ABSTRACT
BACKGROUND: Advanced pancreatic adenocarcinoma lacks effective treatment options, and systemic gemcitabine-based chemotherapy offers only marginal survival benefits at the cost of significant toxicities and adverse events. New therapeutic options with better drug availability are warranted. This study aims to evaluate the safety and efficacy of digital subtraction angiography (DSA)-guided pancreatic arterial infusion (PAI) versus intravenous chemotherapy (IVC) using the gemcitabine and oxaliplatin (GEMOX) regimen in unresectable locally advanced or metastatic pancreatic cancer (PC) patients. MATERIALS AND METHODS: This study prospectively enrolled 51 eligible treatment-naive patients with unresectable PC to receive GEMOX treatment via PAI or IVC (1:1 ratio randomization) from December 2015 to December 2019. Cycles were repeated monthly, and each process consisted of two treatments administered bi-weekly. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), 1-year survival, 6-month survival, tumor-site subgroup survival, and incidences of adverse events were compared. RESULTS: The median OS of the PAI and IVC groups were 9.93 months and 10.07 months, respectively (p = 0.3049). The median PFS of the PAI and IVC groups were 5.07 months and 4.23 months (p = 0.1088). No significant differences were found in the ORR (11.54% vs. 4%, p = 0.6312), DCR (53.85% vs. 44%, p = 0.482), and 1-year OS rate (44% vs. 20.92%, p = 0.27) in PAI and IVC groups. The 6-month OS rate was significantly higher in the PAI group (100%) than in the IVC group (83.67%) (p = 0.0173). The median OS of patients in PAI group with pancreatic head and neck tumors were significantly higher than those of body and tail tumors (12.867 months vs. 9 months, p = 0.0214). The incidences of hematologic disorders, liver function disorders, and digestive disorders in the IVC group were higher than in the PAI group (p < 0.05). CONCLUSION: GEMOX PAI therapy presented a higher 6-month OS rate and fewer adverse events than IVC in advanced pancreatic adenocarcinoma patients. Those with pancreatic head and neck tumors may yield a superior treatment outcome from PAI treatment. TRIAL REGISTRATION NUMBER: NCT02635971. DATE OF REGISTRATION: 21/12/2015.
Subject(s)
Adenocarcinoma , Angiography, Digital Subtraction , Antineoplastic Combined Chemotherapy Protocols , Deoxycytidine , Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/mortality , Male , Female , Middle Aged , Deoxycytidine/analogs & derivatives , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Adenocarcinoma/drug therapy , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Infusions, Intra-Arterial , Adult , Prospective Studies , Oxaliplatin/administration & dosage , Oxaliplatin/adverse effects , Gemcitabine , Infusions, Intravenous , Pancreas/pathology , Pancreas/diagnostic imaging , Organoplatinum CompoundsABSTRACT
Objective: This study aimed to develop and validate a survival prediction model and nomogram to predict survival in patients with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma undergoing treatment with anti-programmed cell death 1 receptor (PD-1). This model incorporates immune-related adverse events (irAEs) alongside common clinical characteristics as predictive factors. Method: A dataset comprising 255 adult patients diagnosed with advanced G/GEJ adenocarcinoma was assembled. The irAEs affecting overall survival (OS) to a significant degree were identified and integrated as a candidate variable, together with 12 other candidate variables. These included gender, age, Eastern cooperative oncology group performance status (ECOG PS) score, tumor stage, human epidermal growth factor receptor 2 (HER2) expression status, presence of peritoneal and liver metastases, year and line of anti-PD-1 treatment, neutrophil-to-lymphocyte ratio (NLR), controlling nutritional status (CONUT) score, and Charlson comorbidity index (CCI). To mitigate timing bias related to irAEs, landmark analysis was employed. Variable selection was performed using the least absolute shrinkage and selection operator (LASSO) regression to pinpoint significant predictors, and the variance inflation factor was applied to address multicollinearity. Subsequently, a Cox regression analysis utilizing the forward likelihood ratio method was conducted to develop a survival prediction model, excluding variables that failed to satisfy the proportional hazards (PH) assumption. The model was developed using the entire dataset, then internally validated through bootstrap resampling and externally validated with a cohort from another Hospital. Furthermore, a nomogram was created to delineate the predictive model. Results: After consolidating irAEs from the skin and endocrine systems into a single protective irAE category and applying landmark analysis, variable selection was conducted for the prognostic prediction model along with other candidate variables. The finalized model comprised seven variables: ECOG PS score, tumor stage, HER2 expression status in tumor tissue, first-line anti-PD-1 treatment, peritoneal metastasis, CONUT score, and protective irAE. The overall concordance index for the model was 0.66. Calibration analysis verified the model's accuracy in aligning predicted outcomes with actual results. Clinical decision curve analysis indicated that utilizing this model for treatment decisions could enhance the net benefit regarding 1- and 2-year survival rates for patients. Conclusion: This study developed a prognostic prediction model by integrating common clinical characteristics of irAEs and G/GEJ adenocarcinoma. This model exhibits good clinical practicality and possesses accurate predictive ability for overall survival OS in patients with advanced G/GEJ adenocarcinoma.
