The risk of free flap revision and subsequent medical costs in patients with hypopharyngeal cancer.

BACKGROUND: Few studies have examined the preoperative risks and healthcare costs related to free flap revision in hypopharyngeal cancer (HPC) patients. METHODS: A 20-year retrospective case-control study was conducted using the Chang Gung Research Database, focusing on HPC patients who underwent tumor excision and free flap reconstruction from January 1, 2001, to December 31, 2019. The impacts of clinical variables on the need for re-exploration due to free flap complications were assessed using logistic regression. The direct and indirect effects of these complications on medical costs were evaluated by causal mediation analysis. RESULTS: Among 348 patients studied, 43 (12.4%) developed complications requiring re-exploration. Lower preoperative albumin levels significantly increased the risk of complications (OR 2.45, 95% CI 1.12-5.35), especially in older and previously irradiated patients. Causal mediation analysis revealed that these complications explained 11.4% of the effect on increased hospitalization costs, after controlling for confounders. CONCLUSIONS: Lower preoperative albumin levels in HPC patients are associated with a higher risk of microvascular free flap complications and elevated healthcare costs, underscoring the need for enhanced nutritional support before surgery in this population.

Impact of previous S-1 treatment on efficacy of liposomal irinotecan plus 5-fluorouracil and leucovorin in patients with metastatic pancreatic cancer.

BACKGROUND/OBJECTIVES: Liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI + 5-FU/LV) provides survival benefits for metastatic pancreatic adenocarcinoma (mPDAC) refractory to gemcitabine-based treatment, mainly gemcitabine plus nab-paclitaxel (GA), in current practice. Gemcitabine plus S-1 (GS) is another commonly administered first-line regimen before nab-paclitaxel reimbursement; however, the efficacy and safety of nal-IRI + 5-FU/LV for mPDAC after failed GS treatment has not been reported and was therefore explored in this study. METHODS: In total, 177 patients with mPDAC received first-line GS or GA treatment, followed by second-line nal-IRI + 5-FU/LV treatment (identified from a multicenter retrospective cohort in Taiwan from 2018 to 2020); 85 and 92 patients were allocated to the GS and GA groups, respectively. Overall survival (OS), time-to-treatment failure (TTF), and adverse events were compared between the two groups. RESULTS: The baseline characteristics of the two groups were generally similar; however, a higher median age (67 versus 62 years, p < 0.001) and fewer liver metastases (52% versus 78%, p < 0.001) were observed in the GS versus GA group. The median OS was 15.0 and 15.9 months in the GS and GA groups, respectively (p = 0.58). The TTF (3.1 versus 2.8 months, p = 0.36) and OS (7.6 versus 6.7 months, p = 0.83) after nal-IRI treatment were similar between the two groups. More patients in the GS group developed mucositis during nal-IRI treatment (15% versus 4%, p = 0.02). CONCLUSIONS: The efficacy of second-line nal-IRI +5-FU/LV treatment was unaffected by prior S-1 exposure. GS followed by nal-IRI treatment is an alternative treatment sequence for patients with mPDAC.

The Value of the Nutritional Indicators in Predicting Free Flap Failure From a Multicentre Database.

OBJECTIVE: Nutritional and inflammatory statuses have been associated with complications in microvascular-free flaps during head and neck surgeries. This study aimed to evaluate the potential of nutritional indicators in predicting postoperative free flap complications. STUDY DESIGN: We conducted a 20-year retrospective, case-control study within a defined cohort. SETTING: The study involved head and neck cancer patients from the Chang Gung Research Database who underwent simultaneous tumor ablation and free flap wound reconstruction between January 1, 2001, and December 31, 2019. METHODS: We employed logistic regression and stratified analysis to assess the risk of free flap complications and the subsequent need for flap revision or redo in relation to nutritional indicators and other clinical variables. RESULTS: Of the 8066 patients analyzed, 687 (8.5%) experienced free flap complications. Among these, 197 (2.4%) had free flap failures necessitating a redo of either a free flap or a pedicled flap. Beyond comorbidities such as chronic obstructive pulmonary disease, end-stage renal disease, and a history of prior radiotherapy, every 10-unit decrease in the preoperative prognostic nutritional index (PNI) was consistently associated with an increased risk of both free flap complications and failure. The covariate-adjusted odds ratios were 1.90 (95% confidence interval [CI]: 1.42-2.54) and 1.89 (95% CI: 1.13-3.17), respectively. CONCLUSION: A lower preoperative PNI suggests a higher likelihood of microvascular free flap complications in head and neck surgeries. Further randomized controlled trial designs are required to establish causality.

