The Impact of Race on Pancreatic Cancer Treatment and Survival in the Nationwide Veterans Affairs Healthcare System.

OBJECTIVES: Among patients with pancreatic cancer, studies show racial disparities at multiple steps of the cancer care pathway. Access to healthcare is a frequently cited cause of these disparities. It remains unclear if racial disparities exist in an integrated, equal access public system such as the Veterans Affairs healthcare system. METHODS: We identified all patients diagnosed with pancreatic adenocarcinoma in the national Veterans Affairs Central Cancer Registry from January 2010 to December 2018. We examined the independent association between race and 3 endpoints: stage at diagnosis, receipt of treatment, and survival while adjusting for sociodemographic factors and medical comorbidities. RESULTS: We identified 8529 patients with pancreatic adenocarcinoma, of whom 79.5% were White and 20.5% were Black. Black patients were 19% more likely to have late-stage disease and 25% less likely to undergo surgical resection. Black patients had 13% higher mortality risk compared with White patients after adjusting for sociodemographic characteristics and medical comorbidities. This difference in mortality was no longer statistically significant after additionally adjusting for cancer stage and receipt of potentially curative treatment. CONCLUSIONS: Equal access to healthcare might have reduced but failed to eliminate disparities. Dedicated efforts are needed to understand reasons underlying these disparities in an attempt to close these persistent gaps.

Has the trend in pancreatic cancer mortality in Spain started to slow down?

Introduction: the aim of this study was to describe the trends of pancreatic cancer mortality by autonomous communities (ACs) and gender in Spain (1980-2021). Methods: an ecological trend study was performed (with aggregated data obtained from the National Institute of Statistics). Age-standardized mortality rates (ASMRs) for pancreatic cancer (per 100,000) were estimated by direct standardization, using the European standard population. Trends in ASMR (all ages and truncated 35-64 years) were analyzed by sex in each AC using a joinpoint regression model. The annual percent changes (APC) and average annual percentage of change (AAPC) were computed for trends using the joinpoint regression analysis. Results: in both sexes, ASMRs (all ages) increased significantly (p < 0.05) during the study period (AAPC: 1.5 % in males and 1.8 % in females). The joinpoint analysis identified a turning point in the trends in the late 1980s, which delineates two periods: an initial period of significant increase followed by a period of slowing of the increase (APC: 0.9 % and 1.4 % in males and females respectively; p < 0.05). In both sexes, a significant increase in ASMR (all ages) was observed in all ACs, except in Navarre, where the rates remained stable in males. In males, three ACs (Galicia, Madrid and Navarre) showed a point of inflexion in the time trend around the year 2000 (1999, 2000 and 2001 respectively), when the rates, after a period of significant increase (ACs: 2.6 %, 2.4 %, and 2.4 %, respectively; p < 0.05), stabilized (Galicia and Navarre) or the increase slowed (Madrid). In females, only Madrid showed a point of inflection in 1992, when, after a significant increase, the rates slowed down (1992-2021; APC: 1.5 %; p < 0.05).  Conclusions: the upward trend in pancreatic cancer mortality in some ACs seems to have slowed (in both sexes in Madrid), stabilized (in men in Galicia and Navarre) or turned around (in men aged 30-64 in Navarre) (AU)

Disparities in Surgical Treatment of Resectable Pancreatic Adenocarcinoma at Minority Serving Hospitals.

INTRODUCTION: Minority serving hospitals (MSH) are those serving a disproportionally high number of minority patients. Previous research has demonstrated that treatment at MSH is associated with worse outcomes. We hypothesize that patients treated at MSH are less likely to undergo surgical resection of pancreatic adenocarcinoma compared to patients treated at non-MSH. METHODS: Patients with resectable pancreatic cancer were identified using the National Cancer Database. Institutions treating Black and Hispanic patients in the top decile were categorized as an MSH. Factors associated with the primary outcome of definitive surgical resection were evaluated using multivariable logistic regression. Univariate and multivariable survival analysis was performed. RESULTS: Of the 75,513 patients included in this study, 7.2% were treated at MSH. Patients treated at MSH were younger, more likely to be uninsured, and higher stage compared to those treated at non-MSH (P < 0.001). Patients treated at MSH underwent surgical resection at lower rates (MSH 40% versus non-MSH 44.5%, P < 0.001). On multivariable logistic regression, treatment at MSH was associated with decreased likelihood of undergoing definitive surgery (odds ratio 0.91, P = 0.006). Of those who underwent surgical resection, multivariable survival analysis revealed that treatment at an MSH was associated with increased morality (hazard ratio 1.12, P < 0.001). CONCLUSIONS: Patients with resectable pancreatic adenocarcinoma treated at MSH are less likely to undergo surgical resection compared to those treated at non-MSH. Targeted interventions are needed to address the unique barriers facing MSH facilities in providing care to patients with pancreatic adenocarcinoma.

