Relapse-free Survival Research Articles

Survival and Patterns of Relapse of Cutaneous Squamous Cell Carcinoma With Large Nerve Perineural Spread After Skull Base Surgery and/or Radiation Therapy

The aim of our study was to evaluate survival and patterns of relapse for patients with perineural spread (PNS) of cutaneous squamous cell carcinoma (cSCC), who have undergone curative intent skull base surgery and/or radiation therapy. In addition, we modified the classification of zone 2 disease into 2a and 2b and reported the respective outcome. A review of a prospective database of patients who received diagnoses of PNS of cSCC and were treated with curative intent skull base surgery and/or radiation therapy between the years of 2013 and 2020 was conducted. Kaplan-Meier methods were used to estimate relapse-free survival (RFS), disease-specific survival (DSS), and overall survival (OS). Cox proportional hazard modeling was performed to test associations between patient factors and survival outcomes. Eighty patients with a median follow-up of 36 months were included in the study. The 5-year RFS was 61% (95% CI, 48%-71%), the DSS was 77% (95% CI, 63%-86%), and OS was 67% (95% CI, 53%-78%). In multivariable modeling, involvement of 2 or more nerves was strongly associated with worse 5-year RFS (HR, 4.0; P ≤ .001), DSS (HR, 4.5; P = .004), and OS (HR, 4.3; P = .002). Age group (≥65 years) (HR, 5.1; P = .010) and immune compromise (HR, 10.7; P = .001) were strongly associated with worse OS but not DSS or RFS. The majority of relapses (60%) occurred at the local skin sites. Our study demonstrated surgery followed by radiation therapy was safe and effective in the management of cSCC with PNS. We did not detect a difference in outcome between zones 2a and 2b though further study is required. The most common mode of relapse was at the skin epidermis and/or adjacent dermis highlighting the importance of adequate local skin dose delivery.

Mucosal-associated invariant T cells are functionally impaired in pediatric and young adult patients following allogeneic hematopoietic stem cell transplantation and their recovery correlates with clinical outcomes.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells implicated in the response to fungal and bacterial infections. Their contribution to restoring T-cell immunity and influencing hematopoietic stem cell transplant (HSCT) outcomes remains poorly understood. We retrospectively studied MAIT-cell recovery in 145 consecutive children and young adults with hematologic malignancies undergoing allogeneic (allo)-HSCT between April 2019 and May 2022, from unrelated matched donor (MUD, N=52), with standard graft-versus-host-disease (GvHD) prophylaxis, or HLA-haploidentical (Haplo, N=93) donor after in vitro αβT/CD19-cell depletion, without post-HSCT pharmacological prophylaxis. With a median follow-up of 33 months (range, 12-49 months), overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) were 79.5%, 72%, and 7%, respectively; GvHD-free relapse-free survival (GRFS) was 63%, while cumulative incidence of relapse was 23%. While αβT cells were reconstituted 1-2 years post HSCT, MAIT cells showed delayed recovery and prolonged functional impairment, characterized by expression of activation (CD25, CD38), exhaustion (PD1, TIM3) and senescence (CD57) markers, and suboptimal ex vivo response. OS, DFS, and NRM were not affected by MAIT cells. Interestingly, higher MAIT cells at day +30 correlated with higher incidence of grade II-IV acute GvHD (19% vs. 7%, P=0.06). Furthermore, a greater MAIT-cell count tended to be associated with a higher incidence of chronic GvHD (cGvHD) (17% vs. 6%, P=0.07) resulting in lower GRFS (55% vs. 73%, P=0.05). Higher MAIT cells also correlated with greater cytomegalovirus (CMV) reactivation and lower late blood stream infections (BSI) (44% vs. 24%, P=0.02 and 9% vs. 18%, P=0.08, respectively). Future studies are needed to confirm the impact of early MAIT-cell recovery on cGvHD, CMV reactivation, and late BSI.

Primary retroperitoneal lymph node dissection for metastatic non-seminomatous germ cell tumours: outcomes and adjuvant chemotherapy.