A Joint Model Based on Post-Treatment Longitudinal Prognostic Nutritional Index to Predict Survival in Nasopharyngeal Carcinoma.

BACKGROUND: a low PNI in patients with NPC is linked to poor survival, but prior studies have focused on single-timepoint measurements. Our study aims to employ joint modeling to analyze longitudinal PNI data from each routine visit, exploring its relationship with overall survival. METHODS: In this retrospective study using data from the Chang Gung Research Database (2007-2019), we enrolled patients with NPC undergoing curative treatment. We analyzed the correlation between patient characteristics, including the PNI, and overall survival. A joint model combining a longitudinal sub-model with a time-to-event sub-model was used to further evaluate the prognostic value of longitudinal PNI. RESULTS: A total of 2332 patient were enrolled for the analysis. Separate survival analyses showed that longitudinal PNI was an independent indicator of a reduced mortality risk (adjusted HR 0.813; 95% CI, 0.805 to 0.821). Joint modeling confirmed longitudinal PNI as a consistent predictor of survival (HR 0.864; 95% CI, 0.850 to 0.879). An ROC analysis revealed that a PNI below 38.1 significantly increased the risk of 90-day mortality, with 90.0% sensitivity and 89.6% specificity. CONCLUSIONS: Longitudinal PNI data independently predicted the overall survival in patients with NPC, significantly forecasting 90-day survival outcomes. We recommend routine PNI assessments during each clinic visit for these patients.

Clinical Value of Endoscopic Esophageal Screening in Head and Neck Squamous Cell Carcinoma Patients.

OBJECTIVE: To investigate the clinical benefit of routine esophageal screening in newly diagnosed head and neck squamous cell carcinoma (HNSCC) patients. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary medical center. METHODS: This retrospective study selected newly diagnosed HNSCC patients from the Chang Gung Research Database between January 2007 and December 2019. Patients who underwent endoscopic esophageal examinations within 2 months of the initial diagnosis of HNSCC were included in the screening group. The clinical outcomes of the screening and nonscreening groups were analyzed. RESULTS: In total, 13,627 HNSCC patients were included, comprising 1032 females and 12,640 males (mean age 55.0 years), and the esophageal screening group included 7033 (51.4%) patients. The prevalence rate of esophageal tumors was 4.5%. Hypopharyngeal cancer patients were the most likely to have (13.4%) second primary esophageal tumors. The American Joint Committee on Cancer stage of the esophageal tumor was lower in the esophageal screening group than in the nonesophageal screening group. The oral, oropharyngeal, and hypopharyngeal cancer patients in the esophageal screening group had better survival outcomes than their counterparts in the nonesophageal screening group. CONCLUSION: Endoscopic esophageal screening of newly diagnosed HNSCC patients can detect esophageal tumors at an early stage and improve overall survival. Esophageal screening could be a routine survey in HNSCC patients, particularly those with lifestyle risk factors and in countries with a high prevalence of esophageal cancer.

Combined Serum ALBUMIN with Neutrophil-to-Lymphocyte Ratio Predicts the Prognosis of Biliary Tract Cancer after Curative Resection.

