort study.

IntroductionAfter three years of the pandemic, predictors of COVID-19 severity in children are still not completely known. This study was designed to define the high-risk group in hospitalized children.Material and methodsThe analysis covered 2338 children in two centers. Among patients with severe course three groups were identified –requiring and not requiring mechanical ventilation and those who died.ResultsThe median age of seventy children (54% female) with severe COVID-19 was 32 months. In 43 (61%) children comorbidities were present. No one was vaccinated against COVID-19. On admission, medium SpO2 was 89%. 65 (93%) patients presented with dyspnoea, and 49 (70%) with cough. 53 (76%) children required noninvasive oxygen support and 17 (24%) mechanical ventilation. 8(11%) children died. The most significant difference between mechanically ventilated children who recovered and those who died was age – 124 vs 12.8 months (p<0.001). Children requiring mechanical ventilation presented higher CRP (median 33.4 vs 6.7 mg/dl), LDH, and ferritin. In children who died even higher CRP (55.9 vs 7.9 mg/dl), deep lymphopenia (0.65 vs 1.85 x 103/ul), and thrombocytopenia ( 7 vs 237 x 103/ul) were observed.ConclusionsRisk factors for a severe course of COVID-19 were – young age, lack of COVID-19 vaccination, auscultation changes and dyspnea at admission. The presence of comorbidities, high CRP, LDH, and ferritin levels were the predictors of mechanical ventilation necessity and death. Among children mechanically ventilated teenagers had a prognosis of recovery but, infants with comorbidities were at the highest risk of death.

Sufentanil inhibits Pin1 to attenuate renal tubular epithelial cell ischemia-reperfusion injury by activating the PI3K/AKT/FOXO1 pathway.

Renal ischemia-reperfusion injury (RIRI) has become a great concern in clinical practice with high morbidity and mortality rates. Sufentanil has protective effects on IRI-induced organ injury. Herein, the effects of sufentanil on RIRI were investigated. RIRI cell model was established by hypoxia/reperfusion (H/R) stimulation. The mRNA and protein expressions were assessed using qRT-PCR and western blot. TMCK-1 cell viability and apoptosis were assessed using MTT assay and flow cytometry, respectively. The mitochondrial membrane potential and ROS level were detected by JC-1 mitochondrial membrane potential fluorescent probe and DCFH-DA fluorescent probe, respectively. LDH, SOD, CAT, GSH and MDA levels were determined by the kits. The interaction between FOXO1 and Pin1 promoter was analyzed using dual luciferase reporter gene and ChIP assays. Our results revealed that sufentanil treatment attenuated H/R-induced cell apoptosis, mitochondrial membrane potential (MMP) dysfunction, oxidative stress, inflammation and activated PI3K/AKT/FOXO1 associated proteins, while these effects were reversed by PI3K inhibitor, suggesting that sufentanil attenuated RIRI via activating the PI3K/AKT/FOXO1 signaling pathway. We subsequently found that FOXO1 transcriptionally activated Pin1 in TCMK-1 cells. Pin1 inhibition ameliorated H/R-induced TCMK-1 cell apoptosis, oxidative stress and inflammation. In addition, as expected, the biological effects of sufentanil on H/R-treated TMCK-1 cells were abrogated by Pin1 overexpression. Sufentanil reduced Pin1 expression through activation of the PI3K/AKT/FOXO1 signaling to suppress cell apoptosis, oxidative stress and inflammation in renal tubular epithelial cells during RIRI development.

Long-term prognostic factors for PRRT in neuroendocrine tumors.

Peptide receptor radionuclide therapy (PRRT) is an effective and well-tolerated treatment option for patients with neuroendocrine tumors (NETs) that prolongs progression-free survival (PFS). However, the limited overall survival (OS) rates in the prospective phase III study (NETTER1) highlighted the need to identify patient-specific long-term prognostic markers to avoid unnecessary side effects and enable better treatment stratification. Therefore, we retrospectively analyzed prognostic risk factors in NET patients treated with PRRT. A total of 62 NET patients (G1: 33.9%, G2 62.9%, and G3 3.2%) with at least 2 cycles of PRRT with [177Lu]Lu-HA-DOTATATE (mean 4 cycles) were analyzed. Of which, 53 patients had primary tumors in the gastroenteropancreatic (GEP) system, 6 had bronchopulmonary NET, and 3 had NET of unknown origin. [68Ga]Ga-HA-DOTATATE PET/CT scans were performed before PRRT start and after the second treatment cycle. Different clinical laboratory parameters, as well as PET parameters, such as SUVmean, SUVmax, and PET-based molecular tumor volume (MTV), were collected, and their impact on the OS was investigated. Patient data with a mean follow-up of 62 months (range 20-105) were analyzed. According to interim PET/CT, 16 patients (25.8%) presented with partial response (PR), 38 (61.2%) with stable disease (SD), and 7 (11.3%) with progressive disease (PD). The 5-year OS was 61.8% for all patients, while bronchopulmonary NETs showed poorer OS than GEP-NETs. Multivariable Cox regression analysis showed that chromogranin A level and MTV together were highly significant predictors of therapeutic outcome (HR 2.67; 95% CI 1.41-4.91; p = 0.002). Treatment response was also influenced by the LDH level (HR 0.98; 95% CI 0.9-1.0; p = 0.007) and patient age (HR 1.15; 95% CI 1.08-1.23; p < 0.001). ROC analysis revealed baseline MTV > 112.5 ml [Sens. 91%; Spec. 50%; AUC 0.67 (95% CI 0.51-0.84, p = 0.043)] and chromogranin A >1,250.75 μg/l [Sens. 87%; Spec. 56%; AUC 0.73 (95% CI 0.57-0.88, p = 0.009)] as the best cutoff values for identifying patients with worse 5-year survival. Our retrospective analysis defined MTV and chromogranin A in combination as significant prognostic factors for long-term OS. Furthermore, an interim PET/CT after two cycles has the potential in identifying non-responders who may benefit from a change in therapy at an early stage.