To compare the outcomes and treatment burden of primary retroperitoneal lymph node dissection (pRPLND) alone versus pRPLND + adjuvant chemotherapy (AC) in patients with pathological stage II (PSII) non-seminomatous germ cell tumours (NSGCT). Retrospective review of the Princess Margaret Cancer Center eTestes cancer database identified patients with PSII NSGCT after pRPLND between 1995 and 2020. The primary outcome was relapse-free survival (RFS). Secondary outcomes included disease-specific survival (DSS), burden of relapse treatment, and factors associated with relapse. A total of 109 PSII patients were included in the study. There were 96 patients treated with pRPLND alone and 13 treated with pRPLND + AC. The median follow-up was 61 months. The 5-year RFS was 72% for the pRPLND-only group vs 92% for the pRPLND + AC group (hazard ratio [HR] 4.372, 95% confidence interval [CI] 0.59-32.36; P = 0.11). Within the pRPLND-only group the 5-year RFS differed by pN stage (pN1 = 94% vs pN2/N3 = 67%, P = 0.03). Despite a higher relapse rate within the pRPLND-only group, the DSS was similar at 5 years (98% pRPLND only vs 100% pRPLND + AC, P = 0.48). Only 24 (25%) of the patients in the pRPLND-only group required any subsequent chemotherapy. Despite achieving similar survival, the cumulative post-RPLND treatment burden was less for the pRPLND-only group than the pRPLND+AC group overall (average 1.23 vs 2.46 cycles of chemotherapy per patient in group). The majority of patients with PSII NSGCT treated with pRPLND alone do not experience a recurrence or require chemotherapy. Despite a lower relapse risk when AC is given, no difference in survival was seen but higher chemotherapy burden was entertained. AC may constitute overtreatment for most patients with PSII NSGCT treated with pRPLND.

Exploring the Prevalence and Prognostic Impact of Wilms Tumor 1 Exon 7 Mutation Status with Combinations of FLT3-ITD and NPM1 Mutations as Potential Molecular Biomarkers in Acute Myeloid Leukemia Patients with Normal Cytogenetics.

This study explores the prognostic impact of FLT3-ITD, NPM1, and WT1 mutations both independently and in combination in Cytogenetically Normal Acute Myeloid Leukemia (CN-AML) patients as they exhibit varying clinical outcomes. 150 CN-AML patients were selected to assess the prevalence and prognostic significance of WT1 mutations in combination with FLT3-ITD and NPM1 status using polymerase chain reaction (PCR) followed by Sanger sequencing. WT1 exon 7 mutations were present in 12.6% of patients. Elderly individuals, with a mean age of 49.4 years, were more prone to NPM1 mutations, though the association was not statistically significant (p=0.094). Significant associations were observed between lactate dehydrogenase (LDH) and hemoglobin (Hb) levels with FLT3-ITD and NPM1 mutations (p=0.003 and p=0.04, respectively). The M4 subtype exhibited the highest prevalence of WT1 mutations (p=0.0036). Patients with NPM1 mutations had a higher overall survival rate compared to NPM1 wild-type cases (p=0.057). There was no significant correlation between overall survival and WT1 and FLT3-ITD mutations. Regarding relapse-free survival, NPM1 mutation cases exhibited a higher survival probability compared to NPM1 wild-type cases. Similarly, WT1 mutated cases had a higher survival probability compared to WT1 wild-type cases, although these differences were not statistically significant. The combined mutation statuses of NPM1/FLT3-ITD with WT1 did not yield significant outcomes. The study suggests that larger cohort studies may reveal more relevant associations, given the relatively small cohort in this study. This study found a significant association between patient survival outcomes and NPM1 mutation status, as well as the combined FLT3-ITD and NPM1 status. Profiling both NPM1 and FLT3-ITD mutations at the time of diagnosis serves as a robust prognostic marker in AML treatment. WT1 mutation status did not show a significant association with patient outcomes. Larger population studies may provide more relevant insights.

Improving risk stratification for 2022 European LeukemiaNet favorable-risk patients with acute myeloid leukemia

Assignment of patients diagnosed with acute myeloid leukemia (AML) to the 2022 European LeukemiaNet (ELN) Favorable genetic-risk group has important clinical implications, as allogeneic stem-cell transplantation in first complete remission (CR) is not advised due to a relatively good outcome of patients receiving chemotherapy alone and transplant-associated mortality. However, not all Favorable genetic-risk patients experience long-term relapse-free survival (RFS), making recognition of patients who would most likely be cured of high importance. We analyzed 297 patients aged <60 years with de novo AML classified as 2022 ELN Favorable genetic-risk who achieved a CR and had RNA-seq and gene mutation data from diagnostic samples available (Alliance trial A152010). To identify prognostically relevant transcripts that can distinguish patients cured from patients susceptible to lower- or higher-risk of relapse or death, we fit a regularized mixture cure model (MCM), where RNA-seq expression values were our candidate covariates. To validate the identified transcripts, we analyzed 75 patients with de novo AML aged <60 years included in the 2022 ELN Favorable genetic-risk group who achieved a CR in an independent test set from Gene Expression Omnibus (GSE37642). Our MCM identified 145 transcripts associated with cure, or long-term RFS, and 149 transcripts associated with latency, or shorter-term time-to-relapse. The area under the curve and C-statistic were, respectively, 0.946 and 0.856 for our training and 0.877 and 0.857 for our test sets. Our results suggest that the Favorable-risk group includes distinct transcriptionally defined subgroups with different biological properties, which may be useful for refining this genetic-risk category.

