Outcomes In Malignancies Research Articles

Abstract 2547: KRAS Q61 mutations in patients with gastrointestinal malignancies and association with real-world clinical outcomes

Abstract Introduction: Gene-wide KRAS mutation has been associated with worse outcomes in multiple malignancies with newer data suggesting differential impact based on specific allele. Mutation at codon Q61 is relatively infrequent with clinical significance not well understood. Here we aim to investigate the clinical significance of KRASQ61 mutation in gastrointestinal (GI) malignancies. Methods: The Foundry software platform was used to retrospectively query electronic health records to identify patients diagnosed with colorectal (CRC), pancreatic (PDAC), appendiceal (AA), cholangiocarcinoma (CC) and gastroesophageal carcinoma who underwent clinical testing for KRAS mutations in our institution between 2002-2023; clinical, molecular, and overall survival (OS) data were collected. Results: KRAS mutation was tested in 9,088 patients with CRC, PDAC, CC, AA, and gastroesophageal carcinoma. Incidence of KRAS mutation was 47% (n= 3,181) for patient with CRC, 82% for PDAC (n= 579), 16% for CC (n= 76), 51% for AA (n= 236), and 7% for gastroesophageal carcinoma (n= 43). KRASQ61 mutation was in 5% (n=218) of patients with KRAS mutation (n= 4,115). Overall frequency of KRASQ61 was 2% (n= 156) for CRC, 5% (n= 36) for PDAC, 3% (n= 12) for CC, 2% (n= 10) for AA and 1% (n= 4) for gastroesophageal carcinoma. KRASQ61 fraction of KRAS mutations was 5% for CRC, 6% for PDAC, 16% for CC, 4% for AA, 9% for gastroesophageal carcinoma. KRASQ61H was the most frequent KRASQ61 mutation among all tumor types, 57%, 61%, 60%, 50% out of KRASQ61 for CRC, PDAC, AA, and gastroesophageal carcinoma respectively; followed by KRASQ61L (20%) for CRC, but KRASQ61R for PDAC (25%), AA (20%), and gastroesophageal (25%); Patients with CC showed exclusively KRASQ61H mutations. Compared to patients with KRAS wildtype, patients with KRASQ61 mutations had worse OS in PDAC (median OS=20 vs 37 months, HR=1.9, 95%CI=1.2-3, p=0.006), while (55 vs 63 months, HR=1.2, 95%CI=0.98-1.5, p=0.076) for CRC, (29 vs 25 months, HR=1.3, 95%CI=0.64-2.6, p=0.47) for CC, and (33 vs 52 months, HR=1.1, 95%CI=0.5-2.6, p=0.75) for AA. Compared to other KRAS mutations, KRASQ61 median OS was (55 vs 53 months, HR=1, 95%CI=0.81-1.3, p=0.96) for patients with CRC, (20 vs 26 months, HR=1.4, 95%CI=0.91-2.1, p=0.1) for PDAC, (25 vs 28 months, HR=1.1, 95%CI=0.54-2.5, p=0.72) for CC, (33 vs 78 months, HR=1.6, 95%CI=0.72-3.7, p=0.24) for AA. Conclusion: KRASQ61 mutations frequency varied from 1% to 5% across different GI malignancies, with highest frequency in PDAC and CC. KRASQ61 mutations had worse OS in patients with PDAC which may suggest different co-mutations rather than specific KRASQ61 activity difference. Further allele specific analysis of KRASQ61 and co-mutations landscape is underway. Citation Format: Mahmoud Yousef, Abdelrahman Yousef, Saikat Chowdhury, Mohammad Mahdi Fanaeian, Mark Knafl, Paul M. Roy, Ashwathy Pillai, Mohammad Zeineddine, Fadl Zeineddine, Jennifer Peterson, Brandon G. Smaglo, Robert A. Wolff, Shubham Pant, Michael Sangmin Lee, Jason A. Willis, Michael James Overman, Ethan Bernard Ludmir, Mark W. Hurd, John Paul Shen, Dan Zhao. KRAS Q61 mutations in patients with gastrointestinal malignancies and association with real-world clinical outcomes [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 2547.