Subject(s)
Adenocarcinoma , Immune Checkpoint Inhibitors , Nomograms , Stomach Neoplasms , Humans , Male , Female , Middle Aged , Aged , Adenocarcinoma/drug therapy , Adenocarcinoma/mortality , Adenocarcinoma/immunology , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/adverse effects , Stomach Neoplasms/drug therapy , Stomach Neoplasms/mortality , Stomach Neoplasms/immunology , Adult , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/mortality , Esophageal Neoplasms/immunology , Prognosis , Aged, 80 and overABSTRACT
Background: Gallbladder mixed neuroendocrine-non-neuroendocrine neoplasm generally consists of a gallbladder neuroendocrine tumor and a non-neuroendocrine component. The World Health Organization (WHO) in 2019 established a guideline requiring each component, both neuroendocrine and non-neuroendocrine, to account for a minimum of 30% of the tumor mass. Methods: Patients after surgery resection and diagnosed at microscopy evaluation with pure gallbladder neuroendocrine carcinoma (GBNEC), gallbladder mixed adeno-neuroendocrine carcinoma (GBMANEC, GBNEC≥30%), and gallbladder carcinoma mixed with a small fraction of GBNEC (GBNEC <30%) between 2010 and 2022 at West China Hospital of Sichuan University were collated for the analyses. Demographic features, surgical variables, and tumor characteristics were evaluated for association with patients' overall and recurrence-free survival (OS and RFS). Results: The study included 26 GBNEC, 11 GBMANEC, 4 gallbladder squamous-cell carcinoma (GBSCC), and 7 gallbladder adenocarcinoma (GBADC) mixed with a small fraction of GBNEC. All patients had stage III or higher tumors (AJCC8th edition). The majority of included patients (79.17%) underwent curative surgical resection (R0), with only ten patients having tumoral resection margins. In the analysis comparing patients with GBNEC percentage (GBNEC≥30% vs. GBNEC<30%), the basic demographics and tumor characteristics of most patients were comparable. The prognosis of these patients was also comparable, with a median OS of 23.65 months versus 20.40 months (P=0.13) and a median RFS of 17.1 months versus 12.3 months (P=0.24). However, patients with GBADC or GBSCC mixed with GBNEC <30% had a statistically significant decreased OS and RFS (both P<0.0001)) compared with GBNEC and GBMANEC. Patients with GBNEC who exhibited advanced tumor stages and lymphovascular invasion had a higher risk of experiencing worse overall survival (OS) and recurrence-free survival (RFS). However, a 30% GBNEC component was not identified as an independent risk factor. Conclusion: Patients with GBNEC were frequently diagnosed at advanced stages and their prognosis is poor. The 30% percentage of the GBNEC component is not related to the patient's survival.
Subject(s)
Carcinoma, Neuroendocrine , Gallbladder Neoplasms , Humans , Gallbladder Neoplasms/pathology , Gallbladder Neoplasms/mortality , Gallbladder Neoplasms/surgery , Female , Male , Middle Aged , Prognosis , Carcinoma, Neuroendocrine/pathology , Carcinoma, Neuroendocrine/mortality , Carcinoma, Neuroendocrine/surgery , Carcinoma, Neuroendocrine/diagnosis , Aged , Adult , Retrospective Studies , Adenocarcinoma/pathology , Adenocarcinoma/mortality , Adenocarcinoma/surgery , Survival RateABSTRACT
Importance: The prognosis of patients with adenocarcinoma of the esophagus and esophagogastric junction (AEG) is poor. From current evidence, it remains unclear to what extent preoperative chemoradiotherapy (CRT) or preoperative and/or perioperative chemotherapy achieve better outcomes than surgery alone. Objective: To assess the association of preoperative CRT and preoperative and/or perioperative chemotherapy in patients with AEG with overall survival and other outcomes. Data Sources: Literature search in PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and International Clinical Trials Registry Platform was performed from inception to April 21, 2023. Study Selection: Two blinded reviewers screened for randomized clinical trials comparing preoperative CRT plus surgery with preoperative and/or perioperative chemotherapy plus surgery, 1 intervention with surgery alone, or all 3 treatments. Only data from participants with AEG were included from trials that encompassed mixed histology or gastric cancer. Among 2768 initially identified studies, 17 (0.6%) met the selection criteria. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed for extracting data and assessing data quality by 2 independent extractors. A bayesian network meta-analysis was conducted using the 2-stage approach. Main Outcomes and Measures: Overall and disease-free survival, postoperative morbidity, and mortality. Results: The analyses included 2549 patients (2206 [86.5%] male; mean [SD] age, 61.0 [9.4] years) from 17 trials (conducted from 1989-2016). Both preoperative CRT plus surgery (hazard ratio [HR], 0.75 [95% credible interval (CrI), 0.62-0.90]; 3-year difference, 105 deaths per 1000 patients) and preoperative and/or perioperative chemotherapy plus surgery (HR, 0.78 [95% CrI, 0.64-0.91]; 3-year difference, 90 deaths per 1000 patients) showed longer overall survival than surgery alone. Comparing the 2 modalities yielded similar overall survival (HR, 1.04 [95% CrI], 0.83-1.28]; 3-year difference, 15 deaths per 1000 patients fewer for CRT). Similarly, disease-free survival was longer for both modalities compared with surgery alone. Postoperative morbidity was more frequent after CRT plus surgery (odds ratio [OR], 2.94 [95% CrI, 1.01-8.59]) than surgery alone. Postoperative mortality was not significantly more frequent after CRT plus surgery than surgery alone (OR, 2.50 [95% CrI, 0.66-10.56]) or after chemotherapy plus surgery than CRT plus surgery (OR, 0.44 [95% CrI, 0.08-2.00]). Conclusions and Relevance: In this meta-analysis of patients with AEG, both preoperative CRT and preoperative and/or perioperative chemotherapy were associated with longer survival without relevant differences between the 2 modalities. Thus, either of the 2 treatments may be recommended to patients.