Different Prophylaxis Strategies for Central Nervous System Recurrence of Diffuse Large B-Cell Lymphoma

To analyze the effects of highdose methotrexate (HD-MTX) and lenalidomide as central nervous system (CNS) prophylaxis strategies in patients with diffuse large B-cell lymphoma (DLBCL). The data of DLBCL patients with high risk of CNS recurrence who were initially treated in Fujian Provincial Hospital and Fujian Cancer Hospital from January 2012 to June 2022 were analyzed retrospectively. The patients were divided into HD-MTX group and lenalidomide group according to different prophylaxis strategies. Each group was further divided into high-risk group and medium-risk group based on CNS-IPI score and/or testicular involvement. The CNS relapse-free survival (CRFS) rate, adverse effects, and the effects of different prophylaxis strategies on overall survival (OS) rate and progression-free survival (PFS) rate were evaluated in different groups and subgroups. There were 200 patients enrolled in this study, 80 cases in lenalidomide group and 120 cases in HD-MTX group. According to the delivery timing of prophylactic HD-MTX, the patients in HD-MTX group were further divided into two groups: 80 cases at the end of induction chemotherapy and 40 cases during chemotherapy interval. At a median follow-up of 48(14-133) months, the 4-year CRFS rate, 4-year PFS rate, and 4-year OS rate of the HD-MTX group was 93.6%, 57.2%, and 68.8%, respectively, while that of the lenalidomide group was 90.4%, 69.4% and 75.6%. There were no significant differences in 4-year CRFS rate, 4-year PFS rate, and 4-year OS rate between HD-MTX group and lenalidomide group (all P >0.05), but lenalidomide group showed a trend of improvement in PFS. Further subgroup analysis showed that there was no significant difference in 4-year CRFS rate between high-risk patients of the two groups (91.7% vs 83.4%, P >0.05), while 4-year PFS rate showed difference (49.5% vs 64.2%, P <0.05). A total of 248 cycles were collected for adverse reaction analysis in the HD-MTX group, and 25 cycles occurred neutropenia accompanied with infection (10.1%), while in lenalidomide group 240 cycles were collected in which 20 cycles occurred neutropenia accompanied with infection (8.3%). Both the two groups had no treatment-related deaths. Compared with HD-MTX, lenalidomide combined with immunochemotherapy can prevent CNS relapse, at the same time, improve prognosis, which is a safe and well tolerated central prophylaxis strategy.

Evaluation of glucocorticoid-related genes reveals GPD1 as a therapeutic target and regulator of sphingosine 1-phosphate metabolism in CRPC

Prostate cancer (PCa) is an androgen-dependent disease, with castration-resistant prostate cancer (CRPC) being an advanced stage that no longer responds to androgen deprivation therapy (ADT). Mounting evidence suggests that glucocorticoid receptors (GR) confer resistance to ADT in CRPC patients by bypassing androgen receptor (AR) blockade. GR, as a novel therapeutic target in CRPC, has attracted substantial attention worldwide. This study utilized bioinformatic analysis of publicly available CRPC single-cell data to develop a consensus glucocorticoid-related signature (Glu-sig) that can serve as an independent predictor for relapse-free survival. Our results revealed that the signature demonstrated consistent and robust performance across seven publicly accessible datasets and an internal cohort. Furthermore, our findings demonstrated that glycerol-3-phosphate dehydrogenase 1 (GPD1) in Glu-sig can significantly promote CRPC progression by mediating the cell cycle pathway. Additionally, GPD1 was shown to be regulated by GR, with the GR antagonist mifepristone enhancing the anti-tumorigenic effects of GPD1 in CRPC cells. Mechanistically, targeting GPD1 induced the production of sphingosine 1-phosphate (S1P) and enhanced histone acetylation, thereby inducing the transcription of p21 that involved in cell cycle regulation. In conclusion, Glu-sig could serve as a robust and promising tool to improve the clinical outcomes of PCa patients, and modulating the GR/GPD1 axis that promotes tumor growth may be a promising approach for delaying CRPC progression.