SETD2 variation correlates with tumor mutational burden and MSI along with improved response to immunotherapy.

BACKGROUND: SETD2 protects against genomic instability via maintenance of homologous recombination repair (HRR) and mismatch repair (MMR) in neoplastic cells. However, it remains unclear whether SETD2 dysfunction is a complementary or independent factor to microsatellite instability-high (MSI-H) and tumor mutational burden-high (TMB-H) for immunocheckpoint inhibitor (ICI) treatment, and little is known regarding whether this type of dysfunction acts differently in various types of cancer. METHODS: This cohort study used multidimensional genomic data of 6726 sequencing samples from our cooperative and non-public GenePlus institute from April 1 through April 10, 2020. MSIsensor score, HRD score, RNAseq, mutational data, and corresponding clinical data were obtained from the TCGA and MSKCC cohort for seven solid tumor types. RESULTS: A total of 1021 genes underwent target panel sequencing reveal that SETD2 mutations were associated with a higher TMB. SETD2 deleterious mutation dysfunction affected ICI treatment prognosis independently of TMB-H (p < 0.01) and had a lower death hazard than TMB-H in pancancer patients (0.511 vs 0.757). Significantly higher MSI and lower homologous recombination deficiency were observed in the SETD2 deleterious mutation group. Improved survival rate was found in the MSKCC-IO cohort (P < 0.0001) and was further confirmed in our Chinese cohort. CONCLUSION: We found that SETD2 dysfunction affects ICI treatment prognosis independently of TMB-H and has a lower death hazard than TMB-H in pancancer patients. Therefore, SETD2 has the potential to serve as a candidate biomarker for ICI treatment. Additionally, SETD2 should be considered when dMMR is detected by immunohistochemistry.

Acid sphingomyelinase expression is associated with survival in resectable pancreatic ductal adenocarcinoma.

Pancreatic adenocarcinoma (PDAC) is one of the most common cancers worldwide. Unfortunately, the prognosis of PDAC is rather poor, and for instance, in the USA, over 47,000 people die because of pancreatic cancer annually. Here, we demonstrate that high expression of acid sphingomyelinase in PDAC strongly correlates with long-term survival of patients, as revealed by the analysis of two independent data sources. The positive effects of acid sphingomyelinase expression on long-term survival of PDAC patients were independent of patient demographics as well as tumor grade, lymph node involvement, perineural invasion, tumor stage, lymphovascular invasion, and adjuvant therapy. We also demonstrate that genetic deficiency or pharmacological inhibition of the acid sphingomyelinase promotes tumor growth in an orthotopic mouse model of PDAC. This is mirrored by a poorer pathologic response, as defined by the College of American Pathologists (CAP) score for pancreatic cancer, to neoadjuvant therapy of patients co-treated with functional inhibitors of the acid sphingomyelinase, in particular tricyclic antidepressants and selective serotonin reuptake inhibitors, in a retrospective analysis. Our data indicate expression of the acid sphingomyelinase in PDAC as a prognostic marker for tumor progression. They further suggest that the use of functional inhibitors of the acid sphingomyelinase, at least of tricyclic antidepressants and selective serotonin reuptake inhibitors in patients with PDAC, is contra-indicated. Finally, our data also suggest a potential novel treatment of PDAC patients with recombinant acid sphingomyelinase. KEY MESSAGES: Pancreatic ductal adenocarcinoma (PDAC) is a common tumor with poor prognosis. Expression of acid sphingomyelinase (ASM) determines outcome of PDAC. Genetic deficiency or pharmacologic inhibition of ASM promotes tumor growth in a mouse model. Inhibition of ASM during neoadjuvant treatment for PDAC correlates with worse pathology. ASM expression is a prognostic marker and potential target in PDAC.

