Association between Helicobacter pylori infection,mismatch repair,HER2 and tumor-infiltrating lymphocytes in gastric cancer

BACKGROUND The influence of Helicobacter-pylori(H.pylori)infection and the characteristics of gastric cancer(GC)on tumor-infiltrating lymphocyte(TIL)levels has not been extensively studied.Analysis of infiltrating-immune-cell subtypes as well as survival is necessary to obtain comprehensive information.AIM To determine the rates of deficient mismatch-repair(dMMR),HER2-status and H.pylori infection and their association with TIL levels in GC.METHODS Samples from 503 resected GC tumors were included and TIL levels were evaluated following the international-TILs-working-group recommendations with assessment of the intratumoral(IT),stromal(ST)and invasive-border(IB)compartments.The density of CD3,CD8 and CD163 immune cells,and dMMR and HER2-status were determined by immunohistochemistry(IHC).H.pylori infection was evaluated by routine histology and quantitative PCR(qPCR)in a subset of samples.RESULTS dMMR was found in 34.4%,HER2+in 5%and H.pylori-positive in 55.7%of samples.High IT-TIL was associated with grade-3(P=0.038),while ST-TIL with grade-1(P<0.001),intestinal-histology(P<0.001)and no-recurrence(P=0.003).dMMR was associated with high TIL levels in the ST(P=0.019)and IB(P=0.01)compartments,and STCD3(P=0.049)and ST-CD8(P=0.05)densities.HER2-was associated with high IT-CD8(P=0.009).H.pylorinegative was associated with high IT-TIL levels(P=0.009)when assessed by routine-histology,and with high TIL levels in the 3 compartments(P=0.002-0.047)and CD8 density in the IT and ST compartments(P=0.001)when assessed by qPCR.A longer overall survival was associated with low IT-CD163(P=0.003)and CD8/CD3(P=0.001 in IT and P=0.002 in ST)and high IT-CD3(P=0.021),ST-CD3(P=0.003)and CD3/CD163(P=0.002).CONCLUSION TIL levels were related to dMMR and H.pylori-negativity.Low CD8/CD3 and high CD163/CD3 were associated with lower recurrence and longer survival.

Selective killing of K-ras-transformed pancreatic cancer cells by targeting NAD(P)H oxidase

Introduction:Oncogenic aaivation of the K-ras gene occurs in >90%of pancreatic ductal carcinoma and plays a critical role in the pathogenesis of this malignancy.Increase of reactive oxygen species(ROS) has also been observed in a wide spectrum of cancers.This study aimed to investigate the mechanistic association between K-ras-induced transformation and increased ROS stress and its therapeutic implications in pancreatic cancer.Methods:ROS level,NADPH oxidase(NOX) aaivity and expression,and cell invasion were examined in human pancreatic dua epithelial E6E7 cells transfeaed with K-ras^(G12V) compared with parental E6E7 cells.The cytotoxic effea and antitumor effect of capsaicin,a NOX inhibitor,were also tested in vitro and in vivo.Results:K-ras transfeaion caused activation of the membrane-associated redox enzyme NOX and elevated ROS generation through the phosphatidylinositol 3'-kinase(PI3K) pathway.Importantly,capsaicin preferentially inhibited the enzyme aaivity of NOX and induced severe ROS accumulation in K-ras-transformed cells compared with parental E6E7 cells.Furthermore,capsaicin effeaively inhibited cell proliferation,prevented invasiveness of /(-ras-transformed pancreatic cancer cells,and caused minimum toxicity to parental E6E7 cells.In vivo,capsaicin exhibited antitumor aaivity against pancreatic cancer and showed oxidative damage to the xenograft tumor cells.Conclusions:K-ras oncogenic signaling causes increased ROS stress through NOX,and abnormal ROS stress can selectively kill tumor cells by using NOX inhibitors.Our study provides a basis for developing a novel therapeutic strategy to effectively kill K-ras-transformed cells through a redox-mediated mechanism.

