Worse Prognosis Research Articles

Increased Proportion of the Squamous Cell Carcinoma Components Is Associated with Aggressive Behavior and a Worse Prognosis in Resected Pancreatic Adenosquamous Carcinoma.

Pancreatic adenosquamous carcinoma (PASC) is a subtype of pancreatic cancer with a poorer prognosis than pancreatic ductal carcinoma (PDAC). The pathogenesis of this histological subtype has not been fully explained due to its rarity. Of the 245 patients who underwent pancreatic resection for pancreatic cancer, six (2.3%) were diagnosed with PASC. They were retrospectively allocated to Group A (≥ 50% adenocarcinoma components) or Group S (≥ 50% squamous cell carcinoma components). The six patients with PASC were all males between the ages of 63 and 77years, with tumors of 12 to 52mm in diameter. Tumors were located in the pancreatic head (n = 2) and the pancreatic tail (n = 4). Relative to Group A, all three patients in Group S had larger tumors diameters, ≥ 40mm with invasion to other organs. Cancer-specific survival of Group S was worse than that of the PDAC group (median survival, 1.5years vs. 4.1years). All patients in Group A were alive at the end of follow-up. Recurrence-free survival of Group S was inferior to that of the PDAC group (median survival, 0.2years vs. 1.8years; Group A, not defined). Immunohistochemistry revealed the MIB-1 positivity rate in squamous cell carcinoma regions was 1.8 times higher than that in adenocarcinoma regions in the same specimens. In PASC patients, an increased proportion of squamous cell carcinoma components was associated with aggressive behavior and a worse prognosis. This was due to the high MIB-1 positivity rate of squamous cell carcinoma components.

Abstract A032: KRAS mutations have distinct effects on the tumor immune microenvironment in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with abysmal survival rates. The highly immunosuppressive microenvironment of PDAC poses a major barrier to effective therapy. KRAS mutations are near-ubiquitous in PDAC, and studies indicate clinical outcomes vary depending on the specific KRAS genotype. Given that tumor genotype can shape the immune cell composition of tumors, we examined the immune cell composition of pancreatic tumors with specific KRAS mutations, focusing on KRASG12D mutations (representing 40% of PDAC cases which have the worst prognosis) and KRASG12R mutations (which make up 20% of PDAC cases and have a better prognosis). Orthotopically implanted Kras G12R/+ ;Trp53 KO mouse pancreatic tumors have a distinct immune profile in comparison to Kras G12D/+ ;Trp53 KO tumors, characterized by an influx of intratumoral CD3+ T cells and mature dendritic cells. Selective depletion of CD4+ T cells induces a rapid progression in KRASG12R, but not KRASG12D mouse tumors. RNA sequencing of KRASG12R tumor cells revealed enrichment of Type I interferon (IFN) pathways accompanied by related chemokines, CXCL9 and CXCL10 in comparison to KRASG12D tumors. Analysis of publicly available human PDAC cohorts revealed enrichment of genes in inflammatory pathways in KRASG12R tumors. Collectively, these data link the KRASG12R mutation to an immunogenic role that is distinct from KRASG12D tumors. Citation Format: Andrew Wenger, Tal Baron, Adrian Vega-Perez, Whitney Sisso, Maria Paz Zafra, Lukas Dow, Despina Siolas. KRAS mutations have distinct effects on the tumor immune microenvironment in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A032.

Integrative analysis of single-cell and bulk multi-omics data to reveal subtype-specific characteristics and therapeutic strategies in clear cell renal cell carcinoma patients.

