Global Cancer Surgery: pragmatic solutions to improve cancer surgery outcomes worldwide.

The first Lancet Oncology Commission on Global Cancer Surgery was published in 2015 and serves as a landmark paper in the field of cancer surgery. The Commission highlighted the burden of cancer and the importance of cancer surgery, while documenting the many inadequacies in the ability to deliver safe, timely, and affordable cancer surgical care. This Commission builds on the first Commission by focusing on solutions and actions to improve access to cancer surgery globally, developed by drawing upon the expertise from cancer surgery leaders across the world. We present solution frameworks in nine domains that can improve access to cancer surgery. These nine domains were refined to identify solutions specific to the six WHO regions. On the basis of these solutions, we developed eight actions to propel essential improvements in the global capacity for cancer surgery. Our initiatives are broad in scope, pragmatic, affordable, and contextually applicable, and aimed at cancer surgeons as well as leaders, administrators, elected officials, and health policy advocates. We envision that the solutions and actions contained within the Commission will address inequities and promote safe, timely, and affordable cancer surgery for every patient, regardless of their socioeconomic status or geographic location.

Global trends in the incidence and mortality of pancreatic cancer based on geographic location, socioeconomic status, and demographic shift.

BACKGROUND: Pancreatic cancer (PC) is a lethal malignancy with a significantly rising rate of incidence and mortality. This study aims to describe the influence of geography, socioeconomic development (based on the Human Development Index [HDI]), gender, and demographic shift on the temporal trends in the global burden of PC. METHODS: Data (2020-2040) relating to the incidence, mortality of PC, and demographic shifts based on continents and HDI areas were extracted from GLOBOCAN 2020. RESULTS: PC was associated with a higher socioeconomic status. Asia contributed to the majority of the burden, led by China. Advanced age (≥65 years) contributed to the majority of the burden in all socioeconomic regions except in Medium HDI and Low HDI countries, where the younger population (<65 years) contributed more. Females contributed to a higher burden in certain countries. Future trends for 2040 showed a >60% increase in the incidence and mortality of PC with an associated demographic shift. CONCLUSION: The global burden of PC is expected to rise significantly over the next few decades regardless of geography, socioeconomic development, age, and gender. Advance knowledge of this data can help to formulate strategies and public health policies to specifically target countries and populations at risk.

Global epidemiological trends and variations in the burden of gallbladder cancer.

BACKGROUND: Gallbladder cancer (GBC) is a rare but lethal malignancy with a dismal prognosis. The aim of this study is to analyze the burdens and trends of GBC across the world based on geography, socioeconomic development (based on human development index [HDI]), and gender. METHODS: GLOBOCAN 2020 database was used to extract data (2020-2040) relating to the incidence and mortality of GBC across the world. RESULTS: Asia had the highest burden of GBC with India and China contributing to majority of the absolute burden. The burden of GBC by age standardized rate was highest in Latin America (Bolivia and Chile) and Southeast Asia (Bangladesh and Nepal). Medium HDI countries had a higher mortality rate compared to very high HDI countries. Females had a higher predilection for GBC across different regions and socioeconomic groups. GBC burden is expected to significantly increase across the world by 2040 with variable trends across different regions, age groups, and genders. CONCLUSION: The global burden of GBC will significantly increase over the next two decades with marked regional and demographic variations. The results of this study will empower national and global health leaders to develop policies to address the increasing burden of this lethal malignancy.

Prognostic and therapeutic implications of NHERF1 expression and regulation in colorectal cancer.

