The concomitant use of the renin-angiotensin system inhibitors and survival outcomes of patients with pancreatic adenocarcinoma: an analysis from a tertiary center.

Background: The limited efficacy of chemotherapy in improving survival in pancreatic ductal adenocarcinoma (PDAC) necessitates the exploration of novel strategies to overcome treatment resistance. Objectives: This study aimed to investigate the impact of combining renin-angiotensin system (RAS) blockers with chemotherapy on survival outcomes in patients with PDAC. Design: Patients with PDAC were enrolled in the retrospective study. Methods: We analyzed patients with PDAC (n = 384) at our institution between 2014 and 2021. Survival outcomes, including event-free survival (EFS) and overall survival (OS), were analyzed according to the concomitant use of RAS blockers. Results: Among the 384 patients in the study, 70 (18.2%) concomitantly received angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Patients in the ACEI/ARB group, characterized by older age and more comorbidities, displayed a significantly superior 12-month EFS rate (22.86% versus 13.69%, p = 0.008) compared to the non-ACEI/ARB group, while OS remained similar between the groups. In the multivariate analysis, the use of ACEI/ARB was associated with better 12-month EFS (hazards ratio = 0.71, 95% confidence interval: 0.52-0.96; p = 0.024). Poor performance, advanced disease status, and higher CA19-9 levels were associated with poor survival outcomes. Conclusion: Concomitant use of ACEIs/ARBs in patients with pancreatic cancer resulted in significantly better 12-month EFS. Age, performance status, disease status, and higher CA19-9 levels were independent predictors of survival. The combination strategy might provide better treatment outcomes in patients with PDAC.

The efficacy of adjuvant chemotherapy for older adults with stage II/III gastric cancer: a retrospective cohort study.

BACKGROUND: Adjuvant chemotherapy is recommended as the standard treatment for patients with stage II/III resected gastric cancer. However, it is unclear whether older patients also benefit from an adjuvant chemotherapy strategy. This study aimed to investigate the clinical impact of adjuvant chemotherapy in older patients with stage II/III gastric cancer. METHODS: This retrospective, real-world study analyzed 404 patients with stage II/III gastric cancer visited at our institute between January 2009 and December 2019. The clinical characteristics and outcomes of patients aged 70 years or older who received adjuvant chemotherapy were compared with those who did not receive this type of treatment. Propensity score analysis was performed to mitigate selection bias. RESULTS: Of the 404 patients analyzed, 179 were aged 70 years or older. Fewer older patients received adjuvant chemotherapy than did younger patients (60.9% vs. 94.7%, respectively; P < 0.001). Among patients aged 70 years or older, those who received adjuvant chemotherapy had improved disease-free survival (DFS) (5-year DFS rate, 53.1% vs. 30.4%; P < 0.001) and overall survival (OS) (5-year OS rate, 68.7% vs. 52.1%; P = 0.002) compared to those who did not receive adjuvant chemotherapy. A similar survival benefit was observed in the propensity-matched cohort. Multivariate analysis showed that more advanced stage was associated with poorer OS. Receipt of adjuvant chemotherapy was independently associated with a decreased hazard of death (hazard ratio (HR), 0.37; 95% confidence intervals (CI), 0.20-0.68; P = 0.002). CONCLUSIONS: Adjuvant chemotherapy may benefit older stage II/III gastric cancer patients aged ≥ 70 years. Further prospective studies are needed to confirm these findings.

Survival outcomes of patients with head and neck squamous cell cancer with hepatitis B virus infection: An analysis from an endemic tertiary center.