Multicenter Retrospective Analysis of Original versus Modified FOLFIRINOX in Metastatic Pancreatic Cancer: Results of the NAPOLEON Study.

INTRODUCTION: Original FOLFIRINOX (oFFX) is more toxic than other regimens for patients with metastatic pancreatic cancer (mPC); therefore, a modified FFX (mFFX) regimen with a reduced dosage has been used in Japanese clinical practice. However, very few studies have compared these two regimens. METHODS: This study was conducted as part of a multicenter retrospective study of 318 patients with mPC across 14 centers in Japan (NAPOLEON study). To control for potential bias and confounders, we conducted a propensity score-adjusted analysis of patient characteristics and clinical outcomes. RESULTS: oFFX and mFFX were administered to 48 and 54 patients. More patients with younger age and poorer performance status were included in the oFFX group. The overall survival (OS; median, 11.6 vs. 11.3 months; hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.60-1.40; p = 0.67), progression-free survival (PFS) (median, 6.3 vs. 5.7 months; HR, 0.85; 95% CI, 0.56-1.28; p = 0.44), and overall response rate (29 vs. 26%, p = 0.71) were not significantly different for the oFFX and mFFX groups. Thrombopenia and liver dysfunction were significantly more frequent with oFFX than with mFFX. The median received dose intensity of CPT-11 was higher with oFFX than with mFFX (299 vs. 270 mg/m2/week, p < 0.01). The propensity score-adjusted analysis revealed no statistically significant differences in OS and PFS between the two groups. CONCLUSION: In our data, there was no significant difference in efficacy between mFFX and oFFX, and mFFX has fewer adverse events.

Association of Adjuvant Chemotherapy in Patients With Resected Pancreatic Adenocarcinoma After Multiagent Neoadjuvant Chemotherapy.

Importance: The total number of patients with pancreatic ductal adenocarcinoma (PDAC) who receive neoadjuvant chemotherapy (NAC) is increasing. However, the added role of adjuvant chemotherapy (AC) in these patients remains unknown. Objective: To evaluate the association of AC with overall survival (OS) in patients with PDAC who received multiagent NAC followed by curative-intent surgery. Design, Setting, and Participants: This retrospective, matched-cohort study used data from the National Cancer Database and included patients with PDAC diagnosed between 2010 and 2018. The study included patients at least 18 years of age who received multiagent NAC followed by surgical resection and had available records of the pathological findings. Patients were excluded if they had clinical or pathological stage IV disease or died within 90 days of their operation. Exposures: All included patients received NAC and underwent resection for primary PDAC. Some patients received adjuvant chemotherapy. Main Outcomes and Measures: The main outcome was the OS of patients who received AC (AC group) vs those who did not (non-AC group). Interactions between pathological findings and AC were investigated in separate multivariable Cox regression models. Results: In total, 1132 patients (mean [SD] age, 63.5 [9.4] years; 577 [50.1%] male; 970 [85.7%] White) were included, 640 patients in the non-AC group and 492 patients in the AC group. After being matched by propensity score according to demographic and pathological characteristics, 444 patients remained in each group. The multivariable Cox regression model adjusted for all covariates revealed an association between AC and improved survival (hazard ratio, 0.71; 95% CI, 0.59-0.85; P < .001). Subgroup interaction analysis revealed that AC was significantly associated with better OS (26.6 vs 21.2 months; P = .002), but the benefit varied by age, pathological T category, and tumor differentiation. Of note, AC was associated with better survival in patients with any pathological N category and positive margin status. Conclusions and Relevance: In this cohort study, AC following multiagent NAC and resection in patients with PDAC was associated with significant survival benefit compared with that in patients who did not receive AC. These findings suggest that patients with aggressive tumors may benefit from AC to achieve prolonged survival, even after multiagent NAC and curative-intent resection.

