Chylous Ascites Developing Into Bilateral Chylothorax in High-Grade Lymphoma: A Case Report.

Chylothorax and chylous ascites occur when lymphatic fluid accumulates in the pleural space or peritoneum, respectively. They are classified as either traumatic or non-traumatic, and lymphomas are the most common non-traumatic cause. Lymphomas can obstruct the lymphatic architecture causing lipid-rich chyle to leak out below the level of the obstructing mass. Bilateral chylothoraces presenting in the presence of chylous ascites, secondary to Non-Hodgkin Lymphoma, are rare. We describe a case of a 55-year-old man with recurring large-volume chylous ascites secondary to Non-Hodgkin lymphoma who developed bilateral chylothoraces. Initially, he presented with dyspnea and hypoxia and was found to have bilateral pleural effusions, requiring bilateral thoracentesis for diagnostic and therapeutic management. The fluid removed from the pleural space was found to be lymphatic fluid, and the patient was eventually discharged home with instructions to follow up with oncology for further management. The case reveals a temporal relationship where a huge volume of chylous ascites develops into a chylothorax.

Spontaneous posterior lung herniation: A case report and literature review.

Intercostal lung hernias are uncommon and usually a consequence of trauma or surgery. True spontaneous lung hernias are extremely rare, with only 51 cases identified over the past four-and-half decades. We report a case of nontraumatic chest wall ecchymosis secondary to spontaneous posterior-lateral lung herniation followed by a review of the literature. Interesting radiographic images are presented. The pathophysiology and therapeutic options of this condition are discussed. The case highlights that advanced chronic obstructive pulmonary disease (COPD) may be an etiological factor for the development of this rare entity, with cough being the precipitating event. Given the increasing prevalence of COPD, the authors believe further awareness of this pathology is needed.

Complicated Post-Partum HELLP Syndrome Causing Acute Renal Failure and a Spontaneous Acute Subdural Hematoma.

HELLP syndrome is characterized by hemolysis, elevated liver enzymes, and thrombocytopenia. It is a devastating illness that typically occurs in the third trimester of gestation. We present a unique case of complicated post-partum HELLP syndrome. The patient was a 34-year-old Caucasian G1PO woman at 40 weeks' gestational age who presented for induction of labor. She underwent successful vaginal delivery. However, postoperatively the patient developed HELLP syndrome complicated by acute renal failure. She was transferred to the intensive care unit, where her renal function continued to decline, ultimately necessitating hemodialysis. She subsequently spontaneously developed an acute subdural hematoma. Most cases of HELLP syndrome occur in the third trimester, whereas fewer manifest post-partum. The pathophysiology of HELLP syndrome is poorly understood. While the defining organ of injury in HELLP syndrome is the liver, both kidney injury and spontaneous subdural hematomas can occur, as seen in this patient. The gold standard therapy for HELLP syndrome is prompt delivery of the fetus. HELLP syndrome continues to be a serious constellation of symptoms that can affect women late in their gestational period. As illustrated in this case report, prompt diagnosis of HELLP syndrome and appropriate management is critical.

Impending Cardiac Tamponade as the Initial Manifestation of BCR-ABL Positive Chronic Myeloid Leukemia.

Leukemia involves all organs and tissues of the body. Leukemic infiltration of the pericardium has been documented frequently at post-mortem examinations. Clinically, however, pericardial effusion with cardiac tamponade is rare, and only isolated case reports have been described. In all the reported cases, therapeutic pericardiocentesis was required for the relief of cardiac tamponade with the risk of bleeding since these patients often had deranged hemostasis. We are reporting a rare case of hemorrhagic pericardial effusion in chronic myeloid leukemia before starting the tyrosine kinase inhibitors. The patient required therapeutic pericardiocentesis and hydroxyurea treatment.

Tumor stroma interaction is mediated by monocarboxylate metabolism.