Carbon Black CB-EDA Nanoparticles in Macrophages: Changes in the Oxidative Stress Pathway and in Apoptosis Signaling.

The influence of black carbon nanoparticles on J774.A1 murine cells was investigated with the objective of exploring the cytotoxicity of black carbon functionalized with ethylenediamine CB-EDA. The results showed that CB-EDA has a cytotoxic profile for J774.A1 macrophages in a time- and dose-dependent manner. When phagocytosed by the macrophage, CB-EDA triggers a mechanism that leads to apoptosis. In this process, there is an increase in oxidative stress pathways due to the activation of nitric oxide and then ROS. This causes an imbalance in redox function and a disruption of membrane integrity that occurs due to high levels of LDH, in addition to favoring the release of the pro-inflammatory cytokines IL-6, IL-12, and tumor necrosis factor (TNF) in an attempt to modulate the cell. However, these stimuli are not sufficient to repair the cell and the level of mitochondrial integrity is affected, causing a decrease in cell viability. This mechanism may be correlated with the activation of the caspasse-3 pathway, which, when compromised, cleaves and induces cells death via apoptosis, either through early or late apoptosis. In view of this, the potential for cell damage was investigated by analyzing the oxidative and inflammatory profile in the macrophage lineage J774.A1 and identifying potential mechanisms and metabolic pathways connected to these processes when cells were exposed to NP CB-EDA for both 24 h and 48 h.

Evaluation of Pleural Effusion Type Determination Based on Light's and Heffner's Criteria

Pleural effusion is an abnormal accumulation of pleural fluid in the pleural cavity due to excessive transudation or exudation. Light's criteria is used as the standard method to distinguish between exudates and transudates. Some recent studies reported misclassifications which led to development of several alternative criteria, such as Heffner's criteria. The purpose of this study was to determine the sensitivity and specificity of Heffner's criteria to determine the type of pleural effusion. This research was an observational study with a cross-sectional method using a pleural effusion of patients at the Clinical Pathology Laboratory Installation at the Wahidin Sudirohusodo Hospital in July 2018. Total protein, LDH, and cholesterol levels were measured in all samples that met the inclusion and exclusion criteria. There were 45 pleural effusion samples that consisted of 30 transudate and 15 exudate samples. Based on clinical diagnosis, the Light's criteria showed 3 misclassifications and Heffner's criteria obtained showed 2 misclassifications. Based on the data above, the statistical data showed that Light's criteria had a sensitivity of 96.7% and specificity of 86.7%. Heffner's criteria had a sensitivity of 100% and specificity of 86.7%. Heffner's criteria can be used an alternative method to determine the type of pleural effusion because it showed a better sensitivity and specificity than Light's criteria.

Clinical Profile and Determinants of Mortality in Patients with Interstitial Lung Disease Admitted for COVID-19.

Concern has risen about the effects of COVID-19 in interstitial lung disease (ILD) patients. The aim of our study was to determine clinical characteristics and prognostic factors of ILD patients admitted for COVID-19. Ancillary analysis of an international, multicenter COVID-19 registry (HOPE: Health Outcome Predictive Evaluation) was performed. The subgroup of ILD patients was selected and compared with the rest of the cohort. A total of 114 patients with ILDs were evaluated. Mean ± SD age was 72.4 ± 13.6 years, and 65.8% were men. ILD patients were older, had more comorbidities, received more home oxygen therapy and more frequently had respiratory failure upon admission than non-ILD patients (all p < 0.05). In laboratory findings, ILD patients more frequently had elevated LDH, C-reactive protein, and D-dimer levels (all p < 0.05). A multivariate analysis showed that chronic kidney disease and respiratory insufficiency on admission were predictors of ventilatory support, and that older age, kidney disease and elevated LDH were predictors of death. Our data show that ILD patients admitted for COVID-19 are older, have more comorbidities, more frequently require ventilatory support and have higher mortality than those without ILDs. Older age, kidney disease and LDH were independent predictors of mortality in this population.

Vitamin D3 supplementation could ameliorate the inflammatory and redox status in the muscular phase of trichinellosis.

