Diffuse tumors: Molecular determinants shared by different cancer types.

Most cancer types have both diffuse and non-diffuse subtypes, which have rather distinct morphologies, namely scattered tiny tumors vs. one solid tumor, and different levels of aggressiveness. However, the causes for forming such distinct subtypes remain largely unknown. Using the diffuse and non-diffuse gastric cancers (GCs) as the illustrative example, we present a computational study based on the transcriptomic data from the TCGA and GEO databases, to address the following questions: (i) What are the key molecular determinants that give rise to the distinct morphologies between diffuse and non-diffuse cancers? (ii) What are the main reasons for diffuse cancers to be generally more aggressive than non-diffuse ones of the same cancer type? (iii) What are the reasons for their distinct immunoactivities? And (iv) why do diffuse cancers on average tend to take place in younger patients? The study is conducted using the framework we have previously developed for elucidation of general drivers cancer formation and development. Our main discoveries are: (a) the level of (poly-) sialic acids deployed on the surface of cancer cells is a significant factor contributing to questions (i) and (ii); (b) poly-sialic acids synthesized by ST8SIA4 are the key to question (iii); and (c) the circulating growth factors specifically needed by the diffuse subtype dictate the answer to question (iv). All these predictions are substantiated by published experimental studies. Our further analyses on breast, prostate, lung, liver, and thyroid cancers reveal that these discoveries generally apply to the diffuse subtypes of these cancer types, hence indicating the generality of our discoveries.

Circular RNAs in EMT-driven metastasis regulation: modulation of cancer cell plasticity, tumorigenesis and therapy resistance.

The non-coding RNAs comprise a large part of human genome lack of capacity in encoding functional proteins. Among various members of non-coding RNAs, the circular RNAs (circRNAs) have been of importance in the pathogenesis of human diseases, especially cancer. The circRNAs have a unique closed loop structure and due to their stability, they are potential diagnostic and prognostic factors in cancer. The increasing evidences have highlighted the role of circRNAs in the modulation of proliferation and metastasis of cancer cells. On the other hand, metastasis has been responsible for up to 90% of cancer-related deaths in patients, requiring more investigation regarding the underlying mechanisms modulating this mechanism. EMT enhances metastasis and invasion of tumor cells, and can trigger resistance to therapy. The cells demonstrate dynamic changes during EMT including transformation from epithelial phenotype into mesenchymal phenotype and increase in N-cadherin and vimentin levels. The process of EMT is reversible and its reprogramming can disrupt the progression of tumor cells. The aim of current review is to understanding the interaction of circRNAs and EMT in human cancers and such interaction is beyond the regulation of cancer metastasis and can affect the response of tumor cells to chemotherapy and radiotherapy. The onco-suppressor circRNAs inhibit EMT, while the tumor-promoting circRNAs mediate EMT for acceleration of carcinogenesis. Moreover, the EMT-inducing transcription factors can be controlled by circRNAs in different human tumors.

Molecular Mechanism of Breast Cancer and Predisposition of Mouse Mammary Tumor Virus Propagation Cycle.

Over the past few decades, women have been troubled by grave diseases such as breast cancer, which are biologically and molecularly classified as hereditary diseases. Even though the risk of other cancers is relatively different and the downstream pathway of genetic mutation differs from breast cancer, the continued transformation of genes such as BRCA1 and BRCA2 leads to breast cancer malignancy. Notably at the molecular level, a parallel connection between the normal growth of breast and the progression of mammary cancer where the breast cancer stem cells play a crucial role in the advancement of mammary carcinoma. Arguably, several significant signaling pathways, for instance, ER signaling, HER2 signaling, and Wnt signaling control the typical breast development as well as breast stem cells, thereby cell proliferation, cell differentiation, and cell motility are involved. Incidentally, the Mouse Mammary Tumor Virus (MMTV) is notable among the unexplained viral components influenced by virus-corrupting mammary carcinomas. According to the genesis, MMTV proviral DNA is integrated into mammary epithelial cells, and genomic lymphoid cells during viral replication and triggers the progression of cellular oncogenesis. This overview reveals the deadliest theories on breast cancer, molecular mechanisms, and the MMTV transmission cycle. To establish prevention therapies that are both acceptable and efficacious, addressing apprehensions related to the toxicity of these interventions must be a preliminary hurdle to overcome.

The Warburg Effect Reinterpreted 100 yr on: A First-Principles Stoichiometric Analysis and Interpretation from the Perspective of ATP Metabolism in Cancer Cells.

