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MUC16, membrane-bound mucin, plays an oncogenic role in pancreatic ductal adenocarcinoma (PDAC). However, the pathological role of MUC16 in the PDAC progression, tumor microenvironment, and metastasis in cooperation with Kras(G12D) and Trp53(R172H) mutations remains unknown. Deletion of Muc16 with activating mutations Kras(G12D/+) and Trp53(R172H/+) in mice significantly decreased progression and prolonged overall survival in Kras(G12D/+); Trp53(R172H/+); Pdx-1-Cre; Muc16(−/−) (KPCM) and Kras(G12D/+); Pdx-1-Cre; Muc16(−/−) (KCM), as compared to Kras(G12D/+); Trp53(R172H/+); Pdx-1-Cre (KPC) and Kras(G12D/+); Pdx-1-Cre (KC) mice, respectively. Muc16 knockout pancreatic tumor (KPCM) displays decreased tumor microenvironment factors and significantly reduced incidence of liver and lung metastasis compared to KPC. Furthermore, in silico data analysis showed a positive correlation of MUC16 with activated stroma and metastasis- associated genes. KPCM mouse syngeneic cells had significantly lower metastatic and endothelial cell binding abilities than KPC cells. Similarly, KPCM organoids significantly decreased the growth rate than KPC organoids. Interestingly, RNA-seq data revealed that the cytoskeletal proteins Actg2, Myh11, and Pdlim3 were downregulated in KPCM tumors. Further knockdown of these genes showed reduced metastatic potential. Overall, our results demonstrate that Muc16 alters the tumor microenvironment factors during pancreatic cancer progression and metastasis by changing the expression of Actg2, Myh11, and Pdlim3 genes.

Background Triple-negative breast cancer (TNBC) is highly aggressive with an increased metastatic incidence compared to other breast cancer subtypes. However, due to the absence of clinically reliable biomarkers and targeted therapy in TNBC, outcomes are suboptimal. Hence, there is an urgent need to understand biological mechanisms that lead to identifying novel therapeutic targets for managing metastatic TNBC. Methods The clinical significance of MUC16 and ELAVL1 or Hu antigen R (HuR) was examined using breast cancer TCGA data. Microarray was performed on MUC16 knockdown and scramble TNBC cells and MUC16-associated genes were identified using RNA immunoprecipitation and metastatic cDNA array. Metastatic properties of MUC16 were evaluated using tail vein experiment. MUC16 and HuR downstream pathways were confirmed by ectopic overexpression of MUC16-carboxyl-terminal (MUC16-Cter), HuR and cMyc as well as HuR inhibitors (MS-444 and CMLD-2) in TNBC cells. Results MUC16 was highly expressed in TNBC and correlated with its target HuR. Depletion of MUC16 showed decreased invasion, migration, and colony formation abilities of human and mouse TNBC cells. Mice injected with MUC16 depleted cells were less likely to develop lung metastasis (P = 0.001). Notably, MUC16 and HuR were highly expressed in the lung tropic TNBC cells and lung metastases. Mechanistically, we identified cMyc as a HuR target in TNBC using RNA immunoprecipitation and metastatic cDNA array. Furthermore, MUC16 knockdown and pharmacological inhibition of HuR (MS-444 and CMLD-2) in TNBC cells showed a reduction in cMyc expression. MUC16-Cter or HuR overexpression models indicated MUC16/HuR/cMyc axis in TNBC cell migration. Conclusions Our study identified MUC16 as a TNBC lung metastasis promoter that acts through HuR/cMyc axis. This study will form the basis of future studies to evaluate the targeting of both MUC16 and HuR in TNBC patients.

Lung cancer (LC) is a heterogeneous disease consisting mainly of two subtypes, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), and remains the leading cause of death worldwide. Despite recent advances in therapies, the overall 5-year survival rate of LC remains less than 20%. The efficacy of current therapeutic approaches is compromised by inherent or acquired drug-resistance and severe off-target effects. Therefore, the identification and development of innovative and effective therapeutic approaches are critically desired for LC. The development of RNA-mediated gene inhibition technologies was a turning point in the field of RNA biology. The critical regulatory role of different RNAs in multiple cancer pathways makes them a rich source of targets and innovative tools for developing anticancer therapies. The identification of antisense sequences, short interfering RNAs (siRNAs), microRNAs (miRNAs or miRs), anti-miRs, and mRNA-based platforms holds great promise in preclinical and early clinical evaluation against LC. In the last decade, RNA-based therapies have substantially expanded and tested in clinical trials for multiple malignancies, including LC. This article describes the current understanding of various aspects of RNA-based therapeutics, including modern platforms, modifications, and combinations with chemo-/immunotherapies that have translational potential for LC therapies.

