Survival outcome of different treatment sequences in patients with locally advanced and metastatic pancreatic cancer.

BACKGROUND: Despite some therapeutic advances, improvement in survival rates of unresectable and/or metastatic pancreatic ductal adenocarcinoma (PDAC) has been minimal over recent decade. We aimed to evaluate the impact of different treatment sequences on clinical outcomes of advanced PDAC at our academic institution. METHODS: In this single institution retrospective analysis, we assessed characteristics and survival rates of unresectable and/or metastatic pancreatic PDAC patients who started a systemic treatment between 01/2015 and 12/2021. Survival analyses were performed by Kaplan-Meier and Cox proportional hazards model. RESULTS: The number of 285 patients received at least two lines of treatment, but only 137 patients were suitable for third-line treatment. Subgroup analysis showed that thirty-seven patients received A line (gemcitabine/nab-paclitaxel or nab-paclitaxel combined therapy to FOLFIRINOX) therapy, 37 patients received B line (nab-paclitaxel combined therapy to gemcitabine combined therapy to FOLFIRINOX) therapy, 21 patients received C line (nab-paclitaxel combined therapy to gemcitabine combined therapy to oxaliplatin or irinotecan combined therapy) therapy. Survival rates for different treatment lines were significantly different and median overall survival (OS) was 14.00, 18.00, and 14.00 months, respectively (p<0.05). CONCLUSION: Our study provides real-world evidence for the effectiveness of different treatment sequences and underscores the treatment sequences on survival outcome when considering the entire management in advanced PDAC.

A real-world analysis of second-line treatment option, gemcitabine plus anlotinib and anti-PD1, in advanced pancreatic cancer.

BACKGROUND: In the second-line treatment of advanced pancreatic cancer (APC), there is only one approved regimen based on the phase III NAPOLI-1 trial. However, for patients progressing after Nab-paclitaxel and Gemcitabine (Nab-P/Gem) or Nab-P combinations, second-line treatment were very limited. METHODS: This is a retrospective single-center analysis of patients. Our aim was to determine the effectiveness and tolerability of a novel regimen, gemcitabine plus Anlotinib and anti-PD1, in APC patients and to compare it with oxaliplatin, irinotecan, leucovorin, and fluorouracil (FOLFIRINOX) in the second-line setting who have failed on the first-line Nab-P combinations. RESULTS: In total, twenty-three patients received Gemcitabine plus Anlotinib and anti-PD1 in the second-line, 28 patients were treated with FOLFORINOX. There was no significant difference in overall survival (OS) or progression free survival (PFS) for either of the two sequences (p > 0.05). Patients who received Gemcitabine plus Anlotinib and anti-PD1 had a median PFS of 4.0 months (95% CI: 1.1-6.9) versus 3.5 months (95% CI 1.8-5.2) in FOLFORINOX group (p = 0.953). The median OS of Gemcitabine plus Anlotinib and anti-PD1 was 9.0 months (95% CI: 4.0-13.7) and 8.0 months (95% CI: 5.5-10.5) in FOLFORINOX group (p = 0.373). Grade ≥3 treatment-emergent adverse events (AEs) occurred for 13% of patients with Gemcitabine plus Anlotinib and anti-PD1 and 40% for FOLFORINOX. CONCLUSION: Our data confirms the effectiveness of Gemcitabine plus Anlotinib and anti-PD1 as a well-tolerated regimen in the second-line treatment of APC and extends available data on its use as a second-line treatment option when compared with FOLFIRINOX.

A Chinese Retrospective Multicenter Study of First-Line Chemotherapy for Advanced Pancreatic Cancer.