BACKGROUND: Hepatitis B virus (HBV) affects the occurrence and survival outcome of various malignant disorders. The study aimed to evaluate the survival outcome of head and neck squamous cell cancer (HNSCC) patients with or without HBV infection. METHODS: This study included patients with HNSCC who visited Taichung Veterans General Hospital from 2007 to 2015. HBV infection was defined by hepatitis B surface antigen (HBsAg) seropositivity. By propensity score matching, we compared survival outcomes, including progression-free survival (PFS) and overall survival (OS), among patients with or without HBV infection. RESULTS: The prevalence of HBV infection in our cohort was 12.3%. Among the 1,015 patients included in the matched analysis, a higher risk of baseline liver cirrhosis (11.3% vs. 3.4%, p < 0.001) and initial hepatic dysfunction (10.8% vs. 5.4%, p = 0.005) rates were observed than those without HBV infection at baseline. The 5-year OS was 43.1% and 53.2% (p < 0.001) and the 5-year PFS was 37.4% and 42.3% (p = 0.007) in patients with and without HBV infection, respectively. The incidence of subsequent hepatic dysfunction showed no difference between patients with and without HBV infection (29.6% vs. 26.8%, p = 0.439). CONCLUSIONS: Patients with HNSCC and HBV infection were younger and had a higher risk of cirrhosis compared to those without HBV infection. Moreover, HBV infection significantly influenced the OS and PFS outcomes but not subsequent hepatic dysfunction in patients with HNSCC.

Chemotherapy for Metastatic Gastric Cancer: Does Age Matter? A Single-Center, Retrospective, Real-World Study.

Background: Palliative chemotherapy is the preferred standard of care for patients with metastatic gastric cancer (mGC). It remains uncertain whether older patients with mGC would benefit from palliative chemotherapy. This study aimed to investigate the clinical impact of palliative chemotherapy in older patients with mGC. Methods: This single-institute, retrospective, and real-world study included 428 patients with mGC between January 2009 and December 2019. Among them, 306 who received palliative chemotherapy were further stratified into 2 groups according to age: ≤70 (n = 236) and >70 (n = 70) years. The clinical demographics, outcomes, and hematologic toxicities of chemotherapy were compared between the 2 groups. Prognostic factors were determined using the Cox proportional hazards model. Results: Of the screened 428 patients, older patients had worse overall survival (OS) than younger patients. Among patients who received chemotherapy (n = 306), patients aged >70 and ⩽70 years had comparable progression-free survival (PFS) and OS. The incidence of severe hematologic toxicity was similar between the 2 groups. The Eastern Cooperative Oncology Group performance status of 2 or more metastatic sites, elevated carbohydrate antigen 19-9 level, high neutrophil-to-lymphocyte ratio (NLR), and undergoing palliative gastrectomy were independent prognostic factors for OS. Notably, age >70 years was not a significant factor for poor OS. Conclusions: Older age of >70 years might not be considered an obstacle to administering palliative chemotherapy to patients with mGC.

A Rare Case Report of Mesenchymal Chondrosarcoma with Pancreatic Metastasis.

Background: Mesenchymal chondrosarcoma is a rare but aggressive subtype of sarcoma. The majority of involvement locates in the axial skeleton. Treatment modalities include radical surgery, local radiotherapy, and systemic chemotherapy. However, the long-term survival outcome remains poor. Case presentation: We present the case of a 33-year-old male with a palpable chest wall mass for one year, diagnosed with mesenchymal chondrosarcoma with surgical removal. Later, he had an unusual pancreatic tail tumor as the first presentation of disease metastasis which was proven by surgical resection one year later. Conclusion: Although mesenchymal chondrosarcoma locates mainly in the axial skeletal system, extra-skeletal soft tissue or organ involvement might be seen occasionally. Active surveillance with multidisciplinary team management could significantly prolong survival outcomes.

Acute myeloid leukemia relapse after allogeneic hematopoietic stem cell transplantation: a retrospective study from a single institution.

OBJECTIVE: The outcomes of patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are poor. However, the risk factors for relapse in this context remain unclear. METHODS: We retrospectively assessed 84 consecutive adult AML patients who underwent allo-HSCT and achieved complete remission (CR). These patients were dichotomized into non-relapse (n = 58) and relapse (n = 26) groups, and the cumulative relapse rates and associated risk factors were examined. We also examined the treatments for and outcomes of patients with AML relapse after allo-HSCT. RESULTS: Non-CR status before allo-HSCT and high-risk cytogenetics were significant risk factors for AML relapse in univariate analysis, and non-CR status was also identified as a risk factor in multivariate analysis. The cumulative AML relapse rates after allo-HSCT were significantly higher in patients with non-CR (70.0%) compared with patients with CR (25.6%). Only 2 of the 26 relapsed patients remained alive on the study-censored day. CONCLUSIONS: Non-CR status before allo-HSCT was a significant risk factor for AML relapse after allo-HSCT. Patients with AML relapse after allo-HSCT had poor outcomes due to a lack of response to salvage remission-induction chemotherapy or treatment-related adverse events.