Abstract 4748: Aronia berry overcomes gemcitabine resistance by regulating the MYD88/NF-kB/P-glycoprotein pathway in pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is lethal, which is partly due to the limited efficacy of Gemcitabine (Gem)-based chemotherapy, resulting from the development of acquired resistance to this regimen. Aronia berry extract (ABE) is a natural source of phenolic compounds known for its anti-cancer properties. Previous research has highlighted the ability of ABE to help overcome chemoresistance to conventional chemotherapies in various cancers. In this study, we interrogated the ability of ABE to overcome Gem-resistance (Gem-R) in PDAC and identify specific pathway(s) responsible for this anti-cancer efficacy. Methods: We performed a series of in-vitro experiments in Gem-R cells to evaluate the synergistic effect of combined treatment with Gem and ABE. Furthermore, we conducted a genomewide transcriptomic analysis to identify the critical regulatory pathways associated with chemoresistance and potential therapeutic targets of ABE in Gem-R PDAC cells. The cell culture findings were validated in patient-derived 3D organoids. Results: The combined treatment with ABE and Gem in Gem-R cells exhibited significant synergistic anticancer effects on cell viability, proliferation, migration, and invasion. The transcriptomic analysis revealed that the NF-κB signaling pathway was associated with Gem-R (p<0.05), with a significant upregulation of MYD88. Additionally, MYD88 was significantly associated with overall survival in PDAC patients in the TCGA cohort (HR=1.58, P=0.045). The MYD88/NF-κB signaling is associated with chemoresistance as it can upregulate the efflux transporters like P-glycoprotein (P-gp). Our results confirmed that combined treatment inhibited the NF-κB signaling pathway by suppressing MYD88 and downregulating P-gp expression to overcome Gem-R. Finally, the combined treatment demonstrated superior anti-cancer activity in 3D organoids by reducing both their number and size (P<0.05). Conclusion: We provide novel insights into the potential of ABE in overcoming Gem-R in PDAC cells by targeting the MYD88/NF-κb/P-gp axis, which offers a safe and inexpensive approach for improving therapeutic outcomes in this fatal malignancy. Citation Format: Yuan Li, Caiming Xu, Haiyong Han, Ajay Goel. Aronia berry overcomes gemcitabine resistance by regulating the MYD88/NF-kB/P-glycoprotein pathway in pancreatic ductal adenocarcinoma [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 4748.

Accelerating the development of genetically engineered cellular therapies: a framework for extrapolating data across related products

BackgroundSignificant advancements have been made in the field of cellular therapy as anti-cancer treatments, with the approval of chimeric antigen receptor (CAR)-T cell therapies and the development of other genetically engineered cellular therapies. CAR-T cell therapies have demonstrated remarkable clinical outcomes in various hematological malignancies, establishing their potential to change the current cancer treatment paradigm. Due to the increasing importance of genetically engineered cellular therapies in the oncology treatment landscape, implementing strategies to expedite development and evidence generation for the next generation of cellular therapy products can have a positive impact on patients. MethodsWe outline a risk-based methodology and assessment aid for the data extrapolation approach across related genetically engineered cellular therapy products. This systematic data extrapolation approach has applicability beyond CAR-T cells and can influence clinical development strategies for a variety of immune therapies such as T cell receptor (TCR) or genetically engineered and other cell-based therapies (e.g., tumor infiltrating lymphocytes, natural killer cells and macrophages). ResultsBy analyzing commonalities in manufacturing processes, clinical trial designs, and regulatory considerations, key learnings were identified. These insights support optimization of the development and regulatory approval of novel cellular therapies. ConclusionsThe field of cellular therapy holds immense promise in safely and effectively treating cancer. The ability to extrapolate data across related products presents opportunities to streamline the development process and accelerate the delivery of novel therapies to patients.