Clinical impacts of mesothelin expression in gastrointestinal carcinomas

Mesothelin,C-ERC/mesothelin is a 40-kD a cell surface glycoprotein that is normally present on normal mesothelial cells lining the pleura,peritoneum,and pericardium.Moreover,mesothelin has been shown to be overexpressed in several human cancers,including virtually all mesothelioma and pancreatic cancer approximately 70% of ovarian cancer and extra bile duc cancer,and 50% of lung adenocarcinomas and gastric cancer.The full-length human mesothelin gene encodes the primary product,a 71-k Da precursor protein.The71-kD a mesothelin precursor is cleaved into two products40-k Da C-terminal fragment that remains membranebound via glycosylphosphatidylinositol anchor,and a31-kD a N-terminal fragment,megakaryocyte potentiating factor,which is secreted into the blood.The biologica functions of mesothelin remain largely unknown However,results of recent studies have suggested tha the mesothelin may play a role of cell proliferation and migration.In pancreatic cancer,mesothelin expression was immunohistochemically observed in all cases,bu absent in normal pancreas and in chronic pancreatitis Furthermore,the expression of mesothelin was correlated with an poorer patient outcome in severa human cancers.The limited mesothelin expression in normal tissues and high expression in many cancers makes it an attractive candidate for cancer therapy.The present review discusses the expression and function o mesothelin in cancer cells and the utility of mesothelin as a target of cancer therapy.

Pancreatic Carcinoma with Prominent Mucin Production: A Clinicopathologic and Immunohistochemical Study of 9 Cases

Pancreatic carcinoma occasionally associated with prominent mucin production and this type of tumor designated as PCM (pancreatic carcinoma with prominent mucin production) was diagnosed depends on subjective estimation of the amount of mucous area, and there has been no report on a quantitative evaluation of the amount of mucinous area in the tumor. To examine the feature of PCM, we analyzed 9 cases of PCM among 243 cases of pancreas carcinoma and evaluated the amount of mucin by imaging analysis. Morphologically, 5 cases were classified as intradactal papillary mucinous neoplasms (IPMN)-derived PCM and 4 cases were as ductal adenocarcinoma (DA)-derived PCM. Mucous composition was found to be more than 50% in all IPMN-derived PCM cases, and that was 40% - 50% in DA-derived PCM cases with one exception. IPMN-derived PCM cases showed expansive growth with pancreatic duct dilatation filled with mucin, while DA-derived PCM cases possessed mucin infiltration into interstitial tissue. Immunohisto-chemically, three of 4 DA-derived PCM cases were MUC1(–)/MUC2(+), and the results of expressions for p16 and Dpc4 suggesting that DA-derived PCM was similar to IPMN-derived PCM rather than ordinary DA. Survival rate of DA-derived PCM cases was lower than that of IPMN-derived PCM cases. We advocate that DA-derived PCM may constitute a borderline group between IPMN and ordinary DA.

Unmodified autologous stem cells at point of care for chronic myocardial infarction

BACKGROUND Numerous studies investigated cell-based therapies for myocardial infarction(MI).The conflicting results of these studies have established the need for developing innovative approaches for applying cell-based therapy for MI.Experimental studies on animal models demonstrated the potential of fresh,uncultured,unmodified,autologous adipose-derived regenerative cells(UAADRCs)for treating acute MI.In contrast,studies on the treatment of chronic MI(CMI;>4 wk post-MI)with UA-ADRCs have not been published so far.Among several methods for delivering cells to the myocardium,retrograde delivery into a temporarily blocked coronary vein has recently been demonstrated as an effective option.AIM To test the hypothesis that in experimentally-induced chronic myocardial infarction(CMI;>4 wk post-MI)in pigs,retrograde delivery of fresh,uncultured,unmodified,autologous adipose-derived regenerative cells(UA-ADRCs)into a temporarily blocked coronary vein improves cardiac function and structure.METHODS The left anterior descending(LAD)coronary artery of pigs was blocked for 180 min at time point T0.Then,either 18×106 UA-ADRCs prepared at“point of care”or saline as control were retrogradely delivered via an over-the-wire balloon catheter placed in the temporarily blocked LAD vein 4 wk after T0(T1).Effects of cells or saline were assessed by cardiac magnetic resonance(CMR)imaging,late gadolinium enhancement CMR imaging,and post mortem histologic analysis 10 wk after T0(T2).RESULTS Unlike the delivery of saline,delivery of UA-ADRCs demonstrated statistically significant improvements in cardiac function and structure at T2 compared to T1(all values given as mean±SE):Increased mean LVEF(UA-ADRCs group:34.3%±2.9%at T1 vs 40.4±2.6%at T2,P=0.037;saline group:37.8%±2.6%at T1 vs 36.2%±2.4%at T2,P>0.999),increased mean cardiac output(UA-ADRCs group:2.7±0.2 L/min at T1 vs 3.8±0.2 L/min at T2,P=0.002;saline group:3.4±0.3 L/min at T1 vs 3.6±0.3 L/min at T2,P=0.798),increased mean mass of the left ventricle(UA-ADRCs group:55.3±5.0 g at T1 vs 71.3±4.5 g at T2,P<0.001;saline group:63.2±3.4 g at T1 vs 68.4±4.0 g at T2,P=0.321)and reduced mean relative amount of scar volume of the left ventricular wall(UA-ADRCs group:20.9%±2.3%at T1 vs 16.6%±1.2%at T2,P=0.042;saline group:17.6%±1.4%at T1 vs 22.7%±1.8%at T2,P=0.022).CONCLUSION Retrograde cell delivery of UA-ADRCs in a porcine model for the study of CMI significantly improved myocardial function,increased myocardial mass and reduced the formation of scar tissue.