Immune Thrombocytopenia Induced by the Chimpanzee Adenovirus-Vectored Vaccine against SARS-CoV-2 Infection.

We present a case of immune thrombocytopenia (ITP) induced by the chimpanzee adenovirus-vectored vaccine, without evidence of thrombosis, eight days after vaccine administration. The thrombocytopenia condition improved after administering steroid treatment. This adenovirus vaccine had been reported to induce rare side effects, such as immune thrombotic thrombocytopenia. This case report showed that it could also induce immune thrombocytopenia without the presence of thrombosis. Therefore, we should be cautious of this rare side effect as global vaccine administrations against coronavirus disease increase.

Potential Prognostic Biomarkers of OSBPL Family Genes in Patients with Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy with poor survival outcomes. In addition, oxysterol-binding protein-like (OSBPL) family members are reported to be involved in lipid binding and transport and play critical roles in tumorigenesis. However, relationships between PDAC and OSBPL family members have not comprehensively been elucidated. In this study, we used the Oncomine and GEPIA 2 databases to analyze OSBPL transcription expressions in PDAC. The Kaplan-Meier plotter and TIMER 2.0 were used to assess the relationships between overall survival (OS) and immune-infiltration with OSBPL family members. Co-expression data from cBioPortal were downloaded to assess the correlated pathways with OSBPL gene family members using DAVID. The expressions of OSBPL3, OSBPL8, OSBPL10, and OSBPL11 were found to be highly upregulated in PDAC. Low expressions of OSBPL3, OSBPL8, and OSBPL10 indicated longer OS. The functions of OSBPL family members were mainly associated with several potential signaling pathways in cancer cells, including ATP binding, integrin binding, receptor binding, and the renin-angiotensin system (RAS) signaling pathway. The transcription levels of OSBPL gene family members were connected with several immune infiltrates. Collectively, OSBPL family members are influential biomarkers for the early diagnosis of PDAC and have prognostic value, with the promise of precise treatment of PDAC in the future.

A Decade of Lymphoma-Associated Hemophagocytic Lymphohistiocytosis: Does the Outcome Improve?

To investigate the potential treatment evolution and outcome improvement, we retrospectively compared clinical characteristics, therapeutic strategies, treatment responses, and overall survival (OS) in patients diagnosed and treated with lymphoma-associated HLH between 2004-2012 (n = 30) and 2013-2021 (n = 26). Our study showed that the clinical characteristics of lymphoma-associated HLH did not substantially change over the past two decades. However, more patients diagnosed in 2013-2021 were tested for Epstein-Barr virus than those diagnosed in 2004-2012 (69.3% vs. 33.3%; p = 0.021). In addition, Eastern Cooperative Oncology Group performance status 3-4 (hazard ratio (HR): 5.38; 95% confidence intervals (CI): 2.49-11.61; p < 0.001) and jaundice (HR: 2.91; 95% CI: 1.37-6.18; p = 0.006) were poor prognostic factors for lymphoma-associated HLH. With a comparable response rate of lymphoma treatment, patients treated in 2013-2021 had a numerically greater median OS than those treated in 2004-2012 (23.6 ± 19.8 vs. 9.7 ± 4.5 months). However, the difference was not statistically significant (p = 0.334). In conclusion, early diagnosis and tailored treatments that balance efficacy and adverse events remain the key to obtaining a better outcome in lymphoma-associated HLH.

Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy.

The two T cell inhibitory receptors PD-1 and TIM-3 are co-expressed during exhausted T cell differentiation, and recent evidence suggests that their crosstalk regulates T cell exhaustion and immunotherapy efficacy; however, the molecular mechanism is unclear. Here we show that PD-1 contributes to the persistence of PD-1+TIM-3+ T cells by binding to the TIM-3 ligand galectin-9 (Gal-9) and attenuates Gal-9/TIM-3-induced cell death. Anti-Gal-9 therapy selectively expands intratumoral TIM-3+ cytotoxic CD8 T cells and immunosuppressive regulatory T cells (Treg cells). The combination of anti-Gal-9 and an agonistic antibody to the co-stimulatory receptor GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) that depletes Treg cells induces synergistic antitumor activity. Gal-9 expression and secretion are promoted by interferon ß and γ, and high Gal-9 expression correlates with poor prognosis in multiple human cancers. Our work uncovers a function for PD-1 in exhausted T cell survival and suggests Gal-9 as a promising target for immunotherapy.