Quantification of CD3, FoxP3, and granzyme B immunostaining in canine renal cell carcinoma

Tumor-infiltrating lymphocyte (TIL) density plays an important role in anti-tumor immunity and isassociated with patient outcome in various human and canine malignancies. As a first assessment of the immune landscape of the tumor microenvironment in canine renal cell carcinoma (RCC), we retrospectively analyzed clinical data and quantified CD3, FoxP3, and granzyme B immunostaining in formalin-fixed paraffin-embedded tumor samples from 16 dogs diagnosed with renal cell carcinoma treated with ureteronephrectomy. Cell density was low for all markers evaluated. Increased numbers of intratumoral FoxP3 labelled (+) cells, as well as decreased granzyme B+: FoxP3+ TIL ratio, were associated with poor patient outcomes. Our initial study of canine RCC reveals that these tumors are immunologically cold and Tregs may play an important role in immune evasion.

Survival Outcomes in Different Sino-nasal Malignancies: An Institutional Review

Objective: The purpose of this review is to comprehend the treatment outcome of different PNS cancer histologies and their survival. Materials and Procedures: A review of our institutional database from January 2010 to December 2022 included 122 sinonasal cancer patients. After exclusions, 84 patients whose data sets were complete underwent analysis. Overall survival (OS), loco-regional failure-free survival (LRFS), and distant metastases-free survival (DMFS) were the measured endpoints. Results: With a median follow-up time of 26 months, there was no correlation detected between histological type and OS, LRFS, or DMFS. It was discovered that the type of treatment technique was substantially related to LRFS. Surgery plus adjuvant radiation and/or chemotherapy had a minor tendency to be significant in terms of OS, with a median OS of 56 months (95% CI: 38.6–73.3). Conclusions: It showed that the use of different treatment modalities had an impact on LRFS, while the type of histology did not correlate with the effectiveness of the treatment.

IL-22 promotes liver regeneration after portal vein ligation

BackgroundInsufficient remnant liver volume (RLV) after the resection of hepatic malignancy could lead to liver failure and mortality. Portal vein ligation (PVL) prior to hepatectomy is subsequently introduced to increase the remnant liver volume and improve the outcome of hepatic malignancy. IL-22 has previously been reported to promote liver regeneration, while facilitating tumor development in the liver via Steap4 upregulation. Here we performed PVL in mouse models to study the role of IL-22 in liver regeneration post-PVL. MethodsLiver weight and volume was measured via magnetic resonance imaging (MRI). Immunohistochemistry for Ki67 and hepatocyte growth factor (HGF) was performed. IL-22 was analyzed by flow cytometry and quantitative polymerase chain reaction (qPCR) was used for acquisition of Il-33, Steap4, Fga, Fgb and Cebpd. To analyze signaling pathways, mice with deletion of STAT3 and a neutralizing antibody for IL-22 were used. ResultsThe remnant liver weight and volume increased over time after PVL. Additionally, we found that liver regenerative molecules, including Ki67 and HGF, were significantly increased in remnant liver at day 3 post-PVL, as well as IL-22. Administration of IL-22 neutralizing antibody could reduce Ki67 expression after PVL. The upregulation of IL-22 after PVL was mainly derived from innate cells. IL-22 blockade resulted in lower levels of IL-33 and Steap4 in the remnant liver, which was also the case in mice with deletion of STAT3, the main downstream signaling molecule of IL-22, in hepatocytes. ConclusionIL-22 promotes liver regeneration after PVL. Thus, a combination of IL-22 supplementation and Steap4 blockade could potentially be applied as a novel therapeutic approach to boost liver regeneration without facilitating tumor progression after PVL.

Projected Impact of Omidubicel-onlv on Racial/Ethnic Disparities in Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) Outcomes in Hematologic Malignancies.