BACKGROUND Pancreatic cancer (PC) is a common digestive system tumor. For patients with advanced pancreatic cancer (APC), chemotherapy is still the predominant treatment. However, no large-scale clinical studies have been done of it as first-line therapy for APC. The goal of the present study was to assess real-world outcomes with chemotherapy in that setting. MATERIAL AND METHODS We retrospectively analyzed data from 322 patients with APC who were treated with chemotherapy at 4 hospitals in different cities in China. The first-line regimens used were AS (nab-paclitaxel and S-1), AG (nab-paclitaxel and gemcitabine), and FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin). RESULTS Of the patients, 232 received AS, 79 received AG, and 11 received FOLFIRINOX. The median number of chemotherapy cycles was 5. The median overall survival (mOS) was 9 months and the median progression-free survival (mPFS) was 5 months. The AS, AG, and FOLFIRINOX regimens were associated with mOS rates of 9 months, 9 months, and 10 months, respectively. The mPFS rates for the AS, AG, and FOLFIRINOX regimens were 5, 4, and 5 months, respectively. The differences between the PFS rates for the regimens were statistically significant. The overall response rate (ORR) and overall disease control rate (DCR) for chemotherapy were 38% and 81.8%, respectively. The ORRs for the AS, AG, and FOLFIRINOX regimens were 46.9%, 18.7%, and 0%, respectively. The DCRs for the AS, AG and FOLFIRINOX regimens were 87.2%, 69.3%, and 63.6%, respectively. The differences between the ORRs and DCRs for the regimens were statistically significant. The incidences of grade 3/4 adverse events (AEs) associated with the AS, AG, and FOLFIRINOX regimens were 29.9%, 25%, and 36.4%, respectively. CONCLUSIONS The AS regimen was associated with a higher ORR and DCR than the other 2 regimens, with a lower rate of AEs.

Preoperative lung immune prognostic index predicts survival in patients with pancreatic cancer undergoing radical resection.

Background: Lung immune prognostic index (LIPI), a combination of derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH), is currently attracting considerable interest as a potential prognostic indicator in many malignancies. Our study aimed to investigate the prognostic value of preoperative LIPI in patients with pancreatic ductal adenocarcinoma (PDAC) undergoing radical resection. Methods: We retrospectively reviewed PDAC patients treated with radical resection from February 2019 to April 2021 at Chinese People's Liberation Army (PLA) general hospital. Based on the cut-off value of dNLR and LDH identified by X-tile, patients were divided into LIPI good and LIPI intermediate/poor group. Kaplan-Meier curve and log-rank test were used to compare the recurrence-free survival (RFS) and overall survival (OS) of the two groups. Univariate and multivariate Cox regression was used to identify the independent prognostic value of LIPI. Subgroup analysis was performed to identify specific population benefited from radical resection. Results: A total of 205 patients were included and the median RFS and OS was 10.8 and 24.3 months, respectively. Preoperative LIPI intermediate/poor was related to worse RFS and OS (p < 0.05). Preoperative LIPI intermediate/poor, vascular invasion and no adjuvant chemotherapy were indicators of poor OS. Patients with LIPI intermediate/poor had worse OS especially among females and those with adjuvant chemotherapy (p < 0.05). Adjuvant chemotherapy related to better RFS and OS in patients with LIPI good (p < 0.05). Conclusions: Preoperative LIPI intermediate/poor can be an indicator of poor prognosis in patients with PDAC undergoing radical resection. LIPI good could be an effective marker of benefit from adjuvant chemotherapy. Larger studies are warranted for further validation.

Evaluation of circulating tumor DNA as a prognostic biomarker for metastatic pancreatic adenocarcinoma.