Targeted dynamic phospho-proteogenomic analysis of gastric cancer cells suggests host immunity provides survival benefit

Despite of massive emergence of molecular targeting drugs, the mainstay of advanced gastric cancer (GC) therapy is DNA-damaging drugs. Using a reverse-phase protein array-based proteogenomic analysis of a panel of eight GC cell lines, we identified genetic alterations and signaling pathways, potentially associated with resistance to DNA-damaging drugs, including 5-fluorouracil (5FU), cisplatin, and etoposide. Resistance to cisplatin and etoposide, but not 5FU, was negatively associated with global copy number loss, vimentin expression, and caspase activity, which are considered hallmarks of previously established EMT subtype. The segregation of 19,392 protein expression time courses by sensitive and resistant cell lines for the drugs tested revealed that 5FU-resistant cell lines had lower changes in global protein dynamics, suggesting their robust protein level regulation, compared to their sensitive counterparts, whereas the cell lines that are resistant to other drugs showed increased protein dynamics in response to each drug. Despite faint global protein dynamics, 5FU-resistant cell lines showed increased STAT1 phosphorylation and PD-L1 expression in response to 5FU. In publicly available cohort data, expression of STAT1 and NFκB target genes induced by proinflammatory cytokines was associated with prolonged survival in GC. In our validation cohort, total lymphocyte count (TLC), rather than PD-L1 positivity, predicted a better relapse-free survival rate in GC patients with 5FU-based adjuvant chemotherapy than those with surgery alone. Moreover, TLC+ patients who had no survival benefit from adjuvant chemotherapy were discriminated by expression of IκBα, a potent negative regulator of NFκB. Collectively, our results suggest that 5FU resistance observed in cell lines may be overcome by host immunity or by combination therapy with immune checkpoint blockade.

Contribution of Immunoscore to Survival Prediction in Pancreatic Ductal Adenocarcinoma.

The presence of tumor-infiltrating lymphocytes (TILs) has been demonstrated as a prognostic factor in colorectal cancer after surgical resection of malignancy, but knowledge on their role in pancreatic cancer is lacking. The Immunoscore (IS) assesses TILs at the core of the tumor (CT) and invasive margin (IM) and is being evaluated as a new concept in tumor immunity. The aim of this study was to evaluate the relationship between IS and prognosis in PDAC. The IS was analyzed by immunohistochemistry using surgical tissue blocks from 131 patients with pancreatic ductal adenocarcinoma (PDAC) who underwent surgery to investigate the relationship between immune cell infiltration into the tumor and prognosis in PDAC. A high IS in both CT and IM of the tumor was significantly associated with prolonged overall survival (OS) (p<0.01) and relapse-free survival (RFS) (p<0.01). In multivariate logistic regression models adjusted for clinical pathology data, IS predicted survival and recurrence (p<0.01 and p<0.01, respectively). Moreover, in patients who received preoperative chemotherapy, a high IS was statistically significantly associated with longer OS and RFS (p<0.01 and p<0.01, respectively). The immunohistochemically assessed IS might be a useful prognostic marker for patients with PDAC who underwent primary tumor resection.

Tolerability and Safety Assessment of Adjuvant Chemoradiotherapy with S-1 after Limited Surgery for T1 or T2 Lower Rectal Cancer

Background: The short-term outcomes of chemoradiotherapy (CRT) with S-1 (a combination of tegafur, gimeracil, and oteracil) following limited surgery for patients with T1 or T2 lower rectal cancer have shown encouraging results. Objectives: This study was designed to delve deeper into the long-term outcomes of CRT with S-1 after limited surgery, with the goal of evaluating both the long-term efficacy and potential risks associated with this treatment approach in patients diagnosed with T1 or T2 lower rectal cancer. Methods: This was conducted as a multicenter, single-arm, prospective phase II trial. The patient population consisted of individuals clinically diagnosed with either T1 or T2 lower rectal or anal canal cancer, with a maximum tumor diameter of 30 mm and classified as N0 or M0. Patients underwent local excision or endoscopic resection. After surgery, CRT with S-1 was administered to patients meeting several criteria, including the confirmation of well-differentiated or moderately differentiated adenocarcinoma, negative surgical margins, submucosal invasion depth of ≥1000 µm, and high tumor-budding grade (2/3). The primary endpoint of this study was relapse-free survival, while secondary endpoints included local recurrence-free survival, overall survival, anal sphincter preservation rate, and safety. Results: A total of 52 patients were included, with pathological diagnoses revealing T1 in 36 patients and T2 in 16 patients. The 3-year and 5-year relapse-free survival rates were 90.17% and 85.87%, respectively. The 3-year and 5-year local recurrence-free survival rates were 90.17% and 88.07%, respectively, while the 3-year and 5-year overall survival rates were 94.03% and 91.94%, respectively. Conclusions: CRT with S-1 after limited surgery for T1 lower rectal cancer demonstrated favorable outcomes in terms of recurrence, survival, and local control rates while effectively maintaining anal function in patients. However, further treatment approaches may be necessary to improve outcomes for patients diagnosed with stage T2 lower rectal cancer

