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Carcinoid brain metastases are extremely rare and are associated with a poor prognosis. Treatment options are variable, ranging from surgery, radiation, or chemotherapy alone or combined. We report on a case of rectal carcinoid metastatic to the cerebellum and review chemotherapeutic regimens for carcinoid tumor treatment, focusing on the potential role of temozolomide or stereotactic radiosurgery.

Background A significant fraction of oropharyngeal squamous cell carcinoma (SCC) cases is associated with traditional carcinogens; in these patients, treatment response and clinical outcomes remain poor. Methods We evaluated patient, tumor, and treatment characteristics for 200 veterans with oropharyngeal SCC treated at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) between 2000 and 2012. Results Most patients (77%) were white and heavy smokers. Twenty-seven patients required tracheostomy and 63 required gastrostomy placement during treatment. Overall survival (OS) at 5 years was 40%. Survival was impacted by T classification, treatment intensity, completion of treatment, and p16 tumor status. Almost 30% of patients were unable to complete a treatment regimen consistent with National Comprehensive Cancer Network (NCCN) guidelines. Conclusion Oropharyngeal SCC in veterans is associated with traditional carcinogens and poor clinical outcomes. Despite heavy smoking exposure, p16 tumor status significantly impacts survival. Careful consideration must be given to improving treatment paradigms for this cohort given their limited tolerance for treatment escalation. © 2014 Wiley Periodicals, Inc. Head Neck 37: 1246–1253, 2015

Background Racial disparities in oropharyngeal squamous cell carcinoma (SCC) have been demonstrated and attributed to differences in human papillomavirus (HPV) status. The purpose of this study was to examine racial disparities in oropharyngeal SCC among veterans. Methods Retrospective review of patients with oropharyngeal SCC at a tertiary-care Veterans Affairs (VA) hospital. Adjusted Cox proportional hazards models were conducted to examine the effect of race on oropharyngeal SCC outcomes. Results Of 158 patients, 126 (79.7%) were white and 32 (20.3%) were African American. No difference in p16 tumor expression was noted between the groups. Five-year disease-free survival (DFS) was 42.6% and 55.1% for African Americans and whites, respectively (p = .372). Five-year overall survival (OS) for African Americans and whites was 54.6% and 51.8%, respectively (p = .768). On multivariate analysis, there was no significant difference in risk of recurrence or death by race. Conclusion Racial disparities are largely ameliorated in patients with oropharyngeal SCC treated within the VA, there were no racial differences in p16 tumor expression, and outcomes remain poor. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

We report a case of synchronous primary colonic adenocarcinoma and malignant mesothelioma. A 61-year-old male presented with a six-month history of fatigue and weight loss. An abdominal computed tomography (CT) scan showed a 5.8 cm partially obstructing mass in the cecum with ascites and peritoneal thickening. A biopsy of the large mass showed an adenocarcinoma. Because the patient was clinically thought to be a T4 colon carcinoma with peritoneal metastatic lesions (M1), prior to initiating chemotherapy, a debulking right hemicolectomy was performed. Resection of the colon and ileum revealed a T3N0 colonic mucinous adenocarcinoma and concurrent diffuse malignant peritoneal mesothelioma. Presenting synchronous colonic and peritoneal mesothelial primary malignancies are exceedingly rare but must be considered to prevent incorrect clinical staging.

Background: The major pathological finding of gout is the deposition of monosodium urate monohydrate (MSU) crystals with inflammatory infiltrate in the tissue. There have been many reports of in vitro analysis of inflammatory mechanism and comorbidities in gout. However, the associations of immune response cells and comorbidities of gout have not been well documented. Our studies aimed to examine the immune cell types and quantity in gout tissues, and to define the association of individual cell type with comorbidities. Methods: Surgically resected or biopsied tissues from 48 patients diagnosed as gout were used for this study. Cell count was performed on Hemotoxylin and Eosin stained sections for macrophages, plasma cells, neutrophils and on immunostained slides for T and B lymphocytes. Results: Hyperlipidemia, hypertension and diabetes mellitus were seen in 70.8%, 87.5% and 37.5% of patients, respectively. There were 35.6% and 37.8% of patients who admitted history of smoking and alcohol intake, respectively. Mean serum uric acid level was 8.5 mg/dl. The average body mass index was 30.1 kg/m2. H&E stained tissue sections demonstrated the crystalline deposits rimmed by palisading multinucleated giant cells, macrophages, neutrophils, plasma cells, T and B cells. Significant correlations between the clinical features and tissue inflammatory cells were observed in hyperlipidemia with number of T cells (p = 0.0363), hypertension with number of T cells and B cells (p = 0.0138 and 0.0033, respectively), diabetes mellitus with macrophages (p = 0.0016), and uric acid level with giant cells (p = 0.0088). Conclusion: Comorbidity factors including hyperlipidemia, hypertension and diabetes are significantly associated with the inflammatory cells in the tissues.