In a phaseIII clinical trial (NCT02730299), omidubicel-onlv, a nicotinamide-modified allogeneic hematopoietic progenitor cell therapy, showed rapid hematopoietic and immune recovery compared with standard umbilical cord blood (UCB) transplant across all racial/ethnic groups. A decision-tree model was used to project the effect of omidubicel-onlv availability on addressing health disparities in allogeneic hematopoietic cell transplantation (allo-HCT) access and outcomes for patients with hematologic malignancies. The model used a hypothetical population of 10,000 allo-HCT-eligible US adults, for whom matched related donors were not available. Patients received matched or mismatched unrelated donor, haploidentical, UCB transplant, or no transplant. Scenarios with omidubicel-onlv use of 0% (status quo), 10%, 15%, 20%, and 30% were modeled on the basis of proportional reductions in other allo-HCT sources or no transplant by racial/ethnic group. Increased omidubicel-onlv use was associated with a higher proportion of patients undergoing allo-HCT, decreased time to allo-HCT, decreased 1-year non-relapse mortality, and increased 1-year overall survival, particularly among racial minorities. In the scenario modeling 20% omidubicel-onlv use, the proportion of Black patients receiving allo-HCT increased by 129%; increases were also observed in Asian (64%), Hispanic (45%), and other (42%) patient groups. Modeled time to allo-HCT improved among transplanted patients (23%) from 11.4weeks to 8.8weeks. One-year OS in the overall population increased by 3%, with improvements ranging from 3% for White patients to 5% for Black patients. This study demonstrates that broad access to omidubicel-onlv could increase access to allo-HCT and improve outcomes for patients, with the greatest benefits seen among racial/ethnic minority groups.

Long non-coding RNA TINCR suppresses growth and epithelial-mesenchymal transition by inhibiting Wnt/β-catenin signaling pathway in human pancreatic cancer PANC-1 cells: Insights from in vitro and in vivo studies.

There is increasing evidence that long non-coding RNAs (lncRNAs) play a crucial role in the development and progression of malignant tumors, particularly pancreatic cancer. In this study, the influence of the lncRNA TINCR on the behavior of human pancreatic cancer cells was investigated with the aim of deciphering its role in growth, migration, and invasion. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to investigate TINCR expression in pancreatic cancer cells. Ectopic expression of TINCR in PANC-1 cells was induced to evaluate the effects on cell viability and apoptosis, examining the apoptotic genes Bax and Bcl-2. Migration and invasion assays were used to measure the impact of TINCR on these cellular processes. In vivo studies using a xenograft mouse model examined the effects of TINCR on tumor growth, epithelial-to-mesenchymal transition (EMT) markers, and the Wnt/β-catenin signaling pathway. PANC-1 cells showed strikingly low TINCR expression compared to other pancreatic cancer cell lines. Ectopic TINCR expression reduced the viability of PANC-1 cells primarily by inducing apoptosis, as evidenced by increased Bax and decreased Bcl-2 expression. Overexpression of TINCR significantly increased the percentage of apoptotic cells. It also decreased the migration and invasion ability of PANC-1 cells, as demonstrated in wound healing and transwell assays. In addition, overexpression of TINCR-suppressed proteins is associated with the Wnt/β-catenin signaling pathway in PANC-1 cells. In the xenograft mouse model, overexpression of TINCR inhibited tumor growth, EMT markers, and proteins associated with the Wnt/β-catenin pathway. This study sheds light on the tumour-suppressive role of TINCR in PANC-1 cells and suggests its potential as a therapeutic target. These results shed light on the molecular mechanisms underlying the impact of TINCR on pancreatic cancer and offer promising opportunities for innovative therapeutic strategies to improve outcomes in this serious malignancy.

Impact of Skeletal Muscle Depletion on Patients with Myelodysplastic Syndrome Treated with Azacitidine.

Azacitidine (AZA) is the standard treatment for patients with high-risk myelodysplastic syndromes (MDS). The impact of skeletal muscle depletion (SMD), which is associated with outcomes of hematological malignancies, on the clinical course of MDS patients treated with AZA was investigated. This retrospective, observational study included 50 MDS patients treated with AZA. Muscle mass was evaluated using the skeletal muscle index (SMI), which is the area of muscle mass at the third lumbar vertebra on CT images divided by the square of the height. Of the enrolled patients, 39 were males, and their median age was 69.5 years. Twenty-seven (20 male and 7 female) patients showed SMD. The median survival was 13.4 months in the SMD group and 15.2 months in the non-SMD group, with no significant difference and no significant association between the response rate or severe non-hematological toxicities and the presence of SMD. By contrast, grade 3-4 anemia and thrombocytopenia were significantly more frequent in the SMD group than in the non-SMD group. SMD was associated with severe anemia and thrombocytopenia in MDS patients treated with AZA. Reduced skeletal muscle mass may predict severe hematological toxicity in MDS patients treated with AZA.