Background: Kidney renal clear cell carcinoma (KIRC) is the most prevalent subtype of malignant renal cell carcinoma and is well known as a common genitourinary cancer. Stratifying tumors based on heterogeneity is essential for better treatment options. Methods: In this study, consensus clusters were constructed based on gene expression, DNA methylation, and gene mutation data, which were combined with multiple clustering algorithms. After identifying two heterogeneous subtypes, we analyzed the molecular characteristics, immunotherapy response, and drug sensitivity differences of each subtype. And we further integrated bulk data and single-cell RNA sequencing (scRNA-Seq) data to infer the immune cell composition and malignant tumor cell proportion of subtype-related cell subpopulations. Results: Among the two identified consensus subtypes (CS1 and CS2), CS1 was enriched in more inflammation-related and oncogenic pathways than CS2. Simultaneously, CS1 showed a worse prognosis and we found more copy number variations and BAP1 mutations in CS1. Although CS1 had a high immune infiltration score, it exhibited high expression of suppressive immune features. Based on the prediction of immunotherapy and drug sensitivity, we inferred that CS1 may respond poorly to immunotherapy and be less sensitive to targeted drugs. The analysis of bulk data integrated with single-cell data further reflected the high expression of inhibitory immune features in CS1 and the high proportion of malignant tumor cells. And CS2 contained a large number of plasmacytoid B cells, presenting an activated immune microenvironment. Finally, the robustness of our subtypes was successfully validated in four external datasets. Conclusion: In summary, we conducted a comprehensive analysis of multi-omics data with 10 clustering algorithms to reveal the molecular characteristics of KIRC patients and validated the relevant conclusions by single-cell analysis and external data. Our findings discovered new KIRC subtypes and may further guide personalized and precision treatments.

Prognostic factors for intraductal papillary neoplasm of the bile duct following surgical resection: a systematic review and meta-analysis.

Intraductal papillary neoplasm of the bile duct (IPNB) is a biliary neoplasm characterized by intraductal papillary growth and varying degrees of malignant transformation. This study aimed to identify effective prognostic factors (PFs) for predicting the prognosis of IPNB after surgical resection, addressing the gap in the higher level evidence. We systematically searched databases from their inception to October 10, 2023. Data on 12 predetermined PFs were collected and subjected to a meta-analysis. Forest plots were used to summarize the findings. Fifteen studies with a total of 2311 patients were included. Among the PFs examined, extrahepatic tumor location (HR, 2.97; 95% CI 1.68-5.23), subclassification type 2 (HR, 2.62; 95% CI 1.45-4.76), R1 resection (HR, 2.47; 95% CI 1.73-3.51), elevated CA19-9 level (HR, 3.25; 95% CI 1.91-5.54), tumor multiplicity (HR, 2.65; 95% CI 1.40-5.02), and adjacent organ invasion (HR, 3.17; 95% CI 2.01-5.00) were associated with a poorer prognosis. Additionally, the combined HR values indicated that lymph node metastasis and poor tumor differentiation were linked to a worse prognosis, although both exhibited significant heterogeneity. Our study offers valuable insights for enhancing postoperative prognostication and treatment decision-making for IPNB patients with IPNB. These findings warrant further validation in future prospective studies.

H3K27 Acetylation-Activated GLDC Accelerated the Advancement of Oral Squamous Cell Carcinoma by Suppressing the p53 Signaling Pathway.

Glycine decarboxylase (GLDC) has been identified to be dysregulated and plays pivotal roles in various cancers. Besides, studies have suggested that GLDC expression is elevated in oral squamous cell carcinoma (OSCC) and associated with a worse prognosis, but the precise role and molecular mechanism of GLDC in OSCC remain unexplored. The current study first confirmed the high expression of GLDC in OSCC and its correlation with worse survival in patients with OSCC. By knocking down GLDC, it was discovered that the growth and colony formation of OSCC cells, as well as the development of xenograft tumors, were effectively suppressed. In addition, GLDC deficiency inhibited the migration and invasion of OSCC cells in vitro through regulating EMT markers and attenuated lung metastasis in vivo. Mechanistically, GLDC was found to affect the activity of the p53 signaling pathway. GLDC depletion retarded the progression of OSCC by activating the p53 signaling pathway. Moreover, p300 co-functioned with TFAP2A to induce acetylation of GLDC, which resulted in the upregulation of GLDC in OSCC. To conclude, acetylation-induced GLDC upregulation facilitated the tumorigenesis and metastasis of OSCC by its inhibition of the activity of the p53 signaling pathway.