H1N1 influenza A virus can trigger fatal hemophagocytic lymphohistiocytosis in immunocompromised patients and in immunocompetent hosts, usually children. We present a case of a 50-year-old man with low-burden chronic lymphocytic leukemia who had sudden reactivation of his leukemia triggered by influenza A (H1N1) infection with hemophagocytic lymphohistiocytosis during the 2009 H1N1 pandemic. His rapid course was complicated by acute respiratory distress syndrome with diffuse alveolar damage, a 6-fold rise in lymphocyte count, disseminated intravascular coagulation, and, ultimately, cardiac arrest. Major findings at autopsy included: bilateral H1N1 pneumonitis with diffuse alveolar damage, intra-alveolar pulmonary hemorrhage, pulmonary microthromboemboli, pulmonary hemorrhagic infarction, hemophagocytic lymphohistiocytosis in multiple locations, and diffuse chronic lymphocytic leukemia. Hemophagocytic lymphohistiocytosis is a serious and often fatal condition, which may be primary or secondary. It may be associated with high-grade lymphoproliferative malignancies, especially in patients with therapy-related leukocytopenia, but only rarely is it seen in uncomplicated chronic lymphocytic leukemia. Hemophagocytic lymphohistiocytosis may be triggered by a variety of infections (viral, fungal, bacterial and parasitic), but H1N1 influenza A-associated hemophagocytic lymphohistiocytosis is often rapidly fatal, especially in children. This adult patient's clinical presentation with low tumor burden and leukocytosis is thus unique. We review the recently published autopsy findings in fatal influenza A (H1N1) infection and the association with resultant secondary hemophagocytic lymphohistiocytosis.

// Lin-Kin Yong 1, 2 , Syeling Lai 3 , Zhengdong Liang 1 , Ethan Poteet 1 , Fengju Chen 4,5 , George van Buren 4,6 , William Fisher 4,6 , Qianxing Mo 4,5 , Changyi Chen 1,4 , Qizhi Yao 1, 4,7 1 Michael E. DeBakey Department of Surgery, Division of Surgical Research, Baylor College of Medicine, Houston, TX, USA 2 Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA 3 Department of Pathology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA 4 Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA 5 Department of Medicine, Baylor College of Medicine, Houston, TX, USA 6 Michael E. DeBakey Department of Surgery, Division of General Surgery, Baylor College of Medicine, Houston, TX, USA 7 Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX, USA Correspondence to: Qizhi Yao, email: qizhiyao@bcm.edu Keywords: semaphorin 3E, pancreatic cancer Received: July 05, 2016 Accepted: October 17, 2016 Published: November 29, 2016 ABSTRACT Semaphorin-3E (Sema3E) is a member of an axon guidance gene family, and has recently been reported to contribute to tumor progression and metastasis. However, its role in pancreatic cancer is yet unknown and uncharacterized. In this study, we showed that Sema3E is overexpressed in human pancreatic cancer, and that high Sema3E levels are associated with tumor progression and poor survival. Interestingly, we also observed Sema3E expression in the nucleus, even though Sema3E is reported to be a secreted protein. Overexpression of Sema3E in pancreatic cancer cells promoted cell proliferation and migration in vitro , and increased tumor incidence and growth in vivo . Conversely, knockout of Sema3E suppressed cancer cell proliferation and migration in vitro, and reduced tumor incidence and size in vivo . Moreover, Sema3E induced cell proliferation via acting through the MAPK/ERK pathway. Collectively, these results reveal an undiscovered role of Sema3E in promoting pancreatic cancer pathogenesis, suggesting that Sema3E may be a suitable prognostic marker and therapeutic target for pancreatic cancer.