BACKGROUND: The mainstay treatment of biliary tract cancer is complete tumor resection. Prior to surgery, risk stratification may help to predict and plan treatment approaches. In this study, we investigated the possibility of combining serum albumin concentrations and neutrophil-to-lymphocyte ratios (NLR) to create a score as ANS to predict the prognoses of biliary tract cancer before surgery. METHODS: This study retrospectively collected serum albumin concentration, neutrophil, and lymphocyte data measured in biliary tract cancer patients slated to receive complete tumor resections within two weeks before surgery. From January 2013 to December 2019, 268 biliary tract cancer patients who had received tumor resections at our hospital were categorized into 3 ANS groups: ANS = 0 (high albumin and low NLR), ANS = 1 (low albumin or high NLR), and ANS = 2 (low albumin and high NLR). RESULTS: Five-year survival rates were 70.1%, 47.6%, and 30.8% in the ANS = 0, 1, and 2 groups, respectively. The median overall survival time for the ANS = 0 group could not be determined by the end of the study, while those for ANS = 1 and ANS = 2 groups were 54.90 months and 16.62 months, respectively. The results of our multivariate analysis revealed that ANS could be used as an independent predictor of overall and recurrent-free survival. A high ANS was also correlated with other poor prognostic factors. CONCLUSIONS: The ANS devised for this study can be used to predict postoperative survival in patients with BTC and to guide treatment strategies.

The Impact of Clinical Prognosis of Viral Hepatitis in Head and Neck Cancer Patients Receiving Concurrent Chemoradiotherapy.

This study evaluated the clinical characteristics of head and neck cancer (HNC) patients with hepatitis B (HBV) or hepatitis C (HCV) who underwent concurrent chemoradiotherapy (CCRT) and examined the prognostic impact of antiviral therapies. In a 19-year retrospective analysis of 8224 HNC patients treated with CCRT, 29.8% (2452) were diagnosed with HBV or HCV, of whom 714 received antiviral therapy. For non-metastatic HNC patients on CCRT, factors such as gender, Charlson Comorbidity Index (CCI), liver cirrhosis markers (Fibrosis-4, APRI), and initial tumor stage were significant determinants of their overall survival. However, the presence of HBV or HCV and the administration of antiviral treatments did not yield distinct survival outcomes. In summary, antiviral therapy for HBV or HCV did not affect the 5-year survival rates of non-metastatic HNC patients undergoing CCRT, while gender, tumor stage, CCI, and liver cirrhosis were notable prognostic indicators.

Prognosis of Midkine and AT1R expression in resectable head and neck squamous cell carcinoma.

BACKGROUND: Research studies have demonstrated that Midkine (MDK) can influence the expression and activity of Renin-angiotensin system (RAS) components. Angiotensin II is involved in tumor growth and angiogenesis in different cancers. We previously observed Angiotensin II receptor blockers (ARBs) improve the survival rates of patients with oral cancers. These findings have prompted us to investigate whether MDK can influence the RAS pathway, mainly through its association with angiotensin II type 1 receptor (AT1R), which contributes to the observed poor prognosis in head and neck squamous cell carcinoma (HNSCC) patients. METHODS: MDK and AT1R expressions were examined in 150 HNSCC patients post-operation by immunohistochemical staining between 1 January 2010 and 31 December 2016. We tested the over-expression and silencing of MDK to evaluate the AT1R expression and functional biological assays in HNSCC cell lines HSC-3 and SAS. RESULTS: Positive expression of MDK is correlated with positive AT1R expression. MDK predicted poor NSCC patients' survival. Silencing MDK could suppress AT1R and pAKT expression and reduce the growth, migration, and invasion of HNSCC cells. ARB also inhibits MDK stimulating HNSCC cell proliferation. Overexpression of MDK could upregulate AT1R and pAKT. CONCLUSIONS: MDK is an independent prognostic factor of HNSCC post-operation, and AT1R regulates HNSCC cell growth, invasion, and migration. Positive MDK and AT1R expressions are highly correlated. Mechanistically, the interaction between MDK and AT1R is crucial for MDK-mediated cell viability, and inhibiting AT1R can effectively counteract or abolish these effects. Furthermore, MDK exerts a regulatory role in the expression of AT1R, as well as in the growth and motility of HNSCC cells. These findings highlight the involvement of the interaction between MDK, AT1R, and the pAkt signaling pathways in HNSCC cell viability growth.