Hepcidin Modulators: A Potential Alternative Treatment of Iron Deficiency and Iron Deficiency Anemia in Heart Failure

Heart failure affects roughly 6.7 million Americans and is associated with many comorbidities and complications, including iron deficiency and anemia. Iron homeostasis is integral to optimal body function. Hepcidin, a hepatically produced peptide, is a major modulator in iron homeostasis. Its synthesis is induced in part by inflammatory states. Iron deficiency in heart failure is currently diagnosed with the assessment of serum ferritin and percent of transferrin saturation. Iron deficiency in the setting of hepcidin excess in inflammatory conditions, such as heart failure, is discussed in this literature review. Iron deficiency is associated with worse prognosis and poorer outcomes in heart failure patients. Targeted treatment of iron deficiency and iron deficiency anemia may provide improved quality of life and decrease mortality and morbidity among heart failure patients. Current treatment options for iron deficiency and anemia include intravenous and oral iron supplementation, as well as other erythropoiesis-stimulating agents. However, concerns regarding safety have been raised in regards to these options. An emerging possibility for the treatment of iron deficiency in the setting of hepcidin overload is hepcidin modulators, including hepcidin antagonists or inhibitors. This review has addressed iron deficiency and anemia in heart failure and suggests that hepcidin antagonists/inhibitors may provide a viable alternative to the classic treatment methods.

Assessment of anti-CD69 antibody therapy alone or in combination with anti-PD-1 in murine GBM

ABSTRACT Background Glioblastoma (GBM) is an aggressive cancer with limited treatment options. Immunotherapy targeting CD69, an early activation marker on T cells, has shown promise in preclinical models of non-CNS malignancies. This study investigates anti-CD69 therapy alone or in combination with anti-PD-1 in a preclinical GBM model. Research design and methods CD69 expression in GBM patient tissues was analyzed using the TCGA database. Therapeutic efficacy of anti-CD69 was tested in a murine GBM model with different regimens. Immune cell populations in the tumor microenvironment (TME) were assessed by flow cytometry. Results Increased CD69 expression was observed in GBM patients compared to normal brain tissue and was associated with worse prognosis. Anti-CD69 treatment reduced percentages of CD69+ immune cells but did not improve survival in GBM-bearing mice. Increased PD-1 expression on NK cells was observed following anti-CD69 treatment. Anti-CD69 treatment was not improved by the addition of anti-PD-1 in vivo. Conclusions This is the first study evaluating anti-CD69 therapy in a preclinical GBM model. Despite promising preclinical data in other cancers, anti-CD69 monotherapy or combination therapy with anti-PD-1 did not improve survival in this GBM model.

The immunological and prognostic significance of the diabetes mellitus-related gene WFS1 in endometrial cancer.

Diabetes is associated with the incidence and prognosis of various malignancies, most notably endometrial cancer (EC). This study investigated the connection between diabetes and EC, with a specific focus on elucidating the biological implications of the diabetes mellitus (DM)-related gene WFS1. Using the CTD, GeneCards, and GSEA databases, we identified WFS1 as a diabetes-related gene and then conducted an extensive investigation focusing on WFS1 in the context of EC. First, we identified WFS1 as the target gene and obtained EC data from the TCGA database. Then, comprehensive analyses and verification experiments, including differential expression analysis, prognostic modeling, functional enrichment analysis, gene mutation profiling, assessment of immune cell infiltration, immunophenoscore (IPS), tumor stemness index scoring, drug sensitivity analysis, single-cell transcriptomic analysis, glycolytic pathway analysis, and clinical verification, were performed to comprehensively evaluate the clinical value of WFS1 in EC. The EC group had significantly lower WFS1 expression, with an AUC of 0.857 for the ROC diagnostic curve. Overall survival analysis revealed that WFS1 was an independent risk factor for EC; low WFS1 expression was correlated with a poor prognosis. Stemness index analysis revealed that decreased WFS1 expression was associated with increased tumor grade and enhanced tumor stemness, suggesting increased malignancy of EC. In addition, WFS1 expression was correlated with tumor microenvironment features such as immune cell infiltration. WFS1 was also associated with tumor drug resistance. EC patients with low WFS1 expression have a worse prognosis. WFS1 can be used as diagnostic and prognostic marker for EC.