Epidemiologia do câncer de pâncreas na América Latina e no Brasil / Epidemiology of pancreatic cancer in Latin America and Brazil

Introdução: O câncer de pâncreas é um tumor de alta letalidade, é o décimo segundo tipo mais comum e a sétima causa de morte, em ambos os sexos, no mundo. Estima-se que o câncer de pâncreas terá um aumento contínuo de incidência e mortalidade nos próximos 20 anos e isso causará um enorme ônus econômico para as populações em todo o mundo. Para o monitoramento e vigilância epidemiológica em câncer, pode-se apoiar em dados secundários como no Sistema de Informação em Mortalidade e dos registros de câncer (de base populacional e hospitalares) e estimativas a partir destes dados; por essa razão, investigou-se a epidemiologia do câncer de pâncreas na América Latina e no Brasil. Métodos: A tese compreende três manuscritos: (i) tendências de incidência, mortalidade e anos de vida ajustados por incapacidade (DALYs), bem como a fração de mortes por câncer de pâncreas atribuíveis a fatores de risco comportamentais e metabólicos em países da América Latina e Caribe (LAC) entre 1990 e 2019 (Global Burden Disease, 2019); (ii) mortalidade por câncer de pâncreas no Brasil e unidades da federação entre 1979 e 2019, dados do Sistema de Informação em Mortalidade (SIM); (iii) comparabilidade, validade, completude e pontualidade para cinco tumores gastrointestinais, câncer de esôfago, estômago, colorretal, fígado e pâncreas, em Registros de Câncer de Base Populacional (RCBPs) brasileiros. Resultados: Observou-se um aumento na incidência, mortalidade e DALYs para o câncer de pâncreas em ambos os sexos na maioria dos países da América Latina e Caribe; as maiores taxas de incidência e mortalidade foram observadas no Uruguai e as menores no Haiti. Redução na fração de mortes atribuíveis ao tabagismo entre 1990 e 2019, para ambos os sexos nos países da LAC; entretanto, aumento dentre os fatores metabólicos. No Brasil, entre 1979 e 2019, foram notificados um total de 209.425 óbitos por câncer de pâncreas, com tendência de aumento de 1,5% ao ano em homens e 1,9% em mulheres. Houve tendência de aumento da mortalidade na maioria dos estados brasileiros, com maiores tendências nas regiões Norte e Nordeste, e correlação positiva entre o índice de desenvolvimento humano e a tendência de aumento da mortalidade por câncer de pâncreas. Dentre os dezesseis RCBPs brasileiros estudados, todos atenderam aos critérios de comparabilidade, porém metade apresentou índices abaixo do esperado para validade e completude para tumores de fígado e pâncreas. Para pontualidade, os dezesseis registros apresentaram mais de 48 meses de atraso na divulgação dos dados em relação ao ano calendário de 2023. Considerações finais: O câncer de pâncreas representa um desafio para a saúde pública nos países da América Latina e no Brasil, diante do desafio na redução da incidência e da mortalidade, assim como na vigilância epidemiológica em câncer através dos RCBPs brasileiros que necessitam de suporte para continuidade do monitoramento da incidência do câncer.

Introduction: Pancreatic cancer is a tumor of high lethality, is the twelfth most common type and the seventh cause of death, in both sexes, in the world. It is estimated that pancreatic cancer will have a continuous increase in incidence and mortality over the next 20 years and this will cause a huge economic burden for populations around the world. For epidemiological monitoring and surveillance in cancer, it is possible to use on secondary data such as the Mortality Information System and cancer registries (population-based and hospital) and estimates from these data, for this reason the epidemiology of pancreatic cancer in Latin America and Brazil was investigated. Methods: The thesis comprises three manuscripts: (i) trends in incidence, mortality and disability-adjusted life years (DALYs) as well as the fraction of pancreatic cancer deaths attributable to behavioral and metabolic risk factors in Latin American and Caribbean (LAC) countries between 1990 and 2019 (Global Burden Disease, GBD 2019); (ii) mortality from pancreatic cancer in Brazil and federal units between 1979 and 2019, data from the Mortality Information System (SIM); (iii) comparability, validity, completeness and timeless for five gastrointestinal tumors, esophageal, stomach, colorectal, liver and pancreatic cancers, in the Brazilian Population-Based Cancer Registries (PBCRs). Results: An increase in the incidence, mortality and DALYs of pancreatic cancer was observed in most countries in Latin America and the Caribbean, the highest incidence and mortality rates were observed in Uruguay and the lowest in Haiti. The fraction of pancreatic cancer deaths attributable to smoking reduced between 1990 and 2019 for both sexes in LAC countries, however, it increased for metabolic risk factors. In Brazil, between 1979 and 2019, a total of 209,425 deaths from pancreatic cancer were reported, with a trend of increase of 1.5% per year in men and 1.9% in women. There was an increase in mortality in most Brazilian states, higher in the North and Northeast regions with a positive correlation between the improvement of the human development index and the trend of increased mortality from pancreatic cancer. Among the sixteen Brazilian PBCRs studied, all agreement the criteria of comparability, but half have lower than expected indices for validity and completeness for liver and pancreatic tumors, and as for timeless the sixteen records are more than 48 months late in the release of data in relation to the calendar year 2023. Conclusions: Pancreatic cancer represents a challenge for public health in LAC and Brazil, given the challenge in reducing incidence and mortality, as well as in epidemiological surveillance in cancer through Brazilian PBCRs to ensure the activity and stability for continued monitoring of cancer incidence.