BACKGROUND: Na+ /H+ exchanger regulatory factor 1 (NHERF1) has been implicated in the tumorigenesis of several cancer types and is a potential therapeutic target. The current study evaluated the relationship between NHERF1 expression and clinical outcome in colorectal cancer (CRC). METHODS: NHERF1 expression was evaluated by immunohistochemistry in 167 patients with CRC primary tumors, 37 patients with no disease, and 27 patients with metastatic CRC (mCRC); and in the orthotopically implanted tumors in mice. NHERF1 expression was manipulated in CRC cells using inducible short hairpin RNAs to determine its biological functions. RESULTS: High expression of NHERF1 correlated with CRC progression and metastasis, as well as significantly worse overall survival, recurrence-free survival, and disease-specific survival. Orthotopic implantation studies demonstrated increased NHERF1 expression in liver metastases. Treatment of CRC xenografts with insulin-like growth factor 1 receptor (IGF1R) inhibitors downregulated NHERF1 expression, indicating NHERF1 is downstream of IGF1R signaling. Knockdown of NHERF1 increased apoptosis and reduced X-linked inhibitor of apoptosis protein (XIAP) and survivin expression, indicating NHERF1 is critical for CRC cell survival. CONCLUSION: NHERF1 expression levels correlated with worse prognosis in patients with CRC and plays a critical role in CRC cell survival. Together, our findings establish NHERF1 as a novel potential marker for increased risk of CRC-specific mortality and identify NHERF1 as an attractive therapeutic target for mCRC treatment.

Loss of Trefoil Factor 2 From Pancreatic Duct Glands Promotes Formation of Intraductal Papillary Mucinous Neoplasms in Mice.

BACKGROUND & AIMS: Little is known about the origin of pancreatic intraductal papillary mucinous neoplasms (IPMN). Pancreatic duct glands (PDGs) are gland-like outpouches budding off the main pancreatic ducts that function as a progenitor niche for the ductal epithelium; they express gastric mucins and have characteristics of side-branch IPMNs. We investigated whether PDGs are a precursor compartment for IPMNs and the role of Trefoil factor family 2 (TFF2)-a protein expressed by PDGs and the gastric mucosa that are involved in epithelial repair and tumor suppression. METHODS: We obtained pancreatectomy specimens from 20 patients with chronic pancreatitis, 13 with low-grade side-branch IPMNs, and 15 patients with PDAC; histologically normal pancreata were used as controls (n = 18). Samples were analyzed by immunohistochemistry to detect TFF1 and TFF2 and cell proliferation. We performed mitochondrial DNA mutational mapping studies to determine the cell lineage and fate of PDG cells. Pdx1-Cre;LSL-KRASG12D (KC) mice were bred with TFF2-knockout mice to generate KC/Tff2-/- and KC/Tff2+/- mice. Pancreata were collected and histologically analyzed for formation of IPMN, pancreatic intraepithelial neoplasias, and PDAC, in addition to proliferation and protein expression. Human pancreatic ductal epithelial cells and PDAC cell lines were transfected with vectors to overexpress or knock down TFF2 or SMAD4. RESULTS: Histologic analysis of human samples revealed gastric-type IPMN to comprise 2 molecularly distinct layers: a basal crypt segment that expressed TFF2 and overlying papillary projections. Proliferation occurred predominantly in the PDG-containing basal segments. Mitochondrial mutation mapping revealed a 97% match between the profiles of proliferating PDG cells and their overlying nonproliferative IPMN cells. In contrast to KC mice, 2-month-old KC/Tff2+/- and KC/Tff2-/- mice developed prominent papillary structures in the duct epithelium with cystic metaplasia of the PDG, which resembled human IPMN; these expressed gastric mucins (MUC5AC and MUC6), but not the intestinal mucin MUC2. KC/TFF2-knockout mice developed a greater number and higher grade of pancreatic intraepithelial neoplasias than KC mice, and 1 mouse developed an invasive adenocarcinoma. Expression of TFF2 reduced proliferation of PDAC cells 3-fold; this effect required up-regulation and activation of SMAD4. We found expression of TFF2 to be down-regulated in human PDAC by hypermethylation of its promoter. CONCLUSIONS: In histologic analyses of human IPMNs, we found PDGs to form the basal segment and possibly serve as a progenitor compartment. TFF2 has tumor-suppressor activity in the mouse pancreas and prevents formation of mucinous neoplasms.