Mutation of PTEN: Loss and Likelihood of Being a Non-responder to Trastuzumab in a Sample of Iraqi Her2+ Breast Cancer Patients.

PTEN controls upstream PI3K relatives, such as AKT. PTEN gene mutations have been documented to affect outcomes in main or distant malignancies, including breast cancer (BC). PTEN gene deletions are common in a variety of humancancers. A key factor in the response to this kind of therapy is genetic diversity. The purpose of this research is to determine whether a PTEN loss mutation influences a patient's propensity to not respond to trastuzumab (TRS) in cases of Her2+ BC. Diwaniya Teaching Hospital's oncology ward provided 60 patients with Her2+ BC who had been on TRS for at least 12 months for this study. Patients were split in half using the RECIST criteria for evaluating responses to therapy in solid tumors: responders and non-responders. A PTEN polyclonal primary antibody was used for the detection of PTEN in breast tissue in the current study. This research employs a rating system based on eight specimens (26.67%) among non-responsive women who demonstrated PTEN loss compared with one specimen (3.33%) among responsive women. Statistically, PTEN loss varied significantly between the responsive and non-responsive groups. Loss of PTEN was also not linked to shifts in creatine kinase-myocardial band (CK-MB), troponin T (TnT), or any other biomarker, or troponin I (Tn1) at baseline or after 12 months of TRS therapy. These results give us important information about how PTEN deletion mutations might work as a predictor for TRS response in women with Her2+ BC.

Biology and Therapeutic Properties of Mesenchymal Stem Cells in Leukemia.

This comprehensive review delves into the multifaceted roles of mesenchymal stem cells (MSCs) in leukemia, focusing on their interactions within the bone marrow microenvironment and their impact on leukemia pathogenesis, progression, and treatment resistance. MSCs, characterized by their ability to differentiate into various cell types and modulate the immune system, are integral to the BM niche, influencing hematopoietic stem cell maintenance and functionality. This review extensively explores the intricate relationship between MSCs and leukemic cells in acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia. This review also addresses the potential clinical applications of MSCs in leukemia treatment. MSCs' role in hematopoietic stem cell transplantation, their antitumor effects, and strategies to disrupt chemo-resistance are discussed. Despite their therapeutic potential, the dual nature of MSCs in promoting and inhibiting tumor growth poses significant challenges. Further research is needed to understand MSCs' biological mechanisms in hematologic malignancies and develop targeted therapeutic strategies. This in-depth exploration of MSCs in leukemia provides crucial insights for advancing treatment modalities and improving patient outcomes in hematologic malignancies.

Machine-Learning-Based Classification Model to Address Diagnostic Challenges in Transbronchial Lung Biopsy.

When obtaining specimens from pulmonary nodules in TBLB, distinguishing between benign samples and mis-sampling from a tumor presents a challenge. Our objective is to develop a machine-learning-based classifier for TBLB specimens. Three pathologists assessed six pathological findings, including interface bronchitis/bronchiolitis (IB/B), plasma cell infiltration (PLC), eosinophil infiltration (Eo), lymphoid aggregation (Ly), fibroelastosis (FE), and organizing pneumonia (OP), as potential histologic markers to distinguish between benign and malignant conditions. A total of 251 TBLB cases with defined benign and malignant outcomes based on clinical follow-up were collected and a gradient-boosted decision-tree-based machine learning model (XGBoost) was trained and tested on randomly split training and test sets. Five pathological changes showed independent, mild-to-moderate associations (AUC ranging from 0.58 to 0.75) with benign conditions, with IB/B being the strongest predictor. On the other hand, FE emerged to be the sole indicator of malignant conditions with a mild association (AUC = 0.66). Our model was trained on 200 cases and tested on 51 cases, achieving an AUC of 0.78 for the binary classification of benign vs. malignant on the test set. The machine-learning model developed has the potential to distinguish between benign and malignant conditions in TBLB samples excluding the presence or absence of tumor cells, thereby improving diagnostic accuracy and reducing the burden of repeated sampling procedures for patients.