The role of locoregional treatment (LRT) remains controversial in de novo stage IV breast cancer (BC). We sought to analyze the role of LRT and prognostic factors of overall survival (OS) in de novo stage IV BC patients treated with LRT utilizing the National Cancer Data Base (NCDB). The objective of the current study is to create and internally validate a prognostic scoring model to predict the long-term OS for de novo stage IV BC patients treated with LRT. We included de novo stage IV BC patients reported to NCDB between 2004 and 2015. Patients were divided into LRT and no-LRT subsets. We randomized LRT subset to training and validation cohorts. In the training cohort, a seventeen-point prognostic scoring system was developed based on the hazard ratios calculated using Cox-proportional method. We stratified both training and validation cohorts into two “groups” [group 1 (0–7 points) and group 2 (7–17 points)]. Kaplan–Meier method and log-rank test were used to compare OS between the two groups. Our prognostic score was validated internally by comparing the OS between the respective groups in both the training and validation cohorts. Among 67,978 patients, LRT subset (21,200) had better median OS as compared to that of no-LRT (45 vs. 24 months; p

Although lung cancer is the leading cause of cancer death in the USA, there have been few studies on patient-centered advanced lung cancer treatment practices. As part of a larger research study on how to use a patient-inclusive approach in late-stage lung cancer treatment, this present study describes patient, caregiver, and provider perspectives on the role of the health care system in helping patients cope with an advanced stage lung cancer diagnosis. Four focus group sessions were conducted with six to eleven participants per group for a total of 36 participants. Two focus groups were held with patients and family members/caregivers and two with physicians and nurses. A major theme that emerged concerned coping with an advanced lung cancer diagnosis, which is the subject of this paper. The patients, caregivers, and providers spoke passionately about interactions with the health care system and volunteered examples of supportive and non-supportive relationships between patients and clinicians. They advocated for better patient-provider communication practices as well as the expanded use of patient navigation and new patient orientation programs. This study contributes additional knowledge by including the perspectives of caregivers and providers who live and work closely with patients with advanced lung cancer. The findings can inform the development of comprehensive patient-centered care plans for patients living with an advanced lung cancer diagnosis.

Advanced thyroid cancer is not amenable to therapy with conventional cytotoxic chemotherapy. However, newer advances in the understanding of the molecular pathogenesis of different subtypes of thyroid cancer have provided new opportunities for the evaluation of molecularly targeted therapies. This has led to multiple clinical trials using various multi-kinase inhibitors and the subsequent US FDA approval of sorafenib for differentiated thyroid cancer and vandetanib and cabozantinib for medullary thyroid carcinoma. This review provides a summary of the current literature for the treatment of advanced thyroid carcinoma and future directions in this disease.

Participatory and patient-centered approaches to cancer research have been highlighted as the most appropriate means of engaging patients in the conduct of clinical research. However, there is a paucity of patient-centered outcomes research (PCOR) on lung cancer. Previous studies seeking to define lung cancer treatment success have generally not included patients' and caregivers' perceptions and views in treatment decision-making. Additionally, little is known about effective strategies for the engagement of lung cancer patients in PCOR. We sought to gain insights into the perceptions of patients, caregivers, and providers on lung cancer treatment success, as well as on strategies for patient engagement in lung cancer PCOR. Four focus groups were conducted with provider, patient, and caregiver participants from four cancer centers in Nebraska and South Dakota. A total of 36 providers, patients, and caregivers participated in this study. Patients and caregivers confirmed that survival alone should not be the measure of lung cancer treatment success and that definitions of treatment success should emphasize factors such as effective clinical guidance throughout treatment, symptom management, functionality, and quality of life. Clinician participants noted that the definition of treatment success evolved over time and appeared to be linked to patients' experiences with chemotherapy. Participants identified barriers to and facilitators of research participation and suggested strategies for the recruitment and retention of research participants. Our study indicates that patients can successfully play active and engaged roles in clinical research, ranging from participant to partner. Judging from the enthusiasm of our focus group attendees, patients and caregivers want to participate and be engaged in clinical research.

Small cell lung cancer (SCLC) is very aggressive clinically, and current cytotoxic therapy has only a limited impact on survival. The development of targeted therapy for SCLC has lagged behind that of non-small cell lung cancer. Current drugs under investigation include those targeting the angiogenetic, apoptotic, sonic hedgehog, and mammalian target of rapamycin (mTOR) pathways. Vaccines seem to be promising adjunctive therapies. This review will present the available data on these agents. Common genetic abnormalities seen in SCLC, which could serve as potential future targets are also discussed.