Factors associated with pancreatic cancer in Spain. What can we learn from epidemiological studies?

The incidence of pancreatic cancer (PC) in Spain has progressively increased over the past 6 decades. Pancreatic ductal adenocarcinoma represents over 80 % of all pancreatic neoplasms. The study by Enrique Gili-Ortiz on pancreatic cancer-related mortality trends in Spain revealed a significant increase in death rates in our country, which may be partly attributed to population ageing and increased smoking, obesity, and diabetes rates. Other known factors, including chronic pancreatitis, seem to play a less significant role from a quantitative perspective.

Brucein D augments the chemosensitivity of gemcitabine in pancreatic cancer via inhibiting the Nrf2 pathway.

BACKGROUND: Gemcitabine (GEM) is the first-line chemotherapeutic drug used to treat pancreatic ductal adenocarcinoma carcinoma (PDAC), but chemoresistance is often encountered clinically. Nrf2, an oxidative stress responsive transcription factor, is an important contributor to chemoresistance and poor prognosis of PDAC. Brucein D (BD), a naturally occurring quassinoid, has been reported to exert anti-tumor effect in several cancers including PDAC. In this study, we aimed to investigate the efficacy of BD and the role of Nrf2 axes on the chemosensitivity of GEM and elucidate the underlying molecular mechanisms. METHODS: Analyses of clinical samples of PDAC and GEPIA database were first conducted to identify the expression of Nrf2 in PDAC. We then established cell lines with stable deletion of Nrf2 through transfecting lentivirus into PDAC cells. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to determine the expression of Nrf2 in these cell lines. The effects of BD and Nrf2 axes on PDAC cell proliferation, colony-formation, tumor growth and chemosensitivity were determined both in vitro and in vivo. Orthotopic xenograft and genetically engineered KPC mouse models of PDAC were used to evaluate the anti-pancreatic cancer effects of BD and GEM. RESULTS: Nrf2 was highly expressed in PDAC in the clinical samples and GEPIA analysis. Gain- and lost-function study demonstrated that Nrf2 affected the chemosensitivity of GEM on PDAC cells both in vitro and in vivo. We further found that BD effectively inhibited PDAC cell proliferation and enhanced the chemosensitivity of GEM. Mechanistic studies revealed that BD sensitized GEM in PDAC cells through the ubiquitin-proteasome-dependent degradation of Nrf2, and downregulating the Nrf2 pathway. Silencing of Nrf2 plus BD treatment resulted in more potent inhibitory effects of GEM. In contrast, Nrf2 activation attenuated the chemosensitivity of GEM, indicating that the action of BD was Nrf2 dependent. Finally, the efficacy of BD alone and in combination with GEM on PDAC was validated on both orthotopic xenograft and genetically engineered KPC mouse models. CONCLUSIONS: BD was able to enhance the chemosensitivity of GEM in PDAC through inhibition of the Nrf2 pathway. Our experimental findings indicate that BD, a potent Nrf2 inhibitor, holds promise for further development into a novel adjuvant therapy for PDAC.

Bayesian Approach to Understand the Association Between Treatment Down-staging and Survival for Patients With Pancreatic Adenocarcinoma.