Epitope Spreading in Immune-Mediated Glomerulonephritis: The Expanding Target

Epitope spreading is a critical mechanism driving the progression of autoimmune glomerulonephritis. This phenomenon, where immune responses broaden from a single epitope to encompass additional targets, contributes to the complexity and severity of diseases such as membranous nephropathy (MN), lupus nephritis (LN), and ANCA-associated vasculitis (AAV). In MN, intramolecular spreading within the phospholipase A2 receptor correlates with a worse prognosis, while LN exemplifies both intra- and intermolecular spreading, exacerbating renal involvement. Similarly, ANCA reactivity in AAV highlights the destructive potential of epitope diversification. Understanding these immunological cascades reveals therapeutic opportunities—targeting early epitope spreading could curb disease progression. Despite promising insights, the clinical utility of epitope spreading as a prognostic tool remains debated. This review provides a complete overview of the current evidence, exploring the dual-edged nature of epitope spreading, the intricate immune mechanisms behind it, and its therapeutic implications. By elucidating these dynamics, we aim to pave the way for more precise, targeted interventions in autoimmune glomerular diseases.

Posttraumatic Stress Disorder and Substance Use Disorder Screening, Assessment, and Treatment.

We review prevalence, etiology, impact on treatment, and best practices for treatment of posttraumatic stress disorder (PTSD) in a substance use disorder (SUD) treatment setting. Recommendations are given related to screening, assessment, and symptom monitoring. PTSD and SUDs are highly comorbid. This comorbidity is associated with higher acuity, more difficulty completing treatment, and worse prognosis. Integrated treatment is recommended, and trauma-focused psychotherapies combined with pharmacotherapy show particular promise. PTSD is highly prevalent in substance using samples, negatively impacting treatment course and worsening prognosis. This comorbidity has been explained by a variety of models, with self-medication having garnered the most support. Trauma-focused psychotherapies combined with pharmacotherapy demonstrate the most efficacy and are recommended when treating co-occurring SUDs and PTSD. Specifically, prolonged exposure (PE), concurrent treatment of PTSD and SUDs using PE (COPE), and cognitive processing therapy (CPT) have been seen as promising trauma-focused treatments. Investigations into ways to best augment therapy are also underway, both through treatment format and neuromodulation. Several recommendations are given.

Light Chain Multiple Myeloma: A Case of Distinctive Presentations

Multiple Myeloma (MM) is a malignancy of immunoglobulin-producing plasma cells. Lambda Light Chain Multiple Myeloma (LCMM) is a less common type of MM with a more aggressive course, which presents a diagnostic challenge due to the absence of typical M-spike on screening and unspecific manifestations. This case presented an initially misdiagnosed patient, who had an uncommon light chain pattern on electrophoresis, atypical plasmocytes in bone marrow smear, particular complications and risks associated with LCMM, and a worse prognosis.

MUC5B rs35705950 Promoter Variant Is Associated with Usual Interstitial Pneumonia in Patients with Antisynthetase Syndrome

Background: The presence of the rs35705950 variant in the MUC5B gene promoter is a critical genetic risk factor in idiopathic pulmonary fibrosis (IPF). It has been associated with usual interstitial pneumonia (UIP) in several interstitial lung diseases (ILDs). In antisynthetase syndrome (ASSD), most high-resolution computed tomography (HRCT) patterns are inflammatory, but up to 13% have UIP, leading to a worse prognosis. Methods: This single-center study included 60 patients with ASSD-ILD. We investigated whether carrying the MUC5B rs35705950 promoter variant was associated with UIP. To estimate the strength of the association between the genotype of the MUC5B rs35705950 promoter variant and the fibrotic pattern we used the odds ratio (cOR), and to assess the effect of confounding variables (age, evolution time, and sex), we performed a logistic regression to obtained the adjusted odds ratio (aOR). Results: The GT genotype of the MUC5B rs35705950 promoter variant is associated with up to a 4-fold increased risk of UIP (cOR 5.0, 95% CI 1.13–22.10), and the effect was even maintained after adjusting for potentially confounding variables such as sex, age, and time to progression (aOR 5.2, 95% CI 1.04–25.89). Conclusions: our study supports the role of MUC5B rs35705950 in ASSD-ILD with UIP. It reinforces that this polymorphism in our population could have a similar genetic basis to that already described in other ILDs that present predominantly fibrotic patterns.