MRI-visualized T2 hyperintense breast lesions: identifying clinical and imaging factors linked to malignant biopsy outcomes.

To determine the malignancy rate for MRI-guided breast biopsies performed for T2 hyperintense breast lesions and to assess additional clinical and MRI characteristics that can predict benign and malignant outcomes. A retrospective chart review of consecutive MRI-guided breast biopsies performed in two tertiary hospitals was conducted over two years. Biopsies performed for T2 hyperintense lesions were selected, and further lesion imaging characteristics and patient risk factors were collected. Univariate and multivariate modeling regression were used to determine additional imaging and patient factors associated with malignant outcomes for biopsies of T2 hyperintense lesions. Out of 369 MRI-guided breast biopsies, 100 (27%) were performed for T2 hyperintense lesions. Two biopsy-proven benign lesions were excluded as the patient was lost on follow-up. With a study cohort of 98 lesions, the final pathology results were benign for 80 (80%) of these lesions, while 18 (18%) were malignant. Using multivariate logistic modeling, patient age > 50 (OR 5.99 (1.49, 24.08 95% CI), p < 0.05) and lesion size > 3cm (OR 5.54 (1.54-18.7), p < 0.01) were found to be important predictors of malignant outcomes for MRI biopsies performed for T2 hyperintense lesions. Our study observed a high malignancy rate, challenging the assumption that T2 hyperintensity can be considered a benign imaging characteristic for otherwise suspicious MRI-detected lesions. Decision-making regarding tissue sampling should be made based on a thorough evaluation of more reliable additional demographic and imaging factors, including patient age and lesion size.

Association of perioperative acute kidney injury with oncological outcomes in patients who undergo radical cystectomy: A multicenter retrospective study.

660 Background: Acute kidney injury (AKI) is a frequent complication in patients with muscle-invasive bladder cancer (MIBC) who undergo radical cystectomy (RC). Previous studies have reported that AKI during cancer treatment was associated with poor oncological outcomes in several malignancies. Moreover, we previously have reported the negative impact of neoadjuvant chemotherapy-induced AKI on oncological outcomes in patients with MIBC. However, the impact of perioperative AKI on oncological outcomes in patients who undergo RC remains unclear. Methods: This multi-institutional retrospective study included 798 patients with MIBC who underwent RC. AKI was defined according to the KDIGO criteria. Stage 1 AKI was diagnosed with an increase in serum creatinine by just 0.3 mg/dL. Patients were divided into two groups: patients who developed AKI after RC (AKI group) and patients who did not (non-AKI group). Multivariable Cox-proportional hazards regression analyses were performed to evaluate the impact of perioperative AKI on recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Results: The median age and follow-up period were 70 years and 64 months, respectively. Of the 798 patients, 408 (51%) developed AKI after RC. Approximately 73% AKI were stage 1 AKI. RFS, CSS, and OS in the AKI group were significantly shorter than those in the non-AKI group ( P = 0.003, P = 0.035, and P &lt; 0.001, respectively). After adjustment for confounding variables, AKI was significantly associated with shorter RFS (hazard ratio [HR] 1.357, P = 0.019), CSS (HR 1.345, P = 0.042), and OS (HR 1.344, P = 0.009). Conclusions: Perioperative AKI was associated with poor oncological outcomes in patients with MIBC who underwent RC. [Table: see text]

CRP-albumin-lymphocyte (CALLY) Index Is an Independent Prognostic Factor for the Esophageal Cancer Patients Who Received Curative Treatment.