Outcome of radiotherapy for metastatic neuroblastoma

Background. Neuroblastoma (NB) is a prevalent solid extracranial tumor that primarily affects children. It is the third most common type of cancer in children, following leukemia and brain tumors. Aim. The study aimed to discuss the clinical outcomes after adjuvant radiotherapy to the primary site in case of metastatic NB after good response to chemotherapy. Methods. A retrospective clinical-dosimetric study of 25 patients metastatic NB treated with radiotherapy at Baghdad Radiotherapy and Nuclear Medicine Center, at Baghdad Medical City Complex, Baghdad, Iraq. Data collection begin from December 2023 and March 2024. Data were collected retrospectively with review of records. The following variables were studied: sex, age, date of diagnosis, site of primary tumor, site of metastasis, chemotherapy, surgery, RT, RT sites, doses of RT, fractions of RT, recurrence sites, date of relapse and survival outcome for each patient. Follow-up period include look up to metastasis, site of metastasis, recurrence, site of recurrence and survival rates. Results. In relation to sex, males (14, 56%) were more than females (11, 44%). The mean age of NB cases was 45.64±17.6 months. In NB, suprarenal masses were the most common site of primary in 21 (84%) of patients. The most common site of metastasis of NB was bone marrow in 12 (48). The multi sites of recurrence was the commonest presentation in 48%. The relapse-free survival (RFS) was 22.38 months. 5 out of 25 patients were alive whereas 20 (80%) of cases were dead. The median follow-up time was 6 years, and the OS of NB in this study after optimal treatment was 2.46 years (95%CI= 1.705-3.21) for survivors. The MS was 4.84 years. The OS was 6 yrs for those diagnosed at 2017, 2 yrs for those diagnosed at 2018, 1.5 yrs for those diagnosed at 2019, 1.75 yrs for those diagnosed at 2020, 3 yrs for those diagnosed at 2021 and 1.5 yrs for those diagnosed at 2022. There was a significant difference among doses (Log Rank (Mantel-Cox)= 11.425, p=0.044). Conclusions. This study is the first study in Iraq that examines the clinical results of radiotherapy on the primary site in cases of metastatic neuroblastoma following induction chemotherapy. The suprarenal masses of neuroblastoma are the most often occurring main site. The primary sites of metastases for neuroblastoma (NB) are the bone marrow and bones. Timely detection and proactive treatment of NB can improve overall results. Reoccurrence of skeletal issues and the infiltration of bone marrow are frequently observed. There were no significant differences observed in terms of relapse-free survival and overall survival based on factors such as sex, age, location of the main tumor, chemotherapy, radiation treatment, surgery, and radiation therapy dosages.

Adjuvant immunotherapy in older patients with stage III and resected stage IV melanoma: Toxicity and recurrence-free survival outcomes from the Dutch melanoma treatment registry

BackgroundAdjuvant anti-PD-1 therapy improves relapse free survival in stage III melanoma, but also leads to immune-related adverse events (irAEs). Older patients are of particular interest due to comorbidities and frailty, which may impact their ability to tolerate irAEs and benefit from anti-PD-1 therapy. This study aimed to explore associations between clinical parameters and the occurrence of grade ≥ 3 irAEs and recurrence-free survival (RFS) in older patients with radically resected stage III/IV cutaneous melanoma treated with adjuvant anti-PD-1 therapy. MethodsPatients aged ≥ 65 with resected stage III/IV cutaneous melanoma treated with adjuvant anti-PD-1 therapy between 2018 and 2022 were selected using real-world data from the nationwide Dutch Melanoma Treatment Registry (DMTR). A univariate and multivariable logistic regression was used to compare determinants of grade ≥ 3 irAEs, and univariate and multivariable Cox-proportional hazard models were fitted to identify factors influencing RFS. ResultsThe study included 885 patients, with 280 aged 75 and older. The incidence of grade ≥ 3 irAEs was 15.5 % in the 65–74 age group and 13.9 % in the ≥ 75 age group. No significant correlation was found between age and grade ≥ 3 irAEs. However, an increasing number of comorbidities was associated with a higher risk of grade ≥ 3 irAEs (multivariable analyses: OR 1.83, 95 % C.I. 0.99–3.40). The 1-year RFS rate of 80.0 % of this study was comparable to those reported in previous registration trials and real-world data. Having ≥ 3 comorbidities was significantly associated with a decrease in RFS (HR: 1.68, 95 % C.I. 1.15–2.44). ConclusionOlder patients had similar benefit of adjuvant immunotherapy compared to older subgroups in previous trials. However, patients with multiple comorbidities were at increased risk of grade ≥ 3 irAEs and had a lower RFS. This should be considered when deciding upon adjuvant treatment.