MGMT METHYLATION AND ITS PROGNOSTIC SIGNIfiCANCE IN INOPERABLE IDH WILDTYPE GLIOBLASTOMA: A SIX-YEAR REVIEW AT A TERTIARY NEURO-ONCOLOGY CENTER

Abstract AIMS IDH wild-type glioblastoma has the worst prognosis among glioma patients. The methylation of the O6- Methylguanine-DNA Methyltransferase (MGMT) gene is a valid biomarker for predicting response to therapy with alkylating agents and, independently, prognosis. Patients undergoing biopsy only without subsequent treatment have poor prognosis. We aimed to study the survival impact of MGMT methylation in this subset of patients. METHOD We collected six-year retrospective (2017-2023) data at a tertiary neuro-oncology center for patients undergoing biopsy as the only surgical procedure for an unresectable IDH wildtype glioblastoma. Data was collected from patient records including neuro-oncology MDT documentation. Patients were grouped into four categories according to different types of treatment received after biopsy (biopsy only, Biopsy + chemotherapy(CT), biopsy + radiotherapy(RT), biopsy + complete/incomplete STUPP, biopsy + STUPP + 2nd Line). Analysis was performed in python and R statistical software. Survival analysis was performed with Kaplan-Meier Analysis in python. RESULTS 166 glioblastoma IDH wildtype patients were included in the study with mean age of 62.5 years (M: F = 1.5: 1). 50% (n=83) patients had unmethylated MGMT status (0-5%), 29.5% (n=49) patients had methylated MGMT status (>15%) and 19.2% (n=32) patients had borderline methylated MGMT status (5-15%). 21%(n=35) patients did not receive any treatment post biopsy,, 6.6% (n=11) received CT only, 15% (n=25) RT only, 27% (n= 45) complete/incomplete STUPP therapy, whereas 13.2% (n=22) received STUPP therapy along with second line treatment. In biopsy only group, there was no notable difference in survival outcomes among the different methylation statuses. For biopsy and any-other-form-of-treatment groups showed a distinct trend of better survival compared to the borderline or unmethylated groups. Overall, methylated patients had better survival as compared to unmethylated or borderline groups. CONCLUSION Methylated MGMT status is a predictor for better overall survival in unresectable IDH wildtype glioblastoma patients undergoing biopsy and treatment.

Clinical features and surgical treatments of neurofibromas associated with neurofibromatosis type 1

To explore the clinical features, surgical treatment, and effectiveness of neurofibromas associated with neurofibromatosis type 1 (NF1). A clinical data of 41 patients with NF1 admitted between December 2018 and April 2024 was retrospectively analyzed. There were 15 males and 26 females, with an average age of 27.5 years (range, 5-61 years). Only one type of neurofibroma existed in 3 patients and the rest of the patients had more than two types of neurofibromas. Fourteen patients had total resection of multiple cutaneous neurofibromas (CNF). Eighteen patients of diffuse neurofibromas underwent total, near-total, or subtotal resection. Among the 13 patients of localized nodular neurofibromas, 9 of benign tumors underwent total sub-capsular resection and 4 of malignant peripheral nerve sheath tumor (MPNST) underwent maginal resection, and only 1 underwent postoperative radiotherapy and chemotherapy. Among the 15 patients of plexiform neurofibromas (PNF), 5 patients underwent both superficial and deep PNF resection, 2 underwent the superficial PNF resection, and 8 underwent the large nodular lesions in the deep PNF resection. There were 8 MPNST, of which 7 cases underwent total sub-capsular resection and large tumor capsule resection under neurophysiological monitoring, and 1 case with the tumor located on the top of the head underwent wide resection and skin grafting. One patient underwent proton knife therapy after surgery, 2 patients did not receive radiotherapy, and the remaining patients received conventional radiotherapy. All patients were followed up after surgery, and the follow-up time was 3-66 months, with an average of 25.0 months. Patients with CNF recovered satisfactorily after surgery, and there was no recurrence during follow-up. Patients with diffuse neurofibromas relieved preoperative symptoms after surgery. Three patients with diffuse neurofibromas located in the head and face recurred during follow-up. The patients with benign localized nodular neurofibromas recovered well after surgery, and only 1 patient had transient regional neuralgia after surgery. Among the patients with MPNST, 2 patients died of recurrence and lung metastasis, while the remaining 2 patients had no recurrence and metastasis during follow-up. All preoperative symptoms disappeared in patients with benign PNF, and no tumor recurrence was observed during follow-up. Two patients with PNF located in the brachial plexus had difficulty in shoulder abduction after surgery, 1 patient with PNF located in vagus developed hoarseness after surgery. Among the 8 patients with MPNST in PNF, 1 died of lung metastases and 1 died of systemic failure. The remaining 6 patients were in stable condition during follow-up, and no tumor recurrence or metastasis was observed. According to the clinical features of neurofibromas in patients with NF1, choosing appropriate surgical approaches can obtain good effectiveness. Because of the difficulty of completely resection, diffuse neurofibromas, especially those located in the head and face, are prone to recurrence after surgery. MPNST has the worst prognosis, high incidence of recurrence/metastasis, and short survival period. Total resection combined with radiotherapy can decrease local recurrence.