The genetics and molecular biology of colonic neoplasia: practical implications for the clinician.

PURPOSE OF REVIEW: Despite the large investment of resources from screening, the fact that colorectal cancer remains the second leading cause of cancer deaths among Americans underscores the need for alternative strategies. Thus, a major clinical and research imperative is personalize clinical care, while focusing on risk stratification for screening, surveillance, chemoprevention, and therapeutic intervention. RECENT FINDINGS: A complicating factor that colorectal cancer is biologically heterogeneous for at least four consensus molecular subtypes presents clear challenges for developing robust molecular biomarkers. SUMMARY: The purpose of the review is to discuss the genetics and molecular biology of colonic neoplasia, high and low penetrance, and racial disparities in colonic neoplasia. Finally, we put forth the emerging concept of greater genomic landscape and the idea of chromatin protection therapy as a novel adjuvant to chemotherapy.

Colorectal cancer-global burden, trends, and geographical variations.

BACKGROUND: The aim of this study is to describe the trends and variations in the global burden of colorectal cancer (CRC). METHODS: Data (2012-2030) relating to CRC was extracted from GLOBOCAN 2012 database and analyzed. RESULTS: The results of our study demonstrate a rising global burden of colorectal cancer which persists until the year 2035 and likely beyond. The rise in the global burden is not uniform with significant variations influenced by geographic location, socio-economic status, age, and gender. Although the EURO region has the highest burden, Asia as a continent continues to bear the heaviest brunt of the disease. Although the burden of disease is higher in more developed regions, mortality is considerably higher in less developed regions and this gap widens over the next two decades. The disease predominantly affects the male gender across all regions of the world. Age has a complex relation with the burden of CRC and is affected by the cross-influences relating to socio-economic status. CONCLUSIONS: The results of our study demonstrate a rising global burden of CRC with some unique variations. Knowledge of this data can increase awareness and help strategic targeting of efforts and resources.

Global trends in the burden of liver cancer.

BACKGROUND: The aim of this study is to describe the influence of geography, socio-economic development, and demographic shift on the trends in global incidence, mortality, and prevalence of liver cancer (LC). METHODS: Data (2012-2030) relating to LC and demographic shifts based on WHO regions and HDI areas were extracted from GLOBOCAN 2012 and analyzed to evaluate trends in incidence, mortality, and prevalence. RESULTS: The results of our study document a rising global burden of LC with the maximum impact in the WPRO region. We did not observe a definite association between LC and higher socio-economic status with the highest burden in the MHD region. For the MHD region, we noticed age reversal in burden from the younger age group currently to the older age group in the future (2030). Another finding is the high burden and early onset of disease in some low-income countries such as Mongolia, Lao PDR, and Vietnam. CONCLUSION: The results of our study demonstrate a rising global burden of LC with some significant but uneven trends based on geography, age, and socio-economic status. This information can be used to shape policy and aid strategic targeting of resources to areas with the highest burden.

Global epidemiological trends and variations in the burden of gallbladder cancer.

BACKGROUND: The aim of this study is to describe the trends and variations in the global burden of gallbladder cancer (GBC) with an emphasis on geographic variations and female gender. METHODS: Data (2012-2030) relating to GBC was extracted from GLOBOCAN 2012 database and analyzed. RESULTS: The results of our study document a rising global burden of GBC with geographic and gender variations. The highest burden was noted in the WPRO region (based on WHO regions), Asia (based on continents) and India, Chile, and China (based on countries). The less developed regions of the world account for the majority of the global burden of GBC. The geographic variations are also present within individual countries such as in India and Chile. Females are afflicted at a much higher rate with GBC and this predilection is exaggerated in countries with higher incidence such as India and Chile. In females, people of certain ethnic groups and lower socio-economic standing are at a higher risk. CONCLUSIONS: Our study demonstrates a rising global burden of GBC with some specific data on geographic and gender-based variations which can be used to develop strategies at the global as well as the high-risk individual country level.