Human breast tumors contain significant amounts of stromal cells. There exists strong evidence that these stromal cells support cancer development and progression by altering various pathways (e.g. downregulation of tumor suppressor genes or autocrine signaling loops). Here, we suggest that stromal carcinoma-associated fibroblasts (CAFs), shown to be generated from bone marrow-derived mesenchymal stem cells, may (i) recycle tumor-derived lactate for their own energetic requirements, thereby sparing glucose for neighboring glycolytic tumor cells, and (ii) subsequently secrete surplus energetically and biosynthetically valuable metabolites of lactate oxidation, such as pyruvate, to support tumor growth. Lactate, taken up by stromal CAFs, is converted to pyruvate, which is then utilized by CAFs for energy needs as well as excreted and shared with tumor cells. We have interrogated lactate oxidation in CAFs to determine what metabolites may be secreted, and how they may affect the metabolism and growth of MDA-MB-231 breast cancer cells. We found that CAFs secrete pyruvate as a metabolite of lactate oxidation. Further, we show that pyruvate is converted to lactate to promote glycolysis in MDA-MB-231 cells and helps to control elevated ROS levels in these tumor cells. Finally, we found that inhibiting or interfering with ROS management, using the naturally occurring flavonoid phloretin (found in apple tree leaves), adds to the cytotoxicity of the conventional chemotherapeutic agent doxorubicin. Our work demonstrates that a lactate-pyruvate, reciprocally-supportive metabolic relationship may be operative within the tumor microenvironment (TME) to support tumor growth, and may be a useful drug target.

The Lung Point Sign, not Pathognomonic of a Pneumothorax.

Since the development of portable ultrasonography equipment, this technology has provided clinicians the ability to evaluate a variety of lung pathology at the bedside, but we are still learning how to accurately interpret the acquired images. Adequate interpretation and recognition of certain signs is crucial to diagnosing pathological processes. In addition, such signs must be adequately correlated with the patient's medical condition. For instance, the "lung point sign" has been traditionally considered to be pathognomonic for the presence of a pneumothorax, yet such finding may be present in patients with bullous lung disease without a pneumothorax.We present a case of an 83-year-old man with underlying chronic obstructive pulmonary disease. Bedside ultrasonography identified a "lung point sign" initially suggesting a possible pneumothorax. Further evaluation demonstrated absence of pneumothorax, with the patient having a large bulla.To our knowledge, this is the first case reported demonstrating that the "lung point sign" is not always indicative of a pneumothorax. We discuss the importance of both clinical correlation and understanding of the underlying pathophysiology when reviewing ultrasound images to accurately interpret ultrasound findings.

Establishing the link between hepatitis B virus infection and colorectal adenoma.

BACKGROUND: Chronic hepatitis B (CHB) infection has been associated with malignancy, most notably hepatocellular carcinoma. Previous research has shown that hepatitis C is associated with increased colorectal adenomas and neoplasia. Currently, there are no studies on the association of CHB and colorectal adenomas. We aimed to identify a possible link between CHB and colorectal adenoma. METHODS: A retrospective chart review was performed on 588 consecutive patients undergoing screening or diagnostic colonoscopy that were previously screened or diagnosed with hepatitis B. Comparisons between categorical variables were analyzed with Chi Square test and t-test for continuous variables. Unconditional logistic regression was used to generate age-, gender-and race-adjusted odds ratios and their 95% confidence intervals (CI) comparing medication users with non-users. Statistical analyses were performed with SAS 9.3 software. RESULTS: A total of 487 patients were analyzed in the control group vs. 71 in the hepatitis B group. The adenoma detection rate was 23.9% in hepatitis B vs. 15.9% in the non-hepatitis B group for all cause colonoscopy; however this did not reach statistical significance. There was a significantly higher number of adenomas present in the distal colon compared to control (OR =2.16; 95% CI, 1.06-4.43; P=0.04). There were no significant findings between hepatitis B infection with size, multiplicity or presence of proximal adenomas. There was a significant difference noted in regards to smoking history, BMI and age between two groups. CONCLUSIONS: Although the adenoma detection rate was higher in hepatitis B population vs. the non-hepatitis B group this did not reach statistical significance. However, we did find an association between CHB infection and the presence of distal colorectal adenomas. Larger prospective studies are needed to strengthen our findings along with future studies examining hepatitis B virus (HBV) and mechanisms inducing colorectal carcinogenesis.