A case of isolated cutaneous myeloid sarcoma preceding acute myeloid leukemia and literature review

Isolated Cutaneous Myeloid Sarcoma (icMS) and Aleukemic Leukemia Cutis (ALC) are cutaneous extramedullary manifestations of leukemia in which leukemic cells infiltrate the skin before they can be identified either in the peripheral blood or in the bone marrow. We report the case of a 67-year-old patient who presented with a rapidly developing cutaneous tumour and scaly, erythematous-squamous plaques. Isolated Cutaneous Myeloid Sarcoma was diagnosed which rapidly progressed to terminal-stage Acute Myeloid Leukemia (AML). To highlight the disease characteristics of the adult-onset icMS and ALC cases that preceded AML we additionally compiled the pertinent literature of case reports of these rare conditions. We identified n=15 previously published icMS/ALC cases with adequately detailed clinical data descriptions. We could confirm the medical experience that icMS/ALC patients have an overall worse prognosis. Moreover, we could identify FAB M5 AML subtype as a significant adverse prognosticator of these patients.

The Prognostic Impact of Plasma Cell Chromosome 17 Abnormality Percentage Cut-offs on Patient Outcomes in Multiple Myeloma

Abstract Abnormalities in chromosome 17 encompassing the TP53 locus [deletion of the small arm {del (17p)} and monosomy 17] as identified by fluorescent in-situ hybridization (FISH), are a well-established adverse prognostic factor in multiple myeloma (MM). Previous research suggested that higher percentages of these chromosome 17 abnormalities correlate with worse prognoses, proposing various cutoff points to assess this relationship, ranging between 50-60%. Of note, these studies employed extensive plasma cell enrichment protocols and often included only cases with high plasma cell percentages (70-90%). Our study aims to investigate the relationship between the percentage of plasma cells with chromosome 17 abnormalities and patient outcomes at the time of acquisition of the abnormality, scrutinizing various cut-off points for prognostic significance. We retrospectively reviewed 339 MM patients at our institution, including newly diagnosed and relapsed cases, examining chromosome 17 abnormality levels identified by FISH on bone marrow specimens. After CD138 magnetic bead enrichment, 50 nuclei were scored for these abnormalities and the percentage calculated. It is important to note that the precise percentage of plasma cells in the sample was not quantified. We analyzed survival outcomes across different percentage cut-off points (20%, 40%, 50%, 55%, 60%, and 80%) using Kaplan Meier analysis and log-rank tests. Significant differences in median survival were noted at the 40% and 50% cut-offs. Patients with >40% chromosome 17 abnormalities showed a median survival of 17.5 months compared to 25.8 months for those with ≤40% (p<0.05), an absolute difference of 8.3 months. Similarly, the >50% group had a median survival of 19.4 months versus 24.3 months in the ≤50% group (p<0.05), with an absolute difference of 4.9 months. However, these differences, while statistically significant, may not be clinically substantial. Furthermore, a 55% cut-off did not yield a significant survival difference (23.5 months vs. 19.8 months for ≤55% and >55% groups, p>0.05) in our cohort. Our findings confirm some prognostic value of chromosome 17 abnormality levels in MM but suggest that the absolute differences in median survival at certain cut-offs, based on the test as performed in our laboratory, might not be clinically impactful. This may be due to differences in the proportion of non-plasma cells within the samples being scored, resulting in ambiguity when interpreting FISH results. Future research should aim to improve the consistency of plasma cell enrichment, develop approaches to score only plasma cells, establish risk-specific cut-offs, and explore the relationship between chromosome 17 abnormality levels, treatment response, and overall significance. The study raises important questions about the necessity of stratifying patients based on chromosome 17 abnormality levels versus simply detecting their presence for prognostic assessment.