The Warburg Effect is a longstanding enigma in cancer biology. Despite the passage of 100 yr since its discovery, and the accumulation of a vast body of research on the subject, no convincing biochemical explanation has been given for the original observations of aerobic glycolysis in cancer cell metabolism. Here, we have worked out a first-principles quantitative analysis of the problem from the principles of stoichiometry and available electron balance. The results have been interpreted using Nath's unified theory of energy coupling and adenosine triphosphate (ATP) synthesis, and the original data of Warburg and colleagues have been analyzed from this new perspective. Use of the biomass yield based on ATP per unit substrate consumed, [Formula: see text], or the Nath-Warburg number, NaWa has been shown to excellently model the original data on the Warburg Effect with very small standard deviation values, and without employing additional fitted or adjustable parameters. Based on the results of the quantitative analysis, a novel conservative mechanism of synthesis, utilization, and recycling of ATP and other key metabolites (eg, lactate) is proposed. The mechanism offers fresh insights into metabolic symbiosis and coupling within and/or among proliferating cells. The fundamental understanding gained using our approach should help in catalyzing the development of more efficient metabolism-targeting anticancer drugs.

Recommendations for surveillance of pulmonary dysfunction among childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Childhood, adolescent, and young adult (CAYA) cancer survivors are at risk of pulmonary dysfunction. Current follow-up care guidelines are discordant. Therefore, the International Late Effects of Childhood Cancer Guideline Harmonization Group established and convened a panel of 33 experts to develop evidence-based surveillance guidelines. We critically reviewed available evidence regarding risk factors for pulmonary dysfunction, types of pulmonary function testing, and timings of surveillance, then we formulated our recommendations. We recommend that CAYA cancer survivors and healthcare providers are aware of reduced pulmonary function risks and pay vigilant attention to potential symptoms of pulmonary dysfunction, especially among survivors treated with allogeneic haematopoietic stem cell transplantation, thoracic radiotherapy, and thoracic surgery. Based on existing limited evidence and current lack of interventions, our panel recommends pulmonary function testing only for symptomatic survivors. Since scarce existing evidence informs our recommendation, we highlight the need for prospective collaborative studies to address pulmonary function knowledge gaps among CAYA cancer survivors.

ExtRanFS: An Automated Lung Cancer Malignancy Detection System Using Extremely Randomized Feature Selector.

Lung cancer is an abnormality where the body's cells multiply uncontrollably. The disease can be deadly if not detected in the initial stage. To address this issue, an automated lung cancer malignancy detection (ExtRanFS) framework is developed using transfer learning. We used the IQ-OTH/NCCD dataset gathered from the Iraq Hospital in 2019, encompassing CT scans of patients suffering from various lung cancers and healthy subjects. The annotated dataset consists of CT slices from 110 patients, of which 40 were diagnosed with malignant tumors and 15 with benign tumors. Fifty-five patients were determined to be in good health. All CT images are in DICOM format with a 1mm slice thickness, consisting of 80 to 200 slices at various sides and angles. The proposed system utilized a convolution-based pre-trained VGG16 model as the feature extractor and an Extremely Randomized Tree Classifier as the feature selector. The selected features are fed to the Multi-Layer Perceptron (MLP) Classifier for detecting whether the lung cancer is benign, malignant, or normal. The accuracy, sensitivity, and F1-Score of the proposed framework are 99.09%, 98.33%, and 98.33%, respectively. To evaluate the proposed model, a comparison is performed with other pre-trained models as feature extractors and also with the existing state-of-the-art methodologies as classifiers. From the experimental results, it is evident that the proposed framework outperformed other existing methodologies. This work would be beneficial to both the practitioners and the patients in identifying whether the tumor is benign, malignant, or normal.

Deciphering Stromal Changes between Metastatic and Non-metastatic Canine Mammary Carcinomas.