Predictive global trends in the incidence and mortality of pancreatic cancer based on geographic location, socio-economic status, and demographic shift.

BACKGROUND AND OBJECTIVES: Pancreatic Cancer (PC) is a lethal malignancy that accounts for about 4% of cancer-related deaths worldwide. The aim of this study is to describe the influence of geography (based on WHO regions), socio-economic development (based on Human Development Index [HDI]) and demographic shift on the temporal trends in global incidence and mortality of PC. METHODS: Data (2012-2030) relating to the incidence, mortality of PC and demographic shifts based on WHO regions and HDI areas were extracted from GLOBOCAN 2012. Linear regression was used to evaluate trends in total incidence and mortality. RESULTS: We noted a definite association between PC and higher socio-economic status. Advanced age (age ≥65) contributed to the rising burden in all socio-economic regions of the world except in the Low Human Development (LHD) countries where the disease predominantly affected population <65 years of age. CONCLUSIONS: The global burden of PC is expected to rise significantly over the next few decades regardless of geographic location, socio-economic development, age and gender. Advance knowledge of this data can help formulate strategies to specifically target countries and populations that promote public health policy to tackle this lethal disease on the global stage. J. Surg. Oncol. 2016;114:736-742. © 2016 Wiley Periodicals, Inc.

Akt inhibitor MK-2206 promotes anti-tumor activity and cell death by modulation of AIF and Ezrin in colorectal cancer.

BACKGROUND: There is extensive evidence for the role of aberrant cell survival signaling mechanisms in cancer progression and metastasis. Akt is a major component of cell survival-signaling mechanisms in several types of cancer. It has been shown that activated Akt stabilizes XIAP by S87 phosphorylation leading to survivin/XIAP complex formation, caspase inhibition and cytoprotection of cancer cells. We have reported that TGFß/PKA/PP2A-mediated tumor suppressor signaling regulates Akt phosphorylation in association with the dissociation of survivin/XIAP complexes leading to inhibition of stress-dependent induction of cell survival. METHODS: IGF1R-dependent colon cancer cells (GEO and CBS) were used for the study. Effects on cell proliferation and cell death were determined in the presence of MK-2206. Xenograft studies were performed to determine the effect of MK-2206 on tumor volume. The effect on various cell death markers such as XIAP, survivin, AIF, Ezrin, pEzrin was determined by western blot analysis. Graph pad 5.0 was used for statistical analysis. P < 0.05 was considered significant. RESULTS: We characterized the mechanisms by which a novel Akt kinase inhibitor MK-2206 induced cell death in IGF1R-dependent colorectal cancer (CRC) cells with upregulated PI3K/Akt signaling in response to IGF1R activation. MK-2206 treatment generated a significant reduction in tumor growth in vivo and promoted cell death through two mechanisms. This is the first report demonstrating that Akt inactivation by MK-2206 leads to induction of and mitochondria-to-nuclear localization of the Apoptosis Inducing Factor (AIF), which is involved in caspase-independent cell death. We also observed that exposure to MK-2206 dephosphorylated Ezrin at the T567 site leading to the disruption of Akt-pEzrin-XIAP cell survival signaling. Ezrin phosphorylation at this site has been associated with malignant progression in solid tumors. CONCLUSION: The identification of these 2 novel mechanisms leading to induction of cell death indicates MK-2206 might be a potential clinical candidate for therapeutic targeting of the subset of IGF1R-dependent cancers in CRC.

Expression of core 3 synthase in human pancreatic cancer cells suppresses tumor growth and metastasis.