Embedded pork bone causing esophageal perforation and an esophagus-innominate artery fistula.

Chronically embedded foreign bodies can lead to perforations, mediastinitis, and abscess, amongst a host of other complications. A 20-year-old mentally challenged female presented with "something stuck in her throat," severe dysphagia, and recurrent vomiting. Initial imaging was unremarkable; however, subsequent imaging and esophagogastroduodenoscopy two weeks later revealed an embedded pork bone. Surgery was performed to remove the bone and fix the subsequent esophageal perforation and esophagus-innominate artery fistula. This case helps reinforce the urgency in removing an ingested foreign body and the ramifications that may arise with chronically embedded foreign bodies.

Splenic Avulsion Following PEG Tube Placement: A Rare but Serious Complication.

Placement of a percutaneous endoscopic gastrostomy (PEG) tube is a common procedure to allow for enteral nutrition in patients with multiple indications. PEG tube placement is a safe procedure with minor complications such as site infection and irritation. One of the more severe complications is splenic laceration, which may result in intra-peritoneal bleeding and manifest as an acute abdomen. We present a rare case of intra-abdominal bleeding secondary to catastrophic splenic injury 12 hours after PEG tube placement resulting in hemodynamic compromise. The patient underwent splenectomy and had an uneventful recovery.

Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment.

Human mesenchymal stem cells (hMSCs) are bone marrow-derived stromal cells, which play a role in tumor progression. We have shown earlier that breast cancer cells secrete higher levels of interleukin-6 (IL-6) under hypoxia, leading to the recruitment of hMSCs towards hypoxic tumor cells. We found that (i) MDA-MB-231 cells secrete significantly higher levels of lactate (3-fold more) under hypoxia (1% O(2)) than under 20% O(2) and (ii) lactate recruits hMSCs towards tumor cells by activating signaling pathways to enhance migration. The mRNA and protein expression of functional MCT1 in hMSCs is increased in response to lactate exposure. Thus, we hypothesized that hMSCs and stromal carcinoma associated fibroblasts (CAFs) in the tumor microenvironment have the capacity to take up lactate expelled from tumor cells and use it as a source of energy. Our (13)C NMR spectroscopic measurements indicate that (13)C-lactate is converted to (13)C-alpha ketoglutarate in hMSCs and CAFs supporting this hypothesis. To our knowledge this is the first in vitro model system demonstrating that hMSCs and CAFs can utilize lactate produced by tumor cells.

Histone methyltransferase MLL1 regulates MDR1 transcription and chemoresistance.

The multidrug resistance 1 gene (MDR1) encodes P-glycoprotein (Pgp), a member of the ATP-binding cassette (ABC) transporter family that confers tumor drug resistance by actively effluxing a number of antitumor agents. We had previously shown that MDR1 transcription is regulated by epigenetic events such as histone acetylation, and had identified the histone acetylase P/CAF and the transcription factor NF-Y as the factors mediating the enzymatic and DNA-anchoring functions, respectively, at the MDR1 promoter. It has also been shown that MDR1 activation is accompanied by increased methylation on lysine 4 of histone H3 (H3K4). In this study, we further investigated histone methylation in MDR1 regulation and function. We show that the mixed lineage leukemia 1 (MLL1) protein, a histone methyltransferase specific for H3K4, is required for MDR1 promoter methylation, as knockdown of MLL1 resulted in a decrease in MDR1 expression. The regulation of MDR1 by MLL1 has functional consequences in that downregulation of MLL1 led to increased retention of the Pgp-specific substrate DIOC(2)(3), as well as increased cellular sensitivity to several Pgp substrates. Regulation of MDR1 by MLL1 was dependent on the CCAAT box within the proximal MDR1 promoter, similar to what we had shown for MDR1 promoter acetylation, and also requires NF-Y. Finally, overexpression of the most prevalent MLL fusion protein, MLL-AF4, led to increased MDR1 expression. This is the first identification of a histone methyltransferase and its leukemogenic rearrangement that regulates expression of an ABC drug transporter, suggesting a new target for circumvention of tumor multidrug resistance.