Optimal Trough Concentration of Tacrolimus in Pediatric Patients With Primary Nephrotic Syndrome.

The trough concentration (C0) of tacrolimus in children with nephrotic syndrome (NS) has rarely been explored, so its target level was based on transplant research. This study aimed to determine the optimal tacrolimus C0 in NS children. Data from primary NS children treated with tacrolimus at Wuhan Children's Hospital in the last 10 years were retrospectively collected. According to the cutoff C0 analyzed by receiver-operator characteristics (ROC) analysis, patients were divided into very low- (< 4 ng/mL), low- (4-5 ng/mL), medium- (5-7 ng/mL), and high-concentration (7-10 ng/mL) groups. A total of 196 patients were enrolled for primary outcome analysis. Compared to medium-concentration group, only the very low-concentration group obtained significant inferior primary outcomes, including overall remission rate, relapse-free survival rate, and relapse rate at 6 months. For secondary outcomes, the very low-concentration group experienced more frequent treatment failure in 12 months, whereas the high-concentration group suffered a higher risk of adverse events than the medium-concentration group. For steroid-resistant NS, very low- and low-concentration groups required longer time to achieve remission compared to medium-concentration group. For steroid-sensitive NS, the very low-concentration group suffered a higher relapse frequency than medium-concentration group. Lastly, the dose of tacrolimus required for children with different CYP3A5 genotypes with or without Wuzhi capsules was analyzed. In conclusion, tacrolimus may be targeted to C0 of 4-7 ng/mL during the first 6 months in children with NS. For steroid-resistant NS, C0 of 5-7 ng/mL can achieve a rapid remission.

AMPK agonism optimizes the in vivo persistence and anti-leukemia efficacy of chimeric antigen receptor T cells.

Chimeric antigen receptor T cell (CART) therapy has seen great clinical success. However, up to 50% of leukemia patients relapse and long-term survivor data indicate that CART cell persistence is key to enforcing relapse-free survival. Unfortunately, ex vivo expansion protocols often drive metabolic and functional exhaustion, reducing in vivo efficacy. Preclinical models have demonstrated that redirecting metabolism ex vivo can improve in vivo T cell function and we hypothesized that exposure to an agonist targeting the metabolic regulator AMP-activated protein kinase (AMPK), would create CARTs capable of both efficient leukemia clearance and increased in vivo persistence. CART cells were generated from healthy human via lentiviral transduction. Following activation, cells were exposed to either Compound 991 or DMSO for 96 hours, followed by a 48-hour washout. During and after agonist treatment, T cells were harvested for metabolic and functional assessments. To test in vivo efficacy, immunodeficient mice were injected with luciferase+ NALM6 leukemia cells, followed one week later by either 991- or DMSO-expanded CARTs. Leukemia burden and anti-leukemia efficacy was assessed via radiance imaging and overall survival. Human T cells expanded in Compound 991 activated AMPK without limiting cellular expansion and gained both mitochondrial density and improved handling of reactive oxygen species (ROS). Importantly, receipt of 991-exposed CARTs significantly improved in vivo leukemia clearance, prolonged recipient survival, and increased CD4+ T cell yields at early times post-injection. Ex vivo, 991 agonist treatment mimicked nutrient starvation, increased autophagic flux, and promoted generation of mitochondrially-protective metabolites. Ex vivo expansion processes are necessary to generate sufficient cell numbers, but often promote sustained activation and differentiation, negatively impacting in vivo persistence and function. Here, we demonstrate that promoting AMPK activity during CART expansion metabolically reprograms cells without limiting T cell yield, enhances in vivo anti-leukemia efficacy, and improves CD4+ in vivo persistence. Importantly, AMPK agonism achieves these results without further modifying the expansion media, changing the CART construct, or genetically altering the cells. Altogether, these data highlight AMPK agonism as a potent and readily translatable approach to improve the metabolic profile and overall efficacy of cancer-targeting T cells.