Nutritional supplements, particularly vitamin D, have been widely used worldwide in the treatment of various infections, including parasites. This study aimed to evaluate the potential effects of vitamin D3 supplementation on the muscular phase of trichinellosis in experimental animals. Mice were divided as follows: (group I): infected untreated, (group IIa) infected and treated with vitamin D3 for 12 doses beginning 2weeks before infection and continuing after infection, (group IIb) infected and treated with vitamin D3 for 8 doses beginning on the same day of infection, (group III) normal control, (group IVa) which received vitamin D3 for 12 doses and (group IVb) which received vitamin D3 for 8 doses. Mice were sacrificed 35days after infection and total muscle larval count, and histopathological examination of muscle samples with immunohistochemical staining of cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS) were performed. Muscle relative cathelicidin mRNA expression was assessed, as well as serum levels of muscle enzymes CK and LDH, interleukin-4 (IL-4), IL-10, IL-17 and interferon-gamma (INF-γ). Vitamin D3 supplementation significantly reduced muscle larval count, inflammatory cellular infiltration, COX2 and iNOS expression. Furthermore, it increased cathelicidin gene expression, decreased serum levels of CK and LDH and affected serum cytokine levels, increasing serum IL-4 and IL10 levels while decreasing serum INF γ and IL-17. In conclusion, vitamin D3 supplementation has favorable outcomes on the muscle phase of trichinellosis, including anti-inflammatory, antioxidant, and immunomodulatory effects.

Study of pulmonary hypertension in post-COVID-19 patients by transthoracic echocardiography

BackgroundA devastating medical disorder, the coronavirus pandemic infection (COVID-19), produced by the coronavirus 2 (SARSCoV-2), is primarily characterized by severe pneumonia. Pulmonary hypertension (PH), which may cause right ventricular (RV) involvement and dysfunction, can occur as a result of lung parenchymal injury and disturbed pulmonary circulation. Transthoracic echocardiography (TTE) is a very reliable noninvasive approach to determining the severity of PH. Similar to that, thorax computer tomography (TCT) can effectively detect the severity of lung damage during the acute phase of a COVID-19 infection.AimsThe goal of this research is to examine PH and altered right ventricular function by TTE in post-COVID-19 cases.Patients and methodsThis retrospective case–control study was conducted at Tanta Chest University Hospital, Tanta, Egypt. The study started from October 2021 to September 2022 on 50 post-COVID-19 cases with one or more clinical manifestations of PH. These cases underwent TTE (group I showed normal PAP “control group,” groups II & III with PH further subdivided according to PaO2).ResultsRisk factors of age, BMI, diabetes mellitus, and smoking were substantially raised in group III, but sex and hypertension were insignificant. Symptoms of chest pain, dyspnea, and palpitation were worse in group III. Levels of LDH, d-dimer, ESR, and serum bilirubin were substantially increased in group III in comparison to the other groups. Post-COVID-19-associated lung fibrosis and embolism were higher in group III. Mean values of estimated systolic pulmonary artery pressure (esPAP) and right atrial and right ventricular diameters were substantially increased in groups III and II in comparison to group I. Mean values of RV-GLS and TAPSE were lower in groups III and II in comparison to group I. FEV1, FVC, PEFR, and FEF25–75% percentage of the predicted were significantly low in groups II and III. FEV1/FVC ratio was substantially lower in group II in comparison to groups I and III.ConclusionsThe incidence of pulmonary hypertension in post-COVID-19 patients with suspected manifestations of PH is 70%. Increased age, BMI, DM, smoking, decreased PaO2, increased CORADS score, and abnormal spirometry are risk factors for PH in post-COVID-19 patients. Patients with post-COVID-19 PH stay more either in ICU or ward.

Exploring the clinical significance of specific immune-related adverse events (irAE) in patients with melanoma undergoing immune checkpoint inhibitor (ICI) therapy.

9566 Background: Several studies have demonstrated that patients who experience irAE as a result of ICI treatment, exhibit significantly improved outcomes compared to patients without toxicity. However, data regarding the impact of specific irAE is currently lacking. Methods: This is a real world single-site cohort of advanced melanoma patients who were treated with ICI as first line between 2014 and 2020. This study explores the effects of specific irAE on treatment efficacy. Results: Three hundred and ninety-five (395) patients were treated with either monotherapy anti PD-1 (65.4%), combination ICI (24.3%), or anti CTLA-4 (10.3%). Median age was 68 years (12-99y), and 57% were male. The median follow up was 24.5m. Any-grade irAEs were seen in 72% (n = 299), and 26% experienced high-grade irAE (n = 104). The most frequent irAE were dermatologic (n = 110, 27.8%), vitiligo (n = 48, 12.1%), rheumatologic (n = 68, 17.2%), gastro-intestinal (n = 66, 16.7%), and endocrine (n = 61, 15.4%). The development of irAE was associated with a significantly longer median PFS (19.3m vs 4.5m; HR 0.46, p &lt; 0.001) and median OS (55m vs 16.9m; HR 0.44, p &lt; 0.001). Specific irAE that were significantly associated with survival benefic were rheumatologic (HR 0.34 for PFS, p &lt; 0.001; HR 0.38 for OS, p &lt; 0.001), dermatologic (HR 0.58 for PFS, p &lt; 0.001; HR 0.54 for OS, p = 0.001), vitiligo (HR 0.30 for PFS, p &lt; 0.001; HR 0.29 for OS, p &lt; 0.001) and endocrine (HR 0.6 for PFS, p = 0.01; HR 0.52 for OS, p &lt; 0.001). After adjustment for ECOG performance status, LDH level, type of ICI protocol and M-substage - the rheumatologic, dermatologic and vitiligo irAE remained significant on multivariate analysis for both PFS and OS. Conclusions: The development of rheumatologic, vitiligo and other dermatologic irAE during ICI treatment, is correlated with a noteworthy survival advantage. These irAE may reflect a hyper-activated immune response and thus can serve as meaningful clinical biomarkers.