Genistein and resveratrol, alone and in combination, suppress prostate cancer in SV-40 tag rats.

BACKGROUND: Chemoprevention utilizing dietary agents is an effective means to slow the development of prostate cancer. We evaluated the potential additive and synergistic effects of genistein and resveratrol for suppressing prostate cancer in the Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model, a transgenic model of spontaneously developing prostate cancer. METHODS: Rats were fed genistein or resveratrol (250 mg/kg AIN-76A diet) alone and in combination, and a low-dose combination (83 mg genistein + 83 mg resveratrol/kg diet). Histopathology and mechanisms of action studies were conducted at 30 and 12 weeks of age, respectively. RESULTS: Genistein, resveratrol, and the high-dose combination treatments suppressed prostate cancer. The low-dose combination did not elicit protection against prostate cancer and was most likely below the effective dose for causing significant histopathological changes. Total genistein and resveratrol concentrations in the blood reached 2,160 and 211 nM, respectively in rats exposed to the single treatments. Polyphenol treatments decreased cell proliferation and insulin-like growth factor-1 (IGF-1) protein expression in the prostate. In addition, genistein as a single agent induced apoptosis and decreased steroid receptor coactivator-3 (SRC-3) in the ventral prostate (VP). CONCLUSIONS: Genistein and resveratrol, alone and in combination, suppress prostate cancer development in the SV-40 Tag model. Regulation of SRC-3 and growth factor signaling proteins are consistent with these nutritional polyphenols reducing cell proliferation and increasing apoptosis in the prostate.

Characterization of SV-40 Tag rats as a model to study prostate cancer.

BACKGROUND: Prostate cancer is the second most frequently diagnosed cancer in men. Animal models that closely mimic clinical disease in humans are invaluable tools in the fight against prostate cancer. Recently, a Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model was developed. This model, however, has not been extensively characterized; hence we have investigated the ontogeny of prostate cancer and determined the role of sex steroid receptor and insulin-like growth factor-1 (IGF-1) signaling proteins in the novel SV-40 Tag rat. METHODS: The SV-40 Tag rat was histopathologically characterized for time to tumor development, incidence and multiplicity and in the ventral, dorsal, lateral and anterior lobes of the prostate. Immunoassay techniques were employed to measure cell proliferation, apoptosis, and sex steroid receptor and growth factor signaling-related proteins. Steroid hormone concentrations were measured via coated well enzyme linked immunosorbent assay (ELISA) kits. RESULTS: Prostatic intraepithelial neoplasia (PIN) and well-differentiated prostate cancer developed as early as 2 and 10 weeks of age, respectively in the ventral prostate (VP) followed by in the dorsolateral (DLP). At 8 weeks of age, testosterone and dihydrotestosterone (DHT) concentrations in SV-40 Tag rats were increased when compared to non-transgenic rats. High cell proliferation and apoptotic indices were found in VP and DLP of transgenic rats. Furthermore, we observed increased protein expression of androgen receptor, IGF-1, IGF-1 receptor, and extracellular signal-regulated kinases in the prostates of SV-40 Tag rats. CONCLUSION: The rapid development of PIN and prostate cancer in conjunction with the large prostate size makes the SV-40 Tag rat a useful model for studying prostate cancer. This study provides evidence of the role of sex steroid and growth factor proteins in prostate cancer development and defines appropriate windows of opportunity for preclinical trials and aids in the rational design of chemoprevention, intervention, regression, and therapeutic studies using prostate cancer rodent models.