Subject(s)
Adenocarcinoma , Chemoradiotherapy , Esophageal Neoplasms , Esophagogastric Junction , Network Meta-Analysis , Stomach Neoplasms , Humans , Adenocarcinoma/therapy , Adenocarcinoma/mortality , Esophagogastric Junction/pathology , Esophageal Neoplasms/therapy , Esophageal Neoplasms/mortality , Chemoradiotherapy/methods , Stomach Neoplasms/therapy , Stomach Neoplasms/mortality , Stomach Neoplasms/drug therapy , Male , Preoperative Care/methods , Middle Aged , Female , Aged , Disease-Free SurvivalABSTRACT
PURPOSE: Neuroendocrine carcinoma of the cervix (NECC) is rare but results in poor prognosis. The causes of death (CODs) in NECC patients are rarely reported. Our study aimed to explore the distributions of death causes of NECC patients compared with squamous cell carcinoma (SCC) and adenocarcinoma (ADC) and to develop a validated survival prediction model. METHODS: Patients diagnosed with NECC, SCC, or ADC were identified from the Surveillance, Epidemiology, and End Results Program database from 1975 to 2019. We analyzed the standardized mortality ratio (SMR) to determine each cause of death for each survival time category. The Kaplan-Meier method was used for survival analysis. Univariate and multivariate Cox regression analyses were used to establish a nomogram model. RESULTS: A total of 358 NECC patients were included in this study, and 270 (75.4%) died during the follow-up period. Patients with NECC had 5.55 times (95% CI, 4.53-6.79, p < 0.0001) higher risk of death compared with patients with SCC and 10.38 times (95% CI, 8.28-13.01, p < 0.0001) higher compared with ADC. Cervical cancer is the main cause of death in NECC. As the diagnosis time increased, the risk of death from all causes and cervix cancer gradually decreased. While after at least 10 years of follow-up time, the highest and most dramatical SMR values were observed for metastasis (SMR, 138.81; 95% CI, 37.82-355.40; p < 0.05) and other cancers as the reason for death has an over 7-fold higher SMR (SMR: 7.07; 95% CI: 2.60-15.40, p < 0.05) more than 5 years after the cancer diagnosis. Race, FIGO stage, and surgery were independent risk factors for the overall survival (OS) of NECC patients. For the predictive nomogram, the C-index was 0.711 (95% CI: 0.697-0.725) and was corrected to 0.709 (95% CI: 0.680, 0.737) by bootstrap 1000 resampling validation. CONCLUSION: Compared with SCC and ADC, NECC patients have an elevated risk of mortality due to cervical cancer and metastasis. We successfully constructed a prognostic nomogram for patients with NECC. Based on refractoriness and high mortality of NECC, targeted treatment strategies and follow-up plans should be further developed according to the risk of death and distribution characteristics of CODs.
Subject(s)
Carcinoma, Neuroendocrine , Carcinoma, Squamous Cell , Cause of Death , Nomograms , SEER Program , Uterine Cervical Neoplasms , Humans , Female , Carcinoma, Neuroendocrine/mortality , Carcinoma, Neuroendocrine/pathology , Uterine Cervical Neoplasms/mortality , Uterine Cervical Neoplasms/pathology , Middle Aged , Prognosis , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Adult , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Aged , Kaplan-Meier EstimateABSTRACT
Gastroesophageal adenocarcinoma (GEAC) poses a significant challenge due to its poor prognosis and limited treatment options. Recently, Cancer/testis antigens (CTAs) have emerged as potential therapy targets due to their high expression in tumor cells and their immunogenic nature. We aimed to explore the expression and co-expression of CTAs in GEAC. We analyzed 63 GEAC patients initially and validated our findings in 329 patients from The Cancer Genome Atlas (TCGA) database. CTA expression was measured after RNA sequencing, while clinical information, including survival outcomes and treatment details, was collected from an institutional database. Co-expression patterns among CTAs were determined using Spearman correlation analysis. The majority of the study cohort were male (87%), Caucasian (94%), and had stage IV disease (64%). CTAs were highly prevalent, ranging from 58 to 19%. The MAGE gene family showed the highest expression, consistent across both cohorts. The correlation matrix revealed a distinct cluster of significantly co-expressed genes, including MAGEA3, NY-ESO-1, and others (0.27 ≤ r ≤ 0.73). Survival analysis revealed that individual CTAs were associated with poorer survival outcomes in patients not receiving immunotherapy while showing potential for improved survival in those undergoing immunotherapy, although these findings lacked robust reliability. Our study provides a comprehensive characterization of CTA expression and co-expression in GEAC. The strong correlation among CTAs like MAGE, NY-ESO-1, and GAGE suggests a potential for therapies targeting multiple CTAs simultaneously. Further research, including prospective trials, is warranted to assess the prognostic value of CTAs and their suitability as therapeutic targets.
Subject(s)
Adenocarcinoma , Antigens, Neoplasm , Esophageal Neoplasms , Stomach Neoplasms , Humans , Male , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adenocarcinoma/metabolism , Adenocarcinoma/mortality , Antigens, Neoplasm/genetics , Antigens, Neoplasm/metabolism , Esophageal Neoplasms/pathology , Esophageal Neoplasms/genetics , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/mortality , Stomach Neoplasms/pathology , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Stomach Neoplasms/mortality , Female , Middle Aged , Aged , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Prognosis , Gene Expression Regulation, Neoplastic , Neoplasm Proteins/genetics , Neoplasm Proteins/biosynthesis , AdultABSTRACT
Despite advances in science and technology, lung cancer remains a major public health issue. The discovery of early diagnostic and prognostic markers is still needed to reduce the mortality rate of lung cancer, which is the highest among all cancer types. Aberrations in the DNA methylation system have an important role in human cancer and are promising for the development of early diagnostic and prognostic markers. The present study focused on zinc finger protein (ZNF)577, whose encoding gene was indicated to exhibit promoter hypermethylation together with 9 other genes in lung adenocarcinoma (LADC) in a previous study by our group. ZN577 is a member of the ZNG family and its functional role has so far remained elusive. LADC tissue samples surgically resected at Tokushima University Hospital (Tokushima, Japan) between April 1999 and November 2013 were collected. A total of 73 tumors and 27 paired tumor-adjacent normal tissues were examined for DNA methylation and mRNA expression of ZNF577. A total of 149 LADC tissue samples were collected and evaluated by immunohistochemistry (IHC) for the tissue expression of ZNF577. High methylation (n=27, P<0.0001) and low mRNA expression levels (n=27, P<0.031) of ZNF577 were identified in LADC tissues, and it was demonstrated that methylation levels were inversely correlated with mRNA expression levels (P=0.0116, ρ=-0.2515). Among the LADC tissues, lepidic-patterned samples had lower methylation levels of ZNF577 than other pathological types. In addition, mRNA expression levels of ZNF577 were significantly higher in females, non-smokers and stage I samples. Overall survival [P<0.0001; area under curve (AUC)=0.8658] and disease-free survival (DFS; P<0.0004; AUC=0.7232) rates were significantly higher in the ZNF577 high mRNA expression group than in the ZNF577 low mRNA expression group. Among the 149 LADC samples examined by IHC, 105 were negative and 44 were positive for the tissue expression of ZNF577. Cox regression analysis showed poorer DFS (hazard ratio: 3.917; P=0.023) in patients with lower expression of ZNF577. In conclusion, higher methylation levels of ZNF577 were observed in LADC tissues than in normal lung tissue and low mRNA expression of ZNF577 was associated with unfavorable prognosis.