Perioperative inflammation and the nutritional status affect both short- and long-term oncological outcomes in various malignancies. We clarified the clinical impacts of the CRP-albumin-lymphocyte (CALLY) index in patients with esophageal cancer who received curative treatment. The present study included 180 patients who underwent curative treatment for esophageal cancer between 2005 and 2020. The prognosis and clinicopathological parameters were compared between a high-fibrinogen group and a low-fibrinogen group. The 3- and 5-year overall survival rates were 50.0% and 42.6%, respectively, in the CALLY index-low group, and 75.9% and 66.6% in the CALLY index-high group. The differences between the two groups were statistically significant (p<0.001). Univariate and multivariate analyses demonstrated that the CALLY index was an independent prognostic factor [hazard ratio=2.310, 95% confidence interval=1.416-3.767, p<0.001]. Similar results were observed in recurrence-free survival. When comparing the details of postoperative surgical complications, there was a significant difference in the incidence of anastomotic leakage. The incidence of anastomotic leakage was 40.2% in the CALLY index-low group, while it was 27.5% in the CALLY index-high group (p=0.030). The pretreatment CALLY index is one of the independent prognostic factors for esophageal cancer. The CALLY index might become a promising biomarker for the treatment and management of esophageal cancer.

Current advances in experimental and computational approaches to enhance CAR T cell manufacturing protocols and improve clinical efficacy.

Since the FDA's approval of chimeric antigen receptor (CAR) T cells in 2017, significant improvements have been made in the design of chimeric antigen receptor constructs and in the manufacturing of CAR T cell therapies resulting in increased in vivo CAR T cell persistence and improved clinical outcome in certain hematological malignancies. Despite the remarkable clinical response seen in some patients, challenges remain in achieving durable long-term tumor-free survival, reducing therapy associated malignancies and toxicities, and expanding on the types of cancers that can be treated with this therapeutic modality. Careful analysis of the biological factors demarcating efficacious from suboptimal CAR T cell responses will be of paramount importance to address these shortcomings. With the ever-expanding toolbox of experimental approaches, single-cell technologies, and computational resources, there is renowned interest in discovering new ways to streamline the development and validation of new CAR T cell products. Better and more accurate prognostic and predictive models can be developed to help guide and inform clinical decision making by incorporating these approaches into translational and clinical workflows. In this review, we provide a brief overview of recent advancements in CAR T cell manufacturing and describe the strategies used to selectively expand specific phenotypic subsets. Additionally, we review experimental approaches to assess CAR T cell functionality and summarize current in silico methods which have the potential to improve CAR T cell manufacturing and predict clinical outcomes.

Glutamine metabolism-related genes and immunotherapy in nonspecific orbital inflammation were validated using bioinformatics and machine learning

BackgroundNonspecific orbital inflammation (NSOI) is an idiopathic, persistent, and proliferative inflammatory condition affecting the orbit, characterized by polymorphous lymphoid infiltration. Its pathogenesis and progression have been linked to imbalances in tumor metabolic pathways, with glutamine (Gln) metabolism emerging as a critical aspect in cancer. Metabolic reprogramming is known to influence clinical outcomes in various malignancies. However, comprehensive research on glutamine metabolism's significance in NSOI is lacking.MethodsThis study conducted a bioinformatics analysis to identify and validate potential glutamine-related molecules (GlnMgs) associated with NSOI. The discovery of GlnMgs involved the intersection of differential expression analysis with a set of 42 candidate GlnMgs. The biological functions and pathways of the identified GlnMgs were analyzed using GSEA and GSVA. Lasso regression and SVM-RFE methods identified hub genes and assessed the diagnostic efficacy of fourteen GlnMgs in NSOI. The correlation between hub GlnMgs and clinical characteristics was also examined. The expression levels of the fourteen GlnMgs were validated using datasets GSE58331 and GSE105149.ResultsFourteen GlnMgs related to NSOI were identified, including FTCD, CPS1, CTPS1, NAGS, DDAH2, PHGDH, GGT1, GCLM, GLUD1, ART4, AADAT, ASNSD1, SLC38A1, and GFPT2. Biological function analysis indicated their involvement in responses to extracellular stimulus, mitochondrial matrix, and lipid transport. The diagnostic performance of these GlnMgs in distinguishing NSOI showed promising results.ConclusionsThis study successfully identified fourteen GlnMgs associated with NSOI, providing insights into potential novel biomarkers for NSOI and avenues for monitoring disease progression.