A self-assessment survey to identify the risk of screen failure in phase I clinical trials (SCITEP score).

e18725 Background: Screen failures (SF) in early phase clinical trial are deleterious for patients, physicians and drug companies. It is therefore crucial to identify risk factors of SF, in order to optimize drug development and maximize patient’s benefit. Self- patient reporting is a new method of clinical evaluation based on the patient's experience that can meaningfully evaluate patient’s outcome. Methods: We created a self-assessment survey comprising 15 questions extracted from the ESAS, EQ-5D and PALLIA 10 scores, which evaluate patient’s (pts) symptoms and quality of life, each item being scored from 0 to 10, for a total of 0 to 150. Patients entering a phase I clinical trial at Gustave Roussy cancer center between January 10th and October 26th 2022 were surveyed at screening (T0), and subsequently every month (T1, T2,..) until end of treatment. Results: 227 of 275 pts entering a Ph1T were assessed between January 10th and October 26th 2022. Most frequent tumor types were lung (18%), GI (16%), hematological (10%) and gynecological cancer (9.3%); 56% were female. At data cut off (December 19th 2022), 25 pts were considered SF. There was no difference observed between SF pts and pts who went on with the trial in terms of ECOG, RMH score, albumin and LDH levels, number of previous lines of treatments and of metastatic sites at baseline (Table 1). At T0, there was a significant difference in the SCITEP score between SF pts and the others (median score 41 [IQR 26-63] vs 20 [IQR 10-38], p &lt; 0.001). Internal validity of the score was good (cronbach alpha &gt; 0.7). With a cutoff of ≥35, sensitivity of the survey to identify pts at high risk of SF was of 66.6% and specificity of 70.5%. Regarding overall survival, pts with a score ≥35 (n = 68) at T0 were at higher risk of death (survival rate at 3 months of 53% vs 65%, p &lt; 0.01). Conclusions: Self-assessment of risk of SF by pts entering a phase I clinical trial is feasible with the SCITEP score. A score ≥35 seemed associated with a higher risk of SF and of death at 3 months. Independent cohorts are needed to revalidate this score as a tool to better detect pts at risk of SF and thereby optimize drug development. [Table: see text]

Anti-PD1 plus BRAF/MEK inhibitors (triplet therapy) after failure of standard therapy in patients (pts) with advanced melanoma.

9528 Background: Preclinical models support the combination of immune checkpoint inhibitors (ICI) with targeted therapy (TT), suggesting a synergistic effect; however, clinical trials evaluating the efficacy of triplet combination in first-line setting showed limited advantage compared to TT only. Early data from the phase II TRIDeNT (NCT02910700) study showed promising clinical activity in anti-PD1 refractory pts. We sought to evaluate the efficacy of combined TT plus anti-PD1 after the failure of standard therapy in pts with advanced melanoma. Methods: This retrospective, multicenter study included pts with advanced melanoma who were treated with a BRAF inhibitor and a MEK inhibitor in combination with a PD1 inhibitor after failure of a minimum of one standard therapy in seven major melanoma centers between February 2016 and July 2022. Demographics, disease characteristics, therapy details, and outcome data were evaluated. Results: 59 pts were identified; med age was 48 yrs (range, 24-80), 32 pts (54.2%) were males, 20 pts (33.9%) had ECOG PS 1, 46 pts (78%) had 3 or more metastatic sites, 40 pts (67.8%) had brain metastases, and 25 (42.2%) had LDH levels above the upper limit of normal before initiation of triple therapy. Median follow-up time was 16.2 months (IQR, 6.02-20.81). Median number of previous treatment lines was 2 (range, 1-6); 40 pts (67.8%) were pretreated with at least one line of ICI and TT in any sequence. Of 55 pts who received ICI (n = 41 CTLA4 plus PD1; n = 9 PD1 mono; n = 2 CTLA4 mono; n = 3 PD1-based therapy) prior to triplet therapy, 44 pts (80%) were primary resistant (progressive disease (PD); stable disease (SD) for &lt; 6 months), and 11 pts (20%) secondary resistant (complete response (CR), partial response (PR), SD for &gt; 6 months) to the ICI therapy. Treatment with triplet therapy resulted in an overall response rate (ORR) of 44.1% (n = 26) and a disease control rate (DCR) of 55.9% (n = 33) with a median duration of response of 13.7 months (range, 5.4-33.2). Median PFS for the entire cohort was 6 months (95% CI, 3.88-8.08), with a 12-month PFS of 29.4% (95% CI, 17.8-42.1) and a 24-month PFS of 20.2% (95% CI, 11.0-32.8). Median OS was 15.7 months (95% CI, 8.1-23.3 months), with a 12-month OS of 52.7% (95% CI, 39.1-65.7) and a 24-month OS of 43.2% (95% CI, 29.6-55.9). Pts with extracerebral PD prior to triplet therapy (40.7%, n = 24) showed an ORR of 50%, pts with intracerebral PD (32.2%, n = 19) of 47.4%, and pts with global PD (27.1%, N = 16) of 31.3%. Treatment-related adverse events (TRAE) of grade ≥3 occurred in 17 of 59 pts (28.8%), of which cytokine release syndrome (n = 7) and hepatitis (n = 3) were the most common. In 16.9% (n = 10) of pts, TRAEs led to treatment discontinuation. Conclusions: Triple therapy has shown promising efficacy in heavily pretreated pts with advanced melanoma and may represent a treatment option after failure of standard therapy with ICI and TT.