Subject(s)
Adenocarcinoma of Lung , Adenocarcinoma , Biomarkers, Tumor , DNA Methylation , Gene Expression Regulation, Neoplastic , Lung Neoplasms , RNA, Messenger , Humans , Female , Male , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/mortality , Lung Neoplasms/metabolism , Prognosis , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Adenocarcinoma of Lung/mortality , Adenocarcinoma of Lung/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adenocarcinoma/metabolism , Aged , Middle Aged , RNA, Messenger/genetics , Promoter Regions, Genetic , Adult , Aged, 80 and overABSTRACT
Introduction: Tertiary lymphoid structures (TLSs) are analogues of secondary lymphoid organs that contain various immune cells. The spatial distribution, maturation and composition of TLSs have differential effects on prognosis, and the roles of TLSs in gastric adenocarcinoma (GA) have not been revealed. Methods: Thus, we evaluated the prognostic value of TLSs in GA through analysis of bulk RNA sequencing(RNA-seq) data from public databases and validated our findings in tumour samples from the Fudan University Shanghai Cancer Center (FUSCC) cohort. The spatial distribution,maturation, and composition of TLSs in GA were analysed by reviewing H&E-stained sections and by multiplex immunofluorescence (mIF) staining. Results: We found that TLSs, especially TLSs with germinal centres (GCs) and TLSs located in the invasive margin (IM), were correlated with prolonged overall survival (OS). Second, analysis of public RNA-seq data showed that high dendritic cell (DC) scores were a favourable prognostic factor in GA patients with high scores for both TLSs and GCs. In the FUSCC cohort, DC-LAMP+ DCs weresignificantly enriched in IM-TLSs with GCs, suggesting a potential correlation between the tumour immune activation milieu and the DC abundance. Third, compared to that in TLSs without GCs, the proportion of FOXP3+CD8+ Treg cells was significantly decreased in IM-TLSs with GCs, and the percentage of PD1+CD20+ B cells was significantly increased in TLSs with GCs. Discussion: Our results demonstrate that the spatial arrangement and maturation of TLSs significantly affect prognosis and indicate that TLSs could be a new additional factor for histopathological evaluation.
Subject(s)
Adenocarcinoma , Stomach Neoplasms , Tertiary Lymphoid Structures , Humans , Stomach Neoplasms/immunology , Stomach Neoplasms/pathology , Stomach Neoplasms/mortality , Stomach Neoplasms/genetics , Tertiary Lymphoid Structures/immunology , Tertiary Lymphoid Structures/pathology , Adenocarcinoma/immunology , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Prognosis , Male , Female , Middle Aged , Dendritic Cells/immunology , Aged , Germinal Center/immunology , Germinal Center/pathology , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Tumor Microenvironment/immunologyABSTRACT
To compare the pathological results and long-term survival results of early surgery and surgery after at least one year follow-up for ground-glass component predominant lung adenocarcinoma patients. From January 1, 2013 to August 31, 2017, a total of 279 patients with ground-glass nodules (GGNs) undergoing surgical resection and pathologically proved to be pulmonary adenocarcinoma were included in this study. All patients were divided into early surgery group (ES Group) (210 cases) and surgery after follow-up group (FS Group) (69 cases). Patients in FS group experienced at least one year surveillance. Clinical and imaging features were analyzed by using univariate analysis. After analysis, there was no statistical difference in pathological results and long-term prognosis between the two groups. In the follow-up group, grown GGNs have proved to have more aggressive pathological results. The one-year follow-up may be a feasible management method for patients with ground-glass component predominant GGN.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Humans , Male , Female , Middle Aged , Prognosis , Lung Neoplasms/surgery , Lung Neoplasms/pathology , Lung Neoplasms/mortality , Lung Neoplasms/diagnostic imaging , Adenocarcinoma of Lung/surgery , Adenocarcinoma of Lung/pathology , Adenocarcinoma of Lung/mortality , Adenocarcinoma of Lung/diagnostic imaging , Aged , Follow-Up Studies , Retrospective Studies , Adult , Solitary Pulmonary Nodule/surgery , Solitary Pulmonary Nodule/pathology , Solitary Pulmonary Nodule/diagnostic imaging , Adenocarcinoma/surgery , Adenocarcinoma/pathology , Adenocarcinoma/mortalityABSTRACT
Despite many studies focusing on the prognostic biomarkers in pancreatic adenocarcinomas (PAADs), there is ill-informed about the relationships between their genomic features and immune characteristics. Herein, we deeply investigated the involvement of major driver mutation subtypes with immunophenotypes impacting PAAD outcomes. Based on public data analyses of RNA expression-based immune subtypes in PAAD, in contrast to KRAS G12D & TP53 co-mutant patients with poor outcomes, the best immune subtype C3 (inflammatory) characterized by high Th1/Th2 ratio was relatively enriched in KRASnon-G12DTP53wt patients with better survival, whereas the inferior subtype C2 (IFN-γ dominant) with low Th1/Th2 ratio was more common in the former than in the latter. Moreover, contrary to the highly immunosuppressive microenvironment (high Treg, high ratio of Treg to tumor-specific CD4+ T cell) in KRASG12DTP53mut patients, KRASG12VTP53wt individuals exhibited an inflamed context profiled by multiplex immunohistochemistry. It could be responsible for their outstanding survival advantage over others in postsurgical PAAD patients receiving adjuvant chemotherapy as shown by our cohort. Together, KRASG12VTP53wt may be a promising biomarker for prognostic evaluation and screening certain candidates with PAAD to get desirable survival benefit from adjuvant chemotherapy.