Comparison of Fungal and Non-Fungal Rhinosinusitis by Culture-Based Analysis.

BACKGROUND: Incidence of fungal rhinosinusitis has increased in recent few years. We investigated the differences in microbiological findings between patients with fungal and non-fungal rhinosinusitis by growing microbiological cultures from samples obtained from sinus surgery. METHODS: Using the Chang Gung Research Database, we enrolled all chronic rhinosinusitis (CRS) patients who had ever undergone sinus surgery from 2001 to 2019 and had microbiological culture during sinus surgery. Enrolled patients were divided into fungal and non-fungal groups, based on fungal culture and surgical pathology. RESULTS: A total of 898 patients were diagnosed with fungal rhinosinusitis and 2884 with non-fungal rhinosinusitis. The fungal group had a higher age distribution (56.9 ± 13.1 vs. 47.0 ± 14.9), a larger proportion of females (62.4% vs. 37.0%), more unilateral lesions (80.4% vs. 41.6%), a lower incidence of the need for revision surgery (3.6% vs. 6.0%, p = 0.004), and a higher proportion of Pseudomonas aeruginosa in the culture (14.3% vs. 4.6%, p < 0.001). CONCLUSIONS: This large-scale study showed that Pseudomonas aeruginosa are more commonly found in patients with fungal rhinosinusitis and in patients who needed revision surgery, suggesting that efforts aimed at eliminating Pseudomonas are needed in order to improve the disease outcomes of patients with fungal rhinosinusitis.

Nuclear export signal mutation of epidermal growth factor receptor enhances malignant phenotypes of cancer cells.

Nuclear epidermal growth factor receptor (EGFR) has been shown to be correlated with drug resistance and a poor prognosis in patients with cancer. Previously, we have identified a tripartite nuclear localization signal (NLS) within EGFR. To comprehensively determine the functions and underlying mechanism of nuclear EGFR and its clinical implications, we aimed to explore the nuclear export signal (NES) sequence of EGFR that is responsible for interacting with the exportins. We combined in silico prediction with site-directed mutagenesis approaches and identified a putative NES motif of EGFR, which is located in amino acid residues 736-749. Mutation at leucine 747 (L747) in the EGFR NES led to increased nuclear accumulation of the protein via a less efficient release of the exportin CRM1. Interestingly, L747 with serine (L747S) and with proline (L747P) mutations were found in both tyrosine kinase inhibitor (TKI)-treated and -naïve patients with lung cancer who had acquired or de novo TKI resistance and a poor outcome. Reconstituted expression of the single NES mutant EGFRL747P or EGFRL747S, but not the dual mutant along with the internalization-defective or NLS mutation, in lung cancer cells promoted malignant phenotypes, including cell migration, invasiveness, TKI resistance, and tumor initiation, supporting an oncogenic role of nuclear EGFR. Intriguingly, cells with germline expression of the NES L747 mutant developed into B cell lymphoma. Mechanistically, nuclear EGFR signaling is required for sustaining nuclear activated STAT3, but not for Erk. These findings suggest that EGFR functions are compartmentalized and that nuclear EGFR signaling plays a crucial role in tumor malignant phenotypes, leading to tumorigenesis in human cancer.

Real-World Data Validation of NAPOLI-1 Nomogram for the Prediction of Overall Survival in Metastatic Pancreatic Cancer.