Cancer-associated stroma (CAS) is widely recognized to influence development and progression of epithelial tumours including breast cancer. Canine mammary tumours (CMTs) such as simple canine mammary carcinomas represent valuable models for human breast cancer also with respect to stromal reprogramming. However, it remains unclear whether and how CAS changes in metastatic tumours compared to non-metastatic ones. To characterize stromal changes between metastatic and non-metastatic CMTs and identify potential drivers of tumour progression, we analysed CAS and matched normal stroma from 16 non-metastatic and 15 metastatic CMTs by RNA-sequencing of microdissected FFPE tissue. We identified 1438 differentially regulated genes between CAS and normal stroma, supporting previous results demonstrating stromal reprogramming in CMTs to be comparable with CAS in human breast cancer and validating deregulation of pathways and genes associated with CAS. Using primary human fibroblasts activated by treatment with TGFß, we demonstrate some of the strongest expression changes to be conserved in fibroblasts across species. Furthermore, we identify 132 differentially expressed genes between CAS from metastatic and non-metastatic tumours, with strong changes in pathways including chemotaxis, regulation of apoptosis, immune response and TGFß signalling and validate deregulation of several targets using RT-qPCR. Finally, we identify specific upregulation of COL6A5, F5, GALNT3, CIT and MMP11 in metastatic CAS, suggesting high stromal expression of these targets to be linked to malignancy and metastasis of CMTs. In summary, our data present a resource supporting further research into stromal changes of the mammary gland in relation to metastasis with implications for both canine and human mammary cancer.

ASH2L, a COMPASS core subunit, is involved in the cell invasion and migration of triple-negative breast cancer cells through the epigenetic control of histone H3 lysine 4 methylation.

ASH2L (Absent-Small-Homeotic-2-Like protein) is a core subunit of the COMPASS (COMplex of Proteins ASsociated with Set1) complex, the most notable writer of the methylation of histone H3 lysine 4 (H3K4). The COMPASS complex regulates active promoters or enhancers for gene expression, and its dysfunction is associated with aberrant development and disease. Here, we demonstrated that ASH2L mediated the cell invasion and migration activity of triple-negative breast cancer cells through the interaction with the COMPASS components and the target genomic regions. Transcriptome analysis indicated a potential correlation between ASH2L and the genes involved in inflammatory/immune responses. Among them, we found that the intrinsic expression of IL1B (interleukin 1 beta), an essential proinflammatory gene, was directly regulated by ASH2L. These results revealed a novel role of ASH2L on the maintenance of breast cancer malignancy possibly through H3K4 methylation of the target inflammatory/immune responsive genes.

Diagnostic and management roles of FDG PET/CT imaging in post-transplant lympho-proliferation in pediatric heart transplantation.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of pediatric heart transplant (PHTx). 18F-FDG PET/CT has been used to differentiate early lympho-proliferation from more advanced PTLD. We report our experience with PET/CT in the management of PTLD following PHTx. METHODS: This was a retrospective study of 100 consecutive PHTx recipients at our institution between 2004 and 2018. Patients who underwent PET/CT or conventional CT scans to evaluate for PTLD or high Epstein-Barr viral load were included. RESULTS: Males, eight females. Median age at transplant was 3.5 months (IQR = 1.5-27.5). Median age at PTLD diagnosis was 13.3 years (IQR = 9.2-16.1). Median time between transplant and PTLD diagnosis was 9.5 (IQR = 4.5-15) years. Induction agents were used in 12 patients (50%): Thymoglobulin (N = 9), anti-IL2 (N = 2), and Rituximab (N = 1). Eighteen patients (75%) had PET/CT, of whom 14 had 18FDG-avid PTLD. Six had conventional CT. Nineteen patients (79.2%) had diagnostic biopsy confirmation of PTLD, and 5 (20.8%) had excisional biopsies. Two patients had Hodgkin's lymphoma; nine had monomorphic PTLD; eight had polymorphic PTLD; five were classified as other. Nine patients had monomorphic PTLD, including seven with diffuse large cell lymphoma (DLBC) and one with T cell lymphoma. The majority (16/24) had multi-site involvement at PTLD diagnosis, and PET/CT showed that 31.3% (5/16) had easily accessible subcutaneous nodes. Seventeen patients (overall survival 71%) underwent successful treatment without recurrence of PTLD. Of seven deaths (7/24, 29%), five had DLBC lymphoma, one had polymorphic PTLD and one had T-cell lymphoma. CONCLUSION: PET-CT allowed simultaneous anatomical and functional assessment of PTLD lesions, while guiding biopsy. In patients with multiple lesions, PET/CT revealed the most prominent and active lesions, improving diagnostic accuracy.

KRAS, MYC, and ARF6: inseparable relationships cooperatively promote cancer malignancy and immune evasion.