Subject(s)
Biomarkers, Tumor , Immunophenotyping , Mutation , Pancreatic Neoplasms , Proto-Oncogene Proteins p21(ras) , Tumor Microenvironment , Tumor Suppressor Protein p53 , Humans , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/mortality , Proto-Oncogene Proteins p21(ras)/genetics , Tumor Microenvironment/immunology , Tumor Suppressor Protein p53/genetics , Prognosis , Biomarkers, Tumor/genetics , Adenocarcinoma/genetics , Adenocarcinoma/immunology , Adenocarcinoma/pathology , Adenocarcinoma/mortality , Male , FemaleABSTRACT
INTRODUCTION: Pancreatoduodenectomy (PD) for pancreatic adenocarcinoma (PDAC) presents a significant challenge owing to its aggressive nature. Traditionally performed as open surgery, the advent of minimally invasive surgery (MIS) including laparoscopic and robotic techniques, offers a potential alternative. This study assessed the use and outcomes of MIS and open PD for PDAC treatment. METHODS: We analyzed ACS-NSQIP data (2015-2021) using regression models to compare patient outcomes across open PD, MIS PD, and conversions from MIS to open (MIS-O). RESULTS: Of 19,812 PDAC patients, 1,293 (6.53%) underwent MIS, 18,116 (91.44%) underwent open PD, and 403 (2.03%) underwent MIS converted to open PD (MIS-O). The MIS rate increased from 6.1% to 9.2%. Black patients had a higher MIS-O rate (RR, 1.55; p = 0.025). Open PD was associated with more severe conditions (ASA ≥ III, malnutrition) and prior radiation therapy. MIS patients more often had neoadjuvant chemotherapy. Complex procedures, such as vein resection, favored open PD. Need for arterial resection was associated with MIS-O (RR, 2.11; p = 0.012), and operative time was significantly associated with MIS (OR: 4.32, 95% CI: 3.43-5.43, p-value: < 0.001) No differences in the overall morbidity or 30-day mortality were observed. MIS led to shorter stays but higher risks of reoperation and pulmonary embolism. MIS-O increased the delayed gastric emptying rate (RR, 1.79; p < 0.001). CONCLUSION: During 2015-2021, an increasing number of patients with PDAC are undergoing MIS PD. Morbidity and mortality did not differ between open and MIS PD. MIS was performed more frequently in patients with better nutritional status and lower ASA, or when vascular resection was not anticipated. In well selected patients, short-term outcomes of MIS and open PD seem similar.
Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Pancreaticoduodenectomy , Humans , Pancreatic Neoplasms/surgery , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Pancreaticoduodenectomy/methods , Pancreaticoduodenectomy/adverse effects , Female , Male , Adenocarcinoma/surgery , Adenocarcinoma/pathology , Adenocarcinoma/mortality , Aged , Middle Aged , Treatment Outcome , Laparoscopy/methods , Robotic Surgical Procedures , Minimally Invasive Surgical Procedures/methods , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Retrospective StudiesABSTRACT
Background: Prognostic factors in dogs with nasal tumors include several variables. However, factors that can measure prognosis have not yet been identified due to considerable divergence among reports. Aim: To describe the computed tomography (CT) imaging, treatment, and outcomes of dogs with nasal tumors, as well as detect negative prognostic factors through the analysis of a substantial number of cases from a single institution. Furthermore, based on CT findings, this study aimed to identify independent prognostic factors for nasal tumors in dogs. Methods: A total of 166 client-owned dogs were diagnosed with nasal tumors at Gifu University Veterinary Hospital between 2015 and 2019. Data were retrospectively collected from the electronic medical records. Results: Univariate analysis revealed a significant difference in survival time between adenocarcinoma and squamous cell carcinoma in 166 canine nasal tumors treated with megavoltage (MeV) radiation therapy at a single institution (p = .015). There was a significant difference in survival time between carcinoma and sarcoma (p = .04). Regarding CT imaging findings, significant differences in survival time were observed for frontal sinus invasion (p = .007), cribriform plate destruction (p < .001), and lymph node metastasis (p = .003). Multivariate Cox regression analysis was performed to assess frontal sinus invasion, cribriform plate destruction, histopathologic subtypes, and lymph node metastasis as negative prognostic factors; however, only cribriform plate destruction was a significant negative prognostic factor for survival time (p = .004). Conclusion: Multivariate Cox regression analysis showed that cribriform plate destruction was the main factor in predicting a negative prognosis among 166 canine nasal tumors treated with MeV radiation therapy at a single institution. Therefore, we propose a new 2-tier staging classification for canine nasal tumors with the presence or absence of cribriform plate destruction based on CT examination as the only evaluation factor.