Purpose: Pancreatic cancer is an aggressive solid tumor with a severe prognosis. Although tumor biomarkers are often used to identify advanced pancreatic cancer, this is not accurate, and the currently used biomarkers are not indicative of prognosis. The present study evaluated circulating tumor DNA (ctDNA) as a biomarker for prognosis prediction and disease monitoring in metastatic pancreatic adenocarcinoma (PAC). Methods: From 2017 to 2018, 40 patients with metastatic PAC were enrolled, and tumor tissue and blood samples were collected from 40 and 35 patients, respectively. CtDNA was sequenced by next-generation sequencing (NGS) with a 425-gene capture panel. The association of clinical characteristics, laboratory indicators, and dynamic ctDNA with patient outcomes was analyzed. Results: Mutations in KRAS (87.5%, N = 35) and TP53 (77.5%, N = 31) were most common in 40 tumor tissue. Patients' ECOG score, CA19-9, CEA, neutrophil-lymphocyte ratio (NLR), platelet- lymphocyte ratio (PLR) levels and mutations in ≥ 3 driver genes were strongly correlated with patients' overall survival (OS). Patients' gender, ECOG score, CA19-9, and CEA levels were associated with progression-free survival (PFS) (P<0.05). In 35 blood samples, univariate analysis showed a significant association between ECOG score, CA19-9, KRAS or CDKN2A mutation in ctDNA and OS and between CA19-9, CDKN2A or SMAD4 mutation in ctDNA and PFS. Cox hazard proportion model showed that patients' CDKN2A mutation in ctDNA (HR=16.1, 95% CI=4.4-59.1, P<0.001), ECOG score (HR=6.2, 95% CI=2.4-15.7, P<0.001) and tumor location (HR=0.4, 95% CI=0.1-0.9, P=0.027) were significantly associated with OS. Patients' CDKN2A mutation in ctDNA (HR=6.8, 95% CI=2.3-19.9, P=0.001), SMAD4 mutation in ctDNA (HR=3.0, 95% CI=1.1-7.9, P=0.031) and metastatic organ (HR=0.4, 95% CI=0.2-1.0, P=0.046) were significantly associated with PFS. Longitudinal changes in gene mutation allelic frequency (MAF) value were evaluated in 24 patients. Detection of progression disease (PD) by ctDNA was 0.9 months earlier than by radiological imaging (mean PFS: 4.6m vs 5.5m, P=0.004, paired t-test). Conclusions: The ctDNA has the potential as a specific survival predictive marker for metastatic PAC patients. Longitudinal ctDNA tracking could potentially help identify disease progression and be a valuable complement for routine clinical markers and imaging.

Analysis of a Systemic Inflammatory Biomarker in Advanced Bile Tract Carcinoma Treated with Anti-PD-1 Therapy: Prognostic and Predictive Significance of Lung Immune Prognostic Index Score.

Background: The application of immunotherapy is gradually increasing in advanced bile tract carcinoma (BTC), but only some patients could benefit from it. Validated biomarkers can screen out the beneficiaries. Therefore, the objective of this research is aimed at exploring the predictive value of lung immune prognostic index (LIPI) in advanced BTC patients receiving immunotherapy. Methods: This study was conducted on 110 BTC patients. The cut-off value of the derived neutrophil-to-lymphocyte (dNLR) ratio was obtained by the ROC curves to predict the tumor progression rate at the 6th month. The high levels of dNLR (≥the cut-off value) and lactate dehydrogenase (≥the upper limit of normal) were considered to be two risk factors for LIPI. Based on these two risk factors, patients were categorized into 3 groups based on risk factors: 0 for the good group, 1 for the intermediate group, and 2 for the poor group. Due to the limited number of patients in the poor group, it was integrated into the intermediate group to be the intermediate/poor group. Finally, the subjects were divided into two groups: LIPI-good and LIPI-intermediate/poor. Results: The results shed light on the 110 BTC patients' LIPI in advanced BTC patients receiving immunotherapy, indicating that the cut-off value of dNLR was 1.74. According to the risk stratification, 38 (34.5%) patients had a good LIPI score, whereas the LIPI score was intermediate/poor in 72 (65.5%). In addition, patients with good LIPI were related to longer progression-free survival (PFS) and overall survival (OS), compared to those with intermediate/poor LIPI (12.17 months vs. 3.17 months; 20.2 months vs. 8.7 months). According to multivariate analysis, the intermediate/poor LIPI group was independently correlated with over 2.3 times greater risk of tumor progression (HR = 2.301; 95% CI, 1.395-3.796; P = 0.001) and over 1.8 times greater risk of death (HR = 1.877; 95% CI, 1.076-3.275; P = 0.027) than the good group. Moreover, the result also revealed that there were significant differences of DCR for patients of the good group and the intermediate/poor group (86.8% vs. 65.3%; P = 0.012). Conclusion: Finally, this study verifies, for the first time, that LIPI is an independent factor affecting the survival and clinical efficacy of advanced BTC patients receiving immunotherapy. It may be difficult for patients with intermediate/poor LIPI to benefit from immunotherapy.