Mutations in the KRAS gene and overexpression of protein products of the MYC and ARF6 genes occur frequently in cancer. Here, the inseparable relationships and cooperation of the protein products of these three genes in cancer malignancy and immune evasion are discussed. mRNAs encoded by these genes share the common feature of a G-quadruplex structure, which directs them to be robustly expressed when cellular energy production is increased. These three proteins are also functionally inseparable from each other, as follows.　1) KRAS induces MYC gene expression, and may also promote eIF4A-dependent MYC and ARF6 mRNA translation, 2) MYC induces the expression of genes involved in mitochondrial biogenesis and oxidative phosphorylation, and 3) ARF6 protects mitochondria from oxidative injury. ARF6 may moreover promote cancer invasion and metastasis, and also acidosis and immune checkpoint. Therefore, the inseparable relationships and cooperation of KRAS, MYC, and ARF6 appear to result in the activation of mitochondria and the driving of ARF6-based malignancy and immune evasion. Such adverse associations are frequent in pancreatic cancer, and appear to be further enhanced by TP53 mutations. Video Abstract.

Characterization of breast lesions using multi-parametric diffusion MRI and machine learning.

Objective. To investigate quantitative imaging markers based on parameters from two diffusion-weighted imaging (DWI) models, continuous-time random-walk (CTRW) and intravoxel incoherent motion (IVIM) models, for characterizing malignant and benign breast lesions by using a machine learning algorithm.Approach. With IRB approval, 40 women with histologically confirmed breast lesions (16 benign, 24 malignant) underwent DWI with 11b-values (50 to 3000 s/mm2) at 3T. Three CTRW parameters,Dm,α, andßand three IVIM parametersDdiff,Dperf, andfwere estimated from the lesions. A histogram was generated and histogram features of skewness, variance, mean, median, interquartile range; and the value of the 10%, 25% and 75% quantiles were extracted for each parameter from the regions-of-interest. Iterative feature selection was performed using the Boruta algorithm that uses the Benjamin Hochberg False Discover Rate to first determine significant features and then to apply the Bonferroni correction to further control for false positives across multiple comparisons during the iterative procedure. Predictive performance of the significant features was evaluated using Support Vector Machine, Random Forest, Naïve Bayes, Gradient Boosted Classifier (GB), Decision Trees, AdaBoost and Gaussian Process machine learning classifiers.Main Results. The 75% quantile, and median ofDm; 75% quantile off;mean, median, and skewness ofß;kurtosis ofDperf; and 75% quantile ofDdiffwere the most significant features. The GB differentiated malignant and benign lesions with an accuracy of 0.833, an area-under-the-curve of 0.942, and an F1 score of 0.87 providing the best statistical performance (p-value < 0.05) compared to the other classifiers.Significance. Our study has demonstrated that GB with a set of histogram features from the CTRW and IVIM model parameters can effectively differentiate malignant and benign breast lesions.

Mortality among solid organ transplant recipients with a pretransplant cancer diagnosis.

Little is known about the outcomes among solid organ transplant recipients with a pretransplant cancer diagnosis. We used linked data from the Scientific Registry of Transplant Recipients with 33 US cancer registries. Cox proportional hazards models assessed associations of pretransplant cancer with overall mortality, cancer-specific mortality, and development of a new posttransplant cancer. Among 311 677 recipients, the presence of a single pretransplant cancer was associated with increased overall mortality (adjusted hazard ratio [aHR], 1.19; 95% CI, 1.15-1.23) and cancer-specific mortality (aHR, 1.93; 95% CI, 1.76-2.12); results for 2+ pretransplant cancers were similar. Cancer-specific mortality was not significantly increased for uterine, prostate, or thyroid cancers (aHRs were 0.83, 1.22, and 1.54, respectively) but strongly elevated for lung cancer and myeloma (aHRs were 3.72 and 4.42, respectively). A pretransplant cancer diagnosis was also associated with increased risk of developing posttransplant cancer (aHR, 1.32; 95% CI, 1.23-1.40). Among 306 recipients whose cancer death was confirmed by cancer registry data, 158 deaths (51.6%) were from a de novo posttransplant cancer and 105 (34.3%) from the pretransplant cancer. Pretransplant cancer diagnoses are associated with increased mortality after transplantation, but some deaths are related to posttransplant cancers and other causes. Improved candidate selection and cancer screening and prevention may reduce mortality in this population.

Molecular bases of morphologically diffused tumors across multiple cancer types.