Systemic sclerosis (SSc) is a complex disease involving multiple genetic factors. A recent genome-wide association study (GWAS) indicated that CD247 was strongly associated with SSc, which was subsequently confirmed in a SSc cohort of European population. However, genetic heterogeneity in different ethnic populations may significantly impact the complex trait of SSc. The studies herein aimed to examine whether the SSc-associated SNP rs2056626 of CD247 identified in Caucasian is also associated with Han Chinese SSc. A Han Chinese cohort consisting of 387 SSc patients and 523 healthy controls were examined in the studies. TaqMan assays were performed to examine the SNP. Exact p-values were obtained (Fisher’s test) from 2x2 tables of allele counts and disease status. The results showed that there was no association between rs2056626 of CD247 and SSc or any SSc subtypes of Han Chinese. The negative results are important in understanding genetics of SSc in different ethnic populations, which further suggest complex nature of genetics of SSc.

Catastrophic antiphospholipid syndrome (CAPS) is a severe and rare variant of antiphospholipid syndrome (APS) characterized by acute multiorgan failure due to small vessel thrombi in patients with positive antiphospholipid antibodies. We report a fatal case of catastrophic antiphospholipid syndrome in a young woman with a history of polymyositis and Hodgkin lymphoma. The patient was admitted to hospital because of severe foot pain following several weeks of skin ulcerations. Doppler ultrasonography showed evidence of arterial ischemia of the both lower extremities. Despite anticoagulation, immunosuppression, plasmapheresis and antibiotic therapy, she developed cutaneous gangrene, retroperitoneal hematoma, ileus, and acute respiratory and renal failure that resulted in death. Autopsy showed multifocal vascular injury and microthrombi with associated hemorrhages and infarcts in multiple organs. The patient had normal levels of functional protein C and protein S and a normal level of plasma homocysteine. Tests for common thromophilic gene mutations including prothrombin 20210, factor V Leiden 1691, and methylene tetrahydrofolate reductase 677 were negative. To our knowledge, this is the first CAPS patient with molecular studies for genetic prothrombotic mutations. Our report showed that there was no association between the development of CAPS and inherited thromophilia.

Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death in the US with a 5-year survival rate of less than 6%. There is an urgent need for a better understanding of PDAC in order to find better therapeutic targets. Two recent large-scale genomic analyses of human PDAC have uncovered increased copy numbers of an axon-guidance gene SEMA3E that codes for Semaphorin-3E (Sema3E). Several recent reports have implicated Sema3E in metastasis of breast and colon cancers, particularly in promoting tumor cell migration and invasion, as well as inducing epithelial-to-mesenchymal transition (EMT). Here, we evaluated Sema3E expression levels in human pancreatic cancer tissue samples and correlation with patient survival; we further studied roles of Sema3E in pancreatic cancer cell proliferation. Materials and Methods: To determine expression levels of Sema3E in PDAC, qPCR analysis was performed on resected human PDAC samples and matched tissue controls, and immunohistochemical (IHC) analysis was performed on resected human PDAC tissues and tissues from a mouse model of PDAC. To generate Sema3E-overexpressing stable cells, human PDAC cell lines were transduced with Sema3E-expressing lentivirus or vector control. To generate Sema3E knock-down cell lines, CRISPR/Cas9 system was used to target Sema3E in the genome. MTT assay was performed on Sema3E-overexpressed cells to determine the effects of Sema3E on cell proliferation. Results: Using qPCR, Sema3E was found to be significantly upregulated in 46% of human PDAC samples (n=24), with an average fold-change of 9.54. IHC analyses of human and mouse PDAC revealed higher expression of Sema3E in tumor cells compared to normal cells (n=54). Interestingly, in human PDAC, Sema3E expression was concentrated in the nuclei of tumor cells while it has been reported to be a secreted protein. We found a positive correlation between high N/C ratio of Sema3E expression (i.e. expression in the nucleus relative to the cytoplasm) and poor survival. In addition, we also found overexpression of Sema3E is correlated with patient poor survival by analyzing a TCGA dataset (n=78). Overexpression of Sema3E in human PDAC cell lines enhanced cell proliferation and migration in vitro, while knocking-down Sema3E resulted in reduced cell proliferation. Conclusions: Our findings indicate that Sema3E is overexpressed in PDAC and is correlated with patient poor survival. Sema3E may play a pathogenic role in PDAC progression by enhancing tumor cell proliferation. These findings suggest that Sema3E could be an attractive novel therapeutic target for PDAC. Citation Format: Lin-Kin Yong, Syeling Lai, Zhengdong Liang, Dali Li, Ethan Poteet, William Fisher, Qianxin Mo, Changyi Chen, Qizhi Yao. Overexpression of Semaphorin-3E enhances pancreatic cancer cell proliferation ad is associated with patient poor survival. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A48.