Clinical significance of upregulated Rho GTPase activating protein 12 causing resistance to tyrosine kinase inhibitors in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major health challenge with high incidence and poor survival rates in China. Systemic therapies, particularly tyrosine kinase inhibitors (TKIs), are the first-line treatment for advanced HCC, but resistance is common. The Rho GTPase family member Rho GTPase activating protein 12 (ARHGAP12), which regulates cell adhesion and invasion, is a potential therapeutic target for overcoming TKI resistance in HCC. However, no studies on the expression of ARHGAP12 in HCC and its role in resistance to TKIs have been reported. To unveil the expression of ARHGAP12 in HCC, its role in TKI resistance and its potential associated pathways. This study used single-cell RNA sequencing (scRNA-seq) to evaluate ARHGAP12 mRNA levels and explored its mechanisms through enrichment analysis. CellChat was used to investigate focal adhesion (FA) pathway regulation. We integrated bulk RNA data (RNA-seq and microarray), immunohistochemistry and proteomics to analyze ARHGAP12 mRNA and protein levels, correlating with clinical outcomes. We assessed ARHGAP12 expression in TKI-resistant HCC, integrated conventional HCC to explore its mechanism, identified intersecting FA pathway genes with scRNA-seq data and evaluated its response to TKI and immunotherapy. ARHGAP12 mRNA was found to be highly expressed in malignant hepatocytes and to regulate FA. In malignant hepatocytes in high-score FA groups, MDK-[integrin alpha 6 (ITGA6) + integrin β-1 (ITGB1)] showed specificity in ligand-receptor interactions. ARHGAP12 mRNA and protein were upregulated in bulk RNA, immunohistochemistry and proteomics, and higher expression was associated with a worse prognosis. ARHGAP12 was also found to be a TKI resistance gene that regulated the FA pathway. ITGB1 was identified as a crossover gene in the FA pathway in both scRNA-seq and bulk RNA. High expression of ARHGAP12 was associated with adverse reactions to sorafenib, cabozantinib and regorafenib, but not to immunotherapy. ARHGAP12 expression is elevated in HCC and TKI-resistant HCC, and its regulatory role in FA may underlie the TKI-resistant phenotype.

De-Differentiated Metastatic Melanoma: A Diagnostic Challenge

Abstract Introduction/Objective Melanoma is one of the common malignant neoplasms with several histological appearances. Its diagnosis is usually based on histomorphologic findings and immunohistochemistry (IHC). De-differentiated melanoma (DM) is a special form of malignant melanoma with different histo-morphologic and immunohistochemical characteristics than conventional malignant melanomas. It has a worse prognosis and can impose a diagnostic challenge. Methods/Case Report A 62-year-old male previously had melanoma on his chest, which was surgically removed with negative margins and no involvement of nearby sentinel lymph nodes. The patient presented two months later with a rapidly enlarging mass in the right axillary region. Subsequent lymph node dissection revealed several nodes, the largest measuring 14 cm with extensive necrosis. Microscopic examination of the largest mass revealed clusters of irregularly shaped cells displaying marked nuclear abnormalities, prominent nucleoli, and heightened mitotic activity. Immunohistochemical analysis of this mass showed negative results for SOX-10, HMB45, Melan-A, S100 protein, CAM5.2, BRAF, and myogenin. Conversely, the remaining lymph nodes exhibited typical signs of melanoma metastasis, expressing relevant melanoma markers. Given the patient’s history of melanoma and the presence of metastatic melanoma in nearby lymph nodes, the histological and immunohistochemical findings support the diagnosis of dedifferentiated cutaneous metastatic melanoma. Results (if a Case Study enter NA) N/A Conclusion The distinctive appearance and lack of typical markers in this type of melanoma pose considerable difficulties in distinguishing it from other malignancies like poorly differentiated carcinomas and high-grade sarcomas. Furthermore, dedifferentiated melanoma tends to be highly aggressive, often resisting standard and immunological treatments. Therefore, comprehensive clinical and histomorphological assessments are crucial for accurately diagnosing these complex and challenging cases.