Gastric cancer has two distinct subtypes: the diffuse (DGC) and the intestinal (IGC) subtypes. Morphologically, the former each consists of numerous scattered tiny tumors while the latter each has one or a few solid biomasses. The former tends to be more aggressive and takes place in younger patients than the latter. While these have long been documented, little is known about the underlying causes. Our hypothesis is that the level of sialic acid (SA) accumulation on the cancer cell surfaces is a key reason for the observed differences. Our transcriptomic data-based analyses provide evidence that (i) DGCs tend to deploy more SAs on cancer cell surfaces than IGCs; (ii) this gives rise to considerably stronger cell-cell electrostatic repulsion in DGCs due to the negative charge that each SA carries; and (iii) such repulsion drives stronger cell protrusion and metastasis. Similar observations as well as our transcriptomic data-based predictions hold for multiple other cancer types, namely breast, lung, prostate plus liver and thyroid cancers, each known to have diffuse-like vs. non-diffused subtypes as well as more aggressive behaviors like DGCs vs. IGCs. Hence, we speculate that the discovery presented here applies not only to gastric cancer but multiple and even potentially all cancer types having diffuse-like and non-diffused subtypes.

Long-term outcomes of resection versus transplantation for neuroendocrine liver metastases meeting the Milan criteria.

Liver resection (LR) is considered the treatment of choice for resectable neuroendocrine liver metastases (NELM), while liver transplantation (LT) is currently reserved for highly selected unresectable patients. We retrospectively analyzed data from consecutive patients undergoing either curative resection or transplantation for liver-only NELM meeting Milan criteria at a single center between 1984 and 2019. Patients who fit Milan criteria were 48 in the transplantation group and 56 in the resection group. After a median follow-up of 158 months for the transplantation group and 126 for the resection group, the 10-year survival rate was 93% for transplantation and 75% for resection (p = .007). The 10-year disease-free survival rate was 52% for transplantation and 18% for resection (p < .001). Transplantation was associated with improved survival at univariate analysis. The median disease-free interval between surgery and recurrence was 78 months for transplantation vs. 24 months for resection (p < .001). The transplantation group had more multisite recurrences (12/25, 48% vs. 5/42, 12% in the resection group, p = .001), while most recurrences in the resection group were intra-hepatic (37/42, 88%, versus 2/25, 8% in the transplantation group). In conclusion, LT was associated with improved survival outcomes in NELM meeting the Milan criteria compared with LR.

N(6)-methyladenosine-mediated miR-380-3p maturation and upregulation promotes cancer aggressiveness in pancreatic cancer.

N(6)-methyladenosine (m6A)-modified microRNAs (miRNAs) are relevant to cancer progression. Also, although the involvement of miR-380-3p in regulating cancer progression in bladder cancer and neuroblastoma has been preliminarily explored, its role in other types of cancer, such as pancreatic cancer (PC), has not been studied. Thus, this study aimed to investigate the role of miR-380-3p in regulating PC progression. Here, through performing Real-Time qPCR, we evidenced that miR-380-3p was significantly upregulated in the clinical pancreatic cancer tissues and cells compared to their normal counterparts. Interestingly, miR-380-3p was enriched with m6A modifications, and elimination of m6A modifications by deleting METTL3 and METTL14 synergistically suppressed miR-380-3p expressions in PC cells. Next, the gain and loss-of-function experiments verified that knockdown of miR-380-3p suppressed cell proliferation, epithelial-mesenchymal transition (EMT), and tumorigenesis in PC cells in vitro and in vivo, whereas miR-380-3p overexpression had opposite effects. Furthermore, the underlying mechanisms were uncovered, and our data suggested that miR-380-3p targeted the 3' untranslated regions (3'UTRs) of PTEN for its inhibition and degradation, resulting in the activation of the downstream Akt signal pathway. Moreover, the rescuing experiments validated that both PTEN overexpression and Akt pathway inhibitor LY294002 abrogated the promoting effects of miR-380-3p overexpression on cancer aggressiveness in PC cells. Collectively, this study firstly investigated the role of the m6A-associated miR-380-3p/PTEN/Akt pathway in regulating PC progression, which provided novel therapeutic and diagnostic biomarkers for this cancer.

Cancer Malignancy Is Correlated with Upregulation of PCYT2-Mediated Glycerol Phosphate Modification of α-Dystroglycan.