Multicenter analysis of melanoma recurrence pattern and management after adjuvant immunotherapy.

e21573 Background: PD-1 inhibitors improve outcomes in resected stage II-IV melanoma. However, recurrence patterns and prognostic factors are less known. Methods: We conducted a retrospective study in resected stage II-IV melanoma patients (p) treated with adjuvant PD-1 inhibitors (clinical practice or clinical trials) from 5 centers. Demographic, disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcome were recorded. Descriptive assessment for recurrence patterns and analysis for prognostic factors were performed. Results: From June 2017 to June 2022, 181 p were included. Median age was 59 years [22-81], 57% were male, 85% had cutaneous melanoma, 28% had BRAFV600E mutation. 9 p (5%) presented stage II, 147 (81%) stage III and 25 (14%) stage IV. Ulceration was present in 59% p, mitotic rate &gt;1/mm2 in 84%, Breslow index &gt;3 mm in 65% and elevated LDH in 51%. 81% p received PD-1 inhibitors alone and 19% in combination with other immunotherapies. 52% of p completed treatment, 12% discontinued due to toxicity and 26% due to relapse. 13% of p presented grade 3-4 adverse events and there was a grade 5 myocarditis. With a median follow-up of 18,1 months, 68 (37%) p recurred (Table). Median relapse free survival (RFS) was 48,8 months (95% CI 31,1-66,4). Recurrence was significantly associated with a higher stage, mitotic rate, LDH level and Breslow index, BRAFV600E mutation, non-cutaneous melanoma and delayed initiation of adjuvant immunotherapy in univariate analysis (p&lt;0,05). Stage, non-cutaneous melanoma and initiation of immunotherapy &gt;3 months (16% p) were associated with higher recurrence in multivariate analysis (&lt;0,05). Locoregional recurrence was treated in 23 p with surgery (14p), surgery + RT (7p) or RT alone (2). Systemic recurrence was treated in 50 p: all BRAF mutant p received targeted therapy (24p, 43%) with a disease control rate (DCR) of 91% and a median progression free survival (PFS) of 56 months (95% CI 24,1-NR); BRAF wild type p (26p, 47%) were treated with anti-PD-1 alone (9p) or in combination (7p), anti-CTLA-4 (2p), chemotherapy (1p) or best supportive care (7p), with DCR of 33% and a median PFS of 8 months (95% CI 6,9-10,8). Conclusions: We observed a 37% relapse rate and systemic recurrence were more frequent than locoregional recurrence. Treatment at relapse with targeted therapy in BRAF mutant p achieved higher DCR and PFS than immunotherapy in BRAF wild type p; with better outcomes than previously reported.[Table: see text]

Upfront vs deferred monoclonal antibodies in metastatic colorectal cancer: A target trial emulation using the GEMCAD 14-01 prospective cohort.