Core 3-derived glycans, a major type of O-glycan expressed by normal epithelial cells of the gastrointestinal tract, are downregulated during malignancy because of loss of expression of functional ß3-N-acetylglucosaminyltransferase-6 (core 3 synthase). We investigated the expression of core 3 synthase in normal pancreas and pancreatic cancer and evaluated the biological effects of re-expressing core 3 synthase in pancreatic cancer cells that had lost expression. We determined that pancreatic tumors and tumor cell lines have lost expression of core 3 synthase. Therefore, we re-expressed core 3 synthase in human pancreatic cancer cells (Capan-2 and FG) to investigate the contribution of core 3 glycans to malignant progression. Pancreatic cancer cells expressing core 3 synthase showed reduced in vitro cell proliferation, migration and invasion compared to vector control cells. Expression of core 3 O-glycans induced altered expression of ß1 integrin, decreased activation of focal adhesion kinase, led to the downregulation of expression of several genes including REG1α and FGFR3 and altered lamellipodia formation. The addition of a GlcNAc residue by core 3 synthase leads to the extension of the tumor-associated Tn structure on MUC1. Orthotopic injection of FG cells expressing core 3 synthase into the pancreas of nude mice produced significantly smaller tumors and decreased metastasis to the surrounding tissues compared to vector control FG cells. These findings indicate that expression of core 3-derived O-glycans in pancreatic cancer cells suppresses tumor growth and metastasis through modulation of glycosylation of mucins and other cell surface and extracellular matrix proteins.

Restoration of PTEN activity decreases metastases in an orthotopic model of colon cancer.

BACKGROUND: Mutational loss of tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) is associated with malignant progression in many cancers, including colorectal cancer (CRC). PTEN is involved in negatively regulating the phosphatidylinositol 3-kinase/AKT oncogenic signaling pathway and has been implicated in the metastatic colonization process. Few in vivo models are available to study CRC metastasis. The purpose of this study was to determine the effect of restoring PTEN activity on metastases in an orthotopic murine model. METHODS: Green fluorescent protein labeled TENN, a highly metastatic human colon cancer cell line with mutational loss of PTEN gene and TENN clones (with restoration of PTEN gene) tumors were orthotopically implanted onto the colons of BALB/c nude mice and allowed to develop primary and metastatic tumors. Seven weeks post-implantation, mice were euthanized and organs extracted for examination. RESULTS: Both TENN and TENN clone cell lines demonstrated 100% primary invasion. However, compared with the parental TENN cells, which demonstrated 62% metastases to both lungs and liver, TENN clone cells showed an approximately 50% reduction in metastasis, with only 31.6% liver metastasis and no metastasis to the lungs (P = 0.02). CONCLUSIONS: Our study shows that reactivation of PTEN tumor suppressor pathway leads to a 50% reduction in CRC metastasis without affecting primary tumor formation. Importantly, PTEN restoration also changed the organotropic homing from liver and lung metastasis to liver metastasis only. This in vivo study demonstrates that PTEN might act specifically as a metastasis suppressor and, thus, efforts to target the phosphatidylinositol 3-kinase/PTEN pathway are legitimate.

Histone deacetylase inhibitor belinostat represses survivin expression through reactivation of transforming growth factor beta (TGFbeta) receptor II leading to cancer cell death.

Survivin is a cancer-associated gene that functions to promote cell survival, cell division, and angiogenesis and is a marker of poor prognosis. Histone deacetylase inhibitors induce apoptosis and re-expression of epigenetically silenced tumor suppressor genes in cancer cells. In association with increased expression of the tumor suppressor gene transforming growth factor ß receptor II (TGFßRII) induced by the histone deacetylase inhibitor belinostat, we observed repressed survivin expression. We investigated the molecular mechanisms involved in survivin down-regulation by belinostat downstream of reactivation of TGFß signaling. We identified two mechanisms. At early time points, survivin protein half-life was decreased with its proteasomal degradation. We observed that belinostat activated protein kinase A at early time points in a TGFß signaling-dependent mechanism. After longer times (48 h), survivin mRNA was also decreased by belinostat. We made the novel observation that belinostat mediated cell death through the TGFß/protein kinase A signaling pathway. Induction of TGFßRII with concomitant survivin repression may represent a significant mechanism in the anticancer effects of this drug. Therefore, patient populations exhibiting high survivin expression with epigenetically silenced TGFßRII might potentially benefit from the use of this histone deacetylase inhibitor.