OBJECTIVE: To evaluate the association between staging concordance, treatment sequencing, and response to neoadjuvant therapy (NAT) on the survival of patients with pancreatic ductal adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA: NAT is increasingly utilized in the management of patients with PDAC, but it is unclear whether its benefit is contingent on tumor down-staging. METHODS: This was a cohort study of stage I-III PDAC patients in the National Cancer Database (2006-2015) treated with upfront resection or NAT followed by surgery. We determined staging concordance using patients' clinical and pathological staging data. For NAT patients, we used Bayesian analysis to ascertain staging concordance accounting for down-staging. RESULTS: Among 16,597 patients treated at 979 hospitals, 13,982 had an upfront resection and 2,615 NAT followed by surgery. Overall survival (OS) at 5-years ranged from 26.0% (95% CI 24.9%-27.1%) among cT1-2N0 patients to 18.6% (17.9%-19.2%) among cT1-3N+ ones. Patients with cT3-4 or cN+ tumors had improved OS after NAT compared to upfront surgery (all p< 0.001), while there was no difference among patients with cT1-2N0 (P = 0.16) disease. Relative to accurately staged cT1-2-3N+ or cT4 patients treated with upfront surgery, NAT was associated with a lower risk of death [HR 0.46 (0.37-0.57) for N+; HR 0.56 (0.40-0.77) for T4 disease], even among those without tumor down-staging [HR 0.81 (0.73-0.90) for N+; HR 0.48 (0.39-0.60) for T4]. CONCLUSIONS: NAT is associated with improved survival for PDAC, particularly for patients with more advanced disease and regardless of down-staging. Consideration should be given to recommending NAT for all PDAC patients.

Fungal mycobiome drives IL-33 secretion and type 2 immunity in pancreatic cancer.

TH2 cells and innate lymphoid cells 2 (ILC2) can stimulate tumor growth by secreting pro-tumorigenic cytokines such as interleukin-4 (IL-4), IL-5, and IL-13. However, the mechanisms by which type 2 immune cells traffic to the tumor microenvironment are unknown. Here, we show that oncogenic KrasG12D increases IL-33 expression in pancreatic ductal adenocarcinoma (PDAC) cells, which recruits and activates TH2 and ILC2 cells. Correspondingly, cancer-cell-specific deletion of IL-33 reduces TH2 and ILC2 recruitment and promotes tumor regression. Unexpectedly, IL-33 secretion is dependent on the intratumoral fungal mycobiome. Genetic deletion of IL-33 or anti-fungal treatment decreases TH2 and ILC2 infiltration and increases survival. Consistently, high IL-33 expression is observed in approximately 20% of human PDAC, and expression is mainly restricted to cancer cells. These data expand our knowledge of the mechanisms driving PDAC tumor progression and identify therapeutically targetable pathways involving intratumoral mycobiome-driven secretion of IL-33.

Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity.

The aryl hydrocarbon receptor (AhR) is a sensor of products of tryptophan metabolism and a potent modulator of immunity. Here, we examined the impact of AhR in tumor-associated macrophage (TAM) function in pancreatic ductal adenocarcinoma (PDAC). TAMs exhibited high AhR activity and Ahr-deficient macrophages developed an inflammatory phenotype. Deletion of Ahr in myeloid cells or pharmacologic inhibition of AhR reduced PDAC growth, improved efficacy of immune checkpoint blockade, and increased intra-tumoral frequencies of IFNγ+CD8+ T cells. Macrophage tryptophan metabolism was not required for this effect. Rather, macrophage AhR activity was dependent on Lactobacillus metabolization of dietary tryptophan to indoles. Removal of dietary tryptophan reduced TAM AhR activity and promoted intra-tumoral accumulation of TNFα+IFNγ+CD8+ T cells; provision of dietary indoles blocked this effect. In patients with PDAC, high AHR expression associated with rapid disease progression and mortality, as well as with an immune-suppressive TAM phenotype, suggesting conservation of this regulatory axis in human disease.

Combination therapy for pancreatic cancer: anti-PD-(L)1-based strategy.

Mortality associated with pancreatic cancer is among the highest of all malignancies, with a 5-year overall survival of 5-10%. Immunotherapy, represented by the blocking antibodies against programmed cell death protein 1 or its ligand 1 (anti-PD-(L)1), has achieved remarkable success in a number of malignancies. However, due to the immune-suppressive tumor microenvironment, the therapeutic efficacy of anti-PD-(L)1 in pancreatic cancer is far from expectation. To address such a fundamental issue, chemotherapy, radiotherapy, targeted therapy and even immunotherapy itself, have individually been attempted to combine with anti-PD-(L)1 in preclinical and clinical investigation. This review, with a particular focus on pancreatic cancer therapy, collects current anti-PD-(L)1-based combination strategy, highlights potential adverse effects of accumulative combination, and further points out future direction in optimization of combination, including targeting post-translational modification of PD-(L)1 and improving precision of treatment.