3597 Background: There are no randomized trials comparing the addition monoclonal antibodies (MAB: bevacizumab, cetuximab, panitumumab) to first line chemotherapy (upfront use) versus deferring their addition to the second-line chemotherapy (deferred use) in pts with metastatic colorectal cancer (mCRC). We emulated a target trial comparing upfront vs deferred use of MAB using the GEMCAD 14-01 observational registry. Methods: We first specified the (hypothetical) target trial to fully articulate the research question and then emulated it using real-world data. The eligibility criteria of the target trial were a diagnosis of mCRC, being treatment naïve, and a ECOG PS &lt;2. The target trial would randomize pts to the following strategies: (1) initiation of MAB within 2 months of starting first line chemotherapy (“upfront MAB”) and (2) initiation of MAB within 2 months of starting second line chemotherapy (“deferred MAB”). The primary outcome of the target trial would be overall survival and the causal contrast (or estimand) would be the effect under complete adherence. We emulated this target trial using data from the GEMCAD 1401 registry (ClinicalTrials.gov identifier: NCT02254941), which collected data prospectively from 47 Spanish centers from June 2014 to June 2018. The emulation used the same definitions of eligibility criteria and treatment strategies, and classified individuals according to their baseline data using clones. The effect under complete adherence was estimated by censoring pts when they deviated from the assigned treatment strategy and by using time-varying weights to adjust for baseline and post-baseline confounding. Results: A total of 627 pts were eligible in the ‘’upfront MAB’’ and 397 pts in the ‘’deferred MAB’’. Median age was in the ‘’upfront vs deferred’’ 64.6 (interquartile range: 56-71) vs 67.8 (61-75) years, 96% vs 87% had an ECOG 0-1, 80% vs 79% had a Charlson score &lt; 3, 46% vs 60% had a RAS mutation, 6% vs 4% had a BRAF mutation, 72% vs 69% had left side primary location, 74% in both strategies had liver metastasis and 42% vs 50% had LDH levels above the normal threshold. Pts in the “upfront MAB” group contributed a total 16,057 months of follow-up and 502 if them died. Pts in the “deferred MAB” contributed a total of 7,774 months of follow-up, and 222 of them died. The 48-month overall survival was 26.7% (95% CI 21.4-38.2%) in the “upfront MAB” group and 21.6% (14.2-41.7%) in the “deferred MAB” group, corresponding to a 48-month survival difference (“upfront MAB” is the reference) of -5.0% (95% CI -17.9 to 17.95) and a hazard ratio or 1.15 (0.88-1.40). Conclusions: Our study suggests little or no survival detrimental effect of deferring the use of MAB to the second line of treatment compared with the use of MAB as part of the first line of treatment among pts with mCRC. Clinical trial information: NCT02254941 .

Association of blood donor characteristics with in vitro platelet storage properties

Background and objectiveThe study was planned to determine the association of blood donor characteristics with in vitro quality of platelets. Material and methodsIn the prospective observational study, a total of 85 male whole blood donors in the age group of 18–30 and 45–65 years were enrolled using purposive sampling method. Serum total cholesterol, glycosylated hemoglobin (HbA1c), and LDH levels were performed on donor pre-donation sample. Buffy coat platelet concentrates were prepared from 450 mL quadruple blood bags. Samples from platelets were taken on day one and five of storage and biochemical properties were observed. ResultsMedian MPV was higher in platelets from older blood donors on day five (9.8 vs 9.4, p = 0.037). Median LDH levels were also higher in platelets on day one and five from older donors (Day one: 204.5 vs 147, p = <0.000; day five: 278 vs 224, p = 0.001 respectively). Platelets from donors with high HbA1c levels had lower median pH (Day one: 7.31 vs 7.37, p = 0.024) and higher median glucose levels on day one of storage (Day one: 358 vs 311, p = 0.001). Higher median lactate levels throughout the storage period were also seen in platelets from donors with higher HbA1c levels (Day one: 7 vs 5.7, p = 0.037; Day five: 16 vs 12.2, p = 0.032). Glucose consumption (108 vs 66, p = 0.025) and lactate production (9 vs 6.4, p = 0.019) was higher in platelets from donors with higher HbA1c levels. ConclusionIn vitro platelet storage properties are affected by blood donor characteristics.

Risk reduction of CNS relapse in diffuse large B cell lymphoma with intrathecal methotrexate prophylaxis: A single institution retrospective study.

e19531 Background: Central nervous system (CNS) relapse is an infrequent but serious and challenging complication in diffuse large B-cell lymphoma (DLBCL) that carries a dismal prognosis. While several risk factors have been identified to stratify the risk for CNS relapse including the 2015 CNS internal Prognostic index (CNS-IPI), controversy still remains regarding the indication, timing, and method of CNS prophylaxis. The purpose of this study was to determine whether IT-MTX reduced the risk of CNS relapse, as well as treatment related and financial toxicity of CNS prophylaxis. Methods: We performed a single-center, retrospective analysis on a cohort of 192 patients with DLBCL who had received treatment between January 2010- August 2022. Patients were identified by using ICD10 code diagnosis in the electronic medical records system. We included patients of all stages of disease and CNS-IPI scores along with patients with testis, breast, sinus, and bone marrow extranodal involvement. Patients with primary CNS disease and primary mediastinal disease were excluded from the study. Clinical data collected by chart review included age at time of diagnosis, sex, performance status, LDH level, disease stage, number and type of therapies administered including IT-MTX, extranodal involvement, MYC/BCL2/BCL6 translocation status, HIV status, cell of origin (COO), treatment response. Toxicities and complications thought to be associated with IT-MTX prophylaxis were also documented in addition to total costs of treatment for each patient. Patient characteristics were compared using Fisher exact test or Pearson’s chi-square test. Results: In patients with intermediate to high CNS relapse risk (CNS-IPI 2-5) IT-MTX did not reduce the 1 year risk of CNS relapse (RR 1.1296, 95% CI 0.1933 to 6.6012, P = 0.08924). The median time to CNS relapse was longer in patients who had received IT-MTX (13.5 months) vs those who did not (7 months). Thirty eight (52.8%) patients reported adverse side effects of any kind as a result of IT-MTX administration, with 23.6% of patients developing grade 2-3 adverse events. The average cost for CNS-prophylaxis was estimated to be approximately $8,059.04 over a patient’s treatment course, but as high as $20,140. Conclusions: In conclusion, our study highlights the necessity to develop improved standardized guidelines for use of CNS prophylaxis in patients with DLBCL. The results from our retrospective study add to the growing body of literature showing IT-MTX has limited and potentially transient effectiveness in preventing CNS relapse. Given the high rate of side effects and significant cost of IT-MTX, we recommend that clinicians carefully consider the risks and benefits of prophylaxis before prescribing IT-MTX for CNS-prophylaxis.