BACKGROUND: The nomogram derived from the pivotal phase III NAPOLI-1 study demonstrated a significant ability to predict median overall survival (OS) in gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (PDAC) treated with liposomal irinotecan plus fluorouracil and leucovorin (nal-IRI+5-FU/LV). However, the NAPOLI-1 nomogram has not been validated in a real-world setting and therefore the applicability of the NAPOLI-1 nomogram in daily practice remains unknown. This study aims to evaluate the NAPOLI-1 nomogram in a multicenter real-world cohort. METHODS: The NAPOLI-1 nomogram was applied to a previously established cohort of metastatic PDAC patients treated with nal-IRI+5-FU/LV in nine participating centers in Taiwan. Patients were divided into three risk groups according to the NAPOLI-1 nomogram. The survival impact of relative dose intensity at 6 weeks (RDI at 6 weeks) in different risk groups was also investigated. RESULTS: Of the 473 included patients, the median OSs of patients classified as low (n = 156), medium (n = 186), and high (n = 131) risk were 10.9, 6.3, and 4.3 months, respectively (p < 0.0001). The survival impact of RDI at 6 weeks remained significant after stratification by risk groups, adjustment with Cox regression, inverse probability weighting, or propensity score matching. CONCLUSIONS: Our results support the usefulness of the NAPOLI-1 nomogram for risk stratification in gemcitabine-refractory metastatic PDAC treated with nal-IRI+5-FU/LV in daily practice. We further showed that the RDI at 6 weeks is an independent prognostic factor beyond the NAPOLI-1 nomogram.

Safety and effectiveness of transdermal buprenorphine in cancer pain: An observational study in Taiwan (SOOTHE).

AIM: Buprenorphine is one of the strongest opioids used for the relief of cancer pain. This study aims to evaluate the real-world clinical experiences of transdermal buprenorphine used in moderate to severe cancer pain in the Asian population. METHODS: This is an open-labeled, multicenter, 4-week observational study. Stable cancer pain patients who decided to switch the previous opioid to transdermal buprenorphine will be enrolled in this study. The safety and effectiveness were observed and collected. Pain assessment was performed using a numerical rating scale by the investigators and the Brief Pain Inventory Short Form (BPI-SF) by the patient. The safety profiles included concomitant medications and adverse events (AEs). RESULTS: A total of 83 patients were enrolled in this study. The global pain scores in the BPI, as well as the four individual pain parameters (worst, least, average, and right now), showed a continued decrease (p < .05) from week 2 to week 4. Significant improvements were observed in normal work activities, relations with other people, sleep, enjoyment of life, and global BPI pain interference score on week 4. Pain assessments conducted by investigators demonstrated significant, continuous improvements during the study periods. In addition, transdermal buprenorphine demonstrated good safety/tolerability with limited drug-related AEs in the Asian population with cancer pain. CONCLUSION: This study demonstrated that transdermal buprenorphine in the Asian population has good safety profiles and continued improvements in pain relief, sleep, and pain interferences. Transdermal buprenorphine can be an effective and convenient option as a transdermal opioid for patients with moderate to severe cancer pain in Taiwan. (NCT Number: NCT04315831).

Systemic treatments in pancreatic cancer: Taiwan pancreas society recommendation.

Pancreatic cancer is a highly aggressive malignancy with a poor prognosis. Over the past decade, significant therapeutic advancements have improved the survival rates of patients with pancreatic cancer. One of the primary factors contributing to these positive outcomes is the evolution of chemotherapy, from monotherapy to doublet or triplet regimens, and the integration of multimodal approaches. Additionally, targeted agents tailored to patients with specific genetic alterations and the development of cell therapies show promise in benefiting certain subpopulations. This article focuses on examining pivotal studies that explore the role of chemotherapy in neoadjuvant, adjuvant, maintenance, and salvage settings; highlights interesting findings related to cell therapy; and provides an overview of ongoing trials concerning metastatic settings. This review primarily aimed to offer recommendations based on therapeutic evidence, recent advancements in new treatment combinations, and the most innovative approaches. A unique aspect of this review is the inclusion of published papers on clinical trials and real-world data in Taiwan, thus adding a valuable perspective to the overall analysis.

The impact of starting dose with or without subsequent dose escalation of liposomal irinotecan on treatment outcomes in patients with metastatic pancreatic ductal adenocarcinoma.

Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) improves survival in patients with pancreatic ductal adenocarcinoma (PDAC) after progression to gemcitabine-based therapy. Few studies have examined whether the starting dose and dose escalation of nal-IRI in subsequent treatment cycles may influence patient outcomes and toxicity profiles. A total of 667 patients who received nal-IRI + 5-FU/LV for PDAC treatment between August 2018 and November 2020 at nine medical centers in Taiwan were included and retrospectively analyzed. Patients were allocated to the standard starting dose (SD), reduced starting dose (RD) without escalation, and RD with escalation of nal-IRI groups for comparison of survival outcome and safety. Propensity score matching (PSM) was performed to adjust for possible confounding variables. Nal-IRI was prescribed at SD, RD without escalation, and RD with escalation in 465 (69.7%), 147 (22.0), and 55 (8.2%), respectively. RD with escalation patients had significantly longer treatment cycles (6, range 2-25) than SD (5, range 1-42, P<0.001) and RD without escalation patients (4, range 1-26, P<0.001). The median overall survival (OS) of the patients were as follows: SD, 6.2 months (95% confidence interval [CI], 5.7-6.7); RD with escalation, 7.6 months (95% CI, 6.1-9.2); and RD without escalation, 3.6 months (95% CI, 2.6-4.5). After PSM to adjust for potential confounders, RD without escalation patients still had the poorest OS compared to the other two groups (P<0.001), while the OS difference between SD and RD with escalation patients was insignificant (P=0.10). SD patients had higher incidences of ≥ grade 3 neutropenia and febrile neutropenia than the other two groups. Administering nal-IRI at RD followed by dose escalation in subsequent treatment cycles is safe and does not compromise survival outcomes in selected patients with PDAC receiving nal-IRI plus 5-FU/LV.

Predictive value of albumin combined with neutrophil-to-lymphocyte ratio for efficacy and safety profiles in patients with pancreatic ductal adenocarcinoma receiving liposomal irinotecan plus 5-fluorouracil and leucovorin.

Liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI + 5-FU/LV) treatment has demonstrated survival benefits but noticeable side effects in patients with pancreatic ductal adenocarcinoma (PDAC) that is refractory to gemcitabine-based therapy. This study aimed to explore whether combining albumin with the neutrophil-to-lymphocyte ratio (NLR), herein known as the albumin and neutrophil-to-lymphocyte ratio score (ANS), could be utilized as a simple tool to predict survival and safety profiles in such patient groups. We retrospectively enrolled 434 consecutive PDAC patients treated with nal-IRI + 5-FU/LV between 2018 and 2020 at nine medical centers in Taiwan. Patients were divided into three groups: ANS 0 (high albumin and low NLR), ANS 1 (low albumin or high NLR), and ANS 2 (low albumin and high NLR), for comparison. The median overall survival times for the ANS 0, 1, and 2 groups were 8.7 months (95% confidence interval (CI), 7.0-10.3 months), 5.2 months (95% CI, 4.3-6.0 months), and 2.6 months (95% CI, 1.9-3.3 months), respectively. The ANS was found to be an independent variable for overall survival and time-to-treatment failure in multivariate analyses. Patients in the ANS 2 group had significantly higher incidences of grade 3 or higher treatment-related adverse events than those in the other two groups. The present study showed that the ANS was an independent prognosticator in PDAC patients receiving nal-IRI + 5-FU/LV therapy. The ANS can be a simple predictor of survival outcome and safety profiles in PDAC patients treated with nal-IRI + 5-FU/LV.

Effect of glycated hemoglobin A1c on the survival of patients with oral squamous cell carcinoma: A multi-institutional database cohort study.