Subject(s)
Dog Diseases , Nose Neoplasms , Dogs , Animals , Retrospective Studies , Dog Diseases/radiotherapy , Dog Diseases/mortality , Nose Neoplasms/veterinary , Nose Neoplasms/radiotherapy , Nose Neoplasms/mortality , Male , Female , Prognosis , Tomography, X-Ray Computed/veterinary , Survival Analysis , Carcinoma, Squamous Cell/veterinary , Carcinoma, Squamous Cell/radiotherapy , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/diagnosis , Adenocarcinoma/veterinary , Adenocarcinoma/radiotherapy , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adenocarcinoma/diagnosisABSTRACT
BACKGROUND: Neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC). Mucinous adenocarcinoma (MAC) is a potential poor prognosis subgroup of rectal cancer. However, the predictive value of MAC in NCRT treatment of LARC is controversial. METHODS: A comprehensive literature search of PubMed, Embase, and the Cochrane Library was performed. All studies examining the effect of MAC on CRT response in LARC were included. Outcomes of MAC were compared with non-specific adenocarcinoma (AC) by using random-effects methods. Data were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The main outcomes were the rates of pathological complete response (pCR), tumor and nodal down-staging, positive resection margin rate, local recurrence, and overall mortality. RESULTS: Fifteen studies containing comparative data on outcomes in a total of 9,238 patients receiving NCRT for LARC were eligible for inclusion. MAC had a reduced rate of pCR (OR, 0.38; 95% CI, 0.18-0.78) and tumor down-staging (OR, 0.31; 95% CI, 0.22-0.44) following NCRT compared with AC. MAC did not significantly affect nodal down-staging (OR, 0.42; 95% CI, 0.16-1.12) after NCRT. CONCLUSION: MAC of LARC was found to be a negative predictor of response to NCRT with lower rates of pCR and tumor down-staging for LARC. The nodal down-staging of MAC was relatively lower than that of AC, although the differences were not statistically significant.
Subject(s)
Adenocarcinoma, Mucinous , Neoadjuvant Therapy , Rectal Neoplasms , Rectal Neoplasms/therapy , Rectal Neoplasms/pathology , Rectal Neoplasms/mortality , Humans , Adenocarcinoma, Mucinous/therapy , Adenocarcinoma, Mucinous/pathology , Adenocarcinoma, Mucinous/mortality , Neoplasm Staging , Adenocarcinoma/therapy , Adenocarcinoma/pathology , Adenocarcinoma/mortality , Neoplasm Recurrence, Local , Prognosis , Treatment Outcome , Chemoradiotherapy , Chemoradiotherapy, Adjuvant , Margins of ExcisionABSTRACT
BACKGROUND: Hepatoid adenocarcinoma of the stomach (HAS) is an extremely rare and unique malignant gastric tumor with a significantly worse prognosis than non-hepatoid adenocarcinoma of the stomach (non-HAS). The present study explored the clinicopathological features of HAS and non-HAS patients to provide insights into HAS treatment strategies. METHODS: From December 26, 2023, we performed a comprehensive search of the PubMed, Web of Science, Cochrane Library, and Embase.com databases for relevant studies. Two authors independently screened the studies, evaluated their quality, extracted data, and performed the analyses. This study was registered with PROSPERO on January 2, 2024. RESULTS: Nine retrospective studies were included for analysis after screening 833 articles. A total of 350 and 924 patients were enrolled in the HAS and non-HAS groups, respectively. While no significant differences were observed in age, sex, tumor size, T3 or T4 stage, and N2 or N3 stage between the two groups, the HAS group exhibited higher rates of lymph node metastasis (OR = 1.93, 95% CI: 1.19-3.13, p = 0.007), liver metastasis (OR = 3.45, 95% CI: 2.26-5.28, p < 0.001), and vascular invasion (OR = 2.76, 95% CI: 2.05-3.71, p < 0.001). Additionally, the HAS group had lower 3-year survival rates (HR = 2.35, 95% CI: 1.70-3.25, p < 0.001) and 5-year survival rates (HR = 3.63, 95% CI: 1.49-8.88, p = 0.005), but lower rates of lymphatic permeation (OR = 0.68, 95% CI: 0.47-0.99, p = 0.040). CONCLUSION: Based on the current clinical evidence, patients with HAS present distinct clinicopathological features, greater invasiveness, and poorer prognosis than non-HAS patients. Further research is warranted to develop optimal treatment strategies for HAS.
Subject(s)
Adenocarcinoma , Liver Neoplasms , Stomach Neoplasms , Humans , Stomach Neoplasms/pathology , Stomach Neoplasms/mortality , Adenocarcinoma/pathology , Adenocarcinoma/mortality , Liver Neoplasms/pathology , Liver Neoplasms/mortality , Prognosis , Lymphatic Metastasis , Male , Neoplasm Staging , FemaleABSTRACT
PURPOSE: The optimal treatment for gastroesophageal junction adenocarcinoma (GEJA) remains controversial. We evaluated the treatment patterns and outcomes of patients with locally advanced GEJA according to the histological type. MATERIALS AND METHODS: We conducted a single-institution retrospective cohort study of patients with locally advanced GEJA who underwent curative-intent surgical resection between 2010 and 2020. Perioperative therapies as well as clinicopathologic, surgical, and survival data were collected. The results of endoscopy and histopathological examinations were assessed for Siewert and Lauren classifications. RESULTS: Among the 58 patients included in this study, 44 (76%) were clinical stage III, and all received neoadjuvant therapy (72% chemoradiation, 41% chemotherapy, 14% both chemoradiation and chemotherapy). Tumor locations were evenly distributed by Siewert Classification (33% Siewert-I, 40% Siewert-II, and 28% Siewert-III). Esophagogastrectomy (EG) was performed for 47 (81%) patients and total gastrectomy (TG) for 11 (19%) patients. All TG patients received D2 lymphadenectomy compared to 10 (21%) EG patients. Histopathological examination showed the presence of 64% intestinal-type and 36% diffuse-type histology. The frequencies of diffuse-type histology were similar among Siewert groups (37% Siewert-I, 36% Siewert-II, and 33% Siewert-III). Regardless of Siewert type and compared to intestinal-type, diffuse histology was associated with increased intraabdominal recurrence rates (P=0.03) and decreased overall survival (hazard ratio, 2.33; P=0.02). With a median follow-up of 31.2 months, 29 (50%) patients had a recurrence, and the median overall survival was 50.5 months. CONCLUSIONS: Present in equal proportions among Siewert types of esophageal and gastric cancer, a diffuse-type histology was associated with high intraabdominal recurrence rates and poor survival. Histopathological evaluation should be considered in addition to anatomic location in the determination of multimodal GEJA treatment strategies.