Artificial Intelligence in Clinical and Surgical Gynecology

Clinicians have increasingly been using artificial intelligence (AI) to make decisions and to increase their knowledge in various clinical and surgical gynecological areas. A vast amount of clinical, medical, and biological patient data is processed in fast computer networks using complex algorithms to create mathematical modeling. The development of these mathematical models gives hope of a promising future with their contribution to overcoming the difficulties encountered in the diagnosis, individualization of treatment plans and improving patient outcomes. Virtual AI in clinical gynecology uses pattern recognition to aid diagnosis, plan treatment, and predict outcomes in gynecological malignancies, assisted reproductive techniques, and urogynecology. In gynecological surgery, physical AI combines augmented reality in operations in the form of computer-aided or robotic platforms. However, AI is yet to be fully incorporated into modern medical practice to improve patient outcomes in clinical gynecology.

Computational pathology identifies immune-mediated collagen disruption to predict clinical outcomes in gynecologic malignancies

BackgroundThe role of immune cells in collagen degradation within the tumor microenvironment (TME) is unclear. Immune cells, particularly tumor-infiltrating lymphocytes (TILs), are known to alter the extracellular matrix, affecting cancer progression and patient survival. However, the quantitative evaluation of the immune modulatory impact on collagen architecture within the TME remains limited.MethodsWe introduce CollaTIL, a computational pathology method that quantitatively characterizes the immune-collagen relationship within the TME of gynecologic cancers, including high-grade serous ovarian (HGSOC), cervical squamous cell carcinoma (CSCC), and endometrial carcinomas. CollaTIL aims to investigate immune modulatory impact on collagen architecture within the TME, aiming to uncover the interplay between the immune system and tumor progression.ResultsWe observe that an increased immune infiltrate is associated with chaotic collagen architecture and higher entropy, while immune sparse TME exhibits ordered collagen and lower entropy. Importantly, CollaTIL-associated features that stratify disease risk are linked with gene signatures corresponding to TCA-Cycle in CSCC, and amino acid metabolism, and macrophages in HGSOC.ConclusionsCollaTIL uncovers a relationship between immune infiltration and collagen structure in the TME of gynecologic cancers. Integrating CollaTIL with genomic analysis offers promising opportunities for future therapeutic strategies and enhanced prognostic assessments in gynecologic oncology.

Influence of maximum diameter on fine-needle aspiration biopsy outcomes in ACR TI-RADS 5 thyroid nodules.

Fine needle aspiration (FNA) biopsy is a widely accepted method for diagnosing thyroid nodules. However, the influence of maximum diameter (MD) of ACR TIRADS 5 (TR5) thyroid nodules on the FNA outcomes remains debated. This study examined the influence of MD on the FNA outcomes and investigated the optimal MD threshold for FNA in TR5 nodules. We conducted a retrospective analysis of 280 TR5 thyroid nodules from 226 patients who underwent FNA from January to June 2022 in our department. Probably malignant (PM) group was defined as Bethesda V in cytopathology with confirmed BRAF V600E mutation or Bethesda VI, the other cytopathology outcomes were defined as probably benign (PB) group. We examined factors influencing malignant cytopathology outcomes and determined the optimal MD threshold for FNA in TR5 nodules using logistic regression and restricted cubic spline (RCS) analysis. Among these nodules, 58.2% (163/280) had PM outcomes. The PM group had a significantly larger MD than the PB group [6.5mm (range 5.0-8.4) vs. 5.3mm (range 4.0-7.0), p < 0.001]. In multivariate logistic regression fully adjusted for confounders, MD was significantly associated with PM outcomes [odds ratio 1.16, 95%CI 1.05-1.31; p = 0.042]. The highest quartile of MD had a greater likelihood of PM outcomes compared to the lowest quartile [odds ratio 4.71, 95% CI 1.97-11.69, p = 0.001]. The RCS analysis identified 6.2mm as the optimal MD threshold for FNA in TR5 nodules. MD significantly affects the probability of malignant outcomes in FNA of TR5 thyroid nodules. A MD threshold of ≥6.2mm is suggested for FNA in these nodules.