Prognostic and Predictive Capabilities of Tumor-Infiltrating Lymphocytes in Breast Cancer

The aim of the study is to evaluate the prognostic and predictive capabilities of tumorinfiltrating lymphocytes in breast cancer (BC); to study the prognostic value of T-cell (CD8+, CD3+) lymphocyte infiltration of the tumor and the level of T-regulatory (CD4+) lymphocytes; to study the prognostic and predictive value of the expression of proteins Forkhead Box Protein 3, check-point PD-1, PDL1. Materials and methods. The content of tumor-infiltrating lymphocytes and their quantitative ratio and correlation with regulatory genes were assessed. Archival material was used in the work. The study included archival data from the cancer registry of 1240 patients treated at the N.N. Petrov Cancer Research Institute from 2000 to 2009. Histological preparations stained with hematoxylin and eosin were scanned. Ten-year relapse-free and overall survival were assessed. Results. About 80% of patients with BC have low levels of tumor infiltration by CD8+ cytotoxic T lymphocytes and CD3+ lymphocytes. Expression of the PD-L1 gene was detected more often (29.5%) in triple-negative breast cancer, 1.5 times less often (18.2%) in HER2+ BC and extremely rarely (1.5%) in luminal A subtype. Severe (more than 10%) lymphocytic infiltration of CD8+ and CD3+ with low expression of PD-L1 and FOXP3 improves relapse-free and overall survival of patients with BC. Conclusion. The inclusion of lymphocytic infiltration of the tumor as a prognostic biomarker represents an important step in understanding the biology of BC.

Expression analysis, molecular docking and molecular dynamics simulations to identify potential BTK inhibitors: strategy for targeting pan-cancer

ABSTRACT Bruton's Tyrosine Kinase (BTK), a soluble tyrosine kinase plays an essential role in the growth, development, and signalling of B cells. It is a non-receptor kinase that is crucial for leukemic cell survival, proliferation, and oncogenic signalling in many B cell malignancies. The enhanced metastasis caused by BTK expression may be reduced by BTK inhibitors, which also have powerful therapeutic effects. The goal of the study is to identify potential inhibitors which have good binding affinity with BTK. The current study also aims to investigate the expression pattern and the prognostic significance of BTK across all cancer types. Interestingly, it was found that BTK was highly overexpressed in numerous cancer types including; clear cell renal carcinoma, glioblastoma, head and neck, liver and breast cancer. BTK was found to reduce the relapse-free and overall survival rate. Furthermore, using in silico approach two structural analogues of Pirtobrutinib namely; 163207918 and 129269825 that bind to BTK with higher affinity were identified. Using drug-likeness analysis the therapeutic possibility of screened Pirtobrutinib analogues were evaluated. The Molecular docking and dynamic analysis revealed that the new Pirtobrutinib analogues could be potent inhibitors with higher binding affinity and stability in comparison with the parent compound. In conclusion, after preclinical and clinical research, the identified analogues may open the door for their prospective use in cancer therapy.

Prognostic Significance of Albumin-Globulin Ratio in Urachal Carcinoma

Introduction: Although albumin-globulin ratio (AGR) has been used in the prognostic assessment of multiple solid malignancies, so far no research has confirmed the prognostic significance of AGR as a biomarker for urachal carcinoma. We analyzed the relationship between AGR and prognosis in urachal carcinoma, aiming to identify a promising prognostic biomarker for urachal carcinoma. Methods: We reviewed the clinical data of 25 patients diagnosed with urachal carcinoma in the Xiangya Hospital, Central South University, from January 2008 to October 2021. The best cut-off value of preoperative AGR was determined according to the receiver operator characteristic curve. The Kaplan-Meier curve was used to analyze the effect of preoperative AGR on the overall survival (OS) and relapse-free survival (RFS) of patients. Cox proportional hazards model was used to analyze prognostic factors including preoperative AGR. Results: The best cut-off value of preoperative AGR in urachal carcinoma patients is 1.45. Low preoperative AGR is significantly associated with worse OS and RFS. Univariate analysis and multivariate analysis indicated that low preoperative AGR is an independent and reliable factor to predict poor prognosis, OS, and RFS in urachal carcinoma patients. Conclusion: Urachal carcinoma patients with low preoperative AGR have worse prognosis, and preoperative AGR is a valuable prognostic indicator for urachal carcinoma research.

Efficacy of brachytherapy versus radical prostatectomy for localized prostate cancer–propensity score-matched comparison