Subject(s)
Adenocarcinoma , Esophageal Neoplasms , Esophagogastric Junction , Stomach Neoplasms , Humans , Male , Adenocarcinoma/pathology , Adenocarcinoma/mortality , Adenocarcinoma/therapy , Adenocarcinoma/classification , Female , Stomach Neoplasms/pathology , Stomach Neoplasms/therapy , Stomach Neoplasms/mortality , Stomach Neoplasms/classification , Stomach Neoplasms/surgery , Middle Aged , Esophagogastric Junction/pathology , Esophagogastric Junction/surgery , Retrospective Studies , Aged , Esophageal Neoplasms/pathology , Esophageal Neoplasms/mortality , Esophageal Neoplasms/therapy , Esophageal Neoplasms/surgery , Prognosis , Gastrectomy , Adult , Survival Rate , Esophagectomy , Aged, 80 and overABSTRACT
Gastric cancer (GC) is a prevalent form of cancer worldwide, and TTN (titin) mutations are frequently observed in GC. However, the association between TTN mutations and immunotherapy for GC remains unclear, necessitating the development of novel prognostic models. The prognostic value and potential mechanisms of TTN in stomach adenocarcinoma were evaluated by TCGA (The Cancer Genome Atlas)-stomach adenocarcinoma cohort analysis, and an immune prognostic model was constructed based on TTN status. We validated it using the GSE84433 dataset. We performed Gene Set Enrichment Analysis and screened for differentially expressed genes, and used lasso (least absolute shrinkage and selection operator) regression analysis to screen for survival genes to construct a multifactorial survival model. In addition, we evaluated the relative proportions of 22 immune cells using the CIBERSORT algorithm for immunogenicity analysis. Finally, we constructed the nomogram integrating immune prognostic model and other clinical factors. GESA showed enrichment of immune-related phenotypes in patients with TTN mutations. We constructed an immune prognostic model based on 16 genes could identify gastric cancer patients with higher risk of poor prognosis. Immuno-microenvironmental analysis showed increased infiltration of naive B cells, plasma cells, and monocyte in high-risk patients. In addition, Nomo plots predicted the probability of 1-year, 3-year, and 5-year OS (overall survival) in GC patients, showing good predictive performance. In this study, we identified that TTN gene may be a potential clinical biomarker for GC and TTN mutations may be a predictor of immunotherapy in patients. We constructed and validated a new model for prognosis of GC patients based on immune characteristics associated with TTN mutations. This study may provide potential therapeutic strategies for gastric cancer.
Subject(s)
Connectin , Mutation , Stomach Neoplasms , Tumor Microenvironment , Stomach Neoplasms/genetics , Stomach Neoplasms/immunology , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Humans , Tumor Microenvironment/immunology , Tumor Microenvironment/genetics , Prognosis , Connectin/genetics , Female , Male , Nomograms , Biomarkers, Tumor/genetics , Middle Aged , Adenocarcinoma/genetics , Adenocarcinoma/immunology , Adenocarcinoma/mortality , Adenocarcinoma/pathology , AgedABSTRACT
BACKGROUND: The introduction of the 1 mm cut-off for resection margin according to the Leeds Pathology Protocol has transformed the concept of surgical radicality. Its impact on nodal-positive resected pancreatic ductal adenocarcinoma patients is unclear. The aim of this study was to analyse the effect of margin clearance on survival among resected, nodal-positive pancreatic ductal adenocarcinoma patients whose specimens were analysed according to the Leeds Pathology Protocol. METHODS: Data were collected retrospectively from multicentre clinical databases. Resected patients with nodal involvement were included. Overall survival and disease-free survival were analysed according to minimum reported margin clearances of 0, 0.5, 1, and 2 mm. The results are reported separately for patients who had not undergone venous resection and for patients for whom data were available regarding the superior mesenteric vein-facing margin or the vein specimen. The eighth edition of TNM classification by the AJCC was used. RESULTS: The study comprised 290 stage IIB patients and 215 stage III patients without venous resection. The superior mesenteric vein margin analysis comprised 127 stage IIB patients and 198 stage III patients. The different resection margin distances were not associated with overall survival and disease-free survival among patients without venous resection (P > 0.050). Receiving adjuvant therapy was associated with longer overall survival among stage IIB patients (P = 0.034) and stage III patients (P = 0.003) and with longer disease-free survival among stage III patients (P < 0.001). CONCLUSIONS: In this study, a margin clearance greater than 1 mm showed no clear effect on overall survival in pancreatic ductal adenocarcinoma patients with nodal involvement, whereas adjuvant therapy was confirmed to be essential to ensure longer overall survival.