Racial Disparities in Survival Outcomes of Prostate Cancer Patients after Surgery for Bone Metastases

Introduction: This study reviewed patients’ demographic, clinical and treatment characteristics to identify prognostic factors associated with survival of prostate cancer after developing bone metastases. We explored the racial disparities in these factors and how they relate with survival. Methods: We conducted a retrospective study on 79 men diagnosed with bone metastasis secondary to prostate cancer who underwent surgery at a single institution?from November 1977 to June 2011. Descriptive statistics were used to summarize patients’ characteristics. The Kaplan-Meier method was used to estimate characteristics of the survival distribution using two origination points—diagnosis and surgery. Cox hazard regression explored the relationship between prognostic factors and overall survival. Results: The majority of men were White (n = 63;80%) followed by Black (n = 7;9%), Hispanic (n = 7;9%), and Asian (n = 2;2%). Multivariate factors associated with poorer survival after bone metastasis surgery included race (Black), Gleason score > 8, and radiation treatment. Patients not receiving radiation had a longer survival experience relative to patients who received radiation before or after surgery (10.3 vs 6.5 months;P = 0.030). There was an association of PSA level at the time of bone metastasis diagnosis with survival following diagnosis but prior to surgery. The median time interval (Tm in months) between prostate cancer diagnosis and bone metastasis diagnosis was 39.1 (White), 31.2 (Hispanic), 15 (Blacks) and 43 (Asians). Patients with Tm m > 35 months (HR = 3.22;P Conclusion: The median survival and time interval from prostate cancer diagnosis to bone metastasis diagnosis was shorter in Blacks with respect to other races. The more aggressive nature of the disease in Blacks is likely due to the biology of the disease rather than access to treatment.

Integrative genomic and transcriptomic profiling of pulmonary sarcomatoid carcinoma identifies molecular subtypes associated with distinct immune features and clinical outcomes

Background:Pulmonary sarcomatoid carcinoma(PSC)is a rare and aggressive subtype of non-small cell lung cancer(NSCLC),characterized by the presence of epithelial and sarcoma-like components.The molecular and immune landscape of PSC has not been well defined.Methods:Multiomics profiling of 21 pairs of PSCs with matched normal lung tissues was performed through targeted high-depth DNA panel,whole-exome,and RNA sequencing.We describe molecular and immune features that define subgroups of PSC with disparate genomic and immunogenic features as well as distinct clinical outcomes.Results:In total,27 canonical cancer gene mutations were identified,with TP53 the most frequently mutated gene,followed by KRAS.Interestingly,most TP53 and KRAS mutations were earlier genomic events mapped to the trunks of the tumors,suggesting branching evolution in most PSC tumors.We identified two distinct molecular subtypes of PSC,driven primarily by immune infiltration and signaling.The Immune High(IM-H)subtype was associated with superior survival,highlighting the impact of immune infiltration on the biological and clinical features of localized PSCs.Conclusions:We provided detailed insight into the mutational landscape of PSC and identified two molecular subtypes associated with prognosis.IM-H tumors were associated with favorable recurrence-free survival and overall survival,highlighting the importance of tumor immune infiltration in the biological and clinical features of PSCs.