Integrating clinical and genomic landscape analysis of perineural invasion identify ACTA1 as an oncogene for oral squamous cell carcinoma.

Perineural invasion (PNI) has been shown to be a key pathological feature of several types of cancer, including oral squamous epithelial carcinoma (OSCC). However, the overall clinical and genomic landscape of PNI+ OSCC are still unclear, and the molecular mechanism of PNI remains to be further investigated. 279 OSCC samples were extracted from the TCGA database and grouped according to PNI. The clinicopathological information, prognostic and survival analyses were performed. The Cibersort algorithm and ESTIMATE algorithm was used to estimate the impacts on proportion of immune cells, immune score and stromal score by PNI. Immunotherapy prediction analysis was also performed. 167 differentially expressed genes were screened for functional enrichment analysis. Actin α1 (ACTA1) protein, which was significantly upregulated in the PNI+ group, was selected for validation in our OSCC patient's cohort (n = 70). We next analyzed the ratio and absolute number of key immunocytes in peripheral blood of OSCC patients according to Actin α1 expression by flow cytometry. PNI was more likely to occur in patients with advanced tumors and worse prognosis. Immunomodulation analyses showed that T cells follicular helper and cells were significantly lower, but M2 macrophages and total stromal score was significantly higher in PNI+ OSCC. Immunotherapy prediction analyses showed that PNI+ OSCC may be more sensitive to CTLA4 inhibitor treatment. 167 differentially expressed genes were identified and enriched in muscle structure and cell movement-related pathway. Among them, Actin α1 (ACTA1) was significantly upregulated in PNI+ advanced OSCC with worse clinical outcome whose had relatively low ratio of CD3+CD8+ circulating cytotoxic T cells. PNI+ OSCC patients with upregulated of Actin α1 could benefit from cytotoxic T cell-mediated immunotherapy.

The dyslipidemic effect of cytostatics in the treatment of early breast cancer as a serious risk factor of cardiovascular diseases.

The development of highly effective anti-cancer therapies over the past several decades has dramatically changed the situation of patients with malignant tumor disease, who currently achieve a high rate of cure in the early stages of the disease. Despite tremendous progress, chemotherapy remains the primary treatment modality for early breast cancer. However, chemotherapy-related complications have a major impact on cardiovascular morbidity and mortality in this group of patients. Almost 80% of women diagnosed with breast cancer are over 50 years of age and already have risk factors for cardiovascular disease, such as age, family history, hypertension, elevated cholesterol, smoking, diabetes, and elevated body mass index. Most breast cancer patients do not die and, in line with the general population, cardiovascular disease remains the most common cause of death. Clinical research, extensive retrospective analyzes and prospective works describe the dyslipidemic effect of cytostatics, which may predispose to the development of atherosclerotic cardiovascular diseases. The administration of neoadjuvant or adjuvant chemotherapy based on anthracyclines and taxanes can lead to an increase in total cholesterol, triacylglycerides, LDL cholesterol and a decrease in HDL cholesterol. Abnormally high concentrations of lipids in the blood represent one of the main risk factors for the development and progression of cardiovascular diseases. The works also indicate a correlation between serum lipid levels and the rate of achieving pathological complete remission after the administration of neoadjuvant chemotherapy. Dyslipidemia is associated with a worse prognosis in breast cancer patients treated with neoadjuvant chemotherapy. The aim of the thesis is to point out the dyslipidemic effects of cytostatics and the risks of atherosclerotic cardiovascular diseases in breast cancer patients who have undergone adjuvant or neoadjuvant chemotherapy for early breast cancer. The identification of cardiovascular risk factors at the beginning of oncological treatment, the monitoring of the lipid spectrum during the treatment and the timely intervention of dyslipidemia treatment escape attention at present.