Subject(s)
Carcinoma, Pancreatic Ductal , Margins of Excision , Pancreatic Neoplasms , Humans , Retrospective Studies , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/surgery , Male , Female , Aged , Middle Aged , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/surgery , Disease-Free Survival , Neoplasm Staging , Pancreatectomy , Lymphatic Metastasis , Mesenteric Veins/pathology , Adenocarcinoma/pathology , Adenocarcinoma/mortality , Adenocarcinoma/surgery , Aged, 80 and over , AdultABSTRACT
Although the safety and short-term outcomes of robotic surgery for sigmoid colon and rectal cancer patients are well-documented, there is limited research on the long-term survival outcomes of robotic colorectal surgery. This is a retrospective study that includes 502 patients who underwent either laparoscopic or robotic anterior resection and abdominoperineal resection for rectal or sigmoid colon cancer between August 2016 and September 2021. All patients were diagnosed with rectal or sigmoid colon adenocarcinoma. Propensity score matching (PSM) was implemented to minimize selection bias. Perioperative outcomes, complication rates, and pathological data were evaluated and compared. The 5-year overall survival rate and disease-free survival rate were calculated and compared. Before matching, patients in the robotic group had earlier pathological T and N stages and were more likely to have received neoadjuvant chemoradiotherapy compared to the laparoscopic group. After matching, most clinicopathological outcomes were similar between the two groups, but the robotic group had longer operative times and a lower conversion rate to open surgery compared with laparoscopic group. After matching for clinical factors, the 5-year DFS rates were 88.19% for the robotic group and 82.46% for the laparoscopic group (P = 0.122), and the OS rates were 90.5% and 79.5% (P = 0.342), showing no significant differences. In the stratified analysis, patients in the robotic surgery group had significantly higher 5-year DFS rates in the following subgroups: age < 65 years, TNM stage I-II, received neoadjuvant therapy, and primary tumor located in the rectum. The safety and efficacy of robotic surgery for sigmoid colon and rectal cancer were validated compared to laparoscopic surgery, with both groups of patients exhibiting comparable long-term prognoses.
Subject(s)
Laparoscopy , Rectal Neoplasms , Robotic Surgical Procedures , Sigmoid Neoplasms , Humans , Robotic Surgical Procedures/methods , Laparoscopy/methods , Retrospective Studies , Rectal Neoplasms/surgery , Rectal Neoplasms/mortality , Rectal Neoplasms/pathology , Male , Female , Middle Aged , Sigmoid Neoplasms/surgery , Sigmoid Neoplasms/pathology , Aged , Treatment Outcome , Operative Time , Adenocarcinoma/surgery , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Survival Rate , Propensity Score , Neoadjuvant Therapy , Colon, Sigmoid/surgery , Disease-Free Survival , AdultABSTRACT
Prostate adenocarcinoma (PRAD) is the second most common tumor associated with death. The role and mechanisms of the fragile X mental retardation 1 (FMR1) gene in PRAD remain unknown. We conducted an analysis of FMR1 expression in PRAD to determine its prognostic importance and connection to carcinogenic pathways such as PI3K_AKT_mTOR. Survival analyses were utilized to establish a correlation between FMR1 expression and patient outcomes. We used the integration of genomic data with bioinformatic predictions to predict the regulatory factors of the FMR1 gene in PRAD. Our data revealed that individuals with higher levels of FMR1 expression experience worse survival outcomes compared to those with lower expression (hazard ratio [HR] = 5.08, 95% confidence interval [CI] = 1.07 - 24, p = 0.0412). FMR1 expression was significantly higher in patients with advanced pathological tumor stages, particularly in the pT3 and pT4 combined stages and the pN1 nodal stage. Furthermore, patients with high Gleason scores (GSs) (combined GSs 8 and 9) exhibited increased levels of FMR1 expression. Our results further identify a possible regulatory link between FMR1 and key oncogenic pathways, including PI3K_AKT_mTOR, and predict the possible mechanism by which FMR1 is regulated in PRAD. Our data suggest that the FMR1 gene could serve as a biomarker for PRAD progression. However, in-depth investigations, including those with large patient samples and in vitro studies, are needed to validate this finding and understand the mechanisms involved.
Subject(s)
Adenocarcinoma , Fragile X Mental Retardation Protein , Gene Expression Regulation, Neoplastic , Prostatic Neoplasms , Humans , Fragile X Mental Retardation Protein/genetics , Fragile X Mental Retardation Protein/metabolism , Male , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Prostatic Neoplasms/mortality , Prognosis , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adenocarcinoma/mortality , Aged , Middle Aged , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , TOR Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/genetics , Signal Transduction/genetics , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/geneticsABSTRACT
INTRODUCTION: This multicenter phase I/IIa study aimed to determine the recommended phase II dose (RP2D) and evaluate the safety and preliminary efficacy of liposomal irinotecan (nal-IRI), oxaliplatin, and S-1 (NASOX) as first-line treatment for advanced pancreatic adenocarcinoma. METHODS: Patients with locally advanced or metastatic pancreatic adenocarcinoma without prior systemic treatment for advanced disease, aged ≥ 19 years, with measurable disease, and Eastern Cooperative Oncology Group performance status of 0-1 were eligible. The primary endpoints were to determine the dose-limiting toxicity (DLT) in the phase I cohort and overall response rate (ORR) in the phase IIa cohort. The intention-to-treat (ITT) analysis included patients who received the RP2D. RESULTS: In phase I, seven patients were screened, and six were assessed for DLT. None experienced DLT during the first cycle. The RP2D was determined as nal-IRI 50 mg/m2 and oxaliplatin 60 mg/m2 on day 1, S-1 40 mg/m2 twice daily on days 1-7 every 14 days. For the ITT (N = 41; 7, and 34 from phases I and IIa, respectively), the most common grade 3-4 treatment-emergent adverse events were neutropenia (31.7 %), enterocolitis (9.8 %), anorexia (7.3 %), and diarrhea (2.4 %). The ORR was 58.5 % (1 complete, and 23 partial responses). Two underwent conversion surgery; both achieved R0 resection. With median follow-up of 17.5 months, median progression-free survival was 6.5 months (95 % confidence interval [CI], 5.0-8.1) and median overall survival was 11.4 months (95 % CI, 9.8-15.5). CONCLUSION: NASOX exhibited a manageable safety profile and encouraging efficacy outcomes consistent with NALIRIFOX, showing potential to replace infusional 5-fluorouracil with oral S-1 in the triplet regimen.