Epigallocatechin-3-Gallate suppresses early stage, but not late stage prostate cancer in TRAMP mice: mechanisms of action.

BACKGROUND: Prostate cancer (PCa) is the second leading cause of cancer-related death in men in the United States. Many men have implemented purported chemopreventive agents into their daily diet in an attempt to delay the early onset of a PCa. Green tea polyphenols, one such agent, has been shown to be chemopreventive in skin, breast, and prostate cancers. We hypothesized that Epigallocatechin-3-Gallate (EGCG), the major polyphenol found in green tea, will exert its chemopreventive effect in the prostate via regulation of sex steroid receptor, growth factor-signaling, and inflammatory pathways. METHODS: Five-week-old male TRAMP (Transgenic Adenocarcinoma Mouse Prostate) offspring were fed AIN-76A diet and 0.06% EGCG in tap water. Animals were sacrificed at 28 weeks of age and the entire prostates were scored histopathologically. In addition, animals were sacrificed at 12 weeks of age and ventral (VP) and dorsolateral (DLP) prostates were removed for histopathological evaluation and immunoblot analyses or ELISA. RESULTS: EGCG, inhibited early but not late stage PCa in the current study. In the VP, EGCG significantly reduced cell proliferation, induced apoptosis, and decreased androgen receptor (AR), insulin-like growth factor-1 (IGF-1), IGF-1 receptor (IGF-1R), phospho-extracellular signal-regulated kinases 1 and 2 (phospho-ERKs 1 and 2), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). CONCLUSIONS: The attenuation of the AR, the down-regulation of potent growth factor IGF-1, modulation of inflammation biomarkers, and decrease in the MAPK signaling may contribute to the reduction in cell proliferation and induction of apoptosis and hence provide a biochemical basis for EGCG suppressing PCa without toxicity.

Resveratrol suppresses prostate cancer progression in transgenic mice.

Resveratrol, a natural polyphenolic phytochemical, has been reported to act as an antioxidant and provide anticancer activities. We hypothesized that resveratrol would exert a chemopreventive effect against prostate cancer via regulation of sex steroid receptor and growth factor signaling pathways. In the current study, Transgenic Adenocarcinoma Mouse Prostate males were fed resveratrol (625 mg resveratrol per kg AIN-76A diet) or phytoestrogen-free, control diet (AIN-76A) starting at 5 weeks of age. Mechanisms of action and histopathology studies were conducted at 12 and 28 weeks of age, respectively. Resveratrol in the diet significantly reduced the incidence of poorly differentiated prostatic adenocarcinoma by 7.7-fold. In the dorsolateral prostate, resveratrol significantly inhibited cell proliferation, increased androgen receptor, estrogen receptor-beta, and insulin-like growth factor-1 receptor, and significantly decreased insulin-like growth factor (IGF)-1 and phospho-extracellular regulating kinase 1 (phospho-ERK 1). In the ventral prostate, resveratrol significantly reduced cell proliferation and phospho-ERKs 1 and 2, but did not significantly alter insulin-like growth factor-1 receptor and IGF-1. Serum total testosterone, free testosterone, estradiol, dihydrotestosterone and sex hormone-binding globulin (SHBG) concentrations and Simian Virus-40 large T antigen expression in the prostate were not altered in resveratrol-treated mice. Total resveratrol concentration in the blood serum of 12-week-old mice treated for 3 weeks with 625 mg resveratrol per kg diet was 52 +/- 18 nM. The decrease in cell proliferation and the potent growth factor, IGF-1, the down-regulation of downstream effectors, phospho-ERKs 1 and 2 and the increase in the putative tumor suppressor, estrogen receptor-beta, provide a biochemical basis for resveratrol suppressing prostate cancer development.