Erratum: The stabilization of PD-L1 by the endoplasmic reticulum stress protein GRP78 in triple-negative breast cancer.

[This corrects the article on p. 2621 in vol. 10, PMID: 32905506.].

An Overview of ADAM9: Structure, Activation, and Regulation in Human Diseases.

ADAM9 (A disintegrin and a metalloprotease 9) is a membrane-anchored protein that participates in a variety of physiological functions, primarily through the disintegrin domain for adhesion and the metalloprotease domain for ectodomain shedding of a wide variety of cell surface proteins. ADAM9 influences the developmental process, inflammation, and degenerative diseases. Recently, increasing evidence has shown that ADAM9 plays an important role in tumor biology. Overexpression of ADAM9 has been found in several cancer types and is correlated with tumor aggressiveness and poor prognosis. In addition, through either proteolytic or non-proteolytic pathways, ADAM9 promotes tumor progression, therapeutic resistance, and metastasis of cancers. Therefore, comprehensively understanding the mechanism of ADAM9 is crucial for the development of therapeutic anti-cancer strategies. In this review, we summarize the current understanding of ADAM9 in biological function, pathophysiological diseases, and various cancers. Recent advances in therapeutic strategies using ADAM9-related pathways are presented as well.

The stabilization of PD-L1 by the endoplasmic reticulum stress protein GRP78 in triple-negative breast cancer.

The immune checkpoint blockade therapy has emerged as encouraging treatment strategies in various cancer types. Anti-PD-L1 (programmed death-ligand 1) antibodies have been approved for triple-negative breast cancer, however the response rate yet to be optimized. It would be imperative to further understand and investigate the molecular mechanisms of PD-L1 regulation. Here, we identified glucose regulatory protein 78 (GRP78), a major endoplasmic reticulum (ER) stress responding protein, as a novel binding partner of PD-L1. GRP78 interacts with PD-L1 at the ER region and increases PD-L1 levels via regulating its stability. ER stress, triggered by different stimuli such as conventional chemotherapy, leads to the induction of PD-L1 in a GRP78-dependent manner. We showed that GRP78 modulates the response to chemotherapy, and dual-high levels of GRP78 and PD-L1 correlates with poor relapse-free survival in triple-negative breast cancer. Altogether, our study provides novel molecular insights into the regulatory mechanism of PD-L1 by revealing its interaction with GRP78, and offers a rationale to target GRP78 as a potential therapeutic strategy to enhance anti-tumor immunity.

Therapeutic effects of statins against lung adenocarcinoma via p53 mutant-mediated apoptosis.

The p53 gene is an important tumour suppressor gene. Mutant p53 genes account for about half of all lung cancer cases. There is increasing evidence for the anti-tumour effects of statins via inhibition of the mevalonate pathway. We retrospectively investigated the correlation between statin use and lung cancer prognosis using the Taiwanese National Health Insurance Research Database, mainly focusing on early-stage lung cancer. This study reports the protective effects of statin use in early-stage lung cancer patients regardless of chemotherapy. Statin treatments reduced the 5-year mortality (odds ratio, 0.43; P < 0.001) in this population-based study. Significantly higher levels of cellular apoptosis, inhibited cell growth, and regulated lipid raft content were observed in mutant p53 lung cancer cells treated with simvastatin. Further, simvastatin increased the caspase-dependent apoptotic pathway, promotes mutant p53 protein degradation, and decreased motile activity in lung cancer cells with p53 missense mutations. These data suggest that statin use in selected lung cancer patients may have clinical benefits.

Cytomegalovirus Infection and Treatment in Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Study from a Single Institution in an Endemic Area.