Risk factors and early biomarkers of nephrotoxicity associated with the use of anti-VEGF drugs.

e24079 Background: Anti-angiogenic anticancer drugs that block VEGF can cause kidney damage (Fujii et al., 2019). Among the mechanisms of nephrotoxicity thrombotic microangiopathy (TMA) of renal vessels can be distinguished (Estrada et al., 2019). TMA can be accompanied the development of anemia, excessive schistocytes, as well as increased LDH levels and a low platelet count, which indicated the occurrence of endothelial dysfunction and microangiopathic processes (Hauser et al, 2009). The goal of this study was to assess the risk factors of early nephrotoxicity and the utility of NGAL, KIM-1, HIF-1α and nephrin levels in urine as early biomarkers of nephrotoxicity. Methods: The study included 50 patients who received anti-VEGF drugs (aflibercept, bevacizumab or ramucirumab). Nephrotoxicity was determined as a decrease in glomerular filtration rate (GFR) to &lt; 60 ml/min/1.73m2 at 8 weeks from the initiation of therapy. The laboratory parameters and the levels of KIM-1, NGAL, HIF-1α and nephrin in urine samples were determined by ELISA before treatment and after 1, 2, 4 and 8 weeks of treatment. To assess risk factors for nephrotoxicity we analyzed primary clinical and laboratory parameters. Results: Nephrotoxicity at 8 weeks was achieved in 21 (42%) of patients. A statistically significant decrease in hemoglobin and platelet count by 20 and 26%, respectively, from the initial level was observed. An increase in the number of schistocytes and a slight increase in LDH levels were also observed. The increase in NGAL, KIM-1 and nephrin levels was statistically significant in 1 weeks and the increase of HIF-1α in 2 weeks after the start of therapy (p = 0.001). The unfavorable predictors of nephrotoxicity as well as the favorable predictors in terms of decreasing renal function are presented in Table. ROC analysis demonstrated high sensitivity and specificity: NGAL – AUC 0.7; KIM-1 – AUC 0.69; HIF-1α – 0.7; nephrin – AUC 0.7. Conclusions: We report a significant increase in the parameters of microangiopathic hemolysis and in urine biomarkers of tubular and podocytic damage as well as hypoxia by the 8th week of treatment. We suggest that the TMA process can take part in renal damage. Increased levels of NGAL, KIM-1, HIF-1α and nephrin in the urine reflect the renal damage processes and have higher sensitivity and specificity then serum creatitine. The independent risk factors for nephrotoxicity are determined. [Table: see text]

A prospective non-randomized phase I trial of dendritic cell–based cryoimmunotherapy combined with checkpoint inhibitors in mCRPC.