Dysfibrinogenemia is a disorder of fibrinogen structure and is associated with a functional abnormality. Since fibrinogen is a key component of both the procoagulant and fibrinolytic pathways, defects in fibrinogen function can be associated with increased risk for both hemorrhage and thrombosis. Management of patients with dysfibrinogenemia and a thrombotic tendency usually involves long-term anticoagulation.A 36-year-old male with relapsed nodular sclerosing Hodgkin's was found to have a prolonged prothrombin time, low fibrinogen activity and a normal fibrinogen antigen during evaluation for a hematopoietic peripheral blood stem cell transplant. His past medical history was significant for an acute myocardial infarction and two episodes of acute pancreatitis. His father had dysfibrinogenemia complicated by multiple thrombotic episodes. A trans-esophageal echocardiogram revealed two thrombi, one each in the superior vena cava and the descending aorta. He was treated with enoxaparin and received peripheral blood stem cell transplantation. An effort was made to maintain his fibrinogen activity levels at 200 mg/dL using cryoprecipitate. A month following the transplant he developed a new thrombus in the right internal jugular vein, while on enoxaparin and he was started on argatroban and cryoprecipitate followed by fondaparinux. A repeat echocardiogram six weeks later demonstrated that the burden of thrombus both in the right atrium and descending aorta was significantly lower.This is the first case report of a patient with dysfibrinogenemia undergoing peripheral blood stem cell transplantation. Conventional anticoagulant therapy and cryoprecipitate seem to be a reasonable management strategy to prevent thrombosis in a patient with dysfibrinogenemia and a thrombophilic tendency. Secondly, fondaparinux can be used in cases of failure of therapy with low molecular weight heparins and may actually be superior to low molecular weight heparins, especially in patients with dysfibrinogenemia.

To assess the effect of diabetes mellitus (DM) on the pathogenesis and outcomes from colon cancer.A retrospective chart review was conducted on 1853 patients with colon cancer.A higher percentage of males than females with colon cancer had DM (16.2% vs 11.3%; p0.01). Males had a slightly lower risk of dying from colon cancer (RR - 0.88; p=0.08). There was no difference in the median age of diagnosis of colon cancer in patients with and without DM, but a larger proportion of patients with diabetes mellitus wereor=70 yr at diagnosis (50% vs 43%) (p=0.0004). No significant relationship was noted between stage of colon cancer or survival and presence of DM.DM did not affect either the stage at diagnosis, or outcomes from colon cancer. More males with colon cancer tended to have DM and a larger proportion of patients with DM wereor=70 yr at the time of diagnosis.

The use of autologous hematopoietic SCT (auto-HSCT) has expanded to include older patients. Increasing age is a well-appreciated risk factor for the development of atrial fibrillation and/or atrial flutter (AF/AFL) in the general population. As more elderly patients undergo auto-HSCT, the risk of developing AF/AFL post transplant may also increase. However, few data evaluating other risk factors for the development of AF/AFL following auto-HSCT exist. Therefore, we performed a retrospective study to determine the incidence of AF/AFL following auto-HSCT and to determine the risk factors associated with the development of AF/AFL. Patients who developed AF/AFL were compared with a group of patients who received auto-HSCT within the same time period (April 1999 to May 2005) and were within 5 years of age. Of the 516 patients who underwent auto-HSCT at the University of Nebraska Medical Center 44 (8.5%) developed AF/AFL at a median time of 4 days (range, days 1-9) following auto-HSCT. In multivariate analysis, risk factors for developing AF/AFL were older age, odds ratio and 95% CI of 1.14 (1.07-1.21), elevated serum creatinine level, 2.69 (1.00-7.22), history of previous arrhythmia, 9.33 (3.01-28.99), and history of previous mediastinal irradiation, 11.12 (1.33-92.96).

An 85-yr-old male presented with complaints of a 40-lb weight loss and a dull left upper quadrant abdominal pain. He also complained of decreased appetite, generalized weakness, generally not feeling well, and a dull left upper quadrant abdominal pain that was not relieved by food. He had a ventral and a left-sided inguinal hernia. Laboratory investigations revealed iron deficiency anemia, the cause of which was not apparent despite extensive investigation including computerized tomographic scans, esophagogastroduodenoscopy, and small-bowel follow-through examination. Surgical exploration for possible angiodysplasia, malignancy, and/or mesenteric ischemia revealed an incarcerated hernia, and the histopathological examination of the surgical specimen revealed high-grade angiosarcoma. The tumor showed strong positivity for vimentin and CD31 and a focal positivity for Factor VIII and CD34. At that time he was found to have hepatic metastases. He was started on thalidomide as an experimental measure with no change in the performance status and increasing evidence of necrosis in the metastatic lesion.