OBJECTIVE: Although Cytomegalovirus (CMV) infection is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), the risk factors for CMV reactivation and treatment failure in CMV endemic areas have remained unclear. This study investigated the risk factors for CMV reactivation among allo-HSCT recipients in an area where CMV is highly endemic. MATERIALS AND METHODS: Medical records of 82 allo-HSCT recipients from a CMV endemic area were retrospectively reviewed. The patients were stratified into two groups: those with CMV reactivation (n=32) and those without CMV reactivation (n=50). We investigated possible variables associated with CMV reactivation and treatment failure. RESULTS: Univariate analyses showed that non-remission disease status [hazard ratio (HR): 2.15; p=0.032] and ≥grade III acute graft-versus-host disease (GVHD) (HR: 3.07; p=0.002) were associated with CMV reactivation. Multivariate analysis further demonstrated that older age (HR: 1.03; p=0.029) and ≥grade III acute GVHD (HR: 2.98; p=0.012) were associated with CMV reactivation. Overall survival time seemed lower among patients with CMV reactivation than among patients without CMV reactivation, although the difference was not statistically significant (p=0.165). The absence of ≥grade III acute GVHD was associated with successful CMV treatment in the current study (odds ratio: 4.40; p=0.008). CONCLUSION: Prophylactic anti-CMV therapy might need to be considered for allo-HSCT recipients who have ≥grade III GVHD.

Palonosetron versus first-generation 5-hydroxytryptamine type 3 receptor antagonists for emesis prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation.

First-generation 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists (RAs) are currently the standard of care for prophylaxis against allo-HSCT-induced emesis. However, the efficacy of this combination in allo-HSCT recipients is not entirely satisfying. We sought to compare the efficacy of first-generation 5-HT3 RAs with that of second-generation 5-HT3 RAs in emesis prevention in allo-HSCT recipients. A total of 51 consecutive patients undergoing allo-HSCT for various hematological diseases in our institution were retrospectively reviewed. Patients who received daily first-generation 5-HT3 RAs, and 60-h palonosetron for emesis prophylaxis were stratified into the standard (n = 23) and palonosetron (n = 28) groups, respectively. Emesis severity and rescue therapy requirements in patients between these two groups were compared. Our results showed patients in standard and palonosetron groups had comparable severity of both acute and delayed emesis. However, 52.2 % of the patients in the standard group required rescue therapy, compared to only 21.4 % of the patients in the palonosetron group (p = 0.046). Subgroup analysis showed rescue therapy for acute emesis was required by 26.1 % of the patients in the standard group and by only 3.6 % of the patients in the palonosetron group (p = 0.037). In conclusion, palonosetron and first-generation 5-HT3 RAs were at least equally effective in emesis prophylaxis for allo-HSCT recipients. Patients receiving palonosetron, especially for acute emesis, required rescue therapy less frequently than those receiving first-generation 5-HT3 RAs.

Design and evaluation of a portable optical-based biosensor for testing whole blood prothrombin time.

Point-of-care diagnostics (POCD) for blood coagulation benefit patients on-site, but available POCD devices are too expensive to be affordable in many countries. Optically based methodologies are cheap and reliable, and have been exploited in bench-top coagulometers to monitor coagulation with plasma, but not whole blood, which contains cellular components that cause massive interference. However, the POCD testing of whole blood gives a more accurate picture of physiological conditions than does testing plasma. In this study, a portable device for performing the prothrombin time (PT) test was designed, comprising an optical sensor, an electrical processing and control circuit to monitor the optical changes that occurred during the coagulation process in whole blood. The PT was when the slope of the first-order derivative of the coagulation curve, recorded from real-time light transmittance signals, was maximal. The POCD PT testing of 167 samples revealed that 153 (91.6%) were successfully detected and the results were highly consistent with the results of whole blood international normalized ratio (INR) (r=0.985, p<0.001) by the conventional manual method and those of plasma INR (r=0.948, p<0.001) with the ACL TOP 700 bench-top coagulometer (Beckman Colter). Hematological parameters were further analyzed, revealing that fibrinogen titers (p=0.036), red blood cell numbers (p=0.017) and distribution of red cell width (p=0.015) affected the effectiveness of the current POCD PT determination. Furthermore, a highly positive correlation was revealed between fibrinogen titers and the maximum speed of change in transmittance (v/t) (r=0.805, p<0.001), suggesting that fibrinogen might be evaluated simultaneously in this POCD testing. In conclusion, the proposed portable optical-based device performs the highly sensitive and accurate determination of whole blood PT and has commercial potential because of its small volume and low fabrication cost.