e14708 Background: Despite improvements, metastatic castration-resistant prostate cancer (mCRPC) still has dismal overall survival (OS). We treated 18 mCRPC patients with dendritic cell (DC)-based cryoimmunotherapy (CryoIT) as monotherapy or combined with checkpoint inhibitors to determine safety and immune response. Methods: mCRPC patients were biopsied before cryoablation, and subsequently injected intratumorally with autologous immature DCs. DC doses were escalated in a 3+3 design (n=9) followed by dose expansion combined with either ipilimumab (n=6) or pembrolizumab (n=3). The disease burden was assessed by PSA values, iRECISTv1.1 (PET/CT, MRI and bone scintigraphy at baseline, 14, 22 and 46 weeks) and circulating tumor cells (CTC; CellSearch). Immune response was monitored by ultradeep T-cell receptor sequencing. Results: The patients had aggressive cancer, with ISUP grade group 4 and 5 in 72% (13/18) at diagnosis and in 100% at inclusion. At baseline, higher ALP correlated with higher regulatory T cells (p=0.047), FoxP3+/CD3+ratios (p=0.014) and FoxP3+/CD8+ratios (p=0.004) in tissues. Median OS and progression-free survival (PFS) were 40.7 and 10.5 months, respectively. Of the 8 patients alive 43 to 85 months post-CryoIT, 7 had progressed and received other treatment. Early decreases in PSA (p=0.002) and LDH (p=0.01) levels 6 weeks after CryoIT indicated better outcomes at 22 weeks. Longer OS correlated with lower tissue ratios of CD4+/CD3+cells (p=0.002) and CD4+/CD8+cells (p=0.007). All patients with increased numbers of new T-cell clonotypes after CryoIT and CTC at the pretreatment level of 1-4 cells/ 7.5 mL blood changed to negative during follow-up up to 72 weeks. Conclusions: CryoIT demonstrates non-inferior OS and PFS compared to other mCRPC trials, and therapy response was suggested by decreased CTCs and induction of new T-cell clonotypes post-CryoIT. Lower CD4+cell fractions of lymphocytes in the TME indicate better OS after CryoIT. CryoIT appears not to decrease effects of post-treatment recurrence therapies. Clinical trial information: NCT02423928 . [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type I (HTLV-1), endemic in some areas of the world, such as Brazil. Between 3% and 5% of HTLV-1-infected individuals develop ATL after a long latency. The clinical features are heterogeneous and classified into acute, lymphoma, chronic and smoldering types. Acute and lymphoma types are defined as aggressive whereas the others as indolent ATL. On April 2017, the T-cell Brazil project was launched. Methods: Ambispective observational study design collected 90 ATL patients from 606 registered cases in the T-Cell Brazil Project. Its main goal is to describe demographic and clinical features, analyze the overall and progression-free survival (OS and PFS), and try to identify factors that could influence them. REDcap Platform has been used to collect and store data, and the IBM-SPSS version 24 for statistical analysis. Results: The median age was 50 years (23–88), 59% female; 50% was lymphoma subtype, followed by 33% acute (both aggressive), 12% chronic and 5% smoldering (indolent); 87% had advanced stage disease (III-IV, Ann Arbor), 57% had B symptoms and 11% had Central Nervous System involved. Both indolent and aggressive had elevated serum LDH levels. 25% received chemotherapy plus immunotherapy, whilst 46% took chemotherapy alone with anthracycline-based regimens (46% CHOEP; 33% CHOP; 21% others). The best response (complete plus partial) after 1st line of treatment reached 50%; 31% had no response or progression; 13% was undetermined due early death; 5% were on treatment, and 1% had stable disease (without treatment). Median follow-up was ten months (0–78) and 18 months for 35% of alive cases. OS for 24 months was 34% (95% CI: 24%–44%), whereas 24-month PFS was 20% (95% CI: 12%–28%). Indolent presented better OS and PFS when compared with Aggressive; 86% versus 33%, P = 0.001 for OS and 45% versus 12%, P = 0.002 for PFS. Public medical care had worst OS and PFS than private (P = 0.14 and P = 0.05). The multivariate Cox Regression for OS resulted hypoalbuminemia - albumin <3.5 g/dL (HR 2.13 CI95% 1.10–4.12, P = 0.024) plus LDH twice the normal value (HR 2.49 CI95% 1.17–5.32, P = 0.018) as predictors. And for PFS were male (HR 1.83 CI95% 1.03–3.24, P = 0.037), ECOG > 1 (HR 2.01 CI95% 1.10–3.70, P = 0.023) and hypoalbuminemia (HR 3.35 CI95% 1.82–6.17, P < 0.0001). The research was funded by: Educational Support by Takeda Keyword: aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

EXCELLENT OUTCOMES OF SUBCUTANEOUS PANNICULITIS‐LIKE T‐CELL LYMPHOMA TREATED WITH CYCLOSPORIN‐BASED REGIMEN, A MULTICENTER RETROSPECTIVE STUDY IN THAILAND

Background: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of cytotoxic T-cell lymphoma, characterized by primary cutaneous tissue involvement mimicking inflammatory panniculitis. Treatment for this disease is still under debated between conventional chemotherapy or immunosuppressive agents like cyclosporin and prednisolone. Material and Methods: A multicenter retrospective study was conducted among adult patients who was diagnosed as subcutaneous panniculitis-like T-cell lymphoma from January 2013 to December 2020, in 15 medical centers in Thailand. The patient demographic data, treatment regimens which divided into conventional chemotherapy or immunosuppressive agents, and treatment outcomes were retrieved from the Thai lymphoma registry database. All of aspects were analyzed and compared between the treatment group. Results: A total of 34 patients were reviewed in this cohort. The median age was 30 years (range;16–64) with female predominance (67.6%). The majority of patients was diagnosed as advanced stage of disease as Ann Arbor stage IV (58.8%). All patients presented with skin and subcutaneous involvement while one-fourth of them had extra-cutaneous lesions including liver (14.7%) and bone marrow (11%). B symptom was observed in 64% and elevated LDH level in 70.6% of the patients which represented the high disease burden. However, almost all of our patients were in good performance status (ECOG 1–2). For treatment options, 41% of the patients received conventional chemotherapy, mostly CHOP, while 38% received cyclosporin containing regimens. The overall response rate (ORR) was 64% in chemotherapy group and 76% in cyclosporin group, which was comparable. Precisely 57% and 76% of the patients in conventional chemotherapy and cyclosporin treatment, respectively, had complete remission. Patients with Ann Arbor stage IV were received conventional chemotherapy as first-line treatment for 69%, on the other hand, 31% received cyclosporin-based treatment, which was in complete remission around 60% on both groups. With median follow up time of 35.2 months, the overall survival and progression free survival were not reached in both groups. Conclusions: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of cytotoxic T-cell lymphoma which predominantly affects young female and usually presents with extranodal lesions especially skin and subcutaneous tissues, bone marrow, and liver. Patients were responded well to cyclosporin-based treatment both limited and advanced stages of the disease. Keywords: chemotherapy, cyclosporin, Subcutaneous panniculitis-like T-cell lymphoma Keyword: Cutaneous non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.