Clinical Application of Artificial Dermis and Autologous Skin in Repairing Skin and Soft Tissue Defects of Hands and Feet with Bone Exposure Injuries.

Patients with skin and soft tissue defects are very common. Mild trauma often causes mild skin damage, while severe injuries are often accompanied by bone and tendon exposure, which brings great pain to patients. For the defect of skin and soft tissue, the traditional treatment methods are mostly medium or full-thickness skin or skin flap transplantation. These methods are effective in wound repair, but there are still many problems. In recent years, with the improvement of tissue engineering technology, the use of artificial skin to repair various skin wounds is gradually becoming clinical, and the key technology of skin tissue engineering lies in the development of dermal substitutes. The appearance of artificial dermis not only solves the shortage of autologous skin source but also makes the operation simple and easy. The purpose of this study was to investigate the clinical effect of artificial dermis combined with autologous skin grafts in repairing hand and foot skin and soft tissue defects with bone exposure. The results show that the use of artificial dermis combined with autogenous blade thick skin to treat patients with hand and foot soft tissue injury with bone exposure has a good clinical effect, and the skin is alive and has fewer complications, which is worthy of promotion.

A Composite Biomarker of Derived Neutrophil-Lymphocyte Ratio and Platelet-Lymphocyte Ratio Correlates With Outcomes in Advanced Gastric Cancer Patients Treated With Anti-PD-1 Antibodies.

BACKGROUND: The highly heterogeneous characteristics of GC may limit the accuracy of a single biomarker for screening populations benefiting from immunotherapy. However, the combination of multiple indicators can provide more directed information for the detection of potential immune benefit subgroups. At present, there are no recognized complex indexes to identify advanced GC (AGC) in patients who likely benefited from immunotherapy. The objective of this research is to explore whether the composite biomarker of derived neutrophil-lymphocyte ratio (dNLR) and platelet-lymphocyte ratio (PLR) can be used as a reliable prognostic factor for the survival of AGC patients receiving immunotherapy. METHODS: From December 2014 to May 2021, a total 238 AGC patients at a single Center were included in this retrospective cohort research study. The cutoff value of dNLR was obtained by the ROC curves to predict the disease progression rate at the 8th month and the cutoff value of PLR was estimated by the median value. The cutoff values of dNLR and PLR were 1.95 and 163.63, respectively. The high levels of dNLR (≥1.95) and PLR (≥163.63) were considered to be risk factors. Based on these two risk factors, patients were categorized into 3 groups: the risk factor number for the "good" group was 0, that for the "intermediate" group was 1, and that for the "poor" group was 2. The subjects were divided into two groups: dNLR/PLR-good and dNLR/PLR-intermediate/poor. RESULTS: Of the 238 patients, the median overall survival (mOS) and progression-free survival (mPFS) were 12.5 and 4.7 months, respectively. Multivariate analysis revealed that the good dNLR/PLR group was independently associated with better prognosis. The intermediate/poor dNLR/PLR group was independently correlated with an over 1.4 times greater risk of disease progression (4.1 months vs. 5.5 months; p = 0.016) and an over 1.54 times greater risk of death (11.1 months vs. 26.3 months; p = 0.033) than the good dNLR/PLR group. However, no clear differences in the disease control rate (DCR) and overall response rate (ORR) were observed between the intermediate/poor dNLR/PLR group and the good dNLR/PLR group (51.5% vs. 56.3%, 26.3% vs. 29.6%; p = 0.494, p = 0.609). CONCLUSION: Our study firstly verifies that the composite biomarker of dNLR and PLR is an independent prognostic factor affecting survival of advanced AGC patients receiving immunotherapy. It may be difficult for patients with the intermediate/poor dNLR/PLR group to benefit from immunotherapy.