ObjectiveThe brachytherapy (BT) and radical prostatectomy (RP) are two methods recommended in current guidelines for the treatment of localized prostate cancer (PCa). It is difficult to compare the oncological results of these two treatments because of differences in baseline characteristics and treatment selection.we sought to compare the efficacy of BT and RP after propensity score matching(PSM)analysis.MethodsBetween January 2009 and December 2021, our institution treated 657 patients with localized PCa (BT: n = 198; RP: n = 459)and followed up for > 2 years. Biochemical recurrence was defined as prostate-specific antigen (PSA) levels of nadir plus 2 ng/ml or higher (Phoenix definition) for BT, and as PSA0.2 ng/ml or greater for RP. PSM was applied based on the age, body mass index, PSA, prostate volume, clinical T-stage, Gleason grade, percentage of positive puncture needles ≥ 1/2, maximum tumor diameter ≥ 5 mm, and follow-up period.ResultsMedian follow-up was 63 months for BT and 52 months for RP. After propensity score adjustment, a total of 294 (147 each) patients remained for further analysis.Kaplan–Meier curves showed no statistically significant difference in clinical relapse-free survivals (cRFS) (p = 0.637),overall survival (OS) (p = 0.726),and cancer-specific survival (CSS) (p = 0.505).BT was associated with improved biochemical relapse-free survivals (bRFS) compared to RP (p = 0.022), Logistic multivariate analysis based on the whole cohort revealed that clinical T stage ≥ T2b (p = 0.043) and tumor maximum diameter ≥ 5 mm (p = 0.044) were associated with significantly bRFS.ConclusionThe BT and RP group patients exhibited similar cRFS, OS, and CSS. However, patients in the BT groups exhibited better bRFS than those in the RP group.Clinical T stage ≥ T2b and a maximum tumor diameter ≥ 5 mm were independent prognostic factors.

Oncological long-term outcomes of laparoscopic versus open gastrectomy for cT3-4 gastric cancer at surgical staging: a propensity-score matched cohort study.

The oncological efficacy of laparoscopic surgery for advanced gastric cancer (AGC) has been evaluated by several randomized trials. However, the inclusion of earlier-stage disease was a limitation in previous studies. Patients with cT3-4 gastric cancer, determined by surgical staging to minimize migration of earlier stages, treated at a tertiary cancer center from 2009 to 2018 were included. Based on the surgical approach, the patients were divided into two groups: the laparoscopic gastrectomy (LG) and the open gastrectomy (OG) and matched for age, sex, macroscopic appearance (type 4 or non-type 4), body mass index, estimated tumor size, clinical stage T3'T4, clinical N stage, pathologic T stage (T3 or T4), and type of surgery (total or distal gastrectomy). 588 patients (221 LG, 367 OG) were included in the analysis. After 1:1 propensity-score matching, 386 patients (193 LG, 193 OG) were assigned for analysis. In the LG group, operation time was longer with lower blood loss. The incidence of postoperative complications (≥ grade III) did not differ significantly between the groups (OG: 8.3%, vs. LG: 9.3%). Overall survival (OS) was longer in the LG group (5-year OS: 79.3 vs. 73% HR 0.66, 95% CI 0.44-0.99, P = 0.0497). Relapse-free survival (RFS) did not show a statistical difference (5-year RFS: 69.5 vs. 68.7 HR 0.88, 95% CI 0.62-1.26, P = 0.487). Subgroup analysis for OS also demonstrated equivalent outcomes. LG demonstrates comparable safety and efficacy to OG for advanced gastric cancer at surgical staging, with similar rates of severe complications and long-term oncological outcomes. Further research is needed to validate these findings, particularly for total gastrectomy and for patients from Western populations.

A Pan-Cancer Analysis of GAPDH as a Common Biomarker for Various Cancers

Objective: To investigate the expression levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and explore its prognostic value across 24 different human cancers. This investigation was conducted using comprehensive bioinformatics and in vitro approaches, incorporating multiple layers of analysis. Methods: GAPDH expression and methylation levels were assessed using bioinformatics tools and validated in cell lines through RNA-seq and targeted bisulfite-seq analyses. The potential prognostic significance of GAPDH was evaluated using the KM plotter. Additionally, cBioPortal was employed to investigate genetic alterations associated with this gene. Pathway analysis was conducted using DAVID. Furthermore, a correlation analysis between GAPDH expression and CD8+ T immune cells was performed using TIMER and CDT. Finally, a gene-drug interaction network analysis was conducted using Cytoscape to examine the relationship between GAPDH and various drugs. Results: GAPDH was found to be commonly upregulated in 24 types of human cancers, with its upregulation significantly correlated with poor relapse-free survival (RFS) and overall survival (OS) in BLCA, CESC, HNSC, KIRP, LIHC, and LUAD. This suggests that GAPDH plays a significant role in the development of these cancers. GAPDH upregulation was also associated with various clinicopathological features in patients with BLCA, CESC, HNSC, KIRP, LIHC, and LUAD. Pathway analysis revealed GAPDH’s involvement in diverse pathways. Additionally, notable correlations were observed between GAPDH expression and its promoter methylation level, genetic alterations, and CD8+ T immune cell levels. Moreover, several regulatory drugs targeting GAPDH were identified, with the potential to modulate its expression and potentially prevent conditions such as BLCA, CESC, HNSC, KIRP, LIHC, and LUAD. Conclusion: Based on our findings, GAPDH emerges as a promising diagnostic and prognostic biomarker for BLCA, CESC, HNSC, KIRP, LIHC, and LUAD.