Modification of the 8^th AJCC staging system of pancreatic ductal adenocarcinoma

Accurate cancer staging is critical not only for planning the clinical management, but also for predicting prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). The former American Joint Committee on Cancer (AJCC) staging system (7th edition) for PDAC has failed to show prognostic relevance of T stage since vast majority (>90%) of patients who underwent pancreatectomy were classified as T3 (1,2). Moreover, the definition of T3 as tumor extension beyond pancreas without involvement of the celiac axis or superior mesenteric artery (SMA) gave rise to significant inter-observer/institutional variability due to lack of true capsule in the pancreas and highly variable distribution of adipose tissue surrounding the pancreatic parenchyma. To address these issues, the current AJCC staging system for PDAC (8th edition) uses only tumor size for T1 to T3 (T1,≤2 cm;T2, >2 cm and ≤4 cm;T3, >4 cm), but maintains the T4 definition as tumor of any size involving the celiac axis, SMA and/or common hepatic artery. The current AJCC staging also subclassifies lymph node (LN) positive group into N1 (1-3 positive LNs) and N2 (≥4 positive LNs). The current 8th AJCC staging system allows for better reproducibility for T stage classification and better patient stratification compared to AJCC 7th edition (1).

Predictive molecular markers in the era of immunotherapy

Recent development in anticancer therapeutics has been centered on immune checkpoint inhibitors(ICIs).Despite early success of ICIs in several cancer types,majority of cancer patients do not respond to ICI therapy.Therefore,predictive biomarkers are urgently needed to select patients who would likely benefit from ICI therapy.Currently immunohistochemical(IHC)assay for programmed cell death ligand 1(PD-L1)and microsatellite instability(MSI)testing are the only Food and Drug Administration-approved predictive biomarkers for ICI therapies.Tumor mutation burden(TMB)and tumor infiltrating lymphocytes(TILs)are emerging markers,which may prove to be useful predictive markers for ICIs.The guidelines for MSI testing have been well established.However,rigorous quality controls and systemic standardization for PD-L1 IHC testing and analysis of TMB and TILs,such as sample selection,tissue fixation,assay/platform selection,scoring methods,and clinically meaningful cutoff values etc.are needed to improve their clinical utility as predictive biomarkers for ICI therapy.Studies have suggested that the results of PD-L1 expression in tumor cells from various PD-L1 IHC assays are concordant and may be interchangeable.However,the variations and poor interobserver concordance of PDL1 expression in immune cells is a major issue to be addressed for the interchangeability of different PD-L1 IHC assays,especially for carcinomas of the gastrointestinal tract.Development of new predictive biomarkers and better understanding the difference in tumor immune microenvironments between ICI-sensitive and ICI-resistant tumors will help to develop more effective strategies for immunotherapy.

Single-cell transcriptomic analysis uncovers intratumoral heterogeneity and drug-tolerant persister in ALK-rearranged lung adenocarcinoma

Dear Editor,Non-small cell lung carcinoma(NSCLC)accounts for more than 85%of all lung cancers[1].Lung adenocarcinomas(ADCs)arising from never-smokers have been frequently found to be associated with oncogenic driver mutations,including anaplastic lymphoma kinase(ALK)rearrangement.Echinoderm microtubule-associated protein-like 4(EML4)is the most common fusion partner of the ALK gene[2].Tyrosine kinase inhibitors(TKIs)are currently the first-line treatment for advanced EML4-ALKrearranged lung ADC.

Targeting non-coding RNAs to overcome cancer therapy resistance

It is now well known that non-coding RNAs(ncRNAs),rather than protein-coding transcripts,are the preponderant RNA transcripts.NcRNAs,particularly microRNAs(miRNAs),long non-coding RNAs(lncRNAs),and circular RNAs(circRNAs),are widely appreciated as pervasive regulators of multiple cancer hallmarks such as proliferation,apoptosis,invasion,metastasis,and genomic instability.Despite recent discoveries in cancer therapy,resistance to chemotherapy,radiotherapy,targeted therapy.