Correlation Between Baseline Serum Tumor Markers and Clinical Characteristic Factors in Patients with Advanced Pancreatic Cancer.

PURPOSE: In pancreatic cancer (PC), CA 19-9, CEA and CA 125 are the most widely used tumor markers. The aim of this study was to explore the prognostic significance of baseline levels of serum CA 19-9, CEA, and CA 125, and to evaluate the clinical significance of these markers in PC patients. PATIENTS AND METHODS: A total of 278 patients with advanced PC that had received first-line chemotherapy treatments were examined. Correlation analysis between the tumor markers and clinical characteristics was performed using a Pearson's Chi-squared test or Fisher's exact test. A Pearson's correlation test was utilized to investigate the relationship between tumor markers and peripheral blood parameters. Univariate analysis was estimated using a Kaplan-Meier analysis and compared using a Log rank test. Multivariate analysis was performed using a Cox proportional hazards regression model. RESULTS: Both individually and collectively, the baseline CA 19-9, CEA and CA 125 levels were positively associated with the primary tumor site (p < 0.01), liver metastasis (p < 0.05), and number of organ metastases (p < 0.05). Furthermore, CA 19-9, CEA and CA 125 were correlated to baseline WBC (p < 0.001) and LDH (p < 0.01) levels. Additionally, CA 19-9 was correlated with years of smoking (p = 0.024); diabetes and years of diabetes (p = 0.012); baseline glycemic levels (p = 0.004); and neutrophil counts (p < 0.001). Moreover, CA 125 levels were associated with the baseline neutrophil counts (p < 0.001) and peritoneal metastasis (p = 0.008). When examining neutrophil, LDH, CA 19-9 and CA 125 levels were found to be associated with overall survival (OS) and shown to be independent prognostic factors. CONCLUSION: CA 19-9, CEA and CA 125 are correlated with multiple clinical factors. Baseline neutrophil, LDH, CA 19-9 and CA 125 levels are associated with OS and may potentially serve as prognostic factors.

Preoperative CA19-9 levels predict disease-free survival and overall survival in pancreatic adenocarcinoma patients after resection.

BACKGROUND: This study investigates the association between the preoperative serum CA19-9 and the effects of adjuvant chemotherapy (CT), and its impact on survival in patients undergoing curative resection for pancreatic adenocarcinoma (PAC). METHODS: From January 01, 2015 to June 30, 2017, we retrospectively reviewed 421 PAC patients who underwent radical resection. The association between preoperative CA19-9 and disease-free survival (DFS), and overall survival (OS) was analyzed using Kaplan-Meier method and Cox proportional hazards model. RESULTS: A total of 354 patients eligible for this study were classified into three groups according to preoperative CA19-9: G1 (≤87 U/mL), G2 (87-322 U/mL) and G3 (>322 U/mL), in tertiles. Multivariable analysis showed preoperative CA19-9 and adjuvant CT were both independent predictors of DFS and OS. Subgroup analyses showed the multivariable-adjusted hazard ratios (HR) of DFS for patients treated with adjuvant CT were 0.54 (95% CI, 0.33-0.86), 0.63 (95% CI, 0.40-0.97) and 0.32 (95% CI, 0.21-0.49) in G1, G2 and G3, respectively. A trend of decreasing HR of recurrence risk was observed in the higher preoperative CA 19-9 group treated with CT. CONCLUSIONS: High preoperative CA19-9 is an emerging biomarker that identifies a more aggressive PAC subgroup, which might benefit more from postoperative CT.