Laser Heating Study of the High-Temperature Interactions in Nanograined Uranium Carbides.

Nanograined nuclear materials are expected to have a better performance as spallation targets and nuclear fuels than conventional materials, but many basic properties of these materials are still unknown. The present work aims to contribute to their better understanding by studying the effect of grain size on the melting and solid-solid transitions of nanograined UC2-y. We laser-heated 4 nm-10 nm grain size samples with UC2-y as the main phase (but containing graphite and UO2 as impurities) under inert gas to temperatures above 3000 K, and their behavior was studied by thermal radiance spectroscopy. The UC2-y solidification point (2713(30) K) and α-UC2 to ß-UC2 solid-solid transition temperature (2038(10) K) were observed to remain unchanged when compared to bulk crystalline materials with micrometer grain sizes. After melting, the composite grain size persisted at the nanoscale, from around 10 nm to 20 nm, pointing to an effective role of carbon in preventing the rapid diffusion of uranium and grain growth.

Effects of vacancy defects on the interfacial shear strength of carbon nanotube reinforced polymer composite.

We investigate the effects of the vacancy defects (i.e., missing atoms) in carbon nanotubes (CNTs) on the interfacial shear strength (ISS) of the CNT-polyethylene composite with the molecular dynamics simulation. In the simulation, the crystalline polyethylene matrix is set up in a hexagonal array with the polymer chains parallel to the CNT axis. Vacancy defects in the CNT are introduced by removing the corresponding atoms from the pristine CNT (i.e., CNT without any defect). Three patterns of vacancy defects with three different sizes are considered. Two types of interfaces, with and without cross-links between the CNT and the matrix are also considered here. Polyethylene chains are used as cross-links between the CNT and the matrix. The Brenner potential is used for the carbon-carbon interaction in the CNT, while the polymer is modeled by a united-atom potential. The nonbonded van der Waals interaction between the CNT and the polymer matrix and within the polymer matrix itself is modeled with the Lennard-Jones potential. To determine the ISS, we conduct the CNT pull-out from the polymer matrix and the ISS has been estimated with the change of total potential energy of the CNT-polymer system. The simulation results reveal that the vacancy defects significantly influence the ISS. Moreover, the simulation clarifies that CNT breakage occurs during the pull-out process for large size vacancy defect which ultimately reduces the reinforcement.

Uranium Carbide Fibers with Nano-Grains as Starting Materials for ISOL Targets.

This paper presents an experimental study about the preparation, by electrospinning, of uranium carbide fibers with nanometric grain size. Viscous solutions of cellulose acetate and uranyl salts (acetate, acetylacetonate, and formate) on acetic acid and 2,4-pentanedione, adjusted to three different polymer concentrations, 10, 12.5, and 15 weight %, were used for electrospinning. Good quality precursor fibers were obtained from solutions with a 15% cellulose acetate concentration, the best ones being produced from the uranyl acetate solution. As-spun precursor fibers were then decomposed by slow heating until 823 K under argon, resulting in a mixture of nano-grained UO2 and C fibers. A last carboreduction was then carried out under vacuum at 2073 K for 2 h. The final material displayed UC2-y as the major phase, with grain sizes in the 4 nm-10 nm range. UO2+x was still present in moderate concentrations (~30 vol.%). This is due to uncomplete carboreduction that can be explained by the fiber morphology, limiting the effective contact between C and UO2 grains.

Correction: Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy.

[This corrects the article DOI: 10.18632/oncotarget.23749.].