Objectives: Few studies have evaluated the impact of blood glucose levels on cancer prognosis. We investigated the association between hemoglobin A1c (HbA1c) and survival in oral squamous cell carcinoma (OSCC) patients. Materials and Methods: A 19-year retrospective cohort study of OSCC patients was performed using the Chang Gung Research Database to identify and enroll 7279 patients diagnosed with OSCC between January 2001 and June 2020. A total of 3600 patients were recruited after performing 1:2 frequency-matching between patients with DM and non-DM. A Cox's regression model was used to evaluate the relative hazards of all-cause mortality (ACM) and disease-specific mortality (DSM) in relation to HbA1c. Results: An unadjusted Cox's regression model indicated that DM, in addition to high levels of HbA1c, were statistically prognostic of poor survival. An adjusted hazard ratio (aHR) of HbA1c ≥ 8% interval at the initial diagnosis of OSCC was statistically higher for DSM (1.25 to 2.24) compared to the non-DM group in different regression models. Considering the effect of sustained HbA1c control in 699 patients, the aHR of mean HbA1c ≥ 9% interval was statistically higher for ACM (1.78 to 2.13) compared to the reference group (7% ≤ HbA1c< 8%). In addition, increased hazards of ACM (2.09 to 2.18) and DSM (2.20 to 2.41) were consistently observed in the highest quartiles of average real variability of HbA1c. Conclusion: Poor and unstable control of HbA1c could strongly predict the risks of mortality in OSCC patients with DM.

Clinical Characteristics and Predictive Outcomes of Recurrent Nasopharyngeal Carcinoma-A Lingering Pitfall of the Long Latency.

Purpose: To investigate the clinical characteristics, risk factors, and clinical outcomes of long-latent recurrence (>five years) of nasopharyngeal carcinoma (NPC). Methods: This retrospective study enrolled newly diagnosed NPC patients from the Chang Gung Research Database between January 2007 and December 2019. We analyzed the patients' characteristics and survival outcomes after recurrence. Results: A total of 2599 NPC patients were enrolled. The overall recurrence rate was 20.5%, while 8.1% of patients had long-latent recurrence (>five years). These patients had a higher percentage of initial AJCC (The American Joint Committee on Cancer) stage I/II (60.5%, p = 0.001) and local recurrence (46.5%, p < 0.001). Unresectable rT3 and rT4 were found in 60% of patients when recurrence and 30% of local recurrence occurred in the skull base, which could not be detected by the regular endoscopy. The five-year overall survival rate of long-latent recurrence was 19.7%. Alive patients tended to be asymptomatic but have regular follow-ups with the interval less than six months. Multivariate analysis showed age and initial advanced AJCC stages were independent risk factors of death after recurrence. In contrast, patients with recurrence between two and five years, salvage surgeries, and regional recurrence had favorable survival outcomes. Conclusion: Long-latent NPC recurrence is not rare, and the survival outcome is poor. Regular follow-up for early detection of NPC recurrence is necessary even after five years of disease-free period.

Aberrant miR-874-3p/leptin/EGFR/c-Myc signaling contributes to nasopharyngeal carcinoma pathogenesis.

BACKGROUND: Leptin is important in physiological and pathological functions in various cancers, however, the significance and mechanisms of leptin in nasopharyngeal carcinoma remain ambiguous. METHODS: Leptin expression was analyzed by QPCR, immunohistochemistry, Western blotting, and TCGA database. The impact of gain- or loss-of-function of leptin were determined by MTT, colony formation, wound healing, and Transwell assays in NPC cells, and by a xenograft tumor model. Leptin-modulated glucose consumption and lactate production were assessed by ELISA. Furthermore, leptin-regulated signaling pathways were examined by QPCR and Western blotting assays. The immunoprecipitation assay was conducted to determine interaction between leptin and EGFR. In addition, miR-874-3p-regulated leptin expression was evaluated using bioinformatics, QPCR, luciferase assay, AGO2-RIP assay, and Western blotting. RESULTS: In this study, we found that leptin was highly expressed in the sera and tumor tissues of patients with NPC, and elevated leptin expression was associated with advanced clinical features and poor prognosis. Functional assays demonstrated that leptin remarkably promoted NPC cell growth, motility, and glycolysis in vitro and in vivo. Mechanistically, leptin associated with EGFR, resulting in enhanced cell growth through the regulation of cell-cycle related markers, glycolysis-related genes, and EGFR/AKT/c-Myc signaling. Moreover, leptin potentiated the invasive capacity of NPC cells by promoting EMT. We further explored that miR-874-3p influenced leptin-mediated NPC progression. Overexpression of miR-874-3p prevented cell growth, motility, glucose consumption, and lactate production in NPC cells, whereas miR-874-3p inhibition had the opposite effects. AGO-RIP assays confirmed that Argonaute 2 (AGO2), a protein associated with miR-874-3p, regulated leptin expression in NPC cells. The rescue assays indicated that inhibition of leptin suppressed the effects of miR-874-3p inhibitor. In clinical specimens, miR-874-3p was negatively correlated with leptin. CONCLUSIONS: Leptin may serve as a novel prognostic factor and potential therapeutic target for patients with NPC. In addition, a newly discovered regulatory axis of leptin/EGFR/AKT/c-Myc can provide a novel therapeutic strategy for NPC.