Background: There are many published studies of comorbidities and in vitro analysis of inflammatory mechanism in gout, but only few in vivo tissue examinations for immune response cells were reported. The association of comorbidities and immune cell response has not been well documented. Our objective is to examine the immune cell types and quantity in gout tissue, identify clinical parameters of gout associated risk factors in corresponding patients, and analyze the association of individual cell type with comorbidities. Methods: Biopsied or resected tissues from 33 patients diagnosed as gout were used for this study. Cell count was performed on Hematoxylin and Eosin stained sections for macrophages, plasma cells, neutrophils and on immunostained slides for T- and B-lymphocyte. Results: The mean patient age was 62 year-old with 57.6% patients over 60 year-old. Mean serum uric acid level was 8.5 mg/dl. The average body mass index was 30.6 kg/m2. Majority of the patients had history of hypertension (93.9%). There were 34.4% and 28.1% of patients admitted history of smoking and alcohol intake, respectively. Hyperlipidemia and diabetes mellitus were seen in 78.8% and 45.5% of patients, respectively. H and E stained sections demonstrated the crystalline deposits rimmed by palisading multinucleated giant cells, macrophages, and chronic inflammatory cells. Average cell counts of T-cells, B-cells, multinucleated giant cells, mononucleated macrophages, plasma cells and neutrophils are: 33.0, 11.8, 7.3, 26.8, 0.38, and 7.4 cells/ High Power Field respectively. Of significant values are associations of plasma cells and B-cell with hypertension, T-cell with hyperlipidemia, uric acid with smoking as well as multinucleated giant cells with uric acid. Conclusion: Most of the gout patients showed an elevated uric acid level. The participating inflammatory cells in local tissues were predominantly T-lymphocytes, macrophages and multinucleated giant cells. Comorbidity factors including hypertension, hyperlipidemia, diabetes, smoking and drinking may precipitate gout by stimulating immune cell proliferation.

Approximately 30-40% of estrogen receptor alpha (ERalpha)-positive breast tumors express high levels of the cyclooxygenase-2 (COX-2) protein, and these high levels have been associated with a poorer prognosis in breast cancer patients. We speculate that high levels of COX-2 induce drug resistance in ERalpha-positive breast tumors, thus reducing the survival rate of patients with such tumors. Human breast cancer cell lines that express high levels of COX-2 are generally ERalpha negative. To determine whether COX-2 induces drug resistance, plasmids encoding the COX-2 gene were stably transfected into ERalpha-positive MCF-7 human breast cancer cells (MCF-7/COX-2). MCF-7/COX-2 cells were resistant to the selective estrogen receptor modulator tamoxifen but not to its analog, raloxifene. MCF-7/COX-2 cells were also resistant to the retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) but not to its analog, all-trans retinoic acid. In contrast, the sensitivities of MCF-7/COX-2 cells to doxorubicin and paclitaxel were similar to those of the parental MCF-7 cells. We then determined which COX-2 product, prostaglandin E2 (PGE2) or prostaglandin F2alpha is involved in the COX-2-mediated drug resistance. PGE2, but not PGF2alpha, blocked the antiproliferative effects of tamoxifen and 4-HPR. Agonists that activate PGE2 receptors and their downstream kinase effectors, protein kinases A and C, also blocked the growth inhibitory effects of these drugs. Increased levels of Bcl-2 and Bcl-XL proteins have been reported in mammary tumors of COX-2 transgenic mice and in human colon cancer cell lines that have high levels of COX-2. However, we did not observe any changes in Bcl-2, Bcl-XL, or Bax expression induced by COX-2 or PGE2. Here we report the novel findings that COX-2 uses PGE2 to stimulate the activities of protein kinases A and C to induce selectively tamoxifen and 4-HPR resistance in ERalpha-positive breast cancer cells.