Prediction of overall survival in patients with pancreatic ductal adenocarcinoma: histogram analysis of ADC value and correlation with pathological intratumoral necrosis.

BACKGROUND: To evaluate the utility of histogram analysis (HA) of apparent diffusion coefficient (ADC) values to predict the overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC) and to correlate with pathologically evaluated massive intratumoral necrosis (MITN). MATERIALS AND METHODS: Thirty-nine patients were included in this retrospective study with surgically resected PDAC who underwent preoperative magnetic resonance imaging. Twelve patients received neoadjuvant chemotherapy. HA on the ADC maps were performed to obtain the tumor HA parameters. Using Cox proportional regression analysis adjusted for age, time-dependent receiver-operating-characteristic (ROC) curve analysis, and Kaplan-Meier estimation, we evaluated the association between HA parameters and OS. The association between prognostic factors and pathologically confirmed MITN was assessed by logistic regression analysis. RESULTS: The median OS was 19.9 months. The kurtosis (P < 0.001), entropy (P = 0.013), and energy (P = 0.04) were significantly associated with OS. The kurtosis had the highest area under the ROC curve (AUC) for predicting 3-year survival (AUC 0.824) among these three parameters. Between the kurtosis and MITN, the logistic regression model revealed a positive correlation (P = 0.045). Lower survival rates occurred in patients with high kurtosis (cutoff value > 2.45) than those with low kurtosis (≤ 2.45) (P < 0.001: 1-year survival rate, 75.2% versus 100%: 3-year survival rate, 14.7% versus 100%). CONCLUSIONS: HA derived kurtosis obtained from tumor ADC maps might be a potential imaging biomarker for predicting the presence of MITN and OS in patients with PDAC.

Angiotensin blockade therapy and survival in pancreatic cancer: a population study.

BACKGROUND: Pancreatic cancer (PC) is one of the most aggressive and challenging cancer types to effectively treat, ranking as the fourth-leading cause of cancer death in the United States. We investigated if exposures to angiotensin II receptor blockers (ARBs) or angiotensin I converting enzyme (ACE) inhibitors after PC diagnosis are associated with survival. METHODS: PC patients were identified by ICD-9 diagnosis and procedure codes among the 3.7 million adults living in the Emilia-Romagna Region from their administrative health care database containing patient data on demographics, hospital discharges, all-cause mortality, and outpatient pharmacy prescriptions. Cox modeling estimated covariate-adjusted mortality hazard ratios for time-dependent ARB and ACE inhibitor exposures after PC diagnosis. RESULTS: 8,158 incident PC patients were identified between 2003 and 2011, among whom 20% had pancreas resection surgery, 36% were diagnosed with metastatic disease, and 7,027 (86%) died by December 2012. Compared to otherwise similar patients, those exposed to ARBs after PC diagnosis experienced 20% lower mortality risk (HR=0.80; 95% CI: 0.72, 0.89). Those exposed to ACE inhibitors during the first three years of survival after PC diagnosis experienced 13% lower mortality risk (HR=0.87; 95% CI: 0.80, 0.94) which attenuated after surviving three years (HR=1.14; 95% CI: 0.90, 1.45). CONCLUSIONS: The results of this large population study suggest that exposures to ARBs and ACE inhibitors after PC diagnosis are significantly associated with improved survival. ARBs and ACE inhibitors could be important considerations for treating PC patients, particularly those with the worst prognosis and most limited treatment options. Considering that these common FDA approved drugs are inexpensive to payers and present minimal increased risk of adverse events to patients, there is an urgent need for randomized clinical trials, large simple randomized trials, or pragmatic clinical trials to formally and broadly evaluate the effects of ARBs and ACE inhibitors on survival in PC patients.