Dosing Pattern and Early Cumulative Dose of Liposomal Irinotecan in Metastatic Pancreatic Cancer: A Real-World Multicenter Study.

Introduction: This multicenter, real-world cohort study aimed to evaluate the effectiveness of early cumulative dose administration and dosing pattern of liposomal irinotecan plus fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (mPDAC). Material and Methods: The electronic medical records of mPDAC patients treated with nal-IRI+5-FU/LV in nine participating centers were manually reviewed. To accommodate to the NAPOLI-1 study population, only patients with an Eastern Cooperative Oncology Group Performance Score of 0-1 were included. The survival impact of the relative 6-week cumulative dose and dosing pattern (standard vs. reduced starting dose, with and without further dose modification) were investigated. Results: Of the 473 included patients, their median overall survival (mOS) was 6.8 [95% CI, 6.2-7.7] months. The mOS of patients who received a relative 6-week cumulative dose of >80%, 60%-80%, and <60% were 7.9, 8.2, and 4.3 months, respectively (p<0.0001). Their survival impact remained significant after covariate adjustment using Cox regression. The mOS was 8.0-8.2 months in patients with a standard starting dose with and without early dose modification, and 9.3 and 6.7 months in those who had a reduced starting dose with and without escalation in the subsequent treatment, respectively. The incidence of grade 3-4 neutropenia and diarrhea was 23.3% and 2.7%, respectively. Conclusion: Our results support the use of nal-IRI+5-FU/LV in gemcitabine-refractory mPDAC and suggest that a lower starting dose followed by a re-escalation strategy could achieve clinical outcomes comparable to those with standard starting doses in real-world practice.

The impact of spleen volume on the survival of metastatic pancreatic adenocarcinoma patients receiving nanoliposomal irinotecan.

Nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (NalFL) comprises the current standard for gemcitabine-failed metastatic pancreatic ductal adenocarcinoma (PDAC). As liposomes generally accumulate in the spleen, we evaluated the impact of spleen volume on prognosis. We enrolled patients with metastatic PDAC who failed gemcitabine-based therapy and were initiated on NalFL between August 2018 and November 2020. The spleen volume before NalFL administration was evaluated. They were stratified into dose subgroups (i.e. low, < 48 mg/m2; intermediate, 48 - < 64 mg/m2; high, ≥ 64 mg/m2) by the average nal-IRI dose during the entire treatment, and multivariate analysis of overall survival (OS) was performed. We included 547 patients with a median age of 63 years (range, 27-89 years) and a median of 1 (range, 0-7) palliative chemotherapy regimen. The median spleen volume was 245 mL (range, 82-817 mL). Among patients with splenomegaly (≥ 245 mL), the low-dose subgroup had the worst median time to treatment failure (TTF, 1.8 months vs. 2.5 months vs. 2.5 months, P = 0.020) and OS (3.3 months vs. 5.9 months vs. 6.6 months, P = 0.018) as against no prognostic impact in patients without splenomegaly. In the multivariate analysis of patients with splenomegaly, performance status (PS) ≥ 2, body surface area (BSA) < 1.6 m2, prior fluoropyrimidine use, liver metastasis, and low-dose subgroup were independent poor prognostic factors. A low average nal-IRI dose was significantly associated with poor prognosis, especially among patients with splenomegaly. Further pharmacological studies should validate the relevance of spleen volume on the treatment outcomes of nal-IRI.