The dystrophin-glycoprotein complex connects the cytoskeleton with base membrane components such as laminin through unique O-glycans displayed on α-dystroglycan (α-DG). Genetic impairment of elongation of these glycans causes congenital muscular dystrophies. We previously identified that glycerol phosphate (GroP) can cap the core part of the α-DG O-glycans and terminate their further elongation. This study examined the possible roles of the GroP modification in cancer malignancy, focusing on colorectal cancer. We found that the GroP modification critically depends on PCYT2, which serves as cytidine 5'-diphosphate-glycerol (CDP-Gro) synthase. Furthermore, we identified a significant positive correlation between cancer progression and GroP modification, which also correlated positively with PCYT2 expression. Moreover, we demonstrate that GroP modification promotes the migration of cancer cells. Based on these findings, we propose that the GroP modification by PCYT2 disrupts the glycan-mediated cell adhesion to the extracellular matrix and thereby enhances cancer metastasis. Thus, the present study suggests the possibility of novel approaches for cancer treatment by targeting the PCYT2-mediated GroP modification.

Hsa_circ_0006692 Promotes Lung Cancer Progression via miR-205-5p/CDK19 Axis.

Circular RNA (CircRNA) is related to tumor development. Nevertheless, the regulation and function of hsa_circ_0006692 and its interactions with miR-205-5p and CDK19 in the development of non-small-cell lung cancer (NSCLC) were un-explored. The correlations of expression levels of hsa_circ_0006692 in NSCLC specimens and cells with pathological characteristics were studied. The interactions of hsa_circ_0006692 with miR-205-5p and CDK19 were assessed with real-time PCR, RNA-binding protein immunoprecipitation (RIP), luciferase reporter, RNA pull-down, and fluorescence in situ hybridization (FISH). The roles of hsa_circ_0006692 on cell growth, invasion, and migration in vitro and metastasis in vivo were evaluated. Hsa_circ_0006692 was over-expressed in 60 cases of NSCLC specimens and cells, which was positively correlated with TNM stage, tumor size, and invasion of the lung basal layer. The results of the in vitro and in vivo studies revealed that the over-expression of hsa_circ_0006692 facilitated NSCLC cell growth, migration, and invasion, cell cycle arrest at the S phase, and the activation of BCL-2, CCND1, and PCNA. The results of the dual-luciferase reporter assay, RNA immunoprecipitation, and pull-down assays indicated that hsa_circ_0006692 sponged miR-205-5p, which targeted CDK19 and facilitated the malignant behaviors of lung cancer cells. Hsa_circ_0006692 modulated EMT of lung cancer cells via the stimulation of CDH1, CDH2, VIMENTIN, and MMP7. This study revealed that hsa_circ_0006692 promoted NSCLC progression via enhancing cell growth, invasion, and metastasis through sponging mir-205-5p, up-regulating the downstream oncogene CDK19 and modulating EMT of lung cancer cells. The circ-0006692/mir-205-5p/CDK19 axis might serve as a prognosis biomarker and target for drugs aimed against NSCLC.

Macropinocytosis and Cancer: From Tumor Stress to Signaling Pathways.

Macropinocytosis is an evolutionarily conserved endocytic pathway that mediates the nonselective acquisition of extracellular material via large endocytic vesicles known as macropinosomes. In addition to other functions, this uptake pathway supports cancer cell metabolism through the uptake of nutrients. Cells harboring oncogene or tumor suppressor mutations are known to display heightened macropinocytosis, which confers to the cancer cells the ability to survive and proliferate despite the nutrient-scarce conditions of the tumor microenvironment. Thus, macropinocytosis is associated with cancer malignancy. Macropinocytic uptake can be induced in cancer cells by different stress stimuli, acting as an adaptive mechanism for the cells to resist stresses in the tumor milieu. Here, we review the cellular stresses that are known to promote macropinocytosis, as well as the underlying molecular mechanisms that drive this process.

Donor-derived duodenal adenocarcinoma of a bladder-drained pancreas allograft.

The subset of the population that received bladder-drained allograft pancreata during peak utilization of the technique in the 1990s is approaching 20-30 postoperative years. This time frame is salient, as it parallels the time in which patients in the urologic literature develop adenocarcinomas after bladder reconstruction using gastrointestinal segments. We present the case of a 57-year-old simultaneous pancreas/kidney recipient who presented with microhematuria twenty-four years after transplantation and was found to have an adenocarcinoma of the duodenum of his failed, bladder-drained pancreas. After allograft pancreatectomy/duodenectomy, he remains disease-free eleven months postoperatively. As this patient population ages, practitioners should consider pathology of the donor duodenum and pancreas in recipients who present with gross or microscopic hematuria.