The genetic landscape of pancreatic head ductal adenocarcinoma in China and prognosis stratification.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the major subtype of pancreatic cancer and head PDACs show distinct characteristics from body/tail PDACs. With limited studies based on Asian population, the mutational landscape of Asian PDAC remains unclear. METHODS: One hundred fifty-one Chinese patients with head PDAC were selected and underwent targeted 425-gene sequencing. Genomic alterations, tumor mutational burden, and microsatellite instability were analyzed and compared with a TCGA cohort. RESULTS: The genomic landscape of Chinese and Western head PDAC had identical frequently-mutated genes including KRAS, TP53, SMAD4, and CDKN2A. KRAS hotspot in both cohorts was codon 12 but Chinese PDACs containing more G12V but fewer G12R variants. Potentially pathogenic fusions, CHD2-BRAF and KANK1-MET were identified in two KRAS wild-type patients. Serum cancer antigens CA125 and CA19-9 were positively associated with SMAD4 alterations while high CEA was enriched in wild-type CDKN2A subgroup. The probability of vascular invasion was lower in patients with RNF43 alterations. The nomogram developed including histology grade, the mutation status of SMAD4, TGFBR2, and PREX2 could calculate the risk score of prognoses validated by Chinese and TCGA cohort. CONCLUSIONS: Chinese head PDAC contained more KRAS G12V mutation than Western population. The well-performed nomogram may improve post-operation care in real-world practice.

Platelet to Lymphocyte Ratio Correlates With Carcinoma Progression in Pancreatic Intra Epithelial Neoplasia.

BACKGROUND/AIM: Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion to pancreatic adenocarcinoma (PDAC). Yet no criteria to quantify patients at risk for progression to PDAC with PanIN exist. Platelet to lymphocyte ratio is an inflammatory marker that has been associated with overall survival in patients with invasive malignancies including pancreatic cancer. Preoperative sarcopenia has been linked to more aggressive diseases in pancreatic neoplasms. We aimed to assess a relation between PLR and sarcopenia as predictors for tumor progression in patients undergoing pancreatic resection for IPMN. PATIENTS AND METHODS: We retrospectively reviewed 102 patients (46 females, 56 males) who underwent pancreatic resection for PanIn. PLR was calculated and quantified using a cutoff of 110, sarcopenia was quantified using the skeletal muscle index (SMI) on preoperative abdominal imaging. Both were co-evaluated with additional demographic, clinical, pathological, and imaging data for possible correlation with PanIN associated PDAC. RESULTS: PLR was significantly elevated in patients with PanIN - associated PDAC (p=0.006). In the multivariate analysis, invasive carcinomas were significantly more prevalent in patients with PLR above 110 (OR=4.06, 95%CI=3.91-4.12, p=0.04). Patients with elevated PLR had a two-times higher risk to die in the postoperative period (HR=2.26, 95%CI=1.04-2.21, p=0.001). Patients with elevated PLR, preoperative jaundice and sarcopenia were the most likely to have PanIN-associated PDAC (OR=3.48, 95%CI=2.98-8.41, p=0.02). CONCLUSION: PLR is an independent predictive marker for the presence of PanIN associated invasive carcinoma.

Association of facility type with overall survival in patients with nonsurgically managed pancreatic cancer.

Aim: To investigate the association between receiving treatment at academic centers and overall survival in pancreatic ductal adenocarcinoma patients who do not receive definitive surgery of the pancreatic tumor. Methods: Using the National Cancer Database, patients who were diagnosed with pancreatic ductal adenocarcinoma between 2004 to 2016 were identified. Results: Of 262,209 patients, 101,003 (38.5%) received treatment at academic centers. In the multivariable Cox regression analysis, patients who received treatment at a nonacademic facility had significantly worse overall survival compared with patients who were treated at an academic center (hazard ratio: 1.279; 95% CI: 1.268-1.290; p = 0.001). Conclusion: Compared with treatment at academic centers, treatment at nonacademic centers was associated with significantly worse overall survival in patients with nonsurgically managed pancreatic ductal adenocarcinoma.

The aim of this study is to examine the association between receiving treatment at academic hospitals and overall survival in patients diagnosed with pancreatic cancer who do not receive definitive surgery of the pancreatic tumor. The authors used the National Cancer Database to identify patients who were diagnosed with pancreatic cancer between 2004 and 2016. The authors' study included 262,209 patients. The authors found that patients who received treatment at nonacademic hospitals were on average 28% more likely to die of any cause compared with patients who were treated at academic centers (hazard ratio: 1.279; 95% CI: 1.268­1.290; p < 0.001). Patients who received treatment at nonacademic hospitals were more likely to die of any cause compared with patients who received treatment at academic hospitals.